Compassionate use of interventions : results of a European Clinical Research Infrastructures Network ( ECRIN ) survey of ten European countries

Background: ’Compassionate use’ programmes allow medicinal products that are not authorised, but are in the development process, to be made available to patients with a severe disease who have no other satisfactory treatment available to them. We sought to understand how such programmes are regulated in ten European Union countries. Methods: The European Clinical Research Infrastructures Network (ECRIN) conducted a comprehensive survey on clinical research regulatory requirements, including questions on regulations of ‘compassionate use’ programmes. Ten European countries, covering approximately 70% of the EU population, were included in the survey (Austria, Denmark, France, Germany, Hungary, Ireland, Italy, Spain, Sweden, and the UK). Results: European Regulation 726/2004/EC is clear on the intentions of ‘compassionate use’ programmes and aimed to harmonise them in the European Union. The survey reveals that different countries have adopted different requirements and that ‘compassionate use’ is not interpreted in the same way across Europe. Four of the ten countries surveyed have no formal regulatory system for the programmes. We discuss the need for ‘compassionate use’ programmes and their regulation where protection of patients is paramount. Conclusions: ’Compassionate use’ is a misleading term and should be replaced with ‘expanded access’. There is a need for expanded access programmes in order to serve the interests of seriously ill patients who have no other treatment options. To protect these patients, European legislation needs to be more explicit and informative with regard to the regulatory requirements, restrictions, and responsibilities in expanded access programmes. Background ’Compassionate use’ programmes in Europe allow a medicinal product, without marketing authorisation, to be given to patients with a life-threatening disease when no alternative authorised treatment exists [1]. The goal of ‘compassionate use’ is to serve the interests of the patient. European Regulation 726/2004/EC legislates for ‘compassionate use’ programmes in the European Union [1]. It allows groups of patients with a chronic, seriously debilitating, or life-threatening disease, without a satisfactory authorised treatment available, and who cannot take part in a clinical trial, access to an unlicensed medicinal product [1,2]. The medicinal product concerned * Correspondence: kate.whitfield@ctu.rh. dk Copenhagen Trial Unit (CTU), Centre for Clinical Intervention Research, Copenhagen University Hospital (DCRIN), Copenhagen, DK-2100, Denmark Full list of author information is available at the end of the article Whitfield et al. Trials 2010, 11:104 http://www.trialsjournal. com/content/11/1/104 TRIALS © 2010 Whitfield et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. must either be the subject of a marketing authorisation application, or under evaluation in a clinical trial. ‘Compassionate use’ differs from ‘off-label’ use. In ‘offlabel’ use a licensed medicinal product is prescribed for an indication, or to a patient for which the product is not specifically licensed, whereas, in ‘compassionate use’ the medicinal product is not licensed and not used as a treatment for any disease. Key differences between ‘compassionate use’, ‘off-label use’ and randomised clinical trials are summarised in Table 1. An example of a ‘compassionate use’ programme is that for the intravenous formulation of Tamiflu (oseltamivir phosphate powder for solution for intravenous infusion) [3,4]. This medicinal product is not licensed but is available to critically ill adults and children with pandemic H1N1 or seasonal influenza A or B infection who did not respond to authorised antivirals or who cannot take Tamiflu orally [3,4]. Regulation 726/2004/EC states that there is a need for a common approach across Europe regarding the criteria and conditions for ‘compassionate use’ [1]. The European Medicines Agency (EMA) has a role in this harmonisation objective. The EMA’s scientific committee, the Committee for Medicinal Products for Human Use (CHMP), can adopt and publish its opinions on the ‘compassionate use’ programme and the patients targeted [1]. In January 2010 the CMPH published its first opinions on ‘compassionate use’ programmes in the EU on the EMA website [5]. However, neither Regulation 726/2004/EC nor the CMPH’s recommendations are binding on the member states [1]. In order to determine if there is a common approach in Europe, the European Clinical Research Infrastructures Network (ECRIN) surveyed the nature of the national legislation and practice in ten European countries [6], covering approximately 70% of the EU population. Here we describe the results and discuss the impact of ‘compassionate use’ programmes on clinical practice and clinical intervention research in Europe. Methods The ECRIN working group on regulatory requirements and interaction with competent authorities designed and conducted an international survey [6]. The survey covered national regulations and regulatory procedures for clinical research. The ECRIN working group on regulatory requirements and interaction with competent authorities was composed of two chairpersons, at least one expert from each European ECRIN country, and an ECRIN European correspondent (a person trained in clinical research, working at the national coordination on the implementation of the ECRIN project) from each of following countries: Austria, Denmark, France, Germany, Hungary, Ireland, Italy, Spain, Sweden, and the United Kingdom. The survey was developed in five main phases: drafting, consensus, data collection, validation, and finalising [6]. The two co-chairpersons and two members of the working group on regulatory requirements and interaction with competent authorities drafted the survey. Reaching consensus on the questions in the survey took Table 1 Access to medicinal products, through ‘compassionate use’, ‘off-label’ use and randomised clinical trials ’Compassionate use’ European regulation Off-label use Randomised clinical trial Purpose Serves the needs of patients where no alternative treatment exists Serves the needs of patients with an indication other than that the product is marketed for Serves the needs of society and future patients and may benefit some of the included participants Party involved Patients Patients Participants Disease A life-threatening or chronically or seriously debilitating disease Any indication for which the product is not authorised Any Informed consent Required in some member states Not required Required License Medicinal product is not yet licensed Medicinal product is licensed for other indication(s) Medicinal product can be licensed and not licensed Responsible party Prescribing physician with approval from the regulatory authorities Prescribing physician Sponsor with approval from the regulatory authorities Control group Without control group Without control group With control group Data In some member states, some data are reported to the regulatory authorities Spontaneous adverse events may be reported Outcome measure and adverse event data are reported to the regulatory authorities Access to the intervention Medicinal product accessed through the programme, afterwards those patients can have access before the product is licensed Medicinal product available on prescription Declaration of Helsinki stipulates that participants “are entitled to.share any benefits that result from the trial, for example, access to interventions. ” Whitfield et al. 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