Surviving an FDA Inspection of Your Clinical Trial Site

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The Investigational New Drug (IND) regulations went into effect in 1963. Ever since, the U.S. Food and Drug Administration (FDA) has conducted clinical site inspections under what is known as the Bioresearch Monitoring Program. The agency now conducts several hundred inspections of clinical investigators annually to obtain compliance with the regulations and to ensure that data submitted to the FDA are substantiated by appropriate records.

An FDA inspection is not an indictment and generally does not mean that the investigator's work is suspect. It's simply a quality assurance process used to verify clinical data and regulatory compliance. That said, it can still be an unnerving experience, particularly if you are not prepared. Hopefully, the information presented here, much of it taken directly from information provided by the FDA, will help you and your staff better understand the process and how to "survive" it.

The Types of Inspections

The most common type of inspection is classified by the FDA as a "Routine" inspection and is generally triggered by a New Drug Application (NDA) submission. Routine inspections account for over 80% of the inspections performed by the FDA each year. Generally, the clinical investigators who enroll the most patients in the NDA's pivotal trials are the most likely candidates for a routine inspection.

"For Cause" inspections are much more infrequent and generally arise only when the agency receives reports of, or otherwise becomes aware of, suspicious behavior by a clinical investigator. What might prompt the Food and Drug Administration to conduct a For Cause inspection? Here's a few things that certainly raise the odds of you getting selected for an audit.

• conducting a large volume of clinical trials;
• conducting clinical studies outside of one's field of specialization;
• reporting significantly better efficacy, fewer adverse effects, or different laboratory results than other investigators studying the same drug;
• having apparent access to too many patients with a specific disease state for the locale or practice setting;
• complaints from a patient or sponsor of an alleged violations of the regulations, protocol, or human rights.

Doctor, the FDA is on the Phone!

The FDA will usually call to schedule the inspection at a mutually agreeable time that is not overly disruptive to your clinical practice. However, expect no more than 5 to 14 days notice. I've recently heard of sites receiving only two days notice. The inspector will usually spend two to three days at your site.

You should ask which specific study will be reviewed and who should be available during the visit. It's a good idea to immediately contact the study sponsor. The sponsor may offer useful suggestions and your call is the only way the sponsor will know the site is being audited; the FDA does not directly notify the sponsor of a clinical site inspection.

Prior to the inspection, assemble the following documents in a private area, removing any materials related to any other study:

• Protocol
• Investigator's Brochure and IND Safety Reports
• Form FDA 1572 with accompanying CVs
• IRB correspondence, including approval documentation and final report to IRB and Sponsor
• IRB-approved Informed Consent form
• IRB-approved advertising
• Study-related correspondence, excluding investigator agreement and financial information
• Monitor sign-in Log
• Laboratory certification documents
• Drug accountability records
• Each subject's signed informed consent
• Also, assess the support areas (pharmacy, lab) to be sure they are properly prepared; the FDA may tour the facility.
• Finally, be prepared to answer the following questions:
• Where was the study done?
• What special equipment was used?
• Who assisted in performing the study?
• What were each person's specific duties?
• Describe the sponsor's monitoring procedures and your interaction with the monitor.
• How did you account for the drug received, dispensed to/returned from subjects? Was all drug returned to the sponsor?

Coach all staff as to how they should interact with the FDA. You will want to be professional and direct in answering questions, but do not provide unrequested information. In an attempt to impress the FDA inspector, some investigators have made the unfortunate mistake of providing unsolicited information and even offering up records from other studies only to be later cited for deficiencies in areas that were not part of the original inspection plan.

He's Heeeeeerrrrrrrrreeeeee!

When the inspector arrives, be sure to check his or her identification; you don't want to allow an unauthorized person access to confidential records. The Inspector will complete a Notice of Inspection (FDA Form 482) and leave it with you.

The FDA Inspector's first task is to determine the nature of the investigator's conduct of the study. He may want to take a tour of the facility and interview all of the staff who participated in the study. He seeks to determine the degree of delegation of the investigator's authority, where specific procedures were conducted, where and how the data were recorded, and where the drug was accounted for and stored.

The following items are routinely examined:

• adequacy of communication with the IRB, including the initial submission document, adverse event reporting, and progress reports;
• completeness of accountability documentation for the receipt, storage, administration and return of test article (drug, device, etc.);
• compliance with the study protocol and documentation that each deviation/amendment received IRB and sponsor approval;
• appropriateness of the informed consent process (Was the patient was properly consented? Was the correct IRB-approved version used?);
• prompt and complete reporting of adverse events to the IRB and sponsor;
• compliance with the record retention requirements and that the investigator had immediate access to the study records during the trial; and
• adequate monitoring of the site and communication with the sponsor.

The Inspector's next step is to audit the data. He will compare the data that was submitted to the agency with the medical charts and source documents supporting the data. This would include medical charts, laboratory reports, the drug accountability logs, pharmacy records, and similar study documents.

This review will not be limited to the data collected during the trial. The inspector will review data both before and after the subject's participation. This is done to ensure the subject had the medical condition under treatment and that excluded medications were not given to the subject during the study period. Generally, only a subset of the data will be reviewed. But, this could be expanded if the inspector finds problems with the initial sample.

When the Inspector has completed his audit, he will meet with the investigator to discuss his findings. Any discrepancies will be noted on FDA Form 483 and a copy given to you. The study sponsor will probably request a copy of this report.

After his visit, the FDA Inspector will write an Establishment Inspection Report (EIR) and submit it to FDA headquarters. It is not routinely sent to the investigator or sponsor. After the report has been evaluated, you will then receive a letter. There are three possible scenarios for this letter.

The letter may simply acknowledge that the inspection has been completed and no significant deficiencies have been found. Only 20% of the inspections result in this type of letter.

The letter may list deficiencies noted during the investigation, but indicate that no specific response is necessary. However, the investigator should take voluntary steps to correct and improve this situation as these areas will be the focus of the next investigation. About 70% of inspections result in this type of letter.

The third type of letter, comprising the last 10%, describes serious negative findings identified by the inspector. In this case, the investigator's status as well as the data collected during the trial are in serious jeopardy. An immediate detailed response is required to explain how these discrepancies will be addressed. This would be an ideal time to get help from the sponsor; the pharmaceutical company has a lot at stake here as well! Failure to adequately respond can result in the investigator being disqualified from conducting other studies, rejection of the study data and perhaps the entire marketing application, and even potential criminal proceedings.Those investigators referred for criminal prosecution are generally clinical investigators who have knowingly or willingly submitted false information to a research sponsor.

Within four to six months, the EIR is available upon request to the investigator, the sponsor, and the general public (including other potential sponsors) via the Freedom of Information Act. Sponsors and Contract Research Organizations (CRO's) routinely obtain this information when evaluating potential research sites. If your site had a discrepancy noted by the FDA inspector, it will not necessarily cause you to get passed over for future studies, but you will certainly need to show the potential sponsor that you have addressed the discrepancy and have implement procedures to prevent future recurrences.