Bioequivalence Common Deficiencies in Generic Products Submitted for Registration to the South African Health Products Regulatory Authority (SAHPRA).

Abstract

The cost of healthcare has become expensive globally, of which the greater part of the money is spent on buying innovator medicines. In order to make medicine affordable, the development of generic medicines has become paramount. The science of bioequivalence studies of generic products to demonstrate therapeutic equivalence with innovator products has been developed over the last 50years. These studies cost far less as compared to innovator products thereby reducing the cost of medicines. Accelerating access to medicines has become an increasing challenge due to insufficient resources from regulatory authorities, while pharmaceutical industry continues to expand. An investigation on the deficiencies identified during scientific assessments by SAHPRA in submitted bioequivalence studies is therefore paramount. Identification and publication of these deficiencies will assist in accelerating the access of medicines to patients. The aim of the study is to investigate the types and frequency of the common deficiencies observed in the bioequivalence section of generic submissions to SAHPRA. The study was conducted retrospectively over a 7-year period (2011-2017) for generic products that were finalised by the Pharmaceutical and Analytical pre-registration Unit. A more recent analysis on common deficiencies witnessed for applications assessed between 2020 and 2021 was also done to illustrate the consistency in the evaluation practises adopted by SAHPRA. There were 3148 applications finalised between 2011 and 2017, and to attain a representative sample for the study, statistical sampling was conducted. The multi-stage sampling called stratified systematic sampling was selected as the method of choice. The sample size was obtained using the statistical tables found in the literature and confirmed by a sample size calculation resulting in the selection of 325 applications (Fig. 2a). Additionally, 300 master applications were assessed between 2020 and 2021 for up-to-date data (Fig. 2b). All the deficiencies were collected and categorised according to the ICH E3 guideline and components relevant to biostudies. A total of 2458 deficiencies were collected from the selected sample size for applications finalised between 2011 and 2017 where a biostudy was submitted. The majority of the identified deficiencies were from the following categories; in vitro dissolution testing and specifications (18%), study design (17%), details on the test and reference products (16%), issues on sample analysis (16%), and statistical analysis (10%) (Fig. 3). From the applications assessed in 2020-2021, 492 deficiencies were identified with a similar trend compared to those finalised between 2011 and 2017. Comparison of the deficiencies with those reported by the USFDA and WHO PQTm is discussed with similarities outlined. The five most common deficiencies observed were extensively discussed. The outcomes of this study will guide pharmaceutical companies, sponsors, and Clinical Research Organisations (CROs) in submitting quality biostudies which will reduce turnaround times for registration and accelerate access to medicines for patients. In addition, the deficiencies identified will assist assessors from the different regulatory authorities to improve on their bioequivalence assessment.