Novartis's recent legal action against the UK National Health Service to prevent the off-label use of Avastin for macular degeneration challenges the current regulatory structures ensuring accountability for the safety and quality of drugs.
In April, Novartis announced that it would seek a judicial review to overturn reimbursement for Avastin (bevacizumab), a monoclonal antibody from Genentech/Roche that is prescribed by the UK National Health Service (NHS) for the treatment of the eye condition wet age-related macular degeneration (AMD). Avastin isn't officially approved for this condition in the UK, and Novartis asserts that its use for AMD undermines regulations meant to ensure patient safety.
Yet, since 2011, the NHS has allowed the reimbursement of off-label Avastin as a cheaper alternative to the licensed AMD therapy Lucentis (ranibizumab). Lucentis, also developed by Genentech and marketed outside of the US by Novartis, costs approximately £1,250 ($1,950) per injection, in contrast to the £30–50 cost per injection of Avastin.
Avastin and Lucentis are both monoclonal antibodies targeting vascular endothelial growth factor, which drives the pathological growth of abnormal blood vessels in AMD. While Lucentis was being developed, some ophthalmologists prescribed Avastin (which had already been approved for intravenous use as a cancer therapy) for AMD with encouraging results. Even after the approval of Lucentis, Avastin continued to also be used as an AMD therapy in many countries because of its lower cost. In the US, decisions about the use of Avastin and Lucentis have depended on individual circumstances and the policies of health insurance providers, leading to increasing use of Avastin (BMJ 344, e2941, 2012).
In the UK, Lucentis is recommended for the treatment of wet AMD by the National Institute for Health and Clinical Excellence (NICE), which makes its recommendations on drugs approved for a particular indication. Until very recently, no large comparative-efficacy trials for Lucentis and Avastin had been carried out. Typically, comparative-efficacy trials would be carried out with the assistance of an industry partner, but Roche has been unwilling to consider licensing Avastin for AMD or to conduct clinical studies to compare Lucentis and Avastin. But two such publicly funded trials have now indicated that both therapies have similar safety and efficacy profiles (Ophthalmology doi:10.1016/j.ophtha.2012.03.053, 2012; Ophthalmology doi:10.1016/j.ophtha.2012.04.015, 2012).
Novartis has argued that the higher incidence of side effects in the individuals treated with Avastin (40%) compared with Lucentis (32%) in one of the trials raises serious safety concerns for using Avastin for AMD. But it's unclear whether these differences can be attributed to the treatments, as the trial was carried out in patients with a median age of over 80 years old, who may be prone to other medical problems. So, further comparative efficacy trials will be necessary to satisfy all parties. Nevertheless, in the UK, NICE has already been asked to consider a formal appraisal of Avastin for AMD, using the data from the two recent trials in this evaluation.
This isn't the first time Novartis has taken legal action to restrict Avastin use: they previously attempted to block off-label use of Avastin for AMD in Germany. In the US, Genentech tried to stop the supply of Avastin to pharmacies that were reformulating the drug for use in AMD and has also made payments to US doctors who administer large numbers of Lucentis injections to discourage the use of Avastin (http://www.nytimes.com/2010/11/04/business/04eye.html?pagewanted=all 3 November 2010). In response to the latest comparative trial results, Novartis is in discussions with the Department of Health and NICE about pricing Lucentis in the UK more competitively. In these discussions, Novartis may ask NICE to widen reimbursement for Lucentis for its approved uses in other eye conditions, such as diabetic macular edema and macular edema secondary to retinal vein occlusion, conditions for which NICE currently does not support reimbursement.
These attempts of drug companies to protect their revenue stream seem hard to swallow. The NHS could save an estimated £84.5 million a year by switching from Lucentis to Avastin for the treatment of AMD. Given the current economic climate, healthcare providers should be allowed to investigate the possibility of more cost-effective options without obstructions from companies.
This case points to a gray area in the existing regulatory and access process for drugs. Typically, regulatory agencies such as the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) play a key part in evaluating drug efficacy and safety but do not necessarily make calls on access to drugs. Instead, health technology assessors, such as NICE in the UK and the Centers for Medicare and Medicaid Services (CMS) in the US, make recommendations about drug coverage on the basis of cost-benefit considerations. Although these organizations helped spur support for the two publically funded comparative trials, their interests are distinct from those of drug regulatory agencies: the cost of a drug is ignored by the FDA and EMA but is a major factor for the CMS and NICE.
If access to Avastin for AMD treatment is broadened, a regulatory structure will be needed to ensure accountability for the safety and efficacy of this type of off-label use, as well as guidelines to allow clinicians and patients to make informed choices about the potential treatment options. Although drug regulatory agencies could have a potential role in devising such frameworks, under the current system, it is difficult to see how they can intervene to evaluate off-label use without a pharmaceutical sponsor submitting its product for expanded licensing. Who should take on these responsibilities? Collaborative efforts from many different parties, including healthcare providers, health technology assessors and perhaps also professional bodies such as the UK Royal College of Ophthalmologists, will be required to ensure that these responsibilities to prescribing physicians and to patients are met.