Clinical Trial Risk in Hepatitis C: Endpoint Selection and Drug Action

Abstract

Background and Aims. This study analyzed the risk of clinical trial failure of new drugs for hepatitis C between January 1998 and January 2015. Methods. Hepatitis C drug development trials that were in phases I-III of clinical trial testing were obtained from the publicly accessible clinical trial repository and other publicly available databases. Drug compounds were excluded from the study if they began their phase I testing before 1998, if they were not industry sponsored, or if they treated secondary complications of hepatitis C. Clinical trial success rates were analyzed in comparison to industry expectations. Further analysis was conducted on the molecule classifications, the mechanisms of action, and the trial endpoints. Results. One hundred and twenty-three unique drug compounds were found to fulfill the inclusion criteria, eight of which had FDA approval. The overall cumulative pass rate for hepatitis C drugs was 20%, which is double the industry expectation rate. Viral inhibitor small molecule drugs significantly reduced the risk of drug failure during clinical trials compared to other mechanisms of action. Conclusion. On average, one in every five drugs that began clinical testing will be approved for market. Viral inhibitor small molecule drugs are the most promising and hold the least risk.

Figure 1

Clinical trial success rates. Clinical trial success rates in hepatitis C are compared against the industry expectations for each phase of clinical trial testing. The transition probability indicates the likelihood that a drug will successfully complete the phase of testing and will transition to the next phase or FDA approval for those in phase III. Cumulative pass rates represent the product of the probabilities of all three clinical trial phases. The sample size, n, indicates the number of drug compounds that have successfully completed that phase.

Figure 2

Clinical trial failures. The causes of clinical trial failures in the development of hepatitis C drugs are divided into medical failures and commercial failures. The number of drugs contributing to each type of failure in each clinical trial phase is shown. The total number of drug compounds that have passed the phase is depicted for reference.

Figure 3

Endpoint selection. The surrogate endpoints for the phase II and III clinical trials were categorized based on the FDA recommended primary surrogate endpoint, SVR12/SVR24. Other surrogate endpoints included changes in baseline level of HCV RNA, EVR, RVR, SVR48, SVR72, and normalization of ALT levels. The success rates of drug trials with other surrogate endpoints versus those with the SVR12/SVR24 endpoints were contrasted by observing the total drug programs versus the successful programs.

Figure 4

Success rate based on mechanism of action. The clinical trial success rates were further analyzed based on the mechanism of action of the drug compound. The four categories, immunotherapy, host inhibitors, viral inhibitors, and other, were compared against the industry expectation for the transition probability of that drug class. The cumulative pass rate indicates the overall probability that a drug from that class will be successful in all phases and achieve FDA approval.

Figure 5

Success rate based on drug class. Clinical trial success rates in hepatitis C based on the drug class, being either a small molecule drug or a biologic. The transition probabilities for each phase as well as the cumulative pass rates were calculated. It is apparent that there are many more small molecule drugs in development and they have a much higher cumulative pass rate than biologics.