In February 2013 the U.S. Food and Drug Administration (FDA) announced the finalization of “Guidance for Clinical Investigators, Industry, and FDA Staff [on] Financial Disclosures by Clinical Investigators.” The Federal Register notice describes the guidance document as intended to assist in interpreting and complying with regulations regarding financial disclosure by clinical investigators, including providing answers to frequently asked questions on the topic. 

The draft guidance document was initially released in May 2011. To address comments, FDA has clarified the terms “due diligence,” “covered clinical study,” and “material support;” identified who is a “dependent child;” and explained the review it undertakes of clinical investigator financial disclosure information. In addition, the guidance document considers and responds to a 2009 Office of Inspector General (OIG) Department of Health and Human Services report on “The Food and Drug Administration’s Oversight of Clinical Investigators’ Financial Information,” whose recommendations were intended to strengthen FDA oversight and review of these disclosures, including the sponsor’s responsibility to collect disclosure information prior to investigator parti-cipation and to ensure that all required materials are submitted. Significantly, FDA updates its policy regarding public release of individual clinical investigator financial disclosure information.

Financial Disclosure Obligations
Part 54 enumerates rules governing financial disclosure by clinical investigators, which is required from those submitting drug, biologic, or device marketing applications.  The applicant must provide, among other things, certain information regarding compensation to and financial interests and arrangements of any clinical investigator conducting clinical studies used to establish that a product is effective or that makes a significant contribution to the demonstration of safety. Applicant obligations include certifying as to the absence of certain financial interests or arrangements of investigators (i.e. those that could affect the reliability of the data), and FDA may refuse to file an application that does not contain such certification or a certification specifying the sponsor was unable to obtain the information despite exercising due diligence.

“Disclosable financial interests and arrangements” include:

1. Any compensation made by any sponsor to an investigator of the covered clinical study in which the value of compensation could be affected by study outcome;
2. A proprietary interest in the tested product including, but not limited to, a patent, trademark, copyright or licensing agreement;
3. 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 (applicable to interests held while the clinical investigator is involved and for one year following study completion);
4. 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 (applicable to interests held while the clinical investigator is involved and for one year following study completion); and
5. Significant payments of other sorts (SPOOS), which are payments having a cumulative monetary value of $25,000 or more and are made by any sponsor of a covered study to the investigator or the investigator’s institution while the clinical investigator is carrying out the study and for one year following study completion, including payments supporting investigator activities (excluding the costs of conducting the clinical study or other clinical studies) or to provide other reimbursements.

The amounts triggering reporting are the combined financial interests of the investigator, spouse, and dependent children.

If FDA determines an investigator’s financial interests or arrangements raise a serious question about data integrity, it will act to ensure the data’s reliability by one or more means, including initiating audits of the data derived from the clinical investigator in question; requesting submission of further data analyses; requesting additional independent studies to confirm the questioned study’s results; and/or refusing to treat the covered clinical study as one providing data that can form the basis for agency action.

Clarified Terms
In the final guidance document, FDA clarified the following terms to address comments received about the draft as well as OIG recommendations.

• Due Diligence: In describing what “due diligence” means, FDA introduces the term as “a measure of activity expected from a reasonable and prudent person under a particular circumstance, in this case, collecting information about financial interests or arrangements,” consistent with the draft terminology. However, in the final document, FDA further states it expects this information to be typically available “because investigators are required to provide financial disclosure information before participating in a clinical study.” The original language focused on the sponsor’s “responsib[ility] for obtaining financial disclosure information from clinical investigators prior to allowing them to participate in a clinical study.” Additionally, FDA removed language recommending minimum location efforts, replacing the specific number of telephone calls and certified letters with language that “[s]ponsors and applicants should exercise reasonable judgment regarding the appropriate amount of effort to expend when attempting to contact investigators, which may include consideration of the role of the investigator in the study and the importance of the investigator’s data contribution.” FDA suggests that more than one attempt be made and more than one method of contact be utilized.

In the event a clinical investigator cannot be located or the information not otherwise obtained, FDA reminds sponsors that they should have access to certain disclosable financial information by other means, such as payments made specifically to the investigator. Furthermore, FDA recommends that sponsors make efforts to obtain disclosable financial information from other reasonably available, reliable public sources of information (e.g., proprietary interest information from the Patent and Trademark Office). Another source of information to consider includes the investigator’s institution, which may have collected financial information and may be able release this information if asked.

• Covered Clinical Study: Consistent with the original release, the definition of “covered clinical study” follows Part 54: “any study of a drug or device in humans submitted in a marketing application or reclassification petition subject to this part that the applicant or FDA relies on to establish that the product is effective (including studies that show equivalence to an effective product) or any study in which a single investigator makes a significant contribution to the demonstration of safety. This would, in general, not include [Phase I] tolerance studies or pharmacokinetic studies, most clinical pharmacology studies (unless they are critical to an efficacy determination), large open safety studies conducted at multiple sites, treatment protocols and parallel track protocols.” FDA adopted additional language to elaborate on the definition, specifically listing clinical studies submitted to support new drug applications, abbreviated new drug applications, premarket notification submissions, reclassification petitions, premarket approval applications, and biologics licensing applications, as well as those supporting amendments or supplements to any such applications. Covered clinical studies would generally not include expanded access. “Expanded access protocols” were included in the original but omitted from the final definition.
• Material Support: For purposes of identifying a covered study’s sponsor(s), the final guidance document defines the term “material support,” which was not included in the draft. Parties supplying “material support” include those providing direct funding or other monetary support such as through a grant, or providing services or materials. However, if a party receives reimbursement for the services and/or materials provided, it would not generally be considered a sponsor.

Additional Changes
In addition to clarifying the terms above, FDA made several additions to or amendments of the “Questions and Answer” (Q&A) portion of the document. Notably:

• New Q&A B.2.: Stating an applicant, for purposes of Part 54 disclosure or certification, may not simply rely on investigator compliance with his institution’s policies or procedures, as this mechanism is not adequate for FDA to make its own determination of the investigator’s financial interests and arrangements.
• Revised Q&A B.6.: Regarding who, specifically, is responsible for signing financial certifications by clarifying “other responsible corporate official or representative,” recommending that such person be a senior official with authority to ensure the information is collected and reported accurately, acknowledging that depending on company structure, the individual could be the person in charge of regulatory or clinical affairs.
• New Q&A C.6.: Directing the threshold amount for reporting SPOOS is based on the cumulative amount received by the clinical investigator over the course of the study and for one year following its completion, rather than on an annualized basis.
• New Q&A D.5.: Explaining that a “dependent child” is the investigator’s child (whether by blood or adoption), stepchild or foster child who is unmarried, and for whom the investigator provides more than one-half of the child’s support, including a child who, at any time during the course of the study and for one year following completion of the study, is under the age of 19, under the age of 24 if a full-time student, or who is permanently and totally disabled.
• New Q&A G.3.: Explaining “any study in which a single investigator makes a significant contribution to the demonstration of safety” by example and including studies designed to address a particular safety concern. These studies could have a single or more than one investigator. If each investigator makes a significant study contribution and, therefore, to a demonstration of safety, such studies would be subject to financial disclosure. Studies generally not covered are large open safety studies, typically involving a large number of investigators, designed to look at adverse events ubiquitously rather than specific safety concerns.
• New Q&A G.4.: Specifying that a literature report could be considered a covered clinical study if it is being relied upon by the applicant or FDA to establish the product is effective or where a single investigator makes a significant contribution to the demonstration of safety.
• Revised Q&A H.3.: Elaborating what FDA reviewers will consider when evaluating financial disclosure information and acknowledging Part 54 does not categorically prohibit financial interests or arrangements. The guidance document indicates that when an investigator has disclosable interests or arrangements, the FDA reviewer will carefully consider the steps taken by the sponsor to minimize bias, including study design, use of multiple clinical investigators/study sites, and replication of study results, and will make a judgment as to whether the disclosed interests or arrangements may have affected the study results or otherwise warrant further action.
• Revised Q&A H.6.: Restating FDA intends to provide summary information regarding the number of investigators with disclosable financial interests or arrangements in new product reviews it posts, in the context of the total clinical investigators, but not to identify investigators by name. 

References

1. A copy of the final guidance document is available at: http://www.fda.gov/downloads/RegulatoryInformation/Guidances/UCM341008.pdf. The guidance document replaces the March 2001 “Guidance for Industry: Financial Disclosure by Clinical Investigators.”
2. 21 C.F.R. Part 54. 

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Colleen Heisey is a partner in the Washington, D.C. office of Hunton & Williams LLP (www.hunton.com) in the Firm’s Food and Drug Practice. She can be reached at cheisey@hunton.com.