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Applied Clinical Trials
Clinical trials should meet ethical and GCP standards no matter where in the world they are conducted.
It is becoming rare to hear a conversation among pharmaceutical researchers, drug company executives, or regulatory officials anywhere in Europe these days that does not contain the word "ethics."
This is, of course, as it should be. But the insistent regularity of allusions to ethics inevitably gives the impression that until now, things haven't been as ethical as they might be.
Fresh out in the middle of April, a paper emerged from the European Medicines Agency titled "Reflection Paper on Ethical and GCP Aspects of Clinical Trials of Medicinal Products for Human use Conducted Outside of the EU/EEA and Submitted in Marketing Authorization Applications to the EU Regulatory Authorities."
Flagged up as creating "a robust global framework for conduct and oversight of clinical trials," the paper aims to "strengthen existing processes to provide assurance to regulators and stakeholders that clinical trials meet the required ethical and GCP standards, no matter where in the world they have been conducted."
The reflection paper is part of the agency's strategy to address the challenges arising from the increasing globalization of clinical research. It puts forward plans for international cooperation in the regulation of clinical trials, and it clarifies how EU regulators can be sure that ethical and GCP standards are applied to clinical trials, both during development and while the marketing authorization is being applied for.
The paper emphasizes the role of independent local ethics committees in the oversight of clinical trials and stresses the importance of obtaining trial subjects' consent. It discusses issues such as whether an active comparator or placebo is used in a trial, or access to treatment after a trial, especially in the context of the vulnerability of trial subjects.
The new approach comes into effect immediately, and is more than a wish-list. "Non-compliance that significantly affects the rights, safety, or well-being of the subjects or the quality and integrity of the data reported is not acceptable, and will result in rejection of data and/or other regulatory actions," says the EMA, unambiguously.
When evaluating a marketing authorization application, authorities are to disregard "any data generated from a clinical trial for which the protocol was not submitted to an independent ethics committee," or when informed consent of the trial subjects was not obtained.
Applications for marketing authorizations are required to provide information summarizing the conduct of the trial and its compliance with ethical and GCP standards, and the public assessment report on the evaluation of the application will have to describe the assessment of the compliance with these standards.
This is no starry-eyed brainchild from an ivory tower in the agency's Canary Wharf headquarters, either. It has been endorsed by the agency's own senior scientific body, the Committee for Medicinal Products for Human Use, as well as by the Coordination Group for Mutual Recognition and Decentralized Procedures, the agency's management board, and the heads of EU medicines agencies.
Earlier in April, the agency tightened its conflicts-of-interests policies with immediate effect. Its updated policy gives clearer guidance on the involvement of experts in academic trials and publicly funded research. It also aligns restrictions for the different roles in the scientific decision-making process. And it imposes stricter rules on grants from the pharmaceutical industry.
As this column reported last month, the agency's new Executive Director, Guido Rasi, who took over less than six months ago, has been insistent on bringing greater transparency to the way the agency does its job, and he has acted quickly to sweep away the previous rules—themselves in effect only since September last year—as part of his drive to repair the agency's credibility.
The new rules are accompanied by a new policy on suspected breaches of trust, which sets out a procedure for dealing with incorrect or incomplete declarations of interests by the agency's experts and committee members. Members of the agency's management board are also, for the first time, covered by a policy on conflicts of interests.
The rules follow new procedures introduced in January this year to allow the agency to conduct cross-checks at national and at European levels of the information provided on declarations of interests, publication of the risks levels for European experts in February, and pre-vetting requirements for experts.
In the same spirit of ensuring access to the agency's affairs as a matter of public interest, since March a list of new human medicines under evaluation has been published, and will be regularly updated.
The list includes the international non-proprietary names and therapeutic areas for all innovative medicines, along with information on the type of salt, ester, or derivative of the active substance. For generic and biosimilar medicines, it includes the INN and therapeutic area. "This initiative forms part of the drive towards increased transparency on its activities by the agency and other European regulatory authorities," said an agency statement.
The European medicines industry has been trying to burnish its own reputation for ethics as well. The main industry association, EFPIA, has been quietly running an exercise rather coyly termed "e4ethics," aimed predominantly at guiding company links with doctors, particularly at events purporting to be scientific. "Conscious of the importance of providing accurate, fair, and objective information about medicinal products so that rational decisions can be made as to their use," EFPIA operates a code on the promotion of prescription-only medicines to, and interactions with, healthcare professionals. This "seeks to ensure that pharmaceutical companies conduct such promotion and interactions with prescribers in a truthful manner, avoiding deceptive practices and potential conflicts of interest with healthcare professionals, and in compliance with applicable laws and regulations."
"Any practice that might create confusion about the real scientific and educational purpose of scientific events sponsored by industry" is not to be tolerated, says EFPIA. But the concerns run wider than guidance on scientific events. Accusations of exerting undue influence on legislators have been levelled at the industry, eliciting a robust defense of its practices by EFPIA's own new Executive Director, Richard Bergstrom, at the end of March. "EFPIA supports full transparency of lobbying activities of itself and its members," he said. He did not deny that "we also proactively try to influence policy-making." But he went on to justify such action: "That is our job, as is it for all other stakeholders in a democracy. Pharma is heavily regulated, so it would be strange if we did not try to influence legislation," he said. And he promised to "always be open on what our policies are and what we are asking for."
Scientific conferences and lobbying are not the only subjects that are provoking questions over industry ethics. Currently, debates are raging in Europe over whether to tighten the legislation on information to the public about prescription medicines. These discussions have been given new impetus by factors such as the growth of Internet-based information, and the perceived potential for confusion between industry-sourced information and disguised advertising. EFPIA was prompted to issue a statement in mid-April expressing muted disapproval of tactics employed by its own Belgian member association in sponsoring supplements in daily newspapers that mentioned prescription medicines in connection with apparently disinterested healthcare advice.
"We are not in support" of such actions, the EFPIA said, expressing a clear preference for "pull" information-provision (that is, in response to direct requests from the public) rather than through "pushing" information. "This Belgian case showcases the difficulties that industry and third parties (including media) face, as current legislation provides little guidance," said EFPIA, in a gesture of sympathy. But EFPIA's underlying concerns were clear from a sting in the tail of its statement: if European governments are unable to find a workable compromise addressing the issue, "EFPIA may have to consider its options as an industry organization to safeguard industry reputation as a responsible and reliable source of information." In other words, if national authorities—and, as a consequence, national drug industry associations or companies at national level—do not make sure that the industry is operating ethically in its promotional practices, then EFPIA may have to step in and become the industry own ethics police.
Meanwhile, Eric Abadie, MD, has resigned as Chair of the European Medicines Agency's Committee for Medicinal Products for Human Use. In early April, in a brief statement, the agency said that Abadie "has informed the European Medicines Agency of his intention to resign." The statement went on to add only that "Executive Director Guido Rasi has accepted his resignation with immediate effect, and Dr. Tomas Salmonson, Vice-Chair of the CHMP, will lead the Committee in the meantime to ensure continuity of operations."
No explanation was offered at the time for this abrupt change at a senior level in the agency. Subsequently, the French national medicines agency, where Abadie was employed at top level until recently, indicated that Abadie was no longer on its payroll. It later emerged that the EMA had declined to take him on as an employee. The French regulatory agency has undergone major reforms in recent months, in the wake of concerns over the handling of Mediator, the Servier anti-diabetic eventually withdrawn after numerous reports of serious adverse effects, and the more recent revelations about oversight inadequacies in respect of breast implants produced by a French company. While only a handful of French politicians have suggested any professional failings on Abadie's part, his departure demonstrates that in a tougher climate than ever before, even the most respected figures are not immune to external pressures.
Peter O'Donnell is a freelance journalist who specializes in European health affairs and is based in Brussels, Belgium.