Effective May 30, 2012, a clinical investigator deemed ineligible to receive one type of test article (e.g., drug, device or new animal drug) due to repeated or deliberate violations of the U.S. Food and Drug Administration’s (FDA) clinical research regulations will now be ineligible to conduct a clinical research investigation that supports an application for a research or marketing permit for other kinds of products regulated by the FDA.  In this newsletter, we provide a brief summary of the final rule that implements this change, the FDA’s discussion of the evidentiary criteria it applies and the collateral effect of disqualification, and we describe some of the implications.

To disqualify a clinical investigator, the U.S. Food and Drug Administration (FDA) Commissioner must determine, through an administrative proceeding, that the investigator “repeatedly or deliberately” failed to comply with the FDA’s clinical trial regulations or submitted false information to the FDA or the sponsor in a required report.  Currently, investigators that have been disqualified from conducting clinical investigations with respect to one type of test article (e.g., human drugs) remain eligible to conduct clinical investigations with other types of test articles (e.g., devices, biologics, animal drugs).

Effective May 30, 2012, however, a clinical investigator that is disqualified from conducting clinical investigations under Part 312 (Investigational New Drugs, or INDs), Part 511 (New Animal Drugs for Investigational Use) or Part 812 (Investigational Device Exemptions, or IDEs) will be ineligible to conduct a clinical investigation that supports an application for a research or marketing permit for “products regulated by FDA, including drugs, biologics, devices, new animal drugs, foods, including dietary supplements, that bear a nutrient content claim or a health claim, infant formulas, food and color additives, and tobacco products,” regardless of whether or not the violations occurred in investigations with just one type of product.  This significant expansion to the scope of clinical investigator disqualification is intended to “protect the rights and safety of subjects involved in FDA-regulated investigations, and to ensure the reliability and integrity of the data used to support marketing of products regulated by the FDA.”

While the expansion of the scope of a disqualification had been under consideration by the FDA for many years, the FDA’s responses to comments on the proposed rule provided by stakeholders includes highly valuable and rarely viewed information on the criteria and evidentiary thresholds used by the FDA in its disqualification proceedings.  Because of the effect a disqualification has on the investigator and on clinical trial data, this information is significant to all participants in the clinical trial process.

Thus, in the final rule the FDA provides important information on several aspects related to clinical investigator disqualifications, including:

• Definition of the term “repeatedly.”  According to the FDA, a violation occurs “repeatedly” if it happens more than once (i.e., more than once in a single study or one time in each of two studies).  For example, the FDA suggests that even enrolling two subjects who were ineligible due to concomitant illnesses in a single study could lead the FDA to institute disqualification proceedings. 
• Definition of the term “deliberately.” A violation is considered “deliberate” if it is “willful” or demonstrates reckless disregard for the relevant regulatory requirements; according to the FDA, meeting this standard does not necessarily require a showing of subjective intent on the part of the investigator.  That is, the investigator need not have specific knowledge that the conduct in question violates the law.  Therefore, even if an investigator did not intend for the violations to occur, conduct demonstrating a “reckless disregard” for the relevant regulatory requirements may trigger disqualification proceedings.  The FDA argues that this lower burden of proof is appropriate because the disqualification analysis should focus on prevention of risk rather than “imposing punishment on culpable conduct.”  
• Extent to which FDA will investigate a disqualified investigator’s data.  The FDA explains that it does not place limits on how far back it can or will go to find applications and submissions by other sponsors that may be affected by a disqualified investigator that conducted trials with FDA-regulated articles.  As such, each application or submission that contains data from a disqualified investigator—including applications that have already been approved—is subject to examination to determine whether the investigator submitted unreliable data “essential to” the approval of marketing application or “essential to” the continued marketing of the product.  While the FDA notes that often there may be sufficient data from other sources to support the continued approval of a product, the FDA nonetheless states that it may look beyond the current application.

Implications

The FDA’s expansion of the scope of investigator disqualification to other regulated articles is consistent with the agency’s enhanced enforcement posture, and similar to that in other contexts, such as exclusion by the U.S. Department of Health & Human Services’ Office of Inspector General.  While the FDA has previously set forth its positions on the evidentiary criteria for disqualification in Commissioner decisions, sponsors and clinical investigators may find the regulatory interpretations far more accessible now that they have been published in the Federal Register in connection with the expansion of the scope of disqualification. 

Given this enforcement trend and the wider availability of this information, sponsors and clinical investigators should take careful note of the agency’s interpretation of the disqualification criteria to ensure an understanding of the type (or amount) of activity that may trigger disqualification proceedings, and the potential consequences of such a determination.     

Because most disqualification actions by the FDA end up with consent agreements between the agency and the investigator, the evidentiary standard of proof set forth by the FDA for disqualification remains largely untested.  Therefore, in view of the expanded scope of disqualification and the effect it may have on other marketing applications, it will also be important for sponsors, clinical investigators, contract research organizations and others involved in clinical research to scrutinize FDA disqualification proceedings to ensure they comport with due process and are reserved for the most serious and persistent violations.  Such scrutiny becomes more important in view of the many years it takes for a disqualification charge to be fully adjudicated. 

Clients and stakeholders who wish to consider the implications of the FDA’s final rule in more detail, and how best to ensure compliance with the FDA’s clinical research regulations, may contact one of the authors.