Ethical Review

ALTHOUGH SAFEGUARDS are in place to ensure that research involving human subjects is carried out ethically, a recent investigation by the Government Accountability Office (GAO) ironically found that the system for reviewing the ethics of clinical trials is vulnerable to unethical manipulation.

Under federal law, all clinical research including human testing must first be approved by an institutional review board (IRB)—a panel of at least five experts, including one scientist and one nonscientist, that reviews the study for purposes of protecting the rights and welfare of human subjects.

The Department of Health & Human Services' (HHS) Office for Human Research Protections (OHRP) and the Food & Drug Administration oversee various aspects of the IRB system.

Historically, IRBs were located at academic institutions or hospitals where clinical trials are conducted. But today, hundreds of private, for-profit IRBs have entered the marketplace. These so-called independent IRBs typically provide services to private pharmaceutical companies or device makers that conduct or sponsor clinical trials.

Because of concerns about the quality of some IRBs, the Oversight & Investigations Subcommittee of the House Energy & Commerce Committee asked GAO to conduct an undercover operation to test the IRB review process.

Details of the investigation came to light during a hearing of the subcommittee in late March. GAO concluded that the IRB system is vulnerable to manipulation by companies or individuals who intend to abuse the system or to commit fraud.

As described at the hearing by Gregory D. Kutz, managing director of GAO's Forensic Audits & Special Investigations Unit, GAO investigators submitted a bogus research study involving a fictitious medical device to three independent IRBs for review. One of them, Coast IRB of Colorado Springs, Colo., said the device was "probably very safe" and gave the green light to test the device on human subjects. The other two IRBs did not approve the study, citing safety concerns about the device.

Coast Chief Executive Officer and President Daniel S. Dueber defended his company at the hearing, saying that Coast was a victim of what it deemed as an extensive fraud perpetrated by GAO. He emphasized that Coast changed its standard operating procedures after it had been "hoodwinked" by the federal government.

FDA EVALUATED the information provided by GAO and immediately took action against Coast. In mid-April, Coast voluntarily agreed to stop reviewing new trials that involve FDA-regulated products, and subsequently the company provided FDA with a corrective action plan.

But experts are concerned that Coast is just one of many IRBs that fail to perform robust reviews of clinical trials before approving them. The GAO investigation revealed that anyone could create an IRB and register it with HHS regardless of their credentials.

As part of the investigation, GAO created a fictitious IRB using clever names such as April Phuls, at phony locations such as Phulovit Lane, Chetesville, Ariz. It then registered the fictitious IRB with HHS via an online registration form, Kutz noted. HHS did not question the application and issued the phony IRB a registration number.

When lawmakers asked why OHRP did not question the blatantly phony registration, Jerry A. Menikoff, director of OHRP, replied that the system wasn't designed to catch fake data. He emphasized that registration in the OHRP database does not mean that an IRB is endorsed by the federal government. However, the perception in the marketplace is that registration with OHRP gives credibility to an IRB, Kutz noted.

Joanne R. Less, director of FDA's Good Clinical Practice Program, defended FDA's role in protecting the safety and rights of human participants in clinical trials that involve FDA-regulated products. She emphasized that GAO's faux trial would not have started because trials that involve FDA-regulated products such as a drug or medical device need approval from both an IRB and FDA before they can begin.

But only about 25% of the 25 million humans enrolled in clinical trials each year are treated with an FDA-regulated product, says Adil E. Shamoo, a biochemist and bioethicist at the University of Maryland School of Medicine and cofounder of the advocacy group Citizens for Responsible Care & Research.

Safeguards are also in place for trials involving human subjects that are funded by the federal government. Such trials must be carried out in compliance with ethical principles and OHRP regulations. About 40–45% of all human subjects are enrolled in clinical trials that are funded by the federal government, Shamoo tells C&EN.

In a continuing effort to establish oversight on trials that do not involve FDA-regulated products and are not funded with federal dollars, Rep. Diana DeGette (D-Colo.) has introduced a bill, the Protection for Participants in Research Act (H.R. 1715), in each of the past three Congresses. The bill would reform federal regulation and oversight of research on humans, making federal regulations applicable to all research that involves human subjects regardless of the funding source.

Some observers are hopeful that this will be the year that the legislation passes. "Reforms are way overdue," Shamoo says. As the GAO sting revealed, he notes, "the system is completely broken."