BY CHARLES W. SCHMIDT

Clinical trial conduct reaches global harmonization.

Globalization is uniting distant regions of the world like never before—and profoundly changing how U.S. companies conduct their operations. the U.S. pharmaceutical industry is no exception. Not only is the drug marketplace becoming more international, but clinical R&D is becoming a global undertaking. although figures for the industry as a whole aren’t currently available, many companies are increasing their number of foreign clinical trials projects. for example, merck & company, inc., now conducts approximately 35% of all its clinical trials overseas, a percentage that Jacobo Sabbaj, Merck’s vice president of clinical research operations worldwide, says is increasing steadily. in a typical example, Merck recently completed clinical trials on VIOXX, a new anti-inflammatory drug, in more than 40 countries throughout the Americas, Europe, Asia, and the pacific, on approximately 8000 patients.

More clinical trials overseas
Experts date the growth of international R&D in the pharmaceutical industry to the mid-1980s and attribute the rising trend to a variety of factors. Helen Davies, senior vice president for clinical development services at Quintiles Transnational, a clinical development organization based in Research Triangle Park, NC, says that the practice enables companies to open more commercial markets for their products. This is in part because foreign regulatory agencies may be reluctant to pass registration on drugs that haven’t been tested on their own populations. Multinational clinical trials also save time. Some diseases, such as pneumonia, are seasonal and strike in different regions at different times of the year. Global seasonal patterns allow infectious disease studies to go on year round, which speeds the process of making new medicines available to patients. Furthermore, overseas research makes it easier to assemble thousands of patients for a single clinical trial and to study drug behavior among ethnic populations in the regions where they live. Adds Bert Stilker, senior vice president for science and regulatory affairs at PhRMA, “Companies want to conduct clinical trials in multiple countries at once so they can send data to regulatory agencies and doctors at the same time. In the past, drug approval in different regions was sequential, but now it’s simultaneous. This puts pressure on companies to perform global clinical trials.”

As clinical trials become more global, how do pharmaceutical companies handle the regulatory, ethical, and cultural uncertainties of working in other countries? Various critics have attacked the process as exploiting underprivileged people (especially in developing countries) as human guinea pigs and have claimed that it is motivated by financial concerns, as if overseas clinical trials somehow cost less than those conducted at home. Are these concerns justified? Robert H. Rubin, associate professor at the Harvard–MIT Division of Health Sciences and Technology, says the answer is an unequivocal no. “The costs are a wash,” he says. “Companies still have to monitor study subjects carefully to get regulatory approval, no matter where they are. There may have been a time when you could have pushed through shoddy data, but not anymore. The FDA and the other regulatory agencies would throw out the whole package.”

The international enforcer
In recent years, international clinical trials have become so standardized that requirements for experimental quality and safety are virtually identical, regardless of where the studies are performed. At the heart of the process is an international, nongovernmental organization with formal ties to the United Nations called the International Conference on Harmonization (ICH). The ICH was born out of a desire among European countries to harmonize regulations for the pharmaceutical industry during the mid-1980s. Formally established in 1990, when it was signed by the United States, the European Union (then called the European Commission), and Japan at a meeting in Brussels, the ICH has since sought to institutionalize the “ICH Process” for providing guidance on technical issues. Its goals include synchronizing technical procedures and standards in the three regions, improving the quality and reliability of research data, and protecting the rights and welfare of all subjects.

In 1996, the ICH released a pivotal document called the Harmonized Tripartite Guidelines for Good Clinical Practice (GCP). Today, these standards are accepted as official guidance for conducting clinical trials in the United States as well as relevant agencies in the European Union countries and Japan. The guidelines lay out a detailed road map designed to lead investigators and sponsors through the clinical trial process, including aspects as broad as communication with Institutional Review Boards (which monitor the safety of subjects and informed consent), procedures for informed consent of subjects, appropriate study designs and protocols, and essential documentation.

According to David Lepay, the acting senior adviser for clinical science at the FDA, U.S. pharmaceutical companies engaged in overseas clinical trials must adhere to the regulations contained in 21 CFR 312.120 describing criteria for acceptance of foreign data for regulatory review. These regulations stipulate that the data must meet the ethical principles contained in either the Declaration of Helsinki (a set of recommendations guiding biomedical research using human subjects, adopted by the World Medical Association in 1964 and updated regularly since) or the laws and regulations of the relevant country—whichever are most protective. This distinction is becoming moot: The domestic laws and regulations regarding clinical trials in all the ICH countries are consistent with the GCP and in many instances use the same language. Under the FDA’s interpretation of 21 CFR 312.120, the GCP guidelines exceed the ethical criteria of the Declaration of Helsinki, and therefore they represent the highest available standards for ethics and safety.

Even countries that have not officially signed on to the ICH defer to these standards. “The rest of the world is rising to meet them,” says Stilker. “It’s likely that some standards won’t be up to the same level in some of the poorer countries. But U.S. pharmaceutical companies are looking forward to the day that these standards rise up to the same level worldwide, which is gradually happening.”

In November 2000, the ICH released its highly anticipated Common Technical Document (CTD), which describes a common format for presenting study data in applications submitted for regulatory review within the three regions. Roger Williams, executive vice president and CEO of U.S. Pharmacopoeia, describes the CTD as a “very powerful document” that delineates a logical flow of data, from kinetic modeling to clinical benefit measures, in a way that provides “clinically useful information”.

Working through cultural barriers
But even as standards for clinical trials gradually equilibrate around the world, U.S. pharmaceutical companies still face basic cultural differences when conducting research overseas. And despite their detail, the GCP guidelines are fairly general, with room for interpretation by physicians, clinical investigators, and officials in individual countries. Multinational companies such as Merck have a certain advantage in these situations because they typically staff overseas offices with fluent nationals and employees who can communicate directly with foreign researchers. Merck contains a single consistent ethical standard for conducting clinical trials around the world. “We have a network that reports directly to our research division,” says Merck’s Sabbaj. “Usually, these are local M.D.s who have good relationships with the investigators in those countries and can explain what the study is about.”

Other companies may not have this advantage, however, and it is partly for this reason that rising global R&D has been accompanied by the growth of contract research organizations (CROs) that perform clinical trials on behalf of their pharmaceutical clients. Some of the larger CROs, such as Quintiles, have a substantial overseas presence, which allows them to interact directly with foreign personnel. Whether a multinational clinical trial is managed by a company or through a contractual arrangement with a CRO, coordination issues are substantial. For example, every clinical facility engaged in a research trial will have its own IRB (typically referred to as an ethics committee in countries outside the United States), and it is critical to ensure that the standards each IRB upholds are at least as rigorous as U.S. standards. Quintiles’ Davies says that her company delegates ultimate responsibility to a single project manager who coordinates multinational staff and processes data in a format suitable for presentation in a final report.

One pervasive problem faced by U.S. pharmaceutical companies working overseas is a chronic shortage of trained clinical investigators. The problem is most acute for investigations of rare diseases. Says Rubin, who is codirector of the Clinical Investigator Training Program, a two-year educational program run cooperatively between Beth Israel Deaconess Medical Center (the Harvard–MIT Division of Health Sciences and Technology) and Pfizer, Inc., “This is a problem that everyone recognizes, and there’s a big push going on to try to fix this.”

Rubin is enthusiastic about the prospect of increasing overseas clinical trials, especially given the explosion of information on human genomics, for instance, pharmacogenomics, which is the study of how ethnic differences in drug metabolism may be written into the genetic code. “The GCP is providing a set of international standards that we can all agree to,” he says. “The important thing is that they provide guidance on the nonnegotiable issues, including informed consent, IRBs, and regulatory requirements, which are required wherever in the world you’re doing your studies.”

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Charles W. Schmidt is a freelance writer based in Portland, ME. Send your comments or questions regarding this article to mdd@acs.org or the Editorial Office by fax at 202-776-8166 or by post at 1155 16th Street, NW; Washington, DC 20036.

 © 2001 American Chemical Society.  

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