by Michael R. Hamrell, Ph.D., RAC, FRAPs, CCRA, RQAP-GCP, MORIAH ConsultantsYou have just been informed by your boss that the FDA is coming to conduct an inspection of a clinical study recently completed at your facility. Does this raise your anxiety level and that of your staff to near panic levels? A FDA inspection can bring on images in your mind of a large room, bright lights and grueling questions. Probably no other agency of our government can evoke a more frightening scenario, except for maybe an IRS audit. However, with proper planning and preparation, a FDA inspection does not have to be a nightmare experience.
Regardless of your motivation or fears, proper preparation is the key to doing well in a FDA inspection. The good news is that routine clinical inspections, unlike GMP inspections, are usually pre-announced and scheduled. The bad news is that without good practices and proper procedures in place, no amount of advanced notice will give you enough time to build in compliance. There is just no substitute for a prospective, quality approach to clinical research.
The Food and Drug Administration each year conducts approximately 900-1,100 worldwide inspections of clinical investigators involved in investigational studies for drugs, medical devices and biologic products. These inspections are carried out under the agency’s Bioresearch Monitoring Program (BIMO), which is designed to assess the quality and integrity of data that are submitted to the FDA to support product approval applications and to examine the human subject protection aspects of the study. The BIMO program comprises randomly selected, routine, on-site inspections and data audits to monitor all aspects of the conduct and reporting of FDA-regulated research. On occasion, the FDA will conduct a directed inspection of a specific site or study to look for problems that may have already been identified. The BIMO program is a global initiative and focuses on data collected at sites worldwide. On the rare occasions that the inspection of a clinical study uncovers evidence of fraud or misconduct, the FDA must decide how to discipline the investigator and how to deal with the suspect data.
So, how can a site or company or CRO prepare for an audit? There are a few key items and considerations to think about in preparing for a future audit.
- Do you have SOPs for every operation and procedure that is part of your organization’s standard practice?
- Did you hire qualified individuals for each job function?
- Is everyone working on the project trained on their job functions and your expectations?
- Do you keep good, up-to-date training records for each employee?
- Do you use sound documentation practices?
- Are all the data in order and can you find and document everything that happened on the study?
- Do you have a schematic for your organization (i.e., organization chart in writing)?
- Is all equipment properly maintained, calibrated and serviced?
Site personnel should also be trained in and aware of FDA inspection procedures and how to interact with the FDA. It is also important to know and understand the various regulations, guidelines and industry practices for Good Clinical Practice (GCP). This should be part of your training effort for all of your staff. Another important key to a successful inspection is recognizing that an FDA inspection is part of the process of clinical research and the review and approval process at FDA. When you and your management team truly understand this, your planning and preparation will pay off on the inevitable day when the FDA calls
So, what exactly, will the FDA want to see during the inspection? Everything, probably! You should contact the sponsor (& CRO) for the clinical study immediately after you have an established date for the inspection. Start pulling together and reviewing all of the source documents and reports that cover the entire period of the study. A ‘standard’ GCP site inspection will also include a tour of the facility and a thorough review of the documentation.
A list of the types of documents and information they are likely to ask for is included below but this is not necessarily exhaustive.
- Documents in the project folders filed during the course of the trial
- List of the study subjects and their corresponding study numbers
- All of the correspondence with the IRB, sponsor/monitor
- Original signed consent forms for all the subjects
- Case report forms (CRFs) for all the subjects
- Source documentation (Patient medical records, clinic and hospital charts)
- If electronic, how will the auditor access records?
In addition to the details on subjects who enrolled and completed the study, the FDA is often also interested in reviewing the records of subjects who were study dropouts or lost to follow-up. Is the reason they left the study complete and well documented?
An inspection will, of course, also focus in the investigational supply storage facilities and accountability records and safety reports, especially Serious Adverse Event Reports and documentation
The numerous logs we keep as part of the study documentation will also be important for review during the inspection. This includes:
- Site delegation log
- Monitor visit log
- Enrollment/screening logs
The key focus of the inspection will be adequate and accurate case histories for each subject to clearly demonstrate that they met the study inclusion/exclusion criteria as defined in the protocol. Make sure that each subject’s medical record has clear documentation that this was reviewed and assessed prior to their enrollment in the study. It is also important to document that the test article was properly administered as required by the protocol and that all concomitant medications and treatments that might compromise the study results are documented and explained, if needed.
Ultimately, the FDA inspection is to compare:
- Source document/medical record data
- Case report forms
- Data listings submitted to FDA
Does the data reported in the clinical study match the data collected by the sponsor? Is it reflective of the subject’s medical record and condition?
The FDA is entitled to access, review and/or copy all original study records, including a subject’s medical chart. This includes any electronic version of medical records, so think about how you would provide them the access or ability to review such records. You don’t need to ask FDA to sign a HIPAA form or confidentiality form. First of all, they are not authorized to sign anything and second, it is not required since the subject already granted permission for the sponsor, third party organizations (CRO), the IRB and regulatory agency personnel to review their records (check the language in the informed consent form).
The IRB Communication information is also essential. Make sure that you have documented proper approval and records for protocol and informed consent, all communication/correspondence between Investigator and IRB and that continuing review was performed as required.
Remember, an FDA inspection is an essential part of PMA/510K/NDA/BLA review process. You need to know your rights and what documents need to be provided. During the trial use the sponsor/CRO to help you to prepare. Most importantly, also build quality into your work. An FDA inspection can also be an interesting adventure. Learn to expect the unexpected and be prepared to present your organization as a well-run site that knows and understands and follows the regulations. Of course, it will help if you have an operation that actually reflects this reality.
Note: The views expressed in this article are those of the author and do not necessarily represent those of his or her employer, GxP Lifeline, its editor or MasterControl Inc.
MORIAH Consultants is a regulatory affairs, clinical research and information systems consulting firm located near Los Angeles, CA.
Dr. Michael R. Hamrell, Ph.D. the founder and president, has over 30 years’ experience in international product development and global compliance in academia and the pharmaceutical industry, including experience with drug, biologic and medical device regulatory affairs. He has worked in pharmaceuticals, contract research, government, and biotech industries, in domestic and international regulatory affairs and clinical research. In addition, Dr. Hamrell also worked at the National Institutes of Health and as a reviewer in CDER at the Food and Drug Administration (FDA).
He’s published numerous papers in pharmacology, regulatory affairs, product development, clinical research, computers and information systems. Dr Hamrell serves on the Editorial Board of several leading journals in clinical research and regulatory affairs.
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