On February 27, 2014 - as reported by newspapers and newscasts - the Italian Antitrust sanctioned Roche and Novartis with an overall fine equivalent to 180 million euros. According to the Antitrust motivation, the two multinationals would have illicitly agreed to prevent the diffusion of a much cheaper drug, bevacizumab (Avastin®), in order to advantage another much more expensive medicine, ranibizumab (Lucentis®), therefore causing an overall expense increase equivalent to 540 million euros for 2013 only. As already discussed by Focus, in the September 2012 issue, bevacizumab was approved in 2005 as systemic anti-cancer therapy, whilst ranibizumab was authorized in 2007 for age-related macular degeneration (AMD). However, even before completing the clinical trials on ranibizumab, effectiveness evidences in favour of bevacizumab had appeared in the literature. For this reason, in May 2007, bevacizumab was listed by the Italian Medicines Agency (AIFA) as drug completely covered by the National Health Service (SSN, law 648/96) for the treatment of age-related macular degeneration. After some time, despite the approval of ranibizumab for age-related macular degeneration and the restrictions for off-label drug use introduced by the financial budget law in 2007 (according to which a drug could have been administered off-label provided it had passed phase 2 clinical trials, at least), bevacizumab became the most used drug in AMD in Italy.
In March 2009, after the ranibizumab approval, bevacizumab was kept in the list of drugs covered by the National Health Service (law 648/96) for the treatment of all non-age-related exudative maculopathies, for neovascular glaucoma and for age-related macular degeneration, only for the patients already in therapy with the drug. After the pronouncement of the Regional Administrative Court (TAR) of Lazio - that intervened following the appeal of Pfizer, producer of pegaptanib (another drug indicated for age-related macular degeneration) - bevacizumab was removed from the 648/96 list for the treatment of age-related macular degeneration. In December 2012 the AIFA Technical Commission removed bevacizumab from the 648 list, because of the presence on the market of another drug with the same indications and stating that bevacizumab was less safe.
According to the Antitrust, behind these events there are economic motivations, favoured by the inter-connections between Roche and Novartis: both drugs, in fact, have been developed by Genentech, firm controlled by Roche (holder of bevacizumab) which gets royalties from Novartis (holder of ranibizumab). The latter, in turn, owns more than 30% of Roche. Increasing ranibizumab sales at the expense of bevacizumab, then, was profitable for both the companies. In this situation the Regional Council of Emilia-Romagna (RER), already in October 2009, voted a resolution for keeping the off-label use of bevacizumab in its own Regional Health Service, because of the elevate difference in costs in case of exclusive use of ranibizumab (with no advantages for the patient). A similar deliberation was approved by the Veneto Region. Novartis appealed against the RER approval, but the Regional Administrative Court, agreeing with the RER stance on the illegitimacy of the in-force law about off-label use, remanded to the Constitutional Court, which will be sentencing shortly. In the meantime the Government has issued a decree which considers the possibility, in particular cases, of favouring and promoting the off-label use of a drug for therapeutic indications different from those authorized for its commercialization. The text of the decree explains that, even in presence of validate alternatives within the authorized drugs, it is possible to add to the 648 list (off-label) those drugs that can be used for therapeutic indications different from the authorized ones, on condition that this indication is known and consistent with researches conducted within the medical-scientific national and international community, according to appropriateness and economy criteria. The inclusion must undergo AIFA evaluation, with consequent supply covered by the National Health Service. In case of inclusion of an off-label drug in the 648 list, AIFA will activate adequate monitoring instruments in order to ensure patients’ safety and promptly take the necessary actions.
Recently, preliminary data from a systematic revision conducted by the Italian Cochrane Centre, and requested by the Emilia-Romagna Regional Health Service, have been disseminated. Data are preliminary and have not been published yet and suggest that – considering all the available information from randomized and controlled clinical trials – there are no evidences that Lucentis® is safer than Avastin®. The abstract of this revision has been just published by the Italian Cochrane Centre (http://www/cochrane.it).
On April 15, 2014 the Superior Health Council (CSS) stated that the two drugs “do not present statistically significant differences in regard to effectiveness and safety for the treatment of age-related macular degeneration”.
Finally, on June 9 and 10, the AIFA Technical Scientific Commission voted in favour of the re-admission of bevacizumab in the list of the drugs totally covered by the National Health Service according to the law 648/96 for the treatment of age-related macular degeneration. The Commission granted the request for the off-label use of the drug, unanimously identifying a series of indispensable conditions for the patients’ safety:
- In order to guarantee sterility, mono-dose packaging of bevacizumab for intravitreal use will be only and exclusively provided by hospital pharmacies in possess of the necessary requisites;
- Intravitreal bevacizumab administration will only be provided by highly specialized ophthalmic centres within public hospitals identified by the Regions;
- The drug administration will take place only subject to the patient’s subscription of the informed consent, which needs to include the scientific motivations and adequate information on the existence of approved therapeutic alternatives, even though a higher cost for the National Health Service;
- The activation of a monitoring register which provides also the adverse drug reaction reporting form.
The appeal presented by Roche to the Regional Administrative Court (TAR) of Lazio in regard to the Antitrust sanction will be discussed on November 5, 2014.
The editorial staff of Focus would like to highlight few key-points of this sad story. Firstly, the supposed minor safety of bevacizumab, especially on cardiovascular reactions, was not subscribed by the European Medicines Agency (EMA).
As from the Antitrust sentence motivations at page 83, The EMA scientific committee, more in detail, clearly stated in its Avastin Report that: “… the CHMP agreed that detailed safety information …. is reassuring and no evidence can be provided that bevacizumab is systematically more unsafe than ranibizumab and vice-versa”. and, in the Lucentis Report that the analysed data were ‘insufficient to justify a different indication that gave the impression that Lucentis was safer than other anti-VEGF treatments under the profile of systemic adverse events”. It is however hard to explain why these decisions by EMA are to be known by Regulator Agencies only (except specific cases like the Antitrust sentence) and are not available to the scientific community. It should be also reminded that in April 2013 the World Health Organization included bevacizumab in the WHO EM list as (only) antiangiogenic drug for the treatment of sight diseases.
The second problem, not less important, concerns the effects that the exclusion of bevacizumab from the 648 list has determined for patients in terms of cure accessibility. The disappearance of a drug equivalent for safety and effectiveness (bevacizumab) but much less expensive of ranibizumab, not only affected the already struggling budgets of Regional Health Services, but because of hospitals and clinics expense limits could have prevented many patients to get access to the treatment or could have caused much delay in receiving it. Focus believes that collusive behaviour among pharmaceutical industries, as those recognized by the Antitrust in this case, and the interpretation of ruless and studies in univocal and partial way have lead to extremely sad pages in the history of regulatory activity. It is Focus opinion that only profound and radical changes could regain the trust of the citizens.