The Rise of Unregulated Drug Trials in South America
“Drug companies come to Latin America because they think IRBs will be less strict and knowledgeable,” says Miguel Kottow, a Chilean bioethicist. Many critics cite the case of Carlos Vallejos, a former Peruvian health minister who now heads INEN, the public cancer hospital, while remaining a major shareholder in a private health insurance company serving cancer patients.
But Agueda Muñoz del Carpio Toia, a bioethics professor who teaches at Peru’s Catholic University and chairs its IRB, believes Peru has strong regulations and a competent IRB system, though she concedes that the country should be more vigilant against financial conflicts of interest. “We need better ways to identify and deal with these problems,” she said.
Muñoz has received training from the NIH through its Fogarty Center, the world’s largest trainer of research ethics in the developing world. She is confident that the training she and others like her have received has helped make IRBs stronger in many Latin American countries. Others say Fogarty does more harm than good, particularly by enabling a double standard for research ethics: one for poor people in the third world, the other for rich people in the United States and Europe.
In the early 2000s, Fogarty funded a US researcher at the University of Miami who wanted to determine if massage therapy would boost the immune systems of HIV-positive children in the Dominican Republic. They were dying of AIDS but not taking antiretroviral drugs available in the United States at the time (not all clinical trials involve drugs or devices). The researcher paid forty-eight families $5 per clinic visit, twice a week for twelve weeks. The children were “randomized” into two groups. One received therapeutic massage; the other, made up of twelve HIV-positive children, met with a nurse for “reading, talking, playing quiet games” as part of “the friendly visit control group.” When the study was finished, according to a report in The Journal of Alternative and Complementary Medicine, the researchers apparently packed their bags and left without offering any of the dying children life-saving drugs.
“This is a terrible study for a number of reasons, including the fact that it is biologically implausible,” says Marcia Angell, a senior lecturer in social medicine at Harvard Medical School and former editor of The New England Journal of Medicine. “This would have been impossible to do in the US. No reasonable IRB would approve it. The worst part is that this was supported by the NIH, which could afford to treat those children.” The University of Miami has not responded to requests for comment.
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An emerging “standard of care” debate asks if drug companies conducting trials should be able to do in a third world country what they can’t do in the United States. This is a key question to ask as global guidelines evolve. For years, the FDA made its researchers conform to the Declaration of Helsinki, an international human rights document developed by the World Medical Association to protect human subjects from unethical research. In 2008, in a highly controversial move, the FDA replaced Helsinki with “good clinical practice” (GCP), a set of industry-backed technical standards meant to harmonize research.
The FDA claims that the switch to GCP grew out of concerns that the Helsinki amendment process could create confusion by contradicting US regulation (the document has been amended six times since its inception). But Ruth Macklin, a well-known bioethicist from the Albert Einstein College of Medicine who collaborates with the Fogarty Center, says that wasn’t the real reason it was dropped. “I think the agency abandoned Helsinki because it has strong prohibitions against the use of placebo trials when there exists an effective medication,” she said. “The FDA wants placebo controls because they are the gold standard of research. And companies want them because it is cheaper.”
Drug companies would have you believe that the ethical standards for drug testing abroad remain high. In a statement last year, the industry’s trade association, PhRMA, argued that “the same strict regulatory standards apply to foreign trials as trials conducted domestically.”
PhRMA is right to say that the FDA “has jurisdiction over clinical trials conducted in foreign countries for drugs approved in the U.S. or being studied for approval in the U.S.” Investigational new drug applications, or INDs, can serve as a layer of oversight and legitimacy, a way for companies to get pre-approval from the FDA while giving the agency a chance to monitor studies in real time. But the industry is increasingly finding—and, many argue, the US government is helping to create—regulatory loopholes to avoid such close scrutiny.
For years the FDA required drug companies doing IND studies outside the United States to follow US regulations concerning institutional review boards. But the agency regularly grants waivers to the IRB requirement. “Nowadays, it is generally acceptable for a sponsor wanting a waiver to do little more than state that it intends to use an IRB that complies with GCP,” says Michael Carome, a former associate director of the HHS Office for Human Research Protections who now works for the advocacy group Public Citizen.
US law requires all studies for new drugs (and old drugs marketed for new uses) to get an IND, but drug companies don’t have to get FDA pre-approval for foreign studies, even though they are able to submit the results of these off-the-record studies for FDA consideration. So if a non-IND study goes badly, a company can simply bury the problem. But if the study goes well, the firm introduces the data to the FDA with a promise that GCP was followed.
“The FDA is supposed to protect people and ensure data quality,” said Liz Woeckner, who directs CIRCARE, a group advocating stronger human research protections. “But they only find out about these foreign non-IND studies after they are closed, sometimes years after. How can you protect people and verify data quality in that situation?” You can’t.
Gerald Schatz, an attorney and retired associate professor at Michigan State University who now serves as vice president at CIRCARE, believes that foreign non-IND studies are “the crux of the matter”: “A big fear is that reckless researchers or firms may find it easy to go far from regulatory scrutiny and conduct preliminary, early-phase research off the record to find out whether to abandon the idea or to pursue it in the licit, on-the-record procedures.”
PhRMA’s claim that “the same strict regulatory standards apply” around the globe is disingenuous for another reason: GCP isn’t a universal set of guidelines; it is only a model for countries to use when developing their own regulations. In some places, like the United States, national regulations have stricter standards than GCP. But developing countries eager to court foreign business have an incentive to be more relaxed in their approach. “The problem is that the FDA doesn’t rigorously assess what GCP means in the country where the research is being conducted,” says Carome. “Because each country has different interpretations of GCP, there is great variability in how GCP is implemented and, by extension, in how well human subjects are protected.”
Amid allegations of regulatory failure, in July the HHS issued a notice of proposed revisions to US laws to address “how current regulations for protecting human subjects who participate in research might be modernized and revised to be more effective.” It sounds like a step in the right direction, but some critics are worried that the revisions, if enacted, would further erode existing standards in the name of improving them.
Asked to comment on such concerns, Julie Kaneshiro, of the division of policy and assurances at the HHS Office for Human Research Protections, insists that the revisions would “increase protections for individuals” and would replace IRB oversight with “mandatory standards for data security and information protection.”
But Schatz counters that they would “weaken existing protections by removing from IRB oversight large portions of research, primarily in the behavioral and social sciences, notwithstanding the extent to which such research might constitute invasion of personal privacy.” What’s more, he says, the proposal threatens to dispense with the legal requirement “to protect the rights of human subjects of behavioral and social research and biomedical research.”