Congress may be looking to limit the flexibility that firms have in conducting clinical trials following a study that revealed operational shortcomings in the conduct and registration of Institutional Review Boards.

At a March 26 hearing, both the Department of Health and Human Services and Coast IRB took heat from the House Subcommittee on Oversight and Investigations for lapses in their watchdog roles. HHS registered a fraudulent IRB and Coast IRB approved a fraudulent trial protocol - both submissions fabricated by Government Accountability Office agents in a "congressional sting operation."

"I can't tell you whether our two undercover successful tests are isolated cases or the tip of the iceberg," GAO Managing Director Forensic Audits and Special Investigations Gregory Kutz testified to the committee. "What I can tell you is that given the history of human subject testing, it's hard to believe that anybody could be comfortable with the integrity of the current system."

While the nature of the subcommittee's inquiry into IRB behavior appears novel, the conduct of for-profit IRBs long has been a concern for congressional Democrats (¹ [A#00620250020], p. 26).

More recently, Subcommittee Chairman Bart Stupak, D-Mich., has examined fraud in the pivotal trials for Sanofi-Aventis' antibiotic Ketek (² Also see "Ketek Is Emerging As Lens For Wider Hill Scrutiny Of Clinical Trial Integrity" - Pink Sheet, 18 February, 2008., p. 11), and the handling of data from trials for Merck/Schering's cholesterol agent Vytorin (³ Also see "House Energy & Commerce To Continue Foraging Through Vytorin Data" - Pink Sheet, 23 February, 2009., p. 6).

Questions around IRBs also have attracted academic attention, and while industry may be heartened by the streamlining principles put forth, it should also be cautious of any momentum it puts behind reform efforts directed by Stupak.

Former director for the NIH National Human Genome Research Institute Francis Collins, speaking at a Council for American Medical Innovation lunch March 19, acknowledged the difficult situation facing IRBs.

"We need to re-energize our approach to human subject protection, which right now is very confusing. Investigators spend vast amounts of time on paperwork which doesn't seem to do much to protect human subjects. It has become very bureaucratic," he said.

"IRBs are very confused about what's expected of them, huge amounts of busy people's time is wasted in an enterprise that really seems fairly pointless most of the time. So there is a desperate need to reawaken our ideas about how to take these critical principles about how to protect human subjects but implement them more effectively."

Does IRB Shopping Sell A "Piece Of Junk?"

The Commerce subcommittee hearing was a rough ride for Coast CEO Daniel Dueber. His firm's board unanimously approved a trial protocol of a bogus product ("Adhesiabloc") by a bogus company ("Device Med Systems") to be carried out by a fake doctor with an expired medical license. Two other firms (Argus IRB and Fox IRB) had rejected the protocol, calling it "awful," a "piece of junk," and "the riskiest thing I've ever seen on this board."

The disparity in the approaches by the IRBs could lead to efforts to prevent "IRB shopping," or the practice of researchers shopping protocols around to different IRBs until they get approval.

Stupak noted that in 2002, FDA considered regulations to reign in IRB shopping by requiring disclosure of prior decisions in order to alert other boards of past study rejections. The proposal was withdrawn in 2006 after FDA concluded that IRB shopping was not a problem that warranted rule-making. Stupak indicated that the present situation illustrated that it was still a concern.

One member of the subcommittee, Rep. Diana Degette, D-Colo., has already put forward legislation on standards for IRBs. Introduced March 25, the Protection for Participants in Research Act (H.R. 1715) would expand the number of trials subject to federal regulation to all research that is "in or affects interstate commerce." It also charges HHS with trying to better harmonize clinical study rules for FDA-regulated and government-funded trials and includes some additional requirements for training IRB members and for federal monitoring of IRBs.

Trying To Coast Through

In contrast to the dismissive comments about the fake GAO protocol from the other IRBs, according to Coast board meeting minutes, the doctor with primary responsibility for reviewing the study said the protocol "looks fine" and that the one-liter substance - all the ingredients of which were not specified in the protocol - to be injected into the abdominal cavity of study subjects was "probably very safe."

Dueber maintained in questioning from subcommittee staff prior to the hearing that Coast's medical review of the protocol was adequate, that none of the board members raised concerns with the protocol, and that his sense remained that the study was not particularly risky.

The committee was put off by Dueber's testimony, in which he claimed the federal government unfairly perpetrated an extensive fraud against Coast without probable cause and wasted five weeks of his time and $100,000 of his company's money.

"I think it's pretty clear that the GAO and this subcommittee are providing a real service to your company, sir," Rep. Edward Markey, D-Mass., said. "I think we are trying to help to protect against such a lackadaisical system upon human beings, and yet you seem to be outraged, actually, at our pointing out this deficiency in the way in which your company conducts business."

"Perhaps now you are being advised by your counsel to take the position which you are taking in your testimony today, but it's not helpful to you to be denying the obvious," Markey said.

This is not Coast's first regulatory foible - the IRB received an FDA warning letter last year for having an inexperienced member of the firm conduct an expedited review of a trial advertisement that did not meet the criteria for such a review; FDA regulation says only the IRB chairperson or an experienced reviewer designated by the chairperson may use the expedited review process.

Stupak asked FDA Director Good Clinical Practice Program Joanne Less what action the agency would take against Coast for its current misstep.

"We will need to take all of that information into account," Less said. "Normally if we've issued one warning letter, the next warning letter would include sanctions and we would take more serious action. But not knowing the specifics and not having reviewed the entire case I can't comment on this specific one."

Stupak's questioning suggests a desire for FDA to take stronger action sooner after it finds a violation. He has made a similar case for agency aggressiveness in the context of manufacturing problems with the generic firms Ranbaxy and Actavis. The agency was aware of production trouble - and had even cited the firms - long before recalls began (⁴ Also see "Dingell May Tighten Inspection Provisions In Safety Bill, After Ranbaxy Alert" - Pink Sheet, 22 September, 2008., p. 3).

Such concerns suggest a way for industry to engage on the issue without sounding like it is opposed to increased oversight: Industry could suggest that existing regulations can be better enforced; new laws and requirements are not necessarily needed.

Did HHS Check The Zip Code For Chetesville, AZ?

GAO's investigation also raised red flags about the registration process of IRBs with HHS. The fake IRB that GAO submitted was called "Maryland Hause," advertised through a fake Web site, and its president was actually a three-legged dog named Trooper. Kutz said after registering with HHS, the fake IRB received real inquiries from real researchers and had one research protocol submitted for review.

Congressmen accused HHS of taking no care in its certification of IRBs. "So what good is it to register with your agency when you put a stamp of approval on a [fraudulent] IRB that is then system-wide usable for others to go through to certify human tests?" Stupak asked.

Ranking Member Greg Walden, R-Org., echoed the sentiment: "What in the devil is going on in your agency that allows you to think you can ignore the law and regulations governing the adequacy of IRBs and simply enter whatever is e-mailed your way and put the U.S. government stamp of approval on an IRB?"

He continued: "Nobody picked up on names like 'Phake Medical Devices,' 'April Phuls,' 'Timothy Wittless,' and 'Alan Ruse?' Or the town of 'Chetesville, AZ'?"

HHS Director Office for Human Research Protections Jerry Menikoff told the committee, "We do not have the staff going through the names to see whether people have put funny names on the list," and that "unless someone sat there and tried to pronounce the names and addresses, they would not pick up on those things."

- Jamie Hammon (j.hammon@elsevier.com)

IRB Problems Will Increase Congressional Pressure On Industry Trial Designs

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