Rule2024-02741
Biologics License Applications and Master Files
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
February 12, 2024
Effective
March 13, 2024
Issuing agencies
Health and Human Services DepartmentFood and Drug Administration
Abstract
The Food and Drug Administration (FDA, the Agency, or we) is issuing a final rule to amend its regulations to address the use of master files by applications licensed under the Public Health Service Act (PHS Act). This final rule codifies FDA's existing approach that former approved applications for certain biological products under the Federal Food, Drug, and Cosmetic Act (FD&C Act) that have been deemed to be licenses for the biological products under the PHS Act may continue to incorporate by reference drug substance, drug substance intermediate, or drug product (DS/DSI/DP) information contained in a drug master file (DMF) if such information was being referenced at the time the application was deemed to be a license. This final rule also codifies FDA's general practices regarding the referencing of information in master files by applications licensed under the PHS Act, including applications for combination products licensed under the PHS Act, and by investigational new drug applications (INDs) for products that would be subject to licensure under the PHS Act.
Full Text
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[Federal Register Volume 89, Number 29 (Monday, February 12, 2024)]
[Rules and Regulations]
[Pages 9743-9757]
From the Federal Register Online via the Government Publishing Office [<a href="http://www.gpo.gov">www.gpo.gov</a>]
[FR Doc No: 2024-02741]
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DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
21 CFR Part 601
[Docket No. FDA-2019-N-1363]
RIN 0910-AH50
Biologics License Applications and Master Files
AGENCY: Food and Drug Administration, HHS.
ACTION: Final rule.
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SUMMARY: The Food and Drug Administration (FDA, the Agency, or we) is
issuing a final rule to amend its regulations to address the use of
master files by applications licensed under the Public Health Service
Act (PHS Act). This final rule codifies FDA's existing approach that
former approved applications for certain biological products under the
Federal Food, Drug, and Cosmetic Act (FD&C Act) that have been deemed
to be licenses for the biological products under the PHS Act may
continue to incorporate by reference drug substance, drug substance
intermediate, or drug product (DS/DSI/DP) information contained in a
drug master file (DMF) if such information was being referenced at the
time the application was deemed to be a license. This final rule also
codifies FDA's general practices regarding the referencing of
information in master files by applications licensed under the PHS Act,
including applications for combination products licensed under the PHS
Act, and by investigational new drug applications (INDs) for products
that would be subject to licensure under the PHS Act.
DATES: This rule is effective March 13, 2024.
ADDRESSES: For access to the docket to read background documents or
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 final rule 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.
[[Page 9744]]
FOR FURTHER INFORMATION CONTACT: Natalia Comella, Center for Drug
Evaluation and Research, Food and Drug Administration, 10903 New
Hampshire Ave., Bldg. 51, Rm. 3141, Silver Spring, MD 20993-0002, 301-
796-6226, <a href="/cdn-cgi/l/email-protection#6e000f1a0f02070f400d01030b02020f2e080a0f4006061d40090118"><span class="__cf_email__" data-cfemail="e6888792878a8f87c885898b838a8a87a6808287c88e8e95c8818990">[email protected]</span></a>; or James Myers, Center for
Biologics Evaluation and Research, Food and Drug Administration, 10903
New Hampshire Ave., Bldg. 71, Rm. 7301, Silver Spring, MD 20993-0002,
240-402-7911.
SUPPLEMENTARY INFORMATION:
Table of Contents
I. Executive Summary
A. Purpose and Coverage of the Final Rule
B. Summary of the Major Provisions of the Final Rule
C. Legal Authority
D. Costs and Benefits
II. Table of Abbreviations/Commonly Used Acronyms in This Document
III. Background
A. History of This Rulemaking
B. Summary of Comments to the Proposed Rule
IV. Legal Authority
V. Comments on the Proposed Rule and FDA Response
A. Introduction
B. Specific Comments and FDA Response
VI. Effective/Compliance Date
VII. Economic Analysis of Impacts
VIII. Analysis of Environmental Impact
IX. Paperwork Reduction Act of 1995
X. Federalism
XI. Consultation and Coordination With Indian Tribal Governments
XII. References
I. Executive Summary
A. Purpose and Coverage of the Final Rule
This final rule amends FDA's regulations to codify FDA's existing
approach that former approved applications for biological products
under the FD&C Act that have been deemed, pursuant to the Biologics
Price Competition and Innovation Act of 2009 (BPCI Act), to be licenses
for the biological products under the PHS Act can continue to
incorporate by reference DS/DSI/DP information contained in a DMF if
such information was referenced at the time the application was deemed
to be a license, in order to avoid the risk of unnecessary disruptions
and potential drug shortages for these products. This final rule also
amends the regulations to reflect FDA's longstanding practices
regarding the referencing of information contained in master files by
biologics license applications (BLAs). The final rule codifies FDA's
practice and policy that INDs for products that would be subject to
licensure under the PHS Act may incorporate by reference any
information in a master file. The final rule also amends the
regulations to address the use of master files for the constituent
parts of combination products licensed under the PHS Act.
B. Summary of the Major Provisions of the Final Rule
Under this final rule, FDA is amending its regulations to address
the use of master files by BLAs and INDs for products subject to
licensure under the PHS Act. This final rule confirms that former
approved applications for biological products in new drug applications
(NDAs) under the FD&C Act that have been deemed, pursuant to the BPCI
Act, to be licenses for the biological products under the PHS Act may
continue relying on DMFs for information on DS/DSI/DP if such
information in a master file was relied on at the time the application
was deemed to be a license under the PHS Act. For BLAs outside the
scope of the circumstances described in the preceding sentence, the
final rule also codifies FDA's existing practice that BLAs may not rely
on a master file for DS/DSI/DP information but may rely on a master
file for other kinds of information.\1\ This final rule also codifies
FDA's practice that an IND for a product that would be subject to
licensure as a BLA may incorporate by reference any information,
including DS/DSI/DP information, contained in a master file. This final
rule also provides that, while BLAs under the PHS Act may not
incorporate by reference DS/DSI/DP information contained in master
files for biological product constituent parts of combination products,
they may do so for non-biological product constituent parts.
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\1\ FDA notes that an applicant may seek guidance from the
relevant review division at the Agency if the applicant is unsure
whether information in a master file constitutes DS/DSI/DP
information in the context of a particular BLA.
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C. Legal Authority
This final rule amends FDA's regulations, as part of FDA's
implementation of the BPCI Act, as amended by the Further Consolidated
Appropriations Act, 2020 (FCA). FDA's authority for this rule also
derives from the biological product licensing provisions of the PHS Act
and the provisions of the FD&C Act applicable to drugs; the FD&C Act
provisions are applicable to biological products under the PHS Act.
D. Costs and Benefits
By allowing certain BLAs to continue referencing a DMF for DS/DSI/
DP information, FDA avoids imposing a potential new regulatory burden.
Affected entities will incur minimal costs to read and understand the
rule. FDA estimates that over 10 years at a discount rate of 7 percent,
the final rule will generate annualized net cost savings ranging from
$0.40 million to $5.19 million with a primary estimate of $2.80
million; at a discount rate of 3 percent, the final rule will generate
annualized net cost savings ranging from $0.37 million to $5.17 million
with a primary estimate of $2.77 million.
II. Table of Abbreviations/Commonly Used Acronyms in This Document
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Abbreviation/acronym What it means
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BLA................................. Biologics License Application.
BPCI Act............................ Biologics Price Competition and
Innovation Act of 2009.
DMF................................. Drug Master File.
DP.................................. Drug Product.
DS.................................. Drug Substance.
DSI................................. Drug Substance Intermediate.
FD&C Act............................ Federal Food, Drug, and Cosmetic
Act.
FDA................................. U.S. Food and Drug Administration.
FCA Act............................. Further Consolidated
Appropriations Act, 2020.
IND................................. Investigational New Drug
Application.
IVD................................. In Vitro Diagnostic.
NDA................................. New Drug Application.
PHS Act............................. Public Health Service Act.
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III. Background
A. History of This Rulemaking
In the proposed rule,\2\ FDA announced its intention to amend its
regulations to address the use of master files by BLAs. Section
7002(b)(1) of the BPCI Act revised section 351(i) of the PHS Act (42
U.S.C. 262(i)), in part, to amend the definition of a ``biological
product'' to include a ``protein (except any chemically synthesized
polypeptide).'' Section 605 of the FCA Act (Pub. L. 116-94) later
amended this definition to remove the parenthetical ``(except any
chemically synthesized polypeptide).'' \3\ Also, section 7002(e)(4) of
the BPCI Act provided that, on March 23, 2020, an approved application
for a biological product under section 505 of the FD&C Act (21 U.S.C.
355) ``shall be deemed to be a license for the biological product
under'' section 351 of the PHS Act.\4\ A number of products that were
[[Page 9745]]
approved in NDAs under section 505 of the FD&C Act met the revised
definition of a biological product and the applications for these
products were deemed to be biologics license applications on March 23,
2020 (deemed BLAs). The proposed rule described FDA's interpretation of
the ``deemed to be a license'' provision of the BPCI Act with respect
to the use of master files by BLAs.\5\
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\2\ ``Biologics License Applications and Master Files,'' 84 FR
30968 (June 28, 2019).
\3\ See FDA's final rule issued on February 21, 2020, regarding
its interpretation of the term ``protein'' as used in section
351(i)(1) of the PHS Act (definition of the term ``Biological
Product,'' 85 FR 10057).
\4\ Section 607 of Division N of the FCA Act, 2020 (Pub. L. 116-
94, 133 Stat 3127), amended section 7002(e)(4) of the BPCI Act to
provide that FDA will continue to review an application for a
biological product under section 505 of the FD&C Act after March 23,
2020, so long as that application was submitted under section 505 of
the FD&C Act, is filed not later than March 23, 2019, and is not
approved as of March 23, 2020. If such an application is approved
under section 505 of the FD&C Act before October 1, 2022, it will be
deemed to be a license for the biological product under section 351
of the PHS Act upon approval (see section 7002(e)(4)(B)(iii) and
(vi) of the BPCI Act).
\5\ For more information about FDA's interpretation of the
``deemed to be a license'' provision of the BPCI Act, see the
guidance for industry entitled ``Interpretation of the `Deemed to be
a License' Provision of the Biologics Price Competition and
Innovation Act of 2009'' (Ref. 1). We update guidances periodically.
To make sure you have the most recent version of a guidance, check
the FDA Drugs guidance web page 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>.
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The preamble to the proposed rule described FDA's current
regulatory framework and practices regarding the use of master files by
BLAs and INDs. The proposed rule also described a mechanism to provide
for continued use of DMFs referenced by deemed BLAs. The preamble to
the proposed rule further noted that there are combination products
approved in BLAs under the PHS Act and that the rationale described in
the proposed rule for the Agency's proposed approach to BLAs also
applied to the biological product constituent part(s) of such
combination products. FDA sought comments on whether applications for
combination products submitted in BLAs under the PHS Act should be
permitted to incorporate by reference DS/DSI/DP information for any
non-biological product constituent part (for example, the drug
constituent part of an antibody-drug conjugate).
In this final rule, FDA is finalizing the approach described in the
proposed rule with several changes. Based on comments received, FDA is
adding provisions codifying the use of master files by BLAs under the
PHS Act for combination products. In addition, FDA is making
nonsubstantive changes to the structure of the codified language to
improve its readability.
B. Summary of Comments to the Proposed Rule
We received fewer than 30 comment letters on the proposed rule.
Several comments generally support the proposed rule, in whole or in
part. Several comments recommend revisions to, or disagree with,
individual provisions in the proposed rule. Some comments address the
use of master files for combination products in response to FDA's
request for public comment in the preamble to the proposed rule.
IV. Legal Authority
We are issuing this final rule under section 7002(e) of the BPCI
Act, as amended by section 607 of the FCA Act. FDA's authority for this
final rule also derives from the biological product licensing
provisions of the PHS Act and the provisions of the FD&C Act (21 U.S.C.
321, et seq.) applicable to drugs. Under these provisions, FDA has the
authority to issue regulations designed to ensure, among other things,
that biological products are safe, pure, and potent and manufactured in
accordance with current good manufacturing practice. FDA also has
general authority to issue regulations for the efficient enforcement of
the FD&C Act under section 701 of the FD&C Act, which is applicable to
biological products pursuant to section 351(j) of the PHS Act.
V. Comments on the Proposed Rule and FDA Response
A. Introduction
We received fewer than 30 comment letters on the proposed rule by
the close of the comment period, each addressing one or more issues. We
received comments from industry, individuals, and a trade organization.
We describe and respond to the comments in section V.B below. We
have numbered each comment topic to help distinguish between the issues
raised in the comments. We have grouped similar comments together under
the same number, and, in some cases, we have separated different issues
discussed in the same comment for purposes of our responses. The number
assigned to each comment topic is purely for organizational purposes
and does not signify the comment's value or importance or the order in
which comments were received.
In addition, FDA has restructured the codified language to address
comments and for ease of reading. The paragraph numbers in the codified
text and preamble of this final rule differ from those used in the
proposed rule. Where applicable in this preamble, we identify the
paragraphs as numbered in the proposed, as well as final, codified
language. Although the codified language has been restructured for ease
of reading into a new Sec. 601.2(g), the separate paragraphs of this
rule, applicable to certain deemed BLAs, to INDs for products that
would be subject to licensure as a BLA, and to non-biological product
constituent parts of combination products regulated under the PHS Act,
each function independently to address specific circumstances and
codify FDA's practices for those circumstances. In the event of a stay
or invalidation of any paragraph of new Sec. 601.2(g), those
paragraphs that remain in effect would continue to function sensibly
\6\ to address their respective circumstances. For example,
invalidation of Sec. 601.2(g), which is specific to certain deemed
BLAs, would have no effect on the provisions applicable to applications
outside the scope of that paragraph.
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\6\ See, e.g., Belmont Mun. Light Dep't v. FERC, 38 F.4th 173,
188 (D.C. Cir. 2022) (finding severability of portion of an
administrative action, applying principle that severability is
appropriate where ``the agency prefers severability to overturning
the entire regulation'' and where the remainder of the regulation
``could function sensibly without the stricken provision'')
(citations omitted).
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B. Specific Comments and FDA Response
1. Final Sec. 601.2(g)(1) (Proposed Sec. 601.2(g))
We proposed that an application for a biological product submitted
to FDA for licensure under section 351 of the PHS Act, licensed under
section 351 of the PHS Act, or, except as provided in proposed Sec.
601.2(h), deemed to be licensed under section 351 of the PHS Act, may
not incorporate by reference DS/DSI/DP information contained in a
master file (see proposed Sec. 601.2(g)). We also proposed that
amendments and supplements to these applications may not incorporate by
reference such information contained in a master file.
FDA received several comments addressing this aspect of the
proposed rule, some of which agree with the need for the provision and
with FDA's rationale, and some of which disagree. Some of the comments
that disagree propose that FDA permit BLAs more generally to
incorporate by reference information on DS/DSI/DP contained in master
files or permit this on a case-by-case basis. A few comments suggest
that BLAs should be permitted to incorporate certain kinds of DS/DSI/DP
information by reference or that BLAs for certain products should be
permitted to incorporate by reference DS/DSI/DP
[[Page 9746]]
information. For the reasons described below, we are not changing our
approach in finalizing this proposal. However, because the final
regulation also addresses combination products licensed in BLAs, final
Sec. 601.2(g)(1) (as well as final Sec. 601.2(g)(3)) includes
references to such applications. In addition, because Sec. 601.2(g)(1)
applies to a BLA regardless of submission type (e.g., application for
approval, licensed BLA, amendment, supplement), we have removed the
reference to ``amendments'' and ``supplements.''
(Comment 1) FDA received three comments disagreeing with FDA's
proposed approach and suggesting that FDA instead permit BLAs more
generally to incorporate by reference DS/DSI/DP information contained
in master files on a case-by-case basis. One of these comments asserts
that FDA's proposal is inconsistent with applying a risk-based approach
to regulatory review of applications, and, in support of a case-by-case
approach, specifically suggests that FDA permit BLAs to incorporate by
reference this information when it does not increase risk to the
patient.
(Response 1) FDA disagrees that its proposal is inconsistent with
applying a risk-based approach and declines to revise its proposal to
permit incorporation by reference of DS/DSI/DP information contained in
a master file on a case-by-case basis.
FDA agrees that it is important to employ a science- and risk-based
approach to its regulation of BLAs. Accordingly, FDA considers the
establishment and function of a robust quality assurance program to be
essential for evaluating, controlling, and mitigating product quality
risks. The Agency has carefully considered the (generally) complex
characteristics of most biological products and the risks to product
quality inherent in the manufacture of these products. As stated in the
preamble to the proposed rule, most biological products tend to have
certain features (e.g., amino acid sequence, glycosylation, folding,
cellular phenotype) essential to their intended effect and can be very
sensitive to changes to the manufacturing process. In addition,
biological products isolated from biological sources may be complex
heterogeneous mixtures. As a result of such characteristics, the
manufacture of most biological products carries increased potential
risk to product quality. As a scientific matter, for biological
products, the Agency considers it to be generally impractical for the
applicant to confirm DS/DSI/DP quality characteristics without complete
knowledge of, and control over, all aspects of the manufacturing
process, including the manufacturing process for the DS/DSI/DP. Absent
such knowledge and control, the applicant generally cannot operate a
quality assurance program that independently identifies, assesses, and
mitigates quality risks, which is critical to assuring the quality of a
biological product.
For biological products, FDA has found that the fragmentation of
DS/DSI/DP information between a master file and a BLA results in a risk
to quality that is very difficult to mitigate. Therefore, requiring DS/
DSI/DP information to be submitted as part of the BLA, rather than
incorporated by reference to a master file, is consistent with FDA's
scientific assessment of the risks associated with this category of
products and the need for BLA applicants to have direct knowledge of
and control over the entire manufacturing process.
As we acknowledged in the preamble to the proposed rule, there may
be some biological products for which referencing a DMF for DS/DSI/DP
information presents somewhat less risk. However, FDA declines to adopt
a case-by-case approach to BLAs incorporating by reference DS/DSI/DP
information contained in master files. Given the complex
characteristics of most biological products, the importance of the
applicant's knowledge of and direct control over the manufacturing
processes for biological products, and the advantages in administrative
efficiency and predictability, the Agency is proceeding with an
approach that draws a distinction between BLAs and NDAs with regard to
the referencing of master files for DS/DSI/DP information, except for
certain deemed BLAs (see section V.B.2).
(Comment 2) One comment suggests that it would be unfair to
prohibit sponsors of applications for ``biological products'' from
incorporating by reference DS/DSI/DP information contained in master
files while permitting sponsors of applications for ``drug products''
to do so because it would create unequal starting points and incentives
for product development.
(Response 2) FDA disagrees that it would be unfair to prohibit BLAs
from incorporating by reference DS/DSI/DP information contained in
master files while permitting applications under the FD&C Act to do so.
FDA's longstanding practice of not permitting BLAs to incorporate by
reference DS/DSI/DP information contained in master files is based on
the differences in risk generally associated with products regulated
under the PHS Act and products regulated under the FD&C Act, as
described above and in the preamble to the proposed rule.
With regard to a difference in starting points and incentives,
nothing in this rule prohibits an IND for a product that would be
subject to licensure under section 351 of the PHS Act from
incorporating by reference DS/DSI/DP information contained in a master
file, in the same way that an IND can for a product that would be
subject to approval under the FD&C Act. Therefore, the starting points
for INDs for products that would be regulated under the PHS Act and
products that would be regulated under the FD&C Act are the same in
this regard. Furthermore, it should be noted that at the BLA stage the
inability to incorporate by reference DS/DSI/DP information contained
in a master file does not remove BLA applicants' incentives or ability
to proceed with product development. An applicant who does not intend
to manufacture all aspects of the product for licensure may, as stated
in the preamble to the proposed rule, consider other types of
cooperative manufacturing arrangements, while still assuming
responsibility for meeting the applicable product and establishment
standards.\7\ These other arrangements would provide alternatives in
cases where the incorporation by reference of a master file is not
permitted.
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\7\ See the guidance for industry ``Cooperative Manufacturing
Arrangements for Licensed Biologics'' (Ref. 2).
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(Comment 3) Two comments assert that BLAs should be permitted to
incorporate by reference DS/DSI/DP information contained in master
files because IND applications are permitted to do so.
(Response 3) FDA disagrees with these comments. FDA requires an
applicant to be able to submit DS/DSI/DP information directly to the
BLA because, at the time a BLA is submitted, FDA expects the sponsor to
have knowledge of and direct control over the manufacturing process.
As described in the preamble to the proposed rule, INDs are
permitted to incorporate by reference DS/DSI/DP information contained
in master files for several reasons, including the following: exposure
to the investigational product is limited to subjects enrolled in
clinical trials, which are typically carried out in controlled
settings; the sponsor and FDA can mitigate risk by closely monitoring
patients in clinical trials to evaluate the safety of the
investigational
[[Page 9747]]
product; and permitting INDs to incorporate by reference DS/DSI/DP
information contained in master files may facilitate product
development because a sponsor might otherwise choose not to make the
significant investment to manufacture the DS/DSI/DP for the product at
the early, investigational stage. None of these situations apply at the
time of BLA submission.
Because the rationale for permitting INDs to incorporate by
reference DS/DSI/DP information contained in a master file does not
apply at the BLA stage, FDA declines to change its approach and permit
BLAs to incorporate such information by reference.
(Comment 4) One comment contends that BLAs should be permitted to
incorporate by reference DS/DSI/DP information contained in master
files because, if there are concerns with the safety of a product
during the BLA review process, FDA can issue a complete response letter
or request mandatory postmarketing studies and postmarketing
surveillance.
(Response 4) Complete response letters are regulatory responses
that convey deficiencies identified by FDA during the review and
evaluation of an application. Postmarketing requirements, postmarketing
commitments, and postmarketing surveillance are regulatory tools that
can be used to assess and address potential product risks after the
product is licensed. Complete response letters, postmarketing study
commitments, and postmarketing surveillance are application-specific
actions. For the reasons discussed above, FDA declines to take a case-
by-case (i.e., application-specific) approach to BLAs' incorporation by
reference of DS/DSI/DP information contained in master files.
Furthermore, complete response letters, postmarketing study
commitments, and postmarketing surveillance are relevant only after the
product has been developed and an application has been submitted to and
reviewed and evaluated by the Agency. In contrast, given the importance
of the applicant's knowledge of and direct control over the
manufacturing processes for biological products, a clear rule that
applies to all BLAs provides all applicants with administrative
efficiency and predictability early in the development process about
the Agency's expectations regarding the use of master files, allowing
applicants to take these expectations into account in their product
development plan and when preparing content to be submitted in the
application.
For the reasons discussed above, FDA declines to take a case-by-
case approach, and has concluded that the availability of complete
response letters, postmarketing study commitments, and postmarketing
surveillance does not provide a suitable alternative to FDA's approach,
which is, among other things, intended to provide predictability
regarding the use of master files for BLAs.
(Comment 5) One comment proposes that FDA permit BLAs to
incorporate by reference certain kinds of DS/DSI/DP information
contained in a master file, advocating for the ability of BLAs to
reference DS/DSI/DP information that is not ``highly product-
specific.'' As an example, the comment asserts that ``drug product
information'' could be interpreted to encompass extensive aseptic
processing information and, in certain circumstances, this information
could be appropriately managed in a master file because elements of
aseptic processing can cut across multiple products and very few
elements of aseptic processing are drug product-specific. The comment
also suggests that platform data to support viral clearance could be
more appropriately captured once in a DMF instead of being repeated in
multiple BLAs, thereby reducing burden on the Agency and sponsors.
(Response 5) FDA declines to change its approach in order to permit
BLAs to incorporate by reference certain DS/DSI/DP information
contained in a master file as suggested by the comment.
The comment uses, but does not explain what it means by, the term
``highly product-specific information,'' other than providing examples
of information that the comment considers not to be ``highly product-
specific,'' such as platform data to support viral clearance and
aseptic processing information. It is unclear whether these examples
would, in fact, be DS/DSI/DP information in the context of a particular
BLA. FDA notes that an applicant may seek guidance from the relevant
review division at the Agency if the applicant is unsure whether
information in a master file constitutes DS/DSI/DP information in the
context of a particular BLA.
Accordingly, FDA declines to change this provision to treat DS/DSI/
DP information that is not ``highly product-specific'' different from
any other kind of DS/DSI/DP information contained in master files.
(Comment 6) One comment largely agrees with FDA's proposal and the
rationale provided to support it but expresses concern about its
application to purely synthetic drug substance intermediates, asserting
that the considerations articulated in the proposed rule are
appropriate only for biological products. The comment notes that a
chemically synthesized polypeptide does not meet the definition of a
biological product under section 7002(b) of the BPCI Act, which
amended, in part, the definition of a ``biological product'' in the PHS
Act to include a ``protein (except any chemically synthesized
polypeptide).'' The comment requests clarity on the use of DMFs for
drug substance intermediates for chemically synthesized polypeptides.
The comment contends that some biological products may integrate drug
substance intermediates that are chemically synthesized polypeptides.
The comment asserts that the potential risks to quality are less
significant in such cases because, according to the comment, these
chemically synthesized polypeptides are not technically biological
products. The comment contends that, under such circumstances, reliance
on a DMF may be appropriate, and proposes that FDA allow reliance on a
DMF for a drug substance intermediate that is purely synthetic.
(Response 6) FDA notes that, after the comment period for the
proposed rule closed, section 605 of the FCA Act further amended the
definition of a ``biological product'' in section 351(i) of the PHS Act
to remove the parenthetical exception for ``any chemically synthesized
polypeptide'' from the statutory category of ``protein.'' Accordingly,
the comment's assertion that BLAs should be permitted to reference a
DMF for information about a drug substance intermediate that is a
chemically synthesized polypeptide because a chemically synthesized
polypeptide does not meet the definition of a biological product is no
longer applicable.
In addition, the inclusion of chemically synthesized polypeptides
into the definition of a biological product does not change our overall
concerns and approach with respect to biological products. Because
chemically synthesized polypeptides can present many of the same issues
and concerns as do other biological products, FDA's approach should be
the same. When manufacturing processes for chemically synthesized
polypeptides are appropriately designed, manufacturers can control the
amino acid sequence and modifications to amino acids; however, the
manufacturing of chemically synthesized polypeptides may still present
risks to quality. As stated in the preamble to the proposed rule, most
biological products tend to be
[[Page 9748]]
very sensitive to changes in their manufacturing process. For example,
aspects of the manufacturing process (e.g., temperature) can affect the
folding of polypeptides. Therefore, even for chemically synthesized
polypeptides, it is important for the applicant to have knowledge of
and control over all aspects of the manufacturing process and to
implement a robust quality assurance program. For this reason, the
final rule requires that information about chemically synthesized drug
substance intermediates be submitted directly to the application,
rather than be incorporated by reference to a master file.
(Comment 7) One comment requests that BLAs for in vitro diagnostic
(IVD) products, including those for licensed donor IVD screening tests,
be excluded from the limitation on BLAs' incorporating by reference DS/
DSI/DP information contained in master files, asserting that the
reasons for limiting the use of master files for this kind of
information in BLAs for therapeutic products do not apply to BLAs for
IVDs.
(Response 7) FDA declines to exclude BLAs for IVD devices from the
limitation on BLAs' use of master files for DS/DSI/DP information
because such an exclusion is generally not necessary.
IVD devices subject to a BLA are intended for use in screening
donated human cells, tissues, and cellular and tissue-based products
(HCT/Ps) and donated blood in order to ensure the compatibility between
donors and recipients and the absence of infectious agents. These
assays are performed on samples collected from the HCT/P or blood
donor.
Generally, the terms drug substance, drug substance intermediate,
and drug product are not applicable to IVD devices. Therefore, the
limitation in this rule on BLAs' use of master files for DS/DSI/DP
information is not expected to affect BLAs for IVD devices. For this
reason, the Agency considers it unnecessary to exclude BLAs for IVD
devices from the scope of the rule's limitation on BLAs' use of master
files for DS/DSI/DP information.
2. Final Sec. 601.2(g)(2) (Proposed Sec. 601.2(h))
Final Sec. 601.2(g)(2) (proposed Sec. 601.2(h)) addresses
applications that have been deemed to be BLAs pursuant to section
7002(e)(4) of the BPCI Act, as amended by the FCA Act. This paragraph
provides that a deemed BLA can continue to incorporate by reference DS/
DSI/DP information contained in a DMF if such information was
referenced at the time the application was deemed to be a BLA. We
received several comments on this provision, most of which agree with
this provision and the rationale provided in the proposed rule. A few
comments disagree and several request clarification regarding certain
aspects of this paragraph. For the reasons given below, we decline to
make the changes suggested by the comments and are, therefore,
finalizing this requirement without substantive change.
(Comment 8) One comment requests clarification regarding proposed
Sec. 601.2(h). The comment requests that FDA explain whether all
biological products approved in NDAs will be permitted to continue
incorporating by reference DS/DSI/DP information contained in DMFs or
whether it is only a specific subset of biological products, because
the preamble to the proposed rule notes that it would allow ``certain''
biological products originally approved in an NDA under the FD&C Act to
continue relying on a DMF for information on DS/DSI/DP after the NDA is
deemed to be a license for the biological product.
(Response 8) As explained in the preamble to the proposed rule and
described in proposed Sec. 601.2(h), a deemed BLA that was relying on
DS/DSI/DP information in a DMF at the time the application was deemed a
BLA may continue to incorporate by reference that DS/DSI/DP information
contained in that DMF. The reference in the preamble to the proposed
rule to ``certain'' applications refers to deemed BLAs that
incorporated by reference DS/DSI/DP information contained in a DMF at
the time the application was deemed a BLA. These are the same
applications specified in Sec. 601.2(g)(2) in this final rule.
(Comment 9) One comment requests clarification regarding whether
applications that reference DMF information may continue referencing
the DMF if changes are made to the DMF.
(Response 9) The preamble to the proposed rule explains that the
rule is not intended to limit or restrict the changes that may be made
to any master file, including a DMF containing DS/DSI/DP information.
Changes made to such a DMF, including changes to previously referenced
DS/DSI/DP information, do not restrict the ability of a deemed BLA to
continue to incorporate by reference the DS/DSI/DP information in that
DMF for the same purpose for which it was incorporated by reference at
the time the application was deemed to be a BLA. For example, consider
a former NDA that incorporated by reference information contained in a
DMF regarding the manufacture of its drug substance and that, after the
application was deemed to be a BLA, continues to incorporate by
reference that drug substance information. If the DMF holder
subsequently modifies drug substance manufacturing (for example, by
making changes to the analytical methods or purification process for
the drug substance), the deemed BLA may continue to incorporate by
reference this modified drug substance information, provided that the
BLA applicant informs the Agency of the change in the BLA in accordance
with Sec. 601.12 (21 CFR 601.12). Alternatively, if the DMF holder
adds information about manufacturing of drug product to the same DMF,
FDA does not intend to permit the deemed BLA to incorporate by
reference that new drug product information because it is not the type
of information that was referenced by the former NDA at the time it was
deemed to be a BLA.
(Comment 10) One comment requests further information on the
circumstances in which submission of a supplement to a BLA would not be
sufficient and the submission of a new BLA would be required.
(Response 10) FDA notes that a description of the kinds of changes
that cannot be addressed through a supplement is outside the scope of
this rule. The Agency has generally described its thinking on what
constitutes a separate original application, amendment, or
supplement.\8\
---------------------------------------------------------------------------
\8\ For example, see the guidance for industry and FDA Staff
``Bundling Multiple Devices or Multiple Indications in a Single
Submission'' (Ref. 3).
---------------------------------------------------------------------------
(Comment 11) One comment suggests that deemed BLAs are best
described as ``expected to transition.''
(Response 11) The applications described in Sec. 601.2(g)(2) in
this final rule have already been deemed to be BLAs by operation of the
statute (section 7002(e)(4) of the BPCI Act, as amended by section 607
of the FCA Act). Therefore, referring to deemed BLAs as ``expected to
transition'' would be inaccurate.
(Comment 12) One comment suggests that FDA change proposed Sec.
601.2(h) to state that any new BLAs will not be allowed to incorporate
by reference DS/DSI/DP information contained in master files after
March 23, 2020.
(Response 12) The Agency declines to make the suggested change.
Except as noted in final Sec. 601.2(g)(2) and (3), final Sec.
601.2(g)(1) applies to all BLAs, whether new or existing. Therefore,
the suggested change is not needed because,
[[Page 9749]]
under the final codified, a new BLA may not incorporate by reference
DS/DSI/DP information contained in any master file.
(Comment 13) One comment asserts that the BPCI Act was enacted to
guarantee appropriate regulation of biological products to support
public health and to ensure that only safe and effective products enter
the market. The comment further maintains that the intent of the deemed
BLA provision of section 7002(e)(4) of the BPCI Act is to ensure that
scientific and technical complexities associated with the generally
larger and typically more complex structure of biological products, as
well as the processes by which such products are manufactured, are not
overlooked. The comment asserts that it would therefore defeat the
purpose of the BPCI Act to allow biological products initially approved
in an NDA under the FD&C Act to continue to rely on a DMF for DS/DSI/DP
information after the NDA is deemed to be a license for the biological
product under the PHS Act. The comment recommends that deemed BLAs be
regulated like other biological products with respect to use of master
files.
(Response 13) FDA agrees that, in general, scientific and technical
complexities associated with the typically more complex structures of
biological products, as well as the processes by which such products
are manufactured, must not be overlooked (see section V.B.1). However,
with respect to deemed BLAs that previously, as former NDAs, referenced
a DMF for DS/DSI/DP information at the time of the transition, FDA
considered the intent underlying the BPCI Act and, as elaborated in the
proposed rule, took into account the following considerations that are
specific to such deemed BLAs: (1) these applications have already been
approved, and the applicants have marketed the product, in certain
instances for decades, without overt safety concerns; (2) the deemed
BLAs that incorporate by reference DS/DSI/DP information comprise only
a small subset of all BLAs and reference a very small number of DMFs;
and (3) many of these BLA applicants have accumulated knowledge about
the products and have been able to implement appropriate control
strategies based on this product knowledge. In addition, prohibiting
these deemed BLAs from continuing to incorporate by reference DS/DSI/DP
information in these DMFs might have the effect of halting or
curtailing production of these products, resulting in drug shortages.
FDA interprets the applicable statutory provisions such that the
transition was not meant to interrupt access to these products.
Therefore, on balance, FDA believes that public health is best served
by allowing the small number of deemed BLAs to continue referencing DS/
DSI/DP information contained in DMFs on which they relied at the time
of transition.
(Comment 14) One comment acknowledges that the general concern
about fragmentation of DS/DSI/DP information associated with the use of
DMFs is lessened for deemed BLAs by the existence of generally
longstanding relationships between the deemed-BLA applicants and the
DMF holders because the applicants may have accumulated knowledge about
the quality of the DS/DSI/DP supplied by the DMF holder over an
extended period. The comment agrees that this accumulated knowledge
allows a deemed BLA applicant to implement a more robust control
strategy to mitigate the risk to product quality posed by the
applicant's limited knowledge of the manufacturing process described in
the DMF. The comment questions how this approach would change if the
contents of the DMF change or the holder of the DMF changes.
(Response 14) FDA does not consider that a change to the holder of
the DMF or a change in previously referenced DS/DSI/DP information in
the context of a DMF is inconsistent with the rationale for permitting
deemed BLAs that previously referenced a master file for DS/DSI/DP
information to continue referencing the DMF for the same type of
information. The generally longstanding relationships between the
deemed BLA applicant and the DMF holder, the knowledge accumulated by
the deemed BLA applicant, and the knowledge accumulated by the DMF
holder collectively provide some assurance about the quality of a
product. When changes are made to a DMF, these assurances should
continue to apply in most cases. In addition, the comparability studies
required to demonstrate the safety, purity, and potency of post-change
and pre-change material should provide further assurance of quality.
When the DMF remains the same but the DMF holder changes, the
deemed BLA applicant's product and process knowledge still remains; the
deemed BLA applicant will also have designed and implemented a control
strategy that is independent of the identity of the holder of the DMF.
These measures collectively should provide continued assurance of
quality under such circumstances. Therefore, it is appropriate to
permit deemed BLAs to continue to incorporate by reference the same
type of DS/DSI/DP information contained in a DMF after a change in the
content of the DMF or the holder of the DMF.
(Comment 15) One comment asserts that FDA's rationale for allowing
deemed BLAs to continue incorporating by reference information on DS/
DSI/DP contained in DMFs is insufficient because it is based on a small
subset of the deemed BLAs and a very small number of DMFs.
(Response 15) This comment appears to misunderstand the set of
deemed BLAs on which FDA's rationale is based. It is true that FDA's
approach to deemed BLAs and their use of DMFs for DS/DSI/DP information
applies to a small number of applications and DMFs. Deemed BLAs are a
small subset of all BLAs, and deemed BLAs that reference a master file
for DS/DSI/DP information are, in turn, a subset of all deemed BLAs.
However, FDA's risk-based assessment of deemed BLAs' continued
referencing of DMFs for DS/DSI/DP information is based on a
consideration of the entire set of deemed BLAs that reference DMFs for
such information, and it is only those deemed BLAs that will be able to
continue referencing DS/DSI/DP information in a DMF. In other words,
FDA considered the entire set of applications and DMFs that will be
affected by final Sec. 601.2(g)(2).
As elaborated in the preamble to the proposed rule, FDA considered
the length of time these products have been marketed without being
withdrawn or removed for reasons of safety or effectiveness; the
acceptable quality of drug substances provided over decades through
this incorporation by reference to DMFs; and the impact of disallowing
use of DMFs for these deemed BLAs, which has the potential to curtail
or halt production of some of these products, resulting in drug
shortages with considerable negative impacts on public health. Based on
these reasons, and the fact that there are a small number of deemed
BLAs and a small number of master files referenced by these
applications, the Agency has determined that it serves the public
health best to permit these deemed BLAs to continue incorporating by
reference the DS/DSI/DP information contained in this small set of
master files.
(Comment 16) One comment proposes that a biosimilar product that
references a deemed BLA that incorporates by reference DS/DSI/DP
information contained in a master file should also be permitted to
incorporate by reference
[[Page 9750]]
the same information to assist in demonstrating biosimilarity.
(Response 16) FDA recognizes that an applicant might submit a BLA
for a biosimilar or interchangeable biosimilar product to a reference
product that is approved in a deemed BLA and is permitted under the
exception in final Sec. 601.2(g)(2) to continue incorporating by
reference DS/DSI/DP information contained in a DMF. However, for the
reasons outlined below, FDA declines to amend the proposed rule to also
except such BLAs for biosimilar or interchangeable biosimilar products
from final Sec. 601.2(g)(1).
Consistent with FDA's longstanding practice for BLAs, and as
codified in final Sec. 601.2(g)(1), a BLA may not reference a master
file for DS/DSI/DP information because a BLA applicant needs to
demonstrate knowledge of and direct control over the manufacture of the
drug product, which includes manufacture of the drug substance and drug
substance intermediate. For reasons discussed above, FDA believes that
the public health is best served by allowing a small number of deemed
BLAs--those that, in former approved applications under section 505 of
the FD&C Act, relied on DMFs for DS/DSI/DP information--to continue
referencing that information after being deemed a BLA. However, these
reasons, such as avoiding disruptions in existing supply chains for
products with deemed BLAs, do not apply to new BLAs, including BLAs for
products that are biosimilar to or biosimilar and interchangeable with
reference products in such deemed BLAs. We continue to consider that an
approach which draws a clear distinction between deemed BLAs and other
BLAs with regard to the referencing of master files for DS/DSI/DP
information is the most appropriate.
FDA notes that the lack of ability to reference a master file for
DS/DSI/DP information should not preclude the development of a
biosimilar or interchangeable biosimilar product to a reference product
in a deemed BLA that is permitted to continue incorporating by
reference DS/DSI/DP information from a DMF. For example, an application
for licensure as a biosimilar typically will include data derived from
comparative analytical studies between the proposed biosimilar and the
reference product, which should be feasible even if the biosimilar or
interchangeable biosimilar product application does not reference DS/
DSI/DP information that is incorporated by reference by the deemed BLA
for the reference product. Moreover, data derived from comparative
clinical studies, among other things, often will be included as part of
a demonstration of biosimilarity. In general, a biosimilar applicant
should be able to conduct such studies regardless of whether the
biosimilar applicant can reference the same DMF for DS/DSI/DP
information as the reference product.
Furthermore, an applicant for a biosimilar or interchangeable
biosimilar product that is not permitted to incorporate DS/DSI/DP
information by reference to the DMF is not required to manufacture the
DS/DSI/DP; as noted above and in the preamble to the proposed rule,
alternatives are available, including the use of cooperative
manufacturing arrangements that ensure that the licensee for the final
product assumes responsibility for compliance with the applicable
product and establishment standards.
Overall, we do not believe that an applicant for a proposed
biosimilar or interchangeable biosimilar product would face a barrier
to generating the data necessary to demonstrate the biosimilarity or
interchangeability of its proposed product to a reference product that
incorporates by reference DS/DSI/DP information in a DMF, even if the
biosimilar applicant is not permitted to incorporate by reference that
same DS/DSI/DP information. Therefore, FDA declines to modify this
provision as suggested.
We note that the Agency has taken steps to help create a more
competitive market for biological products, including encouraging the
development of biosimilar products, and is working to implement
additional measures to maximize clarity and efficiency in biosimilar
development.\9\ The Agency invites prospective applicants who seek
advice relating to the development and review of a biosimilar or
interchangeable biosimilar product, including advice on the feasibility
of licensure under section 351(k) of the PHS Act for a particular
product, to contact the Agency. For Center for Drug Evaluation and
Research (CDER)-regulated products, you may contact CDER-Biologics
Biosimilars Inquiries at <a href="/cdn-cgi/l/email-protection#9dded9d8cfb0dff4f2f1f2faf4feeedff4f2eef4f0f4f1fcefeed4f3ece8f4eff4f8eeddfbf9fcb3f5f5eeb3faf2eb"><span class="__cf_email__" data-cfemail="7f3c3b3a2d523d1610131018161c0c3d16100c161216131e0d0c36110e0a160d161a0c3f191b1e5117170c51181009">[email protected]</span></a>; for Center for Biologics
Evaluation and Research (CBER)-regulated products, you may contact CBER
at <a href="/cdn-cgi/l/email-protection#a0c9cec4d5d3d4d2d98ec2c9cfcccfc7c9c3d3e0c6c4c18ec8c8d38ec7cfd6"><span class="__cf_email__" data-cfemail="a8c1c6ccdddbdcdad186cac1c7c4c7cfc1cbdbe8ceccc986c0c0db86cfc7de">[email protected]</span></a>.
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\9\ See ``Biosimilars Action Plan: Balancing Innovation and
Competition,'' pgs. 5-7 (Ref. 4).
---------------------------------------------------------------------------
3. Final Sec. 601.2(g)(4) (Proposed Sec. 601.2(i))
Final Sec. 601.2(g)(4) (proposed Sec. 601.2(i)) codifies the
Agency's practice of permitting BLAs to incorporate by reference
information other than DS/DSI/DP information contained in master files,
including in DMFs. Comments that address this proposed provision did
not object to FDA's overall approach or the underlying rationale, and
some focused on operational aspects of the provision. Therefore, we are
finalizing Sec. 601.2(g)(4) without substantive changes. Because this
provision applies to a BLA regardless of submission type, we have
removed the reference to amendments and supplements.
(Comment 17) Three comments request clarification or codification
of the type of data and information that constitutes information other
than DS/DSI/DP information that is contained in master files and can be
leveraged by BLAs.
(Response 17) In the preamble to the proposed rule, we provided
examples of the kinds of information that are not DS/DSI/DP
information, including excipients, stabilizers, penetrants, container
closure, and other materials. However, we decline to codify in this
rule an exhaustive list of the specific types of information that are
not DS/DSI/DP information and that can be included in a master file and
incorporated by reference by a BLA. A potential applicant may seek
additional guidance from the relevant review division if the applicant
is unsure whether it is appropriate to incorporate by reference a
particular type of information contained in a master file.
(Comment 18) One comment requests that FDA codify the tests and
analyses that should be performed by the applicant when data or
information is being incorporated by reference by the BLA.
(Response 18) FDA declines to codify the tests and analyses that
the applicant should perform because these depend on, among other
things, the nature of the data and information contained in the master
file and incorporated by reference.
(Comment 19) One comment requests that FDA clarify whether proposed
Sec. 601.2(i) applies to master files held by contract manufacturing
organizations (CMOs). The comment reasons that sponsors developing
biological products frequently incorporate into BLAs information other
than DS/DSI/DP (e.g., for a fill or incorporation of a device, such as
an autoinjector) by referencing a master file held by a CMO.
(Response 19) FDA clarifies that this final rule applies to all
master files containing information that is being considered for
incorporation by reference by a BLA, regardless of the ownership of the
master file. Therefore, BLAs may incorporate by reference information
(other than DS/DSI/DP
[[Page 9751]]
information) that is contained in master files held by CMOs.
(Comment 20) One comment requests that FDA update the proposed rule
to explicitly state that Type V DMFs can be used for certain non-
product-specific equipment and facility information, including
sterilization validation information, to support multiple NDAs/BLAs.
(Response 20) Final Sec. 601.2(g)(4) codifies that BLAs may
incorporate by reference information other than DS/DSI/DP information
contained in master files. Information in Type V DMFs, like information
in all master files, may be incorporated by reference by multiple
applications, provided that the information is not DS/DSI/DP
information. We do not consider it necessary to explicitly reference
Type V DMFs in the codified language.
(Comment 21) One comment requests that FDA qualify proposed Sec.
601.2(i) by adding that nothing in proposed Sec. 601.2(g) limits or
alters a license holder's ability to modify a product under Sec.
601.12, nor is it intended to expand or reduce the changes allowed to a
deemed BLA that incorporates by reference information contained in
master files.
(Response 21) FDA declines to change proposed Sec. 601.2(i) (final
Sec. 601.2(g)(4)) as the comment requests. As stated in the preamble
to the proposed rule, this codification of current practice is not
intended to alter an applicant's existing ability to modify a product
under Sec. 601.12. We further stated in the preamble to the proposed
rule that the proposed rule is also not intended to expand or reduce
the changes allowed to a deemed BLA that incorporates by reference
information contained in master files.
4. Combination Products Approved in BLAs
The Agency recognized in the preamble for the proposed rule that
there are combination products approved in BLAs. Although the proposed
rule did not focus on combination products in BLAs, in the preamble, we
stated our position that the rationale for the treatment of BLAs for
biological products also applies to the biological product constituent
part(s) of combination products licensed under the PHS Act (i.e., BLAs
should not be permitted to incorporate by reference DS/DSI/DP
information contained in master files for a biological product
constituent part of a combination product for the same reasons that
BLAs for biological products should not be permitted to do so).\10\
Additionally, the Agency specifically requested comments on whether
BLAs should be permitted to incorporate by reference DS/DSI/DP
information for any non-biological product constituent part of a
combination product.
---------------------------------------------------------------------------
\10\ The Agency intends to continue to take a consistent
approach to biological product constituent parts of combination
product applications subject to regulation under other (non-BLA)
marketing applications (i.e., non-BLA marketing applications for
combination products should not be permitted to incorporate by
reference DS/DSI/DP information contained in master files for
biological product constituent parts).
---------------------------------------------------------------------------
We received several comments disagreeing with our position that,
since BLAs for biological products cannot incorporate by reference DS/
DSI/DP information contained in a master file, then BLAs should also
not be permitted to incorporate by reference such information for a
biological product constituent part of a combination product. We also
received comments both in support and not in support of permitting BLAs
to incorporate by reference DS/DSI/DP information for the non-
biological product constituent part(s) of a combination product. We did
not receive any comments discussing whether BLAs should be able to
reference master files for information other than DS/DSI/DP information
for either the biological or non-biological product constituent parts
of a combination product.
Based on our consideration of the comments regarding BLAs'
incorporation by reference of information contained in master files for
constituent parts of combination products, we are addressing
combination products approved as BLAs under section 351 of the PHS Act
in the final rule.
a. BLAs referencing a master file for DS/DSI/DP information for a
biological product constituent part of a combination product: final
Sec. 601.2(g)(1) (proposed Sec. 601.2(g)). We received several
comments disagreeing with our position that BLAs will not be permitted
to incorporate by reference DS/DSI/DP information contained in a master
file for a biological product constituent part of a combination
product.
(Comment 22) The comments disagreeing with FDA's proposal regarding
biological product constituent parts of a combination product refer to
the reasons that the commenters disagree with the Agency's rationale
for not permitting BLAs generally to reference master files for DS/DSI/
DP information but do not provide a reason for their disagreement that
is specific to a biological product constituent part of a combination
product.
(Response 22) The comments do not provide any reason why a BLA
should be permitted to reference a master file for DS/DSI/DP
information for a biological product constituent part of a combination
product. Instead, the comments refer to the arguments they provide for
why BLAs more generally should be permitted to incorporate by reference
DS/DSI/DP information. In section V.B.1 of this preamble, we explain
why we disagree with that position. None of the comments suggest that
there is anything unique about a biological product constituent part of
a combination product that warrants not extending the approach for BLAs
to a biological product constituent part of a combination product in a
BLA. Accordingly, we have modified final Sec. 601.2(g)(1) to state
that, except as provided, a BLA may not incorporate by reference DS/
DSI/DP information contained in a master file, including for a
biological product constituent part of a combination product.
b. BLAs referencing a master file for information other than DS/
DSI/DP information for a constituent part of a combination product:
final Sec. 601.2(g)(4) (proposed Sec. 601.2(i)). With regard to the
referencing of a master file for information other than DS/DSI/DP
information, we did not receive any comments objecting to BLAs'
referencing this information for either a biological product
constituent part or a non-biological product constituent part of a
combination product. Therefore, FDA has decided that these BLAs, like
all other BLAs, may incorporate by reference information other than DS/
DSI/DP information contained in master files (see section V.B.3).
Accordingly, final Sec. 601.2(g)(4) covers the incorporation by
reference of information contained in master files that is not DS/DSI/
DP information by all BLAs, regardless of whether such information is
incorporated by reference for the product or for a constituent part of
a combination product.
c. BLAs referencing a master file for DS/DSI/DP information for a
non-biological product constituent part of a combination product: final
Sec. 601.2(g)(3) (new). As discussed above, in the preamble of the
proposed rule, the Agency specifically requested comments on whether
applications for combination products submitted in BLAs should be
permitted to incorporate by reference DS/DSI/DP information for any
non-biological product constituent part of a combination product. FDA
received numerous comments on this topic. Most
[[Page 9752]]
of the comments support permitting BLAs to reference master files for
DS/DSI/DP information with respect to the non-biological product
constituent part(s) of a combination product, while a few comments are
against such an approach. The comments we received helped inform our
decision to clarify in this final rule that a BLA may incorporate by
reference DS/DSI/DP information contained in any master file for any
non-biological product constituent part of a combination product.
(Comment 23) Several comments support codifying in the final rule
that BLAs are permitted to incorporate by reference DS/DSI/DP
information contained in master files for the non-biological product
constituent parts of combination products, but the comments do not
provide a rationale. Another comment reasons that DMFs for drug
products have been relied on for decades and enabling continued
referencing of DS/DSI/DP information for the non-biological product
constituent part(s) of a combination product in a BLA will allow
further development of ``superior treatments.'' An additional comment
suggests that permitting BLAs to reference a master file for DS/DSI/DP
information for the non-biological product constituent part(s) of a
combination product would enable biological product and small molecule
manufacturers to collaborate more efficiently. Finally, one comment
analogizes that, because a BLA would be permitted to incorporate any
information from the device master file system for a medical device
constituent part of a combination product, BLAs should also be able to
reference DMFs for DS/DSI/DP information for drug constituent parts.
(Response 23) We agree that BLAs should be permitted to reference
master files for DS/DSI/DP information with respect to the non-
biological product constituent part(s) of combination products. As we
explained in the preamble to the proposed rule, historically, the
Agency has, as a scientific matter, expected applicants to submit
information about DS/DSI/DP directly to the BLA for a biological
product, rather than have the BLA incorporate it by reference to a
master file. However, as a scientific matter, a similar expectation
would not apply to applications for non-biological products regulated
under the FD&C Act, which are permitted to incorporate by reference DS/
DSI/DP information contained in a master file.
Much of the rationale for why a BLA is not permitted to reference a
master file for DS/DSI/DP information does not apply in the case of a
non-biological product constituent part of a combination product in a
BLA. As we explained in the preamble to the proposed rule, the risk
associated with the manufacture of biological products is generally
significantly higher than that associated with the manufacture of
products regulated under NDAs, which are often less complex.\11\ This
is because most biological products tend to have certain features
(e.g., amino acid sequence, glycosylation, folding, cellular phenotype)
essential to their intended effect and can be very sensitive to changes
to their manufacturing process, which makes them less amenable to
characterization than small molecule chemical entities. While these
considerations apply to biological product constituent parts of
combination products, they generally do not apply to non-biological
product constituent parts, which are often relatively simple,
homogenous, and fully characterizable by extensive analytical testing.
As such, the need for direct knowledge and control in the manufacturing
of a non-biological product constituent part is generally mitigated by
the ability to define the non-biological constituent part through
analytical testing, and the risk associated with such manufacturing is
generally lower than that associated with the manufacture of the
biological product constituent part.
---------------------------------------------------------------------------
\11\ As addressed in the preamble to the proposed rule, the
Agency recognizes that, in limited circumstances, this may not
always be the case.
---------------------------------------------------------------------------
As two comments suggest, such an approach is consistent with how a
non-biological product constituent part of a combination product, such
as a drug constituent part, would be treated if it were a standalone
product regulated under the FD&C Act. Additionally, we agree with the
comment that permitting such referencing of information for non-
biological product constituent part(s) could foster innovation by
enabling more efficient collaboration between the manufacturer of the
non-biological product constituent part and the manufacturer of the
final product submitted in a BLA.
Accordingly, final Sec. 601.2(g)(3) permits BLAs to incorporate by
reference DS/DSI/DP information contained in a master file for the non-
biological product constituent part(s) of a combination product.
(Comment 24) One comment does not support allowing BLAs to
incorporate by reference DS/DSI/DP information for the non-biological
product constituent part(s) of a combination product. The comment
contends that the lack of knowledge and control over a drug constituent
part for which a master file is referenced for DS/DSI/DP information
introduces risk when that drug constituent part is combined with a
biological product constituent part.
(Response 24) We understand that permitting a BLA to reference a
master file for DS/DSI/DP information for a non-biological product
constituent part, such as a drug constituent part, that is then
combined with a biological product constituent part may introduce
additional risk for the final combination product. However, the Agency
considers it generally practical for the BLA applicant to confirm the
DS/DSI/DP quality characteristics of the non-biological product
constituent part through testing. This feasibility of testing and
characterizing the non-biological product constituent part generally
enables the BLA applicant to implement a robust control strategy for
the final combination product that can mitigate the risks to quality
arising from the applicant's lack of access to the DS/DSI/DP
information for the non-biological product constituent part.
Furthermore, the applicant would still be expected at the time of
review of the BLA to have sufficient control strategies for the entire
combination product, including an appropriate control strategy to
mitigate the risk of the applicant not having access to the
manufacturing information for the non-biological product constituent
part.
(Comment 25) Another comment is concerned with non-biological
product constituent parts categorically being permitted to reference a
master file for DS/DSI/DP information because special controls may be
necessary for drug constituent parts that are cytotoxic in nature, such
as in the case of an antibody-drug conjugate combination product
licensed in a BLA.
(Response 25) FDA acknowledges that the manufacture of cytotoxic
drugs requires special expertise and controls to address the risks
associated with the toxic nature of the drug, such as the
implementation of special air-handling systems to reduce the risk of
exposure to the cytotoxic drug by manufacturing personnel. We point
out, however, that such controls to address toxicity-related risks
differ from the controls that are discussed elsewhere throughout this
rulemaking, which address the risks associated with the generally
complex manufacturing of biological products. Permitting a BLA to
incorporate by reference DS/DSI/DP information contained in a master
file for a cytotoxic drug constituent part of a combination product
does not increase the toxicity-related risks associated with either the
[[Page 9753]]
manufacture of the cytotoxic drug constituent part or the manufacture
of the combination product that contains the cytotoxic drug constituent
part. Furthermore, the toxicity-related risks associated with the
manufacture of a cytotoxic drug constituent part of a combination
product licensed in a BLA are unlikely to differ significantly from the
toxicity-related risks associated with the manufacture of cytotoxic
drug products that are not constituent parts of combination products
licensed in BLAs. Therefore, FDA declines to treat cytotoxic drug
constituent parts differently from other non-biological product
constituent parts and will permit BLAs to incorporate by reference DS/
DSI/DP information contained in master files for cytotoxic drug
constituent parts of combination products.
(Comment 26) One comment expresses concern that the BLA applicant
would have a greater burden to establish a quality assurance program to
mitigate the risk if the BLA incorporates by reference DS/DSI/DP
information contained in a master file for the non-biological product
constituent part of a combination product and this would be costlier
and more complex than if the BLA is not permitted to rely on a master
file for such information for the non-biological product constituent
part.
(Response 26) To the extent that there is concern that an applicant
would find it costlier and more complex to establish a quality
assurance program to mitigate the risk associated with the use of a
master file for DS/DSI/DP information for the non-biological product
constituent part of a combination product than it would be to directly
include such information in the BLA, we point out that FDA is not
mandating the use of master files under such circumstances.
5. Final Sec. 601.2(g)(5) (Proposed Sec. 601.2(j))
FDA proposed in Sec. 601.2(j) of the proposed rule that INDs for
products that would be subject to licensure under the PHS Act not be
restricted from incorporating by reference any information, including
DS/DSI/DP information, contained in a master file, including a DMF
submitted under Sec. 314.420 (21 CFR 314.420). Several comments
support the proposed approach. However, a few comments disagree and
recommend that, as is the case for BLAs, an IND for a product that
would be subject to licensure under the PHS Act not be permitted to
incorporate by reference DS/DSI/DP information.
(Comment 27) One comment disagrees with FDA's proposed approach of
permitting INDs for products that would be subject to licensure under
the PHS Act to incorporate by reference DS/DSI/DP information contained
in a master file. The comment contends that the approach is
unreasonable because, while exposure to the biological product is
limited during the IND stage, the IND should still ensure that clinical
trial subjects are not exposed to what the comment considers
unreasonable harm should the IND incorporate by reference DS/DSI/DP
information contained in a master file.
(Response 27) FDA agrees that it is important to ensure that
clinical trial subjects are not exposed to an unreasonable risk of harm
but disagrees with the comment's assessment of FDA's approach.
During early preclinical development for a new product, the primary
goal of FDA and sponsors is to ensure that the product is reasonably
safe for initial use in humans and to determine whether the test
product exhibits pharmacological activity that justifies commercial
development. When a product is identified as a viable candidate for
further development, the sponsor then focuses on collecting the data
and information necessary to establish that the product will not expose
humans to unreasonable risks when used in limited, early-stage clinical
studies.
Clinical trials permit the assessment of the safety and efficacy of
investigational products from early drug development through the
approval process and beyond. To ensure that clinical trial subjects are
not exposed to unreasonable risk of harm, FDA has issued numerous
regulations governing human subject protection and the conduct of
clinical trials, including regulations regarding informed consent (part
50 (21 CFR part 50)) and institutional review boards, which also
participate in the oversight of clinical trials (21 CFR part 56).
All subjects in clinical trials under an IND receive appropriate
informed consent that discusses the known benefits and risks. With
limited exceptions, investigators must obtain the informed consent of
subjects (or their legally authorized representatives) in clinical
trials under IND (Sec. 50.20). In seeking informed consent, certain
information is provided to subjects, including a description of
reasonably foreseeable risks and a description of benefits that may
reasonably be expected (Sec. 50.25).
Furthermore, safety monitoring is not static and continues to apply
as product development progresses. IND regulations in part 312 (21 CFR
part 312) set forth safeguards that are designed to ensure such safety.
Sponsors are expected to continue to ensure the safety of subjects and,
as new safety information is identified, to take appropriate steps,
which may include incorporating additional safety monitoring and
updating the informed consent form. FDA has authority to place an
investigation on clinical hold (Sec. 312.42) if it finds that human
subjects are or would be exposed to an unreasonable and significant
risk of illness or injury. IND regulations at Sec. 312.56 state that a
sponsor who determines that its investigational drug presents an
unreasonable and significant risk to subjects must discontinue those
investigations that present the risk.
As explained above and in the preamble to the proposed rule,
exposure to the investigational product is limited at the IND stage
because the product is only administered to subjects enrolled in
clinical trials, which are typically carried out in controlled
settings. The controlled nature of a clinical trial allows for close
safety monitoring of these subjects, rapid identification of any safety
issues that may arise, and implementation of corresponding mitigation
strategies.
For these reasons, FDA considers that the existing safeguards
available in the IND process are sufficient to ensure that subjects
participating in clinical trials, including those for products that
would ultimately be regulated under BLAs and for which the INDs
incorporate by reference DS/DS/DP information contained in master
files, are not exposed to unreasonable risk of harm.
(Comment 28) Another comment expresses concern that the sponsor of
an IND for a product that would be subject to licensure under the PHS
Act that incorporates DS/DSI/DP information by reference to a master
file may not be able to develop the necessary knowledge and control
over the manufacturing process when product development reaches the BLA
stage. Therefore, the comment suggests setting a deadline during the
development stage by which time the sponsor needs to demonstrate
knowledge and control over the manufacturing process and can no longer
incorporate by reference DS/DSI/DP information from a master file.
(Response 28) FDA notes that a deadline to develop the requisite
knowledge and direct control is not necessary because the submission of
the BLA effectively serves as a deadline. As
[[Page 9754]]
noted in the preamble to the proposed rule, it has been FDA's practice
to permit INDs for products that would be subject to licensure under
the PHS Act to incorporate by reference DS/DSI/DP information contained
in a master file. By later stages of development, however, FDA requires
the sponsors to have knowledge of and direct control over the
manufacturing process, and to be able to submit DS/DSI/DP information
directly to the BLA. A sponsor can plan its product development to
ensure that, at the time the BLA is submitted, the sponsor is able to
meet these requirements.
(Comment 29) Several comments agree with the Agency's proposed
approach with respect to INDs for products that would be subject to
licensure under the PHS Act and the referencing of master files for
information including DS/DSI/DP information. One comment suggests that
allowing the referencing of DS/DSI/DP information at the IND stage
could promote product development and proposes that this benefit be
explicitly included in the corresponding codified section. Another
comment advises that permitting INDs for products that would be subject
to licensure under the PHS Act to reference master files for DS/DSI/DP
information ensures that previous knowledge is leveraged.
(Response 29) We agree that not limiting the ability of INDs for
products that would be subject to licensure under the PHS Act to
reference a master file for DS/DSI/DP information may facilitate
product development. As we explained in the preamble of the proposed
rule, and as discussed above, without this option a sponsor might not
choose to make the significant investment to manufacture the necessary
DS/DSI/DP for a product at this early stage of development. However, we
do not think it is necessary to add an explicit reference to the
benefit of promoting product development to the codified language.
6. Other Issues Raised by Commenters
(Comment 30) One comment suggests that it would be helpful if the
Agency defined the term ``drug substance intermediate,'' especially in
reference to combination products.
(Response 30) FDA is not defining the term ``drug substance
intermediate'' in this rule because such a definition would have
implications beyond the scope of this rule. FDA will consider whether
to provide a definition in rulemaking that has a broader scope since
the term is used throughout the BLA regulations.\12\
---------------------------------------------------------------------------
\12\ FDA notes that an applicant may seek guidance from the
relevant review division at the Agency if the applicant is unsure
whether information in a master file constitutes DS/DSI/DP
information in the context of a particular BLA.
---------------------------------------------------------------------------
(Comment 31) One comment requests that FDA outline any plans for
publication of guidances that more clearly articulate the Agency's
current thinking on specific kinds of master files (e.g., those
containing information on autoinjectors, on fillers, or those owned by
CMOs) that may be referenced in BLAs, to enable appropriate referencing
of relevant master files, thereby promoting improved compliance and
reducing the risk of delays in application reviews.
(Response 31) FDA will take this suggestion under consideration
with respect to the development of future guidances. FDA annually
publishes nonbinding lists of new and revised draft guidance documents
that it plans to publish in the upcoming calendar year. In addition, a
potential applicant may also seek additional guidance from the relevant
review division if the applicant is unsure whether it is appropriate to
incorporate by reference a particular type of information contained in
a master file.
(Comment 32) One comment encourages FDA to undertake modifications
to internal processes and training of staff and revise the DMF guidance
to implement this rule. Specifically, the comment requests that FDA:
(1) update its internal training procedures and relevant procedural
documents to ensure that Agency reviewers consistently implement and
apply proposed Sec. 601.2(i) during application assessment; (2) update
the DMF guidance to improve the format and layout of a DMF to avoid
duplicating the content of DMFs across multiple applications and
supplements; (3) explore potential technological solutions to permit
cross-linking between BLAs and DMFs; and (4) incorporate the feedback
provided in this comment into the revised draft guidance ``Drug Master
Files'' (Ref. 5).
(Response 32) FDA agrees that consistency in the implementation of
final Sec. 601.2(g)(4) (proposed Sec. 601.2(i)) is important. As with
any regulation, FDA will work to ensure correct and consistent
implementation of this rule.
Regarding the DMF guidance, we note that the revised draft guidance
was issued on October 21, 2019, and reflects additional information to
assist sponsors in improving the format of DMFs. Comments to guidance
documents may be submitted at any time.
Regarding technological solutions to permit cross-referencing
between BLAs and DMFs, FDA believes that its recent efforts in the area
of electronic submissions of DMFs may address some of the
concerns.<SUP>13 14</SUP>
---------------------------------------------------------------------------
\13\ See the revised draft guidance for industry ``Drug Master
Files'' (Ref. 5).
\14\ See the guidance for industry ``Providing Regulatory
Submissions in Electronic Format--Certain Human Pharmaceutical
Product Applications and Related Submissions Using the eCTD
Specifications'' (Ref. 6) for relevant discussion of FDA's current
thinking on electronic submissions.
---------------------------------------------------------------------------
(Comment 33) One comment requests that there should also be
provisions established that would notify applicants referencing a DMF
when that DMF has been altered (without disclosing proprietary
information). The comment notes that such notification would be
beneficial to regulators and applicants who would be aware of any
changes made by the DMF holder that may improve quality or safety of
the final product.
(Response 33) The purpose of this rule is to clarify when BLAs and
INDs for products subject to licensure under the PHS Act can use master
files. The operation of a DMF, which is addressed under Sec. 314.420,
falls outside the scope of this rule; accordingly, FDA declines to
address this issue in this rule.
(Comment 34) One comment observes that, if a DMF were reviewed
prior to submission of an NDA or abbreviated new drug application
(ANDA), it would allow companies, especially less established ones, to
avoid any issues with referencing an incomplete DMF for their NDA or
ANDA filing. Additionally, the comment suggests that FDA should
consider eliminating assessment fees to encourage smaller biotech and
pharmaceutical companies to develop biosimilars.
(Response 34) FDA declines to make changes to this final rule that
would address these suggestions because the process for incorporating
by reference information contained in master files, the timing of such
referencing, and the fees related to assessment of DMFs are outside the
scope of this rule.
(Comment 35) One comment notes, without suggesting any changes,
that in the description of the proposed rule for proposed paragraph
Sec. 601.2(h), FDA should include information on the impact of the
transition of an NDA to a BLA on exclusivity of the product.
(Response 35) Exclusivity considerations are outside the scope of
this rule. We note that FDA has issued guidance that, in part,
addresses FDA's
[[Page 9755]]
current thinking about its interpretation of section 7002(e) of the
BPCI Act and exclusivity.\15\
---------------------------------------------------------------------------
\15\ See the guidance for industry ``Interpretation of the
`Deemed to be a License' Provision of the Biologics Price
Competition and Innovation Act of 2009'' (Ref.1).
---------------------------------------------------------------------------
(Comment 36) One comment requests that FDA approve stem cells as an
alternative to surgery that can be covered by insurance; another
comment relates to ``pandemic flu'' and acquired immunity.
(Response 36) These topics are outside the scope of this rule.
VI. Effective/Compliance Date
This final rule is effective 30 days after the date of publication
in the Federal Register.
VII. Economic Analysis of Impacts
We have examined the impacts of the final rule under Executive
Order 12866, Executive Order 13563, Executive Order 14094, the
Regulatory Flexibility Act (5 U.S.C. 601-612), the Congressional Review
Act/Small Business Regulatory Enforcement Fairness Act (5 U.S.C. 801,
Pub. L. 104-121), and the Unfunded Mandates Reform Act of 1995 (Pub. L.
104-4).
Executive Orders 12866, 13563, and 14094 direct us to assess all
benefits, costs, and transfers of available regulatory alternatives
and, when regulation is necessary, to select regulatory approaches that
maximize net benefits (including potential economic, environmental,
public health and safety, and other advantages; distributive impacts;
and equity). Rules are ``significant'' under Executive Order 12866
Section 3(f)(1) (as amended by Executive Order 14094) if they ``have an
annual effect on the economy of $200 million or more (adjusted every 3
years by the Administrator of the Office of Information and Regulatory
Affairs (OIRA) for changes in gross domestic product); or adversely
affect in a material way the economy, a sector of the economy,
productivity, competition, jobs, the environment, public health or
safety, or State, local, territorial, or tribal governments or
communities.'' OIRA has determined that this final rule is not a
significant regulatory action under Executive Order 12866 Section
3(f)(1).
Because this rule is not likely to result in an annual effect on
the economy of $100 million or more or meets other criteria specified
in the Congressional Review Act/Small Business Regulatory Enforcement
Fairness Act, OIRA has determined that this rule does not fall within
the scope of 5 U.S.C. 804(2).
The Regulatory Flexibility Act requires us to analyze regulatory
options that would minimize any significant impact of a rule on small
entities. Because this rule does not impose new regulatory burden on
small entities, other than administrative costs of reading and
understanding the rule, we certify that the final rule will not have a
significant economic impact on a substantial number of small entities.
The Unfunded Mandates Reform Act of 1995 (section 202(a)) requires
us to prepare a written statement, which includes estimates of
anticipated impacts, before issuing ``any rule that includes any
Federal mandate that may result in the expenditure by State, local, and
tribal governments, in the aggregate, or by the private sector, of
$100,000,000 or more (adjusted annually for inflation) in any one
year.'' The current threshold after adjustment for inflation is $177
million, using the most current (2022) Implicit Price Deflator for the
Gross Domestic Product. This final rule will not result in an
expenditure in any year that meets or exceeds this amount.
Allowing deemed BLAs for biological products to continue
referencing DMFs for DS/DSI/DP information will generate net cost-
saving benefits for the private and government sectors. Furthermore,
the final rule will provide certainty, promote continuity, and help
avoid potential disruptions in the supply of certain biological
products that were approved in applications under section 505 of the
FD&C Act and deemed, pursuant to section 7004(e) of the BPCI Act, to be
licenses for the biological products under section 351 of the PHS Act.
By allowing certain BLAs to continue referencing a DMF for DS/DSI/
DP information, FDA avoids imposing a potential new regulatory burden.
Affected entities will incur minimal costs to read and understand the
rule. FDA estimates that over 10 years at a discount rate of 7 percent,
the final rule will generate annualized net cost savings ranging from
$0.40 million to $5.19 million with a primary estimate of $2.80
million; at a discount rate of 3 percent, the final rule will generate
annualized net cost savings ranging from $0.37 million to $5.17 million
with a primary estimate of $2.77 million. Table 1 summarizes our
estimate of the annualized costs and the annualized cost-saving
benefits of the final rule.
Table 1--Summary of Benefits, Costs, and Distributional Effects of the Final Rule
[Millions in 2022 dollars]
--------------------------------------------------------------------------------------------------------------------------------------------------------
Units
------------------------------------------
Category Primary Low estimate High Period Notes
estimate estimate Year dollars Discount covered
rate (%) (years)
--------------------------------------------------------------------------------------------------------------------------------------------------------
Benefits:
Annualized Monetized $millions/year. $2.81 $0.41 $5.20 2022 7 10 Cost savings.
$2.78 $0.38 $5.18 2022 3 10 Cost savings.
Costs:
Annualized Quantified............... ............ ............ ............ ............ 7 ............ ..........................
3
Qualitative......................... ............ ............ ............ ............ ............ ............ ..........................
Annualized Monetized $millions/year. $0.01 $0.01 $0.01 2022 7 10 ..........................
$0.01 $0.01 $0.01 2022 3 10 ..........................
Annualized Quantified............... ............ ............ ............ ............ 7 ............ ..........................
3
Qualitative......................... ............ ............ ............ ............ ............ ............ ..........................
Transfers:
Federal Annualized Monetized ............ ............ ............ ............ 7 ............ ..........................
$millions/year. 3
--------------------------------------------------------------------------------------------------------------------------------------------------------
From/To............................. From:
To: ............
--------------------------------------------------------------------------------------------------------------------------------------------------------
[[Page 9756]]
Other Annualized Monetized $millions/ ............ ............ ............ ............ 7 ............ ..........................
year. 3
--------------------------------------------------------------------------------------------------------------------------------------------------------
From/To............................. From:
To: ............
--------------------------------------------------------------------------------------------------------------------------------------------------------
Effects:
--------------------------------------------------------------------------------------------------------------------------------------------------------
State, Local, or Tribal Government:
None.
Small Business: None................
Wages: None.........................
Growth: None........................
--------------------------------------------------------------------------------------------------------------------------------------------------------
We have developed a comprehensive Economic Analysis of Impacts that
assesses the impacts of the final rule. The full analysis of economic
impacts is available in the docket for this final rule (Ref. 7) and at
<a href="https://www.fda.gov/about-fda/economics-staff/regulatory-impact-analyses-ria">https://www.fda.gov/about-fda/economics-staff/regulatory-impact-analyses-ria</a>.
VIII. Analysis of Environmental Impact
We have determined under 21 CFR 25.30(h) that this action is of a
type that does not individually or cumulatively have a significant
effect on the human environment. Therefore, neither an environmental
assessment nor an environmental impact statement is required.
IX. Paperwork Reduction Act of 1995
This final rule contains no collection of information. Therefore,
clearance by the Office of Management and Budget under the Paperwork
Reduction Act of 1995 is not required.
X. Federalism
We have analyzed this final rule in accordance with the principles
set forth in Executive Order 13132. We have determined that the rule
does not contain policies that have substantial direct effects on the
States, on the relationship between the National Government and the
States, or on the distribution of power and responsibilities among the
various levels of government. Accordingly, we conclude that the rule
does not contain policies that have federalism implications as defined
in the Executive Order and, consequently, a federalism summary impact
statement is not required.
XI. Consultation and Coordination With Indian Tribal Governments
We have analyzed this rule in accordance with the principles set
forth in Executive Order 13175. We have determined that the rule does
not contain policies that have substantial direct effects on one or
more Indian Tribes, on the relationship between the Federal Government
and Indian Tribes, or on the distribution of power and responsibilities
between the Federal Government and Indian Tribes. Accordingly, we
conclude that the rule does not contain policies that have tribal
implications as defined in the Executive Order and, consequently, a
tribal summary impact statement is not required.
XII. References
The following references are on display at the Dockets Management
Staff (see ADDRESSES) and are available for viewing by interested
persons between 9 a.m. and 4 p.m. Monday through Friday; they are also
available electronically at <a href="https://www.regulations.gov/">https://www.regulations.gov/</a>. Although FDA
verified the website addresses in this document, please note that
websites are subject to change over time.
1. FDA, Guidance for Industry, ``Interpretation of the `Deemed
to be a License' Provision of the Biologics Price Competition and
Innovation Act of 2009,'' December 2018. Available at <a href="https://www.fda.gov/media/119272/download">https://www.fda.gov/media/119272/download</a>. Accessed May 12, 2023.
2. FDA, Guidance for Industry, ``Cooperative Manufacturing
Arrangements for Licensed Biologics,'' November 2008. Available at
<a href="https://www.fda.gov/media/70712/download">https://www.fda.gov/media/70712/download</a>. Accessed May 12, 2023.
3. FDA, Guidance for Industry and FDA Staff, ``Bundling Multiple
Devices or Multiple Indications in a Single Submission,'' June 2007.
Available at <a href="https://www.fda.gov/media/73500/download">https://www.fda.gov/media/73500/download</a>. Accessed May
12, 2023.
4. FDA, ``Biosimilars Action Plan: Balancing Innovation and
Competition,'' July 2018. Available at <a href="https://www.fda.gov/media/114574/download">https://www.fda.gov/media/114574/download</a>. Accessed May 12, 2023.
5. FDA, Draft Guidance for Industry, ``Drug Master Files
(Rev.1),'' October 2019. Available at <a href="https://www.fda.gov/media/131861/download">https://www.fda.gov/media/131861/download</a>. Accessed May 12, 2023.
6. FDA, Guidance for Industry, ``Providing Regulatory
Submissions in Electronic Format--Certain Human Pharmaceutical
Product Applications and Related Submissions Using the eCTD
Specifications (Rev. 7),'' February 2020. Available at <a href="https://www.fda.gov/media/135373/download">https://www.fda.gov/media/135373/download</a>. Accessed May 12, 2023.
7. Final Regulatory Impact Analysis, ``Biologics License
Applications and Master Files.''
List of Subjects in 21 CFR Part 601
Administrative practice and procedure, Biologics, Confidential
business information.
Therefore, under the Public Health Service Act and under authority
delegated to the Commissioner of Food and Drugs, 21 CFR part 601 is
amended as follows:
PART 601--LICENSING
0
1. The authority citation for part 601 is revised to read as follows:
Authority: 15 U.S.C. 1451-1561; 21 U.S.C. 321, 351, 352, 353,
355, 356b, 360, 360c-360f, 360h-360j, 371, 374, 379e, 381; 42 U.S.C.
216, 241, 262, 263, 264; sec 122, Pub. L. 105-115, 111 Stat. 2322
(21 U.S.C. 355 note), sec 7002(e), Pub. L. 111-148, 124 Stat. 817,
as amended by sec. 607, Division N, Pub. L. 116-94, 133 Stat. 3127.
0
2. In Sec. 601.2, add paragraph (g) to read as follows:
Sec. 601.2 Applications for biologics licenses; procedures for
filing.
* * * * *
(g) Master files--(1) Biologics license applications under section
351 of the Public Health Service Act not permitted to incorporate by
reference drug substance, drug substance intermediate, or drug product
information contained in a master file. Except as provided in
paragraphs (g)(2) and (3) of this section, a biologics license
application under section 351 of the Public Health Service Act may not
incorporate by reference drug substance, drug substance
[[Page 9757]]
intermediate, or drug product information contained in a master file,
including a drug master file submitted under Sec. 314.420 of this
chapter, for the product, including for a biological product
constituent part of a combination product.
(2) Former approved applications deemed to be licenses for
biological products pursuant to section 7002(e)(4) of the Biologics
Price Competition and Innovation Act of 2009. An application for a
biological product that:
(i) Is a former approved application under section 505 of the
Federal Food, Drug, and Cosmetic Act that, pursuant to section
7002(e)(4) of the Biologics Price Competition and Innovation Act of
2009, has been deemed to be a license for the biological product under
section 351 of the Public Health Service Act; and
(ii) At the time it was so deemed, incorporated by reference drug
substance, drug substance intermediate, and/or drug product information
contained in a drug master file submitted under Sec. 314.420 of this
chapter, may continue to incorporate by reference the information
contained in that drug master file. Amendments and supplements to such
applications may also continue to incorporate by reference the
information contained in that drug master file.
(3) Non-biological product constituent parts of combination
products regulated under biologics license applications under section
351 of the Public Health Service Act. A biologics license application
under section 351 of the Public Health Service Act may incorporate by
reference drug substance, drug substance intermediate, and/or drug
product information contained in a master file, including a drug master
file submitted under Sec. 314.420 of this chapter, for any non-
biological product constituent part of a combination product.
(4) Biologics license applications under section 351 of the Public
Health Service Act permitted to incorporate by reference information
contained in a master file that is not drug substance, drug substance
intermediate, or drug product information. Nothing in paragraph (g)(1)
of this section limits or restricts a biologics license application
under section 351 of the Public Health Service Act from incorporating
by reference information contained in any master file, including a drug
master file submitted under Sec. 314.420 of this chapter, that is not
drug substance, drug substance intermediate, or drug product
information.
(5) Investigational new drug applications. Nothing in paragraph
(g)(1) of this section limits or restricts an investigational new drug
application for a product that would be subject to licensure under
section 351 of the Public Health Service Act from incorporating by
reference any information, including drug substance, drug substance
intermediate, and drug product information, contained in a master file,
including a drug master file submitted under Sec. 314.420 of this
chapter.
Dated: January 30, 2024.
Robert M. Califf,
Commissioner of Food and Drugs.
[FR Doc. 2024-02741 Filed 2-9-24; 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 February 12, 2024.
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