When conducting clinical trials, it is of utmost importance that the data generated be free from threats to the validity and integrity of the research. As demonstrated in many FDA warning letters, a commonly cited source of bias in clinical research can be found in the financial ties between investigators and sponsors. It is not unusual for the innovations of individual physician investigators to receive research and development funding from larger organizations that possess the resources to bring these innovations to market, and under 21 CFR 54, it is the responsibility of sponsors to collect for each investigator who is not a full-or part-time employee either a certification of no financial conflict of interest (Form FDA 3454), or a disclosure of the financial arrangements between the sponsor and investigator (Form FDA 3455). These financial disclosures must be updated by the investigators if there are any changes in financial disclosure status throughout the study, until one year after the study is completed.
When on site during a periodic monitoring visit, a monitor should ensure that financial disclosures or certifications for each investigator are both submitted to the Sponsor as well as kept on file at the site. This documentation should include complete records of any financial arrangements between the investigator and Sponsor; complete records of any significant payments of other sorts made by the Sponsor to the investigator; and complete records of any financial interests held by an investigator.
The investigator should state:
- Compensation that is determined by the outcome of the study (such as royalties)
- Significant payments of other sorts in excess of $25,000 outside of the negotiated study budget to either the investigator or the institution
- Proprietary interests in the investigational product, such as trademarks, patents, licenses, or copyrights
- Equity interest in a publicly traded company involved with the clinical trial (such as the Sponsor) whose value exceeds $50,000, or, equity interest such as ownership interest or stock options whose value cannot be readily determined through reference to public prices
Furthermore, these financial records should be maintained and available to the FDA for no less than a period of two years after the approval of the product application.
If a financial disclosure is found for an investigator at a site, the monitor should also be sure to note any special requirements of the Sponsor, IRB or FDA regarding the investigator’s role and potential conflict of interest in the trial. For instance, a hypothetical investigator with a significant financial stake in a trial’s investigational product may possibly be barred from participating in the informed consent process by the site’s IRB, and it would be the responsibility of the monitor to ensure that those site-specific regulations are complied with.
It is in the best interest of patients and the success of the trial that records of financial disclosure be properly and transparently maintained. The FDA might implement one or all of several consequences of the financial relationship between an investigator and sponsor that could lead to significant bias, including audit of the data, a request to further analyze or conduct independent studies of the data, or the decision to not include the data altogether. In order to aid the clinical research industry with the FDA’s latest ideas and thoughts on the financial disclosure regulations found in 21 CFR 54, the agency has released a new Guidance for Industry in May 2011, which is currently in draft form and open for comments.
What are your organization’s best practices to maintain compliance with 21 CFR 54?
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