In December 2012, the Food and Drug Administration (FDA) published a draft guidance entitled, Enrichment Strategies for Clinical Trials to Support Approval of Human Drugs and Biological Products, to address approaches on selecting a study population in clinical trials for new drugs and biologics. The issuance fulfills one of the performance goals to which FDA committed as part of the reauthorization of the Prescription Drug User Fee Act (PDUFA) IV. The guidance delineates several tactics for “enrichment,” which it defines as “the prospective use of any patient characteristic to select a study population in which detection of a drug effect … is more likely than it would be in an unselected population.” While the draft is not legally binding, it provides FDA’s current thinking. Comments on the draft guidance may be submitted to FDA until February 15, 2013.
As background, FDA has explained that the main goal of enrichment is study efficiency, i.e., increasing the chance of study success, frequently with a smaller sample size. Enrichment can also provide individualization by directing treatment where it will do the most good (i.e., personalized medicine) while sparing those that might not benefit from a potential treatment. The draft guidance explains that such study designs can have many benefits, including an improved risk-benefit evaluation if a population with an increased likelihood of response can be identified, and efficiency in drug development when smaller studies are sufficient to demonstrate effectiveness.
This bulletin highlights some of the major points described in the draft guidance. It is not intended to address all of the technical issues.
Three Principal Enrichment Strategies
• Decreasing Heterogeneity – Practical Enrichment
To increase a trial’s ability to demonstrate a treatment effect, FDA suggests certain strategies to decrease heterogeneity, or the variability of effects not related to the drug.
Some of the recommendations include, but are not limited to:
(1) Define entry criteria carefully.
• exclude patients unlikely to tolerate the study drug
(2) Find likely compliers prospectively before randomization.
• encourage patient compliance with the study by familiarizing patients with the
• exclude those who might drop out for non-medical reasons
(3) Eliminate placebo responders in a lead-in period.
• treat patients with a placebo prior to randomizing them, in order to eliminate patients from the trial who improve spontaneously or have large
• this approach attempts to eliminate those patients that might have improved for reasons other than the study drug
(4) Eliminate people taking drugs with the same effect as the study drug.
However, the agency cautions against certain strategies, such as removing patients from the study with “concomitant illness likely to lead to early death or … drop-out,” because doing so may not provide enough information about the range of people who may receive the treatment in practice, such as the elderly or people with multiple illnesses. Further, the guidance noted there is uncertainty as to whether these illnesses do not affect survival or other clinical endpoints (a sign of one of the target outcomes of the trial).
• Prognostic Enrichment — Identifying High-Risk Patients
Another way sponsors may be able to more readily detect a treatment effect is through prognostic enrichment strategies, where sponsors choose patients more likely to have the medical condition under study (study endpoint) or have a large change in the endpoint being measured during the study. FDA particularly encourages these strategies for cardiovascular disease or cancer trials aiming to reduce the rate of death or serious events, as well as trials intending to delay progression of diseases such as Alzheimer’s or Parkinson’s. These strategies may allow for a trial to have a smaller sample size, because they increase the trial’s “absolute effect size.”
• Predictive Enrichment — Choosing Patients More Likely to Respond to Treatment
In order to increase a trial’s absolute and relative effect size, the agency recommends utilizing predictive enrichment strategies, where a sponsor selects patients with a greater likelihood of responding to the study drug. The agency advises using these strategies particularly early in studies to demonstrate effectiveness, because they can provide “proof of concept” (feasibility of conducting a study) and facilitate selection of appropriate doses for subsequent studies. FDA also suggests that a predictive enrichment strategy is appropriate to show effectiveness when the number of patients responding to the drug is a “small fraction of all patients, say 20%,” and even facilitates “development and approval” for significantly toxic drugs, because it avoids toxicity exposure in patients not benefiting from treatment.
FDA describes a number of factors to take into account when selecting subjects, including patient characteristics (e.g., pathophysiology, genomic) or empiric factors (e.g., patient history of response to similar drugs, past response to the test drug in a randomized withdrawal study).
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