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Outsourcing clinical trials: Is it ethical to take drug studies abroad?

It is much cheaper to conduct a research trial in India than in the U.S. But sometimes, research subjects in developing countries pay the price.

By Kevin B. O'Reilly amednews correspondent — Posted Sept. 7, 2009

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Deciding whether to participate in a clinical trial is not easy, no matter where the study takes place. Patients are faced with a mountain of information about the potential risks and uncertain benefits of becoming research subjects.

Add to that heady brew the stark disparity among patients in rich countries and those in developing nations, and concerns mount quickly about the growing number of global clinical trials tapping the poor as research subjects.

Compare, for example, the United States and India.

The average American income is $47,000 a year -- 16 times what the average Indian takes home, according to the CIA World Factbook. There is one doctor for every 384 Americans, while there are 1,667 patients for each Indian doctor, the World Health Organization says. The average American patient consumes nearly $7,000 in medical care each year; the average Indian's annual health care tally is $39. Nearly every American adult can read, but 39% of Indians are illiterate.

What does it mean for research subjects around the world to give informed consent when the playing field is so uneven?

It costs about $2,000 to track the progress of a single Indian patient in a clinical trial, GlaxoSmithKline CEO Jean-Pierre Garnier wrote in the May 2008 Harvard Business Review, before retiring that month. It costs 10 times more in the U.S.

With the price of developing a single drug tabbed at more than $800 million, it is easy to see why pharmaceutical companies increasingly are shifting clinical research to developing countries such as India.

The 20 largest U.S.-based drugmakers conduct about a third of their phase III clinical trials outside the country, and a majority of their study sites also are elsewhere, says a Feb. 19 article in The New England Journal of Medicine. Two decades ago, nearly all of these trials were done in the U.S. The number of trials in developing countries has grown 8% a year since 1997, according to Food and Drug Administration data.

The concern is not just hypothetical, as a December 2008 St. Petersburg Times series documented. One patient, Ramsakhi Devi, had a cancerous tumor removed from her cheek at a government hospital in India. But if the 55-year-old woman from West Bengal wanted follow-up chemotherapy and radiation treatment, she would have to sign up for a clinical trial. Otherwise, her doctors told her, she had to go home.

The consent forms were in English and Hindi, but Devi is illiterate. Her 21-year-old son, Bablu Gupta, tried to help her navigate the process. But he misunderstood the forms. He thought there was only one available treatment option in the trial instead of three. And Devi said she was not told she could drop out. She had to finish, medical professionals said, to be "fully cured."

Stories such as Devi's exemplify the concerns many doctors, medical ethicists and other experts have about outsourcing clinical trials. Patients like Devi -- who lack money, education and regular access to medical care -- are found easily in developing countries and are effortless to recruit, said Jill A. Fisher, PhD, assistant professor at the Vanderbilt University Center for Biomedical Ethics and Society in Tennessee.

"There are just going to be more people in other parts of the world who are having health issues that need to be addressed and are ready to consent to clinical trials, because really it is the only mechanism for receiving care," said Fisher, author of Medical Research for Hire: The Political Economy of Pharmaceutical Clinical Trials, published in January. "And clinical trials are a problematic kind of care, because it comes in the context of a study intervention. But people are ready to enroll, because they see it as such an incredible advantage over basically nothing."

Overseas trials "a mess"

Charles M. van der Horst, MD, has been conducting clinical research to improve care for AIDS patients in South Africa and Malawi since 2001. The circumstances surrounding clinical research vary among developing countries, he said, but there are some common factors that add up to big problems.

"There are language issues, there's corruption in the government, desperate poverty, horrible inequity in male-female relations," said Dr. van der Horst, associate chief of the infectious diseases division at the University of North Carolina School of Medicine. "It's just a mess. There's an enormous amount of unethical research going on."

Fewer than six in 10 trial protocols in developing countries get reviewed by an ethics committee, stated a February 2004 Journal of Medical Ethics survey of nearly 700 researchers. Only one in 10 Chinese trial protocols got an ethics review, according to an April 24, 2008, article in the journal Trials. Four in five of those protocols failed to discuss informed consent adequately.

Moreover, not even half of study volunteers in industrialized nations finish the trial. Completion rates in developing countries, by contrast, frequently approach 90%, raising concerns about whether participants feel free to quit.

Then there are the high-profile cases, such as the controversy over Pfizer Inc.'s two-week trial of an antibiotic during a 1996 meningitis epidemic in Kano, Nigeria. A 2000 Washington Post story criticized trial investigators for allegedly allowing children to die while taking the study drug, sparking lawsuits from families and the Nigerian government. The case inspired the novel and film, The Constant Gardener. Pfizer reached a $75 million settlement with Kano in July, according to news reports.

Still, some experts reject hand-wringing about clinical-trial outsourcing. They include Kenneth A. Getz, a senior research fellow at Tufts University Center for the Study of Drug Development, a nonprofit research group in Massachusetts.

Getz said drugmakers have a strong financial interest in ensuring that trials are carried out in an ethically and scientifically rigorous fashion. "The market incentives are all aligned to make sure that companies are compliant," said Getz, a former drug-development consultant for pharmaceutical companies.

As for the charge that research sponsors and investigators exploit the world's poor, Getz counters: "Who are we to deny patients around the world access to potential experimental treatments that might improve their lives or ease their suffering? What right do we have to be so paternalistic that we deny people the right to make these decisions -- with the right education and support -- on their own?"

Others said the debate should focus less on the decision-making skills of potential research subjects in developing countries and more on whether they benefit from taking part in clinical trials. "The question is not whether the prospect of getting medical care so dazzles people that they can't think straight anymore," said Daniel Wikler, PhD, professor of ethics and population health at the Harvard School of Public Health in Massachusetts. "The question is, how bad of a deal are we offering these folks? On balance, what's been the net effect on participants? We don't know the answer to this question."

Wikler plans to survey research subjects in developing countries to help unravel that puzzle.

No global cop

There are international standards governing clinical research. Most famous is the World Medical Assn.'s Declaration of Helsinki, first adopted in 1964, which says potential research subjects must be adequately informed of risks and benefits, as well as the right to refuse to participate and to quit the study.

American Medical Association policy says independent review boards' job of protecting the welfare of human research subjects in other countries "can best be achieved by assuring that a suitable informed consent process is in place." The Pharmaceutical Research and Manufacturers of America, which declined comment for this story, has adopted similar policy and says all clinical trial protocols should be reviewed by an ethics panel.

The FDA requires that drugmakers seeking approval in the U.S. abide by guidelines formulated by the International Conference on Harmonization, a collaboration among industry groups and regulatory agencies in Europe, Japan and the U.S. The document contains extensive language regarding informed consent, stating that "neither the investigator, nor the trial staff, should coerce or unduly influence a subject to participate or continue to participate in a trial."

Yet the FDA doesn't have resources to keep an eye on clinical trials worldwide, critics say.

"They just don't have the staff or the infrastructure to do it," said Sonia Shah, author of the 2006 book, The Body Hunters: Testing New Drugs on the World's Poorest Patients. "What is the quality of the ethics committees in these developing countries? It took 40 years for [the U.S.] to build that whole infrastructure."

Seth W. Glickman, MD, agreed. He is assistant professor of emergency medicine at the University of North Carolina at Chapel Hill School of Medicine and lead author of the February NEJM article on clinical-trial outsourcing.

"In many parts of the world, including developing countries, people are conducting good clinical research," Dr. Glickman said. "They are doing it ethically, in terms of how they recruit patient subjects, and they are adhering to rigorous science in how they collect data and how they report it. But on the other hand, there are concerns about how research is being conducted in these same countries by different investigators. It's hard to know who's adhering to those standards and who's not.

"There should be a better mechanism for regulatory agencies to be able to monitor investigators and clinical research going on in their own domestic markets and to be able to share that information so it doesn't fall on the FDA to be the police for global clinical research," he said. The FDA did not respond to interview requests by this article's deadline.

In addition to creating a formal mechanism to allow regulatory agencies to share data, Dr. Glickman and his co-authors suggest a public registry of independent review boards, while boosting training of ethics review members and clinical investigators. "A rigid set of rules alone is not going to suffice," he said.

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ADDITIONAL INFORMATION

The rise of trial outsourcing

In 1990, 96% of clinical trial principal investigators were based in the U.S. By 2007, the figure stood at 57%. Cost considerations increasingly are driving research sponsors toward trial sites in developing countries. Percentage of clinical trials registered with the FDA, by site:

United StatesWestern EuropeRest of world
199786%9%5%
199980%9%12%
200177%10%13%
200370%11%19%
200562%13%25%
200757%14%29%

Note: Not all percentages total 100% due to rounding.

Source: Tufts Center for the Study of Drug Development analysis of FDA data

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View in PDF

Click to see data in PDF.

Research sites, rich and poor

Clinical trials take place in the richest countries in the world as well as in some of the poorest nations. Experts argue that huge disparities in income, literacy rates and access to quality medical care have contributed to an increase in trials outsourced to developing countries.

Sources: ClinicalTrials.gov; The World Factbook, Central Intelligence Agency; World Health Organization, Accessed Aug. 25

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The ethical dilemma of "extra" care

During a clinical trial testing a vaginal microbicide among sex workers in the west African country of Benin, researchers discovered that one of the participants had pelvic inflammatory syndrome due to an ectopic pregnancy.

A local gynecology clinic asked for money up front to perform the needed operation, according to a discussion of the case at a February 2004 research ethics panel held in Cape Town, South Africa. After an ethics committee review, the research sponsors agreed to pay for the operation, even though the condition was not a result of the patient's participation in the study.

The case highlights an ethical dilemma confronting clinical researchers in developing countries, where research subjects often have limited access to medical care.

When patients have a health problem unrelated to the intervention being studied, what extra care do clinical investigators and research sponsors owe them? And could the provision of this ancillary care heighten the risk of coercion, with communities in developing countries seeing participation in medical experiments as a ticket to free medical care?

Physician-investigators and research sponsors do have some duty to provide extra care, but that obligation has limits, according to a May 2008 PLoS Medicine article.

"Having elicited private medical information from the participants in order to conduct research, it is wrong for the researchers simply to turn their back on the medical needs that this information reveals," said Henry S. Richardson, PhD, a Georgetown University philosophy professor who worked on the PLoS Medicine paper, the result of a workshop involving 15 doctors and ethicists from around the globe.

According to the panel, physician-investigators and research sponsors working in developing countries should develop plans for each protocol on how to meet foreseeable ancillary-care needs, work with the local health system and consider setting aside a certain percentage of the budget to hire a physician to help out.

That said, doctors and research sponsors do need to draw a line on how much extra care to provide, said Dr. Malcolm E. Molyneux, who attended the Georgetown workshop.

"Ignoring ancillary care completely is wrong on general humanitarian grounds, but providing a luxury service, grossly out of keeping with that available to others in the local population, is not only an undue inducement but can also be socially divisive and unsustainable," said Dr. Molyneux, professor of medicine at the University of Malawi College of Medicine in southeast Africa. "How to strike the right balance requires local discussion and careful attention to local circumstances -- there is no single formula by which this can be calculated for all situations."

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External links

"Ethical and Scientific Implications of the Globalization of Clinical Research," abstract, New England Journal of Medicine, Feb. 19 (link)

"Testing Grounds: Our medicine at what cost?" St. Petersburg Times, December 2008 (link)

"Declaration of Helsinki: Ethical Principles of Medical Research Involving Human Subjects," World Medical Assn., October 2008 (link)

"Guidance for Industry: E6 Good Clinical Practice," Food and Drug Administration, 1996, in pdf (link)

"The Ancillary-Care Obligations of Medical Researchers Working in Developing Countries," PLoS Medicine, May 20, 2008 (link)

Map of all studies in ClinicalTrials.gov, U.S. National Institutes of Health (link)

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