Conducting Clinical Trials Beyond Europe

Every now and then it's good to step back and take a broader view. The natural focus of Brussels tends to be introverted—as was so tellingly demonstrated, for instance, by the September spats about French treatment of Roma. French President Nicolas Sarkozy was struggling to win popular support in the run-up to national elections by forcibly repatriating immigrants from Eastern Europe under the slender pretext of criminality. When the European Commissioner for Justice publicly criticized these actions, Sarkozy's response was "Are you ready to take them in your country?" And the chattering classes in Brussels became obsessed with discussions of the legal details of whether citizens of Romania, Bulgaria, and Slovakia—all of them EU member states—could legitimately be "repatriated," and on what grounds.

Peter O'Donnell

All very spirited, of course, but none of it really contributing towards any type of solution to the long-standing challenge of integrating—or at least not discriminating against—millions of marginalized European Union citizens.

A similar introversion is evident in European discussions of clinical trials. The need for reform of the EU clinical trials directive, the fine-tuning of the new pharmacovigilance rules, the limits on what adverse drug reaction information the European Medicines Agency (EMA) could, or should, disclose. These are topics that have absorbed political attention in Brussels, almost to the exclusion of any other consideration.

Consequently, it is a breath of fresh air to look for a moment beyond the shores of Europe, and beyond the confines of one of the richest corners of the world, and to consider the relation between clinical trials and those who live in far less comfortable conditions.

In early September, the EMA held a three-day international workshop to discuss a global framework of clinical trials. The heart of the discussions was how to protect the rights, safety, and well-being of patients participating in clinical trials anywhere in the world. Some 170 participants from around 50 countries from the Americas, Asia, Africa, and Europe came to London, representing patient organizations, health-related non-governmental organizations, clinical trial sponsors, the pharmaceutical industry, ethics committees, regulatory authorities from all continents, and intergovernmental organizations.

The workshop was part of the consultation process on a reflection paper from the agency on ethical and Good Clinical Practice aspects of clinical trials conducted in third world countries and used in support of marketing authorization applications to the agency. The motivation is administrative as much as humanitarian, but is nonetheless to be welcomed. As the agency points out, with the increasing globalization of clinical research, less than 40 percent of patients enrolled in pivotal clinical trials for marketing authorization applications to the agency received their treatments at clinical trial sites in western Europe. These trials involved more than 44,000 clinical trial sites in 89 countries. As Fergus Sweeney, head of inspections at the agency, put it: "Wherever in the world we stand, the majority of clinical trials are being conducted somewhere else in the world, under a different regulatory framework and in different cultural settings."

The practical problem from this is, he went on, that "we all rely on the same trials to make decisions: as regulators, to allow or disallow marketing authorizations, and as patients and healthcare providers, to use or not to use a medicine." But the quality of the trials may not always be the same.

And from a broader humanitarian or ethical perspective, there are challenges too. As the meeting took its course, some consensus emerged around the conviction that EU regulators should never accept (or require) studies conducted beyond the EU that would be ethically unacceptable in the EU. There should not, became the refrain, be a different standard applied to trials conducted in the EU compared to those conducted elsewhere.

Achieving this refined state will depend, participants underlined, on cooperation and networking between regulatory authorities and ethics committees involved in the supervision of clinical trials. It will also require greater transparency of clinical trials, including clinical trial registries and the provision of information about ethical and GCP aspects in the European Public Assessment Report that the agency produces on each application it processes. In addition, patients will have to be involved early on in the design of protocols, to ensure the adequate protection of clinical trials subjects, participants suggested.

European reflections

The EMA's principal role is obviously to reach opinions on medicine matters that affect Europe. But it is also empowered to give a scientific opinion, in cooperation with the World Health Organization, on the evaluation of medicines intended exclusively for markets outside the EU, based on the same standards that apply to assessments of medicines intended for use in Europe.

The latest rewrite of EU pharmaceutical legislation also spells out a duty to provide for the ethical requirements laid down in the clinical trials directive when clinical trials are conducted outside the EU on products destined to be authorized within the community. When evaluating authorization applications for such medicines, the agency must verify that the way the trials were conducted met EU good clinical practice standards and ethical requirements.

The agency's reflection paper points out that most countries now have a regulatory authority to which application should be made before a clinical trial can commence—and insists that these requirements must be met in each country in which a clinical trial is conducted. Regulators must support compliance with local requirements in each country as well as reinforcing international ethical and good clinical practice standards, it emphasizes. In addition, every trial must receive a positive opinion or approval from an ethics committee with appropriate jurisdiction for the investigator sites and trial concerned.

In countries with what the reflection paper politely terms "limited frameworks for ethical review or regulatory oversight," sponsors should seek an additional review of the study protocol with an ethics committee in a country with EU-level standards. EU regulators should refuse to consider data from any trial where an independent ethics committee has not assessed the protocol. Informed consent must be assured, and appropriately renewed as necessitated by significant changes in the conditions or procedures of the research or if relevant new information becomes available. In developing countries, the research project should ensure that informed consent can indeed be obtained legitimately within different linguistic and cultural settings.

Similar constraints should be imposed on information to trial subjects, on the protection of personal data, on the observation of special considerations for trials conducted with pediatric populations, on archiving of trial documentation, and on insurance.

And in respect to groups, such as racial minorities, the economically disadvantaged, the very sick, and the institutionalized, protection should be provided against the danger of being involved in research solely for administrative convenience, or because they are easy to manipulate as a result of their illness or socioeconomic condition.

Similarly, economic or logistical reasons for the unavailability of an established effective intervention cannot justify a placebo-controlled study in a country of limited resources when it would be unethical to conduct a study with the same design in a population with general access to the effective intervention outside the study. Regardless of the location of the trial, all patients participating in these trials should receive the same or a similar standard of care and comparable treatment options as trial participants within the European Economic Area.

Who benefits?

When considering whether it is appropriate to conduct a specific research study within a low- or middle-income country, one issue that should be considered by the sponsor, ethics committee, and national authorities, is whether the intervention being studied is likely to be available in that country if it is shown to be effective. If a product developed or knowledge generated by research is unlikely to be reasonably available to, or applied to the benefit of, the population of a proposed host country or community after the conclusion of the research, and if the sponsor does not foresee arrangements to make it available, the ethics of conducting the research in that country or community need to be carefully considered, reflecting on the need for access to treatment and on the risks and benefits that would apply to those participating in the trial and to their community including the medical care environment of that country/community.

There are often great attractions in conducting trials beyond Europe, the reflection paper acknowledges. These may range from the obvious availability of patients willing to participate in clinical trials and with the relevant disease profile, to availability of qualified investigators willing and available to conduct the trials, and include lower costs or more rapid approval of trials. But sponsors should provide appropriate justification for the location of a clinical trial and detail its plan for addressing ethical and operational issues related to its proposed development plan.

Future action

The agency recognizes that there is no one-stop-shop solution for these complex issues. It is minded to establish a pool of experts to provide advice in assessing the ethical aspects of such clinical trials submitted in support of applications in Europe. A program of routine inspections is likely to be set up, with facilities for responding to specific triggers of concern too. Priority will be given to the countries that have recently featured most frequently among sites where non-EU trials are conducted in support of EU marketing authorization applications including South Africa, India, the Philippines, China, Thailand, Brazil, Costa Rica, Peru, Russia, and Ukraine.

The intention—and it is a laudable one—is to ensure that patients in the richer parts of the world are not benefiting unduly from the exposure of patients in the poorer parts of the world in the assessment of new treatments. This is a nobler pursuit than an internal slanging match between EU leaders on how to redistribute unwanted immigrants.

Peter O'Donnell is a freelance journalist who specializes in European health affairs and is based in Brussels, Belgium.