Why Are Innovative Drugs Failing in Phase III?

Drug development aims to achieve evidence-based milestones, progressing in a disciplined fashion from discovery through each phase of clinical development. The foundation of rational drug development is the informed design of a potential medicine based on an understanding of the underlying biology. Translational research establishes the relevance of a biological target for a particular condition prior to studies in humans. Following initial phase I safety trials, pharmacology is confirmed in proof-of-mechanism studies that ensure the intervention is active as designed. Phase IIa proof-of-concept trials then establish efficacy in the intended population and are typically followed by phase IIb dose-finding studies. It is imperative that response-exposure relationships for key efficacy variables be thoroughly explored in phase II in order to optimize dosing regimens in confirmatory trials. Identifying patients who are more or less likely to respond to a drug is complex but can also be addressed in phase II. For example, subjects can be identified post hoc who show a vigorous response to an active drug and in a follow-up trial, rerandomized to active drug or placebo to confirm their responsiveness. The phase III trial could then be enriched for patients with similar characteristics. There is also interest in identifying patients, possibly by genotyping, who may be particularly likely to respond to placebo so these patients can be avoided in future trials. Sponsors might pay a penalty for these methods in that a drug could be approved with a more restrictive label, but one which identifies a subpopulation more likely to benefit. Advancing into phase III trials, the most expensive and challenging to execute, without having rigorously managed the risks associated with each earlier phase of development, can lead to costly failures.

Assuming the completion of a rigorous phase I development program, failure of a phase III study could be related to an inadequate phase II program. For example, an effect size estimate from a phase II study may not be replicated in phase III. This could be driven by a marked increase in variance during phase III from a number of factors, including less experienced sites with less experienced clinical raters; increases in population heterogeneity as studies are carried out in more languages and different cultures; and inclusion of sites contributing very few subjects. In addition, there is evidence from trials in mania and depression that the ability to detect drug-placebo differences actually decreases as the number of subjects and the number of sites increase (1, 2). Naturally, if the primary efficacy outcome measure or analysis in phase III is altered from that used in phase II, assumptions regarding extrapolation to phase III may not hold, with a resultant attenuation of effect size.

Phase II programs may not provide adequate information regarding dose-response relationships. By attempting to accelerate development and/or to reduce the overall cost, many programs overburden early proof-of-concept trials and minimize or even skip phase IIb. This has the potential for bringing forward less than optimal dosing regimens into phase III. Thus, failure may be due to suboptimal dosing. This has been evaluated in post hoc analyses of phase III trial data, demonstrating exposure-response relationships predictive of success had the majority of patients reached appropriate exposure levels.

At the 2017 meeting of the International Society for CNS Clinical Trials and Methodology, study sponsors used their databases to identify factors in trial implementation that may have led to negative results. In one large trial that focused on negative symptoms in schizophrenia, a number of factors were identified that appeared to be associated with a lack of separation between drug and placebo. These included entering subjects on multiple antipsychotics, including subjects who had inadequate drug exposure based on plasma levels, and including individuals who had substantial changes in negative symptoms between screening and baseline. A trial from another company also found that dropping subjects who had substantial changes in symptoms prior to randomization decreased the placebo response. Among study sponsors, there was agreement that changes late in trials to increase the number of subjects tended to lead to an increase in the placebo response. These issues in implementation may occur because the financial incentives for investigators and contract research organizations, and even perhaps within the sponsoring companies, encourage enrollment with ambitious timelines. This may reinforce a tendency to focus on quantity rather than quality and to relax enforcement of entry criteria later in studies.

These observations suggest a number of approaches for improving the ability of phase III trials to detect a signal. Consider first the different possible sources of the problem in the conduct of large phase III clinical trials. These include the patients who are enrolled, the investigators and contract research organizations that conduct these trials, and the pharmaceutical companies that provide overall management for these trials. We will focus here on the following four areas to look for remedies for trying to improve the conduct and effectiveness of phase III trials, assuming that phase II preparation has been adequate: patient selection, severity rating instruments and their use, study design and controlling for the effects of being in a trial, and sponsor policies and procedures regarding trial conduct.