Avastin Briefing July 17

Caveat – I am not a lawyer. Get good legal advice.

1) Introduction, context and ask.

Treatment with a drug known as Lucentis or Eylea is now recommended best practice in many ophthalmic

diseases. This treatment prevents or delays sight loss in over 90% of recipients when given as injections for

periods of up to two years.

Some discussion has taken place on the use of avastin in ophthalmic conditions. This paper sets out some

considerations.

There are many and complex legal and regulatory issues surrounding this issue. These are set out in the recent

BMJ investigation1.

NHS Clinical Commissioners has recently entered into this debate calling for a number of parties to work

together to address this problem. NHSCC have already set out a set of Q&A on this matter. There were a few

additional issues that may arise.

NICE have published draft guidance on AMD. This will likely reignite the debate.

what are the potential policy propositions

There are a number of options available to any CCG. Some considerations are set out below each. These are

not mutually exclusive.

a) To set out a commissioning policy that Avastin will be funded as an option in ophthalmic indications

in the same clinical cohorts as NICE have currently approved Eylea or Lucentis.

Novartis have previously indicated they may take legal action. This would follow their previous action against

SHIP PCT cluster.

This step across many CCGs would be more difficult to fight.

b) To set out a commissioning policy of only funding Lucentis or Eylea as a second line treatment

following loss of response to Avastin.

This would require legal advice. Secretary of State funding directive for TA recommended treatments states

that CCG should make funding available should a clinician choose to use that treatment.

The Mandate states that patients are entitled to NICE approved treatments.

This policy would essentially the same as saying that Eylea and Lucentis will not be routinely funded first line,

this might be construed as in direct contravention of the TA funding directive.

c) To commission an alternative provider for AMD intra vitreal injections who uses Avastin as a first

line treatment.

This was the route taken by Stockport PCT and a number of Greater Manchester PCTs went through this route.

This would involve entering into a contract with a provider other than the current provider set and offering

patients choice of providers. There may be a range of procurement issues to contend with.

d) other considerations

Working the clinical commissioning policy through the lens of commissioning, contracting and financial

envelope, including risk / gain sharing is also strongly recommended.

There’s also considerations around phasing in, and considering this indication by indication. The NICE CG

applies to AMD only, obviously. There are multiple TAs across ophthalmic indications, there is a consistent

evidence base from primary studies (RCTs and observational) indicating little if any measurable difference

(especially in absolute terms) between the available aVEGF drugs.

summary

Given all the above, the opportunity cost and the broader financial position of the NHS, it is difficult to see it as

ethically or morally defensible to continue with eyela or lucentis as first line in the indications they are

currently used.

There is a need to discuss and agree the potential policy proposition.

It is recommended legal advice is sought.

The remainder of the document is very detailed brief on some of the aspects of this debate.

2) License and regulatory framework

Avastin doesn’t have market authorisation in this indication, licensed in cancer.

a) Its worth a note here on the "licensing" process

Its purpose is to protect patients from pharmaceutical companies promoting ineffective or unsafe products.

It does not regulate clinical practice.

One interpretation of GMC advice is that it has taken industry regulation and applied it to clinical practice

This is a commercial decision by Roche and their subsidiary, Genentech –the manufacturer has not applied for

this presumably on commercial grounds. A number of states (taxpayers) have very kindly paid for a number of

de facto Phase III studies (IVAN, CATT, GEFAL

IVAN and CATT were set up as trial to mimic a Phase III licensing study. And more than adequately passed the

bar - against an active comparator, not a placebo.

Similar study now in DMO and LEAVO will do similar in Vein occlusion

Were this a drug that Roche had commercial interest in getting license it would have done so

Given the good quality evidence of efficacy and safety simple cost minimization would suggest that Avastin is

the drug of choice in ophthalmic indications where aVEGF is used.

Avastin does not, however, have market authorisation for this indication.

b) Position of regulators

Avastin is licensed for colorectal cancer therapy and has similar properties. In the UK, the MHRA consider

Avastin unlicenced in ophthalmic use

The FDA and EMA consider it to be an off label use of a licenced medicine. There is valid debate to be had

whether the EMA position is actually the “official” position given that the licence is Europe.

EMA view = 1) we don't recognise the term unlicensed, it has no meaning in law and 2) avastin in

retina conditions is off label use.

c) Responding to the line of - “Prescribing of unsafe unlicensed drugs undermines the regulatory

system”.

Many have made accusations about commissioners seeking to give preferential weight to “unsafe unlicensed

drugs”. There are many that would level an accusation that this is about NHS commissioners “trying to do

things on the cheap” and save money by using “unsafe” and unlicensed drugs.

All commissioners are conscious of the history of the licensing process, why it exists and the safeguards it

brings for patient safety. This is not in dispute. It would seem that Bev has not been brought to market for

commercial reasons, not safety reasons. This represents significant lost value for the broader population who

will bear the opportunity cost of the investment in Lucentis and Eylea. One must ask whether it is efficient, fair

or equitable that patients with other diseases bear this opportunity cost.

Turning the initial accusation about “doing things on the cheap” on its head to frame it as a question of “how

many sight years do you want to buy for a very limited budget”.

Finally on this issue, it is worth reflecting that the most likely reason Roche has not sought Market

Authorisation for Avastin is a commercial not a clinical one. The safety argument per se was settled with the

Cochrane review.

The views and likely positions of a number of influential bodies are set out in the BMJ Investigation. It is

unknown whether any of these views will change in the wake of the NHSCC pressure and the BMJ

investigation.

d) GMC position / R C Pharm

Slight change to GMC guidance on px.

http://www.gmc-uk.org/guidance/28349.asp

Seems down toned compared to previous guidance to me

is GMC about threat rather than action. Can GMC credibly take an individual doctor to task, if she has

institutional backing, especially in circumstances where avastin is the drug of choice in private practice.

Can the GMC credibly take an individual doctor to task if a commissioning policy has (in effect) set a

“commissioning position” or set of instructions to health care providers, and this process has been agreed with

due diligence.

One might re ask the GMC to publish the legal advice on which they based their advice for docs. The smart

money says the legal advice is a fudge and they don't want to publish.

The rapid responses to Deb Cohen’s BMJ article are worth a read

This one from Prof Evans2 on the GMC guidance for doctors – in full:

the GMC is applying law that applies to MARKETING and not to PRESCRIBING.

The Directive cited by Mr Dickson specifically states as part of Article 3 of that Directive-

"This Directive shall not apply to:

1. Any medicinal product prepared in a pharmacy in accordance with a medical

prescription for an individual patient (commonly known as the magistral formula).

2. Any medicinal product which is prepared in a pharmacy in accordance with the prescriptions of a

pharmacopoeia and is intended to be supplied directly to the patients served by the pharmacy in

question (commonly known as the officinal formula)."

The use of bevacizumab requires the intervention of a pharmacy. No-one can MARKET the product

without a Marketing Authorisation.

If it is true that this Directive has been and is used to define Clinical Practice then this seems to be new.

The EMA and the European Commission have responsibilities in relation to companies and to national

regulatory authorities. They do not have responsibility for individual practice. The whole tenor of the

EU and the Directive in question is about trade and it is interesting that it staes in relation to public

health-

" The essential aim of any rules governing the production, distribution and use of medicinal products

must be to safeguard public health." but goes on to state-

" However, this objective must be attained by means which will not hinder the development of the

pharmaceutical industry or trade in medicinal products within the Community. "

It certainly seems that this Directive is intended to benefit industry, including homeopathy (where

most scientists dispute any suggestions of efficacy)!

My reading of the law is perhaps naive but it seems a pity that law intended for one purpose is used

for another.

e) It is worth noting that Nial Dickson responsed on behalf of the GMC3

“The critical factor here is that our guidance must be lawful, and the law on this matter is

unequivocal. Doctors cannot prescribe an unlicensed medicine on grounds of cost where a licensed

product is available. This was confirmed by a ruling in the case of European Commission v Republic of

Poland (C-185/10) in 2012.

At the same time we do support the efficient use of NHS resources and we are sympathetic to the

argument that a better solution needs to be found for the use of Avastin in the treatment of wet age-

related macular degeneration (AMD). We recognise too that doctors are placed in an invidious

position as things currently stand.

Nevertheless, our guidance must support doctors to act within the law as it currently stands. We do

make it clear that doctors may prescribe unlicensed medicines, including medicines for

‘off-label’/unlicensed use, outside the grounds for which they are licensed, where the doctor judges it

to be in the patient’s interests and there is no licensed alternative.”

f) My (GF) view, as per BMJ rapid response:

These are seeming irresolvable differences in interpretations of what the law ACTUALLY says with

regard to PRESCRIBING of an unlicensed medicine between the GMC (Dickson’s response) about the

GMC position and Prof Evan’s view that the case law cited4 is about MARKETING not PRESCRIBING.

Given that it seems one of the pinchpoints of this debate it would seem there is an over ridging public

interest in the GMC publishing any legal advice or opinion that they considered in drawing up the 2013

guidance for doctors on prescribing. It seems untenable that any party can maintain that this is an

area that is not in the public interest.

It is understandable that the lawyer(s) in question wish to remain in the shadows, but it is the opinion

used, rather than the source that should be released.

Openness and transparency are the cornerstones of good clinical practice and the GMC should practice

what they preach to those that they regulate. Without this, it is impossible to judge the validity of the

GMC’s view.

Perhaps the only way to resolve this issue is in court, obviously that would imply more time, more

expense on lawyers and that is on an assumption that there are two opposing parties.

The above is all, of course, notwithstanding the nuance of whether the use of bevacizumab in

ophthalmology is actually an off label use of a licensed medicine, as seems to be the view of EMA5 and

FDA. If indeed bevacizumab is off label then perhaps a different line should be taken.

The Aronson and editorial6 has inadvertently contributed to the propagation of an error. They state

that a a step in the process that is about dilution of bevacizumab to package it for ophthalmic use.

There is no dilution step. It is just drawing up into a syringe. Avastin is supplied in two forms. One

form is 100mg in 1ml and an aliquot of 50 micolitres is a dose of 1.25mg which is the standard dose.

The other is 4mg in 16ml and again an aliquot of 50 micolitres is a dose of 1.25mg. There is no

dilution/concentration step by the pharmacist for the standard dose.

It would take some very detailed research to find out how this misconception was started. The MHRA

may wish to consider this point in future deliberations.

g) Aronson and Ferner’s BMJ editorial7 was also very helpful in this regard. I have directly quoted

three elements here

An ophthalmologist who drew up a solution of bevacizumab for intravitreal injection from a vial marketed for treating cancer would be using it off-label. If a pharmacist diluted the solution before use, the secondary formulation would be unlicensed. How much manipulation results in an unlicensed product is debatable. Unlicensed medicines can be supplied by so-called “special order” manufacturers, paradoxically under licence from the MHRA, obviating the need for a marketing authorisation, although MHRA guidance states that “an unlicensed product should not be usedwhere a product available and licensed within the UK could be used to meet the patient’s special need.” (emphasis added) 15

The use of the word “unlicensed” in these statements suggests that they do not cover off-label use. The MHRA, following a judgment of the European Court relating to importation, not off-label use or secondary formulations,17 specifically excludes “cost, convenience [and] operational needs” as criteria of special need.The licensing system is intended to protect patients from the use of medicines with a poor benefit to harm balance, based on quality, efficacy, and safety, not cost.

Secondary formulations of licensed products, produced by licensed specials manufacturers, should be considered to be licensed.

h) Finally in this section I would recommend a very careful read of Aronson and Ferner’s article8

The key passages and sections in my view page 6 and 7

Licence, GMC and regulatory - in summary:

Avastin has an EMA licence, thus license is European

EMA view = off label use of licensed indication

MHRA view = unlicensed.

Whether MHRA view has primacy is (highly) debatable

Till we actually leave the EU EMA remains the regulator.

3) Legal

I AM NOT A LAWYER, I HAVE A DECENT UNDERSTANDING OF THE LAW IN THIS AREA. GET LEGAL ADVICE

The issue that it is illegal to make the determination of “special need” a priori for a population- it must be done

individual by individual.

There are multiple interpretations of this case law. David Lock QC has published his view 9 in the BMJ. This

updates a previous opinion published as a BMJ Blog10. Poland v ECJ was about importation not prescribing.

a) Novartis and JR threat

Novartis had previously indicated they would take the JR route.

SHIP PCT cluster settled out of court. Terms undisclosed. I'm led to believe the judge wanted the case to be

heard in open court as there was a legitimate public interest to be heard. Novartis didn't want this to happen.

Judge was of opinion this was a case about right to make a profit not a safety issue.

Threat of legal action remains - though may be lower as Novartis now have other drugs and their profit not so

dominated by a single medicine. Bayer also have a wider product line. Difficult to judge this one.

b) Letter from Freeman to CCGs saying use of avastin is illegal.

This seems to be disputed by the advice published by David Lock QC in the BMJ, at same time as the Cohen

investigation. There is no case law in this respect.

c) Novartis v Poland

Much is made of the Poland case. Can be argued to be a red herring as that was about importation not

prescribing or injecting.

My understanding is that the Polish case involved the use of the same drug made generically while the original

drug was still patented. This breaks IP law.

Avastin is a different drug and is not a boot-legged generic.

I am no lawyer but I do not see how the Polish case is relevant - smokes and mirrors from usual suspects?

d) Italy - govt going to ECHR to challenge Novartis.

Will watch that one with interest.

e) The Lock article in BMJ summed up the legal issues

The key points of the article by Lock, a guide through the legal maze11

Prescribing a drug “off-label” – a guide to the law

· The marketing authorisation defines the patient group for which the drug can be advertised.

· A drug that does not have a marketing authorisation is unlicensed and (broadly) can be sold in

the EU only if there are no licensed alternatives. But the licensing regime does not impose legal

obligations on doctors to use drugs only for the conditions set out in the licence. Using a licensed

drug for conditions that are outside those described in the licence is commonly called “off-label”

prescribing.

· Use of bevacizumab for AMD would be off-label. (of note this is the EMA view)

· No court has stopped a clinician from using bevacizumab rather than ranibizumab, and an

attempt by Novartis, which holds the European intellectual property rights for ranibizumab, to

get a German court to prevent a company from providing syringes

· prefilled with bevacizumab for wet AMD failed.

Could a doctor who prescribes bevacizumab for wet AMD be prosecuted for a breach of the criminal

law?

no

Could a doctor who prescribes bevacizumab for wet AMD be sued in negligence?

· highly unlikely that a doctor would breach a duty of care by appropriately prescribing

bevacizumab provided the patient made an informed choice to select the drug.

· NICE TAs have established that Patients have a legal right to be prescribed it on the NHS. Doctors

should inform relevant patients of that option.

· They should also explain that unlike ranibizumab, bevacizumab has not been through a formal

testing procedure to secure a product licence (because the manufacturer has not applied for a

licence).

· Doctors may explain that as ranibizumab has a product licence patients have additional legal

rights to sue the manufacturer if the drug proves faulty.

· However, doctors would also be entitled to say that the two drugs have been shown to be largely

equally effective and that it is better for the NHS generally if the cheaper drug is used because the

money saved can be used to treat other patients. If, having this information, the patient chooses

bevacizumab rather than ranibizumab, the doctor is highly unlikely to be acting negligently.

Could a doctor who prescribes bevacizumab for wet AMD be reported to the GMC?

· theoretical possibility

· GMC guidance requires doctors to make resource allocation decisions that take account of their

responsibilities towards patients and the wider population.

· GMC guidance about prescribing off-label suggests that doctors should not make prescribing

decisions for resource allocation reasons.

· GMC guidance does not explain how doctors should respond when a clinically proved drug is “off

label” only because the drug company has not applied for a licence.

· The pharmaceutical industry lobbied the GMC about its guidance in this area, which may explain

why it has not resolved the tension between the guidance about off-label prescribing and the

doctors’ duty to make the best use of scarce NHS resources for the benefit of patients generally.

· Doctors in the UK have been prescribing bevacizumab rather than ranibizumab for wet AMD for

many years (both in the NHS and privately), and there is no record of any doctor being formally

investigated by the GMC for doing so.

Can a CCG make arrangements to provide bevacizumab for NHS patients?

· Because NICE has conducted a TA of ranibizumab CCGs must fund the drug for patients who meet

NICE criteria.

· However, this does not prevent CCGs offering alternative treatments to NHS patients.

· No court has ruled that CCGs should not offer bevacizumab but equally no court has ever ruled it

is lawful to offer patients a choice. Some CCGs have provided patients with a choice for several

years without being subject to a legal challenge.

· Novartis has advanced arguments against giving patients a choice but these seem unlikely to

succeed.

4) Evidence of efficacy

For wAMD, five trials are currently comparing the efficacy of Lucentis® and Avastin® to answer the question of

whether Avastin® is not inferior to Lucentis® with respect to visual acuity. Two of these have now reported 12 13

14, concluding there is limited if any difference in the efficacy or the safety profiles of Lucentis or Avastin.

There is now RCT evidence demonstrating equivalent efficacy in DMO15, particularly when visual acuity at

commencement was mild. There is also substantial evidence highlighting efficacy of Avastin in RVO.

Its also worth reading the SCORE 2 study – multiple aVEGFs in RVO16. NIH sponsored

-

The editorials carry a number of caveats, each of which are easily turned round. If this study had been

published and there was commercial interest in introduction there would be a clamour to introduce worldwide

and all the naysayers writing cautiuous caveats would be sidelined. LEAVO will hopefully be published in due

course.

Safety

There was a Cochrane Review published in late 2014 that considered the available RCT and observational

evidence; it concluded that there were no differences in the safety profiles of the available anti VEGF

medicines17.

Manufacturing standards important - produced in a specials lab with appropriate accreditation - Liverpool and

Moorfields.

Proving a patient has a systemic AE that is causally attributable to a specific drug is likely impossible.

5) NICE and other central bodies

Lack of central guidance

NHSCC18 have called for “central guidance” and for government to remove the hurdles to Avastin use; it is

doubtful whether this guidance will ever be produced.

NICE have published a draft CG for AMD.

a) NICE

NICE want to appraise avastin in a TA, either as 1) proprietary agent or 2) as comparator in all indications, this

was the subject of a number of exploratory multi stakeholder meetings.

Prevented by doing so in 1) as there isn’t a commercial interest to refer it, and in 2) as judgement made not in

routine use in NHS (my view is that is avoiding the elephant in the room and a technicality). On the issue of

comparator the appraisal of immunosuppressive agents19 is interesting - ‘Under an exceptional directive from

the Department of Health, the appraisal committee was allowed to make recommendations about using drugs

outside the terms of their marketing authorisations if there was compelling evidence of their safety and

effectiveness’. One might question why this principle doesn’t apply in the context of avastin in ophthalmic

indications given evidence of saferty and effectiveness.

AMD CG20 have avoided making a definitive recommendation on avastin (stating legal and regulatory issues as

primary drivers). This is not surprising, most likely on the grounds of institutional risk management. The

recommendation (or lack of) is NOT in keeping with the evidence base reviewed and clearly stated in the detail

of the full guideline. Some of which is reproduced here.

Recommendation re avastin

Effectiveness – p161

Choice of agent – p166

Cost effectiveness p 166

Raftery21 suggested in a straight forward cost minimization exercise that lucentis (only comparator at that

time) would need to be 3 times more effective than avastin to be judged cost effective at the upper end of the

normally approved threshold range. Subsequent RCTs have proven this not to be the case.

Frequency of injection – p 166

Frequency of injection (p166)

Evidence around stopping criteria – p196

Uncertain question of whether an area would wish to go against NICE TA recommendation and disallow first

line use. Legal issues – against SoS funding directive on CCG, not necessarily same issue for prescriber, but can

be considered against NHS constitution.

Stopping and switching recommendations p 198

Have been established by RCOpth – essentially don’t treat before 6/12, don’t treat after 6.90

On switching there is also a point of logic around why would one switch to an agent that NICE have assessed to

be very unlikely to be cost effective and an ICER well above £20,000 / QALY. Obviously it is accepted this is very

difficult territory.

NICE are also clear that the evidence base to guide switching and or the clinical effectiveness of sequential use

of different aVEGF agents is very poor

b) RCOpth

RC Opth22 have also called for central guidance.

A recent article23 in Eye – the journal of RCOpth - is worth reading. Obviously it doesn’t represent a change in

College policy, but may be an indication.

“to conclude, UK regulation has resulted in an unnecessarily expensive choice of aVEGF treatment

despite good evidence of safety, efficacy and cost savings and support from the respected medical

bodies for the use of bevacizumab, despite repeated requests to Government”

Of note I can see no mention of the issue of injection frequency in this one – see later.

6) Patient preferences & views of patient groups

Should be tested.

Empirical evidence (Foss, Nottingham) suggests that patients care about outcomes not the means or specific

drugs used.

Rotherham conducted public survey - 2012/2013?, broadly concluded same.

Patient group support is important. It is unknown whether there are local appropriate patient groups.

RNIB been vociferously opposed to any move to use Avastin. Their corporate conflict of interest is well

documented. There are perhaps some recent very subtle signs regarding softening of this.

The Macular Society have historically been more supportive. Some discussion with them would be warranted.

7) Funding and money – Size of prize, financially speaking

The funds freed up by such a proposition may depend on the precise nature of the proposition. Here I will

assume that we are talking about new starts - ie the incident population - in macular clinic across the three

main indications (AMD, DMO, RVO).

Incident population

Estimate that 5,5 and 3 patients start in macular clinic with AMD, DMO and RVO per week in Sheffield, thus 15,

15, and 9 across SYB. For each I have estimated a mean of 7 injections. My estimate is that the cost of treating

100% of the new incident population with lucentis / eylea across SYB is £6.3m per year, or £709k with avastin

(difference = £5.7m), and over five years the difference is £28.4m.

This needs robust testing, and it will be complicated by use of steroid treatments in DMO / RVO on account of

clinical situation and to ease pressure in macular clinics.

Prevalent population (ie the current spend on aVEGF)

For now I have not considered the prevalent population and or the impact of switching from lucentis / eylea

to avastin in those with either stable vision or those with unstable / non or poor responders. See note above re

switching however.

working it through with some assumptions

For AMD, I have seen clinic data that suggests the following:

· Mean no of injections = 5.8 with lucentis. So that’s 5.8 (lets call it 6) * £450 + 6* injection cost +

Monitoring

· Mean = 4.0 with eylea - 4* £450 + 4* injection cost + Monitoring

· Mean = x with avastin ……… x* £50 + x* injection cost + Monitoring

Thus the value of x is critical

I don’t know what x is – there may be some merit working this out

Same needs to be done with RVO and DMO

Injection frequency is perhaps a key point. See above re NICE considerations in AMD

the issue of injection frequency is also looking set to be the next “thing”. Its cropped up a lot for me

Hypothesis = we must give avastin monthly as that’s where the evidence is, this blows the savings and makes it

not worth the bother

The basic premise put to me is that real world data world data would indicate the size of the prize is

considerably less than may have been estimated if we consider the same injection frequency for avastin as per

lucentis or eyela.

Thinking hard on this issue of monthly injection as that's what the evidence says , there are a number of

issues worth considering.

a) clinical evidence

I've not yet been to pick over CATT / GEFAL in great detail, but I relooked at IVAN yesterday

The 2 year data on IVAN (and with IVAN / CATT meta analysis)

http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(13)61501-9/fulltext

the key bit to me seems to be this one:

“Bevacizumab was neither inferior nor non-inferior to ranibizumab because the 95% CIs include zero

and the non-inferiority margin (figure 1). Similarly the discontinuous regimen was neither inferior

nor non-inferior to the continuous regimen. Therefore, the primary hypotheses about the non-

inferiority of discontinuous bevacizumab to continuous ranibizumab were not supported.”

Table 1 - Looks like marginal differences to me between the 4 arms

“Interpretation

After 2 years in the IVAN trial, the comparisons of the effect of the drugs and of discontinuous versus

continuous treatment on best corrected visual acuity were inconclusive.

However, when we pooled data from the two trials, bevacizumab was non-inferior to ranibizumab. It

is now established that bevacizumab is not inferior to ranibizumab after 2 years of either

continuous or discontinuous treatment with respect to visual acuity, and that total lesion thickness

is also not significantly different by drug.”

I had clocked the accompanying editorial. I’d missed it at the time – but injection frequency was

picked up as unresolved business here.

If I recall, at that time, it was recommended to give lucentis monthly (in practice this not adhered to

- patient prefetrence and clinic capacity). And again if I recall – and happy to stand corrected, I will

contact Usha, IVAN was designed to test ran v bev and monthylu v bi monthly, but arguably not

powered to detect (using non inferiority margins) differences between drugs AND injection freq?

I guess this may get us into the interpretation of fiddly statistical terms like non inferiority, and “not

inferior”. Also even if there is statistical non inferiority, the clinical differences between the arms of

the study are negligible in absolute terms. Statiscical vs clinical relevance?

The editorial also picked up on safety concerns – since largely put to bed with the Cochrane review.

I also clocked the extensive set of conflicts that went with it!

From memory there were mixed signals around non inferiority of avastin between the 1&2 year

data, and also conflicting signals on non inferiority when considering IVAN, CATT & GEFAL in the

round.

In addition it's an assumption based on RCT data, not real world data, so it makes it hard to discredit

a model of saving based on RCT data and NICE, when the critical chunk of the case you put is one

arm of one RCT.

I would guess that NICE have considered the question of injection frequency in detail and used all

the RCT and observational data in the round.

even if there is statistical inferiority of bi monthly avastin, I’d need to get a sense of the clinical

sigifnicance of this. I’d need to take statistician advice on the validity of comparing single arms of the

various studies in the way suggested to draw a conclusion that the evidence base only supports

monthly avastin injections.

It would seem reasonable to interpret from the data more frequent injection beats less frequent,

and that rbz = bvz. Given all the above esp the meta analysis of all the data Im less sure it’s robust to

conclude that BVZ is only non inferior to RBZ if given monthly. Then we get into the clinical

differences (vs the stat) in the various studies.

the TANDEM study will help answer this question but haven't opened the randomisation black box

NICE will also help.

CATT 5 year outcomes

https://www.ncbi.nlm.nih.gov/pubmed/27156698

Injection frequency……..

This is the CATT 5 year follow up

Quickly skimmed

If I’ve read this right in the 3 years between end of RCT phase and 5 yr point, mean number of eyes

injected in the observational phase was 15.4.

Lets call it 16 to be kind

So that’s 16 injections over 3y

5 a year

Hardly monthly injections??

Yes there’s more complexity in terms of visits v injections etc etc….. but……

NIH EYE summary

https://nei.nih.gov/news/pressrelease/AMD_before_after_anti-VEGF_drugs

b) Biological plausibility issues

I relooked at the TANDEM protocol. It was the the biological plausibility points that led to the study

in the first place

Avastin is a full antibody - and thus passive immunity last approximately 6 months, both eylea and

lucentis are polypeptides within SC fragments and is thought to be biologically active for

considerably less than 6 months.

I would imagine there is (or is going to be) industry manipulation of the message on dosing

frequency. Bayer funded studies say you can inject eylea less frequently but we’d recommend

avastin more frequent etc

c) Real world use of avastin

I keep being told that the real world data is PRN use of all three agents and real-world injection

frequency. Of course avastin is the standard of care in most of the world – its only England and

Wales where on account of NICE and garunteed reimbursement there’s v little use of avastin.

I haven’t yet SEEN any useful data on this. I will try to get real world data ….

I'd be sure - I've not looked yet - there are giant observational studies that may inform assumptions

about real world use. The Curtis et al / Duke Uni study was the last one I looked at in any detail, but

that was some years ago.

given that this effectively no use of avastin as nice as recommended that leaves us with what

happens in private practice I guess there's very little data one way or the other.

Oraya

The oraya data was really interesting. I'd be keen to watch this one as it develops.

My views on it are quite well known – that view is a year old now and based on the evidence I’d seen

at that time, I'll watch the evidence as it develops.

From the data I’ve seen more recently might be concluded that there is a 20% reducutoin in

injection volume. Obvously that’s big news.

My concerns are as follows:

· Radiotherapy failed as a single agent. But the device was already made when this became

clear and the company became desperate for an application and this was found by "data

dredging"

· Radiotherapy works by killling cells when they divide. Endothelial cells have slow turnover

(two years) and so real risk of late atrophy. Thus one might say we need at least three

years follow-up to ensure that this is not an issue.

· Obviously all the usual issues with before and after data and needs RCT, I’ll look forward to

the STAR study.

Of course there's no real reason why avastin couldn't be substituted for lucentis in this context.

Other than perhaps a market authorisation issue?

So - I'm still not buying the hypothesis of we'd need to give avastin monthly as that's where the

evidence is, and that would blow the prize and sink macular clinic.

Obviously you'd picked up that I'd said some things in a meeting somewhere.

Be fascinated to know what I've said, and where I said it! I thought I'd been quite careful re saying

things in public on this one!

As I say, any numbers would have been based on either what somebody told me (Bradford or

Nottingham opth team in the main) or something drawn from NICE appraisal or similar. Id be happy

to defend it

Other points on the issue of money

a) It's worth counting the opportunity cost over the years and making this public

b) Loss of R&D income may be a concern to trust.

c) May be an issue around NHSLA costs? Ungorundedm but that’s for NHSLA to determine

d) QC costs for court will be needed.

8) Views of local clinicians.

The views of local clinicians on this matter are not well known.

AVASTIN IS STANDARD OF CARE IN PRIVATE PRACTICE (AND ACROSS THE WORLD)

9) Switching and sequential use – also see above in the NICE AMD section

We want to get into the business of switching and stopping criteria. That is largely beyond the scope of what

Im writing here. I’d encourage any CCG to be very cautious getting into the business writing policies that would

require switching stable patients. My view is that it goes beyond the role of “commissioning”, certainly

commissioning narrowly defined, and strays too far into the realms of clinical practice. I know others have

other views.

Sequential use and and STOPPING There is little evidence on which to base criteria for stopping treatment and

so there is considerable uncertainty about precisely how much treatment may be needed in the longer term.

There is recent data24 indicating that there are considerably fewer patients stopping treatment than had

originally been anticipated when NICE first appraised Lucentis25 and Eylea.

There is a legitimate argument to be made that if a patient is not responding to aVEGF x, there is little to be

gained from switch to aVEGF y or z as they are essentially the same molecule. In addition there is little good

evidence that supports switching in non responders to first treatment. Thus there might be a legitimate case

for a policy of NOT supporting aVEGF switching. There is an equally powerful argument (esp from opportunity

cost basis) for stopping.

There are further complex issues with regard to switching and sequential use, NICE is silent on these matters in

technology appraisals (TAs). The London Medicines Evaluation Network Review recently concluded26 there was

limited evidence to guide practice here.

10) what are the potential policy propositions

what are the potential policy propositions

There are a number of options available to any CCG. Some considerations are set out below each. These are

not mutually exclusive.

a) To set out a commissioning policy that Avastin will be funded as an option in ophthalmic indications

in the same clinical cohorts as NICE have currently approved Eylea or Lucentis.

Novartis have previously indicated they may take legal action. This would follow their previous action against

SHIP PCT cluster.

This step across many CCGs would be more difficult to fight.

b) To set out a commissioning policy of only funding Lucentis or Eylea as a second line treatment

following loss of response to Avastin.

This would require legal advice. Secretary of State funding directive for TA recommended treatments states

that CCG should make funding available should a clinician choose to use that treatment.

The Mandate states that patients are entitled to NICE approved treatments.

This policy would essentially the same as saying that Eylea and Lucentis will not be routinely funded first line,

this might be construed as in direct contravention of the TA funding directive.

c) To commission an alternative provider for AMD intra vitreal injections who uses Avastin as a first

line treatment.

This was the route taken by Stockport PCT and a number of Greater Manchester PCTs went through this route.

This would involve entering into a contract with a provider other than the current provider set and offering

patients choice of providers. There may be a range of procurement issues to contend with.

d) other considerations

Working the clinical commissioning policy through the lens of commissioning, contracting and financial

envelope, including risk / gain sharing is also strongly recommended.

There’s also considerations around phasing in, and considering this indication by indication. The NICE CG

applies to AMD only, obviously. There are multiple TAs across ophthalmic indications, there is a consistent

evidence base from primary studies (RCTs and observational) indicating little if any measurable difference

(especially in absolute terms) between the available aVEGF drugs.

GF. Oct 17

Conflict statement

I have participated in Ad Boards for Bayer opthal, my employer was reimbursed for my time.

I am also chair of the TANDEM steering committee, a member of the LEAVO steering committee, and have

been a member (not current) of a NICE TA committee that has considered aVEGFs on many occasions.

I am also a member of the RCGP Over diagnosis Group.

References

1. http://www.bmj.com/content/350/bmj.h1654

2. http://www.bmj.com/content/350/bmj.h1654/rr-1

3. http://www.bmj.com/content/350/bmj.h1654/rr

4. European Commission v Republic of Poland (C-185/10)

5. BMJ 2015;350:h1654

6. BMJ 2015;350:h1723

7. http://www.bmj.com/content/350/bmj.h1377 and http://blogs.bmj.com/bmj/2014/09/26/david-lock-avastin-and-lucentis-its-

time-for-nhs-commissioners-to-act-rationally/

8. http://blogs.bmj.com/bmj/2014/09/26/david-lock-avastin-and-lucentis-its-time-for-nhs-commissioners-to-act-rationally/

9. http://www.bmj.com/content/350/bmj.h1377

10. CATT http://www.aao.org/newsroom/release/20120502.cfm

11. GEFAL http://www.ncbi.nlm.nih.gov/pubmed/23916488

12. IVAN http://www.ncbi.nlm.nih.gov/pubmed/22555112

13. Diabetic Retinopathy Clinical Research Network. NEJM 2015. DOI: 10.1056/NEJMoa1414264

14. Bevacizumab vs Aflibercept for Macular Edema Due to Retinal Vein Occlusion

http://jamanetwork.com/journals/jama/fullarticle/2626260

15. http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD011230.pub2/figures

16. http://www.nhscc.org/latest-news/doctors-unite-seeking-support-commissioning-safe-effective-eye-care-services-will-save-

nhs-millions/

17. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1954941/

18. https://www.nice.org.uk/guidance/indevelopment/gid-cgwave0658/documents

19. https://www.rcophth.ac.uk/2014/11/rcophth-calls-for-review-of-avastin-for-use-in-amd-treatment/

20. Licence to save: a UK survey of anti-VEGF use for the eye in 2015 : Eye

http://www.nature.com/eye/journal/v30/n11/full/eye2016154a.html

21. http://dx.doi.org/10.1016/j.ophtha.2013.11.031 .

22. TA155

23. http://www.medicinesresources.nhs.uk/en/Communities/NHS/SPS-E-and-SE-England/LNDG/London-Wide-Reviews/LMEN-

Review-Evidence-for-switching-between-VEGF-inhibitors-in-wet-AMD-September-2014/

1 http://www.bmj.com/content/350/bmj.h1654 2 http://www.bmj.com/content/350/bmj.h1654/rr-1

3 http://www.bmj.com/content/350/bmj.h1654/rr4 European Commission v Republic of Poland (C-185/10)5 BMJ 2015;350:h16546 BMJ 2015;350:h1723 7 http://www.bmj.com/content/350/bmj.h17238 Unlicensed and off-label uses of medicines:definitions and clarification of terminology https://www.ncbi.nlm.nih.gov/pubmed/28779556 9 http://www.bmj.com/content/350/bmj.h1377 and http://blogs.bmj.com/bmj/2014/09/26/david-lock-avastin-and-lucentis-its-time-for-nhs-commissioners-to-act-rationally/ 10 http://blogs.bmj.com/bmj/2014/09/26/david-lock-avastin-and-lucentis-its-time-for-nhs-commissioners-to-act-rationally/ 11 http://www.bmj.com/content/350/bmj.h137712 CATT http://www.aao.org/newsroom/release/20120502.cfm 13 GEFAL http://www.ncbi.nlm.nih.gov/pubmed/23916488 14 IVAN http://www.ncbi.nlm.nih.gov/pubmed/22555112 15 Diabetic Retinopathy Clinical Research Network. NEJM 2015. DOI: 10.1056/NEJMoa141426416 Bevacizumab vs Aflibercept for Macular Edema Due to Retinal Vein Occlusion http://jamanetwork.com/journals/jama/fullarticle/2626260 17 http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD011230.pub2/figures 18 http://www.nhscc.org/latest-news/doctors-unite-seeking-support-commissioning-safe-effective-eye-care-services-will-save-nhs-millions/ 19 https://www.nice.org.uk/guidance/ta481/resources/immunosuppressive-therapy-for-kidney-transplant-in-adults-pdf-82605021450181

20 https://www.nice.org.uk/guidance/indevelopment/gid-cgwave0658/documents 21 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1954941/ 22 https://www.rcophth.ac.uk/2014/11/rcophth-calls-for-review-of-avastin-for-use-in-amd-treatment/ 23 Licence to save: a UK survey of anti-VEGF use for the eye in 2015 : Eyehttp://www.nature.com/eye/journal/v30/n11/full/eye2016154a.html 24 http://dx.doi.org/10.1016/j.ophtha.2013.11.031 .25 TA15526 http://www.medicinesresources.nhs.uk/en/Communities/NHS/SPS-E-and-SE-England/LNDG/London-Wide-Reviews/LMEN-Review-Evidence-for-switching-between-VEGF-inhibitors-in-wet-AMD-September-2014/