[Federal Register Volume 86, Number 154 (Friday, August 13, 2021)]
[Notices]
[Pages 44731-44736]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2021-17378]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. FDA-2020-N-1245]


Drug Products Approved in Abbreviated New Drug Applications 
Before the Enactment of the Hatch-Waxman Amendments; Establishment of a 
Public Docket; Request for Comments

AGENCY: Food and Drug Administration, Health and Human Services (HHS).

ACTION: Notice; establishment of a public docket; request for comments.

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SUMMARY: The Food and Drug Administration (FDA or Agency) is announcing 
the establishment of a public docket to solicit comments on several 
issues related to FDA's post-approval regulation of certain drug 
products approved in abbreviated applications before the Drug Price 
Competition and Patent Term Restoration Act of 1984 (Hatch-Waxman 
Amendments) amended the Federal Food, Drug, and Cosmetic Act (FD&C Act) 
to establish the current abbreviated new drug application (ANDA) 
process. Because these pre-Hatch-Waxman abbreviated new drug 
applications (referred to in this notice as ``PANDAs'') were submitted 
and approved under the provisions of the FD&C Act that apply to 505(b) 
new drug applications, they can serve as a reference listed drug (RLD) 
for ANDAs and can also be a listed drug relied on by 505(b)(2) 
applications. PANDAs have historically been overseen by FDA's Office of 
Generic Drugs, and FDA is aware that there may be some confusion about 
the applicability of certain statutory and regulatory provisions to 
PANDAs. FDA is seeking input from holders of PANDAs and other 
interested persons regarding whether there are regulatory or policy 
rationales for treating PANDAs differently from other 505(b) 
applications in certain respects.

DATES: Submit either electronic or written comments by December 13, 
2021.

ADDRESSES: FDA is establishing a docket for public comments on this 
document. The docket number is FDA-2020-N-1245. The docket will close 
on December 13, 2021. Submit either electronic or written comments by 
that date. Please note that late, untimely filed comments will not be 
considered. Electronic comments must be submitted on or before December 
13, 2021. The https://www.regulations.gov electronic filing system will 
accept comments until 11:59 p.m. Eastern Time at the end of December 
13, 2021. 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.
    You may submit comments as follows:

Electronic Submissions

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

Written/Paper Submissions

    Submit written/paper submissions as follows:

[[Page 44732]]

     Mail/Hand Delivery/Courier (for written/paper 
submissions): Dockets Management Staff (HFA-305), Food and Drug 
Administration, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852.
     For written/paper comments submitted to the Dockets 
Management Staff, FDA will post your comment, as well as any 
attachments, except for information submitted, marked and identified, 
as confidential, if submitted as detailed in ``Instructions.''
    Instructions: All submissions received must include the Docket No. 
FDA-2020-N-1245 for ``Drug Products Approved in Abbreviated New Drug 
Applications Before the Enactment of the Hatch-Waxman Amendments; 
Establishment of a Public Docket; Request for Comments.'' 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, 240-402-7500.
     Confidential Submissions--To submit a comment with 
confidential information that you do not wish to be made publicly 
available, submit your comments only as a written/paper submission. You 
should submit two copies total. One copy will include the information 
you claim to be confidential with a heading or cover note that states 
``THIS DOCUMENT CONTAINS CONFIDENTIAL INFORMATION.'' The Agency will 
review this copy, including the claimed confidential information, in 
its consideration of comments. The second copy, which will have the 
claimed confidential information redacted/blacked out, will be 
available for public viewing and posted on https://www.regulations.gov. 
Submit both copies to the Dockets Management Staff. If you do not wish 
your name and contact information to be made publicly available, you 
can provide this information on the cover sheet and not in the body of 
your comments and you must identify this information as 
``confidential.'' Any information marked as ``confidential'' will not 
be disclosed except in accordance with 21 CFR 10.20 and other 
applicable disclosure law. For more information about FDA's posting of 
comments to public dockets, see 80 FR 56469, September 18, 2015, or 
access the information at: https://www.govinfo.gov/content/pkg/FR-2015-09-18/pdf/2015-23389.pdf.
    Docket: For access to the docket to read background documents or 
the electronic and written/paper comments received, go to https://www.regulations.gov and insert the docket number, found in brackets in 
the heading of this document, into the ``Search'' box and follow the 
prompts and/or go to the Dockets Management Staff, 5630 Fishers Lane, 
Rm. 1061, Rockville, MD 20852, 240-402-7500.

FOR FURTHER INFORMATION CONTACT: Melissa Mannion, Center for Drug 
Evaluation and Research, Food and Drug Administration, 10903 New 
Hampshire Ave., Bldg. 75, Room 1611, Silver Spring, MD 20993, 301-796-
2747, [email protected].

SUPPLEMENTARY INFORMATION:

I. Background

A. Abbreviated New Drug Applications Before the Hatch-Waxman Amendments

    After the enactment of the FD&C Act (Pub. L. 75-717) in 1938, new 
drug products were required to be approved on the basis of safety 
before they could be marketed. Between 1938 and 1962, if a drug product 
obtained approval, FDA considered drug products that were identical, 
related, or similar to the approved product to be covered by that 
approval; such identical, related, or similar products were marketed 
without independent approval. An identical, related, or similar drug 
includes another brand, potency, dosage form, salt, or ester of the 
same drug moiety related in chemical structure or known pharmacological 
properties (see 21 CFR 310.6(b)(1)). In 1962, the Kefauver-Harris Drug 
Amendments (Pub. L. 87-781) amended the FD&C Act to require that new 
drug products also be shown to be effective in order to obtain approval 
of a new drug application (NDA). After the enactment of the Kefauver-
Harris Drug Amendments, FDA initiated the Drug Efficacy Study 
Implementation (DESI) to evaluate the effectiveness of drug products 
that had been approved between 1938 and 1962 solely on the basis of 
safety. DESI also covered the identical, related, or similar products 
that had entered the market without approval. If drug products were 
determined to be effective for one or more indications,\1\ 
manufacturers that were already marketing under an NDA were required to 
submit a supplement to update the application and revise the product 
labeling as necessary. Manufacturers of drug products that were 
identical, related, or similar were required to submit applications for 
their drug products.
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    \1\ If a drug product was found to be less than effective for 
one or more labeled indications in FDA's initial DESI review, the 
Agency provided an opportunity to submit additional data and 
eventually an opportunity for a hearing on those indications found 
to be less than effective. FDA considered the basis of any hearing 
request and either granted or denied the hearing request and 
published its final determination in the Federal Register. If FDA's 
final determination classified a drug product as effective for an 
indication, those marketing that drug product and drugs identical, 
related or similar to it were required to obtain approved 
applications for continued marketing for that indication. If FDA's 
final determination classified the drug product as lacking 
substantial evidence of effectiveness for an indication, the product 
and those identical, related or similar to it could no longer be 
legally marketed for that indication.
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    FDA introduced the concept of an ``abbreviated new drug 
application'' in 1968 \2\ as a vehicle for approval of certain drugs 
affected by the DESI review, and in 1970, FDA published a final rule 
establishing a regulatory pathway for submission of abbreviated 
applications for these drugs (see 35 FR 6574 (April 24, 1970); see also 
34 FR 2673 (February 27, 1969)). This abbreviated approval mechanism 
was created to offer manufacturers of certain drugs a streamlined and 
more administratively efficient path to seek FDA approval as part of 
the DESI review (47 FR 46622 at 46631 to 46632 (October 19, 1982)).
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    \2\ See the Washington briefing on FDA's drug efficacy review, 
FDA Papers, at pp. 10-12 (March 1968) and Address of Commissioner 
James L. Goddard, M.D., at the Alpha Omega Alpha Lecture at Yale New 
Haven Medical Center on New Drug Research and Development (April 17, 
1968).
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    When a drug product subject to the DESI review was determined to be 
effective for one or more indications, FDA would issue a Federal 
Register notice (DESI notice) for that drug product describing the DESI 
review findings and stating whether abbreviated new drug applications 
that met specified criteria could be submitted to FDA (see generally 35 
FR 11273 (July 14, 1970); 35 FR 6574) for products that had not been 
marketed under an NDA. Such a finding allowed manufacturers to submit 
an abbreviated new drug application (i.e., a PANDA) in lieu of an NDA.
    For approval of PANDAs, FDA relied on the evidence of effectiveness 
that had been provided, reviewed, and accepted during the DESI process. 
FDA evaluated the safety of these drug products on the basis of 
information included in NDAs submitted prior to 1962, as well as the 
subsequent marketing experience with the drugs (see 54 FR 28872 at 
28873 (July 10, 1989)). PANDAs were submitted under section 505(b) of 
the FD&C Act and approved under section 505(c) of the FD&C Act.\3\
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    \3\ The content of section 505(b) of the FD&C Act regarding the 
required contents of an application remained largely unchanged 
following the enactment of the Hatch-Waxman Amendments, except for 
changes related to new patent submission requirements and, for 
applications submitted pursuant to section 505(b)(2) of the FD&C 
Act, patent certification requirements.

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[[Page 44733]]

    Because the history of FDA review of applications for antibiotic 
drug products is more complex and historically many were subject to 
section 507 of the FD&C Act (21 U.S.C. 357 (1994 ed.); repealed upon 
the enactment of the Food and Drug Administration Modernization Act of 
1997 (Pub. L. 105-115)), the scope of this notice is limited to drug 
products approved in PANDAs under section 505 of the FD&C Act prior to 
the Hatch-Waxman Amendments; this notice does not cover applications 
for antibiotic drug products that were originally submitted under 
section 507 of the FD&C Act.\4\
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    \4\ Prior to the enactment of the Food and Drug Administration 
Modernization Act of 1997, applications for antibiotic drugs were 
generally approved for safety and effectiveness under section 507 of 
the FD&C Act rather than under section 505 of the FD&C Act. For 
purposes of section 507, the term ``antibiotic drug'' was defined as 
any drug intended for use by man containing any quantity of any 
chemical substance which is produced by a microorganism and which 
has the capacity to inhibit or destroy microorganisms in dilute 
solution (including the chemically synthesized equivalent of any 
such substance). See 21 U.S.C. 357 (1964 ed.; 1994 ed.). Although 
there was a mechanism for approving abbreviated applications for 
antibiotics under section 507 that pre-dated the Hatch-Waxman 
Amendments, in this notice the term PANDAs refers only to those 
applications submitted under section 505(b) of the FD&C Act, and not 
to applications for antibiotic drug products submitted under section 
507 of the FD&C Act. FDA intends to address these antibiotic 
products separately.
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    Because PANDAs could be for products that were ``similar or 
related'' to, and not just ``duplicates'' \5\ of, drug products 
approved in NDAs before October 10, 1962, and listed in DESI notices 
(pre-1962 NDA drug products), FDA's ``Approved Drug Products With 
Therapeutic Equivalence Evaluations'' (Orange Book) lists both unique 
products approved in PANDAs (i.e., no NDA was ever approved for the 
identical drug product), and products approved in PANDAs that may be 
duplicates of pre-1962 NDA drug products. In the Orange Book, a product 
approved in a PANDA typically is identified as an ``ANDA.'' (The 
application type for a product is identified in the Orange Book by 
either an ``N'' (for an NDA) or an ``A'' (for an ANDA) before the 
application number.)
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    \5\ In the context of PANDAs, the term `duplicate' applied to a 
drug product that was the same as an already approved drug product 
in dosage form, route of administration, kind and amount of active 
ingredient, indication(s), and any other conditions of use. See 54 
FR 28872 at 28872 (July 10, 1989).
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    Although the regulations establishing the pathway for PANDAs were 
similar in some respects to the ANDA pathway created by the Hatch-
Waxman Amendments and described in section 505(j) of the FD&C Act, the 
requirements under the old regulatory pathway (which evolved over the 
decade-plus in which it was operational before the Hatch-Waxman 
Amendments) also differed in many respects from current ANDA 
requirements. For example, although the conditions of use and labeling 
for PANDA products had to be in accord with the relevant DESI notice 
(which frequently covered a class of drugs that included multiple 
products and multiple active ingredients) (see, e.g., 36 FR 11227 (June 
10, 1971); 35 FR 18215 (November 28, 1970); and 35 FR 12356 (August 1, 
1970)), PANDA products were not required to have the same labeling as a 
particular pre-1962 NDA drug product listed in the DESI notice. In 
addition, although PANDAs were required to include adequate data to 
assure biological availability of the drug if the relevant DESI notice 
for that drug specified that such data should be submitted for the 
formulation intended for marketing, PANDAs generally did not have to 
include data to demonstrate bioequivalence to a particular pre-1962 NDA 
drug product (see, e.g., 21 CFR 130.4(f)(3) (1971 ed.) and 21 CFR 
314.2(f)(3) (1984 ed.)). In addition, drug products with a different 
formulation, active ingredient, route of administration, dosage form, 
or strength than the pre-1962 NDA drug products listed in the DESI 
notice could be submitted in PANDAs. Prior to the Hatch-Waxman 
Amendments, there were also no requirements related to patent listing 
or patent certification or exclusivity for PANDAs or other applications 
approved under section 505(c) of the FD&C Act.

B. Hatch-Waxman Amendments

    In 1984, the Hatch-Waxman Amendments added section 505(b)(2) and 
section 505(j) to the FD&C Act. These sections provide an abbreviated 
approval pathway for submission of two types of applications: Section 
505(b)(2) new drug applications (505(b)(2) applications) and section 
505(j) abbreviated new drug applications (for purposes of this notice, 
referred to hereinafter as ``505(j) ANDAs''). A 505(b)(2) application 
is an NDA submitted under section 505(b)(1) and approved under section 
505(c) of the FD&C Act that contains full reports of investigations of 
safety and effectiveness, where at least some of the information 
required for approval comes from studies not conducted by or for the 
applicant and for which the applicant has not obtained a right of 
reference or use (e.g., the Agency's finding of safety and/or 
effectiveness for a listed drug). A 505(j) ANDA is an application that 
requests FDA approval to market a duplicate of a listed drug.\6\ 
Regulations implementing the Hatch-Waxman Amendments define a listed 
drug as a new drug product that has been approved under section 505(c) 
of the FD&C Act for safety and effectiveness or under section 505(j) of 
the FD&C Act, which has not been withdrawn or suspended under section 
505(e)(1) through (5) or section 505(j)(6) of the FD&C Act, and which 
has not been withdrawn from sale for what FDA has determined are 
reasons of safety or effectiveness. Listed drug status is evidenced by 
the drug product's identification in the current edition of FDA's 
``Approved Drug Products With Therapeutic Equivalence Evaluations'' 
(the list) as an approved drug. A drug product is deemed to be a listed 
drug on the date of approval for the NDA or ANDA for that drug product. 
(See Sec.  314.3(b) (21 CFR 314.3(b)), as amended at 81 FR 69580 at 
69638 (October 6, 2016); see also section 505(j)(2)(A), (j)(7) of the 
FD&C Act).
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    \6\ In the context of the Hatch-Waxman Amendments, the term 
duplicate generally refers to a ``drug product that has the same 
active ingredient(s), dosage form, strength, route of 
administration, and conditions of use as a listed drug . . .'' 54 FR 
28872 at 28877.
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    FDA regulations require an applicant to refer in its 505(j) ANDA to 
the specific listed drug on which the applicant relies in seeking 
approval of the 505(j) ANDA (Sec.  314.94(a)(3) (21 CFR 314.94(a)(3)); 
see also section 505(j)(2) of the FD&C Act). The listed drug that a 
generic applicant seeks to duplicate is commonly referred to as the 
reference listed drug (RLD) (see definition in Sec.  314.3(b)). A 
505(j) ANDA applicant must show, among other things, that the proposed 
generic drug is bioequivalent to the RLD, and that it has the same 
active ingredient(s), conditions of use, route of administration, 
dosage form, strength, and (with limited exceptions) labeling as the 
RLD (section 505(j)(2)(A), (j)(2)(C), and (j)(4) of the FD&C Act; see 
also Sec.  314.94(a)). We note that certain differences between an RLD 
and a proposed generic drug product may be permitted in an ANDA if 
these differences are the subject of an approved suitability petition 
(see section 505(j)(2)(C) of the FD&C Act and 21 CFR 314.93). An 
applicant may submit a suitability petition to FDA requesting 
permission to submit an ANDA for a generic drug product that differs 
from an RLD in its route of administration, dosage form, or strength or 
that has one different active ingredient in a fixed-combination drug 
product (ibid.).
    Because a 505(j) ANDA applicant is relying on FDA's finding that 
the RLD

[[Page 44734]]

is safe and effective, FDA's general practice is to designate as RLDs 
drug products that have been approved under section 505(c) for safety 
and effectiveness. Similarly, FDA regulations require a 505(b)(2) 
applicant to identify in its application each listed drug for which FDA 
has made a finding of safety and effectiveness on which the applicant 
relies in seeking approval of its proposed drug product (21 CFR 
314.54(a)(1)(iii)).
    Listed drugs appear in the Orange Book, and beginning in 1992, the 
Orange Book also began identifying which listed drugs were designated 
as RLDs to aid 505(j) ANDA applicants. The listed drugs that were 
designated as RLDs were labeled with a ``+'' sign in the paper version 
of the Orange Book, and with the word ``Yes'' in the column titled RLD 
in the electronic version of the Orange Book. Before 2017, the ``+'' 
sign and the word ``Yes'' in the column labeled RLD were used to denote 
at times an RLD and at other times a reference standard, which is the 
drug product selected by FDA that an applicant seeking approval of a 
505(j) ANDA must use in conducting an in vivo bioequivalence study 
required for approval of the ANDA (Sec.  314.3(b)).
    The reference standard selected by FDA is ordinarily the RLD. 
However, at times the reference standard is a drug product other than 
the RLD. For example, if the NDA RLD is no longer marketed, FDA 
generally will select as the reference standard a previously approved 
505(j) ANDA that refers to that RLD. Where the RLD was no longer 
marketed and FDA selected a new reference standard, FDA's practice 
prior to 2017 was to identify the reference standard with the ``+'' 
sign in the paper version of the Orange Book and ``Yes'' in the RLD 
column of the electronic version of the Orange Book; FDA also would 
move the previously identified RLD to the discontinued section of the 
Orange Book without a ``+'' sign in the paper version or RLD 
designation in the electronic version of the Orange Book.
    Because the ``+'' sign or RLD designation in some cases identified 
drug products that were RLDs as well as reference standards, and in 
other cases identified reference standards that were not also the RLD, 
there may have been some confusion among 505(j) ANDA applicants about 
which product to cite as the RLD when the reference standard and RLD 
were not the same drug product. Inconsistent use of terminology, as 
well as certain long-standing FDA practices, may have added to this 
confusion.

C. FDA's Current Identification of RLDs and Reference Standards in the 
Orange Book

    In 2017, FDA began to separately identify in the Orange Book which 
listed drugs, including some in the ``Discontinued Drug Product List'' 
(discontinued section), are designated as RLDs, and which listed drugs 
in the Active Section (i.e., in the sections entitled ``Prescription 
Drug Product List'' and ``Over-the-Counter Drug Product List'') are 
selected as reference standards. In the electronic version of the 
Orange Book, there is one column that identifies RLDs and a separate 
column that identifies reference standards. In the printed version of 
the Orange Book, the RLDs and reference standards are identified by 
distinct symbols.
    These changes to the Orange Book were intended to provide clarity 
to 505(j) ANDA applicants as to which listed drugs are the RLDs (versus 
the reference standards) for a drug product. For some drug products, 
however, these changes revealed that no product is identified as being 
approved under an NDA (in either the active or discontinued sections of 
the Orange Book) that could serve as an RLD for a 505(j) ANDA. The lack 
of an RLD is confusing because the Orange Book reflects that there are 
approved ANDAs for the drug product, including ANDAs identified as 
reference standards. One reason for this lack of an RLD is that some of 
the products listed in the Orange Book and identified as being approved 
in an ``ANDA'' are actually drugs that were approved for safety and 
effectiveness under section 505(c) of the FD&C Act in PANDAs that 
appeared to have been identified as RLDs before the 2017 update to the 
Orange Book. As noted previously, products approved in PANDAs could be 
unique products that differed from products approved under pre-1962 
NDAs in various ways, including in their active ingredient, route of 
administration, dosage form, or strength. In addition, even when 
certain listed drugs approved in a PANDA appear to be pharmaceutical 
equivalents (as defined in Sec.  314.3(b)) of products approved under 
an NDA, these products can differ from the products approved under the 
NDA in other respects, including in the approved conditions of use 
reflected in the labeling or in their formulation, and may not have 
been determined to be bioequivalent to the products approved under an 
NDA. Further, even if the drug product approved in a PANDA was a 
duplicate of a drug product that was at one time also approved and 
marketed under an NDA, if the product approved under the NDA was no 
longer marketed when the Orange Book was first published in October 
1980, it was not listed in the Orange Book.

D. Designation of Additional Drugs as RLDs

    In light of the changes to the Orange Book in 2017, FDA examined 
the types of products for which there were no RLDs designated and 
determined that many were approved in PANDAs. After consideration of 
the history of PANDAs, FDA determined that it was appropriate and 
consistent with FDA's general practice regarding the designation of 
RLDs to designate PANDA products as RLDs because these products were 
approved for safety and effectiveness under section 505(c) of the FD&C 
Act. In addition, as noted in section I.C, many of these products 
appeared to have been identified as RLDs before the 2017 update to the 
Orange Book. Designation of the PANDA products as RLDs provides clarity 
both to prospective 505(j) ANDA applicants seeking to make generic 
versions of these products, and to applicants of 505(b)(2) applications 
that there is a finding of safety and effectiveness for these products 
that may be relied upon for approval. In addition, it is aligned with 
FDA's efforts to help advance competition and increase patient access 
to more affordable medicines.
    FDA has begun adding RLD designations for PANDAs to the Orange Book 
and will continue making these designations as expeditiously as 
resources permit. If a prospective 505(j) ANDA applicant is seeking to 
duplicate a product approved in a PANDA that has not yet been 
designated as an RLD by FDA, the prospective applicant may submit 
controlled correspondence to FDA identifying the drug it intends to 
duplicate and asking FDA to designate that drug as an RLD (see FDA's 
guidance for industry, ``Controlled Correspondence Related to Generic 
Drug Development,'' announced in 85 FR 81928 (December 17, 2020)).\7\
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    \7\ For the most recent version of a guidance, check the FDA 
guidance web page at https://www.fda.gov/regulatory-information/search-fda-guidance-documents.
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    To aid stakeholders in identifying PANDAs, FDA has posted a list of 
the products currently included in the Orange Book and identified as an 
``ANDA'' in the Orange Book that were approved in a PANDA for safety 
and effectiveness under section 505(c) prior to the enactment of the 
Hatch-Waxman Amendments. This list includes only PANDAs described in 
this notice, i.e.,

[[Page 44735]]

those abbreviated applications submitted under section 505(b) of the 
FD&C Act and does not include applications for antibiotic drug products 
approved under section 507 of the FD&C Act before the enactment of the 
Food and Drug Administration Modernization Act of 1997 (FDAMA). This 
list is available under ``Additional Resources'' on FDA's ``Approved 
Drug Products with Therapeutic Equivalence Evaluations (Orange Book)'' 
web page (available at https://www.fda.gov/drugs/drug-approvals-and-databases/approved-drug-products-therapeutic-equivalence-evaluations-orange-book). In addition, the Orange Book provides information about 
the approval date of listed drugs,\8\ allowing interested persons to 
refer to this information to determine which products identified as 
being approved in an ANDA in the Orange Book were approved before the 
enactment of the Hatch-Waxman Amendments.\9\
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    \8\ For products approved prior to January 1, 1982, the 
electronic version of the Orange Book indicates the product was 
``Approved Prior to Jan. 1, 1982'' under Product Details in the 
Approval Date field, and the printed version of the Orange Book has 
a blank Approval Date field. For products approved on or after 
January 1, 1982, the electronic and printed versions of the Orange 
Book provide the specific date of approval in the Approval Date 
field.
    \9\ The Hatch-Waxman Amendments were signed into law on 
September 24, 1984. PANDAs that were submitted before September 24, 
1984, were processed by FDA in accordance with the procedures that 
existed before the passage of the Hatch-Waxman Amendments. See 
November 16, 1984, letter to interested persons from Harry M. Meyer, 
Jr., M.D., Director, FDA's Center for Drugs and Biologics. The list 
of PANDAs posted on FDA's Orange Book web page (https://www.fda.gov/drugs/drug-approvals-and-databases/approved-drug-products-therapeutic-equivalence-evaluations-orange-book) includes all the 
abbreviated applications approved on or before September 24, 1984. 
FDA is aware that certain applications submitted before this date 
but approved after this date and identified as ANDAs in the Orange 
Book were approved under section 505(c) of the FD&C Act; FDA will 
update this list as appropriate to include such applications. If a 
prospective 505(j) ANDA applicant is seeking to duplicate a product 
approved after September 24, 1984, and the applicant believes the 
application for the product was submitted before that date and 
approved under section 505(c) of the FD&C Act, the prospective 
applicant may submit controlled correspondence to FDA identifying 
the drug they intend to duplicate and asking FDA to designate that 
drug as an RLD. The controlled correspondence should include any 
information known to the prospective applicant that supports the 
belief that the identified drug was approved in a PANDA. When FDA 
receives such designation requests, it will evaluate whether the 
product was approved under section 505(c) of the FD&C Act in 
determining whether to grant the request.
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II. Additional Issues for Consideration and Request for Comments

    The Agency is seeking input from holders of PANDAs and other 
interested stakeholders on several issues related to FDA's post-
approval regulation of drug products approved in PANDAs. As explained 
in section I of this notice, PANDAs were submitted under section 505(b) 
and approved under section 505(c) of the FD&C Act, which are the same 
provisions under which NDAs are submitted and approved. However, PANDA 
products have historically been overseen by FDA's Office of Generic 
Drugs and are included in the definition of abbreviated new drug 
application for user fee purposes under the Generic Drug User Fee 
Amendments (GDUFA),\10\ which specify that this term includes an 
abbreviated new drug application submitted pursuant to regulations in 
effect prior to the implementation of the Drug Price Competition and 
Patent Term Restoration Act of 1984 (see 21 U.S.C. 379j-41). PANDAs are 
not included in the FD&C Act statutory definition of the term 
abbreviated drug application, which is limited to applications 
submitted under section 505(j) of the FD&C Act (see 21 U.S.C. 321(aa)).
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    \10\ See Title III of the Food and Drug Administration Safety 
and Innovation Act (Pub. L. 112-144) and Title III of the FDA 
Reauthorization Act of 2017 (Pub. L. 115-52).
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    FDA recognizes that PANDAs may have been treated similarly to 
505(j) ANDAs in some respects over the decades after the enactment of 
the Hatch-Waxman Amendments, and that there may be confusion among 
holders of PANDAs about the applicability of certain statutory and 
regulatory provisions to their products and in particular, whether 
their products are subject to the requirements that apply to other 
505(b) applications or to those that apply to 505(j) applications (to 
the extent there are differences between the two), including with 
respect to requirements regarding labeling updates, patent listing, 
eligibility for exclusivity, and certain drug safety-related 
requirements or procedures.
    For example, with respect to labeling updates, FDA is aware that 
some PANDA holders have followed procedures applicable to 505(b) 
applications when proposing labeling updates for their products (e.g., 
submitting labeling supplements and making labeling changes independent 
of the pre-1962 NDA product or products that were listed in the DESI 
notice). However, FDA is also aware that some PANDA holders have 
followed procedures applicable to 505(j) ANDA holders when proposing 
labeling updates for their products (e.g., submitting labeling 
supplements to conform to labeling changes approved for a pre-1962 NDA 
product listed in a relevant DESI notice).
    With respect to patent listing, to FDA's knowledge, PANDA holders 
have neither sought to list patent information in the Orange Book for 
their products after the enactment of the Hatch-Waxman Amendments, nor 
have they submitted patent listing information when submitting 
supplements to their approved applications during the years after the 
enactment of the Hatch-Waxman Amendments. Similarly, PANDA holders have 
generally not submitted supplements containing reports of new clinical 
investigations or sought exclusivity under provisions applicable to 
505(b) applications (see, e.g., section 505(c)(3)(E)(iv) and 
505(j)(5)(F)(iv) of the FD&C Act) following enactment of the Hatch-
Waxman Amendments.
    FDA is also aware that there may be confusion among PANDA holders 
about the applicability of certain safety-related requirements to their 
applications. For example, section 505(o) of the FD&C Act, which 
relates to postmarket studies and clinical trials and labeling, and 
section 505-1 of the FD&C Act, which relates to risk evaluation and 
mitigation strategies, reflect some differences in the safety-related 
requirements or procedures that apply to 505(b) application holders 
versus 505(j) ANDA holders, and PANDA holders may consider the 
requirements that apply to 505(j) ANDA holders to also apply to their 
applications.
    Although, as noted in section I of this notice, PANDAs are section 
505(b) applications, FDA understands, as outlined above, that the 
holders of some PANDAs may have been following various requirements 
applicable to 505(j) ANDAs over the years after the enactment of the 
Hatch-Waxman Amendments, and that for them to instead follow 
requirements applicable to 505(b) applications could be a change in 
practice. FDA also understands that PANDAs are a unique category of 
505(b) applications and that there could be valid reasons to treat 
PANDAs differently from other 505(b) applications in certain 
circumstances, to the extent permitted by the applicable statutory 
provisions.
    FDA is seeking input from PANDA holders and other interested 
stakeholders on whether there are regulatory or policy reasons for 
treating PANDAs differently from other 505(b) applications, consistent 
with the statutory requirements for applications submitted under 
section 505(b) and approved under section 505(c) of the FD&C Act. To 
facilitate this input, FDA has developed the following list of 
questions. These questions are not meant to be exhaustive, and FDA is 
also

[[Page 44736]]

interested in any other pertinent information stakeholders would like 
to share on this topic. In all cases, FDA encourages stakeholders to 
provide the specific rationale and basis for their comments, including 
any available supporting data and information.
Questions
    1. Given the legal requirements in place for applications submitted 
under section 505(b) and approved under section 505(c) of the FD&C Act, 
are there regulatory or policy rationales for treating PANDAs 
differently from other 505(b) applications in certain respects, in 
particular with respect to the following:
    1.1. Labeling requirements, including requirements related to 
updating product labeling to reflect certain types of newly acquired 
safety-related information by submitting a ``changes being effected'' 
(CBE-0) supplement to FDA?
    1.2. Patent listing requirements?
    1.3. Eligibility for exclusivity?
    1.4. Certain safety-related requirements, such as the postmarket 
studies and clinical trials or safety-labeling change requirements in 
section 505(o) of the FD&C Act or the risk evaluation and mitigation 
strategies requirements in section 505-1 of the FD&C Act?
    In responding to the questions above, please provide a specific 
rationale for treating these applications differently.
    2. To the extent that PANDA holders are expected to make changes to 
their current practices, what factors should FDA consider in 
determining a reasonable amount of time for PANDA holders to make such 
changes to their practices?
    3. Are there additional steps FDA should take to highlight for 
PANDA holders that their ``abbreviated new drug application'' is a 
PANDA, i.e., that it is a 505(b) application?
    4. Are there additional steps FDA should take beyond posting the 
list on the Orange Book website to aid other interested persons in 
identifying PANDAs?
    5. Are modifications needed to the list of PANDAs posted on the 
Orange Book website for accuracy? For example, are some PANDAs missing 
from the list?
    6. Are there other issues FDA should consider in assessing the 
regulatory framework for PANDAs under the FD&C Act? Please provide 
specific examples and explain FDA's authority to address these issues.

    Dated: August 10, 2021.
Lauren K. Roth,
Acting Principal Associate Commissioner for Policy.
[FR Doc. 2021-17378 Filed 8-12-21; 8:45 am]
BILLING CODE 4164-01-P