title: Interchangeability between first-line generic antiretroviral products prequalified by WHO using adjusted indirect comparisons.
abstract: BACKGROUND
  The scaling-up of access to antiretroviral therapy, particularly in low- to middle-income countries, was facilitated by the introduction and widespread use of generic antiretroviral medicines and fixed-dose combinations. Generic medicines are approved by regulatory authorities based on the demonstration of bioequivalence with the innovator or reference product, as well as meeting quality standards. In clinical practice, however, it is not unusual for generics to be interchanged between each other. This study investigated the differences in bioavailability between WHO-prequalified first-line antiretroviral generics by means of adjusted indirect comparisons to ensure interchangeability between these generics.
  
  
  METHODS
  Data on 34 products containing emtricitabine, tenofovir disoproxil fumarate, lamivudine and efavirenz in single formulations or fixed-dose combinations were included in the analysis. The 90% CI for the adjusted indirect comparisons was calculated using the homoscedastic method that uses the conventional t-test, and assumes homogeneity of variances between the studies and small sample sizes. The combined standard deviation of both bioequivalence studies was calculated from the variability of each individual study.
  
  
  RESULTS
  The adjusted indirect comparisons between generics showed that the differences, expressed as 90% CIs, are less than 30%. Confidence in the interchangeability of two generic products was reduced if the mean difference between the test and reference in the original studies is more than 10%.
  
  
  CONCLUSIONS
  From a bioequivalence perspective, the generic antiretroviral medicines prequalified by WHO are interchangeable with the reference, as well as between each other without safety or efficacy concerns.
authors.affiliation: Utrecht Institute for Pharmaceutical Sciences (UIPS), Utrecht, the Netherlands.|Medicines Control Authority of Zimbabwe, Harare, Zimbabwe.
authors.forename: Luther
authors.initials: L
authors.lastname: Gwaza
authors.affiliation: Division of Biopharmaceutics Evaluation, Bureau of Pharmaceutical Sciences, Therapeutic Products Directorate, Health Canada, Ottawa, Canada.
authors.forename: John
authors.initials: J
authors.lastname: Gordon
authors.affiliation: Medicines Evaluation Board, Utrecht, the Netherlands.
authors.forename: Jan
authors.initials: J
authors.lastname: Welink
authors.affiliation: Sub department of Biostatistics and Pharmacokinetics, Federal Institute for Drugs and Medical Devices, Bonn, Germany.
authors.forename: Henrike
authors.initials: H
authors.lastname: Potthast
authors.affiliation: Utrecht Institute for Pharmaceutical Sciences (UIPS), Utrecht, the Netherlands.|Medicines Evaluation Board, Utrecht, the Netherlands.
authors.forename: Hubert
authors.initials: H
authors.lastname: Leufkens
authors.affiliation: The Prequalification of Medicines Programme Quality Assurance and Safety: Medicines, Essential Medicines and Health Products, World Health Organization, Geneva, Switzerland.
authors.forename: Matthias
authors.initials: M
authors.lastname: Stahl
authors.affiliation: División de Farmacología y Evaluación Clínica, Departamento de Medicamentos de Uso Humano, Agencia Española de Medicamentos y Productos Sanitarios, Madrid, Spain.
authors.forename: Alfredo
authors.initials: A
authors.lastname: García-Arieta
mesh_terms: D000480:Alkynes; D019380:Anti-HIV Agents / Q000493:pharmacokinetics*; D019540:Area Under Curve; D048588:Benzoxazines / Q000493:pharmacokinetics*; D001682:Biological Availability; D003521:Cyclopropanes; D004338:Drug Combinations; D016568:Drugs, Generic / Q000493:pharmacokinetics*; D000068679:Emtricitabine / Q000493:pharmacokinetics*; D015658:HIV Infections / Q000188:drug therapy / Q000821:virology; D006801:Humans; D019259:Lamivudine / Q000493:pharmacokinetics*; D015233:Models, Statistical; D000068698:Tenofovir / Q000493:pharmacokinetics*; D013810:Therapeutic Equivalency; D014944:World Health Organization
chemical_list: D000480:Alkynes; D019380:Anti-HIV Agents; D048588:Benzoxazines; D003521:Cyclopropanes; D004338:Drug Combinations; D016568:Drugs, Generic; D019259:Lamivudine; D000068698:Tenofovir; D000068679:Emtricitabine; C098320:efavirenz