Investigator Final Reports: A Tool for FDA Inspection Readiness

For Pharmaceuticals and Biotechnology

During the time I was an FDA field investigator I encountered many clinical investigators who were totally unprepared for the FDA inspection. I would receive a "deer gazing into the headlights" response from the PI who obviously didn't remember a thing about the audited study. There is an old saying, "you only get one chance to make a good first impression." Often they would turn to their study coordinator and ask for the answer, joking to me, "They do all the work anyway."

One of the most important parts of an FDA inspection is determining the involvement of the clinical investigator (often referred to as the "PI") and how the study was supervised.

That is absolutely the wrong thing to say to an FDA investigator. A clinical investigator is responsible for administering the study drug "only to subjects under the investigator's personal supervision or under the supervision of a sub-investigator responsible to the investigator."¹ One of the most important parts of an FDA inspection is determining the involvement of the clinical investigator (often referred to as the "PI") and how the study was supervised. Preparing a clinical investigator for an FDA inspection is essential for every sponsor of a clinical trial. The sponsor has his own responsibilities, including monitoring the progress of the investigation.²

This isn't always easy. Clinical investigators are usually busy people and a clinical trial may be inspected by FDA years after the conduct of the study. However, there is an overlooked requirement that can be used as a tool to help prepare investigators and their clinical staff for an FDA inspection. The drug and biologic IND regulations require that an investigator submit a final report to the sponsor shortly after the investigator's participation in the study is concluded.³ The medical device IDE regulations have the same type of requirement.⁴

This is different from the final report required by IRBs. Many times I am asked if the PI can just use the final report submitted to the IRB. The answer is probably, but why? FDA has guidance documents such as their Compliance Program Guidance Manual⁵ that tell you what an FDA investigator will want to know during an inspection. Why not prepare the answers in advance? If there is a short report with the relevant details prepared at the end of the study, then it can be used to prepare the investigator down the road when FDA comes knocking. When an investigator is well-prepared for an inspection, he is demonstrating his knowledge of the study and making the right first impression on the FDA. This starts the inspection off in the best direction. Here are some basic elements for a final report taken from FDA guidance documents including the CDRH "Device Advice."⁶

1. IND or IDE number
2. Investigation product name
3. Indications for use
4. Brief summary of study progress in relation to investigational plan
5. Number of subjects enrolled, dropped, completed
6. Amount of investigational product received, used, and the final disposition of unused IP
7. Brief summary of results and conclusions
8. Summary of anticipated and unanticipated adverse device effects or adverse drug experiences
9. Description of any deviations from investigational plan
10. Reprints of any articles published by the investigator in relation to the study

Finally, there are some important dates that take place. Including these in the final report will keep the PI one step ahead of the FDA investigator's questions:

1. The dates of IRB approvals (human studies) including initial review of the protocol, all amendments, the informed consent document and all revised informed consent documents
2. When the Form FDA 1572 or Investigator Agreement (for devices) was signed by the clinical investigator
3. When the first subject was screened
4. When the first subject signed the informed consent form
5. First administration of the test article; and
6. Last follow-up for any study subject.

This is all information that you would expect a sponsor and a clinical investigator to have for an adequate and well-controlled trial. Keeping on top of this information during the conduct of the study and using it to prepare a final report as required by the regulations will go a long way in preparing for a successful FDA inspection.

References:

1. 21 CFR 312.61
2. 21 CFR 312.56(a)
3. 21 CFR 312.64(c)
4. 21 CFR 812.150(a)(6)
5. FDA Compliance Program Guidance Manual, CP 7356.811, Clinical Investigators: https://www.fda.gov/ICECI/EnforcementActions/BioresearchMonitoring/ucm133562.htm
6. FDA Device Advice: https://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/HowtoMarketYourDevice/
   InvestigationalDeviceExemptionIDE/ucm046717.htm#invann