finding of inquest...4 1. introduction 1.1. these are the findings of the court in respect of an...
TRANSCRIPT
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.
2
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 17th 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 .................................................................................................................... 4
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 ......................................................................... 12
3. Consolidation chemotherapy for AML – an overview ................................................ 14
4. The RAH AML consolidation chemotherapy protocol ............................................... 17
5. The FMC AML consolidation chemotherapy protocol ............................................... 20
6. The promulgation of the erroneous protocol at the RAH ............................................ 22
7. The promulgation of the erroneous protocol at the FMC ............................................ 33
8. The patients are administered consolidation chemotherapy pursuant to the
erroneous protocol ....................................................................................................... 66
8.6. The circumstances relating to the underdosing of Mrs Pinxteren .................... 66
8.26. The circumstances relating to the underdosing of Mr McRae ......................... 71
8.40. The circumstances relating to the underdosing of Mrs Bairnsfather ............... 74
8.50. The circumstances relating to the underdosing of Mr Higham ........................ 77
9. The error is discovered................................................................................................. 81
10. The error is acted upon at the RAH ............................................................................. 91
11. The discovery of the error at the FMC......................................................................... 97
12. The circumstances relating to the underdosing of Mr Knox ...................................... 106
13. Was Mrs Pinxteren ever advised of the error? ........................................................... 114
14. Mr McRae is advised of the error .............................................................................. 121
15. Mrs Bairnsfather is advised of the error .................................................................... 124
16. Mr Higham is advised of the error ............................................................................. 125
17. Mr Knox is advised of the error ................................................................................. 127
18. The evidence of Professor Peter Bardy ...................................................................... 130
19. The evidence of David Swan ..................................................................................... 132
20. The expert witnesses - causation................................................................................ 135
21. The evidence of Professor Boddy .............................................................................. 138
22. The evidence of Associate Professor Wei ................................................................. 149
23. The evidence of Professor John Gibson..................................................................... 159
24. The evidence of Dr Stephen Vaughan ....................................................................... 172
25. The literature .............................................................................................................. 180
25.22. Conclusions from the literature ...................................................................... 189
26. Conclusions regarding causation ............................................................................... 190
27. Recommendations ...................................................................................................... 196
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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
induced in the patient. Following the achievement of complete remission all four
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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 can control and,
perhaps, to provide a cure for the patient. In essence the purpose of consolidation is to
1 Transcript, page 268
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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
circumstances in which this error occurred were the subject of detailed inquiry during
7
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 Mr Knox’s
treatment will become readily apparent. It has also been necessary to refer to certain
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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 underdosing
that occurred in his second cycle of consolidation therapy would have been avoided
altogether.
9
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.
• Whether the erroneous treatment that was administered pursuant to the erroneous
protocol contributed to the deaths of the four deceased patients.
10
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
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
11
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;
• Associate Professor Agnes Yong;
• Dr Devendra Hiwase;
• Dr David Ross.
12
• 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.
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.
13
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
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.
14
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 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
15
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 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.
16
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 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.
17
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
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
2 The original protocol is Exhibit C9b
18
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 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
3 Transcript, page 2765 4 Transcript, page 2772
19
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 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
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.
20
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.
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
21
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
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,
6 Exhibit C50, pages 13-17
22
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.
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
23
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
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
7 Transcript, page 1881 8 Exhibit C9b 9 Exhibit C49, page 143
24
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.
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
10 Exhibit C49, page 146
25
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
Chemotherapy
Idarubicin 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
11 Exhibit C149, page 175 12 Exhibit C9a
26
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 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
13 Transcript, page 931
27
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
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
14 Transcript, page 928 15 Transcript, page 1886
28
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
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
16 Transcript, pages 1887-1888 17 That is, SA Health
29
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 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
18 Exhibit C49, page 197
30
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.
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
19 Transcript, page 1944 20 Transcript, page 1945 21 Transcript, page 1949
31
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 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.
22 Transcript, page 1949 23 Transcript, page 1954 24 Transcript, page 1918 25 Transcript, pages 1956-1957
32
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.
• 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
33
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 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
34
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
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
26 Transcript, page 1409 27 Transcript, page 1538 28 Transcript, page 1692
35
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 was going
36
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
29 Transcript, page 1920 30 Transcript, page 1921 31 Transcript, page 1920 32 Transcript, page 1645
37
knowledge that the FMC were adopting their protocol. The rather 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
33 Transcript, page 1419
38
physicians and the person who was said to be 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
included in his original email. In Ms Teh’s email she queried whether the patient
39
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.
Thanks
Ashanka'
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 clinically because
34 As indicated earlier, different considerations applied to patients who were CBF
40
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 protocol’35. To this he
35 Transcript, page 1653
41
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.
36 Transcript, page 1653 37 Transcript, page 2378 38 Dr Beligaswatte was the sole recipient of this email
42
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 1888-1889 40 Transcript, pages 1420-1421 41 Transcript, page 1422
43
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 2401 43 Variously Exhibits C48a and C50, page 95
44
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 2014.
45
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 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.
46
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
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
44 Transcript, page 1434
47
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.
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
45 Transcript, page 1549 46 Transcript, page 1649 47 Transcript, page 1645 48 Transcript, page 1646 49 Transcript, page 1644 50 Transcript, page 1678
48
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.
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
51 Transcript, page 1552
49
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 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
52 Transcript, page 1545
50
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 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
53 Transcript, page 1559 54 Transcript, page 1560 55 Transcript, page 1623 56 Transcript, page 1627
51
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 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,
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
52
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 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
53
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.
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
59 Transcript, page 1973 60 Transcript, page 1973 61 Transcript, page 2009-2010
54
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 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
62 Transcript, page 2011 63 Transcript, page 2011 64 Transcript, page 2013
55
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 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
65 Transcript, page 1978 66 Transcript, page 1979 67 Transcript, page 2057
56
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.
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
68 Transcript, page 2062 69 Transcript, page 2062 70 Transcript, page 2063
57
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 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
71 Transcript, page 2057 72 Transcript, page 2060 73 Transcript, page 2017 74 Transcript, page 2017
58
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 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
75 Transcript, page 2018
59
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 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
76 Transcript, page 2061 77 Transcript, page 2016
60
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.
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
78 Transcript, page 2105 79 Transcript, page 2078
61
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 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
80 Transcript, page 1998
62
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 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
81 Transcript, page 2431 82 Transcript, page 2470 83 Transcript, page 2471
63
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.
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
84 Transcript, page 2457 85 Exhibit C55, pages 55-56 86 Transcript, pages 2474-2475
64
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 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
87 Transcript, page 2460
65
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
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.
66
• 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
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.
67
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
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
68
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.
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
88 Transcript, page 1331 89 Transcript, page 1356 90 Transcript, page 1353
69
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.
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
91 Transcript, page 1354 92 Transcript, page 1354 93 Transcript, page 1392 94 Transcript, page 1330
70
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.
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
71
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 result95. 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 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
95 Transcript, pages 1374-1376 96 Transcript, page 1389 97 Transcript, page 1377 98 Transcript, page 1377
72
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 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
73
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 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
74
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
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
75
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 therapy had
been changed from twice daily to once daily on days 1, 3 and 5100. 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
99 Transcript, page 1252 100 Transcript, page 1253 101 Transcript, page 1253
76
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.
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
102 Transcript, page 1257 103 Transcript, page 1258
77
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.
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.
104 Exhibit C45, Tab 3
78
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
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
105 Exhibit C45, page 20
79
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.
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
106 Transcript, pages 1293-1294 107 Transcript, page 1267 108 Transcript, page 1285
80
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.
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.
109 Transcript, page 1285 110 Transcript, page 1287
81
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.
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.
82
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 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.
83
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.
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
84
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
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
85
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 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
111 Transcript, page 1726
86
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.
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.
112 Transcript, page 1727
87
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.
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
88
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 uploaded
Attachments: 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 15th 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 Officer
C/o Haematology Clinical Trial Office
Level 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 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.
89
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
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
113 Transcript, page 1463 114 Transcript, page 1464
90
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 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.
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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
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
92
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 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
115 Transcript, page 1891 116 Transcript, page 1892
93
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.
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.
117 Transcript, pages 1892-1893 118 Transcript, page 1901 119 Transcript, page 1894
94
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
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
120 Transcript, page 1735 121 Exhibit C52, Tab 5
95
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 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
122 Transcript, page 1781
96
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 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
97
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 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
98
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 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
123 Transcript, page 1465
99
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 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
124 Transcript, page 1570 125 Transcript, page 1570 126 Transcript, page 1571 127 Transcript, page 1573 128 Transcript, page 1572
100
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 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.
129 Transcript, page 2433
101
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 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
130 Exhibit C55, Tab 8
102
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 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
103
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
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
131 Transcript, page 2002 132 Exhibit C50, page 71 133 Exhibit C50, page 71 134 Transcript, page 2382
104
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 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.
135 Exhibit C31a 136 Exhibit C47b
105
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.
• 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.
106
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
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.
107
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.
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
137 Transcript, page 1174
108
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 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
138 Transcript, page 1175 139 Transcript, page 1177
109
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 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
140 Transcript, page 1178 141 Transcript, page 1189
110
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 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.
142 Transcript, page 1190 143 Transcript, page 1191 144 Exhibit C43, page 64 145 Exhibit C43, page 67
111
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:
'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
146 Transcript, page 1197 147 Transcript, page 1197 148 Transcript, page 1199 149 Transcript, page 1200
112
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 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
150 Transcript, page 1200 151 Transcript, page 1203 152 Transcript, page 1203 153 Transcript, page 1206 154 Transcript, page 1208 155 Transcript, page 1218
113
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.
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.
156 Transcript, page 1220
114
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.
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
157 Transcript, page 1331 158 Transcript, page 1333
115
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 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.
159 Exhibit C46, page 45 160 Transcript, page 1338
116
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
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
161 Transcript, page 1337
117
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 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
162 Exhibits C4 and C5 respectively 163 Exhibit C4, page 5
118
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.
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
119
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 (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
164 Transcript, pages 1348-1349 and 1390 165 Transcript, pages 1366-1367
120
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.
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
121
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 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
122
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 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
166 Transcript, page 1794 167 Transcript, page 1795
123
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 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,
168 Exhibit 12C, Volume 4
124
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:
'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
169 Transcript, page 205 170 Transcript, page 206
125
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:
'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
171 Exhibit C11a, pages 9-10
126
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 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.
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
127
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
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.
173 Transcript, page 146 174 Supra para 7.76 herein 175 Exhibit C16c, pages 840-841
128
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, 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
176 Exhibit C16c, page 907
129
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. 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
177 Transcript, page 638
130
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 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
178 Exhibits C53 and C53a
131
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 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.
179 Transcript, page 2242 180 Transcript, page 2243
132
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.
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
181 Transcript, page 2249 182 Transcript, page 2259 183 Transcript, page 2258 184 Transcript, page 2269
133
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 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
185 Transcript, page 2294 186 Transcript, page 2336 187 Transcript, page 2346 188 Transcript, page 2347 189 Transcript, page 2342
134
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 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
190 Transcript, page 2304 191 Transcript, page 2306 192 Transcript, page 2308 193 Transcript, page 2326
135
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
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
194 Transcript, page 2326 195 Transcript, page 2351
136
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 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
137
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 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.
138
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
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
196 Exhibit C19
139
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.
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
197 Transcript, page 382 198 Transcript, page 379
140
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.
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
199 Transcript, page 380 200 Transcript, page 380 201 Transcript, page 383
141
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 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
202 Transcript, page 386 203 Transcript, page 433 204 Transcript, page 480 205 Transcript, page 409
142
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 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.’
206 Transcript, page 509 207 Transcript, page 532
143
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
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.
208 Transcript, page 3006
144
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
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
209 Transcript, page 3008 210 Transcript, page 2992 211 Transcript, page 2966 212 Transcript, page 2969
145
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 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
213 Transcript, page 2976 214 Transcript, page 3011 215 Transcript, page 3012
146
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 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
216 Transcript, page 394 217 Transcript, page 395 218 Transcript, page 395 219 Transcript, page 398 220 Transcript, pages 399-400
147
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 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
221 Transcript, page 400 222 Transcript, page 412 223 Transcript, page 412 224 Transcript, page 414 225 Transcript, page 416 226 Transcript, page 415
148
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 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.
227 Transcript, page 408 228 Transcript, page 408 229 Transcript, page 426 230 Transcript, page 438 231 Transcript, page 435
149
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
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.
232 Transcript, page 433 233 Transcript, page 510
150
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 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
234 Exhibit C19k and Exhibit C36, Tab 5 235 Exhibit C36, Tab 1 236 At Transcript, pages 146-147
151
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 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
152
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
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.
237 Exhibit C9a 238 Transcript, page 2771
153
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.
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
239 Transcript, page 2784 240 Transcript, page 2786 241 Transcript, page 2788 242 Transcript, page 2788
154
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 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
243 Transcript, page 2790 244 Transcript, page 2792 245 Transcript, page 2827 246 Transcript, page 2828 247 Transcript, page 2832
155
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
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
248 Transcript, page 2832
156
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
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
249 Transcript, page 2839 250 Transcript, page 2836
157
trialled on once a day administration on days 1, 3 and 5251. 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
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.
251 Transcript, page 2848 252 Transcript, page 2849 253 Transcript, page 2849 254 Transcript, pages 2866 and 2871 255 Transcript, page 2876
158
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
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
256 Transcript, page 2804 257 Transcript, page 2802 258 Transcript, page 2796 259 Transcript, page 2807 260 Transcript, page 2807
159
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
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
261 Transcript, page 2815
160
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 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.
262 Exhibit C1 263 Transcript, page 94 264 Transcript, page 95 265 Transcript, page 96 266 Transcript, page 110 267 Transcript, pages 261 and 266-267
161
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 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
268 Transcript, page 692
162
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
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
269 Transcript, page 725 270 Transcript, page 726 271 Transcript, page 780 272 Transcript, page 736
163
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
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.
273 Transcript, page 132 274 Transcript, page 132 275 Transcript, page 139 276 Transcript, page 158
164
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.
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.
277 Transcript, page 251 278 Transcript, page 166 279 Transcript, page 170
165
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
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
280 Transcript, page 205 281 Transcript, page 205 282 Transcript, page 211 283 Transcript, page 214 284 Transcript, page 252
166
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 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
167
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
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.
285 Transcript, page 245 286 Transcript, page 580
168
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 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
287 Transcript, page 609 288 Exhibit C1c
169
individuals, but was 65 and not far from his 66th 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
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
289 Transcript, page 628 290 Transcript, page 638 291 Transcript, page 639
170
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:
'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.
292 Transcript, page 646 293 Transcript, page 653 294 Transcript, page 654
171
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 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
295 Transcript, page 657 296 Transcript, page 661 297 Transcript, page 662 298 Transcript, page 694
172
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 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.
299 Transcript, page 697
173
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 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
300 Exhibit C56a 301 Transcript, page 2514
174
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 people302. 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
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
302 Transcript, page 2515 303 Transcript, page 2523 304 Transcript, page 2523 305 Transcript, pages 2531 and 2534
175
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 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.
306 Transcript, page 2539 307 Transcript, page 2539 308 Transcript, page 2543 309 Transcript, page 2543
176
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.
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
310 Transcript, page 2643 311 Transcript, page 2644 312 Transcript, pages 2684-2685 313 Transcript, page 2685 314 Transcript, page 2686 315 Transcript, page 2719
177
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 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
316 Transcript, pages 2726-2727 317 Transcript, page 2656 318 Transcript, page 2755 319 Transcript, page 2756 320 Transcript, page 2567 321 Transcript, page 2569 322 Transcript, page 2567 323 Transcript, page 2573 324 Transcript, page 2752 325 Transcript, pages 2575-2577
178
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
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
326 Transcript, page 2579 327 Transcript, page 2580 328 Transcript, page 2581 329 Transcript, page 2743 330 Transcript, page 2584 331 Transcript, page 2588 332 Transcript, page 2594 333 Transcript, page 2596 334 Transcript, page 2599
179
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.
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.
335 Transcript, page 2599 336 Transcript, page 2599 337 Transcript, page 2599 338 Transcript, page 2609 339 Transcript, page 2609 340 Transcript, page 2746 341 Transcript, pages 2638-2639
180
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 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
342 Transcript, page 2639 343 Transcript, page 2640 344 Transcript, page 2642
181
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 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
345 Exhibit C36, Tab 8, page 7
182
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
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
346 Exhibit C36, Tab 8, page 8 347 Exhibit C36, Tab 8, page 9 348 Exhibit C36, Tab 10 349 Exhibit C36, Tab 10, page 552
183
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 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.
350 Exhibit C36, Tab 11 351 Exhibit C36, Tab 11, page 559 352 Exhibit C19l
184
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
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
353 Exhibit C36, Tab 4
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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.
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
354 Exhibit C36, Tab 12 355 Exhibit C36, Tab 16
186
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.
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.
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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 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
356 Exhibit C36, Tab 5 357 Table 8 358 Exhibit C19ma
188
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
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
359 Exhibit C19m
189
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 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
360 Exhibit C47e, page 75, article 9
190
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 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
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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
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.
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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.
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
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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 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.
361 Transcript, page 3288
194
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 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
195
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.
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.
196
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
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.
197
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 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.
198
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 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.
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• 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
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
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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
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
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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
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)