Risk factors associated with post-marketing changes in specific obligations of conditionally authorised products in the EU

Abstract

Background: To minimise post-marketing uncertainties for products with a Conditional Marketing Authorisation (CMA) in Europe, specific obligations (e.g. interventional and observational studies) are imposed as a condition to the marketing authorisation (MA). A yearly follow-up of these requirements and assessment of study results is conducted during annual renewal (AR). Objectives: To characterise changes in descriptions and due dates of obligations over time, and identify drug and obligation-related factors associated with these changes. Methods: We performed a retrospective cohort study of obligations imposed on the CMA of products licensed (excluding vaccines) since 2006 with at least one year follow-up or one AR (until 31/12/ 16). Changes in wording or due date of obligations were identified by comparing the MAs of products at granting, AR(s) and conversion of the CMA. Unconditional logistic regression was performed to calculate odds ratios (OR) and 95% confidence intervals (CI) for the association between factors extracted from documentation of the European Medicines Agency and post-marketing changes in completed obligations. Results: For 26 CMA products 79 obligations were requested (median: 2, interquartile range [IQR]: 1-3.75) with a median follow-up of 2 ARs (IQR: 1-3). Of these, 67 were imposed at time of MA and 12 during AR (6 products). In total, 31 changes were observed in 25 obligations (32% of all obligations). Changes concerned a change (delay) of due date (n = 19, 61%), description (n = 4, 13%) or both (n = 8, 26%). Six drug-related factors for changes in 61 completed obligations were identified: prospective use of CMA (OR 0.2, 95% CI 0.06-0.8), CHMP agreement on MA (majority vs. consensus; OR 3.9, 95% CI 1.2-12.4), indication (oncology vs. infectious disease; OR 3.9, 95% CI 1.1-14.0), duration of MA procedure (> 1 vs. ≤ 1 year, including clock stop time; OR 3.4, 95% CI 1.03-11.1), biologicals vs. small molecules (OR 3.3, 95% CI 1.03-10.6) and argumentation for unmet medical need (no satisfactory treatment available vs. major therapeutic advantage; OR 0.2, 95% CI 0.03- 0.8). No obligation-related risk factors were identified. Conclusions: In almost one-third of obligations imposed as a condition to a CMA, at least one change in initial wording or planning was identified. We found six factors associated with risk of change that can inform strategies for better prospective planning of post-marketing studies to reduce uncertainties.