Following the release of five guidances to broaden cancer clinical trial eligibility
earlier this week, the US Food and Drug Administration (FDA) is out with draft guidance Thursday on the risk-based monitoring (RBM) of trials and final guidance on enrichment strategies for trials to support determinations of effectiveness.
The eight-page RBM draft guidance comes in the form of eight questions and answers and expands on guidance from August 2013, known as “Oversight of Clinical Investigations--A Risk-Based Approach to Monitoring
,” by providing additional guidance on planning a monitoring approach, developing the content of monitoring plans and addressing and communicating monitoring results.
The draft notes that although FDA’s regulations require sponsors to monitor the conduct and progress of their clinical investigations, there are no specifics on how to conduct such monitoring. The RBM draft guidance, however, discusses the importance of “identifying critical data and processes necessary for human subject protection and integrity of the investigation, conducting a risk assessment, and developing a monitoring plan specific to the investigation.”
The Q&A portion of the draft delves into topics such as the purpose of the risk assessment; whether sponsors should monitor only risks that are important and likely to occur; factors to consider when determining the timing, types, frequency and extent of monitoring activities; how RBM can help to minimize missing data, protocol violations or protocol deviations; and elements sponsors should include in monitoring plans, among other details.
The 41-page draft guidance on enrichment strategies finalizes a draft on the same topic from December 2012 and is meant to help industry develop strategies that can be used in clinical investigations intended to demonstrate effectiveness (and in some cases safety) of human drugs and biologics.
The guidance discusses three broad categories of enrichment strategies: strategies to decrease variability (including encouraging adherence and decreasing placebo responses and spontaneous improvement), prognostic enrichment strategies (including identifying high-risk patients) and predictive enrichment strategies (identifying more-responsive patients).
“The principal concerns with the use of enrichment strategies relate to the generalizability and applicability of the study results,” the guidance says. “When considering use of an enrichment design, sponsors should consider whether the enrichment strategy could be used in practice to identify the patients to whom the drug should be given and whether the drug might be useful in a broader population.”
As far as regulatory issues sponsors should consider, FDA notes that, “A critical question is almost always how much data will be needed in the off-target (nonenriched) population, particularly for predictive enrichment strategies.”
The guidance also says that sponsors should consider the following two questions when contemplating the use of enrichment designs: Does the enrichment strategy identify the patients to whom the drug should be given? and might the drug be useful in a broader population than was studied?
A Risk-Based Approach to Monitoring of Clinical Investigations Questions and Answers: Draft Guidance for Industry
Enrichment Strategies for Clinical Trials to Support Determination of Effectiveness of Human Drugs and Biological Products: Guidance for Industry