RBM’s Impact on Regulatory Inspections

I recently read a white paper authored by Covance on regulatory inspections using a risk-based approach to monitoring. There has been much discussion in the industry on the shift to risk-based monitoring (RBM). What does it mean? What does it entail? How will we implement it? What impact will it have on the way we conduct clinical research and what will the role of the monitor look like under a risk-based monitoring paradigm? I found Covance’s white paper interesting because it looks ahead to what regulatory inspections will look like for studies utilizing RBM.

Of note, the Covance paper states:

• We believe that it is unlikely for there to be any fundamental change in the underlying approach to regulatory inspections in response to the use of RBM techniques. While single issues that are not managed appropriately in the clinical trial may be raised as findings during a regulatory inspection, the focus in RBM trials, just as in non-RBM trials, will be on identifying systematic issues that cast doubt on the protection of clinical trial subjects and/or the integrity of the data generated in the clinical trial. The difference, in an RBM environment, is that additional activities related to the identification, assessment and mitigation of risks and the timely resolution of issues will likely be of increasing importance during regulatory inspections.

In reviewing the Bioresearch Inspection Monitoring Compliance Guides for both Clinical Investigators and Sponsors, Clinical Research Organizations (CROs) and Monitors, it struck me that while the Compliance Program Guidance Manual (CPGM) for Sponsors, CROs and Monitors speaks to monitoring and notes that regulations do not prescribe how monitoring must be carried out, there is no guidance provided to field inspectors on how to assess the identification, assessment and mitigation of risks or the assessment of the Sponsor’s quality risk management.

Interestingly, the FDA feels that the CPGMs for inspection are in alignment with the RBM guidance released in 2013.

• FDA has communicated the goals of, and recommendations for, risk-based monitoring to FDA staff in review, inspection, and compliance functions. FDA’s bioresearch monitoring compliance program guidance manuals (CPGMs) for sponsors, CROs, and monitors (CPGM7348.810)15 and for CIs and sponsor-investigators (CPGM 7348.811)16 are compatible with the approaches described in this guidance. For example, CPGM 7348.810 informs FDA field staff that the regulations do not prescribe a specific monitoring technique. While CPGM 7348.810 refers to site visits and does not discuss centralized monitoring, the focus is on the review of monitoring activities through documentation and whether these activities were carried out in accordance with the sponsor’s (or CRO’s) monitoring procedures.

What is puzzling to me is how the risk-based monitoring program will be evaluated as suggested by the Covance white paper when there is no guidance provided to inspectors in the CPGMs and given they are not supposed to inspect based on guidance documents. “Approaches that differ from those described in FDA’s guidance documents should not be listed on the 483 unless they constitute deviations from the regulations.” ¹ Covance suggests, in their white paper, that the risk assessment, monitoring and mitigation will become increasingly important in regulatory inspections. I completely agree, but I do feel that some changes to the CPGM will be required to give that authority and guidance to field inspectors. As it stands right now, I don’t feel the CPGM contains the necessary information. What do you think? Let me know in the comments section. I look forward to your feedback!

Until next time,
th

 

 

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¹ http://www.fda.gov/ICECI/EnforcementActions/BioresearchMonitoring/ucm134110.htm