The draft guidance from December, called FDA Enrichment Strategies for Clinical Trials to Support Approval of Human Drugs and Biological Products, offers advice on the ways in which companies can more easily select patients to demonstrate a potential drug’s effect.
Examples of such enrichment strategies include selecting patients “whose disease does not spontaneously disappear or exhibit a large degree of variability, who are likely to comply with treatment, who are likely to have a high rate of disease progression, or who have some characteristic that suggests they can respond to the treatment.”
Pfizer commends the draft for including details and examples illustrating approval pathways for past products but it calls for additional examples from multiple therapeutic areas, including oncology, infection and respiratory.
“The many examples and literature cited in the guidance are informative, but sometimes they appear to mask the principles, which we believe are more generalizable and hence more important, since situations invariably differ among applications,” Eli Lilly says in its comment, noting that it would like the FDA to distinguish between “a possible approach or a preferred one.”
Sanofi goes one step further and asks for numerical examples on population size to help industry in its decision making with the notoriously difficult-to-find “enriched populations.” The company also asks for more clarity on when enrichment strategies might work for non-inferiority assessments.
Similarly, PhRMA (Pharmaceutical Research and Manufacturers of America) requests more detail on technical and statistical issues related to enrichment designs, such as those with the potential for inflated false positive rates.
The guidance also could more clearly delineate when enrichment strategies should be used for exploratory trials versus trials to obtain marketing approval, Generic drugmaker Teva says.
A number of other companies are also requesting the FDA provide more guidance on the use of diagnostics and the ways in which they can be used as enrichment strategies.
For example, Novartis says: “Potential multiplicity issues often arise in simultaneous development of a new drug with a companion diagnostic for identification of patients who are likely to benefit from the drug. While the primary objective of such a study is usually to demonstrate efficacy in a specific patient subpopulation, guidance on whether the utility of the companion diagnostic should be included in a multiplicity adjustment would be helpful.”
Roche also requests more guidance on whether a diagnostic assay for a biomarker used as an enrichment tool will be required to be approved as an in vitro diagnostic (IVD) or a companion diagnostic at the time of drug approval.
Similar questions on IVDs were raised by Lilly, which noted that since FDA guidance on IVDs “is still in draft form, it would be helpful to have some guidance language on timing and requirements for developing companion diagnostics when the classifier is not known at the start of the trial.”