The review of drug applications submitted to the European Medicines Evaluation Agency: frequently raised objections, and outcome.

OBJECTIVE: To study the issues raised during the review of drug applications submitted to the European Medicines Evaluation Agency for approval in the European Union and to identify important predictors of outcome.
METHODS: All consecutive applications submitted since September 1997 and which had reached an outcome by May 2001 were included. The factors considered in this exploratory analysis were: year of submission, anatomical therapeutic chemical classification (ATC code), type of medicinal product (biopharmaceuticals vs. new chemical entities), and common "major objections" raised during the review. Predictors were identified using multivariate logistic regression on outcome (positive opinion vs. negative opinion or withdrawal). Examples have been provided to illustrate some of the weaknesses of the applications received, the types of objections raised by the reviewers, and the strategies used to address them.
RESULTS: This series consisted of 111 successive applications for which the review had started between September 1997 and April 2000. It included 73 (66%) new chemical entities and 38 (34%) biopharmaceuticals, the most represented agents being anti-neoplastic and immunomodulating agents, and anti-infectives for systemic use, with 25 (22%), and 19 (17%) applications, respectively. Overall the proportion of drug applications that failed to reach a positive outcome was 32/111 (29%). The most frequent major objections raised were those related to the safety database and to serious adverse events. These clinical safety objections were raised in 54 (48.6%) applications. Another frequent objection was the clinical efficacy objection on the lack of adequate randomised controlled trials, which was raised in 47 (42.3%) applications. This clinical efficacy objection was the only factor that was retained after multivariate selection (P<0.01). The odds of a positive outcome for an application lacking adequate randomised controlled trials were: 0.46 (95% confidence interval 0.29-0.71) times the odds of an application without this objection (P=0.0006).
CONCLUSIONS: Despite the existence of various mechanisms that allow important deficiencies to be resolved, failure to establish clinical efficacy due to the lack of adequate randomised controlled trials remained problematic, leading to a high risk of rejection.