Design and rationale for the WARFA trial: a randomized controlled cross-over trial testing the therapeutic equivalence of branded and generic warfarin in atrial fibrillation patients in Brazil

Carolina Gomes Freitas,Álvaro Nagib Atallah,Michael Walsh

doi:10.1186/s12872-017-0584-4

Abstract

BackgroundWarfarin is a commonly used anticoagulant. Whether a given dose of the different formulations of Brazilian warfarin will result in the same effect on the international normalized ratio (INR) is uncertain. The aim of the WARFA trial is to determine whether the branded and two generic warfarins available in Brazil differ in their effect on the INR.MethodsWARFA is a cross-over RCT comparing three warfarins. The formulations tested are the branded Marevan® (Uniao Quimica/Farmoquimica) and two generic warfarin (manufactured respectively by Uniao Quimica Farmaceutica Nacional and Laboratorio Teuto Brasileiro). All of them were manufactured in Brazil, are available in all settings of the Brazilian healthcare system and were purchased from retail drugstores. Eligible participants had atrial fibrillation or flutter, had been using warfarin for at least 2 months with a therapeutic range of 2.0–3.0 and had low variability in INR results during the 1st period of the trial. Our primary outcome, for which we have an equality hypothesis, is the difference between warfarins in the mean absolute difference between two INR results, obtained after three and 4 weeks with each drug. Our secondary outcomes, that will be tested for inequality (except for the mean INR, which will be tested for equality), include the difference in the warfarin dose, and time in therapeutic range. Clinical events and adherence were also recorded and will be reported.DiscussionTo our knowledge, WARFA will be the first comparison of the more readily applicable INR results between branded and generic warfarins in Brazil. WARFA is important because warfarins are commonly switched between in the course of a chronic treatment in Brazil. Final results of WARFA are expected in May 2017.Trial registrationClinicalTrials.gov NCT02017197 . Registered 11 December 2013.

Highlights

For generic drugs in solid oral dosage formulations, bioequivalence studies are a requisite [2,3,4]. These studies assess whether the amount of drug absorbed and the rate of absorption between the generic and the branded drug do not show differences greater than prespecified limits [2]
Besides assessing therapeutic equivalence between the effect of generics and the branded drug, an unmet need in Brazil, we will focus on comparing among generic drugs
Despite not devised to be therapeutically equivalent to each other, generic drugs from different manufacturers are commonly switched in the course of a chronic treatment in Brazil, and it is desirable to evaluate their suitability for this purpose

Summary

Introduction

The aim of the WARFA trial is to determine whether the branded and two generic warfarins available in Brazil differ in their effect on the INR. Follow different regulations and instead, are required to demonstrate their similarity to the branded product, already proven efficacious and safe [1]. For generic drugs in solid oral dosage formulations (e.g. tablets), bioequivalence studies are a requisite [2,3,4]. These studies assess whether the amount of drug absorbed and the rate of absorption between the generic and the branded drug do not show differences greater than prespecified limits [2]. In Brazil all bioequivalence claims must still show evidence that the 90% confidence interval (CI) of the difference or of the ratio between the means of the generic and the branded drug comply with the limits of +20% and −20% of the branded drug mean1 [5, 6], whereas a recent guideline set narrower limits for low therapeutic index drugs [2]

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