Clinical Trial Investigations: Making Headlines
By: GAIL F. BRANDT
April 2005
You agreed to be an investigator in a clinical study because you felt it was important work or because the additional revenue would boost your practice’s bottom line. Now Food and Drug Administration (FDA) inspectors are on your doorstep asking for all records related to the study. Images flash through your mind of yourself on the cover of national magazines featuring headlines such as “Research for Hire: Doctor’s Drug Studies Turn into Fraud” (an actual New York Times headline from 1999).
High profile cases related to mishaps in research have made the news in recent years, including current scandals regarding Paxil, Zoloft and Vioxx—all based on allegations of failure to disclose adverse reactions from the clinical trials. As a result of heightened public awareness, the National Institutes of Health and the National Academies Institute of Medicine have begun major initiatives to raise standards for the protection of human subjects. In addition, the FDA has increased its vigilance related to research institutions and individual investigators, and now conducts 600-700 clinical investigator inspections each year.
The FDA oversees clinical studies involving human subjects when data from the study will be used to support an application to the FDA for a new drug or device. Before a drug or device goes to market, studies support the trial sponsor’s application. After-market studies support a new indication, dosage or a change in a previously approved drug’s or device’s labeling. All such studies are subject to FDA oversight, and if you participate in a clinical trial, you will be subject to this oversight, and could find yourself responding to FDA inquiries.
What will the inspectors be looking for from a clinical investigator?
- Verification of informed consent of study participants, with an emphasis on what makes the participant “fully informed.”
- Rigorous adherence to the study protocol, especially inclusion and exclusion criteria. Investigators cannot deviate on the inclusion and exclusion criteria even if the deviation is approved by the sponsor.
- Independence of the investigator. Financial conflicts of interest, including payment for the research reports, ownership of stock or stock options, may undermine the validity of the research data.
- Failure to meet the recordkeeping and reporting requirements required by the study protocol, which could include the informed consent, patient records, test results and other information.
One of the FDA’s most powerful enforcement tools is refusal to consider an investigator’s data in support of an application if the FDA has doubts about the data’s validity. While this is principally a concern for the sponsor of the study, if an investigator’s data is excluded it is unlikely that the sponsor will want to include the investigator in further research. This may also cause harm to the reputation of the investigator since the exclusion of data is public and may be discovered by a reporter or a competitor. The FDA may also disqualify a clinical investigator from all current and future studies if it finds the investigator has repeatedly or deliberately violated regulations or submitted false information.
When the FDA inspects a clinical investigator, it conducts an exit interview, makes recommendations and issues a report of its findings. These reports are public and may contain deficiencies or recommendations for improvement. If deficiencies are serious or repeated, or if the FDA does not believe the investigator will make appropriate changes, the FDA may issue a “Warning Letter”—essentially a public reprimand calling attention to a deficiency. Warning Letters are not subject to challenge before they are issued. Instead, the investigator may seek review of the FDA’s position after the Warning Letter has become public. The public awareness and potential media attention may have a more detrimental effect on the investigator’s reputation or the sponsor’s product than the underlying issue with the FDA. Not surprisingly, the Warning Letter is very effective for the FDA in gaining compliance.
An internal policy outlining how to respond if an FDA investigator or inspector shows up unannounced should be implemented so that you can be cooperative and provide access as required, but also able to assess the situation, contact counsel, and protect your interests. If an FDA agent wants access to your records related to a clinical trial, first verify the individual’s credentials. (FDA representatives will have identification, business cards and an administrative form describing the scope of their review, with a reference to federal statutes and regulations.) Because the FDA may issue a Warning Letter, recall a product, terminate a study or take another intervention before a formal review or appeal of their findings, cooperation is often the more effective strategy in dealing with FDA inspectors. Remember, however, that cooperation does not mean spilling your guts or answering questions off-the-cuff. Ask for the questions in advance, schedule the interview, and take the opportunity to prepare before being interviewed. Remember you can consult with counsel and have counsel present for the interview. Provide the information requested, including patient records, to the extent it is within the scope of the investigation. Keep a log or additional copies of all information and files reviewed by the FDA representative.
A clinical investigator will have the opportunity to respond to the inspection report with a plan for correcting the identified problems or arguing reasons why the issues do not require correction. If a Warning Letter is issued, the recipient has the opportunity to respond and contest the FDA’s findings. Since the investigator’s report and Warning Letters are public, it is important to respond in a manner that controls the damage to the investigator’s reputation and the integrity of the study. In preparing an appropriate response, you should understand the issues raised by the FDA investigator, the impact those issues may have on the validity of the data, and the possible ramifications of the findings. It is also important to request protection for confidential and proprietary information in the response to the FDA in order to prevent public disclosure of that information.
Franklin’s old adage, “an ounce of prevention is worth a pound of cure” is the best advice for compliance with clinical trial obligations. Clinical investigators must adhere to the protocol and comply with requirements for good clinical practice, conflicts of interest, and confidentiality. Good recordkeeping, meticulous attention to informed consent, and rigorous faithfulness to the trial protocols are essential and will help prevent—and help defend the investigator for—any deficiencies.