Thomas Tremblay, director, Clinical Development at Apexlgen Inc. and Michelle Gray, director, Clinical Development, NeuroPhage Pharmaceuticals assess the trends and findings in the FDA Bioresearch Monitoring (BIMO) Program.

The FDA established the Bioresearch Monitoring (BIMO) Program in 1977 to ensure that the safety and welfare of study participants are protected and to safeguard the integrity of data submitted to the Agency. The main activity by which BIMO provides input is through inspections. The number of type of inspections has not changed noticeably in recent history, ranging from a total of approximately 900 to 1,100 inspections per year. Of the 1093 inspections in 2014, 804 involved Clinical Investigators, 152 involved International Review Boards (IRB), and 138 were addressed to Sponsor/Monitors.

Of the 17 Warning Letters posted on the FDA website from 2014 to October 2015, 12 were addressed to Clinical Investigators and four were addressed to Sponsor/Monitors. Listed below are each of the cited observations (in bold) and following is an assessment of the findings (in bulleted format) for those findings that occurred at least twice in the reviewed Warning Letters.

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

  • Enrollment of ineligible subjects
  • Failure to modify, interrupt, and/or withdraw study treatment when protocol-specified criteria met
  • Failure to report Serious Adverse Events
  • Failure to conduct study visits within specified time frames
  • Protocol-specified tests were not obtained prior to randomization
  • Protocol-specified assessments not performed including laboratory assessments
  • Site staff completed subjects’ "self-recorded" pain and pain relief assessments
  • Administering the wrong treatment assignment
  • Improper order of administration of study drugs
  • Did not appropriately adjust dose of investigational product
  • Did not collect all unused study medication
  • Dosing records conflict with Progress Notes
  • Inadequate corrective action plan

You failed to 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)].

  • Poorly identified records
  • Missing or incorrectly identified source documents for protocol-specified assessments including ECGs
  • Missing assessments forms
  • Unexplained changes to source documents regarding clinical [non] significance of laboratory results (delayed) and/or assessment of relationship to study drug (delayed)
  • Conflicting information between source documents with no explanation of discrepancy
  • Discrepancies between adverse events and reported signs and symptoms

You failed to personally conduct or supervise the clinical investigations [21 CFR 312.60]

  • Failure to adequately supervise individuals to whom tasks were delegated led to:
  1. Many violations,
  2. Enrollment of ineligible subjects, and/or
  3. Theft/diversion of the investigational drug

In addition to the cited observations and descriptive findings, the Warning Letters included the following statements:

"Your inappropriate enrollment of… subjects in this study raises significant concerns about the adequacy of your protection of study subjects enrolled at your site and also raises concerns about the integrity of the data generated at your site…"

"Placing responsibility on a study coordinator … raises concern about the adequacy of your oversight of studies."

"….In addition, failure to obtain blood samples … raises concern about the validity and integrity of the data collected at your site. "

"Your failure to maintain adequate and accurate drug accountability records jeopardizes subject safety and welfare, and compromises the validity and integrity of the data at your site."


Of the 4 Warning Letters addressed to Sponsors, all cite "Failure to ensure proper monitoring…"

Although the number of inspections fluctuates from year to year, there is no obvious trend in BIMO inspections that would suggest a lessening in vigilance or oversight by the Agency. BIMO reported metrics do not provide the level of granularity needed to fully understand the details of specific findings; rather one must review publically available Warning Letters that describe the findings in greater detail.

The details included in Warning Letters to Clinical Investigators are largely related to unperformed assessments and inadequate case histories (source documents and case report forms). Although the deficits noted in the case histories could probably only have been identified by on-site monitoring, the missing assessments could have been identified early on with systematic clinical data reviews.

Most electronic data capture (EDC) systems can identify and query the user when data is missing or outside of the protocol-specified window. Unfortunately, the investigational site user is often a data manager who is far removed from the day-to day conduct of the study and sometimes bypasses the query or responds to the query by confirming that the questionable value is correct. Observations of missing or out-of-window assessments may not be communicated to the study coordinator or investigator who does have the responsibility and authority to reconcile discrepancies during these data query interactions.

Some EDC systems also have Study Drug Accountability models to assist in real-time assessment of disposition at investigational sites which may have helped to identify discrepancies between anticipated and reported use.

Ensuring the safety, welfare, and right of study subjects as well as safeguarding the integrity of the data collected in clinical trials remains an ongoing focus of the FDA. No changes in the number of inspections or the types of findings have been identified during BIMO activities from 2007 to 2014.

Warning Letters provide specific details related to non-compliance with regulations that are of concern to BIMO inspectors. All organizations and individuals involved in the clinical trials process should review Warning Letters to have an historical perspective of areas of interest to BIMO inspectors and should review newly released Warning Letters to be alerted to the evolving areas of concerns. Organizations should make sure that historical concerns are included in risk-management programs and that evolving concerns are rapidly incorporated.

The use of centralized monitoring and clinical data review should be incorporated into all Clinical Monitoring Plans and there should be timely communication of non-compliance to clinical investigators with the goal of bringing investigational sites back into compliance as quickly as possible. On-site monitoring will continue to be a required and central element to any monitoring program but use of electronic systems to review activities remotely and identify discrepancies or trends in a timelier manner clearly need to be utilized more. Identification of a communication process whereby Investigators and site staff are notified of findings from centralized monitoring practices would allow a more rapid correction of errors or omissions. This would increase the overall quality of the data as well as increase the Investigators ability to better protect the rights, safety and welfare of study subjects.

Monitoring should use a risk-based approach that incorporates subjects’ safety, assessment of eligibility, missing assessments, areas of other risk (e.g.; investigational product disposition for controlled substances), and other areas of known concern for BIMO inspectors. Monitoring, both on-site and centralized monitoring of electronic systems should focus of safety of subjects, integrity of data, and high levels of protocol compliance.

Study conduct and compliance can affect the overall impression of data quality.


*To read a more in depth take on this article, read Michelle and Thomas’ excellent whitepaper, ‘BIMO Reported Metrics and Clinical Investigator Warning Letters Issued From 2007 to October 2015