For Pharmaceuticals:

Investigating the Investigators: Another Headache for Drug Sponsors
by Michael McCaughan

One leading indicator of a more enforcement-minded approach at the food & drug administration may be a crackdown on clinical trial investigators suspected of fraud. One thing is already clear: sponsors who rely on investigators who trigger suspicions will pay a price in the form of an even tougher time getting the drug through FDA.

This would be a good time for biopharma companies to review their ongoing clinical trials to determine whether any investigators involved in the study are vulnerable to potential disqualification proceedings by the Food & Drug Administration.

It sounds like the agency is getting ready to flex its enforcement muscles in pursuing administrative action against clinical investigators suspected of fraud.

The Center for Drug Evaluation & Research's Office of Compliance director Deborah Autor told the Food & Drug Law Institute's annual Enforcement & Litigation Conference that the Division of Scientific Investigations is "becoming more activist. I think that they are really gaining momentum in what they do from an enforcement context."

Autor's comments verify the perceptions of two attorneys sharing the dais with her—Douglas Farquhar of Hymen Phelps & McNamara and Philip Katz of Hogan & Hartson—who sense greater urgency and a tougher stance from the agency in cases involving clients potentially facing disqualification. FDA is "taking a much tougher stance in terms of how they resolve those issues," Katz said.

Any move by FDA to step up disqualification proceedings against investigators means headaches for industry.

It is not just the individual accused of fraud or their clinical center that suffers in a disqualification proceeding, Katz pointed out. "What you then quickly get to is then what do we do with the data that this disqualified clinical investigator has been involved with?"

And it "is not just the data in the study that was the subject that led FDA to the disqualification proceeding," Katz said, "but also other data with which that investigator was affiliated. That becomes suspect as well."

In some cases, there may be nothing sponsors can do to avoid the taint—except hope that their clinical trial findings are robust enough to support safety and efficacy even if the investigator's site is excluded from the analysis of the trial.

But sponsors can also prepare by double checking whether their investigators have been cited by the agency in public inspection documents (known as FDA 483 reports) or, even more critically, in warning letters from the agency. This is not a good time to assume that an investigator will be able to resolve questions about trial conduct quickly or easily.

Calls for a Crackdown
A crackdown on investigators accused of fraud would hardly be surprising, given the recent round of hearings and Congressional reports focusing on claims that FDA failed to take appropriation action quickly enough to respond to allegations of fraud in clinical trials of the antibiotic Ketek. (See "Data Integrity Delays: Another Key Takeaway from Ketek," The RPM Report, January 2008.)

FDA has plenty of critics who want the agency to take a tougher line on regulated industry—and if history is any guide, the next commissioner's tenure is almost certain to be marked by a more enforcement minded approach. (See "No Walk in the Park.")

In this case, though, the push for a crackdown is coming in part from Texas Representative Joe Barton, the Ranking Republican on the Energy & Commerce Committee and an important political contact for the agency on Capitol Hill. Barton was the only legislator to attend the bill signing for the FDA Amendments Act in 2007.

A report by the committee's minority staff, released in February, lists cases where clinical investigators were determined to have committed fraud, but were not disqualified under FDA's administrative authority. Barton and fellow Republican John Shimkus followed by asking the Government Accountability Office to assess FDA's process for investigating clinical trial fraud and use of the disqualification process.

FDA enforcement officials agree with Barton on one point: the administrative process to punish investigators is too unwieldy.

The agency is working on "streamlining" the process involved in disqualifying clinical investigators when FDA uncovers fraudulent or violative practices, Autor said. She acknowledged that the process can be "Byzantine" and slow-moving—a fact that works to the benefit of investigators facing potential disqualification.

"The agency is working to clean up those procedures," she told the audience, adding the wry observation that "I'm not so sure this is good from your standpoint."

"The regs, as everybody knows, are outdated and don't really fit the way trials are done today," she said. "Hopefully, over time you will see that changing so that clinical trials will really be subject to appropriate regulation for how they are conducted today." The goal will be "putting the onus on sponsors and monitors to ensure quality in clinical trials."

That may sound like yet another regulatory burden on drug development (and it is), but if the alternative is a series of enforcement actions that knock out individual trial sites from multiple applications, this may be a case where industry has a lot to gain from moving to a new regulatory model.

Michael McCaughan is Senior Editor of The RPM Report. McCaughan speaks frequently on regulatory and policy developments affecting the industry, and especially on the impact of the Medicare Modernization Act. McCaughan previously spent 15 years on the staff of "The Pink Sheet," including 10 years as Editor-In-Chief. McCaughan is a summa cum laude graduate of Yale University.

This article is reprinted courtesy of The RPM Report , a Windhover Information publication. For additional related reading, visit http://therpmreport.com/EMS_Base/Agent.aspx?Page=/Content/2008500037.aspx&utm_Source=GxP. The RPM Report is a unique, actionable information resource for biopharmaceutical executives on FDA, CMS and public sector issues.

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available resources.

FDA Link:
Patient Misuse and Investigator Fraud in Clinical Trials: What Can Be Done?
http://www.fda.gov/CDER/present/dia-62000/woolen1/index.htm

Additional Article:
GxP Lifeline: "Top Reason for FDA-483 Citations Among Drug Companies"