The U.S. Food and Drug Administration (FDA) is responsible for overseeing the investigators who conduct clinical research of products that are regulated by the FDA, including drugs, biologics, devices, new animal drugs, foods that bear a nutrient content claim or health claim (including dietary supplements), food and color additives, and tobacco products (collectively known as “FDA-regulated products”). In September 2009, at the behest of certain members of Congress, the U.S. Government Accountability Office (GAO) published a report regarding FDA’s oversight of investigators conducting research of three types of FDA-regulated products: new drugs, biologics, and medical devices. The report, entitled Oversight of Clinical Investigators: Action Needed to Improve Timeliness and Enhance Scope of FDA’s Debarment and Disqualification Processes for Medical Product Investigators,1found that FDA’s disqualification regulations contain a loophole that allows an investigator who has been disqualified from conducting research related to drugs or biologics to continue conducting research related to medical devices, and vice versa. The report further pointed out that an investigator who has been disqualified from researching any of those three categories of products remains eligible to serve as an investigator for any of the remaining types of FDA-regulated products. The report recommended that FDA revise its regulations to prevent a disqualified investigator from participating in clinical investigations of any medical product.

Prior to publication, GAO provided a copy of its report to the Department of Health and Human Services for review. In response, the department submitted written comments from FDA, agreeing with the report’s recommendations. In April 2011, FDA published a Proposed Rule based in part on the GAO’s recommendations. The Proposed Rule would amend the regulations governing clinical investigator disqualification contained in 21 C.F.R. �� 312.70, 511.1(c), and 812.119 (together, “the Disqualification Regulations”) in several ways.

Current Disqualification Procedures

As part of its oversight of the clinical investigation of FDA-regulated products, FDA inspects clinical investigators to ensure that research is conducted in accordance with applicable rules and regulations. One of the goals of these inspections is to determine whether the investigator has engaged in behavior that would warrant the investigator’s disqualification from receiving test articles involved in clinical research. Under the Disqualification Regulations, FDA may consider disqualification of an investigator if it has information that the investigator has (a) repeatedly or deliberately failed to comply with FDA regulations, or (b) repeatedly or deliberately submitted false information to FDA or a clinical trial sponsor in a required report (“Investigator Misconduct”). A multi-step process is in place for disqualifying an investigator.

First, if an FDA inspection uncovers potential Investigator Misconduct, FDA staff will evaluate the information gathered during the inspection, obtain additional information as needed, and determine whether the circumstances warrant a disqualification proceeding. If so, the staff – with input from FDA’s Office of the Chief Counsel – draft a Notice of Initiation of Disqualification Proceedings and Opportunity to Explain (“NIDPOE”) letter and send it to the investigator. The letter initiates from the FDA Center responsible for overseeing the particular type of FDA-regulated product being researched (known as “the applicable Center,” this covers the Center for Drug Evaluation and Research for drugs, the Center for Biologics Evaluation and Research for biologics, the Center for Veterinary Medicine for new animal drugs, and the Center for Devices and Radiological Health for devices).

The NIDPOE letter outlines the allegations of Investigator Misconduct and provides the investigator a deadline by which to respond to the allegations, either in writing or during an informal meeting with FDA officials. Such explanations are evaluated by the applicable Center and its legal counsel. If the explanation is deemed satisfactory, the disqualification process ends and the investigator is not disqualified. But if the applicable Center rejects the investigator’s explanation, or if the investigator fails to respond to the NIDPOE letter in a timely manner, FDA then issues a Notice of Opportunity for Hearing (NOOH) letter. The NOOH letter contains the allegations of Investigator Misconduct from the NIDPOE letter for which a satisfactory explanation has not been given. Upon receipt of the NOOH letter, the investigator has 10 business days to request a Part 16 regulatory hearing regarding the proposed disqualification. Along with the request, the investigator must submit evidence of a genuine and substantial issue of fact that warrants a hearing. If the hearing is requested and granted, the presiding officer issues a report to the Commissioner of Food and Drugs, who then makes a decision on disqualification. If a request for hearing is denied, or if the investigator does not request a hearing, the Commissioner decides the issue of disqualification based on FDA’s investigation of the misconduct. During this process, both the Commissioner and the presiding officer are assisted by FDA counsel that are not affiliated with the applicable Center.

Alternatively, rather than offering an explanation of the Investigator Misconduct alleged in the NIDPOE letter, the investigator may attempt to negotiate a consent agreement with FDA. Consent agreements can and sometimes do extend disqualification beyond the product category for which there was alleged Investigator Misconduct. The ability to enter a consent agreement ceases upon a decision by the Commissioner regarding disqualification.

The Commissioner’s decision whether to disqualify an investigator is governed by three sets of regulations: those for drugs and biologics (� 312.70), new animal drug products (� 511.1(c)), and medical devices (� 912.119). An investigator who is disqualified under one of these sets of regulations is no longer eligible to receive the type of product for which there was a violation, but under current regulations, his ability to receive other types is unrestricted. That is to say, while an investigator who has been disqualified under � 312.70 is no longer eligible to receive drugs and biologics, under the regulations as currently written, the investigator can still receive new animal drugs and medical devices. In addition, an investigator who has been disqualified under any of the three sets of regulations remains eligible to receive all other types of FDA-regulated products, such as food and color additives.

Expanding the Scope of Disqualification

The principal changes sought by the Proposed Rule are threefold. First, the Proposed Rule would expand the scope of investigator disqualification to provide that, when an investigator has been disqualified by the Commissioner from receiving a drug or biologic under � 312.70, a new animal drug product under � 511.1(c), or a medical device under � 912.119, that investigator would no longer be eligible to receive any of these types of products. In addition, the disqualified investigator would become ineligible to conduct any clinical investigation in support of an application for a research or marketing permit for any FDA-regulated product.

Second, reflecting the above change, the Proposed Rule would expand the scope of a Part 16 hearing on the issue of disqualification. The hearing would not only address whether the investigator should remain eligible to receive the specific type of product for which there was Investigator Misconduct, but would also consider whether the investigator should be eligible to conduct clinical research of any FDA-regulated products.

And third, the Proposed Rule would amend �� 312.70(b), 511.1(c)(2), and 812.119(b) to explicitly require FDA to notify the study sponsor when an investigator has been disqualified.
The notice would state the basis for the disqualification and include instructions for ongoing studies as well as for any products whose approval was based in any way on the disqualified investigator’s data. According to FDA, this amendment reflects procedures that the agency already employs.

FDA offers as justification for the Proposed Rule the dual purposes of protecting research subjects involved in clinical research and ensuring the quality and integrity of data submitted to FDA. According to the FDA, the Proposed Rule would achieve these purposes by preventing a clinical investigator who has engaged in Investigator Misconduct from tainting clinical research of any FDA-regulated product. FDA acknowledges, however, that it found little to no evidence that an investigator who has been disqualified from receiving one type of investigational product has gone on to conduct a clinical study of a different type of product. In further support of the Proposed Rule, FDA points to GAO’s observation that a disqualification by consent agreement can be broader than the Commissioner’s own determination of disqualification as governed by the current Disqualification Regulations, a result that FDA deems nonsensical.

Other Proposed Changes

In addition to expanding the scope of investigator disqualification, the Proposed Rule seeks several other changes to FDA regulations, such as harmonizing the language found in the Disqualification Regulations (e.g., in �� 312.70(a) and 511.1(c)(1), adding the phrase “repeatedly or deliberately” before “submitted to FDA or to the sponsor false information

in any required report,” to make these sections consistentwith the language of � 812.119(a)) and implementing grammatical changes.

The changes to FDA regulations set forth in the Proposed Rule are only briefly summarized above and those conducting clinical trials or interacting with investigators conducting such research should consider them fully. To review the changes in more detail, a copy of the Proposed Rule can be obtained from FDA’s website (www.fda.gov). The Proposed Rule is open for comment through July 12, 2011.

Reference

1 Available at http://www.gao.gov/new.items/d09807.pdf(accessed on April 19, 2011).

Colleen Heisey (cheisey@hunton.com) is a partner in the Washington, D.C. office of Hunton & Williams LLP in the Firm’s Food and Drug Practice.Ms. Sharon Mills is an associate in the Firm’s Food and Drug Practice.