OP4-3 - Description of the delay in completion of studies that evaluate the effectiveness of additional risk minimization measures

Background

The evaluation of the effectiveness of additional risk minimization measures (aRMMs) has become an important element of risk management for medicinal products. The effectiveness of aRMMs can be evaluated using routine pharmacovigilance or additional pharmacovigilance activities (i.e. using studies). We evaluated the frequency and duration of delay in completion of studies evaluating the effectiveness of aRMMs for medicines licensed via the central authorization procedure in the European Union (EU).

Methods

We included medicines authorized through the EU centralized procedure between January 2012 and December 2021 using the European Public Assessment Report (EPAR) database. Generic, biosimilar and duplicate applications were excluded. The EPAR related to the marketing authorization (MA) procedure was used to identify aRMMs at MA. For aRMMs implemented at MA, we identified studies evaluating their effectiveness from the approved EU-Risk Management Plan (RMP) at time of MA. For these studies, protocols and final reports were retrieved. The expected date of the final report was collected from the EU-RMP at MA or first study protocol. We checked for each study whether the expected date of final report was before our data lock point (DLP; April 1, 2022). For studies with an expected date of final report before DLP, a Kaplan-Meier analysis was performed to provide insight in the time between the expected final report date and actual final report date. If no final report has been submitted at DLP, studies were censored at DLP. Survival analysis was also performed stratified on study design, which were compared using a log-rank test.

Results

aRMMs were identified for 138 of 538 (25.7%) medicines authorized between 2012 and 2021. Educational material was the most common aRMM, in place for 135 medicines (97.8%). We identified 80 studies for 66 individual medicines (47.8%) with aRMMs. For 70 studies (87.5%), the expected date of final report was provided. The median duration from MA until the expected final report date was 45 months (IQR: 25-60 months). Based on the expected final report date, 44 studies (55.0%) should have been completed at DLP. The majority of these studies (n=35, 79.5%) were delayed for more than three months compared to their expected final report date. Kaplan-Meier survival analysis showed that the probability of finalizing an aRMM effectiveness study within one year after the expected final report date was 30.7%, including studies finished on time. Within two years after the expected final report date, the probability of completing an aRMM effectiveness study increased to 54.7%. The probability of having a final report within two years after the expected final report date was 75.6% for cross-sectional studies (n=27) and 20.2% for cohort studies (n=17), but this difference was not statistically significant (p=0.010).

Conclusion

This study shows that estimates of the duration of aRMM effectiveness studies around MA are too optimistic; 80% of studies were delayed compared to their expected completion date. Additionally, this study suggests that the duration of delay is substantial, with only a 54.7% probability of completing an aRMM effectiveness study within two years after the expected completion date.