Site Enrollment Success: Mixed Methods Evaluation and Modeling of an FDA-Approved Phase III Chronic Obstructive Pulmonary Disease Trial

Abstract

The United States (U.S.) FDA mandates the use of multi-phase clinical trials to elucidate important information on drug safety and efficacy prior to approval and marketing. Since the Kefauver-Harris Drug Amendments of 1962, increasing regulations have focused on the mechanism by which these trials are conducted. Given the requirements for clinical trials, particularly randomized controlled trials, an expansive clinical research industry has emerged, led by contract research organizations (CROs). Consequently, by most estimates the cost to bring a drug to market is at least $2 billion, while the U.S. annual gross research and development (R&D) expenditure is approximately $400 billion and growing. A significant portion of these costs are due to site operations—site initiation activities (including IRB approval) and subject recruitment, amongst others. Despite these investments, the success rate is 11.8% and 13.4% for all new drugs and respiratory (COPD) drugs, respectively. Respiratory drug development is specifically challenging due to the increasing prevalence of diseases such as COPD and the complexities of inhaled therapies. Despite the prohibitive cost of such trials and low drug approval success rates, there are few publications or analysis of the metrics associated with the clinical trial process, or its’ operational results and outcomes. Our study hypothesized that a mixed methods approach coupled with mathematical modeling can effectively analyze and produce evidence quantifying known and identifying unknown problematic operational steps which can then be used to develop probabilities for site enrollment success. An initial qualitative analysis revealed recruitment and study start up delays to be a common factor for concerns in clinical trials. Using data from a Phase III COPD study, we derived a model that includes the factors identified including season, site start-up timing, and competition from other COPD studies. This model allowed us to predict an important operational metric, site enrollment success, which can be incorporated into pre-trial planning utilizing simple clinical informatics tools.