April 25, 2012

EMA Clinical Trial Paper Reflects on the Ethical and GCP Aspects of Conducting Clinical Trials Outside EU/EEA

Thumbnail image for EMA Logo.jpgThe increasing globalization of clinical research has had the effect that most clinical trials are conducted somewhere else in the world, under a different regulatory framework, and in a different cultural setting from the jurisdiction for which the resulting data is likely to be used. Regulators, healthcare professionals, and patients worldwide all rely on the same or similar trial data when making decisions on whether or not to approve a medicine. The European Medicines Agency ("EMA") has issued a reflection paper, which proposes to enhance international cooperation in the regulation of clinical trials and provides practical steps to enable regulators to be assured that ethical and GCP standards have been applied, both during the development and during the marketing-authorization-application phases.

The EMA considers that the best approach for achieving these objectives is "to ensure that a robust framework exists for the oversight and conduct of clinical trials, no matter where in the world the clinical investigators' sites are located and patients recruited." Hence, there is a "need for cooperation between Supervisory Bodies involved in the supervision of clinical trials and the need to extend and link networks to support these activities in particular in countries where the ethics and regulatory systems/aspects are not fully developed/available." All clinical trials from phase I to phase IV (including BE/BA studies) are required to meet internationally agreed ethical and data quality standards or their equivalent. The EMA points out that these standards have to be addressed before and during the conduct of the clinical trials and not by assessment and inspection at the time of evaluating the Marketing Authorization ("MA"), because by this time the trials will have been completed, and in some cases several years earlier.

The ultimate objective is to obtain international cooperation and standardization in the regulation of clinical trials and to permit trials of medicinal products only if the trial is authorized by the national regulatory authority or by the concerned Ethics Committee(s) in that country and that the authority takes action against violations. The paper lists several other key objectives such as requiring Ethics Committees to be truly independent, professionally sound and adequately resourced. A survey of the distribution of patients used in pivotal trials between January 2005 and December 2010 showed that Africa provided 2.76% of the patient total, Middle East/Asia/Pacific 8.7% (with India 1.6%, Israel 1.2%, Philippines and Thailand around 1.0%), Australia 1.5%, Central/South America 8.5% (Brazil 2.5%, Argentina 2% and Mexico 1.3%), Russia 2.8%, USA 30%, and EU/EEA/EFTA 39.4%.

The paper goes on to clarify the practical application of ethical standards in light of the requirements of the EU regulatory authorities. The document emphasizes: "The rights safety and wellbeing of the trials subjects are the most important consideration and should prevail over the interests of science and society", and that "the Ethics Committees should be satisfied that no undue influence, including that of a financial nature (or limiting or increasing access to medical care), will be exerted on persons, to participate in research. In this respect, particular attention must be given to vulnerable or dependent persons." It requires the sponsor in trials conducted in countries with limited Regulatory Authority or Ethics Committees framework or limited oversight ability to put in place alternative solutions in order to ensure that there is an adequate review of the clinical trial protocol, for example, by submitting the study protocol for ethical and scientific review to an Ethics Committee that operates with ethical standards equivalent to those applying in the EU. Any Ethics Committee reviewing the trial should be strong enough to withhold approval of the research proposals, be independent and ensure that there is no conflict of interest that might affect the judgment of any members of the committee.

The paper also requires that an Ethics Committee in the country where the trial is to be conducted should have, as either members or consultants, persons with understanding of the community's customs and traditions. "Such persons should be able, for example, to indicate suitable members of the community to serve as intermediaries between investigators and subjects and to advise on whether material benefits or inducements may be regarded as appropriate in the light of a community's gift-exchange and other customs and traditions".

Further sections of the paper go into topics such as the information/consent procedure for subjects in a trial and how a subject unable to read is to be represented and protected. In each situation it highlights the need to be aware of local customs and the potential problems that can arise. The applicant for a MA needs to provide the EU drug regulatory authorities with a summary of the consent processes used and details regarding any significant variations of those processes and include sample information sheets on consent forms. Concern regarding exploitation of vulnerable populations, e.g., vulnerability of a person due to poverty, lack of adequate health care systems or lack of access to medicines are also addressed, as is the issue of access to treatment post trial for participants.

The report is a very comprehensive document setting out several ways forward to enhance the running of clinical trials around the globe. It aims to provide help and assistance to those regulatory authorities and ethics committees which do not have the resources or capabilities to match international standards and at the same time aims to ensure that sponsors of clinical trials adhere to strict codes of ethics and to provide proof that the subjects in the trials are not misled or exploited.