New FDA Draft Guidance for Industry on Bioequivalence Studies

In August 2021, the U.S. Food and Drug Administration (FDA) has announced the availability of a draft guidance for industry entitled “Bioequivalence Studies With Pharmacokinetic Endpoints for Drugs Submitted Under an ANDA.” The guidance document was published on the FDA's website for comment purposes only. Comments and suggestions should be submitted within 60 days.

The new guidance is structured in the sections summarized below:

Chapter I. (Introduction)

The new draft guidance provides recommendations to applicants planning to include bioequivalence (BE) information in abbreviated new drug applications (ANDAs) and ANDA supplements. It is applicable to dosage forms intended for oral administration and to non-orally administered drug products in which reliance on systemic exposure measures is suitable for establishing BE.

The new document revises the draft guidance for industry on "Bioequivalence Studies with Pharmacokinetic Endpoints for Drugs Submitted Under an ANDA" that was issued in December 2013. 

Chapter II. (Background)

In general, to receive approval for an ANDA, an applicant must demonstrate, among other things, that its proposed drug product is bioequivalent to the reference listed drug (RLD). During BE studies, an applicant compares the systemic exposure profile of a test drug product to that of the RLD.

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Chapter III. (Establishing Bioequivalence)

This chapter is divided into two parts. The first part deals with pharmacokinetic studies. The second part is about general considerations on other bioequivalence studies.

A pilot study in a small number of subjects can be carried out before proceeding with a pivotal BE study. FDA recommends that applicants use one of the following study designs for BE studies:

  • A two-period, two-sequence, two-treatment, single-dose crossover study design using either healthy subjects or other populations
  • A single-dose parallel study design
  • A single-dose replicate study design

In certain circumstances, other types of approaches are recommended to support BE, such as

  • In vitro studies (e.g., dissolution/drug-release testing)
  • In vitro tests predictive of human in vivo bioavailability (In Vitro-In Vivo Correlation Studies or “IVIVC”)
  • Pharmacodynamic studies
  • Comparative clinical endpoint studies

Chapter IV. (Establishing Bioequivalence for Different Dosage Forms)

This chapter of the draft guidance provides recommendations for establishing BE for the following specific dosage forms:

  • Oral solutions
  • Immediate-release products: capsules and tablets
  • Suspensions
  • Modified-release products
  • Chewable tablets
  • Orally disintegrating tablets
  • Sublingual
  • Transdermal

FDA recommends that in vivo BE studies are accompanied by in vitro dissolution profiles.

Chapter V. (Special Topics)

This subjection addresses special consideration. For example, it describes what moieties should be measured and how the consumption of alcoholic beverages can affect the release of a drug substance.

Furthermore, in vitro dissolution testing is explicitly addressed.

For immediate-release products, the FDA recommends that "applicants develop optimal discriminating dissolution methods. Applicants may also use the dissolution method set forth in any related official USP drug product monograph or in FDA’s dissolution database, provided that applicants submit adequate dissolution data/information supporting the discriminating ability of the USP or FDA database method being
proposed for the proposed immediate-release product."

For modified-release drug products, the development of specific discriminating dissolution methods is recommended. The submission should include the dissolution method development and validation report with the complete information/data supporting the proposed method. Alternatively, as for immediate-release products, a USP drug product monograph dissolution method or one set forth in FDA’s dissolution database may be used.

Appendix and Glossary

The annex to the guideline contains information concerning the general design and data handling of BE studies with pharmacokinetic endpoints and two methods for statistical analysis. The guidance ends with a short glossary.

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