Bioequivalence Assessment of Generic Products: An Innovative South African Approach

Abstract

Concurrent with the implementation of new legislation mandating Generic Substitution in South Africa, a new set of guidelines for bioavailability and bioequivalence have been published. Since one of the main objectives of the new legislation in South Africa relating to Generic Substitution is to ensure that medicines of high quality, safety, and efficacy are made more accessible and more affordable to the wider public, the need to speed up approval of such multi-source products has become a regulatory priority. In order to facilitate this process, various bioequivalence issues have been addressed including important issues such as the acceptance criteria and associated bioequivalence intervals, use of a foreign reference product and the issue of assessing highly variable drugs (HVDs). In addition, dispensations have been made with respect to food effect assessment and variability relating to genetic polymorphism in drug metabolism (genotyping/phenotyping). Furthermore, the use of “old” biostudies submitted in support of an application is subject to expiry date. Acceptance of appropriate data requires that specific criteria such as C_max and AUC, in addition to the usual considerations, also meet the limits specified by the particular registration authority of the country where such products are intended to be marketed. Generally, these limits require that the 90% confidence interval (CI) for AUC and C_max test/reference ratios lies within the acceptance interval of 0.80–1.25 calculated using log-transformed data. While such acceptance criteria are, in general, ubiquitous, some differences in acceptance criteria do exist between various countries. The new guidelines for bioavailability/bioequivalence studies developed by the South African regulatory authority, the Medicines Control Council (MCC), makes provision for highly variable drugs and the use of a non-South African reference product. The MCC requires that the acceptance criterion for C_max ratios be set at 0.75–1.33 while maintaining AUC ratios at 0.80–1.25 using a 90% CI. Furthermore, provision is made to apply scaling based on average bioequivalence assessment and, as an interim measure, consideration has also been given to the use of a foreign reference product provided that equivalence between that product and the innovator product currently available on the South African market can be shown using in vitro testing.

Key words: :

• Bioequivalence
• Acceptance Criteria
• Reference Product
• Highly Variable Drugs

Notes

*Note added in proof: New draft guidelines and amendments are imminent and these requirements, amongst others, are being reconsidered.

[1] Bioavailability and Bioequivalence Data Required as Proof of Efficacy. Regulation Gazette No. 7659, Vol. 455, No. 24785, 168-196, Pretoria 2 May 2003

[2] Medicines and Related Substances Control Act, 1965 (Act No. 101 of 1965) as amended by Act No. 90 of 1997 and Act No. 59 of 2002

[6] US Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research, Guidance for Industry: Bioavailability and Bioequivalence Studies for Orally Administered Drug Products – General Considerations. March 19, 2003

[8] US Department of Health and Human Services, Center for Drug Evaluation and Research. Guidance for Industry: Statistical Approaches to Establishing Bioequivalence. January 2003

[9] Health Canada. Therapeutic Products Directorate Guideline: Conduct and Analysis of Bioavailability and Bioequivalence Studies – Part A: Oral Dosage Formulations Used for Systemic Effects. 1992

[10] Health Canada. Report C. Expert Advisory Committee on Bioavailability, Report on Bioavailability of Oral Dosage Formulations, Not in Modified Release Form, of Drugs Used for Systemic Effects, Having Complicated or Variable Pharmacokinetics. 1992

[11] Health Canada. Therapeutic Products Directorate Guideline: Conduct and Analysis of Bioavailability and Bioequivalence Studies – Part B: Oral Modified Release Formulations. 1996

[12] The European Agency for the Evaluation of Medicinal Products. Evaluation of Medicines for Human Use. Committee for Proprietary Medicinal Products (CPMP). Note for Guidance on The Investigation of Bioavailability and Bioequivalence. July 2001

[16] Dissolution Testing. Regulation Gazette Number 7659, Volume 455, No. 24785, 155-167, Pretoria, 2 May 2003

[17] Health Canada, Therapeutics Products Directorate. Drugs Directorate. Policy Issue – Canadian Reference Product. 1995

[18] US Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research. Draft Guidance for Industry: Food-effect Bioavailability and Bioequivalence Studies. December 2002

[19] Therapeutic Goods Administration, Commonwealth Department of Health and Ageing, CPMP Guideline as Adopted in Australia by the TGA, with amendment: Note for Guidance on the Investigation of Bioavailability and Bioequivalence (CPMP/EWP/QWP/1401/98), April 2002