[Federal Register Volume 88, Number 104 (Wednesday, May 31, 2023)]
[Proposed Rules]
[Pages 35694-35728]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2023-11354]



[[Page 35693]]

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  

[[Page 35694]]


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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, 240-402-7500.
     Confidential Submissions--To submit a comment with 
confidential information that you do not wish to be made publicly 
available, submit your comments only as a written/paper submission. You 
should submit two copies total. One copy will include the information 
you claim to be confidential with a heading or cover note that states 
``THIS DOCUMENT CONTAINS CONFIDENTIAL INFORMATION.'' The Agency will 
review this copy, including the claimed confidential information, in 
its consideration of comments. The second copy, which will have the 
claimed confidential information redacted/blacked out, will be 
available for public viewing and posted on https://www.regulations.gov. 
Submit both copies to the Dockets Management Staff. If you do not wish 
your name and contact information to be made publicly available, you 
can provide this information on the cover sheet and not in the body of 
your comments and you must identify this information as 
``confidential.'' Any information marked as ``confidential'' will not 
be disclosed except in accordance with 21 CFR 10.20 and other 
applicable disclosure law. For more information about FDA's posting of 
comments to public dockets, see 80 FR 56469, September 18, 2015, or 
access the information at: https://www.govinfo.gov/content/pkg/FR-2015-09-18/pdf/2015-23389.pdf.
    Docket: For access to the docket to read background documents or 
the electronic and written/paper comments received, go to https://www.regulations.gov and insert the docket number, found in brackets in 
the heading of this document, into the ``Search'' box and follow the 
prompts and/or go to the Dockets Management Staff, 5630 Fishers Lane, 
Rm. 1061, Rockville, MD 20852, 240-402-7500.
    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, 301-796-0151, [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, 240-402-7911.
    With regard to the information collection: Domini Bean, Office of

[[Page 35695]]

Operations, Food and Drug Administration, Three White Flint North, 10A-
12M, 11601 Landsdown St., North Bethesda, MD 20852, 301-796-5733, 
[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

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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\
---------------------------------------------------------------------------

    \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

[[Page 35698]]

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''

[[Page 35699]]

(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

[[Page 35700]]

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

[[Page 35701]]

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

[[Page 35702]]

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

[[Page 35703]]

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.

[[Page 35704]]

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;

[[Page 35705]]

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

[[Page 35706]]

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,

[[Page 35707]]

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

[[Page 35708]]

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

[[Page 35709]]

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)).

[[Page 35710]]

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.

[[Page 35711]]

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 
approved, the applicant must submit a supplement with the PMI 
consistent with Sec.  314.70, 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)(iii)).
    For ANDAs pending on the effective date of the final rule, the 
proposed rule would require applicants to submit an amendment with PMI 
if the PMI for the RLD is approved or if FDA finalizes the PMI template 
and provides notice of the template to the applicant, whichever 
applies, before the ANDA is approved (see proposed Sec.  
208.80(b)(2)(i)). If PMI for the RLD is approved or if FDA finalizes 
the PMI template and provides notice of the template to the applicant 
after the pending ANDA is approved, the ANDA applicant must submit a 
supplement with PMI to FDA consistent with Sec.  314.70, 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)(2)(ii)).
    The proposed rule would require applicants of ANDAs approved on or 
before the effective date of the final rule to submit a supplement with 
a PMI package, consistent with Sec.  314.70.
3. Implementation Schedule for Authorized Dispensers To Provide PMI to 
Patients
    The proposed rule would require authorized dispensers to provide 
FDA-approved PMI, when such PMI is available, beginning 2 years after 
the effective date of a final rule based on this proposed rule (see 
proposed Sec.  208.80(c)). Dispensers should check the FDA labeling 
repository at https://labels.fda.gov on a monthly basis for newly FDA-
approved PMI or revised PMI. It is understood that dispensers may need 
a reasonable amount of time to download PMI after it is published; 
however, it is expected that they will update their systems on a 
monthly basis.
    Although only a small percentage of prescription drug products 
would have approved PMI 2 years after the effective date of the final 
rule, most prescription drug products that previously had Medication 
Guides would have FDA-approved PMI at that point. Once FDA approves PMI 
for a prescription drug product that previously had a Medication Guide, 
dispensers would no longer need to follow the requirements for 
providing the Medication Guide under proposed Sec.  208.96 (see current 
Sec.  208.24).

K. Waivers (Proposed Sec.  208.90)

    The proposed rule would allow for waivers from one or more of the 
proposed requirements for PMI (for example, the format and content of 
PMI and submitting and distributing PMI) if we determine that any 
requirement is inapplicable, unnecessary, impracticable, or contrary to 
patients' best interests for a particular prescription drug product 
(see proposed Sec.  208.90). Waivers could be initiated by FDA or 
requested by a person or entity that is covered by the final rule. 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.
    As an example, FDA proposes that a waiver or extension would be 
considered if FDA determined that complying with the requirements for 
PMI could contribute to a drug shortage or otherwise prevent patient 
access to the drug product.
    As another example, FDA proposes that a waiver or extension would 
be considered if the CDC plans to use its delegated authority to 
develop and issue emergency use instructions for eligible medical 
countermeasures under section 564A(e) of the FD&C Act (21 U.S.C. 
360bbb-3a(e)).
    FDA considers the one-page requirement to be a key feature of PMI. 
We envision rarely granting a waiver to the one-page requirement (see 
proposed Sec.  208.30(a)(2)). However, we may allow PMI to exceed one 
page, if necessary, for the safe and effective use of the prescription 
drug product.
    FDA is seeking comment on possible PMI requirements for which 
waivers could be requested and the criteria that FDA might consider 
when evaluating such requests. Waivers or extensions requested by a 
person or entity covered by the final rule will be reviewed on a case-
by-case basis. Requests for waivers or extensions and the rationale for 
the waiver or extension for PMI requirements for NDAs and BLAs would 
need to be submitted to the director of the FDA division responsible 
for reviewing the marketing application for the drug product. For 
ANDAs, the requests for waivers or extensions and the rationale for the 
waiver or extension would need to be submitted to the Director of the 
Office of Generic Drugs. For biological products, requests for waivers 
or extensions and the rationale for the waiver or extension would be 
submitted to the FDA application division in the office with product 
responsibility.

L. Medication Guides: Patient Medication Information for Blood and 
Blood Components Intended for Transfusion (Proposed Sec.  606.123)

    When finalized, this proposed rule would add proposed Sec.  606.123 
(Medication Guides: Patient Medication Information for blood and blood 
components intended for transfusion). The addition of the proposed 
requirement would ensure that every patient who receives blood or a 
blood component on an outpatient basis receives PMI.
    The proposed rule would require establishments that collect blood 
and blood components for transfusion to create PMI, as described in 
proposed part 208, for distribution to the transfusion service (see 
proposed Sec.  606.123(a)). The proposed rule would

[[Page 35712]]

require licensed blood establishments to submit PMI to FDA for 
approval.
    The proposed rule would require transfusion services, as an 
authorized dispenser, to provide PMI to each patient (or the patient's 
agent) when blood or blood components are administered on an outpatient 
basis when such PMI is available (see proposed Sec.  606.123(b)). 
Although the transfusion service must always have PMI available in 
paper format, the proposed rule is flexible in terms of distribution 
mechanisms. This proposed rule would allow for electronic distribution 
upon request and accommodates future technological advances in 
providing PMI to patients.
    The proposed rule would allow for waivers from one or more of the 
proposed requirements for PMI (for example, the format and content of 
PMI, submitting, and distributing PMI) if we determine that any 
requirement is inapplicable, unnecessary, impracticable, or contrary to 
patients' best interests (see proposed Sec.  606.123(c)). Waivers could 
be initiated by FDA or requested by a blood collection establishment or 
transfusion service. Requests for waivers or extensions and the 
rationale for the waiver or extension must be submitted to the FDA 
application division in the office with product responsibility. FDA is 
seeking comment on possible PMI requirements for which waivers would be 
requested and the nature of such requests.
    In contrast to other prescription drug products, blood and blood 
components intended for transfusion are subject to the labeling 
requirements under Sec. Sec.  606.121 and 606.122, including the 
requirement that a circular of information for prescribers be made 
available for distribution. We currently recognize a circular of 
information prepared jointly by the AABB (formerly known as the 
American Association of Blood Banks), the American Red Cross, America's 
Blood Centers, and the Armed Services Blood Program as acceptable.
    We specifically invite public comments on the following topics with 
respect to PMI for blood and blood components:
    1. Informational materials that are currently available to patients 
who receive blood or blood components for transfusion on an outpatient 
basis, including the adequacy of such information.
    2. The difference in the proposed requirements for applicants that 
FDA should consider in finalizing the rule (i.e., the requirement to 
submit PMI to FDA for approval).
    3. The feasibility of industry jointly developing PMI documents for 
blood and blood components intended for transfusion on an outpatient 
basis and the timeframe needed to develop the documents.
    4. The electronic storage of PMI for blood and blood components on 
the FDA website https://labels.fda.gov.
    We also request public comments on the feasibility of blood 
transfusion services, as the authorized dispenser of blood and blood 
components, providing PMI to patients (or patients' agents) who are 
administered blood or blood components on an outpatient basis.
    At this time, we are not proposing an implementation schedule for 
blood collection establishments to develop PMI and for applicants to 
submit it to FDA for approval. We propose that the final rule may 
include staggered implementation schedules for blood collection 
establishments and transfusion services because of the need to explore 
the feasibility of industry jointly developing PMI documents.

VI. Electronic Repository for Patient Medication Information

    PMI for prescription drug products would be stored electronically 
in the FDA labeling repository at https://labels.fda.gov that currently 
holds PI, FDA-approved patient labeling, and carton and container 
labeling submitted to us under current requirements, such as labeling, 
listing information, and annual reports. PMI for blood and blood 
components will either be stored electronically in the FDA labeling 
repository (https://labels.fda.gov) or a link will be provided at 
https://labels.fda.gov to the site where they are stored 
electronically. The FDA labeling repository is searchable by 
proprietary name (if any), active ingredient, company name, National 
Drug Code number, application number or regulatory citation, and 
proprietary name and company. The labeling found in the repository will 
be compliant with section 508 of The Rehabilitation Act of 1973 
requirements, which can help to provide broader access to patients.
    The purpose of the electronic repository would be to provide a 
single online electronic data source that allows easy open access to 
PMI. Maintaining PMI in an electronic format would allow patients, 
healthcare providers, and pharmacies open access to up-to-date PMI.

VII. Proposed Effective Date

    We propose that a final rule based on this proposed rule become 
effective 6 months after the date the final rule publishes in the 
Federal Register. Given the number of prescription drug products that 
will be impacted by this proposed rule, the constraints on our 
resources, and the need to provide applicants with sufficient time to 
create PMI and submit it to FDA, we understand that 6 months is not 
likely to be sufficient time to fully implement this rule. Thus, we are 
proposing to follow the implementation plan set out in section V.J of 
this document.

VIII. Preliminary Economic Analysis of Impacts

    We have examined the impacts of the proposed rule under Executive 
Order 12866, Executive Order 13563, the Regulatory Flexibility Act (5 
U.S.C. 601-612), and the Unfunded Mandates Reform Act of 1995 (Pub. L. 
104-4). Executive Orders 12866 and 13563 direct us to assess all costs 
and benefits of available regulatory alternatives and, when regulation 
is necessary, to select regulatory approaches that maximize net 
benefits (including potential economic, environmental, public health 
and safety, and other advantages; distributive impacts; and equity). 
The Office of Information and Regulatory Affairs has determined that 
this proposed rule is a significant regulatory action as defined by 
Executive Order 12866, section 3(f)(1).
    The Regulatory Flexibility Act requires us to analyze regulatory 
options that would minimize any significant impact of a rule on small 
entities. Because we find the cost of the proposed rule to be a 
substantial percentage of sales for small businesses, we find that the 
proposed rule will have a significant economic impact on a substantial 
number of small entities.
    The Unfunded Mandates Reform Act of 1995 (section 202(a)) requires 
us to prepare a written statement, which includes an assessment of 
anticipated costs and benefits, before proposing ``any rule that 
includes any Federal mandate that may result in the expenditure by 
State, local, and tribal governments, in the aggregate, or by the 
private sector, of $100,000,000 or more (adjusted annually for 
inflation) in any one year.'' The current threshold after adjustment 
for inflation is $177 million, using the most current (2022) Implicit 
Price Deflator for the Gross Domestic Product. This proposed rule would 
not result in an expenditure in any year that meets or exceeds this 
amount.

A. Summary of Costs and Benefits

    This proposed rule would require that human prescription drug 
products used, dispensed, or administered on an outpatient basis, 
including blood and blood components transfused in an

[[Page 35713]]

outpatient setting, be accompanied by a one-page product information 
document, or Medication Guide, known as Patient Medication Information 
(PMI). Manufacturers of these products would be required to create PMI 
according to standardized content and format requirements. PMI would be 
reviewed and approved by FDA and stored in an online, central 
repository accessible to the public. Firms would incur costs to develop 
PMI. FDA would incur costs to review PMI as well as to establish and 
maintain the online database. For a small subset of drug products, FDA 
would also incur costs to develop a template for PMI. Dispensers may 
face additional costs to print and distribute PMI. Firms that currently 
supply Consumer Medication Information (CMI) to pharmacies may also 
incur costs associated with switching from CMI to PMI. PMI would 
provide the public with FDA-approved labeling that is created 
specifically for patients. 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.
    In our primary analysis, we assume that all products subject to the 
rule would stay on the market. However, we observe that the costs of 
creating, updating, or submitting PMI could exceed the profits for 
certain low-revenue drug products. Some of these products would be 
eligible for a waiver or extension of the requirements of PMI, for 
example, if complying with the requirements could contribute to a drug 
shortage or otherwise impede patient access. For those products not 
eligible for a waiver or extension, firms may choose to discontinue 
marketing the drugs, which would lead to additional social costs under 
the proposed rule. We perform additional analyses to better understand 
how the costs and benefits of the rule would be affected by waivers and 
extensions or discontinuations of drug products.
    The costs and benefits of the proposed rule are summarized in table 
2. This table shows the estimated average annualized net costs of this 
rule, using both 7 and 3 percent annual discount rates over a 10-year 
evaluation period. We estimate that the 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, at a 3 percent discount rate and from $89.0 
to $263.6 million, with a primary estimate of $162.6 million, at 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.
    Table 2 also shows the estimated annualized benefits and other non-
quantified benefits. The monetized benefit of this rule would result 
from decreased search costs for information pertaining to drug, blood, 
and blood component products received in outpatient settings. 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. In addition to these 
monetized benefits, patients may experience a reduction in risk 
associated with drug, blood, and blood component products if PMI leads 
them to make better, more informed healthcare decisions.

              Table 2--Summary of Benefits, Costs, and Distributional Effects of the Proposed Rule
----------------------------------------------------------------------------------------------------------------
                                                                                 Units
                                                                 ------------------------------------
          Category              Primary       Low        High                               Period       Notes
                               estimate    estimate    estimate      Year      Discount     covered
                                                                    dollars    rate (%)     (years)
----------------------------------------------------------------------------------------------------------------
Benefits:
    Annualized Monetized $m/      $180.5       $14.4      $486.8        2020           7          10
     year...................       188.0        14.9       507.9        2020           3          10
    Annualized Quantified...  ..........  ..........  ..........  ..........           7  ..........
                              ..........  ..........  ..........  ..........           3  ..........
                             -----------------------------------------------------------------------------------
    Qualitative.............  Risk reduction from improved access to information.
----------------------------------------------------------------------------------------------------------------
Costs:
    Annualized Monetized $m/        23.2        12.7        37.5        2020           7          10
     year...................        22.6        12.3        36.6        2020           3          10
    Annualized Quantified...  ..........  ..........  ..........  ..........           7  ..........
                              ..........  ..........  ..........  ..........           3  ..........
                             -----------------------------------------------------------------------------------
    Qualitative.............
----------------------------------------------------------------------------------------------------------------
Transfers:
    Federal Annualized        ..........  ..........  ..........  ..........           7  ..........
     Monetized $m/year......  ..........  ..........  ..........  ..........           3  ..........
                             -----------------------------------------------------------------------------------
    From/To.................  From:
                              To:
                             -----------------------------------------------------------------------------------
    Other Annualized          ..........  ..........  ..........  ..........           7  ..........
     Monetized $m/year......  ..........  ..........  ..........  ..........           3  ..........
                             -----------------------------------------------------------------------------------
    From/To.................  From:
                              To:
----------------------------------------------------------------------------------------------------------------
Effects:
    State, Local or Tribal Government: No effect................................................................
    Small Business: Potential for significant impact on the smallest firms......................................

[[Page 35714]]

 
    Wages: No effect............................................................................................
    Growth: No effect...........................................................................................
----------------------------------------------------------------------------------------------------------------

    In calculating the costs discussed above, we have netted out the 
cost savings that would stem from this proposed rule. PMI would replace 
the current Medication Guides and Patient Package Inserts; therefore, 
manufacturers would not need to create or submit updates to their 
Medication Guides and Patient Package Inserts, which would result in 
cost savings to those manufacturers.

B. Summary of Regulatory Flexibility Analysis

    To determine the impact of the proposed rule on small entities that 
manufacture reference drug products, we compare the cost of the rule to 
the total U.S. sales, as reported by Dun and Bradstreet, of the small 
entities. For all such firms with 1,000 or fewer employees, we estimate 
the average cost of PMI to range between 0.2 and 1.0 percent of sales. 
The largest impact would be felt by the smallest firms; for firms with 
one to five employees, we estimate that the cost of PMI would range 
between 1.4 and 7.1 percent of sales. To determine the impact of the 
proposed rule on small entities that manufacture non-reference drug 
products, we estimate the average annualized cost of PMI and compare 
that to the firms' estimated receipts by firm size. For firms that 
manufacture non-reference products with 499 or fewer employees, we 
estimate the average cost of PMI to range between 0.02 and 0.05 percent 
of receipts. The largest impact would again be felt by the smallest 
firms; for such firms with 1 to 19 employees, we estimate the average 
cost of PMI would range between 0.04 and 0.10 percent of receipts. To 
determine the impact of the proposed rule on small entities that 
manufacture blood and blood component products for transfusion in an 
outpatient setting, we estimate the average annualized cost of PMI and 
compare that to the sales data for U.S. firms obtained from Dun and 
Bradstreet. We estimate that the annualized cost of PMI would represent 
less than one tenth of a percent of annual sales under any cost or 
discounting scenario for these firms. Given that we find the cost of 
the proposed rule to be a substantial percentage of sales for small 
businesses that manufacture drug products, the Agency concludes that 
this rule, if finalized, would have a significant adverse impact on a 
substantial number of small entities.
    We have developed a comprehensive Economic Analysis of Impacts that 
assesses the impacts of the proposed rule. The full preliminary 
analysis of economic impacts is available in the docket for this 
proposed rule (Ref. 48) and at https://www.fda.gov/about-fda/reports/economic-impact-analyses-fda-regulations.

IX. Analysis of Environmental Impact

    We have determined under 21 CFR 25.30(h) and (k) that this action 
is of a type that does not individually or cumulatively have a 
significant effect on the human environment. Therefore, neither an 
environmental assessment nor an environmental impact statement is 
required.

X. Paperwork Reduction Act of 1995

    This proposed rule contains information collection provisions that 
are subject to review by OMB under the Paperwork Reduction Act of 1995 
(44 U.S.C. 3501-3521). A description of these provisions is given in 
the Description section of this document with an estimate of the annual 
reporting and third-party disclosure, including an estimate of the one-
time reporting and one-time third-party disclosure. Included in the 
estimate is the time for reviewing instructions, searching existing 
data sources, gathering and maintaining the data needed, and completing 
and reviewing the collection of information.
    FDA invites comments on these topics: (1) whether the proposed 
collection of information is necessary for the proper performance of 
FDA's functions, including whether the information will have practical 
utility; (2) the accuracy of FDA's estimate of the burden of the 
proposed collection of information, including the validity of the 
methodology and assumptions used; (3) ways to enhance the quality, 
utility, and clarity of the information to be collected; and (4) ways 
to minimize the burden of the collection of information on respondents, 
including through the use of automated collection techniques, when 
appropriate, and other forms of information technology.
    Title: Medication Guides: Patient Medication Information (part 
208)--OMB Control Number 0910-0393--Revision.
    Description: We are proposing to amend our regulations governing 
human prescription drug product labeling. The proposed rule would 
revise part 208 concerning Medication Guides and part 606 for blood and 
blood components intended for transfusion. With certain exceptions, the 
proposed rule would require applicants to create a new type of 
Medication Guide, called PMI, for human prescription drug products (for 
the purposes of this proposed rule, a drug product also includes a 
biological product licensed under section 351(a) and (k) of the PHS 
Act), used, dispensed, or administered on an outpatient basis. Blood 
establishments would also be required to create PMI for blood and blood 
components intended for transfusion administered on an outpatient 
basis. The goal of the proposed rule is to improve public health by 
providing clear, concise, accessible, and useful written prescription 
drug product information available in a consistent and easily 
understood format to help patients use their prescription drug products 
safely and effectively.
    Patients need prescription drug product information that is clear, 
concise, and consumer-friendly. To improve how patients receive 
prescription drug product information, we are proposing to require that 
applicants of human prescription drug products used, dispensed, or 
administered on an outpatient basis and establishments that collect 
blood and blood components transfused in an outpatient setting create 
PMI in a one-page document with standardized format and content. All 
PMI would be based on and consistent with the PI and the labeling 
requirements under Sec. Sec.  201.56, 201.57, 201.80, and 606.122. 
Additionally, PMI in electronic format would need to be printable and 
identical to PMI in paper format.
    Applicants of NDAs and BLAs would be required to create PMI and 
submit it

[[Page 35715]]

to FDA for approval. While all blood establishments would be required 
to create PMI, only licensed establishments would be required to submit 
PMI to FDA. The proposed rule covers NDAs including 505(b)(1) and(2) 
applications and BLAs including interchangeable biosimilars and non-
interchangeable biosimilars. Additional information to help with 
drafting biosimilar labeling is available in the final guidance for 
industry entitled ``Labeling for Biosimilar Products'' (available at 
https://www.fda.gov/media/96894/download). Any specific recommendations 
for labeling for interchangeable products will be provided in future 
guidance. We invite comments on whether interchangeable products would 
have to have their own PMI or whether they would copy the PMI of the 
reference product to which they would be interchangeable.
    Applicants of ANDAs for a prescription drug product approved or 
submitted for approval that rely on an RLD with an FDA-approved PMI 
would be required to submit a PMI to FDA for approval. 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 or permissible 
differences pursuant to Sec.  314.94(a)(8)(iv).
    In addition, applicants of ANDAs that refer to a listed drug 
approved under section 505(c) of the FD&C Act for which approval has 
been voluntarily withdrawn before the approval of PMI for the RLD would 
be required to submit a PMI. However, because of the 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. 
The PMI for these ANDAs would be the same as the PMI template that FDA 
created except for changes required or permissible differences pursuant 
to Sec.  314.94(a)(8)(iv).
    Description of Respondents: The respondents to this collection of 
information are applicants of NDAs and BLAs; applicants of ANDAs; and 
authorized dispensers of human prescription drug products used, 
dispensed, or administered on an outpatient basis, including authorized 
dispensers of transfusion services that provide blood or blood 
components for administration on an outpatient basis.
    For the purposes of this analysis, we estimated the burden on 
applicants of ANDAs by estimating the number of ANDA products that 
reference an NDA RLD.
    There are five human blood and blood component products intended 
for transfusion that could be administered on an outpatient basis that 
would need PMI: (1) whole blood, (2) red blood cells, (3) platelets, 
(4) plasma, and (5) cryoprecipitate antihemophilic factor. Based on 
past experience with development of information available for 
distribution with blood and blood components for transfusion (for 
example, circular of information), FDA assumes that a single PMI 
document would be developed for each blood or blood component. Thus, 
for the purposes of this analysis, FDA assumes that five PMI documents 
would be created initially for human blood and blood component products 
and considers this as part of the estimate for BLAs.
    We estimate the burden associated with this collection of 
information as follows:

One-Time Burdens

    If the proposed rule is finalized, it will impose a one-time burden 
for respondents with regard to both reporting and third-party 
disclosure. To minimize this burden on respondents, FDA is proposing a 
5-year implementation schedule as shown in table 3 of this document 
that is proposed to be codified at Sec.  208.80.

                                                              Table 3--One-Time Burden \1\
--------------------------------------------------------------------------------------------------------------------------------------------------------
                                               Years in which burden occurs                      Number of
         21 CFR section and activity            after the effective date of      Number of     responses per       Total      Average burden     Total
                                                      the final rule            respondents     respondent       responses     per response      hours
--------------------------------------------------------------------------------------------------------------------------------------------------------
                         One-Time Reporting for Applicants of Existing and Pending NDAs and BLAs To Create and Submit PMI To FDA
--------------------------------------------------------------------------------------------------------------------------------------------------------
PMI for NDAs and BLAs Submitted Under Sec.    Year 1........................           1,669            0.32             529             320     169,280
 Sec.   314.70 and 601.12 (NDAs and BLAs      Year 2........................           1,669            0.32             529             320     169,280
 approved on or before the effective date of  Year 3........................           1,669            0.32             529             320     169,280
 the final rule based on this proposed rule)  Year 4........................           1,669            0.32             529             320     169,280
 (Sec.  Sec.   208.50 and 208.60, and         Year 5........................           1,669            0.32             528             320     168,960
 606.123(a)).
                                                                             ---------------------------------------------------------------------------
    Subtotal................................  ..............................  ..............  ..............  ..............  ..............     846,080
--------------------------------------------------------------------------------------------------------------------------------------------------------
PMI for Pending NDAs and BLAs Submitted       Year 1........................               7               1               7             320       2,240
 Under Sec.  Sec.   314.60 and 601.2 (NDAs
 and BLAs pending on the effective date of
 the final rule based on this proposed rule)
 (Sec.  Sec.   208.50 and 208.60, and
 606.123(a)).
                                                                             ---------------------------------------------------------------------------
    Subtotal................................  ..............................  ..............  ..............  ..............  ..............     849,166
--------------------------------------------------------------------------------------------------------------------------------------------------------
                             One-Time Reporting for Applicants of Existing and Pending ANDAs To Create and Submit PMI to FDA
--------------------------------------------------------------------------------------------------------------------------------------------------------
PMI for ANDAs Submitted Under Sec.   314.97   Year 1........................             840            1.48           1,240              27      33,480
 (ANDAs approved on or before the effective   Year 2........................             840            1.48           1,240              27      33,480
 date of the final rule based on this         Year 3........................             840            1.48           1,240              27      33,480
 proposed rule) (Sec.  Sec.   208.50 and      Year 4........................             840            1.48           1,240              27      33,480
 208.60).                                     Year 5........................             840            1.48           1,240              27      33,480
                                                                             ---------------------------------------------------------------------------
    Subtotal................................  ..............................  ..............  ..............  ..............  ..............     167,400
--------------------------------------------------------------------------------------------------------------------------------------------------------
PMI for Pending ANDAs Submitted Under Sec.    Year 1........................              13            4.54              59              27       1,593
 314.96 (ANDAs pending on the effective date
 of the final rule based on this proposed
 rule) (Sec.  Sec.   208.50 and 208.60).
                                                                             ---------------------------------------------------------------------------
    Subtotal................................  ..............................  ..............  ..............  ..............  ..............     168,993
--------------------------------------------------------------------------------------------------------------------------------------------------------

[[Page 35716]]

 
                               One-Time Reporting for Waivers for Applicants of NDAs, BLAs, and ANDAs Over a 5-Year Period
--------------------------------------------------------------------------------------------------------------------------------------------------------
Requests for Waiver (Sec.  Sec.   208.90 and  Years 1 through 5.............              76               1              76               4         304
 606.123(c)).
--------------------------------------------------------------------------------------------------------------------------------------------------------
                                                             One-Time Third-Party Disclosure
--------------------------------------------------------------------------------------------------------------------------------------------------------
Downloading and Integrating PMI Sec.  Sec.    ..............................          49,279               1          49,279              16     788,464
 208.70 and 606.123(b).
                                                                             ---------------------------------------------------------------------------
    Total...................................  ..............................  ..............  ..............  ..............  ..............   1,806,927
--------------------------------------------------------------------------------------------------------------------------------------------------------
\1\ Numbers have been rounded to the nearest hundredth.

    Applicants of NDAs and BLAs will incur a one-time regulatory burden 
for applications that are approved on or before or are pending on the 
effective date of the final rule based on this proposed rule associated 
with creating PMI and submitting PMI to FDA for approval as required 
under proposed Sec. Sec.  208.50, 208.60, and 606.123(a). We also 
anticipate that applicants of ANDAs will incur a one-time regulatory 
burden associated with creating PMI and submitting PMI to FDA for 
approval as required under proposed Sec. Sec.  208.50 and 208.60 for 
applications that are approved on or before or are pending on the 
effective date of the final rule. This one-time regulatory burden for 
all affected applicants with applications approved on or before the 
effective date would be distributed over a 5-year implementation period 
after the effective date of the final rule based on the proposed rule. 
The implementation schedule is shown in table 3 of this document and is 
proposed to be codified at Sec.  208.80.
    Proposed Sec.  208.80(a) would require an implementation schedule 
for applicants of NDAs and BLAs approved on or before the effective 
date of the final rule (existing drug products) to submit PMI for 
applications on a staggered basis, beginning 1 year after the effective 
date of the final rule. The timeframe by which applicants would be 
required to submit PMI to FDA for approval would primarily be based on 
when the application or the application's efficacy supplement was 
approved. Table 3 of this document provides an estimate of the one-time 
reporting burden for existing drug products associated with creating 
PMI and submitting PMI to FDA in a supplement. Based on information 
available in our establishment and product listing database for drug 
and biological products, we estimate that 1,669 applicants of NDAs and 
BLAs (1,453 NDA applicants + 216 BLA applicants) will be affected by 
this proposed rule. Collectively, these respondents are responsible for 
submitting a labeling supplement with PMI for 2,644 existing drug 
products. The number of existing drug products was estimated based on 
an analysis of data from the Orange Book: Approved Drug Products With 
Therapeutic Equivalence Evaluations (available at https://www.accessdata.fda.gov/scripts/cder/ob/default.cfm) and the Purple 
Book: Lists of Licensed Biological Products With Reference Products 
Exclusivity and Biosimilarity Interchangeability Evaluation (available 
at https://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplications/TherapeuticBiologicApplications/Biosimilars/ucm411418.htm) to determine 
the number of unique products on the market that are used primarily in 
outpatient settings. These applicants would submit a labeling 
supplement with PMI for approximately 528.8 products each year over a 
5-year implementation period (a total of 2,644 products), beginning 1 
year after the effective date of the final rule based on this proposed 
rule and continuing for 5 years (table 3 of this document).
    Additionally, applicants of applications pending at the time the 
final rule becomes effective may need to amend their NDAs and BLAs to 
comply with the PMI requirements in proposed part 208. Based on our 
experience with labeling submissions, we have estimated that 5 percent 
of 134 NDAs and BLAs submitted under Sec. Sec.  314.60 and 601.2 will 
be pending at the time the final rule based on this proposed rule 
becomes effective. Therefore, we assume that approximately seven 
applicants of NDAs and BLAs will submit amendments to their NDA or BLA 
to include PMI for seven pending applications on the effective date of 
the final rule (table 3 of this document).
    Based on our experience with labeling submissions for medication 
guides and PPIs, we estimate that approximately 320 hours, on average, 
would be needed for applicants of NDAs and BLAs to create PMI and 
submit PMI to FDA for approval. This estimate subtotals 849,166 hours 
for applicants of NDAs and BLAs that are approved on or before or are 
pending on the effective date of the final rule (846,080 hours for NDAs 
and BLAs approved on or before the effective date of the final rule + 
2,240 hours for NDAs and BLAs pending on the effective date of the 
final rule) (table 3 of this document).
    Under proposed part 208, applicants of ANDAs approved on or before 
the effective date of the final rule (existing ANDAs) would be required 
to submit PMI to FDA in a supplement after the PMI is approved for the 
RLD product or after the PMI template that FDA created is provided, 
whichever applies. Table 3 of this document provides an estimate of the 
one-time reporting burden associated with existing ANDAs. Based on 
information available in our establishment and product listing database 
for drug and biological products, we estimate that 840 applicants of 
existing ANDAs will be affected by this proposed rule. Collectively, 
these respondents are responsible for submitting a labeling supplement 
with PMI for approximately 6,200 existing ANDAs (estimate based on data 
from the Orange Book from May 2018 of non-RLD ANDAs on the market) over 
a 5-year period, beginning 1 year after the effective date of the final 
rule based on this proposed rule and continuing for 5 years 
(approximately 1,240 per year).
    Additionally, applicants of ANDAs pending at the time the final 
rule becomes effective would be required to submit PMI in an amendment 
after the PMI is approved for the RLD product or after the PMI template 
that FDA created is provided, whichever applies. Table 3

[[Page 35717]]

of this document provides an estimate of the one-time reporting burden 
associated with pending ANDAs. Using our experience with labeling 
submissions, we have estimated that 5 percent of the 1,186 ANDAs will 
be pending when the final rule based on this proposed rule becomes 
effective (59 pending ANDAs). We estimate that approximately 13 
applicants of ANDAs will submit amendments to their ANDA to include PMI 
for 59 pending ANDAs.
    Based on our experience with labeling and submissions, we estimate 
that approximately 27 hours, on average, would be needed for applicants 
of ANDAs to create PMI and submit PMI to FDA for approval. This 
estimate subtotals 168,993 hours for applicants of existing and pending 
ANDAs (167,400 hours for existing ANDAs + 1,593 for pending ANDAs) 
(table 3 of this document).
    In some circumstances, an applicant may request or FDA may initiate 
a waiver under proposed Sec.  208.90 or proposed Sec.  606.123(c) of a 
PMI requirement, such as the content and format requirements. Based on 
our experience with labeling submissions, we estimate that 3 percent of 
the 2,529 applicants of existing and pending NDAs, BLAs, and ANDAs 
(1,669 applicants for existing NDAs and BLAs + 7 applicants of pending 
NDAs and BLAs + 840 applicants of existing ANDAs + 13 applicants of 
pending ANDAs) will request a waiver for a PMI requirement, 
approximately 76 applicants (table 3 of this document). We estimate 
that each applicant would submit one request, for a total of 76 
requests. These requests would be submitted to us beginning 1 year 
after the effective date of the final rule and would be submitted 
throughout the 5-year implementation timeframe (table 3 of this 
document). The average burden per response is the estimated number of 
hours an applicant would spend creating and submitting the request to 
FDA. Based on our experience with labeling submissions, we estimate 
that approximately 4 hours, on average, would be needed per submission, 
subtotaling 304 hours (table 4 of this document).
    To reduce the burden for authorized dispensers, FDA will submit PMI 
electronically for storage in a central repository. As a part of 
authorized dispensers' and transfusion services' normal business 
workflow, they will be able to download PMI from the central 
repository, integrate PMI into their existing software system, and 
provide PMI to patients as required under proposed Sec. Sec.  208.70 
and 606.123(b). As such, authorized dispensers and transfusion services 
will incur a one-time burden to download and integrate PMI into their 
existing software system. While a healthcare provider can administer or 
provide a prescription drug product directly to a patient, FDA expects 
authorized dispensers will generally be pharmacists at retail 
pharmacies in most instances. Based on an analysis of pharmacy 
ownership and the number of owners with multiple pharmacies, we expect 
that 44,318 pharmacies could incur the burden associated with these 
activities. Additionally, we have estimated that 4,961 transfusion 
services will incur the burden associated with these activities, 
totaling 49,279 respondents for this burden. The average burden per 
recordkeeping is the estimated number of hours an authorized dispenser 
would spend downloading PMI into their existing software system. FDA 
estimates that approximately 16 hours would be needed to download and 
integrate PMI into the existing software system, totaling 788,464 hours 
(table 3 of this document).

Reporting

    Table 4 shows the estimated annual reporting burden associated with 
this collection of information.

                               Table 4--Estimated Annual Reporting Burden \1\ \2\
----------------------------------------------------------------------------------------------------------------
                                                           Number of
      21 CFR section and activity          Number of     responses per   Total annual   Average burden    Total
                                          respondents     respondent       responses     per response     hours
----------------------------------------------------------------------------------------------------------------
PMI for NDAs and BLAs (Sec.  Sec.                  108             1.1             119             320    38,080
 208.50(a) and 208.60(a), and
 606.123(a))..........................
PMI for ANDAs (Sec.   208.50(b) and                251            4.73           1,186              27    32,022
 208.60(b))...........................
Waiver Requests for PMI requirements             1,489               1           1,489               4     5,956
 (Sec.  Sec.   208.90 and 606.123(c)).
Medication Guides Submitted with NDAs               57               1              57             320    18,240
 and BLAs (Sec.   208.94 (previously
 Sec.   208.20))......................
Medication Guides Submitted as                     108               1             108              72     7,776
 Supplements or Updates (Sec.   208.94
 (previously Sec.   208.26(a))).......
Exemptions and Deferrals for                         1               1               1               4         4
 Medication Guides (Sec.   208.98
 (previously Sec.   208.20))..........
                                       -------------------------------------------------------------------------
    Total.............................  ..............  ..............  ..............  ..............   102,078
----------------------------------------------------------------------------------------------------------------
\1\ There are no capital costs or operating and maintenance costs associated with this collection of
  information.
\2\ Numbers have been rounded to the nearest hundredth.

    Under proposed Sec. Sec.  208.50(a), 208.60(a), and 606.123(a), 
applicants of NDAs or BLAs would be required to create PMI and submit 
PMI to FDA as part of the respective application. Based on our review 
of the annual Prescription Drug User Fee Act performance reports from 
1993 to 2014, we estimate that 108 applicants of NDAs and BLAs will 
submit an NDA under Sec.  314.50 or a BLA under Sec.  601.2 for 119 new 
drug products annually, on average. Based on our experience with the 
information collection, we estimate that this activity will require 320 
hours per submission. We calculate, therefore, an annual burden of 
38,080 hours as reflected in table 4 of this document.
    Under proposed Sec. Sec.  208.50(b) and 208.60(b), applicants of 
ANDAs (new ANDAs) would be required to submit PMI to FDA as a part of 
the application. Accordingly, based on current data, we estimate that 
251 ANDA applicants will submit PMI to FDA for approval, resulting in 
1,186 submissions annually. Based on our experience with labeling 
submissions, we estimate that this activity will require an average of 
27 hours per submission for a total of 32,022 hours annually as 
reflected in table 4 of this document.
    Under proposed Sec. Sec.  208.90 and 606.123(c), any covered entity 
may submit a request for a waiver. Covered entities would include 
applicants and authorized dispensers. Based on our experience with 
labeling submissions, we estimate that 3 percent of the 359 applicants 
(108 NDA applicants and BLA applicants + 251 ANDA applicants) of new 
drug products and new ANDAs will request a waiver from a PMI 
requirement, approximately 11 applicants submitting 1 NDA, BLA, or ANDA 
each. The average burden per response is the estimated number of hours 
an applicant would spend creating and submitting the request to FDA. 
Based on our experience with labeling submissions, we estimate that

[[Page 35718]]

approximately 4 hours, on average, would be needed per submission, 
subtotaling 44 hours. Additionally, under proposed Sec.  208.90, 
authorized dispensers and under proposed Sec.  606.123(c) transfusion 
services may request a waiver for any requirement related to providing 
PMI to patients. Based on our experience with the information 
collection, we estimate that 1,478 authorized dispensers and 
transfusion services (3 percent of 49,279 authorized dispensers and 
transfusion services) will each request 1 waiver from a PMI 
requirement. We estimate that the average burden per response is 4 
hours. Therefore, we estimate that 1,489 covered entities/respondents 
(11 applicants of NDAs, BLAs, and ANDAs + 1,478 authorized dispensers 
and transfusion services) will request 1 waiver from a PMI requirement, 
totaling 5,956 hours (44 hours for NDA, BLA, or ANDA applicants + 5,912 
hours for authorized dispensers and transfusion services), as reflected 
in table 4 of this document.
    We propose to relocate current Sec. Sec.  208.20 and 208.26(a) to 
proposed Sec. Sec.  208.94 and 208.98. We have retained the estimates 
for current Sec. Sec.  208.20 and 208.26(a) as previously approved by 
OMB under control number 0910-0393 as reflected in table 4 of this 
document.

Third-Party Disclosure

    Table 5 shows the estimated annual third-party disclosure 
associated with this collection of information.

                                             Table 5--Estimated Annual Third-Party Disclosure Burden \1\ \2\
--------------------------------------------------------------------------------------------------------------------------------------------------------
                                                                 Number of
        21 CFR section and activity             Number of     disclosures per     Total annual        Average burden per disclosure         Total hours
                                               respondents       respondent       disclosures
--------------------------------------------------------------------------------------------------------------------------------------------------------
Downloading PMI into Database (Sec.  Sec.            49,276                 12          591,312  0.5 (30 minutes).......................         295,656
 208.70 and 606.123(b)).
Providing PMI to Patients (Sec.  Sec.                93,697          45,924.63    4,303,000,000  0.02 (1 minute)........................      86,060,000
 208.70 and 606.123(b)).
Medication Guide from Packer/Distributor to             191              9,000        1,719,000  1.25...................................       2,148,750
 Authorized Dispenser (Sec.   208.96
 (previously Sec.   208.24(c)).
Medication Guide from Authorized Dispenser           88,736              5,705      506,238,880  0.05 (3 minutes).......................      25,311,944
 to Patient (Sec.   208.96 (previously Sec.
   208.24(e)).
                                            ------------------------------------------------------------------------------------------------------------
    Total..................................  ..............  .................  ...............  .......................................     113,816,350
--------------------------------------------------------------------------------------------------------------------------------------------------------
\1\ There are no capital or operating and maintenance costs associated with this collection of information.
\2\ Numbers have been rounded to the nearest hundredth.

    Authorized dispensers, including transfusion services, would also 
be required to download updated PMI into their existing software system 
on a regular basis to ensure that patients receive the most up-to-date 
PMI. We anticipate that PMI would be updated in the central repository 
monthly. Therefore, authorized dispensers would need to download 
updated and new PMI from the central repository monthly. Consistent 
with our estimates to download and integrate PMI, we anticipate that 
49,276 authorized dispensers could incur the burden associated with 
this activity. The average burden per recordkeeping is the estimated 
number of hours an authorized dispenser would spend downloading updated 
PMI into their existing software system. We estimate that 0.5 hours (30 
minutes) would be needed to update PMI monthly, totaling 295,656 hours 
as reflected in table 5 of this document.
    Proposed Sec. Sec.  208.70(a) and 606.123(b) would require that 
authorized dispensers of human prescription drug products and 
transfusion services, respectively, provide FDA-approved PMI to 
patients when such PMI is available. Authorized dispensers and 
transfusion services must be capable of providing PMI in paper format 
to patients; however, they may provide PMI in electronic format to 
patients. Estimated printing costs will be equivalent to current 
printing costs, because dispensers already provide written information 
in paper format to patients. Further, we do not expect that dispensers 
will incur additional costs when printing PMI, because the length of 
PMI will be shorter than written information currently provided to 
patients. Because providing prescription drug product information to 
patients is currently a part of authorized dispensers' business 
practices and we are proposing that PMI be limited to one page, we 
anticipate time and effort for dispensers will be reduced.
    Authorized dispensers and transfusion services may provide PMI in 
electronic format to patients when requested. Based on the normal 
course of their activities, many pharmacies may already have the 
contact information in patients' profiles. As a result, dispensers 
could expeditiously provide patients with PMI electronically.
    Based on current data, we estimate that 88,736 pharmacies and 4,961 
transfusion services could be affected by proposed Sec. Sec.  208.70 
and 606.123(b), respectively. These respondents would be responsible 
for providing to patients PMI for human prescription drug products 
used, dispensed, or administered on an outpatient basis or when 
patients receive transfusions on an outpatient basis. Collectively, 
these respondents are responsible for dispensing 4.3 billion 
prescriptions annually and 3 million transfusions annually. We estimate 
that it will take dispensers an average of 0.02 hours (1 minute) to 
provide PMI to patients for a total of 86,060,000 hours annually as 
reflected in table 5 of this document.
    We propose to relocate current Sec.  208.24(c) and (e) to proposed 
Sec.  208.96. We have retained the estimates for current Sec.  
208.24(c) and (e) as previously approved under OMB control number 0910-
0393 as reflected in table 5 of this document.
    To ensure that comments on information collection are received, OMB 
recommends that written comments be submitted 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.'' 
All comments should be identified with the title of the information 
collection.
    In compliance with the Paperwork Reduction Act of 1995 (44 U.S.C. 
3407(d)), we have submitted the information collection provisions of 
this proposed rule to OMB for review. These information collection 
requirements will not be effective until FDA publishes a final rule, 
OMB approves the information collection requirements, and the rule goes 
into effect. FDA will announce OMB approval of these requirements in 
the Federal Register.

XI. Federalism

    We have analyzed this proposed rule in accordance with the 
principles set

[[Page 35719]]

forth in Executive Order 13132. We have determined that this proposed 
rule does not contain policies that have substantial direct effects on 
the States, on the relationship between the National Government and the 
States, or on the distribution of power and responsibilities among the 
various levels of government. Accordingly, we conclude that the 
proposed rule does not contain policies that have federalism 
implications as defined in the Executive order and, consequently, a 
federalism summary impact statement is not required.
    We are aware that States have laws or regulations that require 
pharmacists to counsel patients on the use of prescription drug 
products. We do not believe this proposed rule on PMI conflicts with 
such laws or regulations because this proposed rule would not affect 
any oral counseling requirements imposed by State laws or regulations. 
Nevertheless, we will continue to examine State laws for federalism 
purposes. We invite comments from interested persons, particularly with 
respect to State initiatives, to provide information to patients on 
prescription drug products used, dispensed, or administered on an 
outpatient basis.

XII. Consultation and Coordination With Indian Tribal Governments

    We have analyzed this proposed rule in accordance with the 
principles set forth in Executive Order 13175. We have tentatively 
determined that the proposed rule does not contain policies that would 
have a substantial direct effect on one or more Indian Tribes, on the 
relationship between the Federal Government and Indian Tribes, or on 
the distribution of power and responsibilities between the Federal 
Government and Indian Tribes. The Agency solicits comments from tribal 
officials on any potential impact on Indian Tribes from this proposed 
action.

XIII. References

    The following references marked with an asterisk (*) are on display 
at the Dockets Management Staff (see ADDRESSES) and are available for 
viewing by interested persons between 9 a.m. and 4 p.m., Monday through 
Friday; they are also available electronically at https://www.regulations.gov. References without asterisks are not on public 
display at https://www.regulations.gov because they have copyright 
restriction. Some may be available at the website address, if listed. 
References without asterisks are available for viewing only at the 
Dockets Management Staff. FDA has verified the website addresses, as of 
the date this document publishes in the Federal Register, but websites 
are subject to change over time.

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Written Prescription Information Provided in Community Pharmacies: A 
Study in Eight States,'' Journal of the American Pharmacists 
Association, Vol. 43, Issue 3, pp. 383-393, 2003, doi:10.1331/
154434503321831102.
2. Lam, W.Y. and P. Fresco, ``Medication Adherence Measures: An 
Overview,'' BioMed Research International, pp. 217047, 2015, 
doi:10.1155/2015/217047.
3. Abegaz, T.M., A. Shehab, E.A. Gebreyohannes, et al., 
``Nonadherence to Antihypertensive Drugs: A Systematic Review and 
Meta-analysis,'' Medicine (Baltimore), Vol. 96, Issue 4, pp. e5641, 
2017, doi:10.1097/MD.0000000000005641.
4. Kim, J., K. Combs, J. Downs, et al., ``Medication Adherence: The 
Elephant in the Room,'' U.S. Pharmacist, Vol. 43, Issue 1, pp. 30-
34, 2018 (available at: https://www.uspharmacist.com/article/
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room#:~:text=Nonadherence%20can%20account%20for%20up,chronic%20medica
tions%20is%20around%2050%25), accessed May 12, 2023.
5. Cutler, R.L., F. Fernandez-Llimos, M. Frommer, et al., ``Economic 
Impact of Medication Non-adherence by Disease Groups: A Systematic 
Review,'' BMJ Open, Vol. 8, pp. e016982, 2018, doi:10.1136/bmjopen-
2017-016982.
6. Chin, J., H. Wang, A.W. Awwad, et al., ``Health Literacy, 
Processing Capacity, Illness Knowledge, and Actionable Memory for 
Medication Taking in Type 2 Diabetes: Cross-Sectional Analysis,'' 
Journal of General Internal Medicine, Vol. 36, Issue 7, pp. 1921-
1927, 2021, doi:10.1007/s11606-020-06472-z.
7. Park, L.M., P.R. Jones, B.M. Pearsall, et al., ``An Update on 
Medication Guides,'' Pharmacoepidemiology and Drug Safety, Vol. 27, 
Issue 2, pp. 129-132, 2017, doi:https://doi.org/10.1002/pds.4370.
*8. PHS, ``Healthy People 2000: National Health Promotion and 
Disease Prevention Objectives and Full Report, With Commentary,'' 
Washington, DC, U.S. Government Printing Office, DHHS publication 
no. (PHS) 90-50212, 1991.
*9. Steering Committee for the Collaborative Development of a Long-
Range Action Plan for the Provision of Useful Prescription Medicine 
Information, ``Action Plan for the Provision of Useful Prescription 
Medicine Information,'' Report Presented to the Honorable Donna E. 
Shalala, Secretary of the U.S. Department of Health and Human 
Services, 1996 (available at https://wayback.archive-it.org/7993/20170112233205/http://www.fda.gov/downloads/aboutfda/centersoffices/officeofmedicalproductsandtobacco/cder/reportsbudgets/ucm163793.pdf 
(under Background Information)), accessed May 12, 2023.
*10. FDA, ``Public Workshop on Current Status of Useful Written 
Prescription Drug Information for Patient--Meeting Summary,'' 2000 
(available at https://wayback.archive-it.org/7993/20170723111358/https://www.fda.gov/AboutFDA/CentersOffices/OfficeofMedicalProductsandTobacco/CDER/ucm091780.htm), accessed May 
12, 2023.
11. Svarstad, B.L., J.K. Mount, and E.R. Tabak, ``Expert and 
Consumer Evaluation of Patient Medication Leaflets Provided in U.S. 
Pharmacies,'' Journal of the American Pharmacists Association, Vol. 
45, Issue 4, pp. 443-451, 2005.
*12. Svarstad, B.L. and J.K. Mount, ``Evaluation of Written 
Prescription Information Provided in Community Pharmacy, 2001'' 
Final Report to the U.S. Department of Health and Human Services and 
the Food and Drug Administration, 2001 (available at https://wayback.archive-it.org/7993/20170112233207/http://www.fda.gov/aboutfda/centersoffices/officeofmedicalproductsandtobacco/cder/ucm169753.htm), accessed May 12, 2023.
*13. Kimberlin, C.L. and A.G. Winterstein, ``Expert and Consumer 
Evaluation of Consumer Medication Information,'' Final Report to the 
U.S. Department of Health and Human Services and the Food and Drug 
Administration, 2008 (available at https://wayback.archive-it.org/7993/20170723155336/https://www.fda.gov/AboutFDA/CentersOffices/OfficeofMedicalProductsandTobacco/CDER/ReportsBudgets/ucm163777.htm), accessed May 12, 2023.
*14. FDA, ``Public Hearing on Use of Medication Guides to Distribute 
Drug Risk Information to Patients,'' Meeting Summary and 
Transcripts, 2007 (available at https://www.fda.gov/Drugs/DrugSafety/ucm172845.htm), accessed May 12, 2023.
*15. National Association of Chain Drug Stores, National Community 
Pharmacists Association, Food Marketing Institute, et al., Citizen 
Petition Requesting FDA Action on a ``One Document Solution'' For 
All Pharmacy-Based Communications, Docket No. FDA-2008-P-0380-0001, 
2008 (available at https://www.regulations.gov/), accessed May 12, 
2023.
*16. National Association of Chain Drug Stores, National Community 
Pharmacists Association, Food Marketing Institute, et al., 
Withdrawal of Citizen Petition Requesting FDA Action on a ``One 
Document Solution'' for All Pharmacy-Based Communications, Docket 
No. FDA-2008-P-0380-0008, 2010 (available at https://www.regulations.gov/), accessed May 12, 2023.
*17. FDA, Minutes of the Risk Communication Advisory Committee, FDA, 
February 26 and 27, 2009 (available at https://wayback.archive-
it.org/7993/20170405014416/https://www.fda.gov/AdvisoryCommittees/
CommitteesMeetingMaterials/

[[Page 35720]]

RiskCommunicationAdvisoryCommittee/ucm116558.htm), accessed May 12, 
2023.
*18. FDA, ``Providing Effective Information to Consumers About 
Prescription Drug Risks and Benefits: The Issues Paper, Background 
Paper,'' 2009.
*19. FDA, ``Prototype 1 Rheutopia,'' 2009.
*20. FDA, ``Prototype 2 Rheutopia,'' 2009.
*21. FDA, ``Prototype 3 Rheutopia,'' 2009.
*22. FDA, ``Prototype 4 Rheutopia,'' 2009.
*23. FDA, ``Providing Effective Information to Consumers About 
Prescription Drug Risks and Benefits, Workshop Summary,'' September 
24 and 25, 2009.
*24. Engelberg Center for Healthcare Reform at the Brookings 
Institution, ``Patient Medication Information,'' 2014.
*25. Engelberg Center for Healthcare Reform at the Brookings 
Institution, ``Expert Workshop: The Science of Communicating 
Medication Information to Consumers,'' 2010.
*26. Engelberg Center for Healthcare Reform at the Brookings 
Institution, ``Ensuring Access to Effective Patient Medication 
Information,'' 2010.
*27. Engelberg Center for Healthcare Reform at the Brookings 
Institution, ``Designing Pilot Programs to Distribute Patient 
Medication Information,'' 2011.
28. Wilson P. and S. Ramspacher, ``Making Prescription Information 
User-Friendly: The Time Has Come,'' PM360, 2013 (available at 
https://www.pm360online.com/making-prescription-medication-information-user-friendly-the-time-has-come/), accessed May 12, 
2023.
*29. Engelberg Center for Healthcare Reform at the Brookings 
Institution, ``Exploring the Promise of Patient Medication 
Information,'' 2014.
*30. FDA, ``Development and Distribution of PMI for Prescription 
Drugs; Public Hearing,'' 2010 (available at https://www.regulations.gov/#!documentDetail;D=FDA-2010-N-0437-0018), 
accessed May 12, 2023.
31. Kish-Doto, J., M. Scales, P. Eguino-Medina, et al., 
``Preferences for Patient Medication Information: What Do Patients 
Want?,'' Journal of Health Communication: International 
Perspectives, vol. 19, pp. 77-88, 2014, doi:10.1080/
10810730.2014.946114.
32. Koo, M.M., I. Krass, and P. Aslani, ``Factors Influencing 
Consumer Use of Written Drug Information,'' The Annals of 
Pharmacotherapy, Vol. 37, Issue 2, pp. 259-267, 2003, doi:10.1345/
aph.1C328.
33. Buck, M.L., ``Providing Patients With Written Medication 
Information,'' The Annals of Pharmacotherapy, Vol. 32, Issue 9, pp. 
962-969, 1998, doi:10.1345/aph.17455.
34. Aker, J., M. Beck, J.I. Papay, et al., ``Consumers Better 
Understand and Prefer Simplified Written Drug Information: An 
Evaluation of 2 Novel Formats Versus the Current CMI,'' Therapeutic 
Innovation and Regulatory Science, Vol. 47, Issue 1, pp. 125-132, 
2013, doi:10.1177/0092861512462371.
35. Nathan, J.P., T. Zerilli, L.A. Cicero, et al., ``Patients' Use 
and Perception of Medication Information Leaflets,'' The Annals of 
Pharmacotherapy, Vol. 41, Issue 5, pp. 777-782, 2007, doi:10.1345/
aph.1H686.
36. Mansoor, L. and R. Dowse, ``Written Medicines Information for 
South African HIV/AIDS Patients: Does It Enhance Understanding of 
Co-Trimoxazole Therapy?'', Health Education Research, Vol. 22, Issue 
1, pp. 37-48, 2007, doi:10.1093/her/cyl039.
37. Gustafsson, J., S. K[auml]lvemark, G. Nilsson, et al., ``Patient 
Information Leaflets--Patients' Comprehension of Information About 
Interactions and Contraindications,'' Pharmacy World and Science, 
Vol. 27, Issue 1, pp. 35-40, 2005, doi:10.1007/s11096-005-1413-x.
38. Wolf, M.S., J. King, E.A. Wilson et al., ``Usability of FDA-
Approved Medication Guides,'' Journal of General Internal Medicine, 
Vol. 27, Issue 12, pp. 1714-1720, 2012, doi:10.1007/s11606-012-2068-
7.
*39. ER/LA Opioid Analgesics REMS Program Company, ``ER/LA Opioid 
Analgesics REMS: The Extended-Release and Long-Acting Opioid 
Analgesics Risk Evaluation and Mitigation Strategy,'' 2014.
40. Raynor, D.K. and D. Dickinson, ``Key Principles to Guide 
Development of Consumer Medicine Information--Content Analysis of 
Information Design Texts,'' The Annals of Pharmacotherapy, Vol. 43, 
Issue 4, pp. 700-706, 2009, doi:10.1345/aph.1L522.
41. Hartley, J., Handbook of Research on Educational Communication 
and Technology, ``Designing Instructional and Informational Text,'' 
pp. 917-947, Lawrence Erlbaum Associates, Mahwah, NJ, 2004.
42. Knapp, P., D.K. Raynor, A.H. Jebar, et al., ``Interpretation of 
Medication Pictograms by Adults in the UK,'' The Annals of 
Pharmacotherapy, Vol. 39, pp. 1227-1233, 2005, doi:0.1345/aph.1E483.
43. Badarudeen, S. and S. Sabharwal, ``Assessing Readability of 
Patient Education Materials: Current Role in Orthopaedics,'' 
Clinical Orthopaedics and Related Research, Vol. 468, Issue 10, pp. 
2572-2580, 2010, doi:10.1007/s11999-010-1380-y.
44. Gill, P.S., ``Prescription Painkillers and Controlled 
Substances: An Appraisal of Drug Information Provided by Six US 
Pharmacies,'' Drug, Healthcare and Patient Safety, Vol. 5, pp 29-36, 
2013, doi:10.2147/DHPS.S42508.
45. Lorch Jr., R.F., E.P. Lorch, K. Ritchey, et al., ``Effects of 
Headings on Text Summarization, Contemporary Educational 
Psychology,'' Vol. 26, Issue 2, pp. 171-191, 2001, doi:10.1006/
ceps.1999.1037.
46. Kools, M., R.A. Ruiter, M.W.J. van de Wiel, et al., ``The 
Effects of Headings in Information Mapping on Search Speed and 
Evaluation of a Brief Health Education Text,'' Journal of 
Information Science, Vol. 34, Issue 6, pp. 833-844, 2007, 
doi:10.1177/0165551508089719.
47. Cowburn, G. and L. Stockley, ``Consumer Understanding and Use of 
Nutrition Labelling: A Systematic Review,'' Public Health Nutrition, 
Vol. 8, Issue 1, pp. 21-28, 2004, doi:10.1079/PHN2004666.
*48. Preliminary Regulatory Impact Analysis, Initial Regulatory 
Flexibility Analysis, and Unfunded Mandates Reform Act Analysis for 
Medication Guides: Patient Medication Information available at 
https://www.fda.gov/about-fda/reports/economic-impact-analyses-fda-regulations.

List of Subjects

21 CFR Part 201

    Drugs, Labeling, Reporting and recordkeeping requirements.

21 CFR Part 208

    Labeling, Prescription drugs, Reporting and recordkeeping 
requirements.

21 CFR Part 314

    Administrative practice and procedure, Confidential business 
information, Drugs, Reporting and recordkeeping requirements.

21 CFR Part 606

    Blood, Labeling, Laboratories, Reporting and recordkeeping 
requirements.

21 CFR Part 610

    Biologics, Labeling, Reporting and recordkeeping requirements.

    Therefore, under the Federal Food, Drug, and Cosmetic Act and under 
authority delegated to the Commissioner of Food and Drugs, the FDA 
proposes to amend 21 CFR parts 201, 208, 314, 606, and 610 as follows:

PART 201--LABELING

0
1. The authority citation for part 201 continues to read as follows:

    Authority:  21 U.S.C. 321, 331, 343, 351, 352, 353, 355, 358, 
360, 360b, 360ccc, 360ccc-1, 360ee, 360gg-360ss, 371, 374, 379e; 42 
U.S.C. 216, 241, 262, 264.

0
2. In Sec.  201.57, revise the last two sentences of paragraph (c)(18) 
to read as follows:


Sec.  201.57  Specific requirements on content and format of labeling 
for human prescription drug and biological products described in Sec.  
201.56(b)(1).

* * * * *
    (c) * * *
    (18) * * * Any FDA-approved patient labeling printed immediately 
following this section or accompanying the labeling is subject to the 
type size requirements in paragraph (d)(6) of this section, except for 
a Medication Guide to be provided to patients in compliance with 
Sec. Sec.  208.70 and 208.96 of this chapter. Medication Guides for

[[Page 35721]]

distribution to patients are subject to the type size requirements set 
forth in Sec. Sec.  208.30 and 208.94 of this chapter.
* * * * *
0
3. In Sec.  201.80, revise the last two sentences of paragraph (f)(2) 
to read as follows:


Sec.  201.80  Specific requirements on content and format of labeling 
for human prescription drug and biological products; older drugs not 
described in Sec.  201.56(b)(1).

* * * * *
    (f) * * *
    (2) * * * Any FDA-approved patient labeling must be referenced in 
this section, and the full text of such patient labeling must be 
reprinted immediately following the last section of labeling or must 
accompany the prescription drug product labeling. The type size 
requirement for the Medication Guide set forth in Sec. Sec.  208.30 and 
208.94 of this chapter does not apply to the Medication Guide that is 
reprinted in or that accompanies the prescription drug product labeling 
unless such Medication Guide is to be detached and provided or 
distributed to patients in compliance with Sec. Sec.  208.70 and 208.96 
of this chapter.
* * * * *
0
4. In Sec.  201.100, add paragraph (g) to read as follows:


Sec.  201.100  Prescription drugs for human use.

* * * * *
    (g) When a Medication Guide is required under part 208 or Sec.  
606.123 of this chapter, the drug must have an approved Medication 
Guide and be dispensed with a Medication Guide (as described in part 
208 or Sec.  606.123 of this chapter).
0
5. Revise part 208 to read as follows:

PART 208--MEDICATION GUIDES

Sec.
Subpart A--General Provisions for Patient Medication Information
208.10 Scope and purpose.
208.20 Definitions.
Subpart B--General Requirements for Patient Medication Information
208.30 Format of Patient Medication Information.
208.40 Content of Patient Medication Information.
208.50 Development of Patient Medication Information for new drug 
applications, biologics license applications, and abbreviated new 
drug applications.
208.60 Submission of Patient Medication Information for new drug 
applications, biologics license applications, and abbreviated new 
drug applications.
208.70 Providing Patient Medication Information to patients.
208.80 Schedule for implementing the general requirements for 
Patient Medication Information.
208.90 Waivers.
Subpart C--General Provisions for Medication Guides for Prescription 
Drug Products
208.91 Scope and purpose.
208.92 Definitions.
Subpart D--General Requirements for Medication Guides for Prescription 
Drug Products
208.94 Content and format of a Medication Guide.
208.96 Distributing and providing a Medication Guide.
208.98 Exemptions and deferrals.

    Authority:  21 U.S.C. 321, 331, 351, 352, 353, 355, 356, 357, 
360, 371, 374; 42 U.S.C. 262.

Subpart A--General Provisions for Patient Medication Information


Sec.  208.10  Scope and purpose.

    (a) Scope. Subparts A and B of this part set forth requirements for 
patient labeling for prescription drug products used, dispensed, or 
administered on an outpatient basis. This patient labeling is a type of 
Medication Guide called Patient Medication Information. Any 
prescription drug product that is approved or submitted for approval 
under section 505 of the Federal Food, Drug, and Cosmetic Act (21 
U.S.C. 355) or section 351(a) or (k) of the Public Health Service Act 
(42 U.S.C. 262(a) or (k)) and that is used, dispensed, or administered 
on an outpatient basis is required to have the Food and Drug 
Administration (FDA)-approved Patient Medication Information, with the 
exception of excluded entities identified in paragraph (d) of this 
section.
    (b) Purpose. Patient Medication Information for prescription drug 
products required under this part provides concise, accessible, and 
useful written prescription drug product information for patients. 
Patient Medication Information must be delivered in a consistent and 
easily understood format to help patients use their prescription drug 
products safely and effectively.
    (c) Covered entities. (1) Applicants of prescription drug products 
approved or submitted for approval under section 505 of the Federal 
Food, Drug, and Cosmetic Act (21 U.S.C. 355) or section 351(a) or (k) 
of the Public Health Service Act (42 U.S.C. 262(a) or (k)) must have 
FDA-approved Patient Medication Information for each prescription drug 
product used, dispensed, or administered on an outpatient basis, with 
the exception of excluded entities identified in paragraph (d) of this 
section.
    (2) Authorized dispensers are required to provide patients with 
FDA-approved Patient Medication Information each time a prescription 
drug product is used, dispensed, or administered on an outpatient basis 
when such Patient Medication Information exists.
    (d) Excluded entities. Applicants of prescription drug products 
that are preventive vaccines that do not have a Medication Guide (as 
required under subparts C and D of this part) are not required to 
submit Patient Medication Information to FDA for approval for those 
products unless FDA determines that Patient Medication Information is 
required for safe and/or effective use of the product.


Sec.  208.20  Definitions.

    The following definitions apply to this part:
    Administered means the act of directly providing a prescription 
drug product to a patient by injection, inhalation, ingestion, 
application, or any other means by a licensed healthcare provider (or a 
licensed healthcare provider's agent) or by a patient (or a patient's 
agent) under the direction of a licensed healthcare provider (or a 
licensed healthcare provider's agent). In some circumstances, a product 
can be both administered and dispensed at the same time.
    Applicant means all of the following:
    (1) Any person who submits an application or abbreviated 
application or an amendment or supplement to their application under 
part 314 or part 601 of this chapter to obtain FDA approval of a new 
drug or biological product and,
    (2) Any person who owns an approved application or an abbreviated 
application.
    Authorized dispenser means 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.
    Dispensed means the act of providing a prescription drug product to 
a patient (or a patient's agent) in either of the following ways:
    (1) By a licensed healthcare provider (or a licensed healthcare 
provider's agent), either directly or indirectly, for administration by 
the patient (or the patient's agent) under or outside of the licensed 
healthcare provider's direct supervision.
    (2) By an authorized dispenser (or an authorized dispenser's agent) 
under a

[[Page 35722]]

lawful prescription of a licensed healthcare provider.
    Drug name means the proprietary name, if any, and the established 
name of the drug (as defined in section 502(e)(3) of the Federal Food, 
Drug, and Cosmetic Act (21 U.S.C. 352(e)(3)) or, for biological 
products, the proper name (as defined in Sec.  600.3 of this chapter) 
including any appropriate descriptors.
    Drug product means a finished dosage form (for example, tablet, 
capsule, solution), as defined in Sec.  210.3 of this chapter, that 
contains a drug substance, generally, but not necessarily, in 
association with one or more other ingredients. For the purposes of 
this part, drug product also includes a biological product licensed 
under section 351(a) and (k) of the Public Health Service Act (42 
U.S.C. 262(a) and (k)).
    Licensed healthcare provider means an individual who is licensed, 
registered, or otherwise permitted by the jurisdiction in which the 
individual practices to prescribe drug products in the course of 
professional practice.
    Manufacturer means all of the following:
    (1) For a drug product that is not a biological product, the 
manufacturer as described in Sec.  201.1 of this chapter.
    (2) For a drug product that is a biological product, the 
manufacturer as described in Sec.  600.3(t) of this chapter.
    Patient means any individual to whom a drug product is intended to 
be or has been used, dispensed, or administered.
    Patient Medication Information means a type of FDA-approved 
Medication Guide--a form of patient labeling--that conforms to the 
specifications set forth in subparts A and B of this part.
    Revision date means the date (month/year) on which Patient 
Medication Information was initially approved or the date on which any 
changes have been made to the Patient Medication Information, whichever 
applies and whichever date is later.
    Used (in relation to prescription drug products and Patient 
Medication Information) means the act of a patient (or a patient's 
agent) directly applying a prescription drug product to the body of the 
patient by injection, inhalation, ingestion, application, or any other 
means.

Subpart B--General Requirements for Patient Medication Information


Sec.  208.30  Format of Patient Medication Information.

    (a) Patient Medication Information must meet the following 
requirements:
    (1) Patient Medication Information must be written in English; 
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.
    (2) Patient Medication Information provided to a patient in paper 
format must be legible and printed on a single side of an 8\1/2\ by 11-
inch sheet of paper. It must not exceed a single page in length.
    (3) Patient Medication Information provided in electronic format 
must be printable and produce a document that is identical to the 
Patient Medication Information in paper format.
    (4) The required Patient Medication Information headings, 
subheadings, title ``PATIENT MEDICATION INFORMATION,'' and drug 
name(s), phonetic spelling of the drug name(s), dosage form(s), and 
route(s) of administration must appear in bold, beginning on the line 
immediately below the title.
    (5) The title ``PATIENT MEDICATION INFORMATION'' must be presented 
in all uppercase letters. The proprietary name (if any) 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.
    (6) 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 beginning immediately below the title must 
appear centered at the top of the page.
    (b) Patient Medication Information must not contain any of the 
following:
    (1) Letter type that is less than 10-point font (1 point = 0.0138 
inches) for any section of Patient Medication Information. However, the 
manufacturer's, packer's, and/or distributor's name and place of 
business (and 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 can be less than 10-point 
font.
    (2) Reverse type, lightface, shading, condensed type, or narrow 
fonts.
    (3) Colors other than black type.
    (4) Page number.


Sec.  208.40  Content of Patient Medication Information.

    (a) General content requirements for Patient Medication 
Information. Patient Medication Information must meet all general 
content requirements as follows:
    (1) Patient Medication Information must be easily read and 
understood by the general population, including individuals with low 
literacy and comprehension levels.
    (2) Patient Medication Information must not be promotional in tone.
    (3) The content of Patient Medication Information must be 
scientifically accurate, must not be false or misleading in any 
particular, and must be based on and consistent with the Prescribing 
Information (PI) for the prescription drug product required under 
Sec. Sec.  201.56, 201.57, 201.80, and 606.122 of this chapter and 
section 505 of the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 
355). Patient Medication Information for new drug applications and 
biologics license applications must be updated when new information 
becomes available that would cause the Patient Medication Information 
to become inaccurate, false, or misleading in accordance with 
Sec. Sec.  314.70 and 601.12 of this chapter.
    (4) The title ``PATIENT MEDICATION INFORMATION'' must appear at the 
top of the page.
    (5) The drug name(s) must appear immediately below the title 
``PATIENT MEDICATION INFORMATION'' and must include the phonetic 
spelling of the proprietary name, if any, and the established name (or 
the proper name) of the prescription drug product. The drug name(s) 
must be followed by the dosage form(s) and route(s) of administration. 
If the drug name needs to be used again throughout Patient Medication 
Information, only the proprietary name (if any) must be used. Those 
prescription drug products not having a proprietary name must use the 
established name or the proper name.
    (6) The statement ``The content of this Patient Medication 
Information has been approved by the U.S. Food and Drug 
Administration'' must appear at the bottom of the page followed by the 
revision date.
    (7) The name and place of business of the manufacturer, packer, or 
distributor of a prescription drug product that is not also a 
biological product must be included in Patient Medication Information 
below the statement required in paragraph (a)(6) of this section and 
the revision date. The licensed manufacturer's name, address, and U.S. 
license number of a prescription drug product that is also a biological 
product must be included in Patient Medication Information below the 
statement required in paragraph (a)(6) of this section and the revision 
date. The name and place of business of

[[Page 35723]]

the authorized dispenser may also be included in Patient Medication 
Information.
    (8) Any heading, subheading, or specific information required under 
paragraphs (b) and (c) of this section that is inapplicable must be 
omitted from Patient Medication Information.
    (b) Required headings for Patient Medication Information. Patient 
Medication Information must contain these headings in the following 
order if not omitted under paragraph (a)(8) of this section: [Insert 
drug name] is, Important Safety Information, Common Side Effects, 
Directions for Use.
    (c) Specific content required under headings for Patient Medication 
Information. Each heading must contain the specific information as 
follows if not omitted under paragraph (a)(8) of this section:
    (1) [Insert drug name] is. A concise summary of the outpatient 
indications and uses for the prescription drug product listed in the 
prescription drug product's Prescribing Information (PI). The 
information in this section would be consistent with the information 
found in the INDICATIONS AND USAGE section of the PI.
    (2) Important Safety Information. This heading must contain these 
subheadings in the following order if not omitted under paragraph 
(a)(8) of this section:
    (i) Warnings. A concise summary of serious warnings from the use of 
the prescription drug product, including any that may lead to death or 
serious injury. 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.
    (ii) Do not take. A statement of the circumstances (if any) under 
which the prescription drug product should not be used because the risk 
of use outweighs any benefit. 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.
    (iii) Serious side effects. 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 information on 
when to call a healthcare provider or when and how to obtain emergency 
help if certain clinically significant adverse reactions occur. The 
information in the Serious side effects subheading must be consistent 
with either:
    (A) 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 
of this chapter; or
    (B) The ``WARNINGS'' section and the ``PRECAUTIONS'' section for 
drug labeling that must meet the format and content requirements of 
Sec.  201.80 of this chapter.
    (iv) Tell your health care provider before taking. A statement that 
identifies specific populations and conditions (if any) 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.
    (3) Common Side Effects. A statement of frequently occurring 
adverse reactions (if any) from the use of the prescription drug 
product, followed by the statement ``These are not all of 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].''
    (4) Directions for Use. The statement ``Use exactly as prescribed'' 
must appear first after this heading. This statement must be followed 
by how the prescription drug product must be administered and the route 
of administration. ``Directions for Use'' also must 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 
includes 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 found in:
    (i) The ``DOSAGE AND ADMINISTRATION'' section of the PI; and
    (ii) 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 of this chapter or the ``HOW SUPPLIED'' 
section for drug labeling that must meet the format and content 
requirements of Sec.  201.80 of this chapter. Additional FDA-approved 
patient labeling must be referenced, when applicable.


Sec.  208.50  Development of Patient Medication Information for new 
drug applications, biologics license applications, and abbreviated new 
drug applications.

    (a) New drug applications and biologics license applications. The 
applicant of a new drug application (NDA) or a biologics license 
application (BLA) for a prescription drug product used, dispensed, or 
administered on an outpatient basis must create Patient Medication 
Information in accordance with the requirements set forth in this part 
and other applicable regulations. In certain circumstances, FDA may 
require more than one Patient Medication Information for a prescription 
drug product, associated with a single PI, when one Patient Medication 
Information cannot adequately convey the safe and effective use of the 
drug to patients.
    (b) Abbreviated new drug applications. (1) Except as provided in 
paragraph (b)(2) of this section, the applicant of a prescription drug 
product approved or submitted for approval under section 505(j) of the 
Federal Food, Drug, and Cosmetic Act (21 U.S.C. 355(j)) must have 
Patient Medication Information that is the same as that of the 
reference listed drug upon which its approval is based except for:
    (i) Changes required because of differences approved under a 
suitability petition (see 505(j)(2)(C) of the Federal Food, Drug and 
Cosmetic Act and Sec.  314.93 of this chapter); or
    (ii) Changes permitted pursuant to Sec.  314.94(a)(8)(iv) of this 
chapter.
    (2) The applicant of a prescription drug product approved or 
submitted for approval under section 505(j) of the Federal Food, Drug, 
and Cosmetic Act (21 U.S.C. 355(j)) that refers to a listed drug 
approved under section 505(c) of the Federal Food, Drug, and Cosmetic 
Act (21 U.S.C. 355(c)) for which approval has been voluntarily 
withdrawn before the approval of the Patient Medication Information for 
the reference listed drug must have Patient Medication Information that 
is the same as that of the Patient Medication Information template that 
FDA creates for the prescription drug product except for:
    (i) Changes required because of differences approved under a 
suitability petition (see 505(j)(2)(C) of the Federal Food, Drug and 
Cosmetic Act and Sec.  314.93 of this chapter); or
    (ii) Changes permitted pursuant to Sec.  314.94(a)(8)(iv) of this 
chapter.

[[Page 35724]]

Sec.  208.60  Submission of Patient Medication Information for new drug 
applications, biologics license applications, and abbreviated new drug 
applications.

    (a) New drug applications and biologics license applications. The 
NDA or BLA applicant must submit to FDA for approval as part of the 
application the Patient Medication Information along with the PI upon 
which the Patient Medication Information is based. If Patient 
Medication Information is submitted after approval of the NDA or BLA, 
the Patient Medication Information, along with the PI upon which the 
Patient Medication Information is based, must be submitted to FDA for 
approval in a prior approval supplement pursuant to Sec. Sec.  
314.70(b)(2)(v)(B) and 601.12(f)(1) of this chapter.
    (b) Abbreviated new drug applications. The abbreviated new drug 
application (ANDA) applicant must submit Patient Medication Information 
to FDA for approval after either Patient Medication Information for the 
reference listed drug is approved or FDA has finalized the Patient 
Medication Information template and provides notice of the template to 
the applicant, whichever applies. If Patient Medication Information is 
submitted after the original approval of the ANDA, Patient Medication 
Information must be submitted in a supplement to the ANDA consistent 
with Sec.  314.70 of this chapter.


Sec.  208.70  Providing Patient Medication Information to patients.

    (a) When a prescription drug product is used, dispensed, or 
administered to a patient (or the patient's agent) on an outpatient 
basis, the authorized dispenser of a prescription drug product for 
which Patient Medication Information is required under subparts A and B 
of this part must provide FDA-approved Patient Medication Information 
to each patient (or the patient's agent). Authorized dispensers may 
provide Patient Medication Information to the patient electronically; 
however, paper distribution must always be available.
    (b) An authorized dispenser is not subject to section 510 of the 
Federal Food, Drug, and Cosmetic Act (21 U.S.C. 360) (which requires 
the registration of those that engage in the manufacture, preparation, 
propagation, compounding, or processing of drugs and the listing of 
certain drugs in commercial distribution) solely because of an action 
performed by the authorized dispenser under this part.


Sec.  208.80  Schedule for implementing the general requirements for 
Patient Medication Information.

    (a) Implementation schedule for applicants to submit Patient 
Medication Information for NDAs and BLAs. NDA and BLA applicants must 
submit to FDA Patient Medication Information that conforms to the 
requirements in subparts A and B of this part. If an approved NDA or a 
BLA has one or more approved efficacy supplements, use the NDA, BLA, or 
efficacy supplement approval date that triggers the earliest submission 
for the following implementation schedule:
    (1) For products for which an NDA, a BLA, or an efficacy supplement 
is submitted for approval on or after [EFFECTIVE DATE OF FINAL RULE 
WILL BE ADDED], a Patient Medication Information must be submitted to 
FDA as part of the application.
    (2) For products for which an NDA, a BLA, or an efficacy supplement 
is pending on [EFFECTIVE DATE OF FINAL RULE WILL BE ADDED], a 
supplement or, if appropriate, an amendment, with Patient Medication 
Information must be submitted to FDA no later than 1 year after the 
date of approval of the pending application.
    (3) For products with an FDA-approved Medication Guide (as required 
under subparts C and D of this part) or an FDA-approved patient package 
insert (as required under Sec.  310.501 or Sec.  310.515 of this 
chapter) for which an NDA or a BLA has been approved on or any time 
before [EFFECTIVE DATE OF FINAL RULE WILL BE ADDED], a supplement with 
Patient Medication Information must be submitted to FDA no later than 
[DATE 1 YEAR AFTER EFFECTIVE DATE OF FINAL RULE WILL BE ADDED]. Once 
the product with an FDA-approved Medication Guide (as required under 
subparts C and D of this part) or an FDA-approved patient package 
insert (as required under Sec.  310.501 or Sec.  310.515 of this 
chapter) has FDA-approved Patient Medication Information, the 
Medication Guide requirements (under subparts C and D of this part) and 
the patient package insert requirements (Sec. Sec.  310.501 and 310.515 
of this chapter) are no longer applicable to such product.
    (4) For products without an FDA-approved Medication Guide or an 
FDA-approved patient package insert for which an NDA, a BLA, or an 
efficacy supplement has been approved any time from January 1, 2013, up 
to and including [EFFECTIVE DATE OF FINAL RULE WILL BE ADDED], a 
supplement with Patient Medication Information must be submitted to FDA 
no later than [DATE 2 YEARS AFTER EFFECTIVE DATE OF FINAL RULE WILL BE 
ADDED].
    (5) For products without an FDA-approved Medication Guide or an 
FDA-approved patient package insert for which an NDA, a BLA, or an 
efficacy supplement has been approved from January 1, 2008, up to and 
including December 31, 2012, a supplement with Patient Medication 
Information must be submitted to FDA no later than [DATE 3 YEARS AFTER 
EFFECTIVE DATE OF FINAL RULE WILL BE ADDED].
    (6) For products without an FDA-approved Medication Guide or 
without an FDA-approved patient package insert for which an NDA, a BLA, 
or an efficacy supplement has been approved from January 1, 2003, up to 
and including December 31, 2007, a supplement with Patient Medication 
Information must be submitted to FDA no later than [DATE 4 YEARS AFTER 
EFFECTIVE DATE OF FINAL RULE WILL BE ADDED].
    (7) For products without an FDA-approved Medication Guide or 
without an FDA-approved patient package insert for which an NDA, a BLA, 
or an efficacy supplement has been approved on or before December 31, 
2002, a supplement with Patient Medication Information must be 
submitted to FDA no later than [DATE 5 YEARS AFTER EFFECTIVE DATE OF 
FINAL RULE WILL BE ADDED].
    (b) Implementation schedule for applicants to submit Patient 
Medication Information for ANDAs. ANDA applicants must submit to FDA 
Patient Medication Information that conforms to the requirements in 
subparts A and B of this part and other applicable regulations.
    (1) For products for which an ANDA is submitted for approval on or 
after [EFFECTIVE DATE OF FINAL RULE WILL BE ADDED], Patient Medication 
Information must be submitted to FDA as follows:
    (i) If the Patient Medication Information for the reference listed 
drug is approved at the time the ANDA is submitted or if FDA has 
finalized the Patient Medication Information template and provides 
notice of the template to the applicant, whichever applies, Patient 
Medication Information must be submitted to FDA as part of the 
application.
    (ii) If the Patient Medication Information for the reference listed 
drug is not approved or if FDA has not finalized the Patient Medication 
Information template and provided notice of the template to the 
applicant, whichever applies, at the time the ANDA is submitted but 
such Patient Medication Information is approved for the reference 
listed drug or FDA

[[Page 35725]]

finalizes the template and provides notice of the template to the 
applicant before the ANDA is approved, the applicant for the ANDA must 
submit Patient Medication Information in an amendment to the pending 
application after the approval of the Patient Medication Information 
for the reference listed drug or after FDA finalizes the Patient 
Medication Information template and provides notice of the template to 
the applicant, whichever applies.
    (iii) If the Patient Medication Information for the reference 
listed drug is not approved or if FDA has not finalized the Patient 
Medication Information template and provided notice of the template to 
the applicant, whichever applies, before the submitted ANDA is 
approved, a supplement with the Patient Medication Information must be 
submitted to FDA, consistent with Sec.  314.70 of this chapter, after 
the approval of the Patient Medication Information for the reference 
listed drug or after FDA finalizes the Patient Medication Information 
template and provides notice of the template to the applicant, 
whichever applies.
    (2) For products for which an ANDA is pending on the [EFFECTIVE 
DATE OF FINAL RULE WILL BE ADDED], Patient Medication Information must 
be submitted as follows:
    (i) If the Patient Medication Information for the reference listed 
drug is approved or if FDA finalizes the Patient Medication Information 
template and provides notice of the template to the applicant before 
the ANDA is approved, an amendment to the pending application with 
Patient Medication Information must be submitted to FDA after the 
approval of the Patient Medication Information for the reference listed 
drug or after FDA finalizes the Patient Medication Information template 
and provides notice of the template to the applicant, whichever 
applies.
    (ii) If the Patient Medication Information for the reference listed 
drug is approved or if FDA finalizes the Patient Medication Information 
template and provides notice of the template to the applicant after the 
pending ANDA is approved, a supplement with Patient Medication 
Information must be submitted to FDA, consistent with Sec.  314.70 of 
this chapter, after the approval of the Patient Medication Information 
for the reference listed drug or after FDA finalizes the Patient 
Medication Information template and provides notice of the template to 
the applicant, whichever applies.
    (3) For products for which an ANDA has been approved on or any time 
before [EFFECTIVE DATE OF FINAL RULE WILL BE ADDED], a supplement with 
Patient Medication Information must be submitted to FDA, consistent 
with Sec.  314.70 of this chapter, after the approval of the Patient 
Medication Information for the reference listed drug or after FDA 
finalizes the Patient Medication Information template and provides 
notice of the template to the applicant, whichever applies.
    (c) Implementation schedule for authorized dispensers to provide 
Patient Medication Information to patients. Authorized dispensers must 
begin to provide FDA-approved Patient Medication Information as 
required under this section on [DATE 2 YEARS AFTER EFFECTIVE DATE OF 
FINAL RULE WILL BE ADDED] and must continue to provide FDA-approved 
Patient Medication Information thereafter. Once a product with an FDA-
approved Medication Guide (as required under subparts C and D of this 
part) has FDA-approved Patient Medication Information, the requirements 
for providing a Medication Guide (under Sec.  208.96) are no longer 
applicable for such product.


Sec.  208.90  Waivers.

    On its own initiative or in response to a request from a covered 
entity, FDA may waive any Patient Medication Information requirement on 
the basis that the requirement is inapplicable, impracticable, or 
contrary to a patient's best interests (for example, impedes patient 
access to the drug product). FDA may consider an applicant's request 
for an extension from the specified implementation date to comply fully 
with the Patient Medication Information requirements. Written requests 
for waivers must be submitted to the director of the FDA division 
responsible for reviewing the marketing application for the drug 
product. For ANDAs, the requests for waivers and the rationale for the 
waiver would need to be submitted to the Director of the Office of 
Generic Drugs. For biological products, requests would be submitted to 
the FDA application division in the office with product responsibility.

Subpart C--General Provisions for Medication Guides for 
Prescription Drug Products


Sec.  208.91  Scope and purpose.

    (a) Subparts C and D of this part set forth requirements for 
patient labeling for human prescription drug products, including 
biological products, that FDA determines pose a serious and significant 
public health concern requiring distribution of FDA-approved patient 
information. It applies primarily to human prescription drug products 
used on an outpatient basis without direct supervision by a health 
professional. Subparts C and D of this part apply to new prescriptions 
and refill prescriptions.
    (b) The purpose of patient labeling for human prescription drug 
products required under this part is to provide information when FDA 
determines in writing that it is necessary to patients' safe and 
effective use of drug products.
    (c) Patient labeling will be required if FDA determines that one or 
more of the following circumstances exists:
    (1) The drug product is one for which patient labeling could help 
prevent serious adverse effects.
    (2) The drug product is one that has serious risk(s) (relative to 
benefits) of which patients should be made aware because information 
concerning the risk(s) could affect a patient's decision to use or to 
continue to use the product.
    (3) The drug product is important to health, and patient adherence 
to directions for use is crucial to the drug's effectiveness.
    (d) Drug products described in Sec.  208.10 must comply with 
subparts A and B of this part according to the implementation plan in 
Sec.  208.80. Once a drug product has FDA-approved Patient Medication 
Information, the requirements for Medication Guides under subparts C 
and D of this part are no longer applicable.


Sec.  208.92  Definitions.

    The following definitions apply to subparts C and D of this part:
    Authorized dispenser means an individual who is licensed, 
registered, or otherwise permitted by the jurisdiction in which the 
individual practices to provide prescription drug products in the 
course of professional practice.
    Dispensed means the act of providing a prescription drug product to 
a patient (or a patient's agent) by either of the following ways:
    (1) By a licensed healthcare provider (or a licensed provider's 
agent), either directly or indirectly, for administration by the 
patient (or the patient's agent) or outside the licensed provider's 
direct supervision.
    (2) By an authorized dispenser (or authorized dispenser's agent) 
under a lawful prescription of a licensed healthcare provider.
    Distribute means the act of delivering, other than by dispensing, a 
drug product to any person.
    Distributor means a person who distributes a drug product.

[[Page 35726]]

    Drug product means a finished dosage form (for example, tablet, 
capsule, solution) that contains a drug substance, generally, but not 
necessarily, in association with one or more other ingredients. For the 
purposes of this part, drug product also includes a biological product 
licensed under section 351(a) and (k) of the Public Health Service Act 
(42 U.S.C. 262(a) and (k)).
    Licensed healthcare provider means an individual who is licensed, 
registered, or otherwise permitted by the jurisdiction in which the 
individual practices to prescribe drug products in the course of 
professional practice.
    Manufacturer means all of the following:
    (1) For a drug product that is not also a biological product, both 
the manufacturer as described in Sec.  201.1 of this chapter and the 
applicant as described in Sec.  314.3(b) of this chapter.
    (2) For a drug product that is also a biological product, the 
manufacturer as described in Sec.  600.3(t) of this chapter.
    Medication Guide means FDA-approved patient labeling conforming to 
the specifications set forth in subparts C and D of this part and other 
applicable regulations.
    Packer means a person who packages a drug product.
    Patient means any individual to whom a drug product is intended to 
be, or has been, used, dispensed, or administered.
    Serious risk or serious adverse effect means an adverse drug 
experience, or the risk of such an experience, as that term is defined 
in Sec. Sec.  310.305, 312.32, 314.80, and 600.80 of this chapter.

Subpart D--General Requirements for Medication Guides for 
Prescription Drug Products


Sec.  208.94  Content and format of a Medication Guide.

    (a) A Medication Guide must meet all of the following conditions:
    (1) The Medication Guide must be written in English, in 
nontechnical, understandable language, and shall not be promotional in 
tone.
    (2) The Medication Guide must be scientifically accurate and must 
be based on, and must not conflict with, the approved professional 
labeling for the drug product under Sec.  201.57 of this chapter, but 
the language of the Medication Guide need not be identical to the 
sections of approved labeling to which it corresponds.
    (3) The Medication Guide must be specific and comprehensive.
    (4) The letter height or type size must be no smaller than 10 
points (1 point = 0.0138 inches) for all sections of the Medication 
Guide, except the manufacturer's name and address and the revision 
date.
    (5) The Medication Guide must be legible and clearly presented. 
Where appropriate, the Medication Guide must also use boxes, bold or 
underlined print, or other highlighting techniques to emphasize 
specific portions of the text.
    (6) The words ``Medication Guide'' must appear prominently at the 
top of the first page of a Medication Guide. The verbatim statement 
``This Medication Guide has been approved by the U.S. Food and Drug 
Administration'' must appear at the bottom of a Medication Guide.
    (7) The brand name and established or proper name of the drug 
product must appear immediately below the words ``Medication Guide.'' 
The established or proper name must be no less than one-half the height 
of the brand name.
    (b) A Medication Guide must contain those of the following headings 
relevant to the drug product and to the need for the Medication Guide 
in the specified order. Each heading must contain the specific 
information as follows:
    (1) The brand name (e.g., the trademark or proprietary name), if 
any, and the established or proper name. Those products not having an 
established or proper name must be designated by their active 
ingredients. The Medication Guide must include the phonetic spelling of 
either the brand name or the established name, whichever is used 
throughout the Medication Guide.
    (2) The heading ``What is the most important information I should 
know about (name of drug)?'' followed by a statement describing the 
particular serious and significant public health concern that has 
created the need for the Medication Guide. The statement must describe 
specifically what the patient should do or consider because of that 
concern, such as weighing particular risks against the benefits of the 
drug, avoiding particular behaviors (e.g., activities, drugs), 
observing certain events (e.g., symptoms, signs) that could prevent or 
mitigate a serious adverse effect, or engaging in particular behaviors 
(e.g., adhering to the dosing regimen).
    (3) The heading ``What is (name of drug)?'' followed by a section 
that identifies a drug product's indications for use. The Medication 
Guide must not identify an indication unless the indication is 
identified in the INDICATIONS AND USAGE section of the professional 
labeling for the product as required under Sec.  201.57 of this 
chapter. In appropriate circumstances, this section may also explain 
the nature of the disease or condition the drug product is intended to 
treat, as well as the benefit(s) of treating the condition.
    (4) The heading ``Who should not take (name of drug)?'' followed by 
information on circumstances under which the drug product should not be 
used for its labeled indication (its contraindications). The Medication 
Guide must contain directions regarding what to do if any of the 
contraindications apply to a patient, such as contacting the licensed 
provider or discontinuing use of the drug product.
    (5) The heading ``How should I take (name of drug)?'' followed by 
information on the proper use of the drug product, such as:
    (i) A statement stressing the importance of adhering to the dosing 
instructions, if this is particularly important;
    (ii) A statement describing any special instructions on how to 
administer the drug product, if they are important to the drug's safety 
or effectiveness;
    (iii) A statement of what patients should do in case of overdose of 
the drug product; and
    (iv) A statement of what patients should do if they miss taking a 
scheduled dose(s) of the drug product, where there are data to support 
the advice, and where the wrong behavior could cause harm or lack of 
effect.
    (6) The heading ``What should I avoid while taking (name of 
drug)?'' followed by a statement or statements of specific, important 
precautions patients should take to ensure proper use of the drug, 
including:
    (i) A statement that identifies activities (such as driving or 
sunbathing) and drugs, foods, or other substances (such as tobacco or 
alcohol) that patients should avoid when using the medication;
    (ii) A statement of the risks to mothers and fetuses from use of 
the drug during pregnancy if specific, important risks are known;
    (iii) A statement of the risks of the drug product to nursing 
infants if specific, important risks are known;
    (iv) A statement about pediatric risks if the drug product has 
specific hazards associated with its use in pediatric patients;
    (v) A statement about geriatric risks if the drug product has 
specific hazards associated with its use in geriatric patients; and
    (vi) A statement of special precautions if any, that apply to the 
safe and effective use of the drug product in other identifiable 
patient populations.

[[Page 35727]]

    (7) The heading ``What are the possible or reasonably likely side 
effects of (name of drug)?'' followed by:
    (i) A statement of the adverse reactions reasonably likely to be 
caused by the drug product that are serious or occur frequently.
    (ii) A statement of the risk, if there is one, of patients' 
developing dependence on the drug product.
    (iii) For drug products approved under section 505 of the Federal 
Food, Drug, and Cosmetic Act, the following verbatim statements: ``Call 
your doctor for medical advice about side effects. You may report side 
effects to FDA at 1-800-FDA-1088.''
    (8) General information about the safe and effective use of 
prescription drug products, including:
    (i) The verbatim statement ``Medicines are sometimes prescribed for 
purposes other than those listed in a Medication Guide'' followed by a 
statement that patients should ask health professionals about any 
concerns and a reference to the availability of professional labeling;
    (ii) A statement that the drug product should not be used for a 
condition other than that for which it is prescribed or be given to 
other persons;
    (iii) The name and place of business of the manufacturer, packer, 
or distributor of a drug product that is not also a biological product, 
or the name and place of business of the manufacturer or distributor of 
a drug product that is also a biological product, and in any case, the 
name and place of business of the dispenser of the product may also be 
included; and
    (iv) The date, identified as such, of the most recent revision of 
the Medication Guide, placed immediately after the last section.
    (9) Additional headings and subheadings may be interspersed 
throughout the Medication Guide, if appropriate.


Sec.  208.96  Distributing and providing a Medication Guide.

    (a) The manufacturer of a drug product for which a Medication Guide 
is required under this part must obtain FDA approval of the Medication 
Guide before the Medication Guide may be distributed.
    (b) Each manufacturer who ships a container of drug product for 
which a Medication Guide is required under this part is responsible for 
ensuring that Medication Guides are available for distribution to 
patients by either:
    (1) Providing Medication Guides in sufficient numbers to 
distributors, packers, or authorized dispensers to permit the 
authorized dispenser to provide a Medication Guide to each patient 
receiving a prescription for the drug product; or
    (2) Providing the means to produce Medication Guides in sufficient 
numbers to distributors, packers, or authorized dispensers to permit 
the authorized dispenser to provide a Medication Guide to each patient 
receiving a prescription for the drug product.
    (c) Each distributor or packer that receives Medication Guides or 
has the means to produce Medication Guides from a manufacturer under 
paragraph (b) of this section must provide those Medication Guides or 
the means to produce Medication Guides to each authorized dispenser to 
whom it ships a container of drug product.
    (d) The label of each container or package, where the container 
label is too small, of drug product for which a Medication Guide is 
required under this part must instruct the authorized dispenser to 
provide a Medication Guide to each patient to whom the drug product is 
dispensed and must state how the Medication Guide is provided. These 
statements must appear on the label in a prominent and conspicuous 
manner.
    (e) Each authorized dispenser of a prescription drug product for 
which a Medication Guide is required under this part must, when the 
product is dispensed, provide a Medication Guide directly to each 
patient (or to the patient's agent) unless an exemption applies under 
Sec.  208.98.
    (f) An authorized dispenser or wholesaler is not subject to section 
510 of the Federal Food, Drug, and Cosmetic Act, which requires the 
registration of producers of drugs and the listing of drugs in 
commercial distribution, solely because of an act performed by the 
authorized dispenser or wholesaler under this part.


Sec.  208.98  Exemptions and deferrals.

    (a) FDA on its own initiative or in response to a written request 
from an applicant may exempt or defer any Medication Guide content or 
format requirement--except those requirements in Sec.  208.94(a)(2) and 
(6)--on the basis that the requirement is inapplicable, unnecessary, or 
contrary to patients' best interests. Requests from applicants should 
be submitted to the director of the FDA division responsible for 
reviewing the marketing application for the drug product, or for a 
biological product, to the FDA application division in the office with 
product responsibility.
    (b) If the licensed provider who prescribes a drug product subject 
to this part determines that it is not in a particular patient's best 
interest to receive a Medication Guide because of significant concerns 
about the effect of a Medication Guide on the patient, the licensed 
provider may direct that the Medication Guide not be provided to the 
particular patient. However, the authorized dispenser of a prescription 
drug product subject to this part must provide a Medication Guide to 
any patient who requests information when the drug product is 
dispensed, regardless of any such direction by the licensed provider.

PART 314--APPLICATIONS FOR FDA APPROVAL TO MARKET A NEW DRUG

0
6. The authority citation for part 314 continues to read as follows:

    Authority:  21 U.S.C. 321, 331, 351, 352, 353, 355, 355a, 355f, 
356, 356a, 356b, 356c, 356e, 360cc, 371, 374, 379e, 379k-1.

0
7. In Sec.  314.70, revise paragraph (b)(2)(v)(B) and add paragraph 
(c)(6)(iv) to read as follows:


Sec.  314.70  Supplements and other changes to an approved NDA.

* * * * *
    (b) * * *
    (2) * * *
    (v) * * *
    (B) If applicable, any change to Medication Guides required under 
part 208 of this chapter, except for changes in the information 
specified in Sec. Sec.  208.40(a)(4), (7), and (8), and (c)(3) of this 
chapter, and Sec.  208.94(b)(8)(iii) and (iv) of this chapter; and
* * * * *
    (c) * * *
    (6) * * *
    (iv) Addition of Patient Medication Information for a drug approved 
under an ANDA if the proposed Patient Medication Information is the 
same as that approved for the reference listed drug or the same as the 
Patient Medication Information template finalized by FDA, whichever 
applies, except for permissible differences consistent with Sec.  
314.94(a)(8)(iv).
* * * * *

PART 606--CURRENT GOOD MANUFACTURING PRACTICE FOR BLOOD AND BLOOD 
COMPONENTS

0
8. The authority citation for part 606 continues to read as follows:

    Authority:  21 U.S.C. 321, 331, 351, 352, 355, 360, 360j, 371, 
374; 42 U.S.C. 216, 262, 263a, 264.

0
9. Add Sec.  606.123 to subpart G to read as follows:

[[Page 35728]]

Sec.  606.123  Medication Guides: Patient Medication Information for 
blood and blood components intended for transfusion.

    Medication Guides: Patient Medication Information (as described in 
part 208 of this chapter) must be provided to a patient who is 
administered blood or blood components on an outpatient basis unless a 
waiver is granted.
    (a) Blood establishments must make Patient Medication Information 
(as described in part 208 of this chapter) available for distribution 
to the transfusion service. Licensed blood establishments must submit 
Patient Medication Information to FDA for approval (as described in 
part 208 of this chapter).
    (b) When blood or blood components are administered on an 
outpatient basis, the transfusion service must provide Patient 
Medication Information to each patient (or the patient's agent). The 
transfusion service may provide Patient Medication Information to the 
patient electronically; however, paper distribution must always be 
available.
    (c) On its own initiative or in response to a written request from 
a blood collection establishment or transfusion service, FDA may waive 
any Patient Medication Information requirement on the basis that the 
requirement is inapplicable, unnecessary, impracticable, or contrary to 
a patient's best interests. Written requests for waivers must be 
submitted to the FDA application division in the office with product 
responsibility.

PART 610--GENERAL BIOLOGICAL PRODUCTS STANDARDS

0
10. The authority citation for part 610 continues to read as follows:

    Authority:  21 U.S.C. 321, 331, 351, 352, 353, 355, 360, 360c, 
360d, 360h, 360i, 371, 372, 374, 381; 42 U.S.C. 216, 262, 263, 263a, 
264.


Sec.  610.60  [Amended]

0
11. Amend Sec.  610.60 by removing paragraph (a)(7).

    Dated: May 19, 2023.
Robert M. Califf,
Commissioner of Food and Drugs.
[FR Doc. 2023-11354 Filed 5-30-23; 8:45 am]
BILLING CODE 4164-01-P


