Legislation to tighten up the oversight of institutional review boards (IRBs) could be in the pipeline after a US Congressional hearing was told of serious flaws in the national system for ethical review and monitoring of clinical trials.

Concerns about rubber-stamping by a fast-proliferating independent IRB network – there are currently more than 6,000 institutional review boards registered with the US Department of Health and Human Services’ (HHS) Office for Human Research Protections (OHRP) – were lent weight by the success of a ‘sting’ operation conducted by the US Government Accountability Office (GAO).

One IRB, Coast, approved a trial protocol submitted by the fictitious Device Med Systems of Clifton, Virginia for a fake medical device called Adhesiabloc. According to Representative Henry Waxman, chairman of the House Committee on Energy and Commerce, over the past five years Coast has reviewed a total of 356 study protocols and approved all of them, by a unanimous board vote on all but one occasion.

Over the same period Coast’s revenues have more than doubled, from US$4.4 million in 2005 to over US$9.3 million in 2008, Waxman added.

The Committee started investigating IRBs in 2007 after learning that one such organisation, Copernicus, had allowed a clinical study of Sanofi-Aventis’ controversial antibiotic Ketek (telithromycin) to proceed despite evidence that the trial included fraudulent data.

The GAO was asked to pursue undercover testing of the IRB review process to determine, among other things, whether government oversight of institutional review boards was adequate and whether clinical researchers were “IRB shopping” – i.e., choosing review boards based on how quickly and inexpensively they would approve studies.

The Energy and Commerce Committee’s Oversight & Investigations Subcommittee, which held last week’s session on ‘Institutional Review Boards that Oversee Experimental Human Testing for Profit’, heard how Coast aggressively marketed its services, sending a coupon to the GAO’s bogus medical device company “good for a one-time research protocol review worth US$1,300”, and stating: “Take us for a free test drive”, followed by “Coast through your next study”.

Serious questions

Bart Stupak, chairman of the Oversight and Investigations Subcommittee, said the GAO’s findings raised “serious questions not only about the specific IRB involved in this investigation but with the entire system for approving experimental testing on human beings”.

The GAO approached three independent institutional review boards – selected because they had “less burdensome initial paperwork requirements than other IRBs for protocol submission” – with the protocol for Adhesiabloc, a post-surgical healing device for women that was based on several examples of “significant risk” devices identified in Food and Drug Administration guidance. The protocol involved pouring a litre of Adhesiabloc gel into a woman’s abdominal cavity after surgery.

While Coast determined that the procedure was “probably very safe”, the two other IRBs contacted by the GAO described it variously as “awful”, “a piece of junk”, and “the worst I’ve ever seen”. Coast continued to stand by its actions, though, despite admitting it had only discovered the fraud after receiving a request for documents from the House Energy and Commerce Committee.

Testifying at the hearing, the IRB’s chief executive officer, Daniel Dueber, insisted the GAO had violated state and federal criminal laws in perpetrating the sting. “Mr Chairman, the question confronting me, and which I hope will occur to you, is whether this Committee and the GAO have lawful authority to defraud an innocent party to prove a political point,” Dueber commented.

Bogus IRB

As part of its investigation, the GAO also set up a bogus IRB – whose alleged president was named after a Congressional staffer’s three-legged dog – and managed to register it with the HHS through an online registration form.

Additional bogus IRBs created by the GAO and listed on the HHS database were called E-Z Reviews and Phaké Med Devices. As if this were not enough of a hint, E-Z Reviews’ address was given as 1234 Phulovit Lane SE, Chetesville, and its staff included April Phuls, Timothy Wittless and Alan Ruse.

The GAO created a website for its bogus IRB, advertising the board’s services in newspapers and online with particular emphasis on its flexibility and the speed of its review process. This prompted a real company to submit a research protocol seeking the fake IRB’s approval to add one of its clinics as a new test site for ongoing clinical trials involving invasive surgery.

Moreover, GAO investigators used the HHS registration obtained for the bogus IRB successfully to apply for HHS assurance for the Office’s aforementioned fictitious medical device company – the whole process again being conducted without any actual human interaction.

An assurance is a statement by researchers to the HHS that a study with human subjects will follow ethical principles and federal regulations. It is a prerequisite if the sponsor wants to secure federal funding for the research.

The HHS later told the GAO it has just three OHRP employees reviewing some 300 IRB registrations and 300 assurance applications each month. Officials said the department does not review IRB registrations or assurance applications to check whether the information submitted is factual.

Although HHS is “required by law to consider the adequacy of IRBs listed on assurance applications when reviewing applications, the director of OHRP stated that his office would require more staff to do so”, the GAO noted.

The GAO’s investigation “shows that the IRB system is vulnerable to unethical manipulation, particularly by companies or individuals who intend to abuse the system or commit fraud, or who lack the aptitude or qualifications to conduct and oversee clinical trials”, stated Gregory Kutz, managing director, forensic audits and special investigations, in his testimony to the Subcommittee.

“This vulnerability elevates the risk that experimental products are approved for human subjects testing with little or no substantive due diligence,” Kutz warned.