Risk-based Approach to Monitoring

On August 24th 2011, FDA released the draft guidance "Oversight of Clinical Investigations - A Risk-Based Approach to Monitoring" following partial completion of the agency/industry Clinical Trials Transformation Initiative (CTTI) work "Effective and Efficient Monitoring as a Component of Quality." This document, especially Section IV.A.2, should be read by all involved in clinical trial management.

FDA makes a number of very interesting observations in their draft guidance, not least of which is that many government/academic sponsored trials have dramatically less than 100% source data verification (SDV) and that monitoring visits occur much less frequently than in industry trials - yet those trials are relied upon by themselves, clinicians, and industry alike as valid and useful. Further, FDA notes that despite ICH GCP's explicitly allowing less than 100% SDV, that a perception has grown up that it is FDA's expectation that 100% SDV in industry-sponsored trials will take place - and that is a perception they explicitly refute.

What FDA is now indicating is that various techniques and technologies (such as use of EDC) can increase the utility of remote or centralized monitoring and reduce the need for 100% SDV. FDA's position is that the use of range and edit checks looking for unusual distributions of data, protocol violations, aggregate statistics and other performance metrics can not only reduce the amount of on-site monitoring needed, but in fact improve data quality overall by targeting "at risk" sites for in-person visitation with specific foci of activities rather than frequent visits to all sites. This latter concept is very important, as FDA, probably appropriately, is not positing that this modality should be adopted because it is less expensive or less burdensome (which may or may not be the case), but rather that it is a superior approach, or at least potentially so.

In the draft guidance, FDA theorizes how the perception that 100% SDV was, if not required by them, then highly preferred, came about. Absent from those musings, however, was the concept of risk, which was somewhat ironic given the title of the draft guidance.

It has been my experience, and that of many colleagues, that FDA has in the past been somewhat less than reliable in sticking to the original agreement between the sponsor and the agency in terms of NDA/IDE trial requirements. This arises often when agency personnel change roles (almost always causing sponsor panic) and the new reviewers bring different expectations to the table.

Sponsors cannot control the agency's behavior in this regard, so they seek to control what they can in order to mitigate risk to their submission's success. 100% SDV, and frequent site visitation is extraordinarily expensive and burdensome, yet it has been seen as mitigating sponsor risk of agency rejection of monitoring activities as insufficient, and thus data quality suspect, irrespective of reviewer.

In order for the sponsor community to feel comfortable in the risk-based monitoring less than 100% SDV/frequent visit posited approach by FDA and CTTI, the agency must give, and live by, assurances that whatever is agreed as an appropriate methodology at the commencement of the trial will remain so throughout trial conduct and during the submission process. In this manner, sponsors can reduce uncertainty and risk, and perhaps we can begin to adopt innovative and superior methods without concern.

Timothy Pratt CRUCIAL Clinical Business Consulting. E-mail: prattusa@gmail.com