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Statistical approaches to indirectly compare bioequivalence between generics: a comparison of methodologies employing artemether/lumefantrine 20/120 mg tablets as prequalified by WHO

  • Pharmacokinetics and Disposition
  • Published:
European Journal of Clinical Pharmacology Aims and scope Submit manuscript

Abstract

Purpose

The objective of this study was to compare different methods of adjusted indirect comparisons that can be used to investigate the relative bioavailability of different generic products. To achieve this goal, generic artemether/lumefantrine 20/120 mg tablets that have been prequalified by the World Health Organization (WHO) were selected as model products for study.

Methods

Data from three bioequivalence studies conducted independently that compared three generics with the same reference product were used to indirectly determine the relative bioavailability between the generics themselves.

Results

The different methods of indirect comparison examined in this study provide consistent results. Methods based on the assumption of a large sample size give slightly narrower 90 % confidence intervals. Therefore, the use of methods based on the t test is recommended. Given the precision of the area under the time–concentration curve (AUC) data, it is possible to conclude that the extent of exposure of artemether and lumefantrine is bioequivalent between the different generics studied. However, given the precision of the drug peak concentration (Cmax) data, it is not possible to demonstrate equivalence within the conventional acceptance range for all comparisons; it is possible to conclude bioequivalence within the widened acceptance range 75–133 %.

Conclusions

From a clinical viewpoint, not only are these prequalified generics bioequivalent and interchangeable with the reference product (Coartem, Novartis), but also the existing indirect evidence makes it possible to conclude that these WHO prequalified products are bioequivalent between themselves with respect to the AUC. The lack of the necessary precision to demonstrate bioequivalence between generics with respect to the Cmax within the conventional acceptance range does not preclude considering them as interchangeable, if necessary, since Cmax is considered to be of less clinical relevance for the relevant therapy.

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Notes

  1. The WHO Prequalification of Medicines Programme was launched in 2001, in partnership with UNAIDS, UNICEF, and UNFPA, with support from the World Bank. Its original focus was the evaluation of medicines for treatment of human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS), malaria, and tuberculosis. Products in other therapeutic categories are now also assessed. The Programme reviews product dossiers, mainly for generic products, according to stringent, internationally accepted criteria, including data on product quality and bioequivalence, and inspects the corresponding manufacturing sites to assess compliance with good manufacturing practices (GMP). It also inspects contract research organizations (CROs) to verify compliance of the bioequivalence studies with good clinical practice (GCP) and good laboratory practices (GLP).

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Authors and Affiliations

  1. Evaluation and Registration Unit, Medicines Control Authority of Zimbabwe, Harare, Zimbabwe

    Luther Gwaza

  2. School of Pharmacy, University of Zimbabwe, Harare, Zimbabwe

    Luther Gwaza

  3. Division of Biopharmaceutics Evaluation, Bureau of Pharmaceutical Sciences, Therapeutic Products Directorate, Health Canada, Ottawa, Canada

    John Gordon

  4. Medicines Evaluation Board, Utrecht, The Netherlands

    Jan Welink

  5. Subdepartment of Biostatistics and Pharmacokinetics, Federal Insitute for Drugs and Medical Devices, Bonn, Germany

    Henrike Potthast

  6. Efficacy and Safety Department 1, Medical Products Agency, Uppsala, Sweden

    Henrik Hansson

  7. The Prequalification of Medicines Programme Quality Assurance & Safety: Medicines Essential Medicines and Health Products, World Health Organization, Geneva, Switzerland

    Matthias Stahl

  8. División de Farmacología y Evaluación Clínica, Subdirección de Medicamentos de Uso Humano, Agencia Española de Medicamentos y Productos Sanitarios, C/ Campezo 1. Edificio 8, Planta 2 Oeste, 28022, Madrid, Spain

    Alfredo García-Arieta

Authors
  1. Luther Gwaza
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  2. John Gordon
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  4. Henrik Hansson
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  6. Alfredo García-Arieta
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Corresponding author

Correspondence to Alfredo García-Arieta.

Additional information

This manuscript represents the personal opinion of the authors and does not necessarily represent the views or policy of their corresponding Regulatory Agencies or the World Health Organization

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Gwaza, L., Gordon, J., Welink, J. et al. Statistical approaches to indirectly compare bioequivalence between generics: a comparison of methodologies employing artemether/lumefantrine 20/120 mg tablets as prequalified by WHO. Eur J Clin Pharmacol 68, 1611–1618 (2012). https://doi.org/10.1007/s00228-012-1396-1

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  • DOI: https://doi.org/10.1007/s00228-012-1396-1

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