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US: FDA reduces number of samples to retain for BA/BE testing

2024/03/28  US FDA

This guidance is intended to provide recommendations for applicants of new drug applications (NDAs) and abbreviated new drug applications (ANDAs), including supplemental applications, and contract research organizations (CROs), regarding the procedures for handling reserve samples from relevant bioavailability (BA) and bioequivalence (BE) studies, as required by §§ 320.38 and 320.63 (21 CFR 320.38 and 320.63), and recommendations regarding responsibilities of each party involved in the study pertaining to reserve samples. In the context of §§ 320.38 and 320.63, the term applicant includes, as appropriate, study sponsor and/or drug manufacturer and the term CRO refers to any party contracted to help conduct BA or BE testing, including, as appropriate, site management organizations (SMOs), investigators, and testing sites.

The guidance highlights:

  • How the test article (T) and reference standard (RS) for BA and BE studies should be distributed to the testing sites
  • How testing sites should randomly select samples for testing and material to maintain as reserve samples
  • How the reserve samples should be retained.
  • Addresses the requirement at 21 CFR 320.38(c) to retain reserve samples of sufficient quantity to permit FDA to perform five times all the release tests required in an application or supplemental application
  • Describes the conditions under which the Agency does not generally intend to take enforcement action against an applicant or CRO for retaining less than the quantity of reserve samples of the test article and reference standard that were used in the BA or BE study as specified in 21 CFR 320.38(c).

The guidance also provides clarifying recommendations related to certain other relevant requirements in §§ 320.38 and 320.63.

This guidance is a revision of the final guidance Handling and Retention of BA and BE Testing Samples (May 2004) (“the 2004 Guidance”). This guidance is issued in part as final guidance and in part as draft guidance. Specifically, Section IV.B. of this guidance is issued as final guidance. It revises and supersedes the agency’s compliance policy related to the quantity of BA and BE samples retained under § 320.38(c) described in the final guidance Compliance Policy for the Quantity of Bioavailability and Bioequivalence Samples Retained Under 21 CFR 320.38(c) (August 2020) (“the 2020 Compliance Policy”), which is hereby withdrawn. Section IV.B also describes the conditions under which the agency generally does not intend to take enforcement action against an applicant or CRO that retains less than the quantity of reserve samples (that is, samples of the T and RS that were used in an in vivo BA or in vivo or in vitro BE study) specified in the regulation. This revised compliance policy is for immediate implementation. It also supersedes statements related to quantity of reserve samples in section IX. Number of Reserve Samples for BA and BE Testing of the draft guidance Nasal Aerosols and Nasal Sprays for Local Action (April 2003). This revised compliance policy is applicable to all reserve samples for BA and BE studies held to date, including reserve samples from previously completed BA or BE studies.

The rest of this guidance is issued as draft guidance for public comment purposes only. It discusses additional recommendations around the handling and retention of BA and BE testing samples. When finalized, it will represent the agency’s current thinking on this topic.

In general, FDA’s guidance documents do not establish legally enforceable responsibilities. Instead, guidances describe the Agency’s current thinking on a topic and should be viewed only as recommendations, unless specific regulatory or statutory requirements are cited. The use of the word should in Agency guidances means that something is suggested or recommended, but not required.

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