Off-label prescribing in macular degeneration

The drug company Novartis stands to lose a hefty slice of income if most patients with macular degeneration in the United Kingdom are treated with the cheap cancer drug bevacizumab (Avastin) instead of the more expensive eye drug ranibizumab (Lucentis), which, unlike bevacizumab, is licensed specifically for that condition (www.inpharm.com/news/168782/novartis-lucentis-price-cut-switzerland). Both drugs are made by Roche, and the more expensive one is marketed in the UK by Novartis.

Novartis has produced research showing that patients do not like the idea of being given an unlicensed drug for their condition. And now some newspapers are claiming that doctors are being pushed into prescribing the cheaper drug. But are they really being pressurised to do so, and would it matter if they were? The background is this: bevacizumab costs about £85 (€98, $134) an injection, compared with £740 for ranibizumab (http://blogs.bmj.com/bmj/2011/06/28/james-raftery-avastin-lucentis-and-nice). Ranibizumab is licensed to treat macular degeneration; bevacizumab is not, but it has been proved to be just as effective in doing so.

Evidence that some places are seeking savings by turning to bevacizumab comes from the SHIP (Southampton, Hampshire, Isle of Wight, and Portsmouth) cluster of primary care trusts, which recently calculated that it could save £4m-5m a year by switching to bevacizumab and is planning to do so (www.havantccs.org.uk/ENEWS/ENEWS%20081%20AVASTIN%20NOTES.pdf). In its consultation document it says, “The evidence base on Avastin is already substantial and a trial called CATT in the USA has demonstrated equivalence between Avastin and Lucentis in the 12 month interim analysis.”

The Daily Mail reported, “A Daily Mail investigation reveals that, despite safety fears, dozens of primary care trusts have told consultants to use Avastin rather than Lucentis to treat wet age-related macular degeneration, an eye disorder that can lead to blindness” (www.dailymail.co.uk/health/article-2046714/Doctors-pushed-using-cheap-eye-disease-drug.html).

The Financial Times said, similarly, “Doctors are coming under growing budgetary pressure to prescribe a cancer drug for patients with a severe eye disease instead of a more expensive authorised alternative . . . the safety of the treatment has been questioned by ophthalmologists as well as Roche and Novartis, the drug companies which jointly developed and sell both medicines. Clara Eaglen, policy and campaigns manager at the Royal National Institute for the Blind, said, ‘We’re fully aware of the financial pressures facing the NHS, but . . . safety is paramount and PCTs [primary care trusts] should not abandon evidence-based medicine and prescribe Avastin off-label for quick financial gain” (www.ft.com/cms/s/0/0fca81d0-eb7e-11e0-a576-00144feab49a.html#axzz1a5dkvn5t).

Is this true? Is such off-label prescribing really a threat to patient safety? The General Medical Council consulted in 2011 about guidance for doctors in this area, and at about the same time, Novartis, which markets ranibizumab, commissioned a survey of patients and doctors. The findings were press released and headed “Demands on physicians to save money may be increasing pressure to use unlicensed medicines over licensed alternatives. 82% of patients would be worried if they were prescribed a treatment which was not licensed for their specific condition when there is a licensed alternative available, on the basis of cost.”

They noted that, of doctors, most expressed “concern about safety data (76%) and safety monitoring (71%) . . . Geraldine Mynors of the Patient Information Forum agreed that it was important for patients to understand the importance of the regulatory system . . . ‘Patients need to be involved about decisions about medicines and to have full and transparent information about any treatment that their doctor is recommending.’”

There was no mention of the interest Novartis might have in the answers to the survey, either in the questions or subsequent press release. (This press release was released on 28 April 2011 broadly to UK journalists but is not available on their website.) Asked if it thought this was fair, given how the results might be used, Novartis said in a statement, “The survey was designed not to ask physicians and members of the public about specific drugs and disease areas so as to remove any preconceived ideas. As mentioned, the purpose of the survey was to ascertain the perspectives of physicians and the general public on the use of unlicensed medicines generally, which is an important debate facing the NHS and our industry at this time. Novartis believes that the principle of favouring the use of an unlicensed medicine over a medicine that has undergone the full rigour of regulatory approval will mean the interests of patients will not be served in the long term.” Novartis also told me that it had held telephone briefings with journalists in connection with this survey.

More recently sight threatening infections, most likely introduced when bevacizumab has been divided into aliquots, have led to the decision by the US Department of Veterans’ Affairs to stop using bevacizumab in treating eye conditions (BMJ 2011;343:d6169, doi:10.1136/bmj.d6169). After this, a consensus statement was released by, among others, the European Alliance for Access to Safe Medicines (EAASM) and the European Federation of Neurological Associations, stating, “Our message is: enough is enough,” said Jim Thomson, chairman of EAASM. “The FDA [US Food and Drug Administration] was able to act because it was made aware of the problem. In Europe it’s a matter of chance as to whether the regulatory authorities are made aware of similar problems because there is no mandatory mechanism to report adverse events in medicines used this way. We strongly believe unlicensed and off-label medicines should only be used when a licensed product is unavailable. In addition, patients should be informed and provide written consent for the medicine to be used” (www.prnewswire.co.uk/cgi/news/release?id=333443).

The Patient Information Forum has, as one of its supporters, the Association of the British Pharmaceutical Industry (www.pifonline.org.uk/ask-about-medicines/about-aam/supporters/); the European Alliance for Access to Safe Medicines has Novartis as a funding partner (www.eaasm.eu/About_the_EAASM/Members_and_funders); and Novartis has provided substantial funding to the European Federation of Neurological Associations (www.efna.net/aboutUs/grants.asp). The Royal National Institute of Blind People has also taken funding from Novartis. The CATT trial showed that the two drugs had “effects on vision that were equivalent” (N Engl J Med 2011;364:1897-908, doi:10.1056/NEJMoa1102673), and a large retrospective cohort study has provided reassuring results about safety (Arch Ophthalmol 2010;128:1273-9, doi:10.1001/archophthalmol.2010.223).

Ironically, while primary care trusts wrangle with cost effectiveness, the private sector is already embracing the ability to offer patients the choice of cheaper bevacizumab. This may be a case of the public sector catching up with the private.