Why have UK doctors been deterred from prescribing Avastin?
BMJ 2015; 350 doi: https://doi.org/10.1136/bmj.h1654 (Published 01 April 2015) Cite this as: BMJ 2015;350:h1654
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In his response to Deborah Cohen's article Dr Fell has misinterpreted our editorial. We wrote as follows: "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."
The first sentence reflects the way in which an ophthalmologist would draw up the necessary dose of bevacizumab from the marketed solution, using a small (e.g. 50 microliter) syringe. The second sentence, which begins "if", describes the hypothetical action of a pharmacist preparing a secondary solution by dilution, as has been done for other purposes [1], entailing a "manufacturing" step. We believe that the MHRA would regard the resulting formulation as being unlicensed, as they apparently would formulations prepared by dividing an undiluted solution into several aliquots [2]. The third sentence questions this view.
[1] Kaja S, Hilgenberg JD, Everett E, Olitsky SE, Gossage J, Koulen P. Effects of dilution and prolonged storage with preservative in a polyethylene container on Bevacizumab (Avastin™) for topical delivery as a nasal spray in anti-hereditary hemorrhagic telangiectasia and related therapies. Hum Antibodies 2011; 20(3-4): 95-101.
[2] Poku E, Rathbone J, Everson-Hock E, Essat M, Wong R, Pandor A, Wailoo A. Bevacizumab in eye conditions: issues related to quality, use, efficacy and safety. Report by the Decision Support Unit, August, 2012. http://www.nicedsu.org.uk/Bevacizumab%20report%20-%20NICE%20published%20....
Competing interests: As stated in our editorial.
If – as Cohen suggests,1 and Dixon appears to confirm2 – it is the rule that a doctor could be struck of for prescribing one product – no matter that guidance suggests it is as safe and effective for the purpose as another – simply because it is not explicitly licensed for that purpose, whereas another product is so licensed – then this has very wide ramifications.
In the field of vaccination the UK “bible”, the Green Book explicitly states:
“Recommendations on immunisation procedures are based on currently available evidence and experience of best practice. In some circumstances, this advice may differ from that in vaccine manufacturers’ Summaries of Product Characteristics (SPCs). When this occurs, the recommendations in this book (which are based on current expert advice received from the Joint Committee on Vaccination and Immunisation (JCVI) should be followed. Further guidance can be found at: www.gmc-uk.org/guidance/ethical_guidance/prescriptions_faqs.asp.”3
This suggests that vaccine practitioners should consider that the Green Book recommendations should outrank the guidance in the SPCs, including regarding licensing.
Other national guidance also conflicts with this principle. Guidance on meningococcal chemoprophylaxis, for example states:
“Ciprofloxacin is recommended for use in all age groups and in pregnancy.”4
Rifampicin is licensed for this recommendation in all ages,5 6 whereas ciprofloxacin is only licensed for use in adults.7
I am sure that practitioners in other fields will be aware of many other examples where authoritative guidance conflicts with product licenses. Where does this leave practitioners who follow authoritative guidance? Or who produce or advise others to follow it?
REFERENCES
1. Cohen D. Why have UK doctors been deterred from prescribing Avastin?, 2015 (http://www.bmj.com/bmj/350/bmj.h1654.full.pdf).
2. Dickson N. Re: Why have UK doctors been deterred from prescribing Avastin? (Rapid response). 2015; Updated 2 April; Accessed: 2015 (10 April): (http://www.bmj.com/content/350/bmj.h1654/rr).
3. Public Health England. Chapter 4: Immunisation procedures. Immunisation against infectious disease. Published 20 March 2013 ed. London: HMSO, 2013:25-34 (https://www.gov.uk/government/publications/immunisation-procedures-the-g...).
4. Health Protection Agency Meningococcus and Haemophilus Forum. Guidance for public health management of meningococcal disease in the UK. London: Health Protection Agency, 2012 (9 March); 1-57 (https://www.gov.uk/government/publications/meningococcal-disease-guidanc...).
5. Summary of Product Characteritics (SPC): Rifadin 300mg Capsules. 2014; Updated 15 September 2014; Accessed: 2015 (18 March): (http://www.medicines.org.uk/emc/medicine/21223).
6. Summary of Product Characteritics (SPC): Rifadin Syrup 100mg/5ml. 2014; Updated 10 September 2013; Accessed: 2015 (18 March): (http://www.medicines.org.uk/emc/medicine/21222).
7. Summary of Product Characteritics (SPC): Ciprofloxacin 250 mg film-coated tablets. 2014; Updated 28 November 2014; Accessed: 2015 (18 March): (http://www.medicines.org.uk/emc/medicine/19016).
Competing interests: I have received payments for giving talks and writing articles for various vaccine manufacturers.
Evans vs GMC
There are seeming irresolvable differences in interpretations of what the law ACTUALLY says with regard to PRESCRIBING of an unlicensed medicine between Mr Dickson’s response about the GMC position and Prof Evans' view that the case law cited 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 line.
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 EMA and FDA. If indeed bevacizumab is off label then perhaps a different line should be taken.
The Aronson and Ferner editorial 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.
Competing interests: I have participated in an Advisory Board for Bayer HealthCare for which my employer was reimbursed for my time.
That Lucentis and Eylea are effective and have transformed the landscape and outcomes for patients is not disputed. But, so is a substantially cheaper medicine that may never have market authorisation for its use in ophthalmology. The piece by Cohen sheds a very interesting light on some of the areas of this complex area that have not yet received much space.
“Unsafe, unlicenced drugs”
Some have made accusations about commissioners seeking to give preferential weight to “unsafe and 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. Given the Cochrane review on safety, the “unsafe” label seems hard to justify.
Whether Avastin is off label or unlicensed seems to be up for debate. Two of the world’s major medicines regulators, the FDA and the EMA, seem to be of the opinion that Avastin in ophthalmic indications is an off label use of an unlicensed medicine.
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 Avastin 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.
Turning the accusation about “doing things on the cheap” on its head, then it can be framed as a question of “how many sight years do you want to buy for a very limited budget?’
Off label or unlicensed?
Avastin received marketing authorisation at the European level rather than a national level for cancer use. The EMA provides advice to the European Commission, who then approves it. The inconsistencies between the MHRA's description of repackaged ophthalmic Avastin as being an unlicensed use, and the EMA's as being 'off-label' use, mean there are questions as to whether the EMA's position should trump that of the MHRA.
That Avastin in ophthalmology is “off label” certainly seems to be the opinion expressed in Lock’s piece – a licensed medicine being manufactured by a specials manufacturer with a MHRA licence to do so, but suddenly the medicine in such circumstances is unlicensed. There seems flawed logic here in the MHRA’s argument.
Evidence, free market and opportunity cost
Watching this evidence develop over the years has been instructive. We now have pretty robust evidence that Avastin is as safe and effective as Lucentis. In AMD in particular there seems very little to choose between the two drugs effectiveness wise . Thus the standard approach in a free market would be to use the cheapest – this is basic cost minimisation. It would seem that some stakeholders have seemingly gone to great lengths to ensure that the market is not free and that the status quo is maintained.
That opportunity cost is readily countable; for example we are aware of some areas where the threshold for cataract operations is raised. There are downstream consequences of this -falls, loss of independence etc - but it is a reflection of what commissioners DO have budgetary control over (they don't have control over NICE Technology Appraisal recommendations). RNIB, rightly from their perspective want BOTH lower thresholds and Lucentis. What they can't have is both. Which would they give up?
It is easy to understand the commercial pressures on Novartis and Bayer. This isn't disputed. They have sought to maximise the return to their shareholders, the primary goal. However trying to meet all competing demands for health care resources is also complex, and requires many difficult trade offs.
Maybe, given what we now know, the trade off should be that the NHS uses Avastin and doesn’t make anonymous patients bear the opportunity cost.
Refs
Cohen D. Why have UK doctors been deterred from prescribing Avastin? BMJ 2015;350:h1654
Moja L, Lucenteforte E, Kwag KH, et al. Systemic safety of bevacizumab versus ranibizumab for neovascular age-related macular degeneration. Cochrane Database Syst Rev2014;9:CD011230.
Lock D. Avastin and Lucentis: a guide through the legal maze. BMJ 2015;350:h1377
CATT Research Group, Martin DF, Maguire MG, et al. Ranibizumab and bevacizumab for treatment of neovascular age-related macular degeneration: two-year results. Ophthalmology2012;119:1388-98.
. Chakravarthy U et al Alternative treatments to inhibit VEGF in age-related choroidal neovascularisation: 2-year findings of the IVAN randomised controlled trial.
Lancet. 2013 Oct 12;382(9900):1258-67.
Competing interests: No competing interests
I could be wrong but I think that 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.
Competing interests: I am a European Commission appointed Independent Expert Member of the Pharmacovigilance and Risk Assessment Committee at the European Medicines Agency which assesses safety of drugs and vaccines that are marketed in the EU.
I have been involved in a similar debate with our Area Prescribing team concerning Lyrica which is licensed for neuropathic pain only. The drug tariff pays the higher price for both generic and branded Pregabalin. The argument here is that the contract lies with the NHS, not individual GPs and that a GP could prescribe generically. However, it defies comprehension for the more expensive tariff paid to pharmacists regardless of generic or branded formulation. I suppose the drug tariff here may follow the same principle making it costlier for the NHS regardless of brand. It would be useful to know if this is the case for Avastin.
In terms of choosing a formulation, I do not believe individual GPs or ophthalmologists could legally have their hands tied to prescribing one brand only. As long as their is evidence to support its use, a combination of both evidence-base and cost should be taken into account. NICE regularly talks about cost effective alternatives. It must be made clear that no institition can force prescribing, hence the 'recommendations'. The RCGP makes it clear to involve patients in prescribing decisions. I am sure most patients will not object to the cheaper version once they have been fully informed of the choices available to them. I am therefore surprised by the GMC response above. If Avastin, for example, is available I don't think anyone can stop clinicians from prescribing given the informed discussions they must undertake with their patients. Patients too have the right to choose.
Competing interests: No competing interests
It is quite wrong to suggest the GMC's position is unclear or that it is we who are putting doctors in a difficult position. It is also wrong to imply our guidance has recently been altered. Our prescribing guidance, which remains unchanged, was issued in January 2013.
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.
Competing interests: No competing interests
An Alternative Solution to the Avastin problem?
In Ferner & Aronson's editorial they state that applicants are granted licenses to market medicinal products and that the terms of the product's license (the label) are then described in the Summary of Product Characteristics. Of course usually, and perhaps always , this application would be made by the company who have developed the drug and have the patent for it's use.
Perhaps it is time to allow other bodies, for example Royal Colleges or NICE or NHS England, to be able to apply for a 'license to allow use of' a medicinal product for an off label use . This application would have to be supported by an equivalent amount of evidence as would be normally be provided when a pharmaceutical company applies for a marketing licence; but in the case of bevacizumab this evidence seems to be there.
This would not of course allowing the body applying for this license to produce or market the drug but would protect doctors wishing to prescribe it off label without the threat of litigation.
If this requires a change in the law then is this something we should be suggesting to our potential parliamentary candidates in the run up to the election.
Of course a simpler solution would be a change in GMC guidance but Dr Niall Dickson's response suggests that there significant difficulties with this in the current legal climate.
I would be interested in any feedback particularly from those with expertise in legal medicine or from the MHRA or EMA . Reply to frances.fermer@nhs.net
Competing interests: No competing interests