U.S. Code of Federal Regulations

The editorial regarding conflict of interest1 provides an important reminder of the ethical concerns and responsibilities of clinical investigators. While institutions may set varying limits on faculty and staff involvement with commercial sponsors, the more subtle influences of personal opinion and the impact of experts will always play a role in research bias. On the regulatory side, the U.S. Food and Drug Administration (FDA) has specific requirements regarding the disclosure of financial relationships. These regulations apply to any clinical investigation conducted to support marketing approval of a medical device, drug, or biologic product. Under the U.S. Code of Federal Regulations (21 CFR 54), sponsors of clinical research studies must take appropriate steps to minimize bias that can occur in the design, conduct, reporting, and analysis of studies.2 The sponsor must “completely and accurately disclose” information concerning financial interests to FDA whenever clinical investigators or their immediate family members exceed specified limits. It is important to recognize that the government regulations do not prohibit or limit any particular financial arrangements. However, certain arrangements must be disclosed in the sponsor's application to FDA. To do this, the investigator is obligated to provide the sponsor with “sufficient accurate information” for subsequent disclosure to the agency. In this way, FDA reviewers can include the information when assessing an application to determine whether, among other things, investigator bias could have adversely affected the adequacy of the study data. Most sponsors ask directly for written certification from participating investigators to document that they do or do not have any of 5 specific financial involvements related to the research trial. These can be briefly stated to include (1) the value of compensation or an equity interest that could be affected by the outcome of the study or product sales, such as royalties; (2) significant payments, such as a grant, equipment, retainers, or honoraria during or for 1 year after the study that exceed a value of $25,000 (not including the cost of conducting a clinical study); (3) a proprietary interest in the product, such as a patent, trademark, or licensing agreement; (4) a significant equity interest in the sponsor that exceeds $50,000 during or within a year after the study; and (5) equity interest for which a public price cannot be readily determined, such as stock options or ownership interest. These limits apply to an investigator's spouse and minor children as well. Disclosure of these arrangements does not automatically make an investigator's data suspect or indicate that fraud would be likely. But as implied in the editorial, unintentional bias may be difficult to recognize and requires scrutiny that can only be provided through full disclosure. Clinical investigators should be sure that they understand their local and FDA disclosure requirements. If a study sponsor has not asked them about their financial interests at the beginning of a trial (a sponsor may not necessarily know an investigator owns their stock), they should ask the sponsor about the disclosure mechanism and have a summary certification placed in the study records even if no financial interests exist. When investigators' interests change during or shortly after a trial, they remain obligated to report the changes to the sponsor. The FDA has published a guidance document to explain the reporting requirements in detail. It can be found at http://www.fda.gov/oc/guidance/financialdis.html.3 The FDA guidance provides background information and a series of frequently asked questions with answers for clinical investigators and sponsors alike. Jan S. Peterson MS, PhD aPotomac, Maryland, USA