What’s New in the BIMO Manual? Selection and Monitoring of Clinical Investigators

Our last post gave a high-level overview of recent changes to FDA’s Bioresearch Monitoring (BIMO) Compliance Program Manual (CPM) for Sponsors and Contract Research Organizations, which is FDA’s procedure for conducting sponsor inspections. Today we look at the section on Selection and Monitoring of Clinical Investigators, where there are no sweeping changes, but a few new steps have been added, and inspectors are now provided with more detail for conducting each step.

Step 1. In the previous version of the manual, this section started with a step to “obtain a list of all investigators and determine if there is a form FDA or signed investigator agreement for each clinical investigator identified.”  The update gives more detail about the contents of the list, including

• Site number
• Site location
• Identification of sites that received a waiver from the 1572 requirement
• Identification of ex-US sites that did not conduct the study under an IND
• Identification of terminated investigators and reason for termination
• Identification of investigators on enrollment hold and reasons for the hold
• Identification of “any healthcare providers of facilities contracted to provide data relating to patient health status and/or the delivery of health care collected to support a marketing application”

Obviously, sponsors and CROs should be prepared with a list that fulfills all these criteria.  In the past, many sponsors have preferred to use the list of investigators from the BLA/NDA, so that there is no opportunity for conflict with other information held by the inspector, but this site list will not have all these elements.

Step 2. The previous version directed the inspector to “determine the sponsor’s…criteria for selecting clinical investigators.”  The update adds some examples:  “e.g., requirements for site
selection, sponsor’s previous experience with the clinical investigator or site, workload of the clinical investigator and study staff, and resource availability.” This question has long been a difficult one for sponsors who don’t formally document their criteria for site selection. If criteria were not documented pre-selection, the inspection team should prepare to discuss the implicit criteria for selection and perhaps consider a CAPA to make formal documentation of selection criteria required in an SOP.

Step 3.  A new step directs inspectors to “verify whether the clinical investigators are qualified by training and experience to conduct the study,” including review of protocol-specific requirements, with a focus on the “sponsor’s overall practices.” If no training and experience requirements have been defined in the selection criteria, then the FDA inspector may substitute their own opinions regarding what level of training and experience are required.

Step 4.  Another new step tells the inspector to determine “whether the sponsor has procedures for checking the FDA Department List (Drug Product Applications) and previous administrative and regulatory actions against a clinical investigator.” Many sponsors that outsource site monitoring rely on their CROs’ procedures in this area; pre-inspection, sponsors should review their CRO’s procedure to determine whether checks are thorough, timely and well-documented.

Step 5.  The former Step 3 stated, “Determine if the sponsor/CRO provided the investigators with all necessary information prior to initiation of a clinical trial.  This may include clinical protocols or investigational plans, labeling, investigator brochures, and previous study experience.” The updated step adds other examples of information to be provided: “site user manuals for electronic systems (e.g., Interactive Web Response System (IWRS), electronic data capture (EDC) system, or other web-based portal for exchanging information) or digital health technologies (e.g., electronic patient-reported outcome (ePRO), wearables) used in the trial, and contingency plans as appropriate for how the site is to conduct study processes and procedures in the event of their inability to access electronic systems or when there is a malfunction or failure of the electronic systems. Collect and review a list of the documents (e.g., investigator manual, electronic system guide, newsletters) provided to the clinical investigators.” Again, many sponsors rely on CRO SOPs, which may not be this detailed; during study start-up, the sponsor may wish to ensure that the site start-up plan or site monitoring plan details the information to be shared with the sites.

This step goes on to direct the inspector, “Determine what training was supplied to the sites.” Best practice is to version and date all investigator meeting slide decks and site initiation visit slide decks and to record which versions were delivered to which sites.  Frequently, sponsors find that they can’t tell with certainty which training materials a site reviewed.

Step 6.  The former Step 4 stated, “Determine how the sponsor/CRO handles serious deviations from the approved investigational plan (which includes the study protocol) or FDA regulations.”  The update omits the word “significant” and provides more detail on what to look for:  “i.e., determine how deviations are communicated, to whom, and in what timeframe; determine if the sponsor has an escalation plan and how escalation is documented.” Protocol deviations are frequently a sore spot in inspections; sponsors should review escalation and follow-up requirements throughout the study to determine if they are being followed.

Step 7. This step asks the inspector to determine if the sponsor identified non-compliant investigators and determine if non-compliance was corrected or if the site’s participation was terminated. While the previous version (former Step 5) asked the inspector to determine whether the “sponsor or CRO” was responsible for following up on non-compliance, the revised step states, “Determine who (i.e., (i.e., what company, what department, which individual) has the responsibility.”  The revised step also advises the inspector to review monitoring reports and evaluate whether a “corrective action plan” was put into place.

Step 8 deals with sites that were terminated early.  The update adds requirements to determine how subjects at the terminated site were dispositioned and whether the sponsor followed its “written plan on site termination and subject transfer.” As noted above, many sponsors do not maintain SOPs at this level of detail; as part of their inspection preparations, they should review CRO SOPs and study-specific plans to ensure these steps are adequately described.

The previous version (former Step 6) required the inspector to determine whether the termination was reported to FDA; the update also asks the inspector to determine if the IRB was notified.

In cases where an entire investigation was terminated due to risk, the update also requires the sponsor to determine if the sponsor notified FDA, all reviewing IRBs and clinical investigators who participated in the study at any time of the risk.

Step 9, formerly Step 6, asks inspectors to identify non-compliant investigators who were neither brought into compliance nor terminated.  This step is reworded slightly but essentially unchanged.

Step 10 is a new requirement to identify “changes to the clinical investigators responsible for conducting the study,” including the reason for the change and names of the new clinical investigators.  Most sponsors do not have a formal process for capturing reasons for change of Principal Investigators; this may be a useful storyboard topic.

In summary, for inspection readiness.

• Prepare a detailed site list with all the requirements in Step 1, ensuring it aligns with the list in the BLA/NDA.  Be prepared to incorporate other information that may be requested during the inspection, such as enrollment figures, study coordinator names, or IRB names.  Determine the “source of truth” for creating these lists so the team isn’t scrambling to reconcile different pieces of information during the inspection.
• Determine whether there are adequate procedures for debarment checks, documentation of site selection criteria, provision of information to sites during start-up, site early termination, subject disposition and transfer. These procedures may be sponsor SOPs, CRO SOPs, study-specific plans, or the protocol. Note which elements are described in which procedures.  Where no written procedure exists, document what you actually did on a storyboard.
• Version and date all site training material and note (for example, in the SIV report or investigator meeting minutes) which version was delivered to each site.
• Capture the rationale for any PI changes.