[Federal Register Volume 84, Number 125 (Friday, June 28, 2019)]
[Proposed Rules]
[Pages 30968-30976]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2019-13753]


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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: Proposed rule.

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SUMMARY: The Food and Drug Administration (FDA, the Agency, or we) is 
proposing to amend its regulations concerning the use of master files 
for biological products. This action, if finalized, will allow certain 
biological products approved under the Federal Food, Drug, and Cosmetic 
Act (FD&C Act) to continue to incorporate by reference information 
about drug substances, drug substance intermediates, or drug products 
contained in master files after those products are deemed to be 
licensed under the Public Health Service Act (PHS Act) on March 23, 
2020. The proposed rule also codifies FDA's practice of permitting 
applications for biological products submitted under the PHS Act to 
incorporate by reference information other than drug substance, drug 
substance intermediate, or drug product information contained in a 
master file. In addition, the proposed rule codifies FDA's practice of 
permitting investigational new drug applications to incorporate by 
reference any information contained in a master file for products 
subject to licensure under the PHS Act.

DATES: Submit either electronic or written comments on the proposed 
rule by August 27, 2019.

ADDRESSES: You may submit comments as follows. Please note that late, 
untimely filed comments will not be considered. Electronic comments 
must be submitted on or before August 27, 2019. The https://www.regulations.gov electronic filing system will accept comments until 
11:59 p.m. Eastern Time at the end of August 27, 2019. Comments 
received by mail/hand delivery/courier (for written/paper submissions) 
will be considered timely if they are postmarked or the delivery 
service acceptance receipt is on or before that date.

Electronic Submissions

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

Written/Paper Submissions

    Submit written/paper submissions as follows:
     Mail/Hand Delivery/Courier (for written/paper 
submissions): Dockets

[[Page 30969]]

Management Staff (HFA-305), Food and Drug Administration, 5630 Fishers 
Lane, Rm. 1061, Rockville, MD 20852.
     For written/paper comments submitted to the Dockets 
Management Staff, FDA will post your comment, as well as any 
attachments, except for information submitted, marked and identified, 
as confidential, if submitted as detailed in ``Instructions.''
    Instructions: All submissions received must include the Docket No. 
FDA-2019-N-1363 for ``Biologics License Applications and Master 
Files.'' Received comments, those filed in a timely manner (see 
ADDRESSES), will be placed in the docket and, except for those 
submitted as ``Confidential Submissions,'' publicly viewable at https://www.regulations.gov or at the Dockets Management Staff between 9 a.m. 
and 4 p.m., Monday through Friday.
     Confidential Submissions--To submit a comment with 
confidential information that you do not wish to be made publicly 
available, submit your comments only as a written/paper submission. You 
should submit two copies total. One copy will include the information 
you claim to be confidential with a heading or cover note that states 
``THIS DOCUMENT CONTAINS CONFIDENTIAL INFORMATION.'' The Agency will 
review this copy, including the claimed confidential information, in 
its consideration of comments. The second copy, which will have the 
claimed confidential information redacted/blacked out, will be 
available for public viewing and posted on https://www.regulations.gov. 
Submit both copies to the Dockets Management Staff. If you do not wish 
your name and contact information to be made publicly available, you 
can provide this information on the cover sheet and not in the body of 
your comments and you must identify this information as 
``confidential.'' Any information marked as ``confidential'' will not 
be disclosed except in accordance with 21 CFR 10.20 and other 
applicable disclosure law. For more information about FDA's posting of 
comments to public dockets, see 80 FR 56469, September 18, 2015, or 
access the information at: https://www.gpo.gov/fdsys/pkg/FR-2015-09-18/pdf/2015-23389.pdf.
    Docket: For access to the docket to read background documents or 
the electronic and written/paper comments received, go to https://www.regulations.gov and insert the docket number, found in brackets in 
the heading of this document, into the ``Search'' box and follow the 
prompts and/or go to the Dockets Management Staff, 5630 Fishers Lane, 
Rm. 1061, Rockville, MD 20852.

FOR FURTHER INFORMATION CONTACT: Kavita Vyas, Center for Drug 
Evaluation and Research, Food and Drug Administration, 10903 New 
Hampshire Ave. Bldg. 51, Rm. 4154, Silver Spring, MD 20993-0002, 301-
796-4787, kavita.vyas@fda.hhs.gov; or Stephen Ripley, 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 of the Proposed Rule
    B. Summary of the Major Provisions of the Proposed Rule
    C. Legal Authority
    D. Costs and Benefits
II. Table of Abbreviations/Commonly Used Acronyms in This Document
III. Background
    A. Introduction
    B. FDA's Current Regulatory Framework
    C. Need for the Regulation
    D. History of the Rulemaking
IV. Legal Authority
V. Description of the Proposed Rule
    A. Proposed Provision of Paragraph (g)
    B. Proposed Provision of Paragraph (i)
    C. Proposed Provision of Paragraph (j)
    D. Proposed Provision of Paragraph (h)
    E. Proposed Records/Record Retention Requirements
    F. Proposed Enforcement Provisions
    G. Proposed Technical/Conforming Amendments
VI. Proposed Effective/Compliance Dates
VII. Preliminary 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. Reference

I. Executive Summary

A. Purpose of the Proposed Rule

    FDA proposes to amend its regulations to implement certain aspects 
of section 7002(e) of the Biologics Price Competition and Innovation 
Act of 2009 (BPCI Act). The proposed rule is necessary to avoid 
unnecessary disruptions with respect to biological products originally 
approved under section 505 of the FD&C Act (21 U.S.C. 355) when their 
applications are deemed to be licenses under the PHS Act and to prevent 
potential drug shortages when those products are transitioned to being 
regulated under section 351 of the PHS Act (42 U.S.C. 262). The 
proposed rule will also update the regulation to reflect FDA's 
longstanding practices regarding the use of master files referenced in 
applications for biological products submitted under section 351 of the 
PHS Act.

B. Summary of the Major Provisions of the Proposed Rule

    FDA proposes to amend its regulations concerning the use of master 
files for biological products. The proposed rule would allow certain 
biological products, originally approved in a new drug application 
(NDA) under the FD&C Act, to continue relying on a drug master file for 
information on a drug substance, drug substance intermediate, or drug 
product (DS/DSI/DP) after the NDA is deemed to be a license for a 
biological product under the PHS Act on March 23, 2020. The proposed 
rule also codifies FDA's existing practice that a biological product in 
a biologics license application (BLA) under the PHS Act may rely on a 
master file, except for information regarding a drug substance, drug 
substance intermediate, or drug product. In addition, the rule codifies 
FDA's practice that an investigational new drug application (IND) for a 
biological product may incorporate by reference any information, 
including drug substance, drug substance intermediate, and drug product 
information, contained in a master file.

C. Legal Authority

    FDA is proposing to amend its regulations, in part, to implement 
section 7002(e) of the BPCI Act. FDA's authority for this rule also 
derives from the biological product provisions of the PHS Act (42 
U.S.C. 262 and 264), and the provisions of the FD&C Act (21 U.S.C. 321, 
et seq.) applicable to drugs, including section 701 (21 U.S.C. 371); 
the FD&C Act provisions are applicable to biological products under 
section 351(j) of the PHS Act.

D. Costs and Benefits

    FDA anticipates that affected entities would incur minimal costs to 
read and understand the rule. By allowing transitioned products to 
continue to incorporate by reference information contained in existing 
master files, FDA avoids imposing a potential new regulatory burden. 
FDA projects that over 10 years at a discount rate of 7 percent the 
proposed rule would generate annualized net cost savings ranging from 
$0.3 million to $4.6 million with a primary estimate of $2.5 million; 
over 10 years at a discount rate of 3 percent the proposed rule would 
generate annualized net cost savings ranging from $0.3 million to $4.8

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million with a primary estimate of $2.6 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.
IND.................................  Investigational New Drug
                                       Application.
NDA.................................  New Drug Application.
PHS Act.............................  Public Health Service Act.
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III. Background

A. Introduction

    This proposed rule, when finalized, would amend FDA regulations 
relating to the use of master files in applications for biological 
products subject to regulation under the PHS Act. Section 7002(b)(1) of 
the BPCI Act revised section 351(i) of the PHS Act, in part, to amend 
the definition of a ``biological product'' to include a ``protein 
(except any chemically synthesized polypeptide).'' \1\ A number of 
products approved in NDAs under section 505 of the FD&C Act meet the 
revised definition of biological product. Also, section 7002(e)(4) of 
the BPCI Act provided that, on March 23, 2020, an application for a 
biological product approved under section 505 of the FD&C Act ``shall 
be deemed to be a license for the biological product under'' section 
351 of the PHS Act. This rule implements FDA's interpretation of the 
``deemed to be a license'' provision of the BPCI Act with respect to 
the use of master files.\2\ In addition, this rule codifies current 
Agency practices relating to the use of master files referenced in 
applications for biological products.
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    \1\ On December 12, 2018, FDA issued a proposed rule regarding 
its interpretation of the terms ``protein'' and ``chemically 
synthesized polypeptide'' as used in section 351(i) of the PHS Act 
(``Definition of the term `Biological Product' '', 83 FR 63817).
    \2\ For more information about FDA's interpretation of the 
``deemed to be a license'' provision of the BPCI Act, see guidance 
for industry entitled ``Interpretation of the `Deemed to be a 
License' Provision of the Biologics Price Competition and Innovation 
Act of 2009'' (December 2018). We update guidances periodically. To 
make sure you have the most recent version of a guidance, check the 
FDA Drugs guidance web page at https://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm.
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B. FDA's Current Regulatory Framework

1. What are master files?
    Master files are submissions to the Agency that may be used to 
provide detailed, confidential information to the Agency about 
facilities, processes, or articles used in the manufacturing, 
processing, packaging, or storing of one or more human drugs. 
Information contained in a master file can be used to support a 
submission to FDA by an applicant or sponsor. The holder of a master 
file can authorize one or more applicants or sponsors to incorporate by 
reference information contained in the master file to support a 
submission to FDA without having to disclose the information in that 
master file (which may contain trade secrets or other confidential 
commercial information) to the applicants or sponsors.3 4 
The submission of a master file is at the sole discretion of the master 
file holder. Ordinarily, FDA neither independently reviews nor approves 
submissions to a master file; instead, the Agency reviews such 
information only in the context of an application that incorporates by 
reference information contained in that master file.
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    \3\ See, e.g., 21 CFR 314.420 and 47 FR 46622 at 46642 (October 
19, 1982).
    \4\ The holder of a master file (including a drug master file) 
who expects that information in the file will be incorporated by 
reference both in a BLA and in an NDA or abbreviated new drug 
application (ANDA) need only submit the master file to the Agency 
once.
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    a. Drug master files. Some master files contain information that is 
relevant to applications for drug products. For products regulated 
under section 505 of the FD&C Act, FDA defines the term ``drug master 
file'' (DMF) in its drug regulations (Sec.  314.420(a) (21 CFR 
314.420(a))) and explicitly provides that ``[a]n investigational new 
drug application or an application, abbreviated application, amendment, 
or supplement may incorporate by reference all or part of the contents 
of any drug master file in support of the submission'' if the holder of 
the master file authorizes the incorporation (Sec.  314.420(b)). 
Section 314.420 also describes several types of DMFs, each of which 
typically contains certain kinds of information (Sec.  314.420(a)): 
Drug substance, drug substance intermediate, and materials used in 
their preparation, or drug product (referred to as Type II DMFs); 
packaging materials (Type III); excipient, colorant, flavor, essence, 
or materials used in their preparation (Type IV); and FDA-accepted 
reference information (Type V). (See also FDA Guidance for Industry 
entitled ``Drug Master Files: Guidelines,'' September 1989, available 
at https://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm122886.htm (accessed March 2019).)
    b. Other master files. FDA also permits reference to master files 
that are not addressed by Sec.  314.420, some of which contain 
information that is relevant to applications for biological 
products.\5\ The Agency's approach to the terminology for types of 
master files used for products regulated under the PHS Act has 
generally tracked its approach to the types of DMFs (e.g., Type II, 
Type III) used for products regulated under the FD&C Act.
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    \5\ See, e.g., 21 CFR 601.51(a).
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2. Biologics License Applications and Master Files
    a. FDA generally permits BLAs to incorporate by reference 
information contained in master files. Just as FDA permits NDAs and 
ANDAs under the FD&C Act to incorporate by reference certain 
information contained in DMFs, the Agency also generally permits 
applications under the PHS Act (BLAs) to incorporate by reference 
certain information contained in master files, including DMFs.
    For most categories of information and most application types 
(including BLAs and INDs), the needs of master file holders, applicants 
and sponsors, and FDA have been adequately met through this 
incorporation-by-reference mechanism. This mechanism allows applicants 
and sponsors to refer to information contained in master files without 
having knowledge of the contents of those master files (Sec.  314.420; 
47 FR 46622 at 46642). For products licensed under section 351 of the 
PHS Act, FDA has permitted, and will generally continue to permit, the 
use of information contained in most types of master files (such as 
information about excipients, stabilizers, penetrants, or materials 
used in the preparation of DS/DSI/DP) because the applicant generally 
has the ability to independently identify and mitigate the risk posed 
to product quality by such components. For example, applicants are 
permitted to incorporate by reference in their BLA information on 
container closures contained in a master file. This is the case because 
an applicant can independently identify the risk to product quality 
posed by a container closure (for example, by leachables in the 
closure) by performing appropriate studies on stability and 
adequateness for intended use and then taking steps to

[[Page 30971]]

mitigate any risks identified (for example, by implementing appropriate 
testing and controls). Thus, in such cases, the feasibility of testing 
to confirm the adequateness of intended container closures mitigates 
the risks to quality arising from the applicant's lack of access to the 
information contained in the master file.
    Accordingly, proposed Sec.  601.2(i) would codify FDA's 
longstanding practice of permitting biological products in BLAs to 
incorporate by reference most categories of information contained in 
master files (other than information about DS/DSI/DP, discussed below).
    b. FDA currently does not permit biological products in BLAs to 
incorporate by reference drug substance, drug substance intermediate, 
or drug product information in master files. Although FDA's approach to 
the use of master files in BLAs largely parallels its approach to the 
use of DMFs in applications under the FD&C Act, there is a significant 
difference: Unlike applications submitted under section 505 of the FC&C 
Act, for biological products in BLAs, the Agency has, as a scientific 
matter, expected applicants to submit information about DS/DSI/DP 
directly to the BLA rather than incorporating it by reference to a 
master file. (See, e.g., FDA Guidance for Industry entitled ``Quality 
Considerations in Demonstrating Biosimilarity of a Therapeutic Protein 
Product to a Reference Product'' April 2015, available at https://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm291134.pdf (accessed March 2019).)
    The risk associated with the manufacture of complex biological 
products is generally significantly higher than that associated with 
the manufacture of chemical entities, which are often less complex.\6\ 
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. In addition, biological products 
derived from biological sources may be complex heterogeneous mixtures, 
which provides another basis for having consistent process controls to 
ensure quality.
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    \6\ The Agency recognizes that, in limited circumstances, this 
may not always be the case; however, for purposes of administrative 
efficiency and predictability, the Agency is proposing a bright line 
between BLAs and NDAs regarding the referencing of master files for 
DS/DSI/DP information for biological products.
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    For these reasons, the Agency considers the establishment and 
function of a robust quality assurance program, with intimate knowledge 
of all manufacturing steps, to be essential for controlling and 
evaluating the process and the biological product, and for mitigating 
product quality risks. The applicant for a BLA is expected to have 
knowledge of and direct control over the manufacturing process for the 
DS/DSI/DP for a biological product (21 CFR 601.2 and 601.20). Absent 
this knowledge and control, the applicant generally cannot operate a 
robust quality assurance program that independently identifies and 
mitigates quality risks, which is critical to assuring the quality of a 
biological product.
    As a scientific matter, given the complexity of biological 
products, the Agency considers it generally impractical for the 
applicant to confirm the DS/DSI/DP quality characteristics of a 
biological product without complete knowledge of, and control over, all 
aspects of the manufacturing process. FDA has concluded that the risk 
to quality arising from the fragmentation of information about DS/DSI/
DP for a biological product between a master file and a BLA is very 
difficult to mitigate. As a result, FDA believes that this type of 
information is generally best submitted to the Agency directly in the 
BLA, and that a BLA that incorporates by reference DS/DSI/DP 
information for a biological product contained in a master file is 
generally inconsistent with biological product licensing 
requirements.7 8
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    \7\ FDA may permit, and generally will continue to permit, an 
applicant to incorporate by reference certain information about a 
product that is not the subject of the applicant's own BLA, such as 
information about a comparator product used in studies intended to 
support approval of the applicant's BLA. Incorporation of such 
information by reference generally does not raise similar concerns 
relating to an applicant's knowledge and control over all aspects of 
the manufacturing process for the product that is the subject of the 
applicant's own BLA.
    \8\ In lieu of the use of master files, other types of contract 
manufacturing arrangements can be considered if the sponsor does not 
intend to manufacture all aspects of the product for licensure and 
the licensee assumes responsibility for compliance with the 
applicable product and establishment standards. (See, e.g., FDA 
guidance for industry entitled ``Cooperative Manufacturing 
Arrangements For Licensed Biologics,'' November 2008, available at 
https://www.fda.gov/ucm/groups/fdagov-public/@fdagov-bio-gen/documents/document/ucm069908.pdf (accessed March 2019).)
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    Accordingly, proposed Sec.  601.2(g) would codify FDA's 
longstanding practice of not permitting a biological product in a BLA 
to incorporate by reference information regarding DS/DSI/DP contained 
in master files.
3. The Biologics Price Competition and Innovation Act of 2009
    Section 7002(b) of the BPCI Act amended, in part, the definition of 
a ``biological product'' in the PHS Act to include a ``protein (except 
any chemically synthesized polypeptide).'' \9\ Accordingly, under 
section 351(i) of the PHS Act, a ``biological product'' is now defined 
as ``a virus, therapeutic serum, toxin, antitoxin, vaccine, blood, 
blood component or derivative, allergenic product, protein (except any 
chemically synthesized polypeptide), or analogous product, or 
arsphenamine or derivative of arsphenamine (or any other trivalent 
organic arsenic compound), applicable to the prevention, treatment, or 
cure of a disease or condition of human beings'' (section 351(i) of the 
PHS Act; emphasis added).
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    \9\ See footnote 1.
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    Some protein products have historically been approved under section 
505 of the FD&C Act. However, section 7002(e) of the BPCI Act provides 
that a marketing application for a ``biological product'' must be 
submitted under section 351 of the PHS Act (subject to certain 
exceptions during a transition period ending on March 23, 2020). 
Section 7002(e) of the BPCI Act also provides that, on March 23, 2020, 
an application for a biological product approved under section 505 of 
the FD&C Act ``shall be deemed to be a license for a biological product 
under section 351'' of the PHS Act.\10\ Such approved applications are 
referred to as ``deemed BLAs'' in this document.
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    \10\ See FDA Guidance for Industry entitled ``Interpretation of 
the `Deemed to be a License' Provision of the Biologics Price 
Competition and Innovation Act of 2009'' (December 2018). Available 
at https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM490264.pdf 
(accessed March 2019).
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C. Need for the Regulation

1. The Biologics Price Competition and Innovation Act of 2009 and the 
Use of Drug Master Files in BLAs
    The BPCI Act is silent about implementation of the ``deemed to be a 
license for a biological product'' provision. In March 2016, FDA 
published a draft guidance for industry entitled ``Interpretation of 
the `Deemed to be a License' Provision of the Biologics Price 
Competition and Innovation Act of 2009'' (see 81 FR 13373, March 14, 
2016). Footnote 12 of that draft guidance explained that for sponsors 
of proposed protein products who intend to submit a BLA, a Type II DMF 
for a drug substance, drug substance intermediate, or drug product 
would not be acceptable for a BLA

[[Page 30972]]

because a license holder is expected to have knowledge of and control 
over the manufacturing process for the biological product for which it 
has a license. The footnote went on to provide that FDA is considering 
a mechanism that, in limited circumstances, would allow holders of 
approved applications under section 505 of the FD&C Act that reference 
a Type II DMF to continue to reference the DMF after the application is 
deemed to be a license under the PHS Act on March 23, 2020. FDA 
finalized this guidance in December 2018 (available at https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM490264.pdf (accessed March 2019)), after considering 
comments in its draft recommendations and without including the 
corresponding footnote from the draft guidance because this proposed 
rule would establish such a mechanism, while also codifying the general 
longstanding practice that BLAs and INDs for biological products can 
reference information in master files except, in the case of BLAs, for 
DS/DSI/DP information for a biological product.
2. Mechanism To Permit the Continued Use of Currently Referenced DMFs 
by ``Deemed BLAs''
    Biological products regulated under the FD&C Act have been able to 
incorporate by reference DS/DSI/DP information contained in DMFs to 
support the approval of NDAs. As explained above, for biological 
products licensed under section 351 of the PHS Act, incorporating by 
reference information contained in master files on DS/DSI/DP generally 
is not permitted.
    This proposed regulation addresses, in part, a specific issue 
related to implementation of the ``deemed to be a license'' provision 
of the BPCI Act: Whether applications approved under section 505 of the 
FD&C Act may continue to incorporate by reference DS/DSI/DP information 
contained in DMFs once the applications are deemed to be BLAs subject 
to licensure and regulation under the PHS Act.
    To date, FDA has identified approximately 89 applications approved 
under the FD&C Act that will be deemed licensed under the PHS Act on 
March 23, 2020. Approximately 17 of these applications incorporate by 
reference information on DS/DSI/DP contained in DMFs. Furthermore, the 
DS/DSI/DP information incorporated by reference into these 17 
applications is drawn from only 7 DMFs. Thus, this use of DMFs for DS/
DSI/DP information involves a small subset of the deemed BLAs and only 
a very small number of DMFs.
    In light of FDA's longstanding practice of not permitting a 
biological product in a BLA to incorporate by reference information 
regarding DS/DSI/DP contained in a master file, the Agency is 
considering the appropriate regulatory approach to the relatively few 
deemed BLAs that reference DS/DSI/DP information contained in DMFs. The 
Agency is evaluating the risks and benefits of allowing these deemed 
BLAs to continue incorporating by reference this type of information 
from those DMFs. The analysis takes into account clinical 
considerations and product availability, as well as the limited number 
of applications and the limited number of DMFs that are involved. Based 
on this analysis, the Agency proposes that for biological products, the 
appropriate mechanism with respect to addressing incorporation by 
reference of DS/DSI/DP information contained in DMFs would be to 
implement the least disruptive approach.
    Some of the deemed BLAs that currently incorporate by reference 
information contained in DMFs to support the application were approved 
by the Agency based in part on DS/DSI/DP information contained in those 
DMFs. Many of these products have been marketed for decades. Over this 
period, none of these products have been withdrawn or removed from the 
market for reasons of safety or effectiveness. For these products, the 
Agency has no reason to believe that the March 23, 2020, transition in 
and of itself introduces new risks to product safety, purity, and 
potency.
    For some biological products, such as certain reproductive 
hormones, treating the deemed BLAs like other applications for 
biological products under the PHS Act with regard to the use of DS/DSI/
DP information contained in a DMF would present a considerable 
challenge. Nearly all approved applications for these biological 
products incorporate by reference DS/DSI/DP information contained in a 
DMF. This incorporation by reference has resulted in drug substances 
for these products of acceptable quality for decades. For example, 
multiple Human Chorionic Gonadotropins from urinary sources have been 
on the market since the mid-1970s using DMFs for information on the 
drug substance, with changes to the product being handled through the 
DMF pathway. Disallowing use of DMFs for these deemed BLAs would 
curtail or halt production of these products, resulting in imminent or 
immediate drug shortages with considerable negative impacts on public 
health. FDA does not believe it was Congress's intent when enacting 
section 7002(e) of the BPCI Act that deemed BLAs would need to be 
removed from the market on March 23, 2020.
    Furthermore, the general concern about fragmentation of DS/DSI/DP 
information associated with the use of DMFs is lessened in the case of 
the deemed BLAs by the existence of generally longstanding 
relationships between the deemed-BLA applicants and the DMF holders. 
For example, the license holder of a deemed BLA may have accumulated 
knowledge about the quality of the biological product supplied by the 
DMF holder over an extended period. This accumulated knowledge allows 
the deemed BLA holder 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.
    In light of these facts, FDA believes that permitting a limited 
number of deemed BLAs to continue to incorporate by reference DS/DSI/DP 
information contained in a limited number of DMFs will, on balance, 
protect and promote the public health. In contrast, if non-deemed BLAs 
were to reference an existing DMF, they would generally not have the 
benefit of this accumulated knowledge, and thus would not be able to 
mitigate the resulting fragmentation of information and risk to product 
quality as effectively. Similarly, while the lack of overt safety 
signals and the absence of concerns about efficacy provide a rationale 
for allowing a deemed BLA to continue to rely on DS/DSI/DP information 
contained in a DMF, it may not be appropriate to extend this rationale 
to a non-deemed BLA. For these reasons, in proposed Sec.  601.2(h), FDA 
would permit only deemed BLAs that incorporate by reference information 
on DS/DSI/DP contained in particular DMFs in their approved 
applications under section 505 of the FD&C Act to continue doing so 
after these products are deemed to be licensed under the PHS Act on 
March 23, 2020. BLAs for other biological products will continue to not 
be permitted to incorporate by reference DS/DSI/DP information 
contained in a master file, consistent with FDA's longstanding 
practice. Also, to enable innovation for deemed BLAs that reference an 
existing DMF, it is important to preserve the ability to make changes 
to the existing DMFs. Therefore, the proposed rule will permit holders 
of existing DMFs referenced for deemed BLAs before transition to modify 
these DMFs under Sec.  314.420 after March 23, 2020.

[[Page 30973]]

3. Investigational New Drug Applications and Master Files
    Section 314.420(b) provides that ``[a]n investigational new drug 
application . . . may incorporate by reference all or part of the 
contents of any drug master file in support of the submission'' with 
the DMF holder's consent. In addition, FDA typically permits an IND for 
a biological product to incorporate by reference information contained 
in other master files, in addition to DMFs. Furthermore, it has been 
FDA's practice to permit sponsors of INDs for biological products to 
incorporate by reference DS/DSI/DP information contained in a master 
file.
    FDA permits the use of DS/DSI/DP master files in biological product 
INDs for several reasons. Exposure to the investigational product is 
limited in the IND stage because it is only administered to subjects 
enrolled in clinical trials, which are typically carried out in 
controlled settings. Accordingly, the sponsor and FDA can mitigate risk 
more effectively by closely monitoring patients in those trials, in 
order to evaluate the safety of the investigational product, which is a 
necessary component of the licensing process.
    Permitting the sponsor of an IND for a biological product to 
incorporate by reference DS/DSI/DP information contained in master 
files may also facilitate product development. Without this option, a 
sponsor might choose not to make the significant investment to 
manufacture the necessary DS/DSI/DP for a biological product at this 
early stage of development. However, even in cases where an IND sponsor 
of a biological product incorporates by reference DS/DSI/DP information 
contained in a master file, FDA expects the sponsor to have knowledge 
of and direct control of the manufacturing process by later stages of 
development.
    Therefore, in proposed Sec.  601.2(j), FDA clarifies and codifies 
this practice.

D. History of the Rulemaking

    In response to the BPCI Act, public meetings were held to discuss 
various aspects of the statute. Also, public comments on the current 
FDA practice for biological products of not accepting DMFs for 
biological products in BLAs were received in the context of the draft 
guidance for industry entitled ``Interpretation of the `Deemed to be a 
License' Provision of the Biologics Price Competition and Innovation 
Act of 2009'' (see 81 FR 13373). Comments, in part: (1) Urged FDA to 
clarify its position on the use of Type II DMFs for applications that 
will be deemed BLAs on March 23, 2020, and, at least for pancreatic 
enzyme products, recommended FDA permit applications to reference Type 
II DMFs after March 23, 2020, even if the application was not approved 
as an NDA prior to the transition date; \11\ (2) urged FDA to adopt a 
flexible approach toward the continued referencing of existing DMFs; 
\12\ and (3) sought clarity on the use of other categories of DMFs 
(e.g., Type III DMFs).\13\ FDA finalized this guidance in December 2018 
after considering comments in its draft recommendations. With respect 
to the comments concerning DMFs, the Agency undertook an analysis of 
the number of DMFs, the number of applications referencing these DMFs, 
and considered the consequences of not taking any action or taking the 
proposed action. The Agency addressed all the concerns identified in 
the public comments through the actions described in this proposed 
rule, which includes allowing the incorporation by reference of DS/DP/
DSI information contained in DMFs, provided the DMFs were referenced 
prior to the application being deemed a BLA on March 23, 2020, and 
providing clarity on the use of other categories of DMFs in BLAs.
---------------------------------------------------------------------------

    \11\ See Comment from Curemark, LLC to Docket No. FDA-2015-D-
4750 (available at https://www.regulations.gov).
    \12\ See Comment from Pharmaceutical Research and Manufacturers 
of America (PhRMA) to Docket No. FDA-2015-D-4750 (available at 
https://www.regulations.gov).
    \13\ See Comments from Biotechnology Innovation Organization and 
from Novo Nordisk, Docket No. FDA-2015-D-4750.
---------------------------------------------------------------------------

IV. Legal Authority

    FDA is proposing to amend its regulations, in part, to implement 
certain aspects of section 7002(e) of the BPCI Act. FDA's authority for 
this proposed 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 promulgate regulations for the efficient 
enforcement of the FD&C Act and the PHS Act, under section 701 of the 
FD&C Act and section 351(j) of the PHS Act.

V. Description of the Proposed Rule

    We propose to amend Sec.  601.2 to add new paragraphs (g), (h), 
(i), and (j). Specifically, the proposed rule will allow applications 
for biological products approved under section 505 of the FD&C Act to 
continue to incorporate by reference DS/DP/DSI information contained in 
DMFs, provided the DMFs were referenced before March 23, 2020. Also, 
this proposed rule essentially codifies, for biological products, the 
longstanding Agency practices of permitting BLAs to incorporate by 
reference information other than on DS/DP/DSI contained in master files 
and INDs to incorporate any information contained in master files. FDA 
is aware that there are combination products approved in BLAs under the 
PHS Act and considers that the rationale described in this rule for 
biological products also applies to the biological constituent part of 
such combination products. FDA seeks 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 constituent part (for example, the drug constituent part 
of an antibody drug conjugate).

A. Proposed Provision of Paragraph (g)

    Proposed new paragraph (g) codifies the Agency's practice of not 
permitting applications for biological products submitted under section 
351 of the PHS Act to incorporate by reference information on DS/DSI/DP 
contained in a master file. Deemed BLAs are excluded from this 
provision and are addressed in proposed new paragraph (h).

B. Proposed Provision of Paragraph (i)

    Proposed new paragraph (i) codifies the Agency's practice of 
permitting applications for biological products submitted under section 
351 of the PHS Act to incorporate by reference information other than 
DS/DSI/DP information contained in master files, including in DMFs.

C. Proposed Provision of Paragraph (j)

    Proposed new paragraph (j) codifies the Agency's practice of 
permitting INDs to incorporate by reference information contained in 
master files, including information on DS/DSI/DP.

D. Proposed Provision of Paragraph (h)

    Proposed new paragraph (h) addresses applications transitioning on 
March 23, 2020, under section 7002(e) of the BPCI Act. It allows an 
application for a biological product that has been approved under 
section 505 of the FD&C Act and that incorporates by reference DS/DSI/
DP information contained in a DMF to continue to do so after that 
application is deemed to be a BLA.

[[Page 30974]]

    The proposed rule is intended to preserve the status quo both for 
the small number of deemed BLAs and for all other applications for 
biological products submitted under section 351 of the PHS Act: Deemed 
BLAs that incorporate by reference information on DS/DSI/DP contained 
in a DMF at the time of their transition will be permitted to continue 
to do so, but no other applications for biological products will be 
permitted to incorporate by reference DS/DSI/DP information contained 
in any master files.
    The proposed rule is not intended to alter a license holder's 
ability to modify a product under Sec.  601.12 (21 CFR 601.12). 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. Under the proposed rule, an applicant would 
be permitted to supplement a deemed BLA within the same application, as 
it would any other BLA under Sec.  601.12 and the applicable bundling 
policy.\14\ However, if modifications to the deemed BLA are required 
that could not be effected in a supplement and a new application is 
required, that new BLA would not be considered a deemed BLA. As is the 
case with other (non-deemed) applications for biological products, the 
new BLA would not be permitted to reference DS/DSI/DP information 
contained in any master file and would need to submit this information 
as part of the new BLA itself.
---------------------------------------------------------------------------

    \14\ See guidance for industry entitled ``Submitting Separate 
Marketing Applications and Clinical Data for Purposes of Assessing 
User Fees'' (December 2004). Available at https://www.fda.gov/ucm/groups/fdagov-public/@fdagov-drugs-gen/documents/document/ucm079320.pdf. (accessed March 2019).
---------------------------------------------------------------------------

    The proposed rule is also not intended to limit or restrict the 
changes that may be made to any master file, including a DMF for DS/
DSI/DP information.
    The proposed rule thus preserves the relationship between a DMF and 
the application that references it. This ensures that the transition to 
regulation under the PHS Act does not interrupt the supply of 
biological products that have already been shown to be safe and 
effective.

E. Proposed Records/Record Retention Requirements

    None; existing records and retention requirements will continue to 
apply.

F. Proposed Enforcement Provisions

    None; existing enforcement regulations will continue to apply.

G. Proposed Technical/Conforming Amendments

    None necessary.

VI. Proposed Effective/Compliance Dates

    If finalized on or before February 22, 2020, this rule would take 
effect on March 23, 2020.

VII. Preliminary Economic Analysis of Impacts

    We have examined the impacts of the proposed rule under Executive 
Order 12866, Executive Order 13563, Executive Order 13771, the 
Regulatory Flexibility Act (5 U.S.C. 601-612), and the Unfunded 
Mandates Reform Act of 1995 (Pub. L. 104-4). Executive Orders 12866 and 
13563 direct us to assess all costs and benefits 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). Executive Order 13771 
requires that the costs associated with significant new regulations 
``shall, to the extent permitted by law, be offset by the elimination 
of existing costs associated with at least two prior regulations.'' We 
believe that this proposed rule is not a significant regulatory action 
as defined by Executive Order 12866.
    The Regulatory Flexibility Act requires us to analyze regulatory 
options that would minimize any significant impact of a rule on small 
entities. Because the proposed rule does not impose any new burdens, we 
propose to certify that the proposed 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 an assessment of 
anticipated costs and benefits, before proposing ``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 $154 million, using the most current (2018) Implicit 
Price Deflator for the Gross Domestic Product. This proposed rule would 
not result in an expenditure in any year that meets or exceeds this 
amount.
    Table 1 summarizes our estimate of the annualized costs and the 
annualized cost-saving benefits of the proposed rule.

                                    Table 1--Summary of Benefits, Costs, and Distributional Effects of Proposed Rule
--------------------------------------------------------------------------------------------------------------------------------------------------------
                                                                                                      Units
                                                                                   ------------------------------------------
                Category                     Primary    Low estimate      High                                     Period                Notes
                                            estimate                    estimate    Year dollars    Discount       covered
                                                                                                    rate (%)       (years)
--------------------------------------------------------------------------------------------------------------------------------------------------------
Benefits:
    Annualized Monetized $millions/year.         $2.48         $0.33         $4.64          2017             7            10  Cost savings.
                                                 $2.56         $0.32         $4.80          2017             3            10  Cost savings.
    Annualized Quantified...............  ............  ............  ............  ............             7  ............  ..........................
    Qualitative.........................  ............  ............  ............  ............             3  ............  ..........................
Costs:
    Annualized Monetized $millions/year.         $0.00         $0.00         $0.00          2017             7            10  ..........................
                                                 $0.00         $0.00         $0.00          2017             3            10
    Annualized Quantified...............  ............  ............  ............  ............             7  ............  ..........................
    Qualitative.........................  ............  ............  ............  ............             3  ............  ..........................
Transfers:
    Federal Annualized Monetized          ............  ............  ............  ............             7  ............  ..........................
     $millions/year.                                                                                         3
--------------------------------------------------------------------------------------------------------------------------------------------------------
    From/To.............................  From:
                                          To:
--------------------------------------------------------------------------------------------------------------------------------------------------------

[[Page 30975]]

 
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.
--------------------------------------------------------------------------------------------------------------------------------------------------------

    In line with Executive Order 13771, in table 2 we estimate present 
and annualized values of costs and cost savings over an infinite time 
horizon. Based on these cost savings, this proposed rule would be 
considered a deregulatory action under Executive Order 13771.

                                                            Table 2--E.O. 13771 Summary Table
                                                  [$ million in 2016 dollars over an infinite horizon]
--------------------------------------------------------------------------------------------------------------------------------------------------------
                                                            Lower bound                     Upper bound     Lower bound                     Upper bound
                                                               (7%)        Primary (7%)        (7%)            (3%)        Primary (3%)        (3%)
--------------------------------------------------------------------------------------------------------------------------------------------------------
Present Value of Costs..................................           $0.02           $0.02           $0.02           $0.02           $0.02           $0.03
Present Value of Cost-Savings...........................           $2.49          $18.66          $34.83           $2.80          $22.47          $42.14
Present Value of Net Costs..............................         ($2.47)        ($18.64)        ($34.81)         ($2.77)        ($22.45)        ($42.12)
Annualized Costs........................................           $0.00           $0.00           $0.00           $0.00           $0.00           $0.00
Annualized Cost-Savings.................................           $0.17           $1.31           $2.44           $0.08           $0.67           $1.26
Annualized Net Costs....................................         ($0.17)         ($1.30)         ($2.44)         ($0.08)         ($0.67)         ($1.26)
--------------------------------------------------------------------------------------------------------------------------------------------------------

    We have developed a comprehensive Preliminary Economic Analysis of 
Impacts that assesses the impacts of the proposed rule. The full 
preliminary analysis of economic impacts is available in the docket for 
this proposed rule (Ref. 1) and at https://www.fda.gov/AboutFDA/ReportsManualsForms/Reports/EconomicAnalyses/default.htm.

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 proposed rule refers to previously approved collections of 
information that are subject to review by the Office of Management and 
Budget (OMB) under the Paperwork Reduction Act of 1995 (44 U.S.C. 3501-
3520). The collections of information in 21 CFR part 314 and 21 CFR 
part 601 have been approved under OMB control numbers 0910-0001 and 
0910-0338, respectively.

X. Federalism

    We have analyzed this proposed rule in accordance with the 
principles set forth in Executive Order 13132. We have determined that 
this proposed 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 proposed rule in accordance with the 
principles set forth in Executive Order 13175. We have tentatively 
determined that the rule does not contain policies that would have a 
substantial direct effect 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. The Agency solicits comments from tribal 
officials on any potential impact on Indian Tribes from this proposed 
action.

XII. Reference

    The following reference is on display at the Dockets Management 
Staff (see ADDRESSES) and is available for viewing by interested 
persons between 9 a.m. and 4 p.m., Monday through Friday; it is also 
available electronically at https://www.regulations.gov.

1. FDA, Preliminary 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, we propose that 21 CFR 
part 601 be 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.


[[Page 30976]]


0
2. Amend Sec.  601.2 by adding paragraphs (g), (h), (i), and (j) to 
read as follows:


Sec.  601.2  Applications for biologics licenses; procedures for 
filing.

* * * * *
    (g) Except as provided in paragraph (h) of this section, an 
application for a biological product submitted to the Food and Drug 
Administration for licensure under section 351 of the Public Health 
Service Act; licensed under section 351 of the Public Health Service 
Act; or deemed, under section 7002(e) of the Biologics Price 
Competition and Innovation Act of 2009, to be licensed under section 
351 of the Public Health Service Act may not incorporate by reference 
drug substance, drug substance intermediate, or drug product 
information contained in a master file, including a drug master file 
submitted under Sec.  314.420 of this chapter. Amendments and 
supplements submitted in support of these applications also may not 
incorporate by reference such information contained in a master file.
    (h) An application for a biological product that:
    (1) Was approved under section 505 of the Federal Food, Drug, and 
Cosmetic Act;
    (2) Was deemed on March 23, 2020, to be a license for the 
biological product under section 351 of the Public Health Service Act; 
and
    (3) On March 23, 2020, 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 after March 23, 2020. Amendments and supplements 
submitted in support of these applications may also incorporate by 
reference the information contained in that drug master file.
    (i) Nothing in paragraph (g) of this section limits or restricts an 
application for a biological product submitted to the Food and Drug 
Administration for licensure under section 351 of the Public Health 
Service Act; licensed under section 351 of the Public Health Service 
Act; or deemed, under section 7002(e) of the Biologics Price 
Competition and Innovation Act of 2009, to be licensed 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. 
Amendments and supplements submitted in support of these applications 
may also incorporate by reference such information contained in a 
master file.
    (j) Nothing in paragraph (g) of this section limits or restricts an 
investigational new drug application for a biological product 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: June 17, 2019.
Norman E. Sharpless,
Acting Commissioner of Food and Drugs.
    Dated: June 21, 2019.
Eric D. Hargan,
Deputy Secretary, Department of Health and Human Services.
[FR Doc. 2019-13753 Filed 6-27-19; 8:45 am]
 BILLING CODE 4164-01-P


