Research, Investigator Conduct Under Scrutiny

Congressional leaders are calling for stronger rules and more effective enforcement of clinical research, putting pressure on the Food and Drug Administration to stiffen its enforcement policy. "It may be time to seriously rethink the regulatory framework for the clinical trial industry and Institutional Review Boards and Contract Research Organizations," stated Rep. Bart Stupak (D-MI), chairman of the Subcommittee on Oversight and Investigations of the House Energy and Commerce, at a February 2008 hearing.

Jill Wechsler

At issue is why FDA officials failed to take action against the sponsor and other parties involved in clinical trials supporting approval of the antibiotic Ketek (telithromycin). Evidence of investigator fraud has generated questions about the adequacy of oversight by the CRO and IRB involved, whether the sponsor Aventis (now Sanofi-Aventis) withheld damaging information from FDA, and whether agency officials knew about these problems when they evaluated the drug.

Stupak and Energy and Commerce chairman John Dingell (D-MI) are urging FDA and the Justice Department to further investigate possible fraud by Aventis and other parties. The Congressmen have suggested, moreover, that FDA Commissioner Andrew von Eschenbach misled them in testimony last March (2007) about what FDA knew regarding "data irregularities" when it approved Ketek in 2004. House and Senate leaders have been furious at FDA for refusing to hand over all the documents on the case and for preventing agency investigators from testifying before Congress.

Cracking down

The Ketek case points out the importance of effective research monitoring and oversight by sponsors to ensure the integrity of research data submitted to FDA. Due to limited resources supporting its Bioresearch Monitoring (BIMO) program, the agency usually inspects only a few key sites to check whether investigators followed the rules in conducting an important clinical trial. FDA relies largely on sponsors to monitor that investigators follow good clinical practices (GCPs) and other rules while trials are going on, which is important in protecting the rights and safety of research subjects as well as for ensuring data validity.

Continued Congressional focus on research lapses related to Ketek, though, is encouraging a more activist FDA role in clinical trial oversight. At a February conference on FDA enforcement sponsored by the Food and Drug Law Institute (FDLI), Deborah Autor, director of the Office of Compliance in the Center for Drug Evaluation and Research (CDER), noted that Congress' concerns about clinical research has made this "an area of emphasis for us as well." Autor cited more warning letters to pharmaceutical companies that call for systematic changes in clinical trial monitoring and oversight. FDA is investigating data integrity concerns related to Theravance's antibiotic telavancin and cancelled an advisory committee meeting pending further site inspection.

With more funding, FDA's BIMO program could be more active, Autor observed. CDER's Division of Scientific Investigations (DSI) moved back into her compliance office two years ago, where it is poised to become more involved in compliance. FDA also hopes to revise many clinical research regulations, which Autor considers "very outdated." The agency issued draft guidance last year clarifying how principal investigators should ensure that research site staff follow GCPs and other rules. Another draft guidance aims to clarify responsibilities of sponsors, IRBs, and investigators in reporting adverse events. FDA's BIMO council is working to streamline and coordinate these and other research policies across all Centers.

More disqualifications

One area of focus is FDA's cumbersome process for disqualifying clinical investigators who violate GCPs repeatedly or commit fraud. Rep. Joe Barton (R-TX), top Republican on the E&C Committee, released a report in February criticizing FDA for not using its authority to exclude convicted individuals or firms from involvement in the drug regulatory process. Under current law, FDA can debar law breaking entities from participating in generic drug development and production, and it can disqualify investigators from conducting trials.

Unfortunately, "it takes absolutely forever" to disqualify an investigator, commented attorney Phil Katz of Hogan & Hartson at the FDLI conference. The agency's Byzantine rules require formal notification and a lengthy hearing, review, and appeals process. FDA issued a guidance several years ago to clarify that it can impose a clinical hold on a study where an investigator fails to meet GCPs or submits fraudulent data—which reflects how clinical holds can more effectively halt unethical behavior and better protect patients than can the disqualification process.

As a result, FDA has not implemented disqualification procedures that often, but, Katz said, "that may be changing." Autor reported that FDA wants to streamline the process for disqualifying violative investigators and is working to "clean up those procedures."

More monitoring

The Ketek case may spur such action. Most evidence of fraud and misconduct for this drug involves a huge multisite safety study launched by Aventis in 2001 to address FDA concerns about liver toxicity and other safety signals from clinical trials. This "usual care" trial (study 3014) enrolled 24,000 patients at 1800 sites in three months, but was rife with problems ranging from "deviations" and sloppy record keeping to data fabrication and fraud. Congressional critics say FDA and Aventis ignored or covered up the trouble signs and want the Justice Department to pursue an investigation.

A rural Alabama site under Dr. Anne Kirkman-Campbell stood out for its high enrollment and poor records. Ann Marie Cisneros, a former staffer with PPD Inc., the CRO hired by Aventis to oversee the study, told the E&C committee in February that there were a host of "red flags" signaling trouble when she visited the site in 2002. The investigator/physician had enrolled 400 subjects (at $400 a head), compared to a dozen at another local site. There were discrepancies in informed consent forms, under-reporting of adverse events, no patient withdrawals, and no patients lost to follow-up. A lack of variability in blood samples suggested sample "splitting" among study subjects.

Cisneros says she reported these findings to PPD and to the Copernicus Independent Review Board, the IRB of record for the study, but nothing happened. Copernicus Chairman Sharon Price claimed she never received Cisneros' message. Aventis acknowledges troubling reports from PPD, but claims that the violations did not constitute fraud—an important distinction because knowingly filing false data with FDA can be a criminal offense.

FDA field investigators uncovered enough problems for its Office of Criminal Investigations (OCI) to investigate. Kirkman-Campbell went to jail for fraud in late 2003, but OCI special agent Robert West told the House committee that he was unable to expand the fraud investigation to other sites or to Aventis.

When FDA finally approved Ketek in April 2004, it decided not to rely on the tarnished data from study 3014, partly because there was ample clinical trial evidence plus safety data from some 3.7 million patients in other countries where the drug already was approved. Over the next two years, though, reports of serious liver toxicity prompted FDA to reconsider Ketek's labeling, resulting in stronger warnings and narrower indications for the product.

Was FDA justified in approving Ketek for market based on noninferiority studies documenting efficacy (which FDA accepted at that time) in the face of serious safety signals and questionable data from a major study? Although some critics say the drug has harmed thousands, FDA and public health officials point to the desperate need for more new antibiotics as drug-resistant infections multiply.

But the evaluation of even a potentially important medication should be based on accurate information. At the February hearing, FDA agent Douglas Loveland challenged Aventis' claims that study 3014's problems reflected sloppy record keeping and not research fraud. Either way, "we want reliable data at FDA," he said. "Whether it's fraudulent or sloppy, it's not reliable."

Sanofi has made changes in its research program to prevent such abuses from occurring in future trials, Paul Chew, Sanofi-Aventis R&D president, told the E&C panel. The company now has stronger training for research personnel, stricter site enrollment limits, and more oversight. There also is a plan to validate investigator qualifications prior to study enrollment. While these policies are fine, they might have saved the company a lot of trouble if they had been established five years ago. And they may not be enough to head off further investigation by Congress and law enforcement agencies.

The Ketek case also increases the pressure on FDA to demonstrate that it can police the research community and that it is not trying to protect pharmaceutical companies that bend the rules. This investigation, stated Chairman Dingell, "raises questions about the very integrity of the drug approval process." In the current climate, questionable research activities may keep even a potentially beneficial drug off the market.

Jill Wechsler is the Washington editor of Applied Clinical Trials, (301) 656-4634 jwechsler@advanstar.com