On August 24, 2026, ANVISA published the 6th edition of its Questions and Answers document on Resolution RDC No. 742/2022, which sets out the criteria for conducting relative bioavailability/bioequivalence (BA/BE) studies and pharmacokinetic studies in Brazil. The update, led by the General Management of Medicines (GGMED) through the Therapeutic Equivalence Coordination (CETER), revises one existing item and adds two new sections to the document.

The role of the Q&A document

Resolution RDC No. 742/2022 brings together the technical criteria for demonstrating bioequivalence between generic, similar, and reference medicinal products, structured on currently available scientific knowledge and aimed at international regulatory convergence. Since its publication, the Resolution has received targeted adjustments — such as those introduced by Resolution RDC No. 931/2024 — and is complemented by specific normative instructions, including IN No. 327/2024, on the pharmacodynamic study for topical dermatological corticosteroids. The Q&A document works as a living clarification tool, updated whenever the Agency identifies recurring questions from the pharmaceutical industry sector regarding the Resolution’s application.

What changes with the August update

Item 3.4.11, on demonstrating steady state in multiple-dose studies, was revised. The document details the two accepted methodologies for this demonstration — carried out individually, per participant and per period: (1) evaluating the difference between three concentrations taken immediately before dosing across the study’s last three administrations, which must be no more than ±20% of the mean of those three concentrations; or (2) evaluating the linear regression of those same three concentrations over time, with steady state considered reached when the 90% confidence interval for the estimated variation over the dosing interval falls between 80% and 125%. 

The update also reinforces that the effect of drug absorption at different times of day must be taken into account — evaluation time points must always correspond to the same time of day, and the area under the curve (AUC) analyzed must cover at least a 24-hour interval, even where the dosing interval is shorter.

The new item 3.6 addresses the bioanalytical stage of BA/BE studies and clarifies that, in truncated studies, the absence of samples collected during the terminal phase of the pharmacokinetic profile does not automatically require excluding that participant’s data — samples from all participants who completed the clinical stage must be quantified. Where terminal-phase samples are missing, the analysis must be conducted considering both the inclusion and the exclusion of the affected participant; if this comparison leads to different study conclusions, the company must submit a technical justification supporting the approach adopted, along with a comparative assessment of the results.

The new item 3.7 addresses the calculation of the coefficient of variation (CV) in studies involving highly variable drugs. ANVISA clarifies that the N used for the CV calculation must be the same N used for the study’s other bioequivalence parameters — participants with missing data for one of the reference product periods cannot be retained solely for the CV calculation. Per the Agency’s example, if a study enrolls 60 participants but 10 lack complete data for one period, the CV and the AUC/Cmax parameters must be calculated based on the remaining 50 participants — since a larger N tends to produce a lower CV, which could otherwise lead to an improper widening of the acceptance interval for highly variable drugs.

Practical impact for the pharmaceutical industry sector

For Bioequivalence Centers and study sponsors, these changes reinforce the need for methodological rigor in demonstrating steady state, handling sample losses during the bioanalytical stage, and calculating CV for highly variable drugs — points that directly affect study design, the statistical robustness of results, and, ultimately, ANVISA’s acceptance of the bioequivalence dossier. As a general recommendation, study designs that depart from the standard model described in Resolution RDC No. 742/2022 may still be submitted for CETER’s prior review, under subject code 10608 – Therapeutic Equivalence – Study Protocol.