Handling and Retention of Bioavailability and Bioequivalence Testing Samples; Guidance for Industry (Part Draft, Part Final); Availability, 21255-21257 [2024-06500]

Download as PDF khammond on DSKJM1Z7X2PROD with NOTICES Federal Register / Vol. 89, No. 60 / Wednesday, March 27, 2024 / Notices define when dental services are inextricably linked to a covered medical service. Additional clarifications were included in the CY2024 MPFS final rule. CMS further established a process by which the agency will consider clinical evidence for future policy clarification consideration. CMS anticipates that these regulatory policy clarifications will result in more dental provider participation in the Medicare program. As a result, the Agency’s General Counsel has advised that CMS should begin to accept dental claim formats to remain in compliance with the Health Insurance Portability and Accountability Act (HIPAA) (Pub. L. 104–191). Therefore, CMS through its Part B Medicare Administrative Contractors (MACs) will begin accepting and processing claims submitted by dental providers on the ADA Dental Claim form and HIPAA-standard electronic format equivalent (837D). Form Number: CMS–10883; Frequency: Occasionally; Affected Public: Private Sector, Business or other for-profits; Number of Respondents: 50,000; Total Annual Responses: 50,000; Total Annual Hours: 12,500. (For policy questions regarding this collection contact Charlene Parks at 410–786– 8684). 2. Type of Information Collection Request: Extension of currently approved Information Collection; Title of Information Collection: Machine Readable Data for Provider Network and Prescription Formulary Content for FFM QHPs; Use: Under 45 CFR 156.122(d)(1)(2), 156.230(b), and 156.230(c), as finalized in the rule, the Patient Protection and Affordable Care Act; HHS Notice of Benefit and Payment Parameters for 2018 (CMS–9934–F), established standards for qualified health plan (QHP) issuers for the submission of provider and formulary data in a machine-readable format to the Department of Health and Human Services (HHS) and for posting the data on issuer websites. These standards provide greater transparency for consumers, including by allowing software developers to access formulary and provider data to create innovative and informative tools. On September 30, 2015, the Office of Management and Budget (OMB) granted approval to the data collection Information Collection for Machine Readable Data for Provider Network and Prescription Formulary Content for FFE QHPs under OMB control number 0938–1284. OMB approval was granted again on November 3, 2017, and March 22, 2021. The Centers for Medicare and Medicaid Services (CMS) is continuing that VerDate Sep<11>2014 17:03 Mar 26, 2024 Jkt 262001 information collection request (ICR) in connection with these machine-readable standards. This ICR serves as a formal request for the renewal of the data collection clearance. The burden estimate for the ICR included in this package reflects the time and effort for QHP and SADP issuers to update and publish the appropriate data and submit it to CMS. No comments were received in response to the 60-day Federal Register notice. Form Number: CMS– 10558 (OMB control number: 0938– 1284); Frequency: Annually; Affected Public: Private Sector, State, Business, and Not-for-Profits; Number of Respondents: 434; Number of Responses: 434; Total Annual Hours: 39,126. (For questions regarding this collection, contact Ana Alza at (667) 290–8569, ext. 70008569). William N. Parham, III, Director, Division of Information Collections and Regulatory Impacts, Office of Strategic Operations and Regulatory Affairs. [FR Doc. 2024–06439 Filed 3–26–24; 8:45 am] BILLING CODE 4120–01–P 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. 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 SUMMARY: PO 00000 Frm 00023 Fmt 4703 Sfmt 4703 21255 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. You may submit comments on any guidance at any time as follows: ADDRESSES: 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 E:\FR\FM\27MRN1.SGM 27MRN1 khammond on DSKJM1Z7X2PROD with NOTICES 21256 Federal Register / Vol. 89, No. 60 / Wednesday, March 27, 2024 / Notices 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-201509-18/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. VerDate Sep<11>2014 17:03 Mar 26, 2024 Jkt 262001 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, Melissa.Mannion@fda.hhs.gov. 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 §§ 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 § 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 (§ 10.115 (21 PO 00000 Frm 00024 Fmt 4703 Sfmt 4703 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 (§ 10.115(g)(2)). FDA has made this determination under § 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 (§ 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, §§ 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 E:\FR\FM\27MRN1.SGM 27MRN1 khammond on DSKJM1Z7X2PROD with NOTICES Federal Register / Vol. 89, No. 60 / Wednesday, March 27, 2024 / Notices 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 §§ 320.38 and 320.63. 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, 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 § 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. VerDate Sep<11>2014 17:03 Mar 26, 2024 Jkt 262001 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 (§ 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. PO 00000 Frm 00025 Fmt 4703 Sfmt 4703 21257 III. Electronic Access Persons with access to the internet may obtain the guidance at https:// www.fda.gov/drugs/guidancecompliance-regulatory-information/ guidances-drugs, https://www.fda.gov/ regulatory-information/search-fdaguidance-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 DEPARTMENT OF HEALTH AND HUMAN SERVICES Food and Drug Administration [Docket No. FDA–2023–N–4181] Agency Information Collection Activities; Submission for Office of Management and Budget Review; Comment Request; Cattle Materials Prohibited From Use in Animal Food or Feed AGENCY: Food and Drug Administration, HHS. ACTION: Notice. The Food and Drug Administration (FDA) is announcing that a proposed collection of information has been submitted to the Office of Management and Budget (OMB) for review and clearance under the Paperwork Reduction Act of 1995. DATES: Submit written comments (including recommendations) on the collection of information by April 26, 2024. SUMMARY: To ensure that comments on the information collection are received, OMB recommends that written comments be submitted to https:// www.reginfo.gov/public/do/PRAMain. Find this particular information collection by selecting ‘‘Currently under Review—Open for Public Comments’’ or by using the search function. The OMB control number for this information collection is 0910–0627. The title of this information collection is ‘‘Cattle Materials Prohibited From Use in Animal Food or Feed.’’ Also include the FDA docket number found in brackets in the heading of this document. FOR FURTHER INFORMATION CONTACT: Rachel Showalter, Office of Operations, Food and Drug Administration, Three White Flint North, 10A–12M, 11601 Landsdown St., North Bethesda, MD 20852, 240–994–7399, PRAStaff@ fda.hhs.gov. ADDRESSES: E:\FR\FM\27MRN1.SGM 27MRN1

Agencies

[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.

-----------------------------------------------------------------------

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

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