Considerations for Comparing a Test Drug with Standard of Care in Phase 2 Clinical Trials of Central Nervous System Disorders

An increasing need exists to understand the benefits of a test drug compared with standard of care (SoC) earlier in development. Even if a drug is superior to placebo, it may not be worthwhile to continue development unless it has advantages over SoC. However, efficacy and safety comparisons versus SoC in early phase studies can be challenging. Analytic studies were conducted to illustrate that in common scenarios simply randomizing a few patients to SoC will frequently yield misleading results. It may take samples sizes at least fivefold greater to achieve reliable comparisons of a test drug with SoC than when comparing versus placebo. Therefore, it is important that the rate of false positive and false negative results be quantitatively evaluated before determining the sample size and the criteria upon which the test drug and SoC will be compared. Because test drugs often have no benefit, comparing a test drug with SoC may unnecessarily use resources that could be devoted to investigating other drugs. Moreover, it can be difficult to construct valid comparisons of a test drug versus SoC without experience with the test drug regarding appropriate dosing, patient population, and so on. An example with actual clinical trial data is used to illustrate how the trade-off between the need and the difficulties in comparing a test drug with SoC in phase 2 can be mitigated using a literature database of placebo-controlled studies to construct a historical comparison.