FDA Steps Up Efforts to Find, Remove Violators of Clinical Trial Regulations

Researchers who flout regulations for the conduct of clinical trials or who commit crimes related to clinical research may face swifter repercussions as the US Food and Drug Administration (FDA) intensifies its efforts to identify and remove violators from the drug and device development process.

Since the 1960s, the FDA has had the authority to disqualify or remove from FDA-regulated trials any clinical investigators who have “repeatedly or deliberately” ignored regulations designed to protect human research participants or who have repeatedly or deliberately submitted false information to the agency or the sponsor of their research. But this process often took years to complete.

In 1992, Congress granted the FDA the additional authority to bar researchers who have been convicted of felonies related to drug development from working in the pharmaceutical industry. It also authorized the agency to bar generic drug companies convicted of felonies from submitting drug applications to the FDA. The legislation followed a scandal in which some generic drug companies had bribed FDA staffers or manipulated the data in their abbreviated drug applications. Yet a 2008 report by minority members of the Committee on Energy and Commerce found that the agency had never debarred a company and had inconsistently debarred clinical investigators convicted of wrongdoing and also that the agency might take years to carry out such actions.

Over the past 2 years, however, the FDA has begun to make changes designed to speed up both processes.

Changes to the disqualification procedures began in late 2007, said Joanne Less, PhD, director of the FDA's Office of Good Clinical Practice. Among them are a new guide for staff, which sets an 18-month target for completing a disqualification procedure. The agency reorganized some units and hired more employees, including a full-time project manager who oversees the completion of disqualification procedures once the clinical investigator is offered the opportunity for a hearing, Less said. To improve consistency and timeliness, an administrative law judge (rather than FDA medical officers) generally presides over disqualification hearings.

“The goal in doing this is to protect human subjects involved in FDA-regulated trials and help ensure the quality and integrity of the data that we rely on in our decision-making process,” Less said.

Since the changes began, agency staff have completed 10 backlogged cases and only have 1 left to go, Less said. They have also initiated 11 new cases since 2008 and completed 8 of these. That tally, accomplished in less than 2 years, contrasts strongly with past performance. In the program's 50-plus years, the FDA says 190 investigators have been disqualified, or about 4 per year on average.

Common violations resulting in disqualification are conducting a study without obtaining informed consent or approval from an institutional review board (IRB), failure to report adverse events that pose a threat to patient safety, and falsifying data, Less said. When the FDA initiates the disqualification process, the investigator, the sponsor, and the IRB overseeing the trial are notified, Less said. The IRB may then notify the researcher's institution. The agency also posts the information online so that other sponsors, academic institutions, journal editors, or other interested parties can access it (http://www.fda.gov/ICECI/EnforcementActions/DisqualifiedRestrictedAssuranceList/default.htm).

Changes to the debarment procedures began in March 2009, said Matthew Warren, JD, regulatory counsel in the Office of the FDA Commissioner. He explained that previously debarment actions had been carried out by staff in each of the FDA's centers, but now those actions are all handled by the Office of Enforcement. That office has a temporary staff member working on the cases full time and plans to hire a permanent staff member for this position. Two other employees in the office are also working on these cases as part of their duties.

The US Food and Drug Administration (FDA) and its European counterpart, the European Medicines Agency (EMEA), have recently launched a pilot program to better harmonize their respective oversight of clinical trials of experimental drugs.

The agencies, which have previously collaborated on oversight of good manufacturing practices, have decided to boost cooperative efforts to enforce good clinical practices in clinical trials sponsored by companies seeking approval from each agency to market their drugs within their respective jurisdictions, said Leslie Ball, MD, director of the division of scientific investigation in the FDA's Center for Drug Evaluation and Research. Ball said the initiative, which was launched September 1, will include a pilot trial of joint FDA-EMEA inspections of clinical trial sites, greater sharing about findings from separate inspections, and efforts to more proactively share information about what each agency considers to be good clinical practices.

“The development of new drugs has become a global enterprise, and increasingly, clinical trials are being conducted by clinical investigators who are scattered throughout the globe,” said Ball.

Ball explained that greater collaboration between the agencies would allow each to use its limited inspection resources more efficiently. Also, joint inspections may lessen the regulatory burden of sponsors by reducing the disruption caused by separate inspections, something sponsors had complained to both agencies about. She said that a few sponsors who have submitted applications separately to the FDA and EMEA to market their drug have volunteered for the pilot and that the agencies would select those applications that were most appropriate for joint inspection.

To facilitate harmonization, the 2 agencies are stepping up their efforts to share information about their good clinical practice inspections and requirements. Ball explained that the FDA and EMEA have shared such information in the past under an existing confidentiality agreement but were devising more secure, more efficient, and more effective avenues for information sharing. These include adopting a standardized format for data, scheduling regular telephone conferences between FDA and EMEA staff, and having staff from each agency attend training hosted by the other.

The FDA has also had talks with other international regulatory agencies that are interested in similar collaboration, Ball said.

In addition to reducing the regulatory burden of inspections, Ball said “we hope the initiative will make it easier to conduct high-quality research by improving [investigators’] understanding of what the FDA and EMEA expect in clinical trials and minimizing differences in the interpretation of good clinical practice regulations.”—B.K.

The Office of Enforcement is working with the Department of Justice and the FDA's Department of Criminal Investigations to identify all relevant convictions that have occurred in the past 5 years (the statute of limitations on debarments) and will pursue debarment in appropriate cases, Warren said. Moving forward, the new procedures call on FDA staff to notify the Office of Enforcement of convictions related to drug products, and to set a target of completing debarments within a year of the date of conviction of a company or individual by a federal or state court, Warren said.

“Our goal is to remove bad actors from the drug approval process as soon as possible,” Warren said.

The FDA has debarred 75 individuals to date, but over the past decade the pace of debarments had slowed to 2 or 3 per year on average, according to the agency. Since October 2008, the agency has debarred 2 individuals and has initiated 14 additional actions.

Some examples of recent convictions that have led the FDA to pursue debarment include a case in which an investigator falsified laboratory data for a patient who would not have qualified for enrollment and who subsequently died as a result, and an investigator who created a fake medical license. A list of individuals who have been debarred is available online at http://www.fda.gov/ICECI/EnforcementActions/FDADebarmentList/ucm2005408.htm.

The FDA's effort to speed enforcement was well received by some experts. But those same experts called for greater efforts to ensure high-quality research and to eliminate malfeasance.

Alistair Wood, MB, ChB, managing director of Symphony Capital and an emeritus professor of medicine at Vanderbilt University, said it is appropriate for the agency to quickly remove such individuals from the process to ensure the integrity of the research enterprise, but that flagrant misconduct is relatively rare. Wood said he would also like to see more effort, perhaps by the National Institutes of Health (NIH), expended on ensuring that clinical investigators are adequately trained and have the tools and skill sets necessary to produce high-quality data.

“We don't have a great infrastructure for training clinical investigators; that's part of the problem,” he said. “The better trained researchers are, the less likely we will run into problems,” he said.

Curt D. Furberg, MD, PhD, professor of public health science at Wake Forest University in Winston-Salem, NC, strongly supported the FDA's effort to speed these disciplinary processes and to make information about the proceedings publicly available. But he cautioned that putting the information online may not be enough.

“It's only useful if it's being looked at,” he said.

Given the serious nature of the infractions that lead to disqualification and debarment, Furberg said that such researchers should face greater consequences than just being barred from FDA-related studies. He said it is likely that an IRB would notify the investigator's supervisors, and emphasized how important such notification is. He noted that a medical school's dean may wish to dismiss a faculty member who, for example, has falsified data. Additionally, he said dishonest researchers should be barred from receiving NIH funding for at least some period. He suggested that the FDA coordinate efforts with the Department of Health and Human Services' Office of Research Integrity, which bars researchers who have committed misconduct from receiving support from any organization within the public health service, which includes the NIH, the US Centers for Disease Control and Prevention, and the Agency for Healthcare Research and Quality.

“It goes beyond the FDA in my mind,” Furberg said.