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Why Are Innovative Drugs Failing in Phase III?

There is a disturbing trend in studies of new drugs for psychiatric disorders. A number of innovative and promising drugs that appear to show effectiveness in phase II trials fail in phase III. In some cases, the study sponsormay discontinue further development of the drug based on the results. It is possible that the phase II results weremisleading and that the program should have never moved to phase III because of a lack of efficacy or adverse effects. This commentary addresses an alternative explanation; that is, effective drugs are failing because of systematic problems in the methods for carrying out large, multinational phase III trials. If this is the case, it is vital for our field to address this problem because medications that can improve the lives of people with serious mental illness may never reach the clinic. In addition, the failure of these trials appears to have convinced some companies to limit investment in the CNS area and in psychiatry in particular, substantially decreasing the resources available for drug development. In phase II drug trials, the agent is administered to patients with a particular disease or condition. These studies usually include hundreds of patients and are essential for establishing the agent’s effect size, dose range, and general safety and tolerability profile. Phase III trials are much larger and can involve 300 to 3,000 participants. These studies can confirm the phase II findings and provide additional safety information. Recently, these trials have been global and have included as many as 200 different research sites. An important observation from a number of recently completed phase III trials is that the active drug resulted in similar symptom reduction as in the phase II trials. However, the placebo response was substantially greater, and the active drug did not separate from placebo. Another characteristic of these studies is that they often have aggressive timelines. Sites and contract research organizations are reimbursed based on the number of subjects who are randomized, and there is often pressure to meet deadlines.