[Federal Register Volume 89, Number 60 (Wednesday, March 27, 2024)]
[Notices]
[Pages 21255-21257]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2024-06500]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. FDA-2002-D-0176 (Formerly Docket No. 2002D-0350)]


Handling and Retention of Bioavailability and Bioequivalence 
Testing Samples; Guidance for Industry (Part Draft, Part Final); 
Availability

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice of availability.

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SUMMARY: The Food and Drug Administration (FDA or Agency) is announcing 
the availability of a guidance for industry entitled ``Handling and 
Retention of BA and BE Testing Samples.'' 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, and recommendations regarding 
responsibilities of each party involved in the study pertaining to 
reserve samples. Additionally, this guidance 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 specified in the regulation.

DATES: Submit either electronic or written comments on the draft 
portion of this guidance by May 28, 2024 to ensure that the Agency 
considers your comment on this draft guidance before it begins work on 
the final version of the guidance. Comments on the final portion of 
this guidance may be submitted at any time for Agency consideration.

ADDRESSES: You may submit comments on any guidance at any time as 
follows:

Electronic Submissions

    Submit electronic comments in the following way:
     Federal eRulemaking Portal: https://www.regulations.gov. 
Follow the instructions for submitting comments. Comments submitted 
electronically, including attachments, to https://www.regulations.gov 
will be posted to the docket unchanged. Because your comment will be 
made public, you are solely responsible for ensuring that your comment 
does not include any confidential information that you or a third party 
may not wish to be posted, such as medical information, your or anyone 
else's Social Security number, or confidential business information, 
such as a manufacturing process. Please note that if you include your 
name, contact information, or other information that identifies you in 
the body of your comments, that information will be posted on https://www.regulations.gov.
     If you want to submit a comment with confidential 
information that you do not wish to be made available to the public, 
submit the comment as a written/paper submission and in the manner 
detailed (see ``Written/Paper Submissions'' and ``Instructions'').

Written/Paper Submissions

    Submit written/paper submissions as follows:
     Mail/Hand Delivery/Courier (for written/paper 
submissions): Dockets Management Staff (HFA-305), Food and Drug 
Administration, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852.
     For written/paper comments submitted to the Dockets 
Management Staff, FDA will post your comment, as well as any 
attachments, except for information submitted, marked and identified, 
as confidential, if submitted as detailed in ``Instructions.''
    Instructions: All submissions received must include the Docket No. 
FDA-2002-D-0176 (formerly Docket No. 2002D-0350) for ``Handling and 
Retention of BA and BE Testing Samples.'' Received comments will be

[[Page 21256]]

placed in the docket and, except for those submitted as ``Confidential 
Submissions,'' publicly viewable at https://www.regulations.gov or at 
the Dockets Management Staff between 9 a.m. and 4 p.m., Monday through 
Friday, 240-402-7500.
     Confidential Submissions--To submit a comment with 
confidential information that you do not wish to be made publicly 
available, submit your comments only as a written/paper submission. You 
should submit two copies total. One copy will include the information 
you claim to be confidential with a heading or cover note that states 
``THIS DOCUMENT CONTAINS CONFIDENTIAL INFORMATION.'' The Agency will 
review this copy, including the claimed confidential information, in 
its consideration of comments. The second copy, which will have the 
claimed confidential information redacted/blacked out, will be 
available for public viewing and posted on https://www.regulations.gov. 
Submit both copies to the Dockets Management Staff. If you do not wish 
your name and contact information to be made publicly available, you 
can provide this information on the cover sheet and not in the body of 
your comments and you must identify this information as 
``confidential.'' Any information marked as ``confidential'' will not 
be disclosed except in accordance with 21 CFR 10.20 and other 
applicable disclosure law. For more information about FDA's posting of 
comments to public dockets, see 80 FR 56469, September 18, 2015, or 
access the information at: https://www.govinfo.gov/content/pkg/FR-2015-09-18/pdf/2015-23389.pdf.
    Docket: For access to the docket to read background documents or 
the electronic and written/paper comments received, go to https://www.regulations.gov and insert the docket number, found in brackets in 
the heading of this document, into the ``Search'' box and follow the 
prompts and/or go to the Dockets Management Staff, 5630 Fishers Lane, 
Rm. 1061, Rockville, MD 20852, 240-402-7500.
    You may submit comments on any guidance at any time (see 21 CFR 
10.115(g)(5)).
    Submit written requests for single copies of the guidance to the 
Division of Drug Information, Center for Drug Evaluation and Research, 
Food and Drug Administration, 10001 New Hampshire Ave., Hillandale 
Building, 4th Floor, Silver Spring, MD 20993-0002. Send one self-
addressed adhesive label to assist that office in processing your 
requests. See the SUPPLEMENTARY INFORMATION section for electronic 
access to the guidance document.

FOR FURTHER INFORMATION CONTACT: Melissa Mannion, Center for Drug 
Evaluation and Research, Food and Drug Administration, 10903 New 
Hampshire Ave., Silver Spring, MD 20993, 240-672-5296, 
[email protected].

SUPPLEMENTARY INFORMATION:

I. Background

    FDA is announcing the availability of a guidance for industry 
entitled ``Handling and Retention of BA and BE Testing Samples.'' This 
guidance is a revision of the previously issued final guidance of the 
same name from May 2004 and is intended to provide recommendations for 
applicants of NDAs and ANDAs, including supplemental applications, and 
CROs, regarding the procedures for handling reserve samples from 
relevant BA and BE studies, as required by Sec. Sec.  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. Additionally, this guidance revises and supersedes the 
Agency's compliance policy related to the quantity of BA and BE samples 
retained under FDA regulations described in the final guidance entitled 
``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.
    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 for immediate implementation. It revises and 
supersedes the Agency's compliance policy related to the quantity of BA 
and BE samples retained under Sec.  320.38(c) (21 CFR 320.38(c)) 
described in the 2020 Compliance Policy, and 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 test article (T) and 
reference standard (RS) that were used in an in vivo BA or in vivo or 
in vitro BE study) specified in the regulation. 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 entitled 
``Nasal Aerosols and Nasal Sprays for Local Action'' (April 2003).
    In accordance with section 701(h)(1)(C)(i) of the Federal Food, 
Drug, and Cosmetic Act (21 U.S.C. 371(h)(1)(C)(i)) and the good 
guidance practices (GGP) regulation (Sec.  10.115 (21 CFR 10.115)), the 
Agency is immediately implementing section IV.B. of the guidance on the 
quantity of reserve samples without prior public comment because FDA 
has determined that prior public participation is not feasible or 
appropriate as public comment would not affect the specifications of 
FDA's testing of retention samples (Sec.  10.115(g)(2)). FDA has made 
this determination under Sec.  10.115(g)(2) because, with technological 
advances, the reduced quantity of reserve samples is sufficient for FDA 
testing; this reduced quantity will provide a less burdensome approach 
for applicants and CROs but remains consistent with the Agency's 
mission to ensure public health. Although this subsection of the 
guidance document is immediately in effect, it remains subject to 
comment in accordance with FDA's GGP regulation and FDA will consider 
all comments received and revise the guidance document as appropriate 
(Sec.  10.115(g)(3)). The remainder of the guidance is being issued in 
draft, consistent with the GGP regulation, to solicit public comment 
prior to implementation.
    In the Federal Register on November 8, 1990 (55 FR 47034), FDA 
issued an interim rule that amended, in relevant part, part 320 (21 CFR 
part 320), by adding a requirement to retain reserve samples of certain 
drug products (that is, samples of the drug products that were used to 
conduct BA or BE studies) for a specified period and, when specifically 
requested, to release the reserve samples to the Agency. The interim 
rule was intended largely to help ensure BE between generic drugs and 
their reference listed drugs and to help FDA investigate possible fraud 
in BA and BE testing. After consideration of public comments, FDA 
published a final rule in the Federal Register on April 28, 1993 (58 FR 
25918).
    In the final rule, Sec. Sec.  320.38 and 320.63 require an NDA or 
ANDA applicant (or, if testing is performed under contract, its CRO) to 
retain reserve samples of the T and RS that were used to conduct 
certain in vivo BA studies or an in vivo or in vitro BE study submitted 
in support of the approval of an application or supplemental 
application. In the preamble to the final rule, the Agency stated that 
the study sponsor and/or drug manufacturer should not separate out the 
reserve samples of the T and RS before sending the drug product to the 
testing site, to ensure that the reserve samples are in fact 
representative of the drug product provided by the study sponsor and/or 
drug manufacturer for the testing. The

[[Page 21257]]

Agency also noted that the organization that conducts the BA or BE 
study is responsible for retaining the reserve samples to eliminate 
potential sample substitution by the study sponsor and/or drug 
manufacturer and alteration of any reserve samples from a study before 
release of drug product samples to FDA.
    FDA has observed a number of concerning handling and retention 
practices upon inspections of clinical and analytical sites that 
perform BA and BE studies for study sponsors and/or drug manufacturers 
seeking approval of drug products under NDAs and ANDAs. Based on this 
experience, FDA is updating and clarifying our recommendations for 
applicants of NDAs and ANDAs, including supplemental applications, and 
CROs regarding the procedures related to the handling and retention of 
reserve samples from relevant BA and BE studies, as required by 
Sec. Sec.  320.38 and 320.63. In the context of Sec. Sec.  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, investigators, and testing sites. 
Specifically, the guidance highlights: (1) how the T and RS for BA and 
BE studies should be distributed to the testing sites, (2) how testing 
sites should randomly select samples for testing and material to 
maintain as reserve samples, and (3) how the reserve samples should be 
retained. Examples of typical roles of each stakeholder for the 
handling and retention of reserve samples in various study settings are 
also discussed in the guidance.
    In response to comments received to the August 2020 Compliance 
Policy, the Agency has updated its policy on the conditions under which 
FDA generally does not intend to enforce the quantity requirement at 
Sec.  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) to reduce further the 
recommended minimum quantity of reserve samples to be retained. The 
additional reduction in the recommended minimum quantity described in 
this guidance relative to what was described in the August 2020 
Compliance Policy is reflective of adjustments made to the Agency's 
procedures to accommodate continued concerns from industry, 
particularly for studies involving multiple shipments to multiple 
testing sites, regarding the ability to retain a sufficient quantity of 
reserve samples.
    FDA has determined that, using the Agency's current testing 
methodology, the updated recommended minimum quantities of reserve 
samples described in this guidance are sufficient for FDA to conduct 
the necessary testing of the T and RS samples used in a BA or BE study 
as intended by the regulation. Accordingly, at this time and based on 
FDA's current understanding of the risks involved, FDA generally does 
not intend to enforce the requirement to retain a sufficient quantity 
to perform five times all the release tests required in the application 
or supplemental application, so long as the recommended lower 
quantities in this guidance are retained. This 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.
    This guidance is being issued consistent with FDA's GGP regulation 
(Sec.  10.115). The draft portion of the guidance, when finalized, will 
represent the current thinking of FDA on ``Handling and Retention of BA 
and BE Testing Samples.'' A guidance does not establish any rights for 
any person and is not binding on FDA or the public. You can use an 
alternative approach if it satisfies the requirements of the applicable 
statutes and regulations.

II. Paperwork Reduction Act of 1995

    While this guidance contains no collection of information, it does 
refer to previously approved FDA collections of information. The 
previously approved collections of information are subject to review by 
the Office of Management and Budget (OMB) under the Paperwork Reduction 
Act of 1995 (PRA) (44 U.S.C. 3501-3521). The collections of information 
in 21 CFR part 312 for investigational new drug products have been 
approved under OMB control number 0910-0014. The collections of 
information in 21 CFR part 314 for new drug applications and 
abbreviated new drug applications have been approved under OMB control 
number 0910-0001. The collections of information in part 320 for 
``Investigational New Drug Safety Reporting Requirements for Human Drug 
and Biological Products and Safety Reporting Requirements for 
Bioavailability and Bioequivalence Studies in Humans'' have been 
approved under OMB control number 0910-0672. The recordkeeping 
requirement for current good manufacturing practice sample retention in 
21 CFR 211.170 has been approved under OMB control number 0910-0139.

III. Electronic Access

    Persons with access to the internet may obtain the guidance at 
https://www.fda.gov/drugs/guidance-compliance-regulatory-information/guidances-drugs, https://www.fda.gov/regulatory-information/search-fda-guidance-documents, or https://www.regulations.gov.

    Dated: March 22, 2024.
Lauren K. Roth,
Associate Commissioner for Policy.
[FR Doc. 2024-06500 Filed 3-26-24; 8:45 am]
BILLING CODE 4164-01-P