- Post date:
- Friday, 13 March 2015
Radhika Holmstrom examines the arguments on whether a drug to treat wet AMD will ever the go-ahead.
A matter of cost
Successive trials have found that bevacizumab – better known under its name of Avastin – is as effective as ranibizumab (Lucentis) for treating “wet” age-related macular degeneration (AMD). Bevacizumab was licensed as a cancer treatment in 2005, while ranibizumab was licensed for treating AMD in 2007. Both treatments were developed by researchers working for the company Genentech, which was bought by Roche in 2009. However, outside the US, ranibizumab is sold by the company Novartis. The exact prices of ranibizumab are confidential (see below), but it is still more expensive than bevacizumab.
Both drugs are anti-vascular endothelial growth factors (anti-VEGFs), because in wet AMD, the eye produces too much VEGF and instead of producing needed, healthy blood vessels, it produces unwanted, unhealthy ones which then leak blood or fluid, scarring the macula and leading to the loss of central vision.
The two drugs are very similar chemically. In 2012, the two-year Comparison of AMD Treatments Trials (CATT) trial in the US, which published its results in 2012, and the Inhibition of VEGF in Age-related Choroidal Neovascularisation (IVAN) trial in the UK both concluded that the two treatments are equally effective, while a recent Cochrane review (which looked at the different trials to date) quashed fears that there is a greater risk of death or serious side effects using the cheaper drug. “In the US, bevacizumab is the market-leading drug for wet AMD because a lot of people can’t afford the more expensive option: in fact, it’s often the market leader in countries where there is not the same regulatory issue,” Lotery points out.
In the UK, however, the regulatory framework is very much in evidence. Roche has not submitted bevacizumab for licensing as a treatment for wet AMD. As a result, NICE has not recommended it as a treatment for AMD; the only way to prescribe it is “off-label”, which lands the prescriber in a very grey and potentially dangerous area, as it means going against General Medical Council (GMC) guidance that off-label treatment should only be used if doing so would better serve a patient’s needs than using an appropriately licensed alternative (whereas bevacizumab is more cost-effective, but not more clinically effective). There have been attempts – notably the SHIP cluster of PCTs in south west England in 2011 – to recommend Avastin, but Novartis first announced it would bring a judicial review against the cluster and then lowered the UK price of Lucentis (although the actual price remains confidential).
Ranibuzumab v bevacizumab
Outside the UK, concerns have also been raised at government level about the push and/or pressure to use ranibuzumab rather than bevacizumab. Last year (2014), Italian authorities levied a €180 million charge against Roche and Novartis for “channeling demand toward the much more expensive drug Lucentis, through an artificial distinction between the two products”, while French lawmakers voted to allow the use of bevacizumab for AMD, and the national medicine agency ANSM wrote to Roche in November asking for more information about the drug.
Roche’s response, in the UK and elsewhere, is that the drug has not been tested for AMD and there are no plans for doing so. In a statement issued in November 2014, the company said that in order to get Avastin registered for use in the eye, “Roche would need to initiate a full clinical development programme (including Phase 2 and Phase 3 clinical trials) involving large numbers of patients and implement changes to the formulation, which would take years to complete”.
Roche is pushing hard with bevacizumab as an expensive cancer drug, not a cheap eye drug. In fact, the cost means that NICE does not always recommend it for the full range of cancers where it is a potential treatment; it is one of the drugs on the Cancer Drugs Fund, which can fund drugs not approved by NICE – but from March 2015, several forms of bevacizumab will be removed from this (so new patients will not be able to receive it).
Getting clarity in the UK
Lotery and McEwen’s editorial, therefore, is not a new argument, but a rallying call to start getting some clarity in the UK – as well as reiterating the point that in fact bevacizumab has already stood up to rigorous testing and analysis as an AMD treatment.
“The thing that’s struck me, through all this, is how little advice there is from the Department of Health,” says Lotery. “The IVAN study was funded governmentally, and I’m surprised that it was funded if the government wasn’t going to act on the results. Taxpayers’ money paid for research that concluded that this was equivalent to more expensive options; and multiple other clinical trials and a Cochrane review have concluded that there is no significant difference to support the preferential use of one drug over another. It does seem that it would need considerable effort at government level to untangle the bureaucracy, but the NHS could save a staggering amount of money. My view is that there needs to be unequivocal support from the Department of Health and the General Medical Council (GMC) to support the use of bevacizumab. There are hurdles, but it requires a central government response.” He points out that bevacizumab could also be explored for the other conditions for which anti-VEGFs are now being used – diabetic retinopathy and retinal vein occlusions – leading to further savings (and, by implication, a further dent in the Novartis budget).
Proper guidance needed
McEwen’s organisation is less forthright, preferring to call on the government and regulatory authorities to come up with a solution to the barriers that prevent the use of bevacizumab.
She adds: "Because Avastin is not licensed for use in AMD, the constraints placed on clinicians in 2011 are still in place today and in an age where evidence based medicine should prevail this is disappointing.
"We believe that ophthalmologists should be in a position to treat patients according to sound scientific and clinical evidence which is in keeping with the guidance on Good Medical Practice, issued by the GMC in 2013.
"The College is also mindful of evaluating the associated costs of medicines. In a time of NHS funding constraints, where a medicine is shown to be clinically safe and effective and could save the NHS, as in the case of Avastin £102million, it should not be ignored.
"We would welcome an urgent review of this issue by the UK regulatory bodies to review this issue and to how this unusual situation can be remedied."
Cathy Yelf of the Macular Society takes this point up, explaining that the only way the logjam can be broken is if the issue is taken up at Government level (as it was in France). “We feel very strongly that the NHS should go about this in an orderly way. If the NHS thinks it’s in the public interest to use Avastin, we feel there should be a proper appraisal of it, and someone should take national responsibility for that decision. In 2010, NICE held a scoping workshop that said they felt they were capable of holding an appraisal, but it requires a government minister to require them to do this. That hasn’t happened, so at the moment the position appears to be that, legally, we are not sure how the NHS can introduce Avastin.”
As the run-up to the General Election continues, it does not look as if it will get the ministerial push it requires
. The Government appears to have ruled out the use of Avastin to treat macular diseases saying it would be unlawful and against the wider public interest to do so.
The company remains adamant that it is not going to submit the drug for licensing, and without licensing it remains an “off-label” option – cheaper, known to be effective, but also capable of landing the prescribing body in the courts.
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