Most US late-stage human clinical trials done abroad

Most Clinical Trials Done Abroad, by Shirley S Wang
WSJ, Feb 19, 2009

Most testing for the U.S. drug industry's late-stage human trials is now done at sites outside the country, where results often can be obtained cheaper and faster, according to a study.

The study found that 13,521 of 24,206 sites being used in November 2007 for studies sponsored by the 20 largest U.S. drug makers were international, and that the number of countries conducting testing has doubled over the past 10 years. The study was published in Wednesday's New England Journal of Medicine.

The findings add to concerns about the ethical treatment of participants and the integrity of the research data produced in developing countries. Experts also say patients in developing countries may be taken advantage of because they are poorer and less familiar with the research process.

In November, Indian drug regulators halted a trial of a Wyeth vaccine after an infant died, in order to investigate whether babies were properly screened before being enrolled in the study. In a Polish study in 2007 of a bird-flu vaccine being developed by Novartis AG, two elderly patients died who should have been excluded based on age. Other companies faced criticism earlier in the decade about testing drugs in populations that couldn't afford the medicines.

"Clearly there are major challenges both in terms of ethical oversight of the research and the scientific rigor," said Seth Glickman, an assistant professor of emergency medicine at the University of North Carolina-Chapel Hill who was first author of the study.

Helping to make overseas trials cheaper and faster, patients in developing countries are often more willing to enroll in studies because of lack of alternative treatment options, and often they aren't taking other medicines. Such "drug-naive" patients can be sought after because it is easier to show that experimental treatments are better than placebos, rather than trying to show an improvement over currently available drugs.

Reviewing published studies, authors of the journal article found proper research oversight and adequate informed consent for participants was inconsistent in developing countries. In one study reviewed, only 56% of 670 researchers who conducted trials in those countries said their studies had been approved by ethics boards or health officials. In another study, only 18% of researchers appropriately informed participants about the study before enrolling them.

The article comes at a time when some say the U.S. is moving in the wrong direction with regard to ethical treatment of study participants. Last year, the Food and Drug Administration updated its guidelines for conducting international clinical trials, adopting a standard used by many countries and organizations known as "good clinical practices."

The shift has been controversial. Critics believe the updated guidelines are less ethically rigorous and more industry friendly compared to the former guidelines, known as the Declaration of Helsinki. One version of that declaration forbade placebo-controlled trials and had provisions in it about companies' obligations to provide access to medicines to those populations in which the treatments had been tested.

It "set a higher standard," said Sonal Singh, an assistant professor at Wake Forest who studies international clinical trials and wasn't involved in Wednesday's report. "You're kind of dispensing with an ethical document," he said of the updated guidelines.

The FDA says that placebo-controlled trials are necessary under certain circumstances and that it also encourages post-market medication access to be discussed during protocol design. The new standards ensure protection for participants by mandating that studies be reviewed by international ethics committees and that informed consent be obtained from all participants, the agency says.

"Good clinical practice is meant to assure quality clinical trials, as well as the implementation of high-level clinical trial ethics," said David Lepay, senior adviser for clinical science at the FDA. "We do not see that there are fundamental differences between [good clinical practice] and other ethical standards in assuring the fundamental rights of subjects."

The authors of the new report also suggest that bureaucracy and regulatory hurdles in the U.S. are partly responsible for making going abroad so enticing. The requirements stretch out the amount of time it takes to complete a study and can add to costs as well. "Many of the policies in regards to the regulatory framework are well intentioned," said Dr. Glickman. "They have the unintended effect of being very onerous from the administrative standpoint."

In the U.S., each site seeking to conduct a study must have its ethics board approve it. But many studies these days are considered "multisite," where one company or sponsor runs the same trial at different centers and pools the data. The U.S. review process means redundant effort for such studies, according to Kevin Schulman, a professor of medicine and business administration at Duke University and another study author.