Why using Avastin for eye disease is so difficultBMJ 2012; 344 doi: https://doi.org/10.1136/bmj.e3012 (Published 01 May 2012) Cite this as: BMJ 2012;344:e3012
Ranibizumab (Lucentis) and bevacizumab (Avastin) are both commonly used to treat wet age related macular degeneration (AMD) in the United Kingdom. Many primary care trusts, which pay for treatments in England, see little difference between them, other than the price: ranibizumab costs around 12 times more than bevacizumab.1
But Novartis insists there are subtle and important differences between them in terms of effectiveness and safety, and, most importantly, ranibizumab is licensed for wet AMD and is recommended by the National Institute for Health and Clinical Excellence (NICE), whereas bevacizumab is not. Some cynics might describe it as clever marketing.
Both drugs were developed by Genentech, which is now owned by Roche. They are derived from the same antibody and work by blocking vascular endothelial growth factor (VEGF) to slow down or stop abnormal growth of blood vessels. Bevacizumab was developed as an anticancer drug and licensed in Europe in 2005. Ranibizumab was licensed for macular degeneration in 2007. Roche holds the licence for bevacizumab and in the US sells ranibizumab through Genetech, while outside the US Novartis manufactures and holds the licence for ranibizumab.
Before ranibizumab was licensed, ophthalmologists realised that bevacizumab was likely to have the same effect and some started using it off-label for wet AMD.
With primary care trusts under financial pressure, an increasing number are considering allowing ophthalmologists to use the cheaper bevacizumab for wet AMD, a move that would affect Novartis’s profits dramatically.
Novartis argues that ranibizumab is the more effective and safer product for the indication and points out that there are potential repercussions for doctors and hospitals using bevacizumab off-label rather than ranibizumab, which NICE recommends. Much of this argument is delivered through sponsored meetings and interactions between individual company representatives and ophthalmologists, primary care trust (PCT) staff, or journalists.
And with the imminent move to clinical commissioning groups, Novartis is beginning to target general practitioners who will be holding the purse strings with educational meetings on commissioning in ophthalmology. One is due to be held in London on 14 June.
Two major non-pharmaceutical company funded trials comparing bevacizumab and ranibizumab are currently underway to clarify whether ranibizumab is really more effective and safer: the Comparison of Age-related Macular Degeneration Treatments Trials (CATT) in the US funded by the National Eye Institute, and the Inhibit VEGF in Age-related choroidal Neovascularisation (IVAN) trial in the UK funded by the Health Technology Assessment Clinical Trials programme of the UK National Institute for Health Research.
The first year results from CATT, published last May, suggest that bevacizumab and ranibizumab are equally effective. Novartis highlighted that the two drugs had different side effect profiles, with a higher risk of stroke and death with bevacizumab.2 The second year CATT data and first year IVAN data will be unveiled at the Association for Research in Vision and Ophthalmology meeting in Florida in May. In preparation Novartis is briefing key journalists. In April it held a media roundtable to recap the CATT first year data and IVAN trial design and discuss implications for interpreting the final results of these trials.
The board of North Yorkshire and York PCT has been discussing allowing use of bevacizumab for some time,3 but, aware that such a decision is likely to elicit a legal challenge from Novartis, in January its board decided to await the outcome of the IVAN and CATT trials.4 If it does give the green light to bevacizumab, it is likely to create difficulties for some providers. York Teaching Hospital NHS Foundation Trust has received funding from Novartis for a mobile eye unit for patients on the east coast of Yorkshire, so that patients do not have to make an 80 mile round trip to York Hospital once a month for their ranibizumab injections. 5
And North Yorkshire and York is right to be wary. Novartis has started judicial review proceedings against SHIP PCT cluster, which is made up of Southampton City, Hampshire, Isle of Wight and Portsmouth City PCTs, after it agreed in September 2011 to allow ophthalmologists the option of prescribing bevacizumab.
Elsewhere, a meeting organised with ophthalmologists by a PCT in Hertfordshire to discuss the potential use of bevacizumab was followed by a call the next day from a Novartis representative to check that ranibizumab was still the only drug being funded. Two weeks later the Royal National Institute of Blind People, a patient organisation with links to Novartis, made a Freedom of Information request asking whether bevacizumab was commissioned for wet AMD. The accounts for the RNIB show that it received £851 000 (€1m; $1.4m) from Novartis in 2010-11. In September 2011, the RNIB’s policy and campaigns manager Barbara McLaughlan joined Novartis as national cancer policy lead.
But even when PCT clusters allow the use of bevacizumab, it does not mean that ophthalmologists will use it. While some may happily use bevacizumab for private patients, who benefit from the cost saving, they are reticent to use it off-label for NHS patients.
A paper issued by the Royal College of Ophthalmologists in December last year concluded that both bevacizumab and ranibizumab “are equally effective in the treatment of AMD and have a similar safety profile.”1 But both the college and patients’ representative organisations back the use of ranibizumab for wet AMD because it is licensed and approved by NICE.
James Talks, a consultant ophthalmologist at Royal Victoria Infirmary in Newcastle and a member of the college council says: “From a lot of doctors’ point of view, the effectiveness evidence appears very similar, but then you are then trying to persuade the patient that they should have a treatment that is not the NICE approved one. Essentially it is a cheaper drug, but there isn’t really any benefit from the individual patient’s point of view, it is a benefit from the community point of view. Doctors want reassurance that it is not going to come back to haunt them.”
Novartis is keen to point out the medicolegal pitfalls for both doctors and hospitals of opting to use an off-licence drug instead of one that is licensed and recommended by NICE. Last May, it held a meeting on establishing safety and examining the medicolegal implications of unlicensed prescribing.
The current General Medical Council guidelines, Good Practice in Prescribing Medicines, state that in order to use a medicine off-label doctors must “be satisfied that it would better serve the patient’s needs than an appropriately licensed alternative.” These guidelines are being revised, and one of the proposals is to allow doctors to take the cost of the medicine into account for the benefit of the wider health system. Publication has been delayed repeatedly and is now expected in June, but without the controversial chapter on off-label and unlicensed prescribing, on which the GMC is seeking legal advice.
Talks adds that even revised GMC guidance will not resolve the issue completely: “The hospital doesn’t want to get sued because someone gets an infection using something that is against the current NICE guidance. It is probably very unlikely, but it is possible. The process of manufacture, the process of distribution, is not the same as it would be for a licensed product.”
Infection is a risk whenever any drug is injected into the eye, but Novartis argues that the risk is greater with bevacizumab because it distributes it in quantities that are much too large for injection. Special compounding pharmacies have to split it into smaller dose, and this process increases the infection risk. There have been cases in Florida linked to a compounding pharmacy and outbreaks at two Veterans Affairs hospitals in the US. In the UK, Moorfields Pharmaceuticals was forced to recall batches of bevacizumab in March after suspected cases of sterile endophthalmitis.6
In the wake of the Moorfields incident the European Alliance for Access to Safe Medicines, a patient safety group that receives funding from Novartis,7 stated there was an urgent need to address patient safety around the use of unlicensed and off-label medicines, which should be used only when there is no licensed product available.
Helen Jackman, chief executive of the Macular Disease Society, says there is anecdotal evidence that when patients pay for wet AMD treatment privately, they are usually happy to have bevacizumab rather than ranibizumab, but she emphasises that the NHS should be using ranibizumab because it has been fully appraised and licensed.
“There are a number of conditions that ranibizumab is not available for—diabetic macular oedema, retinal vein occlusion, and so on—and we are quite happy to support patients to try to receive bevacizumab for those conditions,” she says.
Novartis is understood to be in discussion with the Department of Health and NICE about lowering the price of ranibizumab in exchange for recommendation by NICE for a wider range of indications. Such a deal would certainly be in Novartis’s interest given that, in the UK, there are around 100 000 patients a year with diabetic macular oedema compared with 20 000-25 000 with wet AMD.8 Last year NICE decided it could not recommend ranibizumab for diabetic macular oedema because it was too expensive. In October last year Novartis cut the cost of ranibizumab in Switzerland by 30%.9
“We know how cash strapped PCTs are at the moment and ranibizumab is an expensive treatment. If the Department of Health or NICE or whoever can come to an agreement with Novartis that lowers the cost of ranibizumab and makes it available to a wider set of indications and those patients could benefit, we would strongly urge the department to pursue those discussions with energy,” Jackman says.
The imminent launch of another more competitively priced VEGF blocker may make a price cut more likely. Aflibercept, codeveloped by Bayer and Regeneron Pharmaceuticals, was licensed in the US for wet macular degeneration in November last year. In the US, it costs $1850 per dose versus $2000 for ranibizumab. However, as aflibercept requires bimonthly injection rather than monthly, the annual cost of aflibercept is estimated to be $16 000 compared with $24 000 for ranibizumab.10
In 2010 the Department of Health asked NICE to explore the feasibility of appraising bevacizumab for wet AMD. NICE concluded that a technology appraisal would be possible if the Department of Health referred it and the Medicines and Healthcare Products Regulatory Agency (MHRA) did an assessment of safety and quality.11 Both the Macular Disease Society and the Royal College of Ophthalmologists have urged the Department of Health to refer bevacizumab for appraisal,1 12 but it has not.
Jackman says: “This could potentially set a difficult precedent in terms of being a sort of backdoor approach to the regulation of medicine, which you know is not something that would necessarily be a good thing. Talks agrees, adding that the department “wants pharmaceutical company investment in this country; we are losing a lot of it as it is.”
So could another body refer bevacizumab to NICE? Not unless it is licensed, and Roche is unlikely to submit an application to the MHRA for wet AMD.
“An application (generic/biosimilar) by an independent third party referring to bevacizumab may not be accepted until the 10 years’ data exclusivity period for bevacizumab has elapsed,” a spokesman for the MHRA said. “In the interim, should a third party wish to apply for a product containing the active substance bevacizumab, the applicant would be required to submit results of their own pharmaceutical, preclinical, and clinical data to fully support their application.”
By the sound of it, unless the Department of Health is successful in pushing for a lower price for ranibizumab, we may have to wait until after 2015 to see a really competitively priced anti-VEGF for wet AMD licensed and recommended to the NHS.
Ranibizumab and bevacizumab: a complex story
When were they licensed? Bevacizumab (Avastin) was licensed as a cancer treatment in 2005. Ranibizumab (Lucentis) was licensed for the treatment of age related macular degeneration (AMD) in 2007. Both treatments were developed by Genentech, which was bought by Roche in 2009. Novartis holds the license to sell ranibizumab outside the US. Novartis retains data exclusivity for ranibizumab until 2015.
Why is bevacizumab the cheaper drug? The dose required for intravenous use in cancer treatment is much larger than that used for intravitreal injection in AMD, which brings the price down. The cost per injection for AMD is about 12 times lower than that for ranibizumab.
What needs to happen for a drug to be available for a specific indication in the UK? Drug companies must submit their drug for licensing to the MHRA, which decides whether it is effective and safe. A third party can apply for a licence for a generic or biosimilar version but must either wait for the company’s exclusive rights to the data to elapse or provide its own preclinical and clinical data. For a drug to be appraised by the National Institute for Health and Clinical Excellence (NICE), it must be referred by the Department of Health. Health commissioners in the UK can still allow the use of a drug even if it is unlicensed for a particular indication and NICE hasn’t recommended it. This is what Southampton City, Hampshire, Isle of Wight and Portsmouth PCTs has done in the case of bevacizumab.
What are the key clinical trials for these drugs? There are two major non-drug company funded trials. The Comparison of Age Related Macular Degeneration Treatment Trials (CATT) in the US is funded by the National Eye Institute. The first year CATT results were published last May and suggested that bevacizumab and ranibizumab are equally effective. Second year results will be published this month. Also this month comes first year data from another major trial, the Inhibit VEGF in Age Related Choroidal Neovascularisation (IVAN) trial in the UK, funded by the UK National Institute for Health Research.
Cite this as: BMJ 2012;344:e3012
Competing interests: The author has completed the ICJME unified disclosure form at www.icmje.org/coi_disclosure.pdf (available on request from the corresponding author) and declares no support from any organisation for the submitted work; no financial relationships with any organisation that might have an interest in the submitted work in the previous three years; and no other relationships or activities that could appear to have influenced the submitted work.
Provenance and peer review: Commissioned; not externally peer reviewed.