Health Letter, March 2013
The trend toward increased corporate globalization, in which U.S. companies relocate production to lower-cost, “developing” countries, is readily seen in the pharmaceutical sector. Drug companies have outsourced to the developing world not only the production of medicines, but increasingly, the clinical trials necessary to market those drugs. With the increasing privatization of clinical drug research, the developing world has emerged as the ideal environment for a business model that relies on quicker, less-expensive trials and minimal regulatory oversight.
Over the past 20 years, the number of clinical drug trials conducted outside of the U.S. has skyrocketed. The U.S. government estimated in 2010 that between 40 and 65 percent of clinical trials investigating products regulated by the Food and Drug Administration (FDA) are conducted, at least in part, outside of the U.S. Approximately one-third of trials sponsored by the 20 largest drug companies are conducted exclusively in foreign sites. Eighty percent of the marketing applications for drugs and biologics approved in fiscal year 2008 contained at least some data from foreign clinical trials.
Though most foreign-trial subjects and sites are still located in Western Europe, the developing world is the fastest-growing setting for the multimillion-dollar clinical trials upon which the drug industry relies. This growth has far outpaced the ability of U.S. and domestic regulatory agencies to ensure that the trials are conducted ethically, with far-reaching consequences for millions of potential human subjects in the developing world.
Ethical standards debated
The ethics of conducting clinical trials in mostly impoverished, developing countries has long been debated, as the patients recruited for such trials invariably represent a more vulnerable population for whom special considerations must be applied.
One question is whether subjects should be exposed to the risks inherent in all pharmaceutical trials if they will not benefit in the form of access to the medicines after the trial’s completion. The Declaration of Helsinki, an internationally recognized code of universal principles concerning the protection of human subjects, states that subjects exposed to the risks of clinical research should stand to benefit from its results. Despite a global movement advocating for increased access to essential medicines (such as antiretrovirals for AIDS patients) that has had some success in opening up markets for generic drugs, the reality remains that many — if not most — drugs tested at foreign sites and subsequently approved for marketing are currently priced out of reach of the vast majority of those in the developing world.
Another issue involves the obligation of trial investigators to administer adequate treatment to study subjects. This is most relevant when considering one of the more common designs employed in pre-approval pharmaceutical studies, the placebo-controlled trial, in which patients with a disease are randomly divided into two groups, with one group receiving an investigative medical intervention and the other receiving a placebo, or inactive therapy.
The ethics of conducting a placebo-controlled trial when there are effective treatments available, particularly if the disease is serious or life-threatening, has been fiercely debated over the years. The Declaration of Helsinki expressly states that “the benefits, risks, burdens and effectiveness of a new intervention must be tested against those of the best current proven intervention,” with exceptions for cases in which no effective treatment is available, or in which the potential harm to subjects receiving no therapy is not “serious and irreversible.” For this reason, investigators typically (but don’t always) shy away from such placebo-controlled studies for serious or life-threatening diseases in the developed world.
Some have defended the use of placebo-controlled trials in the developing world, arguing that experiments should only meet the standard of care offered in those countries and that subjects getting placebos would be no better off had they not participated in the trial. But subjects offer a crucial financial benefit to drug companies through their participation, and there are moral implications of actively withholding effective medical therapy from those under one’s care. This line of thinking led to the approval of two controversial clinical trials that highlighted the double standard often applied to subjects in rich countries versus poor ones.
A lower standard for the developing world
In 1997, Public Citizen documented 18 controlled clinical trials of interventions to prevent perinatal HIV transmission from HIV-positive mothers to infants. The trials were all initiated after a 1994 study showing that giving antiretroviral drugs to pregnant women reduced the HIV transmission rate by two-thirds. The studies recruited pregnant women in Africa, Asia and the Caribbean. Half the women in these trials received AZT, a therapy proven to help prevent HIV transmission to the fetus, while the other half received placebos.
In the two studies performed in the U.S., the patients in all the study groups had unrestricted access to zidovudine or other antiretroviral drugs. In 15 of the 16 trials in developing countries in Africa, Asia and the Caribbean, however, some or all of the patients in the control groups were not provided antiretroviral drugs. (Nine of the 15 studies being conducted outside the U.S. were funded by the U.S. government.) Despite Public Citizen’s call to halt the unethical trials, many of the studies proceeded without alteration, and dozens of infants in the placebo group of one study in Thailand were needlessly infected with HIV.
In another case, in January 2001, the FDA internally circulated a memorandum of a presentation entitled “Use of Placebo-Controls in Life Threatening Diseases: Is the Developing World the Answer?” The presentation concerned the proposed design of a study that would have explored the effectiveness of the drug Surfaxin in the treatment of Respiratory Distress Syndrome, a sometimes-fatal disease of premature infants, in hundreds of infants in four Latin American countries.
Although four similar surfactant drugs had already been approved in the U.S. and had been shown to reduce mortality rates by about one-third, the company proposed giving half of the patients a placebo, reasoning that in those countries people did not receive surfactant anyway. (Another study planned by the company in Europe gave all infants either the company’s surfactant or another surfactant known to be effective. That study did not use placebos.)
In February 2001, Public Citizen wrote to then-Health and Human Services (HHS) Secretary Tommy Thompson, urging him both to prevent the FDA from endorsing the study as designed and to require the company to give all subjects effective treatment with surfactant therapy. Three months later, the company agreed to alter the trial protocol and administer effective surfactant therapy to all subjects.
An analogous historical case from the West is found in the infamous Tuskegee syphilis experiments conducted in the early 20th century, in which African-American men infected with syphilis were followed for decades to document the natural progression of the disease. Penicillin therapy, discovered to be effective in eradicating the disease after the trial was started, was withheld from the men for years. These men were largely poor and marginalized, similar to the study populations predominant in the developing world, which made it easier for the unethical study to continue for so long under the radar.
Lax regulatory oversight enables dubious trials in the developing world
Current U.S. law allows placebo-controlled trials, such as in the Surfaxin and HIV cases discussed above. In addition, enforcement of existing regulations also is notoriously lax, increasingly so with the proliferation of foreign trials.
The FDA is responsible for overseeing the operations of clinical trials, both domestic and foreign, that are conducted in support of a future application for a new drug approval in the U.S. Though companies are required to report such trials to the FDA before they begin, the agency has virtually no capacity to follow through with inspections once the trials are under way. In fiscal year 2008, the FDA inspected only 0.7 percent of all foreign clinical trial sites. (The rate of inspection was only marginally greater, 1.2 percent, at U.S. sites.)
Regulatory agencies in developing countries are even less equipped to deal with the flood of new trials, meaning that virtually all trials conducted in the developing world effectively operate in a vacuum of regulatory oversight, with no governmental review until after the trial is completed (and then, usually only in cases in which the trial is successful and presented to American or European regulatory agencies as part of a marketing application).
In the absence of governmental oversight, institutional review boards (IRBs, which are frequently associated with academic medical institutions) are almost always the only independent entities capable of ensuring ethical integrity in clinical trials by declining to approve those trials not meeting accepted ethical standards. Established in the 1970s in response to revelations of past human study scandals, such as the Tuskegee experiments, IRBs are expert panels tasked with affirming that studies involving human subjects are ethically designed and implemented.
A recent investigation by the Government Accountability Office (GAO) suggested potentially glaring gaps in IRB oversight. In 2009, the GAO created a fictitious medical company that proposed a clinical trial for a risky, unapproved medical device to three IRBs in the U.S. One of the three approved the trial, with few questions asked and without verifying the credentials or even the existence of the fictitious company. The GAO’s investigation revealed the potential for dubious clinical trials to proceed within the U.S.
The globalization of clinical research raises additional questions regarding oversight and accountability. Foreign clinical trials can be overseen by a U.S.-based or local IRB in the study country. U.S.-based IRBs, located far from study sites, may be less able to monitor the conduct of an ongoing trial, while IRBs located in the developing world may face staffing or financial barriers, or they may lack the organizational capacity to provide adequate oversight. One 1999 survey found that U.S. and foreign researchers reported that in their experience, developing countries’ IRBs were less likely to raise procedural and substantive issues with studies than were U.S. boards.
There is currently no regulatory or legal mechanism in place to prevent more unethical trials, like the Surfaxin and antiretroviral trials, from going forward. As more trials are outsourced overseas, increasingly by for-profit corporations, a dearth of oversight leaves millions of vulnerable patients in the developing world at the mercy of drug companies’ interests.