Table 3 Regulatory uncertainties identified
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 |