FDA Inspections: Findings for Clinical Investigators

=As we have done in past years, IMARC examined the warning letters posted on the FDA’s website to compile the top findings from BIMO inspections. This year, we are reflecting on the top findings of previous years and discussing trends seen in 2018.

Established in 1977 by the FDA, the Bioresearch Monitoring (BIMO) program ensures that study participants’ safety and welfare are protected while preserving data integrity. BIMO provides input and enforces FDA regulations primarily through inspections. A warning letter is then issued by the FDA after the inspection if serious deficiencies or violations were noted.

Why might a Clinical Investigator receive a Warning Letter?

The FDA Inspections of Clinical Investigators Guide states that a Warning Letter is issued for violations of regulatory significance “which may lead to enforcement action if not promptly and adequately corrected.” The recipient of the Warning Letter is requested to secure voluntary compliance, correct the violations, and provide an adequate written response to the agency.

In order to understand why a Clinical Investigator might receive a Warning Letter following an inspection, let’s reflect on the past.

Reflecting on the previous five years (2013-2017) of published BIMO Metrics, an average of 1137 BIMO inspections were conducted, which includes the inspection of Clinical Investigators (CI), IRBs, Sponsors, Monitors, CROs, and Good Laboratory Practices. In the previous five years, the percentage of Clinical Investigator investigations has increased, while the warning letter frequency has varied over time.

While the number of inspections varied each year, there has been a noticeable consistent trend in the inspection findings. Year after year, the FDA cites the same Clinical Investigator deficiencies from the BIMO inspections.

Listed are the top three Warning Letter findings for Clinical Investigato

rs in the past five years.

Number Three

Failure to maintain adequate records and accountability for the investigational product

Examples include:

• Records of the investigational product, including dates, quantity, and use by subjects, were not maintained
• Failure to maintain any drug disposition records or product accountability log
• Failure to produce the unused supply of investigational product or drug with no other records indicating the use or disposal of the unused supply

Number Two

Failure to maintain adequate and accurate case histories that record all observations and other data pertinent to the investigation on each individual in the investigation

Examples include:

• Failure to report adverse events accurately and correctly to the IRB
• Revisions on source worksheets were unclear
• Failure to document dates related to serious adverse events

Number One

Failure to ensure that the investigation was conducted according to the investigation plan

Examples include:

• Failure to perform study visits at the location specified in the protocol
• No investigator oversight of inclusion/exclusion criteria
• Patient self-reported items were instead carried out by study personnel

Honorable Mentions

Failure to protect the rights, safety, and welfare of clinical trial subjects

Examples include:

• Failure to report Serious Adverse Events (SAEs) according to the protocol
• Failure to provide timely treatment to subjects experiencing symptoms

Failure to obtain informed consent in accordance with 21 CRF Part 50

Examples include:

• A consent form was used that was not approved by an IRB
• Failure to record subjects’ consent to optional studies

While the FDA has not yet published the 2018 BIMO metrics, preliminary findings from inspections demonstrate similar Clinical Investigator deficiencies as past years

. During the 2018 BIMO inspections, 400 violations were cited for Clinical Investigators. See the table below for the frequency of each Clinical Investigator violation found during the BIMO 2018 inspections. Like years past, the most frequent inspection observation in 2018 was failing to follow the investigation plan, with 118 instances occurring.