POSITION PAPER. Promotion of off-label use of medicines by European healthcare bodies in indications where authorised medicines are available

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1 POSITION PAPER Promotion of off-label use of medicines by European healthcare bodies in indications where authorised medicines are available EFPIA May 2014 EFPIA represents the pharmaceutical industry operating in Europe. Through its direct membership of 33 national associations and 40 leading pharmaceutical companies, EFPIA provides the voice of 1,900 companies committed to researching, developing and bringing new medicines to improve health and quality of life around the world. The pharmaceutical sector directly employs some 700,000 people in Europe including 116,000 working in research and development.

2 Summary Healthcare bodies promoting economic driven off-label use when licensed alternatives exist, as reflected in recent legislative changes in France and Italy, undermine the European regulatory framework, potentially compromise patient safety and create legal uncertainty. Such practices may lead to secondary, national marketing authorizations, thereby undermining the EU regulatory framework as developed over the past 20 years, as well as putting into question the European Commission s competence to authorize new medicines. To preserve the high standards of patient safety in the EU, healthcare bodies should adhere to EU law and refrain from promoting off-label use for economic reasons. These medicines have not been tested and assessed to the same stringent standards for the off-label indication, putting patients health and safety at risk for the sake of cost savings. Promotion of economic driven off label use will discourage pharmaceutical companies from undergoing the costly and time-consuming authorization process for new indications if public authorities favour off-label use of other, cheaper medicines which have not undergone the same stringent safety and efficacy assessment. BACKGROUND Article 168 of the Treaty on the Functioning of the European Union (TFEU) states that a high level of human health protection shall be ensured in the definition and implementation of all Union policies and activities. The European Union thus adopted a robust and stringent approval system for medicines which aims at guaranteeing the highest level of patient safety. The thorough and comprehensive testing, such as several years of clinical trials, and extensive analysis of the benefits versus the potential risks required to obtain a marketing authorisation for a medicine is designed to ensure that only those medicines which are both safe and effective for a specific indication are marketed in the EU. For biologic drugs the centralized procedure is mandatory and results in a single marketing authorisation that is valid in all European Union countries. However, healthcare bodies 1 in some European countries have begun promoting offlabel use 2 of medicines in indications where there are already approved medicines available effectively bypassing the rigorous regulatory framework. Off-label use of medicines should always be limited to individual decisions of the treating physician based on medical needs when patients cannot be treated 1 For the purpose of this paper healthcare bodies include national healthcare administrations, HTA/ costeffectiveness bodies, social insurance bodies and other governmental agencies, excluding regulatory authorities. 2 Off-label use for the purpose of this position paper is defined as any use of an authorised medicinal product not covered by the terms of the marketing authorisation, including the use of the product for a different indication, different dose or dosage or for a patient group not specified on the summary of the product characteristics (SmPC). 2

3 satisfactorily by a licensed medicine 3. Promoting off-label use without a medical rationale but rather for economic reasons and especially in cases where licensed alternatives exist not only puts patient safety at risk and undermines the integrity of the European medicine approval system but is in contradiction to EU law. The Court of First Instance ruled that there is a general principle, identified in the case-law, that protection of public health must unquestionably take precedence over economic considerations 4. In Commission vs Poland the Court of Justice confirmed that financial reasons do not justify derogation from the marketing authorisation requirements 5. This principle was reiterated by Paola Testori Coggi, Director General of DG SANCO, European Commission, in a letter dated 13 March 2014 to Luca Pani, Director General, AIFA stating that Financial considerations must not take precedence over the safety of patients 6, Despite the already existing EU case law, several Member States have adopted or considered adopting regulatory measures encouraging the use of medicines beyond their authorised indications on the ground that they are less expensive than those medicines duly authorised in specific indications. On 17 December 2012 France amended Article L of its Code de la santé publique to authorise the government to issue recommendations encouraging off-label use of a medicine despite the existence of authorised therapeutic alternatives, for solely economic reasons. On 20 March 2014 Italy adopted a Law Decree n 36 promoting economic driven off label use even if licensed medicines are available. The Italian Law Decree empowers the Italian Medicine Agency to assess the safety and efficacy of the given medicine in the off-label indications, taking into account the relative burden of the licensed medicine for the healthcare system. Furthermore, it threatens to name and shame pharmaceutical companies which do not agree with the off-label use of their medicine and notwithstanding the fact that pharmaceutical companies are strictly forbidden from promoting off-label use of their medicines 7. In the UK, the National Institute for Health and Clinical Excellence (NICE) has included off-label recommendations in some of its clinical guidelines and has used an off-label medicine as a relevant comparator in the scope of a cost-effectiveness assessment 8 and plans to continue off-label comparators in the future despite on-going criticism of such practices 910. In Germany, several sickness funds entered into agreements with doctors associations which provide financial incentives to use off-label medicines General Medical Council, Good practice in prescribing medicines, para 19 and 20 4 Court of First Instance, Artegodan GmbH and others, 26 November 2002, joined cases T-74/00 and others, para 173, 5 Judgment of 29 March 2012, Case C 185/10, Commission vs Poland, paragraphs 37 and 38 6 APM Health Europe, 14 April 2014, ggi.pdf 7 Articles 86 and 87 of Directive 2001/83 8 NICE has included an off-label recommendation for sertraline in its Anxiety (GAD) guideline (CG 113). In addition, NICE has included off-label Avastin as a comparator in the scope of the assessment of the clinical and cost-effectiveness of Ozurdex (Allergan) for the treatment of macular oedema caused by retinal vein occlusion (guidance TA 229). Furthermore, NICE has recently stated that it can appraise the cost-effectiveness of Avastin in wet-age-related macular degeneration (AMD), although the drug has only been licensed for oncology indications (so-called Exploratory work of bevacizumab in eye conditions ). 9 Public and patient interests relating to the use of unlicensed products as comparators in cost effectiveness appraisals of licensed medicines 10 APM News, Thursday, 20 March 2014 NICE's Dillon stands firm on use of generics, off-label drugs as HTA comparators 11 Frankfurter Allgemeine Zeitung, 24 February 2011, page N1. 3

4 In addition, clinical trials sponsored by healthcare bodies comparing approved medicines with off-label medicines are regularly reported to be held in several European countries 12. The aim of these trials is to investigate the safety and efficacy of the cheaper off-label medicine against the approved treatment. KEY ISSUES 1. Primum non nocere. Decisions to prescribe a medicine off-label shall remain in the hands of the treating physician based on the medical need of the individual patient Financial consideration by national healthcare bodies must not compromise patient safety and EU law. EU law provides that medicinal products must receive a Marketing Authorisation (MA) before being marketed and used to treat a specific condition. The MA is granted after establishment of benefit vs. risk following a rigorous assessment of quality, safety and efficacy by the competent regulatory authority. The regulatory framework was designed with a view to safeguarding high levels of public health as enshrined in Art 168 TFEU. The use of medicines in indications for which they are not authorized entails health and patient safety risks due to the lack in same stringent controls and safeguards including adverse events monitoring and reporting. EU law prohibits the promotion of medicines for unlicensed uses (Art. 87 of Directive 2001/83/EC). Under EU law, the supply of medicines for unauthorised uses is an exception to the requirement that a medicinal product should either have an MA or be used in the context of a clinical trial. Other uses may, at the option of the Member State, be permitted in order to fulfil special needs, in response to a bona fide unsolicited order from a physician for use in treating their individual patient s special needs (Art. 5.1 of Directive 2001/83/EC) 13. Financial considerations of the healthcare system do not qualify as a special need 14. The cost of treating a patient with a medicine authorised for a given disease is not a relevant criterion to promote off-label use and is contrary to the principle that protection of public health shall be given precedence over economic considerations Comparative trials have been or are being sponsored by government agencies in Austria, France, Germany, Norway and the U.K. to evaluate the safety and efficacy of two anti-vegf drugs, Lucentis (ranibizumab) and off-label Avastin (bevacizumab) in the treatment of wet age-related macular degeneration (AMD). Austria (MANTA) see 12, Germany (VIBERA) see France (GEFAL) Norway (LUCAS) - UK (IVAN) see urnals/lancet/article/piis (13) /abstract 13 In some instances off-label use can be medically appropriate and an important element of high-quality patient care, but only in the context of existing, stringent statutory requirements. Physician decisions whether to prescribe a drug off-label should be guided by evidence-based medicine and the best interest of patients. 14 Case C 185/10, Commission vs Poland, paragraph EU Directive 2001/83 is underpinned by the principle that public health prevails over economic considerations and the system of medicines licensing is fundamental to this. The Court of Justice of the EU (CJEU) has also stated that public health must override any budgetary concerns [Case C-180/96R UK v Commission (BSE)] 4

5 Physicians shall prescribe medicines off-label only in case of medical need on a case-by-case assessment of the individual patient Promotion of economic driven off-label use by healthcare bodies undermines the European regulatory framework, may compromise patient safety and creates legal uncertainty with regard to product liability Promotion of off-label use by healthcare bodies bypasses and indeed undermines the rigorous regulatory approval process, which is designed to ensure patient safety. It raises serious concerns over patient safety as it is promoting the use of medicines in indications for which the competent regulatory authorities have not performed a risk-benefit analysis following established safety and efficacy criteria. With respect to biologicals for which the centralised approval procedure is mandatory, economic off-label use promotion by national healthcare systems leads to secondary, national marketing authorizations, putting the regulatory framework and the EU s competence to authorize new medicines in question. Promotion of off-label use by healthcare bodies also creates legal uncertainty associated with pharmacovigilance requirements and product liability, in particular the question of who would be accountable for safety issues associated with the offlabel use. There are additional practical concerns as to how the new information generated by non-industry funded clinical trials would be disseminated (if not in the summary of the product characteristics (SPC) or patient information leaflet (PIL)) or updated (e.g. reacting to adverse event reporting). In many countries other information sources, e.g., websites, derive patient information from the official PILs. If non-regulatory authorities, governmental agencies and HTA/ cost-effectiveness bodies such as NICE, promote off-label use of medicinal products, the position and authority of the competent regulatory authorities at EU and national level is undermined. Ultimately, it could lead to double standards for medicines and thus compromise patient safety and public health. 3. Promotion of off-label use by healthcare bodies sets double standards Promotion of off-label use by healthcare bodies leads to a distortion in the regulatory approval process and gives the impression that these bodies may have the discretion to override the regulatory approval process. EU law prohibits the promotion of medicines for unlicensed uses (Art. 87 of Directive 2001/83/EC) and rightly threatens companies with heavy sanctions in case of off-label promotion. Government agencies have the right to assess the value of new and existing medicines and to fund clinical trials where companies have not carried out direct comparisons. In order to maintain the same regulatory standards and not to compromise patient safety, clinical trials on off-label uses should meet the same criteria as those sponsored by companies, including trial design and statistical plans. The results must be analysed under the same regulatory standards that review submissions from companies. Conducting HTA to support access decisions of new pharmaceuticals requires the comparison with standard of care. In some instances health technology 16 Court of First Instance, Artegodan GmbH and others, 26 November 2002, joined cases T-74/00 and others, para 173, general principle, identified in the case-law, that protection of public health must unquestionably take precedence over economic considerations 17 Judgment of 29 March 2012, Case C 185/10, Commission vs Poland, paragraphs 37 and See also: General Medical Council, Good practice in prescribing medicines, para 19 and 20; English_0313.pdf_ pdf 5

6 assessment bodies require pharmaceutical companies to compare their compounds against other compounds for which they do not have the same license or indication. Industry does not support selection of comparators which are not in line with the standard of care, except in some rare diseases where there is no appropriately studied standard of care. 4. Economic off-label use promotion by healthcare bodies discourages the development of new medicines and/or indications and constitutes a disincentive for innovation. A generalised promotion of the use of medicines beyond their authorised indications would constitute a significant disincentive for innovation. 19 Pharmaceuticals companies will be less ready to undergo the very costly and timeconsuming authorization process for a given indication if public authorities will prefer off-label use of other, cheaper drugs for financial reasons which have not undergone the same stringent safety and efficacy assessment. This question is particularly acute as regards to orphan drugs: the promotion of offlabel use would remove the benefit of the 10-year market exclusivity and jeopardise the efforts to encourage pharmaceuticals companies to invest in orphan drugs. The national promotion of unauthorised use of medicines risks would lead to a fragmentation of the EU regulatory framework for medicines, therefore preventing a rapid diffusion of new medicines across Europe 20. Creating significant uncertainties with respect to the marketing authorisation process would ultimately impact Europe s attractiveness and the perspective of growth of emerging companies. CONCLUSIONS AND RECOMMENDATIONS EFPIA considers that it is not appropriate for healthcare bodies in Europe to promote the use of a medicine for an indication for which it has not been approved to the extent it compromises patient safety, leads to legal uncertainty with regard to product liability, sets double standards undermining the regulatory framework and authority of the EMA and the EU Commission, and creates disincentives for continued research. The decision to prescribe a medicine off-label should be left to a physician based on the concrete medical needs of the individual patient and with his/her consent. For the sake of patient safety, healthcare bodies must adhere to EU law and refrain from promoting off-label use for economic reasons or be held liable for the consequences of their decisions. Off-label use of medicines is acceptable in certain circumstances. The promotion of off-label use, regardless if by companies or governments, is never acceptable. The European Commission has announced a project to launch a study in order to better understand the various aspects of off-label prescribing, a phenomenon that is not currently regulated at EU level. EFPIA calls for the active involvement and inclusion of stakeholders including the pharmaceutical industry in the study in order to understand the role of the EU competent authorities, and to clarify the responsibilities in situations where governments promote off-label use for economic considerations regardless of the potential impact on patients safety. 19 Should cost prevail over safety? The risks of promoting unauthorised pharmaceuticals and off-label use for budgetary considerations, James Killick and Pascal Berghe, Bio-Science Law Review (2014), Vol 13 Issue 5, Ibid. 6