Article type
Year
Abstract
Background: US FDA and the European Medicines Agency (EMA) are responsible for the evaluation and the approval of medicines developed by drug companies. These evaluations are based on the results of marketer studies and submitted to the medicine regulatory agencies. Currently, efficacy proof relies on clinical studies considered individually, whereas meta-analytical evidence are not required. A recent example of the approval process concerns a nasal spray of esketamine (S-ket) for the treatment of treatment-resistant depression in 2019 by the FDA and EMA.
Objectives: Using the example of S-ket, to underline the importance of meta-analyses in regulatory processes, aiming to draw implications for clinical practice, research and regulatory science.
Methods: We performed a systematic-review and meta-analysis of trials on S-ket submitted to the FDA and EMA.
Results: We found 4 Phase III trials:3 short-term placebo-controlled (PLB) efficacy trials and 1 withdrawal trial (table 1). Only 1 short-term efficacy trial found a difference between S-ket+antidepressant (AD) and PBL+AD. Re-analysis of the efficacy data of the 3 short-term studies revealed an overall mean difference of -4.08 in MADRS-score (95%CI -6.20 to 1.97, figure 1), suggesting that S-ket may improve depressive symptoms compared to PLB. Pooled data on acceptability showed that S-ket was significantly less acceptable than PLB (Figure 2). Moreover, S-ket increased by 7 times the risk of dissociation over PLB, with approximately 25% of S-ket treated patients experiencing severe dissociation during treatment (Figure 3). The withdrawal trial showed that participants who discontinued S-ket after improvement with S-ket+AD were more likely to relapse compared to patients that did not discontinue. However, this design carries several limitations; generalizing results from this type of design to patients with a current depressive episode may be challenging.
Conclusions: Re-analysis of the clinical data on S-ket submitted to the FDA and EMA on acceptability and safety outcomes showed a significantly worst profile of S-ket compared to PLB. The statistically significant superiority of S-ket to PLB regarding efficacy can hardly be considered clinically significant. Further, it does not overweight the risks related to the acceptability and tolerability profile of S-ket. This information can only be generated using secondary, i.e. meta-analytical data, the exclusion of which is a real disservice for the approval process.
The case of S-ket offered a unique opportunity to reflect on the evidence supporting the licensing of new agents and, generally, to critically appraise the approval process for new drugs.
We propose that the evaluation process of medicines should be complemented by regulatory meta-analyses of all relevant clinical studies. Based on meta-analytical evidence, agencies could develop a more systematic and transparent approach to summarise the submitted evidence and its quality, using, for example, the Grading of Recommendations, Assessment, Development and Evaluations tool (GRADE).
Objectives: Using the example of S-ket, to underline the importance of meta-analyses in regulatory processes, aiming to draw implications for clinical practice, research and regulatory science.
Methods: We performed a systematic-review and meta-analysis of trials on S-ket submitted to the FDA and EMA.
Results: We found 4 Phase III trials:3 short-term placebo-controlled (PLB) efficacy trials and 1 withdrawal trial (table 1). Only 1 short-term efficacy trial found a difference between S-ket+antidepressant (AD) and PBL+AD. Re-analysis of the efficacy data of the 3 short-term studies revealed an overall mean difference of -4.08 in MADRS-score (95%CI -6.20 to 1.97, figure 1), suggesting that S-ket may improve depressive symptoms compared to PLB. Pooled data on acceptability showed that S-ket was significantly less acceptable than PLB (Figure 2). Moreover, S-ket increased by 7 times the risk of dissociation over PLB, with approximately 25% of S-ket treated patients experiencing severe dissociation during treatment (Figure 3). The withdrawal trial showed that participants who discontinued S-ket after improvement with S-ket+AD were more likely to relapse compared to patients that did not discontinue. However, this design carries several limitations; generalizing results from this type of design to patients with a current depressive episode may be challenging.
Conclusions: Re-analysis of the clinical data on S-ket submitted to the FDA and EMA on acceptability and safety outcomes showed a significantly worst profile of S-ket compared to PLB. The statistically significant superiority of S-ket to PLB regarding efficacy can hardly be considered clinically significant. Further, it does not overweight the risks related to the acceptability and tolerability profile of S-ket. This information can only be generated using secondary, i.e. meta-analytical data, the exclusion of which is a real disservice for the approval process.
The case of S-ket offered a unique opportunity to reflect on the evidence supporting the licensing of new agents and, generally, to critically appraise the approval process for new drugs.
We propose that the evaluation process of medicines should be complemented by regulatory meta-analyses of all relevant clinical studies. Based on meta-analytical evidence, agencies could develop a more systematic and transparent approach to summarise the submitted evidence and its quality, using, for example, the Grading of Recommendations, Assessment, Development and Evaluations tool (GRADE).