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Table 3 Regulatory uncertainties identified

From: Evidence supporting regulatory-decision making on orphan medicinal products authorisation in Europe: methodological uncertainties

Uncertainty Description Affecting mainly
Lack of clinical trials in MAA N = 15 (12% of all MAA) not including clinical trials, but based on bibliographic reports, observational retrospective studies or compassionate programs. Case-series are not conclusive on causality or size of the effect; safety information was collected in a non-systematic way, making it difficult to quantify risks. Chronic progressive conditions led by multiple system/organs Conditions with single acute episodes
Lack of 2 pivotal trials in MAA N = 87 EPARs (70% of all MAA) not based on at least 2 pivotal trials. The control of type 1 error that is achieved by replication of experiments was lacking. Chronic staged conditions Chronic progressive conditions led by multiple system/organs
Negative trials as the only basis for pivotal regulatory assessment N = 13 EPARs (11.8% of MAA based on clinical trials) based on negative trials as the only basis for assessment. Risk of approval of ineffective therapies based on insufficient evidence. Chronic progressive multidimensional conditions Acute single episodes
Low level of evidence of pivotal data Pivotal clinical trials in MAA using open label (N = 75, 47.2% of all pivotal trials), non-randomised (N = 50, 31.4% of all pivotal trials) and/or not controlled designs (N = 53, 33.3% of all pivotal trials). Lack of robustness for causality assessment, risk of bias and risk of overestimation of benefits. Conditions with single acute episodes Chronic progressive conditions led by one system/organ Chronic progressive conditions led by multiple system/organs
Use of surrogate or intermediate primary variables N = 119 (74.8% of all trials) using intermediate variables as main end-point. Risk that improvements in intermediate parameters are not reliable indicators of clinical benefit, and risk of overestimation of benefits. Chronic conditions with stable or slow progression Chronic progressive conditions led by one system/organ Chronic progressive conditions led by multiple system/organs Chronic staged conditions
Conclusions based on post-hoc analyses 20 pivotal trials (12.6% of all pivotal trials) concluded based on subgroup analysis, of which 5 were not pre-defined. Risk of type 1 error and bias due to data-guided analysis. Chronic progressive conditions led by one system/organ Chronic progressive conditions led by multiple system/organs
Small extent of population exposure to assess clinical safety Mean size of the available safety population smaller than recommended by ICH E1; much lower amongst ultra-rare conditions. Lack of knowledge on frequently expected events do not allow a reliable risk/benefit assessment. Ultrarare conditions Chronic progressive conditions led by multiple system/organs
  1. EPAR European Public Assessment Report, MAA Marketing Authorisation Application