Global Harmonization of Comparator Products for Bioequivalence Studies

Comparator products should be the products that were shown to be safe and efficacious in pivotal clinical trials to ensure prescribability of generics. The use of a common comparator ensures switchability between generics. The selection of the comparator is a national responsibility and may be different between countries. This paper discusses the current recommendations on selection of comparators, the associated problems, and the possibility of harmonization. Most countries follow the World Health Organization (WHO) recommendations for selecting comparator products and require the comparator product to be obtained from their national markets to ensure switchability between the local comparator and their generics. These recommendations are only feasible in the few countries where the repetition of the bioequivalence study is economically feasible, but they are impracticable in all other countries. Furthermore, the exclusive use of the local comparator to ensure switchability is ethically and scientifically questionable. The innovator product from well-regulated markets should be the global comparator. This harmonization is feasible as the concept already applies in the WHO prequalification program. It is ineffectual to harmonize only the requirements for performing bioequivalence studies, if such a study has to be repeated for every single country simply because of the different comparator products

Global Harmonization of Comparator Products for Bioequivalence Studies

Comparator products should be the products that were shown to be safe and efficacious in pivotal clinical trials to ensure prescribability of generics. The use of a common comparator ensures switchability between generics. The selection of the comparator is a national responsibility and may be different between countries. This paper discusses the current recommendations on selection of comparators, the associated problems, and the possibility of harmonization. Most countries follow the World Health Organization (WHO) recommendations for selecting comparator products and require the comparator product to be obtained from their national markets to ensure switchability between the local comparator and their generics. These recommendations are only feasible in the few countries where the repetition of the bioequivalence study is economically feasible, but they are impracticable in all other countries. Furthermore, the exclusive use of the local comparator to ensure switchability is ethically and scientifically questionable. The innovator product from well-regulated markets should be the global comparator. This harmonization is feasible as the concept already applies in the WHO prequalification program. It is ineffectual to harmonize only the requirements for performing bioequivalence studies, if such a study has to be repeated for every single country simply because of the different comparator products

Regulatory Requirements for the Development of Second-Entry Semisolid Topical Products in the European Union

The development of second-entry topical products is hampered by several factors. The excipient composition should be similar to the reference product because excipients may also contribute to efficacy. Conventional pharmacokinetic bioequivalence studies were not considered acceptable because drug concentrations are measured downstream after the site of action. There was no agreed methodology to characterize the microstructure of semisolids, and waivers of therapeutic equivalence studies with clinical endpoints were not possible. Only the vasoconstrictor assay for corticosteroids was accepted as a surrogate. This paper describes the implementation of the European Union’s stepwise approach for locally acting products to cutaneous products, discusses the equivalence requirements of the EMA Draft Guideline on the Quality and Equivalence of Topical Products, and compares them with the US Food and Drug Administration recommendations. Step 1 includes the possibility of waivers for simple formulations based on in vitro data only (Q1 + Q2 + Q3 + IVRT). Step 2 includes step 1 requirements plus a kinetic study (TS/IVPT/PKBE) to compare the local availability of complex formulations. Step 3 refers to clinical studies with pharmacodynamic/clinical endpoints. As excipients may affect the local tolerability and efficacy of the products, the similarity of excipient composition is required in all steps, except where clinical endpoints are compared

Co-administration of a commonly used Zimbabwean herbal treatment (African potato) does not alter the pharmacokinetics of lopinavir/ritonavir

ObjectiveAfrican potato (Hypoxis obtusa) is commonly used in Sub-Saharan Africa as a complementary herbal remedy for HIV-infected patients. It is unknown whether or not co-administration of African potato alters the pharmacokinetics of protease inhibitor antiretrovirals. The objective of this study was to investigate the impact of the African potato on the steady-state pharmacokinetics of ritonavir-boosted lopinavir (LPV/r).MethodsSixteen adult volunteers were administered LPV/r 400/100 mg twice a day for 14 days, followed by concomitant administration with African potato given once daily for 7 days. Lopinavir plasma exposure as estimated by the area under the concentration-time curve over the 12-h dosing interval (AUC(0-12h), AUCτ) was determined on day 14 and again on day 21. Lopinavir in plasma was analyzed using a validated liquid chromatography with tandem mass spectrometry (LC-MS/MS) method. Steady-state AUCτ and the maximum concentration following dose administration (C(max)) were determined using non-compartmental methods using WinNonlin Professional version 5.2.1. Statistical analyses were performed using Stata version 12.1.ResultsCo-administration of African potato was not associated with any change in lopinavir AUCτ, C(max), or C(trough).ConclusionsAfrican potato when taken concomitantly with LPV/r is well-tolerated and not associated with clinically significant changes in lopinavir pharmacokinetics

Interchangeability between first-line generic antiretroviral products prequalified by WHO using adjusted indirect comparisons

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% confidence interval 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% confidence intervals, 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

Interchangeability between first-line generic antiretroviral products prequalified by WHO using adjusted indirect comparisons

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% confidence interval 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% confidence intervals, 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