[Federal Register Volume 88, Number 104 (Wednesday, May 31, 2023)]
[Proposed Rules]
[Pages 35694-35728]
[FR Doc No: 2023-11354]

Vol. 88

Wednesday,

No. 104

May 31, 2023

Part VI

Department of Health and Human Services

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Food and Drug Administration

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21 CFR Parts 201, 208, 314, et al.

Medication Guides: Patient Medication Information; Proposed Rule

Federal Register / Vol. 88 , No. 104 / Wednesday, May 31, 2023 /
Proposed Rules

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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Parts 201, 208, 314, 606, and 610

[Docket No. FDA-2019-N-5959]
RIN 0910-AH68

Medication Guides: Patient Medication Information

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 human prescription drug product labeling
regulations for Medication Guides (FDA-approved written prescription
drug product information distributed to patients). This action, if
finalized, will require applicants to create a new type of Medication
Guide, referred to as Patient Medication Information (PMI), for
prescription drug products, including biological products, used,
dispensed, or administered on an outpatient basis and for blood and
blood components transfused in an outpatient setting. PMI would be a
one-page document with standardized format and content that would be
submitted to FDA for approval. This proposed rule is intended to
improve public health by providing patients with clear, concise,
accessible, and useful written prescription drug product information
delivered in a consistent and easily understood format to help patients
use their prescription drug products safely and effectively.

DATES: Either electronic or written comments on the proposed rule must
be submitted by November 27, 2023. Submit written comments (including
recommendations) on the collection of information under the Paperwork
Reduction Act of 1995 by November 27, 2023.

ADDRESSES: You may submit comments as follows. Please note that late,
untimely filed comments will not be considered. The https://www.regulations.gov electronic filing system will accept comments until
11:59 p.m. Eastern Time at the end of November 27, 2023. Comments
received by mail/hand delivery/courier (for written/paper submissions)
will be considered timely if they are received 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 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-5959 for ``Medication Guides: Patient Medication
Information.'' 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,<PHONE_NUMBER>.
     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,<PHONE_NUMBER>.
    Submit comments on the information collection under the Paperwork
Reduction Act of 1995 to the Office of Management and Budget (OMB) at
https://www.reginfo.gov/public/do/PRAMain. Find this particular
information collection by selecting ``Currently under Review--Open for
Public Comments'' or by using the search function. The title of this
proposed collection is ``Medication Guides: Patient Medication
Information.''

FOR FURTHER INFORMATION CONTACT: With regard to the proposed rule:
Chris Wheeler, Center for Drug Evaluation and Research, Food and Drug
Administration, 10903 New Hampshire Ave., Bldg. 51, Rm. 3330, Silver
Spring, MD 20993,<PHONE_NUMBER>, [email protected]; or Diane
Maloney, Center for Biologics Evaluation and Research, Food and Drug
Administration, 10903 New Hampshire Ave., Bldg. 71, Rm. 7301, Silver
Spring, MD 20993-0002,<PHONE_NUMBER>.
    With regard to the information collection: Domini Bean, Office of

Operations, Food and Drug Administration, Three White Flint North, 10A-
12M, 11601 Landsdown St., North Bethesda, MD 20852,<PHONE_NUMBER>,
[email protected].

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. Need for the Regulation
    C. History of the Rulemaking
IV. Legal Authority
V. Description of the Proposed Rule
    A. Placement and Removal of the Current Requirements for
Medication Guides for Prescription Drug Products (Proposed
Sec. Sec.  208.91, 208.92, 208.94, 208.96, and 208.98)
    B. Removal of the Requirement for Patient Package Inserts
(Sec. Sec.  310.501 and 310.515)
    C. Scope and Purpose (Proposed Sec. Sec.  208.10 and 606.123)
    D. Definitions (Proposed Sec.  208.20)
    E. Requirements for the Format of Patient Medication Information
(Proposed Sec.  208.30)
    F. Requirements for the Content of Patient Medication
Information (Proposed Sec.  208.40)
    G. Development of Patient Medication Information for New Drug
Applications, Biologics License Applications, and Abbreviated New
Drug Applications (Proposed Sec.  208.50)
    H. Submission of Patient Medication Information for New Drug
Applications, Biologics License Applications, and Abbreviated New
Drug Applications (Proposed Sec.  208.60)
    I. Providing Patient Medication Information to Patients
(Proposed Sec.  208.70)
    J. Schedule for Implementing the General Requirements for
Patient Medication Information (Proposed Sec.  208.80)
    K. Waivers (Proposed Sec.  208.90)
    L. Medication Guides: Patient Medication Information for Blood
and Blood Components Intended for Transfusion (Proposed Sec.
606.123)
VI. Electronic Repository for Patient Medication Information
VII. Proposed Effective Date
VIII. Preliminary Economic Analysis of Impacts
    A. Summary of Cost and Benefits
    B. Summary of Regulatory Flexibility Analysis
IX. Analysis of Environmental Impact
X. Paperwork Reduction Act of 1995
XI. Federalism
XII. Consultation and Coordination With Indian Tribal Governments
XIII. References

I. Executive Summary

A. Purpose of the Proposed Rule

    FDA is proposing to amend its prescription drug product labeling
regulations for Medication Guides to require a new type of Medication
Guide, referred to as PMI, for prescription drug products used,
dispensed, or administered on an outpatient basis, including blood and
blood components transfused in an outpatient setting. For the purposes
of this proposed rule, a prescription drug product also includes a
biological product licensed under the Public Health Service Act (PHS
Act). Currently, Medication Guides are required only for certain
prescription drug products that FDA determines pose a significant and
serious public health concern and are used primarily on an outpatient
basis.
    We have long recognized the importance of providing patients with
written information about their prescription drug products because
there is evidence that such information may help patients use
prescription drug products safely and effectively and may potentially
reduce preventable adverse drug reactions and improve health outcomes.
Patients may currently receive one or more types of written patient
information regarding prescription drug products, including patient
package inserts (PPIs), Medication Guides, consumer medication
information (CMI), and Instructions for Use documents. This written
patient information, in certain instances, has been duplicative,
incomplete, conflicting, or difficult to read and understand, and has
not been sufficient to meet the needs of patients. PMI is intended to
improve public health by providing patients with clear, concise,
accessible, and useful written prescription drug product information
delivered in a consistent and easily understood format to help patients
use their prescription drug products safely and effectively.

B. Summary of the Major Provisions of the Proposed Rule

    Under the proposed rule, PMI would highlight essential information
that the patient needs to know about the prescription drug product and
basic directions on how to use the product. PMI would be a one-page
document that follows standardized format and content requirements. PMI
would consist of the following headings:

 [Insert Drug Name] is
 Important Safety Information
 Common Side Effects
 Directions for Use

    In determining specific headings and information to be included in
PMI, we researched scientific literature, conducted studies examining
several PMI prototypes, held public workshops and hearings, and
obtained stakeholder input on what information patients need in order
to use their prescription drug products safely and effectively.
    When finalized, this proposed rule would require applicants of all
new and approved new drug applications (NDAs) and biologics license
applications (BLAs) to create PMI for prescription drug products that
are to be used, dispensed, or administered on an outpatient basis.
Applicants of NDAs and BLAs would be required to submit PMI to FDA for
approval. The proposed rule covers NDAs and BLAs for interchangeable
biosimilars and non-interchangeable biosimilars.
    When finalized, the proposed rule would also require applicants of
new and approved abbreviated new drug applications (ANDAs) that refer
to a listed drug for which FDA has approved PMI to have PMI that is the
same as that of the reference listed drug (RLD) except for certain
differences in labeling permitted under the law. As described further
in this document, FDA will create a PMI template for approved ANDAs if:
(1) the ANDA references a listed drug whose approval has been withdrawn
and (2) no PMI was approved for the RLD before the approval of the RLD
was withdrawn.
    PMI would be stored in an online central repository managed by FDA
and would be freely accessible to the public, including patients,
healthcare providers, and authorized dispensers.
    Authorized dispensers would be required to provide PMI to patients
each time a prescription drug product for which an FDA-approved PMI
exists is used, dispensed, or administered on an outpatient basis. The
default method of distribution for PMI is in paper form. Although
authorized dispensers would be required to have paper distribution of
PMI available upon request, this proposed rule would allow for
electronic distribution instead of paper distribution upon a patient's
request and would accommodate future technological advances in the
methods used to provide PMI upon a patient's request.
    When finalized, this proposed rule would require that PMI be
available for distribution to transfusion services of blood and blood
components, unless a waiver applies. The requirement to create PMI and
make it available for distribution to transfusion services applies to
all establishments that collect blood and blood components for

transfusion. However, only licensed blood establishments would be
required to submit PMI to FDA for approval. Each time blood or blood
components are administered on an outpatient basis, transfusion
services would be considered authorized dispensers and would be
required to provide PMI to each patient. This approach would ensure
that every patient who receives blood or a blood component with an
associated PMI on an outpatient basis would receive that PMI.
    FDA would withdraw the current regulations requiring Medication
Guides for certain prescription drug products after all prescription
drug products that currently have Medication Guides have FDA-approved
PMI. During the proposed 5-year implementation schedule of the final
rule, the current regulations governing Medication Guides would remain
in place but would no longer be applicable to a prescription drug
product once that prescription drug product has FDA-approved PMI.
    FDA would also withdraw the current regulations requiring PPIs for
oral contraceptives and estrogen-containing products after all such
prescription drug products that had PPIs have FDA-approved PMI. During
the proposed 5-year implementation schedule of the final rule, the
current regulations for PPIs would remain in place but would no longer
be applicable to a prescription drug product once that prescription
drug product has FDA-approved PMI. Under this proposed rule, once
finalized, we would no longer accept voluntary submissions of PPIs for
prescription drug products.

C. Legal Authority

    FDA's proposed revisions to the format and content requirements for
prescription drug labeling are authorized by the Federal Food, Drug,
and Cosmetic Act (FD&C Act) and the PHS Act.

D. Costs and Benefits

    This proposed rule would require that all human prescription drug
products used, dispensed, or administered on an outpatient basis,
including blood and blood components transfused in an outpatient
setting, be accompanied by a one-page product information document, or
Medication Guide, known as PMI. The public would benefit from this
labeling with decreased search costs for information. The public may
also benefit from a reduction in risk associated with their drug
products, including blood and blood component products transfused in
outpatient settings, due to the availability of PMI if the new labeling
helps patients make better healthcare decisions. We estimate that the
present discounted value of these potential benefits from PMI over 10
years would range between $127.5 million and $4.3 billion using a 3
percent discount rate, with a primary estimate of $1.6 billion; using a
7 percent discount rate, the present-value benefits from PMI would
range between $101.0 million and $3.4 billion, with a primary estimate
of $1.3 billion. Annualized over 10 years, we estimate that the benefit
from PMI would range between $14.9 and $507.9 million per year, with a
primary estimate of $188.0 million, using a 3 percent discount rate;
with a 7 percent discount rate, we estimate the annualized benefit to
range between $14.4 and $486.8 million, with a primary estimate of
$180.5 million per year. We estimate that annual benefits would be
constant beginning in year 5.
    The proposed rule would impose costs on industry, the majority of
which would stem from developing PMI. The proposed rule would also
impose costs on FDA, primarily from reviewing PMI submissions,
developing PMI templates for a small subset of drugs, and establishing
and maintaining the online PMI database. We estimate that the total
present value of net costs over 10 years would range from $105.0 to
$312.5 million, with a primary estimate of $192.8 million, using a 3
percent discount rate and from $89.0 to $263.6 million, with a primary
estimate of $162.6 million, using a 7 percent discount rate.
Annualizing these costs over 10 years, we estimate the cost would range
from $12.3 to $36.6 million per year at a 3 percent discount rate, with
a primary estimate of $22.6 million per year, and from $12.7 to $37.5
million per year using a discount rate of 7 percent, with a primary
estimate of $23.2 million. We estimate that annual costs would be
constant beginning in year 5. Dispensers may face additional costs to
distribute PMI that we cannot estimate at this time.

II. Table of Abbreviations and Acronyms Commonly Used in This Document

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     Abbreviation/acronym                    What it means
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ANDA.........................  Abbreviated New Drug Application.
BLA..........................  Biologics License Application.
CDC..........................  Centers for Disease Control and
                                Prevention.
CMI..........................  Consumer Medication Information.
DESI.........................  Drug Efficacy Study Implementation.
FD&C Act.....................  Federal Food, Drug, and Cosmetic Act.
FDA..........................  Food and Drug Administration.
HHS..........................  Department of Health and Human Services.
NDA..........................  New Drug Application.
NVICP........................  National Vaccine Injury Compensation
                                Program.
OMB..........................  Office of Management and Budget.
PHS Act......................  Public Health Service Act.
PI...........................  Prescribing Information.
PMI..........................  Patient Medication Information.
PPI..........................  Patient Package Insert.
RCAC.........................  FDA Risk Communication Advisory
                                Committee.
REMS.........................  Risk Evaluation and Mitigation Strategy.
RLD..........................  Reference Listed Drug.
VISs.........................  Vaccine Information Statements.
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III. Background

A. Introduction

    Currently, patients may receive one or more types of written
patient prescription drug product information in an outpatient setting
when they receive a prescription medication, including: (1) PPIs, (2)
Medication Guides, (3) CMI, and (4) Instructions for Use documents.
Medication Guides and some PPIs are required under the FD&C Act (see
section 505-1 of the FD&C Act (21 U.S.C. 355-1)) and FDA regulations
(see part 208 (21 CFR part 208)) and Sec. Sec.  310.501 and 310.515 (21
CFR 310.501 and 310.515)). CMI is produced by voluntary private sector
entities and is intended to provide general written patient
prescription drug product information to patients. An Instructions for
Use document is developed by applicants and is intended for patients
who use prescription drug products that have complicated or detailed
patient-use instructions.
1. Patient Package Insert (PPI)
    A PPI is written prescription drug product information developed by
applicants for patients. Current FDA regulations require that
applicants develop PPIs for oral contraceptives and estrogen-containing
products (see Sec. Sec.  310.501 and 310.515). Applicants must submit
the required PPIs to FDA for approval and provide FDA-approved PPIs
with each package of the drug product that the manufacturer or
distributor intends to dispense to patients. Applicants can also
voluntarily create a PPI for other prescription drug products and may
submit it to FDA for approval as part of a prescription drug product's
labeling. However, distribution of a voluntarily submitted PPI is not
required, even if it is FDA-approved.
    FDA can require a risk evaluation and mitigation strategy (REMS)
when FDA determines a REMS is necessary to ensure that the benefits of
a prescription drug product outweigh the risks (see section 505-1 of
the FD&C Act). Under section 505-1(e) of the FD&C Act, PPIs are one
potential element of a REMS if FDA determines that a PPI may help
mitigate a serious risk of the prescription drug product.\1\
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    \1\ Currently, there are no REMS that contain a PPI as an
element.
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2. Medication Guide for Prescription Drug Products
    Currently, a Medication Guide is FDA-approved written patient
prescription drug product information for certain prescription drug
products that are used primarily on an outpatient basis (see part 208).
Under current regulations, FDA requires a Medication Guide when FDA
determines one or more of the following circumstances exist: (1) the
prescription drug product is one for which patient labeling could help
prevent serious adverse effects; (2) the prescription drug product is
one that has a serious risk or risks (relative to benefits) of which
patients should be made aware, because information concerning the risk
or risks could affect a patient's decision to use or continue to use
the product; or (3) the prescription drug product is important to
health, and patients' adherence to directions for use is crucial to the
prescription drug product's effectiveness (Sec.  208.1(c) (21 CFR
208.1(c))).
    FDA can also require Medication Guides as an element of a REMS
under section 505-1(e) of the FD&C Act. In the Federal Register of
November 18, 2011 (76 FR 71577), FDA published a notice of availability
of a guidance for industry entitled ``Medication Guides--Distribution
Requirements and Inclusion in Risk Evaluation and Mitigation Strategies
(REMS)'' (available at: https://www.fda.gov/media/79776/download) to
clarify when Medication Guides would be a part of a REMS and to clarify
when FDA intended to exercise enforcement discretion regarding when a
Medication Guide must be provided to a patient.
    Medication Guides contain information that is necessary to a
patient's safe and effective use of a prescription drug product. For
those selected prescription drug products that currently have
Medication Guides, Medication Guides are developed by applicants,
approved by FDA, and required to be distributed to patients.
3. Consumer Medication Information (CMI)
    CMI is written patient prescription drug product information that
is developed by organizations or individuals in the private sector
other than the applicant of the prescription drug product. CMI is
intended for voluntary distribution to patients when a prescription
drug product is dispensed from a pharmacy. CMI is not developed by or
in consultation with the applicant, is not approved by FDA, and is not
required by FDA to be distributed to patients.
    Different organizations and individuals create CMI and make it
available to pharmacies for purchase. FDA provides recommendations for
creating useful CMI through guidance (available at: https://www.fda.gov/media/72574/download). However, CMI is not standardized,
and the content, even for the same prescription drug product, can vary
greatly depending on which organization or individual created the CMI.
4. Instructions for Use
    For certain prescription drug products that have complicated or
detailed patient-use instructions, applicants may develop an
Instructions for Use document. The Instructions for Use document, if
developed, is reviewed and approved by FDA and is generally provided
when the drug is dispensed to the patient. In the Federal Register of
July 15, 2022 (87 FR 42485), FDA published a notice of availability of
a final guidance for industry entitled ``Instructions for Use--Patient
Labeling for Human Prescription Drug and Biological Products--Content
and Format'' (available at: https://www.fda.gov/media/128446/download)
to provide recommendations for developing the content and format of an
Instructions for Use document for human prescription drugs and
biological products and drug-device or biologic-device combination
products submitted under an NDA or BLA. This guidance represents FDA's
current thinking on this topic.

B. Need for the Regulation

    We have long recognized the importance of providing written
information to patients about their prescription drug products. There
is evidence that prescription drug product information may help
patients use their prescription drug products safely and effectively,
which may reduce preventable adverse drug events and improve health
outcomes. For example, written prescription drug product information is
an important part of patient counseling because it reinforces verbal
instructions or warnings given by healthcare providers, may improve
patient understanding and recall of instructions, and provides patients
with supplemental information about the prescription drug product after
visits with healthcare providers (Ref. 1). We evaluated the current
system for written prescription drug product information, which
includes Medication Guides, PPIs, CMI, and Instructions for Use. Based
on that evaluation (discussed below in detail), we have determined that
the current system does not consistently provide patients with clear,
concise, accessible, and sufficiently useful written prescription drug
product information delivered in a consistent and easily understood
format to help patients use their prescription drug

products safely and effectively. Therefore, we are proposing a new type
of Medication Guide to help patients use their prescription drug
products safely and effectively.
    In addition, a common major public health problem is that some
patients do not adhere to prescription drug therapy (e.g., for
antihypertensive drugs), and some patients do not use their prescribed
drugs as directed by their healthcare providers (Refs. 2 through 4).
Reports show that patients' nonadherence to long-term prescription drug
product therapies negatively affects patient outcomes and has led to
preventable healthcare costs (Refs. 3 and 5). It is estimated that
nonadherence contributes to as many as 25 percent of hospital
admissions (Ref. 4), 50 percent of treatment failures, and
approximately 125,000 deaths in the United States per year (Refs. 2 and
4).
    Although the reasons for medication nonadherence are
multidimensional (Ref. 2), patients' knowledge about prescription drug
products is important for adherence (Ref. 6). To help increase
patients' knowledge, information about prescription drug products
should be communicated to patients when these products are dispensed,
administered, or used on an outpatient basis (Ref. 2). This information
can remind patients about important information regarding the
prescription drug product and answer questions that arise after
patients have visited a healthcare provider (Ref. 7).
1. Previous Efforts To Provide Written Prescription Drug Product
Information to Patients
    Since the 1970s, we have required that useful patient prescription
drug product labeling written in nontechnical language be distributed
to patients every time certain prescription drug products are
dispensed. Specifically, we published regulations requiring that
manufacturers/distributors of oral contraceptive drug products (see
Sec.  310.501; 35 FR 9001, June 11, 1970; and 43 FR 4214, January 31,
1978) and estrogen-containing drug products (see Sec.  310.515 and 42
FR 37636, July 22, 1977) provide patients with PPIs containing
information about the prescription drug product's benefits and risks.
    In the Federal Register of July 6, 1979 (44 FR 40016), we published
a proposed rule that would have required written patient information
for most prescription drug products in addition to PPI for oral
contraceptives and estrogen-containing products. However, in the
Federal Register of September 12, 1980 (45 FR 60754), the final rule
instead required procedures for preparing and distributing PPIs for a
limited number of prescription drug products in addition to PPI for
oral contraceptives and estrogen-containing products.
    FDA proposed to revoke the final rule in the Federal Register of
February 17, 1982 ((47 FR 7200) and reprinted February 19, 1982 (47 FR
7458)). In the Federal Register of September 7, 1982 (47 FR 39147), we
revoked the final rule.
    In the Federal Register of August 24, 1995 (60 FR 44182), we
published a proposed rule entitled ``Prescription Drug Product
Labeling: Medication Guide Requirements'' (1995 proposed rule)
(available at: https://www.govinfo.gov/content/pkg/FR-1995-08-24/pdf/95-21020.pdf), which was intended to help patients receive useful
written information about prescription drug products. If finalized, the
1995 proposed rule would have set specific distribution and quality
goals and timeframes for distributing useful written patient
information. The proposed rule would have required applicants to
prepare and distribute Medication Guides or provide the means to
distribute Medication Guides for a limited number of prescription drug
products (primarily used on an outpatient basis) that FDA determined
posed a serious and significant public health concern requiring the
immediate distribution of FDA-approved patient information.
    Consistent with the health promotion and disease prevention
objectives of Healthy People 2000 (Ref. 8), the 1995 proposed rule
would have also set a goal for distributing useful written patient
information for those prescription drug products that did not require
Medication Guides. The goal was that the private sector initiatives
would result in the distribution of useful written patient information
to 75 percent of individuals receiving new prescriptions by 2000 and to
95 percent of individuals receiving new prescriptions by 2006.
    The 1995 proposed rule described criteria to determine the
usefulness of written patient information. We described useful written
patient information as information written in nontechnical language and
containing a summary of the most important information about a drug
product. We also specified that the usefulness of written patient
information would be evaluated based on scientific accuracy,
consistency with a standard format, nonpromotional tone and content,
specificity, comprehensiveness, understandable language, and
legibility.
    If the 1995 proposed rule had been finalized, we would have
periodically evaluated and reported on the private sector's progress
towards achieving the target goals. If the goals were not met in the
specified timeframes, we proposed that we would either implement a
mandatory comprehensive Medication Guide program or seek public
comments on whether a comprehensive program should be implemented.
Additionally, we would try to determine whether any other steps were
needed to meet the goals of patient prescription drug product
information.
    As we were reviewing the public comments to the 1995 proposed rule,
Congress enacted Public Law 104-180 (the Agriculture, Rural
Development, Food and Drug Administration, and Related Agencies
Appropriations Act, 1997) on August 6, 1996. A goal of section 601(b)
of Public Law 104-180 was for the private sector to distribute useful
written prescription information to 75 percent of individuals receiving
new prescriptions by 2000 and to 95 percent of individuals receiving
new prescriptions by 2006, consistent with the goals of the 1995
proposed rule. Section 601(a) of the law also required the Secretary of
the Department of Health and Human Services (Secretary) (HHS) to
organize a committee of interested stakeholders to develop a long-
range, comprehensive action plan to achieve this goal.
    Section 601(d) of the law prohibited us from taking further
regulatory steps at that time to require a uniform content or format
for written prescription drug product information that was voluntarily
provided to patients if private sector initiatives met the goal within
the specified timeframes. FDA was charged with evaluating the private
sector's progress in meeting the goal of distributing useful written
prescription drug product information beginning January 1, 2001. If,
after reviewing the private sector initiatives, FDA determined that the
goals of the law had not been met, FDA could seek public comments on
alternative initiatives to meet the goal.
    In response to the Public Law 104-180 mandate, the Secretary
convened a steering committee composed of healthcare professionals,
consumer organizations, pharmaceutical manufacturers, prescription drug
wholesalers, drug information database companies, CMI developers, and
others. The steering committee created a long-term action plan for
improving oral and written prescription drug product information,
reported in the 1996 ``Action Plan for the Provision of Useful
Prescription Medicine Information''

(Keystone Action Plan) (Ref. 9). The Keystone Action Plan endorsed the
elements specified in Public Law 104-180 for defining the usefulness of
prescription drug product information, specifically that the materials
should be scientifically accurate, unbiased in content and tone,
sufficiently specific and comprehensive, and presented in an
understandable and legible format that is readily comprehensible to
patients and is timely and up to date. The Keystone Action Plan
explained that written prescription drug product information that meets
these criteria for usefulness would enable patients to use their
prescription drug products properly and appropriately, receive the
maximum benefit from the prescription drug products, and avoid harm.
    In the Federal Register of December 1, 1998 (63 FR 66378), we
published a final rule requiring the mandatory distribution of
Medication Guides for a small number of prescription drug and
biological products that FDA determines pose a serious and significant
public health concern requiring distribution of FDA-approved patient
medication information. FDA anticipated that on average, no more than 5
to 10 prescription drug products per year would require such
information. However, because of the types and characteristics of the
prescription drug products approved, the number of prescription drug
products required to have Medication Guides has increased significantly
to over 550 Medication Guides since publication of the final rule in
1998 (approximately 20 to 25 per year).
2. FDA's Evaluation of the Private Sector's Progress To Provide Written
Prescription Drug Product Information to Patients
    Consistent with Public Law 104-180, the Keystone Action Plan
required the development of mechanisms to periodically assess the
quality of written prescription drug product information. We were
charged with evaluating the private sector's progress toward meeting
the goal of distributing useful written prescription drug product
information (Ref. 9). Subsequently, we contracted with the National
Association of Boards of Pharmacy and a group of academics to conduct
several studies to determine the private sector's progress toward
meeting the goal of Public Law 104-180.
    In 1999, an initial study assessed the CMI that was voluntarily
provided to patients receiving new prescriptions at pharmacies (the
1999 study) (Ref. 1). The 1999 study assessed the percentage of trained
shoppers (acting as patients) who received any written information when
receiving a new prescription and the quality of this information
received from 306 randomly selected community pharmacies in 8 States. A
panel of experts evaluated the written information for usefulness (as
defined in the Keystone Action Plan) and quality, using explicit
criteria. The results showed that of the 918 new prescriptions
presented at pharmacies, the following occurred (Ref. 1):
     87 percent were dispensed with CMI.
     81 percent were dispensed with information that was
considered unbiased in content and tone.
     69 percent were dispensed with acceptable information
about adverse drug reactions and what to do if an adverse drug reaction
occurred.
     68 percent were dispensed with acceptable information
about the drug product and its indications for use.
     49 percent were dispensed with acceptable directions about
how to use the prescription drug product, receive maximum benefits from
the drug product, and interpret the benefits of the drug product.
     19 percent were dispensed with acceptable information
about the drug products' contraindications and what to do if a
contraindication existed.
    FDA presented these 1999 study results at a public workshop held on
February 29 and March 1, 2000 (Ref. 10).
    A second study was performed in 2001 (the 2001 study) to determine
whether the private sector had made further progress toward meeting the
goal of Public Law 104-180. The 2001 study expanded upon the initial
1999 study and included 384 randomly selected pharmacies in 44 States.
All CMIs received by trained shoppers (acting as patients) with new
prescriptions at the pharmacy were sent to an expert panel (consistent
with the 1999 study) to evaluate against eight general criteria
described in the Keystone Action Plan. The criteria specified that the
written patient information must include the following: (1) drug names
and indications for use; (2) contraindications and what to do, if
applicable; (3) specific directions about how to use, monitor, and get
the most benefit; (4) specific precautions and how to avoid harm while
using the prescription drug; (5) symptoms of serious or frequent
adverse reactions and what to do; (6) general information, a
disclaimer, and encouragement to ask questions; (7) scientifically
accurate, unbiased, and up-to-date information; and (8) a written
format that is legible and comprehensible to the consumer. Consumers
were also recruited to evaluate the written information and the extent
to which the information was comprehensible, legible, and useful (Ref.
11).
    The results of the 2001 study were presented in a final report to
HHS and FDA in 2001 and were also published in 2005. The results showed
that 89 percent of the 1,367 new prescriptions were dispensed with CMI
(Refs. 11 and 12). However, the expert panel judged that fewer than 20
percent of CMI met the criteria for specificity, legibility, and
comprehensibility (Ref. 11). Fewer than 10 percent of all leaflets met
the quality criteria regarding contraindications, precautions, and how
to avoid harm (Ref. 11). Assessments from consumers, consistent with
assessments from expert panels, showed that most CMI did not meet the
criteria (as described in the Keystone Action Plan) for font size,
spacing, use of bullets, and reading difficulty. The 2001 study
concluded that CMI ``falls short of the information quality level
required in the 1996 federal legislation,'' and additional efforts were
needed to meet the federally mandated distribution and quality goal
(Ref. 11).
    In the Federal Register of May 26, 2005 (70 FR 30467), we published
a notice of availability of a draft guidance for industry entitled
``Useful Written Consumer Medication Information (CMI).'' In the
Federal Register of July 18, 2006 (71 FR 40724), we published a notice
of availability of a final guidance for industry (the 2006 CMI
guidance, available at: https://www.fda.gov/media/72574/download). The
2006 CMI guidance is intended to assist organizations and individuals
in developing useful CMI.
    A third study, conducted in 2008 as a followup to the 1999 and 2001
studies, evaluated the quality and usability of CMI provided with new
prescriptions. The results were presented to HHS and FDA in a final
report published in 2008 (the 2008 study) (Ref. 13). This study used
methods similar to those used in the 2001 study, but the 2008 study
also incorporated information from the 2006 CMI guidance on developing
useful written CMI. The 2006 CMI guidance, which was written in part
based on the results of the 1999 and 2001 studies, assists individuals
and organizations in developing useful written CMI.
    The 2008 study included 365 pharmacies in 41 States (Ref. 13). The
results indicated that although 94 percent of patients received CMI
with new prescriptions, only about 70 percent of this information met
the minimum criteria for usefulness, and a number of additional
deficiencies were noted. Despite the FDA guidance, the

2008 study identified various shortcomings of the evaluated CMI,
including lack of information about the management of the prescription
drug product, significant redundancy of information that resulted in
excessively long leaflets, poor formatting, and inadequate legibility
and an inappropriately high reading level. Only half of CMI had
specific information about what patients would need to monitor and
manage when using their prescription drug therapies and actions to take
when side effects or other problems occur. The 2008 study found that
the length and format of CMI and the percent of items covered continued
to vary considerably from pharmacy to pharmacy. The majority of CMI did
not satisfy the criteria recommended in the 2006 CMI guidance. The 2008
study also noted that, although progress had been made, CMI continued
to fall short of the Congressionally mandated goal of Public Law 104-
180 that 95 percent of new prescriptions be accompanied by useful
written patient information by 2006 (Ref. 13).
3. FDA 2007 Public Hearing
    In the Federal Register of April 9, 2007 (72 FR 17559), we
announced a public hearing entitled ``Use of Medication Guides to
Distribute Drug Risk Information to Patients'' (the 2007 FDA public
hearing) to be held on June 12 and 13, 2007 (Docket No. 2007N-0121). At
the 2007 FDA public hearing, we obtained feedback and requested
information and views on specific issues associated with the
development, distribution, comprehensibility, and accessibility of
Medication Guides. FDA officials heard testimony from one member of
Congress; 40 individuals representing academia, consumers and consumer
groups; the pharmaceutical industry; healthcare professional groups;
physicians; pharmacists; and pharmacy organizations (Ref. 14). Although
stakeholders stated it was important that patients receive appropriate
risk information in the form of Medication Guides to make informed
decisions about certain prescription drug products, stakeholders
suggested that the current Medication Guide program was too cumbersome
and lacked a standard distribution system. Stakeholders urged FDA to:
(1) increase awareness of Medication Guides, (2) make Medication Guides
easier to read and understand, (3) move toward facilitating the
distribution of Medication Guides by electronic means, and (4) consider
combining the information in Medication Guides with other information,
such as CMI (Ref. 14).
4. Citizen Petition
    In June 2008, we received a citizen petition (the 2008 citizen
petition) from a large group of stakeholders representing pharmacy
practice, medical consumers, and medical communications companies
(Docket No. FDA-2008-P-0380). The 2008 citizen petition asked us to
adopt an FDA-approved, concise, plain language, single-page patient
information document for prescription drugs. The 2008 citizen petition
requested that the one-page ``single patient document'' combine and
simplify the many documents that patients currently receive at the
pharmacy for prescription drug products (Ref. 15). In 2010, the
petitioners voluntarily withdrew the 2008 citizen petition, citing
FDA's significant work and strides toward achieving the goals of the
2008 citizen petition with the ongoing development of PMI (Ref. 16).
5. The FDA Risk Communication Advisory Committee Meeting
    In February 2009, the FDA Risk Communication Advisory Committee
(RCAC), which included some members of the FDA Drug Safety and Risk
Management Advisory Committee, met to explore approaches to improve the
communication of prescription drug product information to patients,
specifically regarding CMI, Medication Guides, and PPIs (Ref. 17). The
RCAC recommended that FDA adopt a single standard document for
communicating essential information about prescription drug products to
patients. The single document was proposed as a replacement for CMI,
Medication Guides, and PPIs. The RCAC also recommended that the
standard document be FDA-approved and subject to a rigorous empirical
evaluation of its effectiveness (Ref. 17).
    We have determined that the current system fails to consistently
provide patients with sufficient information to help them use
prescription drug products safely and effectively. Based on the results
of the 1999, 2001, and 2008 studies, comments from stakeholders at the
2007 FDA public hearing, the 2008 citizen petition, and recommendations
from the 2009 RCAC, we are proposing a new type of Medication Guide to
help patients use their prescription drug products safely and
effectively.
6. Development of Prototypes
    Prior to the development of this proposed rule, FDA developed
prototypes for the proposed new type of Medication Guide, called PMI,
based on stakeholders' input, research findings, and our knowledge and
experience. To solicit further public input on the PMI prototypes and
PMI in general, FDA held a public workshop, participated in a series of
workshops convened by the Engelberg Center for Health Care Reform at
the Brookings Institution (Brookings Institution), held a public
hearing following the procedures set forth in part 15 (21 CFR part 15),
and research was conducted on prototypes for PMI (OMB control number
0910-0691; Ref. 31).

C. History of the Rulemaking

1. FDA 2009 Public Workshop
    On September 24 and 25, 2009, we convened a public workshop (the
2009 public workshop). Participants discussed the optimal content and
format of written prescription drug product information to ensure that
the information is comprehensible, accurate, and more easily accessible
to patients (see 74 FR 33265, July 10, 2009, Docket No. FDA-2009-N-
0295). The 2009 public workshop explored the following questions:
     What content is critical for patients to receive and in
what order and format?
     How can access be improved?
     How should this information be distributed to patients?
     What parameters are appropriate with regard to evaluating
the usefulness of the materials?
    We prepared an issue paper to serve as context and background for
the 2009 public workshop (Ref. 18).
    At the 2009 public workshop, we presented four PMI prototypes for a
fictitious drug that used different labeling formats. FDA developed the
PMI prototypes based on stakeholders' input, patient information
studies and pilots, consumer-focused research, and our knowledge and
experience with patient information and current labeling practices. All
four PMI prototypes consisted of the same core content, including uses,
side effects, what to do while taking the drug, what to avoid while
taking the drug, and how to take the drug.
    Prototype 1 was modeled on the format of the over-the-counter
``Drug Facts'' section of labeling (see 21 CFR 201.66), was one page in
length, and was the most succinct (Ref. 19). Prototype 2 was modeled on
the format of the ``Highlights of Prescribing Information'' section of
labeling (see Sec.  201.57(a) (21 CFR 201.57(a)), was one page, and was
more detailed than Prototype 1 (Ref. 20). Prototype 3 was modeled on
the format of the Prescribing Information (PI) and

contained two levels of information (see Sec.  201.57). The first level
summarized the information in a concise manner (similar to Highlights
of Prescribing Information), and the second level explained the
information in detail (similar to the Full Prescribing Information).
Prototype 3 was two pages in length, appeared in question-and-answer
format, and repeated information (Ref. 21). Prototype 4 was modeled on
the current Medication Guide requirements (see part 208), was four
pages in length, and was more detailed and comprehensive than the other
three prototypes. It appeared in paragraph format and contained
standard statements (Ref. 22).
    During the 2009 public workshop, attendees identified the strengths
and weaknesses of the four PMI prototypes pertaining to format,
presentation, and context. Academic panelists described the key
attributes and goals of written patient prescription drug product
information as follows (Ref. 23):
     Patients should be able to understand what the
prescription drug product is used for and how to use it appropriately.
     Patients should be able to find, understand, and retain
information about the prescription drug product's contraindications and
side effects.
     Patients should know where they can locate additional
information about the prescription drug product that is not included in
the written prescription drug product information.
    Attendees also suggested that user testing of written prescription
drug product information during the development stage should be
mandatory to ensure that the final product is consumer friendly.
2. Brookings Institution Workshops and Distribution Studies
    Based on a cooperative agreement with FDA, the Brookings
Institution convened a series of four public workshops that discussed
optimizing, implementing, and evaluating the adoption of PMI (Ref. 24).
    On July 21, 2010, the Brookings Institution hosted the first
workshop. Experts from academia, medical professional groups,
stakeholders from the private sector (applicants, consumer
organizations, and publishers of CMI), and FDA met to discuss improving
written patient prescription drug product information. The following
objectives were discussed at the workshop (Ref. 25):
     The overarching principles for effectively communicating
prescription drug product information to patients.
     The metrics for evaluating CMI and the most useful content
and format of a single paper document for prescription drug product
information as represented in FDA's PMI prototypes.
     FDA's proposed strategy for evaluating the PMI prototypes.
     How patients will receive prescription drug product
information in the future and whether this has implications for near-
term initiatives centered around a single-document solution.
    FDA further refined the PMI prototypes based on feedback provided
at the first Brookings Institution workshop.
    On October 12, 2010, the second Brookings Institution workshop was
held to discuss strategies for making PMI easily accessible and how to
most effectively distribute PMI to patients. As in July 2010, experts
from academia and medical professional groups, stakeholders from the
private sector (applicants, consumer organizations, and publishers of
CMI), and representatives from FDA explored the following topics at the
workshop (Ref. 26):
     Patient preferences for access to and distribution of PMI.
     Potential roles that applicants, publishers, distribution
partners, pharmacists, and physicians can play in the development and
distribution of PMI.
     Models for effective distribution of PMI within current
and future healthcare delivery systems.
     Potential strategies for monitoring and ensuring the
effectiveness of PMI.
    The third Brookings Institution workshop was held on February 23,
2011. It summarized the first two Brookings Institution workshops and
further discussed how to design pilot studies to test the distribution
of PMI. The experts discussed the following topics (Ref. 27):
     The goals and objectives of demonstration pilots designed
to evaluate feasibility of different methods to distribute the PMI
prototype and to assess patient and provider preferences for the PMI
prototype that was distributed to patients.
     How to develop a PMI prototype for use in the distribution
pilots.
     The framework, development, and evaluation strategy for
proposed distribution pilots.
    As a result of discussions about PMI distribution at the third
Brookings Institution workshop, Catalina Health (now Adheris Health)
launched an 8-week quality improvement initiative in August 2012 to
disseminate newly designed patient information to patients filling
prescriptions at participating pharmacies (Ref. 28). The newly designed
patient information was based on FDA's PMI prototypes. Through
voluntary telephone and online responses, Catalina Health: (1) surveyed
patients to confirm that they received Catalina Health's patient
information with their prescription drug product, (2) assessed whether
they found the information useful, and (3) determined how they would
like to receive this newly formatted patient information in the future.
The results revealed that:
     More than 90 percent of patients recalled receiving
Catalina Health's patient information and considered the written
patient information useful (Ref. 28).
     The majority of patients surveyed (>=92 percent), across
all age groups, reported that the new PMI was either ``very useful'' or
``somewhat useful''. Few respondents found this information to be
either ``not very useful'' or ``not useful at all'' (<=9 percent across
age groups). (Ref. 28).
    On July 1, 2014, the Brookings Institution held a fourth public
workshop to explore the following (Ref. 29):
     Lessons learned from health literacy researchers engaged
in PMI projects.
     The role of stakeholders in moving the PMI initiative
forward.
    Stakeholders leveraged key findings from the previous three
Brookings Institution workshops. Stakeholders developed methods and
conducted research geared toward assessing the effectiveness of FDA's
PMI prototypes and strategies to distribute PMI. Based on the previous
findings and their research, the participants emphasized that enough
information now exists to create effective PMI that will provide more
value than currently available written prescription drug product
information (Ref. 29).
3. FDA 2010 Part 15 Public Hearing
    On September 27 and 28, 2010, we hosted a part 15 public hearing to
solicit input on a new framework for the development and distribution
of PMI to be provided to patients who are prescribed drug products. The
purpose of the 2010 part 15 public hearing was to solicit input on the
processes and procedures for standardizing PMI using a quality system
approach for monitoring the development and distribution of PMI (see 75
FR 52765, August 27, 2010, Docket No. FDA-2010-N-0437).
    The hearing was attended by experts from academia, medical
professional groups, stakeholders from the private sector (applicants,
consumer

organizations, and publishers of CMI), and FDA. Presentations and
comments from the attendees offered support for the following
principles:
     PMI should be available at pharmacies and should use the
existing distribution capabilities of the pharmacy.
     FDA should have an active role in the development and
approval of PMI and should design content and format guidelines.
     Plain language should be used to increase comprehension.
     PMI should be consumer tested.
     A range of distribution methods should be used for PMI.
    However, attendees disagreed on whether the length of PMI should be
limited to one page (Ref. 30).
4. FDA's Research on PMI Prototypes
    In developing the four PMI prototypes, FDA focused on creating a
standardized format that patients would become familiar with to help
them use and understand PMI. Based on the RCAC recommendations,
discussions from the 2009 public workshop, the Brookings Institution
workshops, the 2010 part 15 public hearing, and comments from
stakeholders, we further narrowed down our four PMI prototypes to two
PMI prototypes. The two PMI prototypes tested, formatted in either
``Bubbles'' or ``Over-the-Counter'' formats, were based on existing
Medication Guide regulations, and developed to be representative of
real Medication Guides. These prototypes were selected through an
iterative process involving recommendations and empirical data gleaned
from several sources, including: (1) input from the previously
mentioned entities (e.g., public stakeholders and risk communication
experts from government, industry, and academia (Ref. 17)); (2) the
application of plain language principles to the content and formatting
of these handouts; and (3) findings from qualitative research with
patients who had one of the medical conditions (e.g., rheumatoid
arthritis) that the fictitious drug described in these PMI prototypes
(i.e., Rheutopia) was indicated to treat (Ref. 17).
    We announced our research study entitled ``Experimental Study of
Patient Information Prototypes'' and requested comments on the proposed
collection of information (75 FR 23775, May 4, 2010, Docket No. FDA-
2010-N-0184). We explained that the study was designed to use different
prototypes to test whether consumers were able to comprehend serious
warnings, directions for use, drug indications and uses,
contraindications, and side effects in the material presented.
    In 2012, RTI International, contracted by FDA, conducted a research
study using variations of the two PMI prototypes to test different ways
of presenting information about prescription drug products to patients
who had obtained a prescription drug product. The study examined the
impact of the PMI prototypes on outcomes, including perceived risk,
recall, and ease of understanding the information.
    The research study included qualitative components and quantitative
components to assess the comprehension and the use of the two PMI
prototypes for a fictitious drug, Rheutopia, in individuals with and
without the chronic health condition for which Rheutopia was indicated.
The qualitative phase of RTI International's research explored
preferences for format and font used in the PMI prototypes and assessed
readability and comprehension. The quantitative phase of RTI
International's research investigated whether either of the two PMI
prototypes resulted in better recall of the information, increased
perceived risk, or increased ease of understanding. The results suggest
that content and format may be important predictors of recall of
factual information about prescription drug products. We used the
results of the 2012 research study in conjunction with additional
research to develop several aspects of this proposed rule (Ref. 31).
    The information obtained from the hearings, the results of the
research performed, and the recommendations provided by stakeholders
highlights the importance of providing clear, concise, and accessible
information to patients as this may help them to use their prescription
drug products safely and effectively.

IV. Legal Authority

    In this proposed rule, FDA is addressing legal issues relating to
FDA's proposed action to revise the regulations regarding format and
content for prescription drug labeling. Our proposed revisions to the
format and content requirements for prescription drug labeling are
authorized by the FD&C Act (21 U.S.C. 321 et seq.) and by the PHS Act
(42 U.S.C. 262 and 264).
    The FD&C Act provides that a drug shall be deemed to be misbranded
if the requirements of section 502 of the FD&C Act are not met (21
U.S.C. 352). This provision applies to all drugs, including those that
are also regulated as biological products under the PHS Act. In
addition, section 351(b) of the PHS Act (42 U.S.C. 262(b)) provides
that ``no person shall falsely label or mark any package or container
of any biological product or alter any label or mark on the package or
container of the biological product so as to falsify the label or
mark.''
    Section 502(f) of the FD&C Act deems a drug to be misbranded if its
labeling lacks adequate directions for use and adequate warnings
against use in those pathological conditions where its use may be
dangerous to health, as well as adequate warnings against unsafe dosage
or methods or duration of administration or application, in such manner
and form, as are necessary for the protection of users. This section of
the FD&C Act further authorizes FDA, on authority delegated from the
Secretary, to issue regulations exempting a drug or device from the
requirement to bear adequate directions for use upon a determination
that such directions are not necessary for the protection of users.
    It is well-established that a drug must have adequate directions
for use unless the drug is exempt from that requirement by regulation.
For a prescription drug to avoid being misbranded under section 502(f)
of the FD&C Act, its labeling must conform to regulations issued by
FDA. (See, e.g., U.S. v. Articles of Drug, 625 F.2d 665, 672 (5th Cir.
1980).) FDA has, since 1952, had a regulation that states the
conditions under which a prescription drug must be labeled in order to
be exempt from the adequate directions for use requirement. (See 17 FR
6818 (July 25, 1952).) The current version of that rule is codified in
Sec.  201.100 (21 CFR 201.100). This proposed rule, if finalized, would
modify the existing exemption from adequate directions for use for
prescription drugs (Sec.  201.100). We are proposing this rule based on
our determination that an additional condition must be present for a
prescription drug to be exempt from the requirement to provide adequate
directions for use. This additional condition is that, when PMI is
required under part 208 or proposed Sec.  606.123 (21 CFR 606.123), the
drug must have FDA-approved PMI and be dispensed with such PMI (as
described in proposed part 208 or Sec.  606.123) as applicable.
    In addition, section 502(a) of the FD&C Act deems a drug to be
misbranded ``if its labeling is false or misleading in any
particular.'' Under section 201(n) of the FD&C Act (21 U.S.C. 321(n)),
when considering whether labeling is misleading, FDA shall consider
whether the labeling fails to reveal facts that are material with

respect to consequences that may result from the use of the drug under
the conditions of use prescribed in the labeling or advertising thereof
or under usual or customary conditions of use. If a prescription drug
does not have PMI after it is required for that drug, its labeling will
fail to reveal material information to patients.
    Furthermore, the premarket approval provisions for drugs require
that product labeling adequately address the safety and effectiveness
of the drug product. Under section 505 of the FD&C Act (21 U.S.C. 355),
we will approve an NDA only if the drug is shown to be both safe and
effective for use under the conditions set forth in the drug's
labeling. Under 21 CFR 314.125, we will not approve an NDA unless,
among other things, there is adequate safety and effectiveness
information for the labeled uses and the product labeling complies with
the requirements of 21 CFR part 201. Under section 351(a)(2)(C)(i)(I)
of the PHS Act, we are authorized to license a biological product only
upon a demonstration that the biological product is safe, pure, and
potent. This demonstration would be assessed in the context of the
labeling for that product.
    Section 701(a) of the FD&C Act (21 U.S.C. 371(a)) authorizes us to
issue regulations for the efficient enforcement of the FD&C Act.
Section 361 of the PHS Act (42 U.S.C. 264) authorizes us to make and
enforce regulations determined to be necessary to prevent the
introduction, transmission, or spread of communicable disease into the
United States or from one State or possession into any other State or
possession. For blood and blood components intended for transfusion on
an outpatient basis, the proposed requirement to include information on
the risks associated with blood transfusion, including transfusion-
transmitted infections, in PMI may aid in preventing the introduction,
transmission, or spread of communicable disease.
    Furthermore, section 505-1 of the FD&C Act, authorizes FDA to
require a Medication Guide, such as PMI, as one element of a REMS when
necessary to help mitigate a serious risk of the prescription drug
product.
    With regard to generic drug products, section 505(j)(2)(A)(v) of
the FD&C Act requires an ANDA to include information showing that the
proposed generic drug product's labeling is the same (with some
exceptions) as the labeling approved for the corresponding RLD. Thus,
because under this proposal PMI will be approved drug labeling, FDA has
authority to require drug product manufacturers seeking approval of
ANDAs to adopt PMI that is the same as the PMI for the RLD, if an
approved PMI for their RLD exists, except that the PMI for the ANDA
could reflect certain permissible differences in accordance with
section 505(j)(2)(A)(v) of the FD&C Act and Sec.  314.94(a)(8)(iv) (21
CFR 314.94(a)(8)(iv)). If the ANDA is already approved when the PMI for
its RLD is first approved, FDA believes it is appropriate that the ANDA
product also adopt PMI that is the same as that approved for the RLD,
except that again, the PMI for the ANDA could reflect certain
permissible differences. The statutory bases for this requirement with
respect to approved ANDAs are the misbranding provisions cited
previously. Where an ANDA applicant seeks approval of an ANDA
referencing a listed drug whose approval has been withdrawn and for
which no PMI was approved for the RLD before the approval of the RLD
was withdrawn, the ANDA applicant must submit PMI that corresponds to
an FDA-created template once FDA has provided a template. Again, the
statutory bases for this requirement are the misbranding provisions.
    We note that Federal courts have affirmed that FDA has authority to
require the dispensing of patient labeling for prescription drugs and
that such requirements do not interfere with the practice of medicine.
(See Pharmaceutical Manufacturers Association v. Food and Drug
Administration, 484 F. Supp. 1179 (D. Del. 1980), aff'd per curiam, 634
F. 2d 106 (3rd Cir. 1980).)

V. Description of the Proposed Rule

    We are proposing to revise the part heading and all subparts of
current part 208. The part heading would be revised to ``Medication
Guides.'' FDA is proposing to require a new type of Medication Guide
for patients that will be called PMI. These proposed requirements for
patient labeling would ensure that clear, concise, accessible, and
useful written prescription drug product information would be delivered
to patients in a consistent and easily understood format to help
patients use all of their prescription drug products safely and
effectively when dispensed in an outpatient setting.
    Proposed part 208 (Medication Guides) would be the successor
regulation to current part 208 (Medication Guides for Prescription Drug
Products). Therefore, current Medication Guides would continue to be
available as a potential element of a REMS under section 505-1(e) of
the FD&C Act as described in section V.J of this document until FDA has
approved PMI for the prescription drug product.
    Consistent with proposed part 208, FDA is proposing to add Sec.
606.123 to part 606, subpart G, to require establishments that collect
blood and blood components intended for transfusion to create and
distribute PMI consistent with proposed part 208.
    A detailed description of the proposed revisions and a description
of each proposed section are provided in sections V.A through V.L of
this document.

A. Placement and Removal of the Current Requirements for Medication
Guides for Prescription Drug Products (Proposed Sec. Sec.  208.91,
208.92, 208.94, 208.96, and 208.98)

    Medication Guides are currently required under part 208 for certain
prescription drug products that FDA determines pose a serious and
significant public health concern, requiring distribution of FDA-
approved patient information. Medication Guides contain information
that FDA believes is necessary to a patient's safe and effective use of
a prescription drug product. Once a prescription drug product has FDA-
approved PMI, its current Medication Guide requirement (if any) would
no longer be applicable (see also discussion in section V.J of this
document). FDA would withdraw the current regulations governing
Medication Guides in part 208 after all prescription drug products that
had Medication Guides have FDA-approved PMI.
    We believe it is important that patients continue receiving FDA-
approved patient information for prescription drug products that we
previously determined posed a serious and significant public health
concern during the implementation of the final rule. Therefore, we
propose that the provisions in current part 208 requiring Medication
Guides for select prescription drug products would remain in effect as
described in section V.J of this document.
    For current part 208 to remain in effect until all prescription
drug products that had Medication Guides have FDA-approved PMI, we
propose that current Sec. Sec.  208.1 and 208.3 be relocated to
Sec. Sec.  208.91 and 208.92, subpart C, respectively. Current
Sec. Sec.  208.20, 208.24, and 208.26 would be relocated to proposed
Sec. Sec.  208.94, 208.96, and 208.98, subpart D, respectively. The
definitions in proposed Sec.  208.92 would be revised for clarity and
consistency with definitions in proposed Sec.  208.20; however, the
substantive meaning of the definitions would remain the same.

B. Removal of the Requirements for Patient Package Inserts (Proposed
Sec. Sec.  310.501 and 310.515)

    PPIs for oral contraceptives and estrogen-containing drug products
are required under Sec. Sec.  310.501 and 310.515, respectively. PPIs
provide detailed information to patients about the benefits and risks
involved with using these prescription drug products and contain
information to help patients use them safely and effectively. We have
determined that once an oral contraceptive or estrogen-containing
prescription drug product has FDA-approved PMI, PPIs would no longer be
necessary for the safe and effective use of these products (see also
discussion in section V.J of this document). FDA would withdraw the
current regulations in Sec. Sec.  310.501 and 310.515 for NDAs, BLAs,
and ANDAs that have FDA-approved PPIs after all such prescription drug
products have FDA-approved PMI.
    We believe it is important that patients continue to receive FDA-
approved patient information for oral contraceptives and estrogen-
containing products during the implementation of PMI. Therefore, we
propose that Sec. Sec.  310.501 and 310.515 would remain in effect as
described in section V.J of this document.
    Under this proposed rule, when finalized, we would no longer accept
voluntary submissions of PPI for prescription drug products.
Prescription drug products used, dispensed, or administered on an
outpatient basis would be required to have FDA-approved PMI, with the
exception of excluded products identified in proposed Sec.  208.10(d)).

C. Scope and Purpose (Proposed Sec. Sec.  208.10 and 606.123)

    Currently, Medication Guides are required only for prescription
drug products that FDA determines pose a serious and significant public
health concern requiring distribution of FDA-approved patient
information. In contrast, when finalized, this proposed rule would
require the creation and distribution of a new type of Medication
Guide, called PMI, for any prescription drug product that is approved
or submitted for approval under section 505 of the FD&C Act that is
used, dispensed, or administered on an outpatient basis with the
exception of excluded entities identified in proposed Sec.  208.10(d).
For the purposes of this proposed rule, a drug product also includes a
biological product licensed under section 351(a) or (k) of the PHS Act.
PMI would improve public health by providing patients with clear,
concise, accessible, and useful written prescription drug product
information delivered in a consistent and easily understood format to
help patients use their prescription drug products safely and
effectively.
    PMI content would be based on information required in the PI as
described in Sec. Sec.  201.56, 201.57, and 201.80 (21 CFR 201.56,
201.57, and 201.80), and/or the circular of information described in
Sec.  606.122 (21 CFR 606.122). In cases where marketing of an
application has been discontinued but approval of the application has
not been withdrawn under 21 CFR 314.150 or section 505(e) of the FD&C
Act, the applicant must continue to comply with all applicable
statutory and regulatory requirements, including the requirements set
forth in this proposed rule, if finalized.
    Authorized dispensers would be required to provide patients with
FDA-approved PMI, when such PMI exists, each time a prescription drug
product is used, dispensed, or administered on an outpatient basis.
This would ensure that patients receive the information to help them
use their prescription drug products safely and effectively.
Prescription drug products used, dispensed, or administered on an
outpatient basis are those prescription drug products that are
dispensed outside of an inpatient setting (which include a hospital or
long-term care facility, such as a nursing home or rehabilitation
facility). The most common outpatient settings are retail pharmacies
and hospital ambulatory care pharmacies, where the patient takes the
prescription drug product home and uses it. Outpatient settings also
include those in which the prescription drug product is dispensed to a
healthcare provider who administers it to the patient. This includes,
but is not limited to, clinics, healthcare providers' offices, dialysis
centers, and infusion centers, including those administering blood and
blood component transfusions. In all of these outpatient settings, we
believe that patients should be able to take home important information
about the prescription drug product, such as information about
potential side effects that may occur, when to notify a healthcare
provider, or followup that may be required after receiving a
prescription drug product.
    PMI would not be required for prescription drug products used,
dispensed, or administered by a healthcare provider in an emergency
(for example, an emergency room visit), including a public health
emergency setting, including natural and/or human-made disasters, or an
inpatient setting (for example, a hospital or a nursing home). PMI
would not be required for a product under Emergency Use Authorization,
which may require patient or provider Fact Sheets. In these situations,
a healthcare provider provides the patient or a patient's caregiver
with information about the drug product and the potential side effects
that may occur and also answers questions the patient may have.
Further, in these situations and settings, the healthcare provider is
responsible for monitoring the patient, as necessary, after the
prescription drug product is used, dispensed, or administered. Finally,
Emergency Use Authorizations are not FDA approved applications;
therefore, products authorized under Emergency Use Authorizations would
not require PMI.
    With few anticipated exceptions, we propose to exclude
manufacturers of preventive vaccines that do not have a Medication
Guide from the requirement to create and distribute PMI. The Centers
for Disease Control and Prevention (CDC) manages a comprehensive
preventive vaccine program that includes providing information on
preventive vaccines to patients. We have determined that the current
system for developing and providing vaccine information statements
(VISs) to patients meets the goal of PMI for these products. Under the
National Childhood Vaccine Injury Act of 1986, the Secretary is
required to develop and disseminate vaccine information materials for
distribution by all U.S. healthcare providers (see section 300aa-26 of
the National Childhood Vaccine Injury Act of 1986 (42 U.S.C. 300aa-1 to
300aa-34)). Healthcare providers must distribute the information to
patients (or the parent or legal representative of a child) who receive
vaccines under the National Vaccine Injury Compensation Program of 1986
(NVICP) (Pub. L. 99-660). Development and revision of VISs have been
delegated to CDC. CDC also develops VISs for vaccines that are not
covered by NVICP. VISs are available on the internet at https://www.cdc.gov/vaccines/hcp/vis/current-vis.html.

D. Definitions (Proposed Sec.  208.20)

    This proposed rule would provide definitions for the purposes of
this rule for the terms administered, applicant, authorized dispenser,
dispensed, drug name, drug product, licensed healthcare provider,
manufacturer, patient, Patient Medication Information, revision date,
and used. This proposed rule would also revise definitions from current
part 208 for clarity and consistency;

however, the substantive meaning of those definitions would remain the
same.
    Specifically, this proposed rule would define authorized dispenser
as an individual(s) or entity who is licensed, registered, or otherwise
permitted by the jurisdiction in which the individual(s) or entity
practices to provide prescription drug products in the course of
professional practice. We believe that, in most instances, the
authorized dispenser will be a pharmacist. However, an authorized
dispenser may also include physicians, nurses, or other licensed
healthcare providers legally permitted under State law to provide
prescription drug products to patients.
    This proposed rule would also define Patient Medication Information
as a type of Medication Guide--a form of patient labeling--which meets
the requirements set forth in this proposed rule. PMI would be labeling
under section 201(m) of the FD&C Act.

E. Requirements for the Format of Patient Medication Information
(Proposed Sec.  208.30)

    The proposed rule would establish the general format requirements
for PMI (see proposed Sec.  208.30). The proposed rule would require
PMI to have a uniform format that will make it easier for patients to
read, understand, and use PMI. The formatting of written patient
prescription drug product information has a large effect on the ease of
understanding and use of the information (Ref. 32). The formatting
requirements are consistent with the guidelines from patient education
experts (Refs. 32 and 33). These formatting requirements are intended
to make it easier for patients to read and comprehend the important
information contained in PMI and help them use their prescription drug
products safely and effectively (Refs. 32 and 33).
    Consistent with current FDA regulations (see Sec.  201.15(c)(1) (21
CFR 201.15(c)(1))), the proposed rule would require that PMI be written
in the English language; provided, however, that in the case of
articles distributed solely in the Commonwealth of Puerto Rico or in a
Territory where the predominant language is one other than English, the
predominant language may be substituted for English (see proposed Sec.
208.30(a)(1)).
    FDA strongly encourages applicants to work with retailers and other
organizations to ensure that PMI is accessible to individuals with
limited English proficiency. To the extent an applicant, retailer, or
other organization receives Federal financial assistance from HHS, they
are required to take reasonable steps to provide meaningful access to
their programs and activities by individuals with limited English
proficiency under Title VI of the Civil Rights Act of 1964 and its
implementing regulations.\2\
---------------------------------------------------------------------------

    \2\ 42 U.S.C. 2000d, et seq.; 45 CFR part 80; see also Section
1557 of the Affordable Care Act, 42 U.S.C. 18116, which provides
similar protections as those under Title VI in health programs and
activities receiving Federal financial assistance.
---------------------------------------------------------------------------

    Currently, translations in languages other than English of written
prescription drug information (including Medication Guides and Patient
Package Inserts) are provided in numerous ways--by drug applicants,
retailers, and other organizations. These organizations create written
translations of medication information, and they also provide live oral
sight translations by an interpreter (for example, via telephone) of
medication information in multiple languages. For example, the American
Society of Health-System Pharmacists provides more than 1,500
monographs covering prescription and nonprescription drugs in both
English and Spanish.\3\ Translations of PMI could similarly be made
available by retailers and other organizations.
---------------------------------------------------------------------------

    \3\ https://www.ashp.org/products-and-services/database-licensing-and-integration/ashp-patient-medication-information.
---------------------------------------------------------------------------

    In accordance with current FDA regulations at Sec.  201.15(c)(1)
and proposed Sec.  208.30(a)(1), when PMI is provided in a language
other than English it must be distributed along with English language
PMI, with the limited exception of articles distributed solely in the
Commonwealth of Puerto Rico or in a Territory where the predominant
language is one other than English (and PMI is provided in such
predominant language).
    FDA acknowledges the benefits of having translated prescription
drug information for individuals with limited English proficiency. This
proposed rule provides flexibility to allow for multiple approaches to
provide access to PMI for individuals with limited English proficiency
through a variety of different mechanisms. FDA seeks further
information regarding what actions applicants and other organizations
might take to make PMI accessible to individuals with limited English
proficiency.
    The proposed rule would require that PMI be provided to a patient
in paper format and be legible and printed on a single side of an 8\1/
2\ by 11-inch sheet of paper and not exceed one page (see proposed
Sec.  208.30(a)(2)). Studies show that patients prefer a simplified
one-page format for written patient information and are more likely to
read information that is short and concise (Refs. 34 and 35). Studies
also show that patients understand more information when it is
contained in a shorter document and are better able to understand
information when it is presented in a simplified one-page format (Refs.
34, 36, and 37). In contrast, patients are often overwhelmed by and
have difficulty understanding lengthy patient information materials
(Refs. 35 and 38).
    We have determined that written patient prescription drug product
information can be appropriately provided in a single page. For
example, FDA has successfully created one-page Medication Guides for
extended-release and long-acting opioid analgesics (Ref. 39) and
immediate-release opioid analgesics. As stated previously, this one-
page format is also supported by feedback obtained from stakeholder
input, advisory committees, workshops, and public hearings.
    As discussed in section V.K of this document, proposed Sec.  208.90
would allow for a waiver from one or more of the proposed requirements
for PMI if we determine that any requirement is inapplicable,
unnecessary, impracticable, or contrary to patients' best interests for
a particular prescription drug product. We envision rarely granting a
waiver to the one-page format requirement. FDA may consider an
applicant's request for an extension from the specified implementation
date to fully comply with the PMI requirements. Such requests will be
evaluated on a case-by-case basis. Under this proposed rule, PMI would
be stored electronically in a central repository managed by FDA (as
discussed in section VI of this document). The proposed rule would
require that PMI provided in electronic format be printable to ensure
that all patients have access to the written patient prescription drug
product information, including patients who do not have access to the
electronic version of PMI (see proposed Sec.  208.30(a)(3)). To
maintain standardization for ease of use by patients, electronic and
printed PMI must be identical and meet the format and content
requirements specified in this proposed rule.
    The proposed rule would require that all headings and subheadings
(as required in proposed Sec.  208.40(b) and (c)(2)) and that the title
``PATIENT MEDICATION INFORMATION'' (as required in proposed Sec.
208.40(a)(5)) appear in bold type (see proposed Sec.  208.30(a)(4)).
The proposed rule would also require bold type for the drug name(s),
phonetic spelling of the drug name(s), dosage form(s), and

route(s) of administration listed at the top of the page on the line
immediately below the title ``PATIENT MEDICATION INFORMATION'' (see
proposed Sec.  208.30(a)(4)). Bold headings would introduce each
section and draw distinction between sections. We believe that the use
of bold type would emphasize PMI headings and help patients scan for
information contained in PMI (Ref. 40). Only PMI headings, subheadings,
the title ``PATIENT MEDICATION INFORMATION,'' and the drug name(s),
phonetic spelling of the drug name(s), dosage form(s), and route(s) of
administration at the top of the page must appear in bold type. The
drug name(s) used in other parts of PMI must not appear in bold. In
general, bold text should not be used for any other information in the
document.
    The proposed rule would require the title ``PATIENT MEDICATION
INFORMATION'' to appear in all uppercase letters. Using all uppercase
letters for the title will alert patients to the purpose of the
document. The proprietary name (if any) of the prescription drug
product may be presented in all uppercase letters. Generally, no other
words may be presented in all uppercase letters with the exception of
commonly used acronyms (for example, GERD in place of gastroesophageal
reflux disease) (see proposed Sec.  208.30(a)(5)). However, when an
acronym is used, it should be defined the first time it appears in PMI
(for example, gastroesophageal reflux disease (GERD)). Other
information should be composed of both uppercase and lowercase type or
just lowercase type. The use of text set in all uppercase type is more
difficult to read (Ref. 41). The proprietary name of the prescription
drug product, if used, may be written in all uppercase type, which will
prominently display the proprietary name so patients can easily
identify and associate PMI with the correct prescription drug product.
For drug products without a proprietary name, the nonproprietary name
should be written in title case letters.
    The proposed rule would require that the title ``PATIENT MEDICATION
INFORMATION'' (as described above) and the drug name(s), phonetic
spelling of the drug name(s), dosage form(s), and route(s) of
administration beginning immediately below the title must appear
centered at the top of the page (see proposed Sec.  208.30(a)(6)). This
will ensure that the title and purpose of the document are easy for
patients to find.
    The proposed rule would require that PMI be presented in a minimum
of 10-point font with 1 point equal to 0.0138 inches (see proposed
Sec.  208.30(b)(1)). This size type is intended to make it easier for
patients to read the important information contained in PMI (Ref. 33).
This proposed requirement applies to all sections of PMI except the
name and address of the manufacturer, packer, and/or distributor; the
U.S. license number of the prescription drug product that is a
biological product; the statement ``The content of this Patient
Medication Information has been approved by the U.S. Food and Drug
Administration;'' and the revision date.
    The proposed rule would prohibit PMI from containing any reverse
type (such as white or neutral color type on a darker color
background), lightface, shading, condensed type, or narrow fonts (see
proposed Sec.  208.30(b)(2)). These effects can make reading more
difficult for patients (Ref. 40).
    The proposed rule would prohibit PMI from containing any colors
other than black type to facilitate readability for patients (see
proposed Sec.  208.30(b)(3)). Black type on a white background
maximizes contrast and therefore legibility of words (Ref. 40).
Furthermore, certain colors and combinations of colors do not print
clearly on paper (Ref. 41). This proposed requirement also considers
feedback from stakeholders regarding pharmacies' printing limitations
(for example, certain pharmacies are limited to printing in black and
white).
    Because PMI is a one-page document, the proposed rule would
prohibit PMI from containing a page number (see proposed Sec.
208.30(b)(4)). This would prevent patient confusion if the applicant
submits PMI to FDA with other documents that may include page numbers.
    We are proposing that pictograms and icons not be used in PMI for
several reasons. For example, research indicates that different
cultures may have different interpretation of pictograms and icons
(Refs. 40 and 42). Pharmacies' printing limitations were also taken
into consideration.

F. Requirements for the Content of Patient Medication Information
(Proposed Sec.  208.40)

    We propose that PMI would highlight the most important information
that patients need to know to help them use their prescription drug
products safely and effectively. PMI is not intended to be a substitute
for the PI described in Sec. Sec.  201.56(d), 201.57, and 201.80 or the
circular of information described in Sec.  606.122 (while PMI would
highlight the most important information, it is not intended to and
would not include all the essential scientific information needed for
the safe and effective use of the drug) or to be a replacement for
patient counseling by a healthcare provider. PMI, while meant to help
patients safely and effectively use prescription drug products, would
not be considered to be adequate directions for use as described in 21
CFR 201.5. Rather, PMI would be provided to patients with prescription
drug products that are used, dispensed, or administered on an
outpatient basis to help them safely and effectively use the
prescription drug product.
    In determining specific headings and information to be included in
PMI, we researched scientific literature, conducted studies examining
several PMI prototypes, held public workshops and hearings, and
obtained stakeholder input on what information patients need in order
to use their prescription drug products safely and effectively. The
proposed content of PMI would highlight essential information found in
the PI that the patient needs to know about the prescription drug
product and would include basic directions on how to use the
prescription drug product. Some information included in the drug
product's PI may not be regularly included in PMI. Detailed
instructions for use that cannot be adequately conveyed in PMI would
continue to be approved by FDA in other labeling (for example, in the
PI or in the Instructions for Use for the drug product).
    The proposed rule would require PMI to be written in terms that are
likely to be read and understood by most individuals (see proposed
Sec.  208.40(a)(1)). The use of overly technical language may deter
patients from reading and understanding the important information
contained in PMI. Based on the National Adult Literacy Survey, nearly
half of the U.S. adult population is functioning at or below an eighth-
grade reading level (Ref. 43). Other studies have also found that the
average American adult reads at an eighth-grade or ninth-grade reading
level (Ref. 44). The Keystone Action Plan advocates that prescription
drug product information intended for patients be written at a sixth-
grade through eighth-grade reading level (Ref. 9).
    We believe that the approaches taken will help to improve
accessibility of medication information for all patients, including
patients with low health literacy, who may be dispensed a prescription
drug product in an outpatient setting. FDA seeks comment on whether the
proposed format and content requirements support the accessibility of
patient medication information for all intended users,

including patients with low health literacy.
    FDA is aware that consumer testing, such as the testing of
readability and comprehension, may be used to inform the development of
written patient materials such as PMI and may improve the usability of
these materials. We are not proposing to require consumer testing for
PMI at this time, because FDA lacks empirical evidence demonstrating
that consumer-tested PMI directly results in benefits to patients over
non-consumer-tested PMI. However, FDA recognizes the potential value in
consumer testing and is aware that some stakeholders are engaged in
consumer testing of written patient materials for their drug products.
We note that FDA carefully considered the question of whether consumer
testing of PMI would be an appropriate requirement for this regulation,
and we understand that some stakeholders advocate for the requirement
of such testing to increase the potential usefulness of the PMI. In
response to this proposal, we invite comment on this question, and in
particular, the submission of empirical evidence supporting the value
of such consumer testing. We also ask those in the public who would
oppose a requirement of consumer testing to submit comments explaining
their position on this issue. FDA will consider this option as a
requirement in the final rule if compelling evidence concerning the
value of consumer testing is submitted.
    Rather than require consumer testing, FDA is considering the
establishment of a publicly available database, potentially through a
public-private partnership, of consumer-tested phrases and terms that
would assist in the development of written patient materials, including
PMI. FDA expects to implement the use of common terms and consistent
descriptions as part of the patient labeling review process, when
appropriate, across drug products to facilitate consumers'
understanding of these phrases and terms across written materials,
including PMI. FDA seeks comments on the development and maintenance of
such a database.
    The proposed rule would require that PMI must not be promotional in
tone (see proposed Sec.  208.40(a)(2)). As noted above, the primary
purpose of PMI is to highlight the most important information that
patients need to know to help them use their prescription drug products
safely and effectively. This approach of conveying important
information in an objective manner is consistent with the existing
regulatory provision pertaining to the FDA-approved PI that states that
a prescription drug product's PI must not be promotional in tone (Sec.
201.56(a)(2)). This proposed rule is not intended to address the use of
other avenues, outside of PMI, to communicate to patients, including to
provide promotional messaging.
    The proposed rule would also require PMI to be scientifically
accurate, not to be false or misleading in any particular, and to be
based on and consistent with the prescription drug product's PI, as
described in Sec. Sec.  201.56, 201.57, and/or 201.80 or in the
circular of information described in Sec.  606.122 (see Sec. Sec.
202.1 and 201.100(d)(1) and section 505 of the FD&C Act (see proposed
Sec.  208.40(a)(3)). The proposed rule would require that PMI for NDAs
and BLAs be updated when new information becomes available that would
cause PMI to become inaccurate, false, or misleading in accordance with
Sec.  314.70 (21 CFR 314.70) and Sec.  601.12 (21 CFR 601.12) (see
proposed Sec.  208.40(a)(3)). This provision would require that PMI for
ANDAs be updated when the PMI for the RLD is updated or the FDA-created
template is updated (for ANDAs with withdrawn RLDs).
    The proposed rule would require that the title ``PATIENT MEDICATION
INFORMATION'' appear at the top of the page (see proposed Sec.
208.40(a)(4)). This title would inform readers that the document has
prescription drug product information intended for patients.
    The proposed rule would require that the drug name(s) be listed at
the top of the page on the line below the title, ``PATIENT MEDICATION
INFORMATION'' (see proposed Sec.  208.40(a)(5)). We propose that the
phonetic spelling(s) of the proprietary name (if any) and the
established name (or the proper name) must also be included to help the
patient pronounce the name(s) of the prescription drug product. If the
drug name is used again throughout the PMI, only the proprietary name
(if any) would be used. Those prescription drug products not having a
proprietary name would use the established name or the proper name.
    The proposed rule would require the statement ``The content of this
Patient Medication Information has been approved by the U.S. Food and
Drug Administration'' to appear at the bottom of the page, followed by
the revision date (see proposed Sec.  208.40(a)(6)). The revision date
would be the initial date the first PMI was approved or the date on
which any changes have been made to PMI, whichever applies and is
later, and would appear in numeric format (for example, Revised: 10/
2025). This would alert patients to any revision to the PMI since the
patient last received the information.
    The proposed rule would require that the name and place of business
of the manufacturer, packer, or distributor of the prescription drug
product that is not a biological product appear in the PMI below the
statement required in Sec.  208.40(a)(6) and the revision date (see
proposed Sec.  208.40(a)(7)). The proposed rule would require the
licensed manufacturer's name, address, and U.S. license number of the
prescription drug product that is a biological product to appear in the
PMI (the distributor's or marketer's name and address may also be
included) (see proposed Sec.  208.40(a)(7)). The authorized dispenser
may include their name and place of business. While the manufacturer or
distributor information may be available on the original carton or
container for the product or in the prescribing information, patients
generally do not receive the carton or container or the prescribing
information when the prescription drug product is dispensed at a
pharmacy. Thus, including this information on the PMI helps to ensure
the patient receives it.
    The proposed rule would require that any heading, subheading, or
specific information (see proposed Sec.  208.40(b) and (c)) that is
clearly inapplicable to the prescription drug product be omitted from
the PMI (see proposed Sec.  208.40(a)(8)) because such heading or
specific information is not required for the patient to safely or
effectively use the prescription drug product. The omission of any
required heading, subheading, or specific information would be
indicated only in the absence of the required heading, subheading, or
specific information in the PMI.
    The proposed rule would require specific headings in the following
order: ``[Insert drug name] is,'' ``Important Safety Information,''
``Common Side Effects,'' and ``Directions for Use'' (see proposed Sec.
208.40(b)). The use of headings helps to highlight specific information
and helps patients locate information in the document and better
understand it (Refs. 45 and 46). The proposed rule would require the
headings to appear in a specified order and would ensure consistency in
formatting for all PMI. This proposed requirement would help patients
become familiar with both the type and location of relevant information
in PMI. This will help them to quickly and accurately locate
information about how to safely and effectively use the prescription
drug product (Ref. 47).
    The proposed rule would require specific information to be included
under each required heading (see

proposed Sec.  208.40(c)). We propose that the information in each
section must be concise and based on and consistent with the
prescription drug product's PI.
    Under the heading, ``[Insert Drug Name] is,'' the proposed rule
would require a concise summary of the approved outpatient indications
and uses of the prescription drug product listed in the prescription
drug product's PI (see proposed Sec.  208.40(c)(1)). The information in
this section would be consistent with the information found in the
INDICATIONS AND USAGE section of the PI. FDA is aware that certain
prescription drug products have a large number of approved indications
and uses. Therefore, this section of PMI is not meant to list all
approved indications and uses verbatim as described in the PI, but
rather to summarize the approved outpatient indications and uses in
language that is most useful for patients.
    Under the heading ``Important Safety Information,'' the proposed
rule would require specific subheadings in the following order:
``Warnings,'' ``Do not take,'' Serious side effects,'' and ``Tell your
health care provider before taking'' (proposed Sec.  208.40(c)(2)).
    The proposed rule would require the subheading ``Warnings'' to be
followed by a concise summary of serious warnings, including those that
may lead to death or serious injury from the use of the prescription
drug product (see proposed Sec.  208.40(c)(2)(i)). The ``Warnings''
subheading must include a summary of the information found in the
prescription drug product's boxed warning, if any, that is most
relevant for patients to know for the safe and effective use of the
prescription drug product.
    The proposed rule would require the subheading ``Do not take'' to
be followed by a statement of the circumstances (if any) in which the
prescription drug product should not be used because the risk of use
outweighs any benefit (see proposed Sec.  208.40(c)(2)(ii)). The
information in the ``Do not take'' subheading would be consistent with
the most relevant information to patients found in the
``CONTRAINDICATIONS'' section of the PI. Because PMI is intended to aid
patients on how to safely and effectively use their prescription drug
product after it has been prescribed, patients need to be aware of
contraindications (if any) associated with the prescription drug
product.
    The proposed rule would require the subheading ``Serious side
effects'' followed by: (1) a listing of the clinically significant
adverse reactions or risks associated with the use of the prescription
drug product that are most relevant to the patient and (2) information
on when to call a healthcare provider or when and how to obtain
emergency help if certain clinically significant adverse reactions
occur (see proposed Sec.  208.40(c)(2)(iii)). The information under
this subheading must be consistent with either: (1) the most relevant
information to patients found in the ``WARNINGS AND PRECAUTIONS''
section for drug labeling that must meet the format and content
requirements of Sec. Sec.  201.56(d) and 201.57 or (2) the ``WARNINGS''
section and the ``PRECAUTIONS'' section for drug labeling that must
meet the format and content requirements of Sec.  201.80. Side effects
that may not meet the preceding criteria may still be considered
serious side effects when, based on appropriate medical judgment, they
may jeopardize the patient and may require medical or surgical
intervention to prevent one of the outcomes previously listed (see FDA
Guidance for Industry, ``Adverse Reactions Section of Labeling for
Human Prescription Drug and Biological Products--Content and Format,''
January 2006 (available at https://www.fda.gov/media/72139/download).)
    The proposed rule would require the subheading ``Tell your health
care provider before taking'' followed by a statement that identifies
specific populations and conditions that may have clinically important
differences in response to the prescription drug product or may change
the recommendation for use of the prescription drug product (for
example, pregnancy or lactation) (see proposed Sec.  208.40(c)(2)(iv)).
    Under the heading ``Common Side Effects,'' the proposed rule would
require a statement of frequently occurring adverse reactions from the
use of the prescription drug product (see proposed Sec.  208.40(c)(3)).
The listed common side effects would have to be consistent with the
``ADVERSE REACTIONS section'' of the prescription drug product's PI.
Under this heading, the most common adverse reactions that would be
listed are those that are likely to be caused by use of the drug
product or that are meaningful to the patient in terms of seriousness
and frequency. We propose that the listed common side effects must
focus on the most clinically relevant and the important adverse
reactions to inform the patient. In determining whether a less common
adverse reaction should be included, consideration may be given to a
combination of factors, which include the seriousness of an adverse
reaction, the likelihood that the reaction could affect patients'
adherence or continuation of therapy, and the importance of identifying
the adverse reaction and treating it at an early stage (see FDA
Guidance for Industry, ``Adverse Reactions Section of Labeling for
Human Prescription Drug and Biological Products--Content and
Format.'').
    The proposed rule would require that the following statement follow
the summary of adverse reactions: ``These are not all the possible side
effects of [Insert Drug Name]. Call your health care provider if you
have side effects that worsen or do not go away. You may also report
side effects to FDA at [insert current FDA telephone number and web
address for voluntary reporting of adverse reactions]'' (see proposed
Sec.  208.40(c)(3)). Including information in PMI about how to report
side effects to FDA is consistent with our efforts to encourage
patients and healthcare providers to report suspected adverse reactions
to FDA.
    Under the heading ``Directions for Use,'' the proposed rule would
require the statement ``Use exactly as prescribed'' to appear first
after the heading to emphasize the importance of taking the
prescription drug product as directed by the healthcare provider (see
proposed Sec.  208.40(c)(4)). We propose that the statement ``Use
exactly as prescribed'' must be followed by a summary of how the
prescription drug product must be administered and the route of
administration. This section of PMI would also contain basic directions
for use and any special instructions on how to administer the drug (for
example, whether it should be taken with food or taken at a period of
time before or after eating certain foods, or what to do if a patient
misses a scheduled dose). If applicable, this section would include a
statement of special handling, storage conditions, and disposal
information. The dosing and administration and the storage, handling,
and disposal information must be consistent with the most relevant
information to patients that is found: (1) in the ``DOSAGE AND
ADMINISTRATION'' section of the PI and (2) in the ``HOW SUPPLIED/
STORAGE AND HANDLING'' section for drug labeling that must meet the
format and content requirements of Sec. Sec.  201.56(d) and 201.57 or
the ``HOW SUPPLIED'' section for drug labeling that must meet the
format and content requirements of Sec.  201.80.
    We intend that detailed instructions for patients' use of drug
products, known as ``Instructions for Use,'' will continue to be
available as a separate document and approved by FDA, where

appropriate, for drug products with complicated administration
instruction (for example, inhalers or injectables). We propose that PMI
would direct patients to the FDA-approved Instructions for Use, when
applicable.

G. Development of Patient Medication Information for New Drug
Applications, Biologics License Applications, and Abbreviated New Drug
Applications (Proposed Sec.  208.50)

    The proposed rule would require the applicant of an NDA or a BLA
for a prescription drug product used, dispensed, or administered on an
outpatient basis to create PMI (see proposed Sec.  208.50(a)). PMI
would be required for NDAs and BLAs pending or submitted on or after
the effective date of the final rule, based on this proposed rule, and
NDAs and BLAs that were approved by FDA before the effective date of
the final rule, pursuant to the implementation schedule described in
section V.J of this document. In certain circumstances, FDA may require
more than one PMI for a prescription drug product, associated with a
single PI, when one PMI cannot adequately convey the safe and effective
use of the drug to patients. This may occur in instances where there
are two or more formulations of a prescription drug product described
in a PI. For example, more than one PMI would be needed where a product
with a single PI has both an injection form and a pill form and the
patient would benefit from separate PMI for the respective forms.
    The proposed rule would require PMI for a prescription drug product
approved or submitted for approval as an ANDA under section 505(j) of
the FD&C Act that refers to a listed drug approved under section 505(c)
of the FD&C Act for which FDA has approved PMI (see proposed Sec.
208.50(b)(1)). The PMI for these ANDAs would be the same as the PMI
approved for the RLD upon which its approval is based except for
changes required: (1) because of differences approved under a
suitability petition (see 505(j)(2)(C) of the FD&C Act and Sec.  314.93
(21 CFR 314.93)) or (2) because the drug product and the reference
listed drug are produced or distributed by different manufacturers (see
section 505(j)(2)(A)(v) of the FD&C Act and Sec.  314.94(a)(8)(iv)).
    The proposed rule would also require PMI for a prescription drug
product approved or submitted for approval as an ANDA under section
505(j) of the FD&C Act that refers to a listed drug approved under
section 505(c) of the FD&C Act for which approval of the RLD has been
voluntarily withdrawn and the approval of the RLD is withdrawn before
the approval of PMI for the RLD (see proposed Sec.  208.50(b)(2)).
However, due to limitations of 505(j) of the FD&C Act and to ensure
that all ANDAs that refer to an RLD have the same PMI, FDA would create
a PMI template for these ANDAs. Except for permissible differences
consistent with Sec.  314.93 and Sec.  314.94(a)(8)(iv), the PMI for
these ANDAs would be the same as the content in the PMI template
created by FDA.
    FDA recognizes that there is a class of ANDAs that was approved
under section 505(c) prior to the 1984 Hatch-Waxman Amendments to the
FD&C Act. These pre-Hatch-Waxman ANDAs could be for products that are
duplicates of a pre-1962 innovator drug product(s) that was subject to
the Drug Efficacy Study Implementation (DESI) review and listed in a
DESI notice, or they could be for similar or related products. These
pre-Hatch-Waxman ANDAs did not rely on a specific listed drug as their
basis of submission, but instead relied on the evidence of
effectiveness that had been provided, reviewed, and accepted during the
DESI process. The safety of these drugs had been determined on the
basis of information included in the innovator new drug application(s)
submitted prior to 1962 and by the subsequent marketing experience with
the drug(s). In some circumstances these ANDAs have been treated
similarly to ANDAs approved under section 505(j) of the FD&C Act in
that they have followed changes in labeling made by the innovator
product that was the subject of the DESI notice they relied on as their
basis of submission. In other cases, some products have been treated
similarly to other products approved under section 505(c) of the FD&C
Act and have labeling that differs from the innovator product that was
the subject of the DESI notice. In many cases, the innovator product(s)
listed in the DESI notices are no longer marketed. FDA currently
expects to address these ANDAs in the final rule in a similar manner as
ANDAs approved under section 505(j) of the FD&C Act by requiring PMI
for drugs covered by these ANDAs that either follows PMI created by an
innovator drug product listed in the DESI notice they relied on as
their basis of submission or, in appropriate circumstances, that
follows a template created by FDA. FDA asks for comments on this
proposal for this class of ANDAs.

H. Submission of Patient Medication Information for New Drug
Applications, Biologics License Applications, and Abbreviated New Drug
Applications (Proposed Sec.  208.60)

    The proposed rule would require NDA or BLA applicants (as described
in this proposed rule) to submit PMI, along with the PI upon which the
PMI is based, to FDA for approval (see proposed Sec.  208.60(a)). For
NDAs and BLAs submitted on or after the effective date of the final
rule based on this proposed rule, PMI would be submitted as part of the
application. For NDAs and BLAs approved before the effective date of
the final rule or pending when the final rule becomes effective, the
applicant would submit PMI to FDA in a prior approval supplement
pursuant to Sec.  314.70(b)(2)(v)(B) and Sec.  601.12 or as an
amendment as applicable. Section V.J of this document further explains
when applicants would submit PMI to FDA for approval.
    The proposed rule would also require ANDA applicants to submit PMI
to FDA for approval after either: (1) PMI for the RLD is approved or
(2) FDA has finalized the PMI template and provides notice of the
template to the applicant, whichever applies (see proposed Sec.
208.60(b)). Applicants of ANDAs submitted on or after the effective
date of the final rule that rely on an RLD with an approved PMI or for
which FDA has created a PMI template would be required to submit PMI to
FDA as a part of the original ANDA. At the time the final rule becomes
effective, applicants of pending ANDAs that reference an RLD for which
there is no PMI will be required to submit an amendment once PMI is
available for the RLD or once FDA has created a PMI template, if this
occurs before the ANDA is approved. Applicants of ANDAs approved before
the effective date of the final rule or before PMI is approved for
their RLD or before FDA makes a template available, as applicable,
would be required to submit a supplement with PMI to FDA, consistent
with Sec.  314.70. Generally, applicants would submit a supplement to
FDA with PMI that is the same as that for the RLD or FDA-created
template except for changes required: (1) because of differences
approved under a suitability petition (see 505(j)(2)(C) of the FD&C Act
and Sec.  314.93) or (2) because the drug product and the reference
listed drug are produced or distributed by different manufacturers (see
section 505(j)(2)(A)(v) of the FD&C Act and Sec.  314.94(a)(8)(iv)).

I. Providing Patient Medication Information to Patients (Proposed Sec.
208.70)

    Proposed Sec.  208.70(a) would require authorized dispensers to
provide FDA-approved PMI to patients (or their agents) every time a
prescription drug product is used, dispensed, or administered on an
outpatient basis when such PMI is available. Providing PMI when the
prescription drug product is used, dispensed, or administered on an
outpatient basis will help remind and reinforce for the patient the
essential information the patient needs to know about the prescription
drug product and the basic directions on how to use the product. This
will also ensure that patients receive any updated information about
their prescription drug product when it is available. It is not
anticipated that PMI would be provided each and every time a
prescription drug is used (for example, every time a patient is
provided with a pill or capsule from a prescription) or administered
(for example, each time a cream is applied), but rather the first time
the prescription is used, dispensed, or administered and each time a
prescription is dispensed (for example, when a prescription is
refilled). Although authorized dispensers would be required to always
have PMI available in paper format, this proposed rule is flexible in
terms of distribution mechanisms. This proposed rule would allow for
electronic distribution (in addition to paper format) and accommodates
for future technological advances in providing PMI to patients.
    Section 510 of the FD&C Act requires all persons engaged in
manufacturing, preparing, issuing, compounding, or processing a drug to
register with FDA and provide us with a list of drug products in
commercial distribution. Under section 510(g)(1) of the FD&C Act,
however, certain pharmacies are exempt from such registration and
listing requirements. The distribution of PMI by a pharmacy does not
limit this exemption. Accordingly, under proposed Sec.  208.70(b), an
authorized dispenser would not be subject to the registration and
listing requirements under section 510 of the FD&C Act solely because
of an action performed by the authorized dispenser to comply with this
proposed rule.

J. Schedule for Implementing the General Requirements for Patient
Medication Information (Proposed Sec.  208.80)

1. Implementation Schedule for Applicants To Submit PMI to FDA for
NDAs, BLAs, or Efficacy Supplements
    FDA is proposing a 5-year implementation schedule for PMI. The
proposed implementation schedule for PMI is summarized in table 1 of
this document.

                    Table 1--Implementation Schedule
------------------------------------------------------------------------
                                               Time by which PMI must be
     NDAs, BLAs, and efficacy supplements           submitted to FDA
------------------------------------------------------------------------
Applications submitted on or after the         Time of submission (part
 effective date of the final rule\1\.           of application).
Applications pending at the time of the        No later than 1 year
 effective date of the final rule.              after the date of
                                                approval of the pending
                                                application.
Applications approved on or before the         No later than 1 year
 effective date and that have a Medication      after the effective date
 Guide required under part 208 or a PPI         of the final rule.
 required under Sec.   310.501 or Sec.
 310.515.
Applications approved from January 1, 2013,    No later than 2 years
 up to and including the effective date of      after the effective date
 the final rule that do not have a Medication   of the final rule.
 Guide required under part 208 or a PPI
 required under Sec.   310.501 or Sec.
 310.515.
Applications approved from January 1, 2008,    No later than 3 years
 up to and including December 31, 2012, that    after the effective date
 do not have a Medication Guide required        of the final rule.
 under part 208 or a PPI required under Sec.
  310.501 or Sec.   310.515.
Applications approved from January 1, 2003,    No later than 4 years
 up to and including December 31, 2007, that    after the effective date
 do not have a Medication Guide required        of the final rule.
 under part 208 or a PPI required under Sec.
  310.501 or Sec.   310.515.
Applications approved on or before December    No later than 5 years
 31, 2002, that do not have a Medication        after the effective date
 Guide required under part 208 or a PPI         of the final rule.
 required under Sec.   310.501 or Sec.
 310.515.
------------------------------------------------------------------------
\1\ Final rule refers to a final rule that may publish based on this
  proposed rule.

    The proposed rule would require a staggered implementation schedule
for applicants to submit PMI to FDA for NDAs, BLAs, and efficacy
supplements (see proposed Sec.  208.80(a)). As indicated in table 1 of
this document, for the purposes of this rule, the time by which
applicants would be required to submit PMI to FDA would primarily be
based on when the NDA, BLA, or efficacy supplement was approved. If an
NDA or a BLA has one or more approved efficacy supplements, the
approval date of the efficacy supplement that triggers the earliest PMI
submission would be used to determine the submission date. We propose
that the final rule based on this proposed rule become effective 6
months after the date of publication in the Federal Register. The
proposed rule would require applicants of NDAs, BLAs, or efficacy
supplements submitted for approval on or after the effective date of
the final rule to include PMI as part of the application submitted to
FDA (see proposed Sec.  208.80(a)(1)). The proposed rule would require
the applicants of NDAs, BLAs, or efficacy supplements pending on the
effective date of the final rule to submit PMI to FDA no later than 1
year after the date of approval of the pending application (see
proposed Sec.  208.80(a)(2)). A pending application's approval would
not be delayed because of the new requirements for PMI.
    The implementation schedule in proposed Sec.  208.80(a)(3) would
require applicants of NDAs and BLAs that have a current FDA-approved
Medication Guide required under part 208 or an FDA-approved PPI
required under Sec. Sec.  310.501 or 310.515 to submit PMI to FDA no
later than 1 year after the effective date of the final rule. Because
these prescription drug products already have approved patient
labeling, FDA believes that 1 year will be sufficient to convert the
existing FDA-approved Medication Guide and FDA-approved required PPIs
to meet the requirements of the final rule. This proposed rule does not
modify or affect the REMS requirements. As previously discussed in
sections V.A and V.B of this document, once a prescription drug product
has FDA-approved PMI, the current requirements for Medication Guides
and PPIs would no longer be applicable to such product.
    Apart from applications that have an existing FDA-approved
Medication Guide or FDA-approved PPI, the implementation schedule
proposed in Sec.  208.80(a)(4) through (a)(7) would generally require
applicants to submit PMI for newer products first, followed by older
products. Newer prescription drug products would generally have PMI at
the earliest possible date because these prescription drug products may
be less familiar to patients. Staggering the PMI implementation is
intended to provide applicants with sufficient time to create PMI and
submit it to FDA and would also allow FDA to best use our resources to
approve PMI efficiently.

2. Implementation Schedule for Applicants To Submit PMI to FDA for
ANDAs
    The labeling for the ANDA drug product must be the same as the
labeling for its RLD at the time of the ANDA's approval, as required in
Sec.  314.94(a)(8)), except for changes required: (1) because of
differences approved under a suitability petition (see 505(j)(2)(C) of
the FD&C Act and Sec.  314.93) or (2) because the drug product and the
reference listed drug are produced or distributed by different
manufacturers (see section 505(j)(2)(A)(v) of the FD&C Act and Sec.
314.94(a)(8)(iv)). Therefore, the proposed rule would require that
applicants for which an ANDA is submitted for approval on or after the
effective date of the final rule must submit PMI to FDA as part of the
application if the PMI for the RLD is approved at the time the ANDA is
submitted, or if FDA has finalized the PMI template and provided notice
of the template to the applicant (see proposed Sec.  208.80(b)(1)(i)).
If PMI for the RLD is not approved or if FDA has not finalized the PMI
template and provided notice of the template to the applicant,
whichever applies, at the time the ANDA is submitted but such PMI is
approved for the RLD or FDA finalizes the template and provides notice
of the template to the applicant before the ANDA is approved, the
applicant for the ANDA must submit PMI in an amendment to the pending
application after the approval of the PMI for the RLD or after FDA
finalizes the PMI template and provides notice of the template to the
applicant, whichever applies (see proposed Sec.  208.80(b)(1)(ii)). If
PMI is approved for the RLD or if FDA finalizes the PMI template and
provides notice of the template to the applicant after the ANDA is