Document ID: FDA-2020-N-1069-0001
Agency: fda
Document Type: Notice
Title: Approved Drug Products With Therapeutic Equivalence Evaluations (the ‘‘Orange Book’’); Establishment of a Public Docket; Request for Comments
Posted Date: 2020-06-01T04:00Z

[Federal Register Volume 85, Number 105 (Monday, June 1, 2020)]
[Notices]
[Pages 33165-33167]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2020-11683]

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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. FDA-2020-N-1069]

Approved Drug Products With Therapeutic Equivalence Evaluations 
(the ``Orange Book''); Establishment of a Public Docket; Request for 
Comments

AGENCY: Food and Drug Administration, 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 FDA's 
publication entitled ``Approved Drug Products With Therapeutic 
Equivalence Evaluations'' (commonly known as the ``Orange Book''). The 
Orange Book identifies drug products approved by FDA under the Federal 
Food, Drug, and Cosmetic Act (FD&C Act) and includes related 
information. As part of FDA's Drug Competition Action Plan and our 
continued effort to improve transparency and provide useful information 
to regulated industry and the public, we are seeking comments on how 
stakeholders and the public use the Orange Book and whether it can be 
improved.

DATES: Submit either electronic or written comments by August 31, 2020.

ADDRESSES: 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:
     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-1069 for ``Approved Drug Products With Therapeutic 
Equivalence Evaluations (the 'Orange Book'); 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.
     Confidential Submissions--To submit a comment with 
confidential information that you do not wish to be

[[Page 33166]]

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.

FOR FURTHER INFORMATION CONTACT: Lisa Bercu, Center for Drug Evaluation 
and Research, Food and Drug Administration, 10903 New Hampshire Ave., 
Bldg. 75, Rm. 1672, Silver Spring, MD 20993, 240-402-6902, 
Lisa.Bercu@fda.hhs.gov.

SUPPLEMENTARY INFORMATION: 

I. Background

    As its core function, the Orange Book identifies drug products 
approved by FDA under the FD&C Act and includes patent and exclusivity 
information related to those drug products. The main criteria for the 
inclusion of a drug product in the Orange Book are that the drug 
product is the subject of an approved application and that FDA has not 
determined the drug product to have been withdrawn for safety or 
efficacy reasons. The Orange Book includes drug products approved prior 
to the 1962 amendments to the FD&C Act on the basis of safety and found 
to be effective through the Drug Efficacy Study Implementation process. 
However, pre-1938 drug products not subject to the premarket approval 
authorities of the FD&C Act are excluded from the Orange Book. In 
addition, drug products that were not marketed at the time of the first 
publication of the Orange Book or were discontinued between 1980 and 
1987, prior to the identification of discontinued products, are also 
not included in the list.
    The Orange Book also contains therapeutic equivalence evaluations 
for approved multisource prescription drug products. Therapeutic 
equivalents are approved drug products that FDA has determined are 
pharmaceutical equivalents for which bioequivalence has been 
demonstrated, and can be expected to have the same clinical effect and 
safety profile when administered to patients under the conditions 
specified in the labeling (Sec.  314.3(b) (21 CFR 314.3(b))). The 
therapeutic equivalence evaluations in the Orange Book serve as public 
information available to prescribers, pharmacists, Federal and State 
health agencies, and private formularies, among others, to promote 
public education in the area of drug product selection and to foster 
the containment of health care costs. Therapeutic equivalence 
evaluations in the Orange Book are not official FDA actions affecting 
the legal status of products under the FD&C Act.
    The Orange Book is composed of four main parts: (1) The 
Prescription Drug Product List, which is a list of approved marketed 
prescription drug products with therapeutic equivalence evaluations; 
(2) the OTC Drug Product List, which is a list of marketed over-the-
counter (OTC) drug products that have been approved in new drug 
applications (NDAs) or abbreviated new drug applications (ANDAs); (3) 
the Drug Products with Approval under section 505 of the FD&C Act (21 
U.S.C. 355) administered by the Center for Biologics Evaluation and 
Research List; and (4) the Discontinued Drug Product List, which is a 
cumulative list of approved drug products that have never been 
marketed, are for exportation, are for military use, are not 
commercially distributed by a Federal or State government entity, have 
been discontinued from marketing and FDA has not determined that they 
were withdrawn from sale for safety or effectiveness reasons, or have 
had their approvals withdrawn for other than safety or efficacy reasons 
subsequent to being discontinued from marketing. The Orange Book also 
includes indices of prescription and OTC drug products by proprietary 
name (brand name or trade name) or, if no proprietary name exists, 
established name of the active ingredient and by applicant name, which 
have been abbreviated for this publication. The Addendum to the Orange 
Book provides patent information for certain listed drugs, and 
identifies drugs that qualify under the FD&C Act for periods of 
exclusivity, as described in detail below.
    The Orange Book was first published on October 31, 1980. On 
September 24, 1984, the President signed into law the Drug Price 
Competition and Patent Term Restoration Act of 1984 (Pub. L. 98-417) 
(Hatch-Waxman Amendments), which required that FDA make publicly 
available a list of approved drug products with monthly supplements 
(section 505(j)(7)(A) of the FD&C Act). The Orange Book and its monthly 
Cumulative Supplements satisfy this requirement.
    Since that time, the Orange Book has played an essential 
administrative role in FDA's implementation of the FD&C Act. For 
example, the FD&C Act requires NDA holders to submit the patent number 
and expiration date of any patent which claims the drug or a method of 
using such drug and for which a claim of patent infringement could 
reasonably be asserted against a person engaged in the unlicensed 
manufacture, use, or sale of the drug (see section 505(b)(1) and 
505(c)(2) of the FD&C Act; see also 21 CFR 314.50(h), 314.53, and 
314.70(f)). The FD&C Act requires FDA to publish this patent 
information (see section 505(b)(1) and 505(c)(2) of the FD&C Act). This 
patent information submitted by NDA holders is listed in the Orange 
Book.
    In addition, section 505(j)(7)(A)(i)(III) of the FD&C Act requires 
that FDA publish and make publicly available information to show 
whether in vitro or in vivo bioequivalence studies, or both studies, 
are required for ANDAs that refer to an NDA, and FDA has determined 
that the therapeutic equivalence codes for multisource products in the 
Orange Book satisfy this requirement.
    The Orange Book also identifies drugs that qualify under the FD&C 
Act for periods of exclusivity. An NDA or ANDA holder is eligible for 
exclusivity if statutory and regulatory requirements are met. 
Exclusivities under the FD&C Act include pediatric exclusivity, 
Generating Antibiotic Incentives Now or GAIN exclusivity, 180-day 
exclusivity, competitive generic therapy exclusivity, new chemical 
entity exclusivity, 3-year exclusivity, and orphan drug exclusivity 
(see sections 505(c)(3)(E), 505(j)(5)(B)(iv), 505(j)(5)(B)(v),

[[Page 33167]]

505(j)(5)(F), 505A (21 U.S.C. 355a), 505E (21 U.S.C. 355f), 506H (21 
U.S.C. 356h), and 527 (21 U.S.C. 360cc) of the FD&C Act; see also 21 
CFR 314.108, 316.31, 316.34). The exclusivities identified above are 
set forth on a product-specific basis in the Orange Book. This 
information is used by a wide range of stakeholders, including 
applicants of ANDAs and 505(b)(2) applications, in planning product 
development.
    The Orange Book also plays an essential administrative role in 
FDA's implementation of recent statutory provisions related to drug 
product regulation. For example, section 505(j)(12) of the FD&C Act, 
added by the FDA Reauthorization Act of 2017 (Pub. L. 115-52) (FDARA), 
requires FDA to publish on its website and update at least every 6 
months a list of approved NDA products that are off-patent and off-
exclusivity, and for which FDA has not approved an ANDA referencing 
that NDA drug product, and FDA uses the Orange Book to populate this 
list. Section 506I of the FD&C Act requires NDA and ANDA holders to 
provide a written notification to FDA 180 days prior to withdrawing an 
approved drug from sale, to provide written notification to FDA within 
180 days of the date of approval of a drug if that drug will not be 
available for sale within 180 days of the date of approval, and to have 
reviewed information in the Orange Book and submitted a one-time 
marketing status report. This information is used by FDA to move drugs 
that are not available for sale from the ``Prescription Drug Product 
List'' to the ``Discontinued Drug Product List'' in the Orange Book 
(see section 506I(e) of the FD&C Act).
    FDA has historically sought to update and enhance the Orange Book 
to make it more accessible and useful to regulated industry and the 
public. Below are examples of updates FDA has made to the publication:
     In 1985, FDA added to the Orange Book a list of OTC drug 
products that have been approved in NDAs or ANDAs.
     In 1997, FDA published the Orange Book on the internet.
     In 2003, FDA started publishing an indicator as to whether 
a listed patent contains drug substance and/or drug product claims.
     In 2005, FDA made the Orange Book available for download 
off the Agency's website.
     In 2005, FDA switched from publishing patent listings in a 
public docket to publishing them daily in the Orange Book.
     In 2005, FDA switched from publishing generic drug 
approvals monthly to publishing them daily.
     In 2015, FDA launched a mobile application, ``Orange Book 
Express,'' to put timely information in the hands of those using 
smartphones and tablets.
     In 2016, FDA redesigned the Orange Book website to include 
commonly used features on the home page and to allow users to better 
navigate the Orange Book and customize their search.
     In 2017, FDA revised the Orange Book so that drug listings 
now clarify which listed drugs are RLDs and which are reference 
standards (see Sec.  314.3(b)), as well as to clarify which products in 
the ``Discontinued Drug Product List'' may be referred to as an RLD.
     In 2017, FDA revised the Orange Book to include listed 
patent submission dates, when available.
     In 2017, FDA added the patent disputes list to the Orange 
Book website, which informs stakeholders which patents have been 
disputed by an outside party to FDA.
     In 2018, FDA updated the Orange Book to include 
descriptions indicating which indication(s) are protected by orphan 
drug exclusivity.
    As part of FDA's Drug Competition Action Plan \1\ and our continued 
effort to provide more accessible and useful information in the Orange 
Book, FDA is considering whether there are other opportunities to 
enhance the publication. The Drug Competition Action Plan aims to 
facilitate more generic competition, promote patient access, and 
improve the economics of developing generic medicines. Soliciting 
public comment on this topic will help guide the Agency's priorities as 
we consider enhancing the Orange Book.
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    \1\ Available at https://www.fda.gov/drugs/guidance-compliance-regulatory-information/fda-drug-competition-action-plan.
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II. Establishment of a Public Docket and Request for Comments

    FDA is establishing a public docket to solicit input from a broad 
group of stakeholders, including patients, health care providers, drug 
manufacturers, public policy makers (e.g., Federal and State health 
agencies), individuals involved in patent litigation (e.g., patent 
counsel), and any other interested parties, on whether and how the 
Orange Book can be improved. (To note, FDA intends to publish a 
separate Federal Register notice seeking public input specifically on 
patent listings in the Orange Book in the near future, and thus is not 
soliciting comment on that topic now.) In addition to general comments, 
FDA is interested in responses to the following questions:
     What types of people or entities use the Orange Book?
     What sections of the Orange Book do these different types 
of people or entities use?
     For what reasons do these people or entities use the 
Orange Book? What additional information or features (e.g., additional 
search functions) could be incorporated into the Orange Book to make it 
more useful?
     Is the information in the Orange Book regarding 
therapeutic equivalence generally useful?
    [cir] How useful is the second letter of a therapeutic equivalence 
evaluation code?
    [cir] How could the therapeutic equivalence information be made 
more user-friendly or otherwise be tailored to meet the needs of people 
or entities that use the Orange Book (e.g., the therapeutic equivalence 
evaluation code)?
    [cir] If you use the information regarding therapeutic equivalence, 
how do you use it?
    [cir] Does the information regarding therapeutic equivalence 
promote drug competition? And if so, how?
     Is there any other information regarding the Orange Book 
that would be useful for FDA to consider?

    Dated: May 26, 2020.
Lowell J. Schiller,
Principal Associate Commissioner for Policy.
[FR Doc. 2020-11683 Filed 5-29-20; 8:45 am]
BILLING CODE 4164-01-P