An undercover investigation performed by the Government Accountability Office (GAO) revealed that some companies responsible for monitoring clinical trials involving humans may be “rubber stamping” trials without ethical considerations.
Institutional Review Boards (IRBs) are tasked with reviewing requests for clinical trials that involve humans to ensure they are ethical and safe for the subjects. Before a trial can begin, the trial’s sponsors must commission an IRB, which has the authority to approve the trial plan, require modifications before approval, or disapprove the research. The boards must ensure the risks are minimal and reasonable, the selection of subjects is equitable, and informed consent is obtained from all subjects. After the study begins, the board continues to monitor the research and may suspend or terminate a trial that produces unexpected harm or is not being conducted in accordance with protocol.
IRBs overseeing trials that have federal funding are regulated by the U.S. Department of Health and Human Services Office for Human Research Protections (OHRP). The FDA oversees IRBs involved in trials that concern FDA-regulated products. Both agencies require that IRBs be composed of scientists and lay people and also give consideration to the race and gender of proposed participants to try to have a balanced review system.
Although IRBs, as independent boards without a stake in the trial outcome, play an important role in ensuring the safety of people involved in trials, there has been concern in the industry that some IRBs are “rubber stamping” trials to obtain more clients, and researchers are taking advantage of this by “IRB shopping.” In 2007, an IRB allowed a trial of the antibiotic drug Ketek to continue even though employees at the company conducting the research for the manufacturer and staffers at the FDA warned the group that there were signs of fraud. The trial continued even after subjects began dying of liver failure, prompting the U.S. House of Representatives Committee on Energy and Commerce to request that the GAO conduct an investigation into IRBs.
GAO investigators went undercover to find out how easy it is to do three things: establish an IRB, obtain OHRP assurance, and convince an actual IRB to approve a trial. First, the GAO created an IRB with made-up company officials and only a mailbox for a business location. It registered the IRB with the OHRP and set up a Web site and advertisements. The OHRP, which uses the registration to collect data and does not verify the submitted information, registered the company and listed it in its directory. A company seeking an IRB for its trial sent the phony IRB a research protocol for an ongoing trial involving invasive surgery, which the IRB could have approved without registering with a federal agency because the trial did not receive federal funding or involve an FDA-regulated product.
The GAO next created a fictitious medical device company and sought OHRP “assurance,” which is required for researchers to receive federal funding. To receive assurance, companies have to designate at least one IRB to review the research. The GAO investigators listed their fake IRB and received assurance, which would have allowed the company to conduct human subjects research even though the business was not legitimate.
Finally, the GAO’s fake company sent a bogus research protocol for a trial to three different IRBs. The unproven product was a solution that supposedly helps postsurgery patients heal, and the trial required one liter of the product to be poured into abdominal cavities after surgery. The protocol falsely claimed that the FDA had cleared the device for marketing and mentioned previous animal studies without providing the results. The study details were vague and matched multiple examples of devices previously found by the FDA to be of “significant risk.” Although two of the IRBs provided extensive comments listing problems with the proposed study, the third one, Coast Institutional Review Board, approved the research without requesting further information. Board meeting minutes later obtained from the company showed that they found it to be “probably very safe” and unanimously approved it.
Noting that the undercover operation shows the “potential for unethical manipulation in the IRB system,” the GAO report said it “raises concerns that other IRBs may conduct protocol reviews without exercising due diligence, thereby exposing research volunteers to significant risk.” Human Subjects Research: Undercover Tests Show the Institutional Review Board System is Vulnerable to Unethical Manipulation, GAO, No. GAO-09-448T (Mar. 26, 2009), available at www.gao.gov.
In a March hearing conducted by the Energy and Commerce Committee’s Subcommittee on Oversight and Investigations, Chairman Bart Stupak expressed concern. “Why was this review so shoddy? The evidence suggests that Coast was more concerned with its financial bottom-line than protecting the lives of patients.” Arguing that the GAO investigation raises serious questions about the entire human trial system, Stupak said that “as a society, we have a moral obligation to ensure that human testing is done in the most responsible and ethical manner.” Opening State. of Chairman Bart Stupak, Institutional Review Boards that Oversee Experimental Human Testing for Profit, U.S. H.R. Comm. on Energy & Com., Oversight & Investigations Subcomm. (Mar. 26, 2009), available at http://energycommerce.house.gov.
Although Stupak noted that Coast only discovered the fraud five months after it approved the study, Daniel S. Dueber, Chief Executive Officer of Coast, argued that his company discovered the fraud on its own and that the fraud “would have persisted to this day had I not discovered it and had Coast not terminated the clinical trial.” Opening State. of Daniel S. Dueber (Mar. 26, 2009), available at http://energycommerce.house.gov. Dueber accused the GAO of illegally “perpetrating an extensive fraud” against the company without probable cause and said he had notified law enforcement authorities.
In April, the FDA imposed restrictions on Coast, requiring it to stop reviewing new FDA-regulated studies and enrolling new subjects in ongoing studies. “FDA determined that Coast IRB committed several violations of the laws and regulations intended to protect the rights and welfare of human research subjects in clinical trials and that the company failed to perform the robust review needed to approve a study,” the agency said in a statement. Press Release, FDA Imposes Restrictions on Coast IRB Due to Violations, FDA News (Apr. 14, 2009), available at www.fda.gov.
The OHRP issued a proposed rulemaking seeking comments on whether it should hold IRBs accountable for meeting regulatory requirements. In the past, the agency has enforced compliance only on the private institutions engaged in the research, dissuading them from seeking external IRBs in favor of the smaller in-house IRBs they typically use. 74 Fed. Reg. 9578 (Mar. 5, 2009). Comments are due by June 3, 2009.