Clinical Research Ethics, Oversight Draws Scrutiny

National and international authorities have been struggling for decades to ensure the protection and appropriate care of patients participating in biomedical research studies. The task has become even more challenging as more clinical trials take place outside the United States and Europe—not only to reduce costs and access patients more readily, but for global pharmaceutical companies to be able to develop products appropriate for foreign populations.

Jill Wechsler

The lack of common international standards and rules, however, gives rise to perennial scandals and abuses. Research sponsors struggle regularly with concerns about adequate informed consent, patient selection, study oversight, placebo controls, access to resulting therapies, and standard of care for research participants. These issues once again have come to the fore following revelations last fall about highly unethical medical studies conducted in Guatemala 65 years ago supported by the US Public Health Service. President Barack Obama has asked the Presidential Commission for the Study of Bioethical Issues to examine what took place in Guatemala and whether today's standards are strong enough to prevent such practices from recurring today.

The short answer to the second question, according to research experts, is "probably not." While the Tuskegee syphilis study, which began in 1932, was infamous for withholding treatment from some syphilis patients, the Guatemalan study is even more shocking because researchers intentionally infected mental patients and prison inmates. Scientists and ethicists advising the commission at its first meeting on the subject last month said that rules and policies developed over the last 50 years would prevent the design and conduct of such a study. But they admitted that no law actually blocks such action by a privately funded researcher who is not seeking regulatory approval for a new medical product—a situation likely to generate proposals for stricter standards and oversight.

The bioethics commission is scheduled to report back to the White House by September, putting this review at the top of its priority list. Commission Chair Amy Gutmann, President of the University of Pennsylvania, opened the March 1, 2011 meeting by acknowledging that the Guatemalan prisoners and patients in the study were treated unethically. "A civilization can be judged by the way it treats its most vulnerable individuals," she observed, setting the stage for a thorough examination of the adequacy of existing research standards and how they relate to international clinical trials.

Instead of producing a fat study that sits on the shelf, Eric Meslin, Professor and Director of the Indiana University Center for Bioethics, encouraged the panel to define a more coherent, unified, transparent US research policy to replace today's "leaky system." Robert Califf, Vice Chancellor for Clinical Research at Duke University, advised the Commission to clearly define the important attributes of the research ecosystem and then identify ways to measure them.

Considering context

To start, commission investigators are examining documents and information on the Guatemalan study, which was uncovered by Wellesley College Professor Susan Reverby as part of her research on Tuskegee. The staff will report on what specifically happened in Guatemala in the 1946-1948 trials and to what extent the US government and medical establishment facilitated these studies. It's likely that other unknown research projects of a similar nature will be discovered.

The investigators acknowledge the importance of examining these events in their historical context to assess the extent the studies conformed with or diverged from the relevant ethical standards of the time. Back when these studies occurred, explained biomedical historian Susan Lederer, University of Wisconsin School of Medicine and Public Health, there were few policies on the organization of clinical trials or the roles of researchers, participants, control groups, and randomization. Medical Ethics Professor Dan Brock of Harvard Medical School noted that in 1946 many ethical practices considered standard today were not yet on the table, although they were emerging following revelations about medical experimentation in Nazi Germany. Meanwhile, researchers studying the spread of sexually transmitted infectious disease during World War II were anxious to document effective prevention and treatment strategies for clinicians.

Better today?

In addition to delving into past practices, the Commission is reviewing the current state of biomedical research and how well US regulations and international standards protect the health and wellbeing of patients participating in US-funded studies. A special panel on international research, which includes ethics and research experts from the United States, Guatemala, India, China, Egypt, Africa, South America, and Europe, is assessing driving influences on research ethics outside the United States and how best to address conflicts between US and international policies.

Eric Meslin noted that not only has the volume of international studies grown, but so has the number of countries that host studies and the diversity in funding sources, many involving large collaborations and partnerships. There is more emphasis on community engagement in research plans and on determining an appropriate standard of care for research participants, along with a proliferation of research guidelines and standards, and a deeper understanding of ethical issues on all sides. The massive shift in medical research from the United States, observed Califf, reflects the desire of all countries to have clinical research done in the context of their populations due to genetic variation, cultural perceptions, and differences in medical treatment. US studies not only are very expensive, he noted, but also often yield poor data due to high dropout rates.

More investigations

An important goal for this examination is to bolster public trust and confidence in the ability of the research community to protect patients enrolled in clinical studies and to ensure that resulting data is valid and impartial. Revelations about the Guatemala study undermine this perception, as does a steady stream of reports on unethical research practices.

A muckraking article in the January 2011 issue of Vanity Fair, for example, blasted the globalization of clinical research, citing deaths of hundreds of poor research participants and the tendency of sponsors to hide studies that produce negative results. A study published last year in the journal Pediatrics cites an increase in pediatric studies being conducted outside the United States as raising questions about whether the foreign data is meaningful for US patients, and whether study participants can gain access to the medicines under study. Pfizer continues to face litigation and criticism stemming from a 1996 study of the effectiveness of the experimental antibiotic Trovan in treating Nigerian children with meningitis; several patients died, leading to lawsuits and allegations of unethical practices.

Research globalization, moreover, is prompting the Justice Department to investigate whether pharmaceutical companies conducting overseas clinical trials may be violating the Foreign Corrupt Practices Act. Fees to foreign investigators, clinicians, or laboratory officials who work for government health systems could be considered payments to foreign officials, and the feds are looking at whether such sponsor payments influence the reliability of data from foreign clinical trials.

This federal probe reflects reports from the Health and Human Services Office of the Inspector General (OIG) documenting inadequate FDA oversight of a growing volume of foreign clinical data in new drug applications. A 2001 OIG analysis reported a rise in recorded foreign clinical investigators from only 271 in 1990 to almost 4,500 by 1999. The OIG warned that more clinical research in Eastern Europe and Latin America would involve more inexperienced investigators and weak regulatory oversight, making it difficult to assure adequate protection of human subjects.

In a June 2010 report, the OIG urged FDA to look more closely at the results from trials not conducted under an investigational new drug application and to expand its volume of overseas inspections. The analysts calculated that in 2008, up to 65 percent of clinical trials supporting registration of products in the United States were conducted outside the country. And while FDA inspected nearly 2 percent of domestic clinical trials sites in 2008, it visited less than half that proportion of foreign sites (see Applied Clinical Trials, "View from Washington " August 2010).

Proposals for FDA to expand its oversight of clinical studies ignore the agency's limited resources to do so. The administration's budget plan for 2012, which requests a little additional funding for FDA, is not likely to survive the budget-cutting campaign on Capitol Hill. Most of the extra money would come from higher user fees on pharmaceutical and biotech companies, and is targeted to support special projects, such as development of biosimilars and medical countermeasures, import monitoring, and efforts to ensure the safety of high-risk therapies. Everyone wants FDA to conduct more inspections of food processors and foreign drug manufacturers, as well as research sites, but there's scant funding to support those efforts.

Jill Wechsler is the Washington editor of Applied Clinical Trials, (301) 656-4634 jwechsler@advanstar.com