Regulatory impediments jeopardizing the conduct of clinical trials in Europe funded by the National Institutes of Health

Abstract

Background A number of reports have highlighted problems of conducting publicly funded trials in Europe as a consequence of the European Union (EU) Clinical Trials Directive. The impact of the EU Directive on multi-national trials, which include sites in Europe that are funded by the US National Institutes of Health (NIH) have not been described. Methods Four problems in the conduct of two international HIV treatment trials funded by NIH in the EU are described: (1) conflicting regulations on the continuing review of protocols by Institutional Review Boards/Research Ethics Committees; (2) US regulations requiring Federalwide Assurances for sites which are only partially funded by NIH; (3) EU guidance on the designation of studies as a trial of an investigational medicinal product; and (4) EU guidance on trial sponsorship and the requirements for insurance and indemnification. Following the description of the problems, recommendations for improving global collaborations are made to the US Office of Human Research Protections, to NIH, and to the EU and its Member States. Results A lack of harmonization of regulations at multiple levels caused enrollment in one study to be interrupted for several months and delayed for one year the initiation of another study aimed at obtaining definitive evidence to guide the timing of the initiation of antiretroviral therapy for individuals infected with HIV. The delays and the purchase of insurance resulted in substantial increases in trial costs and caused substantial disruption at clinical sites among staff and study participants. Limitations The problems cited and recommendations made pertain to trials funded by NIH and conducted by sites in the EU. There are many other challenges in the conduct of international research, public and private, that global harmonization would alleviate. Conclusions Disharmony, at multiple levels, in international regulations and guidelines is stifling publicly funded global research. International scientific organizations and government groups should make the documentation and solution of these problems a priority.

In need of remedy: US policy for compensating injured research participants

“…As research becomes increasingly globalised, sponsors of research must increasingly comply with other countries’ research regulations 1 12 42. Research sponsors that are unwilling to compensate injured research participants in ways that contravene local law risk having their research embargoed by foreign research ethics committees, losing access to international research sites, or being punished for failing to comply with other countries’ requirements 1 12 42…”

“…In 2008, a major trial funded primarily by the National Institutes of Health (NIH) was to be rolled out at 200 international sites 42. Late in the planning stages, NIH notified those involved that it would not serve as sponsor if required to compensate injured research participants, and asked the University of Minnesota to assume sponsorship of the trial 42.…”

On making clinical trials possible

“…Going from the micro to the macro scale, we have the fortuitous pairing of two articles in this issue on the regulatory and legal barriers to conducting international, multicenter clinical trials, one by my illustrious predecessor at this journal, Jim Neaton [2,3]. As Yusuf [4] highlights in his editorial, these barriers, while arising from good intentions, are in fact undermining much of the good that the research is designed to promote.…”

Damage to important clinical trials by over-regulation

“…In this issue of the journal, two articles [3,4] describe the impediments and inefficiencies that these guidelines have created, undermining trials for neglected diseases or publicly funded studies of important questions for HIV. Each of these articles describe specific problems that were created by the ICH-GCP guidelines and related regulations (e.g., EU directive or the US regulations -the common rule), and propose specific solutions.…”

“…As Neaton et al [3] describe, the mandate to obtain insurance of indemnification for the latter two types of trials, where the risks to subjects are negligible can be a huge burden. This requirement has sometimes blocked the conduct of trials, despite a lack of evidence that insurance or indemnification protects subjects.…”