Enrichment Designs: Efficiency in Development of Cancer Treatments

The analysis of an enrichment study design by Friedlin and Simon in this issue of the Journal of Clinical Oncology addresses the critical drug development issue of efficiency. It has long been recognized that it is possible to identify patient subpopulations selected from the general population in which it is more likely to show a drug benefit than it would be in an unselected population. The selection of such populations has been called enrichment and ranges from practical, variance-decreasing maneuvers (choosing people likely to stay in study and follow directions, people whose blood pressure remains elevated after a period of observation, or people with stable exercise tests); to pathophysiologic selection of people with potentially responsive disease (breast cancer patient with Her2-positive tumors to test trastuzumab); to selection of people likely to have an event that is being measured (people with a past history of an acute infarction, very high cholesterol, or elevated C-reactive protein to test a treatment to prevent reinfarction, because they are more likely to have another infarction; people with rapidly increasing prostate-specific antigen, who are more likely to die of prostate cancer, for a survival trial of a prostate cancer adjuvant treatment). All these selection maneuvers are reasonably well established and not controversial, except insofar as the generalizability of the study results to the general population may arise. A less common enrichment design is to use early response to the test drug to choose the people who will be randomly assigned into a long-term study. A classic example of this design was the Cardiac Arrhythmia Suppression Trial (CAST), which randomly assigned postinfarction patients to a long-term survival study of encainide/flecainide compared with placebo only if they had 70% reduction of ventricular premature beat (VPB) rates during a prerandomization trial period. The rationale for this design was that if a drug had no effect on VPB rate, the postinfarction signal of risk, it could not affect survival. Despite the imaginative design, the result of CAST greatly enhanced nervousness about reliance on surrogate end points in cardiovascular medicine, as it showed a substantially increased mortality in the treated patients, despite their excellent VPB response. Friedlin and Simon explore a study design for cytostatic drugs that is similar in concept to that used in the CAST, although it is different in detail because of different circumstances. Although the CAST investigators could simply look for the desired short-term VPB response, withdraw the drug, and randomly assign the responders to the longterm treatment, it would not be satisfactory in patients with malignancy to withdraw everyone from treatment after a 16-week period to examine response, await some return of tumor growth, and then randomly assign the patients to drug or placebo. Instead, they examined a randomized withdrawal design in which after a 16-week treatment period, some of the treated patients (the ones doing reasonably well) would be randomly assigned to continued treatment or receive placebo, and considered how this approach compared with ordinary upfront randomization with respect to efficiency (sample size needed to attain adequate power) in demonstrating an effect on progression rates. In addition to efficiency, of course, the design is attractive to patients and physicians because everyone has a chance to receive the new treatment. Not surprisingly, but now shown quantitatively, the efficiency of the randomized withdrawal design depends on the behavior of the tumor. If the main determinant of response is the inherent growth rate of the tumor (they respond if their growth rate is below some threshold), upfront randomization is generally more efficient. But if there is a responder subpopulation (independent of growth rate), and patients chosen for randomization are those with stable disease ( 10% growth in tumor diameter at 16 weeks), the randomized withdrawal JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 23 NUMBER 22 AUGUST 1 2005