Influence of Scientific Advice on Marketing Authorisation and post-authorisation withdrawal of ATMPs

Abstract

Background: Regulators from the European Medicines Agency (EMA) provide comprehensive guidelines and expert guidance before Market Authorisation Application (MAA) to enhance the chance of Market Authorisation (MA). The primary objective of this study is to ascertain the influence of Scientific Advice (SA) on Advanced Therapeutic Medicinal Products (ATMPs) at different stages of development on the MA and to investigate its potential impact on withdrawal decisions. Methods: In-depth analysis of scientific literature was used to gain valuable insights into the impact of SA on various pharmaceuticals. Based on this, regulatory research was conducted to gain further insight into ATMPs. Articles were retrieved from PubMed. The Medicines Evaluation Board (MEB) database was used to collect SAs from ATMPs, while the EMA website, ClinicalTrials.gov, and AdisInsight were used to gather data on the ATMPs. The results from the scientific literature were compared to the results of the regulatory research. Results: SA is offered by regulatory authorities to generate robust and reliable data by minimizing Major Objections (MOs) and thus effectively facilitate MAA. Pharmaceuticals which asked for MAA can be approved, rejected or pre- or post-authorisation withdrawn. From all SAs found between 2009 and 2022, 437 SAs were found according to 263 ATMP products, of which 35 ATMP products were asking for MAA. Scientific literature revealed that 23 (68%) ATMPs that underwent MAAs were initially developed by small- and medium-sized enterprises (SMEs) and 20 (59%) were applied by SMEs. However, the MAA outcome was more often positive for non-SMEs, with 12 out of 14 (86%) receiving approval compared to 12 out of 20 (60%) for SMEs. After MA, post-authorisation withdrawal was observed for both 4 (25%) SMEs and non-SMEs. The number of sought SAs differed among ATMPs, but the ATMPs which obtained MA asked for advice an average of four times. In contrast, pre-authorisation withdrawals asked for advice an average of two times. Early SA was strongly recommended based on the scientific literature. Regulatory research showed that five (29%) marketed ATMPs sought advice before the trial start, while twelve (71%) marketed ATMPs sought advice during the trial. The ATMPs that were post-authorisation withdrawn all sought advice during the trial, while none asked before the trial. Furthermore, compliance with SA before and during the trial was researched. The ATMP SAs which were compliant with the study had more influence on MAA success rate when given during the main study. On the other hand, ATMP SAs which were given before the main study had no post-authorisation withdrawals at all, independent of compliance. Conclusions: SA should be actively sought by enterprises multiple times in order to facilitate the MAA. Adherence to SA raises the suspicion of a positive relationship with MA, but it was not proven. Moreover, early (before trial start) SA decreases the chance of post-authorisation withdrawal.