CORONERS ACT, 2003

SOUTH AUSTRALIA

FINDING OF INQUEST

An Inquest taken on behalf of our Sovereign Lady the Queen at

Adelaide in the State of South Australia, on the 7th day of July 2016, the 8th day of August

2016, the 13th day of September 2016, the 9th day of December 2016, the 21st, 22nd and

28th days of February 2017, the 17th and 26th days of May 2017, the 17th day of August

2017, the 20th, 21st and 29th days of September 2017 the 7th, 8th, 13th, 14th, 15th, 16th,

20th, 21st, 23rd, 24th, 27th, 28th, 29th and 30th days of November 2017, the 1st, 5th, 6th,

7th, 8th and 11th days of December 2017, the 7th, 8th, 9th, 10th, 11th, 14th, 16th, 17th and

23rd days of May 2018, the 1st, 20th, 21st and 27th days of June 2018 and the 22nd day of

March 2019, by the Coroner’s Court of the said State, constituted of Anthony Ernest

Schapel, Deputy State Coroner, into the deaths of Joanna Pinxteren, Christopher McRae,

Bronte Ormond Higham and Carol Anne Bairnsfather.

The said Court finds that Joanna Pinxteren aged 76 years, late of

1 Valley View Drive, Highbury, South Australia died at the Royal Adelaide Hospital, North

Terrace, Adelaide, South Australia on the 23rd day of June 2015 as a result of e-coli

bacteraemia secondary to refractory acute myeloid leukaemia.

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The said Court finds that Christopher McRae aged 67 years, late of

2 McArthur Street, Vale Park, South Australia died at Mary Potter Hospice, 89 Strangways

Terrace, North Adelaide, South Australia on the 22nd day of November 2015 as a result of

acute myeloid leukaemia.

The said Court finds that Bronte Ormond Higham aged 68 years, late

of Daw House Hospice, Goodwood Road, Daw Park, South Australia died at Daw Park,

South Australia on the 7th day of August 2016 as a result of acute myeloid leukaemia.

The said Court finds that Carol Anne Bairnsfather aged 70 years, late

of 18 Mayall Avenue, Kensington Gardens, South Australia died at the Royal Adelaide

Hospital, North Terrace, Adelaide, South Australia on the 17 th day of February 2017 as a

result of acute myeloid leukaemia.

The said Court finds that the circumstances of their deaths were as

follows.

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Table of Contents

1. Introduction....................................................................................................................1.29. Legal representation.........................................................................................11

2. A brief overview of the course of treatment and of the longevity of the four deceased persons following diagnosis.........................................................................

3. Consolidation chemotherapy for AML – an overview................................................4. The RAH AML consolidation chemotherapy protocol................................................5. The FMC AML consolidation chemotherapy protocol................................................6. The promulgation of the erroneous protocol at the RAH............................................7. The promulgation of the erroneous protocol at the FMC............................................8. The patients are administered consolidation chemotherapy pursuant to the

erroneous protocol........................................................................................................8.6. The circumstances relating to the underdosing of Mrs Pinxteren....................668.26. The circumstances relating to the underdosing of Mr McRae.........................718.40. The circumstances relating to the underdosing of Mrs Bairnsfather...............748.50. The circumstances relating to the underdosing of Mr Higham........................77

9. The error is discovered.................................................................................................10. The error is acted upon at the RAH.............................................................................11. The discovery of the error at the FMC.........................................................................12. The circumstances relating to the underdosing of Mr Knox......................................13. Was Mrs Pinxteren ever advised of the error?...........................................................14. Mr McRae is advised of the error..............................................................................15. Mrs Bairnsfather is advised of the error.....................................................................16. Mr Higham is advised of the error.............................................................................17. Mr Knox is advised of the error.................................................................................18. The evidence of Professor Peter Bardy......................................................................19. The evidence of David Swan.....................................................................................20. The expert witnesses - causation................................................................................21. The evidence of Professor Boddy..............................................................................22. The evidence of Associate Professor Wei..................................................................23. The evidence of Professor John Gibson.....................................................................24. The evidence of Dr Stephen Vaughan.......................................................................25. The literature..............................................................................................................

25.22. Conclusions from the literature......................................................................18926. Conclusions regarding causation................................................................................27. Recommendations......................................................................................................

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1. Introduction

1.1. These are the findings of the Court in respect of an inquest into the cause and

circumstances of the deaths of four individuals. They are as follows:

Johanna Pinxteren aged 76 years who died on 23 June 2015

Christopher McRae aged 67 years who died on 22 November 2015

Bronte Ormond Higham aged 68 years who died on 7 August 2016

Carol Anne Bairnsfather aged 70 years who died on 17 February 2017

1.2. The cause of Mrs Pinxteren’s death was e-coli bacteraemia secondary to refractory

acute myeloid leukaemia (AML). She was originally diagnosed with AML in

November 2014 at the age of 75. She was treated at the Royal Adelaide Hospital (the

RAH).

1.3. The cause of Mr McRae’s death was AML. He was originally diagnosed with AML

in May 2014 at the age of 66. He was treated at the RAH.

1.4. The cause of Mr Higham’s death was AML. He was originally diagnosed with AML

in November 2014 at the age of 66. He was treated at the Flinders Medical Centre

(the FMC).

1.5. The cause of Mrs Bairnsfather’s death was AML. She was originally diagnosed with

AML in October 2014 at the age of 68. She was treated at the RAH.

1.6. All four deceased persons died of or from the complications of AML.

1.7. All four deceased persons had been accurately diagnosed as suffering from AML. An

individual patient’s prognosis following diagnosis may be affected by a number of

factors, the presence or absence of which are known to potentially affect treatment

outcomes. I shall describe those factors in the course of these findings. It should be

understood that left untreated, AML will cause the death of the afflicted person

usually within a matter of months.

1.8. Following diagnosis all four deceased persons were treated by way of chemotherapy.

In the first instance the chemotherapy in respect of each patient was delivered by way

of what is known as induction therapy. In each instance complete remission was

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induced in the patient. Following the achievement of complete remission all four

persons underwent consolidation chemotherapy, otherwise known as post-remission

therapy, the purpose of which I shall briefly explain in a moment.

1.9. The duration of remission in each instance varied, but in due course all four patients

experienced a relapse of AML and then underwent varying regimes of further

treatment. Ultimately, however, they succumbed to the disease.

1.10. There is no suggestion other than that each of the four deceased persons had received

induction therapy that was in correct accordance with chemotherapy protocols as they

existed at the time of their treatment.

1.11. It should be borne in mind throughout that there is nothing extraordinary about a

relapse following appropriate chemotherapy. The fact of relapse will not of itself

bring into question the quality and nature of the chemotherapy that was delivered as

part of a patient’s treatment.

1.12. However, there is no doubt that early relapse can carry serious implications in terms

of the patient’s life expectancy from that point forward. Professor John Gibson who

is an independent expert in the field of haematology gave evidence which I accept that

an early relapse is an unfavourable circumstance and that even if a person attains a

second remission, the second remission will generally be less robust and of shorter

duration than the first. Thus the ideal treatment outcome is a long first remission1.

1.13. I now turn to the issue of consolidation chemotherapy. It was explained to the Court

that even with complete remission of AML, a majority of patients who receive no

further treatment will subsequently relapse due to residual disease which cannot be

detected within the body. However, in order to reduce the likelihood of relapse

occurring, consolidation chemotherapy is offered to the AML patient and is

administered as soon as possible after the achievement of complete remission.

Consolidation therapy can be and is offered to both the young and the elderly.

1.14. The evidence before the Court is that the idea underlying consolidation is to

‘consolidate’ remission by way of the administration of further cycles of

chemotherapy, the purpose being to gradually eradicate the leukaemic cells in the

body or to diminish the number of cells to a level that the body’s own immune system

1 Transcript, page 268

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can control and, perhaps, to provide a cure for the patient. In essence the purpose of

consolidation is to reduce residual disease, to reduce the likelihood of relapse, to

prolong remission and possibly to effect a cure.

1.15. There are a number of differing consolidation therapy protocols that dictate the nature

of the chemotherapy administration regime in an individual patient. The evidence is

that the consolidation therapy pertaining to the four deceased persons is usually

administered in two separate cycles of chemotherapy. The regimen in question

consisted of the administration of chemotherapy over five days. The drug cytarabine,

otherwise described as ‘Ara-C’, was administered on the first, third and fifth days.

The drug idarubicin was administered on the first and second of those days. Both

drugs were administered intravenously (IV) over a number of hours.

1.16. The four deceased persons underwent consolidation therapy after the achievement of

complete remission in each case. There was some doubt expressed during the inquest

as to whether Mr McRae achieved complete remission, but in my view the evidence

demonstrated that he did and I so find. Mr McRae and Mr Higham underwent two

cycles of consolidation therapy. Mrs Pinxteren underwent one cycle of consolidation

therapy. She did not recover well or quickly after this cycle. She relapsed before a

second cycle could be administered. Mrs Bairnsfather underwent one cycle of

consolidation therapy. Mrs Bairnsfather experienced poor bone marrow recovery

following her one cycle of consolidation. As well, following that one cycle it was

thought that she had reverted to an underlying myelodysplastic syndrome and a

differing regime of treatment was undertaken instead of a second cycle.

1.17. The consolidation therapy in the case of each deceased person miscarried because it

was undertaken not in accordance with the consolidation therapy protocol that had

been determined to be appropriate for those persons. What happened was that the

first cycle of consolidation therapy in each case involved the provision of once daily

administrations of cytarabine over the three alternate days when the intended protocol

called for administration twice daily over three alternate days. The miscarriage of

treatment was the result of an error that was contained within the written protocol

pertaining to the consolidation treatment for these patients. The error was due to the

inclusion of the word ‘ONCE’ instead of the word ‘twice’, or the expression ‘bd’

which is well understood medical terminology indicating twice daily administration.

It had been intended that the protocol should specify twice daily administration. The

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circumstances in which this error occurred were the subject of detailed inquiry during

the course of the inquest. The evidence is that the error originated within the

Haematology Department at the RAH and was replicated at the FMC which had

adopted the erroneous RAH protocol. The error was the result of woefully inept

clinical governance at both hospitals.

1.18. Each of the single cycles of consolidation therapy administered to Mrs Pinxteren and

Mrs Bairnsfather respectively at the RAH were delivered in accordance with the

erroneous protocol.

1.19. Both cycles of the two consolidation therapies each administered to Mr McRae at the

RAH and to Mr Higham at the FMC were delivered in accordance with the erroneous

protocol.

1.20. The four deceased individuals were not the only persons who received consolidation

chemotherapy for AML that was not in accordance with the correct protocol for

administration. Six other patients also underwent consolidation chemotherapy that

was delivered pursuant to the terms of the erroneously worded protocol. Two of those

additional patients underwent their treatment at the RAH. Four of them underwent

their treatment at the FMC. In all a total of ten patients, five patients in each of the

two hospitals, were the subject of the incorrect administration of consolidation

chemotherapy for AML pursuant to the same erroneous protocol. As indicated, this

inquest relates to the deaths of four affected persons. The Court has also examined in

detail the circumstances surrounding the treatment of one of the surviving persons

affected by the protocol error. That person is Mr Andrew Knox. Mr Knox was

treated at the FMC. He underwent successful induction chemotherapy as well as two

cycles of the erroneous consolidation chemotherapy. Ultimately Mr Knox also

relapsed but has since undergone further treatment. The evidence as to the details of

his matter was the subject of objection on the grounds that the evidence was not

relevant in any consideration of the cause and circumstances of the deaths of the four

individuals or any of them. The objection was taken by the legal representatives of a

number of medical practitioners (hereinafter referred to as ‘the doctors’) who had

various involvements in the promulgation of the chemotherapy error or with the

treatment of the affected patients. I overruled that objection and admitted detailed

evidence in relation to the circumstances surrounding the treatment of Mr Knox. I

delivered written reasons for that decision. The relevance of the evidence relating to

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Mr Knox’s treatment will become readily apparent. It has also been necessary to refer

to certain facets of the treatment of four of the other individuals. It is not necessary to

refer to all of those individuals by their full names. They are a Mr G who was treated

at the RAH, a Ms MR who was also treated at the RAH, a Ms Mc who was treated at

the FMC and Ms Jennifer Crannage who was treated at the FMC. Ms Crannage was

represented by counsel at the inquest.

1.21. The evidence is that the protocol error was discovered and recognised as such at the

RAH no later than Monday 19 January 2015. I say no later than 19 January because

there is no doubt that on that day the error in the actual protocol document was

recognised. However, the error was discovered as the result of the identification of a

prescription discrepancy on Friday 16 January. The discrepancy was discovered

within the prescription for consolidation chemotherapy for the patient Ms MR at the

RAH. It was identified by an RAH pharmacist when he noticed that one doctor had

prescribed once daily therapy but another more senior doctor, correctly, had

prescribed twice daily. In my opinion there is no question but that the discrepancy

could and should have led to the protocol error being identified on the Friday.

Moreover, the error should also have been communicated to the FMC on the same

day. The error would not be recognised at the FMC until the end of January 2015. If

the error had been identified at both hospitals on Friday 16 January 2015, there is a

case for concluding that the underdosing of Mrs Pinxteren in respect of her third

alternate daily administration of therapy on Saturday 17 January at the RAH probably

would have been avoided.

1.22. Similarly there is a case for concluding that if adequate procedures had been in place

for the reporting of adverse incidents across the entire South Australian public health

system, the underdosing of Mr Higham on the afternoon of 16 January and on

18 January 2015, during his second cycle of consolidation therapy, probably would

have been avoided.

1.23. I have already referred to a surviving patient, Mr Andrew Knox, who had been treated

at the FMC. The circumstances surrounding the treatment of Mr Knox are unique in

that Mr Knox was the only patient who was treated in accordance with the erroneous

protocol at a time after the error had positively been identified at the RAH on

19 January 2015. Had the error also been recognised at the FMC on the same day, the

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underdosing that occurred in his second cycle of consolidation therapy would have

been avoided altogether.

1.24. In the course of these findings I will deal with the manner in which the protocol error

was promulgated and also with the issue as to the circumstances in which the error

was discovered and was sought to be rectified at both the RAH and the FMC.

1.25. This inquest investigated a number of matters connected with the cause and

circumstances of the death of the four individuals including the following:

The nature of the disease of AML and its usual course of treatment, particularly as

it related to elderly patients.

The courses of treatment of the four deceased patients and to Mr Knox.

The circumstances in which the protocol error was promulgated within the RAH

protocol.

The circumstances in which the protocol error was promulgated within the FMC

protocol.

The circumstances in which the erroneous consolidation therapy came to be

administered to the four deceased patients and to Mr Knox.

The discovery of the error at the RAH and the timeliness of the error being

rectified at that hospital.

The discovery of the error at the FMC and the timeliness of the error being

rectified at that hospital.

Whether more timely rectification of the error at each hospital had any

consequences for any of the deceased patients or Mr Knox.

Whether the quality of clinical governance at either hospital or across the South

Australian public health system impacted on the promulgation of the error and/or

on its failure to be discovered and rectified in a timely manner.

The manner of and timeliness of the communication of the erroneous treatment to

the affected patients and to their general practitioners.

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Whether the erroneous treatment that was administered pursuant to the erroneous

protocol contributed to the deaths of the four deceased patients.

1.26. It will be seen therefore that this inquest was principally concerned with the cause of

the deaths of the four deceased patients, and in particular whether any error in

treatment contributed to their deaths, or at least contributed to outcomes that were

more adverse than what they would have been if a treatment error had not occurred.

The Court also of course examined the circumstances surrounding their deaths, and in

particular how it was that erroneous chemotherapy treatment was provided to them.

The Court was unable to deal in a fulsome manner with broader issues such as the fine

detail of adverse incident reporting systems and that of open disclosure policies and

manners of implementation. I have dealt in these findings with some aspects of those

topics, but to a limited degree only. In this regard I am aware of the fact that prior to

the holding of this inquest other independent inquiries had been conducted including a

review conducted by a panel headed by Professor Villis Marshall AC. As well, I am

aware of a review conducted by a panel headed by Mr Kieran Pehm, former Health

Care Complaints Commissioner New South Wales, under the auspices of the

Australian Commission on Safety and Quality in Healthcare. As a result of both

inquiries certain recommendations including those relating to matters including

adverse event reporting and open disclosure were made. I should add that unlike the

public inquiry that this Court has conducted, the reports of the inquiries to which I

have referred for the most part de-identify the relevant participants in the affair except

by reference to their occupations and positions within the institutions to which this

inquest relates.

1.27. I add that the findings of fact that I have made have been made solely on the evidence

that has been presented in this inquest.

1.28. There is one further general matter that I should mention. Having regard to the

importance and public notoriety of this matter and of the issues that I have identified

in the preceding paragraphs, in my view this matter should have been the subject of a

commission of inquiry pursuant to the Royal Commissions Act 1917. Such a

commission of inquiry would have had the ability to thoroughly inquire into not only

the causes and circumstances of the deaths of the four individuals with which this

inquest is concerned, but also into the circumstances surrounding the underdosing of

all of the six other individuals who were treated both at the RAH and the FMC. With

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appropriately crafted terms of reference, such a commission of inquiry would not

have been distracted, as this inquest was, by unnecessary and time consuming

argument about the Court’s jurisdiction and arguments about, for instance, the

relevance of the circumstances surrounding the treatment of Mr Andrew Knox, all of

which arguments I carefully considered and ultimately dismissed with detailed written

reasons. It goes without saying that a commission of inquiry would have been

furnished with greater resources than this Court could possibly muster. When

considering the resources that this Court can bring to a matter of this complexity it has

to be remembered that the Court and its officers including counsel assisting the Court

are required to perform other duties quite apart from the duties that were occasioned

by this inquest. I should add that it is remarkable that counsel assisting the coroner,

Ms Naomi Kereru, without the assistance of other counsel assisting or without the

benefit of an instructing solicitor, was able to conduct this inquest with the

conspicuous competence with which she conducted it when all the while she was

concurrently burdened with her duties as counsel assisting the coroner in other

complex coronial matters. I place on record my indebtedness both to Ms Kereru and

to the lay staff of the office of the State Coroner who assisted her in the conduct of

this matter.

1.29. Legal representation

In the inquest Ms Naomi Kereru was counsel assisting the Coroner.

Mr Mark Griffin QC was counsel for the following:

Mr William Pinxteren who was the husband of Mrs Pinxteren;

Mrs Ricki Higham who was the wife of Mr Higham;

Ms Rebecca Emery who was the daughter of Mr McRae;

Mr Andrew Knox;

Ms Jennifer Crannage.

Mr Darrell Trim QC and Mr Tom Besanko were counsel for the following (the

doctors):

Associate Professor Ian Lewis;

Associate Professor Briony Kuss;

Dr Douglas Coghlan;

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Associate Professor Agnes Yong;

Dr Devendra Hiwase;

Dr David Ross.

Mr Ralph Bonig was counsel for the following:

Mr Russell Baldock;

Mr Abhi Phatak;

Ms Kirsty Scarborough;

Associate Professor Peter Bardy;

Ms Kailin Teh;

Dr Naranie Shanmuganathan.

Ms Joanne Cliff was counsel for the following:

Dr Ashanka Beligaswatte;

Professor Alex Gallus.

Mr Michael Tilley was counsel for the following:

Mrs Che To;

Professor Luen Bik To.

Mr Todd Golding was counsel for the following:

The Minister for Health;

The Chief Executive of SA Health, Mr David Swan.

I express my gratitude for the assistance provided by all counsel and those instructing

them.

2. A brief overview of the course of treatment and of the longevity of the four

deceased persons following diagnosis

2.1. I have found that all four deceased persons have died of or from the complications of

AML.

2.2. All four deceased persons were above the age of 65 years at the time of their

respective diagnoses. Mr Knox was 65 years and 11 months at the time of his

diagnosis.

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2.3. All four deceased persons achieved complete morphological remission following

induction chemotherapy. They all underwent consolidation chemotherapy. In due

course all four persons relapsed and ultimately died.

2.4. Mrs Pinxteren was diagnosed on 19 November 2014. Complete remission following

induction chemotherapy was confirmed on 31 December 2014. Mrs Pinxteren’s date

of relapse was 2 March 2015. Mrs Pinxteren died on 23 June 2015. Mrs Pinxteren’s

duration of complete remission was approximately 62 days. Mrs Pinxteren’s duration

of survival from diagnosis was approximately seven months and four days.

2.5. Mr McRae was diagnosed on 13 May 2014. Complete remission following induction

chemotherapy was confirmed on 9 July 2014. Mr McRae’s date of relapse was

confirmed by way of a bone marrow biopsy on 10 March 2015. Mr McRae died on

22 November 2015. Mr McRae’s duration of complete remission was eight months.

Mr McRae’s duration of survival from diagnosis was approximately 18 months and

nine days.

2.6. Mr Higham was diagnosed on 7 November 2014. Complete remission following

induction chemotherapy was confirmed on 4 December 2014. Mr Higham’s date of

relapse was 18 April 2016. Mr Higham died on 7 August 2016. Mr Higham’s

duration of complete remission was approximately 16 months and 14 days.

Mr Higham’s duration of survival from diagnosis was approximately 21 months.

2.7. Mrs Bairnsfather was diagnosed between 15 and 17 October 2014. Complete

remission following induction chemotherapy was confirmed on 14 November 2014.

Bone marrow examinations in January and February 2015 suggested that Mrs

Bairnsfather was no longer in remission. However, a further conclusion was reached

based on a bone marrow result later in February that she had not relapsed but that she

may have reverted to pre-existing myelodysplasia which had led to her leukaemia in

the first place. Ultimately it was confirmed that Mrs Bairnsfather had relapsed as of

28 September 2016. Mrs Bairnsfather died on 17 February 2017. Mrs Bairnsfather’s

duration of complete remission was approximately 22 months and 14 days.

Mrs Bairnsfather’s duration of survival from diagnosis was approximately two years

and four months.

2.8. In relation to Mr Andrew Knox who has survived, Mr Knox was diagnosed on

26 November 2014. He achieved a complete remission following induction treatment

15

on 22 December 2014. Mr Knox’s relapse was confirmed by bone marrow biopsy on

15 December 2016. Mr Knox’s duration of complete remission was approximately 23

months and 23 days.

2.9. It will be seen that the remission durations and survival durations of the four deceased

persons varied. Mr Knox, while having relapsed following a period of complete

remission, has survived.

3. Consolidation chemotherapy for AML – an overview

3.1. It was universally accepted within the evidence taken before the Court that an

untreated individual who is diagnosed with AML would survive for approximately

two months. It is therefore obvious that all four deceased persons and Mr Knox

positively responded to cytarabine induction chemotherapy insofar as it resulted in a

complete morphological remission in each case and a period of survival beyond that

period of two months. This is so despite what in some cases were adverse prognostic

features that I will discuss. I have already alluded to the fact that in each of the five

cases to which these findings relate induction chemotherapy was administered in

accordance with the correct induction protocol. There is no suggestion that the

induction treatment of any of these five patients in any way miscarried.

3.2. An individual AML patient’s prognosis may be affected by a number of factors.

These include the age and performance status of the patient at the time of diagnosis,

the presence or otherwise of predisposing myelodysplasia, medical and psychological

comorbidities, the presence of significant extramedullary disease and cytogenetic risk.

There is also the influence of molecular factors such as mutations which have a

bearing on the treatment outcome of a patient. This particular factor might be viewed

on the one hand as a prognostic factor, or on the other as a factor that might render

chemotherapy treatment less effective in the case of a particular patient. It is

worthwhile observing at this point that Mr Knox had a number of factors that operated

in his favour. They included the fact that he was of a slightly lesser age than the other

patients; he was approaching his 66th birthday at the time of diagnosis. As well, he

did not have predisposing myelodysplasia. His cytogenetic factors were favourable as

were his molecular factors. Mr Knox had no comorbidities other than a known

history of raised blood pressure which does not appear to have had any influence on

his treatment or prognosis. The evidence satisfied me that at diagnosis Mr Knox in

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particular had a reasonable expectation of a favourable outcome and a long remission,

and possibly even a cure of his disease. Nevertheless, as indicated, Mr Knox

ultimately relapsed after a period that was just short of two years remission. In the

period of time since his relapse Mr Knox has undergone transplant therapy in

Victoria. As will be seen, Mr Knox underwent two flawed cycles of consolidation

chemotherapy, the circumstances surrounding the second cycle being especially

egregious.

3.3. Having undergone induction therapy in each instance, and having achieved complete

morphological remission in each case, the four deceased persons and Mr Knox

underwent consolidation chemotherapy. Consolidation chemotherapy is administered

to the patient as soon as possible after the achievement of complete remission. The

evidence suggested that an ideal timeframe for the commencement of consolidation

chemotherapy would be four weeks since the beginning of induction therapy.

However, the timing of the commencement of consolidation chemotherapy will

depend upon the degree of a patient’s recovery from the effects of induction

chemotherapy, and in particular the recovery of red blood cell, white blood cell and

platelet counts, recognising of course that chemotherapy has a toxic and destructive

effect not only on leukaemic cells, but also on normal cells. Mrs Pinxteren did not

recover well from her single cycle of consolidation as will be seen.

3.4. The duration and frequency of administration of consolidation chemotherapy, and its

dosage, is designed to strike a balance between efficacy and its anti-leukaemic effect

on the one hand, and on the other the toxicity that the treatment presents to the patient.

The strategy is to subject the body to the maximum possible exposure to the active

chemotherapy drug but balancing the need to limit the toxic effects of the drug upon

the individual. A body of evidence suggested that a once daily administration of

cytarabine chemotherapy on alternate days would not provide the ideal exposure of

leukaemic cells to the drug. In this sense, the drug was said to be ‘schedule-

dependent’. It is a drug the efficacy of which is dependent on matters such as the

frequency at which it is administered and on the duration between administrations.

3.5. As seen earlier, Mr McRae and Mr Higham underwent two cycles of consolidation

chemotherapy. Mrs Pinxteren underwent one cycle of consolidation chemotherapy.

Mrs Bairnsfather underwent one cycle of consolidation chemotherapy. For reasons I

will mention in due course, a differing regime of treatment was undertaken instead of

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a second cycle in her case. Mr Knox whose original induction therapy had also

induced complete remission, underwent two cycles of consolidation chemotherapy

during the course of his remission.

3.6. Throughout the evidence, and in particular the expert evidence that was adduced in

this inquest, differing regimens of consolidation chemotherapy for AML were

described. I heard much oral expert evidence about this. The issue is also referred to

in the voluminous amount of medical literature that was tendered to the Court. It was

common ground during the course of the inquest that consolidation therapy might

well be administered once daily. However, when this occurs it is administered daily

over a number of consecutive days, possibly five or six, not on alternate days as was

the case here. There is no question but that the protocol that should have been

followed in respect of each of these patients is a well-recognised protocol for the

administration of consolidation chemotherapy. I was satisfied that the correct

protocol had a sound scientific basis. I was not satisfied that the incorrect protocol

had such a basis.

3.7. The one matter that the expert evidence in this inquest clearly did demonstrate was

that a protocol in which cytarabine is administered once daily for a period of three

hours on alternate days 1-3-5 was not known to chemotherapy medicine. Any

suggestion that there could have been sound clinical grounds for administering the

consolidation therapy in the manner in which it was administered to these patients

must be rejected. And it is worthwhile noting that, subject possibly to one aspect

within the treatment of Mrs Pinxteren that I will expand on in due course, the once

daily administration of cytarabine on three alternate days was not prescribed on

clinical grounds. It was not due to any conscious clinical decision to deviate from the

norm by administering once daily and not twice daily therapy. As will be seen, the

deviation occurred simply due to the fact that the prescribing clinicians mechanically

followed the incorrectly worded protocol. Put simply, the protocols at both hospitals

were wrong and the patients’ treatments were wrong.

3.8. The evidence satisfied me that such a regime of treatment would be wrong in

scientific and medical principle and in general terms would be less efficacious than

protocols that included the administration of cytarabine twice daily on alternative

days, or once daily on consecutive days. However, the evidence did raise a question

as to whether or not, due to a number of factors that were discussed in the course of

18

the expert evidence, consolidation chemotherapy will be as effective in the elderly as

it is in younger persons. An associated question is whether or not there is an

identifiable minimal dosage regime that is effective in the elderly.

4. The RAH AML consolidation chemotherapy protocol

4.1. The various chemotherapy treatment regimens for AML that were utilised at the RAH

were contained within a database maintained by SA Pathology. In fact, the consultant

haematologists employed both at the RAH and at the FMC were employees of SA

Pathology. The haematologists had computerised access to the protocols.

4.2. Tendered in evidence was the RAH protocol for AML chemotherapy that had been in

existence prior to the promulgation of the erroneous protocol in July 20142. This

protocol was dated 17 May 2012. It purports to have been authorised by Associate

Professor Ian Lewis who was the senior haematologist at the RAH at all material

times. This protocol, insofar as it provided for consolidation chemotherapy, was age

based. In the case of patients up to 65 years of age the protocol called for the

administration of 3gm of cytarabine per square metre of body surface area to be

administered intravenously twice daily on days 1, 3 and 5. Patients between the ages

of 66 and 70 years were administered 2gm of cytarabine per square metre at the same

frequency of delivery. Patients over 70 years were administered with cytarabine at

1.5gm per square metre to be administered once a day on six consecutive days. It will

be noted that each of these three age based regimens called for six individual doses of

cytarabine. Importantly, there was no consolidation regime that called for the

administration of cytarabine once daily on days 1, 3 and 5 which naturally would

involve three doses only. The administration of idarubicin was not part of any of

these age based regimens.

4.3. Against that background, it is necessary to explain how and why the amended AML

consolidation chemotherapy protocol came into existence in 2014. Evidence was

provided to the Court about the activities of the Australasian Leukaemia and

Lymphoma Group (ALLG). Associate Professor Wei who is the Head of Human

Molecular Pathology at the Alfred Hospital in Melbourne gave evidence about these

activities and how they resulted in suggested modifications to existing consolidation

2 The original protocol is Exhibit C9b

19

chemotherapy regimens for AML. Associate Professor Wei told the Court that he was

in charge of the acute leukaemia practices within his hospital and that his duties

include the determination of treatments that should be used. He also operated the

clinical trial program at the Alfred Hospital. He also practices in the field of acute

leukaemia treatment with a heavy focus on patients with AML. Associate Professor

Wei explained that as half of the patient population fell into the age category of 60

years and over, a large part of his practice was directed towards the treatment of

patients with AML who were ‘older than the age of 60-65’3.

4.4. Associate Professor Wei explained that it had been identified in the early part of this

decade that patients over the age of 50 experienced a much higher toxicity from high

dose cytarabine, that is to say delivery of 3gm per square metre twice per day.

Among other considerations was a recognised desire to include idarubicin in

consolidation chemotherapy. In addition, some consolidation regimens involved

differing high dose cytarabine administration such as the 3gm and 2gm twice per day

regimens. Associate Professor Wei also explained that a new trial for the introduction

of a maintenance chemotherapy regime following consolidation therapy had been

contemplated. This trial was referred to as the M15 study. The maintenance therapy

would involve the repeated administration of oral lenalidomide. Associate Professor

Wei explained that the lenalidomide maintenance therapy was thought to have

involved an augmentation of the immune system to help eradicate residual leukaemia

after the completion of chemotherapy. To this end patients would be invited to

participate in the lenalidomide trial for 12 months in order to determine if this would

further augment the existing chemotherapy outcome. Participation in the trial would

be provided to patients between the ages of 18 to 65. Patients over the age of 65

would not be included in the trial because according to Associate Professor Wei it was

well known that outcomes for patients above the age of 65 were substantially worse

than in younger patients, meaning that it would be very difficult to establish the

benefit of maintenance therapy in a cohort of older patients. Nevertheless, it was

considered that for the sake of uniformity patients over the age of 65 would also

receive the same new consolidation therapy4.

4.5. In order to set up the trial it was considered desirable that consolidation therapy

practice for AML should be uniform. The heterogeneity in consolidation practices

3 Transcript, page 27654 Transcript, page 2772

20

was problematic. One can readily understand that trial results would have limited

utility if the therapy leading up to the trial had not been standard.

4.6. Another consideration that was taken into account in altering the consolidation

regimes was emerging literature to the effect that a dose of cytarabine above 1gm per

square metre was unlikely to be beneficial and that dosages in excess of that were

only serving to increase toxicity in the patient.

4.7. A group of experts from around Australia conferred in teleconferences and workshops

and ultimately a consensus was reached as to the most appropriate treatment to be

used for older patients. It was agreed that in line with international practice, two

cycles of consolidation chemotherapy involving an intermediate dose of cytarabine at

1gm per square metre twice a day on days 1, 3 and 5 would be optimal and would be

standard for patients of or above the age of 56 who were not patients with core

binding factor (CBF) AML 5. This therapy would be combined with the

administration of idarubicin on days 1 and 2 of this five day cycle. None of the five

patients with which this inquest is concerned were CBF patients. Thus, this new

chemotherapy regime, that would become known as HiDAC 2 – Ida, was the regime

that would have been administered to the affected patients but for the error.

4.8. Associate Professor Ian Lewis of the RAH gave evidence in respect of the

introduction of the revised protocol at that hospital. Associate Professor Lewis

explained that each individual teaching hospital in South Australia was autonomous in

respect of the manner in which clinical services were delivered. This meant, for

instance, that the FMC decided on the content of chemotherapy protocols

independently of the RAH. The same applied in respect of The Queen Elizabeth

Hospital which used chemotherapy protocols promulgated by an entity known as

EviQ. I add here that the erroneous protocol was not adopted at The Queen Elizabeth

Hospital because they followed the EviQ chemotherapy regimens which did not

contain an error.

4.9. Associate Professor Lewis explained that when a protocol change had been

recommended or a new investigation had become available, protocol issues at the

RAH would be discussed at multidisciplinary team meetings. Associate Professor

5 CBF AML is a reference to the disease accompanied by what is termed the core binding factor. It is generally regarded as a favourable prognostic factor. None of the patients who were the subject of this inquest, nor Mr Knox, had core binding factor AML.

21

Lewis was the lead haematologist for the RAH acute leukaemia team as well as for

the bone marrow transplant team. He was member of the ALLG as of 2014. Indeed,

Associate Professor Lewis was the Chair of the Bone Marrow Transplant Group at

ALLG and in 2014 was elected as the Deputy Chair of the Scientific Advisory

Committee. He was not a member of the distinct sub-group within ALLG for AML,

although he attended their meetings.

4.10. Naturally Associate Professor Lewis became aware of the pilot study to explore the

efficacy of lenalidomide in maintenance therapy for AML sufferers.

4.11. In another section of these findings I will discuss the circumstances in which the

amended and ultimately erroneously worded protocol came into existence at the RAH.

5. The FMC AML consolidation chemotherapy protocol

5.1. Although the haematologists at both the RAH and the FMC were employees of SA

Pathology which maintained the chemotherapy protocols database, the FMC had

autonomy from the RAH in terms of protocol maintenance and content. This

circumstance is odd in that a patient’s consolidation chemotherapy for AML might

vary depending upon the hospital at which it was administered, even though the

medical practitioners administering it were employed by the same government entity,

namely SA Pathology. Nevertheless, that was the position in 2014.

5.2. Unlike the SA Pathology maintained protocols, the FMC maintained its protocols on

chemotherapy templates that were created and maintained by the FMC haematology

pharmacists, although the content of the templates was dictated by medical

practitioners. As at July 2014 at the FMC there were a number of AML consolidation

chemotherapy templates including templates for high dose cytarabine administration

twice daily on days 1, 3 and 5.

5.3. A chemotherapy template not only housed the relevant protocol but it also operated as

a proforma computerised document that could be completed depending upon an

individual patient’s consolidation chemotherapy needs. The resulting completed

document, that is to say completed on the computerised template, would serve as the

patient’s prescription for consolidation chemotherapy.

22

5.4. The nature of this documentation, how an individual template was created and how in

turn an individual patient’s prescription was created was explained in the course of

the evidence by Ms Kailin Teh who was a pharmacist within the Haematology

Department at the FMC. Ms Teh had worked fulltime as a clinical pharmacist within

that Department since March 2014. Ms Teh explained to the Court that she had an

occasional responsibility in relation to the creation of protocols and in particular she

had a role in relation to the checking of protocols that had been promulgated by

medical staff. In 2014 the chemotherapy protocol templates were maintained on the

haematology server that was peculiar to the FMC. Although she had access to the

RAH created protocols via the SA Pathology website, the FMC used its own

templates as already described. In respect of the creation of new templates, Ms Teh

explained that this would be based on the contents of a reference document that was

provided by the requesting medical practitioner. This information would be populated

on an Excel spreadsheet and would be sent back to the requesting doctor for checking

of content accuracy. If accurate it was then saved on the server and would then act as

the basis for patient prescriptions.

5.5. As an aside at this point, I understood from the evidence as a whole that this system is

akin if not identical to a system that has for some years been advocated as a fail-safe

prescription system that should be adopted across the board in this State, namely a so-

called electronic prescription system. Ms Teh made it plain, as did another witness,

Professor Peter Bardy who was the Clinical Director of Cancer Services at the RAH,

that the accuracy of electronic prescriptions is only as good as the accuracy of the

templates that they are based upon, which in turn is only as good as the information

that was originally provided when the template was created. Thus the fact that the

prescription may be electronically generated is of itself no guarantee of accuracy of

the patient’s chemotherapy regimen. In this regard, the scientific adage ‘garbage in,

garbage out’ readily springs to mind. As we will see, what happened here classically

illustrates the point.

5.6. In the course of the oral evidence given by Associate Professor Bryone Kuss who is

the Head of the Haematology Department at FMC, and therefore Associate Professor

Lewis’ RAH counterpart, she produced a series of AML consolidation chemotherapy

templates that had been in use prior to July 20146. Two such templates, namely

6 Exhibit C50, pages 13-17

23

HiDAC2 and HiDAC3, called for twice daily administration of cytarabine on days 1,

3 and 5. The respective therapies called for high doses of 2,000mg and 3,000mg per

square metre of body surface area. There was no existing regimen that involved once

daily cytarabine administration on alternate days. The new protocol was designed

among other things to reduce the dosage of cytarabine with the addition of idarubicin,

but maintaining the twice daily administration of cytarabine. As will be seen, when

in July 2014 the FMC altered its consolidation chemotherapy template to align with

what the RAH was doing at that time, the requirement for twice daily administration

was erroneously not included.

5.7. In another section of these findings I will discuss the circumstances in which the new

and erroneous consolidation chemotherapy protocol that had been created at the RAH

was adopted at the FMC.

6. The promulgation of the erroneous protocol at the RAH

6.1. I have already referred to Associate Professor Ian Lewis. In 2008 Associate Professor

Lewis was appointed Head of the Clinical Haematology Unit at the RAH. Shortly

after that appointment SA Pathology was created. This became the entity that had

overarching responsibility for government pathology services in South Australia. It

also employed the haematologists at both the RAH and the FMC. In 2014 Associate

Professor Lewis was appointed Clinical Director of the Haematology Directorate of

SA Pathology. This position was based at the RAH. SA Pathology had the delivery

of laboratory haematology services as one of its principal responsibilities. In terms of

the provision of those clinical services those responsibilities devolved to individual

hospitals in South Australia. Each hospital had its own Head of Haematology to

oversee the provision of clinical services. In the case of the RAH that person was

Associate Professor Lewis. Professor Luen Bik To was appointed Clinical Director.

In 2014 there were approximately nine full time haematology consultancy positions

distributed over a group of thirteen such haematologists. There were a number of

registrars. There were two haematology teams, the dichotomy being based on

whether or not a patient would undergo bone marrow transplantation. All of the

consultants had specific interests within haematology, including of course in AML.

Associate Professor Lewis was the lead haematologist for the acute leukaemia team as

well as the bone marrow transplant team. As I understood the evidence bone marrow

transplantation was not available at the FMC.

24

6.2. In his oral evidence Associate Professor Lewis told the Court that he presented the

ALLG M15 study to the RAH haematologists to determine its level of interest and

whether it was thought appropriate that the RAH should participate in the study.

Associate Professor Lewis’ presentation occurred in September 2011 and was based

on an ALLG pilot study of June of that year. A decision was made at the RAH to

proceed with the study. Associate Professor Lewis explained that the study needed to

be submitted to the RAH Ethics Committee which involved submitting a number of

documents including the trial protocol and other documentation. Ultimately the

Ethics Committee approved the study. Associate Professor Lewis told the Court that

informal discussions among clinicians at the RAH who were also members of the

ALLG took place. These discussions occurred within the monthly RAH AML

multidisciplinary team meetings in which patient cases were discussed and protocols

were canvassed in an ‘ad-hoc informal manner’7. The proposition that high dose

cytarabine was not adding any benefit over and above intermediate dose cytarabine

was well accepted at these meetings. The high dose of 3gm per square metre did not

appear to provide any extra anti-leukaemia efficacy but was associated with increased

toxicity. Following these informal discussions Associate Professor Lewis set about

implementing the appropriate protocol changes.

6.3. In his evidence Associate Professor Lewis identified the protocol8 that was in force

between 2012 and 2014 prior to its alteration. I have already explained the nature of

the pre-existing RAH protocol and the manner in which it was maintained.

6.4. Mrs Che To is a registered nurse who had worked in intensive care and in

haematology at the RAH. At all material times she was a project officer which was

principally an administrative position within the hospital. As part of her

responsibilities she would receive protocols from the doctors and would format them,

amend them as required and upload them onto the SA Pathology system. Mrs To is

the wife of Professor Luen Bik To, the Clinical Director of Haematology at the RAH.

6.5. On Saturday 12 July 2014 Associate Professor Lewis sent an email to Mrs To

concerning the need for the AML protocol to be altered9. In his email Associate

Professor Lewis described the changes as ‘reasonably significant’. The email makes

7 Transcript, page 18818 Exhibit C9b9 Exhibit C49, page 143

25

reference to the fact that Associate Professor Lewis had made manuscript changes on

a copy of the existing protocol and would leave that document with his secretary.

Attached to the email was the ALLG summary of AML induction and consolidation

regimens, adding ‘hopefully our protocols will be aligned’. The attached

documentation10 set out in a clear format that for AML consolidation chemotherapy in

non-CBF patients over 55 years the regimen would involve the administration of

cytarabine at 1,000mg per square metre of body surface area ‘BD', meaning twice a

day, on days 1, 3 and 5. As well, idarubicin would be administered on days 1 and 2.

6.6. Associate Professor Lewis did not keep a copy of his handwritten changes as set out

on a printed copy of the existing protocol. Nevertheless I was satisfied that it had

been Associate Professor Lewis’ clear intention that the reconstituted non-CBF AML

consolidation protocol would make a reference to the need for cytarabine to be

administered twice daily. I would add here that as seen earlier the existing 2012

consolidation regimens already provided for twice daily administration of cytarabine

in those regimens where the chemotherapy was administered on alternate days,

namely days 1, 3 and 5. Thus any alteration from twice daily to once daily within

such a consolidation protocol would have been, and ought to have been regarded as, a

radical change and have raised eyebrows as to whether such a radical change was

intended. As we know it was not intended. There were other significant changes that

were intended including a reduction in the actual dosage to 1gm from 2 or 3gms, the

introduction of idarubicin and the deletion of the age stratification in the elderly

group. The actual content of Associate Professor Lewis’ email to Mrs To did not in

terms identify the changes except that there was oblique reference to idarubicin and to

a change of another associated drug that is of little relevance. That said, the changes

were, I find, clear enough on the handwritten altered document that Associate

Professor Lewis left with his secretary as well as within the attachment to the email

that summarised the ALLG changes. This email was sent to Mrs To on a Saturday

afternoon.

6.7. As things transpired Mrs To was due to go on leave during the course of the following

week, her last day at work being Wednesday 16 July 2014.

10 Exhibit C49, page 146

26

6.8. In her evidence Mrs To acknowledged that she received the email of 12 July 2014.

She said she had no appreciation of the reason why the alterations were being made.

6.9. On Tuesday 15 July 2014 at 5:16pm Mrs To sent an email to Associate Professor

Lewis attaching the modified protocol documents for his review. One of those

documents was a version of the AML protocol draft containing the alterations that

Mrs To believed Associate Professor Lewis wanted, based upon the handwritten

document that had been provided to her. As I understood the evidence this amended

version of the existing 2012 protocol, as sent by Mrs To to Associate Professor Lewis,

did not in fact incorporate the intended amendments to the relevant age based

consolidation protocol, but simply put lines through the three different age based

regimens.

6.10. However, on the same day at 9:46pm Associate Professor Lewis sent Mrs To an email

thanking her for her work and setting out what he described as ‘minor changes’ to the

AML protocol. It stated:

'Change aged based cytarabine consolidation to cytarabine 1 g/mʌ2 d1, 3 & 5, idarubicin 12 mg/mʌ2 d1, 2, x 2 cycles' 11

It will be noted that this regimen is silent one way or the other as to whether the

cytarabine should be administered once daily or more than once daily on days 1, 3 and

5. However, in the absence of any specific instruction the lay reader might well have

inferred that a reference to administration on days 1, 3 and 5 would mean nothing

other than once daily administration. Clearly that was not Associate Professor Lewis’

intention. His intention was to indicate that the administration should occur twice

daily on days 1, 3 and 5. The instruction within his email should have said twice

daily, or in the abbreviated form ‘BD'. It did not.

6.11. Late in the afternoon of the following day, namely Wednesday 16 July, Mrs To

presented the amended AML protocol, that included a number of changes including

the changes to the relevant AML consolidation chemotherapy regimen, to Associate

Professor Lewis for his approval. Mrs To’s amended protocol12, as presented to

Associate Professor Lewis, stated as follows:

'3.6. HiDAC 1 - Ida Consolidation

11 Exhibit C149, page 17512 Exhibit C9a

27

ChemotherapyIdarubicin 12 mg/m2 IV bolus over 10-15 minutes ONCE daily Day 1, Day 2,

Cytarabine IV 1 g/m2 ONCE daily Day 1, 3, 5'

It will be noted that once daily administration of cytarabine might be considered not

to be inconsistent with the instructions given within Associate Professor Lewis’s

email of the evening before, but was clearly inconsistent with the ALLG summary

document that Associate Professor Lewis provided Mrs To as an attachment to his

email of 12 July 2014. I am not certain how or whether the reference to once daily

corresponded with Associate Professor Lewis’ handwritten alterations that he made

available to Mrs To through his secretary. That document is no longer available.

Mrs To told the Court that she disposed of this document.

6.12. In the course of her evidence Mrs To was examined closely about the circumstances

in which she came to present this erroneous document to Associate Professor Lewis

on Wednesday 16 July 2014. She took the amended protocol to Associate Professor

Lewis at his clinic room at around the time of the conclusion of Associate Professor

Lewis’ outpatient clinic. Mrs To was going on leave as of that evening. She told the

Court that there was an urgency involved with the authorisation of the protocol

because she was going on leave for ten days and wanted to get it done and finalised

before starting her leave. In her evidence Mrs To acknowledged that it was

inappropriate to have presented the document to Associate Professor Lewis in this

rushed fashion.

6.13. In cross-examination by Mr Griffin QC who represented Mr Knox, Ms Jennifer

Crannage and members of the families of some of the deceased persons, Mrs To

stated that Associate Professor Lewis examined the document for about 15 minutes

while apparently checking it. She sat quietly during this process. He gave it back to

her and said that the document was fine and so she concluded that she would be able

to promulgate the document. In her cross-examination Mrs To stated that although

she was not responsible for the error given that Associate Professor Lewis had

responsibility for checking the document and had ostensibly checked it to his

satisfaction, she felt that morally she had made a mistake by hurrying Associate

Professor Lewis in the carrying out of that process. Mrs To acknowledged that she

had not been under any pressure other than that placed upon her by herself13. She said

13 Transcript, page 931

28

it had not been stipulated that the document had to be promulgated on the last day of

her work before leave was taken. I pass no judgment on those matters.

6.14. As to how the error crept into the draft that Associate Professor Lewis approved, the

answer is not certain but it may be that Mrs To inferred from Associate Professor

Lewis’ email of Tuesday evening 15 July 2014 that the absence of any reference to

dosage frequency per day meant that only once a day administration was intended.

On the other hand, in her evidence Mrs To seemed to reject this possibility because as

she asserted, ‘even is once daily it should be written as once daily’14. Mrs To stated

that she should have checked the frequency in any event. She went on to say that the

very omission within Associate Professor Lewis’ emailed instruction of any reference

to dosage frequency per day should have provided the necessary stimulus for her to

have performed that check.

6.15. As for Associate Professor Lewis’ involvement in the promulgation of the protocol,

he acknowledged that the lack of any reference to the frequency of dosage as being

once daily or twice daily in his email of the evening of 15 July 2014 was ‘likely to be

an oversight or an omission on my part’15. He acknowledged, as he must, that there

should have been such a reference within his email. He stated that he was aware that

Mrs To was about to go on leave. He said that when Mrs To presented the draft to

him he spent about 5 to 10 minutes scrutinising the document and he stated to the

Court that he was feeling under pressure to get it done because she was about to

embark on her holiday.

6.16. I find that Associate Professor Lewis was presented with a draft that was erroneous in

that the frequency was stated to be once daily and not twice daily as he had intended,

and as had been set out in the ALLG summary document that he had attached to his

original email of 12 July 2014. I find that Mrs To, believing that the approved

document accurately reflected Associate Professor Lewis’ intentions, then

promulgated and distributed the erroneous document as an official protocol. She

uploaded it to the SA Pathology server where it would remain and be used in the

prescriptions of RAH AML patients until January 2015.

6.17. Associate Professor Lewis told the Court that he accepted responsibility for the error.

He acknowledges that the error occurred because of a number of shortcomings

14 Transcript, page 92815 Transcript, page 1886

29

including his imprecise instructions to Mrs To, a failure to perform appropriate due

diligence when checking the final version of the protocol, not presenting the amended

protocol in an appropriate clinical forum and by not having a second clinician check

the protocol. In Court Associate Professor Lewis without prompting publicly said as

follows:

'This error was a significant error and I would like to express my sincere apologies for the error. The error has caused significant implications for large numbers of people. First and foremost I would like to offer my profuse apologies to the patients and their families who have suffered as a consequence of this error. AML is a devastating disease and to receive treatment on a protocol and receive the less than intended dose of chemotherapy is truly devastating and I realise that this will have effects on your lives for a long period of time and I just cannot imagine how that's made you feel so please accept my apologies. The error has also impacted on many of my professional colleagues who I respect and they have become involved in this episode because of my error and so I would also like to express my apologies to my fellow consultant haematologists, haematology registrars, pharmacists, nursing staff and administrative staff.' 16

6.18. At 5:59pm on Wednesday 16 July 2014, which I find was after Mrs To had presented

the amended protocol to Associate Professor Lewis and after he had approved it,

Mrs To sent an email to a number of persons within ‘Health’17, the subject being

described as ‘New AML (excluding APML) protocol uploaded’ and attaching the

uploaded and erroneous consolidation protocol which called for the administration of

cytarabine only once daily on days 1, 3 and 5. In her email Mrs To simply referred to

the fact that ‘significant changes’ had been made to the protocol. Her email asserted

that Associate Professor Lewis himself would send an email to highlight the changes.

Included among the recipients of Mrs To’s email, of which there were in excess of

fifty, were Associate Professor Lewis himself, Professor Peter Bardy, Dr Ashanka

Beligaswatte, Dr Douglas Coghlan, Dr Devendra Hiwase, Dr Noemi Horvath,

Dr Naranie Shanmuganathan (a Registrar), Associate Professor Agnes Yong and

Dr Luen Bik To. They were clinicians at the RAH. It was also circulated to doctors

at the FMC including Professor Alex Gallus, Dr David Ross (who also worked at the

RAH) and Associate Professor Bryone Kuss who was Associate Professor Lewis’

counterpart at the FMC. A number of these doctors would have an involvement with

the treatment of the patients under discussion. With the exception of Associate

Professor Agnes Yong, none of these practitioners would identify the error in the

circulated protocol. Ultimately Associate Professor Yong was responsible for

16 Transcript, pages 1887-188817 That is, SA Health

30

identifying the error, but not until January 2015. That the error was not identified

earlier owes itself to a number of circumstances as will be discussed, including the

fact that this and other emails were not read by the medical practitioners to whom

they were circulated and secondly to an imperfect understanding of the scientific

principles underlying the administration of consolidation chemotherapy using the

agent cytarabine. On the part of some, there was also a perplexing level of apparent

insouciance in relation to the whole affair.

6.19. On the subject of emails, there is a measure of arrogance and self-importance

underlying the tacit if not express proposition advanced by some that it is somehow

acceptable within the profession in question not to read emails as and when they are

received. The reverse side of this is the equally unacceptable notion that one can

assume that when an individual sends an email he or she has little or no expectation

that they will be read. The other aspect of the manner in which emails were sent and

received is that they tended to be sent to multiple recipients who were members of a

large distribution list that included different types of professionals, some of whom had

little or no interest in the content, with the result that their importance was lost on the

persons who really had to take the content of these emails on board.

6.20. As predicted by Mrs To in her email of 16 July 2014, on Saturday 19 July Associate

Professor Lewis sent an email which set out a summary of the changes to the new

AML protocol which had been uploaded. The email was sent to all of the persons

whom I mentioned in the previous paragraph and also to Mrs To herself. Associate

Professor Lewis’ email, insofar as it related to changes to consolidation therapy for

non-CBF AML in respect of patients of or greater than 56 years of age, stated that the

therapy had been changed to:

‘Cytarabine 1g/mʌ2 bd d 1 3 5 plus idarubicin 12mg/mʌ2 d1 and 2 for 2 cycles (replacing age based cytarabine consolidation).’ 18 (the emboldening and underlining of ‘bd’ is that of the Court)

It will immediately be noted that this description of the altered regimen included

reference to the fact that cytarabine would be administered twice daily as represented

by the letters ‘bd'. While this was in fact correct, it did not reflect the erroneous

content of the protocol that Mrs To had uploaded and distributed by email on 16 July.

What the email of Associate Professor Lewis does do though is confirm beyond doubt

18 Exhibit C49, page 197

31

that he had intended the protocol to reflect twice daily administration. It also serves

to indicate that he either misread the draft protocol when it was presented to him by

Mrs To on the Wednesday afternoon or did not notice reference to the erroneous

‘ONCE’ in connection with that regimen. It is also clear that when Mrs To circulated

the amended protocol in her email of the evening of Wednesday 16 July 2014,

Associate Professor Lewis did not trouble to read the circulated and uploaded

amended protocol at that point, no doubt on the assumption that it corresponded with

what Mrs To had presented to him earlier that afternoon and which he had approved.

6.21. As indicated earlier Mrs To commenced her leave on Thursday 17 July 2014. In her

evidence she stated that she had the ability to check emails while on leave and on

weekends. As far as Associate Professor Lewis’ email of Saturday 19 July is

concerned, she told the Court that she either did not read the email if she saw it at all

or would not have seen it on 19 July 2014 as she was attending a camp cooking for

university students and had been thinking about other things. In any event when she

returned from leave and read the email it did not dawn on her that she had made a

mistake in the uploaded protocol. I find that Mrs To either did not notice within the

body of Associate Professor Lewis’ email that the regimen called for twice daily

administration, or if she did notice that, it did not occur to her that the protocol that

she had uploaded said something different. I infer and find that no person drew the

error to the attention of either Associate Professor Lewis or of Mrs To at any time

prior to the early part of the following year.

6.22. In cross-examination by counsel assisting, Ms Kereru, Associate Professor Lewis

stated, somewhat surprisingly, that there were no formal processes in place to govern

protocol changes such as occurred here19. It was pointed out to him that he had

acknowledged in the course of the investigation into this affair conducted by the

Australian Health Practitioner Regulation Agency (AHPRA) that the changes were

not of such a magnitude as to require formal presentation at either a unit protocol

meeting or to the AML sub specialty group. However, he said that ‘in retrospect’ he

should have presented the protocol at either the unit protocol meeting or at the AML

multidisciplinary team meeting. He conceded in cross-examination that he no longer

held the view that he had expressed to AHPRA that the changes were of not such a

magnitude that they did not require formal presentation to the entities concerned20.

19 Transcript, page 194420 Transcript, page 1945

32

Associate Professor Lewis also acknowledged that in respect of his responsibility to

manage and document a process of consensus among specialists as to what an agreed

consolidation treatment for AML should consist of, he did not discharge that

responsibility to an adequate standard21. He also agreed that he did not discharge his

responsibility to ensure that changes to an RAH protocol were accurately transcribed

and recorded to an adequate standard22.

6.23. In answer to me, Associate Professor Lewis asserted that if prior to promulgation the

defective document had been presented to his colleagues within the forums that he

described, he would have expected the error to have been detected23. In cross-

examination by Mr Griffin QC, Associate Professor Lewis was asked who of his RAH

colleagues would have been the most appropriate person to have checked the accuracy

of the amended protocol. In answer he stated that this person would probably have

been Associate Professor Agnes Yong24. It is appalling, and of course tragic, that an

experienced collegial resource such as Associate Professor Yong was not brought into

the promulgation process at least as a checker. It was Associate Professor Yong who

would identify the irregularity of once daily administration when it came to her

attention for the first time in January 2015. I have no doubt that had she been

consulted about the matter in July 2014 when the altered protocol was promulgated,

Associate Professor Yong would have identified the irregularity and have brought it to

Associate Professor Lewis’ attention. Quite apart from the failure to present this

altered protocol to the relevant entity that should have approved it, checking by at

least one of Associate Professor Lewis’ peers should undoubtedly have occurred.

6.24. I accept and acknowledge all of Associate Professor Lewis’ self-criticism. I make

specific findings that all of that criticism is accurate and valid.

6.25. Unfortunately protocol changes that were contemplated were not routinely discussed

at Heads of Unit meetings that from time to time were attended by the Heads of

Haematology at the different tertiary hospitals. So, for instance, Associate Professor

Lewis’ counterpart at FMC, Associate Professor Bryone Kuss, would not routinely

have been made aware of contemplated changes to RAH protocols or have been asked

21 Transcript, page 194922 Transcript, page 194923 Transcript, page 195424 Transcript, page 1918

33

to pass any comment in respect of such contemplated change or changes25, and this

would be so notwithstanding the fact that the various Unit heads were all employees

of SA Pathology.

6.26. I make the following findings:

The process by which the RAH consolidation chemotherapy protocol was altered

was sloppy, ad hoc and prone to introduce error. The introduction of the error was

caused by poor communication as between Associate Professor Lewis and Mrs

To. The error was introduced to the document by Mrs To.

Associate Professor Lewis failed to properly check the protocol draft. He did not

allow himself sufficient time to enable a proper check of the document to take

place. He should not have been asked to check the document while either he or

Mrs To were under pressure for time.

Associate Professor Lewis should have presented the protocol at either a Unit

Protocol meeting or at the AML Multi-disciplinary team meeting before it was

promulgated.

Associate Professor Lewis did not discharge to an adequate standard his

responsibility to manage and document a process of consensus amongst specialists

as to what an agreed consolidation treatment for AML should consist of.

Associate Professor Lewis should have at the very least asked a responsible

colleague to check the final draft. Associate Professor Yong would have been the

most appropriate person in that regard. I find that Associate Professor Yong

would probably have identified the error if she had been asked to check the final

and erroneous draft.

Email was an inappropriate and clumsy way of advising professional people of

important information. Mrs To’s email and attachment and Associate Professor

Lewis’ email in effect contradicted each other as to the required frequency of

administration of cytarabine. The contradiction could only have been identified if

a recipient of both emails compared the content of the protocol alteration within

the protocol itself with the content of Associate Professor Lewis’ email. No

person identified the contradiction.

25 Transcript, pages 1956-1957

34

The introduction of the error into the RAH protocol was directly the cause of the

erroneous protocol being applied to the consolidation chemotherapy for Mrs

Pinxteren, Mr McRae and Mrs Bairnsfather at the RAH and was also responsible

indirectly for the erroneous protocol being applied to the clinical treatment of Mr

Higham and Mr Knox at the FMC. As will be seen, there were further missed

opportunities for the error to have been identified at the FMC.

7. The promulgation of the erroneous protocol at the FMC

7.1. I have already referred to the fact that each of the public hospitals at which

haematological services were provided had complete autonomy as far as the content

of its chemotherapy protocols was concerned. The fact that FMC utilised templates

which served as the basis of a patient’s prescription meant that there was no actual

need for a clinician to check the actual protocol that existed on the SA Pathology

database when prescribing consolidation chemotherapy. Thus the fact that the RAH

had altered that protocol did not of itself mean that the alteration would be drawn to

the attention of other hospitals or that the alteration would in any other way be

identified by haematology staff at the FMC.

7.2. In the event it would be a medical practitioner concurrently working within the

Haematology Departments of both the RAH and the FMC who was the instrument in

introducing the new and erroneous protocol at the FMC. That medical practitioner

was Dr Ashanka Beligaswatte.

7.3. Dr Beligaswatte obtained his basic medical degree from the University of Colombo,

Sri Lanka in 2000. Following the receipt of his degree he entered into the physician

training program in Sri Lanka. He obtained a Doctorate of Medicine in 2005. He

worked within a number of hospitals within Sri Lanka. Dr Beligaswatte came to

Australia in 2007. His aim in coming to Australia was to undergo training in clinical

and laboratory haematology. He began work at the RAH as a resident medical officer

and in 2009 entered into the advanced training program in haematology. He

completed his training over the next four years, ultimately obtaining fellowships in

the Colleges of Pathology and Physicians in 2012 and 2013.

7.4. In 2013 Dr Beligaswatte began working as an Acute Leukaemia Fellow at the RAH

and later in that year obtained a locum consultant position part time at the FMC.

During the course of 2014 he worked between the RAH and FMC Haematology

35

Departments, for the most part working at the FMC. Early in 2015 he had a 0.1

appointment at the RAH which was devoted to ward service. His last working day at

the RAH was 30 January 2015. Thereafter he worked at the FMC as a consultant

haematologist on a 0.9 basis. His principal area within the field of haematology is in

respect of malignant conditions of the blood and his special interest is in acute

leukaemias. Dr Beligaswatte told the Court that at the FMC he was considered to be

the clinical lead for acute leukaemia. This meant that he would take the lead in

developing protocols and would also be the principal investigator for any acute

leukaemia trials that might be activated at the FMC. These claims came as a surprise

having regard to his relative inexperience. However, as at July 2014, when he still

had a substantial involvement within the Haematology Department of the RAH, he

had not been involved in protocol development26. Dr Beligaswatte said that in 2014

he was a member of the ALLG and that in late July 2014 he became a member of the

ALLG’s acute leukaemia group which is the entity within the ALLG that assists in the

designing of clinical trials. Dr Beligaswatte told the Court that being in the early

stage of his career as a haematologist, he began to become involved in the activities of

that group27. Dr Beligaswatte acknowledged that between July 2014 and February

2015 he was a relatively junior haematologist28.

7.5. Dr Beligaswatte gave evidence at considerable length. He was represented by

Ms Joanne Cliff of counsel.

7.6. Dr Beligaswatte told the Court that in 2014, in his capacity as a Fellow in the

Haematology Department of the RAH, he became aware that consideration was being

given to developing new AML protocols. His understanding was that the protocols

were being developed as a result of consultation among national AML experts.

Dr Beligaswatte himself was not privy to any of those discussions, but was aware that

AML protocols were to be revised on the basis that exposure to cytarabine should

probably be reduced because of a perception that higher dosages were causing

unnecessary toxicity. As well, it was contemplated that idarubicin would be

incorporated into consolidation treatment regimens.

7.7. On 16 July 2014 at an FMC ward meeting attended by his haematology colleagues,

Dr Beligaswatte participated in a discussion along the lines that it would be desirable

26 Transcript, page 140927 Transcript, page 153828 Transcript, page 1692

36

to synchronise the approach of FMC to that of the RAH given that the RAH was the

State’s stem cell transplant centre and that the FMC would be likely to refer patients

to the RAH for that treatment. It was thought that it would be reasonable to align the

FMC consolidation chemotherapy protocols with those of the RAH. Dr Beligaswatte

asserted that to that end an in-principle decision to adopt the RAH standard

consolidation protocol was made at that meeting. Dr Beligaswatte believed that

Ms Kailin Teh, the FMC haematology pharmacist I have referred to earlier, was

present at this meeting and that perhaps Dr Douglas Coghlan, an FMC haematology

consultant, was also present. Dr Beligaswatte did not suggest that Associate Professor

Bryone Kuss who was the Head of the Haematology Department at the FMC was

present at this meeting, but it is clear that he and she had been involved in some

earlier discussion about the matter. In fact Associate Professor Kuss was on leave on

16 July and did not return to work at the FMC until Monday 21 July 2014, the events

of which day have some significance in terms of the introduction of the error into the

FMC chemotherapy regimen.

7.8. Dr Beligaswatte said that although he did not have any understanding about the

manner in which the FMC dealt with the introduction of protocols, he had personally

advocated for the RAH protocols to be adopted at the FMC. To his knowledge this

was the first occasion on which a new protocol had been developed since he had

started work at the FMC in November 2013. He said he had no understanding of the

procedure for such development. In his evidence-in-chief Dr Beligaswatte was asked

whether anyone at the 16 July ward meeting had suggested that the adoption of a

protocol needed to take place via a formal FMC process for the development of FMC

protocols. He said that he could not recall any discussion on this but suggested that if

such a process had been drawn to his attention he would have complied with it. As

will be seen, Associate Professor Kuss suggested in her evidence that there was such a

process, although not documented at that point in time.

7.9. One matter is reasonably clear and I so find is that Dr Beligaswatte did not raise with

Associate Professor Lewis at the RAH the idea of harmonising consolidation

therapies as between the two hospitals. Associate Professor Lewis said in evidence

that he had no recollection of any proposed harmonisation process that would involve

the FMC adopting RAH protocols and in particular anything based on the ALLG M15

study. Associate Professor Lewis said that Dr Beligaswatte never told him that he

37

was going to uplift the RAH protocol and have it adopted at the FMC29.

Dr Beligaswatte did expressly not assert otherwise.

7.10. I find that in July 2014 and for the rest of that year Associate Professor Lewis was

unaware that the FMC were using the new protocol that he had instigated at the

RAH30. However, I am not certain that even if Dr Beligaswatte had told Associate

Professor Lewis of his intentions regarding the adoption of the protocol at the FMC

that it would have prevented the error being reproduced in any revised FMC

chemotherapy regimen. This is so because in his evidence before the Court Associate

Professor Lewis suggested that the FMC would have had their own protocol approval

processes and that he would have expected them to have followed those processes,

meaning that Associate Professor Lewis would not have had any personal input or

other involvement in the adoption of the protocol at the FMC31.

7.11. When asked by Dr Beligaswatte’s own counsel as to whether he had advised anyone

at the RAH that the FMC had decided to adopt the RAH protocol, Dr Beligaswatte

said that he might have had informal conversations in that regard but he could not

recall doing that32. I find that he did not tell anyone at the RAH that the FMC was

going to adopt or had adopted the protocol. However, I note that in an email that

Dr Beligaswatte would send to a number of people in Health at 9:08am on Monday

21 July 2014, he forwarded Mrs To’s email of 16 July 2014 that attached the updated

RAH protocol as well as Associate Professor Lewis’ email of 19 July which correctly

set out the protocol changes. As will be seen in a moment, the text of

Dr Beligaswatte’s email referred among other things to the ‘aim’ of the RAH protocol

and to the details of the intended revised protocol which as it happened, and quite

bizarrely so having regard to what ultimately would be the adoption of an incorrect

version of the protocol, also spelt out the correct frequency of administration. One of

the recipients of Dr Beligaswatte’s email was the person who was said to be the

transplant coordinator at the RAH. It would not have taken much for the astute reader

of Dr Beligaswatte’s email in conjunction with the forwarded emails of Mrs To and

Associate Professor Lewis to deduce that the FMC were intending to adopt an RAH

protocol. In some senses then, the RAH through its transplant coordinator was

cloaked with the knowledge that the FMC were adopting their protocol. The rather

29 Transcript, page 192030 Transcript, page 192131 Transcript, page 192032 Transcript, page 1645

38

ironic difficulty with Dr Beligaswatte’s email, however, is that he had described the

protocol correctly and so for that reason knowledge on the part of anyone at the RAH

that the FMC were in the process of adopting an RAH protocol, gained by reading

Dr Beligaswatte’s email, would not necessarily have led to a detection of the error.

One would have needed to read the actual uploaded protocol itself in order to detect

the error.

7.12. As a measure of Dr Beligaswatte’s enthusiasm to have the RAH protocol adopted at

FMC it will be observed that as of Wednesday morning 16 July 2014 which

Dr Beligaswatte asserts was the day on which in-principle approval was given at the

FMC for the adoption of the RAH protocol, the draft had yet to be approved by

Associate Professor Lewis at the RAH. It will be recalled that it was during the late

afternoon and evening of 16 July that Mrs To at the RAH would obtain Associate

Professor Lewis’ approval of the draft and then circulate the amended and uploaded

protocol. According to Dr Beligaswatte a reason for haste was the fact that an AML

patient at the FMC, Ms Jennifer Crannage, was about to undergo consolidation

chemotherapy treatment in the coming days and a decision needed to be made

whether this patient would be treated according to their current practice or whether

she would be treated in accordance with the new RAH protocol33. As things would

transpire Ms Crannage would be treated at the FMC in accordance with the adopted

and erroneous RAH protocol. Ms Crannage is one of the ten persons affected by the

error and is one of the surviving patients.

7.13. This brings me to the mechanism by which the error was introduced into the FMC

processes notwithstanding that Dr Beligaswatte had correctly described the regimen in

his email of 9:08am on 21 July.

7.14. As at Monday 21 July 2014 the patient Ms Crannage was due for her first

consolidation chemotherapy cycle at the FMC. Ms Crannage was actually Associate

Professor Kuss’ patient. However, Dr Beligaswatte was her prescribing

haematologist on this occasion as Associate Professor Kuss had been on leave until

that day. At 9:08am on Monday 21 July 2014 Dr Beligaswatte sent an email to the

following recipients: Ms Kailin Teh an FMC haematology pharmacist, Dr Douglas

Coghlan an FMC haematology consultant, Associate Professor Kuss the head of

haematology at the FMC, other FMC physicians and the person who was said to be

33 Transcript, page 1419

39

the transplant coordinator at the RAH. Among other things, Dr Beligaswatte’s email

explained in some detail the rationale behind the protocol alterations that included

reference to the reduction of cytarabine and the intensifying of the idarubicin

component of the treatment, the idea being to reduce toxicities to a point that would

allow additional therapies to be delivered such as maintenance therapy as it became

available. Specifically addressed to Ms Kailin Teh was a request for her to prepare a

‘template protocol’ for consolidation for the patient Ms Jennifer Crannage. The email

went on to state:

'According to the latest protocol she will need cytarabine 1g/m2 BD on days 1, 3, 5, and idarubicin 12mg/m2 on days 1, 2.' (the emboldening and underlining of ‘BD’ is that of the Court)

It will immediately be observed that Dr Beligaswatte told Ms Teh, and as copied to

the other recipients, that cytarabine would be administered to Ms Crannage twice a

day as represented by the term ‘BD’. Moreover, this part of the instruction to Ms Teh

was said by Dr Beligaswatte to accord ‘to the latest protocol’. The latest protocol of

course was the RAH protocol which as of 21 July 2014 stated erroneously that

cytarabine would be administered only once daily. Clearly, Dr Beligaswatte did not

refer to the actual protocol when drafting this email instruction to Ms Teh. If he had

consulted the document he would have seen at that point that it said once daily. I will

come to the reason why in his email Dr Beligaswatte indicated twice daily in due

course.

7.15. As indicated earlier, Dr Beligaswatte’s email of 9:08am on 21 July 2014 forwarded

the email of Mrs To of the afternoon of Wednesday 16 July 2014 in which she

attached the updated AML protocol that Associate Professor Lewis had approved only

a short time before. As well, within that chain of emails sent by Dr Beligaswatte at

9:08am there was Associate Professor Lewis’ email of Saturday 19 July 2014 in

which Associate Professor Lewis explained to the various recipients that included

Dr Beligaswatte, Dr Coghlan and Associate Professor Kuss the changes to the

consolidation therapy protocol which made specific reference to the need for

cytarabine to be administered twice daily.

7.16. At 10:15am on Monday 21 July 2014 Ms Teh responded by way of email to

Dr Beligaswatte’s email of that morning. With the exception of the RAH transplant

coordinator, Ms Teh’s email was sent to the recipients whom Dr Beligaswatte had

40

included in his original email. In Ms Teh’s email she queried whether the patient

Ms Crannage was non-CBF. The patient under discussion, Ms Crannage, was not

CBF34. Ms Teh’s email went on to state as follows:

'Can you please confirm – From the new protocol the cytarabine is 1g/m2 DAILY on d1, 3, 5 (not BD).'

It is evident from this query that Ms Teh had gone to the RAH protocol and had seen

for herself that it specified once daily administration and not BD administration.

7.17. Any recipient reading Ms Teh’s email should have identified an issue as to whether

cytarabine was to be administered once daily or twice daily in Ms Crannage’s

consolidation chemotherapy and that the issue was going to require resolution before

Ms Crannage could be treated. Further, the issue of dose frequency was a matter dealt

with in Associate Professor Lewis’ earlier forwarded email where he too had referred

to twice daily administration. There is no evidence that any person, including

Dr Coghlan and Associate Professor Kuss, recognised from this chain of emails that

there was an issue regarding frequency of administration that needed to be resolved

before Ms Crannage’s prescription could be completed. The day on which this chain

of emails occurred was Associate Professor Kuss’ first day back from leave. To my

mind the resolution of the issue encapsulated within the email exchange called for

intervention either by Dr Coghlan and/or Associate Professor Kuss. Notable is the

fact that Associate Professor Lewis was not copied into the email exchange between

Dr Beligaswatte and Ms Teh and thus the email chain was not capable of alerting

Associate Professor Lewis to the issue of once daily versus twice daily administration

that had arisen.

7.18. At 11:34am on Monday 21 July 2014 Dr Beligaswatte replied to Ms Teh’s email with

his own email. Dr Beligaswatte did not send this email to any person other than

Ms Teh. I set out below the full text of the email:

'Hi Kailin,Yes she is non-CBF and you are right it is a daily dose of cytarabine.ThanksAshanka'

This piece of information was correct if one was talking exclusively about the

erroneous once daily stipulation within the protocol, but it was wholly incorrect

34 As indicated earlier, different considerations applied to patients who were CBF

41

clinically because the M15 study called for twice daily administration of cytarabine

and the promulgator of the study at the RAH, Associate Professor Lewis, had never

intended once daily administration. Of course, once Dr Beligaswatte instructed

Ms Teh that the frequency was daily, he was then in conflict with what Associate

Professor Lewis had stated in his email of 19 July and was in conflict with what he

himself had said in his own originating email of a couple of hours before. Knowing

as he should have that his superior at the RAH, Associate Professor Lewis, had

stipulated twice daily in his email of 19 July, an email that Dr Beligaswatte himself

had forwarded to FMC clinicians, Dr Beligaswatte never made any attempt to

‘correct’ Associate Professor Lewis. I place the word ‘correct’ in inverted commas

because, as is clear, Associate Professor Lewis in his email had been correct all along.

If Dr Beligaswatte had been sufficiently diligent and astute to raise the issue with

Associate Professor Lewis as he should have, there is little doubt that the error within

the protocol would, at that point in time, have been identified both at the RAH as well

as at the FMC. Dr Beligaswatte’s failure to do this was a glaring missed opportunity

to correct the protocol error. There were other equally spectacular missed

opportunities as will be seen.

7.19. During the course of this exchange of emails between Dr Beligaswatte and Ms Teh of

21 July 2014 it is alleged that they engaged in an important telephone conversation. I

say alleged because Dr Beligaswatte in his evidence was not prepared to explicitly

acknowledge that it occurred. But I find that it did occur. It is an important

conversation as to my mind it exonerates Ms Teh of any serious wrongdoing or

neglect but invites criticism of Dr Beligaswatte in a significant manner.

7.20. The evidence as to this conversation unfolded in the following manner. Mr Bonig of

counsel for Ms Teh suggested to Dr Beligaswatte in cross-examination that following

the receipt of Ms Teh’s email of 10:15am in which she had queried whether the

frequency of administration of cytarabine was daily and not BD, Ms Teh telephoned

him and asked whether he could provide her with the underlying source

documentation that supported the protocol. Dr Beligaswatte answered Mr Bonig by

saying that he could not remember the conversation but that he was not denying that it

happened. It was also suggested to him by Mr Bonig that he had responded to

Ms Teh by saying ‘you don’t have any of the source documents, just rely on the

42

protocol’35. To this he said that he could not recall the conversation36 and so he did

not know how to answer that question.

7.21. In Ms Teh’s oral evidence she testified that she had noticed a difference between the

RAH protocol which stipulated once daily administration and what Dr Beligaswatte

had requested in his email of 9:08am which set out twice daily. She said that she

decided to seek a reference document that would support the template and to that end

telephoned Dr Beligaswatte. Asked by her counsel Mr Bonig as to why she had

wanted such a document she said:

'To ensure accuracy. That is generally what we would use to create a template.' 37

7.22. Ms Teh testified that in response to her request for the document Dr Beligaswatte told

her that as this was a trial protocol from the RAH there would be no published article

available. The RAH was the trial investigator and the protocol was the reference

document. In the event Ms Teh would make reference only to that protocol in

creating the new FMC template.

7.23. Any assertion by Dr Beligaswatte to the effect that there was no supporting

documentation other than the RAH protocol was not accurate. On Friday 18 July

2014 at 6:07pm Dr Michelle Damin who was a Registrar at the RAH had sent an

untitled email to Dr Beligaswatte38 that attached a document described as ‘the role of

HiDAC’. This attachment was the three page document that had originally been

forwarded by Associate Professor Lewis to Mrs To and which appears to be a

summary of the ALLG document setting out the new AML consolidation

chemotherapy regimens, including the regimen in question for non-CBF persons over

55 years. This was the document that correctly identified cytarabine administration

twice daily on days 1, 3 and 5. Dr Damin’s email was sent to Dr Beligaswatte

without any commentary. This email served to place Dr Beligaswatte in possession of

a document that demonstrated that the ALLG consensus was that cytarabine would be

administered twice daily in respect of people over the age of 55 years. The content of

that document also served to confirm the accuracy of the email that would be sent by

Associate Professor Lewis on Saturday 19 July 2014 in which he specified twice daily

administration.

35 Transcript, page 165336 Transcript, page 165337 Transcript, page 237838 Dr Beligaswatte was the sole recipient of this email

43

7.24. In respect of this document Dr Beligaswatte told the Court that his recollection was

that he had asked Dr Damin whether she was aware of any publications that used the

specific protocols and she had told him that Associate Professor Lewis had circulated

a document. Associate Professor Lewis’ evidence confirms that Dr Damin had

approached him for documentation supporting the protocol change and that he

provided it to her39. As a result of this Dr Damin sent the document to

Dr Beligaswatte by way of email. Dr Beligaswatte told the Court as follows:

'When you read this document it was clear to me that it was written by experts at the Australasian Leukaemia & Lymphoma Group, the ALLG and that it was advocating for a certain approach to changing the current way in which AML patients were treated. It was clear to me that it did not mention that there were any specific - however, it was clear to me that this document when you read the text of it isn't citing a specific study that our protocols would have used exact regimens so therefore I read this document primarily to understand what those - what the philosophy would have been for the change in AML protocols. My understanding from reading this document was that expert opinion was advocating for a reduction in cytarabine exposure and at the same time intensifying anthracycline exposure because of evidence in other studies that that might be beneficial. So that was the message I took out of this document. ' 40

Dr Beligaswatte was asked by his own counsel whether he had read the third page of

the document which set out the chemotherapy regimens including the regimen in

question:

'Q. Just so we can be clear, did you read this page when you received the email from Ms Damin (sic).

A. My focus was entirely on understanding the rationale for the changes in the RAH's 2014 protocol and when I read the first page I understood what this particular document could and could not provide me. I don't remember whether I glanced at the final page or not but it was certainly not the primary focus of my reading of this document. ' 41

Clearly, if Dr Beligaswatte had read and digested that third page he would have

noticed as early as 18 July 2014 that twice daily administration of cytarabine was

required in respect of patients such as Ms Crannage. True it is that the first two pages

have as their primary focus induction chemotherapy in relation to younger patients

with AML, but that was no reason not to read the third page. After all, he had

instigated the request of Dr Damin for documentation that evidenced the protocol.

39 Transcript, pages 1888-188940 Transcript, pages 1420-142141 Transcript, page 1422

44

7.25. I find that the telephone conversation as described by Ms Teh did in fact occur.

Dr Beligaswatte did not deny that it occurred and it was not suggested in Ms Teh’s

cross-examination that it did not occur. It seemed to me logical and likely that

Ms Teh would have sought a source document other than the bare RAH protocol so as

to ensure accuracy as she asserted. According to Associate Professor Kuss, the

obtaining and sighting of a source document was a requirement in the process of

protocol development. It is likely for that reason that Ms Teh would have sought such

a document and in the circumstances have sought it from Dr Beligaswatte. The fact

that Dr Beligaswatte regarded the document that he did have as not being a suitable

document to have provided to Ms Teh is consistent with the notion that

Dr Beligaswatte told Ms Teh that he had nothing to give her other than the RAH

protocol.

7.26. To my mind it was splitting hairs to suggest that this document would not have been

suitable as a source at least to confirm in the eyes of the pharmacist, Ms Teh, the

details of the particular regimen that would be used as a prescription for

Ms Crannage. It was the document that Associate Professor Lewis had relied upon

and which he had provided to Mrs To. It was a document that reflected Associate

Professor Lewis’ intentions regarding frequency of dosage. To suggest that it would

not have been worthwhile to have provided that document to Ms Teh in my opinion

was specious. In this regard it is important to appreciate that in her oral evidence

Ms Teh said that if she had been provided with this document she would have read it

and would have raised a concern that the document did not support the RAH

protocol42. I unhesitatingly accept that evidence. It is an inevitable conclusion,

therefore, that if Ms Teh had raised a concern the error would have been detected.

Accordingly, the promulgation of the error would in my view been avoided at the

FMC if Dr Beligaswatte had provided Ms Teh with the document as he undoubtedly

should have. Dr Beligaswatte himself would also have been made aware of the error.

7.27. I should also mention that there was another more detailed ALLG document in

existence that set out chapter and verse the rationale of the M15 study and which

clearly set out the protocol43. This document dated 26 September 2012 was entitled

‘A pilot study exploring high-dose lenalidomide maintenance therapy in adult AML’.

Its protocol number was AMLM15. It stipulated that the recommended consolidation

42 Transcript, page 240143 Variously Exhibits C48a and C50, page 95

45

chemotherapy as the precursor for enrolment in the M15 study involved twice daily

administration of cytarabine. I can see no reason why this document could not have

been made available to Ms Teh. It clearly should have been made available to her by

somebody. If it had been made available it too would have alerted her to the fact that

the RAH protocol did not conform to it. If Dr Beligaswatte had read this document he

also could have come to no other conclusion.

7.28. Dr Beligaswatte was in possession of the document forwarded to him from Dr Damin.

He was also in possession of Associate Professor Lewis’ email that described twice

daily administration. A doubt had been raised by Ms Teh about whether or not

administration was daily or twice daily. It was unfortunate that Ms Teh in her

telephone conversation with Dr Beligaswatte did not discuss with him the

inconsistency that she had obviously identified, but she was told that she should rely

on the RAH protocol and a prescription for the patient Ms Crannage needed to be

compiled. In those circumstances it is difficult to be overly critical of Ms Teh.

Nevertheless, Dr Beligaswatte had been in a position to clarify the matter because all

he had to do was raise the matter with Associate Professor Lewis. If this had taken

place on 21 July 2014 no doubt Associate Professor Lewis would have clarified the

matter and have advised that twice daily dosing was required. As part of that process

there is little doubt that the error in the RAH protocol would have been identified and

corrected. If that had occurred, much of the underdosing that would subsequently

occur at the RAH would have been avoided.

7.29. In the event, at 12:15pm on 21 July 2014 Dr Beligaswatte emailed Ms Teh and

indicated that he had signed the protocol and that it was on the server available for

checking. This was effectively the prescription for Ms Crannage. Ms Teh rechecked

it and applied her electronic signature to the document. Thus, the error was set in

concrete within the FMC consolidation chemotherapy template. The result was that

Ms Crannage was administered the unintended regimen of consolidation

chemotherapy as were four other individuals who were treated at the FMC during the

remainder of that year and in January of the following year.

7.30. There is one circumstance connected with the promulgation of the error at the FMC

that defies all rational explanation. On 18 July 2014 Dr Beligaswatte, who was Mr

McRae’s haematologist at the RAH, signed off on the prescription for the first cycle

of consolidation therapy for Mr McRae. This would commence on Monday 21 July

46

2014. The prescription was created in accordance with the revised protocol that had

been promulgated earlier in the week and which contained the error of once daily

administration. However, it will be noted that 18 July was also the day on which

Dr Beligaswatte had received the document from Dr Damin that specified twice daily

administration. During the intervening weekend Associate Professor Lewis sent his

email dated 19 July 2014 in which Associate Professor Lewis stated that consolidation

therapy had been changed in a number of facets but that it would be administered

‘bd’, that is twice daily. This email had been sent to many recipients including

Dr Beligaswatte. The confounding circumstance is that, as seen above, at 9:08am on

Monday 21 July 2014 Dr Beligaswatte circulated that email to his FMC colleagues

including Dr Coghlan and Associate Professor Kuss with tacit approval. Moreover,

on that same day, namely Monday 21 July 2014, Dr Beligaswatte stated in his own

email to Ms Teh, and copied to Dr Coghlan and Associate Professor Kuss, that the

consolidation treatment for Ms Crannage would be ‘BD’. Bizarrely, all this occurred

notwithstanding the fact that Dr Beligaswatte himself had prescribed once daily

administration for Mr McRae on the Friday. In fact the treatment for Ms Crannage

should have been clinically identical to the treatment of Mr McRae. There was

nothing clinically to distinguish Mr McRae’s treatment from Ms Crannage’s treatment

that would in any way have dictated a different frequency of administration. And yet

Dr Beligaswatte, at least to begin with, in effect prescribed for Ms Crannage twice

daily administration when only three days beforehand he had prescribed once daily

for Mr McRae. It was only when Ms Teh queried whether the protocol was meant to

specify daily and not BD that Dr Beligaswatte confirmed that Ms Crannage’s

treatment was to be daily. In the event, Mr McRae and Ms Crannage would be

administered once daily administration in both rounds of their consolidation

chemotherapy.

7.31. This set of circumstances raises serious questions as to why Dr Beligaswatte failed to

realise that he had contemplated differing regimes of treatment for essentially

identical patients and why this in itself did not raise a query in his own mind as to

which of the two differing treatments was the correct one rather than have waited for

Ms Teh to raise that query. As well, if Dr Beligaswatte when writing his email of 21

July at 9:08am thought that twice daily was the appropriate frequency, it would raise a

question as to why he would not have corrected his prescription of once daily in the

47

case of Mr McRae who was due to have his first consolidation dose that afternoon. In

truth, there are no sensible answers to any of these questions.

7.32. In the course of his evidence Dr Beligaswatte was closely questioned about a number

of matters in connection with his involvement in the promulgation of the erroneous

template at the FMC. This included an examination of the source of

Dr Beligaswatte’s assertion made within his initiating email of 21 July 2014 that

specified twice daily administration, correctly, and why this was not acted upon. It

also included an examination of why it was that when confronted with the possible

inconsistency between daily and twice daily he did not clarify the matter by going to

the original source, namely Associate Professor Lewis. In addition, there was a

question as to why he chose to send his email of 11:34am of 21 July 2014 in which he

confirmed daily dosage of solely to Ms Teh and not copy it to Dr Coghlan, a clinician

who was experienced in AML treatment, or Associate Professor Kuss.

7.33. Of course, the question that Dr Beligaswatte had considerable difficulty in answering

in his evidence was how it had come to pass that he had indicated to Ms Teh that

Ms Crannage’s treatment would be twice daily and why he in effect gave his

imprimatur to the suggestion in Associate Professor Lewis’ originating email that it

would be twice daily administration when he had prescribed only once daily

administration for Mr McRae. This set of circumstances, together with the manner in

which consolidation chemotherapy was prescribed for other affected patients, fuelled

the impression that in prescribing consolidation chemotherapy some physicians who

lacked familiarity with the AML disease would follow what virtually amounts to a

chemotherapy recipe without regard to scientific principle or clinical need. As will be

seen, Associate Professor Agnes Yong was a notable exception and that it was as a

result of her intervention that the error was discovered.

7.34. Asked by his counsel Ms Cliff whether, in the light of Ms Teh’s query whether it was

once daily or twice daily, he had given any consideration to contacting Associate

Professor Lewis to clarify, Dr Beligaswatte said that in retrospect he should have done

that, he said:

'I recognised (sic) that that was a significant opportunity to have prevented all of this from happening and I deeply regret it.' 44

44 Transcript, page 1434

48

This is an acknowledgement well made, especially having regard to the fact that he

had himself forwarded Associate Professor Lewis’ email which said twice daily. It is

very difficult for Dr Beligaswatte now to be heard to say that he did not really

appreciate the significance of Associate Professor Lewis’ email when he himself had

received it, had also forwarded it to his colleagues with tacit approval and had given a

set of instructions to Ms Teh in respect of Ms Crannage’s prescription that aligned

with Associate Professor Lewis’ email. If Dr Beligaswatte had paid proper attention

to the contents of Associate Professor Lewis’ email either he would have realised that

he may have incorrectly prescribed once daily chemotherapy for Mr McRae the day

before, or have concluded that Associate Professor Lewis had got it wrong when he

had specified twice daily in his email.

7.35. When Dr Beligaswatte was asked about those matters he had no sensible explanation.

He said that he did not know why he had correctly inserted twice daily in the email to

Ms Teh regarding Ms Crannage’s prescription45. He said in his evidence that he had

specified twice daily cytarabine in respect of the Ms Crannage template ‘for reasons

that I can’t fathom’46. He agreed that Associate Professor Lewis’ email should have

rung alarm bells with him47, but said that he could not explain why it did not ring

those bells and suggested that it may be that he wrote BD ‘reflexly’48. Puzzlingly,

Dr Beligaswatte said that he could not recall whether he used the content of Associate

Professor Lewis’ email to specify the requirements for Ms Crannage’s template49. But

the tragic irony was that Dr Beligaswatte had it right in his first email to Ms Teh.

There are two possible reasons that come to mind as to why Dr Beligaswatte wrote

BD on his instruction to Ms Teh in respect of Ms Crannage’s prescription. Either he

derived this from the document that Dr Damin had sent him on the Friday, or he

derived it from Associate Professor Lewis’ email of the Saturday. I suppose there are

other hidden possibilities. In the event it is not necessary for me to make any finding

about the source of Dr Beligaswatte’s BD instruction. The plain fact of the matter is

that this instruction was correct and Ms Teh’s query should have resulted in its

accuracy being established.

45 Transcript, page 154946 Transcript, page 164947 Transcript, page 164548 Transcript, page 164649 Transcript, page 1644

49

7.36. Dr Beligaswatte did say that if he had gained any sense that there was a discrepancy

between the Associate Professor Lewis email and the protocol he would have

contacted Associate Professor Lewis50. So much is obvious and the same applies of

course if he had sensed, as he should have, that there was a discrepancy between what

he had prescribed Mr McRae on the one hand and on the other the content of

Associate Professor Lewis’ email and the content of his own email to Ms Teh.

7.37. Dr Beligaswatte was naturally cross-examined about his knowledge of what the usual

requirements in cytarabine consolidation chemotherapy were having regard to the fact

that a similar protocol had called for twice daily administration as seen from the pre-

existing FMC protocols to that point. At one point during the course of his evidence

Dr Beligaswatte was asked by Mr Griffin QC in effect whether he had thought that a

once daily dosing on days 1, 3 and 5 for consolidation therapy was clinically unusual,

to which Dr Beligaswatte suggested that although he could not remember what he had

thought at the time, there had been a number of changes in the protocol including the

incorporation of idarubicin, the fact that all patients from the age of 56 were being

treated with the one regimen and that there was also a reduction in the actual dosages

of cytarabine to 1g/m2, thereby providing an explanation as to why the frequency of

administration of cytarabine may also have been altered. He added:

'So for a junior consultant seeing something that I had not seen before doesn't necessarily mean that it's something that couldn't be what was intended. So I don't recollect my reaction to this protocol at that time but the fact that I had not seen it before doesn't necessarily mean that it wasn't something that was intended. So I referred to the authorised protocol. ' 51

I think Dr Beligaswatte was suggesting there that he was not an AML expert and was

a junior consultant, but I do note that throughout the course of his evidence

Dr Beligaswatte was nevertheless prepared to pontificate extensively about the

scientific principles underlying cytarabine therapy. The fact was, of course, that there

had never been, as far as the evidence establishes in this case, a consolidation

chemotherapy regimen in which cytarabine was administered on alternate days but

only once per day. The evidence that I heard and that I will deal with in due course

very much suggests that such a pattern of administration would be scientifically

wrong in principle and could have a tendency to render the therapy less efficacious.

50 Transcript, page 167851 Transcript, page 1552

50

7.38. There are other matters upon which Dr Beligaswatte was questioned and had

difficulty in answering. There was the difficulty occasioned by the fact that when

ultimately he responded to Ms Teh in his email of 11:34am on Monday 21 July 2014

in which he confirmed once daily administration, thereby locking in the error, he did

not include in its recipients those persons to whom that day he had sent his earlier

emails and to whom Ms Teh had sent her email querying Dr Beligaswatte’s dosage

frequency. Had he done so, he may have alerted those recipients to the error. In this

regard Dr Beligaswatte rejected the suggestion that a possible explanation for this was

that he had been embarrassed in effect by the fact that what he had thought was his

error had been exposed by a pharmacist.

7.39. Nevertheless, it is odd that Dr Beligaswatte, knowing that an issue had been raised by

a pharmacist querying his initiating email and its content, would not have wanted to

disabuse his colleagues, Dr Coghlan and Associate Professor Kuss in particular, of

any doubt or misgivings that they may have gleaned from the email chain themselves.

The fact is, however, that once he instructed Ms Teh that the dosage for Ms Crannage

was once daily it should have signified in his mind that the content of Associate

Professor Lewis’ email of 19 July was not correct and also that Drs Coghlan and

Associate Professor Kuss had so far been misled by his own email in respect of the

same issue regarding frequency of administration. The irony of course is that in his

original email he had not been in error regarding that issue.

7.40. In cross-examination by Mr Griffin QC, Dr Beligaswatte asserted that no-one had

alerted him to the fact that there was any special process to be followed in the

adoption of protocols apart from preparing the templates for use at FMC according to

whatever source was to be followed52. In the event Dr Beligaswatte would not

provide to anyone at the FMC a source document other than the updated and

erroneous RAH protocol which was provided to FMC on 21 July 2014 when he

forwarded the originating email from Mrs To of 16 July 2014. In this regard

Dr Beligaswatte said this:

'I am not sure that I would have thought that there would be any such document at all, these were protocols that were developed by AML experts who have access to information such as trial data that are coming out even before publication. Now, whether or not those discussions were formalised in a document between the experts or not, I have no idea. So, all I knew was there was this new thinking and that that was prompting

52 Transcript, page 1545

51

development of a new approach or a new protocol range, but I had no other source, and in fact for me I am interested in what the RAH's final decision was, the outcome of those deliberations. I was not going to go and look at that protocol to try to debate with Professor Lewis as to the appropriateness of those protocols, all I wanted to know was what did the experts actually end up deciding, and for me that was what the RAH protocols showed.' 53

7.41. Dr Beligaswatte conceded that this was not the way that the matter should have been

undertaken54, adding that he was not aware of any process for protocol development as

he had never been involved in that sphere either at the RAH or the FMC.

7.42. In his evidence-in-chief, Dr Beligaswatte said nothing about the important issue as to

whether or not in advocating the adoption of the RAH protocol at the FMC he had

spoken to Associate Professor Kuss about the matter given that she was the head of

the Haematology Department at the FMC. However, Mr Trim QC for Associate

Professor Kuss extracted an acknowledgement from Dr Beligaswatte that during the

course of a performance review in April 2014 he had told Associate Professor Kuss

that he would like to harmonise AML protocols between the FMC and the RAH so

that FMC patients would be eligible to participate in trials conducted at the RAH and

would not be disadvantaged in relation to transplants which were conducted at the

RAH55. Dr Beligaswatte asserted that Associate Professor Kuss responded to this by

indicating that it was a good idea. Ultimately the template that was created at the

FMC and which adopted the RAH protocol was not presented to a clinical meeting56.

7.43. To my mind there was an abundance of opportunities for a reasonably astute man who

had an eye for detail to have considered and identified the dilemma posed by

Ms Teh’s email in conjunction with the other documentation to which

Dr Beligaswatte had access and to have dealt with that dilemma. Unfortunately,

Dr Beligaswatte was not that man.

7.44. I now turn to the evidence of Associate Professor Bryone Kuss in relation to her

knowledge of the adoption of the RAH protocol at the time of its adoption. Associate

Professor Kuss is the Head of Clinical and Laboratory Haematology and Genetic

Pathology at FMC. She has an Associate Professorship of molecular medicine and

pathology at the FMC School of Medicine. In respect of her duties at the FMC she

53 Transcript, page 155954 Transcript, page 156055 Transcript, page 162356 Transcript, page 1627

52

was employed by SA Pathology on a 0.6 FTE basis. Her particular interest within the

haematology sphere is chronic lymphocytic leukaemia. She has been a member of the

ALLG and was a member of the scientific subcommittee of that group in 2014. As

the Head of the Haematology at the FMC her responsibilities included oversight of

the clinical service. Associate Professor Kuss had a large number of administrative

responsibilities attending to both SA Pathology based administrative and FMC

administrative issues. She was first appointed as a haematology consultant at the

FMC in 2003.

7.45. Associate Professor Kuss was on leave as at 16 July 2014 which was the day on

which Mrs To emailed the updated protocol. She was still on leave on 19 July 2014

which was the day on which Associate Professor Lewis sent his email setting out the

changes to the protocol including the reference to BD administration. Monday

21 July 2014 was Associate Professor Kuss’ first day back at work from leave.

7.46. In her oral evidence Associate Professor Kuss told the Court that she was aware of the

process that involved written templates for the prescription of chemotherapy at the

FMC. Shortly after she was appointed as a haematology consultant she embarked

upon the task of developing the template process for the Haematology Department.

She performed that function in conjunction with a pharmacist. As at mid-2014 there

were 61 templates in place. Associate Professor Kuss explained that within

haematology it was impossible for every clinician to be abreast of all literature within

that discipline and that for that reason it was considered advantageous to have a lead

clinician in each of the major disease areas including acute leukaemia. The lead

clinician for each of those sub categories was responsible for leading changes in

protocol development and for the management principles for those particular diseases.

7.47. According to Associate Professor Kuss no written protocol development process was

in place at the time of the events with which this inquest is concerned. However,

Associate Professor Kuss tendered to the inquest a document that she has

subsequently prepared in connection with the Marshall review57 and which sets out the

process that she says was understood and in place as at July 201458. The document

sets out a staged process for protocol development that includes the following

57 An independent review, led by Professor Villis Marshall Chair of the Board of the Australian Commission on Safety and Quality in Health Care (ACSQHC), was conducted into the incorrect dosing of cytarabine to ten patients with Acute Myeloid Leukaemia (AML)

58 Exhibit C50, page 172

53

parameters namely, the tabling by a consultant at a ward meeting of a proposal for

protocol development, the discussion of the proposal with nursing, medical and

pharmacy staff, the reaching of an agreement to proceed with the development and the

primary consultant working with a pharmacist in conjunction with ‘source documents’

that included published literature, presentations and trials evidencing the rationale for

the protocol development. The pharmacist would then provide a completed draft

protocol to the primary consultant for review. In addition the agreed draft protocol

would then be emailed to all consultants and to the senior nursing manager for

comment. The comments would then be provided to the pharmacist and a finalised

protocol would be reviewed by the primary consultant and then saved as a template on

the haematology server. The relevant persons would then be notified that the protocol

was ready for use.

7.48. This elaborate procedure was not reduced to writing at the time the FMC was

contemplating adopting the RAH protocol, but Associate Professor Kuss told the

Court that the procedure was nevertheless in place. It is perplexing how a process as

detailed as this was meant to be absorbed by clinical staff without any written

guidelines. All the more so in the case of a person such as the relatively

inexperienced Dr Beligaswatte. It is no wonder the process was not followed at the

FMC in this instance. In reality none of these requirements, if they existed at the

time, were met except to the extent that, as Dr Beligaswatte asserted, the need to align

the FMC protocol with the RAH protocol was mentioned at a ward meeting on

16 July 2014. Certainly no source documentation was provided to the pharmacist.

Insofar as any draft protocol was developed by the pharmacist it would not be emailed

to all consultants and the senior nursing staff for comment. This set of circumstances

could owe itself to a number of possibilities including a lack of experience with

protocol development on the part of Dr Beligaswatte, a lack of knowledge on his part

of the requirements or because the procedures as described by Associate Professor

Kuss were ad hoc and inconsistently understood and applied.

7.49. In her evidence Associate Professor Kuss emphasised that the pharmacists played a

critical role in protocol development and maintenance. She said that they would work

with the senior consultant in the development of the protocol and described the

pharmacists as ‘the keepers’ of the templates. To my mind this overstated the role of

the pharmacist insofar as the pharmacist was only as good as the information that he

54

or she was provided by a consultant. The same must apply to the chemotherapy

prescription templates that the pharmacists brought into existence. If the consultant

was in error then such an error stood a very good chance of being perpetuated by the

pharmacist in the development of the template. The only rider that would need to be

added here is that insofar as there was any requirement for the pharmacist to satisfy

him or herself that the source documents underpinning the protocol did in fact support

the protocol, that requirement was not met in this case. As has been seen, the FMC

pharmacist Ms Teh had been given to understand that there was no documentation

other than the RAH protocol.

7.50. Associate Professor Kuss explained that the protocol development process would

normally take several weeks, but if there was a perceived urgency for implementation

it could be accommodated by a shortened process involving the pharmacy and lead

consultant generating the protocol in response to a clinical need. In these

circumstances there would be less discussion within the department overall. The

pharmacist would draft the completed protocol and the protocol would then be placed

in a section on the designated server to be reviewed or confirmed. As indicated

earlier, there was in fact a clinical need in the sense that the patient Ms Crannage was

due for consolidation therapy, but to my mind this circumstance would not have

prevented at least some of the purported checks and balances to have been applied

such as the protocol being verified by a source document and the draft protocol being

distributed to all haematology consultants for their comment and approval. And it

was not as if Ms Crannage was a one-off case to which special clinical considerations

applied and one that would not be replicated down the line.

7.51. Associate Professor Kuss said that as Dr Beligaswatte had only been a consultant at

the FMC for some months, she was uncertain as to whether he would have been

familiar with the protocol development steps that she testified to59. Associate

Professor Kuss did give evidence about Dr Beligaswatte’s performance review of

April 2014 and of Dr Beligaswatte’s stated desire to harmonise the AML protocols

across the State so as to better facilitate access to clinical trials conducted at the RAH

and to make the process of transplantation more seamless60. In her evidence Associate

Professor Kuss confirmed that to her this had sounded like a good idea.

59 Transcript, page 197360 Transcript, page 1973

55

7.52. In cross-examination by Mr Griffin QC, Associate Professor Kuss conceded that she

had been content for Dr Beligaswatte simply to have worked with the pharmacist

Ms Teh to develop a new protocol if they thought one needed to be introduced and

that the protocol would then just be applied at FMC61. She added that Dr Beligaswatte

had spent two years at the RAH as a Leukaemia Fellow under the tutelage of

Associate Professor Lewis and although he was not appointed as a consultant at that

time, he was functioning as one. She also said that she expected that the pharmacist

Ms Teh would distribute by email a draft template to the other consultants which was

the usual practice62. So, she had worked on the basis that Dr Beligaswatte must have

devised the protocol appropriately with the assistance of Ms Teh63. As far as any

expectation that Ms Teh would distribute the new template to other consultants is

concerned, it is apparent from the email chain that was developed in relation to this

matter that although Associate Professor Kuss was initially included in the chain in

which the protocol changes were contemplated, and in which Ms Teh had raised a

query about whether the frequency of dosage was once daily or twice daily, Associate

Professor Kuss did not receive anything further from Ms Teh nor from

Dr Beligaswatte in the nature of a protocol or template draft.

7.53. Associate Professor Kuss accepted the proposition that where a question of

inconsistency or otherwise had been raised in relation to the accuracy of a proposed

protocol, the consultant in the case, Dr Beligaswatte, ought to have approached either

Associate Professor Lewis or have gone to the primary source documents himself to

ascertain whether the protocol to be adopted was correct. Associate Professor Kuss

added that although in her view the M15 study did not represent a primary source

document because it related to a trial, she would have expected Dr Beligaswatte to

have raised any question of inconsistency with Associate Professor Lewis. In any

event she said that she would disapprove of a consultant simply referring to the RAH

published protocol and assuming that it must be right because it was on the RAH

website64.

7.54. It is difficult to agree with Associate Professor Kuss’ characterisation of the M15

protocol as simply representing a trial document and for that reason was not a primary

source document. Although it was promulgated in anticipation of a trial, it

61 Transcript, page 2009-201062 Transcript, page 201163 Transcript, page 201164 Transcript, page 2013

56

nevertheless represented the manner in which consolidation therapy in respect of the

elderly was going to be administered at the RAH. The RAH protocol, save for the

error, had been based on it. In any event, as indeed conceded by Associate Professor

Kuss, if the document had been consulted then it would have confirmed that the

suggestion that cytarabine ought to be administered only once daily did not conform

with the document and therefore needed to be corrected and exposed as an error. This

is obviously so regardless of whether the ALLG M15 pilot study could be

characterised as a ‘source document’ or not.

7.55. As I have mentioned Associate Professor Kuss was the Head of the Haematology

Department at the FMC. She was in fact the primary haematology consultant for

Ms Crannage. Ms Crannage had been placed under Associate Professor Kuss’ care

when the latter had been on ward duty. It was Associate Professor Kuss who had

been responsible for the prescription of Ms Crannage’s induction chemotherapy65.

Associate Professor Kuss had delegated the responsibility for creating the new

template for AML consolidation chemotherapy to Dr Beligaswatte and stated that she

was not involved in that process66. Associate Professor Kuss said that she had left it to

Dr Beligaswatte and Dr Coghlan to implement the proposed consolidation round for

Ms Crannage. She said that she had been on leave and had discussed Ms Crannage’s

management with Dr Beligaswatte. At the time she returned from leave she was not

aware of Ms Crannage’s current clinical status and therefore considered it not

appropriate for her to be prescribing chemotherapy without her actually seeing the

patient.

7.56. Associate Professor Kuss was not familiar with the document that Dr Damin had

provided to Dr Beligaswatte. This of course was the document on which it was

stipulated that twice daily dosing was the required frequency of administration and

which had been provided by Associate Professor Lewis to Mrs To in the first instance.

7.57. As to the email chain of 21 July 2014, Associate Professor Kuss’ first day back at

work from leave, she said that she did not recall reading the 9:08am email of

Dr Beligaswatte, but would have read it within a few days of 21 July 2014. She said

that she did not recall the 10:15am email of Ms Teh. In cross-examination by Mr

Griffin QC, Associate Professor Kuss stated that she did not necessarily read the

65 Transcript, page 197866 Transcript, page 1979

57

21 July 2014 emails ‘in real time’67 and that the email exchange was probably 24

hours or so old by the time she read it. Associate Professor Kuss also said in her

evidence that she did not read Associate Professor Lewis’ email in which the twice

daily frequency was mentioned by him and of course that would mean that she did not

read it when it was circulated directly to her by Associate Professor Lewis on 19 July

2014 nor when it was forwarded to her with Dr Beligaswatte’s 21 July 2014 email in

which he also mentioned twice daily administration in respect of the treatment of

Ms Crannage, one of Associate Professor Kuss’ patients68.

7.58. Of course, Associate Professor Kuss was not copied into and did not see

Dr Beligaswatte’s ultimate email in which he told Ms Teh exclusively that it was to

be a daily dose of cytarabine.

7.59. Associate Professor Kuss was asked by Mr Griffin QC in cross-examination what she

would have done if she had been made privy to Ms Teh’s being told by

Dr Beligaswatte that it was only once daily administration. To this Associate

Professor Kuss said that this would be speculation. She said:

'It's difficult for me to say now how I would have reacted to that when I didn't really pick up on the previous - the lower emails. I didn't read Associate Professor Lewis's email and I don't believe - it's difficult for me to say exactly how I would have responded to that. I suspect I may have questioned things further, but I did not. ' 69

However, she agreed that she would not need to be a doctor to identify from the email

chain that Dr Beligaswatte had said two conflicting things to Ms Teh and agreed that

if she had picked up on that she would inevitably have queried Dr Beligaswatte’s

intent. She said:

'Yes, if I was paying attention to the full email trail, looking at the whole thing, I would clearly have contacted both of them and said 'I think there is a concern here'. ' 70

She went on to agree that if she had raised a concern it inevitably would have meant

that the source documentation would have been referred to and that this in turn would

have established that the correct protocol called for twice daily administration. She

agreed that this would have prevented the fiasco that then ensued.

67 Transcript, page 205768 Transcript, page 206269 Transcript, page 206270 Transcript, page 2063

58

7.60. A letter that Associate Professor Kuss’ solicitor sent to AHPRA for the purposes of

that agency’s investigation was tendered to the inquest. By letter dated 9 June 2016

Mr Geoff Black of Wallmans Lawyers addressed certain questions posed to Associate

Professor Kuss by AHPRA for the purposes of its investigation. That letter asserted

among other things that on her return from leave Associate Professor Kuss had

observed the exchange of emails between Ms Teh and Dr Beligaswatte as a result of

which Associate Professor Kuss considered that the issue between them, that is to say

the issue regarding whether it was once or twice daily administration, ‘had been

resolved’. The email that had actually given rise to anything that could be described

as a resolution of the issue was of course Dr Beligaswatte’s email of 11:34am on

21 July 2014 in which he had said that the prescription for Ms Crannage was to be

once daily and which was only sent to Ms Teh. Associate Professor Kuss was not a

recipient of that email. When asked in her evidence as to whether it was correct that

having read the exchange of emails she considered the issue to have been resolved,

she said that she believed so71, although it was in that context that she now asserted

that she had not necessarily read the emails in real time. In my view, regardless of

when she read the email exchange, or to what extent she read it, Associate Professor

Kuss could not possibly have regarded the issue as resolved without having seen

Dr Beligaswatte’s email to Ms Teh not copied to her. In the course of her evidence

before the Court she was asked by me:

'Q. … So how then was the issue resolved in your mind when you returned from leave, when you did not actually get copied into Dr Beligaswatte's reply that it was once daily.

A. That's a very good point. Once again, I'm uncertain as to whether I read that at a subsequent date, and, because there further email exchanges, and whether it was included in that. And I believe that if there was a problem, that they would've come to me and discussed it further; and as I received no further information and saw nothing querying this particular thing any further, I presumed the questions were resolved between the consultant and the pharmacist. ' 72

The difficulty with the suggestion that the issue had been resolved in Associate

Professor Kuss’ mind is that there had never been a protocol prior to 2014 that had

called for the administration of cytarabine once daily on days 1, 3 and 573. She

agreed with the proposition that an experienced haematologist, that is to say one who

has had experience in the treatment of AML, ought to have detected that a protocol

71 Transcript, page 205772 Transcript, page 206073 Transcript, page 2017

59

that called for once daily administration on days 1, 3 and 5 was highly unusual and

that she would have expected an experienced haematologist to query whether it was

correct74. In particular, she asserted in her evidence that if she had been called upon to

deliver such a consolidation round she would have queried it because it would be

different and in pure pharmacokinetic terms it would be unusual and so unusual that

she would query whether it was right75. So, in my opinion whatever resolution there

had been, it would and should have smacked of error. If the true nature of the

resolution had been revealed to Associate Professor Kuss, it is likely that it would

have been viewed by her as a questionable resolution at best and a deeply flawed

resolution at worst. Thus in my view any resolution in favour of once daily

administration should have triggered in Associate Professor Kuss’ mind a legitimate

enquiry as to whether the issue had been resolved correctly or not. All that said,

Associate Professor Kuss asserted in her evidence that Dr Coghlan told her at some

unspecified point that he had seen the protocol and had himself thought that the

protocol had reflected the RAH’s intention as the once daily administration was

directly from the RAH protocol. Associate Professor Kuss’ evidence about this was

vague and I am not certain that Dr Coghlan gave any such reassurance to Associate

Professor Kuss at the time of Ms Crannage’s treatment. I think it more likely that any

such conversation may have occurred later.

7.61. In short, I do not believe that Associate Professor Kuss came to any understanding

that an issue as between once daily administration as against twice daily

administration had been resolved in July 2014. I think it more likely that for a

significant period of time Associate Professor Kuss existed in blissful ignorance of the

whole issue.

7.62. Also in that letter to AHPRA Mr Black on Associate Professor Kuss’ behalf detailed

her understanding of the circumstances that led to the development of the protocol

and pointed out that she had been on leave between 5 July and 20 July 2014. Dealing

with the email exchange between Ms Teh and Dr Beligaswatte on Monday 21 July

2014, the letter argues that Associate Professor Kuss had not been asked to comment

upon nor address any specific issue raised in the email that Associate Professor Lewis

had written on 19 July 2014. That email had not been flagged specifically for

Associate Professor Kuss’ attention having regard to the fact that the RAH sends

74 Transcript, page 201775 Transcript, page 2018

60

group emails of this type regularly to the same multiple recipients without

requirement for action or comment.

7.63. A further assertion in the Wallmans letter is to the effect that on the face of it a daily

dose of cytarabine did not stand out as being incorrect to Associate Professor Kuss.

The difficulty with that of course is her evidence as already seen about her

understanding of pharmacokinetic principles. It was at least questionable regardless

of whether a daily dosage could be immediately flagged as being manifestly incorrect.

On the whole I do not believe that Associate Professor Kuss really digested the email

exchange of 21 July 2014.

7.64. As to the assertion that on the face of it a ‘daily dose’ did not stand out as being

incorrect to Associate Professor Kuss, the point also has to be made, as it was made to

her in cross-examination by Mr Griffin QC, that even though strictly speaking that is

valid, the point is that this was a once daily dose administered not daily in the sense of

every day but on alternate days. When asked as to why she had not pointed this

dichotomy of administration out to AHPRA, she said ‘I cannot say’76. She said it was

not a deliberate avoidance of the issue. She then said that she believed that once daily

administration on alternate days ‘should have stood out’77.

7.65. Finally, as far as the AHPRA letter is concerned, an assertion in the letter that Ms Teh

had distributed the protocol to the relevant consultants and registrars prior to 21 July

2014 was simply not correct. In her evidence Associate Professor Kuss

acknowledged that she now believed that assertion not to have been correct.

7.66. When exposed to the cold stare of cross-examination in the course of the inquest,

many of Associate Professor Kuss’ excuses that were articulated in the Wallmans

letter fell to the ground.

7.67. I find that any faith that Associate Professor Kuss had that Dr Beligaswatte in

conjunction with pharmacy staff would satisfactorily and accurately promulgate the

adoption of the RAH protocol and do so without her oversight was misplaced. I do

not say that just with the wisdom of hindsight. Associate Professor Kuss knew that

there were procedures that needed to be adhered to. I accept Dr Beligaswatte’s

evidence that he was not completely au fait with those procedures. Associate

Professor Kuss could not legitimately have assumed otherwise and a close eye should

76 Transcript, page 206177 Transcript, page 2016

61

have been kept on Dr Beligaswatte and his activities in respect of the protocol

alteration.

7.68. Thus to my mind Associate Professor Kuss was dilatory when on 21 July 2014 she

failed to read carefully or read at all the email chain that Dr Beligaswatte initiated at

9:08 that morning. Regardless of whether or not Associate Professor Kuss should

have read Associate Professor Lewis’ email of 19 July 2014 or even Mrs To’s email

of 16 July 2014, a comparison which of itself would have revealed the discrepancy

between the protocol and Associate Professor Lewis’ description of the new protocol,

she should have read Dr Beligaswatte’s email at the time of its receipt. I say that even

allowing for the fact that 21 July 2014 was her first day back at work. The circulation

of the email was much more restricted to FMC haematology staff, including herself

and Dr Coghlan. To my mind Associate Professor Kuss should have carefully read

and have understood Ms Teh’s query about whether it was once or twice daily. To

my mind it was incumbent on her to have identified the conflict and to have

intervened in its resolution. Indeed, as Associate Professor Kuss herself has alluded

to, the issue did require resolution and in my opinion Associate Professor Kuss as the

Head of the Haematology Department should have ensured that the issue was resolved

satisfactorily and correctly.

7.69. Associate Professor Kuss also gave evidence concerning the process that needed to be

followed in order to author a protocol given that the process was not documented at

the time with which these events are concerned. She told the Court that

Dr Beligaswatte had not himself created a chemotherapy protocol template and that

she had not told him that there were certain processes in place in relation to the

development of protocol templates78. To my mind, Associate Professor Kuss should

have ensured that Dr Beligaswatte was informed of the necessary process and ensured

that he followed it.

7.70. The other matter worthy of note in Associate Professor Kuss’ evidence was that she

rightly suggested that email chains such as that of 21 July 2014 were an unsatisfactory

method of conducting important communications79. It is hard to disagree, especially

when the recipients of those emails choose not to read them.

78 Transcript, page 210579 Transcript, page 2078

62

7.71. In the course of her evidence before the Court, Associate Professor Kuss was asked

the following question by her counsel Mr Trim QC, and gave the following answer:

'Q. Is there anything you'd like to say about the failure of Flinders Medical Centre to detect the error that had occurred at the Royal Adelaide Hospital in respect of the protocol.

A. Yes, thank you for the opportunity. It was deeply concerning and with deep regret that the processes that I had put in place, that I thought were safe, that were considered to be rigorous by current standards, failed us in this instance and resulted in an error involving five patients treated at Flinders Medical Centre. That was clearly never an intended error and we deeply regret the anxiety and the angst going forward that this has caused our patients and we are continuing to try to improve on those processes and avoid any further possibility of error.' 80

7.72. I turn now to the evidence of Dr Coghlan in respect of this topic. Dr Coghlan is a

member of the ALLG and has an interest in clinical trials. He told the Court he was

not involved in the treatment of any of the patients in question, and I take it that that

would include Ms Crannage. I do not understand from Dr Beligaswatte’s evidence

that Dr Coghlan had any particular involvement in her treatment. In his evidence

Dr Coghlan did explain that he has had considerable experience with the AML

disease and is familiar with the principles underlying consolidation chemotherapy for

that disease.

7.73. Dr Coghlan told the Court that in July 2014 he had been aware of a plan to align

protocols as between the RAH and FMC but did not see the supporting

documentation. He said that they were always hesitant about adopting a protocol

without a written published reference and that to adopt a protocol that was based on a

consensus and not based on published data was always ‘somewhat uncomfortable’.

However, he observed that in this instance the RAH had adopted the protocol and that

they were the leading institution in relation to acute leukaemia. As well, Associate

Professor Lewis was one of the consensus group within the ALLG and he formed part

of the steering committee in regard to acute leukaemia management in ALLG.

Dr Coghlan said that it therefore seemed reasonable for the FMC to accept a template

that the RAH had provided.

7.74. In his evidence-in-chief Dr Coghlan said that he did not recall receiving the email

from Mrs To of 16 July 2014 even though he was one of the recipients. Asked as to

the reason why he would not have a recollection of that he said that he had last 80 Transcript, page 1998

63

worked at the RAH in 1986 and for reasons that he had never been able to ascertain

he was still on the mailing list of the Central Adelaide Local Health Network which

operates the RAH. He said he received five to ten emails a day and his practice

essentially was to ignore them. One wonders whether it ever occurred to Dr Coghlan

that he was possibly being sent these emails in his capacity as an employee of SA

Pathology as were the haematologists at the RAH or had received them as a member

of a wider haematological community. In any event he said that for the same reason

he had no recollection of reading the email of Associate Professor Lewis of 19 July

2014. He said he did not read it81. In respect of the email of 21 July from

Dr Beligaswatte to Ms Teh, Dr Coghlan suggested that he would have received it and

would have read it as the email was internally generated within the FMC. However,

he had no specific recollection of it. The same applied in relation to Ms Teh’s

emailed response which questioned Dr Beligaswatte’s assertion that Ms Crannage’s

regimen required BD administration. He said that all the consultants would be copied

into any email discussion regarding protocols and their implementation so he would

have received this as part of that process. However, he said that the email required no

action from him. He asserted that the same applied to Dr Beligaswatte’s ultimate

email in which he stated to Ms Teh that it was a daily dose of cytarabine that was

required. He said that this did not involve any action or response from him, although

I observe of course that that particular email was not sent to anyone other than

Ms Teh herself. I therefore infer that neither Dr Coghlan nor Associate Professor

Kuss received it or saw it on 21 July 2014.

7.75. In other words Dr Coghlan said that although he would assume that he would have

read correspondence pertinent to FMC in relation to the adoption of a protocol, he did

not pay any attention to any of these emails as they did not require any action from

him. This to my mind represents an abdication of responsibility. One would have

thought that given the fact that the email chain contained differing versions of what an

important chemotherapy protocol required, ‘action’ such as intervening in the

discussion would have been called for. The same applies to Associate Professor

Kuss.

7.76. As to whether the Dr Beligaswatte/Ms Teh exchange would have raised an alarm bell

with him due to the inconsistency between what the doctor had prescribed and what

81 Transcript, page 2431

64

the protocol had said, Dr Coghlan said that it was a difficult question to answer. He

then provided the Court with an expose on the properties of cytarabine and suggested

that if one thought that the ALLG were moving to a once daily regime because of

toxicity issues and that this reflected a form of compromise relating to efficacy versus

potential toxicity, one would not necessarily immediately leap to a conclusion that

there had been an error in the protocol82. That said, Dr Coghlan acknowledged that he

had never seen a regime involving once daily dosage even in elderly AML sufferers83.

But he said that he would not immediately have leapt to the conclusion that once daily

represented underdosing84.

7.77. As against this, however, in 2015 after the error was discovered Dr Coghlan engaged

in an email exchange with Dr Beligaswatte in which Dr Coghlan pointedly suggested

that Dr Beligaswatte had somewhat missed the point when Dr Beligaswatte had

claimed that there was no evidence to suggest that giving a smaller dose of cytarabine

per cycle would have adversely affected Mr Higham’s leukaemia control. In his

emailed reply, Dr Coghlan had attempted to pour cold water on that theory and

suggested to Dr Beligaswatte that a once daily on alternate days regime would have

been wrong in principle due to the pharmacokinetic properties of cytarabine. He said

to Dr Beligaswatte, as copied to other haematologists including Associate Professor

Kuss and Associate Professor Lewis without demur from them: ‘…practically the

kinetics have relied on twice daily dosing rather than total dose. The concern I have

with the error in the protocol does not relate to the dose per se but rather the kinetics

of a single dose’85. This was an accurate observation as it aligns nicely with the

independent expert evidence that was adduced in the inquest that cytarabine is a

schedule-dependent drug the pharmacokinetics of which are such that it acts at only

one phase of the leukaemic cell cycle. The ‘concern’ that Dr Coghlan had, as

expressed in that passage, was not misplaced. In his evidence before the Court,

Dr Coghlan endeavoured to bat this all away by saying that his challenging of

Dr Beligaswatte’s assertions was in the nature of an ‘academic discussion’86, but in

my opinion the emailed observation reproduced above more accurately reflects

Dr Coghlan’s mindset in relation to the significance of the error than anything he said

in his evidence before the Court.

82 Transcript, page 247083 Transcript, page 247184 Transcript, page 245785 Exhibit C55, pages 55-5686 Transcript, pages 2474-2475

65

7.78. In any case Dr Coghlan’s argument that once daily administration would not

necessarily have led to a conclusion that it represented underdosing, or that the

protocol was in error, also somewhat missed the point. The point is that if

Dr Coghlan had seen Dr Beligaswatte’s email suggesting twice daily, had then seen

this being queried by Ms Teh and had noticed that there had been no resolution to the

issue, this set of circumstances ought to have been enough to have rung the ‘alarm

bells’. It was the inconsistency between the approaches of Dr Beligaswatte and

Ms Teh that was an issue that required resolution. Clearly the resolution did not make

its way to Dr Coghlan. Dr Coghlan said, and I accept this evidence, that putting

himself in Dr Beligaswatte’s shoes he would have recognised that what was in the

protocol was different from what Associate Professor Lewis had indicated in his email

as far as frequency of dosage was concerned. He agreed with the further proposition

that he would have contacted Associate Professor Lewis before actioning anything

because he would have recognised a substantial change and would have queried

whether there was an error in Associate Professor Lewis’ email – in other words did

Associate Professor Lewis really mean bd? Dr Coghlan would have clarified the

issue with the primary source before administering therapy to the patient, the primary

source in this case being Associate Professor Lewis87. There seems little doubt that

had he done so the error would have been identified.

7.79. In my view the promulgation of the error at the FMC and the RAH could and should

have been prevented if either Associate Professor Kuss or Dr Coghlan had read the

email chain instigated by Dr Beligaswatte on the morning of Monday 21 July 2014,

insofar as it was sent to them, and had contacted Associate Professor Lewis.

7.80. As for Ms Teh’s involvement, she had also received the email chain that

Dr Beligaswatte initiated that included the emails from Mrs To and Associate

Professor Lewis. She was astute enough to observe that there was an inconsistency

between the protocol that had been circulated and Dr Beligaswatte’s instructions that

twice daily dosage for Ms Crannage was indicated. Nevertheless, Ms Teh went ahead

with the creation of the template that was used not only in respect of Ms Crannage’s

treatment, but would also be used in the treatment of others and did so in the

knowledge that there was an issue relating to whether there was once daily or twice

daily treatment indicated. If she had paid close attention to Associate Professor

87 Transcript, page 2460

66

Lewis’ email of 19 July 2014 she would have seen that the origin of the suggestion

that it was twice daily was his. This would naturally have given greater weight to the

notion that twice daily dosing was required and that the discrepancy may have owed

itself to an error within the protocol. However, any shortcomings on her part are

substantially mitigated by the fact that Dr Beligaswatte who was the instigator of the

protocol change had assured her that there was nothing to support the protocol change

save and except for the RAH protocol itself, and also from the fact that she

endeavoured to obtain source material. She was also assured by Dr Beligaswatte that

everything was proper and that the correct protocol involved only daily dosing.

7.81. I make the following findings:

Dr Ashanka Beligaswatte was responsible for the introduction of the error into the

FMC protocol template.

Dr Beligaswatte unreasonably failed to provide the pharmacist Ms Teh with a

document that he could or should have obtained supporting the changes to the

protocol. Having himself sought out and obtained a suitable document from Dr

Damin, it was perverse not to have supplied it to Ms Teh when she asked him for

documentation supporting the protocol template she was asked to create. If Ms

Teh had received that document, the protocol error would have been identified

and the consolidation therapy for all of the affected patients would not have

miscarried.

Dr Beligaswatte failed to appreciate the significance of Associate Professor

Lewis’ email of 19 July 2014. In this regard, he failed to identify or appreciate the

significance of a discrepancy between the content of Associate Professor Lewis’

email and the content of the new RAH consolidation chemotherapy protocol that

had been circulated by Mrs To on 16 July 2014.

Dr Beligaswatte also failed to appreciate that his prescription for Mr McRae that

he had completed on 18 July 2014 conflicted with the content of Associate

Professor Lewis’ email of 19 July 2014 and his own email at 9.08am on 21 July

2014.

Neither Associate Professor Kuss nor Dr Coghlan came to any realisation that

through the receipt of emails sent to them, there was an issue as to whether or not

twice daily administration or once daily administration of Cytarabine was the

67

appropriate frequency of dosage. They should have appreciated that and have

intervened.

Dr Beligaswatte, having regard to his relative inexperience, should not have been

assigned the task of introducing the RAH protocol into the FMC protocol template

without close supervision by Associate Professor Kuss or her nominee if she was

unavailable to do so. The result was that proper procedures for the alteration of

FMC protocols were not adhered to.

Dr Beligaswatte was not properly supervised in his carrying out of the task of

introducing the RAH protocol into the FMC protocol template. I find that the

responsibility of ensuring that Dr Beligaswatte followed all of the necessary

requirements was that of Associate Professor Kuss.

8. The patients are administered consolidation chemotherapy pursuant to the

erroneous protocol

8.1. In this section I will discuss the circumstances in which the four deceased patients

were administered consolidation chemotherapy pursuant to the incorrect protocols

that had been promulgated at both the RAH and the FMC in July 2014.

8.2. In a separate section of these findings I will deal with the patients’ circumstances

upon the discovery of the error in January 2015.

8.3. In a further separate section I will deal with the issue as to whether or not the

consolidation chemotherapy that was not in accordance with the intended protocol

had any effect on the remission status or duration of each patient or of their longevity.

8.4. I will deal with the circumstances surrounding the administration of consolidation

chemotherapy to Mr Knox. Mr Knox’s circumstances were different insofar as his

second cycle of consolidation chemotherapy occurred following, and in spite of, the

discovery of the error at the RAH.

8.5. I will deal with each of the circumstances surrounding the administration of

consolidation chemotherapy to the four deceased persons in turn.

8.6. The circumstances relating to the underdosing of Mrs Pinxteren

On 12 November 2014 Mrs Pinxteren presented at the RAH where she was seen by

68

Dr Devendra Hiwase. She presented with symptoms that gave rise to suspicion of a

blood disorder. Following blood tests and a bone marrow biopsy Mrs Pinxteren was

diagnosed with AML.

8.7. Following induction chemotherapy which was delivered unremarkably and in

accordance with the correct induction chemotherapy protocol, Mrs Pinxteren entered

remission. There is no suggestion that the induction therapy was anything other than

appropriate or that it was not properly administered.

8.8. Following her induction therapy as a result of which Mrs Pinxteren achieved

remission, it then became necessary for consideration to be given to consolidation

chemotherapy. This issue was considered by Dr Hiwase.

8.9. Before turning to the circumstances surrounding the delivery of consolidation

chemotherapy to Mrs Pinxteren it is necessary to say something of Dr Hiwase.

Dr Hiwase obtained his basic medical qualifications in India in 1991 and obtained a

specialist qualification also in India in 1995. That qualification was a Doctor of

Medicine. Dr Hiwase underwent further training in India and he worked both in India

and in Oman as a registrar in haematology and transplant medicine. He came to

Australia in 2001. Between 2001 and 2003 he worked at the Westmead Hospital in

Sydney as a haematology registrar. Following this and until 2005, he worked at the

Alfred Hospital in Melbourne as a senior registrar and transplant fellow. Dr Hiwase

obtained his specialist qualifications in haematology in Australia in 2004. He is a

Fellow of the Royal College of Pathology of Australasia as well as a Fellow of the

Royal Australian College of Physicians. He is a Doctor of Philosophy in chronic

myeloid leukaemia. This was awarded in 2010 through the University of Adelaide.

8.10. Dr Hiwase is a consultant haematologist working fulltime at the RAH. As such he is

an employee of SA Pathology. His particular area of interest within the general field

of haematology is in chronic myeloid leukaemia which is a different illness from

AML, the subject disease in this inquest. His current research focus relates to

myelodysplastic syndrome (MDS). Dr Hiwase’s responsibilities have included the

care of patients with haematological malignancy.

8.11. As at July 2014 Dr Hiwase had been involved in the development of protocols at the

RAH. He was involved in the delivery of the protocol for MDS. He had not been

involved in the development of any protocol at the RAH relating to AML. He told the

69

Court that the lead haematologist for AML was Associate Professor Lewis and that

Lewis had responsibility for developing protocols in respect of that disease stream.

8.12. Dr Hiwase is a member of the Chemo-Governance Committee which is a State-wide

committee. He is a member of the ALLG and in July 2014 was a member of the

ALLG subcommittee for AML and MDS. Although he was a member within those

two sub-groups within the ALLG, he states that he was not particularly heavily

involved in ALLG activities in 2014. However, prior to July 2014 he had been aware

of a discussion among the membership of the ALLG concerning the reduction of

cytarabine dosage in the consolidation phase of chemotherapy for elderly AML

patients.

8.13. Dr Hiwase gave oral evidence in the inquest. He told the Court that he was not an

expert in relation to the pharmacokinetics of the drug cytarabine but understood that

cytarabine had been used for a very long time in the treatment of AML. When asked

whether he had any understanding of the pharmacokinetics of cytarabine he said ‘not

much’88. Dr Hiwase told the Court that he knew of the pre-existing AML aged based

consolidation chemotherapy. He said that prior to the July 2014 change in the

protocol in respect of AML, elderly patients had been given cytarabine twice daily on

days 1, 3 and 589. Dr Hiwase said that he had no recollection of using the pre-existing

twice daily dosing of cytarabine on alternate days as a treatment regimen for the

elderly, but that he may have used it.

8.14. In his evidence Dr Hiwase said that he had been aware of the nature of the

consolidation regimens and the fact that there was more than one. He knew that some

involved daily cytarabine administration. He told the Court that he understood that

there had been a debate among haematologists as to the appropriate treatment options

for elderly patients suffering from AML. In particular he understood that reducing the

dose of chemotherapy specifically in the elderly and frail or vulnerable patients was

said to be due to the complications caused by the chemotherapy and to the need to

reduce the dose of chemotherapy for that reason. He told the Court that he did not

identify any error in the consolidation chemotherapy regimen that he would prescribe

for Mrs Pinxteren.

88 Transcript, page 133189 Transcript, page 1356

70

8.15. Dr Hiwase was naturally asked about the emails of Mrs To and Associate Professor

Lewis of 16 and 19 July 2014 respectively. Dr Hiwase was one of the many

recipients within Health. It will be remembered that Mrs To’s email attached the new

uploaded AML protocol, that is to say the erroneous protocol, whereas Associate

Professor Lewis’ email described twice daily administration which contradicted the

content of the new uploaded AML protocol. In cross-examination by Mr Griffin QC

Dr Hiwase agreed with the proposition that an email subject line containing reference

to a new AML protocol being uploaded would have attracted his attention90. When

asked whether it was reasonable to think that because some of his work involved

treating people with AML he would have taken notice of an email that spoke of a new

AML protocol, Dr Hiwase said that this was possible. However, he said that he could

not say whether it was likely that he would have done so, depending on the time of the

day that the email came in and whether he was conducting a clinic or seeing a patient.

He suggested that emails such as these ‘just go in the back of your mind’91. That said,

Dr Hiwase agreed that he knew that a new protocol had been discussed within his

unit. He agreed that it was possible that he would have noted Associate Professor

Lewis’ email as being relevant92.

8.16. It is obvious that if prior to treating Mrs Pinxteren Dr Hiwase had read both emails as

well as the protocol attached to Mrs To’s, and had compared their content, he would

have noticed the dosage frequency discrepancy between the protocol and Associate

Professor Lewis’ email. When asked by me as to what he would have done in those

circumstances, he said ‘I would have brought it to the attention of the proper

authorities’93. Naturally the proper authorities would have consisted of at least

Associate Professor Lewis. There is no doubt in my mind that had Associate

Professor Lewis been made aware of the discrepancy he would have taken the

necessary steps to rectify the error.

8.17. Dr Hiwase obviously did not at any point in time perform the exercise of comparing

the protocol with Associate Professor Lewis’ email. In dealing with Mrs Pinxteren he

simply followed the erroneous protocol. It did not cross his mind that it was wrong.

90 Transcript, page 135391 Transcript, page 135492 Transcript, page 135493 Transcript, page 1392

71

8.18. He did not identify any error until he became aware of it at a time after

Mrs Pinxteren’s consolidation therapy treatment in January 2015.

8.19. Asked as to why he would not have identified the error he said that the optimal dose

of cytarabine in the elderly patient had been debated and that the thrust of the debate

concerned the need to reduce the dose of cytarabine. He said that in any case he was

‘looking for a lower dose for Mrs Pinxteren because I was concerned about toxicity

in her case, and when I applied the protocol to the lowest that I can give to her, the

1g, it didn’t occur to me that time it is wrong’94. Dr Hiwase seemed to be suggesting

there that the underdosing would have been clinically appropriate in any event. In

another section of his evidence Dr Hiwase also pointed out, as did Dr Beligaswatte in

his evidence, that the new protocol called for the addition of idarubicin whereas the

corresponding alternate daily regimen of administration that had existed prior to the

change did not involve the administration of idarubicin. It is true that the cytarabine

dosage had been reduced from the high dosages that earlier protocols had advised, but

the frequency of dosage was intended to remain the same. The fact that the new

protocol had reduced both dosage and frequency ought to have been a matter that was

questionable in the mind of anyone who had knowledge of the pharmacokinetic

principles underlying the efficacy of cytarabine. The difficulty about that of course

was that Dr Hiwase knew ‘not much’ about that.

8.20. It is against that background that Mrs Pinxteren came to be prescribed and

administered with the consolidation chemotherapy in January 2015.

8.21. Dr Hiwase completed Mrs Pinxteren’s prescription on 12 January 2015. He told the

Court that in doing so he examined the protocol as he did not know the appropriate

prescription off the top of his head. I find that this was the case. Pursuant to that

prescription Mrs Pinxteren underwent her cytarabine treatment on 13, 15 and

17 January 2015. She was only administered once daily cytarabine, and this was

prescribed in accordance with the erroneous RAH protocol. She was also

administered idarubicin. As will be seen in another section, the first two cytarabine

administrations within that cycle preceded the recognition by Associate Professor

Yong on 16 January that there was an irregularity in the prescriptions in relation to

another patient, Ms MR, which led her to identify the protocol error. Mrs Pinxteren’s

third cytarabine dose occurred the day after.

94 Transcript, page 1330

72

8.22. As things transpired, Mrs Pinxteren did not undergo the usual second cycle of

consolidation chemotherapy due to her failure to recover from the first cycle and also

by virtue of the fact that in early March 2015 she was diagnosed as having relapsed.

8.23. I find that it never occurred to Dr Hiwase that the protocol contained an error and that

once daily administration in the case of Mrs Pinxteren was not in accordance with the

intended regimen of treatment. That said, there really can be no reasonable excuse for

Dr Hiwase failing to identify the discrepancy between the protocol, which he

obviously read at some point in order to prescribe for Mrs Pinxteren, and Associate

Professor Lewis’ email. I do not accept that the period of time between July 2014

when the error was identifiable by way of a comparison of the emails, and January

2015 when Dr Hiwase completed Mrs Pinxteren’s prescription provides an excuse for

the erroneous prescription, although it does to an extent mitigate it. Dr Hiwase,

together with all the other recipients of the emails, was cloaked with knowledge that

Associate Professor Lewis in his email had stipulated twice daily administration.

True it is that the protocol placed on the server was the operative document, but there

was material available in July 2014 from which the error ought to have been identified

and corrected. To my mind all recipients of the two emails who were haematologists

had an obligation to properly consider that material. Not one person did, so

Dr Hiwase was not on his own in that regard. I will later come to the circumstances

in which Dr Hiwase became aware of the error in 2015.

8.24. I should also add here that Dr Hiwase gave evidence that having regard to

Mrs Pinxteren’s age, the fact that she was myelodysplastic at diagnosis and that the

myelodysplasia persisted notwithstanding her remission, in his view the achievement

of remission after induction chemotherapy was the best result that she could have

hoped for. He agreed that the remission of the 31 December 2014 was a good result 95.

But he said that Mrs Pinxteren’s period of remission from 31 December 2014 to 2

March 2015 was disappointingly short96.

8.25. When it was suggested by Ms Kereru, counsel assisting, that the duration of

Mrs Pinxteren’s remission of no more than three months may have been due to the

fact that she received only half her dosage at consolidation, Dr Hiwase said that he did

not agree with that completely, but that it was possible. He did say that it was

95 Transcript, pages 1374-137696 Transcript, page 1389

73

difficult to maintain remission in elderly patients for a long time and that the disease

was more aggressive in a patient with myelodysplasia97. He summarised his position

on this issue by saying ‘it’s possible, but I don’t know exactly the result, it’s very hard

to say’98.

8.26. The circumstances relating to the underdosing of Mr McRae

In May 2014 Mr McRae was admitted to the RAH for treatment. He had already been

diagnosed by way of a bone marrow biopsy as suffering from acute erythroid

leukaemia (AEL) which is a type of AML. AEL can be difficult to treat and in the

event there was at one point some uncertainty as to whether or not Mr McRae had

achieved a complete remission following induction chemotherapy. However,

ultimately clinicians were satisfied that he had obtained complete remission.

8.27. Mr McRae was administered standard induction therapy. There is no suggestion that

this was not appropriate. That therapy commenced at the RAH on 29 May 2014.

8.28. Thereafter Mr McRae underwent two rounds of consolidation chemotherapy that

occurred in July and September 2014 respectively.

8.29. Both rounds of consolidation chemotherapy were prescribed by Dr Beligaswatte. I

have already referred to the fact that the prescription in respect of the first cycle of

Mr McRae’s consolidation chemotherapy was executed by Dr Beligaswatte on Friday

18 July 2014. Dr Beligaswatte told the Court that in compiling this prescription he

referred to the then current RAH AML protocol which would have been the one that

had been uploaded on 16 July 2014. The prescription was for once daily

administration. As seen already, there is the strange circumstance that on the

following Monday in the email to Ms Teh he would initially suggest in the case of

Ms Crannage at the FMC that twice daily cytarabine administration was called for.

8.30. Mr McRae was administered the first consolidation round on 21, 23 and 25 July 2014

respectively.

8.31. Following the completion of that consolidation cycle Mr McRae had to undergo a

hospital admission for febrile neutropenia which is a recognised complication of

chemotherapy. This condition places a patient at risk of infection. There were other

complications as well. In August 2014 a bone marrow biopsy was undertaken 97 Transcript, page 137798 Transcript, page 1377

74

because of uncertainty regarding Mr McRae’s remission status at that point in time.

The conclusion was drawn that Mr McRae was technically in a morphological

remission. To my mind the evidence demonstrates that this was a reasonable and

accurate conclusion.

8.32. On 29 August 2014 Dr Beligaswatte saw Mr McRae. It was then approximately five

to six weeks since the beginning of the first consolidation cycle. He listed in the notes

a number of complications that Mr McRae was experiencing and Mr McRae’s

intimation that he did not feel that he had recovered well from the previous cycle.

Nevertheless, given that Mr McRae was in an ongoing complete remission but with

erythroblast percentage higher than expected, a plan was formed to move to the

second cycle of consolidation. However, at that time it appeared that Mr McRae was

not yet feeling up to it.

8.33. On 5 September 2014 a decision was made to proceed with a second consolidation

cycle. Mr McRae was feeling brighter and Dr Beligaswatte discussed the case with

Professor Peter Bardy.

8.34. In the event the second consolidation cycle commenced on 15 September 2014 and

was conducted over that day, 17 September and 19 September 2014. Again once

daily administration occurred. Dr Beligaswatte completed the prescription for that

second cycle again by looking up the RAH AML protocol on the computer.

8.35. At a clinic review on 10 October 2014 Mr McRae seemed to be well. A CT scan of

his chest had shown improvement and his blood counts were reasonable.

8.36. Mr McRae was discharged from hospital on 16 October 2014. It had been decided

that the lenalidomide maintenance therapy, which was the therapy contemplated

pursuant to the ALLG M15 study, would not be implemented in Mr McRae’s case

due to his age as well as his condition and clinical findings.

8.37. It is not necessary to recount Mr McRae’s progress to the point early the following

year when it became apparent that Mr McRae had relapsed. By then Mr McRae’s

care had been taken over by Dr Anya Hotinski who was at that time a registrar. On

27 February 2015 Dr Hotinski wrote to Mr McRae’s general practitioner indicating

that due to a decline in Mr McRae’s platelet count she was concerned that Mr McRae

had relapsed. On 6 March 2015 Dr Hotinski met with Mr McRae, his wife and

75

daughter to inform Mr McRae that not only was it probable that his disease had

relapsed, but also of the cytarabine administration frequency error that had by then

been identified. On 13 March 2015 Associate Professor Lewis accompanied by

Dr Hotinski met with Mr McRae, his wife and his daughter to confirm that

Mr McRae’s AEL had in fact relapsed. The treatment error was also discussed at the

same meeting. In another section and in more detail I shall deal with the

circumstances surrounding the events of February and March 2015 following the

discovery of the error, as they relate to Mr McRae.

8.38. It is evident that Mr McRae’s consolidation chemotherapy was dictated by

Dr Beligaswatte who simply relied in rote fashion on the RAH protocol which had

been compiled and uploaded in error. It is also apparent that at no point during the

currency of Mr McRae’s treatment did Dr Beligaswatte have any realisation that the

protocol pursuant to which he had been treating Mr McRae was erroneous. This

pattern of ignorance would also be replicated by other clinicians, notably Dr Hiwase

in respect of Mrs Pinxteren, a Dr Naranie Shanmuganathan in respect of

Mrs Bairnsfather and another patient Ms MR, and a Professor Alex Gallus in respect

of Mr Higham.

8.39. I have earlier referred to the fact that whereas on Friday 18 July Dr Beligaswatte had

prescribed once daily administration for Mr McRae, he then effectively, in the first

instance, prescribed twice daily for Ms Crannage on the following Monday. If the

initial suggested Crannage prescription had been identified as being correct, as it

should have been, there is a strong possibility that Mr McRae’s prescription for once

daily administration would have been corrected and that his erroneous consolidation

chemotherapy during both cycles, the first of which commenced on the afternoon of

the Monday, would have been avoided altogether.

8.40. The circumstances relating to the underdosing of Mrs   Bairnsfather

Mrs Bairnsfather underwent one round of consolidation chemotherapy at the RAH

that was prescribed for her by Dr Shanmuganathan, a registrar.

8.41. Dr Shanmuganathan obtained her primary medical qualification from the University

of Adelaide in 2007. She obtained her Fellowship of the Royal Australasian College

of Physicians and the Royal College of Pathologists in 2016. That was conferred

upon her completion of training as a haematologist. However, in 2014 and 2015

76

Dr Shanmuganathan was a registrar still undergoing haematology training. Her duties

as a haematology registrar included clinical work involving the conducting of weekly

clinics, the reviewing of ward patients, the writing of chemotherapy prescriptions,

reviewing patients’ laboratory results and making clinical decisions based on those

results. In 2014 and 2015 she was undergoing rotation through the RAH until her

ultimate transfer to The Queen Elizabeth Hospital in 2015. It was during that rotation

that she was involved in the treatment of Mrs Bairnsfather.

8.42. Mrs Bairnsfather’s treating consultant was a Dr Noemi Horvath. Mrs Bairnsfather

underwent her induction chemotherapy in October 2014 following her diagnosis with

AML. Dr Shanmuganathan did not prescribe Mrs Bairnsfather’s successful induction

chemotherapy. Mrs Bairnsfather achieved complete remission. This then called for

the consolidation chemotherapy that Dr Shanmuganathan prescribed.

8.43. Dr Shanmuganathan told the Court that in order to prescribe Mrs Bairnsfather’s

consolidation chemotherapy she used the erroneous RAH AML protocol which was

on the haematology intranet. I find that Dr Shanmuganathan at all times acted on the

basis that the RAH protocol was correct.

8.44. However, in the course of her oral evidence before the Court Dr Shanmuganathan was

naturally asked about the emails that had been circulated on 16 and 19 July 2015, that

is to say the email from Mrs To attaching the uploaded protocol and the conflicting

email of Associate Professor Lewis in which he explained the consolidation regimen

including the reference to twice daily administration. Dr Shanmuganathan was a

recipient of both emails. As to the email of Mrs To of 16 July 2014,

Dr Shanmuganathan said that she would have read the email but not in any significant

detail. She said that she was based in the laboratory at that time and only commenced

actively treating leukaemia patients later in 2014. The same applied in relation to her

receipt of Associate Professor Lewis’ email of 19 July 2014. She stated that she

would have glanced through it. In cross-examination by Ms Kereru, counsel

assisting, Dr Shanmuganathan acknowledged that she had been aware of the protocol

for AML prior to the change in July 2014 and had herself prescribed chemotherapy

for patients based upon that previous protocol99. Thus when the changes occurred and

the new protocol was uploaded onto the intranet she realised that the cytarabine

99 Transcript, page 1252

77

therapy had been changed from twice daily to once daily on days 1, 3 and 5 100.

Dr Shanmuganathan did not query that change or question senior staff about it. She

stated that she had made the assumption that the protocol had been written and

checked through normal governance procedures. She said that she had thought that

there was a reason for the change, namely that once daily dosing was either superior

or less toxic. She acknowledged that she had not been aware of the underlying

evidence, herself being a junior registrar. She said:

'So I was under the impression that all the checks and balances had been done before publication.' 101

Specifically, her understanding was that it had gone through the Drugs and

Therapeutics Committee and that it had been discussed within a committee of

haematologists before being published on the intranet. When asked by me as to

whether she had any understanding as to what had sparked the change,

Dr Shanmuganathan said that she had been under the impression that it had been the

subject of numerous articles, meetings and conferences in which her unit had

participated and that the RAH was following a trend. Being a registrar at that time

and also being in the middle of exams, she assumed that the alteration had been

discussed, planned and appropriately vetted. She believed that the change had been

based on a study, possibly conducted by the ALLG. However, being at a junior level

she had not been involved in any discussion within the department about the actual

reasons for the change.

8.45. Dr Shanmuganathan said that she did not pick up the discrepancy between Associate

Professor Lewis’ email and the amended protocol that had been circulated102. As far

as she was aware no other person had picked up on the discrepancy103. No person on

the distribution list for the two emails drew any such discrepancy to her attention. It

would also follow from Dr Shanmuganathan’s answers that regardless of whether she

observed any discrepancy or not, it does not appear that she took particular notice of

the fact that Associate Professor Lewis’ email called for twice daily administration. It

is obvious that at all times Dr Shanmuganathan based her prescriptions on the

erroneous RAH protocol document on the SA Pathology server.

100 Transcript, page 1253101 Transcript, page 1253102 Transcript, page 1257103 Transcript, page 1258

78

8.46. It was in those circumstances that on 18 November 2014 Dr Shanmuganathan

prescribed Mrs Bairnsfather’s cycle of consolidation chemotherapy which involved

only single daily dosing of cytarabine on 24, 26 and 28 November 2014.

8.47. In the event Mrs Bairnsfather did not undergo a second cycle of consolidation

chemotherapy as already discussed.

8.48. In January 2015 Dr Shanmuganathan would write out another prescription based on

the erroneous protocol for a patient, Ms MR. However, before the prescription was

filled and administered the error was identified when another more senior doctor,

Associate Professor Yong, wrote out a prescription for the same patient which called

for the correct twice daily administration.

8.49. Any criticism that adheres to Dr Shanmuganathan’s involvement in the erroneous

prescription for Mrs Bairnsfather is mitigated by the fact that she was a relatively

junior practitioner who was not involved in the promulgation of the erroneous

protocol. At the time of its promulgation she was not performing clinical duties. She

simply followed the erroneous protocol to the letter and not unreasonably assumed

that the necessary processes for promulgation had been undertaken by more senior

clinicians. However, she had been a recipient of both the email that attached the

erroneous protocol and Associate Professor Lewis’ email which correctly described a

requirement for twice daily administration. A keener eye could have picked up the

discrepancy.

8.50. The circumstances relating to the underdosing of Mr Higham

Mr Bronte Higham was diagnosed with AML in November 2014 at the FMC. He was

one of Dr Beligaswatte’s patients at that hospital. At that time Dr Beligaswatte was

working at both the RAH and the FMC. In November 2014 Mr Higham successfully

underwent induction chemotherapy and attained a complete remission.

8.51. In December 2014 Dr Beligaswatte attended the American Society of Haematology

Conference in the United States of America. He also took leave between 25

December 2014 and 19 January 2015 which was his first day back at work. At that

time he still had two more weeks of clinics at the RAH but also had some work at

FMC, so he would be at both sites. I do not believe that Dr Beligaswatte had an

involvement in Mr Higham’s consolidation chemotherapy.

79

8.52. It was Professor Alexander Gallus, a consultant haematologist at the FMC, who

signed off on the prescriptions for the two cycles of consolidation chemotherapy for

Mr Higham. The first prescription104 is dated 8 December 2014 and bears the

electronic signature of Professor Gallus. This prescription is based upon the template

prepared in July 2014 by Ms Teh and provided for a single dose of cytarabine on

alternate days. Accordingly, Mr Higham received only single daily dosing of

cytarabine and this of course was not in accordance with the intended regimen. The

consolidation cytarabine therapy was administered on 9, 11 and 13 December 2014.

8.53. The same circumstances applied to Mr Higham’s second cycle of consolidation

chemotherapy. Again the electronic signature of Professor Gallus was applied to the

prescription using the same template for single daily dosing. On this occasion the

cytarabine administration took place on 14, 16 and 18 January 2015. The time of

administration on 16 January 2015 appears to be 4:50pm. The time of administration

of cytarabine on 18 January 2015 appears to be 10:10am. Both administrations would

have taken place over three hours and were conducted at the RAH. It is of note that

Friday 16 January 2015 was the day on which the anomaly in the prescriptions of

Ms MR was identified by a pharmacist at the RAH, as a result of which the RAH

protocol error was identified on Monday 19 January. It is possible that Mr Higham’s

erroneous single dosages on 16 January and 18 January 2015 may have been avoided

had the error been positively identified on 16 January 2015.

8.54. Both prescriptions for Mr Higham’s consolidation therapy were also signed by

another doctor who at that time was a registrar. In all the circumstances I did not

believe it was necessary to trouble that person to give oral evidence in the inquest

bearing in mind that person’s junior status and the available conclusion that this

practitioner would have simply been following the template that was already in

existence. Moreover, this practitioner was not a recipient of the email of Mrs To of

16 July 2014 nor of the email of Associate Professor Lewis of 19 July.

8.55. The Court called Professor Gallus to give oral evidence about the circumstances in

which he came to endorse the consolidation chemotherapy for Mr Higham.

Professor Gallus received his basic medical degrees from the University of Melbourne

in 1963. He became a Fellow of the Royal Australian College of Physicians in 1973

and a Fellow of the Royal Australian College of Pathologists in 1980. His specialty is

104 Exhibit C45, Tab 3

80

in general haematology with an emphasis on blood clotting, bleeding disorders, anti-

coagulant management and anaemia. He said that he is not an expert in malignant

haematology. None of his clinics involved patients suffering from AML.

Nevertheless, he would conduct ward service which would involve the treatment and

care of inpatients at the hospital. He was performing these duties in December 2014.

8.56. In his evidence Professor Gallus stated that he recalled Mr Higham. There is an entry

within Mr Higham’s progress notes105 of Professor Gallus seeing Mr Higham in the

course of a ward round at 5:05pm on 10 December 2014 which was the day before the

first day of the first cycle of Mr Higham’s consolidation therapy. Professor Gallus

told the Court that he would have attended the ward round on that day. A similar note

exists in respect of 12 December 2014 involving Professor Gallus seeing Mr Higham

on a ward round wherein it is noted that there would be no change to the plan which

can be taken as a reference to consolidation chemotherapy. There are further entries

in December 2014 involving Professor Gallus seeing Mr Higham that do not need to

be spoken of in any detail.

8.57. As far as the second cycle of consolidation chemotherapy is concerned it appears that

Professor Gallus’ involvement was the same as it had been in the cycle from the

previous month.

8.58. In cross-examination by Ms Kereru, counsel assisting, Professor Gallus stated that in

mid-2014 he was present at a haematology weekly ward meeting at FMC where an

RAH protocol and its adoption at the FMC had been discussed. He told the Court that

the meeting discussed harmonising AML treatment protocols between FMC and

RAH. He did not appreciate the details of exactly what the RAH protocol was going

to be. There had not been any discussion to that level of detail. He added that he did

not have any professional interest in the matter because it was outside his area106.

However, he acknowledged that he would have received Mrs To’s email of 16 July

2014 that attached the revised protocol as well as Associate Professor Lewis’ email of

19 July 2014 which set out the intended twice daily frequency. He said that he would

not have read both emails because neither email dealt with an FMC protocol. Rather,

they concerned an RAH protocol107. He said he would have deleted both emails.

105 Exhibit C45, page 20106 Transcript, pages 1293-1294107 Transcript, page 1267

81

8.59. In cross-examination by Mr Griffin QC, Professor Gallus agreed that the

administration frequency columns within the template were pre-printed and that if

they contained a mistake this would be a matter that he would not check when

completing or signing a prescription. As far as the drug dosages for Mr Higham were

concerned, they were not matters that he would have checked against any existing

protocol. Professor Gallus also said that he would not go to the literature behind the

protocol108. Indeed, he agreed with the proposition put to him by Mr Griffin QC that

as AML was not one of Professor Gallus’ sub specialities, he would not recognise that

the drug cytarabine should routinely be administered bi-daily rather than once daily

just by looking at the frequency administration column of the template.

Professor Gallus said:

'That's correct. I would not. Somebody in their wisdom has decided that this is the way it's going to be. And I mean there is sufficient variation between protocols amongst various places to say, well this is a variant. But I mean from where I sit and from my expertise I would not have picked the fact that the usual way to give this would be twice, no.' 109

Professor Gallus also agreed with Mr Griffin QC’s proposition that unless the

prescription was checked by a consultant who was a specialist in respect of the

treatment of AML, the once daily rather than twice daily administration of cytarabine

discrepancy was unlikely to be detected and added:

‘The very fact that it is a protocol gives it a certain status and if the protocol says it’s a once-daily administration, then your assumption is that this is deliberate.’ 110

8.60. I find that neither Professor Gallus nor any other clinician identified that Mr Higham

should have received twice daily dosing consolidation chemotherapy, or that the

template used for the purposes of prescription was in error in only providing for once

daily administration.

8.61. I also find that Professor Gallus did not receive any communication from any

clinician at the RAH to the effect that the protocol was erroneous or that there was

any other anomaly in respect of the protocol at a time that would have prevented the

miscarriage of Mr Higham’s second cycle of consolidation chemotherapy in January

2015.

108 Transcript, page 1285109 Transcript, page 1285110 Transcript, page 1287

82

8.62. Nevertheless, Professor Gallus had been a recipient of the conflicting emails of Mrs

To and Associate Professor Lewis. On can understand him not paying much attention

to the protocol attached to Mrs To’s email, as it involved an RAH protocol

exclusively. However, he had received Associate Professor Lewis’ email which had

correctly spelt out the twice daily requirement. All that said, Professor Gallus had not

been a recipient of the email chain initiated by Dr Beligaswatte at the FMC on 21 July

2014 that had precipitated the introduction of the error into the FMC template that

would be used in Mr Higham’s consolidation chemotherapy. On the whole, it is

difficult to be critical of Professor Gallus.

8.63. The only other matter surrounding Mr Higham’s consolidation therapy that should be

mentioned is that on 15 January, which was the day between Mr Higham’s first and

third days of cytarabine administration in his second cycle of therapy, he was seen by

Dr David Ross. Dr Ross was a haematologist who like Dr Beligaswatte had an

involvement in both the RAH and the FMC haematology departments. A note made

in respect of this consultation indicates that Dr Ross determined that Mr Higham

should continue with that cycle and that the patient should be followed up with

Dr Beligaswatte after that cycle. In his evidence before the Court Dr Ross said that he

had no recollection of seeing Mr Higham. In any event, it is clear that Dr Ross had

nothing to do with the erroneous chemotherapy prescription that had been filled for

Mr Higham. In January 2015 Dr Ross would have some involvement with Mr Knox’s

care during the course of Mr Knox’s second cycle of consolidation therapy. I will

mention something of this when dealing with Mr Knox’s circumstances.

9. The error is discovered

9.1. On 16 January 2015 Mr Russell Baldock who is a pharmacist at the RAH was

rostered for prescription verification. In the course of his work he encountered a

prescription that had been compiled by Associate Professor Agnes Yong on

15 January 2015. Associate Professor Yong is a consultant haematologist at the

RAH. The prescription was for the second cycle of consolidation chemotherapy for

an AML patient, Ms MR, and it prescribed twice daily administration of cytarabine on

three alternate days, namely 19, 21 and 23 January 2015. 16 January 2015 was a

Friday. Ms MR’s chemotherapy was to commence on Monday 19 January 2015.

83

9.2. As part of the prescription filling process it was necessary for Mr Baldock to check

the prescription against the relevant chemotherapy protocol which he did. On

examining that protocol he realised that the protocol only called for daily

administration of cytarabine. This protocol of course was the erroneous protocol that

had been on the SA Pathology server since mid-July 2014. Mr Baldock also

established that in respect of the patient’s first cycle of consolidation chemotherapy

she had been administered once daily cytarabine on three alternate days which had

been in accordance with the existing erroneous protocol.

9.3. However, as far as the upcoming second cycle for Ms MR was concerned Mr Baldock

also noticed that there was already in existence a prescription for the same

chemotherapy for the same patient, but which had been compiled on 12 January 2015

by Dr Shanmuganathan to whom I have already referred. This prescription called for

only once daily administration on the three alternate days beginning Monday

19 January 2015. Naturally, this prescription had been based on the erroneous

protocol.

9.4. Mr Baldock observed that Associate Professor Yong’s prescription was a variation on

the protocol which, according to Mr Baldock, occasionally occurs. In those

circumstances he decided to seek an explanation from Associate Professor Yong to

ensure that the dose frequency variation to twice daily was an intended adjustment.

The fact that there were two prescriptions in existence for the same treatment was also

irregular.

9.5. Mr Baldock contacted the more senior doctor, Associate Professor Yong, via email

and he also had a conversation with her. Mr Baldock believes that he actually spoke

to Associate Professor Yong before he sent an email to her about the matter at

9:21am. The email was copied to another pharmacist, Mr Abhi Phatak. The email to

Associate Professor Yong mentioned the patient’s name and the fact that

Dr Shanmuganathan had also written a prescription for the patient earlier in the week.

The email only refers to an anomaly in respect of an accompanying drug used in the

chemotherapy, the nature of which does not need to be discussed here, but nothing

about the once daily versus twice daily anomaly. Associate Professor Yong in her

email response at 10:16am stated to Mr Baldock, as copied to Mr Phatak, that the

ALLG M15 study recommended consolidation of twice daily administration of

cytarabine and that this should be followed. It will be observed that these

84

communications between Mr Baldock and Associate Professor Yong occurred early

on that Friday.

9.6. In the event the second consolidation chemotherapy cycle for the patient Ms MR

would be administered on a twice daily basis over the three alternate days in

accordance with the correct and intended regime of administration that Associate

Professor Yong had prescribed. It would not serve to alter the erroneous

administration in respect of Mrs Pinxteren at the RAH nor in respect of Mr Higham at

the FMC over the course of the ensuing weekend.

9.7. Associate Professor Agnes Yong was called to give oral evidence in the inquest. She

was represented by Mr Trim QC and Mr Besanko of counsel. Associate Professor

Yong holds the position of a senior consultant haematologist at the Haematology

Department at the University of Adelaide. Her employer, as with the other

haematologists, is SA Pathology. She is a member of the staff of the Clinical Services

Department and was the deputy to Professor Bik To. She is a clinical associate

professor. Associate Professor Yong arrived in Australia in 2011 and had worked at

the RAH since 2012.

9.8. Associate Professor Yong explained that the majority of her work at the RAH was

clinical and that her particular area of interest within haematology was research in

chronic myeloid leukaemia and transplantation. Associate Professor Yong obtained

her Doctorate of Philosophy in respect of chronic myeloid leukaemia.

9.9. In 2014 Associate Professor Yong was a member of the ALLG and had been aware

through Associate Professor Lewis of the ALLG M15 study. She told the Court that

she was aware of the agreement that the RAH would take part in the M15 study.

9.10. In the course of her evidence-in-chief Associate Professor Yong was shown the

ALLG M15 trial document relating to lenalidomide maintenance therapy. She was

familiar with the study participation requirement that a patient had to undergo

induction chemotherapy and have at least one consolidation cycle of chemotherapy.

She was familiar with the recommended chemotherapy regimen for the 56-65 age

group as set out in that document. Associate Professor Yong herself told the Court

that she had at least three patients who had participated in the trial. Associate

Professor Yong’s familiarity with this study would prove to be an important

circumstance in the detection of the error.

85

9.11. In relation to Associate Professor Lewis’ email of 19 July 2014 she told the Court that

she did not recall seeing that at that time as in 2014 it was not particularly relevant to

her clinical practice. As well, she had not read the updated and erroneous RAH

protocol dated 15 July 2014 which had been uploaded by Mrs To on 16 July 2014. At

all relevant times she worked off the M15 study documentation. It seems, therefore,

that Associate Professor Yong’s clinical practice had not been infected by the

erroneous protocol.

9.12. Associate Professor Yong had assumed Ms MR’s care because she had been on ward

duty at the time of her admission. Associate Professor Yong explained that Ms MR

was diagnosed with AML and had undergone successful induction chemotherapy.

Ms MR was a suitable candidate to take part in the M15 study as she was aged less

than 60 years. When Ms MR came to undergo her first cycle of consolidation

chemotherapy, Associate Professor Yong had been away at a meeting in the United

States. The first cycle of consolidation chemotherapy for Ms MR had been

administered in accordance with the incorrect protocol. However, it was in relation to

the second cycle that the error was detected. Ms MR was due to undergo that second

cycle commencing on Monday 19 January 2015. Associate Professor Yong saw

Ms MR in the days prior to 19 January 2015. Associate Professor Yong wrote out the

second consolidation prescription for Ms MR thereby giving rise to the conflicting

chemotherapy prescriptions, the other having earlier been written by the registrar

Dr Shanmuganathan.

9.13. Associate Professor Yong had compiled her prescription not from the erroneous

protocol, but from the original ALLG M15 study document which of course set out

the correct dosage frequency. She had intended her patient Ms MR to participate in

the study. She did not need to refer to the RAH protocol for these purposes. She told

the Court that she simply used the recommended trial consolidation dose.

9.14. At the time she completed the prescription for the second round of chemotherapy

Associate Professor Yong did not know that there was already in existence another

prescription which had been written out by Dr Shanmuganathan.

9.15. Associate Professor Yong identified the email exchange of 16 January 2015 between

herself and Mr Baldock. It was actually in respect of the involvement of another

drug, that is not relevant for these purposes, that caused Associate Professor Yong and

86

Mr Baldock to have interaction in relation to this prescription and it was in the course

of oral discussions that it was revealed to Associate Professor Yong that the original

prescription of Dr Shanmuganathan was for only once daily administration of

cytarabine.

9.16. According to Associate Professor Yong, the revelation that another doctor had written

out a conflicting prescription in terms of cytarabine frequency did not automatically

lead her to a conclusion that there was in existence a documented error in the RAH

protocol. She told the Court that on Friday 16 January 2015 she was not aware that

the hospital protocol stipulated once daily administration. She had been on leave for

most of December 2014 and wondered whether it had been changed deliberately

without her knowledge. This was a matter that she intended to take up with Mrs To

who was responsible for protocol maintenance. However, Mrs To did not work on

Fridays111.

9.17. Associate Professor Yong told the Court that during the following Monday morning,

19 January 2015, she had a meeting with the pharmacists, Mr Baldock and Mr Phatak,

during which the RAH protocol and the ALLG M15 protocol were brought up on the

screen and the discrepancy was obvious to see.

9.18. On that Monday at 7:58am Associate Professor Yong sent an email to Mrs To

explaining that on the previous Friday the pharmacists, including Mr Baldock, had

brought to her attention that the RAH AML protocol had a different consolidation

regime for patients between 56 to 65 years from that set out in the M15 protocol. She

pointed out the discrepancy as being twice daily against once daily administration.

She also pointed out that it had previously been decided that the RAH protocol would

align with the M15 study as the RAH had wanted to use the ALLG recommended

induction and consolidation protocols. Associate Professor Yong enquired within her

email as follows:

'Please could you check for me – is this a typo?? It’s quite serious as it means that our patients’ consolidation is missing 3g/m2 each cycle if we are only doing 1g/m2 od and not BD.'

9.19. On the face of it this extract from Associate Professor Yong’s email suggests that the

discrepancy between the RAH protocol and the M15 study was something that she

knew about on the Friday after Mr Baldock had drawn the two conflicting 111 Transcript, page 1726

87

prescriptions to her attention. However, on the face of it the email is also consistent

with a lack of appreciation on Associate Professor Yong’s part on the Friday, and

indeed until matters were clarified on the Monday, that the discrepancy was explained

by an actual error within the RAH protocol. Mr Griffin QC has argued that based on

the discrepancy coupled with Associate Professor Yong’s determination that the M15

twice daily regimen should be followed leads to the inescapable conclusion that

Associate Professor Yong consciously realised that there was an error in the RAH

protocol that would have required immediate rectification and that the other

conflicting prescription was as a consequence of that. I do not accept that submission.

I do not believe that Associate Professor Yong did conclude on the Friday that the

RAH protocol was erroneous as a matter of certainty. After all, a state of uncertainty

in that regard is reflected in her query of Mrs To as to whether the inconsistency

between the M15 study and the RAH protocol was due to a typo. I do not doubt,

however, that given Associate Professor Yong’s familiarity with AML consolidation

chemotherapy she had grounds to deeply suspect that the RAH protocol was in error

when it specified only once daily administration. I cannot accept for a moment that

on that Friday it would not have been possible to establish that the RAH protocol was

in error and that the specification of once daily administration of cytarabine was not

deliberate. I have found that while Associate Professor Yong on the Friday did not

establish that the RAH protocol contained an error, the error could easily have been

established that day and that rectification of the protocol and of any outstanding

prescriptions at the RAH could have been achieved.

9.20. As a result of Associate Professor Yong’s email to Mrs To, Mrs To came to her office

in a very upset state saying that she had indeed made an error in typing out the

protocol and that the intended dosage was meant to be twice a day and not once a

day112. Associate Professor Yong’s concern from that point was to correct the protocol

immediately and so she instructed Mrs To to do that. This was in fact done. The

correct prescription as written out by Associate Professor Yong was in fact

administered to Ms MR in respect of her second cycle of consolidation chemotherapy.

9.21. Associate Professor Yong instructed the pharmacy to identify all patients who had

been wrongly administered consolidation chemotherapy in accordance with the

erroneous RAH protocol to that point in time.

112 Transcript, page 1727

88

9.22. There was an issue raised during the course of Associate Professor Yong’s evidence

and the evidence of Mr Phatak as to whether a Safety Learning System report (SLS)

would be initiated and by whom. An SLS report is a document that is intended to

describe and circulate an account of a clinical error or other adverse event that has

been identified. There was a dispute of sorts as between Mr Phatak and Associate

Professor Yong as to whose responsibility it had been to file such a report at the RAH.

In the event an SLS would not be filed until mid-February 2015. I will return to this

issue briefly later, but I do not believe that an SLS filed on or about 19 January would

necessarily have prevented anything that would take place from that point forward,

either at the RAH or the FMC.

9.23. There is also the fact that the FMC was using the same erroneous protocol as of

Monday 19 January 2015. This fact would only be recognised at a later point in time

and indeed too late for Mr Knox to avoid being administered incorrect consolidation

chemotherapy that was ordered based upon the still erroneous FMC template. I will

come to the circumstances in which the error came to be identified at the FMC

independently of the RAH in a moment, but the fact that it was not identified at the

FMC on either Friday 16 January or at the very latest Monday 19 January 2015 owes

itself to poor clinical governance at both hospitals and what appears to be the fact that

government tertiary hospitals in this State act in a silo fashion insofar as each of them

does not appear to know what the others are doing, even though they are working

within the same sphere of medicine. The poor clinical governance is classically

illustrated by the fact that notwithstanding the identification of the error at the RAH

on 19 January 2015, Mr Knox was still allowed to undergo chemotherapy that was

incorrect. I will come to the precise circumstances of that in a moment. A lack of

proper communication and a demonstration of poor clinical governance at either of

these two hospitals should never be tolerated in the future.

9.24. I return to the narrative as it unfolded following Associate Professor Yong’s

identification of the error. At 11:29am on Monday 19 January 2015 Mrs To emailed

Associate Professor Yong and copied it to Associate Professor Lewis. The email

attached an amended and correct protocol which stipulated twice daily administration.

The email requested Associate Professor Yong to examine the change and to approve

it prior to it being uploaded onto the system. A few minutes later Associate Professor

Yong replied outlining a few minor alterations.

89

9.25. The following day, Tuesday 20 January 2015, there was a further email exchange

between Associate Professor Yong and Mrs To about the content of the corrected

protocol in which Mrs To again asked whether the document could be uploaded,

adding ‘I am nervous about any mistake now’. After further correspondence between

Associate Professor Yong and Mrs To the corrected protocol was uploaded onto the

SA Pathology server.

9.26. As a result of the email exchange, at 10:53am on Tuesday 20 January Mrs To sent a

circular email to the many recipients that appear to represent the same or a similar

distribution list to the list that had been circulated in July 2014. The recipients

included Associate Professor Lewis, Professor Bardy, Dr Beligaswatte, Dr Coghlan,

Professor Gallus, Dr Hiwase, Dr Horvath, Associate Professor Kuss, Dr David Ross

and naturally Associate Professor Yong. For reasons that will now become obvious

this email gave rise to a deal of critical commentary during the course of the inquest.

I set out the email in full:

'Subject: updated AML (excluding APML) protocol uploadedAttachments: AML_140715_1_AY edited_ct_cleaned.pdf

Dear all,

Please note that an (sic) revised AML protocol (1.1), with one correct (sic), has been uploaded to the intranet. This version remains as version dated 15 th July 2014 with (1) added to the end to mark the update, as the rest of the information is unchanged.

Associate Professor Yong would like to bring your attention that: under section 3.6 HiDAC 2-ida consolidation: Cytarabine IV 1g/m2 is to be given twice daily.

CHE TO(Working on Monday, Tuesday and Wednesday)

Project OfficerC/o Haematology Clinical Trial OfficeLevel 3, East Wing, Royal Adelaide Hospital, North Terrace, Adelaide, SA 5000, Australia'

9.27. Although the email refers to the protocol as having one correction, the correction is

not identified. There is also no mention of the fact that Associate Professor Yong’s

instruction that cytarabine was to be given twice daily had arisen out of an error in

respect of dose frequency that had been identified in the protocol. Nor did it refer to

any frequency error as being corrected as such. It was generally accepted in the

inquest that this email was a wholly inadequate way of alerting a body of professional

people to the existence of a serious error in a chemotherapy protocol, particularly

when it is borne in mind that a number of the recipients of that email across two

90

hospitals had prescribed chemotherapy in accordance with the original and erroneous

RAH protocol, or in accordance with the FMC template which also up to that point

had provision for only once daily administration of cytarabine consolidation

chemotherapy. Those practitioners included Dr Beligaswatte, Professor Gallus,

Dr Hiwase, Dr Shanmuganathan and Dr Ross.

9.28. Notwithstanding the distribution of this email, Mr Knox at the FMC would be

prescribed his second round of consolidation chemotherapy still in accordance with

the uncorrected FMC chemotherapy template which specified only once daily

administration of cytarabine.

9.29. Dr Beligaswatte had been Mr Knox’s haematology physician at FMC. Mr Knox had

undergone his first cycle of consolidation chemotherapy in December 2014 at the

hands of Dr Beligaswatte. That consolidation chemotherapy had involved only once

daily administration. That of course took place at a time prior to the identification of

the error in mid-January of 2015. However Dr Beligaswatte, who as indicated had

been one of the recipients of Mrs To’s email of 20 January 2015, again prescribed the

erroneous once daily chemotherapy in respect of Mr Knox’s second cycle. The

prescription is dated 22 January 2015 and is signed by Dr Beligaswatte. I accept that

Dr Beligaswatte did not appreciate at that point that the error had been identified

within the RAH protocol or appreciate the significance of the information contained

in Mrs To’s email of 20 January 2015. However, by 20 January 2015 he had returned

from leave. He was asked by his counsel Ms Cliff as to whether he received Mrs To’s

email of 20 January 2015 timed at 10:53am and he said:

'I cannot recall reading this email at this time. I was shown subsequently many months later that I have, but I can't recall reading this.' 113

He acknowledged that the email certainly would have come into his inbox. He

explained that he had just returned from leave and was catching up on his work. He

would have been skimming emails to see which ones he really had to read. He said

that he did not think that the email would have struck him as anything other than a

housekeeping email that would have simply involved the minor editing of a protocol.

He pointed to the fact that the email suggested that the protocol had been ‘cleaned’

which may have made him think that any alteration had simply involved formatting

113 Transcript, page 1463

91

issues and minor things of a like nature. Thus he may have believed that he did not

even need to open the email. Dr Beligaswatte did say this:

'Yes, the document was pertinent. I acknowledge that. I don't think that it flagged the seriousness but I acknowledge that it was pertinent to my practice.' 114

9.30. I found Dr Beligaswatte’s self-analysis as to why he did not take on board the

contents of Mrs To’s email of 20 January 2015 very difficult to accept as being

reasonable. Dr Beligaswatte was still working at the RAH in the period between 20

and 30 January 2015. The email was sent by Mrs To who was a person who had

much to do with the upkeep of chemotherapy protocols. The content of the email, as

distinct from the title of the subject matter, related quite clearly to an AML protocol

that was concerned with consolidation chemotherapy and in particular cytarabine

chemotherapy. Furthermore, it concerned a matter in respect of which

Dr Beligaswatte had a significant personal involvement. He had been instrumental in

introducing the protocol to the FMC. Moreover, he had personally been involved in

the consolidation chemotherapy of a number of individuals, including Mr McRae and

Ms Crannage, wherein he had prescribed once daily treatment. Furthermore, if his

memory had served him well in January 2015, he would have recalled that at the time

of the introduction of that protocol at the FMC in July of 2014 there had in fact been

an issue that had involved whether the therapy would be administered once daily or

twice daily. Mrs To’s email was a document in which a consultant haematologist

senior to him, namely Associate Professor Yong, was saying that in respect of the

very protocol that he had been involved in, and the very treatment that he himself had

administered, the therapy was to be given twice daily, meaning of course that it was

not meant to be given once daily. Even if, say, Dr Beligaswatte had thought that

Associate Professor Yong’s intimation that cytarabine was to be given twice daily was

merely an update, it could not possibly explain why Dr Beligaswatte would prescribe

only once daily administration in respect of Mr Knox’s second cycle of consolidation

chemotherapy which was due to commence later in that week. And consider this;

Associate Professor Yong’s intimation that cytarabine be administered twice daily in

accordance with the RAH protocol meant that there would now be an inconsistency

between the RAH protocol and the existing FMC template. Given that

Dr Beligaswatte had assumed responsibility for the content of the FMC template, one

would have thought that he would have assumed the responsibility of considering

114 Transcript, page 1464

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whether the FMC template also required amendment. I think it is the case that

Dr Beligaswatte simply paid no attention to Mrs To’s email of 20 January 2015. To

my mind that was simply not good enough. On the face of it this email manifestly

related to an important facet of Dr Beligaswatte’s practice at both the RAH and the

FMC. For him the importance of it was underlined by the fact that during the course

of that very week he had the responsibility of formulating a prescription for

Mr Knox’s consolidation chemotherapy at the FMC.

9.31. Mr Knox underwent his second cycle of consolidation chemotherapy from 22 January

to 26 January 2015. The error in the FMC protocol template would not be identified

until 30 January 2015 which was Dr Beligaswatte’s last working day at the RAH.

9.32. Mr Knox was the last person to undergo the incorrect chemotherapy.

9.33. Mr Knox relapsed in December 2016. I understand he underwent further treatment

interstate.

9.34. I make the following findings:

RAH protocol error was discovered following the identification by Associate

Professor Yong and an RAH pharmacist of a discrepancy between the

prescriptions written for Ms MR that had been written by Associate Professor

Yong on the one hand and a Registrar on the other. That discrepancy was

discovered on Friday 16 January 2015. However, this did not lead to the

identification of the error within the RAH protocol on that day. In my view, the

error should have been identified on that day. Had the RAH protocol been

identified on that day, and if the error was quickly identified also at the FMC, it

could have prevented the erroneous administration of consolidation chemotherapy

to Mrs Pinxteren at the RAH and possibly Mr Higham at the FMC. It certainly

would have prevented the erroneous administration to Mr Knox.

The error within the RAH protocol was identified on Monday 19 January 2015.

On Tuesday 20 January 2015 an email circulated by Mrs To and referring to the

requirement described by Associate Professor Yong that cytarabine was to be

administered twice daily was wholly inadequate in that it did not signify that

Associate Professor Yong’s requirement had its origin in the identification of an

93

error within the RAH protocol. This email failed to alert any person at the FMC

that an error existed either in the RAH protocol or FMC protocol or both.

It is uncertain as to why the error was not specified in the email of Mrs To. The

email was so perplexingly and inappropriately banal and matter of fact in its terms

that it attracts suspicion that it was deliberately uninformative. However, there is

insufficient evidence to suggest that it was a deliberate omission or that there was

any sinister motive underlying the omission. Nevertheless, I find that the

omission is utterly astonishing.

10. The error is acted upon at the RAH

10.1. The error was acted on immediately in the sense that it was corrected within the RAH

protocol, but that was about the extent of the action until mid-February 2015. SLS

reports would not be submitted in respect of the underdosing of Mrs Pinxteren, Mr

McRae, Mrs Bairnsfather and the two other affected RAH patients until 12 February

in the case of a patient Ms MR, or until 17 February in the case of the other patients.

Apart from Dr Beligaswatte being made aware of the error, he says, on 30 January

2015, the error would not be formally disclosed to the FMC until, I find, 11 February

2015 when Associate Professor Kuss was made aware of it at a haematology ward

meeting.

10.2. Associate Professor Lewis was not in South Australia between 2 January and

25 January 2015. He was in the United States on leave with his family. He was asked

by his counsel whether he had taken his work phone with him and he said that he had,

but that global roaming was not activated as he only requests this when he goes

overseas for work related matters and that in any event he generally tried to avoid

accessing work emails on family holidays. Thus it was that he says he did not see

Mrs To’s email of 20 January 2015. He admitted, however, that he could have

accessed that email at least by way of wifi which from time to time he was able to

access at ‘various points’115. In the event he was advised of the error by Mr Phatak,

the pharmacist, on Wednesday 28 January 2015 after he returned from leave. It will

be noted that this was two days before Dr Beligaswatte asserts that he was told of the

error by, he says, Mr Phatak. Mr Phatak said there had been five patients affected and

115 Transcript, page 1891

94

their names were mentioned. There was no discussion about using the Safety

Learning System in order to report the matter. As to what action he took after

Mr Phatak advised him of the error, Associate Professor Lewis said:

'I ascertained from Mr Phatak where the patients were in their treatment course and realised that there was no immediate action to take, so no, I did not take any further action.' 116

He acknowledged that further action would have been appropriate in light of his

seniority and training. He said he should have been more proactive and that the lack

of action had left him embarrassed and deeply ashamed. He said that ‘in retrospect’

he should have been much more proactive and have taken action including

ascertaining more detail about the affected patients, establishing whether patients in

other hospitals were affected, notifying his direct line manager, lodging an SLS and

arranging for appropriate and timely open disclosure with the affected patients. He

did not have any discussion about the error with Associate Professor Yong at around

this time, although he said that there may have been some discussion which he did not

recall117. For a significant period of time between 28 January 2015 and 12 February

2015 when he attended a meeting in San Diego with Associate Professor Yong and on

which date he says he first found out that the FMC had inherited the error, Associate

Professor Lewis does not appear to have displayed anything other than complete

insouciance to the whole affair. In his evidence Associate Professor Lewis proffered

as a reason for not taking any positive action that he ‘essentially froze’118. He said he

froze and did not know what to do.

10.3. One of the matters that Associate Professor Lewis acknowledges that he could and

should have done was to establish whether patients at other hospitals were affected by

the error. There were a number of means by which this could have been achieved

including contacting his counterpart the FMC Associate Professor Kuss, by notifying

senior members of SA Pathology who oversaw haematology services in South

Australia and by speaking to relevant clinicians at the RAH including Dr Beligaswatte

who asserts that he did not find out about the error until two days after Associate

Professor Lewis.

116 Transcript, page 1892117 Transcript, pages 1892-1893118 Transcript, page 1901

95

10.4. I will in greater detail deal with the circumstances in which the error was recognised

at the FMC in another section, but it as well to observe here that on 12 February 2015,

which was the day after a ward meeting at the FMC at which the error at the FMC

was disclosed to Associate Professor Kuss, Associate Professor Kuss emailed

Associate Professor Lewis about the matter. Associate Professor Lewis was still in

San Diego at that time. According to Associate Professor Lewis this email was the

first he knew of the fact that the erroneous RAH protocol had been adopted and

utilised at the FMC119. He said he was surprised at this because of the tendency at the

FMC to use their own protocols. He also said that he was ‘horrified’ to learn that

FMC had been using the erroneous protocol and that the failure to report the error in a

timely manner had led to patients at the FMC also receiving less than the intended

dose of chemotherapy. In his reply to Associate Professor Kuss, Associate Professor

Lewis said that he would make the matter his priority when he returned to work the

following week.

10.5. Strangely, according to Associate Professor Lewis, he did not have any discussion

about the error and its discovery with Associate Professor Yong while they were in

San Diego before the February 2015 email exchange that was prompted by Associate

Professor Kuss.

10.6. As for Associate Professor Yong’s part, she told the Court that she regretted not

having taken action in response to the list of affected patients that she was given on 20

January 2015. She spoke to Associate Professor Lewis after he returned to work and

it appeared to her that Associate Professor Lewis knew of the error as the pharmacist,

Mr Phatak, had spoken to him. She had no other involvement in addressing the error

between the time of that conversation with Associate Professor Lewis and her

departure for San Diego. She had not approached either Associate Professor Lewis or

Professor Bik To.

10.7. Associate Professor Yong said that while in San Diego she received a call from

Professor Bik To. She received it when she and Associate Professor Lewis were

attending a session of this meeting. Associate Professor Lewis was with her at that

time. There was discussion about who knew what about the erroneous protocol being

used at the FMC, a matter that Associate Professor Yong said she also had not known

about120. Professor To forwarded a chain of emails to Associate Professor Yong 119 Transcript, page 1894120 Transcript, page 1735

96

concerning the matter which prompted Associate Professor Yong on that day, namely

Saturday 14 February 2015, to send a long email to Professor To copied to Associate

Professor Lewis in which she asserted that if the FMC was using their protocol it had

come with a caveat that they had to take responsibility for not noting that the dose was

discordant with the ALLG M15 protocol. Associate Professor Yong also maintained

that Associate Professor Kuss’ assertion that the FMC pharmacist did not have access

to the M15 protocol was not a valid reason to excuse them because the document was

easily obtained. She asserted in her email that she wrote her own chemotherapy

scripts directly following the ALLG M15 document. This of course accords with her

evidence in relation to the prescription for Ms MR, but she also asserted that even if

she had used the RAH protocol which provided for 1 g/m2 once daily she would have

noted the discrepancy immediately because:

'.. all registrars and consultants should realize this dose is such a low dose, and at least check or ask someone why it was such a low dose?' 121

Associate Professor Yong added that the affected patients, save and except for hers,

‘had their registrars or consultants write this lower AraC dose without thinking!’.

10.8. Also in that same email Associate Professor Yong said that she had not contacted the

other four RAH affected patients but gave a description of the manner in which she

had dealt with the error in relation to her patient (whom we know to be Ms MR) who

at the last minute had been spared a second erroneous cycle as a result of Associate

Professor Yong’s intervention on 16 and 19 January. In her email Associate Professor

Yong stated that she had told the patient that they were giving her twice daily dosing

for her second cycle as she had tolerated the initial lower dose well. She had

explained to the patient that the lower than usual dosing in the first cycle had been

administered because they had not wanted to give her too high a dose in case she

experienced complications, in other words the first cycle had not involved error but

had been administered in accordance with proper and considered clinical practice. In

her evidence before the Court Associate Professor Yong acknowledged that this

advice had been deliberately deceptive insofar as it had been calculated to mislead

Ms MR into believing that the lower dose had not been given in error but had been

administered on legitimate clinical grounds122. I should add that having regard to this

extraordinary admission I exercised caution in relation to the question of Associate

121 Exhibit C52, Tab 5122 Transcript, page 1781

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Professor Yong’s credibility, but I nevertheless found her to be an essentially truthful

witness. That said, the impression that the error and the underdosing was in the minds

of some a matter to be essentially swept under the rug is all the more enhanced.

10.9. As for Professor To, he told the Court that the first he heard of an error was when his

wife, Mrs Che To, had alluded to it in a domestic conversation around 20 January

2015, probably when driving home from work. This error had only been described in

very general terms to him. Professor To had been satisfied with an assurance by his

wife that the error had been corrected. He had not asked her any further questions

which is utterly perplexing.

10.10. It appears that Associate Professor Yong had not told her superior, Professor To,

about the error and this is perhaps explicable on the basis of an assumption that she

may have made that Professor To would be aware of the error through other means.

However, this is not a professional way of going about things and there is no doubt

that Associate Professor Yong should have notified Professor To of the matter and not

have waited for him to raise the matter with her when she was overseas. Associate

Professor Yong told the Court that she was waiting for either Associate Professor

Lewis or Mrs To to raise the matter with her. When Associate Professor Yong was

cross-examined by Mr Griffin QC along the lines that Associate Professor Yong as a

senior member of the haematology team should have spoken to Associate Professor

Lewis and Professor To in a collegial manner and have raised with them the question

of what should be done in respect of patients affected by the error, she agreed but

seized upon two mitigating circumstances. She said that they were so busy and that it

did not cross her mind to say anything to them as Associate Professor Lewis knew

and she believed Professor To also knew. She also said she was not in the fashion of

telling her bosses what to do. She also seized upon a cultural matter insofar as having

come from a patriarchal Chinese family where one does not tell one’s seniors what to

do, she had been reluctant to raise the matter with her seniors in this instance.

Clearly, this was unacceptable having regard to the need for professionalism, candour

and the need to ensure that the affected patients were given appropriate consideration.

10.11. I have also mentioned the role of the pharmacist at the RAH. It will be remembered

of course that members of the pharmacy department had a significant hand in the

discovery of the error at the RAH. It is asserted by Mr Phatak that when he and

Associate Professor Yong spoke on the morning of 19 January 2015 he asked

98

Associate Professor Yong what had to be done about making a report in the SLS.

Mr Phatak gave evidence that Associate Professor Yong responded by saying that she

would handle it. Associate Professor Yong’s version of the conversation is that she

told Mr Phatak that she did not say that and that in any case she did not know how to

compile an SLS report. In this Associate Professor Yong was not on her own.

Witness after witness claimed that they did not know how to use the SLS system

and/or said that they had believed that it was a system exclusively to be used by

nursing staff. As a means of notifying and correcting the underlying factor in an

adverse medical event in a public hospital system, the SLS leaves much to be desired.

10.12. There was further interaction between pharmacy staff, including with Ms Kirsty

Scarborough who was the Acting Deputy Director of Clinical Pharmacy at RAH and

who was the direct line manager to Mr Baldock and Mr Phatak. There was an issue as

to whether or not Ms Scarborough in turn informed Mr Christopher Doecke who was

a Director of Pharmacy Services at the Central Adelaide Local Health Network and

who was her manager. What is apparent is that on 12 February 2015 Mr Doecke

telephoned Professor Peter Bardy who was the Clinical Director of Cancer Services at

the RAH to inform him of the error.

10.13. On the afternoon of 20 January 2015 one of the pharmacists, Mr Baldock, sent a list

of the RAH affected patients to Associate Professor Yong. Mr Baldock was not

aware that the FMC had adopted the erroneous protocol.

10.14. In the event SLSs were filed by Ms Scarborough, although this did not occur until 17

February 2015.

10.15. The issue is somewhat academic as no amount of SLSs filed within the RAH

framework would have alerted the FMC haematologists or pharmacists as to the error

due to the segregation of the haematology clinical staff as between both hospitals.

This is a clear deficiency in clinical governance that I find needs immediate

rectification if it has not already occurred.

11. The discovery of the error at the FMC

11.1. As indicated earlier the error in the FMC template could have been recognised on

Tuesday 20 January 2015 if the FMC haematologists who were the recipients of

Mrs To’s email of that date had paid attention to its content. Allowing for the fact

99

that the email related to an RAH protocol for consolidation chemotherapy, and that

the email was an unsatisfactory means of communicating the fact of the error, it will

be remembered that in 2014 Associate Professor Kuss and Dr Beligaswatte had

discussed the adoption of the RAH protocol at the FMC and that subsequently the

protocol had been adopted and encapsulated in the template that was prepared by

Ms Teh. Even allowing for the fact that Mrs To’s email was somewhat cryptic and

that it did not actually identify Associate Professor Yong’s twice daily administration

edict as reflecting the correction of an error, the email still required attention,

particularly by Dr Beligaswatte as he had the imminent responsibility of preparing Mr

Knox’s prescription for his second chemotherapy cycle commencing that week. I will

deal with the circumstances concerning Mr Knox’s second cycle in the next section.

11.2. In a previous section I dealt with the unsatisfactory aspects of Dr Beligaswatte failing

to absorb the information in Mrs To’s 20 January email. On Friday 30 January 2015

Dr Beligaswatte was working at the RAH. In fact it was his last day of work at that

hospital. Dr Beligaswatte told the Court that it was not until 30 January that the

protocol error was drawn to his attention123. He said he was told about this by Mr

Abhi Phatak, one of the pharmacists at the RAH. The conversation took place at that

hospital. By way of background, one of the affected RAH patients, a Mr G, was

expected to attend the RAH that afternoon. Dr Beligaswatte was intending to see him.

Dr Beligaswatte said that Mr Phatak drew Dr Beligaswatte’s attention to the fact that

Mr G was one of the affected patients. Dr Beligaswatte said that nobody in the ten

days since Mrs To’s email of 20 January 2015 had attempted to contact him about the

error. He had been back at work following a period of leave since Monday 19

January. Dr Beligaswatte told the Court that the error was described to him as

involving the once daily versus twice daily issue.

11.3. Dr Beligaswatte told the Court that Mr Phatak told him that other affected patients

had been prescribed a ‘catch-up dose’ of cytarabine and so on that basis

Dr Beligaswatte prescribed an additional cycle for Mr G. In cross-examination

Dr Beligaswatte acknowledged in effect that there was no evidence to support such a

strategy. In the event, Mr G’s catch-up cycle took place in early February.

11.4. In his evidence Mr Phatak, who testified at a time before Dr Beligaswatte testified,

told the Court in answer to questions from Dr Beligaswatte’s counsel, Ms Cliff, that

123 Transcript, page 1465

100

he did not recall raising with Dr Beligaswatte the matter of Mr G’s chemotherapy or

recall having a conversation in relation to the difficulty with the protocol. When it

was put to Mr Phatak that on 30 January 2015 he had explained to Dr Beligaswatte

what had taken place on 19 and 20 January 2015 in connection with the discovery of

the protocol error at the RAH, Mr Phatak said he could not recall this. Specifically,

when it was put to him that he had asked Dr Beligaswatte what he was going to do

about it in the context of further treatment of the patient Mr G he said he could not

recall that either. It is odd that Dr Beligaswatte, who had been the main driving force

in connection with the introduction of the protocol at the FMC and who also worked

at the RAH, would not have heard about the error in the RAH protocol between 19

and 30 January 2015. On the other hand, Mr Phatak did not deny having had the

conversation with Dr Beligaswatte and there is no evidence to demonstrate that

Dr Beligaswatte had any knowledge of the error at any time prior to Friday

30 January 2015. That said, he had been a recipient of the email of Mrs To of 20

January 2015. If he read it, he of all people could hardly have failed to determine the

significance of Associate Professor Yong’s indication that twice daily administration

of cytarabine was called for. That he either did not read it, or that its content meant

nothing to him, is evidenced by the fact that later in the week he prescribed the

erroneous cytarabine regimen for Mr Knox.

11.5. Regardless of when it was that Dr Beligaswatte first knew of the protocol error at the

RAH there is no evidence that Dr Beligaswatte shared this revelation with any person

at the FMC until at the earliest Wednesday 4 February 2015. Dr Beligaswatte worked

at the FMC on Monday 2 February and Tuesday 3 February 2015 and did not say

anything to any person about the incorporation of the RAH error into FMC protocols.

When cross-examined about his failure on 30 January to say anything to Mr Phatak

about the fact that the same erroneous protocol was in use at the FMC, he said that his

focus had been to decide what he had to do in respect of the patient Mr G whom he

was seeing that day and that secondly he had been given to understand that the RAH

‘was already investigating this’, but acknowledged that the RAH did not know that

the FMC was using the protocol124. He also acknowledged that this would have been a

good opportunity to let the RAH know about the fact that the error had been imported

to the FMC. 125. He also said that it did not occur to him to let Ms Teh at the FMC

know about the error as he was concentrating on his patient’s needs and he did not 124 Transcript, page 1570125 Transcript, page 1570

101

have ‘any immediate problems in the coming days’126. As far as the patients who to

that point in time he had already treated at the RAH and the FMC in accordance with

the erroneous protocol, that is to say Mr McRae, Mr G, Ms Crannage and Mr Knox,

he said ‘I wouldn’t have remembered all the patients what (sic) I would have treated

in the preceding months’127.

11.6. Dr Beligaswatte told the Court that as he knew that no patient was due to receive

consolidation chemotherapy at the FMC in the immediate future he decided to raise

the issue of the error at an FMC haematology group meeting on Wednesday 4

February 2015. Dr Beligaswatte also told the Court that as a follow up on the meeting

he asked Ms Teh to confirm which patients at the FMC had received erroneous

treatments pursuant to the protocol128. There is some controversy as to whether this

revelation was made at this haematology group meeting or at the following

Wednesday’s meeting. The controversy is fuelled by the fact that Ms Teh who would

have been in attendance at both meetings does not appear to have acted upon the

revelation until at the very earliest Wednesday 11 February 2015 which was the day

of the next meeting. Associate Professor Kuss, the head of haematology, was not at

the meeting of 4 February 2015 as she was away. However, she was at the meeting

on 11 February 2015.

11.7. Regardless of whether or not the issue was formally mentioned at the 4 February 2015

meeting there is support for the proposition that Dr Beligaswatte disclosed the error to

a more senior FMC consultant on that day. I have already mentioned Dr Douglas

Coghlan. Dr Coghlan told the Court that he had no recollection of receiving Mrs To’s

email of 20 January 2015 in which it was said that Associate Professor Yong had

stated that cytarabine should be administered twice daily129. He said that the matter

was first raised with him at approximately 10:25am on Wednesday 4 February 2015

when he was approached by Dr Beligaswatte as they were about to go into the ward

meeting.

11.8. Dr Coghlan told the Court that Dr Beligaswatte told him that after he had returned

from leave the previous week, Dr Beligaswatte had been told by a pharmacist at the

RAH that Associate Professor Yong had identified an error in the consolidation

126 Transcript, page 1571127 Transcript, page 1573128 Transcript, page 1572129 Transcript, page 2433

102

protocol that had resulted in patients being given once daily cytarabine administration

when the intention had been twice daily. Dr Beligaswatte sought advice on what he

should do at that point to which Dr Coghlan asked whether there was any urgent

corrective clinical action that needed to be undertaken. Dr Coghlan said that there

was some discussion with Dr Beligaswatte about the clinical status of affected

patients. Dr Beligaswatte told him that after Associate Professor Yong had detected

the error there had been discussion with other practitioners at the RAH including

Associate Professor Lewis and that they were aware of the error and were taking

action to address it. Dr Coghlan advised Dr Beligaswatte that ‘the system’ needed to

be made aware of what had happened so that an analysis could be undertaken and an

appropriate response be delivered. He therefore advised Dr Beligaswatte to document

everything and told him that the issue should be raised as a matter of high urgency

with Associate Professor Kuss upon her return to work. There was also the matter of

the patients being provided with an explanation as to what had taken place.

11.9. Mr Higham was an inpatient at the FMC at that time. Mr Higham had received his

second cycle of consolidation chemotherapy during January but was in hospital with

afebrile neutropenia. There was discussion between Drs Beligaswatte and Coghlan

about Dr Beligaswatte needing to speak to Mr Higham on the following day.

11.10. Although Dr Coghlan related the conversation with Dr Beligaswatte as having taken

place before the ward meeting on Wednesday 4 February, he told the Court that he

had no recollection of the matter being discussed within the ward meeting itself.

When Dr Beligaswatte was cross-examined by Mr Trim QC on behalf of Dr Coghlan,

he said that he could not recall approaching Dr Coghlan and telling him about the

underdosing issue before the ward meeting and could not recall any of the content of

the discussion as put to him by Mr Trim QC. He insisted that he told the 4 February

meeting and those present at it that he had been informed by one of the pharmacists at

the RAH that there had been an underdosing error and that each relevant consultant at

the RAH was managing their patients accordingly. He told Mr Trim QC that he could

not recollect that this disclosure was actually made privately to Dr Coghlan before the

meeting.

11.11. Dr Beligaswatte told the Court that he told Mr Higham of the error on 5 February

2015. In Mr Higham’s progress notes there is a relevant note timed at 10:15am on 5

103

February 2015130. It appears to be a note made in respect of a consultation between

Mr Higham and Dr Coghlan that day. In the note there is no mention of anything

about an error in Mr Higham’s chemotherapy, but there is a notation to the effect that

further chemotherapy would be discussed with Dr Beligaswatte. There is also a note

timed at 8:30am on 6 February 2015 that refers to a discussion with Dr Beligaswatte

that had taken place the day before. It refers to the ‘stuff up’ (presumably Mr

Higham’s descriptor) regarding the cytarabine dose and Mr Higham needing more as

a result. There is a further notation regarding a discussion with the patient concerning

‘the State-wide protocol error’ and the fact that his family were quite stressed about

that. Mr Higham is recorded as being anxious and angry. It appears, therefore, that

Dr Beligaswatte did speak to Mr Higham on 5 February 2015 and disclosed the error

to him on that occasion. However, that does not mean that Dr Beligaswatte disclosed

the matter to the 4 February meeting at large as distinct from mentioning it to

Dr Coghlan privately prior to the meeting. I think it is more likely that the real

impetus for Dr Beligaswatte speaking to Mr Higham on 5 February was his

conversation with Dr Coghlan on 4 February.

11.12. Mr Higham would undergo his catch-up cycle commencing on 2 March 2015. In the

event, Mr Knox would also undergo a catch-up cycle commencing on 25 February

2015. The cycles for both men involved the correct twice daily dosing. The timing of

and the possible beneficial effect of these additional cycles, if any, was the subject of

commentary which I will deal with in a later section of these findings.

11.13. Associate Professor Kuss was on leave until 18 January 2015. She was also on leave

from 28 January to 2 February 2015 inclusive. Associate Professor Kuss was at a

meeting in Sydney on Wednesday 4 February and Thursday 5 February 2015. She

therefore did not attend the ward meeting at FMC on Wednesday 4 February 2015

which was the meeting at which Dr Beligaswatte said he disclosed the error.

However, Associate Professor Kuss did attend the meeting on Wednesday 11

February 2015. In her oral evidence Associate Professor Kuss recalled that

Dr Beligaswatte was present as was the pharmacist Ms Teh. She said that at that

meeting Dr Beligaswatte told those present that an error had been detected in the

RAH protocol. She said that Dr Beligaswatte explained the significance of the error,

that it had originated in an RAH protocol, that it had been transferred to the protocol

130 Exhibit C55, Tab 8

104

template used at the FMC and that a number of patients had been treated at the FMC

in accordance with that erroneous template. Associate Professor Kuss told the Court

that her reaction was one of great concern and that she immediately recognised the

need to investigate who had been affected and what their current clinical status was.

She asked for the protocol to be withdrawn. Associate Professor Kuss’ position was

that she knew nothing of the error until this meeting. She told the Court that

Dr Coghlan had been at the meeting and although no person at the meeting gave any

indication that they had prior knowledge of the issue, she believed that Dr Coghlan

had been aware prior to the meeting. That of course would align with Dr Coghlan’s

evidence as already discussed. Associate Professor Kuss said that she had been at

work on certain days in January and February 2015 and had worked at FMC on some

days, but no person had drawn the error to her attention.

11.14. Associate Professor Kuss also told the Court that Dr Beligaswatte told her that he had

been made aware of the error on 30 January 2015 which accords with

Dr Beligaswatte’s own evidence. When she asked him why it had taken so long for

the FMC to be addressing the problem, Dr Beligaswatte had told her that his primary

concern had been identifying the affected patients and ensuring patient safety and that

he had been requested to speak to a patient at the RAH. He had spoken to the

pharmacist about the error and had given instructions that if appropriate a top-up dose

of chemotherapy should be offered to the patients.

11.15. Associate Professor Kuss was instrumental in having Ms Teh identify the patients at

FMC who had been affected by the error. At the meeting she instructed Ms Teh to do

this131. She did not believe that Dr Beligaswatte had named all of these patients at the

meeting. The affected persons were Mr Knox, Mr Higham, Ms Crannage and two

others.

11.16. I have seen no written evidence of any formal communication within the FMC about

the discovery of the error prior to 11 February 2015. On this date, by email timed at

11:46pm, Associate Professor Kuss advised a number of individuals within SA Health

of the protocol error which, as she described it, had led ‘to a significant unintentional

reduction in AraC in the consolidation phase of treatment’132. At 10:36am on

12 February 2015 Associate Professor Kuss emailed Associate Professor Lewis at the

131 Transcript, page 2002132 Exhibit C50, page 71

105

RAH forwarding her email of the night before. Her email to Associate Professor

Lewis commented, among other things, on the failure by the RAH to alert the FMC to

the problem and it sought Associate Professor Lewis’ ‘take on the issue’133. It will be

remembered that 12 February 2015 was the day on which Associate Professor Lewis

thawed from his hitherto ‘frozen’ condition.

11.17. I accept Associate Professor Kuss’ evidence that she had no knowledge of the error

until the ward meeting of 11 February 2015.

11.18. Ms Teh told the Court that she found out about the protocol error when

Dr Beligaswatte informed the participants of it at one of their weekly haematology

meetings134. According to Ms Teh, at that meeting Dr Beligaswatte said that there was

an issue in relation to an RAH protocol involving an error in respect of the cytarabine

dose and that the FMC had also experienced the error as well. At that meeting

Associate Professor Kuss asked her to identify the affected patients. As seen,

Associate Professor Kuss corroborates this. Ms Teh said that on the same day she

searched the dispensing history and identified a number of patients. In her evidence

Ms Teh was clearly speaking of the ward meeting of Wednesday 11 February 2015,

not Wednesday 4 February 2015. This is so because there is no doubt that Associate

Professor Kuss had not been present at the earlier meeting. There is no evidence that

Ms Teh acted upon her knowledge of the error prior to 11 February 2015. On that day

she was able to compile and email a list of the patients who had been affected135. This

email was sent to a number of persons within SA Health including Associate

Professor Kuss and Dr Beligaswatte. Dr Beligaswatte for his part sent an email to

Ms Teh on 11 February 2015 attaching the ALLG M15 protocol pointing out the

relevant regimens136. This was sent to her to enable her to update the unit templates.

On the same day a template for what has become known as a top-up consolidation

cycle for Mr Higham was created by Ms Teh and signed by Dr Beligaswatte. It called

for twice daily administration. As indicated I will mention something of the top-up

cycles in due course. The irony of Dr Beligaswatte sending Ms Teh the ALLG M15

study document will not be lost on the reader because this was the very document that

he undoubtedly should have provided to her in July of the previous year when she

133 Exhibit C50, page 71134 Transcript, page 2382135 Exhibit C31a136 Exhibit C47b

106

requested the same from him but was told that in effect nothing existed and that she

should work off the RAH protocol.

11.19. Dr Beligaswatte asserted in his evidence that Ms Teh had been instructed on 4

February 2015 to prepare the list of affected patients. Ms Teh in her evidence rejected

that suggestion saying in effect that she would not have delayed such an important

exercise and have delayed reporting on it until 11 February 2015. In my view it is

more likely that she became aware of the error, as she says, on 11 February 2015,

after she was told Associate Professor Kuss to prepare the list. It is more likely that

she did so on that day and reported on that day. It seems to me highly unlikely that

she would have neglected to perform such an exercise for a whole week and without

somebody being on her case about the delay. I prefer her evidence to that of

Dr Beligaswatte. I find that although Dr Beligaswatte informed Dr Coghlan of the

error on 4 February and informed the patient Mr Higham of the error on 5 February,

he did not inform a ward meeting about the error until Wednesday 11 February 2015.

11.20. I make the following findings:

The error within the FMC protocol template was not recognised as a result of Mrs

To’s email of Tuesday 20 January 2015. This, in part, was due to the fact that

although the email referred to the need for cytarabine to be administered twice

daily, it did not expressly refer to the fact that there was a protocol error relating

to that issue.

Associate Professor Yong was a recipient of Mrs To’s email of 20 January 2015.

There was reference to herself in that email. I find that Associate Professor Yong

should have ensured that the content of that email, or the content of a follow up

email, referred to the identification of an error in the RAH protocol. This may

have at least prompted the recipients of the email at the FMC to check the FMC

protocol template.

There is no evidence that any person at the FMC became aware of the error within

the FMC protocol template until 30 January 2015 when Dr Beligaswatte says he

was told about it. In the intervening period Mr Knox at the FMC was

administered an entire second consolidation cycle in accordance with the

erroneous protocol. Dr Beligaswatte was responsible for that erroneous cycle.

107

Dr Beligaswatte was a recipient of Mrs To’s email of 20 January 2015.

Dr Beligaswatte did not appreciate the significance of the reference to Associate

Professor Yong indicating that there was a need for cytarabine to be administered

twice daily. He of all people should have appreciated the significance.

I find that although Dr Beligaswatte spoke to Dr Coghlan about the error on

Wednesday 4 February 2015, and on the day after spoke to Mr Higham and

disclosed the error to him, Dr Beligaswatte did not disclose the error to the ward

meeting of 4 February 2015.

I find that the error within the FMC protocol template was not formally

communicated to any persons in authority at the FMC until a ward meeting of 11

February 2015. I find that this was manifestly too late.

I find that Ms Teh did not know of the FMC protocol error until the ward meeting

of 11 February 2015.

I find that Associate Professor Kuss did not know of the FMC protocol error until

the ward meeting of 11 February 2015.

12. The circumstances relating to the underdosing of Mr Knox

12.1. I deal with Mr Knox’s circumstances at this point because his second cycle of

consolidation chemotherapy occurred after the protocol had been discovered at the

RAH on 19 January 2015 and after Mrs To’s email of 20 January. Mr Andrew Knox

was born on 13 December 1948 and was therefore still 65 years in November of 2014.

He was diagnosed with AML in late November 2014. Mr Knox has survived despite

relapse. The expert evidence that I will mention in due course tended to suggest that

for a number of reasons Mr Knox could have hoped for a better outcome in relation to

the treatment of his illness. Without going into detail at this point these favourable

circumstances included his age, a lack of comorbidities, the cytogenetics connected to

his AML and molecular factors.

12.2. Mr Knox underwent induction chemotherapy at the FMC, beginning on 27 November

2014. The induction chemotherapy was successful in that Mr Knox achieved a

complete remission.

12.3. Mr Knox then underwent two cycles of consolidation chemotherapy. Mr Knox

underwent the first cycle between 29 December 2014 and 2 January 2015. The

108

prescription for this cycle was based on the FMC protocol template which of course

provided for the erroneous once daily administration. The prescription was signed

electronically by Dr Beligaswatte.

12.4. The Court heard that following his first cycle Mr Knox experienced febrile

neutropenia which required admission to the FMC. However, by 22 January 2015 he

was ready for the second cycle of chemotherapy. The prescription for that second

cycle was signed by Dr Beligaswatte on that day and was in identical format to the

prescription for the first cycle. It provided for only once daily administration of

cytarabine. This cycle commenced on 22 January. This prescription was signed two

days after Mrs To’s email to the effect that cytarabine should be administered twice

daily, the email being prompted by Associate Professor Yong’s discovery of the error

between Friday 16 January and Monday 19 January 2015. That email was sent to the

multiple recipients that included Dr Beligaswatte and Dr David Ross to whom I have

referred earlier and who was also, like Dr Beligaswatte, a haematologist who worked

at both the RAH and FMC. The circumstances surrounding Dr Beligaswatte not

registering the content of Mrs To’s email have been discussed.

12.5. Mr Knox underwent his second cycle of consolidation chemotherapy commencing on

Thursday 22 January 2015. The cytarabine was administered on that day and on 24

and 26 January 2015, that is to say on alternate days. It was administered once daily

notwithstanding the fact that this frequency of administration had been recognised as

erroneous only a matter of days prior. As seen, Dr Beligaswatte himself told the

Court that he did not become aware of the error until 30 January 2015 which was the

last day of his work at the RAH. Dr Beligaswatte told the Court that he did not recall

reading the email of Mrs To of 20 January 2015 and was only shown the email many

months later. This was simply inexcusable and his erroneous prescription for Mr

Knox following the discovery of the error at the RAH and after the receipt of Mrs

To’s email of 20 January despite its inadequacies is especially egregious.

12.6. I have from time to time referred to Dr David Ross. Dr Ross obtained his basic

medical degrees from the University of Adelaide in 1996. Dr Ross is also a PhD

which he obtained from the University of Adelaide in 2009. The topic of his doctoral

dissertation was minimal residual disease in chronic myeloid leukaemia. He has been

employed as a consultant haematologist since 2009. He too is employed by SA

Pathology.

109

12.7. Dr Ross worked at both the RAH and the FMC as a haematologist. He told the Court

that across the course of a year he spent 30% of his time at FMC and 70% of his time

at the RAH. This arrangement began in approximately the second half of 2013.

Dr Ross’ duties at the RAH included diagnostic haematology and the provision of

laboratory services including the supervision of laboratory trainees. His clinical

responsibilities were initially limited to the outpatient clinic, although he had

subsequently been added to the ward roster. At FMC he had responsibility on a

rotating basis for inpatient and diagnostic haematology. He was also involved in

outpatient clinics, primarily focussed on chronic myeloid leukaemia which was the

subject of his PhD. As well, he was involved in connection with Philadelphia-

negative myeloproliferative neoplasms. These were his specialties in July 2014.

12.8. Dr Ross told the Court that he was familiar with the treatment of AML. Asked by his

counsel Mr Besanko as to his familiarity with that disease and the treatment of it he

said:

'My familiarity would be equivalent to any practising clinical haematologist.' 137

However, he said that AML was not his specialty.

12.9. Dr Ross told the Court that the haematology unit at the FMC utilised chemotherapy

protocols and that he knew that they were housed within Excel documents which

effectively contained the chemotherapy prescription. Dr Ross said that at one point he

had developed a protocol for AML but had not been involved in the development of

protocols at the FMC since July 2014. However, he told the Court that he was aware

of how protocols were developed at the FMC at that point in time, explaining that if a

new protocol was proposed on the basis of new information becoming available or

because of a need to change an existing protocol, usually one consultant would take

responsibility for that task. The ‘published protocol’ based on the publication of new

results would be converted into one of the Excel templates which reduced the protocol

to a concise prescription for the patient. That process is undertaken in conjunction

with a departmental pharmacist. His understanding was that once the consultant and

pharmacist had prepared the template it would be circulated to the rest of the

department for comment. Any comments were then responded to and a new version

137 Transcript, page 1174

110

was prepared if appropriate. The resulting document would then be tabled at the end

of a departmental meeting138.

12.10. Dr Ross was asked about protocol development at the RAH. He said that he had not

been involved in the development of any protocol at the RAH since July 2014. He

told the Court of his understanding of how protocols were housed at the RAH and of

the differences between RAH procedures and those at the FMC. His understanding of

RAH protocol development was that a disease group leader or leaders would take on

the job of reviewing protocols. Once a protocol was amended by a consultant or the

consultants in question, it would be circulated among the ‘disease group’ for

comment. Once the disease group had agreed on a protocol it would be presented in a

department protocol meeting139.

12.11. Dr Ross is a member of the ALLG. Although Dr Ross was not on the AML

subcommittee of the ALLG, he had been aware of discussion among members of the

ALLG concerning a reduction of the dose of cytarabine for elderly AML patients in

the consolidation phase of chemotherapy. He knew that there was discussion within

the ALLG about standardising approaches to induction consolidation chemotherapy140.

12.12. I mention this in some detail because Dr Ross would be the recipient of relevant

emails both at the time of the promulgation of the new and erroneous protocol at the

RAH in July 2014 as well as the email of Mrs To of 20 January 2015 in which the

assertion was made that Associate Professor Yong wanted to bring to the attention of

the recipients that cytarabine was to be given twice daily. The other relevant matter

as it affects Dr Ross is that he saw Mr Knox on 22 January 2015 which was the day of

Mr Knox’s first administration of cytarabine in his second cycle. He also saw

Mr Knox on 24 January 2015 which was the second day of cytarabine administration

as part of that second cycle. On neither day did Dr Ross identify any irregularity in

the cytarabine administration notwithstanding the fact that he was a recipient of

Mrs To’s email of 20 January 2015 in which it was stipulated that cytarabine was to

be administered twice daily.

12.13. Dr Ross had not been responsible for either of Mr Knox’s consolidation

chemotherapy prescriptions. However, it is to be noted that at the FMC in August

138 Transcript, page 1175139 Transcript, page 1177140 Transcript, page 1178

111

2014 he had been the authorising haematologist in respect of the consolidation

chemotherapy for one of the ten affected patients, a Ms Mc. That prescription was

written on the erroneous FMC template prescribing once daily administration.

Dr Ross explained that at the FMC they simply used the electronic template. When

shown the prescription for Ms Mc by his counsel Mr Besanko, Dr Ross said that he

was now aware that it contained an error but there was nothing that would have

immediately stood out as unusual. He appreciated now, of course, that the template

should have provided for twice daily administration and not once daily

administration141. It is arguable that the involvement of Dr Ross in the prescription for

Ms Mc in 2014 was an opportunity to have corrected the FMC protocol, but Dr Ross

said that he did not identify that the frequency of the dose of cytarabine as recorded

on the prescription template should have said twice daily. Dr Ross said:

'Well, clearly I deeply regret not having detected that there was an error in the document but I was focussing my attention on checking the variable parts of the protocol which are those that pertain to the specific patient. Since this is an approved departmental protocol which has already gone through a checking process I am not consciously reviewing the fixed elements of the protocol.' 142

12.14. Dr Ross told his counsel Mr Besanko that as far as consolidation chemotherapy in

2014 and 2015 was concerned he knew that generally speaking the cytarabine

regimens for consolidation in patients over the age of approximately 55 to 65 years

would involve cytarabine of approximately 1g/m2 per day, ‘typically on six

consecutive days or the equivalent dose divided twice daily on alternate days’. In the

case of Ms Mc, his intention had been simply to give her the regimen that the FMC

Haematology Department had apparently agreed upon and which was reflected in the

template document. Asked by his counsel whether he should have identified that the

frequency should have been described as twice daily, he said:

'I clearly wish that I had, but I'm not certain that I should have done given the nature of the document.' 143

12.15. Thus it was that the error was not identified in August 2014.

12.16. Dr Ross told the Court that he had no recollection of any involvement in the

management of Mr Knox. However, it is apparent from Mr Knox’s progress notes

that on Thursday 22 January 2015 he saw Mr Knox and determined that there would

141 Transcript, page 1189142 Transcript, page 1190143 Transcript, page 1191

112

be no change to the current plan in respect of his treatment. There is a specific note,

‘continue c Chemotherapy’ with a reference to that note being the first day of that

chemotherapy144.

12.17. The note relating to Dr Ross’ attendance upon Mr Knox on 24 January 2015, which is

decipherable as having occurred at 9am, stated that the plan was to continue ‘as per

protocol’145.

12.18. Given that Dr Ross saw Mr Knox on the first two days of his cytarabine consolidation

chemotherapy, and that Dr Ross had been a recipient of Mrs To’s email of 20 January

specifying twice daily administration, it called for an explanation as to why Dr Ross

would not have recognised on either or on both of the two occasions on which he saw

Mr Knox that Mr Knox was not receiving cytarabine chemotherapy in accordance

with Mrs To’s email.

12.19. Dr Ross acknowledged that he was a recipient of Mrs To’s email of 20 January 2015.

He said he did not recall receiving or reading it but that it was likely that he read it

in January or February 2015 given that it was his usual practice to read departmental

correspondence146. Asked as to whether it was likely that he read the attachment to

Mrs To’s email which was the updated and corrected RAH protocol, he said it would

not be likely because it would not have appeared as being particularly relevant to his

practice147. The point needs to be made, however, that one would not have needed to

read the attachment to determine that the protocol called for twice daily

administration because it was spelt out in the body of Mrs To’s email. Moreover, it

said that Associate Professor Yong, who was a colleague of Dr Ross at the RAH,

wanted to bring that requirement to the recipients’ attention, including of course the

attention of Dr Ross who was one of those recipients.

12.20. Asked by me whether he may have reviewed Mr Knox’s prescription if he had taken

on board the information contained in Mrs To’s email, he responded that it was

unlikely that he would have looked at Mr Knox’s prescription because of the use of

the pre-printed proforma template and:

144 Exhibit C43, page 64145 Exhibit C43, page 67146 Transcript, page 1197147 Transcript, page 1197

113

'Therefore as long as any changes to the protocol are reflected in that document, there is no reason to go and check it in subsequent months.' 148

12.21. Dr Ross was asked whether he may have reviewed Mr Knox’s prescription if Mrs

To’s email had spelt out in clear terms that the original protocol had been in error by

specifying once daily when it should have specified twice daily. To this Dr Ross said

that if the matter had been raised as an error in departmental procedure it was likely

that it would have been in the forefront of his mind. The following question and

answer were given:

'Q. So any patient possibly affected by the error or by the correction of the error, such as Mr Knox, you might have reviewed his prescription on 24 January.

A. In the circumstance if that had been raised as an error near to that time, then, yes.' 149

This to my mind classically illustrates the point that Mrs To’s email was inadequate

because it did not draw pointed attention to an actual error. The reality is that

Associate Professor Yong should have seen to it that it did.

12.22. It will be remembered, of course, that Mrs To’s email originated from the RAH and

that its content was expressed in an RAH context. This would raise a question as to

whether or not a recipient would have identified that the email might relate to FMC

protocols as well. Dr Ross was asked about this issue. At first he stated that he was

aware that both hospitals were meant to be using the same protocol which was aligned

with the agreed ALLG procedure150. Dr Ross then said that some protocols were

common to both hospitals but not all and that at the time of receiving the email he

would not have known that the protocol was one that was used at both the RAH and

the FMC and would have needed to check151. However, Dr Ross ultimately agreed

with the proposition put to him by Mr Griffin QC that if he had read Mrs To’s email

he would have been aware that the protocol referred to in the email may have had

application at the FMC as well152.

12.23. Dr Ross said it did not occur to him to check Mr Knox on day one of his

chemotherapy to see whether the protocol was correct or not, but said that there was

148 Transcript, page 1199149 Transcript, page 1200150 Transcript, page 1200151 Transcript, page 1203152 Transcript, page 1203

114

nothing in Mrs To’s email to indicate to him that it necessitated a change to practice at

the FMC153.

12.24. One matter that Dr Ross did acknowledge which is important is that if a person had

shown him a document and had said that there was going to be once daily

administration of cytarabine on days 1, 3 and 5, and that this was an unchecked

protocol which he had never seen before, he expected that he would have questioned

that and would have wanted a direct explanation as to why it departed from what he

would normally have expected154. Dr Ross agreed with counsel assisting Ms Kereru

that cytarabine dosages of 1g/m2 daily on every second day is quite untoward; saying:

'Looking at it now it is clearly unusual.' 155

This was so having regard to the choices of twice daily administration on alternate

days or continuous infusion, neither of which are reflected in the erroneous protocol.

He said that it had not registered with him in the case of Ms Mc in 2014 that he had

been signing off on something that was irregular. This was so notwithstanding the

fact that he would have received Associate Professor Lewis’ email on 19 July 2014

setting out bd administration. Dr Ross said he had no recollection of reading

Associate Professor Lewis’ email and although he treated patients with AML, he

would have expected that the changes to a protocol would be correctly documented.

He expected that he probably did read the email and, asked the obvious question as to

why he would not have picked up the irregularity when he had come to sign the

prescription for Ms Mc, he said:

'That relies both on an infallible memory and on the assumption that I place no trust in an approved departmental document.' 156

12.25. To summarise, in July 2014 Dr Ross (a) did not identify any irregularity within the

correspondence that had been sent by Mrs To and Associate Professor Lewis, (b) that

when he signed off on the prescription for Ms Mc he had simply relied on the

proforma FMC template, (c) that when he saw Mr Knox on two occasions in January

2015 he did not review Mr Knox’s prescriptions, but probably would have done so if

he had paid proper regard to the contents of Mrs To’s email of 20 January 2015 in

which twice daily administration had been directed by Associate Professor Yong.

153 Transcript, page 1206154 Transcript, page 1208155 Transcript, page 1218156 Transcript, page 1220

115

12.26. It will be seen that what happened in respect of Mr Knox is highly relevant because it

demonstrates the poor quality of clinical governance across two major teaching

hospitals in this State and it also reveals a number of other worrying circumstances

such as the fact that clinicians do not read important emails. Further, clinicians seem

to have a tendency to prescribe chemotherapy by reference to what is in effect a

recipe rather than by having regard to the scientific principles underlying the drug

they are prescribing and to the clinical necessities of the patient. This set of

circumstances owes itself to poor communication, poor clinical governance and a

failure by clinical staff to read important communications.

12.27. In the light of the fact that the protocol error had already been identified at the RAH,

and should have been recognised at the same time at the FMC, the fact that Mr

Knox’s second cycle of consolidation chemotherapy miscarried is completely

unforgivable. There are no mitigating circumstances whatsoever.

13. Was Mrs   Pinxteren ever advised of the error ?

13.1. This subject was the topic of some controversy.

13.2. It will be remembered that Mrs Pinxteren underwent only one cycle of consolidation

chemotherapy which concluded on Saturday 17 January 2015. The second cycle of

consolidation chemotherapy was not undertaken because she did not recover

sufficiently from the first cycle and by early March 2015 it was established that she

had relapsed. Her haematologist, Dr Hiwase, was overseas between 18 February and

4 March 2015.

13.3. Dr Hiwase was a recipient of Mrs To’s email of 20 January 2015 in which Associate

Professor Yong’s indication that cytarabine should be given twice daily was reported.

Notwithstanding the receipt of that email Dr Hiwase told the Court that he did not

recall receiving it or reading it and he did not know whether it was likely that he read

it in either January or February 2015157. He told the Court that he did not know when

it was that he first became aware that there had been an error in the protocol, although

he thought that there had been some discussion in the haematology unit about the

error prior to him going overseas in February 2015.

157 Transcript, page 1331

116

13.4. It is clear that by 26 February 2015 while Dr Hiwase was still away, he was aware

that his patient Mrs Pinxteren’s consolidation treatment had been the subject of the

error. On that day Professor To sent an email to Dr Hiwase the topic of which was

the error and its possible impact upon the treatment of the affected patients, including

his patient Mrs Pinxteren. Professor To advised Dr Hiwase that Mrs Pinxteren was

still cytopenic after her underdosed consolidation and would be having a bone marrow

biopsy the following Monday. As a result, her second proposed consolidation cycle

which was booked to start on that day was cancelled as her blood counts had shown

no sign of recovery at that point. Professor To’s email told Dr Hiwase that he had not

informed Mrs Pinxteren and that this would not happen until the result of her bone

marrow biopsy was known. In that email Professor To requested Dr Hiwase to

inform Mrs Pinxteren of the error. On the same day Dr Hiwase responded to

Professor To by way of email.

13.5. According to Dr Hiwase, Professor To’s email was the first he became aware that

Mrs Pinxteren’s treatment specifically had been the subject of the error158. Dr Hiwase

told the Court that his reaction to that news was one of discomfort. When he returned

to work he said that he had checked the pharmacy script for Mrs Pinxteren because he

could not believe that one of his patients had been involved in the error.

13.6. It appears that Dr Hiwase had seen Mrs Pinxteren on 2 February and 16 February

2015. There is no suggestion that on either of these occasions he had raised with

Mrs Pinxteren the error. He told the Court that he was not aware of the existence of

the error when he met with Mrs Pinxteren on 16 February 2015.

13.7. It appears that Dr Hiwase next saw Mrs Pinxteren on 11 March 2015 probably in his

clinic room. He did not recall who was present on that occasion. Although he said

that Mrs Pinxteren’s husband was usually present, he could not positively attest to his

presence on this particular occasion. By then it had been established that

Mrs Pinxteren had relapsed. Dr Hiwase told the Court that at this consultation he told

Mrs Pinxteren of the error and tendered an apology for it. There is a note of this

consultation in Mrs Pinxteren’s outpatient progress notes159 in which there is specific

reference to Mrs Pinxteren being informed about the issue of the underdosing ‘due to

clerical error’, with the rider as follows, ‘but explained that in her case it did not

158 Transcript, page 1333159 Exhibit C46, page 45

117

matter much’. Also on that same page of the progress notes is a further note which

states as follows:

'Addendum (4) I apologise the patient for mistake (sic)'

13.8. The legitimacy of this note and in particular its reference to Mrs Pinxteren being

informed about the error and it not mattering much, as well as the note of the apology,

was contested. Mr Griffin QC on behalf of Mr William Pinxteren urged me to find

that Mrs Pinxteren was not told of the error at that point in time or at all, that no

apology was tendered and that the further conclusion should be reached that any

notations to the contrary are a fabrication.

13.9. Dr Hiwase acknowledged that the ‘addendum’ in which the apology is recorded was

not written on 11 March 2015 when he had explained the underdosing error, but was

written after he tendered an apology for the second time on an occasion that he could

not exactly recall160.

13.10. Dr Hiwase gave evidence that he had been involved in telephone conversations with

both Professor To and Professor Bardy. In the conversation with Professor To,

Professor To had asked him whether he had told his patient about the underdosing

error. Dr Hiwase had responded affirmatively and when asked as to whether he had

explicitly apologised for the error he said that he did not remember the apology

verbatim, but that he had been apologetic. In his conversation with Professor Bardy,

Professor Bardy had asked him whether he had told the patient about the error and

whether he had apologised, to which Dr Hiwase responded by saying that he had been

apologetic, but could not remember his precise wording. Professor Bardy then asked

Dr Hiwase to apologise when he returned from an interstate trip. Dr Hiwase told the

Court that following these conversations Dr Hiwase tendered his apology at a further

consultation with Mrs Pinxteren.

13.11. In Mrs Pinxteren’s outpatient progress notes there are notes of further consultations

over the following weeks, but there is no notation of any apology within those notes

even though Dr Hiwase has seen her repeatedly. That obviously raises a question as

to why if there had been a further consultation at which an apology had been tendered,

there would not be a separate notation of that as distinct from an ex post facto notation

160 Transcript, page 1338

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of an apology appended to an already existing notation, namely the progress note of

11 March 2015.

13.12. In cross-examination Dr Hiwase rejected the suggestion that he had neither explained

the chemotherapy error to Mrs Pinxteren nor had apologised for it at any point in

time. One matter that Dr Hiwase did draw my attention to, and in respect of which

there does not appear to be any doubt, is that during the consultation of 11 March

2015 at which he said he explained the nature of the underdosing, he had drawn on a

piece of paper pictures that illustrated the process of cell recovery. He did this in an

endeavour to explain the process by which Mrs Pinxteren’s blood count had not

recovered since her consolidation chemotherapy161. As well, he explained in some

detail what he meant by the underdosing not mattering much in her case. He said that

he had explained to her that blood counts normally recover within four weeks of

chemotherapy and that the next cycle of chemotherapy is given when the blood counts

normalise, but that in Mrs Pinxteren’s case her blood counts were very low such that

she required platelet and red blood cell transfusions. This meant that in her case the

underdosing ‘did not matter much’ because even with that half dose her blood count

was still low after eight weeks, meaning that if she had been given a higher dose it

would have led to more complications such as even lower blood counts and severe

infections. It is true that Mrs Pinxteren’s blood counts had not recovered to a point

where she was able to undergo a second cycle of chemotherapy. That Dr Hiwase

would want to mitigate the damage of the error in the eyes of Mrs Pinxteren and her

husband does have a ring of truth. In addition, it seems plain that Mrs Pinxteren’s

single but erroneous cycle did have an effect on her. She failed to recover from it

before a relapse was identified.

13.13. However, evidence was given by Mr William Pinxteren, Mrs Pinxteren’s husband,

that he was normally present at consultations that his wife had with Dr Hiwase and

that he and his wife were never told of any error nor were tendered any apology about

anything. There seems little doubt that Mr Pinxteren would have been present on the

occasion of 11 March 2015 because he said he was present when Mrs Pinxteren was

told she had relapsed and he also recalled Dr Hiwase drawing a diagram. I find that

Mr Pinxteren was present at the consultation of 11 March when Dr Hiwase told his

wife that she had relapsed. However, Mr Pinxteren was adamant that Dr Hiwase

161 Transcript, page 1337

119

never said anything about a chemotherapy error or tendered an apology for anything

at any time. He maintains that he did not know anything about any error until after

his wife had died. Also, his wife never mentioned anything to him about an error

which would tend to negate the possibility, although not entirely, that Mrs Pinxteren

may have been told about the error on an occasion when only she and Dr Hiwase were

present. As well, the Pinxteren’s children, Mr Leon Pinxteren and Ms Wendy Cherini

are both adamant in their respective witness statements162 that their mother was at all

times completely open with them about her disease and treatment and that they were

never made aware by their parents about any chemotherapy error. They both assert

that if their mother had been advised of any error in her treatment they would have

been told about it. They assert, as their father also asserts, that the first they were

made aware of an error in treatment was when their father received a letter from SA

Health offering compensation. Mr Leon Pinxteren asserts:

‘Mum never withheld anything from me in relation to her condition or her treatment. Anytime that she received results she would talk to me about them. I just do not accept that she was ever told about this under dosing of medication’.163

However, he also asserts,

‘Mum and dad were never the best, at times, in understanding what was going on and sometimes got confused about what was being discussed, that’s why we were always fully engaged in what was happening’.

There is no suggestion that either Leon Pinxteren or Wendy Cherini were present on

11 March 2105 when Dr Hiwase told Mrs Pinxteren that she had relapsed. However,

an inference is available from their evidence that if Mrs Pinxteren had been told of the

error, both of them, or at least one of them, would have known about it.

13.14. If as has been argued by Mr Griffin QC on behalf of the Pinxteren family the error

was never disclosed to Mr or Mrs Pinxteren and that no apology was ever tendered by

Dr Hiwase, it would mean that Dr Hiwase has fabricated that part of his evidence in

which he says that he did. As bad if not worse, it would also mean that Dr Hiwase

fabricated notations to the contrary in Mrs Pinxteren’s outpatient progress notes.

Mr Griffin QC urges me to make findings accordingly. Dr Hiwase’s counsel, Mr

Trim QC urges me not to make those findings.

162 Exhibits C4 and C5 respectively163 Exhibit C4, page 5

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13.15. To my mind it is clear that the issue as to whether or not Mrs Pinxteren was advised

either in general terms about an error in her treatment or specifically about the fact

that she should have received twice daily administration instead of once daily is a

relevant circumstance surrounding Mrs Pinxteren’s ultimate death from the disease

for which she was being treated. Whether any apology was tendered to her and/or to

her husband is also a relevant circumstance. Therefore, it is open for the Court to

make findings regarding those issues.

13.16. In a letter to Mrs Pinxteren’s general practitioner, Dr Mark Vawser, apparently typed

on 1 April 2015 following a further outpatient clinic on 30 March, Dr Hiwase

explained in considerable detail Mrs Pinxteren’s clinical course, but there is no

mention of any chemotherapy error. Indeed, the one single cycle of consolidation

therapy is described in terms, namely ‘intermediate dose cytarabine D1-3 daily dose’

which would be consistent with a single dosage but on three consecutive days. This

prompted Mr Griffin QC to ask the Court also to find that Dr Hiwase had deliberately

refrained from identifying in the letter any irregularity in Mrs Pinxteren’s treatment

and that this circumstance supported the notion that he had refrained from informing

Mrs Pinxteren and her husband about the error. I add here that there is nothing in the

outpatient progress note relating to the 30 March clinic about the error or any apology

for an error.

13.17. Dr Hiwase said in evidence before this Court that it did not cross his mind to include

reference to the error in his letter to the GP. He denied that he omitted reference to

the error because he did not want the GP to know about it. He acknowledged that he

should have included reference to the issue in the letter and that its absence was

regrettable164. He denied that his reference to daily dosing on days 1 to 3 was

deliberately misleading but acknowledged that it was incorrect165.

13.18. The allegation that Dr Hiwase did not disclose and explain the error to Mrs Pinxteren

nor apologise but subsequently fabricated notations within her progress notes to the

contrary is an extremely serious allegation to make. In my view findings along those

lines would need to be made on cogent evidence in support. I acknowledge of course

that findings to that effect would be made on the balance of probabilities, but I am

also mindful of the principles annunciated by Dixon J in Briginshaw v Briginshaw

164 Transcript, pages 1348-1349 and 1390165 Transcript, pages 1366-1367

121

(1938) 60 CLR 336. A proper reading of Briginshaw does not mean that I would

have to be satisfied beyond reasonable doubt before I made any such findings, but

having regard to the serious nature of such findings and their possible consequences I

would need to be satisfied to a high degree of satisfaction and to ensure that the

findings were not based on questionable evidence.

13.19. There is, I accept, a certain inherent unlikelihood in a responsible medical practitioner

falsifying progress notes, but of course it would not be entirely out of the question.

Be that as it may, the evidence that Dr Hiwase gave to the effect that his prescription

was primarily based on his unquestioning belief that the RAH protocol was accurate

and correct but that one element of his thinking behind the prescription that he wrote

for Mrs Pinxteren was the need to keep her dosages of cytarabine to a minimum

having regard to her clinical circumstances, is inherently credible. Inherently credible

also is that Dr Hiwase might have formed a belief that in Mrs Pinxteren’s case the

underdosing per se would not have had a significant adverse impact, especially as she

had failed to recover from that cycle of chemotherapy. The notation to the effect that

the underdosing did not matter much would be consistent with such a mindset at the

time. It would not be surprising, therefore, that Dr Hiwase would explain the error in

terms that may not necessarily have taken on a high degree of significance in the

minds of Mr or Mrs Pinxteren. It is possible that Dr Hiwase minimised the error to

such an extent that to a large degree its significance was lost in the minds of Mr and

Mrs Pinxteren. Evidence of such minimisation is afforded by his use of the word

‘clerical’ to describe the nature of the error, a descriptor that to my mind was

nevertheless wholly inappropriate. This might explain why Mr Pinxteren has no

recollection of any discussion about an error or of any apology for an error. I am also

mindful of the possibility that the chemotherapy error has had such public ventilation

since the death of his wife that its significance in Mr Pinxteren’s mind may have been

substantially enhanced since the events of March 2015. It may have taken on a

completely different level of significance than what it had at that time. Furthermore,

in assessing the demeanour of Dr Hiwase I detected nothing to suggest an attitude of

evasiveness or lack of candour. It will be remembered that he candidly acknowledged

a number of shortcomings in relation to his performance including his failure to

identify the error in the protocol and his failure to describe or even mention the error

in his letter to Dr Vawser.

122

13.20. I am mindful of the support that the statements of Mr William Pinxteren’s son and

daughter lend to the notion that their mother was not told of the chemotherapy error,

but I am also obliged to have regard to Mr Leon Pinxteren’s assertion within his

statement that his parents had a limited ability to understand what was going on and

were sometimes confused about what was being discussed. If, as is possible,

Dr Hiwase downplayed the error and its significance and had found it necessary to

draw a diagram to illustrate the point that the error did not matter much and to

demonstrate why it was that Mrs Pinxteren had not recovered the from the first

consolidation cycle, it would not be surprising that both Mr and Mrs Pinxteren

regarded any kind of error, especially if described as clerical, as having very limited

overall significance and perhaps not have been worth mentioning.

13.21. For all of the above reasons I am not satisfied on the balance of probabilities that

Dr Hiwase failed to tell Mrs Pinxteren of the error or that he failed to apologise. I am

not satisfied on the balance of probabilities that Dr Hiwase fabricated any notations in

the progress notes. I am not satisfied on the balance of probabilities that Dr Hiwase

deliberately refrained from mentioning the chemotherapy error in his letter to

Dr Vawser. In short, I do not make any findings one way or the other about those

issues.

13.22. My view that I do not need to make any finding about this issue is illustrated by

reason of the fact that knowledge on Mrs Pinxteren’s part that there had been an error

could not in any way have affected her further treatment. It was not as if

Mrs Pinxteren could have been given a second cycle of consolidation chemotherapy,

or a so-called catch-up round of consolidation chemotherapy. This is so because she

simply failed to recover from the first cycle. That was then complicated by the fact

that she relapsed. Accordingly, the issue as to whether or not Mrs Pinxteren was told

about the error on 11 March 2015 or at any other time has limited materiality.

13.23. However, there is one matter in connection with the manner in which the Pinxteren’s

were dealt with that should not go unmentioned. I would regard the word ‘clerical’, if

in truth it was used by Dr Hiwase to describe the error, as a highly inappropriate

description of the nature of the error. While the origin of the error might have

justified such a characterisation, that was so only while the error sat and remained

within the pages of the protocol. In reality it would have clinical consequences that

were anything but clerical. The fact of the matter was that patients were treated

123

incorrectly and not in accordance with an agreed standard. They were treated in

accordance with a standard that was not known to medicine. Regardless of its impact

on an individual patient’s wellbeing, it was a serious clinical error in treatment.

14. Mr   McRae is advised of the error

14.1. On 6 March 2015 Dr Anya Hotinski, a leukaemia fellow at that time, informed

Mr McRae in the presence of his family of two important matters, firstly that he had

probably relapsed and secondly that he had been subjected to the frequency error.

Associate Professor Lewis told the Court that he had asked Dr Hotinski to attend to

that task. As it so happened Associate Professor Lewis was that day enroute to

Sydney. I agree with Associate Professor Lewis’ acknowledgement in his evidence

that it was a significant error to have asked a relatively junior medical practitioner

who had not in any way been responsible for Mr McRae’s underdosing not only to

advise a patient of that underdosing, but also to convey the devastating news that the

patient had relapsed. Associate Professor Lewis acknowledged, appropriately, that he

feels ashamed and embarrassed at having done so. Indeed, it smacks of a complete

abdication of responsibility and of an avoidance of a difficult issue due to a lack of

fortitude. Clearly, Mr McRae and his family should have been told about this earlier

and it is no answer for Associate Professor Lewis to say that he had simply frozen.

14.2. Mr McRae and his family members were unsurprisingly upset by the receipt of this

two pronged piece of information, and it is also not surprising that Dr Hotinski herself

became distressed at having to perform a task which was not hers to perform.

14.3. The circumstances in which this unfolded are as follows. Dr Hotinski endeavoured to

locate Associate Professor Lewis as during her meeting with the McRae family she

was unable to answer the many questions that they had. As indicated above,

Associate Professor Lewis was unavailable on that day. Dr Hotinski asked Associate

Professor Yong to attend the meeting. Associate Professor Yong who did attend the

meeting told the Court that Dr Hotinski was very distressed and very upset, her stated

concern being that Mr McRae and his family had many questions, were very

distressed and that Dr Hotinski could not realistically deal with the situation166.

Associate Professor Yong told the Court that she had no knowledge of Mr McRae’s

circumstances or the course of his disease and only found out about those matters

166 Transcript, page 1794

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when Dr Hotinski asked her for assistance. Associate Professor Yong agreed with the

proposition that it was highly inappropriate for a relatively junior doctor to be tasked

with telling a patient that he was relapsing and, as well, and at the same time, to have

to tell the patient about an error affecting his treatment167.

14.4. When Associate Professor Yong attended she told Mr McRae and his family that the

underdosing error may not have made any difference. There was also a discussion as

to the nature of further treatment that might be provided to him in the coming weeks.

Associate Professor Yong also informed Mr McRae and his family that the discovery

of the frequency error had been due to Associate Professor Yong’s own initiative.

14.5. The day after this meeting Professor Bik To sent an email to Associate Professor

Lewis advising him that Mr McRae had been very upset when told about the

underdosing. There is also mention in the email of Dr Hotinski becoming distressed

herself and of Associate Professor Yong’s having to see the patient as a result. This

email forecast a number of matters that Associate Professor Lewis would have to

consider and explain when he came to see Mr McRae himself, a matter which

Associate Professor Lewis as the head of the haematology unit and the person

principally responsible for the error, should have anticipated. Included among the

issues that Professor To said that Associate Professor Lewis would have to deal with

were the provision of an explanation of the whole event, whether Associate Professor

Lewis could have arranged another consultant to see Mr McRae given that Associate

Professor Lewis had been unable to see him, the nature of the treatment plan from that

point forward and whether azacitidine treatment would be offered or whether if

remission was achieved again he would be offered a transplant.

14.6. Accordingly, Associate Professor Lewis personally saw Mr McRae on 13 March

2015. At this meeting Mr McRae’s relapse was confirmed and the treatment error

was discussed. The nature and origin of the treatment error was openly discussed.

14.7. One matter that was put to Associate Professor Lewis in cross-examination was

whether he had settled on what was referred to as a ‘watch and wait’ policy for

Mr McRae, meaning that one would wait and see how Mr McRae responded to

treatment, and that he had been trying to determine the best time to raise the issue of

underdosing with Mr McRae and his family. Associate Professor Lewis said that was

167 Transcript, page 1795

125

possible. It will be noted that the RAH had known about the error on Monday 19

January. On any level, the delay in informing Mr McRae was unacceptable. So was

the manner in which Mr McRae and his family were informed.

14.8. At the 13 March meeting Mr McRae was taken through his treatment possibilities.

Azacitidine therapy was selected. There is no suggestion that this treatment was

inappropriate. There was no possibility of Mr McRae having a catch-up round of

chemotherapy as he had relapsed.

14.9. There are three further matters I should mention. Firstly, I observe that in

Dr Hotinski’s note of the meeting with the McRae family she recorded that in respect

of the underdosing error she had said to the family ‘I am unsure if this contributed to

the relapse but of course this is a possibility’168. Professor Gibson, the independent

expert who was called to testify as to the possible impact of the error on the individual

patients, stated in evidence that he believed that to have been a reasonably honest

statement169 and not an unreasonable way of looking at the matter170.

14.10. Secondly, by letter dated 27 February 2015 Dr Hotinski had informed Mr McRae’s

general practitioner, Dr Chia, that she was concerned that Mr McRae had relapsed.

Within that letter there is no reference to the dosing frequency error, but I do not

suggest that there is anything sinister adhering to its absence in this instance.

14.11. Thirdly, I did not trouble Dr Hotinski to give evidence in the inquest as I do not

believe she had anything to answer for.

15. Mrs   Bairnsfather is advised of the error

15.1. This subject matter was encapsulated in a letter that was written to Mrs Bairnsfather’s

general practitioner, Dr Andrew Wilson, by Dr Noemi Horvath, a consultant

haematologist at the RAH. The letter is apparently dated 4 March 2015 following a

clinic of that day. The letter indicates that Dr Horvath had informed Mrs Bairnsfather

that because of an error in the RAH AML protocol her consolidation treatment

included a lower dose of cytarabine than she should have received. Dr Horvath goes

on to say in the letter that she did not know whether this was an important factor in

the outcome. She said:

168 Exhibit 12C, Volume 4169 Transcript, page 205170 Transcript, page 206

126

'It is possible that if she had received the full dose, she would have maintained her remission and recovered her blood count sooner. It is also possible that she would have developed even more severe and more prolonged cytopenia and become more unwell. Carol took this information on board very calmly.'

15.2. There is no reason to doubt that this was the advice that was tendered to

Mrs Bairnsfather by her consultant haematologist. The content of that letter was

shown to Professor Gibson in the course of his evidence for his comment. I did not

understand Professor Gibson to be critical of the content of that letter.

15.3. In the event there does not appear to be any basis for concluding that delay in

informing Mrs Bairnsfather of the error impacted on her outcome. Mrs Bairnsfather

only underwent the one cycle of consolidation chemotherapy. Having regard to her

response which involved a suspicion that she had relapsed and had displayed

myelodysplastic syndrome following chemotherapy, notwithstanding remission, a

second cycle of consolidation chemotherapy was not indicated in any event. Rather,

Mrs Bairnsfather was administered a course of azacitidine.

16. Mr   Higham is advised of the error

16.1. I have referred to Dr Beligaswatte’s attendance upon Mr Higham on 5 February 2015

in which Dr Beligaswatte informed Mr Higham of the error. A further meeting was

conducted on 16 February 2015. This meeting was attended by Dr Beligaswatte,

Associate Professor Kuss, other clinicians, Mr Higham, Mr Higham’s wife,

Mr Higham’s son and Mr Higham’s daughter. This meeting was the subject of an

audio recording by Mr Higham’s son. It is not necessary for me to deal with anything

that specifically arises from that meeting, although there does not appear to have been

any express mention of the fact that the error involved the frequency at which

cytarabine had been given.

16.2. On the same day of this meeting Dr Beligaswatte wrote a letter to Dr Christine

Brown171 who was Mr Higham’s general practitioner. The letter makes reference to

the family meeting of that day, the main purpose of the meeting being a discussion of

the implications of an inadvertent underdosing of cytarabine which occurred during

Mr Higham’s consolidation cycle. The letter makes reference to Dr Beligaswatte’s

discussion with Mr Higham on 5 February 2015. In this letter Dr Beligaswatte

asserted as follows:171 Exhibit C11a, pages 9-10

127

'The optimal dose of cytarabine in consolidation has been extensively debated in the literature. Despite multiple clinical trials addressing this issue over the last several decades there is no uniformly accepted standard of care. As such we pointed out to Bronte that there is no evidence that his leukaemia control would have been compromised.'

There is then reference to a recommendation that Mr Higham undergo an additional

cycle of consolidation chemotherapy, the so-called catch-up round. The additional

cycle was described in terms that tended to suggest that this involved a simple matter

of administering a dosage of cytarabine that would bring the total dose up to the

amount of cytarabine that was intended in the first place. Insofar as that suggestion

was supported by scientific grounds, this is a matter that is by no means certain.

16.3. Another relevant aspect of the letter is that although it refers to inadvertent

underdosing, it does not refer to the error having stemmed from incorrect frequency of

dosing. It does not refer to the fact that Mr Higham’s intended frequency of dosing

had been twice daily and not once daily as had been administered. A person not

familiar with the requirements of consolidation chemotherapy for AML in terms of

frequency of dosage in my view would be likely to interpret this letter as asserting

that the error was in respect of dosage magnitude rather than frequency. As far as the

use of the expressions ‘optimal dose’ is concerned, as will be seen the literature does

not support the contention that there is any serious debate relating to frequency of

administration. True it was that there had been some academic opinion expressed as

to optimal dose, particularly as it related to efficacy versus toxicity, a matter to which

I have already referred. However, the literature appears to be virtually unanimous

that cytarabine is a schedule-dependent drug that should be administered twice a day

when administered on alternate days172. To my mind the letter to Dr Brown was

misleading in that it suggested that the underdosing was of limited significance due to

uncertainty about the appropriate magnitude of the dosage, a matter that would be

sought to be rectified by a further cycle of chemotherapy.

16.4. There is in my view a further questionable implication in the letter and that is that

none of this would have made any significant difference to his leukaemia control.

The expression that there was no evidence that Mr Higham’s leukaemia control would

have been compromised has a reassuring air that at that early point in time was not

172 For example Exhibit c19B, ‘Modelling the Pharmacodynamics of Highly Schedule –Dependent Agents: Exemplified by Cytarabine- Based Regimens in Acute Myeloid Leukemia’ – Braess and others, Cancer Therapy: Clinical , Clin Cancer Res 2005;11 (20) October 15, 2005

128

warranted. Whether or not Mr Higham’s treatment had been compromised could not

have been known at that time. I deal with issue of causation later in these findings.

16.5. As for the assertion that there is no uniformly accepted standard of care, this is

misleading. While there are a number of differing standards of care in respect of

consolidation chemotherapy, it is wholly wrong to suggest, as this letter implies, that

the standards of care are so diverse and uncertain that cytarabine can legitimately be

administered outside any existing standard and that non-conformity with a standard

would not make any material difference to the patient’s outcome. In short, there were

uniformly accepted standards of care. Mr Higham’s treatment did not conform to any

of them because, as was pointed out many times during the course of this inquest,

there was no consolidation regimen, or standard of care, that involved once daily

administration of cytarabine on alternate days.

16.6. Professor Gibson whose evidence on this point I accept told the Court that the

assertion that the optimal dose of cytarabine had been extensively debated in the

literature could only be true if Dr Beligaswatte was referring to the dose of cytarabine

and not the frequency with which it was given173.

16.7. In his evidence Dr Beligaswatte denied that he was trying to conceal the real nature of

the frequency error. I will deal with this issue when considering in the next section

the content of a similar letter that he would write to Mr Knox’s general practitioner

and the content of the chain of emails that he exchanged with Dr Coghlan to which I

have already referred174.

16.8. As of 16 February 2015 Mr Higham was still in remission. This enabled him to

undergo a third catch-up cycle of consolidation chemotherapy. As a result of the 16

February 2015 meeting Mr Higham was prescribed that third cycle. The cycle

consisted of 2gm of cytarabine being administered to Mr Higham twice a day on three

alternate days. This commenced on 2 March 2015. Professor Gibson opined that this

treatment was ‘not unreasonable’.

16.9. By 18 April 2016 it was clear that Mr Higham had relapsed. On 7 August 2016 he

died.

17. Mr   Knox is advised of the error

173 Transcript, page 146174 Supra para 7.76 herein

129

17.1. Mr Knox was advised of the error at a meeting on 17 February 2015 attended by

Dr Beligaswatte, Associate Professor Kuss, the clinical nurse consultant and a risk

manager.

17.2. A note compiled by Dr Beligaswatte and placed on Mr Knox’s progress notes states

that the sequence of events was outlined to Mr Knox ‘leading to a total reduction of

6g/m2 ara-C across 2 consolidation cycles’175. The note does not contain any

reference to the error involving frequency of dosing. The note goes on to state: ‘No

evidence that leukaemia control compromised, as no universally accepted evidence

based standard for consolidation’. This was evidently the advice tendered to Mr

Knox.

17.3. Like Mr Higham, Mr Knox was prescribed a third round of consolidation

chemotherapy, a catch-up round. This consisted of 2gm of cytarabine administered

twice per day on three alternate days. The therapy commenced on 25 February 2015.

17.4. Following the meeting Dr Beligaswatte wrote a letter to Mr Knox’s general

practitioner, a Dr S Kim Low176. This letter was in similar terms to that written to

Mr Higham’s general practitioner. The letter is dated 17 February 2015 and refers to

the meeting of that day. The letter also refers to a reduction in the total cytarabine

dose during consolidation in respect of Mr Knox. It then states:

'There are no universally accepted evidence-based standards of care for consolidation chemotherapy in AML. As such there is no evidence that Andrew’s leukaemia control has necessarily been compromised.'

The letter then goes on to describe the proposed additional cycle of cytarabine twice a

day on alternate days in order to ‘catch-up to the total planned cytarabine dose in

consolidation of 12g/m2.’

17.5. I have referred elsewhere to an exchange of emails about the error between

Dr Beligaswatte and Dr Coghlan. The exchange was prompted by an email of 13

February 2015 sent by Associate Professor Kuss to Dr Beligaswatte and Dr Coghlan,

and copied to others including Professor Bardy and Associate Professor Lewis,

informing that the Higham family had made a complaint and seeking from

Dr Beligaswatte information regarding the various AML regimens as soon as

possible. Dr Beligaswatte’s reply to Associate Professor Kuss of the same day, 175 Exhibit C16c, pages 840-841176 Exhibit C16c, page 907

130

copied also to Professor Bardy and Associate Professor Lewis, included a discourse

on the properties of cytarabine and the ‘ongoing debate’. Dr Beligaswatte suggested

in the email that there was no consensus regarding its dose. He referred to dosages

above 1.5g/m2 as being not likely to represent an optimal benefit/risk ratio. He also

said that there was no evidence to suggest that giving a smaller dose of cytarabine per

cycle would adversely affect Mr Higham’s leukaemia control given that he had

offered him a third cycle that would bring the total dose up to the intended level.

Dr Beligaswatte’s email referred to a number of publications that encapsulated an

issue concerning dose magnitude but not frequency. It was this email that prompted

Dr Coghlan’s reply to the effect that Dr Beligaswatte had missed the point, the real

point being that the pharmacokinetics of the drug cytarabine and its required

frequency of twice a day administration were the relevant factors when considering

the impact of the error. There was then a further email from Dr Beligaswatte, which

stated ‘…I wonder whether twice daily dosing really makes a difference for very

slowly cycling cells’.

17.6. It will be remembered that the letter to Mr Higham’s GP was sent on 5 February,

some eight days or so before the exchange of emails between Dr Beligaswatte and

Dr Coghlan.

17.7. In my view the letters to the respective general practitioners of both Mr Higham and

Mr Knox were misleading. A frank and candid item of correspondence between

specialist and general practitioner could not have failed to describe in precise terms

the true nature of the error and its possible consequences, either theoretical or actual.

To my mind the terms of the letter to Mr Knox’s GP were couched in such a way as to

lead that person to view the error as being of little or no consequence.

17.8. The statement in Mr Knox’s GP letter that there are no universally accepted evidence-

based standards of care for consolidation chemotherapy in AML was simply not true.

The ALLG M15 study, that is to say the regimen that was intended to be and should

have been administered to Mr Knox and all of the other affected patients, was clearly

a widely accepted evidence-based standard of care. This aspect of the letter was

misleading. Professor Gibson was asked to comment on the suggestion that there is

no universally accepted evidence based standard for consolidation. He suggested that

the implication that administering cytarabine once daily was acceptable is incorrect.

131

He stated that it is universally agreed that in respect of the regimen under discussion it

has to be given twice daily177. I accept that evidence.

17.9. For the same reasons identified in respect of the content of Dr Beligaswatte’s letter

regarding Mr Higham, the assertion contained in the letter regarding Mr Knox that

there was no evidence that Mr Knox’s leukaemia control has necessarily been

compromised was also misleading.

17.10. Dr Beligaswatte denied that his intent in writing these letters was to conceal the true

nature of the error. I am bound to say that the letters were so outwardly lacking in

candour that a conclusion that Dr Beligaswatte was being deliberately deceptive is

open. However, I hesitate in making that finding because of the distinct possibility

that in February of 2015, as evidenced by his email correspondence with Dr Coghlan,

Dr Beligaswatte genuinely held an unconventional view that dosage frequency was of

little or no relevance to the efficacy of cytarabine administration except to the extent

that the error in administering it only once a day had meant that the patients did not

receive their full numerical measure of that drug, a circumstance that in his mind

could readily be rectified by a third cycle. Of course, there is a possibility that within

that correspondence with Dr Coghlan, Dr Beligaswatte was being disingenuous about

what he truly believed. On the other hand, having regard to his already identified

prominent role in the whole affair, it is possible that out of wishful thinking he held

the views that he appears to have held about the limited relevance of dosage

frequency. In all of the circumstances I cannot discount the possibility that the terms

of Dr Beligaswatte’s letters were influenced by genuinely held views. In the event, I

make no finding as to whether or not Dr Beligaswatte set out to deliberately mislead

the general practitioners of Mr Higham and Mr Knox. In any case I do not believe

that the content of either letter compromised their respective treatments from the dates

of the letters onwards.

18. The evidence of Professor Peter Bardy

18.1. I have already referred to Professor Peter Bardy. At the time with which this inquest

is concerned Professor Bardy was the Clinical Director of the Cancer Service at the

Central Adelaide Local Health Network (CAHLN). In that role he reported to the

Chief Executive Officer of CAHLN. He was the direct line of report for all

177 Transcript, page 638

132

oncologists, radiation oncologists and haematologists in the Cancer Service through

the respective Clinical Heads of Oncology, Radiation Oncology and Haematology.

That was nominally a .4 role with the balance of his work taken up with clinical duties

at the RAH and the QEH. In that role he reported to the Clinical Director of

Haematology in each of the sites at which he worked.

18.2. Professor Bardy provided a statement and annexures to the inquest178. He also gave

oral evidence.

18.3. Professor Bardy told the Court that prior to July 2014 he had not been aware of any

discussion relating to any proposed changes in the relevant protocol. He received the

email from Mrs To of 16 July 2014 that had been sent to a large group of recipients.

He also received Associate Professor Lewis’ email of 19 July 2014 explaining the

changes. He did not check the AML protocol after receiving those emails. Between

July 2014 and January 2015 he was not generally involved with inpatient management

at the RAH and was not responsible for any new patients with AML. He therefore did

not have any reason to refer to the RAH AML protocol during that period.

18.4. Professor Bardy also told the Court that he was unaware of any protocol error or of

underdosing administered pursuant to it until he was told about it by Mr Doecke, the

Director of Pharmacy at the RAH, on 12 February. Professor Bardy informed Mr

Doecke that an SLS incident report should be filed in respect of any incorrect protocol

in use at the RAH. One such report was lodged by Ms Scarborough later that day.

Others were not filed until 17 February 2015.

18.5. Professor Bardy also told the Court that he had not been informed by Associate

Professor Yong on or about 20 January 2015 about the error having been identified at

the RAH. Although he had been a recipient of the 20 January 2015 email sent by Mrs

To, he told the Court that in the absence of knowing that there had been an incident or

an error, the email would not have seemed remarkable to him. I can see why he

would say that. He was alluding to the fact that the email did not specify anything

about an error.

18.6. Professor Bardy told the Court that for some time he had known Associate Professor

Lewis in a professional capacity. He said that when he heard about the error he was

most concerned about the fact that senior clinicians had not shared the information 178 Exhibits C53 and C53a

133

with him as Clinical Director of the Cancer Directorate. He did not know that

Dr Beligaswatte had apparently been informed of the error on or about 30 January

2015 and had provided a further consolidation round of chemotherapy to a patient

commencing on 2 February 2015.

18.7. Other relevant matters dealt with by Professor Bardy included the fact that he himself

had never heard of any regimen whereby single daily dosages of consolidation

chemotherapy would be delivered on alternate days179 and stated that in his view any

clinician with experience in the management of AML would have queried such a

regimen. He held that view even though he was not himself an expert in AML180.

18.8. Professor Bardy also gave evidence that he would regard it as unfortunate if not

unsatisfactory that a relatively inexperienced registrar, not the consultant, would

deliver two-pronged information to a patient that not only was the patient no longer in

remission, but that his treatment had been the subject of an error, as had been the case

with Mr McRae181.

18.9. I have already referred to Professor Bardy in respect of electronic scripts. Professor

Bardy told the Court that as at the time that he gave his evidence in the inquest,

electronic prescriptions had not yet been introduced at the RAH. He told the Court

that electronic prescriptions would mitigate against possible error but only on the

proviso that they were developed with contemporary appropriate governance

processes around it. He agreed with the proposition that such governance processes

are essential to ensure that the data entry in the electronic system is not infected by

error182. Professor Bardy emphasised in his evidence that electronic prescriptions must

go through a process of tight governance183.

18.10. Professor Bardy also gave some evidence about the SLS. He told the Court that

training in the SLS for medical practitioners was very poor184. I would add for my

own part that it does not require any training to know that when an error has been

committed in any professional walk of life, frank and immediate disclosure is called

for.

179 Transcript, page 2242180 Transcript, page 2243181 Transcript, page 2249182 Transcript, page 2259183 Transcript, page 2258184 Transcript, page 2269

134

19. The evidence of David Swan

19.1. Mr Swan was the Chief Executive of SA Health from 2011 to 2016.

19.2. Mr Swan knew nothing of the chemotherapy error or underdosing pursuant to that

error until 16 February 2015, which of course was nearly a month since the error had

been discovered at the RAH. It was, as I have found, five days after the underdosing

at the FMC had been revealed and discussed at the ward meeting attended by

Professor Kuss. That the Chief Executive of the overarching entity in respect of the

administration of the delivery of health in the public sector should not have been

informed of the matter before then is extraordinary. Naturally Mr Swan, who gave

evidence, was questioned about his reaction to that and with some measure of

understatement stated that he had been ‘very disappointed’185.

19.3. Specifically Mr Swan suggested that Mrs To’s email of 20 January 2015 in which she

had outlined Associate Professor Yong’s advice that chemotherapy should be

administered twice daily was not a satisfactory method of communicating the

existence of an error. He made the obvious point that there is an ‘issue’ about a

project officer sending out communiques of that nature regarding a complex

protocol186. He also described the email as ‘completely deficient’187. Mr Swan was

also critical of Associate Professor Lewis and suggested that as soon as Associate

Professor Lewis had returned to work in January 2015 there should have been an

investigation including an immediate conversation with Associate Professor Yong to

ascertain what she had done as far as reporting the incident was concerned188. One

matter that struck me as extraordinary was Mr Swan’s assumption that an SLS report

would have had the effect of notifying the FMC of the difficulty that had been

identified at the RAH. It will be remembered that no SLS was filed in relation to any

of these affected patients until at the very earliest 12 February 2015. Granted that an

SLS should have been filed no later than Tuesday 20 January 2015, but I was not

persuaded that any SLS then filed within the RAH environment would have alerted

any person at the FMC to the fact that there had been an error detected at the RAH, let

alone that the same error was possibly in existence at the FMC. Despite Mr Swan’s

evidence I was not persuaded that any SLS created at the RAH would have been

185 Transcript, page 2294186 Transcript, page 2336187 Transcript, page 2346188 Transcript, page 2347

135

distributed to clinical counterparts at the FMC, let alone have enabled those

counterparts to consider whether there was in existence, and to have identified, any

error that had crept into their processes as well. I was also surprised at Mr Swan’s

revelation that he had no realisation in this context that the FMC Haematology

Department effectively acted autonomously189.

19.4. Mr Swan gave evidence about briefings that were created within SA Health both in

respect of information that was imparted to him and also information that was

imparted to the Minister. Mr Swan referred to a number of different documents in

this regard and suggested in effect that initially, and for some duration, he had been

misled into believing that adequate and timely open disclosure had been made to all of

the affected patients when in reality there had been a distinct lack of that. Moreover,

there had been the fiasco concerning the treatment of Mr Knox. Mr Swan was

initially not made aware of the fact that Mr Knox had been treated pursuant to the

incorrect protocol notwithstanding that the error had been identified at the RAH.

Mr Swan was asked by me to spell out in terms what it was that he had been told in

briefings and which was incorrect, and he said:

'I'd been told that once they identified the error in January, I think it's around 20 January, they'd promptly addressed the protocol. They were advising patients and informing open disclosure, they were moving on with improving their protocols but the events, both of the sense of patients still being treated post that date was a major issue for concern about a breakdown between addressing the issue and what we were being told. The delay in responding to addressing the protocol, we understood that once the protocol was changed in January that all patients would have been promptly responded to with treatment plans and ensuring that they were being informed and involved with that care but that was not the case.' 190

Mr Swan, correctly in my view, said in his evidence that as between a number of

individuals there had been a responsibility to bring to his attention the fact that a

person had been erroneously treated notwithstanding the discovery of the error191.

Asked as to what he had meant when he had told his counsel Mr Golding that he had

not been informed of all the facts, he outlined that there had been a delay in

responding to treatment of individuals and that the response to the treatment error was

not clear at all. He said that what he did not know was that there had been a delay in

developing a response to the care of the patients. He asserted that the response should

have been extremely prompt. That of course goes without saying. In the event, he 189 Transcript, page 2342190 Transcript, page 2304191 Transcript, page 2306

136

had gained a perception from the briefing that people had been responding quickly to

the protocol error and were remediating the situation as much as possible in terms of

both treatment and open disclosure to the affected patients192. He said he was

misinformed about those matters.

19.5. In cross-examination by Ms Johns on behalf of Mr Knox, Ms Crannage and the

family members of affected patients, Mr Swan agreed that it would not have been

acceptable to wait until March 2015 to have informed a patient that there had been an

error while simultaneously informing the patient that the person had also relapsed193.

He also agreed with Ms Johns’ proposition that simply putting the whole thing down

to an error in the dose would not be acceptable without mentioning that the error in

reality was connected with frequency of dosing194.

19.6. Asked as to identify the clinical governance errors that had been responsible for the

chemotherapy underdosing, Mr Swan identified the errors that had crept into protocol

development wherein it had been left to one person to deal with a project officer. He

suggested, rightly in my view, that this process created a risk of error because of its

lack of checks and balances and said ‘you would think that there should be a dual

signing off with probably even a third-party endorsing a recommendation on a

protocol’195.

19.7. Mr Swan’s evidence also led to the revelation that the briefing to the Minister had

contained the tired suggestion that ‘there have been a number of recent review

articles highlighting the current controversy surrounding dose and timing of

cytarabine’ which was capable of implying that the state of the science regarding

consolidation chemotherapy for AML was so uncertain that any error would have had

limited impact, or may not have been an error at all.

19.8. The evidence of Mr Swan made it abundantly plain in my view, if it was not plain

already, that for a long period, and for an unacceptable one, the chemotherapy

protocol error and its consequences or possible consequences had largely been swept

under the rug.

20. The expert witnesses - causation

192 Transcript, page 2308193 Transcript, page 2326194 Transcript, page 2326195 Transcript, page 2351

137

20.1. In this section I shall deal with the issue as to whether or not the administration of

consolidation chemotherapy that was not in accordance with the intended protocol

had any impact on the survivability of any of the deceased persons. I will also deal

with the same issue in relation to Mr Knox and whether any conclusion that I might

draw from Mr Knox’s circumstances has any bearing on the conclusions that I might

draw in relation to the survivability of any of the deceased persons.

20.2. Four independent expert witnesses were called to give oral evidence in this inquest.

They also provided written reports. Each of the four expert witnesses were

independent in the sense that none of them had any connection with the deceased

persons or their courses of treatment, nor with that of Mr Knox or any other affected

patient. Two of the expert witnesses, namely Professor John Gibson, a haematologist,

and Professor Allan Boddy, a pharmacokineticist, were engaged by counsel assisting

the Coroner to provide an expert analysis of the treatment of the four deceased

persons and of Mr Knox. Associate Professor Andrew Wei was engaged by solicitors

acting for a number of medical practitioners who were called to give oral evidence at

the inquest. Dr Stephen Vaughan was originally engaged to provide an expert opinion

by AHPRA for the purposes of that agency’s investigation. Dr Vaughan’s original

written expert report was furnished to the State Coroner along with other material that

was gathered by AHPRA in the course of its investigation. This material was

provided as a result of process issued by the Coroners Court to AHPRA. In the event

the Court decided to call Dr Vaughan to augment his written material by oral

evidence. I indicate that I have had regard to all of the independent expert evidence.

20.3. Other expert opinion was given by a number of the medical practitioners who were

involved in the treatment of the deceased persons or Mr Knox. I have had regard to

their expert opinions as well.

20.4. Professor John Gibson is Senior Staff Specialist and Head of the Department of the

Institute of Haematology at the Royal Prince Alfred Hospital in New South Wales.

He is a Professor of Haematology in the Faculty of Medicine, University of Sydney.

He is the Head of the Blood and Bone Marrow Transplantation Service and the

Sydney South West Area Health Service. He is also the Co-Director of Cell and

Molecular Therapies at the Royal Prince Alfred Hospital. Professor Gibson is a

Doctor of Philosophy and a clinical haematologist. He is a Fellow of the Royal

College of Pathologists of Australasia and a Fellow of the Royal Australasian College

138

of Physicians. Professor Gibson provided a number of reports in relation to the

treatment of the four deceased persons and of Mr Knox. In particular, he provided

opinions in relation to the issue as to whether or not the consolidation therapy that

was administered not in accordance with the correct protocol had any impact on the

duration of complete remission or the duration of survival in relation to the concerned

patients. I recognised and accepted Professor Gibson as an expert witness in the field

of haematology and in particular as an expert in the treatment of AML.

20.5. At the time of the inquest hearing Professor Allan Boddy was a Doctor of Philosophy

and Professor of Pharmacy (Cancer Therapeutics and Personalised Medicine) in the

Faculty of Pharmacy at the University of Sydney. His Doctorate of Philosophy is in

the subject of pharmacokinetics (University of Manchester). Professor Boddy

provided a written report in relation to the therapeutic principles for cancer treatment

and in particular the pharmacology of cytarabine which is the drug utilised in AML

chemotherapy. He gave evidence about the pharmacological principles relative to

cytarabine chemotherapy regimens. He also gave evidence in connection with the

pharmacokinetics associated with the administration of cytarabine. Professor Boddy

provided a report and gave oral evidence in the inquest. In his oral evidence he dealt

with the possible impact that the erroneous administration of consolidation therapy

may have had in respect of each of the five individuals who are the subject of this

inquiry. I regarded Professor Boddy as an expert in pharmacology and

pharmacokinetics. In particular, I regarded him as an expert in respect of the

pharmacological and pharmacokinetic principles as they apply to the drug cytarabine.

20.6. Associate Professor Andrew Wei is a clinical haematologist at the Alfred Hospital in

Victoria. He is Head of Human Molecular Pathology at the same hospital. He is also

an Adjunct Associate Professor at the Monash University in Victoria. He is a Fellow

of the Royal Australasian College of Physicians as well as a Fellow of the Royal

College of Pathologists of Australasia. He has had other memberships in

organisations associated with haematology. It is evident from Associate Professor

Wei’s curriculum vitae that he has been involved in research, particularly in relation

to AML, and has published in respect of that same topic. I was furnished with

Associate Professor Wei’s written report. In his oral evidence Associate Professor

Wei explained that as a full-time clinical haematologist at the Alfred Hospital he is in

charge of acute leukaemia practices within that hospital which includes the

139

determination of treatments that should be utilised. He manages the hospital’s clinical

trial program and states that he and his associates operate potentially the largest

clinical AML program in Australia. Associate Professor Wei also explained that a

large part of his practice is directed towards the treatment of AML patients who are

older than the age of 60-65 years. Associate Professor Wei is a Member of the

Australasian Leukaemia and Lymphoma Group (ALLG). I accepted Associate

Professor Wei as an expert in the field of haematology. He voiced expert opinions in

relation to the question as to whether or not the administration of the erroneous

consolidation chemotherapy had any impact on the remission duration or duration of

longevity of the five individuals the subject of this inquiry.

20.7. Dr Stephen Vaughan is a consultant physician in Haematology/Medical Oncology

both in private practice and in sessional public practice. He has acted as an expert

witness in respect of cancer and blood diseases. He is a clinical associate in

haematology at the Royal Melbourne Hospital. He has admitting rights in a number

of hospitals in Australia. He is a Fellow of the Royal Australian College of

Physicians and is a Fellow of the Royal College of Pathologists Australia

(Haematology). As indicated earlier he originally provided a written expert opinion

to AHPRA for the purposes of that organisation’s investigation. He gave evidence in

this inquest in relation to the treatment of AML including consolidation

chemotherapy. He voiced expert opinion as to whether or not the administration of

erroneous consolidation chemotherapy had any impact on the remission duration or

duration of survival in relation to each of the five individuals the subject of this

inquiry.

20.8. It will be seen that Professor Gibson, Associate Professor Wei and Dr Vaughan gave

evidence essentially in relation to the same broad issues from a clinical perspective.

On the other hand Professor Boddy, who is not a clinician as such, gave evidence

concerning the therapeutic properties of cytarabine administration in the treatment of

AML. He essentially gave expert evidence about the mechanics of how cytarabine

eliminates acute leukaemia within the bone marrow and blood of a person. It was

necessary to adduce this evidence in order to provide the Court firstly with an expert

overview of how the drug cytarabine actually works and secondly with an account of

the principles that apply when the appropriate dosage and frequency of administration

140

of that drug come to be considered. It is as well to commence an analysis of the

expert evidence with the evidence of Professor Boddy.

21. The evidence of Professor Boddy

21.1. Professor Boddy explained the properties of the drug cytarabine in terms that were

very easily understood. This was so both in his report196 and in his oral evidence. He

explained the effect of the drug cytarabine on the creation and proliferation of

leukaemic cells. He told the Court that cytotoxic chemotherapy, in this case

cytarabine therapy, works by targeting cells that are growing and dividing. This

results in a failure of the replication system within those cells and causes the cells to

die. Professor Boddy explained, however, that cells that are not progressing through

the S-phase or synthesis phase of a cell cycle are less sensitive to the actions of

cytarabine. Cells are only susceptible to the actions of anti-metabolites such as

cytarabine when they are in the S-phase of the cell cycle which can occur over a

period of 12 to 24 hours. In order to capture all of the cells in a leukaemic population

it is necessary to maintain the drug within the body and to repeatedly expose those

cells to the drug at different intervals, thereby maximising the number of cells that are

exposed to the cytotoxic action of the drug. In order to maintain effective

concentrations of the drug for an appropriate period of time it is necessary either to

use a continuous infusion of cytarabine or, alternatively, repeated doses. Professor

Boddy pointed out that induction therapy consists of a continuous infusion whereas

the intended consolidation protocol called for shorter durations of infusion over three

hours, but repeated on a 12-hourly basis every second day, in other words, twice daily

on days 1, 3 and 5.

21.2. Professor Boddy also explained that a chemotherapy protocol is designed to provide

the maximum anti-leukaemic effect but takes into account the potential toxicities from

the treatment. The uncontested evidence in the inquest was that cytarabine has an

adverse effect on normal blood cells such as red cells, white cells and platelets and

that the destruction of these cells can cause adverse side effects such as infection and

bleeding. It will be seen that these consequences were experienced in the cases under

discussion. Essentially, cytarabine chemotherapy involves a balance between

maximum exposure of the leukaemic cells to the drug on the one hand and the

minimisation of the toxic effects of the drug on the other.

196 Exhibit C19

141

21.3. Throughout Professor Boddy’s oral evidence he emphasised the importance of the

maintenance of concentration of the drug over time by way of repeated

administration. Its importance is generated by the fact that not all cells within a

population of leukaemic cells will be at the same phase of the cell cycle. Professor

Boddy described cytarabine as a ‘schedule-dependent’ drug, that is to say a drug

which is only active at one phase of the cell cycle197. At any given time different cells

will be at various phases of the cell cycle such that ‘catching as many of them as

possible at that vulnerable S-phase requires prolonged or repeated exposure to the

drug’198. To my mind, this is an important matter as it negates the suggestion that

whether or not the drug will act on leukaemic cells in the S-phase of the cycle is a

matter of pure chance. It is an ongoing process. It would stand to reason, therefore,

that a prolonged absence of the drug in the body, occasioned by infrequent and

interrupted administration, would be an undesirable circumstance.

21.4. The other matter on which Professor Boddy placed great emphasis was the fact that

cytarabine has a short half-life and is only effective for a limited period of time as it is

rapidly eliminated from the body199. For those reasons twice daily administration of

cytarabine during consolidation chemotherapy will provide a greater anti-leukaemic

effect than once daily administration200. In addition, Professor Boddy emphasised the

fact that the literature has suggested it is not a case of how much cytarabine is given

in terms of dosage, ‘but for how long the drug is around in the body, either as the

result of continuous infusion or repeated administration’201. As well, in Professor

Boddy’s opinion the existing literature underlined the importance of repeated

exposure or prolonged exposure to the drug that would be provided by a schedule of

12-hourly administration and indicated that a more prolonged gap between

administrations would render them less effective. The evidence that Professor Boddy

gave in relation to these topics was largely uncontested. Insofar as any other evidence

differed, I preferred the evidence of Professor Boddy, an undoubted expert in relation

to the pharmacology and pharmacokinetics of cytarabine. I accepted all of that

evidence.

197 Transcript, page 382198 Transcript, page 379199 Transcript, page 380200 Transcript, page 380201 Transcript, page 383

142

21.5. Professor Boddy was asked to comment upon various treatment protocols in respect

of cytarabine, particularly in relation to dosage and frequency of administration within

those protocols. He told the Court that dosage schedules are derived from an

understanding of the pharmacology of cytarabine, how it works and how exposure to

different concentrations over different times might influence not only the anti-

leukaemic effect, but also the toxic effect. Thus, the derivation of a schedule is a

reflection of the two factors of anti-leukaemic effect and tolerability of toxicity. The

overall desire is to administer the most effective treatment which would be the one

that would provide the highest dose and the most continuous exposure, but tempered

by questions of tolerability. In particular the schedule of 12-hourly administration on

alternate days had been largely ‘based on those empirical observations of the

tolerability of the treatment and also the anti-leukaemic effect in terms of the purpose

of the consolidation treatment that patients remain in remission’202.

21.6. In his oral evidence Professor Boddy was asked to comment on the suggestions that

had been made either in correspondence or in clinicians’ conversations with the

deceased and their families to the effect that there was no universally accepted

evidence-based standard for consolidation chemotherapy in AML. Professor Boddy

agreed that there is no evidence-based standard in the sense that there has never been,

say, a comparison between twice daily and once daily administration of cytarabine.

But he said ‘just because there isn’t that evidence base, doesn’t necessarily mean that

there isn’t a sound clinical and pharmacological reason for choosing one of those

schedules over the other, ie, the twice daily administration’203. Professor Boddy

expressed the view that a proposal for a comparative study would require ‘some

pretty strong grounds for thinking that an alternative was going to be better’ or at

least as good in terms of efficacy with reduced toxicity204.

21.7. Mr Trim QC in cross-examination put to Professor Boddy the proposition that there

has been no optimal type or number of consolidations identified in the literature.

Although Professor Boddy acknowledged that there had certainly been some debate

as to the number of cycles and the dose of cytarabine that should be administered, as

far as he was aware there has been no active debate that would bring into question

whether 12-hourly administration on days 1-3-5 is the accepted and optimal treatment

202 Transcript, page 386203 Transcript, page 433204 Transcript, page 480

143

for these patients. Professor Boddy made the point that he had not heard of any

proposition postulated within the scientific community that contradicted the notion

that anything other than 12-hourly was the accepted rate of administration. He added

that he had not heard of any proposition suggesting that reducing the repeated or

prolonged exposure to the drug cytarabine would be more or equally beneficial in

terms of anti-leukaemic effect205. I would add for my part that the overwhelming

conclusion from the whole of the evidence, including the literature that I will discuss,

is that there has been no scientific debate regarding dosage frequency. For instance,

no protocol in which cytarabine is administered once daily on alternate days has been

drawn to my attention. In this regard, Professor Boddy contemplated how one could

ethically deal with an issue such as this in a scientific setting and concluded that there

would be no scientific or clinical justification within a clinical trial for putting patients

in the position of being randomised to one dose level and others to a different dosing

level. He said ‘to my knowledge, no clinical or scientific justification for asking that

question’. He stated that this was the overriding ethical issue. In this, Professor

Boddy made complete sense.

21.8. Professor Boddy also expressed the opinion that although there may be other methods

of administering consolidation chemotherapy, that having chosen one of the

recognised options adherence to the protocol described was essential in order to

obtain the expected benefit. He said:

‘The protocol wasn’t adhered to, therefore the anticipated benefit is less likely.’ 206

Professor Boddy acknowledged in a general sense that in an individual case it is not

possible to conclude whether or not departure from the protocol contributed to early

relapse in the patient, but added that if one posed the question as to whether or not the

departure reduced the anti-leukaemic benefit in the patient’s treatment, the answer

would have to be in the affirmative. Professor Boddy summed up his views in this

way:

‘Okay, because the interval between doses has been identified as a factor that limits the anti-leukaemic effect of that treatment, and it departs from the schedule from which an anticipated clinical benefit and risk of toxicity is derived. So departing from that schedule means that calculations that are made about anticipated benefit and anticipated

205 Transcript, page 409206 Transcript, page 509

144

risk are undermined by the application of the non-specified schedule of administration.’ 207

21.9. In his written report Professor Boddy deals with the question, ‘how does a once daily

dose impact on the efficacy of the treatment for elderly patients with AML?’. His

answer in part was as follows:

‘In principle, administration of a lower total dose, and limiting exposure to anti-leukaemic concentrations of cytarabine to a single short period with once daily dosing would provide a less than optimal treatment.’

He also stated:

‘It is possible to say that the regimen of 1g/m2 once daily is likely to have an inferior anti-leukaemic effect compared to 1g/m2 twice daily, as the design of dosage regimens is based on probabilities of optimal treatment.’

and:

‘Administration of cytarabine as a single daily dose would limit the exposure of the patient to effective concentrations of the drug, and reduce the anti-leukaemic effect of the treatment.’

In addition:

‘A greater duration between doses allows leukaemic cells greater time to recover before the next dose is administered and, more importantly, only those cells in the S-phase of the cell cycle during a short window around the time of administration would be affected by the single dose administration. A second dose after 12 hours would be likely to hit those cells which were in the non-replicative phase of cell cycling during exposure from the first dose.’

21.10. I accepted Professor Boddy’s evidence that based on pharmacological and

pharmacokinetic principles, in general terms once daily administration of cytarabine

on alternate days, for the reasons he gave, would not provide as great an anti-

leukaemic effect as twice daily administration. To my mind the evidence was

overwhelming that in principle, and leaving aside for the moment the issue as to the

efficacy of consolidation therapy in the elderly, once daily administration on alternate

days would be less likely to eradicate leukaemic cells and would be more likely to

result in a relapse than otherwise would be the case with twice daily administration.

21.11. One matter that Professor Boddy was at pains to refute was the suggestion put to him

in cross-examination that there was no established optimal treatment regimen or

207 Transcript, page 532

145

standard treatment for elderly AML patients in the consolidation phase. He accepted

that there were a number of alternative regimens but importantly all of them adhere to

the same principles relating to the administration of the drug; which is to provide

repeated exposure to the drug over a period of days without a break of 36 hours208. I

return to the question of the anti-leukaemic effect in the elderly below.

21.12. In his oral evidence Professor Boddy was cross-examined extensively about the

efficacy and value of consolidation chemotherapy in elderly patients. Much of this

cross-examination was based upon literature that I will discuss. Some of Professor

Boddy’s evidence concerning efficacy in the elderly was given upon his being

recalled in light of certain evidence that Associate Professor Andrew Wei gave after

Professor Boddy had given his original evidence.

21.13. As to the definition of elderly, I was not entirely certain where the cohort of elderly

patients began and whether it was at the age of 60 or 65. However, I assume for these

purposes that elderly would include the 60 to 65 age bracket.

21.14. Professor Boddy acknowledged that the anti-leukaemic effect of cytarabine has been

shown to be less in older patients than in younger patients209. He added that the

benefits of chemotherapy in older patients is generally less than that seen in younger

patients. As far as Professor Boddy was concerned the relevant elements in that

regard were an elderly patient’s comorbidities, the greater toxicity that will be

experienced in older patients and the intrinsically greater resistance to treatment

within the leukaemic cells of those patients. However, he added that the response to

therapy will differ from one patient to the next within the same age group and said

that he did not believe that leukaemic cells in the elderly ‘are in some way bullet

proof in terms of cytarabine treatment’210. He added that the cells are sensitive to

cytarabine treatment and that sensitivity is maximised by the twice daily

administration. He repeated as he had on a number of occasions during his evidence

in this context that the duration of exposure and frequency of administration is a

factor that is highly relevant to the anti-leukaemic effect.

21.15. Professor Boddy stated that a study comparing once daily versus twice daily

administration in order to demonstrate that there is no difference in outcome in elderly

208 Transcript, page 3006209 Transcript, page 3008210 Transcript, page 2992

146

AML patients has never been undertaken211. This assertion was universally accepted

in the evidence tendered to the Court. Certainly, no such study was drawn to the

Court’s attention. He acknowledged Associate Professor Wei’s evidence that older

patients with AML were more likely to have mutations that were inherently resistant

to chemotherapy, and also acknowledged that the issues raised by Associate Professor

Wei were more in the realm of a clinical haematologist. However, Professor Boddy

expressed the view that the literature did not necessarily support Associate Professor

Wei’s opinion in that regard212. Specifically, Professor Boddy said that in reviewing

the literature he did not see any distinction drawn between younger patients and older

patients. In addition, Professor Boddy suggested that in the elderly there are other

factors to consider apart from inherent resistance of the leukaemic cells to specific

treatment213.

21.16. Professor Boddy dealt with a matter that had been raised by Associate Professor Wei

and that was Associate Professor Wei’s suggestion that in the elderly a concept

known as ‘drug pumps’ might adversely alter the efficacy of treatment in that cohort

of patients. Professor Boddy told the Court that he was very familiar with the concept

of drug pumps. It was an area in which he had undertaken research. Professor Boddy

stated that he had not been able to locate any specific reference to drug pumps that

were relevant in the context of cytarabine treatment and resistance to therapy in the

elderly214. He stated that cytarabine is not a particularly good substrate for the well-

known pumps that exclude drugs from cells215. In short, Professor Boddy said that

there was no evidence that he could find to suggest that this concept applied to

cytarabine uptake in cells within the elderly. I will deal with this issue in more detail

when dealing with Associate Professor Wei’s evidence.

21.17. The effect of Professor Boddy’s evidence in my view was that in his opinion, having

regard to the pharmacological and pharmacokinetic principles adhering to cytarabine

administration, there is no reason to suppose that consolidation therapy using that

drug has no efficacy in respect of elderly patients. In addition, and in any event, there

was no justification based on scientific grounds that could in any way support the

notion that cytarabine administration once daily on alternate days would have the

211 Transcript, page 2966212 Transcript, page 2969213 Transcript, page 2976214 Transcript, page 3011215 Transcript, page 3012

147

same efficacy as cytarabine administered in accordance with the correct protocol.

Professor Boddy was asked to comment upon the treatment and outcomes of the four

deceased persons and that of Mr Knox. Regarding Mrs Pinxteren, Professor Boddy

pointed out that her remission after the induction phase of her chemotherapy indicated

that her disease was sensitive to the drugs that had been administered to her. As far as

her consolidation therapy was concerned he indicated that in order to achieve an

anti-leukaemic effect there was a necessity to provide prolonged exposure to the drug

or repeated exposure to the drug within a period and that in Mrs Pinxteren’s case

obviously only half of the protocol dose had been administered to her. However, the

more important feature was the lack of the repeat dose within the same 24 hour period

in her case. Her treatment was not in accordance with the protocol. He said:

‘The protocol was derived from established clinical experience and evidence of a certain level of efficacy of that treatment and so she received less than that defined treatment, and so the degree of anti-leukaemic effect that would be the result of her treatment was less than intended in the protocol.’ 216

According to Professor Boddy, based on pharmacological principles the leukaemia

was not treated at the level that it should have been and while he could not say for

certain whether this contributed to Mrs Pinxteren’s early relapse, it ‘shifted the

balance of probability towards an increased likelihood of that happening’217. He

agreed with the proposition that the correct administration of cytarabine in terms of its

frequency being reduced by half was likely to have increased the risk of relapse at

some point218.

21.18. In his evidence Professor Boddy candidly acknowledged that he had struggled with

the question as to whether the protocol error contributed to or brought about

Mrs Pinxteren’s early relapse. Rather, as indicated above, Professor Boddy preferred

to answer a question in terms that suggested that Mrs Pinxteren did not receive the

optimal anti-leukaemic effect and that this would have increased the likelihood of an

early relapse.

21.19. As far as Mr McRae was concerned Professor Boddy similarly opined that the

absence of a second dose within the 24 hour period would lessen the anti-leukaemic

216 Transcript, page 394217 Transcript, page 395218 Transcript, page 395

148

effect of his treatment219. Professor Boddy suggested that with the underdosing of Mr

McRae, the balance of probability shifted towards a reduction in the anti-leukaemic

effect and therefore a reduction in the benefit that Mr McRae would have received

from the treatment he had undergone. He agreed with the proposition that it was a

possibility that the underdosing contributed to, or brought about, Mr McRae’s relapse.

He said:

‘… there’s only one direction that that can push the probabilities if you omit that second dose, and that’s in a negative direction.’ 220

Put in another way, he said that deviating from a protocol dose that had been derived

from a series of clinical investigations to optimise the treatment schedule and dosage

would mean that one is deviating from the expected benefit from that treatment221.

21.20. Again, Professor Boddy was not prepared to state any opinion in specific terms as to

whether Mr McRae’s treatment would have contributed to his relapse, but suggested

in general terms that underdosing or deviating from the protocol has the possibility to

lower the anti-leukaemic effect of the treatment222. In the context of discussing

Dr Hotinski’s meeting with Mr McRae in which she indicated and recorded that she

was unsure if the underdosing contributed to the relapse in Mr McRae’s case,

Professor Boddy noted that ‘of course this is a possibility’223.

21.21. Regarding Mr Higham, Professor Boddy told the Court that in his view it was

possible that the incorrect administration of cytarabine in Mr Higham’s two

consolidation rounds was likely to have increased the risk of relapse. I did not

understand Professor Boddy to be expressing any positive opinion that it did

contribute to the relapse in Mr Higham’s case.

21.22. As to Mr Higham’s so-called ‘catch-up round’ Professor Boddy suggested that its

possible therapeutic effect would in part be a question for a haematologist. He

suggested that it would be difficult to say whether the catch-up round would have

been as beneficial as properly administered consolidation rounds in the first

instance224. However, he indicated that there is no doubt that the catch-up round

would have had some anti-leukaemic effect, but judging the relative impact of it 219 Transcript, page 398220 Transcript, pages 399-400221 Transcript, page 400222 Transcript, page 412223 Transcript, page 412224 Transcript, page 414

149

compared to a situation where it had been given weeks earlier in combination with

idarubicin was very hard to predict with any certainty225. Complicating the issue in Mr

Higham’s case was the delay involved in the administration of the catch-up round. In

this context Professor Boddy pointed out that chemotherapy regimens for

consolidation were designed to follow on from the remission achieved from induction

therapy as soon as was possible226.

21.23. Professor Boddy also commented on Dr Beligaswatte’s letter regarding Mr Higham,

and in particular the assertion within the letter that the optimal ‘dose’ of cytarabine in

consolidation had been ‘extensively debated in the literature’. Professor Boddy

pointed out that all of the studies that he had seen used the 12-hourly repeated

administration of cytarabine. As far as the term ‘dose’ was concerned Professor

Boddy pointed out that the key feature in Mr Higham’s consolidation chemotherapy

was the absence of the second administration within the 24 hour period. He pointed

out that administering a dose in the morning as well as in the evening would involve

an anticipated benefit that would have been greater than if one had given the full dose

as a single dose in the morning. One could administer the ‘same dose’ but not meet

the pharmacological principles in respect of the most effective way in which to

administer the drug227. In the same context he pointed out, as he had repeatedly

pointed out in his evidence:

‘It’s widely accepted that a prolonged or repeated exposure to the drug is the optimal way to use cytarabine.’ 228

21.24. Regarding Mrs Bairnsfather, when asked as to whether the incorrect administration of

the cytarabine in the first and only consolidation round was likely to have increased

the risk of relapse in her case, Professor Boddy said:

‘Yes, that’s certainly possible.’ 229

21.25. Regarding Mr Knox, Professor Boddy dealt with the issue as to whether or not having

regard to Mr Knox’s good cytogenetic and molecular profile upon diagnosis and the

absence of myelodysplasia and comorbidities, the relapse following a successful

induction therapy was surprising. Although Professor Boddy stated that this was a

question for a clinical haematologist, he suggested that these favourable

225 Transcript, page 416226 Transcript, page 415227 Transcript, page 408228 Transcript, page 408229 Transcript, page 426

150

characteristics would have put Mr Knox’s chances of a longer term remission at the

upper end of the scale. Later in his evidence Professor Boddy added that it was

possible that the administration error contributed to, or brought about, Mr Knox’s

relapse230.

21.26. Regarding Mr Knox’s catch-up round and whether that would have provided the same

benefit as two correctly administered consolidation rounds, Professor Boddy

suggested that it would have been of less benefit than if it had been administered as

part of the full protocol231.

21.27. Professor Boddy was also asked to comment upon the assertion that had been made to

Mr Knox and his family on 17 February 2015 that there was no evidence that his

leukaemia control had been compromised as a result of the underdosing as there was

‘no universally accepted evidence-based standard for consolidation’. As already

indicated, Professor Boddy acknowledged that strictly speaking the assertion that

there was no evidence-based standard was true in the sense that there had never been

a scientific or clinical comparison between twice daily and once daily administration.

However, it was in this context that he emphasised that a lack of such an evidence-

based standard did not imply that a sound clinical and pharmacological reason did not

exist for choosing one administration schedule over another, in this instance the

preferred schedule being twice daily administration.232

21.28. When it was suggested in cross-examination to Professor Boddy that it was not

possible to say that it is more likely than not that the departure from the protocol had

an effect on the remission duration of the involved patients, he stated:

‘It’s not possible to say in an individual case yes, this contributed to the early relapse in that patient. But you asked the question of whether or not applying the drug in the way that these patients received reduced the anti-leukaemic benefit from that treatment and the answer is yes.’ 233

22. The evidence of Associate Professor Wei

22.1. I know turn to the evidence of Associate Professor Wei who is a Clinical and

Translational AML Researcher and a Clinical Practitioner Fellow. In 2008 he joined

the Alfred Hospital in Melbourne to develop the AML research program, developing

230 Transcript, page 438231 Transcript, page 435232 Transcript, page 433233 Transcript, page 510

151

and leading, as Chief Investigator, 33 AML trials. He has been the AML Disease

Group Chairperson for Australasian Leukaemia and Lymphoma Group (ALLG) since

2009 and has led multiple nationwide cooperative group studies as Chief Investigator.

He is an Executive Member of the ALLG Scientific Advisory Committee. He is

Chair of the Cancer Council Victoria Clinical Network, a Member of the European

Leukemia Network working party and an abstract reviewer for the American Society

of Hematology meeting. He is also a Member of the Editorial Board of the

publication ‘Blood’ which is the reputable Blood Journal that has been referred to

elsewhere in these findings.

22.2. Associate Professor Wei is one of the contributors to a scientific publication entitled

‘Diagnosis and management of AML in adults: 2017 ELN recommendations from an

international expert panel’234. This article, which I shall mention in more detail in a

later section of these findings, suggests that in respect of intermediate and adverse risk

genetic AML in older patients greater than 60/65 years there was no established value

of intensive consolidation or consolidation therapy. It is fair to say that Associate

Professor Wei’s evidence in the inquest is in keeping with that proposition.

22.3. Associate Professor Wei provided a report dated 7 November 2017235. In that report

Associate Professor Wei supports a definition of greater than 65 years as defining

elderly AML. He cites the article to which I have referred and to which he was

signatory and reiterates that no consensus exists for the consolidation therapy of

elderly patients with AML. Similarly, he also asserts that there remains no

universally acceptable optimal standard consolidation therapy for elderly patients with

AML. Insofar as this implies that there are no accepted standards for the elderly at

all, I reject that for the reasons already given. There are a number of accepted

standards, and they apply to the elderly. The AGGL M15 study, that is to say the

standard that should have been administered in these cases, is one such standard.

22.4. Associate Professor Wei was asked to comment on evidence that Professor Gibson

gave236 to the effect that to Professor Gibson’s knowledge there were no widely

accepted and widely used consolidation regimens that involved once daily

administration of cytarabine in consolidation therapy. Professor Gibson had

suggested that it is a universally accepted pharmacokinetic rationale that once a day

234 Exhibit C19k and Exhibit C36, Tab 5235 Exhibit C36, Tab 1236 At Transcript, pages 146-147

152

administration is insufficient. To this proposition Associate Professor Wei opined

that Professor Gibson was correct in respect of adults below the age of 60-65, but that

the situation was less clear for older patients. In dealing with Professor Gibson’s

evidence Associate Professor Wei referred to the American NCCN guidelines of 2017

as representing the most authoritative set of guidelines in the USA. For post

remission therapy for patients over 60 years the NCCN recommended a number of

clinical measures that included the identical protocol to that which was intended to be

administered to the patients in question in this inquest, plus idarubicin. There is no

recommendation within those guidelines that once daily administration on alternate

days is appropriate. Relying on this guideline and other material, Associate Professor

Wei in his report asserts:

'Therefore, a wide variety of consolidation approaches have been adopted as acceptable in older patients with AML and there is no standard as stated by either the ELN or the NCCN guidelines.'

In addition, Associate Professor Wei asserts that in elderly patients there is no clear

relationship between dose or frequency of cytarabine use and clinical outcome. He

asserts that dosing regimens for consolidation in elderly AML vary widely between

infusion or twice daily and that no single approach is clinically accepted to be more

effective than any other approach. Insofar as these assertions were meant to suggest

that the erroneous regimen that was administered to the patients in question was a

known or acceptable consolidation regimen, this would have to be rejected. There is

simply no evidence that the erroneous regimen is one that is acceptable on any level.

Naturally, Mr Trim QC seizes upon this to argue that the erroneous protocol

administered to the patients in question has legitimacy. I reject that argument. On the

contrary, on any basis it has no legitimacy whatsoever.

22.5. The crux of Associate Professor Wei’s report is that there is no evidence that the

intended consolidation would have improved the clinical outcome within the four

patients who have died and in Mr Knox.

22.6. It is necessary to discuss here in more detail Associate Professor Wei’s oral evidence

regarding the purpose of the ALLG AML M15 study. The ALLG had considered that

standardisation of practice in AML chemotherapy was desirable. Secondly, it was felt

that the higher doses of cytarabine in consolidation therapy was not called for as the

emerging literature suggested that a dose of cytarabine above 1g/m2 was unlikely to

153

be beneficial. Following conferences in which experts around Australia had

participated, a consensus had been reached as to the most appropriate treatment to be

used for older patients, in this case older patients being defined as patients above the

age of 55 years. It was collectively agreed that the 7+3 protocol would remain the

appropriate induction protocol and that two cycles of consolidation of cytarabine at

1g/m2 twice a day on days 1, 3 and 5, with idarubicin, would also be appropriate. The

aim of delivering the highest tolerable dose was in the hope that most patients’

leukaemias would experience some degree of efficacy within that higher tolerable

range. Associate Professor Wei asserted, however, that what was still unknown was

the minimum effective dose. So the practice was to give as much as could be

delivered within acceptable tolerability. There was a balance to be struck between

maximum acceptable dose of chemotherapy to provide optimal efficacy on the one

hand and on the other the minimum amount of toxicity. Associate Professor Wei

explained that the M15 study was designed principally for older patients up to the age

of 65, the aim being that patients up to the age of 65 who had maintained remission

after consolidation therapy as described would be provided with a maintenance

therapy using the drug lenalidomide. To this end it was desirable that all hospitals

within Australia conform to the same protocols for induction and consolidation

therapy. As far as patients over the age of 65 was concerned, it was envisaged that

while they would receive the same chemotherapy regimens as persons younger than

65, including the same consolidation therapy regime, they would not be eligible for

the trial in respect of lenalidomide maintenance therapy. Thus it was that on the

background of the ALLG M15 study the RAH AML protocols were amended in July

2014. I note from that protocol, however, that the RAH protocol was said to apply to

persons of age 56 to 75 years. It was this protocol dated 15 July 2014237 that was in

error in that it only prescribed once daily administration of cytarabine in the HiDAC1-

IDA consolidation therapy where the M15 study had contemplated twice daily

administration.

22.7. Associate Professor Wei explained that the reason the trial was not intended to

include over 65 year old’s was that it is:

'… well-known that the outcomes of patients above the age of 65 were substantially worse than younger patients and hence including patients with a worse prognosis with a good (sic) means it will be very difficult to establish the benefit of the maintenance therapy.' 238

237 Exhibit C9a238 Transcript, page 2771

154

On can readily understand the desirability of avoiding trial outcomes being skewed by

the infiltration of less certain factors, but, as seen, the consolidation therapy would

still be made available to patients over 65 years regardless of their actual participation

in the study. And in any event, I have not seen it written or said that consolidation has

no benefit at all in the elderly cohort or that the practice of consolidation in that group

should be curtailed. Indeed, if it was thought that there was no benefit to be derived

from the practice within the elderly at all, on would have thought that by now every

effort would have been made to spare elderly patients from all of the terrible negative

side effects that the practice entails.

22.8. In his oral evidence Associate Professor Wei restated that there was a diversity of

approaches used in older patients, but I have already found that any suggestion that

the erroneous protocol adopted at the RAH and the FMC was in any sense an

accepted or acceptable protocol would have to be rejected.

22.9. Also in his oral evidence Associate Professor Wei suggested that within older patients

there is substantially higher resistance to the drugs that are used and that for this

reason considerations that include differing doses, differing frequency of doses, be

they daily or alternate daily, and whether the dose is low, high or intermediate have

not made a material difference in the overall survival of patients over the age of 60-65

years239. Associate Professor Wei stated that the sensitivity of the leukaemic cells in

older patients is much less because of more complex chromosomal or other

abnormalities such as the FLT3-ITD mutation and others. That said, Associate

Professor Wei acknowledged that he did not possess any trial data that compared

daily versus twice daily approaches, so in reality all that he could say was that the

impact of the unintended dose in these cases was uncertain. What Associate Professor

Wei was saying to the Court, I think, was that unlike in younger patients where

clinical trials have demonstrated certain benefits in consolidation therapy, there had

been no such trials in respect of the elderly, a matter that the literature does tend to

bear out. As a result, he opines that the minimum effective dose of cytarabine in older

patients is not known240. He was asked these questions:

'Q. Does that mean that the dose actually delivered here, may have had the same therapeutic benefit for this group of patients, as the intended dose.

A. It's a possibility.

239 Transcript, page 2784240 Transcript, page 2786

155

Q. One can't say one way or the other.

A. No.' 241

When asked whether an available extension of that proposition was that it was

possible that the once daily administration was detrimental in respect of the outcome

for these patients, Associate Professor Wei was somewhat vague in his response. He

said:

'We just don't know because we don't have any clinical outcome data with that specific regimen.' 242

Indeed, throughout the entirety of Associate Professor Wei’s evidence he

demonstrated a conspicuous reluctance to make any kind of acknowledgment or

concession that the erroneous frequency of dosage had or even could have had any

detrimental effect. He did say that the only answer that he could give was that twice

daily dosing is based upon pharmacokinetic principles of maximum exposure to cells,

a matter that the pharmacologist Professor Boddy was at pains to point out and which

I unhesitatingly accept243.

22.10. When questioned by me as to whether anyone had ever suggested that once daily

administration on alternate days has the necessary efficacy, Associate Professor Wei

said that he was not aware of any information that would make us sure that it was

adequate. However, he agreed with the proposition that nobody in their right mind

would start treating any patient on that basis except perhaps in older patients with

abnormal kidney function244.

22.11. In cross-examination Associate Professor Wei told Mr Griffin QC for the families of

the deceased and for Mr Knox and Ms Crannage that the intended consolidation

therapy regimen was a regimen designed to provide acceptable levels of toxicity with

the goal of trying to eliminate as many leukaemic cells as possible245. He also agreed

with Mr Griffin QC that in achieving that goal one would need to regard the

frequency with which the drug is delivered, together with its infusion time and the

number of days over which it is delivered, as representing elements that were based

241 Transcript, page 2788242 Transcript, page 2788243 Transcript, page 2790244 Transcript, page 2792245 Transcript, page 2827

156

upon pharmacokinetic principles that dictated the optimal way of delivering the

drug246.

22.12. Also in cross-examination by Mr Griffin QC, Associate Professor Wei acknowledged

that the erroneous once a day administration over days 1, 3 and 5 had not been seen or

employed under any approved or recommended protocol. He also agreed that he

would not recommend it himself; he said ‘we wouldn’t recommend it on the basis that

we haven’t seen it being used and we don’t know what its clinical efficacy is’247.

When Mr Griffin QC put to Associate Professor Wei that once daily delivery would

not maximise the anti-leukaemic effect of the drug, Associate Professor Wei gave a

long answer:

'If you reduce the leukemic burden by 90% and then 90% when you next give it, I guess my point is that, if you're doing this in a petri dish where you know exactly that the cells are dividing every 12 hours, then that frequency is important. In a patient where, as you've mentioned, there's divisions broad spectrum, it could be 12 hours, it could be two days, it could be three days, the reason I'm sitting on the fence about what you're trying to say is that, I don't know whether giving it on day 3 may have been the perfect time to give that treatment, because that's when the patient's cells were dividing and then we reduce 90% of the leukaemia at that point. However, if we gave it 12 hours and they weren't dividing, it could have been ineffective. That's the difficulty of treating leukaemia in patients and the lack of confidence we have with knowing exactly what the minimum effective dose and schedule is, particularly when the leukemic cells are so resistant to begin with.' 248

The reference to the cells dividing in that passage is, of course, a reference to the need

for the drug to be active during the S phase of cell division. Associate Professor

Wei’s assertion that ‘if we gave it 12 hours and they weren’t dividing, it could have

been ineffective’ to my mind ignored the need for the patient to be exposed to the anti-

leukaemic effect for as long as possible and as frequently as possible. The purpose of

providing 12 hourly administration is to maximise the likelihood of the drug being

active when cells are dividing. It stands to reason that the more frequent the

administration, the greater the likelihood of the drug being active during that phase of

the cell cycle and therefore the greater the likelihood that more leukaemic cells will be

eliminated. As Professor Boddy opined, as seen earlier, the S-phase of the cycle is a

continuous circumstance, not one that occurs from time to time. Frankly, I do not see

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157

the logic in Associate Professor Wei’s analysis as set out in the above answer and I

reject it.

22.13. On the other hand, the uncertainty surrounding cell resistance to drug therapy in the

elderly is another matter, and a matter to which I have given anxious consideration.

Associate Professor Wei testified that in the elderly cell resistance to chemotherapy

was likely to lessen the therapeutic effect of the treatment. He told the Court that

acute leukaemia in older patients expresses more mutations that inherently are

resistant to the chemotherapy. As well, there is a greater frequency of leukaemic cells

in the elderly that have what are termed ‘drug pumps’, that is to say cells that tend to

pump the drug out so that no matter how much drug you introduce into the patient the

cell is going to pump it straight out249. Professor Boddy, as seen above, also referred

to the concept of drug pumps, but he suggested that the concept had limited

application to the drug cytarabine. I prefer the evidence of the pharmacologist

Professor Boddy on the subject of drug pumps and find that the concept has no

application to the issues concerning the efficacy of cytarabine consolidation therapy

in the elderly.

22.14. However, when the point was made to Associate Professor Wei by Mr Griffin QC that

increased resistance by the leukaemic cell to this therapy would point to an even

greater need for strict adherence to the recommended regimen of delivery, Associate

Professor Wei repeated that this line of thinking would not necessarily apply in older

people because in elderly patients the leukaemic cells are inherently resistant to being

fully eliminated. On the same topic Mr Griffin QC posed the following question and

Associate Professor Wei gave the following answer:

'Q. And so it's obvious, is it not, that you would not be happy about such a therapy being administered that significantly diminished the exposure of that person to the antileukemic drug during the period of that particular administration of the consolidation.

A. I would be not happy if that was our protocol and somebody didn't give the protocol because of an error. But if as a unit we had agreed on a different protocol, the ones that I've mentioned before, and that was delivered, I wouldn't be unhappy. ' 250

It seemed to me that this was a simple question, the answer to which was obvious,

namely an affirmative answer. It also ignored the fact that on the evidence presented

at the inquest no agreement has ever been reached that the erroneous protocol as used

249 Transcript, page 2839250 Transcript, page 2836

158

in these cases is appropriate. As Associate Professor Wei’s cross-examination by

Mr Griffin QC proceeded it seemed to me that he stopped short, albeit not very much

short, of advocating a proposition that consolidation chemotherapy was virtually

valueless in the elderly. In any case I would reject such a proposition as simply

unsupportable having regard to established clinical practice.

22.15. Associate Professor Wei was cross-examined about the fact that persons over the age

of 65 years, although not participating in the M15 trial, do receive the same

consolidation therapy under the protocol as persons between the ages of 55 and 65

years. Associate Professor Wei acknowledged that in respect of the older patients

who do not undergo the trial, it has never been suggested that in their case they could

be trialled on once a day administration on days 1, 3 and 5 251. Associate Professor

Wei added that if one was to ask another haematologist whether once a day

administration would make any material difference, they would probably say

‘probably not’252. In the light of that assertion, the obvious question was posed to

Associate Professor Wei as to why once a day administration was not routinely tried

in patients over 65 years. To this Associate Professor Wei stated that once a day

administration is indeed provided to this age group but acknowledged, as he must,

that such a regime involved once daily administration every day and not on alternate

days253.

22.16. Later in his evidence Associate Professor Wei pointed out that even in older patients

who have favourable cytogenetics and molecular factors such as the presence of the

NPM1 mutation together with the absence of the FLT3-ITD mutation, a circumstance

that is broadly accepted as giving rise to better prognosis, there are other genes within

the patient that may not be known and which would substantially reduce the survival

outcomes of those patients254. He did agree that there was some significance in an

elderly patient having those two favourable characteristics and agreed that such a

patient would do better because they are more likely to respond favourably to

chemotherapy because of a lesser resistance to it255.

22.17. If I understood the evidence of Associate Professor Wei correctly, it is that the

resistance to therapy within an individual cannot be known with certainty due to the

251 Transcript, page 2848252 Transcript, page 2849253 Transcript, page 2849254 Transcript, pages 2866 and 2871255 Transcript, page 2876

159

possible presence of adverse and unknown molecular factors peculiar to, or at least

more commonly experienced in, the elderly such that the efficacy of consolidation

therapy in an individual cannot be predicted with certainty. On the other hand, I did

not understand him to be saying that consolidation therapy with cytarabine has no

benefit in the elderly whatsoever. I would reject that notion in any case as it would be

completely contrary to established clinical practice in respect of the treatment of

elderly AML patients. The point is worth making here that it is not as if consolidation

chemotherapy in the elderly is an undertaking to be taken lightly or merely in hope.

Regardless of its efficacy in an individual patient, it is not without its serious adverse

consequences for the patient in terms of its side effects.

22.18. Associate Professor Wei commented upon the individual cases with which this

inquest is concerned. Regarding Mrs Pinxteren, Associate Professor Wei

acknowledged that her remission duration of less than three months was a short period

of remission. The question in her case was whether that was consistent with her

clinical and biological characteristics. Although in her case the NPM1 factor was a

favourable factor, other molecular factors that were unknown may have explained

why in her case there was a resistance to chemotherapy such that the patient had such

a quick relapse256. Associate Professor Wei acknowledged that from his point of view

Mrs Pinxteren’s was the clearest example of a very early relapse. He suggested that

he would take a more cautious approach to Mrs Pinxteren’s case. She was of

advanced years. Although she had the NPM1 mutation which is associated with better

outcomes, if she had myelodysplastic syndrome leading to secondary AML, it would

have been difficult to produce a long term remission because eradication of the

myelodysplastic clone is difficult even with intensive chemotherapy257. In the event

he agreed with Professor Gibson that in respect of Mrs Pinxteren it was not possible

to say that the non-protocol dosing contributed to her less than expected outcome258.

22.19. Regarding Mr McRae, Associate Professor Wei suggested there was a question mark

as to whether or not Mr McRae had in fact achieved complete remission. He had

demonstrated persistent myelodysplasia after having intensive chemotherapy. There

may have been persistent erythroleukaemia suggesting perhaps a poorer prognosis.

On the whole Associate Professor Wei suggested that in Mr McRae’s case it was not

256 Transcript, page 2804257 Transcript, page 2802258 Transcript, page 2796

160

possible to make an assessment as to whether he did better or worse than would

normally have been expected259.

22.20. Regarding Mr Higham, Associate Professor Wei stated that it was impossible to say

one way or the other as to whether the consolidation dosage received by him had any

deleterious effect or whether he fared worse than expected having regard to his

remission duration and overall survival260.

22.21. Regarding Mrs Bairnsfather, Associate Professor Wei pointed out that she was of

monosomy 7 which was an adverse finding. He suggested that it was not possible to

say that the consolidation chemotherapy had any deleterious effect, or that having

regard to her survival duration she had a worse outcome with the therapy that had

been administered to her.

22.22. Associate Professor Wei suggested that in the case of Mr Knox it was not possible to

draw any conclusions to whether the actual dose administered had any deleterious

effect. In cross-examination by Ms Kereru of counsel assisting, Associate Professor

Wei stated that he would ‘just’ put Mr Knox into the elderly AML category. He

acknowledged that the presence of the NPM1 mutation and the absence of the FLT3-

ITD mutation were circumstances in Mr Knox’s favour. Associate Professor Wei

dealt with Professor Gibson’s opinion that having regard to Mr Knox’s age, to his de

novo AML and to his good prognostic markers that his was probably the most clear

cut case of an outcome that was less than might reasonably have been expected. To

this proposition Associate Professor Wei said that it was difficult to be sure about that

without knowing the status of other genes in this patient, one of which at least is

known to reduce the survival outcome of patients with the NPM1 mutation. In any

event the timing of Mr Knox’s relapse was consistent with the favourable NPM1

mutation in his case because two years of remission is towards the middle to upper

boundary of what would be expected in a patient in that category.

22.23. As to the so-called catch-up rounds, Associate Professor Wei indicated that in the case

of Mr Higham and Mr Knox the additional rounds of chemotherapy represented

appropriate therapy, but opined that there was no evidence that the extra treatment

was obviously beneficial261. Similarly, in cross-examination by Ms Cliff of counsel,

Associate Professor Wei did not have anything adverse to say about any delay in the

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161

administration of the catch-up rounds and suggested that there were reasonable

clinical circumstances that explained time lapses between the conclusion of

consolidation and the administration of the catch-up round in either case. In the

event, I am not prepared to contend otherwise.

23. The evidence of Professor John Gibson

23.1. I turn to the evidence of Professor John Gibson who is a Fellow of the Royal College

of Pathologists of Australasia, a Fellow of the Royal Australasian College of

Physicians and a Fellow of the First Faculty of Science. He has medical degrees with

first class honours as well as a Doctor of Philosophy. He is the Senior Staff

Specialist, Institute of Haematology at the Royal Prince Alfred Hospital. He is also

Head of the Department, Institute of Haematology at the Royal Prince Alfred

Hospital. He is the Alan Ng Professor of Haematology, Faculty of Medicine,

University of Sydney.

23.2. Professor Gibson had originally been tasked to provide an expert opinion in relation

to the treatment for AML of Mrs Pinxteren, Mr McRae and Mr Higham. His report

was tendered to the inquest262. Upon the death of Mrs Bairnsfather he was asked to

provide a similar expert report in relation to Mrs Bairnsfather’s treatment. Ultimately

Professor Gibson also provided a report in relation to the treatment of Mr Andrew

Knox.

23.3. Like Professor Boddy, Professor Gibson emphasised the importance of twice daily

administration in order to maintain adequate levels for long enough for the drug ‘to

do its job’263. He was asked to comment on the consolidation protocol under which

the affected patients were treated and stated that once daily administration ‘would be

predicted to be less optimal’264. He added that by weight of experience there is good

reason for not administering cytarabine once daily and that based upon the

pharmacokinetics of the drug this would be suboptimal265.

23.4. Before dealing with the patients whose treatment is the subject of this inquest

Professor Gibson made the observation that it is impossible for him to predict

absolutely what would happen in an individual patient who received suboptimal

262 Exhibit C1263 Transcript, page 94264 Transcript, page 95265 Transcript, page 96

162

treatment in consolidation chemotherapy. However, he asserted that based upon the

known pharmacokinetics of the drug cytarabine, on clinical experience and on the fact

that cytarabine is given twice daily, one would have to assume that once daily is not

the optimal way to give it266.

23.5. Professor Gibson also dealt with two other general topics. I have already referred to

Professor Gibson’s opinion that there is an important correlation between early

relapse and diminished period of survival. He also stated that in his view it would be

dangerous to draw any unifying comment about patient outcomes from examining a

cohort of only 10 affected patients. In other words, it would not be possible to draw

conclusions in a given case from the outcomes of the persons involved in the

remaining nine cases267. Professor Gibson also specifically stated that this was so in

the case of Mr Knox. He opined that there was nothing in the history of Mr Knox and

the notes that he had examined in respect of him that throws any further light on the

conclusions in respect of the cause and circumstances of the deaths of the four

deceased persons268. I accept that evidence. However, for reasons already expressed,

in my view the circumstances surrounding the underdosing of Mr Knox were

nevertheless relevant in this inquest.

23.6. Professor Gibson was extensively cross-examined by Mr Trim QC on behalf of the

doctors concerning the efficacy of consolidation chemotherapy in elderly patients.

Professor Gibson acknowledged that Associate Professor Wei was an internationally

recognised authority on the treatment of AML and that he respected his knowledge.

The scientific paper that was authored by Associate Professor Wei and others, to

which I have already referred, was drawn to Professor Gibson’s attention. Professor

Gibson stated that the claim within the paper that there was no established value of

intensive consolidation therapy in the elderly was new information to him, but was

based upon a very authoritative group of individuals’ opinions. Similarly an ELN

guideline that claimed that for patients with intermediate adverse cytogenetics from

the age of 65 there is no established value of intensive consolidation therapy and that

there was no consensus in existence for consolidation therapy of elderly patients with

AML was also drawn to Professor Gibson’s attention. I will deal with this article in

another section below, but to my mind it does not support any positive suggestion that

266 Transcript, page 110267 Transcript, pages 261 and 266-267268 Transcript, page 692

163

consolidation chemotherapy for AML in the elderly is utterly superfluous. It needs to

be repeated that no person, nor the literature that I have read, has suggested that

consolidation therapy for the elderly should no longer be administered. Nor does this

paper nor any other piece of literature that I have seen support a contention that

consolidation chemotherapy can be administered in any manner of ways, including

only once daily on alternate days. This point is illustrated by the following question

and answer in the evidence of Professor Gibson:

'Q. Are they saying in that article that there is no benefit to be derived in patients aged 60 or above with the consolidation, is that your understanding of what they're saying there.

A. I don't think they're saying that, I think they're just saying nobody knows exactly the right way to give it, and there are a number of options that one can contemplate, one can use, and there are some that are more frequently used than others, such as the ALLG proposition of 2014. With increasing evidence in terms of how - and particularly subdividing patients into risk groups, the optimal therapy or what's considered to the optimal therapy changes with time. And that's something that is - that's life in terms of treating leukaemia. ' 269

As to the suggestion, spoken or unspoken, to the effect that the consolidation

chemotherapy can be given whimsically or haphazardly, Professor Gibson stated that

the authors are simply stating that there are a number of possible treatments that one

can consider for the individual patient and that many people would still consider that

cytarabine consolidation as outlined is a very standard and very acceptable therapy

when given in the split dose on alternate days270.

23.7. In questioning by me, Professor Gibson was asked:

'Q. What do you understand the purport of the expression 'No established value of intensive consolidation therapy'.

A. You could interpret that in two ways: my interpretation initially was that there is no value of that as the best consolidation. The other interpretation is there is no value of consolidation, but they don't actually say that. So I think that many people would still consider consolidation on value, but then it comes down to which consolidation regimen you think is the best for your patient.' 271

23.8. Professor Gibson agreed with Mr Trim QC’s proposition that in older patients

leukaemia is more resistant to chemotherapy, irrespective of the fitness of the patient.

Professor Gibson said that that was a valid generalisation272. I do not believe that there 269 Transcript, page 725270 Transcript, page 726271 Transcript, page 780272 Transcript, page 736

164

is any real controversy about that. However, that is not to say that either induction

therapy or consolidation therapy is pointless or has no efficacy whatsoever.

23.9. Professor Gibson provided the Court with an analysis of Mr Higham’s circumstances,

treatment and death. Professor Gibson identified a number of relevant characteristics

in Mr Higham’s AML. Mr Higham had a normal Karyotype of 46XY, but was

FLT3-ITD positive and had likely pre-existing myelodysplasia, the latter two

characteristics being unfavourable prognostic markers. Other risk factors including

his age and pre-existing medical comorbidities presented as risk factors that would

predict for a poor outcome following chemotherapy. Following Mr Higham’s

induction chemotherapy he attained remission, but there were persistent

myelodysplasia changes in his bone marrow. This circumstance would suggest that

Mr Higham was at risk of having a progression of his disease in the future such that

the chances of a relapse in his case were higher than otherwise. On the other hand,

the remission resulted in the FLT3-ITD being absent which Professor Gibson

described as a ‘nice result’273. However, the fact that he had this molecular

abnormality in the first instance was still to be regarded as a ‘bad marker’274. It

remained as a predictor of a poorer outcome notwithstanding that it was no longer

detected in remission.

23.10. Professor Gibson regarded Mr Higham’s consolidation therapy as involving

sub-therapeutic doses. During the course of his evidence Professor Gibson amended

the appropriate terminology from ‘sub-therapeutic’ to ‘non-protocol’. The reason for

this is that the expression sub-therapeutic implied that the patient did not receive a

complete therapeutic benefit and that this was the matter that in his view was

impossible to predict in an individual case. Professor Gibson said:

'All one can do is draw the assumption that based on population data and clinical trials and experience that this is not the right dose to achieve the optimum response.' 275

23.11. Professor Gibson commented upon Mr Higham’s ‘catch-up round’. He regarded this

as a very reasonable thing to have been undertaken. However, Professor Gibson was

not able to say what the efficacy of the catch-up round would have been compared to

the efficacy of a properly administered consolidation regime in the first instance. He

observed that there was no evidence base to demonstrate that the catch-up round was

273 Transcript, page 132274 Transcript, page 132275 Transcript, page 139

165

the correct strategy. He said that it could well have been the case that Mr Higham’s

outcome was exactly the same as if he had proper consolidation, but that was simply

speculation. He said he had no way to prove or deny that proposition.

23.12. Professor Gibson was questioned about Mr Higham’s relapse. Having regard to the

remission duration and period of survival, Professor Gibson stated that he found it

impossible to say what the impact of his erroneous cytarabine dosing might have had,

or what the effect the catch-up round might have been. However, taking into account

the myelodysplastic changes as well as the FLT3-ITD component of Mr Higham’s

presentation, Professor Gibson asserted, ‘he probably had a pretty reasonable

outcome in that context’276.

23.13. Professor Gibson also told the Court that Mr Higham’s period of survival was greater

than the median within population-based statistics. He said that if one examined the

population-based figures of outcomes of therapy in that age group, Mr Higham’s

outlook would have been above the median expected.

23.14. Professor Gibson was asked by me whether in the case of Mr Higham he discounted

the possibility that the incorrect frequency of dosage in his consolidation therapy

compromised his treatment. Professor Gibson said that he did not discount that

possibility277.

23.15. Professor Gibson then analysed Mr McRae’s circumstances. He said that Mr McRae

fitted into the elderly AML category. Mr McRae was diagnosed with acute erythroid

leukaemia of a sub-type that was considered to be a poor risk sub-type for AML. The

findings in his case were consistent with pre-existing myelodysplasia. He was of

normal Karyotype 46XY. In his oral evidence Professor Gibson explained that there

are particular characteristics of erythroid leukaemia that make it somewhat difficult to

manage. This sub-type of acute leukaemia is often associated with significant

cytogenetic abnormalities and often with a pre-existing myelodysplasia and is

therefore frequently quite difficult to treat278. In Mr McRae’s case the FLT3-ITD

factor was negative and this put him, in Professor Gibson’s opinion, into the

intermediate category of AML. However, overall the characteristics of Mr McRae’s

illness were predictors of a less than optimum outcome279.

276 Transcript, page 158277 Transcript, page 251278 Transcript, page 166279 Transcript, page 170

166

23.16. According to Professor Gibson, following his induction therapy Mr McRae’s

remission status at first was not entirely clear as his peripheral blood counts had not

returned to functional levels notwithstanding that his blast count was consistent with

morphological remission. A further bone marrow examination was consistent with

remission, but there was ongoing evidence of previous myelodysplasia in Mr McRae.

However, the recovery of Mr McRae’s neutrophils was quite significant and reflected

the fact that his bone marrow was starting to produce normal numbers of good cells.

23.17. Mr McRae underwent the erroneous consolidation chemotherapy. There were two

rounds.

23.18. Ultimately Mr McRae unfortunately relapsed. As seen earlier in these findings,

Dr Hotinski had noted that she explained the chemotherapy dosing error to the McRae

family and had noted ‘I am unsure if this contributed to the relapse, but of course this

is a possibility’280. Professor Gibson regarded that as a reasonably honest statement.

There had been non-protocol use of the drug during the consolidation chemotherapy

and therefore according to Professor Gibson ‘you would have to draw the assumption

that it could have contributed to a less than optimum response’281. However, he said

that extrapolating the population-based data to the individual was incredibly difficult.

Thus what Dr Hotinski wrote was probably not an unreasonable way of examining the

matter, so said Professor Gibson. Professor Gibson opined that Mr McRae’s period of

remission fell into the median for his age group and, while recognising that the

treatment was not in accordance with the protocol, it also had to be recognised that

there is significant variability around remission figures and for that reason it was

impossible to actually say in an individual case that the remission period was less than

expected or more than expected. Professor Gibson said that Mr McRae’s survival

period was reasonably within the realm of expectation and said that he did not believe

that it could be reflected back to the protocol deviations282. Specifically, when asked

whether he was able to link Mr McRae’s ultimate relapse and death with the non-

protocol doses of cytarabine in the two consolidation rounds, he said:

'Not absolutely, no.' 283

280 Transcript, page 205281 Transcript, page 205282 Transcript, page 211283 Transcript, page 214

167

23.19. Professor Gibson was asked by me whether in the case of Mr McRae he discounted

the possibility that the incorrect frequency of dosage in his consolidation therapy

compromised his treatment. Professor Gibson said that he did not discount that

possibility284.

23.20. I now turn to Professor Gibson’s analysis of Mrs Pinxteren’s situation. Mrs Pinxteren

had been significantly older than the other patients in this cohort. Professor Gibson

noted at least two identifiable risk factors that would predict for a poor outcome

following chemotherapy, namely her advanced age and her pre-existing medical

comorbidities. In addition, there was the not unreasonable prospect that

Mrs Pinxteren had pre-existing myelodysplasia.

23.21. Mrs Pinxteren was FLT3-ITD negative and was NPM1 positive, favourable factors.

23.22. In the event, Mrs Pinxteren only underwent one round of consolidation therapy. This

single round was delivered in accordance with the erroneous protocol. She did not

undergo a second consolidation round due to her relapse. In addition, her second

consolidation round had in any event been delayed due to an incomplete recovery

from the first.

23.23. Professor Gibson stated that there would be many places, particularly in North

America, where Mrs Pinxteren would not have been offered treatment. The data from

a North American study would suggest that for a person in her age demographic the

median survival with treatment was about three months. This was only one month in

excess of the median survival period without treatment. Professor Gibson made the

assumption that her treating team probably believed that induction and consolidation

therapy was the best strategy to maximise quality and quantity of life, a strategy that

he acknowledged was not inappropriate in her case, and indeed it had given rise to a

favourable result. So he expressed the overall opinion that Mrs Pinxteren’s outcome

was disappointing.

23.24. Professor Gibson believed that the result of Mrs Pinxteren’s induction therapy was a

good result. Although there were persisting myelodysplasia changes, her cytogenetic

abnormality had apparently disappeared. He said that hers was as good a result as one

could have expected in a person of her age. As to the overall outcome, Professor

Gibson opined that given the positive results from her induction therapy, it was a 284 Transcript, page 252

168

disappointing outcome for her to have relapsed so quickly after consolidation. He

said:

'My opinion is that’s actually quite a disappointing result for this lady, given her good response to the initial chemotherapy.'

Although he could not absolutely guarantee it, Professor Gibson suggested that he

would have expected Mrs Pinxteren to have remained in remission for longer. That

said, the outcome was within the realms of possibility. Such a short remission

duration was at the lower end of what people report in the literature. Asked therefore

whether it was a possibility that the incorrect doses of cytarabine in her one

consolidation cycle may have contributed to the disappointing early relapse, Professor

Gibson said that it was a possibility, just as the converse was true. As to the

suggestion made to her before her death that the underdosing in her case did not

matter much, Professor Gibson regarded that as an unprovable statement one way or

the other285.

23.25. In his written report Professor Gibson reported that Mrs Pinxteren’s remission

duration and survival, whilst at the lower end of parameters reported for similar

patients, would still fall within those reported in the medical literature. As such he

did not believe that it was possible to definitively state that the cytarabine

underdosing contributed to a ‘less than expected’ outcome. However, Professor

Gibson also expressed the opinion that the overall period of survival, while perhaps

not being inconsistent with publicised literature, was at the lower end of what one

would have hoped for having regard to her very good remission after induction.

23.26. Significantly, Professor Gibson stated that the duration of Mrs Pinxteren’s survival

could be explained by natural variations in responses to treatment, but having regard

to the lower end of expectation, particularly in somebody who had a remission with

the first treatment, the confounding variable would be the protocol deviation and that

this was a possible explanation for her outcome.

23.27. Professor Gibson provided the Court with an analysis of Mrs Bairnsfather’s treatment

and outcome. He described the prognostic characteristics of her disease.

Mrs Bairnsfather was in the elderly patient category although she did not have any

comorbidities that were relevant. However, underlying myelodysplasia had been

285 Transcript, page 245

169

identified as being likely to have pre-existed the diagnosis of AML and that this was a

poor predictor for outcome. Mrs Bairnsfather also had an adverse cytogenetic factor

which in her case was monosomy 7. This is an abnormality generally recognised as

an unfavourable prognostic circumstance. In addition, Mrs Bairnsfather was noted to

have leukaemia in her skin which is another well recognised adverse prognostic

factor. There was also possible central nervous system involvement in her disease as

well.

23.28. Mrs Bairnsfather underwent induction chemotherapy and attained complete remission

which included morphological, cytogenic and flow cytometry remission286.

23.29. In the event Mrs Bairnsfather only underwent one round of consolidation

chemotherapy. The second cycle was in the first instance delayed because her bone

marrow had not recovered to an acceptable level. Ultimately Mrs Bairnsfather did not

undergo a second cycle of consolidation chemotherapy. Instead a different regime of

azacitidine therapy was put in place. The one round of consolidation therapy that

Mrs Bairnsfather underwent was the erroneous therapy.

23.30. At one point in her treatment it was thought that Mrs Bairnsfather may have relapsed,

but a bone marrow biopsy in February 2015 suggested that there was no evidence of

relapsed leukaemia.

23.31. In September 2016 Mrs Bairnsfather underwent another bone marrow biopsy and the

conclusion on this occasion was that her AML had returned with multilineage

dysplasia. The abnormal clone had reappeared, that is the CD7 abnormality which

was the original adverse marker in her case.

23.32. Following her relapse Mrs Bairnsfather underwent other treatment including a

re-induction regime that was unsuccessful. In his report regarding Mrs Bairnsfather,

Professor Gibson states that Mrs Bairnsfather’s remission duration and overall

survival duration was consistent with the ranges reported in the medical literature,

especially when one considers the pre-therapy characteristics that she had including

the adverse prognostic features. In fact, Professor Gibson states in his report that

Mrs Bairnsfather’s reversion to myelodysplasia during her recovery from the first and

only consolidation therapy round may be considered at the lower end of expectation.

However, that scenario is well recognised. As well, the patient’s overall survival 286 Transcript, page 580

170

period was perhaps better than expected. In his oral evidence Professor Gibson stated

that given Mrs Bairnsfather’s adverse prognostic features at diagnosis, she probably

survived as long as one would have expected under those circumstances. Asked as to

whether Mrs Bairnsfather’s relapse could be linked to the one round of underdosing,

he said it was possible but not absolutely provable in her specific case because the

remission duration and overall survival fell within what is reported in the literature287.

23.33. Professor Gibson also dealt with Mr Knox’s circumstances. He produced an

individual report in relation to Mr Knox288. Mr Knox was younger than the four

deceased individuals, but was 65 and not far from his 66 th birthday. Professor Gibson

referred to Mr Knox’s characteristics as involving no significant comorbidities He had

an ECOG of 0 which is as good as one can get, a normal Karyotype, no evidence of

pre-existing myelodysplasia and the presence of the NPM1 mutation. All of these

factors were indicators of a better prognosis than otherwise. Mr Knox also had

FLT3-ITD negativity which in combination with the NPM1 mutation is a favourable

factor. Professor Gibson said ‘this would be a better result than others we have seen’,

referring of course to the four patients the subject of this inquest. Professor Gibson

placed Mr Knox in the de novo AML category and that the only adverse circumstance

in Mr Knox’s pre-treatment variables was his age. All this put him into the group that

would be expected to have a better outcome than average.

23.34. Mr Knox achieved a complete morphological remission following induction

chemotherapy. As well, the marker that had been used to monitor his leukaemic clone

had reverted to normal. Thus his result was essentially as good as one could have

hoped for. Professor Gibson was asked as to what could have been said by his

doctors to Mr Knox about his prognosis at that point. Professor Gibson answered as

follows:

'So I think one could now be more confident in leaning towards a better-than-average outcome. We would recommend at least two courses of consolidation treatment. There would be perhaps a one or 2% chance of mortality during those treatments, but the payoff for that is a prolonged remission and the potential for cure; albeit that would be, the cure would be the less likely outcome, given his age. But certainly one would expect a reasonably long remission.' 289

287 Transcript, page 609288 Exhibit C1c289 Transcript, page 628

171

23.35. Mr Knox underwent two rounds of consolidation therapy, both administered pursuant

to the erroneous protocol. In the light of the revelation that Mr Knox had undergone

the flawed consolidation chemotherapy he underwent a catch-up round using the

correct dosing. However, the third consolidation round was administered without

idarubicin. Professor Gibson stated that the third round was not an unreasonable thing

to administer, but as to its utility he said that this was ‘an evidence free zone’290.

However, he regarded the catch-up round as something that was ‘still less than what

is considered to be optimal’291. In this context he observed that although it meant that

Mr Knox had the total dose of cytarabine that he should have had, it ignored the

question of dose intensity and the time over which it was given. In his case the dose

intensity would have been less.

23.36. Ultimately Mr Knox relapsed in December 2016 which was a little over two years

after his original diagnosis. Asked as to whether that was a period that would be less

than one would expect for someone in Mr Knox’s condition, Professor Gibson said:

'So it is within the realms of possibility but it would be disappointingly less than one would expect but these things happen sometimes.' 292

In his report Professor Gibson stated that although Mr Knox’s remission duration fell

within the ranges reported in the literature, his cytogenetic/molecular profile at

diagnosis had suggested that he fell within a good risk group for his age and that his

outcome could perhaps be statistically predicted to be above the median. In his report

he also stated that based upon the fact that twice daily intermediate dose cytarabine is

believed to be the optimal therapy for AML consolidation, it would be possible to

postulate that Mr Knox’s duration of remission was less than expected. In his oral

evidence Professor Gibson put it in another way. He stated that if Mr Knox had been

administered the correct protocol consolidation his outcome would clearly be a

disappointment but not impossible. However, in the context of the sub protocol

therapy that he did receive it would be disappointing result but maybe a little bit more

expected. I took Professor Gibson to mean that the disappointing length of remission,

or at least a length of remission that was less than what may have been expected, is

explicable on the basis of the incorrect chemotherapy.

23.37. Professor Gibson stated as follows:

290 Transcript, page 638291 Transcript, page 639292 Transcript, page 646

172

'I think of the cases that I have reviewed, this is probably the most clear-cut one where the outcome was less than one might have reasonably expected.' 293

23.38. However, Professor Gibson acknowledged that he agreed with Professor Boddy that it

was possible that the first and second cycles of erroneous consolidation therapy

contributed to or brought about Mr Knox’s relapse, but said that this was ‘not

provable’294.

23.39. When Professor Gibson gave his evidence he had had the benefit of examining a

report from another expert, Dr Vaughan. I deal with Dr Vaughan’s opinions below.

In Dr Vaughan’s opinion, as expressed in his report, in Mr Knox’s case the reduced

dosage of cytarabine in the consolidation cycle was not fully compensated by the third

so called catch-up cycle and as a result there had been some reduction in Mr Knox’s

prospects of long term disease control or cure. Professor Gibson agreed that the third

or catch-up consolidation cycle probably would not have fully compensated for the

erroneous cycles and reiterated his opinion that Mr Knox’s relapse was

disappointingly shorter than he would have expected. He said that he could not be as

‘absolutely dogmatic’ as Dr Vaughan had been, but reiterated that of the five cases

that he had examined Mr Knox was the one most likely to have been affected by the

underdosing295.

23.40. Regarding Mr Higham, Professor Gibson said that he would not be as confident as

Dr Vaughan who expressed the opinion in his report that Mr Higham’s remission

duration would have been longer with correct doses of consolidation chemotherapy.

23.41. Regarding Mr McRae, Professor Gibson said that he had no way of knowing whether

Dr Vaughan was correct when Dr Vaughan opined that there had been some reduction

in Mr McRae’s remission duration as a result of the consolidation underdosing296.

Professor Gibson was of the view that it is impossible to be certain or to make a

definitive statement in respect of Mr McRae and his remission duration.

23.42. Regarding Dr Vaughan’s opinion in respect of Mrs Bairnsfather to the effect that the

under-dose in her one round of consolidation chemotherapy probably did not

materially contribute to a poorer outcome in her case, Professor Gibson repeated that

293 Transcript, page 653294 Transcript, page 654295 Transcript, page 657296 Transcript, page 661

173

she had experienced a reasonable prolongation of survival with azacitidine treatment

which meant that her overall outcome was well within expected limits297.

23.43. Regarding Mrs Pinxteren, Professor Gibson stated that in his opinion Dr Vaughan’s

view that with appropriate consolidation therapy Mrs Pinxteren’s disease may have

had a better outcome was possibly accurate but not provable.

23.44. In cross-examination Professor Gibson reiterated that all of the cases fell within the

range of expectation as far as the patients’ longevity was concerned298. He said that he

could not say yes or no to the proposition that it was possible that the patients

received a dose for them that gave them full therapeutic benefit299.

23.45. One matter that Professor Gibson repeated in his cross-examination was that in his

opinion Mr Knox’s disappointing length of remission and unexpected duration of

remission did not inform in relation to whether or not the outcomes of the four

patients who died had any connection with the underdosing in their cases.

24. The evidence of Dr   Stephen Vaughan

24.1. I have referred to Dr Vaughan in the preceding section. Dr Vaughan was the author

of a report that was commissioned by and provided to AHPRA. The report was in

turn furnished by AHPRA to this Court together with other material that was

summonsed by the Court. I assume that it was in Dr Vaughan’s capacity as an

adverse event investigator that he was commissioned by AHPRA to compile his

report.

24.2. Dr Vaughan is a haematologist and medical oncologist. At one time in his career he

was the Director of Medical Oncology/Haematology at Epworth Health Care across

its four campuses. At the time he gave evidence he was in that role. Dr Vaughan is

also a Clinical Associate of Haematology at the Royal Melbourne Hospital, although

he told the Court that that was a comparatively inactive appointment. He told the

Court that for about six months of the year he works as a locum for other

practitioners, both in medical oncology and in haematology. The remainder of his

time involves the investigation of adverse events. He is notified of all adverse events

within the areas for which he has responsibility. He also told the Court that he had

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174

responsibility for introducing computerised chemotherapy prescribing systems and in

the course of that task he conducted a number of interstate and overseas visits to

examine computerised chemotherapy prescribing. That involved prescribing for the

disease of AML. He told the Court that this also took into account prescribing for

elderly patients suffering from AML. The system that he devised is based on the eviQ

system which is an Australia-wide chemotherapy protocol system managed from

Sydney. Most Australia cities use that as their chemotherapy prescribing basis. I

heard other evidence about the eviQ system. The Queen Elizabeth Hospital has used

that system.

24.3. Dr Vaughan’s report300 was tendered to the Court and he gave oral evidence in the

inquest.

24.4. In his oral evidence Dr Vaughan testified in respect of a number of general matters

concerning the appropriate treatment for AML. Firstly, he repeated other evidence

that had been heard in the inquest to the effect that a person diagnosed with AML and

who remains untreated will probably die within two to three months. This of course

means that there is absolutely no doubt that cytarabine chemotherapy in both the

young and the elderly is effective. The fact that the four deceased and Mr Knox

achieved complete remission after induction chemotherapy is testament to that fact.

Naturally, the focus of Dr Vaughan’s evidence was the effect of consolidation

chemotherapy and whether in the individual cases, or indeed in general, strict

adherence to accepted protocols could have an adverse effect on length of remission

and longevity. Another general point made by Dr Vaughan which I unhesitatingly

accept is that strict adherence to protocols is absolutely essential. Throughout his

evidence Dr Vaughan was highly critical of suggestions, express or otherwise, that

known and accepted protocols can be departed from either in error or in a calculated

fashion. Dr Vaughan summed up his attitude to the adherence to protocol in the

following way:

'Absolutely. I find treating acute myeloid leukaemia a scary business and I'm sure it's for a practitioner and I'm sure it's equally scary for patients. You take patients and administer a treatment which may, depending on age, have a 10% mortality. You wipe out their normal bone marrow for two to three weeks and you have got to undertake to keep them alive during that period. I find it no less scary now after doing it for 35 years than I did initially. It's a dramatic intervention. It's justified because without the intervention as we have previously discussed, the survival is quite short. When you do

300 Exhibit C56a

175

scary things you have got to assure yourself you are doing - you are following the rules exactly and attention to detail is really important.' 301

I was impressed by this observation. It is obvious from the evidence that I have heard

that the administration of consolidation chemotherapy in respect of a person who has

achieved complete remission, including the elderly, is a serious undertaking. In the

elderly it can result in significant and debilitating side effects by reason of the

treatment’s toxicity. On many occasions during the course of his evidence

Dr Vaughan made the point that if it was thought that consolidation chemotherapy is

unlikely to be efficacious in the elderly, or that there was no evidence that it had

efficacy, then he would query why clinicians would nevertheless choose to administer

it. This was a question that in my view was really unanswerable other than by

reference to the fact that it is universally accepted in the haematology community that

consolidation chemotherapy should be administered to both the young and the elderly

in order to maximise the chances of a longer remission. As Dr Vaughan pointed out,

there are two broad objectives in the treatment of leukaemia, one being a cure for

younger people and the other being prolonged disease free survival in older people 302.

In either case Dr Vaughan convincingly pointed out to the Court that meticulous

attention to detail in the treatment of patients is important to minimise toxicity and to

maximise the chance of the two favourable outcomes that he described. In this regard

he referred to the principle of consolidating a remission as soon as the normal bone

marrow has recovered in order to exploit the difference and the delay between the

recovery of leukaemic cells and normal cells. Dr Vaughan stated that if the purpose

of the exercise is to attempt to eliminate leukaemic cells, then one has to expose the

leukaemic cell to the drug for as long as possible consistent with acceptable toxicity.

24.5. Dr Vaughan explained to the Court what he regarded as the ‘trade off’ between the

maximisation of duration of drug exposure in order to overcome cell membrane

resistance against the avoidance of excessive toxicity303. He said that he was of the

view that one would receive reduced effectiveness and reduced toxicity if cytarabine

in consolidation was only administered once daily on alternate days. He stated that

effectiveness and toxicity ‘run in parallel to some degree’304. He stated that the anti-

leukaemic effect of cytarabine would be reduced with once daily administration over

301 Transcript, page 2514302 Transcript, page 2515303 Transcript, page 2523304 Transcript, page 2523

176

alternate days. In accordance with the evidence that I heard as a whole, Dr Vaughan

said that he had never seen a once daily regime of administration on alternate days.

He said that such a regime does not adhere to the ‘trade off’ that he described earlier

in his evidence. In fact he stated that anyone with experience in the treatment of acute

leukaemia, be they a pharmacist or oncology nurse, should have been aware that the

protocol was not a widely used protocol in the consolidation treatment for AML305.

24.6. Dr Vaughan was naturally asked during the course of his evidence as to his views in

respect of the treatment of the elderly with consolidation therapy. Much of

Mr Trim QC’s cross-examination on behalf of the doctors was directed towards this

issue. As to the literature that had utilised expressions such as there having been ‘no

established value of intensive consolidation therapy’, Dr Vaughan said that the fact

that there may be no evidence of the kind that may be obtained by way of a clinical

trial does not mean that there is no evidence supporting the use of, in this case,

consolidation therapy in the elderly. In this regard he asserted that clinical judgment

and established practice could constitute evidence. He said that one does not need a

‘double blind trial’ to know that a particular therapy has an efficacious effect. He

said in respect of consolidation therapy:

'So there are parts of medicine where the trials don't tell you what the answer is; you're relying on principles, like, say, pharmacokinetics, you're relying on established practice, and you're relying on clinical judgment.' 306

Indeed, Dr Vaughan said that if one was to rely only on the evidence from randomised

double blind crossover clinical trials, one would be ‘paralysed’ in practice307. In short,

he stated that there are other types of evidence that one uses in practice all of the time.

Dr Vaughan was making these points to counter the suggestion that because there

have been no trials in respect of the efficacy of consolidation therapy in the elderly, as

distinct from in the young, that does not mean that consolidation therapy in the elderly

is of no practical use or has no effective efficacy.

24.7. Indeed, Dr Vaughan was of the opinion that the age of the patient becomes less

important once a remission had been achieved because induction therapy is a very

strong test of the patient’s functional status. If one survives induction one is regarded

as being tough. Dr Vaughan said it was not appropriate to examine statistics in

305 Transcript, pages 2531 and 2534306 Transcript, page 2539307 Transcript, page 2539

177

relation to all elderly patients across the board because one has to look at the

performance of those patients who achieve remission as was the case with the four

deceased and Mr Knox. He said that ‘these people are survivors’308. Thus in his

opinion in the elderly risk factors such as age and comorbidities are substantially

obviated by the fact that these elderly patients were ‘not all-comers’ but were

survivors who had entered complete remission309.

24.8. In cross-examination Dr Vaughan went further. He pointed out that evidence from

trials within the elderly where part of the experimentation was submitting patients to

only once daily administration on alternate days would ‘not get past the Ethics

Committee’310. Thus that evidence will never eventuate311. He reiterated that one’s

reasoning as far as efficacy of consolidation therapy in the elderly is concerned is

based upon the pharmacokinetics of the drug and the pharmacological principles

underlying it. He suggested that these principles do not change in the elderly.

24.9. Other general comments that Dr Vaughan made in cross-examination included that

although there was evidence that young people do better than the elderly, that doing

nothing in the elderly by way of consolidation is not an option312. As far as he was

aware in Australia all patients are given post-remission therapy. In fact he said he

would be extremely uncomfortable giving anybody between the ages of 60 and 70 no

post-remission treatment313.

24.10. In this regard Dr Vaughan made the valid observation that if it was thought that

consolidation therapy did not provide any benefit, the question would have to be

posed as to why the medical profession would expose patients to half dose

chemotherapy with all of the risks this would involve for the patient but with no

benefit. If it was to be seriously entertained that consolidation therapy had no benefit

in the elderly, providing half of that therapy would expose the patient to the all of

risks without any of the benefits314. I must say I was impressed with this point. It

made much sense.

308 Transcript, page 2543309 Transcript, page 2543310 Transcript, page 2643311 Transcript, page 2644312 Transcript, pages 2684-2685313 Transcript, page 2685314 Transcript, page 2686

178

24.11. Dr Vaughan disagreed with Associate Professor Wei’s conclusion that, in the absence

of evidence, it cannot be established that there was any detriment to the outcome of

the patients who were subjected to the erroneous regime. He said ‘I don’t agree with

that’315.

24.12. Dr Vaughan in a general sense also disagreed with Professor Gibson’s approach to the

use of statistics in analysing remission durations. He said that in a cohort of four or

five patients it is an inappropriate method of viewing the matter. Median survival is

reference to the whole population, not those who have achieved remission who have a

much better outcome. He said ‘it’s impossible statistically because four patients

statistically is just not enough to say anything’316.

24.13. Dr Vaughan also expressed a view in respect of the so-called catch up rounds and

suggested that they were delivered too late and that such an approach contained an

element of ‘winging it’317. On this topic he suggested that ‘consolidation delayed will

be less effective than consolidation given on time’318. He said that this observation

was in keeping with the general principle in leukaemia treatment that as soon as a

patient has recovered one does not delay further treatment. He said that it is believed

that delayed consolidation was less effective consolidation319.

24.14. Dr Vaughan also dealt with the five individual cases. Regarding Mrs Pinxteren he

told the Court that in his opinion the timing of her relapse was ‘in part’ related to the

underdosing of the consolidation having regard to the fact that in his view she

relapsed ‘fairly quickly’320. He agreed with Professor Gibson’s observation that her

short remission duration was at the lower end of what people report in the literature321.

However, Dr Vaughan told the Court that the consideration of her case was difficult

because in her case Mrs Pinxteren was not able to undergo a second cycle of

consolidation chemotherapy because of her inability to recover from the first. It was a

significant possibility that her relapse could be explained by her inability to receive a

second cycle of consolidation chemotherapy322. On the whole, he said that for those

reasons the erroneous single consolidation round may not have ‘made much

315 Transcript, page 2719316 Transcript, pages 2726-2727317 Transcript, page 2656318 Transcript, page 2755319 Transcript, page 2756320 Transcript, page 2567321 Transcript, page 2569322 Transcript, page 2567

179

difference to the leukaemic outcome’323. This evidence tended to support Dr Hiwase’s

assertion that for similar reasons the underdosing in Mrs Pinxteren’s case may not

have had only limited impact. In cross-examination regarding Mrs Pinxteren,

Dr Vaughan said that in a nutshell the underdosing impact could be described as ‘a

little’324.

24.15. Concerning Mr McRae, although there was some slight controversy as to whether he

had achieved complete remission and that his remission status was difficult, on the

whole he believed that Mr McRae had achieved complete remission325. He opined that

Mr McRae’s remission was shorter than what otherwise would have been the case and

that the main reason to explain that was the underdosing326. He said that in his opinion

the erroneous consolidation cytarabine impacted on his remission for the most part

because on pharmacokinetic principles one would think that incorrect doses would be

less likely to be effective327. As to Professor Gibson’s opinion regarding Mr McRae,

he again stated that he tended to disagree with Professor Gibson’s approach to

statistical matters and his reference to median survival rates. He said that of the

patients who achieve complete remission the survival would be significantly longer

than ten months because early deaths pull down the average328. In cross-examination

Dr Vaughan neatly summed Mr McRae’s situation up by suggesting that in his case

the underdosing made the task of keeping him alive a bit longer less likely to be

successful329. That said he did not believe that Mr McRae would have been cured.

24.16. Regarding Mr Higham, Dr Vaughan acknowledged the difficulties posed to

Mr Higham by his comorbidities, his myelodysplasia and the FLT3 mutation. That

said his remission was a good result, especially after one induction330. He opined that

the catch up round was too late331, but may have had some benefit332.

24.17. It was in the context of discussing Mr Higham’s case that Dr Vaughan dealt with

some of the matters as expressed by clinicians either to patients or to their general

practitioners. For example, in respect of Dr Beligaswatte’s assertion about a debate

323 Transcript, page 2573324 Transcript, page 2752325 Transcript, pages 2575-2577326 Transcript, page 2579327 Transcript, page 2580328 Transcript, page 2581329 Transcript, page 2743330 Transcript, page 2584331 Transcript, page 2588332 Transcript, page 2594

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surrounding dosage, Dr Vaughan said there is no debate about the frequency at which

cytarabine should be given and that was twice daily. The only debate concerned the

issue as to whether 3000mg should be given or whether 1000mg should be given and

that had been largely resolved in that 1000mg was considered to be as good as

3000mg333. So, he opined that the treatment given to these patients was not standard

treatment.

24.18. When asked as to whether in his opinion the chemotherapy underdosing impacted on

the duration of Mr Higham’s remission he said ‘I think so, yes’334. He said it was a

more difficult question to determine whether it had any effect on his longevity335.

Dr Vaughan summed up his opinion regarding Mr Higham in this fashion:

'So I'm saying probably he would have got a longer remission. Whether or not he would have had an improved survival, got out to the end of the curve where it's flat, it's hard to say.' 336

24.19. When asked if he could quantify how much longer Mr Higham’s remission may have

been but for the error, Dr Vaughan said that the short answer to that was no, but that

one would hope that he may have achieved another 6 to 12 months of remission337.

24.20. Regarding Mrs Bairnsfather, Dr Vaughan acknowledged that her monosomy 7 status

was a major difficulty for her. There was also the matter of her not undergoing a

second cycle of consolidation therapy due to her slow recovery. That said he

considered that her remission or ‘progression-free survival’ would have been

increased if she had received the intended dose of consolidation. He said ‘she would

have done better in terms of how long the leukaemia stayed away’338. He

acknowledged, however, that Mrs Bairnsfather would have relapsed ultimately but the

correct consolidation would have pushed the relapse ‘out a bit, maybe by several

months, up to six months as a guess’339. However, in cross-examination Dr Vaughan

suggested that he did not think that the underdosing in her one round of consolidation

had a major effect and he did not think that it shortened her lifespan340.

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24.21. Regarding Mr Knox, Dr Vaughan like the other experts placed Mr Knox in a better

prognostic category. He regarded Mr Knox as not being in the elderly category, albeit

not by much. He was a de novo AML sufferer. He opined that Mr Knox’s remission

would have been longer if he had received the correct consolidation therapy and

suggested perhaps that he may have even been cured341. The following passage of

evidence was given:

'Q. As I understand he was in remission for 25 months, so two years and a month.

A. Yes, so he's in remission for a long time and I would have thought with adequate consolidation that period would have been longer and/or maybe not relapsed.

Q. So do you think that Mr Knox, given what you know about his diagnosis of AML and his de novo status, would have been a candidate for cure had everything been in accordance with the correct protocols.

A. I think that's a possibility, but as I've previously discussed two objectives in AML, particularly - and I'm not sure I'm prepared to regard him as elderly, particularly in his presence, but two objectives, prolonging disease free survival, and cure. The worse the prognosis the more the emphasis is on prolonging disease free survival, the better the prognostic factors the emphasis is more on trying to cure them with conventional treatment and using transplant as a sort of backup if they relapse.' 342

24.22. Dr Vaughan regarded Mr Knox’s age as of limited significance343. He pointed out that

Mr Knox survived intensive treatment so the prognostic influence of age did not

feature much in his prognostication.

24.23. Dr Vaughan was critical of the timing of Mr Knox’s catch up round calling it too late

in its delivery.

24.24. Dr Vaughan agreed with Professor Gibson that of all the cases that had been

reviewed, that Mr Knox’s was probably the most clear cut case where the outcome

was less than one might have reasonably expected344.

25. The literature

25.1. A great deal of medical literature was tendered to the inquest and commented upon by

the expert witnesses. Some of the specific scientific articles tendered contained

references to protocols in respect of consolidation therapy for AML. The literature

also dealt with the issue of the efficacy of cytarabine consolidation chemotherapy in

341 Transcript, pages 2638-2639342 Transcript, page 2639343 Transcript, page 2640344 Transcript, page 2642

182

the elderly. Again, the material differed in terms of what was meant by ‘the elderly’

insofar as some publications suggested that it encompassed persons over the age of 60

as distinct from persons over the age of 65.

25.2. Not one article that was tendered to the Court suggested that once daily administration

of cytarabine on alternate days was a legitimate consolidation therapy protocol in

respect of any age group. Nor did the literature suggest that such a regime of

administration would have the same efficacy as twice daily administration. As to the

question of efficacy in the elderly in general, no article suggested in terms that

consolidation therapy in the elderly in any form was a pointless therapy. No article,

for instance, suggested that consolidation chemotherapy in the elderly should no

longer be offered. Indeed, none of the expert witnesses suggested this. Nor did any

of the clinicians called during the course of this inquest, that is to say none of the

clinicians who were involved in the promulgation of the RAH or FMC protocols or

had been involved in the treatment of the patients in question, suggested that

consolidation therapy was a pointless exercise generally or in any particular case or in

the elderly. That said, a recurring theme in a number of articles was to the effect that

while consolidation therapy had established benefits in younger patients as

demonstrated by the results of clinical trials and studies, there was no evidence from a

similar source that positively demonstrated a benefit in the respect of elderly patients.

To my mind that is a different thing from saying that because there is no trial evidence

that consolidation in the elderly is beneficial it must follow that there is no such

benefit.

25.3. I refer to a number of the articles. Some of the articles pre-date the events with which

this inquest is concerned and some of them post-date those events.

25.4. In an article entitled ‘Treatment of Older Patients with Acute Myeloid Leukaemia

(AML): A Canadian Consensus’ published online 5 May 2013 in the American

Journal of Blood Research, it is asserted that patients over 60 years of age comprise a

majority of those diagnosed with AML. This assertion is supported in other literature

that I need not refer to. The article suggests within its Abstract that treatment

approaches in that cohort are variable with many uncertainties and controversies. It

points out that patients over 60 have different biological and clinical features

compared to younger patients in that they are more likely to display cytogenetic

abnormalities and have a history of antecedent haematological disorder and

183

comorbidities that can limit treatment options and lead to reduced dose intensity. One

matter of particular relevance within the article is the assertion that patients with

favourable cytogenetic profile or normal karyotype with a favourable molecular

profile (for example NPM1 mutated – FLT3-ITD negative) should be offered

induction chemotherapy with ‘curative intent’. This is the profile that Mr Knox had

at the time of diagnosis. The article points out that most older patients receive

consolidation therapy, ‘although the magnitude of its benefit in older patients remains

unclear’ 345.

25.5. This article states that while the optimal number of post remission (consolidation)

cycles remains unclear, although one cycle may be sufficient, there is evidence in

younger patients based on retrospective data that consolidation using repetitive cycles

of HiDAC (3g/m2) is associated with improved disease free survival and overall

survival in certain patients.

'We therefore believe it is reasonable to utilize this strategy as well in older fit patients with these abnormalities. However, as HiDAC poses a higher risk of cerebellar toxicity in patients over age 60, such patients should receive a reduced HiDAC dosing schedule, e.g. 1-1.5g/m2 every 12 hours on treatment days 1, 3 and 5.' 346

Save for the addition of idarubicin, the appropriate schedule as described in the above

passage is precisely the cytarabine dosage schedule that was intended to be included

in the RAH protocol, the error of course being the omission to specify administration

every 12 hours (twice daily). The article makes a recommendation that in patients

who achieve complete remission and who are medically fit for chemotherapy, therapy

should be administered for those patients. This recommendation appears to apply to

both younger and older patients. The article also makes a recommendation that

conventional dose consolidation therapy is adequate in patients with adverse risk

cytogenetics347.

25.6. An article in the Blood Journal promulgated by the American Society of Hematology,

Stone and others, 2001 and entitled ‘Postremission therapy in older patients with de

novo acute myeloid leukemia: a randomized trial comparing mitoxantrone and

intermediate-dose cytarabine with standard-dose cytarabine’348 contains certain

observations in relation to the efficacy of post remission therapy in the elderly. The

345 Exhibit C36, Tab 8, page 7346 Exhibit C36, Tab 8, page 8347 Exhibit C36, Tab 8, page 9348 Exhibit C36, Tab 10

184

reference to de novo AML is a reference to patients who have no myelodysplasia

evident at the time of diagnosis.

25.7. This article states that the trials undertaken were unable to demonstrate an

improvement in disease free or overall survival time in older patients randomised to

an intensive post remission chemotherapy regimen. As well, the results suggested

that acute leukaemias in older patients are intrinsically resistant. The article states:

'Based on our results, it is reasonable to question the value of post remission therapy in older patients with AML. Given the certain relapse associated with no post remission therapy in mainly younger patients, most clinicians have been unwilling to conduct further clinical trials in older patients that include a no-treatment arm.' 349

This of course is an acknowledgement that in respect of older patients it would be

inappropriate to experiment with clinical trials in which consolidation therapy was not

administered. However, the article does indicate that within this age cohort, which I

understand from the article to be the 60 to 69 age group, a number of patients

experienced prolonged disease free survival and that favourable outcomes were only

associated with post remission chemotherapy. The article does not suggest that

consolidation chemotherapy in the elderly should be discontinued.

25.8. An article is contained in Leukemia Research 37 (2013), Hassaneine and others,

entitled ‘High-dose cytarabine-based consolidation shows superior results for older

AML patients with intermediate risk cytogenetics in first complete remission’350. The

Abstract to this article refers to the results of a study in patients greater than 60 years

of age which indicated that a high dose cytarabine consolidation regimen produced

superior outcomes in AML patients over 60 years of age with intermediate risk

cytogenetics. The article also refers to what the authors describe as a ‘dogma’351 that

intensification of post remission therapy is of no benefit in most older AML patients.

The article asserts that the study conducted, which is the basis of the article, calls into

question that dogma and indicates that the results suggest that medically fit patients

aged 60 and over with intermediate risk cytogenetics should receive high dose

cytarabine consolidation therapy.

25.9. A Haematologica article by Sekeres entitled ‘Treatment of older adults with acute

myeloid leukemia: State of the art and current perspective’ December 2008, asserts

349 Exhibit C36, Tab 10, page 552350 Exhibit C36, Tab 11351 Exhibit C36, Tab 11, page 559

185

that no randomised study has shown that in older adults some amount of post

remission therapy provided a survival advantage over no post remission therapy. That

there has been no such study appears to be universally accepted.

25.10. An article in the New England Journal of Medicine, Dohner and others, entitled

‘Acute myeloid leukemia’ 2015352, suggests that patients with favourable ELN genetic

risk and no co-existing conditions should receive intermediate dose cytarabine every

12 hours on days 1-3, which is a recognised consolidation regimen, but for patients

with unfavourable genetic risk, co-existing conditions or both, that no value of

intensive consolidation therapy has been established.

25.11. Tendered to the Court was a publication entitled ‘Leukemia’ published in 2005 that

contains what appears to be a keynote address by J M Rowe of the Department of

Hematology and Bone Marrow Transplantation, RAMBAM Medical Center and

Technion, Israel Institute of Technology. The keynote address is entitled ‘Is there a

role for post remission therapy in older adults with acute myelogenous leukemia

(AML)?’. The publication asserts that as of 2005 there had never been a formal study

addressing the question encapsulated in the title of the keynote address in a manner

similar to a study that had taken place in younger adults. I understand from the

literature as a whole that such a study has not since been undertaken. The article

further asserts that the need for post remission therapy has been unequivocally

established for younger adults, but that the issue is still open for older adults as it has

never been unequivocally demonstrated that offering any form of post remission

therapy affects ultimate long term survival in that cohort. The article postulates two

reasons for this, the first being that older patients tend to have biological features that

predict for a poor outcome, including intermediate and unfavourable cytogenetics,

myelodysplasia and leukaemic cell multi-drug resistance. The article also asserts that

the problem with older patients is not one of achieving an initial response. Rather, it

is the fact that no matter what one does, very few remain in remission and very few

survive. It will be remembered of course that in all of these cases remission was

achieved after induction chemotherapy. The article also asserts that there was little

evidence to justify administration of maximally tolerated consolidation.

25.12. I now turn to literature that was published at around the time of, or subsequent to, the

events with which this inquest is concerned. Firstly, I refer to an article in ANN

352 Exhibit C19l

186

Hematol entitled ‘Big data analysis of treatment and patterns and outcomes among

elderly acute myeloid leukemia patients in the United States’353 by Medeiros and

others, published online on 20 March 2015. This article points out that in the USA

the median age at diagnosis of AML is 66 years and that the incidence of the disease

increases with age, with over half of the patients diagnosed at 65 or older. The article

asserts that fewer than half of elderly patients receive anti-leukaemic therapy, that

their outcomes remain dismal and that even after successful induction of remission,

disease relapse is inevitable in the majority of cases despite additional post remission

therapy. However, in its Conclusion, the article states that age alone should not deter

the use of guideline recommended therapies in AML. It then goes on to suggest that

anti-leukaemic regimens should be strongly considered in the majority of older

patients, but that even with treatment, outcomes remain dismal. This observation of

course is based upon the obvious success rate of induction chemotherapy and is not

necessarily a reflection of the efficacy of consolidation chemotherapy. In short, the

article is somewhat silent about the efficacy or value of consolidation chemotherapy

as distinct from induction chemotherapy.

25.13. An article published in the Journal of Clinical Oncology, volume 33, dated 1 April

2015 by Ostronoff and others, is entitled ‘Prognostic significance of NPM1 mutations

in the absence of FLT3-internal tandem duplication in older patients with acute

myeloid leukemia: a SWOG and UK National Cancer Research Institute/Medical

Research Council report’354. The conclusion expressed within this publication is that

NPM1-positive/FLT3-ITD-negative genotype remains a relatively favourable

prognostic factor for patients with AML age 55 to 65 years but not in those aged

greater than 65 years. The body of the article also suggests that as far as the age

bracket of greater than 65 years is concerned that the favourable genotype should not

be considered a favourable risk factor ‘at least not for those treated with standard

induction followed by conventional consolidation’. On the other hand, a study

reported in 2013 by Daver and others published in Clinical Lymphoma Myeloma

Leukemia suggested that patients of 65 years or older who were NPM1 mutated and

FLT3 wild type had significantly improved survival with cytotoxic chemotherapy.

This article does not specifically discuss the benefits of consolidation chemotherapy.

353 Exhibit C36, Tab 4354 Exhibit C36, Tab 12

187

25.14. Mr Knox was NPM1 mutated and was FLT3 wild type and no evidence of

myelodysplasia.

25.15. I now refer to two articles that were published towards the end of 2016. The first

article is published in the American Journal of Hematology in December 2016 entitled

‘Karyotype Plus NPM1 mutation status defines a group of elderly patients with AML

(≥60 Years) who benefit from intensive post-induction consolidation therapy’355. The

article is by Sperr and others. This paper was based on an analysis of 192 consecutive

patients who were de novo AML and aged 60 years or older who were treated with

intensive chemotherapy. De novo AML is AML that is not accompanied by

myelodysplasia so its application does not have universal significance in terms of the

patients under discussion in this inquest. However, the article does express a number

of conclusions as follows:

In the elderly who are eligible for intensive chemotherapy, the same protocols as

applied in younger adults with AML are administered.

Compared to younger patients the outcome is poor for the elderly because of co-

existing unrelated disorders and/or adverse molecular and cytogenetic parameters.

When treated with post remission therapy, long term survival and continuous

complete remission may also be achieved in elderly persons.

Overall the survival in AML patients receiving intensive chemotherapy and full

length consolidation is superior compared to those receiving palliative treatment.

In general, intensive post remission treatment with repetitive cycles of

chemotherapy is considered essential to maintain continuous complete remission

in patients with AML.

It has been previously shown that a consolidation protocol employing cytarabine

at 2 x 1g/m2 on days 1, 3 and 5 for up to four cycles in patients aged 60 and above

is an effective and well tolerated consolidation therapy.

In the elderly with complete haematologic remission no one generally accepted

consolidation strategy is available.

Most patients with cytogenetically normal AML without the NPM1 mutation did

not achieve long term continuous complete remission despite intensive

consolidation.355 Exhibit C36, Tab 16

188

25.16. It will be seen from this article that the consolidation therapy that is contemplated for

the elderly, plus idarubicin, consists of the very consolidation therapy that was

intended to be administered to the patients who are the subject of this inquest. The

other matter that arises from the article is that although it states that there is no

generally accepted consolidation strategy available, it does not support the proposition

that existing consolidation therapy protocols can legitimately be departed from in a

manner that is reflected by the erroneous protocol utilised in this case. On the

contrary, it advocates the use of the consolidation therapy protocol that should have

been utilised in the case of the four deceased persons and Mr Knox.

25.17. The second recent article that I shall refer to is an article in the Blood Journal

originally published online on 28 November 2016 authored by Dohner and others

including Associate Professor Andrew Wei to whom I have referred and who gave

oral evidence in this inquest. The article is entitled ‘Diagnosis and management of

AML in adults: 2017 ELN recommendations from an international expert panel’356. I

have referred to this article earlier. This article deals with many aspects of AML

treatment including consolidation chemotherapy in the elderly. The article states:

'Intensified postremission chemotherapy in high-risk patients, especially older patients is without clear benefit.'

A table that sets out selected conventional care regimens for patients with AML357

recommends for favourable risk genetics patients greater than 60/65 years of age a

number of cytarabine consolidation regimens that are administered on a daily basis,

either once a day or every 12 hours. In respect of intermediate/adverse risk genetics

patients it asserts there is ‘no established value of intensive consolidation therapy’ and

then recommends consideration be given to other treatments. This statement was

seized upon by Mr Trim QC on behalf of the doctors as suggesting that there is in fact

no value in intensive consolidation therapy in elderly persons with intermediate or

adverse risk genetics. However, in reality all the article is asserting is that in the

elderly there is no conclusive evidence as to the value of the therapy. It does not

assert that it has no value at all or that it has been conclusively established that it has

no value. Interestingly, the table also recommends intensive induction chemotherapy

for all ages with the footnote that older patients greater than 65 years of age and

patients with adverse genetics are less likely to respond to conventional induction

356 Exhibit C36, Tab 5357 Table 8

189

therapy and might receive alternative therapy. It is of note that all of the patients the

subject of this inquest, despite their respective ages, broke this mould as they did

respond to conventional induction therapy insofar as they all entered complete

remission following induction.

25.18. The National Comprehensive Cancer Network (NCCN) guidelines were tendered to

the inquest. This is an American guideline for the administration of chemotherapy for

AML. Two versions of this guideline were tendered to the inquest. The first is

version 2.2014 ostensibly promulgated on 28 March 2014358. The other version is

3.2017 evidently promulgated on 6 June 2017359. The 2014 version for age 60 and

above in respect of AML post remission therapy where there has been a complete

response to induction therapy sets out a number of alternative therapies that include

two cytarabine regimens with either idarubicin or daunorubicin. Although neither of

these two regimens reflect the intended regimen in this case, both of them involve the

daily administration of cytarabine. The footnotes to this guideline refer to the

‘excellent outcome’ that had been reported for outpatient consolidation providing

another option for elderly patients.

25.19. The 2017 NCCN version is more detailed and this time includes the intended regimen

that should have been administered in this case but with midostaurin instead of

idarubicin. It does not set out any regimen that would involve once daily

administration on alternate days, that is to say the erroneous protocol. The regimen

set out in this document that would conform to the intended regimen in this case is

said to be appropriate for FLT3 mutation positive AML, an unfavourable prognostic

circumstance. Certainly, the guideline contains nothing to suggest that consolidation

therapy with cytarabine in the case of persons of or above the age of 60 is

inappropriate or should not be offered. The notes to the document repeat reference to

the ‘excellent outcome’ that was reported in the notes within the previous version of

the document.

25.20. A number of other published articles were tendered through Dr Ashanka Beligaswatte

during the course of his evidence. I refer to one of those publications. This is an

article within the Journal of Clinical Oncology, Volume 28, Number 4, February 1

2010 entitled ‘Favorable prognostic impact of NPM1 mutations in older patients with

358 Exhibit C19ma359 Exhibit C19m

190

cytogenetically normal de novo acute myeloid leukemia and associated gene – and

MicroRNA – expression signatures: a cancer and leukemia group B study by Becker

and others’. The article concerns a study involving 148 adults of or greater than the

age of 60 years of age with de novo cytogenetically normal AML. This of course

would include Mr Knox. The conclusion expressed in the article is that NPM1

mutations have favourable prognostic impact in older patients with cytogenetically

normal AML, especially those aged of or greater than 70 years. The article makes it

reasonably plain that in contrast to patients aged 60 to 69 years, those aged of or

greater than 70 years with NPM1 mutations had a longer disease free survival. The

article also makes a universally accepted observation that AML in older patients is

generally associated with poor prognosis, the worse outcome of older patients being

attributed to such factors as preceding haematologic disorders, over representation of

high risk cytogenetics or other adverse prognostic clinical characteristics. However,

the article suggests that the finding from the study was that in older cytogenetically

normal AML patients, NPM1 mutations had a favourable prognostic impact

independent of other molecular and clinical prognosticators. As well, although the

favourable outcome associated with NPM1 mutations was even more pronounced in

the oldest sub-group of or greater than 70 years, older age alone should not exclude

patients from more intensive chemotherapy. The article also suggests that the study

demonstrated that NPM1 mutations in older patients with CN-AML independently

predicted better disease free survival and overall survival.

25.21. The overall conclusion from the article is as follows:

'In conclusion, we show that NPM1 mutations constitute a strong, independent prognostic factor for favorable treatment response and survival in older patients with CN-AML treated with intensive chemotherapy. The gene - and MicroRNA - expression signatures of older NPM1 MUT CN-AML patients appear similar to those in younger patients, thereby suggesting that CN-AML with NPM1 mutations may be a single entity in all age groups.' 360

25.22. Conclusions from the literature

25.23. In my opinion the literature establishes the following propositions:

Whereas in a younger cohort of patients consolidation chemotherapy for AML has

been demonstrated as providing a benefit in terms of longer remission and overall

survival, and that this has been demonstrated by clinical trials, there is no

360 Exhibit C47e, page 75, article 9

191

evidence from a similar source that would support that notion in respect of elderly

patients. For these purposes elderly patients can be regarded as persons of or

above the age of 60 years.

However, this does not of itself mean that consolidation chemotherapy in elderly

patients suffering from AML has no benefit.

There are a number of reasons, however, why in the elderly patient with

unfavourable cytogenetic, molecular and other prognostic factors, that

consolidation chemotherapy for AML may not be as effective as it will be in a

younger patient. However, this is not to say that consolidation chemotherapy for

AML in the elderly patient will be of no therapeutic benefit.

There are a number of recognised and standard consolidation chemotherapy

regimens for AML in respect of the elderly. One of those regimens involves the

twice daily administration of cytarabine on alternate days 1, 3 and 5.

There is no evidence in the literature to support the notion that single daily dosing

of cytarabine on alternate days 1, 3 and 5 is a standard regimen of consolidation

chemotherapy for AML.

The literature generally does not discourage but in fact supports the notion that

consolidation chemotherapy should still continue to be administered to the elderly

in cases where remission has been achieved after induction chemotherapy.

26. Conclusions regarding causation

26.1. As indicated, I have accepted and preferred the evidence of Professor Boddy in

relation to the pharmacological and pharmacokinetic principles associated with the

chemotherapy drug cytarabine.

26.2. I have found that cytarabine is a schedule-dependent drug and that the recommended

frequency of administration is an important component in its efficacy. In particular,

the frequency of its administration is an important factor in eliminating leukaemic

cells at the time that they are within their S-phase. I find that administration on

alternate days where there is only one dose administration per day is likely to mean

that the optimum number of leukaemic cells in the S-phase will not be targeted and

therefore will be less likely to be eliminated. I find that once a day administration on

alternate days is in general likely to be less efficacious than twice daily administration

192

on alternate days. I find that the reduction in frequency will generally dictate a less

favourable treatment outcome and that this may be manifested in either a curtailed

duration of remission and/or duration of overall survival.

26.3. I find that as at the time with which this inquest is concerned, there were a number of

accepted standard consolidation therapies in respect of the disease AML. One such

standard therapy involved the twice daily administration of cytarabine on alternate

days at the dosage of 1g/m2 of body surface area of the patient. This prescription,

together with the administration of idarubicin, was the intended dosage that had been

recommended within the ALLG M15 study as being the appropriate dosage for

persons of or above the age of 56.

26.4. I find that a prescription for consolidation therapy that involved once daily

administration of cytarabine over alternate days was not a standard therapy and was

not recognised as a standard therapy. It will be recalled that this was the therapy that

was administered to the four deceased patients and Mr Knox, together with idarubicin.

It has to be borne in mind that the dosage had been significantly reduced from the

previously recommended higher dosages of 3g/m2 or 2g/m2 of body surface area. The

reduction in those dosages was a reflection of a consensus that the higher dosages

were probably no more efficacious than lower dosages but would increase toxicity

over and above lower dosages. However, there was never any intention that the

frequency of administration when administered over alternate days would also be

reduced. I find that the addition of idarubicin was not in any way intended to allow

for a reduction in frequency of administration of cytarabine, nor had any expert or

scientific or other publication suggested the same. There was no basis for any

clinician to conclude that the addition of idarubicin could mean that the frequency of

administration of cytarabine could be reduced. Indeed, the dosage of cytarabine had

in any event been reduced by way of it being halved or by way of it being reduced to

two thirds of what it originally had been. It is therefore no surprise that Associate

Professor Yong in her email suggested that what had been administered to the

affected patients was ‘such a low dose’.

26.5. It is to be accepted, and I find, that in a younger cohort of AML patients it has been

demonstrated that consolidation chemotherapy has efficacy. I also accept and find

that it has not been proven through any clinical trial or study that in the elderly,

consolidation chemotherapy has efficacy or that if it has efficacy to what extent it has

193

efficacy. However, I find that this fact alone does not mean that consolidation therapy

in the elderly has no efficacy. That said, I find that in general elderly patients, that is

to say persons above the age of 60 years, and particularly those with unfavourable

cytogenetic and molecular markers and those who have pre-existing myelodysplasia,

are less likely to respond favourably to consolidation chemotherapy for the disease

AML.

26.6. I find that all of the deceased patients and Mr Knox were in the elderly category of

patients.

26.7. In my opinion, each of the four deceased and Mr Knox received consolidation

chemotherapy that was potentially less efficacious than the consolidation

chemotherapy that was intended for them. To my mind, it was likely to be less

effective in eliminating residual leukaemic cells than would have been the case if they

had been administered cytarabine twice daily and not once daily. I do not accept that

cytarabine consolidation therapy in the elderly has no efficacy. The fact that it can

have efficacy and prolong remission and overall survival durations is reflected in the

fact that it is still administered to the elderly despite its toxicity and its manifest

potential to cause debilitating and dangerous side effects.

26.8. However, I do not believe that it is possible for this Court to conclude in any of the

five cases which this Court has examined that any remission period or period of

overall survival in the case of the four deceased was significantly foreshortened.

Taking Mr Knox’s circumstances also into account, to my mind the expert evidence

does not allow for such a conclusion in any of the five cases which this Court has

examined. Clearly, however, in each case the patients responded to induction

chemotherapy that utilised the drug cytarabine as they were all successfully brought

into remission after induction chemotherapy. It is probable that all five patients

would have died within a matter of months had they not successfully undergone

induction chemotherapy. All of the five individuals underwent a cycle or cycles of

consolidation chemotherapy during the currency of their periods of remission. It is

difficult to judge what therapeutic effect the cycle or cycles of consolidation therapy

had in each case if any. It is not possible to determine whether or not any deficit in

terms of remission period or overall survival was contributed to by the chemotherapy

frequency error.

194

26.9. I have carefully considered all of the expert evidence. I am mindful of the opinions

expressed by Dr Vaughan to the effect that the remission durations and/or durations of

overall survival of the five individual persons under discussion were in some cases

curtailed. However, in my view his evidence is outweighed by the totality of the

remaining expert evidence that is to the effect that in an individual case it is not

possible to say whether the remission period or period of overall survival was

curtailed.

26.10. During the final address of Mr Trim QC, and in the context of a discussion about

Professor Gibson’s evidence that he could not discount the possibility that the

incorrect frequency of dosage in Mr Higham’s consolidation chemotherapy had

compromised his treatment, and that the same applied to the case of Mr McRae, Mr

Trim QC on behalf of the doctors conceded that it is possible that their treatment was

compromised, adding that it may not have been compromised either361. To my mind

this concession was rightly made. The question of course is whether it has been

demonstrated in the course of this inquest that it was a probability in any given case.

In my view Mr Trim QC is also right when he argues that one cannot say.

26.11. Before dealing with the cases of the individual patients, I should say that I placed

limited weight on suggestions based upon statistical considerations that an

individual’s duration of remission or duration of overall survival accorded with an

established median or average or within a range of expectation. Clearly a median or

average duration does not represent the outcomes of all patients within a confined

group of cases. Some cases will fall below the median or average and some will fall

above it. The fact that a patient’s remission or survival duration fell within a certain

acknowledged range does not of itself mean that their treatment outcome and their

period of remission or survival was not affected by a shortcoming in his or her

treatment. It would also not of itself mean that their remission or survival duration

would not have been longer if they had been given the correct treatment. However,

what it does do is render an anomaly in remission or overall survivability duration as

being less likely the result of a treatment error.

26.12. In relation to Mrs Pinxteren in particular, I find that Mrs Pinxteren’s period of

remission was unexpectedly and disappointingly short. This is so given her

favourable response to induction chemotherapy in the first instance. However, Mrs

361 Transcript, page 3288

195

Pinxteren, was considerably older than the other patients. It is obvious that she

exhibited some response to her one round of consolidation chemotherapy because in

the event she failed to adequately recover from it to enable her to undergo a second

cycle. Although Mrs Pinxteren’s period of remission was unexpectedly short, I am

unable to conclude on the balance of probabilities that chemotherapy delivered in

accordance with the intended protocol would have lengthened her period of remission

or her period of survival. To my mind there is validity in the suggestion that if Mrs

Pinxteren’s one cycle of consolidation chemotherapy had been delivered in

accordance with the intended protocol, then her ability to recover from it could have

been even worse.

26.13. Mr McRae obviously responded to induction chemotherapy. I find that Mr McRae

did successfully attain remission. Mr McRae underwent two rounds of consolidation

chemotherapy not in accordance with the intended protocol. A delay between the first

and second cycles was due to the fact that Mr McRae recovered slowly from the

complications experienced as a result of the first round of consolidation. Although I

find that Mr McRae’s consolidation cycles were sub-therapeutic, his remission and

overall survival fell within the range of expected outcomes. That is not to say that

simply because those durations fell within expected range this of itself means that the

reduction in dosage frequency had no effect on those durations. It is simply

impossible one way or the other to draw any conclusion in that regard.

26.14. Regarding Mr Higham, having regard to prognostic factors in his case his prognosis

was not favourable. He was FLT3 positive and NPM1 positive. The positivity of the

FLT3 factor did not augur for a favourable outcome. Mr Higham would have been

regarded as of a higher risk in terms of prognosis. He also had myelodysplasia and

co-morbidities. He underwent two rounds of consolidation chemotherapy and it will

be remembered that he had a third so-called catch up round. Mr Higham’s remission

and overall survival fell within the range of expected outcomes and as Professor

Gibson indicated, was above the median that would have been expected. However,

this does not of itself mean that Mr Higham would not have enjoyed a longer

remission or longer period of survival if his two rounds of consolidation

chemotherapy had been administered in accordance with the correct protocol. There

is also the complicating factor of the possible effect of any catch up round that was

administered during his period of remission. To my mind, the suggestion from

196

Dr Vaughan that Mr Higham could have had a longer remission of around 6-12

months had he been treated in accordance with the correct protocol is speculative.

26.15. Regarding Mrs Bairnsfather who also underwent a single cycle of consolidation

therapy, the evidence demonstrates that it is not possible to say that whether if in her

case the one round of consolidation chemotherapy would have been administered

correctly it would have altered either her remission period or survival duration.

26.16. Regarding Mr Knox, his was a case where conceivably he may have been cured of his

disease and have not suffered a relapse. He spent approximately two years in

remission following his induction chemotherapy. He underwent two consolidation

therapies not in accordance with the correct protocol. His situation is also

complicated by the administration of a third catch up round prior to his relapse. The

effect of that catch up round, as in the case of Mr Higham, is uncertain. There was

debate in particular between Professor Gibson and Dr Beligaswatte as to whether the

remission period of two years was a period that fell within the range of expected

outcomes having regard to his favourable prognostic factors. In the event, I preferred

the evidence of Professor Gibson, an experienced clinician in the treatment of AML.

I prefer his independence and greater experience in assessing the issue when

compared to that of Dr Beligaswatte. However, as indicated above, I do not

determine these issues simply by reference to statistical expected outcomes.

Professor Gibson stated that of all the cases that he had reviewed, Mr Knox’s case

was probably the most clear-cut where the outcome was less than one might have

reasonably expected. Dr Vaughan also stated that with proper consolidation treatment

Mr Knox may not have relapsed at all or at least his remission might have been

longer. Associate Professor Wei on the other hand suggested that what could not be

known in Mr Knox’s case is whether there was some hidden cytogenetic unfavourable

factor that may have operated to deny Mr Knox the expected favourable outcome. I

agree that this is a matter that cannot be known with certainty. While there is a very

grave suspicion in Mr Knox’s case that the underdosing acted to his detriment, and

that his remission may have been longer without relapse had he been treated in

accordance with the intended protocol, for much the same reasons as expressed in

relation to the other affected patients, it is not possible to conclude that on the balance

of probability his period of remission of remission would have been longer.

197

26.17. I do not believe that the fact of Mr Knox’s relapse and the period of his remission in

his case demonstrates anything of relevance in relation to the remission durations or

survival durations of any of the deceased persons. Nor in my view does it shed any

light upon whether or not in those four cases the remission durations and the survival

durations were affected by the underdosing.

26.18. As it is not possible to determine in a given case whether the incorrect frequency of

dosing had any adverse effect on the patient’s treatment, it must follow that the effect

of the so called catch up rounds is equally uncertain. The same applies to a

consideration of whether any delay in the administration of any catch up round had

any adverse effect.

26.19. In my view it is also not possible to determine whether any delay in advising any

other of the affected patients of the error in treatment resulted in their further

treatment being rendered less effective.

26.20. None of the above should be interpreted as a finding that neither the remission

duration nor the duration of overall survivability of these affected patients was not

affected by the chemotherapy error. It is in my view simply impossible to say one

way or the other. To my mind the possibility that their remission durations and/or

their periods of overall survival would have been longer had they been treated in

accordance with the intended protocol has not in any of the five cases under

discussion been discounted. This possibility remains because of the possibility that in

an individual case an insufficient quantity of leukaemic cells in their S-phase may not

have been eliminated due to the reduced frequency of cytarabine administration and

the consequent absence of the drug from their bodies for extended and, due to the use

of the incorrectly worded protocol, unintended periods of time.

26.21. It would not have been in any sense irrational or unreasonable for the deceased

persons to have spent what remained of their lives following the revelation of the

treatment error to them pondering whether the error had resulted in the foreshortening

of their lives. This in and of itself is a truly dreadful thing.

27. Recommendations

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27.1. Pursuant to section 25(2) of the Coroner’s Act 2003 I am empowered to make

recommendations that in the opinion of the Court might prevent, or reduce the

likelihood of, a recurrence of an event similar to the event that was the subject of the

Inquest.

27.2. I have already referred to the odd circumstance that each of the major tertiary public

hospitals in South Australia had their own protocol systems within Haematology

Departments. I here refer to the RAH, FMC and TQEH. This was even more

surprising having regard to the fact that the consultant haematologists within the

Haematology Departments at each of those hospitals was an employee of SA

Pathology, another Government health entity. There appears to be no sound basis for

having a system whereby each Haematology Department has complete autonomy in

relation to the content of chemotherapy protocols.

27.3. The chemotherapy error at both the RAH and the FMC would have been avoided if

both hospitals, like TQEH, utilised the EviQ chemotherapy protocol system. To my

mind there is a clear need for uniformity as between the chemotherapy prescription

systems across the board in South Australia.

27.4. Another matter that arises from this inquest is that there is a clear need for

pharmacists to be involved in the chemotherapy protocol alteration and promulgation

system. It so happens that at both the RAH and the FMC pharmacists were either

instrumental in identifying the error in the case of the RAH, or in the case of the FMC

at least instrumental in identifying an issue, an issue that clearly should have been

resolved in favour of what the pharmacist had suspected was an error.

27.5. There is also a need for a codification of the manner in which protocols are altered.

The only document that I have seen in this regard was an ex post facto scheme that

was tendered through Associate Professor Kuss and which she asserts was more or

less a codification of already understood processes that had not been in writing.

27.6. Mr Griffin QC has urged the Court to consider making a recommendation that only

clinicians with expertise in the disease AML should be able to prescribe

chemotherapy treatment, but that if the clinician does not have relevant expertise in

that disease, that a primary source document should be viewed by the prescribing

practitioner in addition to the published protocol. He also suggests that the

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prescribing process should involve two separate clinicians signing off on the

prescription. I have given consideration to that suggestion. There is limited evidence

for me to judge one way or the other whether such a process would be feasible having

regard to the fact that (a) different clinicians within haematology departments have

different areas of expertise and (b) AML is a comparatively uncommon disease.

27.7. In my view the Safety Learning System method of reporting adverse incidents does

not work. Not only that, it does not work across the entire SA Health system. It has

not been necessary to go into minute detail about the operation of the Safety Learning

System as it functioned, or rather failed to function, here. However, the fact of the

matter is that it was utilised in the first instance not at all. It was ultimately utilised

late in the piece and it did not in any way serve to ensure that when the chemotherapy

error was identified at the RAH it was also identified simultaneously at the FMC.

27.8. The email system of communication between clinicians and other professionals in

order to impart information concerning protocol changes and content is fraught with

danger. People simply do not read emails that come to them in circular form

involving multiple recipients. Emails such as these and delivered in this fashion tend

to lack obvious relevance to some recipients, lack the necessary impact and in most

cases do not call for any kind of acknowledgement or action on the part of any

recipient. Attachments to emails are described in very general terms and do not really

display any meaningful invitation or incentive that they be read.

27.9. The process of disclosure to the affected patients in this case was unsatisfactory. It

was by no means truly open and in some instances lacked candour, in one instance

was not delivered by an appropriate person, was late and in the first instance was

usually attended by the imparting of inaccurate or incomplete information. The

disclosure was conducted by persons who had either been involved in the

promulgation of the treatment error or had some other personal interest in the matter

at hand. Open disclosure is only truly open when it is conducted by an entity that has

no interest in the outcome of any consequence of the treatment error. Disclosure to

patients of a treatment error should be conducted by an independent entity.

27.10. The Court makes the following recommendations directed to the Minister for Health

and Wellbeing, the Chief Executive of SA Health and the Heads of Haematology at

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the Royal Adelaide Hospital, the Flinders Medical Centre and The Queen Elizabeth

Hospital:

1. That a State-wide chemotherapy protocol system be developed in relation to the

treatment of haematological illnesses. That the system not be individualised in

respect of particular hospitals, but apply to all hospitals who provide

haematological services. The State-wide protocol development system should

encompass the following elements:

A State-wide committee be established to govern protocol development and

alteration. The committee should comprise the Heads of each hospital’s

Haematology Department, the chief haematological pharmacist from each

hospital and in the case of the disease AML, a specialist consultant with

expertise in that disease.

The proposed changes to chemotherapy protocol should be discussed at a

meeting of the committee prior to any changes being made.

Changes to protocol should be presented in draft form to that meeting.

Two separate clinicians should review and sign off on the final protocol

document.

The final protocol document should be presented to all haematology

specialists and registrars to ensure that all such clinicians are aware of and

understand the alterations. These communications should not be made by

circular email.

Any changes to protocol should be based upon documented evidence in

support of the change.

All protocols and alterations to protocols should be uniform across all

Haematology Departments in public hospitals in South Australia.

There should be a State-wide electronic prescription system that is uniform in

its operation within all Haematology Departments in public hospitals in South

Australia. Electronic prescription templates created by pharmacists should

involve checking against the outcome of meetings that have taken place in

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accordance with the system described above. They should be checked against

the written evidence in support of the protocol alteration. The final electronic

prescription should be approved by the committee before it is uploaded onto

any prescription system. It should be recognised that electronic prescriptions

are only as accurate as the information that has been gathered in order for the

prescriptions to be created. It should be recognised that electronic

prescriptions are not necessarily failsafe. Two independent clinicians should

sign off on any prescription.

2. That the current Safety Learning System (SLS) be abandoned and be replaced by

an adverse event reporting system that includes the following elements:

An adverse event such as the detection of a protocol error or the treatment of a

patient in accordance with an erroneous protocol should immediately be

reported to the head of the relevant department and immediately be reported to

the chief administrative officer of the hospital in question. It should also be

immediately be reported to the Chief Executive of the Department of Health

and Wellbeing.

The fact of the adverse event, a detailed description of the event and of

measures taken to rectify any underlying error should immediately be

communicated to the chief administrative officers of each tertiary public

hospital in South Australia and also be reported to the heads of the relevant

departments within those hospitals.

3. That as far as is possible haematology consultants who have a particular expertise

in respect of a particular illness should, generally speaking, treat patients who

have been diagnosed with that illness. It is to be recognised that this may not

always be feasible. I would recommend that if a treating clinician does not have

relevant experience in the particular disease in question, they should take advice

from consultants who do have such expertise.

4. That email should be regarded as a dangerous means of communication in respect

of imparting information regarding protocol changes. I would recommend that

email communication be kept to a minimum. Where email communication is

utilised, emails should not be sent to large numbers of recipients. They should be

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sent to batches of recipients, the commonality in the batches being the particular

field of professional endeavour of the recipient. For example, one email should be

sent to clinicians, another email should be sent to pharmacists and so on. Any

such email should display a flag or other warning that it should immediately be

read and that any attachment should be so read.

5. That in any open disclosure process wherein an error in treatment needs to be

explained to a patient, that an independent entity who has had no responsibility in

relation to the promulgation of the error or has any other interest in the outcome of

any consequences of the error should conduct and oversee the open disclosure

process. The independent person should be involved at the time of such

disclosure and also have an involvement in the formulation of a treatment plan in

respect of a patient, taking into account the error in treatment. I further

recommend that the philosophy underlying any open disclosure system should not

be the protection of a person, persons or entities responsible for the error, but the

welfare of the patient should always be the paramount consideration. Disclosure

to a patient should be timely, candid, complete and have the capacity to

independently inform the patient as to further possible treatment options.

6. That there be a complete overhaul of clinical governance systems as they apply to

Haematology Departments within tertiary public hospitals in South Australia. The

overhaul should involve as its elements:

The identification of suitable clinicians to exercise clinical governance

responsibilities taking into account the expertise, experience and, importantly,

the character of the individual.

The promotion of education in relation to timely, appropriate and candid open

disclosure.

The creation of timely and effective adverse event reporting systems within

the public health system of South Australia.

Key Words: Acute Myeloid Leukaemia; Chemotherapy Underdosing; SA Health

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In witness whereof the said Coroner has hereunto set and subscribed his hand and

Seal the 22nd day of March, 2019.

Deputy State Coroner

Inquest Number 42/2016 (1188/2016, 1189/2016, 1488/2016 and 0295/2017)