The European Medicines Agency (EMA) has finalised the reflection paper it put out for consultation in May 2010 on ensuring appropriate ethical and Good Clinical Practice (GCP) standards for clinical trials conducted outside the European Union or European Economic Area and used in marketing authorisation applications (MAAs) filed within the EU.

Emphasising that third-country trials included in EU regulatory filings should meet equivalent ethical principles and standards to those applied when studies are carried out in the member states, the paper underlines the role of independent local ethics committees in overseeing clinical trials and the importance of obtaining informed consent from study participants.

It also discusses key issues including those around comparators used in clinical trials (active or placebo) and access to treatment once a study has ended, particularly in the context of vulnerable trial subjects.

The reflection paper will enter into force on 1 May 2012.

It was drafted by a Working Group on third-country clinical trials set up by the EMA in 2009 and endorsed by the agency’s Committee for Medicinal Products for Human Use, the Coordination Group for Mutual Recognition and Decentralised Procedures – Human, the EMA’s Management Board and the Heads of EU Medicines Agencies. The consultation process ended on 30 September 2010.

Broader strategy

The guidance is part of a broader strategy to address the challenges of increasing globalisation in clinical research. It includes the following statistics on the distribution of patients who took part in pivotal trials included in MAAs filed with the EMA between January 2005 and December 2010:

•    Africa: 2.76% in total, with South Africa contributing 2.19% of all patients.
•    Middle East/Asia/Pacific: 8.7% in total (India 1.6%, Israel 1.2%, Philippines 1.1%, Thailand 0.9%, China 0.7%).
•    Australia/New Zealand: 1.5% in total, with Australia accounting for 1.3%.
•    Central/South America: 8.5 % in total (Brazil 2.5 %, Argentina 2%, Mexico 1.3%, Costa Rica 0.5%, Peru 0.5%).
•    Commonwealth of Independent States: 3.8% in total (Russia 2.8%, Ukraine 0.8%, Eastern Europe-non EU 0.5%, Croatia 0.3%).
•    North America: 34.54% in total, mainly from the US (29.98%).

•    EU/EEA/EFTA: 39.4% of all participants.   

The EMA’s Working Group was asked to develop “practical proposals for tasks and procedures or guidance” addressing the four areas for action outlined in the EMA’s December 2008 strategy paper, Acceptance of clinical trials conducted in third countries for evaluation in Marketing Authorisation Applications:

- Clarifying the practical application of ethical standards for clinical trials, in the context of EMA activities.

- Determining the practical steps to be taken during the provision of guidance and advice in the course of drug development.                                  

- Determining the practical steps to be taken during the Marketing Authorisation phase.

- International co-operation in the regulation, review and inspection of clinical trials, as well as capacity-building in this field.

Somewhere else

No matter where you live, “most clinical trials are being conducted somewhere else in the world, under a different regulatory framework and in a different cultural setting”, the EMA points out.

“Yet regulators, healthcare professionals and patients worldwide all rely on the same trial data when making decisions on whether to allow a medicine on the market or not and on whether to use a medicine or not.”

These challenges are addressed by the reflection paper in two ways: by proposing steps towards international co-operation in the regulation of clinical trials, with specific emphasis on capacity-building initiatives for a common approach to study oversight; and by clarifying the practical steps EU regulators can take to assure themselves that ethical and GCP standards are applied to all clinical trials for human medicines.

Among the concrete measures outlined in the finalised reflection paper are:

•    Non-compliance that significantly affects the rights, safety or well-being of trial subjects or the quality and integrity of the data reported in a MAA is not acceptable and will result in rejection of data and/or other regulatory actions.    

•    Any data generated from a clinical trial where the protocol was not submitted to an independent ethics committee should be disregarded when evaluating a MAA.        

•    Any data generated from a clinical trial conducted without the informed consent of the trial subjects (or their legal representative) should also be disregarded.        

•    As part of a MAA, pharmaceutical companies should provide EU regulators with information summarising the conduct of third-country trials and their compliance with ethical and GCP standards.