Regulatory registration timelines of generic medicines in South Africa: Assessment of the performance of SAHPRA between 2011 and 2022

Background: Various regulatory authorities are experiencing backlogs of applications which result in delayed access to medicines for patients. The objective of this study is to critically assess the registration process utilised by SAHPRA between 2011 and 2022 and determine the fundamental root causes for the formation of a backlog. The study also aims to detail the remedial actions that were undertaken which resulted in the development of a new review pathway termed the risk-based assessment approach for regulatory authorities experiencing backlogs to implement. Methods: A sample of 325 applications was used to evaluate the end-to-end registration process employed for the Medicine Control Council (MCC) process between 2011 and 2017; 129 applications were used for the backlog clearance project (BCP) between 2019 and 2022; 63 and 156 applications were used for the risk-based assessment (RBA) pilot studies in 2021 and 2022, respectively. The three processes are compared, and the timelines are discussed in detail. Results: The longest median value of 2092 calendar days was obtained for the approval times between 2011 and 2017 using the MCC process. Continuous process optimisation and refinement are crucial to prevent recurring backlogs and hence implementation of the RBA process. Implementation of the RBA process resulted in a shorter median approval time of 511 calendar days. The finalisation timeline by the Pharmaceutical and Analytical (P&A) pre-registration Unit, which conducts the majority of the evaluations, is used as a tool for the direct comparison of the processes. The finalisation timeline for the MCC process was a median value of 1470 calendar days, the BCP was 501 calendar days and the RBA process phases 1 and 2 were 68 and 73 calendar days, respectively. The median values of the various stages of the end-to-end registration processes are also analysed in order to build efficiency within the process. Conclusions: The observations from the study have identified the RBA process which can be implemented to reduce regulatory assessment times while assuring the timeous approval of safe and effective, quality medicines. The continuous monitoring of a process remains one of the critical tools required to ensure the effectiveness of a registration process. The RBA process also becomes a better alternative for generic applications that do not qualify to undergo the reliance approach due to its drawbacks. This robust procedure can therefore be utilised by other regulatory agencies that may have a backlog or want to optimise their registration process. The study assesses three different registration processes used between 2011 and 2022; the MCC process is assessed using a sample of finalised applications between 2011 and 2017; the BCP process is assessed using the applications from three re-submission windows (RW) evaluated in 2020; and the RBA pilot studies assessed in 2021 and 2022 using the sample of applications that were in RW8, 10, 11 and 12. The RBA approach is the robust process that was developed upon further refinement and optimisation of the MCC and BCP process and piloted in 2021 and 2022, titled the RBA pilot study phase 1 and 2. Over the 7-year period, 3148 applications were finalised by the P&A pre-registration Unit within SAHPRA of which 2089 were non-sterile. Thus, due to the large application size at hand, a statistical sampling method became a requirement for this research. The sample selected becomes a true representation of the population and results of the study can be generalised to the population. The method of selection and calculation of the representative sample is comprehensively described by Moeti et al. where a sample size of 325 non-sterile products is obtained and used in the study [13, 18, 19]. By comparing the quality requirements for sterile and non-sterile products it is witnessed that the sterile products require additional assessments in the pharmaceutical development Sect. (3.2.P.2) as well as the process validation and or evaluation Sections (3.2.P.3.5). On the other hand, the non-sterile products would normally require additional assessment in the regional section on bioavailability, therefore, assessment times would be similar for both product types. In order to eliminate the backlog, in 2019 SAHPRA started a project named the BCP [19]. The project was initiated with ~ 8220 applications in the pre-registration phase [16]. The implemented process allowed for applicants to re-submit the dossiers, as some information may be outdated since they were submitted as back as 2008. Resubmission windows (RW) were then created according to therapeutic categories with those considered essential in the earlier windows. The applications selected from the BCP were from three RWs, i.e. RW1, RW5 and RW6. RW1 consisted of medicines in the therapeutic category of Human Immunodeficiency Virus (HIV), tuberculosis (TB), vaccines and hepatitis, RW5 was for medicines targeting diabetes, malaria, maternal and new-born health as well as all the priority APIs and RW6 was for medicines targeting respiratory system diseases [20]. An overall of 129 applications from the three windows was employed and only the applications that utilised the full review pathway for quality and bioequivalence scientific assessments were selected. Note that other pathways include the reliance pathway [21] or applications that have previously received preliminary approval from the P&A pre-registration Unit, however, not yet registered and contained minor variations. Since the approval times for these pathways were shorter, this would alter the calculated timeframes, therefore, the applications that undertook the reliance route were not included in the study. The dates at each stage of the BCP registration process for each application were collected from the electronic database/tracker used by the authority. The risk-based pilot project was initiated in September 2021 within the realm of the BCP using 63 applications from (RW8) as they were next in line to be allocated for initial full review. RW8 comprised of medicines in the therapeutic category that treats haematological/immunological diseases as well as medicines that are analgesics and Non-Steroidal Anti-Inflammatory Drugs (NSAIDs). For further optimisation and reproducibility of the process, the RBA pilot study was up-scaled in April 2022 using 159 applications from RW 10, 11 and 12. The therapeutic categories are; endocrine, nutritional, digestive system and metabolic disease for RW10; skin, subcutaneous tissue, musculoskeletal system and connective tissue for RW11; and eye and ear diseases for RW12 [20]. The implementation was made as an intervention to promote efficiencies within the existing registration process and allow accelerated access to medicines. The dates were collected from the database created during the initiation of the pilot studies wherein all activities and dates were recorded and closely monitored at each stage. The dates were collected and information was populated in the respective Microsoft Excel®, 365, Worksheets. The differences between each activity were calculated for each product and median values were calculated for each, to obtain the time it takes for each activity within the registration process. Finalisation is the conclusion of an assessment by each respective Unit before registration. It should be noted that the finalisation timeline by the Pharmaceutical and Analytical (P&A) pre-registration Unit, is used as a tool for the direct comparison of the processes as the Unit is assessing the bulk of the information submitted by the applicant.