EMEA tightens up supervision of third-country trials

The European Medicines Agency (EMEA) is broadening its efforts to ensure that clinical trials conducted in ‘third countries’ to support drug approval applications in the European Economic Area (EEA) meet the necessary ethical and Good Clinical Practice (GCP) standards.

The move to tighten up supervision of third-country trials is explained in a strategy paper issued by the EMEA. The paper includes a three-year action plan encompassing “all areas of EMEA activity with impact on clinical trials, starting with the early activities such as Scientific Advice, Orphan Designation and Paediatric Investigation Plan and continuing through the finalisation of opinions on initial MAAs [Marketing Authorisation Applications] and clinical trials conducted post-authorisation”.

The agency notes the “growing concern” both among regulators and in public debate about “how well these trials are conducted from an ethical and scientific/organisational standpoint (including GCP compliance) and about the available framework for the supervision of these trials”.

It cites the revised pharmaceutical Directive 2001/83/EC, which refers to the ethical and GCP requirements in the clinical trials Directive, 2001/20/EC, and states: “In particular, with respect to clinical trials conducted outside the Community on medicinal products destined to be authorised within the Community, it should be verified, at the time of the evaluation of the application for authorisation, that these trials were conducted in accordance with the principles of good clinical practice and the ethical requirements equivalent to the provisions of that Directive”.

The number of trials conducted, and the number of patients recruited in, countries outside the traditional territories of Western Europe and North America have been growing for a number of years, the strategy paper points out.

The EMEA has been actively tracking the geographical origins of patients included in pivotal trials submitted with MAAs through the centralised approval procedure. It has found that around a quarter of all patients recruited for pivotal trials filed between 2005 and 2008 were enrolled in Latin America, Asia, the Commonwealth of Independent States and Africa.

EU approval applications already have to include information about the location of clinical trials conducted in third countries and the ethical standards applied, while a system of routine GCP inspection has been in place since 2006. Two key factors in selecting sites and trials for inspection are the presence of vulnerable populations (including children) and of investigator sites in developing countries.

More transparency

Both the review process and inspection programme are being expanded, the EMEA notes. Its work programmes for 2008 and 2009 set out a number of actions including making sure, at the time of MAA evaluation, that trials in third countries have been carried out in accordance with the required GCP and ethical standards.

“There should be greater transparency of this process, and its outcome, which should be described in the EPAR (European Public Assessment Report),” the strategy paper adds. The work programmes also foresee stepping up the number of routine GCP inspections “as part of the need for greater supervision of the conduct and ethical standards of clinical trials performed outside the EEA”.

However, these activities need to be further developed and expanded, the EMEA says. That requires a plan of action extending beyond 2008. The three-year plan laid out in the strategy paper addresses clinical development “not only at the time of Marketing Authorisation Application (by which time the pre-authorisation clinical trials have mostly been completed) but at earlier stages before and during the conduct of the clinical trials”, it stresses.

The strategy outlined in the paper will be translated into an itemised plan of action extending over a three-year period. In terms of planning and development, it includes:

- Clarifying the practical application of ethical standards for clinical trials
- Considering the issues that drive the recruitment of trial subjects in third countries
- Reviewing the actions available in response to non-compliance with ethical and GCP standards
- Ensuring that links are made with other initiatives taken by EEA Member States in this area, in consultation with the European Commission’s Directorate General for Enterprise and the EU’s Heads of Medicines Agencies

Under the heading of ‘practical application’ come:

- Further training and awareness-building for the EMEA, experts and Marketing Authorisation holders/sponsor
- Submission, validation, assessment and inspection
- Transparency, including improvements to the content and consistency of EPARs
- Capacity-building with developing countries in co-operation with the Member States and the Commission