Understanding the basics of a US FDA BIMO Inspection (includes useful links).

The US Food and Drug Administration (“FDA”, or “The Agency”) is empowered to protect public health through, among other activities, conducting routine and targeted inspections of firms, facilities and personnel conducting clinical research with investigational drugs. To achieve this, the Agency will instruct their District Offices to send out field investigators (“inspectors”) to evaluate compliance with the various regulations that apply to clinical trials. In the drug development (“pharma”) world, and medical device world this generally means reviewing compliance with various appropriate parts of Title 21 of the Code of Federal Regulations (“21 CFR”), such as:

21 CFR  Part 11, Electronic Records and Signatures

21 CFR Part 50, Protection of Human Subjects

21 CFR Part 54, Financial Disclosure by Clinical Investigators

21 CFR Part 56, Institutional Review Boards

21 CFR Part 312, Investigational New Drug Application

21 CFR Part 314, Applications for FDA Approval to Market a New Drug

21 CFR Part 812, Investigational Device Exemptions

21 CFR Part 820, Quality System Regulation

In addition, various Guidance Documents, finalized and in draft form, will be used as reference materials to ensure that the public at large are being protected during the industry’s endeavors to develop new medicines and treatments to add to the dispensaries.

FDA inspectors will conduct their inspections by following the relevant FDA Compliance Program Guidance Manual (“CPGM”) that applies to the inspection. In the pharma industry this mainly means the the Bioresearch Monitoring Program (“BIMO”) Compliance Programs:

CPGM 7348.809, Institutional Review Boards

CPGM 7348.810, Sponsors, Contract Research Organizations and Monitors

CPGM 7348.811, Clinical Investigators and Sponsor-Investigators.  

Additionally, regular Pharmacovigilance (safety) inspections are conducted using:

CPGM 7353.001, Postmarketing Adverse Drug Experience (PADE) Reporting Inspections  

In the world of pharma research FDA inspector(s) will visit a facility, review procedural documentation, such as procedure, data, protocols, adverse event records, testing and validation reports, training, etc. They will also interview staff, inspect the facility, and generally build up a picture of how well a clinical study is being conducted, monitored, and overseen, including protection of study subjects, control of investigational materials and adequacy of data handling and reporting methods.

At the conclusion of the inspection, which may last from a few hours to several days over many weeks, depending on the scope of the review and the ongoing findings, the Lead Inspector will present their observations to the auditee(s). In the event that no significant issues have been found this may be a brief discussion, but where the inspector has identified areas of concern a FDA Form 483 (“483”) will be issued.

This, together with the full Establishment Inspection Report (“EIR”), and written response(s) to the 483 from the auditee(s), will be reviewed by the Agency who may take further action such as issuing a formal Warning Letter (“WL”).

Warning Letters are a significant outcome from an inspection and may, in turn, lead to further actions including legal proceedings against the auditee(s).

Warning Letters are made available on FDA’s web site and many pharma companies use these as a barometer to determine how FDA is approaching their inspections program, to identify noncompliant clinical investigators and organizations, and to fine-tune their own quality systems so that they do not have similar findings.

That being said, the Agency is fairly limited in the way in which they compose the text of the Warning Letters, which are also redacted for any commercially sensitive materials.  Although FDA makes effort to classify the inspectors’ observations there are very limited categorizations that can be used, since the inspectors are held to quoting the specific parts of 21CFR which, in themselves can have a very broad scope. For example, two of the more common categories quoted during Clinical Investigator inspections are:

“You failed to ensure that the investigation was conducted according to the investigational plan [21 CFR 312.60]”

and,

“You failed to prepare and maintain adequate and accurate case histories that record all observations and other data pertinent to the investigation on each individual administered the investigational drug or employed as a control in the investigation [21 CFR 312.62(b)]”.

It is therefore important to read the entire context of the Warning Letters, often several times, in order to fully understand the issue being described.

Finally, in the author’s opinion, the Agency often times does not go far enough in following up issues identified. It seems ironic that the industry is expected, quite rightly, to examine in detail the potential impact of instances of noncompliance, whether they be accidental, deliberate, isolated, or systemic, yet the Warning Letters rarely, if ever, anticipate ramifications that extend beyond the initial scope of the inspection.

~ Richard

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With over 25 years experience in Clinical Quality Management and Clinical Operations in both the EU and US, Richard Reeve has a proven track record of establishing and re-engineering GCP quality systems, hosting external inspections by regulators and business partners, and managing inspection planning. Combining a business-focused approach with practical operational experience he is able to quickly identify compliance issues and areas for optimization in the GCP arena.

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