Notice2024-06500
Handling and Retention of Bioavailability and Bioequivalence Testing Samples; Guidance for Industry (Part Draft, Part Final); Availability
Primary source
Metadata and text below are from the Federal Register, a public-domain U.S. government work. Always verify the official published version before relying on it for any legal matter.
Published
March 27, 2024
Issuing agencies
Health and Human Services DepartmentFood and Drug Administration
Abstract
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.
Full Text
<html>
<head>
<title>Federal Register, Volume 89 Issue 60 (Wednesday, March 27, 2024)</title>
</head>
<body><pre>
[Federal Register Volume 89, Number 60 (Wednesday, March 27, 2024)]
[Notices]
[Pages 21255-21257]
From the Federal Register Online via the Government Publishing Office [<a href="http://www.gpo.gov">www.gpo.gov</a>]
[FR Doc No: 2024-06500]
-----------------------------------------------------------------------
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.
-----------------------------------------------------------------------
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:
<bullet> Federal eRulemaking Portal: <a href="https://www.regulations.gov">https://www.regulations.gov</a>.
Follow the instructions for submitting comments. Comments submitted
electronically, including attachments, to <a href="https://www.regulations.gov">https://www.regulations.gov</a>
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 <a href="https://www.regulations.gov">https://www.regulations.gov</a>.
<bullet> 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:
<bullet> 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.
<bullet> 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 <a href="https://www.regulations.gov">https://www.regulations.gov</a> or at
the Dockets Management Staff between 9 a.m. and 4 p.m., Monday through
Friday, 240-402-7500.
<bullet> 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 <a href="https://www.regulations.gov">https://www.regulations.gov</a>.
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: <a href="https://www.govinfo.gov/content/pkg/FR-2015-09-18/pdf/2015-23389.pdf">https://www.govinfo.gov/content/pkg/FR-2015-09-18/pdf/2015-23389.pdf</a>.
Docket: For access to the docket to read background documents or
the electronic and written/paper comments received, go to <a href="https://www.regulations.gov">https://www.regulations.gov</a> 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,
<a href="/cdn-cgi/l/email-protection#327f575e5b4141531c7f535c5c5b5d5c725456531c5a5a411c555d44"><span class="__cf_email__" data-cfemail="367b535a5f454557187b5758585f595876505257185e5e4518515940">[email protected]</span></a>.
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
<a href="https://www.fda.gov/drugs/guidance-compliance-regulatory-information/guidances-drugs">https://www.fda.gov/drugs/guidance-compliance-regulatory-information/guidances-drugs</a>, <a href="https://www.fda.gov/regulatory-information/search-fda-guidance-documents">https://www.fda.gov/regulatory-information/search-fda-guidance-documents</a>, or <a href="https://www.regulations.gov">https://www.regulations.gov</a>.
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
</pre><script data-cfasync="false" src="/cdn-cgi/scripts/5c5dd728/cloudflare-static/email-decode.min.js"></script></body>
</html>Indexed from Federal Register on March 27, 2024.
This is legal information, not legal advice. Laws vary by jurisdiction and change frequently. Always verify current law with official sources and consult a licensed attorney in your jurisdiction for advice on your specific situation.