FDA Revised Guidance on Oversight of Clinical Investigators’ Financial Information Request for Comment

In 1999, the Food and Drug Administration (FDA) began collecting financial disclosure information of clinical investigators.  In 2001, FDA issued a Guidance for Industry: Financial Disclosure by Clinical Investigators. 

FDA recently provided a revised guidance that addresses issues raised by the Office of the Inspector General (OIG), Department of Health and Human Services, in its report, The Food and Drug Administration’s Oversight of Clinical Investigators’ Financial Information.  This guidance is intended to assist clinical investigators, industry, and FDA staff in interpreting and complying with the regulations governing financial disclosure by clinical investigators.

Background

The Financial Disclosure by Clinical Investigators regulation (21 CFR part 54) requires applicants who submit a marketing application for a drug, biological product or device to submit certain information concerning the compensation to, and financial interests and arrangements of, any clinical investigator conducting clinical studies covered by the regulation.

The regulation applies to any clinical study of a drug (including a biological product) or device submitted in a marketing application that the applicant or FDA relies on to establish that the product is effective, including studies that show equivalence to an effective product.

The regulation also applies to studies submitted in a supplement when those studies meet the definition of a covered clinical study. The definition includes studies to support safety labeling changes where individual investigators make a significant contribution to the demonstration safety information. Studies to support the effectiveness of a new claimed indication are also included.

Actual use studies performed to support supplements requesting that FDA approve a switch of a prescription drug to OTC status or who file a new drug application for OTC are considered covered clinical studies if they are used to demonstrate effectiveness in the OTC setting or if they represent a safety study where any investigator makes a significant contribution. Labeling comprehension studies would not be considered covered studies.

The applicant has the same financial disclosure obligations with respect to studies conducted at foreign and domestic sites. In addition, large multi-center efficacy studies with many investigators are considered covered clinical studies within the meaning of the regulation.

Requirements

Under the applicable regulations, an applicant is required to submit to FDA a list of all clinical investigators who conducted covered clinical studies and to identify those who are full-time or part-time employees of the sponsor of each covered study.  For each clinical investigator who was not a full time or part time employee of a sponsor of the clinical study, the applicant must provide the sponsor of the clinical trial either a certification, that no financial interests or arrangements exists, or completely and accurately disclose the nature of those financial interests and arrangements to the agency and describe any steps taken to minimize the potential for bias resulting from those interests and arrangements.  Clinical investigators must update this information if any relevant changes occur during the study and for one year following its completion.

A sponsor is required to obtain clinical investigator financial information before allowing the clinical investigator to participate in a covered clinical study.

If the applicant acts with “due diligence” to obtain the required information but is unable to do so, the applicant may certify that it acted with due diligence but was unable to obtain the information and include the reason the information could not be obtained.  If the applicant does not include certification and/or disclosure, or does not certify that it was unable to obtain the information despite exercising due diligence, the agency may refuse to file the application.

Disclosable Financial Interests and Arrangements

The disclosable financial interests and arrangements are:

• Compensation made to the investigator by any sponsor of the covered clinical study in which the value of compensation could be affected by study outcome.
• A proprietary interest in the tested product including, but not limited to, a patent, trademark, copyright or licensing agreement.
• Any equity interest in any sponsor of the covered clinical study, i.e., any ownership interest, stock options, or other financial interest whose value cannot be readily determined through reference to public prices. This applies to interests held during the time the clinical investigator is carrying out the study and for one year following completion of the study.
• Any equity interest in any sponsor of the covered study if the sponsor is a publicly held company and the interest exceeds $50,000 in value. This applies to interests held during the time the clinical investigator is carrying out the study and for one year following completion of the study.
• Significant payments of other sorts (SPOOS), which are payments that have a cumulative monetary value of $25,000 or more made by any sponsor of a covered study to the investigator or the investigator’s institution, during the time the clinical investigator is carrying out the study and for one year following completion of the study, to support activities of the investigator exclusive of the costs of conducting the clinical study or other clinical studies (e.g., a grant to the investigator or to the institution to fund the investigator’s ongoing research or compensation in the form of equipment), or to provide other reimbursements such as retainers for ongoing consultation or honoraria.

A marketing application must contain a list of all clinical investigators who conducted each covered clinical study, which may include subinvestigators. This list must also identify those clinical investigators who are full or part-time employees of the sponsor of the covered study. The term clinical investigator includes the spouse and each dependent child of a clinical investigator. If a spouse or dependent child is an employee of a sponsor, that clinical investigator should be identified as an employee for purposes of financial disclosure.

In describing financial interests, for example, the applicant might list: stock valued at $77,000, speaking fees of $7500, consulting fees of $22,000, and a grant of $125,000 and include a discussion of the specific steps taken to minimize potential bias.

Generally, reasonable payments made to investigators to cover reimbursable expenses such as transportation, lodgings and meals do not fall within the purview of significant payments of other sorts (SPOOS) and, therefore, would not need to be tracked, whereas entertainment costs would be tracked as SPOOS. Travel costs associated with transporting and/or providing lodgings and meals for family members of investigators should be tracked as SPOOS.

In addition, other payments that exceed reasonable expectations, (for example, if an investigator was flown to a resort location for an extra week of vacation) are considered outside of normal reimbursable expenditures and are not considered expenses that are necessary to conduct the study. Therefore, these types of expenses are also reportable and should be tracked as SPOOS.

If the study sponsor changes during the course of the study, the clinical investigators will need to update their financial disclosure information relevant to the new sponsor. The new sponsor is responsible for collecting this information, and to ensure that the new sponsor has complete financial disclosure information, the new sponsor should seek this information from the original sponsor, and the agency encourages the original sponsor to share their records with the new sponsor.

Agency Actions

FDA may refuse to file a marketing application that does not contain the financial information required by or a certification by the applicant that the applicant has acted with due diligence to obtain the information but was unable to do so stating a sufficient reason.  If FDA determines that the financial interests or arrangements of any clinical investigator raise a serious question about the integrity of the data, FDA will take any action it deems necessary to ensure the reliability of the data including:

• Initiating agency audits of the data derived from the clinical investigator in question;
• Requesting the applicant submit further analyses of data, e.g., to evaluate the effect of the clinical investigator’s data on the overall study outcome;
• Requesting that the applicant conduct additional independent studies to confirm the results of the questioned study; and
• Refusing to treat the covered clinical study as providing data that can be the basis for an agency action.

FDA Review

Clinical investigator financial disclosure information and the steps sponsors have taken to minimize potential bias of the clinical study results, helps FDA staff assess the reliability of the clinical data and “alerts them to financial interests and arrangements that could lead to bias in covered clinical studies.”  FDA will consider many factors in making its evaluation.

First, the type of financial interest or arrangement disclosed is important because some financial interests and arrangements are of greater concern than others. Second, FDA reviewers will consider whether multiple investigators were used (most of whom have no disclosable financial interests), the total number of investigators and subjects in the study, the number and percentage of subjects enrolled by the disclosing investigator, information obtained from on-site inspections, the design of the clinical study (double-blind, single-blind, placebo-controlled, active controlled), the method of randomization, the nature of primary and secondary endpoints (objective, subjective), the method of endpoint assessment, method of evaluation, whether someone other than the disclosing investigator measured the endpoints, and the results of the investigator compared to the results of other investigators in the study.

Reviewers might also compare results from more than one investigator, re-analyze the data excluding the investigator’s results, analyzing the data in multiple ways, and/or determining if results can be replicated over multiple studies.  Moreover, when there are disclosable financial interests or arrangements, the reviewer will address the question of whether these interests and arrangements raise questions about the integrity of the data and describe any actions taken to address the questions or provide an explanation for why no action was indicated.

Public Disclosure

FDA is currently developing its policy on transparency, which may affect what information, and in what manner, FDA may publicly disclose clinical investigators’ financial interests and arrangements.  The agency is considering various options for disclosure, such as including information on clinical investigator financial disclosure information in the documentation released upon product approval for marketing.

Request for Comment

The agency is seeking comments on this issue, including whether the information to be released should be a summary discussion of investigators’ financial disclosures/certifications, a listing of financial interests and arrangements with the clinical investigator’s name de-identified, or a listing by clinical investigator.

In the interval, the agency will carefully evaluate each circumstance on a case-by-case basis.

For more information contact: Leah Ripper in the Center for Drug Evaluation and Research, phone 301-796-1282, Sheila Brown in the Center for Devices and Radiological Health, phone 301-796-6563, and the Office of Communication, Outreach and Development in the Center for Biologics Evaluation and Research, phone 800-835-4709 or 301-827-1800.