The report suggests that Swiss drug firm Novartis was involved in a sustained campaign to block the use of Avastin for AMD. The efforts are reported to include trying to influence clinicians involved with two trials to compare Avastin with Lucentis and using the charity sector to lobby its interests.
Switching to Avastin instead of Novartis’s Lucentis (ranibizumab), which is licensed for use in AMD but may be up to 20 times more expensive, has the potential to save the NHS more than £100m a year.
Although many doctors use Avastin to treat AMD patients, uncertainty remains as to whether they could be held personally liable for prescribing it in an ‘off label’ capacity – that is using the drug for a purpose, or in a dosage or preparation, other than for which it is licensed.
The BMJ report alleges that both Novartis and Roche, which owns the intellectual property rights for both Lucentis and Avastin, refused to fund trials comparing the two drugs in AMD, and worked to “undermine and divert attention from results” of publicly funded comparison trials. The allegations seem to support the ruling from a competition authority in Italy, where both companies are currently subject to fines of over €90m due to “unethical tactics” preventing the use of Avastin for AMD patients.
In an interview with the BBC, a whistleblower described being approached by a representative from Novartis and questioned about a trial of low-dose Avastin for AMD. Speaking to Radio 4’s Today Programme, principal investigator and consultant ophthalmologist at Queen’s Medical Centre in Nottingham, Dr Alex Foss, revealed he was told that continuing with the trial would lead to “quite significant opposition.”
The four-year TANDEM trial was established to test the effectiveness of administering the drug bimonthly at half the dose, compared to a standard dose administered monthly, as for Lucentis, and is due to run until 2016.
Dr Foss told the programme: “If the trial showed that giving [Avastin] bimonthly was as effective, this would, in practical terms...suggest it would be a superior drug, and I therefore suspect they took the view that this was a commercial risk they wished to mitigate.”
The ophthalmologist also indicated the involvement of the charity sector, namely the Royal National Institute of Blind People (RNIB), which passed the study protocol to Novartis.Dr Foss explained explained how he had been told by the Novartis representative that the opposition “wouldn’t be seen to come from [Novartis], but would be seen to come from the RNIB,” who “could be relied on to have concerns.”
Responding to allegations of its involvement, the RNIB told the BBC it had “no opposition” to the use of Avastin for AMD in principle, but rather opposed the TANDEM trial on the basis of its design, which posed a threat to the sight of study participants involved. It has also published a full response on its website.
A spokesperson for Novartis told OT: “Novartis is committed to high standards of ethical business conduct and does not tolerate unethical behavior.
“We take very seriously these claims and the new information from these alleged events, which took place several years ago. The allegations will now require a comprehensive review and therefore it would be premature to comment further.”
While Roche has said that it “firmly supports a physician’s right to make an informed choice of medication for his/her patients, based on the available scientific evidence.”
A spokesperson for Roche told OT: “This includes the possibility of a physician in the UK making an informed choice to use bevacizumab in the treatment of an ophthalmologic disease. However, as bevacizumab does not have a labelled indication for use in the eye, we would not and do not promote its use for the treatment of patients with retinal diseases.”
Both Avastin and Lucentis are antiangiogenics, which block the formation of new blood vessels, but only Lucentis is recommended by the National Institute for Health and Care Excellence (NICE) for the treatment of wet AMD. Avastin, which is indicated for intravenous use in colorectal, ovarian, brain and kidney cancers, can be prepared for intravitreal injection and used to treat AMD in an off label capacity.
While drug companies and sight loss charities have cited potential safety and efficacy issues around off label use of the Avastin, independent analysis published last year by the Cochrane Collaboration suggests the drug has a comparable safety profile to Lucentis in AMD.
Following a letter from experts published in the BMJ last year, including the head of the Royal College of Ophthalmologists, a spokesperson for the Department of Health told OT that only the manufacturer is able to apply for an additional therapeutic evaluation – in this case, for use in AMD.
However, Roche, which owns the intellectual property rights for both Lucentis and Avastin, has not applied to NICE for an appraisal of Avastin for AMD, which the BMJ investigation reports is due to “corporate considerations.”
The BMJ report also highlights the role of the regulator for GPs in the UK, the General Medical Council (GMC), citing the issue of GP liability around off label use of Avastin as a major roadblock. Yet the article points out that off-label prescribing has occurred frequently in the past, as is the case for some pain and anxiety medications (amitriptyline and sertraline respectively).
The GMC is reported to have consulted with both the Medicines and Healthcare Products Regulatory Agency (MHRA) and the pharmaceutical industry’s self-regulator, the Association of the British Pharmaceutical Industry (ABPI) about the off label use of the drug for AMD.
Responses to freedom of information requests from the BMJ are reported to show that regulatory lines were blurred by the GMC reclassifying ‘off-label’ use as ‘unlicensed use,’ a term which holds no legal weight under European law, according to the European Medicines Agency.
In March, leaders from 120 clinical commissioning groups (CCGs) wrote to the GMC, NHS England and the Department of Health to remove current barriers restricting the off-label use of Avastin. Following the call, one CCG, Northern Eastern and Western Devon, backed down on its decision to use Avastin as a first line treatment for AMD due to “issues around the licensing of the drug and compatibility with GMC and NICE guidance.”
Responding to the BMJ article in a statement published earlier this month, head of the GMC, Niall Dickson, said: “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.”
He added: “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.”