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

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

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......................................

    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

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
--------------------------------------------------------------------------------------------------------------------------------------------------------

                               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

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

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

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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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
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*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

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

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

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.

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

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.

    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.

    (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:

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