[Federal Register Volume 71, Number 15 (Tuesday, January 24, 2006)]
[Rules and Regulations]
[Pages 3922-3997]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 06-545]



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Part II





Department of Health and Human Services





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Food and Drug Administration



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21 CFR Parts 201, 314, and 601



Requirements on Content and Format of Labeling for Human Prescription 
Drug and Biological Products and Draft Guidances and Two Guidances for 
Industry on the Content and Format of Labeling for Human Prescription 
Drug and Biological Products; Final Rule and Notices

  Federal Register / Vol. 71, No. 15 / Tuesday, January 24, 2006 / 
Rules and Regulations  

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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Parts 201, 314, and 601

[Docket No. 2000N-1269] (formerly Docket No. 00N-1269)
RIN 0910-AA94


Requirements on Content and Format of Labeling for Human 
Prescription Drug and Biological Products

AGENCY: Food and Drug Administration, HHS.

ACTION: Final rule.

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SUMMARY: The Food and Drug Administration (FDA) is amending its 
regulations governing the content and format of labeling for human 
prescription drug products (including biological products that are 
regulated as drugs). The final rule revises current regulations to 
require that the labeling of new and recently approved products include 
highlights of prescribing information and a table of contents. The 
final rule also reorders certain sections, requires minor content 
changes, and sets minimum graphical requirements. These revisions will 
make it easier for health care practitioners to access, read, and use 
information in prescription drug labeling. The revisions will enhance 
the safe and effective use of prescription drug products and reduce the 
number of adverse reactions resulting from medication errors due to 
misunderstood or incorrectly applied drug information. For both new and 
recently approved products and older products, the final rule requires 
that all FDA-approved patient labeling be reprinted with or accompany 
the labeling. The final rule also revises current regulations for 
prescription drug labeling of older products by clarifying certain 
requirements. These changes will make the labeling for older products 
more informative for health care practitioners.

DATES: This rule is effective June 30, 2006. See section III of this 
document for the implementation dates of this final rule.

FOR FURTHER INFORMATION CONTACT: 
    For information on drug product labeling: Janet Norden, Center for 
Drug Evaluation and Research (HFD-40), Food and Drug Administration, 
10903 New Hampshire Ave., Bldg. 22, rm. 4202, Silver Spring, MD 20993-
0002, 301-796-2270, [email protected], or Elizabeth Sadove, Center 
for Drug Evaluation and Research (HFD-7), Food and Drug Administration, 
5600 Fishers Lane, Rockville, MD 20857, 301-594-2041, 
[email protected].
    For information on labeling of biological products that are 
regulated as prescription drugs: Toni M. Stifano, Center for Biologics 
Evaluation and Research (HFM-600), Food and Drug Administration, 1401 
Rockville Pike, Rockville, MD 20856, 301-827-6190, 
[email protected], or Kathleen Swisher, Center for Biologics 
Evaluation and Research (HFM-17), Food and Drug Administration, 1401 
Rockville Pike, Rockville, MD 20852, 301-827-6210.

SUPPLEMENTARY INFORMATION:

Table of Contents

I. Background
II. Overview of the Final Rule Including Changes to the Proposed Rule
III. Implementation
IV. Overview of Agency Initiatives to Improve the Content and Format of 
Prescription Drug Labeling
V. Implications of This Final Rule for the Electronic Labeling 
Initiative
VI. Comments on the Proposed Rule
VII. Legal Authority
VIII. Paperwork Reduction Act of 1995
IX. Environmental Impact
X. Executive Order 13132: Federalism
XI. Analysis of Economic Impacts
XII. Executive Order 12988: Civil Justice Reform
XIII. References

I. Background

    In the Federal Register of December 22, 2000 (65 FR 81082), FDA 
issued a proposed rule to revise its regulations governing the content 
and format of labeling for human prescription drug products, which 
appear in Sec. Sec.  201.56 and 201.57 (21 CFR 201.56 and 201.57).\1\
---------------------------------------------------------------------------

    \1\ Although Sec. Sec.  201.56 and 201.57 do not specifically 
mention the term ``biologics'', under the Federal Food, Drug, and 
Cosmetic Act (the act), most biologics are drugs that require a 
prescription and thus are subject to these regulations. (See section 
VII of this document for legal authority.) For the purposes of this 
document, unless otherwise specified, all references to ``drugs'' or 
``drug products'' include human prescription drug products and 
biological products that are also drugs.
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A. FDA-Approved Prescription Drug Labeling

    A prescription drug product's FDA-approved labeling (also known as 
``professional labeling,'' ``package insert,'' ``direction circular,'' 
or ``package circular'') is a compilation of information about the 
product, approved by FDA, based on the agency's thorough analysis of 
the new drug application (NDA) or biologics license application (BLA) 
submitted by the applicant. This labeling contains information 
necessary for safe and effective use. It is written for the health care 
practitioner audience, because prescription drugs require 
``professional supervision of a practitioner licensed by law to 
administer such drug'' (section 503(b) of the act (21 U.S.C. 353(b))). 
FDA-approved labeling is defined in section 201(m) of the act (21 
U.S.C. 321(m)) and is subject to all applicable provisions of section 
502 of the act (21 U.S.C. 352). It satisfies the requirement of Sec.  
201.100(d) (21 CFR 201.100(d)) that ``[a]ny labeling, as defined in 
section 201(m) of the act * * * that furnishes or purports to furnish 
information for use or which prescribes, recommends, or suggests a 
dosage for the use of the drug * * * contains * * * [a]dequate 
information for such use,'' as further described in that provision. 
FDA-approved labeling also accompanies ``promotional'' materials, as 
described in Sec.  202.1(l)(2) (21 CFR 202.1(l)(2)). FDA-approved 
labeling also ``bears adequate information'' within the meaning of 
Sec.  201.100(c)(1), which applies to ``labeling on or within the 
package from which a prescription drug is to be dispensed'', referred 
to in this document as ``trade labeling.'' In this document, FDA-
approved labeling for prescription drugs is referred to as ``labeling'' 
or ``prescription drug labeling.''

B. Developing the Proposed Rule

    In recent years, there has been an increase in the length, detail, 
and complexity of prescription drug labeling, making it harder for 
health care practitioners to find specific information and to discern 
the most critical information. Before issuing the proposal, the agency 
evaluated the usefulness of prescription drug labeling for its 
principal audience to determine whether, and how, its content and 
format could be improved. The agency used focus groups, a national 
physician survey, a public meeting, and written comments to develop 
multiple prototypes and to ascertain how prescription drug labeling is 
used by health care practitioners, what labeling information 
practitioners consider most important, and how practitioners believed 
labeling could be improved. The agency developed a prototype based on 
this accumulated information as the model for the proposed rule.

[[Page 3923]]

C. The Proposed Rule

    The agency's proposed changes were designed to enhance the ability 
of health care practitioners to access, read, and use prescription drug 
labeling.
1. Proposed Provisions for New and Recently Approved Drugs
    FDA proposed the following changes for the labeling for 
prescription drugs that were approved on or after the effective date of 
the final rule, drugs that had been approved in the 5 years before the 
effective date of the final rule, and older approved drugs for which an 
efficacy supplement is submitted. FDA believed that applying the 
revised content and format requirements only to more recently approved 
products was appropriate because, among other reasons, health care 
practitioners are more likely to refer to the labeling of recently 
approved products (see comment 113).
     The addition of introductory prescribing information, 
entitled ``Highlights of Prescribing Information'' (Highlights).
     The addition of a table of contents.
     Reordering and reorganizing to make the labeling easier to 
use and read.
     Minimum graphical requirements for format.
     Certain revisions to the content requirements, such as 
modifying the definition of ``adverse reaction'' to make the ``Adverse 
Reactions'' section of labeling more meaningful and useful to health 
care practitioners.
2. Proposed Provisions for Older Approved Drugs
    The agency proposed that older approved drug products would not be 
subject to these proposed changes. These older products would, instead, 
be subject to the labeling requirements at proposed Sec.  201.80. The 
agency proposed to redesignate then-current Sec.  201.57 as Sec.  
201.80 to describe labeling requirements for older drugs and add new 
Sec.  201.57 to describe labeling requirements for new and recently 
approved drugs.
3. Proposed Provisions for All Drugs
    FDA also proposed certain revisions to the requirements governing 
the content of labeling to help ensure that statements appearing in 
labeling related to effectiveness or dosage and administration are 
sufficiently supported. These provisions would have applied to all 
drugs.
     The labeling for all drugs would contain all FDA-approved 
patient labeling (i.e., approved printed patient information and 
Medication Guides) for the drug, not just the information required by 
regulation to be distributed to patients (see table 2).
     Minor revisions would be made to the requirements for 
labels affixed to prescription drug containers and packaging.
    The proposal called for the submission of comments by March 22, 
2001. At the request of the Pharmaceutical Research and Manufacturers 
of America, and to provide all interested persons additional time to 
comment, the comment period was reopened until June 22, 2001 (66 FR 
17375, March 30, 2001). After careful consideration of the comments, 
FDA has revised the proposal and is issuing this final rule.
    The following sections of this document provide:
     An overview of the final rule including changes to the 
proposed rule (section II of this document),
     A discussion of the implementation requirements for the 
final rule (section III of this document),
     An overview of the agency's prescription drug labeling 
initiatives (section IV of this document),
     The implications of this rule for the electronic labeling 
initiative (section V of this document),
     A discussion of the comments received on the proposal and 
the agency's responses to the comments (section VI of this document),
     A statement of legal authority (section VII of this 
document),
     A description of the information collection provisions of 
the rule (section VIII of this document),
     An statement on the environmental impact of the rule 
(section IX of this document),
     A statement on federalism (section X of this document),
     An analysis of the economic impacts of the rule (section 
XI of this document),
     A statement on the impact of the rule on the civil justice 
system (section XII of this document), and
     A list of references (section XIII of this document).

II. Overview of the Final Rule Including Changes to the Proposed Rule

    This final rule amends part 201 (21 CFR part 201) of FDA 
regulations by revising the requirements for the content and format of 
labeling for prescription drug products (see tables 1 and 2 of this 
document). Table 1 lists the sections required for prescription drug 
labeling before the effective date of this final rule (and which will 
remain in effect for older products), and, for new and recently 
approved products, the sections FDA proposed in 2000 and those required 
by this final rule.

BILLING CODE 4160-01-S

[[Page 3924]]

[GRAPHIC] [TIFF OMITTED] TR24JA06.000

    The final rule requires that any FDA-approved patient labeling 
either: (1) Accompany the prescription drug labeling or (2) be 
reprinted at the end of such labeling (Sec. Sec.  201.57(c)(18) and 
201.80(f)(2)). Table 2 lists the requirement in effect before the 
effective date of this final rule, the 2000 proposed requirement, and 
the final requirement (see comment 92 for discussion of FDA-approved 
patient labeling). For the purposes of this document, the term ``FDA-
approved patient labeling'' will be used to refer to any approved 
printed patient information or Medication Guide, unless a comment is 
addressing one or the other specifically.

[[Page 3925]]



 Table 2.--FDA-Approved Patient Labeling with Prescription Drug Labeling
------------------------------------------------------------------------
  Requirement for All
  Products Before the      Proposed Requirement    Final Requirement for
 Effective Date of the       for All Products          All Products
       Final Rule
------------------------------------------------------------------------
To be reprinted at the   To be reprinted at the   To be reprinted at the
 end of labeling:         end of labeling:         end of labeling or to
 Full text of     Full text of     accompany the
 FDA-approved patient     any FDA-approved         labeling:
 labeling that is         patient labeling         Full text of
 required to be                                    any FDA-approved
 distributed to                                    patient labeling
 patients
------------------------------------------------------------------------

    In this rulemaking, the agency finalizes many of the provisions in 
the December 2000 proposal. In addition, the final rule reflects 
revisions the agency made in response to comments on the December 2000 
proposal and revisions made by the agency on its own initiative. FDA 
also has made editorial changes to clarify provisions, correct cross-
references, and support the agency's plain language initiative. Table 3 
lists the substantive changes made to the general provisions and 
Highlights and table 4 lists the substantive changes made to the Full 
Prescribing Information (FPI).

A. Content and Format of Labeling for New and More Recently Approved 
Prescription Drug Products

    The final rule, like the proposed rule, requires that the labeling 
for new and more recently approved drug products comply with revised 
content and format requirements (Sec.  201.56(d)) (see table 1). Like 
the proposed rule, the final rule provides that new and more recently 
approved products include drug products with an NDA, BLA, or efficacy 
supplement that: (1) Was approved between June 30, 2001, and June 30, 
2006; (2) is pending on June 30, 2006; or (3) is submitted anytime on 
or after June 30, 2006 (Sec.  201.56(b)(1)).
    On its own initiative, the agency added a provision on pediatric 
risk information to the general labeling requirements of the final 
rule. Section 11 of the Best Pharmaceuticals for Children Act (Public 
Law 107-109) (BPCA), which was signed into law on January 4, 2001, 
addresses labeling requirements for generic versions of drugs with 
pediatric patent protection or exclusivity. The agency added a 
provision in Sec.  201.56(d)(5) of the final rule to make clear that 
any risk information from the ``Contraindications,'' ``Warnings and 
Precautions,'' or ``Use in Specific Populations'' section is 
``pediatric contraindications, warnings, or precautions'' within the 
meaning of section 11 of the BPCA (21 U.S.C. 355A(l)(2)). By adding 
Sec.  201.56(d)(5), the agency intends to avoid any possible confusion 
as to what information the agency may require in generic labeling that 
otherwise omits a pediatric indication or other aspect of labeling 
pertaining to pediatric use protected by patent or exclusivity.
    In addition, the agency declined to adopt the use of symbols that 
were proposed to emphasize or identify information in prescription drug 
labeling. Based on comments, FDA declined to use the inverted black 
triangle (see comment 15) and the exclamation point (!) to emphasize 
the boxed warning (see comment 43). On its own initiative, for the same 
reasons that FDA rejected use of the two symbols commented upon, FDA 
declined to use the following three proposed symbols:
     The Rx symbol (proposed Sec.  201.57(a)(3)) in Highlights. 
The agency proposed the symbol to identify a product that is available 
only by prescription under section 503(b) of the act. The agency 
decided that the Rx symbol in Highlights is unnecessary because the new 
prescription drug labeling format is so distinct from the over-the-
counter (OTC) drug labeling format that it will be clear to prescribers 
that labeling in the new format is for a prescription drug product.
     The ``R'' symbol in the FPI (proposed Sec.  201.56(d)(2)), 
which would have identified the ``References'' section.
     The ``P'' symbol in the FPI (proposed Sec.  
201.57(c)(18)), which would have identified the ``Patient Counseling 
Information'' section.
1. Highlights of Prescribing Information
    Like the proposed rule, the final rule requires that the labeling 
for new and more recently approved products include introductory 
information entitled ``Highlights of Prescribing Information'' 
(Highlights) (Sec. Sec.  201.56(d)(1) and 201.57(a)) (see table 1).
    The final rule requires the same headings for Highlights as 
proposed, except that, in response to comments, FDA moved ``Most Common 
Adverse Reactions'' from ``Warnings and Precautions'' (proposed Sec.  
201.57(a)(10)) to a new heading entitled ``Adverse Reactions'' 
(Sec. Sec.  201.56(d)(1) and 201.57(a)(11)) (see table 1 and comment 
28). Like the proposed rule, the final rule requires that Highlights, 
except for the boxed warning, be limited in length to one-half of the 
page (Sec.  201.57(d)(8)) (see comment 104).
    The agency is also revising its regulations on supplements and 
other changes to an approved application in Sec. Sec.  314.70 and 
601.12 (21 CFR 314.70 and 601.12) to require applicants to obtain prior 
approval of any labeling changes to Highlights, except for identified 
minor changes (see comment 5).

  Table 3.--Substantive Changes From the Proposed Rule to the Final Rule: General Provisions and to Highlights
----------------------------------------------------------------------------------------------------------------
                                                    Description of Change from Proposed Rule
                              ----------------------------------------------------------------------------------
 21 CFR Section in Final Rule     See comment or section of this document (identified in parentheses) for more
                                                   detailed information regarding the change.
----------------------------------------------------------------------------------------------------------------
201.55, 201.57(c)(4)(v),       Container Labels
 201.57(c)(12)(i)(D), and       Withdrew proposed amendments regarding content of container labels and
 201.100(b)                     associated proposed amendments to the labeling (106 and 107)
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[[Page 3926]]

 
201.56(a)(2)                   General Requirement
                                Revised to clarify that the labeling must be updated when new
                                information becomes available that causes the labeling to become inaccurate,
                                false, or misleading (114)
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201.56(d)                      Product Title
                                Deleted proposed Sec.   201.56(d)(4), which permitted a ``Product
                                Title'' section to be included at the beginning of the FPI (39)
----------------------------------------------------------------------------------------------------------------
201.56(d)(4)                   Format of Contents
                                Revised to require that the Contents identify if sections have been
                                omitted (37)
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201.56(d)(5)                   Pediatric Risk Information
                                Added, on its own initiative, a provision to make clear that pediatric
                                risk information within the meaning of the BPCA may be located in the ``Use in
                                Specific Populations'' section (II.A)
----------------------------------------------------------------------------------------------------------------
201.57 and 201.80              Unsubstantiated Claims
                                Removed the 1-year implementation requirement for provisions in Sec.
                                Sec.   201.57 and 201.80 that prohibit inclusion of unsubstantiated claims in
                                labeling (114)
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201.57                         Promotional Labeling
                                Removed, on its own initiative, the reference to statements made in
                                promotional labeling and advertising in proposed 201.57(a) (111)
----------------------------------------------------------------------------------------------------------------
201.57(a)(1)                   Highlights Limitation Statement
                                Moved the Highlights limitation statement to the beginning of Highlights
                                (35)
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201.57(a)(3)                   Inverted Black Triangle Symbol
                                Instead of an inverted black triangle symbol, labeling will state the
                                ``Initial U.S. Approval'' date (15)
----------------------------------------------------------------------------------------------------------------
201.57(a)(4)                   Boxed Warning
                                Revised to require that Highlights contain a concise summary of any
                                boxed warning in the FPI (16)
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201.57(a)(5)                   Recent Labeling Changes
                                Changed the heading to ``Recent Major Changes'' and revised to identify
                                only substantive changes to the ``Boxed Warning,'' ``Indications and Usage,''
                                ``Dosage and Administration,'' ``Contraindications,'' and ``Warnings and
                                Precautions'' sections and the date of the change(s) (18-22)
----------------------------------------------------------------------------------------------------------------
201.57(a)(6)                   Indications and Usage
                                Revised to require identification of the pharmacologic class of the drug
                                if it is a member of an established pharmacologic class (6)
----------------------------------------------------------------------------------------------------------------
201.57(a)(8)                   How Supplied
                                Changed the heading to ``Dosage Forms and Strengths'' (41)
----------------------------------------------------------------------------------------------------------------
201.57(a)(11)                  Adverse Reactions
                                Moved ``Most Common Adverse Reactions'' from ``Warnings and
                                Precautions'' to a new heading: ``Adverse Reactions'' (28)
                                Revised the criteria used for determining which adverse reactions to
                                include in Highlights and that the criteria used be specified (28)
                                Revised to require that the adverse reactions reporting contact
                                statement be included under the ``Adverse Reactions'' heading of Highlights;
                                deleted proposed Sec.   201.57(c)(6)(v) that would have required that this
                                statement also be included in the FPI (28 and 30)
                                Revised the requirements associated with the adverse reactions reporting
                                contact statement (31 and 32)
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201.58                         Waiver Provision
                                Revised to make clear applicants can request waivers from any
                                requirement under Sec.  Sec.   201.56, 201.57, and 201.80 (104)
----------------------------------------------------------------------------------------------------------------

2. Full Prescribing Information: Contents
    Like the proposed rule, the final rule requires that the labeling 
for new and recently approved products include, after Highlights, a 
list of headings and subheadings contained in the FPI preceded by the 
numerical identifier for the heading or subheading (Sec.  201.57(b)). 
FDA has revised, on its own initiative, the heading for this portion of 
the labeling to read ``Full Prescribing Information: Contents'' 
(Contents) instead of proposed ``Comprehensive Prescribing Information: 
Index.'' FDA made this change for editorial reasons to correctly 
reflect the function of the section. In response to comments, FDA added 
certain format requirements for the Contents (see table 3 and comments 
37 and 101).

[[Page 3927]]

3. Full Prescribing Information
    FDA has revised, on its own initiative, the heading for this 
portion of the labeling to read ``Full Prescribing Information'' 
instead of proposed ``Comprehensive Prescribing Information.'' FDA made 
this change to more accurately reflect that this portion of 
prescription drug labeling contains the information that FDA determined 
is necessary for the safe and effective use of the drug, but may not 
contain all known information about the drug (e.g., details of all 
clinical trials).
    The final rule revises the requirements for the content and format 
of the FPI in former Sec. Sec.  201.56(d) and 201.57 for new and 
recently approved products (see tables 1 and 2). The final rule 
establishes minimum requirements for key graphic elements, including 
bold type, bullet points, type size, spacing and use of vertical and 
horizontal lines. The final rule requires the same sections for the 
labeling of these products as proposed except the major, substantive 
changes listed in table 4, which the agency made in response to 
comments and, in a few cases as noted, on its own initiative. In 
addition, FDA made revisions, none of which changed substantive 
requirements, to the ``Dosage and Administration,'' ``Indications and 
Usage,'' ``Overdosage,'' ``Clinical Pharmacology,'' and ``Drug 
Interactions'' sections. FDA made these changes in response to comments 
that requested FDA to clarify these proposed requirements.
    In addition, FDA has revised, on its own initiative, 
``Contraindications'' to emphasize that the section must only describe 
situations in which the potential risks associated with drug use 
outweigh any possible benefit. FDA believes that including relative or 
hypothetical hazards diminishes the usefulness of the section. For 
clarity and emphasis, FDA is requiring that ``none'' be stated when no 
contraindications are known. Similarly, FDA deleted, on its own 
initiative, proposed Sec.  201.57(c)(9)(iii) because it was redundant 
with requirements in ``Warnings and Precautions'' and 
``Contraindications.''

 Table 4.--Substantive Changes From the Proposed Rule to the Final Rule:
                      Full Prescribing Information
------------------------------------------------------------------------
                          Description of Change From Proposed Rule
                   -----------------------------------------------------
 21 CFR Section in   See comment or section of this document (identified
    Final Rule          in parentheses) for more detailed information
                                    regarding the change.
------------------------------------------------------------------------
201.57(c)(3)        Dosage and Administration
                     Revised to make clear that this section
                     must include dosing recommendations based on
                     clinical pharmacologic data, certain dosage
                     modifications, and specified compliance information
                     (51-54)
------------------------------------------------------------------------
201.57(c)(4) and    How Supplied/Storage and Handling
 201.57(c)(17)       Reorganized information in proposed ``How
                     Supplied/Storage and Handling'' (Sec.
                     201.57(c)(4)) such that the information is now
                     contained in two sections: Sec.   201.57(c)(4)
                     retitled ``Dosage Forms and Strengths'' and ``How
                     Supplied/Storage and Handling'' at Sec.
                     201.57(c)(17) (41)
------------------------------------------------------------------------
201.57(c)(7)        Adverse Reactions
                     Moved the ``Adverse Reactions'' section
                     (proposed Sec.   201.57(c)(9)) to follow ``Warnings
                     and Precautions'' (38)
                     Withdrew the proposed definition of adverse
                     reaction and retained the definition at former Sec.
                       201.57(g) (designated in this final rule at Sec.
                      201.80(g)), with a minor modification (68)
                     Revised the requirements on how to classify
                     and categorize adverse reactions and how to
                     describe adverse reaction rates (71-75)
                     Revised to require a description of the
                     overall adverse reaction profile based on entire
                     safety database (70 and 77)
------------------------------------------------------------------------
201.57(c)(9)        Use in Specific Populations
                     Withdrew the proposed warning statements at
                     Sec.  Sec.   201.57(c)(8)(i)(A)(4) and
                     (c)(8)(i)(A)(5) for pregnancy categories D and X
                     and will continue to require the warning statements
                     at former Sec.  Sec.   201.57(f)(6)(i)(d) and
                     (f)(6)(i)(e) be used (66)
                     Withdrew the proposed revisions for the
                     ``Nursing Mothers'' subsection at Sec.
                     201.57(c)(8)(iii) and will continue to use the
                     language at former Sec.   201.57(f)(8) (66)
------------------------------------------------------------------------
201.57(c)(13)(ii)   In Vitro Data for Anti-infectives
 and 201.80(b)(2)    Deferred action on proposed Sec.  Sec.
                     201.57(c)(13)(ii) and 201.80(b)(2) that would have
                     only permitted in vitro data for anti-infective
                     drugs not shown by adequate and well-controlled
                     studies to be pertinent to clinical use be included
                     in labeling if a waiver was granted (81)
------------------------------------------------------------------------
201.57(c)(18) and   Patient Counseling Information
 201.80(f)(2)        Revised to require that the full text of
                     FDA-approved patient labeling either accompany
                     labeling or be reprinted at the end of the labeling
                     and clarified the type size requirements that apply
                     (93 and 94)(see table 7)
------------------------------------------------------------------------
201.57(d)(6)        Font size
                     Revised to require that font for trade
                     labeling be a minimum of 6-point type instead of 8-
                     point type (102)
------------------------------------------------------------------------
201.57(c)(16) and   References
 201.80(l)           Clarified requirements for including a
                     reference (89)
------------------------------------------------------------------------


[[Page 3928]]

B. Content and Format for Older Prescription Drug Products

    Like the proposed rule, the final rule redesignates former Sec.  
201.57 as Sec.  201.80. New Sec.  201.80 provides content and format 
requirements for labeling of older prescription drug products (older 
products) that are not subject to the labeling requirements at new 
Sec.  201.57 (see tables 1 and 2).
    Section 201.80 is the same as former Sec.  201.57 with the 
following exceptions that are the same as the changes for new and more 
recently approved products:
     Modifications that help ensure that statements currently 
appearing in labeling for older products relating to effectiveness or 
dosage and administration are sufficiently supported (Sec.  
201.80(c)(2)(i), (c)(2)(ii), (j), and (m)(1)).
     Deletion of proposed Sec.  201.80(b)(2) regarding in vitro 
data for anti-infectives (see table 4 and comment 81).
     Deletion of ``induced emesis'' as an example of treatment 
procedures in the ``Overdosage'' section of labeling.
     Revisions that allow manufacturers the option of either 
reprinting the FDA-approved patient labeling immediately following the 
last section of the prescription drug labeling or having it accompany 
such labeling (Sec.  201.80(f)(2))(see table 4 and comment 93).
     Addition of the font size provision to redesignated Sec.  
201.80(f)(2) (on the agency's own initiative with modifications made in 
response to comments) (see table 4 and comments 93 and 94).

C. Content of Prescription Drug Product Labels

    FDA has reconsidered its proposal to revise the requirements for 
the content of prescription drug product labels (proposed Sec. Sec.  
201.55 and 201.100(b)). In response to comments, FDA has decided to 
withdraw these proposed revisions at this time (see comments 106 and 
107). The agency had proposed to move certain information about 
inactive ingredients and storage conditions from the product label to 
the prescription drug labeling and to remove the requirement to include 
the statement ``See package insert for dosage information'' on the 
product label in cases when it is currently required to be used. These 
proposed requirements (proposed Sec.  201.57(c)(4)(v) and 
(c)(12)(i)(D)) were also withdrawn.
    The agency intends to conduct a comprehensive evaluation of 
information required to be contained on product labels. If necessary, 
FDA will propose changes to these requirements after that evaluation 
has been completed.

III. Implementation

    The final rule is effective June 30, 2006. The final rule has the 
same implementation plan as proposed for the revised labeling content 
and format requirements at Sec. Sec.  201.56(d) and 201.57 for new and 
more recently approved products (see table 5). Manufacturers of older 
products that voluntarily elect to revise the format and content of 
their labeling to be consistent with Sec. Sec.  201.56(d) and 201.57 
may submit a supplement with proposed labeling at any time (see table 
5).

                      Table 5.--Implementation Plan
------------------------------------------------------------------------
   Applications (NDAs, BLAs, and
 Efficacy Supplements) Required to    Time by Which Conforming Labeling
      Conform to New Labeling          Must Be Submitted to the  Agency
            Requirements                         for Approval
------------------------------------------------------------------------
Applications submitted on or after   Time of submission
 June 30, 2006
------------------------------------------------------------------------
Applications pending on June 30,     June 30, 2009
 2006 and applications approved 0
 to 1 year before June 30, 2006
------------------------------------------------------------------------
Applications approved 1 to 2 years   June 30, 2010
 before June 30, 2006
------------------------------------------------------------------------
Applications approved 2 to 3 years   June 30, 2011
 before June 30, 2006
------------------------------------------------------------------------
Applications approved 3 to 4 years   June 30, 2012
 before June 30, 2006
------------------------------------------------------------------------
Applications approved 4 to 5 years   June 30, 2013
 before June 30, 2006
------------------------------------------------------------------------
Applications approved more than 5    Voluntarily at any time
 years before June 30, 2006
------------------------------------------------------------------------

    As indicated in the proposed rule, the implementation plan for 
revised labeling for products approved or submitted for approval under 
an ANDA depends on the labeling of the listed drug referenced in the 
ANDA. In accordance with Sec.  314.94(a)(8) (21 CFR 314.94(a)(8)), the 
labeling of a drug product submitted for approval under an ANDA must be 
the same as the labeling of the listed drug referenced in the ANDA, 
except for changes required because of differences approved under a 
suitability petition (Sec.  314.93 (21 CFR 314.93)) or because the drug 
product and the reference listed drug are produced or distributed by 
different manufacturers.
    As the agency proposed (65 FR at 81099), the provisions requiring 
FDA-approved patient labeling to accompany labeling (Sec. Sec.  
201.57(c)(18) and 201.80(f)(2) of the final rule) will be implemented 
by June 30, 2007. The agency clarified this provision at Sec. Sec.  
201.57 and 201.56(e)(6).

IV. Overview of Agency Initiatives to Improve the Content and Format of 
Prescription Drug Labeling

    The agency is engaged in a broad effort to improve the 
communication to health care practitioners of information necessary for 
the safe and effective use of prescription drugs. A major component of 
this effort is improvement of the content and format of prescription 
drug labeling to make the information in labeling easier for health 
care practitioners to access, read, and use.
    Elsewhere in this issue of the Federal Register, the agency is 
announcing the availability of four guidance documents on content and 
format of labeling.\2\ These guidances are intended to assist 
manufacturers and FDA reviewers in developing clear, concise, and

[[Page 3929]]

accessible prescription drug labeling. The four guidances are as 
follows:
---------------------------------------------------------------------------

    \2\ The agency announces the availability of guidances in the 
Federal Register. Draft and final guidances for the Center for Drug 
Evaluation and Research (CDER)-related information are posted on the 
Internet at http://www.fda.gov/cder/guidance/index.htm. The Center 
for Biologics Evaluation and Research (CBER)-related information is 
posted at http://www.fda.gov/cber/guidelines.htm (21 U.S.C. 371(h), 
21 CFR 10.115).
---------------------------------------------------------------------------

    1. A draft guidance entitled ``Labeling for Human Prescription Drug 
and Biological Products--Implementing the New Content and Format 
Requirements'' (the new labeling format guidance). This guidance, which 
is intended to assist manufacturers in complying with the provisions of 
this final rule, includes, among other things, how to determine what 
information from the FPI should be included in Highlights.
    2. A draft guidance entitled ``Warnings and Precautions, 
Contraindications, and Boxed Warning Sections of Labeling for Human 
Prescription Drug and Biological Products--Content and Format'' (the 
``Warnings and Precautions'' section guidance).
    3. A guidance entitled ``Adverse Reactions Section of Labeling for 
Human Prescription Drug and Biological Products--Content and Format `` 
(the ``Adverse Reactions'' section guidance). The agency issued a draft 
of this guidance on June 21, 2000 (65 FR 38563).
    4. A guidance entitled ``Clinical Studies Section of Labeling for 
Prescription Drug and Biological Products--Content and Format'' (the 
``Clinical Studies'' section guidance). The agency issued a draft of 
this guidance on July 9, 2001 (66 FR 35797).
    The agency is also developing two additional guidances on the 
content and format of specific sections of labeling--the ``Clinical 
Pharmacology'' and ``Dosage and Administration'' sections. In the 
future, the agency may develop guidance for additional sections of 
prescription drug labeling, if necessary.
    FDA has undertaken additional rulemaking related to prescription 
drug labeling. The agency published a final rule in the Federal 
Register entitled ``Labeling Requirements for Systemic Antibacterial 
Drug Products Intended for Human Use'' that became effective on 
February 4, 2004 (68 FR 6062, February 6, 2003). This rule requires 
that the labeling for all systemic antibacterial drug products (i.e., 
antibiotics and their synthetic counterparts) intended for human use 
include certain statements about using antibiotics in a way that will 
reduce the development of drug-resistant bacterial strains. The rule 
encourages health care practitioners: (1) To prescribe systemic 
antibacterial drugs only when clinically indicated and (2) to counsel 
their patients about the proper use of such drugs and the importance of 
taking them exactly as directed.
    The agency is also engaged in an effort to revise the regulations 
concerning the content and format of the ``Pregnancy'' subsection of 
prescription drug labeling (see the notice of a 21 CFR part 15 hearing 
to discuss the pregnancy category requirements (62 FR 41061, July 31, 
1997) and the notice of a public advisory committee meeting to discuss 
possible changes to pregnancy labeling (64 FR 23340, April 30, 1999)).

V. Implications of This Final Rule for the Electronic Labeling 
Initiative

    Developing standards for the conversion of paper labeling to an 
electronic format is a high priority for the agency. On December 11, 
2003, FDA published its final rule in the Federal Register entitled 
``Requirements for Submission of Labeling for Human Prescription Drugs 
and Biologics in Electronic Format'' (68 FR 69009). The final rule 
requires the content of prescription drug labeling, including text, 
tables, and figures, to be submitted to FDA in an electronic format 
that the agency can process, review, and archive.
    The agency views this final rule on the content and format of 
labeling as an essential step towards the success of its electronic 
labeling initiative. The labeling format required by this rule for new 
and more recently approved products should facilitate transition to an 
electronic format. The agency believes that an electronic version of 
labeling in the new format, particularly Highlights and Contents, will 
significantly expand health care practitioners' ability to access 
information in prescription drug labeling, enable them to rapidly 
obtain answers to questions for a range of drug products, and 
ultimately facilitate the development of a comprehensive repository for 
drug labeling. For example, FDA envisions that an electronic version of 
the new format will eventually enable health care practitioners to 
quickly access labeling information for all drugs in a pharmacologic or 
therapeutic class with a single electronic query.
    FDA realizes that this final rule will affect the agency's existing 
electronic labeling requirements and guidances and will work to ensure 
consistency with the electronic labeling initiative.\3\ The agency 
believes the electronic labeling initiative, in conjunction with this 
new format for labeling described in this final rule, could 
dramatically improve the way practitioners obtain information about 
prescription drugs and, as a consequence, significantly improve patient 
care.
---------------------------------------------------------------------------

    \3\ See http://www.fda.gov/cder/guidance/index.htm under 
``Electronic Submissions'' and http://www.fda.gov/cber/guidelines.htm for the most recent guidances on submission of 
labeling in an electronic format for drug and biological products, 
respectively.
---------------------------------------------------------------------------

VI. Comments on the Proposed Rule

    The agency received 97 comments on the December 22, 2000, proposal. 
Comments were received from prescription drug manufacturers and related 
companies; trade organizations representing prescription drug 
manufacturers and other interested parties; professional associations 
and organizations representing health care practitioners; health care 
and consumer advocacy organizations; individual physicians, 
pharmacists, and consumers; and others.

A. General Comments on the Proposed Rule

    Most comments expressed broad agreement that prescription drug 
labeling could be more effective in communicating drug information to 
health care practitioners and overwhelming support for the agency's 
goal of improving the content and format of prescription drug labeling 
to make information easier for health care practitioners to access, 
read, and use.
    Many comments expressed approval of all the major features of the 
proposal, indicating that the proposed changes represent an important 
improvement in the organization, clarity, and overall usefulness of 
prescription drug labeling. For example, there was near universal 
support for the proposal to place at the front of labeling those 
sections that practitioners refer to most frequently and consider most 
important, although some comments recommended sequences slightly 
different from those proposed by FDA (see section VI.G of this 
document). There was also broad support for restructuring the old 
``Precautions'' section into new sections devoted to use in specific 
populations, drug interactions, and patient counseling information and 
for combining the remainder of the ``Precautions'' section with the 
``Warnings'' section.
    Comments from manufacturers, while strongly supportive of the 
agency's efforts to improve the content and format of labeling, 
generally expressed concerns about some of the major elements of the 
proposal. In particular, as discussed in greater detail in sections 
VI.C and VI.D of this document, many manufacturers were concerned about 
the inclusion of Highlights. Manufacturers also expressed concern about 
the proposed requirements to re-evaluate, within 1 year of the 
effective

[[Page 3930]]

date of the final rule, all prescription drug labeling to identify and 
remove any claims for indications and dosing regimens that are not 
supported by substantial evidence and to remove in vitro data that are 
not supported by clinical data.
    Specific issues raised by the comments and the agency's responses 
follow.

B. Comments on the Process for Development of the Proposed Rule

    As discussed in detail in the preamble to the proposed rule, FDA 
relied on focus group testing of physicians, a national physician 
survey, and a public meeting held in 1995 to develop the labeling 
prototype that was used as the basis for the proposal (65 FR 81082 at 
81083 through 81085).
    (Comment 1) Several comments questioned the process that FDA used 
to develop the proposed rule. A number of comments expressed concern 
that health care practitioners other than physicians were not surveyed 
or otherwise consulted. Two comments indicated that a majority of 
pharmacists refer to prescription drug labeling at least once a day. 
The comments cited a survey finding that the sections most frequently 
referred to by pharmacists are, in descending order, ``Dosage and 
Administration,'' ``Adverse Reactions,'' ``Contraindications,'' 
``Indications and Usage,'' ``Warnings and Precautions,'' and ``How 
Supplied/Storage and Handling.'' The comments urged FDA to consult with 
all relevant audiences to revise prescription drug labeling and labels.
    FDA recognizes the important roles that health care practitioners 
other than physicians play in the health care delivery system and 
recognizes that prescription drug information is relied upon by health 
care practitioners other than physicians. The agency focused its 
research efforts on how physicians use labeling, because they are the 
principal intended audience (i.e., they use labeling for prescribing 
decisions). The agency also sought input from all interested parties in 
the development of the proposed rule, especially those whose use of 
labeling could be expected to impact patient safety. Panelists and 
participants in the 1995 public meeting included nurse practitioners, 
pharmacists, and physician assistants. Their comments and observations 
directly contributed to refining the third version of FDA's prototype 
into the version that was the basis for the proposed rule. Moreover, 
the agency has carefully reviewed and considered all comments received 
on the proposed rule, which included comments from a broad range of 
health care practitioners that rely on prescription drug labeling, and 
has determined the optimal ordering for labeling sections, as reflected 
in this final rule.
    FDA notes that the sections most commonly referred to by 
pharmacists in the cited survey are the same as those most commonly 
referred to by physicians, although in a somewhat different rank order. 
FDA believes that, although the rank order of the sections is not 
identical for the two groups, the formatting improvements required by 
this final rule make the information in these sections readily 
accessible to all health care practitioners who use prescription drug 
labeling.

C. Highlights of Prescribing Information--General Comments

    FDA proposed to require that prescription drug labeling for 
products described in proposed Sec.  201.56(b)(1) (i.e., new and more 
recently approved prescription drug products) contain introductory 
prescribing information entitled ``Highlights of Prescribing 
Information'' (proposed Sec. Sec.  201.56(d) and 201.57(a)).
    (Comment 2) Comments expressed different opinions about the utility 
and patient care implications of Highlights. Physicians, pharmacists, 
other health care practitioners, health care advocacy groups, and 
professional societies and organizations representing health care 
practitioners expressed unequivocal enthusiasm about and uniform 
support for Highlights. Manufacturers, with some exceptions, were 
opposed, or strongly opposed, to the inclusion of Highlights.
    Comments supporting Highlights stated that it would be an excellent 
vehicle for drawing attention to the most important information about a 
product, a useful and convenient source for quick reminder information 
in routine prescribing situations, and a useful vehicle to efficiently 
direct practitioners to the more detailed information in the FPI. 
Several comments stated that Highlights is probably the most important 
innovation in the proposed rule. One comment stated that Highlights is 
the element of the proposal that will most enhance the clinical utility 
of prescription drug labeling. Several comments stated that by making 
prescription drug labeling easier to navigate, Highlights would help to 
make labeling easier for patients and health care practitioners to 
understand.
    Several comments endorsed the Highlights format as a means of 
making labeling information more accessible. Some comments stated that 
the proposed format for Highlights is a good design because it makes 
use of multiple formats (e.g., text, tables, bulleted lists) and bolded 
headings, which make the labeling information more accessible. One 
comment noted that, because Highlights contains pointers to the 
location of more detailed information in the FPI, the pointers will 
increase the likelihood that health care practitioners will refer to 
the FPI. The comment also stated that the user-friendly Highlights 
format would be likely to increase the frequency with which health care 
practitioners consult the labeling for drug information and would 
enhance their ability to use the information.
    Comments opposing inclusion of Highlights stated that manufacturers 
would be forced to pick certain important warnings listed in the FPI 
for inclusion in Highlights and, because of space limitations, exclude 
other important information. These comments maintained that, by 
extracting from the FPI only selected portions of the information 
needed for safe and effective use, Highlights would omit important 
information and lack detail and context, and might, therefore, be 
misleading. They contended that these shortcomings might outweigh any 
convenience derived from condensing information into Highlights. One 
comment maintained that the FPI is itself a condensation of a complex 
body of information and that it is problematic and illogical to try to 
further condense the information from the FPI into Highlights.
    Several comments from manufacturers stated that the limited content 
of Highlights is of concern because practitioners would have a tendency 
to rely only on the information in Highlights when making prescribing 
decisions, even though that information alone would not be an adequate 
basis for making such decisions. Some of these comments maintained that 
there is a lack of evidence to support the premise that Highlights will 
facilitate practitioners' access to more detailed information in the 
FPI. They asserted that there is a high likelihood that Highlights 
would be the only part of the labeling read by practitioners.
    Another comment stated that, rather than requiring inclusion of 
Highlights in labeling, the agency and manufacturers should work 
together to make the FPI better.
    FDA has determined that the Highlights provisions of the final rule 
are an essential element of the agency's efforts to improve the 
accessibility, readability, and usefulness of information in 
prescription drug labeling and reduce the number of

[[Page 3931]]

adverse reactions resulting from medication errors due to misunderstood 
or incorrectly applied drug information. By means of focus group 
testing, a nationwide physician survey, and a public meeting, the 
agency carefully evaluated the drug information needs of physicians and 
ways to best address those needs in prescription drug labeling. Some of 
the principal findings were that: (1) The relative importance of 
information in labeling varies, (2) physicians typically refer to 
labeling to answer a specific question, (3) physicians have 
considerable difficulty locating the information they need to make 
prescribing decisions, and (4) physicians strongly prefer to have a 
separate introductory summary of the most important information 
contained in the full prescribing information, located at the beginning 
of labeling, to make it easier to find the information necessary to 
prescribe the drug safely and effectively (65 FR 81082 at 81083 through 
81085; see also Ref. 11). Many of the comments submitted in response to 
the proposed rule concur with these findings, particularly those from 
health care practitioners and their organizations.
    This preference for highlighting the most important information 
that is part of a larger body of information is consistent with good 
risk communication practices and with well-established cognitive 
principles. The agency employed these principles in designing 
Highlights.
    For example, cognitive research has shown that, because there is a 
limit to the amount of information that an individual can hold in 
memory at one time, individuals tend to organize similar information 
into ``chunks'' to: (1) Increase the amount of available space in 
memory and (2) facilitate retrieval of information (Refs. 1 through 3). 
``Chunking'' complex information into smaller, more manageable units 
makes it easier to remember and process information efficiently and 
effectively (decreases ``cognitive load'').
    FDA research conducted during development of new rules for OTC drug 
labeling demonstrated that ``chunking'' information in a standardized 
format with graphic emphasis on the most important information helped 
individuals make correct product use decisions, decreased reading time, 
and increased the individuals' confidence in their ability to use that 
information (Ref. 4). This research supports the approach adopted in 
this final rule for prescription drug labeling.
    In designing Highlights, the agency employed established techniques 
to enhance effective communication of large amounts of complex 
information. Highlights summarizes the information from the FPI that is 
most important for prescribing the drug safely and effectively and 
organizes it into logical groups, or ``chunks,'' to enhance 
accessibility, retention, and access to the more detailed information. 
This design, combined with the use of multiple formats (e.g., tables, 
bulleted lists) and graphic emphasis (e.g., bolded text), improves 
visual and cognitive access to the information so that practitioners 
can more easily find information, and improves recall of the 
information.
    Importantly, Highlights must include identifying numbers indicating 
where in the FPI to find details of the information that is cited or 
concisely summarized in Highlights. In the final rule, FDA has revised 
proposed Sec.  201.57(a)(17) (Sec.  201.56(d)(3) in the final rule) to 
require that any information referenced in Highlights, not just 
subheadings, be accompanied by the identifying number corresponding to 
the location of the information in the FPI. The agency believes that 
these identifying numbers will facilitate access to the detailed 
information in the FPI.
    The Highlights design--a broad array of important information in a 
discrete, visually accessible location--also increases the variety of 
information that a practitioner is exposed to in a typical labeling 
referral. That is, the Highlights design increases the likelihood that 
practitioners will be exposed to and retain critical information about 
a drug in addition to the information that the practitioner sought in 
referring to the labeling, such as the recommended dose. The 
practitioner therefore is likely to know more about a drug after 
exposure to labeling with Highlights than after exposure to labeling 
without Highlights. In addition, by making labeling easier to use and 
an overall better source of drug information, the Highlights design is 
likely to increase the frequency with which practitioners rely on 
labeling for prescription drug information. In a survey regarding 
labeling for vaccines, 71 percent of physicians surveyed indicated that 
they would increase their use of labeling if a summary of prescribing 
information were included in labeling (65 FR 81082 at 81084). 
Highlights should result in health care practitioners being better 
informed about prescription drugs. Therefore, the agency concludes that 
prescription drug labeling with Highlights more effectively 
communicates drug information to prescribers than labeling without 
Highlights.
    (Comment 3) Some comments stated that FDA should do additional 
testing to determine whether Highlights is necessary to accomplish 
FDA's goal of making information in prescription drug labeling more 
useful and accessible or whether the other proposed format changes, 
without Highlights (i.e., an index, reordering of the sections of the 
FPI, and enhanced formatting) would be adequate to accomplish the 
agency's goal. One comment requested that FDA evaluate whether simply 
reordering the sections of the prescribing information would be 
adequate to accomplish the agency's goal. Some comments stated that the 
agency should test whether the proposed format would change prescriber 
behavior as intended and lead to a reduction in medication errors.
    The agency believes it is unnecessary to compare the prototype 
labeling with Highlights to the prototype labeling without Highlights 
(i.e., a version with a table of contents, reordered sections in the 
FPI, and enhanced graphics, or a version with only reordered sections 
and enhanced graphics). The requirements of this final rule are built 
on extensive testing conducted by FDA, established principles of 
cognitive processing, previous research conducted by FDA for OTC drug 
labeling, and evaluation of comments submitted in response to this 
proposal. FDA has determined that Highlights, because it will 
efficiently and effectively convey information about a drug product and 
will help to facilitate the transition to electronic labeling, is a 
vital component of the efforts to reduce the numbers of adverse 
reactions from medication errors due to misunderstood or incorrectly 
applied drug information.
    (Comment 4) In the proposed rule, FDA specifically sought comment 
on whether, and under what circumstances, it might be inappropriate to 
include the proposed Highlights in the labeling of a particular drug or 
drug class.
    The vast majority of comments supported Highlights for all products 
or no products. One comment stated that if the agency retains the 
requirement to include Highlights, all products required to have the 
new format should be required to have Highlights. One comment stated it 
would not be useful to include Highlights if the entire labeling is 
very short (e.g., one page).
    The agency concludes that there should be no exceptions to the 
Highlights requirement for drugs subject to the new content and format 
requirements at Sec. Sec.  201.56(d) and 201.57. The agency 
acknowledges that prescription drug labeling for some drugs may be very 
short and that this

[[Page 3932]]

may result in short Highlights. However, as discussed previously, the 
agency has determined that Highlights improves the usefulness, 
readability, and accessibility of information in prescription drug 
labeling and is consistent with good risk communication practices.
    (Comment 5) Several comments stated that there should be more 
specific criteria for selecting information for inclusion in Highlights 
to ensure consistency for all drug products. These comments stated 
that, without specific criteria, the information in Highlights for 
different drugs within the same drug class may be different, and these 
differences could be used to the competitive advantage or disadvantage 
of some products. Some comments stated that the agency should designate 
the precise information that must be included in Highlights. One 
comment said that, for products with class labeling, FDA must designate 
which class labeling statements must be included in Highlights to 
ensure consistency among drugs in the class. Another comment stated 
that the relative importance of drug information, and, as a result, the 
basis for selecting information for inclusion in the section, can vary 
depending on a drug's indication. The comment maintained that 
Highlights would have to provide for differences in safety profiles for 
drugs with multiple indications and those that are used in different 
populations.
    The agency believes that these concerns are not unique to 
Highlights. The agency agrees that, for a given drug, if there are 
significant differences in safety profiles or dosing considerations for 
different indications or populations, Highlights must reflect these 
differences. The agency also agrees that it is critical to ensure 
accuracy and consistency in the information included in Highlights 
because it contains a summary of the most important information for 
prescribing the drug safely and effectively.
    In general, however, the agency believes that it would not be 
appropriate, or possible, to specify in the final rule the precise 
content of Highlights. Judgment will continue to be necessary to 
determine what information from the broad range of information 
necessary for the safe and effective use of the prescription drug 
appearing in the FPI must also appear in Highlights (e.g., differences 
in safety profiles or dosing considerations for differing indications 
or populations). However, because Highlights is a summary of the most 
important information for prescribing decisions and some comments 
expressed concerns about the difficulty involved in summarizing the 
complex and often lengthy information in the FPI (see e.g., comments 
16, 23 and 27), the agency believes that it is essential for FDA to 
review and approve most proposed changes to the information in 
Highlights. Accordingly, the agency is revising its regulations on 
supplements and other changes to an approved application. Under 
Sec. Sec.  314.70(b)(2)(v)(C) and (c)(6)(iii), and 601.12(f)(1) and 
(f)(2)(i), applicants are required to obtain prior approval of any 
labeling changes to Highlights, except for editorial or similar minor 
changes, including removal of a listed section(s) from ``Recent Major 
Changes'' or a change to the most recent revision date of the labeling. 
Sections 314.70(d)(2)(x) and 601.12(f)(3)(i)(D) allow these editorial 
and similar minor changes in the labeling to be reported in an annual 
report.
    In addition, as noted, the agency is making available guidance to 
assist manufacturers and FDA reviewers in developing prescription drug 
labeling. This guidance addresses, among other things, how to select 
information for inclusion in Highlights (section IV of this document).
    In some instances, a statement for a drug or class of drugs is 
currently required by regulation to be included in a specific section 
of prescription drug labeling (e.g., Sec.  201.21). In these cases, 
when converting labeling to the new format, the statements must be 
included in the corresponding section in the new format (e.g., a 
statement required to be included in the ``Boxed Warning'' section in 
the old format must be included in the ``Boxed Warning'' section in the 
new format). However, some statements are currently required to be 
included in labeling sections that have been altered or eliminated by 
this final rule. In these instances, the statements must be located in 
the FPI as outlined in table 6.

  Table 6.--Location of Statements Required To Be Included in Labeling
------------------------------------------------------------------------
      Location--Old  Format                 Location--New Format
------------------------------------------------------------------------
Warnings                           Warnings and Precautions
------------------------------------------------------------------------
Precautions (General)              Warnings and Precautions
------------------------------------------------------------------------
Precautions (Drug interactions)    Drug Interactions
------------------------------------------------------------------------
Precautions (Specific              Use in Specific Populations
 Populations)
------------------------------------------------------------------------
Precautions (Information for       Patient Counseling Information
 patients)
------------------------------------------------------------------------
How Supplied (or after How         How Supplied/Storage and Handling
 Supplied)
------------------------------------------------------------------------

    Where statements are required in labeling but not in a specific 
labeling section, the agency may specify the location in the FPI for 
the statements for the drug or class of drugs to ensure consistency 
within drug classes. Whether a specific statement required by 
regulation must appear in Highlights will be determined by the agency.
    (Comment 6) Several comments stated that Highlights should mention 
the drug's therapeutic or pharmacologic class. They maintained that 
this information is informative to practitioners when the drug is a 
member of an established class because it puts the drug in a context 
with other therapies and helps prevent duplicative therapy.
    The agency agrees that information about a drug's therapeutic or 
pharmacologic class is important and appropriate for inclusion in 
Highlights. If a drug is a member of an established therapeutic or 
pharmacologic class, the identity of that class can provide a 
practitioner with important information about what to expect from that 
product and how it relates to other therapeutic options. The agency 
also agrees with the comment that making the identity of a drug's class 
more prominent could reduce the likelihood of prescribers placing a 
patient on more than one therapy within the same class when such use 
would not be appropriate.
    The agency believes that information about drug class is an 
important supplement to the information contained in a drug's 
``Indications and Usage'' section and should be placed under that 
heading in Highlights. Accordingly, the agency has revised proposed 
Sec.  201.57(a)(6) to require that when a drug is a member of an 
established pharmacologic class, the class must be identified in the 
``Indications and Usage'' section in Highlights.
    (Comment 7) One comment stated that Highlights should also include 
information about managing drug

[[Page 3933]]

overdose (recommended a new section entitled ``Toxicity and Overdose'') 
and characteristics by which a tablet can be identified (color, 
markings, shape, etc.).
    The agency acknowledges the importance of information about 
managing drug overdose and characteristics by which a tablet can be 
identified and took care to make this information prominent in the FPI. 
However, space for Highlights is limited and the agency has made 
judgments about which information is most important for safe and 
effective use and thus must appear in Highlights. The agency has 
concluded that information about managing overdose or product 
identification characteristics (except scoring) will not be required in 
Highlights. The agency has retained scoring in Highlights because this 
information is needed to appropriately tailor a dose for some patients 
(e.g., a patient is unable to take two tablets of a drug because of a 
particular side effect, but is able to take one-and-one-half tablets).
    (Comment 8) One comment stated that the information presented in 
Highlights should be in bulleted format to the extent possible to avoid 
redundancy with the information in the FPI.
    FDA agrees that information presented in Highlights, not otherwise 
required to be bulleted under Sec.  201.57(d)(4), should be succinctly 
summarized and in a format (e.g., bulleted) that calls attention, and 
provides easy access, to the more detailed information in the FPI. 
Highlights is not a verbatim repetition of selected information 
contained in the FPI.
    (Comment 9) One comment requested that the sections in Highlights 
be reordered to lend more prominence to risk information. The comment 
stated that all risk information, including contraindications and drug 
interactions, should be placed before the ``Dosage and Administration'' 
and ``How Supplied'' sections.
    The order of the sections in Highlights tracks the order of the 
corresponding sections in the FPI. The agency believes the order of 
information in Highlights must be consistent with the FPI so that 
practitioners can efficiently navigate from Highlights to the 
corresponding section of the FPI. As discussed in more detail in the 
preamble to the proposed rule (65 FR 81082 at 81084), the revised order 
of the sections in the FPI was based on extensive focus group testing 
and surveys of physicians to determine which sections they believe are 
most important to prescribing decisions and which sections they 
reference most frequently.
    The agency believes that the order of information in Highlights 
required by the final rule gives sufficient prominence to risk 
information. The agency also believes that the formatting requirements, 
the one-half page length restriction for Highlights (excluding space 
for a boxed warning, if one is required) (Sec.  201.57(d)(8)), and the 
limitations on the amount of information that can be included in 
Highlights will ensure that all the information in Highlights has 
adequate prominence and is visually accessible.
    (Comment 10) One comment expressed concern about the implications 
of Highlights for FDA's initiative to improve pregnancy labeling. The 
comment stated that the preliminary format FDA has discussed in public 
meetings (which would replace the pregnancy category designations) 
could not be readily condensed into an informative single sentence in 
Highlights. The comment suggested that electronic labeling could 
potentially solve this problem by linking to additional information 
about prescribing in specific patient populations and by linking to 
pregnancy registry databases and tertiary specialty texts as well.
    The agency anticipates that the planned revisions to the 
requirements for the ``Pregnancy'' subsection of labeling are unlikely 
to affect the information in Highlights about use of drugs during 
pregnancy. The agency agrees that the electronic labeling initiative 
holds great promise for providing rapid access to related information 
of varying levels of complexity and detail, including information about 
drug exposure during pregnancy.
    (Comment 11) Several comments recommended that there be an 
educational campaign in conjunction with the publication of the final 
rule to ensure that practitioners understand that Highlights contains 
only limited information and should not be relied on without reference 
to the FPI.
    The agency agrees that there should be, and it plans to initiate, 
an educational campaign to familiarize health care practitioners with 
the new labeling format. The agency also agrees that an important 
component of the educational message should be that Highlights alone 
does not contain all the information FDA has determined is needed to 
use a drug safely and effectively.

D. Comments on Product Liability Implications of the Proposed Rule

    In the proposal, FDA requested comments on the product liability 
implications of revising the labeling for prescription drugs.
    (Comment 12) In comments, some manufacturers expressed concerns 
that, by highlighting selected information from the FPI to the 
exclusion of information not highlighted, they make themselves more 
vulnerable to product liability claims. Some of these comments also 
stated that the Highlights limitation statement, which states that 
Highlights does not contain all the information needed to prescribe a 
drug safely and effectively and that practitioners should also refer to 
the FPI, would not constitute an adequate legal defense in a case 
alleging failure to provide adequate warning of a drug's risks.
    Based on the agency's research and analysis in developing the 
prototype labeling that was the basis for the proposed rule (see 
comment 2), the agency has concluded that a labeling format that 
includes Highlights is more effective than a format that omits 
Highlights. In response to the comments and as discussed in the 
response to comment 35, FDA has taken steps to enhance the prominence 
of the Highlights limitation statement. FDA believes the statement will 
be effective in reminding prescribers that the information in the 
Highlights should not be relied on exclusively in making prescribing 
decisions and that it is important to consult the more detailed 
information in the FPI. We also believe that this limitation statement 
will help to ensure that the labeling will be considered in its 
entirety in any product liability action. FDA acknowledges the 
comment's concerns and, as discussed more fully in response to comment 
13, believes that under existing preemption principles such product 
liability claims would be preempted.
    (Comment 13) Some comments stated that the new format requirements 
might have product liability implications for drugs that are not 
subject to the new requirements. These comments expressed concern that 
labeling in the old format might be characterized by plaintiffs as 
inferior to labeling in the new format and, as a result, could be used 
as evidence that a manufacturer did not provide adequate warnings. They 
requested that the agency state in the final rule that FDA approval of 
labeling, whether it be in the old or new format, preempts conflicting 
or contrary State law, regulations, or decisions of a

[[Page 3934]]

court of law for purposes of product liability litigation.
    FDA believes that under existing preemption principles, FDA 
approval of labeling under the act, whether it be in the old or new 
format, preempts conflicting or contrary State law. Indeed, the 
Department of Justice (DOJ), on behalf of FDA, has filed a number of 
amicus briefs making this very point. In order to more fully address 
the comments expressing concern about the product liability 
implications of revising the labeling for prescription drugs, we 
believe it would be useful to set forth in some detail the arguments 
made in those amicus briefs. The discussion that follows, therefore, 
represents the government's long standing views on preemption, with a 
particular emphasis on how that doctrine applies to State laws that 
would require labeling that conflicts with or is contrary to FDA-
approved labeling.
    Under the act, FDA is the expert Federal public health agency 
charged by Congress with ensuring that drugs are safe and effective, 
and that their labeling adequately informs users of the risks and 
benefits of the product and is truthful and not misleading. Under the 
act and FDA regulations, the agency makes approval decisions based not 
on an abstract estimation of its safety and effectiveness, but rather 
on a comprehensive scientific evaluation of the product's risks and 
benefits under the conditions of use prescribed, recommended, or 
suggested in the labeling (21 U.S.C. 355(d)). FDA considers not only 
complex clinical issues related to the use of the product in study 
populations, but also important and practical public health issues 
pertaining to the use of the product in day-to-day clinical practice, 
such as the nature of the disease or condition for which the product 
will be indicated, and the need for risk management measures to help 
assure in clinical practice that the product maintains its favorable 
benefit-risk balance. The centerpiece of risk management for 
prescription drugs generally is the labeling which reflects thorough 
FDA review of the pertinent scientific evidence and communicates to 
health care practitioners the agency's formal, authoritative 
conclusions regarding the conditions under which the product can be 
used safely and effectively. FDA carefully controls the content of 
labeling for a prescription drug, because such labeling is FDA's 
principal tool for educating health care professionals about the risks 
and benefits of the approved product to help ensure safe and effective 
use. FDA continuously works to evaluate the latest available scientific 
information to monitor the safety of products and to incorporate 
information into the product's labeling when appropriate.
    Changes to labeling typically are initiated by the sponsor, subject 
to FDA review, but are sometimes initiated by FDA. Under FDA 
regulations, to change labeling (except for editorial and other minor 
revisions), the sponsor must submit a supplemental application fully 
explaining the basis for the change (Sec. Sec.  314.70 and 601.12(f) 
(21 CFR 314.70 and 601.12(f))). FDA permits two kinds of labeling 
supplements: (1) Prior approval supplements, which require FDA approval 
before a change is made (Sec. Sec.  314.70(b) and 601.12(f)(1)); and 
(2) ``changes being effected'' (CBE) supplements, which may be 
implemented before FDA approval, but after FDA notification (Sec. Sec.  
314.70(c) and 601.12(f)(2)). While a sponsor is permitted to add risk 
information to the FPI without first obtaining FDA approval via a CBE 
supplement, FDA reviews all such submissions and may later deny 
approval of the supplement, and the labeling remains subject to 
enforcement action if the added information makes the labeling false or 
misleading under section 502(a) of the act (21 U.S.C. 352). Thus, in 
practice, manufacturers typically consult with FDA prior to adding risk 
information to labeling. As noted in response to comment 5, however, a 
sponsor may not use a CBE supplement to make most changes to 
Highlights.
    Since the proposed rule was published, FDA has learned of several 
instances in which product liability lawsuits have directly threatened 
the agency's ability to regulate manufacturer dissemination of risk 
information for prescription drugs in accordance with the act. In one 
case, for example, an individual plaintiff claimed that a drug 
manufacturer had a duty under California State law to label its 
products with specific warnings that FDA had specifically considered 
and rejected as scientifically unsubstantiated.\4\ In some of these 
cases, the court determined that the State law claim could not proceed, 
on the ground that the claim was preempted by Federal law,\5\ or was 
not properly before the court by operation of the doctrine of primary 
jurisdiction.\6\ In some cases, however, the court has permitted the 
claim to proceed.\7\
---------------------------------------------------------------------------

    \4\ Dowhal v. SmithKline Beecham Consumer Healthcare, 2002 Cal. 
App. LEXIS 4384 (Cal. Ct. App. 2002), reversed, 2004 Cal. LEXIS 3040 
(Cal. April 15, 2004).
    \5\ E.g., Ehlis v. Shire Richwood, Inc., 233 F. Supp. 2d 1189, 
1198 (D.N.D. 2002), aff'd on other grounds, 367 F.3d 1013 (8th Cir. 
2004).
    \6\ E.g., Bernhardt v. Pfizer, Inc., 2000 U.S. Dist. LEXIS 16963 
(S.D.N.Y. Nov. 16, 2000). This doctrine allows a court to refer a 
matter to an administrative agency for an initial determination 
where the matter involves technical questions of fact and policy 
within the agency's jurisdiction. If a court finds that the agency 
has primary jurisdiction, the court stays the matter and instructs 
the plaintiff to initiate an action with the agency. See, e.g., 
Israel v. Baxter Labs., Inc., 466 F.2d 272, 283 (D.C. Cir. 1972); 
see also 21 CFR 10.60.
    \7\ Dowhal v. SmithKline Beecham Consumer Healthcare, 2002 Cal. 
App. LEXIS 4384 (Cal. Ct. App. 2002), reversed, 2004 Cal. LEXIS 3040 
(Cal. April 15, 2004); Bernhardt v. Pfizer, Inc., 2000 U.S. Dist. 
LEXIS 16963 (S.D.N.Y. November 16, 2000); Motus v. Pfizer, Inc., 127 
F. Supp. 2d 1085 (C.D. Cal. 2000), summary judgment granted, 196 F. 
Supp. 2d 984, 986 (C.D. Cal. 2001), aff'd, 2004 U.S. App. LEXIS 1944 
(9th Cir. February 9, 2004); In re Paxil Litigation, 2002 U.S. Dist. 
LEXIS 16221 (C.D. Cal. August 16, 2002), transferred, 296 F. Supp. 
2d 1374 (J.P.M.L. 2003).
---------------------------------------------------------------------------

    State law actions can rely on and propagate interpretations of the 
act and FDA regulations that conflict with the agency's own 
interpretations and frustrate the agency's implementation of its 
statutory mandate. For example, courts have rejected preemption in 
State law failure-to-warn cases on the ground that a manufacturer has 
latitude under FDA regulations to revise labeling by adding or 
strengthening warning statements without first obtaining permission 
from FDA. (See, e.g., Eve v. Sandoz Pharm. Corp., 2002 U.S. Dist. LEXIS 
23965 (S.D. In. Jan. 28, 2002); Ohler v. Purdue Pharma, L.P., 2002 U.S. 
Dist. LEXIS 2368 (E.D. La. Jan. 22, 2002); Motus v. Pfizer Inc., 127 F. 
Supp. 2d 1085 (C.D. Cal. 2000); Bansemer v. Smith Labs., Inc., 1988 
U.S. Dist. LEXIS 16208 (E.D. Wis. Sept. 12, 1988); McEwen v. Ortho 
Pharm Corp., 528 P.2d 522 (Ore. 1974).) In fact, the determination 
whether labeling revisions are necessary is, in the end, squarely and 
solely FDA's under the act. A manufacturer may, under FDA regulations, 
strengthen a labeling warning, but in practice manufacturers typically 
consult with FDA before doing so to avoid implementing labeling changes 
with which the agency ultimately might disagree (and that therefore 
might subject the manufacturer to enforcement action).
    Another misunderstanding of the act encouraged by State law actions 
is that FDA labeling requirements represent a minimum safety standard. 
According to many courts, State law serves as an appropriate source of 
supplementary safety regulation for drugs by encouraging or requiring 
manufacturers to disseminate risk information beyond that required by 
FDA under the act. (See, e.g., Brochu v. Ortho Pharm. Corp., 642 F.2d 
652 (1st Cir. 1981); Salmon v. Parke-Davis and Co., 520 F.2d 1359 (4th 
Cir. 1975); Caraker v. Sandoz Pharm. Corp., 172 F. Supp. 2d 1018 (S.D. 
Ill.

[[Page 3935]]

2001); Mazur v. Merck & Co., Inc., 742 F. Supp. 239 (E.D. Pa. 1990); In 
re Tetracycline Cases, 747 F. Supp. 543 (W.D. Mo. 1989).) In fact, FDA 
interprets the act to establish both a ``floor'' and a ``ceiling,'' 
such that additional disclosures of risk information can expose a 
manufacturer to liability under the act if the additional statement is 
unsubstantiated or otherwise false or misleading. Given the 
comprehensiveness of FDA regulation of drug safety, effectiveness, and 
labeling under the act, additional requirements for the disclosure of 
risk information are not necessarily more protective of patients. 
Instead, they can erode and disrupt the careful and truthful 
representation of benefits and risks that prescribers need to make 
appropriate judgments about drug use. Exaggeration of risk could 
discourage appropriate use of a beneficial drug.
    State law requirements can undermine safe and effective use in 
other ways. In the preamble accompanying the proposal, FDA noted that 
liability concerns were creating pressure on manufacturers to expand 
labeling warnings to include speculative risks and, thus, to limit 
physician appreciation of potentially far more significant 
contraindications and side effects (65 FR 81082 at 81083). FDA has 
previously found that labeling that includes theoretical hazards not 
well-grounded in scientific evidence can cause meaningful risk 
information to ``lose its significance'' (44 FR 37434 at 37447, June 
26, 1979). Overwarning, just like underwarning, can similarly have a 
negative effect on patient safety and public health. (See section X of 
this document.) Similarly, State-law attempts to impose additional 
warnings can lead to labeling that does not accurately portray a 
product's risks, thereby potentially discouraging safe and effective 
use of approved products or encouraging inappropriate use and 
undermining the objectives of the act. (See, e.g., Dowhal v. SmithKline 
Beecham Consumer Healthcare, 2002 Cal. App. LEXIS 4384 (Cal. Ct. App. 
2002) (allowing to proceed a lawsuit involving a California State law 
requiring warnings in the labeling of nicotine replacement therapy 
products that FDA had specifically found would misbrand the products 
under the act), reversed, 2004 Cal. LEXIS 3040 (Cal. April 15, 2004).)
    State law actions also threaten FDA's statutorily prescribed role 
as the expert Federal agency responsible for evaluating and regulating 
drugs. State actions are not characterized by centralized expert 
evaluation of drug regulatory issues. Instead, they encourage, and in 
fact require, lay judges and juries to second-guess the assessment of 
benefits versus risks of a specific drug to the general public--the 
central role of FDA--sometimes on behalf of a single individual or 
group of individuals. That individualized reevaluation of the benefits 
and risks of a product can result in relief--including the threat of 
significant damage awards or penalties--that creates pressure on 
manufacturers to attempt to add warnings that FDA has neither approved 
nor found to be scientifically required. This could encourage 
manufacturers to propose ``defensive labeling'' to avoid State 
liability, which, if implemented, could result in scientifically 
unsubstantiated warnings and underutilization of beneficial treatments.
    FDA has previously preempted State law requirements relating to 
drugs in rulemaking proceedings. For example:
     In 1982, FDA issued regulations requiring tamper-resistant 
packaging for OTC drugs. In the preamble accompanying the regulations, 
FDA stated its intention that the regulations preempt any State or 
local requirements that were ``not identical to * * * [the rule] in all 
respects'' (47 FR 50442 at 50447, November 5, 1982).
     In 1986, FDA issued regulations requiring aspirin 
manufacturers to include in labeling a warning against use in treating 
chicken pox or flu symptoms in children due to the risk of Reye's 
Syndrome. In the accompanying preamble, FDA said the regulations 
preempted ``State and local packaging requirements that are not 
identical to it with respect to OTC aspirin-containing products for 
human use'' (51 FR 8180 at 8181, March 7, 1986).
     In 1994, FDA amended 21 CFR 20.63 to preempt State 
requirements for the disclosure of adverse event-related information 
treated as confidential under FDA regulations (59 FR 3944, January 27, 
1994). (See also 47 FR 54750, December 3, 1982) (``FDA believes that 
differing State OTC drug pregnancy-nursing warning requirements would 
prevent accomplishment of the full purpose and objectives of the agency 
in issuing the regulation and that, under the doctrine of implied 
preemption, these State requirements are preempted by the regulation as 
a matter of law.'')
    As noted previously, DOJ has made submissions to courts in a number 
of cases in which private litigants asserted a State law basis for 
challenging the adequacy of risk information provided by manufacturers 
for drugs in accordance with FDA requirements under the act. In each 
case, DOJ argued that the doctrine of preemption precluded the 
plaintiff's claim from proceeding.\8\ The practice of addressing 
conflicting State requirements through participation in litigation 
(including product liability cases) in which the Government is not a 
party is not new. For example, DOJ participated on FDA's behalf in 
favor of pre-emption in Jones v. Rath Packing Company, 430 U.S. 519 
(1977), Grocery Manufacturers of America, Inc. v. Gerace, 755 F.2d 993 
(2d Cir. 1985), Eli Lilly & Co., Inc. v. Marshall, 850 S.W.2d 155 (Tex. 
1993), and Buckman Co. v. Plaintiffs' Legal Comm., 531 U.S. 341, 352-53 
(2001). FDA believes that State laws conflict with and stand as an 
obstacle to achievement of the full objectives and purposes of Federal 
law when they purport to compel a firm to include in labeling or 
advertising a statement that FDA has considered and found 
scientifically unsubstantiated. In such cases, including the statement 
in labeling or advertising would render the drug misbranded under the 
act (21 U.S.C. 352(a) and (f)). The agency believes that State law 
conflicts with and stands as an obstacle to achievement of the full 
objectives and purposes of Federal law if it purports to preclude a 
firm from including in labeling or advertising a statement that is 
included in prescription drug labeling. By complying with the State law 
in such a case and removing the statement from labeling, the firm would 
be omitting a statement required under Sec.  201.100(c)(1) as a 
condition on the exemption from the requirement of adequate directions 
for use, and the omission would misbrand the drug under 21 U.S.C. 
352(f)(1). The drug might also be misbranded on the ground that the 
omission is material within the meaning of 21 U.S.C. 321(n) and makes 
the labeling or advertising misleading under 21 U.S.C. 352(a) or (n).
---------------------------------------------------------------------------

    \8\ The DOJ submissions in these cases relied on the doctrine of 
implied preemption or primary jurisdiction. Although the act itself 
contains no general express pre-emption provision for drugs, a 
provision of legislation amending the drug provisions addresses the 
relationship of the legislation to State law. Section 202 of the 
Drug Amendments of 1962 (Public Law 87-781, Title II, section 202, 
76 Stat. 793 (October 10, 1962)) provides: ``Nothing in the 
amendments made by this Act to the Federal Food, Drug, and Cosmetic 
Act shall be construed as invalidating any provision of State law 
which would be valid in the absence of such amendments unless there 
is a direct and positive conflict between such amendments and such 
provision of State law.'' The existence of a legislative provision 
addressing pre-emption does not bar the operation of ordinary 
principles of implied preemption (Geier v. American Honda Motor Co., 
Inc., 529 U.S. 861, 869 (2000)).
---------------------------------------------------------------------------

    Consistent with its court submissions and existing preemption 
principles, FDA believes that at least the following

[[Page 3936]]

claims would be preempted by its regulation of prescription drug 
labeling: (1) Claims that a drug sponsor breached an obligation to warn 
by failing to put in Highlights or otherwise emphasize any information 
the substance of which appears anywhere in the labeling; (2) claims 
that a drug sponsor breached an obligation to warn by failing to 
include in an advertisement any information the substance of which 
appears anywhere in the labeling, in those cases where a drug's sponsor 
has used Highlights consistently with FDA draft guidance regarding the 
``brief summary'' in direct-to-consumer advertising (``Brief Summary: 
Disclosing Risk Information in Consumer-Directed Print 
Advertisements,'' 69 FR 6308 (February 2004)) (see comment 112); (3) 
claims that a sponsor breached an obligation to warn by failing to 
include contraindications or warnings that are not supported by 
evidence that meets the standards set forth in this rule, including 
Sec.  201.57(c)(5) (requiring that contraindications reflect ``[k]nown 
hazards and not theoretical possibilities'') and (c)(7); (4) claims 
that a drug sponsor breached an obligation to warn by failing to 
include a statement in labeling or in advertising, the substance of 
which had been proposed to FDA for inclusion in labeling, if that 
statement was not required by FDA at the time plaintiff claims the 
sponsor had an obligation to warn (unless FDA has made a finding that 
the sponsor withheld material information relating to the proposed 
warning before plaintiff claims the sponsor had the obligation to 
warn); (5) claims that a drug sponsor breached an obligation to warn by 
failing to include in labeling or in advertising a statement the 
substance of which FDA has prohibited in labeling or advertising; and 
(6) claims that a drug's sponsor breached an obligation to plaintiff by 
making statements that FDA approved for inclusion in the drug's label 
(unless FDA has made a finding that the sponsor withheld material 
information relating to the statement). Preemption would include not 
only claims against manufacturers as described above, but also against 
health care practitioners for claims related to dissemination of risk 
information to patients beyond what is included in the labeling. (See, 
e.g., Bowman v. Songer, 820 P.2d 1110 (Col. 1991).)
    FDA recognizes that FDA's regulation of drug labeling will not 
preempt all State law actions. The Supreme Court has held that certain 
State law requirements that parallel FDA requirements may not be 
preempted (Medtronic, Inc. v. Lohr, 518 U.S. 470, 495 (1996) (holding 
that the presence of a State law damages remedy for violations of FDA 
requirements does not impose an additional requirement upon medical 
device manufacturers but ``merely provides another reason for 
manufacturers to comply with * * * federal law''); id. at 513 
(O'Connor, J., concurring in part and dissenting in part); id)). But 
see Buckman Co. v. Plaintiffs' Legal Comm., 531 U.S. 341, 352-53 (2001) 
(holding that ``fraud on the FDA'' claims are preempted by Federal 
law); 21 U.S.C. 337(a) (restricting the act enforcement to suits by the 
United States); In re Orthopedic Bone Screw Prods. Liability Litig., 
159 F.3d 817, 824 (3d Cir. 1998) (``Congress has not created an express 
or implied private cause of action for violations of the FDCA or the 
MDA [Medical Device Amendments]'').

E. Highlights--Comments on Specific Provisions

    The agency received comments on the following provisions of the 
proposed rule relating to the content of Highlights:
     Drug names, dosage form, route of administration, and 
controlled substance symbol (proposed Sec.  201.57(a)(1))
    In proposed Sec.  201.57(a)(1), FDA specified the information 
concerning the identity of the product that would be included at the 
beginning of Highlights.
    (Comment 14) One comment recommended that this information be moved 
above the title ``Highlights of Prescribing Information'' in 
Highlights.
    The agency does not agree that the information required by Sec.  
201.57(a)(1) should be placed above the title ``Highlights of 
Prescribing Information.'' The agency believes that the title of each 
of the three major portions of prescription drug labeling (``Highlights 
of Prescribing Information,'' ``Full Prescribing Information: 
Contents,'' and ``Full Prescribing Information'') should be placed at 
the beginning of the corresponding information so that the title is 
readily apparent to users.
     Inverted black triangle (proposed Sec.  201.57(a)(2))
    FDA proposed to require that products that contain a new molecular 
entity, new biological product, or new combination of active 
ingredients have in their labeling an inverted black triangle to 
indicate that the drug or drug combination had been approved in the 
United States for less than 3 years (proposed Sec.  201.57(a)(2)). This 
proposal also applied to marketed products approved for a new 
indication, for use by a new route of administration, or with a novel 
drug delivery system.
    (Comment 15) Several comments opposed, or expressed reservations 
about, the use of an inverted black triangle to identify a product, 
indication, or dosage form that has been approved for less than 3 
years. There were concerns that the symbol is not universally 
understood and could therefore be confusing to practitioners. One 
comment stated that use of icons to convey public health information 
has historically been unsuccessful. Some of the comments stated that if 
the inverted black triangle were retained, the agency would need to 
conduct an extensive educational campaign to educate practitioners 
about its meaning and purpose. Some comments also expressed the concern 
that labeling containing the symbol could be in circulation much longer 
than 3 years after approval, which would undermine the significance of 
the symbol. One comment stated that the symbol implies, without basis, 
that newer drugs are inherently less safe than older drugs. Some 
comments stated that the criteria for when a new indication would 
extend the time for which a product must have the inverted black 
triangle are not clear.
    Two comments stated that a bold approval date might be more 
informative than the inverted black triangle. Another comment 
recommended using the designation ``New-Rx'' to identify a product that 
has been approved for less than 3 years.
    Other comments expressed strong support for the inverted black 
triangle as a mechanism to prompt practitioners to more carefully 
scrutinize the labeling of newer products and more diligently report 
adverse events. The comments maintained that use of the inverted black 
triangle could lead to earlier detection of rare, serious adverse 
reactions and, thus, could potentially save lives. One comment 
suggested extending the time that the inverted black triangle would be 
required to 5 years.
    The agency has reconsidered its proposal to require use of the 
inverted black triangle to identify products that have been marketed 
for less than 3 years. The agency continues to believe strongly in the 
goals of the inverted black triangle--to help ensure that prescribers 
use a product with particular care during its initial years of 
marketing and to make prescribers more diligent in reporting suspected 
adverse reactions for newer products. However, the agency agrees with 
comments that, in prescription drug labeling, the inverted black 
triangle is not universally

[[Page 3937]]

understood, could be confusing to the prescriber (even with a concerted 
educational effort) and therefore may not serve its intended purpose. 
The agency acknowledges that the recommended ``New-Rx'' designation may 
be more informative than the inverted black triangle, but is concerned 
that the ``New-Rx'' designation might also be confusing because 
practitioners are not familiar with it.
    The agency agrees with comments that use of the initial date of 
approval in the United States would be a better mechanism than the 
inverted black triangle to call attention to the relative newness of a 
product. Therefore, the final rule requires that Highlights include the 
year in which a drug was initially approved in the United States. 
Highlights must contain the phrase ``Initial U.S. Approval'' followed 
by the four-digit year of initial approval in bold face type (Sec.  
201.57(a)(3) and (d)(5)). Because this statement takes up more space 
than the proposed inverted black triangle, the final rule requires that 
the statement be placed on its own line directly below the established 
name of the product (proper name of the product for biological 
products) rather than on the same line as the proprietary name (Sec.  
201.57(a)(3)).
    In contrast to the proposed rule, the final rule does not require 
identification of the initial date of U.S. approval of a new indication 
for a new population, new route of administration, or novel delivery 
system. The agency agrees with comments that expressed concerns that 
also requiring the inverted black triangle for new indications, routes 
of administration, and novel delivery systems could diminish the 
significance of the inverted black triangle and could be confusing to 
practitioners. Similarly, the agency believes that referring to 
multiple dates, including the date of initial approval of a new 
indication, new route of administration, or a novel delivery system for 
a drug would be confusing and would diminish the significance of these 
references. The agency is, therefore, limiting identification of the 
initial date of U.S. approval to new molecular entities, new biological 
products, or new combinations of active ingredients because this is 
sufficient to accomplish the goals of increasing prescriber vigilance 
and reporting of suspected adverse reactions when using newer products.
    The agency believes the date of initial U.S. approval will continue 
to be informative throughout a product's life cycle. Although the 
agency does not subscribe to the view that newer drugs are inherently 
less safe, it does believe that alerting a practitioner to the fact 
that a drug has been marketed for an extended period could provide some 
added assurance about the drug's safety margin based on cumulative, 
safe experience with the product. Therefore, the requirement to include 
the initial date of U.S. approval in Highlights will not lapse 3 years 
after approval of the product for marketing.
     Boxed warnings or contraindications (proposed Sec.  
201.57(a)(4))
    FDA proposed to require that the full text of boxed warning(s) or 
contraindication(s) required by proposed Sec.  201.57(c)(1) be included 
in Highlights unless the boxed warning was longer than 20 lines, in 
which case a summary of the contents of the boxed warning would be 
required (proposed Sec.  201.57(a)(4)). The agency specifically sought 
comment on whether the full text of a boxed warning should be included 
in Highlights, regardless of length.
    (Comment 16) Some comments supported the proposed 20-line 
limitation on the length of a boxed warning in Highlights. Other 
comments recommended that the boxed warning in Highlights always be a 
summarized version of the boxed warning in the FPI. Others expressed 
concern that summarizing boxed warnings might result in the omission of 
key information or lead to misinterpretations of the warning. They 
stated that the boxed warning is already succinct and the language is 
carefully negotiated with FDA and, therefore, that the boxed warning 
should always be included in its entirety in Highlights.
    The agency has retained the 20-line length limitation on boxed 
warnings in Highlights. The agency believes that 20 lines is sufficient 
space to alert practitioners to the critical risk information contained 
in a boxed warning and to refer them to more detailed information in 
the FPI (complete boxed warning and other sections in the FPI).
    The agency agrees with the comments that stated that manufacturers 
should always be required to present summarized boxed warning 
information in Highlights. The agency has determined that information 
from boxed warnings can readily be condensed without omitting critical 
risk information. The agency believes a summarized boxed warning in 
Highlights, with references to more detailed information in the FPI, is 
the most effective way to communicate critical risk information to 
practitioners. The agency has revised proposed Sec.  201.57(a)(4) to 
require that boxed warnings be summarized concisely in Highlights.
    (Comment 17) Several comments stated that inclusion of the full 
boxed warning in Highlights and in the FPI was needlessly duplicative 
and recommended that the boxed warning be included in only one 
location. One comment maintained the boxed warning should appear only 
in the ``Warnings and Precautions'' section in the FPI.
    As discussed in the response to the previous comment, the boxed 
warning in Highlights is required to be a summary of the complete boxed 
warning in the FPI. Thus, the boxed warning in Highlights will not 
duplicate the boxed warning in the FPI. The agency believes that a 
summarized boxed warning must be included in Highlights to ensure that 
practitioners are exposed to critical information at the beginning of 
prescription drug labeling and that the complete boxed warning is 
needed to expand on the summary in Highlights.
    The agency does not agree that the complete boxed warning in the 
FPI should be placed in the ``Warnings and Precautions'' section rather 
than at the beginning of the FPI. Placement of the complete boxed 
warning at the beginning of the FPI, where it can be easily located, is 
consistent with good risk communication practices, as well as health 
care practitioner preferences articulated in public comments and FDA's 
physician surveys and focus group research.
     Recent labeling changes (proposed Sec.  201.57(a)(5))
    FDA proposed to require in Highlights a heading entitled ``Recent 
Labeling Changes'' that identifies the sections in the FPI that contain 
recent FDA-approved or authorized substantive labeling changes 
(proposed Sec.  201.57(a)(5)).
    (Comment 18) In general, comments supported the addition of a 
``Recent Labeling Changes'' heading to labeling and many comments 
thought the information would be very useful to practitioners. However, 
one comment recommended that the proposed heading ``Recent Labeling 
Changes'' be changed to ``Sections Revised'' to accommodate changes 
that, although no longer truly recent, would be important to call to 
the attention of practitioners for an extended period of time (e.g., 
through multiple labeling revisions). Another comment recommended that 
the heading be changed to ``Last Labeling Revisions'' to accommodate 
changes that could no longer reasonably be considered recent (e.g., a 
situation in which years elapse between labeling changes).

[[Page 3938]]

    The agency agrees that the proposed heading should be changed to 
better reflect the function of including the information. Thus, the 
final rule requires the heading ``Recent Major Changes'' (Sec.  
201.57(a)(5)). FDA believes that it is important to characterize the 
changes listed under the heading as both ``recent'' and ``major'' to 
draw attention to the relative newness of the changes and to let 
practitioners know that identified changes are significant to clinical 
use of the drug (i.e., substantive), and not merely editorial.
    (Comment 19) In the proposal, the agency specifically sought 
comment on whether there should be a time limit by which information 
under the proposed heading (now ``Recent Major Changes'') must be 
removed. Some comments supported a 1-year time limit for inclusion of 
information under the proposed heading. Other comments stated that 
there should be no fixed time limit for removal of information 
identified as a recent labeling change. These comments expressed 
concern that requiring labeling to be revised for the sole purpose of 
removing information from under the heading would lead to unnecessary 
expense, and that such information be removed at the next substantive 
labeling revision. Other comments stated that no time limit should be 
imposed for removal, but that removal should occur at the first 
convenient opportunity after 1 year from the date of the labeling 
change. Another comment stated that information should remain under the 
``Recent Major Changes'' heading for 1 to 3 years after the change to 
keep practitioners up-to-date on labeling changes.
    The agency agrees that, although there should not be a rigid time 
limit for removal of information from ``Recent Major Changes,'' the 
information should not remain in Highlights indefinitely. The purpose 
of the heading is to alert practitioners to recent substantive labeling 
changes. The agency is concerned that the information might be ignored 
by practitioners if it often identifies changes that are no longer 
recent. The agency will, therefore, require that labeling changes 
identified under this heading be deleted at the first reprinting of the 
labeling after the change has been in labeling for 1 year. This 
requirement should ensure that labeling changes identified under the 
``Recent Major Changes'' heading are current without imposing 
unnecessary costs on industry by requiring labeling revisions solely 
for the purpose of removing the information.
    (Comment 20) Because there could be multiple changes to labeling in 
a calendar year, some comments recommended that each change appearing 
under ``Recent Major Changes'' be dated in a month/year format so that 
practitioners can readily identify the most recent changes.
    The agency agrees that it would be useful to date the labeling 
changes identified under this heading. The agency has, therefore, 
revised proposed Sec.  201.57(a)(5) to require that sections of 
prescription drug labeling listed under ``Recent Major Changes'' be 
followed by the month and year in which the change was incorporated in 
the labeling.
    (Comment 21) One comment recommended that the rule specify that 
changes should be listed chronologically beginning with most recent.
    The agency does not agree. Where there are multiple recent changes 
and those changes appear in more than one section, to avoid confusion, 
the order in which the sections are listed under ``Recent Major 
Changes'' should be consistent with the order of the sections in the 
FPI. FDA has revised proposed Sec.  201.57(a)(5) accordingly.
    (Comment 22) Some comments requested that the agency clarify how it 
will determine whether a labeling change is substantive and thus 
required to be included under ``Recent Major Changes.''
    The agency recognizes that a product may have a large number of 
labeling changes ranging from inclusion of very important new risk 
information to typographical or editorial changes. Identifying all 
these changes under ``Recent Major Changes'' would obscure the most 
significant changes and would not be informative for practitioners. 
Therefore, the agency has revised proposed Sec.  201.57(a)(5) to 
require that only substantive labeling changes in the ``Boxed 
Warning,'' ``Indications and Usage,'' ``Dosage and Administration,'' 
``Contraindications,'' and ``Warnings and Precautions'' sections be 
included under ``Recent Major Changes.'' These would include only those 
changes that are significant to the clinical use of the drug and, 
therefore, have significant clinical implications for practitioners 
(i.e., substantive changes). Thus, ``Recent Major Changes'' would not 
include any changes in the sections subject to this requirement that 
are typographical or editorial.
     Indications and usage (proposed Sec.  201.57(a)(6))
    FDA proposed to require that Highlights include an ``Indications 
and Usage'' heading that contains a concise statement of each of the 
product's indications, as specified in proposed Sec.  201.57(c)(2), 
with any appropriate subheadings (proposed Sec.  201.57(a)(6)). This 
information would include major limitations of use (e.g., particular 
subsets of the populations, second line therapy status). The agency 
specifically sought comment on whether the information required under 
the ``Indications and Usage'' heading of Highlights should be presented 
verbatim from the FPI or summarized in a bulleted format.
    (Comment 23) Several comments stated that it was important to 
reproduce the ``Indications and Usage'' section verbatim to prevent 
confusion or misinterpretations. Other comments maintained that there 
should be flexibility to reproduce the information in the ``Indications 
and Usage'' section verbatim or summarize it in a bulleted format, 
depending on factors such as the amount of information in the 
``Indications and Usage'' section and whether the information can be 
summarized and still effectively communicate what a practitioner should 
know about a drug's indications. Other comments recommended that there 
be bulleted summaries of the indications in all cases. One of these 
comments suggested that each bullet be preceded by an index number that 
corresponds with the index number of the full description of the 
indication in the FPI.
    The agency has determined that the amount of information that must 
be included in Highlights from the ``Indications and Usage'' section of 
the FPI will vary. In most cases, the ``Indications and Usage'' section 
can be readily condensed (e.g., bulleted format) to provide prescribers 
with an accurate and informative summary, even if there is space 
available in Highlights to reproduce the ``Indications and Usage'' 
section from the FPI in its entirety (i.e., the one-half page limit 
requirement would not be exceeded).
    The agency recognizes that for some products with many indications, 
it may not be possible to limit Highlights to one-half page in length 
(Sec.  201.57(d)(8)), even using a summarized version of the 
``Indications and Usage'' section. In such cases, FDA may waive the 
one-half page requirement and approve the labeling with slightly longer 
Highlights (see comment 104).
     Dosage and administration (proposed Sec.  201.57(a)(7))
    FDA proposed that Highlights include, under a ``Dosage and 
Administration'' heading, the most important information in the 
``Dosage and Administration'' section of the FPI (proposed Sec.  
201.57(a)(7)).
    (Comment 24) One comment recommended that ``Dosage and 
Administration'' in Highlights include,

[[Page 3939]]

in addition to the usual recommended doses, a range of doses known to 
be effective, and in particular, doses lower than the usual recommended 
doses. The comment stated that 76.2 percent of all adverse reactions 
are dose-related and many patients respond to lower doses than those 
recommended in labeling. Therefore, the comment suggested, lower doses 
may prevent adverse reactions.
    FDA agrees that it is important to include in labeling the full 
range of doses that FDA has concluded are effective. The agency has 
revised proposed Sec.  201.57(a)(7) to clarify the range of doses to be 
included under the ``Dosage and Administration'' heading in Highlights.
    (Comment 25) Several comments supported tabular presentation of 
dosage and administration information in Highlights. One comment 
proposed the use of a titration dose column (a visual tool to depict a 
drug's titration regimen) in Highlights for drugs for which titration 
is relevant. One comment maintained that the dosage adjustment 
statement in the prototype that accompanied the proposed rule should be 
highlighted and enlarged.
    FDA agrees with the comment that supported use of a tabular format 
for ``Dosage and Administration'' in Highlights. However, because a 
tabular format or a titration dose column may not be appropriate for 
all drug products, FDA is not requiring use of these formats under the 
``Dosage and Administration'' heading.
    With respect to highlighting and enlarging the dosage adjustment 
statement in the prototype, FDA believes that bolded type is sufficient 
to draw attention to particularly important dosage adjustment 
statements and that enlarging the statement is not necessary. Enlarging 
only dosage adjustment information in Highlights would make this 
information appear more significant than other information in 
Highlights, which would not be appropriate. Therefore, FDA is not 
requiring that dosage adjustment statements in Highlights be in larger 
font than other information in Highlights.
    (Comment 26) One comment requested that when the labeling states 
that there may be a need for dosage adjustments in patients with renal 
or hepatic impairment, it also specify how to adjust the dose or dosing 
interval.
    Highlights identifies important information about the need for 
dosage adjustments in specific populations and refers to the section of 
the FPI where more detailed information about how to adjust doses can 
be obtained. FDA believes that complete information about how to adjust 
dosages for various specific populations would in many cases require a 
great deal of space. Therefore, FDA is not requiring that such 
information be included in Highlights.
     Warnings and precautions (proposed Sec.  201.57(a)(10))
    FDA proposed to require that Highlights include, under a ``Warnings 
and Precautions'' heading, a concise summary of the most clinically 
significant aspects of the ``Warnings and Precautions'' section of the 
FPI (proposed Sec.  201.57(a)(7)). The information chosen from the FPI 
would include those warnings and precautions that affect prescribing 
because of their severity and consequent influence on the decision to 
use the drug, because monitoring of them is critical to safe use of the 
drug, or because measures can be taken to prevent or mitigate harm.
    (Comment 27) Some comments requested clarification of the scope of 
information to be included in Highlights under the ``Warnings and 
Precautions'' heading. Comments expressed concern that summarizing 
selected safety information from the ``Warnings and Precautions'' 
section of the FPI might cause some important safety information to be 
omitted from Highlights.
    ``Warnings and Precautions'' in Highlights serves to: (1) Identify 
the most clinically significant risks discussed in the ``Warnings and 
Precautions'' section in the FPI, (2) concisely summarize the salient 
features of those risks, and (3) direct the practitioner to the more 
detailed discussion of risks in the FPI. Information under the 
``Warnings and Precautions'' heading in Highlights will typically 
include those risks that: (1) Affect decisions about whether to 
prescribe a drug, (2) require monitoring of patients to ensure safe use 
of the drug, or (3) require that measures be taken to prevent or 
mitigate harm. The agency has revised Sec.  201.57(a)(10) to make clear 
the scope of information to include under this heading.
    Because the risks identified under the ``Warnings and Precautions'' 
heading in Highlights will refer the prescriber to the full discussion 
in the ``Warnings and Precautions'' section of the FPI, the agency 
believes that important risk information will not be overlooked by 
practitioners.
    (Comment 28) One comment stated that it would be misleading to 
include the most common adverse reactions under ``Warnings and 
Precautions'' in Highlights because the most common adverse reactions 
are not likely to be discussed in the ``Warnings and Precautions'' 
section of the FPI. Rather, they are more likely to be discussed in the 
``Adverse Reactions'' section of the FPI. The comment recommended that 
the most common adverse reactions be listed under a separate section in 
Highlights immediately following the contact information for reporting 
suspected serious adverse reactions.
    The agency agrees that it may be confusing to include under the 
``Warnings and Precautions'' heading in Highlights information that is 
derived from both the ``Warnings and Precautions'' and ``Adverse 
Reactions'' sections of the FPI. The agency is, therefore, revising 
proposed Sec.  201.57(a) by adding to Highlights a heading entitled 
``Adverse Reactions'' (Sec.  201.57(a)(11)) that is required to follow 
the ``Warnings and Precautions'' section. Information under the 
``Adverse Reactions'' heading must include: (1) A listing of the most 
frequently occurring adverse reactions identified in the ``Adverse 
Reactions'' section in the FPI and (2) contact information for 
reporting suspected adverse reactions. The sequence in which the 
information is presented in Highlights--the most frequently occurring 
adverse reactions followed by contact information for reporting 
suspected adverse reactions--is unchanged from the proposed rule.
    (Comment 29) One comment requested clarification about whether only 
information that is supported by clinical data would be appropriate for 
inclusion in Highlights.
    In most cases, the risk information in Highlights would be based on 
clinical data. However, risk information derived from animal data could 
be appropriate for inclusion in Highlights. For example, warnings about 
a drug's risks in pregnancy could be based entirely on animal data and 
might be appropriate for inclusion in Highlights. In such cases, 
Highlights must present only the clinically significant conclusions 
about risk in pregnancy (e.g., significant teratogen) and not include a 
discussion of the animal data that are the basis for the risk 
information presented.
     ADR reporting contacts (proposed Sec.  201.57(a)(11))
    FDA proposed (proposed Sec.  201.57(a)(11)) to require that 
Highlights include, for drug products other than vaccines, a statement 
following the information under the ``Warnings and Precautions'' 
heading: ``To report SUSPECTED SERIOUS ADRs, call (insert name of 
manufacturer) at (insert manufacturer's phone number) or FDA's MedWatch 
at (insert the current FDA MedWatch number).'' For vaccines, the 
following statement would be required: ``To report

[[Page 3940]]

SUSPECTED SERIOUS ADRs, call (insert name of manufacturer) at (insert 
manufacturer's phone number) or VAERS at (insert the current VAERS 
number).'' The agency specifically requested comment on whether it is 
necessary to include a contact number for reporting suspected adverse 
reactions in both Highlights and the ``Warnings and Precautions'' 
section of the FPI.
    (Comment 30) Some comments stated that the contact information 
should be in both Highlights and FPI to make it more convenient to 
access and increase the likelihood that practitioners will be prompted 
to report suspected adverse reactions. Other comments stated that it 
would not be necessary to include contact information in both places 
because prominent placement of the information in Highlights alone 
would be sufficient to encourage practitioners to report adverse 
reactions. Some comments agreed that one location would be sufficient, 
but because those comments also opposed inclusion of Highlights in 
labeling, they recommended including the contact information in the 
FPI. Other comments suggested locating the contact information at the 
beginning of the labeling or in a ``box'' to increase its prominence. 
One comment recommended that the information be included only once and 
in close proximity to the name and address of the manufacturer in the 
FPI. The comment maintained that it is not intuitive to look for 
adverse reaction reporting contact information under ``Warnings and 
Precautions.'' One comment objected to inclusion of any adverse 
reaction reporting contact information in labeling. That comment 
maintained that contact information is not prescribing information and 
thus not appropriate for inclusion in labeling and, moreover, that 
there is no evidence that inclusion of such information in labeling 
will facilitate reporting of adverse reactions.
    The agency agrees with the comments that support inclusion of 
contact information for reporting adverse reactions only in Highlights. 
Because the contact information is featured prominently in Highlights--
bolded and set apart from other information--the agency believes that 
this is sufficient to make practitioners aware of the appropriate 
contacts to report adverse reactions and to encourage them to report 
suspected adverse reactions. The agency also believes that as 
prescribers become familiar with the content of Highlights, they will 
become increasingly aware of and familiar with the location of the 
adverse reaction reporting contact information. The agency does not 
believe that also including contact information in the FPI, even if 
moved to the beginning of the FPI, would result in meaningfully 
expanding the number of practitioners who become aware of the contact 
information. Therefore repeating the contact information in the FPI 
would not have a meaningful effect on the extent to which practitioners 
report adverse events. The agency also does not believe that placing 
the contact information for reporting suspected adverse reactions only 
in the FPI would afford the information adequate prominence. 
Accordingly, the final rule was revised to delete the proposed 
requirement at Sec.  201.57(c)(6)(v) that contact information for 
adverse reaction reporting be included in the ``Warnings and 
Precautions'' section in the FPI. The agency believes it is unnecessary 
to further increase the prominence of the adverse reaction reporting 
contact information. Its current location--immediately following the 
listing of the most common adverse reactions--is the appropriate 
location, and the bolding and use of capitalization are sufficient to 
call attention to the information and distinguish it from adjacent 
information.
    The agency does not agree that the adverse reaction reporting 
contact information should be omitted from labeling because it is not 
considered prescribing information. Including adverse reaction 
reporting contact information in labeling enables practitioners to 
report adverse reactions to FDA promptly. The agency monitors these 
reports and analyzes the adverse reactions data to determine whether 
labeling revisions are necessary for safe and effective use.
    (Comment 31) Some comments recommended that only the manufacturer's 
phone number be included in prescription drug labeling, while others 
agreed that including the MedWatch phone number is important because 
manufacturers' phone numbers are subject to change. One comment 
requested that a telephone number for the relevant FDA review division 
also be included. Two comments recommended including the manufacturer's 
Web site in the reporting contact information.
    The agency agrees that it is important to include both the 
manufacturer's phone number and FDA's phone number for voluntary 
reporting of adverse reactions. The agency believes that providing 
practitioners two options for reporting adverse reactions will help 
ensure that they always have someone to contact about an adverse 
reaction. The agency believes it is not appropriate to also include the 
phone number of the FDA review division that approved the drug. FDA 
review divisions are not the initial point of contact for postmarketing 
adverse reaction reports; therefore, manufacturers and practitioners 
should not send these reports to the review divisions for processing. 
It is critical that these reports be directed to the location(s) in FDA 
that are responsible for receiving and processing these reports so that 
they are evaluated and analyzed in an appropriate manner.
    The agency agrees with comments recommending that, in addition to 
their phone number, manufacturers include the direct link to the 
section of their Web site for voluntary reporting of adverse reactions. 
The agency has revised proposed Sec.  201.57(a)(11) to require the 
address of the Web site, if one is available. The agency will not 
require that manufacturers create a Web site to meet this requirement.
    The agency has also decided to require that the adverse reaction 
reporting contact information include the FDA Web site address for 
voluntary reporting of adverse reactions (currently, http://www.fda.gov/medwatch for drug products except vaccines and http://www.fda.gov/vaers for vaccines). This Web site has become an 
increasingly important source of adverse reaction reports. The agency 
has concluded that providing practitioners with the convenience of 
being able to submit an adverse reaction report electronically may 
encourage reporting of adverse reactions that might not otherwise be 
reported. Thus, the agency believes it is very important to require 
identification of this Web site address in labeling, in addition to the 
FDA telephone number.
    (Comment 32) Two comments stated that all adverse reactions should 
be reported, and not just serious adverse reactions.
    The agency agrees that practitioners should not be discouraged from 
reporting adverse reactions that might not be considered serious. 
Certain adverse reactions that are not considered serious can be 
clinically significant. Moreover, practitioners may not always be able 
to determine whether an adverse reaction meets the regulatory 
definition of serious (21 CFR 310.305(b), 21 CFR 312.32(a), 21 CFR 
314.80(a), and 21 CFR 600.80(a)). Also, there are limitations on the 
extent to which a drug's risks (serious and nonserious adverse 
reactions) can be delineated before marketing. The agency, therefore, 
believes that practitioners should be encouraged to submit all 
suspected adverse reactions to the manufacturer or FDA, without regard 
to the seriousness

[[Page 3941]]

of the reaction, to facilitate faster and more accurate 
characterization of a drug's risk profile. Accordingly, FDA has revised 
proposed Sec.  201.57(a)(11) to require that the statement for adverse 
reaction reporting contact information refer to all suspected adverse 
reactions, not just serious ones.
     Drug interactions (proposed Sec.  201.57(a)(12))
    FDA proposed to require that Highlights contain a ``Drug 
Interactions'' heading that would include, with any appropriate 
subheadings, a concise summary of the drug interaction information in 
the FPI (i.e., prescription or over-the-counter drugs or foods that 
interact in clinically significant ways with the product)(proposed 
Sec.  201.57(a)(12)).
    (Comment 33) Several comments strongly supported inclusion of 
``Drug Interactions'' as a separate heading in Highlights. One comment 
recommended requiring separate subheadings for drug-drug, drug-food, 
drug-laboratory, and possibly drug-herbal interactions.
    FDA will not require that ``Drug Interactions'' in Highlights 
include specific subheadings depending on whether the interaction is a 
drug-drug, drug-food, drug-herbal, or drug-laboratory interaction. Use 
of these subheadings is typically most appropriate when a drug has a 
large number of interactions in each of these categories. In other 
cases, it is unlikely to provide additional clarification sufficient to 
justify use of space for the subheadings.
     Use in specific populations (proposed Sec.  201.57(a)(13))
    FDA proposed to require that Highlights contain a ``Use in Specific 
Populations'' heading (proposed Sec.  201.57(a)(13)). The agency 
proposed that this heading include, with any appropriate subheadings, a 
concise summary of information from this section of the FPI on any 
clinically important differences in response or use of the drug in 
specific populations.
    (Comment 34) One comment requested that the agency specify that the 
pregnancy category designation be included under the ``Use in Specific 
Populations'' heading in Highlights because the pregnancy category 
quickly communicates whether use of a drug is appropriate during 
pregnancy.
    The agency does not agree that pregnancy category designations are 
appropriate for inclusion in Highlights or that they are effective in 
quickly communicating whether use of a drug is appropriate during 
pregnancy. The agency believes the pregnancy category, in isolation, 
tends to oversimplify the risks of drugs in pregnancy and, as a result, 
may be confusing. Decisions about use of a drug in pregnancy should be 
based on careful consideration of available data, not simply on a 
reference to the pregnancy category.
     Highlights limitation statement (proposed Sec.  
201.57(a)(15))
    FDA proposed (proposed Sec.  201.57(a)(15)) to require that 
Highlights include the statement: ``These highlights do not include all 
the information needed to prescribe (insert name of drug product) 
safely and effectively. See (insert name of drug product)'s 
comprehensive prescribing information provided below.''
    (Comment 35) Several comments recommended that the Highlights 
limitation statement be made more prominent by moving the statement to 
the beginning of Highlights. In addition, several comments recommended 
revisions to the language of the statement, such as including that 
practitioners ``must'' consult the comprehensive prescribing 
information, in addition to Highlights, to use a drug safely and 
effectively.
    The agency agrees that it is important to emphasize to prescribers 
that Highlights does not include all the information needed to use a 
drug safely and effectively and that placement of the statement at the 
beginning of Highlights increases the prominence of this message. 
Therefore, FDA has revised proposed Sec.  201.57(a)(15) to require that 
the statement appear at the beginning of Highlights (Sec.  
201.57(a)(1)).
    The agency does not agree, however, that it is necessary to revise 
the language of the Highlights limitations statement. Recognizing that 
FDA cannot require practitioners to consult the FPI, the agency 
believes that the language in this statement, with two minor editorial 
changes, very clearly states the limitations of Highlights.

F. Comments on the Index (Proposed Sec.  201.57(b))

    FDA proposed to require that prescription drug labeling for 
products described in proposed Sec.  201.56(b)(1) (i.e., new and more 
recently approved prescription drug products) contain an index entitled 
``Comprehensive Prescribing Information: Index'' (proposed Sec.  
201.57(b)). The index would list the subheadings required under 
proposed Sec.  201.56(d)(1), if not omitted under proposed Sec.  
201.56(d)(3), and each optional subheading included in the FPI under 
proposed Sec.  201.56(d)(5). Each subheading would be required to be 
preceded by its corresponding index number or identifier.
    In the proposal, the agency specifically sought comment on whether 
it is necessary to require both an index and Highlights. As discussed 
in section II of this document, the agency has decided, on its own 
initiative, to change the title (now ``Full Prescribing Information: 
Contents'') to better reflect the function of this portion of the 
labeling.
    (Comment 36) Most comments supported inclusion of an index 
(hereafter Contents). They maintained that Highlights alone cannot be 
relied upon to help locate all drug information in the FPI because 
Highlights is not comprehensive (Highlights includes information from 
only certain sections of the FPI). They stated that a table of contents 
is necessary to quickly and easily direct the reader to sections of the 
FPI that are not referred to in Highlights. Other comments stated that, 
despite the distinct purposes served by Highlights and Contents, the 
agency should consider consolidating them to save space. Some comments 
stated that there need not be both because they have similar functions 
and recommended that Contents be deleted if Highlights is retained. One 
comment recommended that prescription drug labeling include neither 
Contents nor Highlights. The comment stated that the reordered and 
reformatted FPI itself is adequate to facilitate practitioners' access 
to information in labeling.
    FDA continues to believe that Highlights and Contents serve 
different purposes and has determined that both should be retained. 
Highlights presents a succinct summary of the information in the FPI 
that is most crucial for safe and effective use, with cross-references 
to direct prescribers to more details in the FPI. In contrast, Contents 
serves as a navigational tool that references all the sections and 
subsections in the FPI, some of which will not be referenced in 
Highlights. Therefore, the agency believes Contents has a unique and 
meaningful function in making information in the FPI accessible to 
practitioners.
    In addition, Highlights and Contents both figure prominently in 
FDA's plans to convert prescription drug labeling to an electronic 
format (see section V of this document). The Contents will provide 
hyperlinks to all sections and subsections of the FPI, enabling 
practitioners to navigate the labeling more easily. Highlights will 
provide hyperlinks to the most frequently referenced and, typically, 
most important prescribing information, allowing rapid access to more 
detailed information on these critical topics.
    (Comment 37) One comment recommended that, for sections of labeling 
that are omitted from the FPI

[[Page 3942]]

because they are not applicable, the agency consider including the 
section number and heading in Contents followed by the statement ``not 
applicable,'' rather than omitting the section number and heading. The 
comment noted that the prototype labeling in the proposed rule omitted 
a section and also omitted the listing of the section heading in 
Contents, and that this omission might confuse practitioners.
    The purpose of Contents is to set forth the sections and 
subsections included in the FPI. For many drug products, some sections 
and subsections are not applicable (e.g., ``Drug Abuse and 
Dependence,'' ``References''). Currently, these sections are, in most 
cases, simply omitted from the labeling without discussion in 
accordance with former Sec.  201.56(d)(3). The agency believes that 
this practice should continue, but recognizes that because identifying 
numbers are now required to be used for labeling of new and recently 
approved products, this practice may initially be confusing for some. 
The agency considered the comment's suggestion that the section 
identifying number and heading be included in Contents followed by the 
statement ``not applicable'' for labeling that omits a required section 
or subsection, but believes that this is not the best approach because 
of space considerations. Instead, to minimize any potential confusion 
regarding omitted sections, the agency has revised proposed Sec.  
201.56(d)(3) (designated in this final rule as Sec.  201.56(d)(4)) to 
require in these cases that the Contents heading be followed by an 
asterisk and that the following statement be included at the end of 
Contents: ``* Sections or subsections omitted from the full prescribing 
information are not listed.''
    In addition, for legal clarity, FDA revised proposed Sec.  
201.56(d)(3) and (e)(3) (Sec.  201.56(d)(4) and (e)(3) in this final 
rule) to make clear that clearly inapplicable sections, subsections, or 
specific information are omitted from labeling.

G. Full Prescribing Information--Comments on the Reorganization

    FDA proposed to revise, for products described in proposed Sec.  
201.56(b)(1) (new and more recently approved prescription drug 
products), the content and format requirements of prescription drug 
labeling at then-current Sec. Sec.  201.56(d) and 201.57. These 
revisions included, in proposed Sec. Sec.  201.56(d) and 201.57(c), 
reordering the information in the FPI to make more prominent those 
sections that the agency identified (based on the physician surveys, 
focus groups, public comments, and its own experience) to be most 
important to, and most commonly referenced by, health care 
practitioners. For example, proposed Sec.  201.57(c)(1) would require 
that any boxed warning(s) be the first substantive information to 
appear in the FPI, proposed Sec.  201.57(c)(2) would require that the 
``Indications and Usage'' section follow any boxed warnings in the FPI, 
and proposed Sec.  201.57(c)(3) would require that the ``Dosage and 
Administration'' section follow the ``Indications and Usage'' section 
in the FPI.
    (Comment 38) Virtually all the comments supported the proposed 
reordering of the FPI to give greater prominence to the sections that 
practitioners consider most important and refer to most often. Many 
comments agreed that the reordering, by better reflecting the way the 
information in the FPI is used, would make the FPI more useful and 
accessible to practitioners. Some comments, while supportive of the 
reordering generally, recommended certain changes to the sequence of 
the sections. One comment requested that the ``Adverse Reactions'' 
section be moved from its present location following the ``Use in 
Specific Populations'' section and be placed immediately after the 
``Warnings and Precautions'' section. The comment also recommended that 
the ``Use in Specific Populations'' section be moved from its location 
following the ``Drug Interactions'' section and be placed immediately 
after the ``Dosage and Administration'' section. The comment maintained 
that use in specific populations frequently involves modifications to 
dose or dosage regimen, so it would be logical to place the section in 
close proximity to the ``Dosage and Administration'' section.
    The agency agrees that it would be advantageous to group together 
the two major risk information sections--the ``Warnings and 
Precautions'' and ``Adverse Reactions'' sections. Placing the two 
sections sequentially consolidates risk information in one location and 
helps put in context the relative seriousness of the adverse reactions 
discussed in labeling. Thus, FDA has revised proposed Sec.  201.57(c) 
to require that the ``Adverse Reactions'' section follow the ``Warnings 
and Precautions'' section.
    The agency does not agree with the recommendation to place the 
``Use in Specific Populations'' section immediately after the ``Dosage 
and Administration'' section. Although some of the information in the 
``Use in Specific Populations'' section will have implications for 
dosing, most of the information in the section will be related to risk. 
The section is, therefore, more appropriately placed among the other 
labeling sections related to risk. In addition, the agency believes 
that all dosing information should be consolidated in a single section. 
If there are specific recommendations for dosage regimen modifications 
for use in specific populations, those modifications must be described 
in the ``Dosage and Administration'' section (see Sec.  201.57(c)(3)).
    (Comment 39) One comment requested that the agency require a 
``Product Title'' section at the beginning of the FPI. The comment 
maintained that the title is short and repeating it would be useful to 
practitioners to avoid confusion.
    The option to include a ``Product Title'' section is a vestige of 
the prescription drug labeling rule finalized in 1979 (44 FR 37434, 
June 26, 1979). The optional ``Product Title'' section was incorporated 
in the labeling regulations at that time in response to a comment to 
the proposed rule that was the basis for the 1979 final rule (44 FR 
37440). The comment stated that the proposed labeling requirements did 
not require identification of the product at the beginning of labeling. 
Instead, the first required element in the proposed labeling 
regulations was the ``Description'' section. The comment recommended, 
and the agency agreed, that certain sections of the ``Description'' 
section could be pulled out of that section and used as a ``Product 
Title'' section at the beginning of labeling.
    Under this final rule, a ``Product Title'' section is not needed 
for labeling subject to the requirements of new Sec.  201.57, because 
under final Sec.  201.57(a)(2), Highlights includes the name of the 
drug, dosage form, and route of administration and, for controlled 
substances, the controlled substance symbol. Because this information 
will appear at the beginning of labeling and is similar to the 
information required under the ``Product Title'' section, the agency 
believes it is not necessary or useful to provide the option to include 
a ``Product Title'' section at the beginning of the FPI. Accordingly, 
the agency has deleted proposed Sec.  201.56(d)(4) from the 
requirements for products described in Sec.  201.57(b)(1) (new and more 
recently approved drug products). This revision does not have any 
effect on the ``Product Title'' provision in current regulations (Sec.  
201.56(e)(4)), which this final rule retains for products subject to 
Sec.  201.80.
    (Comment 40) One comment stated that, if the agency retains the

[[Page 3943]]

requirement for the boxed warning in both Highlights and the FPI, the 
boxed warning in the FPI should be placed in the ``Warnings and 
Precautions'' section rather than at the beginning of the FPI.
    The agency disagrees. The agency believes that the summary sections 
in Highlights should appear in the same order as the corresponding 
sections in the FPI to facilitate access to the more detailed 
information contained in the corresponding sections in the FPI. The 
risk information presented in a boxed warning is of such importance 
that it warrants placement in the most prominent locations.
    (Comment 41) Some comments recommended that the ``How Supplied/
Storage and Handling'' section be kept at the end of the FPI, rather 
than moved toward the front of the FPI, as proposed. The comments 
expressed concern that, because of the variable length of the three 
labeling sections that precede the ``How Supplied/Storage and 
Handling'' section, it would not be in a consistent location; 
therefore, practitioners would have more difficulty locating the 
section than if it were always at the end of the FPI. One comment 
stated that pharmacists frequently access this section for information 
about storage conditions and that it would be more appropriate to place 
the section just before the ``Patient Counseling Information'' near the 
end of the labeling, where pharmacists are accustomed to finding it.
    The proposed placement of the ``How Supplied/Storage and Handling'' 
section following the ``Dosage and Administration'' section was based 
on input from physicians who were surveyed about which information in 
labeling is most important and frequently referenced. Physicians 
indicated that their use of the ``Dosage and Administration'' section 
and the ``How Supplied/Storage and Handling'' section is linked. 
Physicians commonly refer to the ``Dosage and Administration'' section 
for dosing information and then to the ``How Supplied/Storage and 
Handling'' section for available dosage strengths and dosage forms. For 
this reason, the agency believes that keeping dosing and dosage forms 
and strengths information together in the labeling is important.
    However, the agency recognizes that, under proposed Sec.  
201.57(c)(4), the ``How Supplied/Storage and Handling'' section would 
often have contained lengthy lists of available packaging and product 
identification information that may distract prescribers from other 
important information. For this reason, and in view of the comments 
received, the agency has decided to move this section toward the end of 
the labeling (Sec.  201.57(c)(17)). (See comments 55 and 107 for 
discussion of revisions (i.e., addition of imprinting as an example of 
an identifying characteristic and deletion of proposed Sec.  
201.57(c)(4)(v)).) FDA also has decided to require that information 
identified by prescribers as frequently referenced (i.e., dosage forms 
and strengths and some product identification information) be included 
in a section entitled ``Dosage Forms and Strengths'' (Sec.  
201.57(c)(4)) following the ``Dosage and Administration'' section.
    The agency believes that moving the ``How Supplied/Storage and 
Handling'' section toward the end of labeling will make it easier for 
pharmacists to locate product identification, packaging, and storage 
information. Retaining critical prescribing information in the ``Dosage 
Forms and Strengths'' section will continue to meet the needs of 
prescribers by keeping available dosage forms and strengths information 
together with information about dosage and administration. Under this 
final rule, some product identification information (e.g., shape, 
color, coating, scoring, and imprinting) may be required to appear in 
both the ``Dosage Forms and Strengths'' and ``How Supplied/Storage and 
Handling'' sections. FDA believes that the product identification 
information should be included in both sections to preserve the 
integrity and comprehensibility of each section.
    (Comment 42) One comment requested that the agency clarify the 
conditions under which it would be appropriate, when amending existing 
labeling to the new labeling format, to move certain information from a 
section in old labeling to a different section in new labeling. For 
example, the comment asked what criteria would be used to determine 
whether information on use in specific populations, currently contained 
in the ``Clinical Pharmacology'' section, should be moved to the new 
``Use in Specific Populations'' section.
    The agency expects that, in many cases, amending labeling to meet 
new Sec.  201.57(c) will involve rearranging large segments (sections 
and subsections) of information in existing labeling without 
substantially changing the content. In some cases, however, it will be 
necessary to parse information from several parts of the existing 
labeling into a new section. When information is to be consolidated 
into a new section, or when information is required in several places, 
there may be uncertainty about how the information should be divided 
into portions for clarity and to avoid redundancy. The agency 
recognizes the complexity of these issues and, therefore, is making 
available the new labeling format guidance to assist in determining how 
to reorganize existing labeling information into the new format (see 
section IV of this document).

H. Full Prescribing Information--Comments on Specific Provisions

    As noted previously, for products described in proposed Sec.  
201.56(b)(1) (new and more recently approved prescription drug 
products), FDA proposed to revise the content and format requirements 
at then-current Sec.  201.57 (proposed Sec.  201.57(c)). A discussion 
of the comments pertaining to these provisions and the agency's 
responses follow.
     Boxed warning (proposed Sec.  201.57(c)(1))
    FDA proposed to require that a boxed warning in the FPI be preceded 
by an exclamation point (!) for indexing purposes (proposed Sec.  
201.57(c)(1)). The agency specifically requested comment on the 
different types of icons that could be used to signal the boxed warning 
and on the costs and benefits of different icon types.
    (Comment 43) Several comments stated that an icon is unnecessary 
because practitioners are familiar with the meaning of a boxed warning 
and the box itself is sufficient to call attention to the warning. Some 
comments observed that the exclamation point was not a sufficiently 
distinct symbol because it could be confused with the numeral 1 and 
might be particularly difficult to recognize in small font. Some 
comments expressed concern about using any icon that is not universally 
understood. One comment recommended that a stop sign be used as it has 
a universally recognized meaning. Other comments expressed concern 
about added printing and software costs associated with any icon 
requirement.
    FDA has reconsidered requiring an exclamation point, or any other 
icon, to identify a boxed warning. FDA agrees that the single black 
line box around the warning information is understood by practitioners 
in the United States and is sufficient to draw attention to the warning 
information. Therefore, the agency is not requiring an exclamation 
point or any other icon preceding the boxed warning in the FPI. 
Sections 201.56(d)(1), 201.57(a)(4), and (c)(1) of the final rule have 
been revised to remove the requirement.
     Indications and usage (proposed Sec.  201.57(c)(2)(i))
    FDA proposed to require that the ``Indications and Usage'' section 
of the

[[Page 3944]]

FPI (proposed Sec.  201.57(c)(2)(i)) contain the same information as 
required at then-current Sec.  201.57(c)(1) except that outdated 
examples of indications were removed.
    (Comment 44) One comment recommended that the ``Indications and 
Usage'' section be retitled ``Food and Drug Administration--Approved 
Uses.'' The comment stated that the phrase ``indications and usage'' is 
regulatory jargon that is not meaningful to practitioners or patients.
    The agency does not believe it would be worthwhile to change the 
title of the section in the manner recommended by the comment. The 
agency does not agree that ``indications and usage'' is jargon and not 
meaningful to practitioners. FDA believes practitioners are familiar 
with the section heading and understand that the uses described in this 
section are those for which FDA has found to be safe and effective.
    (Comment 45) One comment stated that the ``Indications and Usage'' 
section should include approved uses in pregnancy.
    The agency agrees, in part. Uses that have been specifically 
studied for conditions unique to pregnancy and for which a drug has 
been demonstrated to be safe and effective (e.g., to induce labor) 
would be appropriate for inclusion in the ``Indications and Usage'' 
section. Ordinarily, however, special considerations about the use of a 
drug in pregnancy for indications that do not differ from the general 
population would be placed in the ``Use in Specific Populations'' 
section.
     Indications and usage--scope of information (proposed 
Sec.  201.57(c)(2)(iv)(A))
    FDA proposed to revise the requirement at then-current Sec.  
201.57(c)(3)(i) to state that if evidence is available to support the 
safety and effectiveness of the drug only in selected subgroups of the 
larger population with the disease or condition (e.g., patients with 
mild disease or patients in a special age group) or if evidence to 
support the indication is based on surrogate endpoints, then the 
available evidence and the limitations on the usefulness of the drug 
(or in the case of surrogate endpoints, the limitations of the 
supporting efficacy data) must be described succinctly in the 
``Indications and Usage'' section (proposed Sec.  201.57(c)(2)(iv)(A)). 
FDA proposed, further, to require reference to the ``Clinical Studies'' 
section of the FPI (proposed Sec.  201.57(c)(15)) for a detailed 
discussion of the methodology and results of clinical studies relevant 
to such limitation(s). FDA also proposed to require that this section 
of the FPI identify specific tests needed for selection or monitoring 
of the patients who need the drug and describe, if available, 
information on the approximate kind, degree, and duration of 
improvement to be anticipated.
    (Comment 46) One comment requested that the ``Indications and 
Usage'' section specify the type of clinical trial that has been 
conducted to support each indication (e.g., placebo-controlled, active-
controlled).
    The agency believes that the ``Clinical Studies'' section is the 
appropriate section of labeling to discuss the details (e.g., trial 
design, outcome) of clinical trials, not the ``Indications and Usage'' 
section. The agency has concluded that greater clarity about the scope 
of the information to be included in the ``Indications and Usage'' 
section is warranted and has revised proposed Sec.  201.57(c)(2) 
accordingly. This revision is consistent with having, as stated in the 
preamble to the proposed rule, a more focused ``Indications and Usage'' 
section (65 FR 81082 at 81091).
    (Comment 47) FDA received one comment that strongly supported the 
proposed modification of the ``Indications and Usage'' section to 
require that limitations in usefulness or in data supporting approval 
be specified. One comment stated that the requirement should be 
modified to specifically require discussion of differential drug 
effects in subpopulations with varying genetic characteristics.
    FDA agrees that the ``Indications and Usage'' section must discuss 
differences in drug effectiveness in subgroups for which there is 
substantial evidence for such differences. The proposed language was 
not intended to limit the scope of the requirement to particular 
subgroups. The provision applies to any identifiable subgroup with a 
clearly different response to a drug. The agency believes the language 
in final Sec.  201.57(c)(2)(i)(B) and (c)(2)(i)(D) makes clear that the 
section must discuss differential drug effects for all types of patient 
subgroups for which there is substantial evidence establishing 
differences in effects. If dosage modification is necessary based on 
genetic characteristics, this must be described in the ``Dosage and 
Administration'' section. FDA has revised proposed Sec.  201.57(c)(3) 
accordingly (see Sec.  201.57(c)(3)(i)(H) of final rule).
    (Comment 48) One comment requested that FDA make clear when the 
``Indications and Usage'' section must include specific tests needed 
for selection and monitoring of patients who need a drug (e.g., microbe 
susceptibility testing). The comment stated that it is not practical to 
recommend specific microbial susceptibility testing when empirical 
diagnosis is common.
    Specific tests for selecting and monitoring patients would be 
described when they are necessary for safe and effective use. 
Therefore, the requirement in final Sec.  201.57(c)(2)(i)(C) that the 
``Indications and Usage'' section identify specific tests needed for 
selecting and monitoring patients does not require that the 
``Indications and Usage'' section routinely state that microbial 
susceptibility testing must be done. The requirement addresses 
situations in which a drug is indicated for a specific therapeutic 
niche that can be identified by microbe susceptibility testing. For 
example, the ``Indications and Usage'' section might specify that a 
drug is indicated to treat penicillin-resistant pneumococci. The 
description of the drug's activity provides critical prescribing 
information.
     Indications and usage--lack of evidence statement 
(proposed Sec.  201.57(c)(2)(iv)(D))
    FDA proposed to revise then-current Sec.  201.57(c)(3)(iv), which 
provided that in situations where there is a common belief that a drug 
may be effective for a certain use or condition or the drug is commonly 
used for that condition but the preponderance of the evidence shows the 
drug is ineffective, the ``Indications and Usage'' section must state 
that the drug is ineffective (proposed Sec.  201.57(c)(2)(iv)(D)). The 
revision proposed to expand this requirement to situations in which a 
drug may be effective for a use but the preponderance of the evidence 
shows that the therapeutic benefits of the product do not generally 
outweigh its risks. In such situations, under sections 201(n) (21 
U.S.C. 321) and 502(a) of the act, the agency can require that the 
``Indications and Usage'' section state that there is a lack of 
evidence that the drug is effective or safe for that use.
    (Comment 49) One comment requested that the agency provide examples 
to clarify what it intends by this new requirement.
    Anti-arrhythmia drugs are an example of a category of drugs to 
which the new requirement in final Sec.  201.57(c)(2)(ii) could apply. 
They are typically effective in restoring or maintaining normal sinus 
rhythm for a variety of types of rhythm disturbances, but because of 
the potential for pro-arrhythmic effects, they are typically indicated 
for only the more serious clinical situations in which their benefits 
outweigh their risks. For example, an anti-arrhythmic

[[Page 3945]]

drug may be indicated for sustained ventricular arrhythmia, but 
specifically not indicated for premature ventricular contractions.
     Dosage and administration (proposed Sec.  201.57(c)(3))
    FDA proposed to require that the ``Dosage and Administration'' 
section of the FPI (proposed Sec.  201.57(c)(3)) contain the same 
information as required in then-current Sec.  201.57(j), except that 
the section must include efficacious or toxic drug or metabolite 
concentration ranges and therapeutic concentration windows for drug or 
metabolite(s) where established and when clinically important. FDA 
proposed to require information on therapeutic drug concentration 
monitoring (TDM), when clinically necessary. The proposed provision 
also specified that dosing regimens must not be implied or suggested in 
other sections of labeling if not included in this section. FDA has 
retained this provision in the final rule with some editorial revisions 
(Sec.  201.57(c)(3)).
    (Comment 50) One comment asked the agency to clarify whether the 
language in proposed Sec.  201.57(c)(3), ``upper limit beyond which 
safety and effectiveness have not been established,'' is referring to 
maximum tolerated dose.
    The language does not refer to the maximum tolerated dose. The 
upper limit beyond which safety and effectiveness have not been 
established would ordinarily refer to: (1) The largest dose 
demonstrated to be safe and effective in controlled clinical trials, 
(2) the largest dose evaluated that showed an increase in effectiveness 
(i.e., where studied larger doses provided no additional benefit), or 
(3) the largest dose beyond which safety has not been established or an 
unacceptable risk has been demonstrated.
    (Comment 51) One comment requested that the agency make it clear 
that any dosage adjustments discussed in the ``Drug Interactions'' 
section should also be presented in the ``Dosage and Administration'' 
section.
    The agency agrees that when there is specific information about how 
to adjust dosage because of a drug interaction, this information must 
be included in the ``Dosage and Administration'' section. The ``Dosage 
and Administration'' section should also refer the reader to the more 
detailed discussion of the drug interaction in the ``Drug 
Interactions'' and ``Clinical Pharmacology'' sections. In response to 
this comment, FDA has modified proposed Sec.  201.57(c)(3) to require 
that information on dosage adjustments needed because of a drug 
interaction be included in the ``Dosage and Administration'' section.
    (Comment 52) One comment requested that all intravenous dosing 
regimens in labeling be expressed in rates of milligrams per hour. The 
comment pointed out that rates are expressed in milligrams per minute 
and milligrams per hour. The comment maintained that expressing all 
such rates in milligrams per hour would avoid the need to recalculate 
rates and thus reduce the likelihood of medication errors.
    The agency does not agree that always requiring rates of 
administration for intravenous medications to be expressed in 
milligrams per hour would avoid the need to recalculate rates of 
infusion and thus reduce medication errors. The agency believes that 
these rates should be expressed per time unit that is most appropriate 
to the interval over which a medication is to be administered. This 
approach will eliminate, to the extent possible, the need to 
recalculate rates and should, therefore, minimize error.
    (Comment 53) One comment stated that, with respect to clinically 
important effectiveness and/or toxic drug and/or metabolite 
concentration ranges and therapeutic concentration windows in the 
``Dosage and Administration'' section, effectiveness information other 
than information on TDM would more appropriately be placed in the 
``Clinical Pharmacology'' section. The comment further stated that, if 
the concentration range concerned safety, it would more appropriately 
be included in the ``Warnings and Precautions'' section.
    The ``Dosage and Administration'' section must identify efficacious 
or toxic concentration windows of the drug or its metabolites, if 
established and clinically significant, and information on TDM, when 
TDM is necessary. Clinically relevant background information supporting 
the need for TDM could appear in other sections of labeling as 
appropriate (e.g., ``Clinical Pharmacology,'' ``Clinical Studies,'' 
``Adverse Reactions'').
    (Comment 54) Two comments recommended including instructions on the 
appropriate time of day to take a drug and other dosing conditions 
(e.g., take with food, take on an empty stomach) in the ``Dosage and 
Administration'' section of the labeling. One comment requested that 
the labeling include a section concerning the importance of compliance 
with the dosage regimen and instructions on what to do about missed 
doses and noncompliance in general. The comment requested that, in the 
absence of data to support instructions on what to do about 
noncompliance, the labeling include a statement indicating that there 
is no such information.
    The agency agrees that information about appropriate time of day to 
take a medication or other dosing considerations must be included in 
the ``Dosage and Administration'' section if this information is 
necessary for safe and effective use (e.g., if a significant amount of 
a therapeutic effect is lost if the drug is not taken on an empty 
stomach). Therefore, the agency has revised proposed Sec.  201.57(c)(3) 
to require that clinically significant dosing information (e.g., 
clinically significant food effects) be included in the ``Dosage and 
Administration'' section. Similarly, the agency has revised proposed 
Sec.  201.57(c)(13)(i)(B) of the ``Clinical Pharmacology'' section to 
clarify that certain recommendations regarding pharmacodynamic effects 
included in other sections of labeling, such as the ``Dosage and 
Administration'' section, must not be repeated in the ``Clinical 
Pharmacology'' section.
    The agency agrees that rigid compliance with the dosage regimen can 
be critical to safe and effective drug therapy and information about 
how to manage noncompliance is important for practitioners. Therefore, 
FDA has revised proposed Sec.  201.57(c)(3) to make clear that 
important considerations concerning compliance with the dosage regimen 
must be included.
    The agency believes that the labeling should not include a separate 
section devoted to the importance of compliance with a drug's dosage 
regimen or information on what to do about missed doses, because this 
information is most appropriately contained in other sections of the 
labeling (e.g., ``Dosage and Administration,'' ``Clinical 
Pharmacology,'' ``Patient Counseling Information''). The agency 
believes that it would not be useful to include a statement in the 
labeling indicating that there is no information available about 
management of noncompliance (e.g., missed doses).
     How supplied/storage and handling (proposed Sec.  
201.57(c)(4))
    FDA proposed to require that the ``How Supplied/Storage and 
Handling'' section of the FPI (proposed Sec.  201.57(c)(4)) contain the 
same information as required at then-current Sec.  201.57(k), except 
that a new provision was added at proposed Sec.  201.57(c)(4)(v). 
Proposed Sec.  201.57(c)(4)(v) would require a statement specifying the 
type of container to be used by pharmacists in dispensing the product. 
Comments pertaining to proposed Sec.  201.57(c)(4)(v) are addressed in 
section VI.J of this document (``Comments on Revisions to

[[Page 3946]]

Container Labels''; see comments 106 through 110). Comment 41 addresses 
relocation of the ``How Supplied/Storage and Handling'' section to 
Sec.  201.57(c)(17) and the retention of critical prescribing 
information in the ``Dosage Forms and Strengths'' section at Sec.  
201.57(c)(4). A comment pertaining to the format for and type of 
information contained in these sections is discussed here.
    (Comment 55) One comment recommended including product identity 
markings in this section. The comment also recommended bulleted or 
tabular presentation of product identity markings, color, flavor, 
package sizes, strengths, storage conditions, etc., to make such 
information more accessible.
    FDA agrees with the comment that product identity markings are 
useful for practitioners and, therefore, now includes imprinting as an 
example of an identifying characteristic in both the ``Dosage Forms and 
Strengths'' and the ``How Supplied/Storage and Handling'' sections of 
the final rule. FDA also agrees that presenting information about 
product identity markings, color, flavor, package sizes, strengths, 
storage conditions, and other identifying information in a bulleted or 
table format will make the information more accessible, particularly 
where the product has many dosage forms and strengths. However, because 
the amount and content of information can vary significantly from 
product to product, FDA is not requiring a specific format.
     Warnings and precautions (proposed Sec.  201.57(c)(6))
    FDA proposed to revise the content of the ``Warnings'' and 
``Precautions'' sections. First, FDA proposed to require that 
information on drug interactions, information on specific populations 
(i.e., pregnancy, labor and delivery, nursing mothers, pediatric, and 
geriatric use information), and information for patients be moved from 
the ``Precautions'' section to three new sections (described in 
proposed Sec.  201.57(c)(7), (c)(8), and (c)(17) respectively). Second, 
FDA proposed to require that the remainder of the information in the 
``Precautions'' section, with the information from the ``Warnings'' 
section, be combined into a new section entitled ``Warnings and 
Precautions'' (proposed Sec.  201.57(c)(6)).
    FDA also proposed to require that the ``Warnings and Precautions'' 
section include information on contacts for adverse reaction reporting 
(proposed Sec.  201.57(c)(6)(v)). See comment 30 regarding deletion of 
proposed Sec.  201.57(c)(6)(v).
    Several comments supported reorganizing the ``Warnings and 
Precautions'' section. The comments agreed with FDA's findings, based 
on physician surveys and focus testing, that the distinction between 
warnings and precautions is not meaningful to practitioners who use 
labeling. The comments stated that the combined section would make the 
discussion of risk information in labeling less repetitive, less 
confusing, and more accessible.
    (Comment 56) In the proposal, the agency specifically sought 
comment on whether there should be standardized headings for categories 
of adverse reactions in the proposed ``Warnings and Precautions'' 
section and, if there should be, what standardized headings would be 
appropriate.
    Comments uniformly opposed standardized headings to categorize 
adverse reactions in the ``Warnings and Precautions'' section. Comments 
expressed concern that standardized headings would not provide 
sufficient flexibility to accommodate the diversity of risk information 
that might be appropriate for inclusion in the ``Warnings and 
Precautions'' section.
    FDA agrees that standardized headings should not be required in the 
``Warnings and Precautions'' section because a requirement to place 
risk information under prescribed headings could make the information 
less clear or more difficult to find.
    (Comment 57) One comment requested clarification of the requirement 
in proposed Sec.  201.57(c)(6)(iii) that the ``Warnings and 
Precautions'' section identify any laboratory tests that ``may be 
helpful'' in following a patient's response or identifying possible 
adverse reactions. The comment maintained that the language ``may be 
helpful'' is too vague and recommended that the language be changed to 
specify that only laboratory tests that ``have been shown to be 
helpful'' be required in the ``Warnings and Precautions'' section.
    The agency is concerned that limiting the scope of laboratory 
testing recommendations identified in labeling to only those tests that 
have been ``shown to be helpful'' in monitoring patients could exclude 
sensible and potentially important laboratory testing recommendations. 
The agency agrees, however, that ``may be helpful'' is a vague standard 
and, therefore, has amended the provision to require identifying any 
laboratory tests ``helpful'' in following a patient's response or 
identifying possible adverse reactions.
    (Comment 58) Several comments expressed concern about the proposal 
to change the criteria for inclusion of adverse reactions in the 
``Warnings and Precautions'' section from ``serious'' to ``clinically 
significant'' adverse reactions. There was concern that the 
significance of the adverse reactions discussed in the ``Warnings and 
Precautions'' section would be diluted by the inclusion of less serious 
adverse reactions in the section, thus undermining the value of the 
section. Other comments expressed concern that ``clinically 
significant'' is subject to interpretation and could, in application, 
result in inconsistency across labeling for different products.
    As discussed in the preamble accompanying the proposed rule (65 FR 
81082 at 81092), ``serious'' was changed to ``clinically significant'' 
to expand the scope of the ``Warnings and Precautions'' section to 
allow for inclusion of adverse reactions that may not meet the 
regulatory definition of ``serious'' (Sec.  312.32(a)), but nonetheless 
have a significant impact on clinical use of the drug. The agency 
believes that information on both types of adverse reactions is 
necessary for practitioners to prescribe products safely and 
effectively and must, therefore, be included in the ``Warnings and 
Precautions'' section. The agency acknowledges that inclusion of less 
serious but clinically significant adverse reactions may add to the 
overall length of the ``Warnings and Precautions'' section of labeling 
for certain drugs. The agency does not agree, however, that the effect 
will be to dilute or deemphasize the importance of serious adverse 
reactions contained in the section. The agency believes that limiting 
inclusion of nonserious adverse reactions to only those that have 
significant impact on therapeutic decisionmaking (e.g., may reduce 
compliance with drug therapy) ensures that the intended scope of the 
``Warnings and Precautions'' section is preserved.
    (Comment 59) One comment recommended that the agency describe 
parameters upon which to base decisions about the sequence in which 
adverse reactions are presented in the ``Warnings and Precautions'' 
section.
    There are multiple factors that could influence the sequence in 
which adverse reactions should be presented in the ``Warnings and 
Precautions'' section. The most significant include the relative 
seriousness of the adverse reaction, the ability to prevent or mitigate 
the adverse reaction, the likelihood the adverse reaction will occur, 
and the size of the population affected. In general, the sequence of 
the adverse reactions should reflect the relative public health 
significance, and the seriousness of the adverse reaction

[[Page 3947]]

should weigh more heavily than the likelihood of occurrence or the size 
of the affected population. The agency has added clarifying language to 
this requirement to assist in selecting and organizing information in 
this section. The agency is also making available guidance on the 
``Warnings and Precautions'' section, which provides recommendations on 
sequencing of adverse reactions (see section IV of this document).
    In addition, the final rule (Sec.  201.57(c)(6)(i)) states that FDA 
may require labeling to include a specific warning relating to a use 
that is not provided for under the ``Indications and Usage'' section if 
the drug is commonly prescribed for a disease or condition and such 
usage is associated with clinically significant risk or hazard. FDA 
deleted language from proposed Sec.  201.57(c)(6)(i), (i.e., ``and 
there is a lack of substantial evidence of effectiveness for that 
disease or condition'') because the requirement for a warning is based 
on an assessment of risk. In addition, FDA also clarified that its 
authority under this provision must be exercised in accordance with 
sections 201(n) and 502(a) of the act.
     Drug interactions (proposed Sec.  201.57(c)(7))
    FDA proposed to require a ``Drug Interactions'' section (proposed 
Sec.  201.57(c)(7)) containing the same information as required by the 
``Drug interactions'' subsection of the ``Precautions'' section at 
then-current Sec.  201.57(f)(4).
    (Comment 60) Most comments supported creation of a distinct section 
for drug interactions. These comments maintained that the new section 
would improve the safety of drugs for patients on multiple medications. 
One comment asked FDA to clarify whether discussions of drug 
interaction pharmacokinetic studies should be repeated in the 
``Clinical Pharmacology'' section.
    How to divide information on drug interactions between the 
``Clinical Pharmacology'' and ``Drug Interactions'' sections is a 
matter of judgment. Manufacturers must not include a detailed 
discussion of drug interaction pharmacokinetic studies in both the 
``Drug Interactions'' and the ``Clinical Pharmacology'' sections. 
Ordinarily, clinically significant results and conclusions of such 
studies must appear in the ``Drug Interactions'' section and clinically 
significant information on dosing modifications in the ``Dosage and 
Administration'' section. If additional details about the design or 
conduct of the studies are relevant to the clinical use of the drug, 
the information must be included in the ``Clinical Pharmacology'' 
section. Thus, the agency has revised proposed Sec.  201.57(c)(7)(i) 
and (c)(13)(i)(D) to provide this clarification (see Sec.  
201.57(c)(8)(i) and (c)(13)(i)(C)).
    (Comment 61) One comment stated that the labeling example published 
with the proposed rule included recommended dosage adjustments for drug 
interactions that are not based on clinical experience and requested 
clarification about whether the manufacturer must include speculative 
interactions and dosage adjustments in this section. The comment also 
asked to what extent sponsors would be required to develop clinical 
data to support dosage adjustments for drug interactions.
    Manufacturers must not speculate in labeling. Information from 
clinical experience is clearly the most persuasive, but other relevant 
data, such as pharmacokinetic data, in vitro data, and data from other 
drug products in the same pharmacologic or chemical class, may reliably 
predict the likelihood of an interaction with the drug or provide a 
basis for a dosage adjustment recommendation. Therefore, it would not 
be appropriate to limit the scope of the drug interactions and dosage 
adjustment information in labeling to only those interactions or dosage 
adjustments for which there are clinical data.
    (Comment 62) One comment stated that including discussions of 
dosage adjustments to address drug interactions in both the ``Drug 
Interactions'' and ``Dosage and Administration'' sections would add 
unnecessarily to the length of the labeling.
    FDA does not agree that discussing dosage adjustments for drug 
interactions in both the ``Drug Interactions'' section and the ``Dosage 
and Administration'' section would be unnecessary or repetitive because 
the purposes of the sections are distinct (see comment 51). The ``Drug 
Interactions'' section alerts the prescriber to the existence of 
interactions and provides a place for substantive discussion of the 
nature of the identified interactions, including practical advice about 
preventing or limiting interactions. The ``Dosing and Administration'' 
section provides specific information about how to modify the dose to 
minimize the risk of drug interactions when such information is 
available, but does not provide the details that are discussed in the 
``Drug Interactions'' section.
    (Comment 63) One comment recommended revising the ``Drug 
Interactions'' section to require the presentation of drug interaction 
data ranked by order of the strength of the data supporting the 
existence of an interaction.
    FDA believes that relative clinical significance of the drug 
interaction would ordinarily be the most reasonable basis for 
determining the order of presentation of drug interactions. Because, 
for certain products, this section can be lengthy and complex, the 
agency will not designate a specific order in the regulations.
    (Comment 64) One comment recommended that, in the following 
language from the proposed provision for the ``Drug Interactions'' 
section, the word ``patients'' be replaced with the word ``humans'': 
``Information in this section must be limited to that pertaining to 
clinical use of the drug in patients.'' The comment maintained that 
drug interaction studies often involve healthy volunteers, rather than 
patients, and the language in the regulation should reflect the nature 
of the study participants.
    The agency has revised final Sec.  201.57(c)(8)(i) to clarify the 
scope of the information to be included in this section and this 
sentence was deleted.
    (Comment 65) One comment requested that the agency clarify the 
requirement in the proposed ``Drug Interactions'' section to briefly 
describe the mechanism of interaction for drugs and drug classes that 
interact with a drug in vivo. The comment maintained that the mechanism 
is not always understood and requested that the rule specify that the 
requirement to describe the mechanism applies only if the mechanism is 
understood.
    The agency agrees. Proposed Sec.  201.57(c)(7) (Sec.  
201.57(c)(8)(i) in this final rule) has been revised to state that the 
mechanism of an interaction must be briefly described, if it is known.
     Use in specific populations (proposed Sec.  201.57(c)(8))
    FDA proposed to require a new section entitled ``Use in Specific 
Populations'' (proposed Sec.  201.57(c)(8)) to include the information 
on specific populations required in the ``Pregnancy,'' ``Labor and 
delivery,'' ``Nursing mothers,'' ``Pediatric use,'' and ``Geriatric 
use'' subsections of the ``Precautions'' section at then-current Sec.  
201.57(f)(6) through (f)(10). The agency also proposed to revise 
certain required warning language in the labeling of drugs in pregnancy 
categories D and X (proposed Sec.  201.57(c)(8)(i)(A)(4) and 
(c)(8)(i)(A)(5)). The proposal would have replaced the following 
language from then-current Sec.  201.57(f)(6)(i)(d) and (f)(6)(i)(e): 
``If this drug is used during pregnancy, or if the patient becomes

[[Page 3948]]

pregnant while taking this drug, the patient should be apprised of the 
potential hazard to the fetus.'' The proposed alternative language, 
which was intended to address the concern that any woman with 
reproductive potential should be apprised of the risk associated with 
taking the category D and X drugs during pregnancy, read: ``If this 
drug is administered to a woman with reproductive potential, the 
patient should be apprised of the potential hazard to a fetus.''
    FDA also proposed some changes in terminology to the ``Nursing 
mothers'' subsection (proposed Sec.  201.57(c)(8)(iii)). For example, 
FDA proposed to change the term ``nursing mothers'' to ``lactating 
women.'' Other proposed changes included making assessments based on 
``clinically significant adverse reactions'' rather than ``serious 
adverse reactions.''
    (Comment 66) Several comments supported creation of a section 
devoted to information about use in specific populations. The comments 
indicated that placing all the information on specific populations in 
one labeling section would make the information much easier to locate. 
However, one comment stated that the revised warning statement for 
drugs in pregnancy categories D and X no longer makes clear that a 
pregnant woman receiving the drug should be apprised of the potential 
hazard to the fetus. The comment expressed concern that the phrase 
``women with reproductive potential'' could be interpreted as referring 
only to women with the potential to become pregnant and not to those 
who actually are pregnant.
    The agency is developing a proposal that would revise the 
requirements for the ``Pregnancy,'' ``Labor and delivery,'' and 
``Nursing mothers'' subsections of prescription drug labeling. For this 
reason, the agency has reconsidered the need to make minor, interim 
changes to the warning statements for pregnancy categories D and X in 
this final rule and has decided to retain the language at former Sec.  
201.57(f)(6)(i)(d) and (f)(6)(i)(e). This language clearly addresses 
use of the drug by pregnant women and obviates the need for the changes 
advocated by the comment.
    FDA also decided not to make interim changes to the ``Nursing 
mothers'' subsection of the labeling and will retain the language at 
former Sec.  201.57(f)(8) for this subsection. The agency believes that 
it is best to address all changes to the content of these subsections 
at one time.
    (Comment 67) One comment requested that the agency combine the 
initiative to revise the requirements for the pregnancy labeling with 
this rulemaking to revise the requirements of prescription drug 
labeling generally. The comment maintained that the pregnancy labeling 
requirements need to be changed expeditiously to require that the 
labeling address the likelihood of harm to the fetus based on timing of 
exposure, pharmacokinetic changes in pregnant women, and the relevance 
of animal data to humans.
    The agency does not agree that the two initiatives should be 
combined. The pregnancy labeling initiative focuses exclusively on 
revising the content requirements for the pregnancy subsection of 
labeling to meaningfully describe the risks associated with fetal and 
maternal exposure to a drug and the clinical implications of those 
risks. In contrast, this final rule is focused on revising the format 
and content of labeling to increase its usefulness for health care 
practitioners.
     Adverse reactions--definition of adverse reaction 
(proposed Sec.  201.57(c)(9))
    FDA proposed to revise the definition of ``adverse reaction'' to 
mean a ``noxious and unintended response to any dose of a product for 
which there is a reasonable possibility that the product caused the 
response, i.e., the relationship cannot be ruled out'' (proposed Sec.  
201.57(c)(9)).
    (Comment 68) Several comments objected to the revised definition of 
an adverse reaction in proposed Sec.  201.57(c)(9). The comments 
maintained that this definition would be too restrictive and could 
result in omission of important information. Comments expressed 
particular concern that the terms ``noxious'' and ``unintended'' could 
be applied to exclude important adverse reactions. They also stated 
that important information could be excluded from the ``Adverse 
Reactions'' section because manufacturers could narrowly construe 
whether the drug caused the event. Comments maintained, for example, 
that an adverse reaction that affects compliance could be considered 
clinically meaningful and thus merit discussion in the ``Warnings and 
Precautions'' section, but be excluded from the ``Adverse Reactions'' 
section because it is not considered noxious or unintended. Some 
comments requested clarification of elements of the definition--in 
particular ``noxious,'' ``unintended,'' and ``injurious to health.'' 
One comment recommended that ``unintended'' be changed to 
``unexpected,'' stating that ``unexpected'' may more accurately reflect 
the intent of the definition. One comment requested that FDA issue 
guidance to clarify these concepts and conduct an educational campaign 
to explain the meaning and significance of the new definition. Several 
comments maintained that the definition of an adverse reaction in then-
current Sec.  201.57(g) is a more accurate description of the events 
that should be included in labeling.
    One comment expressed concern that the proposed definition of 
adverse reaction could result in excluding adverse events that should 
be included in the labeling because there is a lack of guidance for 
determining ``reasonable causality'' to identify which adverse 
reactions to list. The comment said that it is commonly known that 
prescription drug labeling lists all adverse reactions that occurred in 
trials, with definite, probable, possible, and remote causality. The 
comment recommended that significant adverse reactions be listed in 
Highlights and reinforced in the full prescribing information. The 
comment also stated that all other events that occurred should still be 
listed, perhaps last in the comprehensive ``Adverse Reactions'' 
section, because the loss of a comprehensive listing of all reported 
events could be detrimental to patient safety.
    Some comments stated that the proposed new definition for an 
adverse reaction was a marked improvement because it would narrow the 
scope of the ``Adverse Reactions'' section. These comments contended 
that narrowing the scope of events considered adverse reactions for 
purposes of the ``Adverse Reactions'' section would help address long-
standing practitioner concerns that the section is not very informative 
because it contains excessively long lists of reactions, many of which 
are not relevant to clinical use of the drug.
    The agency has reconsidered the proposed definition of an adverse 
reaction, which was intended to conform to the definition of adverse 
drug reaction for safety reporting in the International Conference on 
Harmonisation of Technical Requirements for Registration of 
Pharmaceuticals for Human Use (ICH) guidance ``E2A Clinical Safety Data 
Management: Definitions and Standards for Expedited Reporting'' (60 FR 
11284 at 11285, March 1, 1995).
    Upon consideration of the comments submitted in response to this 
proposal, the agency concluded that it should not require use of a new 
definition of adverse reaction for labeling of new and recently 
approved products. The agency believes that the language in the 
definition of adverse reaction at former Sec.  201.57(g) (designated in 
the final rule

[[Page 3949]]

as Sec.  201.57(c)(7)), in particular ``an undesirable effect, 
reasonably associated with use of a drug, that may occur as part of the 
pharmacological action of the drug or may be unpredictable in its 
occurrence'' is appropriate for labeling, but that it requires 
clarification, as described in the next paragraph, to minimize 
including information in labeling that does not help prescribers use 
the drug safely and effectively (i.e., adverse events that are not 
related to use of the drug), and that may result in diluting the 
usefulness of clinically meaningful information. Thus, FDA will, as 
recommended by several comments, continue to use its existing 
definition for adverse reaction.
    The agency believes, as previously indicated, that the definition 
of adverse reaction at former Sec.  201.57(g) requires clarification. 
For this purpose, FDA has revised this definition to make clear that it 
is specific to prescription drug labeling and does not include all 
adverse events observed during use of a drug, but only those adverse 
events for which there is some basis to believe there is a causal 
relationship between the drug and the occurrence of the adverse event. 
There are many factors to consider in assessing the association between 
a drug and a reported adverse event and determining whether a reported 
event is an adverse reaction that should be included in labeling. The 
agency has included clarifying language in this final rule to assist in 
selecting and organizing reactions. To further assist manufacturers and 
reviewers, FDA is making available the ``Adverse Reactions'' section 
guidance (see section IV of this document).
    (Comment 69) One comment expressed concern that inclusion of an 
adverse reaction in the ``Adverse Reactions'' section under the 
proposed definition would be tantamount to an admission that the event 
was caused by a drug for product liability purposes. Another comment 
stated that having two definitions for adverse reactions (i.e., the 
definition in proposed Sec.  201.57(c)(9) for new and recently approved 
drugs and the definition in redesignated Sec.  201.80(g) for older 
drugs) may have implications for product liability. One comment stated 
that application of the proposed adverse reactions definition to drugs 
that have to revise their labeling to implement the new format would 
require reevaluation of clinical data and a new safety review by the 
agency. One comment requested the agency clarify whether manufacturers 
would now have to reclassify or otherwise reassess adverse reactions 
profiles of products with existing labeling.
    The concerns expressed in these comments are based on the proposed 
adverse reaction definition. Because the agency is not adopting this 
definition for the purposes of labeling, FDA believes that the concerns 
expressed in these comments are no longer applicable.
     Adverse reactions--characterization of adverse reactions 
(proposed Sec.  201.57(c)(9)(ii))
    FDA proposed to retain the language from then-current Sec.  
201.57(g)(2) in proposed Sec.  201.57(c)(9)(ii):
    In this listing, adverse reactions may be categorized by organ 
system, by severity of the reaction, by frequency, or by 
toxicological mechanism, or by a combination of these, as 
appropriate. If frequency information from adequate clinical studies 
is available, the categories and the adverse reactions within each 
category must be listed in decreasing order of frequency. An adverse 
reaction that is significantly more severe than the other reactions 
listed in a category, however, must be listed before those 
reactions, regardless of its frequency. If frequency information 
from adequate clinical studies is not available, the categories and 
adverse reactions within each category must be listed in decreasing 
order of severity.* * *
    (Comment 70) One comment requested that the agency reconcile 
apparent inconsistencies between the draft of the ``Adverse Reactions'' 
section guidance in development and the language in the ``Adverse 
Reactions'' section of the proposed rule. The comment maintained that 
the recommended organization in the draft ``Adverse Reactions'' section 
guidance is not consistent with the organization of the ``Adverse 
Reactions'' section in the proposed rule. This comment advocated that 
important points regarding adverse reactions be discussed in both the 
proposed rule and the ``Adverse Reactions'' section guidance, with 
extensive detail provided in the guidance document.
    Based on this comment and on comments received on the draft 
``Adverse Reactions'' section guidance, the agency has revised the 
regulation on the ``Adverse Reactions'' section at proposed Sec.  
201.57(c)(9) (designated in this final rule as Sec.  201.57(c)(7)) to 
clarify the scope of information for this section of labeling. See 
comments 71 through 75.
    The agency recognizes that the ``Adverse Reactions'' section has 
evolved over time to a point where it now typically contains several 
different components (e.g., information from controlled clinical 
trials, uncontrolled clinical trials, and postmarketing experience). 
The agency also recognizes that there exists considerable inconsistency 
in how information in this section is organized and presented across 
different drug products. To address this problem, the agency 
recommends, in the ``Adverse Reactions'' section guidance, an 
organization for the typical components of the ``Adverse Reactions'' 
section.
    Thus, FDA continues, as recommended by the comment, to provide 
general requirements in regulation and detailed recommendations in 
guidance. The ``Adverse Reactions'' section guidance provides 
recommendations for how to select information for inclusion in this 
section, how to characterize the information, and how to further 
organize it (see section IV of this document).
    (Comment 71) One comment recommended that manufacturers be required 
to specify in the ``Adverse Reactions'' section what categorization 
scheme was employed for listing of the adverse reactions.
    The agency believes that, in most cases, the basis for the 
categorization of ``Adverse Reactions'' section will be readily 
apparent to readers. In rare instances in which the basis for 
categorization is not apparent, it would be appropriate to identify the 
categorization scheme employed. The agency has, therefore, determined 
that it is not necessary to require in regulation that the basis for 
categorization of adverse reactions be identified for all labeling.
    The agency has revised, for the reasons described in the response 
to comment 70, proposed Sec.  201.57(c)(9)(ii) (designated in this 
final rule as Sec.  201.57(c)(7)(ii)) to provide clarification for this 
part of the ``Adverse Reactions'' section. The agency changed the term 
``organ system'' to ``body system.'' Although the two terms have been 
used interchangeably, currently, the term ``body system'' is used most 
often.
    In addition, the agency deleted the option to categorize adverse 
reactions by toxicological mechanism. After reviewing the 1975 proposed 
and 1979 final rules, the agency concluded that the term is not clear; 
therefore, categorization by toxicological mechanism is not an 
appropriate option for the ``Adverse Reactions'' section.
    The agency also made clear that, however categorized, adverse 
reactions must be listed in order of decreasing frequency.
    FDA also removed the requirement that significantly more severe 
reactions be listed before other reactions regardless of frequency. In 
most cases, frequency information is paramount, but in other cases, 
severity information may be more important or a combination of

[[Page 3950]]

the two may be the best approach. The categorization scheme selected 
for the ``Adverse Reactions'' section should be appropriate to the 
drug's safety database and reflect the relative public health 
importance of the information.
    The agency also clarified that if data are available and important 
for adverse reactions with significant clinical implications, details 
about the nature, frequency, and severity of the reaction must be 
included. This provision makes clear that, in many cases, in addition 
to lists of adverse reactions, descriptive information is appropriate 
for inclusion in the ``Adverse Reactions'' section.
    (Comment 72) One comment requested that the agency require that 
adverse reactions identified from postmarketing experience be listed 
separately from adverse reactions identified from clinical trials.
    The agency agrees that adverse reactions identified from domestic 
and foreign spontaneous reports after a drug is marketed should be 
listed separately from adverse reactions identified in clinical trials. 
Adverse reaction data from clinical trials and spontaneous reports 
communicate different information to practitioners. In clinical trials, 
subjects are specifically queried about and evaluated for occurrence of 
adverse events and clinical investigators have requirements for 
identifying and reporting such events (21 CFR 312.64(b)). Data from 
clinical trials inform practitioners about the range of adverse 
reactions that may occur. In addition, because there is typically a 
comparison to a control group, these data provide an estimate of the 
incidence and the ability to identify events that, because they are 
likely to be causally related, represent adverse reactions.
    Postmarketing experience with a drug permits observation of 
suspected adverse reactions in a larger, often more diverse, patient 
population. This experience may provide an opportunity to identify low 
frequency reactions and reactions not previously observed because the 
susceptible population was either excluded from the controlled trials 
or only included in small numbers. But, to interpret this information 
accurately, a practitioner must be mindful that postmarketing 
experience, although more closely reflective of clinical practice, 
lacks the structure of a clinical trial setting that permits increased 
precision. For postmarketing reporting, the impetus for reporting, the 
frequency with which a suspected adverse reaction is reported, and the 
number of exposures to the drug compared to the number of suspected 
reactions reported are unknown, making estimation of incidence 
calculations difficult.
    Because these differences significantly affect the interpretation 
of these complementary sets of data, the agency believes it is 
important to separate in labeling adverse reactions identified in 
clinical trials from adverse reactions identified from domestic and 
foreign spontaneous reports. For precisely these reasons, in the draft 
``Adverse Reactions'' section guidance, FDA suggested segregating 
adverse reactions from spontaneous reports in this section of the 
labeling. Thus, the agency has revised proposed Sec.  201.57(c)(9)(ii) 
(Sec.  201.57(c)(7) in this final rule) by creating a separate listing 
for each set of adverse reactions within the ``Adverse Reactions'' 
section.
    The agency clarifies that this distinction is between adverse 
reactions identified in clinical trials and those identified from 
domestic and foreign spontaneous reports after a drug is marketed. 
Adverse reactions that are identified in clinical trials conducted 
after a drug is marketed would be listed under adverse reactions 
identified from clinical trials.
    (Comment 73) One comment requested that, for drugs with multiple 
doses or indications, the ``Adverse Reactions'' section have a separate 
presentation of adverse reactions for each dose or indication.
    The agency agrees that it is important for the ``Adverse 
Reactions'' section to call attention to adverse reactions for which 
there are clinically significant dose-response relationships.
    Thus, the agency has revised proposed Sec.  201.57(c)(9) 
(designated in this final rule as Sec.  201.57(c)(7)) to require 
manufacturers to include details about the relationship of adverse 
reactions to drug dose where sufficient data are available and 
necessary to prescribe the drug safely and effectively. The agency does 
not believe, however, that it needs to require that separate 
presentations of adverse reactions always be included for different 
doses. If there are important differences in adverse reaction rates for 
different doses, the section can include a single table that directly 
compares the adverse reactions rates for different doses. Presenting 
rates for different doses side by side in a table, for example, is an 
effective way to make a dose-response relationship apparent.
    The agency also does not believe that it needs to require a 
separate presentation of adverse reactions for each indication. Such 
information could be appropriate for a drug with multiple indications, 
however, when the adverse reaction profile differs substantially from 
one indication or population to another, the differences are drug 
related, and the data have important clinical implications. On the 
other hand, where differences are relatively minor and not clinically 
meaningful, separate presentations for multiple indications would not 
be informative and would detract from more important information.
    (Comment 74) One comment requested that the ``Adverse Reactions'' 
section discuss differences in adverse reaction rates among different 
demographic subgroups (e.g., men, women, blacks, renally-impaired).
    The agency agrees that the ``Adverse Reactions'' section must 
include information on differences in adverse reactions among 
demographic subgroups where sufficient data are available and 
important. Thus, the agency has revised proposed Sec.  201.57(c)(9) 
(designated in this final rule as Sec.  201.57(c)(7)) to require such 
information in the ``Adverse Reactions'' section.
     Adverse reactions--frequency information (proposed Sec.  
201.57(c)(9)(ii))
    FDA proposed to retain the language from then-current Sec.  
201.57(g)(2) in proposed Sec.  201.57(c)(9)(ii):
    The approximate frequency of each adverse reaction must be 
expressed in rough estimates or orders of magnitude essentially as 
follows:
    The most frequent adverse reaction(s) to (name of drug) is (are) 
(list reactions). This (these) occur(s) in about (e.g., one-third of 
patients; one in 30 patients; less than one-tenth of patients). Less 
frequent adverse reactions are (list reactions), which occur in 
approximately (e.g., one in 100 patients). Other adverse reactions, 
which occur rarely, in approximately (e.g., one in 1,000 patients), 
are (list reactions).
    Percent figures may not ordinarily be used unless they are 
documented by adequate and well-controlled studies as defined in 
Sec.  314.126(b) of this chapter (except for biological products), 
they are shown to reflect general experience, and they do not 
falsely imply a greater degree of accuracy than actually exists.
For biological products, such figures must be supported by substantial 
evidence.
    (Comment 75) One comment asked the agency to clarify an apparent 
inconsistency between the proposed rule and the draft ``Adverse 
Reactions'' section guidance concerning how to characterize the 
incidence of adverse reactions. The comment pointed out that the 
proposed rule (which used the same language as in the 1979 final rule) 
recommended grouping adverse reactions by rough orders of magnitude and 
encouraged use of the terms ``frequent,'' ``infrequent,'' and ``rare'' 
in conjunction with orders of magnitude

[[Page 3951]]

appropriate for a given drug's safety database. The comment observed 
that agency guidance discouraged use of these terms when grouping by 
rough orders of magnitude.
    The agency agrees that clarification is needed regarding 
presentation of incidence information for adverse reactions. The 
language in the proposed rule is not sufficiently precise to accurately 
reflect current practices in characterizing the incidence of adverse 
reactions associated with the use of a drug product. The preamble to 
the 1975 proposed rule indicates that precise percent figures would be 
appropriate if there is scientific evidence from well-controlled trials 
substantiating such figures and when inclusion of percent figures does 
not falsely imply a greater degree of accuracy than actually exists (40 
FR 15392 at 15393, April 7, 1975). The science of clinical trials has 
progressed so substantially over time that ascertaining such rates is 
typically part of virtually all drug development programs.
    Under current labeling practices, rates of incidence for most 
adverse reactions identified in controlled clinical trials are 
expressed as percentages. Current labeling also typically includes 
percentage rates for comparison groups in clinical trials (e.g., 
placebo group) where inclusion of such rates would not be misleading. 
Broader frequency ranges are used only when meaningful percentage rates 
cannot be determined. Therefore, the agency has revised proposed Sec.  
201.57(c)(9) (designated in this final rule as Sec.  201.57(c)(7)) to 
make it clear that when meaningful adverse reaction rates can be 
derived (for drug treatment group and comparison groups) and 
presentation of comparator rates would not be misleading, they must be 
included in labeling.
    The agency also believes it is inappropriate to use nonspecific 
terms such as ``frequent,'' ``infrequent,'' and ``rare'' when 
presenting adverse reaction information. The agency believes the 
science of clinical trials has evolved such that use of those terms in 
the manner recommended by the 1979 rule is confusing because the terms 
do not necessarily refer to the same frequency range across different 
drug products. For example, for product A, ``rare'' might mean an 
incidence of less than 1/500, but for product B, ``rare'' might mean an 
incidence of less than 1/1000. Moreover, the terms are imprecise and, 
even if precise meanings were defined, would reinforce the 
misconception that frequency is synonymous with seriousness.
    The agency believes that identifying the numerical frequency range 
alone is a clearer way to communicate rough rates of incidence for a 
group of adverse reactions. Therefore, the agency has revised proposed 
Sec.  201.57(c)(9) to require that adverse reactions for which 
meaningful percentage rates cannot be reliably determined (e.g., 
adverse reactions were observed only in the uncontrolled trial portion 
of the overall safety database), be grouped within specified frequency 
ranges as appropriate to the safety database of the drug (e.g., adverse 
reactions occurring at a rate of less than 1/100, adverse reactions 
occurring at a rate of less than 1/500) or descriptively identified, if 
frequency ranges cannot be determined.
    (Comment 76) One comment requested clarification on how percentages 
should be used to characterize the frequency of adverse reactions when 
percentages are derived from studies that evaluated greater doses than 
the approved dose. The comment asked whether, in this circumstance, 
rates of adverse reactions should be omitted from the ``Adverse 
Reactions'' section.
    The agency will determine, during review of an application, whether 
adverse reaction rates derived from doses greater than recommended 
doses would be informative for practitioners and not misleading, and 
thus appropriate for inclusion in labeling. Where there are adverse 
reaction data from studies using different doses, including doses 
greater than recommended doses, the agency will evaluate whether 
pooling or otherwise combining adverse reaction data would more 
accurately describe the frequency of adverse reactions.
    (Comment 77) One comment requested clarification on whether 
manufacturers are required to identify the total number of patients 
enrolled in clinical trials in the ``Adverse Reactions'' section.
    FDA has revised proposed 201.57(c)(9)(i) (designated in this final 
rule as 201.57(c)(7)(i)) to clarify that the total number of subjects 
or patients exposed to the drug, and the extent of exposure, must be 
identified in the ``Adverse Reactions'' section, so that practitioners 
can interpret the significance of the data in this section. The 
``Adverse Reactions'' section guidance provides recommendations on how 
to describe the database from which the adverse reaction data in this 
section are derived (see section IV of this document).
     Clinical pharmacology (proposed Sec.  201.57(c)(13))
    FDA proposed to require that the ``Clinical Pharmacology'' section 
(proposed Sec.  201.57(c)(13)) contain three subsections--``Mechanism 
of action,'' ``Pharmacodynamics,'' and ``Pharmacokinetics.'' Proposed 
Sec.  201.57(c)(13) also provided for an optional subsection for 
incorporation of other clinical pharmacology information that does not 
fit into one of the specified subsections.
    (Comment 78) One comment recommended that the ``Clinical 
Pharmacology'' section be revised to require discussion of a drug's 
elimination half-life, indicate differences in elimination half-life as 
a function of age or other subpopulation, and specify the enzyme 
involved in metabolism (e.g., CYP450).
    Under the final rule, elimination half-life of drugs and 
differences in the elimination half-life as a function of specific 
populations (including age-related populations) must be reported in the 
``Pharmacokinetics'' subsection of the ``Clinical Pharmacology'' 
section of the labeling (Sec.  201.57(c)(13)(i)(C)). In addition, if 
there are clinically significant differences in elimination half-lives 
among specific populations and those differences require special 
monitoring or alternate dosing regimens, such information must be 
included in other sections, such as ``Use in Specific Populations,'' 
``Warnings and Precautions,'' and ``Dosage and Administration.'' 
Information about drug metabolism, including metabolic pathways and the 
enzyme systems involved, is also required in the ``Pharmacokinetics'' 
subsection of the ``Clinical Pharmacology'' section.
    (Comment 79) One comment requested that FDA clarify the statement 
in proposed Sec.  201.57(c)(13)(i)(B): ``If pharmacokinetic/
pharmacodynamic relationships are not demonstrated or are unknown, the 
labeling must contain a statement about the lack of information.'' The 
comment asked that FDA clarify whether the provision is referring to 
concentration versus response relationships generally.
    In response to this comment, the agency has rephrased this 
provision, as follows: ``Exposure-response relationships (e.g., 
concentration-response, dose-response) and time course of 
pharmacodynamic response (including short-term clinical response) must 
be included if known.'' (See final Sec.  201.57(c)(13)(i)(B).)
    (Comment 80) One comment stated that the three new subsections in 
the ``Clinical Pharmacology'' section will make it easier to find 
information in the section.
    One comment requested that in vitro data supporting the ``Mechanism 
of action'' subsection in the ``Clinical Pharmacology'' section be 
permitted to

[[Page 3952]]

be included in the subsection because such information is helpful in 
understanding a drug's physiologic activity and in differentiating a 
drug from other therapeutic agents.
    The agency agrees that the three new subsections should make 
information easier to find. Because 201.56(d)(2) (proposed 
201.56(d)(5)) permits additional nonstandard subsections, FDA deleted 
``12.4 other clinical pharmacology information'' (proposed 
201.57(c)(13)(i)(D)) from the final rule.
    The ``Mechanism of action'' subsection must include information 
based on in vitro data if the information is essential to a description 
of the established mechanism of action and the information is 
clinically relevant. Where in vitro information about mechanism of 
action is included, the information must not be used as the basis for a 
clinical comparison (i.e., to differentiate the drug from other 
therapeutic agents).
    (Comment 81) Many comments opposed the proposal (proposed Sec.  
201.57(c)(13)(ii) to revise the current ``Clinical Pharmacology'' 
section to require that in vitro data related to the activity or 
effectiveness of an anti-infective drug be included in the section only 
if a waiver is granted under Sec.  201.58 or Sec.  314.126(c) (21 CFR 
314.126(c)). While comments conceded that in vitro data have their 
limitations, the comments maintained that in vitro data for anti-
infective agents can be an important component of the total information 
available for making prescribing decisions in some situations, 
including: (1) In the absence of susceptibility testing, (2) in 
treating drug resistant pathogens (e.g., drug-resistant pneumococci), 
and (3) in treating rare infections. Some comments stated that 
preventing inclusion of in vitro data that indicate a drug is inactive 
against a microorganism could result in selection of inappropriate 
antibiotics and poor clinical outcomes. One comment maintained that 
some physician organizations effectively endorse use of in vitro data 
by having guidelines that recommend use of in vitro data as an adjunct 
to making educated empirical judgments about appropriate anti-infective 
therapy. Several comments stated that the absence of in vitro data will 
make it difficult for practitioners to identify appropriate broad 
spectrum agents when broad coverage is needed. One comment requested 
that in the event the agency decides to go forward and exclude in vitro 
data related to effectiveness unless a waiver has been granted, the 
agency explain in detail the process by which a waiver could be 
granted.
    Several comments expressed concern about the implications of 
removing in vitro data for devising susceptibility tests for new anti-
infective drugs. They stated that these data are relied on by FDA (the 
Center for Devices and Radiological Health) and by manufacturers of in 
vitro susceptibility tests in selecting appropriate organisms for which 
to devise tests. In addition, comments stated the data are used to 
develop quality control mechanisms for, and to help develop criteria 
for use in the review and clearance of, susceptibility test devices. 
Some comments maintained that removal of in vitro data would cause 
manufacturers not to develop susceptibility tests for organisms for 
which such tests would be desirable.
    One comment supported exclusion of in vitro data from labeling. The 
comment stated that exclusion of in vitro data that are not adequate to 
support therapeutic decisionmaking will improve anti-infective therapy 
and help prevent inappropriate use of antibiotics.
    The agency has reconsidered its proposal to exclude from the 
``Clinical Pharmacology'' section in vitro data for anti-infectives 
that are not supported by clinical data. The agency is considering a 
broad range of issues concerning the development and labeling of anti-
infective products, including the types of data that should be obtained 
to support indications, the way that indications and anti-infectives 
data should be presented in labeling, and ways to meaningfully address 
resistance to anti-infective drugs. The agency believes a comprehensive 
and coordinated approach is needed to address these issues. Thus, FDA 
is deferring any action on the in vitro data proposals in the 
``Clinical Pharmacology'' section of labeling at Sec. Sec.  
201.57(c)(13)(ii) and 201.80(b)(2) until the agency has developed a 
comprehensive plan. At that time, the agency may repropose changes to 
the way in which in vitro data are presented in labeling.
    (Comment 82) Several comments maintained that the algorithm in the 
agency's current guidance for industry (``Clinical Development and 
Labeling of Anti-Infective Drug Products,'' 1992) for determining when 
it is appropriate to include in labeling in vitro data not supported by 
clinical data contains adequate safeguards and should continue to be 
used for determining when to include such data. One comment suggested 
that labeling users be educated about the criteria for inclusion in 
labeling of in vitro data not supported by clinical data and how to use 
such data in making prescribing decisions.
    At this time, the agency will continue to rely on the algorithm in 
its current guidance on clinical development and labeling of anti-
infectives for determining when to include in vitro data in the 
``Clinical Pharmacology'' section of labeling. As part of the 
comprehensive evaluation of the way in which anti-infective therapies 
are currently developed and labeled (see response to comment 81), the 
agency may reconsider use of the algorithm and make any changes that 
may be needed. For this reason, the agency will not at this time 
undertake an educational campaign to educate prescribers about the 
basis for inclusion of in vitro data in labeling.
    (Comment 83) Several comments recommended retaining in vitro data 
for anti-infective drugs in the ``Clinical Pharmacology'' section and 
strengthening the current in vitro disclaimer statement that indicates 
that the clinical significance of the in vitro data is unknown.
    Until FDA has developed a comprehensive plan to address the broad 
range of issues confronting development and labeling of anti-infective 
products, the agency will defer any decisions about the content of the 
disclaimer that accompanies in vitro data indicating that the clinical 
significance of the data is unknown.
    (Comment 84) One comment requested that the agency clarify the 
scope of the proposed exclusion of in vitro data to make clear that it 
does not encompass in vitro data with clinical substantiation. The 
comment maintained that in vitro susceptibility data from large scale 
clinical trials would provide some basis for making an informed 
decision about possible effectiveness in the absence of susceptibility 
testing (e.g., while awaiting such testing) and that this information 
is especially important for antiviral drugs.
    In vitro data that are supported by clinical data have certain 
problems in common with in vitro data not supported by clinical data 
(e.g., antimicrobial susceptibilities are constantly changing and vary 
by location). In vitro and animal data not supported by clinical data 
were the focus of the agency's proposal to exclude in vitro and animal 
data from the ``Clinical Pharmacology'' section (Sec.  
201.57(c)(13)(ii)). As discussed previously, the agency has 
reconsidered its proposal to exclude such data from

[[Page 3953]]

labeling and will defer any action until it has developed a 
comprehensive plan.
    (Comment 85) Several comments recommended that in vitro 
susceptibility data for anti-infectives be retained in labeling and be 
placed in a new labeling section entitled ``Clinical Microbiology.''
    The agency believes that a labeling section devoted specifically to 
clinical microbiology data is not needed at this time. As a result of 
its ongoing comprehensive evaluation of anti-infectives drug 
development and labeling practices, the agency may reconsider the need 
for a separate section on clinical microbiology.
     Nonclinical toxicology (proposed Sec.  201.57(c)(14))
    FDA proposed to require a new section in the FPI entitled 
``Nonclinical Toxicology'' (proposed Sec.  201.57(c)(14)) to contain 
information from then-current Sec.  201.57(f)(5) (the ``Carcinogenesis, 
mutagenesis, impairment of fertility'' subsection) and then-current 
Sec.  201.57(l) (the ``Animal Pharmacology and/or Animal Toxicology'' 
section).
    (Comment 86) One comment requested that FDA provide guidance 
clarifying when it would be appropriate to omit the ``Nonclinical 
Toxicology'' section.
    Although the final rule provides that any section of labeling would 
be omitted if it is clearly inapplicable (see Sec.  201.56(d)(4)), it 
is unlikely that the ``Nonclinical Toxicology'' section, in its 
entirety, would ever be inapplicable. Animal data are often the only 
practical and ethical means to understand a product's potential for 
certain kinds of toxicity (e.g., carcinogenicity, mutagenicity, 
reproductive and developmental toxicity). In addition, even if 
carcinogenicity data are not available, the labeling must state that 
these studies were not done (Sec.  201.57(c)(14)(i)). The final rule 
provides, however, that the ``Animal toxicology and/or pharmacology'' 
subsection must include certain data that do not appear elsewhere in 
the labeling. This means that this subsection would be omitted if all 
the required information appears in one or more of the other labeling 
sections (Sec.  201.57(c)(14)(ii)).
     Clinical studies (proposed Sec.  201.57(c)(15))
    FDA proposed to require a section in the FPI entitled ``Clinical 
Studies'' (proposed Sec.  201.57(c)(15)). The section would be required 
to contain a discussion of clinical studies that are important to a 
prescriber's understanding of the basis for approval of the drug 
product, including the extent and limitation of the product's benefits, 
how the drug was used in clinical trials, who was studied, and critical 
parameters that were monitored.
    (Comment 87) One comment requested that the agency clarify the 
extent to which secondary endpoint data, quality of life data, and 
pharmacoeconomic data would be permitted in the ``Clinical Studies'' 
section.
    The ``Clinical Studies'' section must describe those studies that 
facilitate an understanding of how to use a drug safely and 
effectively. Generally, this means those studies that were essential to 
establishing the drug's effectiveness for the purpose of obtaining 
marketing approval.
    If studies were appropriately designed to evaluate secondary 
endpoints, it may be appropriate to include a discussion of these 
secondary endpoints in the section.
    The agency would evaluate the appropriateness of including quality 
of life and pharmacoeconomic data according to the same standard. The 
data could be appropriate for inclusion in the section if all of the 
following apply: (1) The data are from adequate and well-controlled 
trials that incorporated quality of life or pharmacoeconomic endpoints 
in their design and carried out appropriate analyses, (2) for 
pharmacoeconomic studies, the findings are reasonably generalizable to 
most clinical environments, not just the ones studied, and (3) the 
information would be important to a practitioner's understanding of how 
to use the drug in a clinical setting. The ``Clinical Studies'' section 
guidance contains FDA's recommendations on what studies are appropriate 
for inclusion in the ``Clinical Studies'' section (see section IV of 
this document).
    (Comment 88) Some comments requested that the agency reconsider its 
proposal to bar, in the ``Clinical Studies'' section, inclusion of data 
concerning indications and doses that are not consistent with the 
approved indications and dosing regimens. Comments maintained that such 
information can be important to a practitioner's understanding of a 
product's clinical and safety profile, as well as to an understanding 
of the approved indication. Some comments stated that all studies that 
are scientifically sound and provide medically relevant information 
should be included in the ``Clinical Studies'' section. One comment 
stated that practitioners understand that data presented in the 
``Clinical Studies'' section, as opposed to the ``Indications and 
Usage'' or ``Dosage and Administration'' sections, are intended for 
informational purposes only (i.e., not to suggest claims).
    One comment asked that the agency make clear that the limitation on 
inclusion of information in labeling about unapproved doses and 
regimens would not preclude discussion of a dose ranging study that 
supports approval and includes dosage regimens that were not approved 
for use.
    One comment agreed with the proposed revision to exclude from the 
``Clinical Studies'' section data and information concerning 
indications and dosing that are not consistent with the information in 
the ``Indications and Usage'' and ``Dosage and Administration'' 
sections. The comment maintained that inconsistent information about 
indications and dosing creates confusion and contributes to uncertainty 
and distrust of information in the labeling.
    Some comments stated that if the agency has concerns about the 
implications of labeling on product promotion, these can be addressed 
through its existing legal authority and should be addressed as a 
separate issue.
    The agency requires that claims in any section of labeling, 
expressed or implied, be supported by substantial evidence (Sec.  
201.56(a)(3)). This requirement would not preclude discussing in 
labeling an adequate and well-controlled clinical study, including a 
dose ranging study that has treatment arms with dosing regimens that 
are not recommended, if the data for the use of such regimens are 
important to a practitioner's understanding of how to use the drug 
safely and effectively. For instance, it might be important to include 
such data if the data indicate that a particular dosage regimen is not 
effective, is minimally active, provides no benefit compared to lower 
doses, or is associated with an unacceptable level of toxicity. If data 
that include dosage regimens other than recommended regimens are 
discussed in the ``Clinical Studies'' section, the data must be 
accompanied by a statement appropriately qualifying the data and 
indicating that those dosage regimens have not been found safe and 
effective by FDA, if such a statement is necessary for the labeling to 
be truthful and not misleading.
    The agency agrees that advertising and promotional labeling 
regulations address product promotion issues and that this final rule 
is not an appropriate context for discussion of these issues.
     References (proposed Sec.  201.57(c)(16))

[[Page 3954]]

    FDA proposed to permit references to be included in labeling in 
place of a detailed discussion of a subject that is of limited 
interest, but nonetheless important (proposed Sec.  201.57(c)(16)). The 
proposed provision stated that the reference must be based on an 
adequate and well-controlled clinical investigation under Sec.  
314.126(b) or, for a biological product, upon substantial evidence of 
effectiveness.
    (Comment 89) One comment maintained that requiring that all 
information contained in the ``References'' section be based on 
adequate and well-controlled trials will result in omission of 
important references for many anti-infective products, including 
references for standardized test methodology in in vitro studies.
    The agency believes that inclusion of a reference to clinical data 
will be unusual. Any clinical data that are important to a prescriber's 
understanding of the safe and effective use of the drug must be 
summarized in the ``Clinical Studies'' section, rather than referenced 
in the ``References'' section. The ``References'' section may cite an 
authoritative scientific body, standardized methodology, scale, 
technique, or similar material important to prescribing decisions that 
are mentioned in another section of labeling, but cannot readily be 
summarized. The agency has revised proposed Sec. Sec.  201.57(c)(16) 
and 201.80(l) to make this clear and to delete the requirement that 
limits the ``References'' section to references to adequate and well-
controlled clinical studies.
    (Comment 90) One comment noted that, even though the conditions for 
including references in the proposed rule are essentially the same as 
in the requirements for old labeling, there are substantial differences 
in the way these conditions are applied across new drug reviewing 
divisions.
    As discussed in the response to the previous comment, in this final 
rule, the agency has clarified the conditions under which it is 
appropriate to include a reference in prescription drug labeling. The 
agency appreciates the comment's concern about inconsistent application 
of the criteria for inclusion of references across different new drug 
review divisions. As part of its internal efforts to implement this 
final rule and related labeling initiatives, the agency intends to make 
considerable efforts to ensure consistent application of the 
requirements.
     Patient counseling information (proposed Sec.  
201.57(c)(17))
    FDA proposed that the ``Information for patients'' subsection of 
the ``Precautions'' section (required under then-current Sec.  
201.57(f)(2)) be made a separate section entitled ``Patient Counseling 
Information'' (proposed Sec.  201.57(c)(17)). The section would be 
placed at the end of the FPI.
    The agency also proposed to require in proposed Sec.  201.57(c)(17) 
that any approved printed patient information or Medication Guide be 
referenced in the ``Patient Counseling Information'' section and that 
the full text of the approved printed patient information or Medication 
Guide be reprinted immediately following the section.
    (Comment 91) One comment supported the proposal to put information 
for patients in its own section and change the name from ``Information 
for patients'' to ``Patient Counseling Information.'' The comment 
stated that the name change is important because it emphasizes the need 
to counsel patients on their medications and not just provide printed 
materials.
    As described in the proposed rule, FDA determined to change the 
heading of the information required under then-current Sec.  
201.57(f)(2) from ``Information for patients'' to ``Patient Counseling 
Information'' to clarify that the information under this section is not 
intended to be distributed to patients, but is intended to help 
practitioners communicate important drug information to patients.
    (Comment 92) Some comments requested that the agency clarify the 
meaning of ``any approved printed patient information.'' One comment 
also asked that the agency clarify ``Medication Guide.''
    FDA has revised the terminology in the final rule to clarify the 
meaning of ``any approved printed patient information'' and 
``Medication Guide.'' The term ``FDA-approved patient labeling'' refers 
to any labeling that has been reviewed and approved by the agency that 
provides information for patients and is for distribution to patients 
who are prescribed a drug. This term includes approved printed patient 
information specifically required by regulation (e.g., for oral 
contraceptives (21 CFR 310.501) and estrogens (21 CFR 310.515)) and 
patient labeling that is submitted voluntarily to FDA by manufacturers 
and approved by the agency. FDA-approved patient labeling may have 
different functions reflected in the type of information conveyed to 
patients. For example, some FDA-approved patient labeling contains risk 
information, and some contains only detailed instructions about how to 
administer a drug product.
    Medication Guides are a specific category of FDA-approved patient 
labeling. Under part 208 (21 CFR part 208), FDA can require a 
Medication Guide for a prescription drug product that FDA determines 
poses a serious and significant public health concern requiring 
distribution of FDA-approved patient information (Sec.  208.1(a)). 
Medication Guides are subject to specific content and format 
requirements (Sec.  208.20).
    (Comment 93) Some comments supported the proposed requirement to 
reprint FDA-approved patient labeling at the end of the ``Patient 
Counseling Information'' section so that this information is readily 
accessible for healthcare practitioners. Other comments requested that 
the agency reconsider the proposal to require that FDA-approved patient 
labeling be printed at the end of the FPI. Some comments asked whether 
attaching prescription drug labeling without FDA-approved patient 
labeling to trade packaging and attaching the FDA-approved patient 
labeling separately would satisfy the requirement. Some comments 
expressed concern that prescription drug labeling with the FDA-approved 
patient labeling reprinted at the end may make it more difficult for 
patients to find and read the patient information. One comment stated 
that patient information typically uses larger fonts and may use color 
and illustrations, making it difficult and costly to reprint in the 
prescription drug labeling. Some comments also expressed concern that 
inclusion of FDA-approved patient labeling would make the labeling too 
long and impose additional costs because it could necessitate redesign 
and enlarging of trade packaging. One comment asked whether it would be 
sufficient to provide only a reference to FDA-approved patient labeling 
in the ``Patient Counseling Information'' section instead of reprinting 
the information in the section.
    FDA believes that it is crucial that prescribers have ready access 
to FDA-approved patient labeling so that they are aware that the 
information exists, can familiarize themselves with the content of that 
information, and can explain the information to their patients. The 
agency believes this objective can best be accomplished by requiring 
that this information be reprinted at the end of prescription drug 
labeling. Thus, it would be insufficient to provide only a reference to 
FDA-approved patient labeling in the ``Patient Counseling Information'' 
section.
    However, the agency is persuaded that reprinting the FDA-approved 
patient labeling at the end of the

[[Page 3955]]

labeling is not the only approach that would successfully address the 
need to familiarize prescribers with this information. Therefore, the 
agency has revised the requirements at Sec. Sec.  201.57(c)(18) and 
201.80(f)(2) to require that FDA-approved patient labeling either 
accompany the prescription drug labeling or be reprinted at the end of 
such labeling (i.e., immediately following the ``Patient Counseling 
Information'' section of the FPI for products subject to Sec.  
201.57(c)(18) or after the last section of labeling for products 
subject to Sec.  201.80(f)(2)).
    The agency acknowledges that, in cases for which FDA-approved 
patient labeling is included with prescription drug labeling, 
additional costs will be incurred by the manufacturer. To help minimize 
the added cost, FDA has revised proposed Sec.  201.57(c)(18) to specify 
that the same type size requirements that apply to prescription drug 
labeling (Sec.  201.57(d)(6)) also apply to FDA-approved patient 
labeling that is printed at the end of the labeling or accompanies 
labeling, unless a Medication Guide is to be distributed to patients in 
compliance with Sec.  208.24 (see table 7 of this document). In most 
cases, this will be a minimum type size of 8 points. For trade 
labeling, this will be a minimum type size of 6 points (see response to 
comment 102 for discussion of 6-point minimum type size for trade 
labeling for products subject to Sec.  201.57). For Medication Guides 
to be distributed to patients, the type size requirements set forth at 
Sec.  208.20 apply. With regard to the labeling for products subject to 
Sec.  201.80, the agency clarifies at Sec.  201.80(f)(2) that the font 
size requirement for Medication Guides in Sec.  208.20 does not apply 
to a Medication Guide that is printed in prescription drug labeling 
unless it is intended to comply with Sec.  208.24 (i.e., the 
requirement to distribute Medication Guides to patients). Thus, for 
these products, there is no minimum font size requirement for FDA-
approved patient labeling that is included with labeling but not for 
distribution to patients (see table 7).

 Table 7.--Type Size Requirements for Labeling and FDA-Approved Patient
                     Labeling Included with Labeling
------------------------------------------------------------------------
                                                            Type Size
                                                           Requirements
                  Type Size       FDA-Approved Patient       for FDA-
   Labeling      Requirements    Labeling Included with      Approved
                 for Labeling           Labeling             Patient
                                                             Labeling
------------------------------------------------------------------------
New Format (Sec.   201.57)
------------------------------------------------------------------------
Trade          Minimum 6-point  FDA-approved patient     Minimum 6-point
 Labeling       type             labeling that is not     type
 (i.e.,                          for distribution to
 labeling on                     patients
 or within
 the package
 from which
 the drug is
 to be
 dispensed)
                               -----------------------------------------
               ...............  Any FDA-approved         Minimum 6-point
                                 patient labeling         type
                                 except a Medication
                                 Guide that is for
                                 distribution to
                                 patients
                               -----------------------------------------
               ...............  Medication Guide that    Minimum 10-
                                 is for distribution to   point type
                                 patients
------------------------------------------------------------------------
Other          Minimum 8-point  FDA-approved patient     Minimum 8-point
 Labeling       type             labeling that is not     type
 (e.g.,                          for distribution to
 labeling                        patients
 accompanying
 promotional
 materials)
                               -----------------------------------------
               ...............  Any FDA-approved         Minimum 8-point
                                 patient labeling         type
                                 except a Medication
                                 Guide that is for
                                 distribution to
                                 patients
                               -----------------------------------------
               ...............  Medication Guide that    Minimum 10-
                                 is for distribution to   point type
                                 patients
------------------------------------------------------------------------
Old Format (Sec.   201.80)
------------------------------------------------------------------------
Trade          No minimum       FDA-approved patient     No minimum
 Labeling and   requirement      labeling that is not     requirement
 Other                           for distribution to
 Labeling                        patients
                               -----------------------------------------
               ...............  Any FDA-approved         No minimum
                                 patient labeling         requirement
                                 except a Medication
                                 Guide that is for
                                 distribution to
                                 patients
                               -----------------------------------------
               ...............  Medication Guide that    Minimum 10-
                                 is for distribution to   point type
                                 patients
------------------------------------------------------------------------

    (Comment 94) One comment asked whether the agency meant for the 
prescription drug labeling with the FDA-approved patient labeling 
reprinted at the end to replace the stand-alone FDA-approved patient 
labeling required to be distributed to patients. The comment asked if 
the combined document would satisfy the requirement to distribute the 
FDA-approved patient labeling to patients who have been prescribed the 
drug. Other comments asked whether FDA-approved patient labeling 
attached to prescription drug labeling in a way that would facilitate 
it being torn off (e.g., along a perforation line) would satisfy these 
requirements. One comment noted that if the FDA-approved patient 
labeling is appended to the prescription drug labeling as a perforated 
attachment, it might be more difficult for the patient to receive 
information at the pharmacy because the pharmacist would have to 
separate the patient information from the prescription drug labeling.
    The agency does not mean for prescription drug labeling with the 
FDA-approved patient labeling reprinted at the end to replace the 
stand-alone FDA-approved patient labeling required to be distributed to 
patients. FDA has long stressed the importance of providing such 
information to consumers.
    However, if the FDA-approved patient labeling is appended to the 
prescription drug labeling (e.g., as a perforated attachment that can 
be torn off and given to patients) and is formatted as

[[Page 3956]]

required for distribution to patients (Sec.  208.20), it would meet the 
requirement to provide information to patients. For example, for a 
product subject to Sec.  201.57 with a Medication Guide, trade labeling 
for the product would be required to be in at least 6-point type (see 
comment 102 of this document), while the Medication Guide, if reprinted 
as a perforated attachment to the labeling for distribution to 
patients, would be required to be in a minimum 10-point type (see table 
7). For products subject to Sec.  201.80 with a Medication Guide, there 
is no minimum font size requirement for the labeling, while the 
Medication Guide, if reprinted as a perforated attachment to the 
labeling for distribution to patients, would be required to be in a 
minimum 10-point type (see table 7). The agency does not agree that 
distributing prescription drug labeling with the FDA-approved patient 
labeling appended as a perforated attachment will make it more 
difficult for the patient to receive information at the pharmacy 
because the pharmacists would have to detach the patient information.
    (Comment 95) One comment sought clarification of what information 
should be included in the ``Patient Counseling Information'' section. 
The comment expressed concern about how the information in this section 
is to be communicated to patients.
    The ``Patient Counseling Information'' section contains information 
that the practitioner may decide to convey to the patient at the time 
of prescribing for the drug to be used safely and effectively (e.g., 
warnings about driving if the product causes drowsiness, or the 
concomitant use of other substances that may have harmful additive 
effects). The information in this section will vary depending on the 
safety and efficacy characteristics of the product and how it is taken.
    FDA believes that requiring a separate ``Patient Counseling 
Information'' section and a reminder message in Highlights directing 
practitioners to this section will make patient counseling information 
in labeling more accessible to health care practitioners. These 
requirements will increase the accessibility of the section and should 
reinforce the need for practitioners to counsel their patients, thereby 
fostering communication between practitioners and patients about 
prescribed drugs.
    (Comment 96) One comment asked whether including the FDA-approved 
patient labeling in the ``Patient Counseling Information'' section 
would be sufficient to meet the content requirements for the section.
    Including only the FDA-approved patient labeling in the ``Patient 
Counseling Information'' section is not sufficient to meet the 
requirements of this section. This section, like the other sections of 
prescription drug labeling, is specifically written for health care 
practitioners. Its purpose is to inform practitioners about what 
information is important to convey to the patient at the time of 
prescribing for the drug to be used safely and effectively. FDA-
approved patient labeling, in contrast, is specifically written for a 
lay audience and is intended to be read by patients.
    The agency emphasizes how important it is that prescribers be 
informed about what they should communicate to their patients. On the 
basis of a series of national telephone surveys conducted by FDA to 
assess how patients receive information about their prescription 
medicines, the agency determined that the prescribing physician is the 
primary source of drug information for patients (Ref. 5). The most 
recent survey, conducted in 1998, showed that more patients received 
verbal prescription medicine information at their physician's office 
(69 percent) than at the pharmacy (43 percent) (Ref. 5). In addition, 
although 74 percent of patients reported receiving written information 
at the pharmacy, of those who received written information at the 
pharmacy, 85 percent received instruction sheets and 83 percent 
received stickers on the medicine container, but only 38 percent 
received brochures about the medicine. These results indicate that most 
consumers who receive product information, other than instructions for 
use or the sticker information, receive it orally from their physicians 
during an office visit.
    (Comment 97) One comment asked whether products with existing 
labeling that will be required to convert to the new labeling format 
will be required to have a ``Patient Counseling Information'' section 
if the product's existing labeling does not contain an ``Information 
for patients'' subsection in its ``Precautions'' section.
    If a product that does not have an ``Information for patients'' 
subsection becomes subject to the new content and format requirements 
at Sec.  201.57, the product's manufacturer would be required to 
develop a ``Patient Counseling Information'' section for the product's 
prescription drug labeling unless a ``Patient Counseling Information'' 
section would be clearly inapplicable (see Sec.  201.56(d)(4)) and thus 
not required. The agency anticipates that few products would qualify 
for such an exception. The agency believes that the vast majority of 
products that will be required to have a ``Patient Counseling 
Information'' section will already have an ``Information for patients'' 
subsection in their existing labeling on which to base the ``Patient 
Counseling Information'' section. Thus, this new requirement is 
anticipated to impose minimal burdens on manufacturers.

I. Comments on the Format Requirements (Proposed Sec.  201.57(d))

    FDA proposed new format requirements for prescription drug labeling 
(proposed Sec.  201.57(d)). The proposed provisions set forth minimum 
standards and requirements for many of the key graphic elements of 
labeling (e.g., type size, letter and line spacing, and contrast).
    (Comment 98) Some comments recommended implementation of the 
proposed changes solely or primarily as part of the electronic labeling 
initiative. Some comments requested that the new format requirements 
not be implemented for prescription drug labeling required to be 
distributed with a drug in trade packaging. They pointed out that using 
an electronic format would permit use of larger print size, hypertext 
linking to all sections of labeling, links to newly revised sections of 
labeling, key word searches, and links to patient information without 
affecting the size of trade packaging. The comments maintained that 
larger trade packaging will be required to accommodate larger labeling 
that will result from the new format requirements.
    The agency agrees that use of the required format in conjunction 
with an electronic medium may have benefits over paper labeling. As 
discussed in section V of this document, the agency believes that, in 
the future, the Internet and other electronic sources for labeling will 
most likely be the primary means for delivering drug information to 
practitioners. At the present time, however, some practitioners may not 
have the requisite computer equipment or skills to access prescription 
drug labeling in an electronic format. The agency anticipates that it 
will be several years before the phase-out of paper labeling as the 
major source of prescribing information can begin. Therefore, the 
agency believes that it is important to establish minimum format 
requirements for paper labeling.
    (Comment 99) One comment recommended the use of more blank space 
among sections of Highlights. The comment expressed concern that, 
because Highlights contains a significant amount of information in a 
constrained space and uses a variety of

[[Page 3957]]

formatting techniques, the overall effect would be confusing. One 
comment stated that the placement of the ``Patient Counseling 
Information Statement'' above the ``Highlights Limitation Statement'' 
in Highlights is not ideal because it appears that the ``Patient 
Counseling Information Statement'' is the title of the limitation 
statement. The comment also requested that the FPI be required to be in 
a two-column format because such a format enables users to stay better 
aware of the overall information structure, as well as read individual 
sections more easily.
    The agency believes that use of more blank space in Highlights 
would not be feasible because additional blank space would increase the 
length of Highlights and of labeling generally. The one-half page 
length limitation for Highlights is based on the strong preferences of 
physicians surveyed in developing the prototype for the new labeling 
format in the proposed rule. Physicians reacted negatively to prototype 
Highlights that were one or one and one-half pages long. They indicated 
that the utility of Highlights decreased significantly as its length 
increased. In addition, there was significant concern from 
manufacturers about the costs associated with adding to the length of 
labeling.
    The agency also believes that the formatting techniques used in 
Highlights help make the information accessible, notwithstanding the 
density of the section. Therefore, the agency does not believe that it 
is necessary to include more blank space in Highlights.
    The agency agrees that the formatting and placement of the 
``Patient Counseling Information Statement'' and the ``Highlights 
Limitation Statement'' in Highlights could be improved to better 
communicate the discrete information provided by each statement. For 
this reason, and in response to comments recommending greater 
prominence for the ``Highlights Limitation Statement,'' the agency 
moved this statement to appear at the beginning of Highlights (see 
comment 35). The agency also removed the requirement at proposed Sec.  
201.57(d)(3) that the ``Patient Counseling Information Statement'' be 
presented in the center of a horizontal line, so that it does not 
appear to be a section title.
    The agency agrees that a two-column format is effective, but 
believes other formats may be equally effective in conveying 
prescription drug information and, therefore, is not requiring a two-
column format for the FPI.
     Bolding (Proposed Sec.  201.57(d)(5))
    In the proposal, the agency specifically sought comment on whether 
the requirement in proposed Sec.  201.57(d)(5) to bold the information 
required by proposed Sec.  201.57(a)(1) through (a)(4), (a)(11), and 
(a)(15) (i.e., the following information in Highlights: Drug names, 
dosage form, route of administration, and controlled substance symbol; 
the inverted black triangle symbol; the prescription drug symbol; boxed 
warnings or contraindications; adverse reaction reporting contacts; and 
Highlights limitation statement) would ensure the visual prominence of 
the bolded information or whether different highlighting methods would 
be more effective.
    (Comment 100) Most comments expressed satisfaction that bolding was 
adequate to ensure the visual prominence of the specified information. 
Some comments stated that capitalization, italics, and underlining, 
also effective methods of ensuring prominence and flexibility, should 
be maintained. Some comments expressed concern that possible 
alternative methods of ensuring visual prominence (e.g., color 
printing) would add unnecessary costs. One comment requested that, if 
color is required, specific Pantone colors be assigned to specific 
types of information to ensure consistency in all product labeling.
    The agency recognizes that use of different methods to ensure 
prominence may decrease their impact and significance. Therefore, FDA 
concludes that bolding alone is adequate to achieve visual prominence 
for the specified information in Highlights. The agency also agrees 
that color printing would add cost and impose an additional burden on 
manufacturers that would not be offset by meaningful improvement in 
visual prominence. Therefore, Sec.  201.57(d)(5) requires the following 
Highlights information to be in bold type: Highlights limitation 
statement; drug names, dosage form, route of administration, and 
controlled substance symbol; the initial U.S. approval statement and 
year of this approval; boxed warnings; adverse reaction reporting 
contacts; and the patient counseling information statement.
    (Comment 101) One comment requested that the agency revise the 
format of Contents to make it easier to read and use. The comment 
stated that the information in Contents is not as accessible as it 
could be because it uses straight columns, which make it hard to 
distinguish the major labeling sections (e.g., ``Use in Specific 
Populations'') from subsections (e.g., ``Pregnancy''). The comment 
recommended use of contrasting font types and sizes for the section 
titles and subheadings in each section, underlining section titles, 
indenting subheadings under each section title, and providing more 
blank space between each section. Another comment also recommended 
indenting the subheadings under the major sections to more readily 
distinguish between the major sections and the subheadings within the 
sections.
    The agency agrees that all the recommended revisions to the format 
of Contents could make the information easier to read and use. Because 
of cost and space constraints, however, the agency believes that it is 
impractical to implement all of the recommended changes. FDA has 
revised the format requirements at proposed Sec.  201.57(d) to now 
require that the subheadings under each section heading in Contents be 
indented (Sec.  201.57(d)(10). In addition, the final rule now requires 
that only the headings in Contents be bolded, not the subheadings 
(Sec.  201.57(d)(10)). The agency believes these changes make the 
Contents easier to read and use without increasing its length or 
attendant costs.
    (Comment 102) In the proposal, the agency specifically sought 
comment on whether the proposed requirement (proposed Sec.  
201.57(d)(6)) for a minimum type size of 8 points for all typeface 
information in labeling is sufficient or whether a minimum type size of 
10 points would be more appropriate. Currently, prescribing information 
is usually printed in 6- or 7-point type.
    One manufacturer stated that 6-point type was generally adequate 
for prescribing information, and another manufacturer stated that it 
typically uses 4- to 6-point type. Some manufacturers were concerned 
that a minimum 8-point type would increase the length of labeling to 
such an extent that trade packaging would have to increase in size to 
accommodate the longer labeling and the increase in size would impose 
substantial costs. One comment recommended that prescribing information 
that accompanies trade packaging not be subject to the 8-point type 
minimum, while prescribing information that is distributed in other 
contexts, where it is more likely to be referenced by the prescriber 
(e.g., prescribing information in electronic format, prescribing 
information accompanying promotional materials and product samples), be 
required to be in at least 8-point type. Some manufacturers stated that 
8-point type was adequate for prescribing information included in trade 
packaging, but that a minimum 10-point type would increase the length 
of labeling to such an extent that trade packaging would have to 
increase in

[[Page 3958]]

size to accommodate the larger prescribing information.
    Some consumers and health care advocacy organizations requested 
that the agency reconsider whether the increase to an 8-point minimum 
type size was sufficient to achieve the agency's goal of improving the 
readability of the prescribing information. They stated that, to 
improve readability, labeling should be printed in a type size larger 
than 8 points and with more white space. They urged the agency to test 
prototypes to compare the relative readability of 8-point versus 10-
point type. Some comments advocated that the minimum type size should 
be at least 10 points, and preferably 12 points, for all patient 
information.
    In the preamble accompanying the proposed rule, FDA summarized 
studies that demonstrated the importance of type size in evaluating 
readability of written information and its effect on visibility and 
reading speed (see 65 FR 81082 at 81096 and Refs. 6 through 9). Type 
size combined with other graphical elements (e.g., letter and line 
spacing, contrast, print and background color, and type style) also 
affect readability (Ref. 10).
    The agency carefully considered the literature, the comments 
submitted in response to the font size proposal, and the estimated 
costs of using various font sizes for labeling, and has determined that 
permitting different font sizes for trade labeling (i.e., labeling on 
or within the package from which the drug is to be dispensed) and 
labeling disseminated in other settings (e.g., labeling that 
accompanies prescription drug promotional materials) best achieves the 
agency's objective of ensuring an acceptable base level of readability 
for prescription drug labeling while, at the same time, minimizing 
costs to manufacturers. Even though a larger font size may improve 
readability, the agency believes that an 8-point minimum type size, 
combined with other required graphical elements (e.g., bold type, 
bullets, demarcation lines), is adequate for prescription drug labeling 
disseminated in settings where it is likely to be referred to by 
prescribers (e.g., labeling that accompanies drug promotional 
materials). The agency believes that the 8-point minimum type size 
reasonably balances the agency's objective of improving the readability 
of labeling with the costs associated with the resultant increase in 
the length of the labeling.
    The agency also agrees with the comments requesting that there be 
an exception for trade labeling. FDA believes that a minimum 6-point 
type size requirement is satisfactory for such labeling. FDA's 
telephone survey of office-based physicians showed that the prescribing 
information in trade labeling is referred to by physicians 
substantially less frequently than other sources of prescribing 
information (Ref. 11, p. 30). Because manufacturers could incur 
substantial costs in converting trade labeling to 8-point type and the 
public health benefits of such conversion may not justify these costs, 
the agency believes it is reasonable to allow a 6-point minimum type 
size for trade labeling (see comment 124). Thus, proposed Sec.  
201.57(d)(6) was revised to permit a 6-point minimum type size for 
trade labeling.
    The agency disagrees with the comment that recommended use of type 
sizes smaller than 6 points because such labeling would not be 
sufficiently readable. The final rule on OTC drug labeling requirements 
summarized research on smaller font sizes, noting that a significant 
portion of the adult population is not able to read OTC drug product 
labeling with 4.5-point type size (see 64 FR 13254 at 13264 and 13265, 
March 17, 1999).
    The agency acknowledges those comments that urge even larger 
minimum type sizes to further increase readability. The agency agrees 
that, absent any cost or space constraints, a 10- or 12-point minimum 
type size would be preferable to 8-point. However, the agency believes 
that the 8-point minimum type size requirement for all labeling except 
trade labeling and the variety of formatting techniques incorporated 
into the new labeling format will substantially improve the readability 
of labeling without imposing unreasonable costs on manufacturers. 
Moreover, this final rule establishes minimum type sizes, but does not 
prevent manufacturers from printing labeling in larger type sizes.
    (Comment 103) One comment requested that the agency require Roman 
typeface in labeling for optimal legibility. The comment stated that 
Roman is a major improvement over currently used sans serif, and that 
sans serif is only appropriate in applications where appearance is more 
important than legibility (e.g., advertising).
    The agency does not agree that FDA should require a specific 
typeface for all prescription drug labeling. The agency believes that 
any typeface that is clear and legible should be acceptable in 
labeling.
    (Comment 104) In the proposal, the agency specifically sought 
comment on whether the requirement in proposed Sec.  201.57(d)(8) for a 
one-half page limit on Highlights is adequate or whether there are 
alternatives that would be more appropriate and under what 
circumstances such alternatives should be considered.
    Some comments stated that the one-half page length restriction 
should be required for all products (i.e., there are no circumstances 
in which the limitation should be waived). Other comments maintained 
that it might be difficult to consistently accommodate the information 
required to be in Highlights within one-half page. These comments 
stated that the final rule should allow for some flexibility in the 
length of Highlights in those cases where one-half page may not be 
practical or possible. These comments indicated that some manufacturers 
had done mockups of Highlights and had been unable to get the required 
information on one-half page. Some comments stated that the length 
restriction should be flexible enough to accommodate as many 
disclaimers and qualifying messages as are necessary to guide the 
physician to the more detailed discussion of the desired information in 
the FPI. These comments maintained that the limitation on length could 
result in increased medication errors because important information 
would be too compressed or might be excluded from Highlights.
    The agency believes that a one-half page Highlights is adequate for 
the vast majority of products. As discussed previously, Highlights 
provides introductory information to the more detailed FPI. The agency 
does not agree that multiple disclaimers or qualifying statements would 
be useful or appropriate.
    The agency acknowledges, however, that there may be situations in 
which it may not be possible to accommodate all the information that 
should go into Highlights within one-half page. In such cases, the 
agency may waive the one-half page requirement and approve the labeling 
with slightly longer Highlights. Accordingly, FDA has revised Sec.  
201.58 in this final rule to make clear that FDA can waive any of the 
requirements under Sec.  201.56 or Sec.  201.57.
    The agency strongly believes that limiting the length of Highlights 
is critical to preserving its usefulness. In the physician surveys 
relied on by the agency in developing and refining the new labeling 
format, 80 percent of physicians indicated that a summary or highlights 
section should be no more than one-half page. The surveys found that 
the perceived usefulness of Highlights declined considerably with 
increasing length. Accordingly, the labeling format was designed to 
accommodate, on a single page, a one-

[[Page 3959]]

half page Highlights and a one-half page Contents. To test the 
feasibility of limiting Highlights to one-half of a page, the agency 
did numerous mockups of Highlights for a wide range of products and 
found that the one-half page limit provided adequate space in each 
case. Thus, the agency anticipates that the length restriction will be 
feasible in the vast majority of cases.
    (Comment 105) In the proposal, the agency specifically sought 
comment on whether there are means other than a vertical line that 
would facilitate access to, and identification of, new labeling 
information in the FPI.
    Some comments agreed that it was highly desirable to call attention 
to new information in the FPI and that the vertical line is adequate to 
identify the new information. Other comments stated that it was 
desirable to call attention to new information, but that a vertical 
line in the FPI might not be the best mechanism because it might not be 
understood as a revision mark by practitioners. Some comments 
maintained that use of a vertical line would make the printing and 
graphics process for labeling more complex and costly. One comment 
recommended italicizing new or revised text in the FPI. One comment 
recommended use of an asterisk to identify changes, along with a 
footnote explaining what was changed. Some comments maintained that 
identifying recent changes in narrative in a section of the FPI devoted 
to labeling changes or in the proposed ``Recent Labeling Changes'' 
section in Highlights (now called ``Recent Major Changes'') would alone 
be adequate to call attention to changes in the FPI. Some comments 
stated that the vertical line will call unnecessary attention to minor 
changes. Some comments stated that, by stressing labeling changes, the 
identification of changes in the FPI could dilute the significance of 
unmarked text.
    The agency has retained the proposed requirement at Sec.  
201.57(d)(9) to mark major changes in the FPI with a vertical line in 
the left margin. The agency agrees that it is highly desirable to call 
attention to new information in the FPI and that the vertical line is 
adequate to identify the new information. The agency considered 
bolding, underlining, and italicizing as means to emphasize changes. 
These formatting techniques are all currently used in labeling to add 
emphasis for purposes other than identifying new information, so they 
would not be readily understood as identifying labeling changes. 
Asterisks are also used in labeling for purposes other than identifying 
labeling changes. The agency believes that use of an explanatory 
footnote with the asterisk would not overcome the confusion arising 
from use of an asterisk for multiple purposes in labeling.
    The agency acknowledges that a vertical line in the margin might 
not be universally understood as an indication that the text adjacent 
to the mark has been changed. The agency believes, however, that a 
significant percentage of practitioners have had some experience with 
commercial word processing software and thus some exposure to revision 
marks, including the use of the vertical line to identify changed text. 
The agency also intends to develop for practitioners a comprehensive 
educational campaign to accompany the introduction of the revised 
labeling format. This educational campaign will address, among other 
issues, the significance of the vertical line in the margin.
    The agency does not believe the vertical line will unnecessarily 
call attention to minor changes in labeling. The vertical line will be 
applied only to substantive changes that are identified in the ``Recent 
Major Changes'' (``Recent Labeling Changes'' in the proposed rule) 
section in Highlights. In response to comments requesting that the 
agency clarify what is meant by substantive changes, the agency 
specified in the final rule that only significant changes in the 
``Boxed Warning,'' ``Indications and Usage,'' ``Dosage and 
Administration,'' ``Contraindications,'' and ``Warnings and 
Precautions'' sections of the FPI be listed in the ``Recent Major 
Changes'' section. Nonsubstantive changes such as typographical or 
editorial changes should not be identified. The agency believes that 
focusing on substantive changes in only these sections will avoid 
calling unnecessary attention to minor changes and will ensure that the 
significance of unmarked text is not diluted.
    The agency believes that it would not be adequate to identify 
labeling changes only in a section of the labeling devoted to changes. 
The agency believes it is important to also identify the specific text 
that has been changed so that practitioners will be able to locate 
changes and access the complete text.

J. Comments on Revisions to Container Labels

    In addition to revising its regulations governing the content and 
format of labeling for prescription drugs, the agency also proposed 
certain revisions to the information required to appear on prescription 
drug product labels (proposed Sec.  201.100). The proposed revisions 
were intended to lessen overcrowding on prescription drug labels by 
removing certain information from the container label.
    Current Sec.  201.100(b)(2) requires that the label on a 
prescription drug container bear a statement of the recommended or 
usual dosage. Where it is not possible to present an informative or 
useful statement about the recommended or usual dosage in the space 
available on the container label, current Sec.  201.55 states that the 
requirements of Sec.  201.100(b)(2) may be met by including the 
statement ``See package insert for dosage information.'' The agency 
proposed to eliminate Sec.  201.55. The agency also proposed to 
eliminate the requirement in Sec.  201.100(b)(5) that the label of a 
prescription drug for other than oral use must bear the names of all 
inactive ingredients. The agency proposed to eliminate the requirement 
in Sec.  201.100(b)(7) that the container label bear a statement 
directed to the pharmacist specifying the type of container to be used 
in dispensing the product to maintain its identity, strength, quality, 
and purity. The agency proposed to require instead that these 
instructions be placed in the ``How Supplied/Storage and Handling'' 
section of prescription drug labeling (proposed Sec.  201.57(c)(4)(v)).
    (Comment 106) Several comments opposed the proposal to eliminate 
the requirement that the label of a prescription drug product for other 
than oral use bear the name of all inactive ingredients. The comments 
stated that identification of inactive ingredients is important because 
of their potential to be allergens. Some comments maintained that 
manufacturers should be able to list on product labels selected 
inactive ingredients (e.g., ingredients that are known allergens or are 
associated with adverse reactions). One comment recommended listing the 
diluent that should be used for admixture or those diluents that are 
contraindicated. Two comments supported eliminating the list of 
inactive ingredients from the container label of products for other 
than oral use. They agreed that the presence of such information in the 
``Description'' section of prescription drug labeling would be 
sufficient and that eliminating the information from the container 
label could make other information on the label more accessible and 
legible.
    Several comments also opposed the proposal to eliminate the 
requirement that the label of a prescription drug product bear a 
statement directed to the pharmacist specifying the type of container 
to be used in dispensing the product to maintain its identity,

[[Page 3960]]

strength, quality, and purity. The comments maintained that eliminating 
dispensing information from the container label, and placing it in 
prescription drug labeling, would make the information less accessible 
to pharmacists and would thus be inefficient and frustrating for 
pharmacists. The comments were concerned that making information on 
storage and handling less accessible could lead to inappropriate 
storage and handling. Some comments urged that the label at least be 
required to state any special or unusual conditions for storage. One 
comment recommended mandatory use of a symbol that signifies when a 
product requires special handling. Two comments supported removal of 
information on storage and handling from product labels, agreeing that 
less information on the container label could make other information on 
the label more accessible and legible.
    One comment maintained that manufacturers should be able to remove 
from the label the statement referring practitioners to the full 
prescribing information for dosage information before the manufacturer 
is required to revise its label in accordance with this final rule.
    The agency has reconsidered its proposals to eliminate from 
container labels: (1) The list of inactive ingredients for products 
other than for oral use, (2) the statement directed to the pharmacist 
concerning the type of container in which a product should be 
dispensed, and (3) the statement referring practitioners to the package 
insert for dosage information in situations in which it is not possible 
to include information about the recommended or usual dose on the 
label. The agency decided to withdraw these proposed revisions to 
container labels. The agency believes that what is appropriate content 
for product container labels and how to make that information as 
accessible as possible need to be further evaluated. The agency intends 
to conduct a comprehensive evaluation of information required to be 
included on container labels and, if necessary, will propose changes to 
these requirements at that time.
    At this time, the agency will not require placement of a symbol on 
the container label indicating that the product has special storage and 
handling requirements. The agency will consider this possibility during 
its evaluation of the content of product labels. It would be premature 
to adopt such a symbol at this time.
    (Comment 107) One comment requested that the proposed requirement 
to specify in the ``How Supplied/Storage and Handling'' section the 
type of container to be used in dispensing a product to maintain a 
product's identity, strength, quality, and purity (information formerly 
presented on the product label) should apply only if the product cannot 
be dispensed in the standard amber vial. The comment maintains that 
limiting the scope of the requirement to situations in which 
exceptional storage conditions are required would serve to highlight 
the need for special considerations when dispensing.
    As discussed in the previous comment, the agency has reconsidered 
its proposed changes to the container label, including the proposal to 
remove from the container label information directed at the pharmacist 
concerning the appropriate container in which to dispense a product. 
The agency will continue to require that dispensing instructions appear 
on the container label. Accordingly, proposed Sec.  201.57(c)(4)(v) was 
deleted from the final rule. Storage and special handling conditions 
have to be specified in labeling consistent with the requirements of 
Sec.  201.57(c)(17)(iv) of this final rule.
    (Comment 108) One comment requested that the container label also 
be required to disclose when the container or some component of the 
container contains latex or polyvinyl chloride (PVCs).
    As discussed in the response to comment 106, the agency intends to 
conduct a comprehensive evaluation of the product label and may 
repropose changes in the content of the product label at a later time, 
including changes concerning the presence of latex and PVCs in drug 
containers.
    (Comment 109) One comment urged that there be a mandatory location 
for the ``Rx Only'' symbol on the main part of the label and that there 
be a specified minimum font size for the symbol.
    In rulemaking (initiated under section 126 of the Food and Drug 
Administration Modernization Act of 1997), the agency amended its 
regulation requiring that container labels contain the statement 
``Caution: Federal law prohibits dispensing without prescription'' by 
replacing the statement with the symbol ``Rx Only'' (67 FR 4904, 
February 1, 2002). Comments submitted to the agency in response to this 
proposed change requested that FDA specify the font size and the 
location of the symbol on the container label. The agency declined this 
request in the final rule of February 1, 2002, and declines it again in 
this final rule. As discussed in the preamble to the February 2002 
final rule, existing statutory (section 502(c) of the act) and 
regulatory provisions (Sec.  201.15) requiring that information on 
product labels be prominent and conspicuous so as to render it likely 
to be read and understood by the ordinary individual under customary 
conditions of purchase and use provide the agency adequate authority to 
ensure that the symbol is visually accessible. The agency does not 
believe it is necessary to specify the location of the symbol or its 
font size to ensure that the symbol achieves adequate prominence.
    (Comment 110) One comment expressed concern about the proliferation 
of artwork on label containers and the potential for that artwork to 
make the label more difficult to read and cause medication errors.
    The agency acknowledges the potential for artwork to obscure 
important information on the label. The agency believes, however, that 
its existing authority under 502(c) of the act and Sec.  201.15 is 
adequate to ensure that artwork does not compromise the prominence and 
conspicuousness of information required to be on the label.

K. Miscellaneous Comments

    (Comment 111) One comment requested that the agency clarify how the 
content and format of the brief summary required to accompany 
prescription drug advertising under Sec.  202.1 would be affected by 
the proposed revisions to prescription drug labeling. Another comment 
suggested that the agency entertain the idea that Highlights could 
serve as an alternative to the brief summary because the agency has 
noted that Highlights contains the most important information about 
drug-related risks.
    The proposed regulations were not designed to affect either the 
content or the format of the brief summary of prescribing information 
required to accompany prescription drug advertisements under Sec.  
202.1 (21 U.S.C. 352(n)). As discussed in the proposed rule (65 FR 
81082 at 81087), statements made in promotional labeling and 
advertisements must be consistent with all information included in 
labeling under proposed Sec.  201.57(c) to comply with current 
Sec. Sec.  201.100(d)(1) and 202.1(e).\9\ The agency does believe, 
however, that Highlights communicates important information about a 
drug. The agency therefore will explore further, in conjunction with 
other prescription drug advertising initiatives, the concept

[[Page 3961]]

that Highlights could serve as a brief summary (see also FDA's response 
to comment 112 about the brief summary for consumer directed 
advertisements).
---------------------------------------------------------------------------

    \9\ This requirement at proposed Sec.  201.57(a) has been 
removed because it is not pertinent to the contents of Sec.  201.57 
and is redundant with provisions at Sec. Sec.  202.1 and 201.100.
---------------------------------------------------------------------------

    (Comment 112) Some comments stated that prescription drug labeling 
should be written in language that a lay audience can comprehend. The 
comments noted that consumers need to be able to read and understand 
the labeling because it accompanies the product, and because it is 
often used to provide information for direct-to-consumer (DTC) 
advertisements.
    The purpose of prescription drug labeling is to provide health care 
practitioners information necessary for safe and effective use. The 
agency believes that use of medical and scientific terminology is 
necessary to effectively communicate to practitioners information about 
a product's risks and benefits as required under 21 U.S.C. 352(n) and 
Sec.  201.100. Requiring that language used in prescription drug 
labeling be tailored to a lay audience would result in a loss of the 
clarity and precision needed to effectively communicate to 
practitioners a product's benefits and risks. For example, if a drug is 
associated with a risk of a specific type of blood disorder, the 
disorder must be identified by its technical name (e.g., thrombotic 
thrombocytopenic purpura) so the practitioner can more quickly diagnose 
and treat the disorder when symptoms present. Scientific terminology 
may help to identify types of patients that might be at increased risk 
or otherwise manage the risk of that blood disorder. If the risk can 
only be described in terms that a lay audience can comprehend (e.g., 
blood disorder), the labeling would lack the precision needed to 
communicate the specific risk to prescribers.
    For many products, the final rule will improve the usefulness of 
the brief summary to consumers and health care practitioners by 
improving the usefulness of the prescription drug labeling, on which 
the brief summary is based. To this end, FDA has issued a draft 
guidance document entitled ``Brief Summary: Disclosing Risk Information 
in Consumer-Directed Print Advertisements'' that describes various 
options for presenting this information in DTC print advertisements (69 
FR 6308, February 10, 2004). By providing recommendations on use of 
alternatives to prescription drug labeling to fulfill the brief summary 
requirement, FDA is encouraging manufacturers to develop brief 
summaries for use in consumer-directed advertisements using language 
they can understand.

L. Comments on the Proposed Implementation Plan

    For new and more recently approved drugs, FDA proposed a staggered 
implementation schedule for the labeling requirements, with revised 
labeling required for newer products first (proposed Sec.  201.56(c)). 
The schedule is being finalized as proposed (see table 5 in section III 
of this document). Revised labeling for ANDA products depends on the 
labeling for the reference listed drug. The agency proposed to 
implement no later than 1 year after the effective date of the final 
rule the revised content requirements regarding unsubstantiated claims 
in labeling for newer and older drugs. The agency also proposed to 
implement by 1 year after the effective date of the final rule the 
requirement that any FDA-approved patient labeling be reprinted 
immediately following the ``Patient Counseling Information'' section of 
the FPI for newer products or immediately following the last section of 
the labeling for older products. The agency also proposed to implement 
by 1 year after the effective date of the final rule the requirement 
that in vitro or animal data related to activity or efficacy of a drug 
that have not been shown by adequate and well-controlled studies to be 
pertinent to clinical use be removed from the labeling unless a waiver 
is granted.
    In the proposal, the agency specifically sought comment on whether 
the revised content and format requirements should be applied, as 
proposed, to drug products with an NDA, BLA, or efficacy supplement 
that is pending at the effective date of the final rule, that was 
submitted on or after the effective date of the final rule, or that has 
been approved from 0 up to and including 5 years prior to the effective 
date of the final rule, or whether alternative application criteria 
should be used.
    (Comment 113) Several comments agreed with the categories of 
prescription drugs that would be subject to the new labeling content 
and format requirements in the agency's proposed implementation plan. 
Other comments expressed concern that the proposed implementation plan 
is too narrow. These comments maintained that the new format is 
superior to the old format and the scope of the proposed implementation 
of the new format would leave large numbers of products with inferior 
labeling. Some comments requested that the revised content and format 
requirements eventually be applied to all marketed prescription drugs. 
One comment recommended that the implementation plan also apply to all 
drugs that are among the 150 most frequently prescribed drugs that 
would not otherwise be covered by the implementation plan. The comment 
maintained that under the proposed implementation plan only 1 of the 
current top 15 drugs used in the elderly would be required to implement 
the revised content and format.
    Some comments expressed concern that having different labeling 
formats would be confusing to physicians. One comment expressed concern 
that having two different formats might impact prescribing behavior, 
arguing that prescribers might favor newer, more expensive drugs. Some 
comments maintained that a single standard format is needed to 
facilitate access to labeling in electronic formats. One comment also 
questioned FDA's underlying assumption that there is a lesser need for 
improved labeling for older products because practitioners are more 
familiar with older products and refer to older product labeling less 
frequently than newer product labeling. The comment maintained that 
newer practitioners would need to refer to the labeling of older drugs 
to the same extent as for newer drugs. One comment suggested that 
manufacturers be given the option to revise labeling for older 
products.
    Some comments from manufacturers maintained that it would be most 
practical to apply the new format requirements only to products whose 
applications are submitted on or after the effective date of the final 
rule. They stated that broader implementation would place a substantial 
burden on FDA resources and could interfere with review of new drugs. 
One comment stated that the new format should apply only to drugs that 
are not a member of an existing drug class (i.e., products that would 
be considered the original member of a drug class) or that are a new 
and novel member of an existing drug class and whose applications are 
submitted on or after the effective date of the final rule. The comment 
maintained that having different labeling formats for similar drugs 
within the same drug class would be a competitive disadvantage for one 
format or the other.
    The agency believes the implementation plan as proposed for new and 
more recently approved drug products is the best option for 
implementing the new format requirements. The agency agrees that it is 
desirable for all prescription drugs to be subject to the same labeling 
rules. However, the agency has carefully considered the costs and 
benefits of implementing the revised labeling

[[Page 3962]]

format and determined that requiring broader implementation (e.g., to 
all prescription drugs) of the new format requirements would be an 
excessive regulatory burden.
    This initiative will require substantial resource allocation by the 
agency and industry for a period of several years. The agency's 
proposed implementation plan, which is being finalized in this rule as 
proposed, is intended to make the best use of these resources. As 
discussed in the preamble to the proposed rule (65 FR 81082 at 81098), 
the plan targets newer products because practitioners are more likely 
to refer to the labeling for newer products. In FDA's survey of 
physicians, newness of the product was a reason rated by 87 percent of 
physicians as very likely to trigger a labeling referral for a drug 
(Ref. 11, p. 35). In addition, the labeling for newer products is 
typically longer and more complex and, thus, more likely to benefit 
from a new format that makes the information more accessible. The 
implementation plan will also capture many older products that would 
not otherwise be covered by the plan when manufacturers seek new 
indications for their products (i.e., submit an efficacy supplement). 
For these reasons, the agency believes the implementation as proposed 
is the most reasonable approach to maximizing the public health benefit 
and best utilizing available resources in requiring the new content and 
format for labeling. In addition, manufacturers of older products not 
covered by the implementation plan may voluntarily revise, and submit 
for review, labeling for their products in the new format at any time.
    The agency does not believe that an implementation plan based on 
volume of prescriptions would be prudent. Prescription volume can 
fluctuate considerably over time, and the agency is not aware that 
there are standardized prescription volume data that are generally 
accepted as accurate. Thus, the agency believes it would be very 
difficult to fairly implement and enforce an implementation plan based 
on prescription volume.
    The agency also acknowledges that the existence of two different 
labeling formats may lead to some frustration among practitioners. The 
agency believes, however, that any potential confusion can be 
minimized. Practitioners are already aware of the content and format of 
existing labeling. The agency intends to engage in a comprehensive 
educational campaign to educate practitioners about the major features 
of the new format and why the implementation plan did not encompass all 
prescription drugs.
    FDA is cognizant that the presence of two labeling formats will 
present important challenges when implementing electronic labeling but 
is confident that these challenges can be successfully addressed. For 
example, the ways in which information will be formatted, tagged, and 
stored in the contemplated electronic format will permit access to 
labeling information in both the old and new labeling formats.
    The agency does not agree that the new format should be applied 
only prospectively or that it should be optional for the currently 
approved drugs that would be subject to the new format requirements 
under the proposed implementation plan. This narrower application of 
the new format requirements would fail to reach a significant number of 
products whose labeling is frequently referenced and could benefit from 
the new format requirements.
    (Comment 114) Several comments objected to the proposed requirement 
that, within 1 year of the effective date of the final rule, 
manufacturers review all existing labeling and remove any express or 
implied unsubstantiated claims from the ``Indications and Usage,'' 
``Dosage and Administration,'' ``Clinical Pharmacology,'' and 
``Clinical Studies'' sections. Some comments maintained that this 
requirement would be very burdensome for industry and the agency. They 
disagreed with the agency's contention in the preamble to the proposed 
rule that the labeling changes to remove unsubstantiated claims could 
usually be accomplished without prior approval by the agency (i.e., 
with a ``Changes Being Effected'' labeling supplement). They stated 
that these changes would more often than not require prior approval and 
extensive negotiations between the agency and a manufacturer. Some 
comments maintained that there would be a substantial number of 
requests for waivers under Sec.  201.58 or Sec.  314.126(c) and these 
requests would also be a burden on the agency. Some comments agreed 
with the requirement to remove unsubstantiated claims from existing 
labeling, but stated that 1 year was not enough time for manufacturers 
to accomplish the task. One comment maintained that the burden on the 
agency would compromise the drug approval process. One comment 
requested that the agency clarify what types of statements would have 
to be removed.
    The agency has reconsidered the proposed requirement to have 
manufacturers scrutinize all existing labeling for unsubstantiated 
claims and remove all such claims from labeling within 1 year of the 
effective date of the final rule. The agency agrees that a requirement 
to scrutinize all existing labeling within that timeframe would place 
substantial burdens on manufacturers and the agency and that such 
burdens might not be justified. In the preamble to the proposed rule, 
the agency estimated that no more than 25 percent of labeling for drugs 
other than antibiotics might contain unsubstantiated claims. Based on a 
recent review of a sample of prescription drug labeling, however, the 
agency believes the percentage of products whose labeling might contain 
such claims is considerably lower than 25 percent and not high enough 
to justify a requirement that manufacturers scrutinize all existing 
labeling to identify those claims, particularly in a short timeframe.
    The agency is eliminating only the requirement that manufacturers 
scrutinize all labeling for the presence of unsubstantiated claims 
within 1 year of the effective date of the final rule. The language in 
proposed Sec.  201.57(c)(2), (c)(3), and (c)(15) and Sec.  
201.80(c)(2), (j), and (m)(1) remains in the final rule, requiring that 
the ``Indications and Usage,'' ``Dosage and Administration,'' and 
``Clinical Studies'' sections must not imply or suggest uses not 
supported by substantial evidence and/or dosing regimens not included 
in the ``Dosage and Administration'' section. This language accurately 
reflects the existing regulatory standard for claims presented in 
prescription drug labeling.
    While the agency will not require a systematic evaluation of all 
existing labeling to identify unsubstantiated claims within 1 year of 
the effective date of the final rule, the agency wishes to make it 
clear that manufacturers have an ongoing obligation to ensure that 
claims in labeling have adequate substantiation and are not false or 
misleading. When new information comes to light that causes information 
in labeling to become inaccurate, manufacturers must act to change the 
content of their labeling, in accordance with Sec. Sec.  314.70 and 
601.12 (21 CFR 314.70 and 21 CFR 601.12). To clarify this obligation, 
the agency has revised Sec.  201.56 to specify that manufacturers must 
act to correct labeling that, in light of new information, has become 
inaccurate (see Sec.  201.56(a)(2)).
    (Comment 115) One comment recommended an implementation period of 3 
years, rather than 1 year as proposed, to append any FDA-approved 
patient labeling to the end of the labeling for trade packages. The

[[Page 3963]]

comment maintained that additional time was needed for reconfiguration 
and replacement of packaging equipment.
    The agency believes that the proposed implementation plan is 
appropriate and in the best interest of public health. Including the 
FDA-approved patient labeling in prescription drug labeling ensures 
that this information is available to health care practitioners to 
reinforce the discussions they have with their patients concerning the 
risks and benefits of prescription drugs. The agency considers 
improving physician-patient communication crucial for public health. 
Furthermore, the agency believes that this requirement should not place 
an undue burden on manufacturers because of the approximately 200 
products that would be affected by this provision of the final rule, 
the labeling of more than 60 percent of them already conform with the 
requirement (see section XI.C.1 of this document).
    (Comment 116) Manufacturers of products subject to an ANDA (generic 
products) expressed concern that NDA holders will use the rule's 
implementation provisions as a mechanism to delay approval of generics. 
The specific concern was that NDA holders will obtain approval for a 
new indication near the end of their marketing exclusivity for their 
drug's original indication, revise the labeling for the drug to the new 
format, and receive 3 years' marketing exclusivity for the new 
indication. The comments asked FDA to make it clear that, in such 
situations, manufacturers of generic products would be permitted to 
base their labeling on the old format until the marketing exclusivity 
for the new indication has expired.
    The agency wishes to make clear that the requirement to revise the 
labeling of a reference listed drug in the new format does not have any 
impact on the duration of exclusivity for the drug and, therefore, does 
not prevent a manufacturer of a generic product from using the revised 
labeling of the reference listed drug. Under section 505(j)(2)(A)(v) of 
the act (21 U.S.C. 355(j)(2)(A)(v)) and Sec. Sec.  314.94(a)(8) and 
314.127(a)(7) (21 CFR 314.127(a)(7)) of the agency's regulations, the 
labeling of a drug product submitted for approval under an ANDA must be 
the same as the labeling of the listed drug referenced in the ANDA, 
except for changes required because of differences approved under a 
suitability petition (Sec.  314.93), because the generic drug product 
and the reference listed drug are produced or distributed by different 
manufacturers, or because aspects of the listed drug's labeling are 
protected by patent or exclusivity. This final rule does not change the 
requirement to exclude any condition of use or indication from the 
labeling of a generic product when necessary (e.g., when the reference 
listed drug has patent protection or market exclusivity for an 
indication), nor does it prevent, as described at Sec.  314.127(a)(7), 
approval of an ANDA when the reference listed drug has protected 
labeling.
    In the scenario described, the reference listed drug and the 
generic product would both be required to use the new labeling format. 
The NDA holder could not prevent the manufacturer of the generic 
product from using the new labeling format of the reference listed 
drug, but the NDA holder would still have exclusivity for the new 
indication.
    (Comment 117) One comment recommended that all generic drugs 
pending approval or approved on or after the effective date of the 
final rule be required to submit labeling based on the new format. The 
comment maintained that the content of labeling is not significantly 
changed, just reordered, so this requirement would not be burdensome 
for manufacturers of generic products and the information in the 
labeling of the reference listed drug product and the generic product 
would still be essentially the same.
    The agency does not believe that manufacturers of generic products 
should be required to provide labeling in the new format when seeking 
approval for their product if the reference listed drug product is not 
required to have its labeling in the new format. As discussed in the 
response to comment 115, the act and regulations currently require that 
a generic product have the same labeling as the reference listed drug 
product. Moreover, the agency believes that, to avoid confusion, the 
labeling of a generic product should be in the same format as the 
labeling of the reference listed drug.
    (Comment 118) One comment urged FDA to compile a list of products 
that would be subject to the new format requirements and make the list 
publicly available.
    FDA does not believe that it is necessary to compile such a list. 
Manufacturers can readily determine whether their products are subject 
to these requirements by referring to the implementation plan and the 
effective date of the rule (see section III of this document).
    (Comment 119) Some comments requested that the agency clarify 
whether this final rule has implications for labeling that is 
distributed with prescription drug samples. One comment requested that 
the agency amend the rule to include labeling that is distributed with 
prescription drug samples. The comment maintained that free 
prescription drug samples do not contain adequate information in their 
packaging to keep consumers safe from harm.
    FDA has often emphasized the importance of providing patients with 
useful written prescription drug information (e.g., FDA-approved 
patient labeling) in a variety of settings (see e.g., 63 FR 66378, 
December 1, 1998; 68 FR 33724, June 5, 2003). Prescription drug samples 
must be accompanied by trade labeling (Sec.  201.100(c)), which is 
subject to this final rule. If FDA-approved patient labeling for a 
product is required to be distributed to the patient, the manufacturer 
or distributor of that product must provide it with the samples.

M. Comments on Environmental Impact

    (Comment 120) One comment maintained that FDA failed to adequately 
consider the environmental impact of the additional paper that will be 
required for labeling and the increase in size of packaging and 
shipping containers.
    As stated in section IX of the proposed rule (65 FR 81082 at 
81103), the agency determined that it is not required to do an 
environmental assessment or an environmental impact statement. This is 
an action excluded under Sec.  25.30(h) and (k) (21 CFR 25.30(h) and 
(k)) (i.e., does not individually or cumulatively have a significant 
effect on the human environment). The changes made to the proposal in 
this final rule do not change this conclusion. Therefore, neither an 
environmental assessment nor environmental impact statement is 
required.

VII. Legal Authority

    In this rule, FDA is addressing legal issues relating to the 
agency's action to revise the regulations prescribing content and 
format requirements for prescription drug labeling.

A. Statutory Authority

    FDA's revisions to the content and format requirements for 
prescription drug labeling are authorized by the act and by the Public 
Health Service Act (the PHS Act). Section 502(a) of the act deems a 
drug to be misbranded if its labeling is false or misleading ``in any 
particular.'' Under section 201(n) of the act, labeling is misleading 
if it fails to reveal facts that are material with respect to 
consequences which may result from the use of the drug under the

[[Page 3964]]

conditions of use prescribed in the labeling or under customary or 
usual conditions of use. Section 502(f) of the act deems a drug to be 
misbranded if its labeling lacks adequate directions for use and 
adequate warnings against use in those pathological conditions where 
its use may be dangerous to health, as well as adequate warnings 
against unsafe dosage or methods or duration of administration or 
application, in such manner and form, as are necessary for the 
protection of users. Section 502(j) of the act deems a drug to be 
misbranded if it is dangerous to health when used in the dosage or 
manner, or with the frequency or duration, prescribed, recommended, or 
suggested in its labeling.
    In addition, the premarket approval provisions of the act authorize 
FDA to require that prescription drug labeling provide the practitioner 
with adequate information to permit safe and effective use of the drug 
product. Under section 505 of the act, FDA will approve an NDA only if 
the drug is shown to be both safe and effective for use under the 
conditions set forth in the drug's labeling. Section 701(a) of the act 
(21 U.S.C. 371(a)) authorizes FDA to issue regulations for the 
efficient enforcement of the act.
    Under 21 CFR 314.125, FDA will not approve an NDA unless, among 
other things, there is adequate safety and effectiveness information 
for the labeled uses and the product labeling complies with the 
requirements of part 201. Under Sec.  201.100(d) of FDA's regulations, 
prescription drug products must bear labeling that contains adequate 
information under which licensed practitioners can use the drug safely 
for their intended uses. This final rule amends the regulations 
specifying the format and content for such labeling.
    Section 351 of the PHS Act (42 U.S.C. 262) provides legal authority 
for the agency to regulate the labeling and shipment of biological 
products. Licenses for biological products are to be issued only upon a 
showing that they meet standards ``designed to insure the continued 
safety, purity, and potency of such products'' prescribed in 
regulations (section 351(d) of the PHS Act). The ``potency'' of a 
biological product includes its effectiveness (21 CFR 600.3(s)). 
Section 351(b) of the PHS Act prohibits false labeling of a biological 
product. FDA's regulations in part 201 apply to all prescription drug 
products, including biological products.

B. First Amendment

    FDA's requirements for the content and format of prescription drug 
labeling are constitutionally permissible because they are reasonably 
related to the government's interest in ensuring the safe and effective 
use of prescription drug products and because they do not impose 
``unjustified or unduly burdensome'' disclosure requirements. (See 
Zauderer v. Office of Disciplinary Counsel, 471 U.S. 626, 651 (1985); 
see also Ibanez v. Florida Dep't of Bus. and Prof'l Regulation, 512 
U.S. 136, 146 (1994).) The information required by the final rule to 
appear in labeling is the information necessary to provide facts that 
are material with respect to consequences which may result from the use 
of the drug under the conditions of use prescribed in the labeling or 
under customary or usual conditions of use (sections 201(n) and 502(a) 
of the act); adequate directions for use and adequate warnings (section 
502(f) of the act); and information on the conditions of use in which 
the product would be dangerous (section 502(j) of the act). In 
addition, pursuant to section 505 of the act, the labeling sets forth 
information on the conditions in which the product is safe and 
effective. By its terms, the final rule requires disclosure of the 
essential scientific information necessary for safe and effective use 
of the labeled drug product. Consequently, FDA believes the final rule 
passes muster under the First Amendment.
    In Central Hudson Gas & Electric Corporation v. Public Service 
Commission 447 U.S. 557 (1980), the Supreme Court established a four-
step analysis for assessing the constitutionality of government 
restrictions on the content of commercial speech.
    [First,] we must determine whether the expression is protected 
by the First Amendment. For commercial speech to come within that 
provision, it at least must concern lawful activity and not be 
misleading. [Second,] we ask whether the asserted governmental 
interest is substantial. If both inquiries yield positive answers, 
we must determine [third] whether the regulation directly advances 
the government interest asserted, and [fourth,] whether it is not 
more extensive than is necessary to serve that interest.
    This rule also survives scrutiny under the four-part test in 
Central Hudson. FDA believes that much information required to appear 
in prescription drug labeling is necessary for labeling to be 
nonmisleading. The risk information contained in such labeling, for 
example, constitutes material facts within the meaning of sections 
201(n) and 502(a) of the act. Risk information can also qualify as 
warnings compelled by section 502(f) and (j) of the act. Other 
information, such as information on indications for the product, dosage 
and administration information, and how supplied information, is 
necessary because it provides adequate directions for use. Because not 
all of the information required in labeling clearly is necessary to 
prevent the labeling from being false or misleading, it is necessary 
for FDA to apply the remaining parts of the Central Hudson analysis.
    FDA's interest in protecting the public health has been previously 
upheld as a substantial government interest under Central Hudson. (See 
Pearson v. Shalala, 164 F.3d 650, 656 (D.C. Cir. 1999) (citing Rubin v. 
Coors Brewing Co., 514 U.S. 476, 484-85 (1995).) The final rule's 
labeling requirements directly advance this interest, thereby 
satisfying the third part of Central Hudson, because by requiring 
disclosure of complete information on the conditions under which a 
product can be used safely and effectively, the requirements help to 
ensure that prescription drug products will be prescribed properly by 
health care practitioners and will be used safely and effectively by 
patients.
    Finally, under the fourth part of the Central Hudson test, there 
are not numerous and obvious alternatives (in fact, there are no 
reasonable alternatives) (Cincinnati v. Discovery Network, 507 U.S. 
410, 418 n.13 (1993)) to the content and format requirements of this 
final rule that directly advance the government's interest but are less 
burdensome to speech. Health care practitioners are accustomed to 
looking to the prescription drug labeling as their primary source of 
information about a product, and patients rely for their drug 
information primarily on practitioners. Neither a public education 
campaign, nor encouraging sponsors to provide information on the risks 
and benefits of drugs but not requiring such information, would ensure 
that practitioners have the information they need about the conditions 
in which prescription drugs can be used safely and effectively. 
Requiring disclosures meets the fourth part of the test.
    Accordingly, the agency believes it has complied with its burdens 
under the First Amendment to support the content and format 
requirements for prescription drug labeling.

VIII. Paperwork Reduction Act of 1995

    The final rule contains information collection provisions that are 
subject to review by the OMB under the Paperwork Reduction Act of 1995 
(44 U.S.C. 3501-3520). The title, description and respondent 
description of the information collection provisions are shown below 
with an estimate of the reporting burdens. Included in the estimate is 
the time for reviewing

[[Page 3965]]

instructions, searching existing data sources, gathering and 
maintaining the data needed, and completing and reviewing each 
collection of information. The OMB and FDA received no comments 
concerning the information collection provisions of the proposed rule.
    Title: Requirements on Content and Format of Labeling for Human 
Prescription Drug and Biological Products
    Description: The final rule amends FDA's regulations governing the 
format and content of labeling for human prescription drug products. It 
revises current regulations to require that the labeling of new and 
recently approved products contain highlights of prescribing 
information, a table of contents for prescribing information, 
reordering of certain sections, minor content changes, and minimum 
graphical requirements. The final rule does not subject older drugs to 
the revised labeling requirements. However, it does require, as for new 
and recently approved products, that FDA-approved patient labeling 
accompany or be reprinted immediately following the last section of 
prescription drug labeling.
    As discussed in section VII of this document, FDA's legal authority 
to amend its regulations governing the content and format of labeling 
for human prescription drugs derives from sections 201, 301, 502, 503, 
505, and 701 of the act and from section 351 of the PHS Act.

A. Summary of Prescription Drug Labeling Content and Format 
Requirements in this Final Rule That Contain Collections of Information

    Section 201.56 requires that prescription drug labeling contain 
certain information in the format specified in either Sec.  201.57 or 
Sec.  201.80, depending on when the drug was approved for marketing. 
Section 201.56(a) sets forth general labeling requirements applicable 
to all prescription drugs. Section 201.56(b) specifies the categories 
of new and more recently approved prescription drugs subject to the 
revised content and format requirements in Sec. Sec.  201.56(d) and 
201.57. Section 201.56(c) sets forth the schedule for implementing 
these revised content and format requirements. Section 201.56(e) 
specifies the sections and subsections, required and optional, for the 
labeling of older prescription drugs not subject to the revised format 
and content requirements.
    Section 201.57(a) requires that prescription drug labeling for new 
and more recently approved prescription drug products include 
``Highlights of Prescribing Information.'' Highlights provides a 
concise extract of the most important information required under Sec.  
201.57(c) (the FPI), as well as certain additional information 
important to prescribers. Section 201.57(b) requires a table of 
contents to prescribing information, entitled ``Full Prescribing 
Information: Contents,'' consisting of a list of each heading and 
subheading along with its identifying number to facilitate health care 
practitioners' use of labeling information. Section 201.57(c) specifies 
the contents of the FPI. The final rule reorders information required 
at former Sec.  201.57, makes minor content changes, and provides 
standardized identifying numbers for the required information. Section 
201.57(d) mandates new minimum specifications for the format of 
prescription drug labeling and establishes minimum requirements for key 
graphic elements such as bold type, bullet points, type size, and 
spacing.
    In accordance with the final rule, older drugs not subject to the 
revised labeling content and format requirements in Sec.  201.57 remain 
subject to labeling requirements at former Sec.  201.57, which is 
redesignated as Sec.  201.80 by this final rule. Section 201.80 
contains minor clarifications. In addition, Sec.  201.80(f)(2) requires 
that within 1 year, any FDA-approved patient labeling be referenced in 
the ``Precautions'' section of the labeling of older products and 
either accompany or be reprinted immediately following the labeling.

B. Estimates of Reporting Burden

1. The Reporting Burdens for the General Requirements (Sec.  201.56)
    The reporting burdens for the general requirements in Sec.  
201.56(a) are the same as those for former Sec.  201.56(a) through (c) 
and are estimated in tables 8a and 8b as part of the burdens associated 
with Sec.  201.57. Section 201.56(b) and (c) sets forth the categories 
of affected drugs and their implementation schedule, generating no 
reporting burdens. Section 201.56(d) sets forth the required sections 
and subsections associated with the revised format in Sec.  201.57; 
therefore, its associated reporting burdens are estimated in tables 8a 
and 8b under the requirements at Sec.  201.57. Sections 201.56(e) and 
201.80 codify former labeling requirements at Sec. Sec.  201.56(d) and 
(e) and 201.57, with minor clarifications, for older prescription 
drugs. The requirements in these sections impose no new reporting 
burdens (except those accounted for in section VIII.B.6 of this 
document), as they were previously incurred to produce existing 
labeling.
2. Annual Burden for Labeling Design, Testing, and Submitting to FDA 
for NDAs Submitted on or After the Effective Date of the Final Rule 
(Sec. Sec.  201.56 and 201.57)
    New drug product applicants must: (1) Design and create 
prescription drug labeling containing Highlights, Contents, and FPI, 
(2) test the designed labeling (e.g., to ensure that the designed 
labeling fits into carton-enclosed products), and (3) submit it to FDA 
for approval.
    Based on information received from the pharmaceutical industry, FDA 
estimated that it took applicants approximately 3,200 hours to design, 
test, and submit prescription drug labeling to FDA as part of an NDA or 
BLA under former labeling requirements (see row 1 of table 8a). FDA 
estimates that it will take an additional 149 hours to generate 
Highlights and Contents and otherwise comply with the additional 
requirements of the final rule (see row 2 of table 8a). Therefore, it 
will take a total of approximately 3,349 hours to design, test, and 
submit new labeling. Approximately 85 applicants would submit 
approximately 107 new applications (NDAs and BLAs) to FDA per year, 
totaling 358,343 hours (see Total of table 8a).
3. Burden Associated with Labeling Supplements for Applications 
Approved Within 5 Years Prior to the Effective Date of the Rule (Sec.  
201.57)
    The final rule requires that prescription drug applications 
approved during the 5 years before, or pending on, the effective date 
conform to format and content requirements at Sec.  201.57. For these 
products, applicants must redesign and negotiate the labeling, 
including Highlights and Contents, test the redesigned labeling, and 
prepare and submit that labeling to FDA for approval. Based on 
information provided in the ``Analysis of Economic Impacts'' (economic 
analysis) (see section XI.D.2.a of this document), labeling supplements 
for a total of approximately 344 innovator products would be submitted 
to the FDA over a 5-year period (beginning in year 3 and ending in year 
7 after the effective date of the rule). Approximately 172 applicants 
would submit these labeling supplements. The time required for 
redesigning, testing, and submitting the labeling to FDA is estimated 
to be approximately 196 hours per application, totaling 67,424 hours 
(see row 1 of table 8b).

[[Page 3966]]

4. Burden Associated with Revised Labeling Efficacy Supplements 
Submitted on or After the Effective Date of the Rule (Sec. Sec.  
201.56(d) and 201.57)
    Efficacy supplemental applications for older drugs submitted on or 
after the effective date of the final rule are subject to the content 
and format requirements at Sec. Sec.  201.56(d) and 201.57. To meet 
these requirements, applicants must revise the existing labeling for 
these products. Each year an increasing number of innovator drug 
labeling will have been revised, and over time, very few efficacy 
supplements independently will generate labeling revisions as a result 
of this final rule. According to information in the economic analysis, 
the total number of affected efficacy supplements over 10 years is 
estimated at 324, with a decreasing number each year over the 10-year 
period (see section XI.D.2.a. of this document). For purposes of this 
analysis, the total burden for efficacy supplements is summarized in 
row 2 of table 8b. Over 10 years, approximately 172 applicants will 
trigger approximately 324 efficacy supplements, each one requiring 
approximately 196 hours to revise the labeling in the application, 
totaling 63,504 hours. In addition to this burden, a minimal annual 
reporting burden, probably even lower than the 7 per year estimated in 
year 10 of table 13 of this document, will continue indefinitely.
5. Burden Associated with Revised Labeling for Efficacy Supplements for 
Generic Drug Products (Sec.  201.57)
    The reporting burden for generic products subject to the 
requirements of the final rule has only been estimated for those 
products requiring revisions to their existing labeling. Reporting 
burdens for generating newly approved labeling for generic products 
(Sec.  314.94(8)) is already approved under OMB control number 0910-
0001. According to the data in the economic analysis, beginning in year 
3 and continuing throughout the 10-year period analyzed, approximately 
42 generic applications per year must submit labeling supplements to 
comply with the final rule (see section XI.D.2.a of this document). For 
purposes of this analysis, approximately 336 already approved generic 
drug applications must submit labeling supplements over the 10-year 
period after the effective date of the rule (see section XI.D.2.a of 
this document). The time required to revise and submit this labeling to 
FDA would be approximately 27 hours per application, totaling 9,072 
hours (see row 3 of table 8b). In addition to this burden, a minimal 
reporting burden associated with a very small number of generic 
applications referencing older drugs may continue indefinitely.
6. Requirement That FDA-Approved Patient Labeling Accompany 
Prescription Drug Labeling Within 1 Year (Sec. Sec.  201.57 and 201.80)
    Within 1 year, all FDA-approved patient labeling must either 
accompany or be reprinted immediately following the prescription drug 
labeling (Sec. Sec.  201.57(c)(18) and 201.80(f)(2)). As indicated in 
the economic analysis (section XI.D.1 of this document), an estimated 
80 products will need to revise labeling as a result of this 
requirement. Approximately 18 applicants would be subject to this 
requirement. The agency estimates approximately 38 hours per product as 
a one-time labeling revision, totaling 3,040 hours (see row 4 of table 
8b).

C. Capital Costs

    A small number of carton-enclosed products may require new 
packaging to accommodate longer inserts (see section XI.D.2.c and 
comment 124 of this document). As described in more detail in the 
economic analysis (section XI.D.2.c.ii), up to 5 percent of the 
existing products affected by the rule (i.e., products with new 
efficacy supplements, products approved in the 5 years prior to the 
effective date of the rule, and affected ANDAs) may require equipment 
changes at an estimated cost of $200,000 each product. As shown in 
table 17, the estimated value of equipment changes totals $7.2 million 
and $8.7 million over 10 years discounted at 7 and 3 percent, 
respectively.
    Description of Respondents: Persons and businesses, including small 
businesses and manufacturers.

                       Table 8a.--Estimated Reporting Burden for New Drug Applications\1\
----------------------------------------------------------------------------------------------------------------
 Category (21       Number of       Number of Responses                         Hours  per
 CFR section)      Respondents        per Respondent      Total  Responses       Response         Total Hours
----------------------------------------------------------------------------------------------------------------
Annual burden               85                     1.26             107              3,200            342,400
 associated
 with former
 labeling
 requirements
 (former
 201.56(d) and
 201.57)
----------------------------------------------------------------------------------------------------------------
Additional                  85                     1.26             107                149             15,943
 annual burden
 associated
 with
 requirements
 of this final
 rule
 (201.56(d)
 and 201.57)
----------------------------------------------------------------------------------------------------------------
Total           .................  ....................  .................           3,349            358,343
----------------------------------------------------------------------------------------------------------------
\1\ There are no capital costs or operating and maintenance costs associated with this collection of
  information.


[[Page 3967]]


       Table 8b.--Estimated Reporting Burdens for Labeling Revisions to Already-Approved Drug Products\1\
----------------------------------------------------------------------------------------------------------------
                     Year(s) In
                   Which Burdens                 Number of                                              Total
Category (21 CFR  Occur Following   Number of    Responses       Total       Hours per     Total       Capital
    section)           Rule's      Respondents      per        Responses     Response      Hours        Costs
                   Effective Date               Respondent
----------------------------------------------------------------------------------------------------------------
Burden            Beginning year        172           2.0   344                 196      67,424     $3.3 million
 associated with   3, ending year
 revised           7
 labeling for
 applications
 approved within
 5 years prior
 to the rule's
 effective date
 (201.57)
----------------------------------------------------------------------------------------------------------------
Burden            Beginning year        172           1.88  324                 196      63,504     $2.5 million
 associated with   1, diminishing
 revised           over time
 labeling for
 efficacy
 supplements
 submitted on or
 after the
 rule's
 effective date
 (201.56(d) and
 201.57)
----------------------------------------------------------------------------------------------------------------
Burden            Beginning year         42           8     336 (for years       27       9,072     $2.5 million
 associated with   3, continuing                             1-10)
 revised           annually
 labeling for      thereafter
 efficacy
 supplements for
 generic drug
 products
 (201.57)
----------------------------------------------------------------------------------------------------------------
Burden as a       Year 1 only            18           4.44  80                   38       3,040     $400,000
 result of
 having FDA-
 approved
 patient
 labeling
 accompany drug
 labeling within
 1 year
 (201.57(c)(18)
 and
 201.80(f)(2))
----------------------------------------------------------------------------------------------------------------
Total             ...............  ...........  ..........  ..............  ..........  143,040     Up to $8.7
                                                                                                     million
                                                                                                     (see table
                                                                                                     17)
----------------------------------------------------------------------------------------------------------------
\1\ There are no operating and maintenance costs associated with this collection of information.

    The information collection provisions in this final rule have been 
approved under OMB control number 0910-0572. This approval expires 
December 31, 2008. An agency may not conduct or sponsor, and a person 
is not required to respond to, a collection of information unless it 
displays a currently valid OMB control number.

IX. Environmental Impact

    The agency has 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. Executive Order 13132: Federalism

    We have analyzed this final rule in accordance with the principles 
set forth in Executive Order 13132. Section 4(a) of the Executive order 
requires agencies to ``construe * * * a Federal statute to preempt 
State law only where the statute contains an express preemption 
provision or there is some other clear evidence that the Congress 
intended preemption of State law, or where the exercise of State 
authority conflicts with the exercise of Federal authority under the 
Federal statute.''\10\ Here, FDA has determined that the exercise of 
State authority conflicts with the exercise of Federal authority under 
the act.
---------------------------------------------------------------------------

    \10\ Because we have determined that the act preempts State law 
because the exercise of State authority conflicts with the exercise 
of Federal authority under that statute, we need not construe our 
statutory rulemaking authority as required by section 4(b) of the 
Executive order.
---------------------------------------------------------------------------

    The act gives FDA comprehensive authority over drug safety, 
effectiveness, and labeling. FDA is the expert Federal agency charged 
by Congress with ensuring that drugs are safe and effective and that 
product labeling is truthful and not misleading (sections 505(d) and 
903(b)(2)(B) of the act (21 U.S.C. 393(b)(2)(B))). According to the 
act, a manufacturer of a drug must submit an NDA containing ``full 
reports of investigations which have been made to show whether or not 
such drug is safe for use and whether such drug is effective in use'' 
(section 505(b)(1)(A) of the act; see also 21 CFR 314.50; see also 
United States v. Rutherford, 442 U.S. 544, 555 (1979) (``Few if any 
drugs are completely safe in the sense that they may be taken by all 
persons in all circumstances without risk. Thus, the Commissioner 
generally considers a drug safe when the expected therapeutic gain 
justifies the risk entailed by its use'' (citations omitted))).
    An NDA must include the ``proposed text of the labeling,'' together 
with ``annotations to the information in the summary and technical 
sections of the application that support the inclusion of each 
statement in the labeling * * *'' (21 CFR 314.50(c)(2)(i)). The 
proposed labeling must also provide ``adequate directions for use'' 
(section 502(f) of the act). FDA by regulation has defined this to mean 
``directions under which the layman can use a drug safely * * *'' (21 
CFR 201.5). Because a prescription drug, by definition, cannot be used 
safely by a layperson without professional supervision, FDA regulations 
afford an exemption from the statutory requirement of adequate 
directions for use for a prescription drug whose labeling includes 
``any relevant hazards, contraindications, side effects, and 
precautions under which practitioners licensed by law to administer the 
drug can use the drug safely and for the purposes for which it is 
intended * * *'' (Sec.  201.100(c)(1)). If labeling lacks this 
information, or is otherwise false or misleading in any particular, FDA 
is authorized to refuse to approve the NDA (section 505(d) of the act; 
21 CFR 314.125(b)(6) and (b)(8)).
    The FDA review process for an NDA is thorough and scientifically 
rigorous. An NDA must contain proposed labeling and all information 
about the

[[Page 3968]]

drug (whether favorable or unfavorable) that is pertinent to evaluating 
the application and that is received or otherwise obtained by the 
applicant from any source (21 CFR 314.50 and 601.2(a)). FDA scientists 
evaluate this information, and may request additional information as 
necessary to provide a complete and accurate picture of the product. 
FDA may supplement the expertise of its in-house scientific personnel 
with advice from scientific advisory committees of outside experts (21 
CFR 14.171).
    Under the act and FDA regulations, the agency determines that a 
drug is approvable based not on an abstract estimation of its safety 
and effectiveness, but rather on a comprehensive scientific evaluation 
of the product's benefits and risks under the conditions of use 
prescribed, recommended, or suggested in the labeling (section 505(d) 
of the act). FDA considers not only complex clinical issues related to 
the use of the product in study populations, but also important and 
practical public health issues pertaining to use of the product in day-
to-day clinical practice, such as the nature of the disease or 
condition for which the product will be indicated, and the need for 
risk management measures to help assure in clinical practice that the 
product maintains its favorable benefit-risk balance. The centerpiece 
of risk management for prescription drugs generally is the labeling, 
which reflects thorough FDA review of the pertinent scientific evidence 
and communicates to health care practitioners the agency's formal, 
authoritative conclusions regarding the conditions under which the 
product can be used safely and effectively in accordance with the act.
    FDA carefully controls the content of prescription drug labeling, 
because such labeling is FDA's principal tool for educating health care 
practitioners about the risks and benefits of the approved product to 
help ensure safe and effective use. As FDA noted in the preamble 
accompanying the December 2000 proposed rule amending the 1979 
physician labeling regulations:
    The part of a prescription drug product's approved labeling 
directed to health care practitioners * * * is the primary mechanism 
through which FDA and drug manufacturers communicate essential, 
science-based prescribing information to health care professionals. 
This part of approved labeling is a compilation of information based 
on a thorough analysis of the new drug application (NDA) or 
biologics license application (BLA) submitted by the applicant * * * 
. [T]he primary purpose of prescription drug labeling is to provide 
practitioners with the essential information they need to prescribe 
the drug safely and effectively for the care of patients.
(65 FR 81082 at 81082 and 81083). What distinguishes the prescription 
drug labeling from other information available to practitioners about a 
prescription drug is that the prescription drug labeling ``is intended 
to provide physicians with a clear and concise statement of the data 
and information necessary for the safe and effective use of the drug.'' 
Moreover, the act ``permits labeling statements with respect to safety 
only if they are supported by scientific evidence and are not false or 
misleading in any particular'' (44 FR 37434 at 37435 and 37441).
    Under this final rule, risk information must appear in different 
sections of the prescription drug labeling in a particular order and 
must be based on data derived from human experience whenever possible. 
For example, information included in the contraindications section of 
prescription drug labeling must include only ``[k]nown hazards and not 
theoretical possibilities'' (Sec.  201.57(c)(5)). The adverse reactions 
section must include those adverse events for which there is some basis 
to believe there is a causal relationship between the event and the 
drug (Sec.  201.57(c)(7)).
    The act and FDA regulations prescribe several procedures to ensure 
that FDA receives information about risks that become apparent after 
approval. Because clinical trials involve time-limited administration 
of the investigational product to a relatively small and homogeneous 
population of study subjects, adverse events that were not observed 
during clinical trials may be recognized or identified following 
approval. The act provides that a manufacturer must establish and 
maintain such records, and make such reports, as FDA may require by 
regulation (section 505(k) of the act). To implement this provision, 
FDA has issued regulations requiring prompt reports of serious, 
unexpected drug experiences and periodic reports of all information 
relating to the safety and effectiveness of the drug (21 CFR 314.80 and 
314.81). Manufacturers may also commit to conduct additional safety and 
effectiveness studies following approval and submit data from these 
studies to the agency. (See section 506B of the act (21 U.S.C. 356b).)
    The statutory and regulatory requirements for the submission of 
information to FDA are accompanied by statutory provisions addressing 
the failure of a sponsor to comply with these requirements. A 
manufacturer that introduces a new drug into interstate commerce 
without having submitted the required premarket information has 
violated the act (section 505(a) of the act) and is subject to FDA 
enforcement action. Similarly, if a manufacturer fails to submit 
information required by 21 CFR 314.80 and 314.81, it is subject to 
enforcement action under 21 U.S.C. 331(e). FDA is authorized to 
investigate suspected fraud using its general statutory investigative 
authority (section 702 of the act (21 U.S.C. 372)). The agency is also 
empowered to address fraud by seeking injunctive relief and civil 
penalties (21 U.S.C. 332, 333(g)(1)(A)), and has authority to invoke 
the general federal prohibition on making false statements to the 
Federal Government (18 U.S.C. 1001). In sum, FDA has a variety of 
enforcement options that allow it to make a calibrated response to 
suspected violations of the act's information submission requirements.
    The agency carefully reviews all the information submitted by a 
sponsor in a marketing application to make its statutorily required 
judgment as to whether the product is safe and effective and otherwise 
in compliance with the act. It also reviews adverse event information 
submitted after marketing approval and determines what action, if any, 
should be taken. In rare cases, FDA finds that the information supports 
a determination to withdraw the product from the market (section 505(e) 
of the act; 21 CFR 601.5(b)(1)). In other instances, FDA uses other 
risk management techniques. One such technique is incorporating 
additional risk information into, or otherwise modifying, the 
prescription drug labeling (Sec.  201.57(e)). In many cases, review of 
the submitted reports does not lead to any change, e.g., because FDA 
determines that the event reported is not causally related to the 
product.
    Changes to prescription drug labeling typically are initiated by 
the sponsor, subject to FDA review, but are sometimes initiated by FDA. 
Under FDA regulations, to change prescription drug labeling (except for 
editorial and other minor revisions), the sponsor must submit a 
supplemental application fully explaining the basis for the change 
(Sec. Sec.  314.70 and 601.12(f)). FDA permits two kinds of labeling 
supplements: (1) Prior approval supplements, which require FDA approval 
before a change is made (Sec. Sec.  314.70(b) and 601.12(f)(1)), and 
(2) CBE supplements, which may be implemented before FDA approval, but 
after FDA notification (Sec. Sec.  314.70(c) and 601.12(f)(2)). 
Labeling changes to the FPI to add or strengthen a warning, precaution, 
contraindication, or adverse reaction statement are within the

[[Page 3969]]

category of changes for which CBE supplements are required by FDA 
regulations (Sec. Sec.  314.70(c)(6)(iii) and 601.12(f)(2)(i)) (see 
comment 5). While a sponsor is permitted to add risk information to the 
FPI without first obtaining FDA approval via a CBE supplement, FDA 
reviews all such submissions and may later deny approval of the 
supplement, and the labeling remains subject to enforcement action if 
the added information makes the labeling false or misleading under 
section 502(a) of the act. To mitigate this risk, manufacturers often 
consult with FDA before adding risk information to labeling. As noted 
in response to comment 5, however, a sponsor may not use a CBE 
supplement to make most changes to Highlights.
    As FDA has long recognized, its role is not to regulate medical 
practice. The agency's actions nevertheless affect medical practice in 
a variety of ways. For example, FDA approval decisions affect the 
availability of drugs and medical devices. Also, FDA decisions as to 
the content and format of prescription drug labeling affect health care 
practitioners' communications with patients, to the extent such 
labeling is relied upon by such practitioners to guide their 
discussions of risk with patients. FDA strongly believes that health 
care practitioners should be able to rely on prescription drug labeling 
for authoritative risk information and that health care practitioners 
should not be required to convey risk information to patients that is 
not included in the labeling.
    If State authorities, including judges and juries applying State 
law, were permitted to reach conclusions about the safety and 
effectiveness information disseminated with respect to drugs for which 
FDA has already made a series of regulatory determinations based on its 
considerable institutional expertise and comprehensive statutory 
authority, the federal system for regulation of drugs would be 
disrupted. Where a drug has not been reviewed by FDA and decisions with 
respect to safety, effectiveness, and labeling have not been made by 
the agency, expert determinations would not yet have been made by FDA, 
and such disruption would not occur.
    Section 4(c) of Executive Order 13132 instructs us to restrict any 
Federal preemption of State law to the ``minimum level necessary to 
achieve the objectives of the statute pursuant to which the regulations 
are promulgated.'' This final rule meets the preceding requirement 
because, as discussed in more detail above, it preempts state law only 
to the extent required to preserve Federal interests. Section 4(d) of 
Executive Order 13132 states that when an agency foresees the 
possibility of a conflict between State law and federally protected 
interests within the agency's area of regulatory responsibility, the 
agency ``shall consult, to the extent practicable, with appropriate 
State and local officials in an effort to avoid such a conflict.'' 
Section 4(e) of Executive Order 13132 adds that, when an agency 
proposes to act through adjudication or rulemaking to preempt State 
law, the agency ``shall provide all affected State and local officials 
notice and an opportunity for appropriate participation in the 
proceedings.''
    FDA sought input from all stakeholders on new requirements for the 
content and format of prescription drug labeling through publication of 
the proposed rule in the Federal Register. Although the proposed rule 
did not propose to preempt state law, it did solicit comment on product 
liability issues. FDA received no comments on the proposed rule from 
State and local governmental entities.
    Officials at FDA consulted with a number of organizations 
representing the interests of state and local governments and officials 
about the interaction between FDA regulation of prescription drug 
labeling (including this rule) and state law.
    In conclusion, the agency believes that it has complied with all of 
the applicable requirements under Executive Order 13132 and has 
determined that this final rule is consistent with the Executive order.

XI. Analysis of Economic Impacts

    FDA has examined the impacts of the final rule under Executive 
Order 12866, the Regulatory Flexibility Act (5 U.S.C. 601-612), and the 
Unfunded Mandates Reform Act of 1995 (Public Law 104-4). Executive 
Order 12866 directs agencies 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). Under the Regulatory 
Flexibility Act, unless the agency certifies that the rule is not 
expected to have significant economic impact on a substantial number of 
small entities, an agency must consider alternatives that would 
minimize any significant impact of the rule on small entities.
    Section 202(a) of the Unfunded Mandates Reform Act of 1995 requires 
that agencies prepare a written statement of anticipated costs and 
benefits before proposing any rule that may result in an expenditure by 
State, local, and tribal governments, in the aggregate, or by the 
private sector, of $100 million in any one year (adjusted annually for 
inflation).
    The agency believes that this rule is consistent with the 
regulatory philosophy and principles identified in Executive Order 
12866 and in these two statutes. The final rule would amend current 
requirements for the format and content of human prescription drug 
product labeling. Although the effectiveness of the revised labeling in 
achieving time savings and reductions in adverse reactions is 
uncertain, based on the following analysis as summarized in table 9, 
FDA projects that the present value of the quantifiable benefits of the 
final rule over 10 years range from $330 million to $380 million and 
from $420 million to $480 million at a 7 and 3 percent discount rate, 
respectively. Direct costs of the final rule are projected to range 
from approximately $7 million to $17 million in any one year, for a 
total present value of approximately $90 million and $120 million over 
10 years at a 7 and 3 percent discount rate, respectively. The agency 
thus concludes that the benefits of this final rule outweigh the costs. 
Furthermore, the agency has determined that the final rule is not an 
economically significant rule as described in the Executive order, 
because annual impacts on the economy are substantially below $100 
million. Because the rule does not impose any mandates on State, local 
or tribal governments, or the private sector that will result in an 
expenditure in any one year of $100 million or more, FDA is not 
required to perform a cost-benefit analysis according to the Unfunded 
Mandates Reform Act. The current inflation-adjusted statutory threshold 
is about $115 million.
    The agency believes that this rule would not have a significant 
impact on most small entities. However, it is possible that some small 
firms that produce several affected drugs, or small firms that might be 
required to undertake packaging modifications, may be significantly 
affected by this rule. Therefore, the following analysis, in 
conjunction with the preamble, constitutes the agency's final 
regulatory flexibility analysis as required by the Regulatory 
Flexibility Act.

[[Page 3970]]



                 Table 9.--Summary of Projected Quantifiable Benefits and Costs over 10 Years\1\
----------------------------------------------------------------------------------------------------------------
                                                                                  Present Value ($ million)
                                                         Total ($ million) -------------------------------------
                                                                                3 percent          7 percent
----------------------------------------------------------------------------------------------------------------
Benefits:                                                .................  .................  .................
 
  Health Care Practitioner Time Saved                               150                120                 90
  Cost of Adverse Drug Events Avoided                        360 to 430         300 to 360         240 to 290
----------------------------------------------------------------------------------------------------------------
Total Potential Benefits                                     510 to 580         420 to 480         330 to 380
----------------------------------------------------------------------------------------------------------------
Costs:                                                   .................  .................  .................
 
  Design and Produce Trade Labeling; Modify Packaging                42                 36                 29
   Equipment
  Reformat and Produce Labeling Not Accompanying Drug                36                 30                 25
   Products
  Print Longer PDR                                                   59                 49                 39
----------------------------------------------------------------------------------------------------------------
Total Costs                                                         140                120                 90
----------------------------------------------------------------------------------------------------------------
\1\ Numbers may not sum due to rounding.

A. Purpose of the Final Rule

    The purpose of the final rule is to make it easier for health care 
practitioners to find and read information important for the safe and 
effective use of prescription drugs. As described elsewhere in this 
preamble, the agency has found that the current format of prescription 
drug labeling can be improved to more optimally communicate important 
drug information (see section I of this document). Enhanced 
communication of drug information to physicians should make them better 
informed prescribers. The final rule is designed to achieve these 
objectives by amending the current content and format of the labeling 
for certain human prescription drug products to, among other things, 
highlight frequently accessed and new information, include a table of 
contents for the detailed information in labeling, and reorder this 
detailed information.

B. Comments on the Economic Impact Analysis

    Most comments on the economic analysis of the proposed rule came 
from pharmaceutical manufacturers. Although many manufacturers 
expressed concerns that the agency had significantly underestimated the 
costs to industry, especially the additional packaging costs that would 
be necessary with labeling printed in 8 points, only a few provided 
detailed information about the potential burden they expected the rule 
to impose. The agency welcomes these comments and, whenever possible, 
has incorporated data from these examples in the final analysis of 
economic impacts.
    (Comment 121) Several comments argued that manufacturers would 
incur significant administrative costs when negotiating the content of 
Highlights with FDA.
    Although our analysis did not separate administrative costs from 
other labeling design costs, the agency anticipated that manufacturers 
would require some ``detailed discussions and drug-specific decisions'' 
during the design phase of labeling (e.g., regarding exactly which 
adverse reactions should be listed in Highlights) (65 FR 81082 at 
81106). Currently, manufacturers submitting new applications (i.e., 
NDAs and BLAs) and efficacy supplements have to negotiate the content 
of labeling as part of the review process. Because any information in 
Highlights is also in the FPI, the agency does not agree that 
negotiating the content of Highlights will impose significant 
administrative costs beyond what is currently incurred by these 
manufacturers. As noted, to facilitate this process, the agency is 
making available guidance to assist manufacturers in selecting 
information for inclusion in Highlights (section IV of this document).
    On the other hand, manufacturers of recently approved innovator 
drugs (i.e., approved within 5 years prior to the effective date of the 
final rule) will incur costs to: (1) Prepare and submit their 
redesigned labeling to FDA for approval, which may include negotiations 
concerning the content of Highlights, and (2) replace existing labeling 
with redesigned labeling. To account for these additional actions, the 
one-time design costs for labeling of recently approved products are 
estimated to be about 50 percent higher than for labeling of new 
products (see section XI.D.2 of this document).
    (Comment 122) The agency sought specific comment on whether the 
potential impact of the proposed rule on small entities has been 
accurately estimated by the agency, and whether small business concerns 
have been adequately addressed. One comment stated that because the 
proposal has the potential to substantially affect larger companies 
(could double the length of labeling and require extensive re-
engineering and re-design of packaging lines and ancillary equipment), 
its impact would be even greater on smaller companies.
    Although the agency had requested input from small companies that 
might be affected by the rule, all comments on this question came from 
large companies. FDA believes it is difficult to predict the effect of 
the rule on small firms. While small firms may have lower sales volume 
over which to spread the fixed costs of compliance, some industry 
consultants have found that small pharmaceutical firms have less 
organizational layers and incur lower costs for the same activity than 
large pharmaceutical firms (Ref. 12). Table 22 in section XI.E.2 of 
this document illustrates the potential impact that the final rule 
might have on small firms.
    (Comment 123) One comment maintained that there is no support for 
FDA's identified benefit of reducing the time it takes a prescriber to 
use labeling by 15 seconds. The comment argued that Highlights, because 
it contains incomplete information, would actually increase physician 
reading time and asserts that FDA's assumption would be true only if 
physicians read just Highlights.
    The agency acknowledges that there is not direct empirical support 
for the estimate of 15 seconds time savings, but is persuaded based on 
consultation with physicians that the labeling changes would save time. 
The agency consulted physicians in a national survey, focus groups, and 
a public meeting to design labeling that provides easier and faster 
access to the most important and commonly referenced prescribing

[[Page 3971]]

information (65 FR 81082 at 81083 through 81085; see also Ref. 11). 
Using a standard format with frequently accessed sections at the 
beginning of labeling will help physicians find important information 
quickly and retain that information. Inclusion of Contents and 
references in Highlights to the full prescribing information that is 
cited or concisely summarized will speed access to detailed information 
in the FPI. In the absence of quantitative evidence suggesting a 
different estimate of time savings, the agency is retaining 15 seconds 
as a conservative estimate of the amount of time health care 
practitioners can save when seeking drug product information in 
labeling.
    (Comment 124) Some comments argued that FDA's estimate 
significantly underestimates increased costs for trade packaging, 
shipping containers, and new packaging and shipping equipment to 
accommodate the larger labeling that will result from the new format. 
Some comments argued that the agency's initial estimate of $200,000 to 
adjust or retool existing packaging equipment underestimates the impact 
on industry by almost fourfold. Moreover, one comment stated it could 
cost large manufacturers with many product lines up to $40 million to 
change all packaging lines. Several comments stated that increases of 
this magnitude will require retooling or replacing existing equipment, 
increasing containers to accommodate longer outserts, or, in some 
cases, adding a carton. Comments also stated that longer labeling would 
increase administrative costs.
    FDA allows each manufacturer some flexibility to determine the size 
and shape of a product's trade labeling and packaging. A survey of 
labeling printed in the Physicians' Desk Reference (PDR) for 200 
products showed that, on average, labeling requires 200 square inches 
of surface area when printed in 6.5-point type size. Since prescription 
drug labeling is printed on both sides of the paper, these findings 
suggest that current trade labeling averages 100 square inches. From 
this baseline, the agency calculates that about an additional 92.6 
square inches of paper would be needed to print labeling in 8-point 
type size and to add Highlights and Contents to the labeling.
    To reduce the burden on industry, the final rule requires that 
trade labeling be printed in at least 6-point type size (see comment 
102), similar to the size of the baseline case used in the original 
analysis and a size generally supported by industry comments on the 
proposed rule. Even though some trade labeling is currently printed in 
a size as small as 4 points, on average, trade labeling is in 6 points, 
and thus requiring a minimum type size of 6-point will not increase the 
size of most trade labeling. However for the few products currently 
printed in 4 points, labeling will require approximately 33 percent 
more paper to conform with the 6-point minimum size requirement at 
Sec.  201.57(d)(6). The agency believes that the additional resources 
associated with longer labeling are warranted by the ease of use and 
speed of comprehension by having labeling printed in 6 rather than 4 
points.
    Highlights and Contents will increase trade labeling by 
approximately 40 square inches, requiring an additional 20 square 
inches of paper. Manufacturers submitting NDAs and BLAs have not yet 
designed product labeling or packaging. Thus, the agency does not agree 
that the final rule will impose additional packaging costs on these 
manufacturers. In contrast, manufacturers submitting efficacy 
supplements or having existing labeling for drug products affected by 
the final rule will need to determine if their redesigned trade 
labeling fits on or within existing packaging.
    The final rule will affect less than 15 percent of existing 
products in the United States.\11\ The agency agrees that some 
packaging lines of these products will require adjustment to 
accommodate longer trade labeling, but disagrees that this will be 
necessary for all packaging lines. Based on an analysis of ophthalmic 
products, the agency increased the proportion of existing products 
expected to incur one-time production costs from 1 to 5 percent (see 
section XI.D.2.c.ii of this document).
---------------------------------------------------------------------------

    \11\ Data derived from information in ``Approved Drug Products 
with Therapeutic Equivalence Evaluations,'' December 2001.
---------------------------------------------------------------------------

    (Comment 125) One comment insisted that FDA's estimate of 92.6 
square inches of additional labeling space is not sufficient to 
accommodate the proposed new labeling sections, increase in white 
space, increase in type size, and inclusion of patient information in 
the FPI. The comment suggested that FDA's presentation of how much 
additional labeling space would be needed was confusing.
    The implementation schedule to add FDA-approved patient labeling to 
prescription drug labeling differs from the implementation schedule for 
the formatting and content changes affecting labeling for new and 
recently approved products (i.e., approved within 5 years of the 
effective date of the final rule). Consequently, the agency analyzed 
the impact of each of these requirements separately.
    Within 1 year of the effective date of the final rule, any FDA-
approved patient labeling must either be reprinted immediately 
following the end of labeling or accompany the labeling (Sec. Sec.  
201.57(c)(18) and 201.80(f)(2)). An estimated 150-square inches of 
surface area would be needed to print this information, adding an 
additional 75-square inches to the size of the labeling (65 FR 81082 at 
81109). The agency identified up to 200 products with some form of FDA-
approved patient labeling that will be affected by the final rule. A 
sample of these affected products shows that the labeling of more than 
60 percent already conforms to this provision of the final rule. For 
the final analysis, the agency increased the estimate of the number of 
affected products from 50 to 80, thus increasing the incremental 
printing costs for this provision of the final rule to $0.4 million 
annually (see section XI.D.1 of this document).
    More space will be needed to print longer trade labeling and 
labeling distributed with promotional materials for new and recently 
approved products. The length will depend on the minimum type size 
requirements for the labeling. For trade labeling printed in a minimum 
of 6 points, an estimated 20 square inches of paper is necessary to 
accommodate Highlights and Contents. In contrast, product labeling 
distributed with promotional materials must be printed in a minimum 8-
point type size, requiring about 93 square inches of paper (65 FR 81082 
at 81107). Furthermore, for labeling with FDA-approved patient labeling 
which is not currently appended to the product labeling, after all 
provisions of the final rule are implemented, product labeling will be 
approximately 168 square inches or 65 square inches longer when printed 
in 8-point or 6-point type, respectively.
    (Comment 126) One comment asked the agency to consider the impact 
of the increased number of calls on companies, and possible increases 
in personnel to process calls, as a result of requiring companies to 
include their phone number in the package inserts. Another comment 
raised concerns that requiring corporate telephone numbers for 
reporting of serious adverse reactions in Highlights would require 
companies to change their labeling with each change of their corporate 
telephone number.
    The agency believes that health care practitioners have varied 
access to company information via the Internet and other sources, thus 
including the phone number is unlikely to overly burden a company's 
ability to handle

[[Page 3972]]

incoming calls. The agency believes that changes in corporate phone 
numbers are an ordinary business expense.

C. Benefits of Regulation

    The expected economic benefits of this final rule are the sum of 
the present values of: (1) The reduced time needed by health care 
practitioners to seek desired information in prescription drug 
labeling; (2) the increased effectiveness of drug treatment; and (3) 
the avoided costs of treating drug-related errors due to misunderstood 
or incorrectly applied drug information.
    We acknowledge that the information to estimate the benefits of 
this rule is quite limited. In particular, we do not have direct 
estimates of how much time practitioners might save by using the new 
labeling, or how the new labeling might improve doctors' understanding 
of risks of prescription drugs. There is no formal study that tested 
how alternative labeling formats affect physicians' speed or quality of 
comprehension of information related to potential adverse effects of 
drugs.
1. Decreased Health Care Practitioner Time
    Prescription drug labeling is a major source of information about 
the risks and benefits of prescription drugs. Each year health care 
practitioners spend considerable time seeking medical knowledge about 
the therapeutic risks and benefits of the drugs prescribed to treat 
patients. However, only a few studies have focused on the information-
seeking behavior of health care practitioners. Four studies using 
family practice physicians reported that the PDR, a compilation of 
prescription drug labeling, was the most frequently used reference book 
in a clinical setting (Refs. 13 through 16). In one study published in 
1990, physicians reported using the PDR almost daily (Ref. 13). In 
addition to the PDR, physicians receive prescription drug labeling 
directly from drug manufacturers and their representatives.
    A 1994 FDA survey of physicians found that 42 percent referred to 
prescription drug labeling at least once a day, 33 percent less often 
than once a day but more often than once a week, and 25 percent once a 
week or less (Ref. 11, pp. 30-31). These findings suggest that a 
physician seeks drug information from prescription drug labeling on 
average 212 times each year.\12\ Moreover, comments from a pharmacy 
association, submitted in response to the proposed rule, reported that 
a recent informal survey of pharmacists found that 30 percent refer to 
prescription drug labeling several times each day, 36 percent refer at 
least once per day, and 34 percent refer at least once per week. If 
representative, these findings suggest that the average pharmacist in 
the United States seeks information from prescription drug labeling at 
least 257 times each year.\13\ To put this estimate in perspective, 
approximately 2.85 billion prescriptions were dispensed by retail 
pharmacies in 2001 (Ref. 17). About 60 percent of the 212,660 
pharmacists in the United States work in retail pharmacies (Refs. 18 
and 19) and cumulatively seek information from prescription drug 
labeling about 32.8 million times each year (212,660 pharmacists x 0.6 
x 257 labeling consultations per year), approximately 12 times for 
every 1,000 prescriptions dispensed.
---------------------------------------------------------------------------

    \12\ On average, physicians work 47 weeks per year and consult 
prescription drug labeling 4.51 times each week [(7 consultations 
per week x 42 percent) + (4 consultations per week x 33 percent) + 
(1 consultation per week x 25 percent)] (65 FR 81082 at 81104 
through 81105).
    \13\ On average, it is assumed that pharmacists work 50 weeks 
per year and consult labeling 5.14 times per week [(10 consultations 
per week x 30 percent) + (5 consultations per week x 36 percent) + 
(1 consultation per week x 34 percent)].
---------------------------------------------------------------------------

    For the analysis of the proposed rule, FDA was aware of no data 
estimating the total time physicians spend reading prescription drug 
labeling. It also had no estimates of how much time savings might 
result from possible changes in drug labeling. It therefore 
conservatively assumed that physicians could save an average of 15 
seconds each time they refer to prescription drug labeling in the new 
format (65 FR 81082 at 81104). One comment from a pharmaceutical 
manufacturing organization requested justification for this assumption 
(see comment 123). The comment stated that rather than save time, the 
new format with Highlights would lengthen the time practitioners spend 
looking for information.
    The agency disagrees it will take health care practitioners more 
time to find information with the new format compared to the old 
format. As described elsewhere in the preamble, the agency solicited 
input from health care practitioners to develop a format that presents 
complex drug information in a manner that will enable them to find 
information more rapidly, improving the communication of the risks and 
benefits of the drug (see section I of this document). In comments on 
the proposed rule, organizations representing health care practitioners 
and consumer groups strongly supported the new format as being easier 
and quicker to use (see comment 2). Comments from many drug 
manufacturers agreed that including a comprehensive table of contents 
and reordering of the detailed information would improve clarity of the 
labeling and quickly direct the reader to the appropriate section of 
the FPI, but expressed reservations about the utility of Highlights 
(see comment 2).
    Comments, including one by an expert in human cognition, supported 
Highlights as a way to improve the accessibility of the most heavily 
used information (see comment 2). Moreover, by including references in 
Highlights to specific sections of the FPI, Highlights will also 
enhance the effective use of the information in the detailed sections 
of the labeling. Therefore, based on comments from health care 
practitioners, professional organizations and consumer groups, the 
agency believes that the new format will reduce the time physicians, 
pharmacists, and other practitioners must spend seeking specific 
information in prescription drug labeling and increase the extent they 
rely on labeling for drug information.
    A recent study in Oregon found that primary care physicians on 
average will consult two sources of information, one of which is 
usually the PDR, and spend an average of 12 minutes seeking information 
to answer patient questions (Ref. 16). Another study in Finland logged 
the time physicians spent searching a computerized set of guidelines, 
the ``Physicians' Desk Reference and Database,'' and found the average 
time needed to find and read an article was 4.9 minutes (Ref. 20).
    Although these studies may not be representative of the average 
practitioner in the United States, they suggest that the agency's 
estimate of a 15-second time savings with the new format (once drug 
labeling is at hand) is plausible and conservative in that it is only a 
small improvement relative to time currently spent for most labeling 
referrals. If the new format were implemented for all prescription drug 
products, the nation's 625,100 physicians active in patient care (Ref. 
21) could save a total of about 552,100 hours per year (625,100 
physicians x 212 labeling consultations per year x 15 seconds saved per 
labeling consultation/ 3600 seconds per hour). Likewise, pharmacists 
could save an additional 227,700 hours per year (212,660 pharmacists x 
257 labeling consultations per year x 15 seconds saved per labeling 
consultation/ 3,600 seconds per hour).
    The final rule only applies to new and recently approved products. 
Moreover, implementation for recently approved products is phased in 
over several years.

[[Page 3973]]

 Thus, the final rule will initially apply only to a small percentage 
of prescription drug labeling. The rule's focus on newer products 
includes the prescription drug labeling that health care practitioners 
consult most frequently. In FDA's survey of physicians, newness of the 
product was the factor most often rated by physicians as ``very 
likely'' to trigger referral to prescription drug labeling (Ref. 11, p. 
35). Similarly, the pharmacy association's survey found that 
pharmacists were most likely to consult labeling if the drug was 
recently approved (48 percent).
    Although the average practitioner regularly prescribes from 40 to 
100 pharmaceutical products (Ref. 24), the proportion of these that are 
new drugs is unknown. Because the agency received no comments and has 
no other information on the percentage of reformatted labeling that 
practitioners will consult, the initial assumptions remain unchanged 
(65 FR 81082 at 81104). This analysis, therefore, assumes that the rule 
will begin affecting the length of time needed for prescription drug 
labeling consultations in the second year of implementation, only 
affecting 5 percent of all consultations in that year. The percentage 
of reformatted prescription drug labeling consulted by physicians is 
assumed to increase to 10, 15, and 25 percent in years 3, 4, and 5 
respectively. Thereafter, it is assumed to increase an additional 5 
percent each year, reaching 50 percent in year 10. Thus, in year 10, 
the time savings for physicians and pharmacists is projected to equal 
about 276,000 and 113,900 hours, respectively. FDA has not attempted to 
project impacts beyond 10 years, due to the uncertainty of the longer 
term technological changes that would affect these estimates (see 
section V of this document).
    To estimate the monetary value of the time saved, an hourly loaded 
wage for physicians is calculated using data from the American Medical 
Association (AMA) on the average net annual income of all non-Federal 
physicians (excluding residents), the average weekly workload, average 
number of weeks worked per year and benefits adjusted by the proportion 
of self-employed physicians (Refs. 22 and 23). The loaded wage for 
pharmacists is calculated from Bureau of Labor Statistics data (Ref. 
18). At $88.16 per hour for physicians ([$194,400 x (1 + 0.2)] / [47 
weeks x 56.3 hours / week]) and $46.75 per hour for pharmacists ($33.39 
/ hour x (1 + 0.4)), table 10 shows the annual monetary value of time 
saved and indicates that the present value over 10 years equals 
approximately $90 million or $120 million using a 7 or 3 percent 
discount rate, respectively.

                                               Table 10.--Value of Health Care Practitioner Time Saved\1\
--------------------------------------------------------------------------------------------------------------------------------------------------------
                                                      Current Value ($ million)                                Present Value ($ million)
                                       -----------------------------------------------------------------------------------------------------------------
                 Year                                                                             Total Discounted at 3         Total Discounted at 7
                                          Physicians       Pharmacists           Total                   percent                       percent
--------------------------------------------------------------------------------------------------------------------------------------------------------
1                                                 0                  0                  0                             0                             0
--------------------------------------------------------------------------------------------------------------------------------------------------------
2                                                 2                  1                  3                             3                             3
--------------------------------------------------------------------------------------------------------------------------------------------------------
3                                                 5                  1                  6                             5                             5
--------------------------------------------------------------------------------------------------------------------------------------------------------
4                                                 7                  2                  9                             8                             7
--------------------------------------------------------------------------------------------------------------------------------------------------------
5                                                12                  3                 15                            13                            11
--------------------------------------------------------------------------------------------------------------------------------------------------------
6                                                15                  3                 18                            15                            12
--------------------------------------------------------------------------------------------------------------------------------------------------------
7                                                17                  4                 21                            17                            13
--------------------------------------------------------------------------------------------------------------------------------------------------------
8                                                19                  4                 24                            19                            14
--------------------------------------------------------------------------------------------------------------------------------------------------------
9                                                22                  5                 27                            20                            15
--------------------------------------------------------------------------------------------------------------------------------------------------------
10                                               24                  5                 30                            22                            15
--------------------------------------------------------------------------------------------------------------------------------------------------------
Total                                           120                 30                150                           120                            90
--------------------------------------------------------------------------------------------------------------------------------------------------------
\1\ Numbers may not sum due to rounding.

2. Improved Effectiveness of Treatment
    The final rule will improve prescription drug labeling to make it 
easier to find and use information about the product. More effective 
communication of drug information will better inform practitioners 
about the risks and benefits of drugs prescribed to patients. 
Prescription drug labeling can contain hundreds of facts about a drug, 
increasing the time needed to find specific information, relative to 
simpler labeling. For example, labeling of the drug cisapride contains 
over 470 facts (Ref. 24). Under the final rule, Highlights would 
emphasize those characteristics of drugs that physicians report are the 
most important for decisionmaking. With the Contents and references to 
the FPI in Highlights, practitioners can more quickly find all relevant 
facts about the drug that are specific to their patients. Each format 
change required by the final rule is intended, therefore, to present 
the complex drug information contained in labeling in a way that will 
improve the ability of practitioners to select and prescribe drugs to 
their patients safely and effectively.
    The initial U.S. approval date will alert practitioners to newer 
products that should be used with greater vigilance. There are over 100 
NDAs, including about 30 new molecular entities, approved every year in 
the United States. Initial approval is based on data from clinical 
trials conducted to determine the safety and effectiveness of a 
product. These trials typically include only enough subjects to detect 
1 adverse reaction in every 300 to 500 patients (Ref. 25). It is not 
uncommon for drugs to have significant adverse effects that occur at 
lower frequencies than can be

[[Page 3974]]

detected in premarketing clinical trials. Adding contact information 
where practitioners can report suspected adverse reactions will 
facilitate the collection of drug safety information and make it easier 
for the agency and manufacturers to identify significant safety 
concerns that can emerge after a drug is marketed and a much larger 
population is exposed to the product. Moreover, by identifying those 
sections of the labeling in which there have been important recent 
changes, the new format will also alert practitioners to significant 
new safety concerns and other significant changes to labeling once a 
product has been approved.
    In addition, any FDA-approved patient labeling must be printed at 
the end of the labeling, or accompany the labeling, regardless of when 
the product was approved. Including patient information enhances the 
likelihood that physicians will communicate important information to 
patients, improving patient understanding and adherence to treatment 
recommendations. FDA is unable to quantify the magnitude of these 
expected improvements in treatment effectiveness and health outcomes, 
but the agency believes they could be significant.
3. Decrease in Costs to Treat Avoidable Adverse Reactions
    Although there are multiple causes of adverse reactions, some are 
potentially preventable and can result from misunderstood or 
incorrectly applied drug information (e.g., prescribing too high a dose 
for a patient with poor kidney function, or prescribing a drug to a 
patient with known contraindications). According to a 2000 GAO report 
on adverse drug events, standardized packaging is one of many 
approaches that can be adopted to reduce medication errors (Ref. 26). 
Requiring that prescription drug labeling follow a standardized format 
will better inform health care practitioners about the drugs that are 
prescribed to patients, improve the effectiveness of treatment, and 
reduce the number of preventable adverse reactions experienced by 
patients.
    No national study on the incidence or associated costs of adverse 
reactions has been conducted. Furthermore, it is difficult to compare 
published studies because they are either too limited in scope or 
differ in methodology. Nevertheless, studies of hospitalized patients 
suggest that the rate of preventable adverse events that occur during 
hospitalization is approximately 1.2 to 1.8 adverse events per 100 
patients admitted (Refs. 27 through 29). Moreover, 1 of these studies 
conducted in the early 1990s in the northeastern United States found 
that a majority of preventable adverse events (about 1 adverse event 
per 100 hospital admissions) were related to errors or miscalculations 
in physician ordering, the stage most likely to be affected by improved 
prescription drug labeling information (Ref. 28). A more recent study 
conducted in the southwestern United States reported 4.2 adverse events 
per 100 patients, of which only 15 percent where deemed preventable 
(Ref. 29). Given the approximately 36 million annual hospitalizations 
in the United States (Ref. 30), these data suggest that between 229,000 
and 364,000 adverse reactions among hospitalized patients are 
potentially preventable each year.
    A number of studies show that the occurrence of an adverse event in 
a hospitalized patient increases the costs of caring for the patient by 
an average of between $2,162 and $2,595 (Refs. 28, 29, and 31). Costs 
associated with preventable adverse events were even higher, averaging 
about $4,685 per patient (Ref. 31), or $6,075 in 2000 dollars. If all 
hospitals incur similar costs for preventable adverse events, the 
potentially preventable annual costs from this source could total from 
between $1.4 billion to $2.2 billion nationally (in 2000 dollars).
    Few studies on adverse reactions in outpatient or long-term care 
settings have been conducted. A report from a multidisciplinary 
conference held in 2000 to discuss a national research agenda for 
ambulatory patient safety described a diverse and complex outpatient 
system that was prone to the same types of errors observed in hospital 
studies (Ref. 32). In 1995, FDA estimated that hospitalizations 
associated with outpatient adverse reactions cost $4.4 billion per year 
(60 FR 44182 at 44232; August 24, 1995), equaling $5.2 billion in 2000 
dollars. If the causes of errors in the outpatient setting are similar 
to the causes in hospitals, half of these costs are related to 
physician ordering errors. Thus, about $2.6 billion (in 2000 dollars) 
per year in additional hospital costs result from errors likely to be 
influenced by improved prescribing information.
    FDA lacks data to estimate the actual proportion of the adverse 
reaction costs that would be prevented under the final rule. Combining 
the projected hospital costs attributable to preventable in-hospital 
and outpatient adverse reactions, from $4.0 billion to $4.8 billion per 
year may be potentially avoided through measures that provide better 
information to doctors, such as prescription drug labeling. If the 
final rule reduced these costs by even 1 percent, between $40 million 
and $48 million of the costs of hospitalization could be prevented each 
year. Over 10 years, the present value of these avoided costs would 
total from $240 million to $290 million with a 7 percent discount rate, 
and from $300 to $360 with a 3 percent discount rate (table 11).

[[Page 3975]]

[GRAPHIC] [TIFF OMITTED] TR24JA06.001

    As illustrated in table 12, the magnitude of the potential benefits 
of the final rule will be sensitive to the assumed level of 
effectiveness. At 0.4 percent, the total present value of avoided 
hospital costs for preventable in-hospital and outpatient adverse drug 
events will exceed the total present value of the compliance costs for 
the final rule at both 3 and 7 percent discount rates.

   Table 12.--Impact of Different Effectiveness Levels on the Total Present Value of Avoided Hospital Costs to
                                    Treat Preventable Adverse Drug Events\1\
----------------------------------------------------------------------------------------------------------------
                             Discounted at 3 percent  ($ million)        Discounted at 7 percent  ($ million)
 Effectiveness Estimate  ---------------------------------------------------------------------------------------
        (percent)                 From:                  To:                  From:                  To:
----------------------------------------------------------------------------------------------------------------
0.1                                      30                    36                    24                    29
----------------------------------------------------------------------------------------------------------------
0.4\2\                                  120                   140                    97                   120
----------------------------------------------------------------------------------------------------------------
0.5                                     150                   180                   120                   150
----------------------------------------------------------------------------------------------------------------
1.0                                     300                   360                   240                   290
----------------------------------------------------------------------------------------------------------------
5.0                                   1,500                 1,800                 1,200                 1,500
----------------------------------------------------------------------------------------------------------------
\1\ Numbers may not sum due to rounding.
\2\ Corresponds to the breakeven point where over 10 years, the total present value of hospital costs avoided
  exceeds the total present value of the compliance costs of the final rule.

    When compared with other published studies, the agency's estimate 
of the cost of adverse reactions is likely less than the total social 
cost of such events. In particular, FDA's estimates include only 
hospital costs, and exclude the willingness to pay of patients to 
reduce these risks. Because these risks include fatality risks, the 
willingness to pay may be quite large. Using a restrictive definition 
of adverse events and including direct and indirect costs, a large 
study of hospital discharge records conducted by Thomas and others in 
Utah and Colorado was published in 1999 and estimated that preventable 
adverse events cost society at least $17 billion (in 1996 dollars) each 
year (Ref. 33). In contrast, a 2001 revision of the 1995 Johnson and 
Bootman cost-of-illness model used current costs whenever possible and 
predicted that drug-related illness occurring in ambulatory care 
settings cost about $177.4 billion each year, or more than 40 times the 
estimate of avoided costs that was used in the rest of this analysis

[[Page 3976]]

(Refs. 34 and 35). While we acknowledge that we have no direct evidence 
about how the rule would reduce preventable adverse reactions, if the 
final rule avoided at least one-tenth of a percent of the costs 
predicted by the Thomas study, annual benefits of the rule would 
approximately equal annual costs.

D. Costs of Regulation

    Except as noted below, the methods used to estimate costs for the 
proposed rule remain the same for the final impact analysis (65 FR 
81082 at 81103 through 81112). When possible, unit costs have been 
updated.
    The proposed rule would have required two broad types of changes to 
the labeling of prescription drug products. First, labeling of 
approximately one-third of products already approved for marketing 
would have been revised to delete or add information within 1 year. 
Several comments argued that these changes would be quite costly 
relative to the limited benefits that would be derived and difficult to 
accomplish in the proposed implementation period (see comment 114). In 
response to these comments, the agency removed the requirements to 
delete certain information from all existing prescription drug 
labeling. Only those products with existing labeling that have FDA-
approved patient labeling will be required to revise the labeling 
within 1 year.
    Second, the proposed rule would have revised the content and 
established format requirements for labeling of new and recently 
approved applications. Although the agency modified some specific 
content and format requirements, the staggered implementation schedule 
and most provisions were retained for the final rule. Therefore, direct 
costs incurred to change prescription drug labeling include the costs 
of: (1) Designing or revising prescription drug labeling and submitting 
the new labeling to FDA, (2) producing longer trade labeling including 
any equipment adjustments, (3) layout and artwork for labeling not 
accompanying drug products, (4) producing longer labeling for labeling 
not accompanying drug products, and (5) printing longer labeling in the 
PDR.
1. Labeling Changes for All Approved Prescription Drug Products
    a. Affected products. The agency will require that FDA-approved 
patient labeling accompany the prescription drug labeling, or be 
printed following the last section of the prescription drug labeling 
within 1 year after the effective date of the final rule. The agency 
identified up to 200 products with some form of FDA-approved patient 
labeling that will be affected by the final rule. A sample of these 
affected products shows that the labeling of more than 60 percent 
already conforms to this provision of the final rule. Therefore, the 
labeling of an estimated 80 products will need to be revised.
    b. Prescription drug labeling design costs. On average, 
prescription drug manufacturers will incur about $2,220 per product in 
design and implementation costs to append FDA-approved patient labeling 
to existing prescription drug labeling. Because changes must be made 
within 1 year of the effective date of the final rule, not all firms 
will have sufficient time to deplete their inventories of existing 
prescription drug labeling. With a 12-month implementation period, FDA 
consultants estimate per product inventory losses of approximately 
$630. Thus, including excess inventory losses, the cost to change 
prescription drug labeling is estimated at $2,850 per product (65 FR 
81082 at 81109; and 68 FR 6062 at 6074, reflecting updated costs). As 
shown in table 13, in the first year firms may incur one-time costs of 
$0.2 million to add FDA-approved patient labeling to the labeling of 
the affected products.
    c. Incremental printing costs for prescription drug labeling. 
Printed patient information would add an estimated 2 pages or about 75-
square inches to the length of trade labeling when printed on two sides 
(65 FR 81082 at 81109). Updating the unit printing costs for inflation, 
this additional length would increase the incremental printing costs by 
approximately $6.84 for 1,000 pieces of labeling (75-square inches per 
piece x $0.0000912 per square inch x 1,000 pieces) (68 FR 6062 at 
6074). For the final analysis, FDA estimates that for affected 
products, up to 650,000 pieces of trade labeling would be distributed 
each year (section XI.D.2.c.i of this document). For each of the 
affected products, manufacturers will incur annual incremental costs 
averaging about $4,440 to print the longer trade labeling (650,000 
pieces per product per year x $6.84 per 1,000 pieces). For all 80 
affected products, annual incremental printing costs for trade labeling 
will increase by $0.4 million. Furthermore, manufacturers distributing 
longer prescription drug labeling with promotional materials and 
samples will spend up to an additional $5,125 in annual incremental 
printing costs each year for 3 years (750,000 pieces per year x $6.84 
per 1,000 pieces (approximation based on information in footnote 17 in 
section XI.D.2.e of this document)). Therefore, industry will incur 
additional printing costs with a present value of approximately $3.6 
million or $4.2 million over 10 years at a 7 or 3 percent discount 
rate, respectively (table 13).
    d. Physicians' Desk Reference (PDR) Costs. The agency estimates 
that 75 percent of prescription drug products have labeling already 
printed in the PDR. In 2002, an additional page in the PDR costs 
manufacturers $9,750.\14\ Thus, the per product annual cost to print 
two additional pages is about $19,500 ($9,750 x 2). For the estimated 
60 affected products (80 products x 0.75), the annual PDR costs would 
increase by $1.2 million ($19,500 x 60), equaling a present value of 
approximately $8.2 million or $10.0 million over 10 years with a 7 or 
3-percent discount rate, respectively (table 13).
---------------------------------------------------------------------------

    \14\ Not all of these costs to manufacturers are social costs, 
as the PDR publisher is presumably selling additional pages at more 
than its true opportunity cost. The excess is a transfer, but we do 
not know its magnitude.

 Table 13.--Costs to Include FDA-approved patient labeling With Labeling of Existing Prescription Products\1, 2\
----------------------------------------------------------------------------------------------------------------
                            One-Time Labeling    Annual Incremental
          Year             Revision Costs  ($    Printing Costs  ($   Annual PDR Costs  ($     Total Costs  ($
                                million)              million)              million)              million)
----------------------------------------------------------------------------------------------------------------
1                                         0.2                   0.8                   1.2                   2.2
----------------------------------------------------------------------------------------------------------------
2                                         0.0                   0.8                   1.2                   1.9
----------------------------------------------------------------------------------------------------------------

[[Page 3977]]

 
3                                         0.0                   0.8                   1.2                   1.9
----------------------------------------------------------------------------------------------------------------
4                                         0.0                   0.4                   1.2                   1.5
----------------------------------------------------------------------------------------------------------------
5                                         0.0                   0.4                   1.2                   1.5
----------------------------------------------------------------------------------------------------------------
6                                         0.0                   0.4                   1.2                   1.5
----------------------------------------------------------------------------------------------------------------
7                                         0.0                   0.4                   1.2                   1.5
----------------------------------------------------------------------------------------------------------------
8                                         0.0                   0.4                   1.2                   1.5
----------------------------------------------------------------------------------------------------------------
9                                         0.0                   0.4                   1.2                   1.5
----------------------------------------------------------------------------------------------------------------
10                                        0.0                   0.4                   1.2                   1.5
----------------------------------------------------------------------------------------------------------------
Total Cost                                0.2                   4.8                  11.7                  16.7
----------------------------------------------------------------------------------------------------------------
Present Value of Total                    0.2                   4.2                  10.0                  14.4
 Discounted at 3 percent
----------------------------------------------------------------------------------------------------------------
Present Value of Total                    0.2                   3.6                   8.2                  12.0
 Discounted at 7 percent
----------------------------------------------------------------------------------------------------------------
\1\ Numbers may not sum due to rounding.
\2\ This estimate assumes that products with Medication Guides already conform to this requirement of the final
  rule.

2. Labeling Changes for New and Recently Approved Prescription Drug 
Products
    a. Affected products. The final rule would require that 
prescription drug labeling conform to format and content requirements 
for three categories of products: (1) All NDAs, BLAs, and efficacy 
supplements submitted to FDA on or after the effective date, (2) NDAs, 
BLAs, and efficacy supplements approved over the 5 years preceding the 
effective date or pending on the effective date of the final rule, and 
(3) any ANDA that references a listed drug with labeling conforming to 
the requirements of the final rule. For the first category of products, 
the prescription drug labeling requirements would apply when a sponsor 
files an NDA, BLA or efficacy supplement. Products in the second 
category must file supplemental applications within 3 to 7 years of the 
issuance of the rule, according to the implementation plan described in 
the preamble (see Table 5). For ANDA products (generic products), the 
implementation schedule for the affected reference listed drug applies. 
This rule does not cover labeling for OTC products (including those 
approved under an NDA).
    Estimates of the number of new applications that would be affected 
by the rule are updated and based on application approvals since 1997. 
During this period, an average of 97 NDAs and 10 BLAs were approved 
each year. FDA assumes that this average rate will continue. The number 
of affected products approved within 5 years before the effective date 
are estimated as the number of NDAs approved during the 5-year period 
from 1997 through 2001 without subsequent efficacy supplements.
    Most efficacy supplements are filed and approved within 5 years of 
the approval date of their original application. Over time, 
prescription drug labeling of most products affected by the final rule 
will already conform to the requirements of the final rule when an 
efficacy supplement is submitted. Beginning in year 3, therefore, the 
number of labeling revisions as a result of an efficacy supplement will 
decline over time.
    The initial analysis of impacts did not include estimates of the 
number of generic products that would be affected because the period of 
exclusivity for most innovator products covered by the rule would 
extend beyond the 10-year horizon. However, a subsequent analysis of 
data from ``Approved Drug Products with Therapeutic Equivalence 
Evaluations'' (the Orange Book) found that some older innovator 
products with generic equivalents have recent approvals of efficacy 
supplements or NDAs for new dosage strengths that could trigger 
revision of the labeling of some reference listed drugs. Although the 
overall number of older innovator products affected by the final rule 
is anticipated to be small, normally there are multiple generic 
products for each reference listed drug. Therefore, beginning in year 
3, the final rule is estimated to affect an average of 42 generic 
products annually. Table 14 shows the number of products projected to 
be affected by the final rule during the 10-year period following the 
effective date.

                      Table 14.--Estimated Number of Affected Products by Application Type
----------------------------------------------------------------------------------------------------------------
                                                              Approvals 5 Years
     Year         New NDAs and BLAs   Efficacy Supplements   Prior to Effective        ANDAs           Total
                                                                    Date
----------------------------------------------------------------------------------------------------------------
1                             107                    69                     0               0             176
----------------------------------------------------------------------------------------------------------------

[[Page 3978]]

 
2                             107                    69                     0               0             176
----------------------------------------------------------------------------------------------------------------
3                             107                    52                    69              42             270
----------------------------------------------------------------------------------------------------------------
4                             107                    39                    69              42             257
----------------------------------------------------------------------------------------------------------------
5                             107                    29                    68              42             246
----------------------------------------------------------------------------------------------------------------
6                             107                    22                    69              42             240
----------------------------------------------------------------------------------------------------------------
7                             107                    16                    69              42             234
----------------------------------------------------------------------------------------------------------------
8                             107                    12                     0              42             161
----------------------------------------------------------------------------------------------------------------
9                             107                     9                     0              42             158
----------------------------------------------------------------------------------------------------------------
10                            107                     7                     0              42             156
----------------------------------------------------------------------------------------------------------------
Total                       1,070                   324                   344             336           2,074
----------------------------------------------------------------------------------------------------------------

    b. Prescription drug labeling design costs. The cost of designing 
prescription drug labeling that conforms to the final format and 
content requirements will depend heavily on when, during a product's 
life cycle, labeling design occurs. Costs will be highest for products 
already marketed with approved prescription drug labeling that 
otherwise would not be changed. Conversely, design costs will be lowest 
for products that are closely related to a prior product application 
that has already had its prescription drug labeling changed to the new 
format or for generic drug labeling. Costs for currently marketed 
products that would be undergoing relabeling for other reasons (e.g., 
related to an efficacy supplement) will be in between these extremes.
    FDA has previously estimated that it takes about 2 months of full-
time effort to design a novel patient information guide (for the first 
prescription drug in a therapeutic class), but less than 1 week to 
redesign a guide following a previously approved prototype (i.e., 
innovator drugs in the same therapeutic class for which patient 
information was already developed) (60 FR 44232). The final rule 
requires reordering of the detailed information in the prescription 
drug labeling and addition of Highlights and Contents. Although FDA 
designates the new order, detailed discussion and drug-specific 
decisions (e.g., regarding exactly what should be listed in Highlights) 
may be necessary. Because negotiation of labeling is a routine part of 
the review process, including Highlights and Contents does not increase 
this time burden on manufacturers or the agency. Therefore, the time 
required to revise labeling conforming to the requirements of the final 
rule will fall between the time required to design a novel patient 
information guide and time required to redesign a guide. Although 
sponsors of new applications and efficacy supplements would incur many 
of the same design costs as sponsors of existing innovator products, 
they would experience no additional testing, preparation, and 
application costs. For the initial analysis, it was anticipated that 
manufacturers would incur one-time costs up to $5,000 for each new 
product and $7,500 for each existing product to conform to the format 
and content provisions of the rule (65 FR 81082 at 81106 through 
81107). These one-time per product costs are updated to $6,190 and 
$8,700, respectively. Modifying prescription drug labeling for ANDAs is 
anticipated to cost generic drug manufacturers about $1,300 per 
product, including $830 in labor costs and $470 in material costs for 
artwork and scrap (68 FR 6062 at 6074).
    Once product labeling contains Highlights, any substantive 
revisions of key sections of the labeling must be listed in the recent 
major changes section along with the month and year the revision was 
incorporated. However, the final rule also requires that after 1 year, 
the information about recent major changes must be removed the next 
time the labeling is reprinted. Manufacturers voluntarily change drug 
product labeling frequently during the first 5 years a product is 
marketed. During this period, the agency anticipates that manufacturers 
would remove recent major changes from Highlights at the same time they 
voluntarily change labeling and, thus, would incur no additional costs. 
After 5 years on the market, however, some manufacturers would incur 
additional costs to remove recent major changes in the timeframe 
specified by the final rule. The earliest this might occur is in year 7 
after the initial redesign of the labeling.\15\ Based on the agency's 
experience with products that have been on the market for more than 5 
years, up to 10 percent of the products affected by the final rule 
might be required to remove recent major changes in year 7 or later, at 
a per product cost of approximately $1,600. Over 10 years, the present 
value of these costs could equal about $0.1 million with either a 7 
percent or 3 percent discount rate.
---------------------------------------------------------------------------

    \15\ Recent major changes must remain in the Highlights for at 
least 1 year. Any major change after year 5 would therefore remain 
on the labeling through year 6 or later.
---------------------------------------------------------------------------

    As shown in table 15, the total first-year costs would amount to 
$1.1 million. Costs increase to a high of $1.6 million in years 3 and 
4. After the seventh year, when all products approved within 5 years 
prior to the rule's effective date or pending on the effective date 
have redesigned prescription drug labeling, the costs decline to about 
$0.8 million per year. As a result, the estimated total present value 
of the costs of redesigning prescription drug labeling over 10 years is 
about $8.8 million and $10.5 million with a 7 and 3 percent discount 
rate, respectively.

[[Page 3979]]



                                             Table 15.--Estimated Prescription Drug Labeling Design Costs\1\
--------------------------------------------------------------------------------------------------------------------------------------------------------
                                                                  Current Value ($ million)                               Present Value ($ million)
                                         ---------------------------------------------------------------------------------------------------------------
                  Year                                                   Approvals 5 Years
                                           NDAs and        Efficacy           Prior to         ANDAs       Total     Total Discounted   Total Discounted
                                             BLAs        Supplements       Effective Date                              at 3 percent       at 7 percent
--------------------------------------------------------------------------------------------------------------------------------------------------------
1                                               0.7                0.4                0.0         0.0         1.1                1.1                1.0
--------------------------------------------------------------------------------------------------------------------------------------------------------
2                                               0.7                0.4                0.0         0.0         1.1                1.0                1.0
--------------------------------------------------------------------------------------------------------------------------------------------------------
3                                               0.7                0.3                0.6         0.1         1.6                1.5                1.3
--------------------------------------------------------------------------------------------------------------------------------------------------------
4                                               0.7                0.2                0.6         0.1         1.6                1.4                1.2
--------------------------------------------------------------------------------------------------------------------------------------------------------
5                                               0.7                0.2                0.6         0.1         1.5                1.3                1.1
--------------------------------------------------------------------------------------------------------------------------------------------------------
6                                               0.7                0.1                0.6         0.1         1.5                1.2                1.0
--------------------------------------------------------------------------------------------------------------------------------------------------------
7                                               0.7                0.1                0.6         0.1         1.5                1.2                0.9
--------------------------------------------------------------------------------------------------------------------------------------------------------
8                                               0.7                0.1                0.0         0.1         0.8                0.7                0.5
--------------------------------------------------------------------------------------------------------------------------------------------------------
9                                               0.7                0.1                0.0         0.1         0.8                0.6                0.4
--------------------------------------------------------------------------------------------------------------------------------------------------------
10                                              0.7                0.0                0.0         0.1         0.8                0.6                0.4
--------------------------------------------------------------------------------------------------------------------------------------------------------
Total                                           6.7                2.0                3.0         0.4        12.2               10.5                8.8
--------------------------------------------------------------------------------------------------------------------------------------------------------
\1\ Numbers may not sum due to rounding.

    c. Costs associated with producing longer labeling accompanying 
drug products and drug samples (trade labeling). The proposed rule 
would have required that trade labeling be printed in 8-point minimum 
type size, almost doubling the current average length for the labeling. 
Several comments from pharmaceutical manufacturers stated that the 
agency had underestimated the retooling and packaging line costs that 
would be incurred to include this longer trade labeling (see comment 
124). A few large firms estimated that new equipment would cost between 
$135,000 and $700,000 per packaging line and could total up to $40 
million for a large firm if trade labeling of all products were 
affected. As discussed in section XI.F of this document (``Alternatives 
Considered''), the agency recognized that including all products in the 
final rule would substantially increase costs to industry and, 
therefore, limited the final rule to new and recently approved products 
(see section XI.F.3 of this document). Furthermore, approximately half 
of the affected products shown in table 14 will be new approvals that 
have not yet established packaging. Nevertheless, based on the 
potential economic impact the larger type size might have on 
pharmaceutical manufacturers, for the final rule the agency reduced the 
minimum size requirement for trade labeling to 6 points, a size 
generally reported as acceptable in comments from manufacturers (see 
comment 102). Thus, the new format and content requirements of the 
final rule will lengthen trade labeling by approximately 20 square 
inches when printed on two sides. Longer prescription drug labeling 
increases the cost of paper, ink, and other ongoing incremental 
printing costs. As discussed below, even in 6 points, a small number of 
products are still expected to incur some equipment costs (e.g., 
different insert-folding machinery).
    i. Incremental printing costs for trade labeling. U.S. retail 
pharmacies dispense about 3.3 billion prescriptions per year, of which 
an estimated 790 million are for unit-of-use products that include 
prescription drug labeling within the package (65 FR 81082 at 81107, 
updated using IMS data at http://www.ims-health.com). If the non-unit-
of-use prescriptions average one piece of labeling per 3.3 
prescriptions, the total number of labelings accompanying retail 
products equals roughly 1.5 billion. Further, adding hospital 
pharmaceutical volume, estimated at approximately 54 percent of retail 
volume, yields an annual total of 2.4 billion pieces of trade labeling 
accompanying prescribed products. Allowing 10 percent for wastage 
indicates that manufacturers distribute roughly 2.6 billion pieces of 
labeling with prescribed products each year. Since 60 percent of all 
prescriptions are for branded products, about 1.6 billion pieces of 
labeling are currently included with about 2,440 branded products and 
about 1.0 billion pieces are included with 2,900 generic products.\16\ 
Using 650,000 pieces per innovator product and 370,000 pieces per 
generic product, at a cost of $0.18 and $0.19 per 100 pieces, 
respectively, yields annual per product cost estimates of $1,165 and 
$700, respectively. Table 16 shows the estimated number of revised 
labelings and annual incremental printing costs over 10 years.
---------------------------------------------------------------------------

    \16\ Derived from ``Approved Drug Products with Therapeutic 
Equivalence Evaluations,'' CDER, FDA, 2001. The estimate is a count 
of all branded products marketed under an NDA and differentiated by 
active ingredient, therapeutic equivalence, dosage form, or 
manufacturer, not including multiple dosage strengths. Although not 
counted, adding biologicals would not significantly alter results.
---------------------------------------------------------------------------

    Trade labeling must also accompany drug product samples. However, 
the number of samples distributed for a specific product depends on a 
manufacturer's marketing strategy and may vary from year to year. 
Although IMS Health (IMS) reported that the volume of samples 
distributed in the United States between 1997 and 2000 ranged from 860 
million to 920 million (Ref. 36), sales representatives normally leave 
one piece of labeling for every 10 samples they distribute. Even though 
new products are sampled more often than older products, some 
manufacturers continue to distribute samples throughout the life cycle 
of their product. While the actual number of samples including 
reformatted trade labeling is uncertain, we anticipate that 
manufacturers may spend up to $0.2

[[Page 3980]]

million annually to print longer trade labeling to accompany drug 
samples (table 16).
[GRAPHIC] [TIFF OMITTED] TR24JA06.002

    ii. Equipment costs. The original analysis estimated that 1 percent 
of affected existing products would be required to adjust packaging 
equipment with trade labeling printed in 8 points. According to several 
comments, trade labeling is currently printed in type sizes of 4.5 
points and larger (see comment 102). Thus, it is unlikely that the 
minimum type size requirement of the final rule (i.e., 6 points for 
trade labeling) will require firms to purchase new packaging equipment. 
However, in a few cases where existing labeling is printed in type 
sizes between 4.5 points and 6 points, firms may need to adjust 
packaging lines for longer labeling. Since the labeling of many 
ophthalmic drug products is printed in type sizes smaller than 6 
points, the proportion of recent approvals for ophthalmic products was 
used as a proxy for the proportion of affected products that will incur 
some equipment costs. For the final analysis, 5 percent of existing 
products affected by the rule (i.e., products with new efficacy 
supplements, products approved in the 5 years prior to the effective 
date of the rule, and affected ANDAs) will incur costs of $200,000 each 
product. As shown in table 17, the estimated present value of equipment 
changes totals $7.2 million and $8.7 million over 10 years discounted 
at 7 and 3 percent respectively.

                              Table 17.--Cost of Adjustments to Packaging Lines to Accommodate Longer Trade Labeling\1, 2\
--------------------------------------------------------------------------------------------------------------------------------------------------------
                                                                                                               Present Value ($ million)
                                             Estimated Number of Affected    Total Cost  ($  -----------------------------------------------------------
                    Year                                Products                million)          Total Discounted at 3         Total Discounted at 7
                                                                                                         Percent                       Percent
--------------------------------------------------------------------------------------------------------------------------------------------------------
1                                                                    3                  0.7                           0.7                           0.6
--------------------------------------------------------------------------------------------------------------------------------------------------------
2                                                                    3                  0.7                           0.7                           0.6
--------------------------------------------------------------------------------------------------------------------------------------------------------
3                                                                    8                  1.6                           1.5                           1.3
--------------------------------------------------------------------------------------------------------------------------------------------------------
4                                                                    8                  1.5                           1.3                           1.1
--------------------------------------------------------------------------------------------------------------------------------------------------------
5                                                                    7                  1.4                           1.2                           1.0
--------------------------------------------------------------------------------------------------------------------------------------------------------
6                                                                    7                  1.3                           1.1                           0.9
--------------------------------------------------------------------------------------------------------------------------------------------------------
7                                                                    6                  1.3                           1.0                           0.8
--------------------------------------------------------------------------------------------------------------------------------------------------------
8                                                                    3                  0.5                           0.4                           0.3
--------------------------------------------------------------------------------------------------------------------------------------------------------
9                                                                    3                  0.5                           0.4                           0.3
--------------------------------------------------------------------------------------------------------------------------------------------------------
10                                                                   2                  0.5                           0.4                           0.2
--------------------------------------------------------------------------------------------------------------------------------------------------------

[[Page 3981]]

 
Total                                                               50                 10.0                           8.7                           7.2
--------------------------------------------------------------------------------------------------------------------------------------------------------
\1\ Numbers may not sum due to rounding.
\2\ For products with labeling printed in type sizes smaller than 6 points, the final rule may require that some packaging lines be retooled. Based on
  NDA, ANDA or efficacy supplements approvals for ophthalmic drug products between 1997 and 2001, an estimated 5 percent of the existing products
  affected by the rule will require some change to packaging equipment at an average cost of $200,000 per product.

    d. Layout and design costs for prescription drug labeling not 
accompanying drug products. The final rule specifies a minimum type 
size of 6 points for trade labeling and 8 points for all other 
prescription drug labeling distributed by a manufacturer (e.g., 
labeling required to be distributed with promotional materials or in 
promotional settings). Firms choosing to print all prescription drug 
labeling for a product in the same type size (8 points or larger) will 
incur no additional design costs. However, if trade labeling is printed 
in a type size smaller than 8 points, a firm will incur additional 
costs of $810 per product to change and proof read the layout, and to 
prepare artwork for the labeling not accompanying the drug product. It 
is uncertain how many firms will print labeling in different type 
sizes. However, if all new and recently approved innovator products are 
affected, the total present value of the additional design costs is 
approximately $1.0 million or $1.2 million over 10 years discounted at 
7 or 3 percent respectively (table 18).

                         Table 18.--Estimated One-Time Layout and Design Costs for Labeling Not Accompanying Drug Products\1,2\
--------------------------------------------------------------------------------------------------------------------------------------------------------
                                                                                                               Present Value ($ million)
                                                                            Total Costs  ($  -----------------------------------------------------------
                  Year                      Number of Affected  Products        million)          Total Discounted at 3         Total Discounted at 7
                                                                                                         Percent                       Percent
--------------------------------------------------------------------------------------------------------------------------------------------------------
1                                                                  176                  0.1                           0.1                           0.1
--------------------------------------------------------------------------------------------------------------------------------------------------------
2                                                                  176                  0.1                           0.1                           0.1
--------------------------------------------------------------------------------------------------------------------------------------------------------
3                                                                  228                  0.2                           0.2                           0.2
--------------------------------------------------------------------------------------------------------------------------------------------------------
4                                                                  215                  0.2                           0.2                           0.1
--------------------------------------------------------------------------------------------------------------------------------------------------------
5                                                                  204                  0.2                           0.1                           0.1
--------------------------------------------------------------------------------------------------------------------------------------------------------
6                                                                  198                  0.2                           0.1                           0.1
--------------------------------------------------------------------------------------------------------------------------------------------------------
7                                                                  192                  0.2                           0.1                           0.1
--------------------------------------------------------------------------------------------------------------------------------------------------------
8                                                                  119                  0.1                           0.1                           0.1
--------------------------------------------------------------------------------------------------------------------------------------------------------
9                                                                  116                  0.1                           0.1                           0.1
--------------------------------------------------------------------------------------------------------------------------------------------------------
10                                                                 114                  0.1                           0.1                           0.0
--------------------------------------------------------------------------------------------------------------------------------------------------------
Total                                                            1,738                  1.4                           1.2                           1.0
--------------------------------------------------------------------------------------------------------------------------------------------------------
\1\ Firms are expected to only print this type of labeling for 3 years after the launch of a new innovator drug product.
\2\ Numbers may not sum due to rounding.

    e. Costs associated with producing longer prescription drug 
labeling not accompanying drug products. In contrast to trade labeling, 
with the new content and format requirements the length of current 
labeling will increase an average of about 93 percent when printed in 
8-point type size. At this length, the incremental printing costs will 
increase by $0.85 per 100 pieces. To calculate the annual cost to print 
prescription drug labeling not accompanying drug products, FDA 
estimated that pharmaceutical representatives detailing drug products 
would distribute approximately 50 million pieces of prescription drug 
labeling annually. Because most detailing involves relatively new 
products, the products most affected by this rule, FDA assumed that 
manufacturers would incur additional printing costs for all of this 
labeling, amounting to about $0.4 million annually.
    Finally, FDA estimated that about 730,000 pieces of prescription 
drug labeling per approval would be distributed each year by mail or at 
conferences to physicians, other health care practitioners, consumers, 
retail pharmacy outlets, and hospital pharmacies for 3 years following 
approval of a new drug.\17\ As shown in table 19, annual total costs 
peak at $4.4 million in year 5. Over 10 years with a 7 or 3 percent 
discount rate, the present value of the incremental printing costs

[[Page 3982]]

for longer prescription drug labeling not accompanying drug products 
would be about $24 million or $29 million, respectively.
---------------------------------------------------------------------------

    \17\ For each approval, it was assumed that all physicians 
involved in primary care and 25 percent of physicians practicing a 
medical specialty would receive two mailings per year, or an 
estimated 646,150 pieces (i.e., (222,400 x 2) + (0.25 x 402,700 x 
2)), for 3 years following product launch. An additional 10 percent 
or 64,615 pieces are estimated to be distributed annually for 3 
years to other health care practitioners or consumers. Furthermore, 
FDA assumes that 55,581 retail pharmacy outlets and 8,020 hospital 
pharmacies would receive 1 mailing to announce the launch of a new 
innovator product in the year of approval (65 FR 81082 at 81108, 
updated).
[GRAPHIC] [TIFF OMITTED] TR24JA06.003

    f. Physicians' Desk Reference (PDR) Costs. FDA estimates that the 
new Highlights, including any boxed warnings, and Contents would add 
about a half page to the PDR labeling of each affected prescription 
drug product. Based on conversations with Medical Economics (the 
publisher of the PDR) on the cost per printed page, FDA estimates that 
the annual publishing costs of the extra space required for printing 
the expanded prescription drug labeling would be about $5,550 for each 
affected product, plus an additional cost if the product was included 
in one of two annual supplements. FDA assumed that these costs would be 
incurred by the pharmaceutical industry via publishing fees paid to 
Medical Economics. The agency assumed that 75 percent of the new drugs 
and efficacy supplements would be published in the PDR (some smaller 
firms decline to publish labeling in the PDR). FDA also assumed that 90 
percent of the new drugs published would be included in the PDR 
supplements and 33 percent of the published efficacy supplements would 
be included in the PDR supplements (about half are actually included, 
but only two-thirds of these include full prescription drug labeling; 
the remainder include only the added indication). FDA also assumed that 
the prescription drug labeling changes made as a result of the 5-year 
rule (applications approved in the 5 years preceding the effective date 
of the final rule) would not be included in the PDR supplements. Based 
on these assumptions, the estimated cost of publishing the extended 
prescription drug labeling in the PDR would be about $1.2 million for 
year 1. These costs would continue to increase over time as all drug 
approvals after the effective date of the rule would have longer PDR 
listings. The estimated annual and total costs of printing longer PDR 
listings are shown in table 20.

                                                Table 20.--Cost To Print Longer Listings in the PDR\1, 2\
--------------------------------------------------------------------------------------------------------------------------------------------------------
                                                     Current Value ($ million)                                 Present Value ($ million)
                                     -------------------------------------------------------------------------------------------------------------------
                Year                                                                              Total Discounted at 3         Total Discounted at 7
                                        PDR Bound         PDR Supplement         Total Costs             Percent                       Percent
--------------------------------------------------------------------------------------------------------------------------------------------------------
1                                             0.7                         0.5           1.2                           1.2                           1.1
--------------------------------------------------------------------------------------------------------------------------------------------------------
2                                             1.5                         0.5           2.0                           1.8                           1.7
--------------------------------------------------------------------------------------------------------------------------------------------------------
3                                             2.4                         0.5           2.9                           2.6                           2.4
--------------------------------------------------------------------------------------------------------------------------------------------------------

[[Page 3983]]

 
4                                             3.3                         0.5           3.8                           3.3                           2.9
--------------------------------------------------------------------------------------------------------------------------------------------------------
5                                             4.2                         0.4           4.6                           4.0                           3.3
--------------------------------------------------------------------------------------------------------------------------------------------------------
6                                             5.0                         0.4           5.4                           4.5                           3.6
--------------------------------------------------------------------------------------------------------------------------------------------------------
7                                             5.8                         0.4           6.2                           5.0                           3.9
--------------------------------------------------------------------------------------------------------------------------------------------------------
8                                             6.3                         0.4           6.7                           5.3                           3.9
--------------------------------------------------------------------------------------------------------------------------------------------------------
9                                             6.8                         0.4           7.2                           5.5                           3.9
--------------------------------------------------------------------------------------------------------------------------------------------------------
10                                            7.2                         0.4           7.6                           5.7                           3.9
--------------------------------------------------------------------------------------------------------------------------------------------------------
Total                                        43.1                         4.5          47.6                          39.1                          30.5
--------------------------------------------------------------------------------------------------------------------------------------------------------
\1\ Numbers may not sum due to rounding.
\2\ Printed in 6.5-point type size at an average per page cost of $9,755.

    Table 21 summarizes the estimated compliance costs for the three 
major cost categories over a 10-year period.

                               Table 21.--Compliance Costs Over 10-Year Period\1\
----------------------------------------------------------------------------------------------------------------
                                             Cost Category ($ million)
             ----------------------------------------------------------------------------------------    Total
    Year           Design and Producing Trade                                                          Costs  ($
                   Labeling; Modify Packaging      Reformat and Producing Labeling Not  Printing PDR   million)
                           Equipment                    Accompanying Drug Products
----------------------------------------------------------------------------------------------------------------
1                                            3.1                                  1.7           2.4         7.3
----------------------------------------------------------------------------------------------------------------
2                                            3.1                                  2.8           3.1         9.0
----------------------------------------------------------------------------------------------------------------
3                                            4.9                                  4.2           4.1        13.2
----------------------------------------------------------------------------------------------------------------
4                                            4.6                                  4.4           4.9        13.9
----------------------------------------------------------------------------------------------------------------
5                                            4.6                                  4.6           5.8        15.0
----------------------------------------------------------------------------------------------------------------
6                                            4.8                                  4.4           6.6        15.8
----------------------------------------------------------------------------------------------------------------
7                                            5.0                                  4.3           7.4        16.6
----------------------------------------------------------------------------------------------------------------
8                                            3.8                                  3.6           7.9        15.3
----------------------------------------------------------------------------------------------------------------
9                                            4.0                                  3.1           8.3        15.5
----------------------------------------------------------------------------------------------------------------
10                                           4.0                                  2.7           8.8        15.5
----------------------------------------------------------------------------------------------------------------
Total                                       42.0                                 35.9          59.3       137.2
 Current
 Value
----------------------------------------------------------------------------------------------------------------
Total                                       35.7                                 30.5          49.0       115.3
 Present
 Value
 Discounted
 at 3
 Percent
----------------------------------------------------------------------------------------------------------------
Total                                       29.2                                 24.9          38.8        92.9
 Present
 Value
 Discounted
 at 7
 Percent
----------------------------------------------------------------------------------------------------------------
\1\ Numbers may not sum due to rounding.

E. Impacts on Small Entities

1. The Need for and the Objective of the Rule
    Developments in recent years have contributed to an increase in the 
length and complexity of prescription drug labeling, making it more 
difficult for health care practitioners to quickly find specific 
information about a drug. Therefore, practitioners expend time that 
could be spent with patients and may miss critical information about 
the safe and effective use of prescription drug products. The objective 
of the requirements is to improve prescription drug labeling by making 
it easier for health care practitioners to access, read, and use 
labeling information about prescription drug products. The agency 
believes that having better access to critical information will improve 
the use of prescription drugs and lead to a decrease in the number of 
preventable adverse reactions that occur in the United States each 
year.

[[Page 3984]]

2. Description and Estimate of the Number of Small Entities Affected
    This final rule would affect all small entities required to design 
their prescription drug labeling to comply with this rule. The Small 
Business Administration (SBA) considers Pharmaceutical Preparation 
Manufacturing firms (NAICS 325412) and Biological Product Manufacturing 
firms (NAICS 325414) with fewer than 750 and 500 employees, 
respectively, to be small. U.S. Census reports in 1999 there were 265 
biological product manufacturing firms (Ref. 37) and 749 pharmaceutical 
preparation manufacturing firms (Ref. 38). However, employment size 
classes for pharmaceutical preparation manufacturing do not correspond 
to SBA size categories. Nevertheless, 1999 Census data suggest that 
approximately 94 percent of biological product manufacturing firms and 
at least 87 percent of the pharmaceutical preparation manufacturing 
firms could be considered small. Despite the large number of small 
manufacturers, large companies manufacture most prescription drug 
products. Although the agency cannot predict the number of new 
approvals granted to small entities, the following estimates are based 
on 5 years of recent submissions (65 FR 81082 at 81110, updated for 
1997-2001). On average, 17 small entities will receive product 
approvals each year. In addition, about 64 small entities will be 
affected during years 3 to 7 of the rule, when applicants with products 
approved 5 years prior to the effective date of the final rule must 
submit reformatted prescription drug labeling for approval. Only six 
firms will have more than two existing products affected by the rule. 
Of these six, four firms will have two products affected in the same 
year and one firm will have three products affected in a single year.
    The compliance requirements for small entities under this final 
rule are the same as those described above for other affected entities. 
Compliance primarily involves: (1) designing prescription drug labeling 
that conforms to the content and format requirements, and (2) once the 
labeling is approved by FDA, ensuring that all future printed 
prescription drug labeling is in the new format with the required 
minimum type size. Because manufacturers already submit labeling with 
NDAs, BLAs and efficacy supplements to FDA, no additional skills will 
be required to comply with the final rule.
    The group of small entities likely to bear the highest total costs 
under this final rule are those firms that have: (1) Existing products 
with prescription drug labeling that must be revised in the first year 
or (2) more than one affected high-volume product per year, such as a 
small firm with two or three recently approved, high-volume products 
that must undergo prescription drug labeling reformatting 
simultaneously in the same year. However, the high-cost small entities 
are also the small firms with the highest sales of affected product; 
thus, their incremental cost per unit sold is likely to be relatively 
low. In contrast, small firms with a single, low-volume product would 
have lower costs of compliance, but the incremental cost per unit sold 
would be higher.
    Although the agency solicited comment on the initial regulatory 
flexibility analysis from small entities, the only comments submitted 
specifically about the impact on small entities were from large firms 
(see comment 122). The following examples illustrate possible impacts 
on small entities with different production volumes. Prescription drug 
labeling costs are estimated for a small firm with a single carton-
enclosed product (marketed under an NDA) that must: (1) Have its 
labeling reformatted in year 3 of the rule and (2) add patient 
information in year 1. Table 22 outlines the projected per-unit and 
total costs to the firm with 3 different levels of production: 1,000, 
10,000, and 100,000 units produced per year.
    In addition to the costs identified in table 22, a very small 
number of small firms might incur equipment costs to include longer 
prescription drug labeling in carton-enclosed products. It is likely, 
however, that this one-time capital cost (estimated at $200,000) will 
affect a total of no more than two or three small firms in the 10 years 
following implementation of the rule. Based on this analysis, FDA 
believes that the final rule would not have a significant impact on 
most small entities in this industry, but it is possible that a few 
small firms may be significantly affected by the final rule.

 Table 22.--Estimated Costs for Hypothetical Small Firm with a Single Product, Under Three Alternative Levels of
                                                  Production\1\
----------------------------------------------------------------------------------------------------------------
                                                           Number of Units Produced and Sold Each Year
                 Cost Category                 -----------------------------------------------------------------
                                                       100,000               10,000                 1,000
----------------------------------------------------------------------------------------------------------------
Example 1--Revise labeling of product approved  ....................  ....................  ....................
 less than 1 year prior to effective date:
Prescription drug labeling redesign/                       $8,700                $8,700                $8,700
 application
Printing trade labeling\2\                                   $200                   $20                    $2
Printing prescription drug labeling not                    $1,050                  $105                   $10
 accompanying drug products\3\
----------------------------------------------------------------------------------------------------------------
Total                                                      $9,950                $8,825                $8,712
----------------------------------------------------------------------------------------------------------------
Additional cost per unit sold                                  $0.10                 $0.88                 $8.71
----------------------------------------------------------------------------------------------------------------
Example 2--Add printed patient information to   ....................  ....................  ....................
 existing labeling for a product:
Prescription drug labeling redesign                        $2,850                $2,850                $2,850
Printing trade labeling\4\                                   $750                   $75                    $8
Printing longer PDR\5\                                    $19,500               $19,500                   N/A
----------------------------------------------------------------------------------------------------------------
Total                                                     $23,100               $22,425                $2,858
----------------------------------------------------------------------------------------------------------------
Additional cost per unit sold                                  $0.23                 $2.24                 $2.86
----------------------------------------------------------------------------------------------------------------
\1\ Numbers may not sum due to rounding.
\2\ Number of pieces of trade labeling printed is calculated as units produced/year plus 10 percent wastage
  factor, at an incremental printing cost of $0.001791 per labeling.

[[Page 3985]]

 
\3\ To calculate the cost for printing labeling not accompanying drug products, the number of units is adjusted
  by the ratio of the average number of pieces printed for mailings to the average number printed as trade
  labeling (i.e., 1.126), and multiplied by the incremental printing cost of $0.0085 per piece.
\4\ Number of pieces of trade labeling printed is calculated as units produced/year plus 10 percent wastage
  factor, at an incremental printing cost of $0.006837 per labeling.
\5\ Assume that prescription drug labeling is already being printed in the PDR. Most low-volume products (i.e.,
  less than 10,000 units per year) will not have labeling in the PDR.

F. Alternatives Considered

1. Do Nothing
    The agency considered and rejected this option. The current 
prescription drug labeling is complex, requiring health care 
practitioners to spend unnecessary time seeking information they need 
for the safe and effective use of drug products by their patients. 
Preventable adverse reactions have many causes and are a serious public 
health issue. Changing prescription drug labeling to meet the needs of 
health care practitioners that use it is one of many public health 
initiatives aimed at reducing these adverse reactions and improving 
health care.
2. Formatting Alternatives
    FDA has considered numerous alternative formats, including a longer 
Highlights. Highlights is limited to one-half page in 8 points to 
respond to health care practitioners' concerns about length as well as 
to reduce the incremental printing costs to manufacturers.
    The agency also considered requiring larger minimum type sizes. A 
10-point minimum size requirement would increase the amount of paper 
needed to print the average reformatted labeling by about 200-square 
inches at an incremental cost of $18,000 per million pieces. Over 10 
years, the total present value of producing longer trade labeling in 10 
points compared to 6 points would equal $95 million or $120 million 
with a 7- or 3-percent discount rate, respectively. In addition to 
higher incremental printing costs, requiring 10-point minimum type size 
would make labeling so large that many manufacturers would be forced to 
modify or replace packaging equipment. The agency therefore rejected 
this option because the potential benefits of the larger type size did 
not outweigh the costs.
    The agency also considered and rejected a 10-point minimum size 
requirement for labeling not accompanying drug products. Compared to 
the minimum requirement of 8 points in the final rule, this larger type 
size would have taken about 100-square inches more paper at an 
incremental cost of $9,000 per million pieces.
    Finally, the agency proposed a minimum size requirement of 8 points 
for trade labeling instead of the 6-point requirement in the final 
rule. At 6 points, the average revised labeling will increase by about 
20-square inches. Requiring the larger minimum size would take another 
70-square inches of paper and cost industry about $6,000 per million 
pieces of trade labeling. Because this requirement would be burdensome 
on industry, the agency rejected the 8-point minimum type size.
3. Alternative Categories of Affected Products
    Three alternative categories of products to be covered by the rule 
were considered: (1) All drugs, (2) a set of innovator and generic 
drugs on a ``top 200 most prescribed'' list, and (3) the ``top 100'' or 
``top 200'' drugs with the most adverse reactions. The agency believes 
including only labeling of new and more recently approved drug products 
is the best option for implementing the new format requirements (see 
comment 113). Even this limited set of products will require 
substantial resources from both industry and the agency for a period of 
several years. The agency's proposed implementation plan, which is 
being finalized in this rule as proposed, is intended to make the best 
use of these resources. Because there is a lack of standardized data on 
prescription volume and volumes can fluctuate considerably over time, 
the agency does not believe that categories based on volume would be 
prudent or feasible. As discussed in the preamble to the proposed rule 
(65 FR 81082 at 81098), the plan targets newer products because 
practitioners are more likely to refer to the labeling for newer 
products. Internal agency analysis finds that fully 40 percent of 
adverse reaction reports submitted to the FDA are for drugs approved 
within the last 3 years. Therefore, the agency rejected these three 
alternative categories in order to focus efforts on recently approved 
drug products whose labeling is more likely to be consulted by 
physicians.
4. Alternative Implementation Schedule
    FDA considered a shorter implementation schedule of 3 years after 
the effective date for all applications and efficacy supplements 
approved 5 years prior to the effective date. The agency selected the 
more gradual implementation schedule of up to 7 years to reduce the 
cost impact of the rule, especially on small entities.

XII. Civil Justice Reform

    This rule has been reviewed under Executive Order 12988, Civil 
Justice Reform. This regulation meets the applicable standards set 
forth in sections 3(a) and 3(b)(2) of Executive Order 12988.

XIII. References

    The following references have been placed on display in the 
Division of Dockets Management (HFA-305), Food and Drug Administration, 
5630 Fishers Lane, rm. 1061, Rockville, MD 20857, and may be seen by 
interested persons between 9 a.m. and 4 p.m., Monday through Friday. 
(FDA has verified the Web site addresses, but FDA is not responsible 
for any subsequent changes to the Web sites after this document 
publishes in the Federal Register.)
    1. Miller, G. A., ``The Magical Number Seven, Plus or Minus Two: 
Some Limits on Our Capacity for Processing Information,'' 
Psychological Review, 101(2):343-352, 1994.
    2. Shiffrin, R. M., and R. M. Nosofsky, ``Seven Plus or Minus 
Two: A Commentary On Capacity Limitations,'' Psychological Review, 
101(2):357-361, 1994.
    3. Allen, P. A., and L. C. Crozier, ``Age and Ideal Chunk 
Size,'' Journal of Gerontology: Psychological Sciences, 47(1):47-51, 
1992.
    4. Food and Drug Administration, ``Consumer Comprehension and 
Preference for Variations in the Proposed Over-the-Counter Drug 
Labeling Format,'' in OTC vol. 28, Docket No. 96N-0420, Division of 
Dockets Management.
    5. National Surveys of Prescription Medicine Information 
Received by Consumers, http://www.fda.gov/cder/ddmac/y2ktable.htm.
    http://www.fda.gov/cder/ddmac/y2kTITLE.htm.
    6. Kripalani, S., ``The Write Stuff: Simple Guidelines Can Help 
You Write and Design Effective Patient Education Materials,'' Texas 
Medicine, 91:40-45, 1995.
    7. Backinger, C. L., and P. A. Kingsley, ``Write It Right: 
Recommendations for Developing User Instructions for Medical Devices 
Used in Home Health Care,'' Department of Health and Human Services, 
Publication No. FDA 93-4258, 1993.
    8. Mettger, W., and J. Mara, ``Clear & Simple: Developing 
Effective Print Materials for Low-Literate Readers,'' Bethesda, MD, 
National Cancer Institute, Publication No. NIH 95-3594, 1994, http://oc.nci.nih.gov/services/Clear_and_Simple/HOME.htm.
    9. Silver, N. C., and C. C. Braun, ``Perceived Readability of 
Warning Labels

[[Page 3986]]

with Varied Font Sizes and Styles,'' Safety Science, 16:615-625, 
1993.
    10. Wilkins, A. G., and M. I. Nimmo-Smith, ``The Clarity and 
Comfort of Printed Text,'' Ergonomics, 30:1705-1720, 1987.
    11. Transcript of public meeting on prescription drug labeling, 
Docket No. 95N-0314, October 30, 1995.
    12. Eastern Research Group, Inc., ``Cost Impacts of the Over-
the-Counter Pharmaceutical Labeling Rule,'' appendix A, March 5, 
1999.
    13. Connelly, D. P. et al., ``Knowledge Resource Preferences of 
Family Physicians,'' Journal of Family Practice, 31(2):121-122, 
1990.
    14. Ely, J. W. et al., ``What Clinical Information Resources Are 
Available in Family Physicians' Offices?'' Journal of Family 
Practice, 48(2):135-139, 1999.
    15. Ely, J. W. et al., ``The Information Needs of Family 
Physicians: Case-Specific Clinical Questions,'' Journal of Family 
Practice, 35(3):265-269, 1992.
    16. Gorman, P., ``Information Needs in Primary Care: A Survey of 
Rural and Nonrural Primary Care Physicians,'' Medinfo, 10 (Pt. 
1):338-342, 2001.
    17. National Association of Chain Drug Stores, ``Industry Facts-
at-a-Glance--Rx Sales 2001,'' http://www.nacds.org/wmspage.cfm?parm1=507#rx (last viewed 8/27/02).
    18. U.S. Department of Labor, Bureau of Labor Statistics, ``2000 
National Occupational Employment and Wage Estimates--29-1051 
Pharmacists,'' http://www.bls.gov/oes/2000/oes291051.htm (last 
viewed 8/27/02).
    19. U.S. Department of Labor, Bureau of Labor Statistics, 
Occupational Outlook Handbook, 2002-03, Pharmacists (occupation code 
29-1051), 2002, http://www.bls.gov/oco/ocos079.htm (last viewed 9/
13/02).
    20. Jousimaa, J. et al., ``Physicians' Patterns of Using a 
Computerized Collection of Guidelines for Primary Care,'' 
International Journal of Technology Assessment in Health Care, 
14(3):484-493, 1998.
    21. U.S. Census Bureau, ``Table 153, Physicians by Selected 
Activity: 1980 to 1999,'' Statistical Abstract of the United States: 
2001, p. 106.
    22. U.S. Census Bureau, ``Table 157, Medical Practice 
Characteristics by Selected Specialty: 1985 to 1998,'' Statistical 
Abstract of the United States: 2001, p. 108.
    23. American Medical Association, ``Medical Education FAQs,'' 
http://www.ama-assn.org/ama/pub/category/3627.html (last viewed 9/
13/02).
    24. Woosley, R. L., ``Drug Labeling Revisions--Guaranteed to 
Fail?'' Journal of the American Medical Association, 284(23):3047-
3049, 2000.
    25. Friedman, M. A. et al., ``The Safety of Newly Approved 
Medicines: Do Recent Market Removals Mean There Is a Problem?'' 
Journal of the American Medical Association, 281(18):1728-1734, 
1999.
    26. U.S. General Accounting Office, ``Adverse Drug Events: The 
Magnitude of Health Risk Is Uncertain Because of Limited Incidence 
Data,'' GAO/HEHS-00-21, January, 2000.
    27. Bates, D. W. et al., ``Incidence of Adverse Drug Events and 
Potential Adverse Drug Events,'' Journal of the American Medical 
Association, 274(1):29-34, 1995.
    28. Classen, D. C. et al., ``Adverse Drug Events in Hospitalized 
Patients: Excess Length of Stay, Extra Costs, and Attributable 
Mortality,'' Journal of the American Medical Association 277(4):301-
306, 1997.
    29. Senst, B. L. et al., ``Practical Approach to Determining 
Costs and Frequency of Adverse Drug Events in a Health Care 
Network,'' American Journal of Health-Systems Pharmacy, 58:1126-
1132, 2001.
    30. 2000 hospital discharges data from the Agency for Health 
Care Policy and Research (AHCPR), June 25, 1998, http://www.ahrq.gov/HCUPnet.htm (last viewed 8/13/02).
    31. Bates, D. W. et al., ``The Costs of Adverse Drug Events in 
Hospitalized Patients,'' Journal of the American Medical 
Association, 277(4):307-311, 1997.
    32. Medical Group Management Association, AHRQ, CMS and 
Partnership for Patient Safety, ``Ambulatory Patient Safety: What Do 
We Know?'' An Agenda for Research in Ambulatory Patient Safety--
Synthesis of a Multidisciplinary Conference, 2000, http://www.ahcpr.gov/about/cpcr/ptsafety/ambpts2.htm (last viewed 10/10/
02).
    33. Thomas, E. J. et al., ``Costs of Medical Injuries in Utah 
and Colorado,'' Inquiry, 36:255-264, 1999.
    34. Johnson, J. A., and J. L. Bootman, ``Drug-Related Morbidity 
and Mortality: A Cost-of-Illness Model,'' Archives of Internal 
Medicine, 155:1949-1956, 1995.
    35. Ernst, F. R., and A. J. Grizzle, ``Drug-Related Morbidity 
and Mortality: Updating the Cost-of-Illness Model,'' Journal of the 
American Pharmaceutical Association, 41(2):192-199, 2001.
    36. IMS Health, ``Product Sampling Continues to Spike in U.S.,'' 
2001, http://www.imshealth.com/public/structure/dispcontent/1,2779,1362-1362-143626,00.html (last viewed 9/23/02).
    37. U.S. Census Bureau, ``Statistics of U.S. Businesses; 1999; 
Pharmaceutical preparation mfg, United States,'' http://www.census.gov/epcd/susb/1999/us/US325412.htm (last viewed 9/12/02).
    38. U.S. Census Bureau, ``Statistics of U.S. Businesses; 1999; 
Biological product (except diagnostic) mfg, United States,'' http://www.census.gov/epcd/susb/1999/us/US325414.htm (last viewed 9/12/02).

List of Subjects

21 CFR Part 201

    Drugs, Labeling, Reporting and recordkeeping requirements.

21 CFR Part 314

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

21 CFR 601

    Adminstrative practice and procedure, Biologics, Confidential 
business information.

0
Therefore, under the Federal Food, Drug, and Cosmetic Act and under 
authority delegated to the Commissioner of Food and Drugs, 21 CFR parts 
201, 314, and 601 are amended as follows:

PART 201--LABELING

0
1. The authority citation for 21 CFR part 201 continues to read as 
follows:

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

0
2. Section 201.56 is revised to read as follows:


Sec.  201.56   Requirements on content and format of labeling for human 
prescription drug and biological products.

    (a) General requirements. Prescription drug labeling described in 
Sec.  201.100(d) must meet the following general requirements:
    (1) The labeling must contain a summary of the essential scientific 
information needed for the safe and effective use of the drug.
    (2) The labeling must be informative and accurate and neither 
promotional in tone nor false or misleading in any particular. In 
accordance with Sec. Sec.  314.70 and 601.12 of this chapter, the 
labeling must be updated when new information becomes available that 
causes the labeling to become inaccurate, false, or misleading.
    (3) The labeling must be based whenever possible on data derived 
from human experience. No implied claims or suggestions of drug use may 
be made if there is inadequate evidence of safety or a lack of 
substantial evidence of effectiveness. Conclusions based on animal data 
but necessary for safe and effective use of the drug in humans must be 
identified as such and included with human data in the appropriate 
section of the labeling.
    (b) Categories of prescription drugs subject to the labeling 
content and format requirements in Sec. Sec.  201.56(d) and 201.57. (1) 
The following categories of prescription drug products are subject to 
the labeling requirements in paragraph (d) of this section and Sec.  
201.57 in accordance with the implementation schedule in paragraph (c) 
of this section:
    (i) Prescription drug products for which a new drug application 
(NDA), biologics license application (BLA), or efficacy supplement was 
approved by the Food and Drug Administration (FDA) between June 30, 
2001 and June 30, 2006;
    (ii) Prescription drug products for which an NDA, BLA, or efficacy 
supplement is pending on June 30, 2006; or
    (iii) Prescription drug products for which an NDA, BLA, or efficacy 
supplement is submitted anytime on or after June 30, 2006.

[[Page 3987]]

    (2) Prescription drug products not described in paragraph (b)(1) of 
this section are subject to the labeling requirements in paragraph (e) 
of this section and Sec.  201.80.
    (c) Schedule for implementing the labeling content and format 
requirements in Sec. Sec.  201.56(d) and 201.57. For products described 
in paragraph (b)(1) of this section, labeling conforming to the 
requirements in paragraph (d) of this section and Sec.  201.57 must be 
submitted according to the following schedule:
    (1) For products for which an NDA, BLA, or efficacy supplement is 
submitted for approval on or after June 30, 2006, proposed conforming 
labeling must be submitted as part of the application.
    (2) For products for which an NDA, BLA, or efficacy supplement is 
pending on June 30, 2006, or that has been approved any time from June 
30, 2005, up to and including June 30, 2006, a supplement with proposed 
conforming labeling must be submitted no later than June 30, 2009.
    (3) For products for which an NDA, BLA, or efficacy supplement has 
been approved anytime from June 30, 2004, up to and including June 29, 
2005, a supplement with proposed conforming labeling must be submitted 
no later than June 30, 2010.
    (4) For products for which an NDA, BLA, or efficacy supplement has 
been approved anytime from June 30, 2003, up to and including June 29, 
2004, a supplement with proposed conforming labeling must be submitted 
no later than June 30, 2011.
    (5) For products for which an NDA, BLA, or efficacy supplement has 
been approved anytime from June 30, 2002, up to and including June 29, 
2003, a supplement with proposed conforming labeling must be submitted 
no later than June 30, 2012.
    (6) For products for which an NDA, BLA, or efficacy supplement has 
been approved anytime from June 30, 2001, up to and including June 29, 
2002, a supplement with proposed conforming labeling must be submitted 
no later than June 30, 2013.
    (d) Labeling requirements for new and more recently approved 
prescription drug products. This paragraph applies only to prescription 
drug products described in paragraph (b)(1) of this section and must be 
implemented according to the schedule specified in paragraph (c) of 
this section.
    (1) Prescription drug labeling described in Sec.  201.100(d) must 
contain the specific information required under Sec.  201.57(a), (b), 
and (c) under the following headings and subheadings and in the 
following order:
Highlights of Prescribing Information
    Product Names, Other Required Information
    Boxed Warning
    Recent Major Changes
    Indications and Usage
    Dosage and Administration
    Dosage Forms and Strengths
    Contraindications
    Warnings and Precautions
    Adverse Reactions
    Drug Interactions
    Use in Specific Populations
Full Prescribing Information: Contents
Full Prescribing Information
    Boxed Warning
    1 Indications and Usage
    2 Dosage and Administration
    3 Dosage Forms and Strengths
    4 Contraindications
    5 Warnings and Precautions
    6 Adverse Reactions
    7 Drug Interactions
    8 Use in Specific Populations
     8.1 Pregnancy
     8.2 Labor and delivery
     8.3 Nursing mothers
     8.4 Pediatric use
     8.5 Geriatric use
    9 Drug Abuse and Dependence
     9.1 Controlled substance
     9.2 Abuse
     9.3 Dependence
    10 Overdosage
    11 Description
    12 Clinical Pharmacology
     12.1 Mechanism of action
     12.2 Pharmacodynamics
     12.3 Pharmacokinetics
    13 Nonclinical Toxicology
     13.1 Carcinogenesis, mutagenesis, impairment of fertility
     13.2 Animal toxicology and/or pharmacology
    14 Clinical Studies
    15 References
    16 How Supplied/Storage and Handling
    17 Patient Counseling Information
    (2) Additional nonstandard subheadings that are used to enhance 
labeling organization, presentation, or ease of use (e.g., for 
individual warnings or precautions, or for each drug interaction) must 
be assigned a decimal number that corresponds to their placement in 
labeling. The decimal numbers must be consistent with the standardized 
identifying numbers listed in paragraph (d)(1) of this section (e.g., 
subheadings added to the ``Warnings and Precautions'' section must be 
numbered 5.1, 5.2, and so on).
    (3) Any reference in Highlights to information appearing in the 
full prescribing information must be accompanied by the identifying 
number (in parentheses) corresponding to the location of the 
information in the full prescribing information.
    (4) Omit clearly inapplicable sections, subsections, or specific 
information. If sections or subsections required under paragraph (d)(1) 
of this section are omitted from the full prescribing information, the 
heading ``Full Prescribing Information: Contents'' must be followed by 
an asterisk and the following statement must appear at the end of 
Contents: ``* Sections or subsections omitted from the full prescribing 
information are not listed.''
    (5) Any risk information that is required under Sec.  
201.57(c)(9)(iv) is considered ``appropriate pediatric 
contraindications, warnings, or precautions'' within the meaning of 
section 505A(l)(2) of the Federal Food, Drug, and Cosmetic Act (the 
act) (21 U.S.C. 355A(l)(2)), whether such information appears in the 
``Contraindications,'' ``Warnings and Precautions,'' or ``Use in 
Specific Populations'' section of labeling.
    (e) Labeling requirements for older prescription drug products. 
This paragraph applies only to approved prescription drug products not 
described in paragraph (b)(1) of this section.
    (1) Prescription drug labeling described in Sec.  201.100(d) must 
contain the specific information required under Sec.  201.80 under the 
following section headings and in the following order:
    Description
    Clinical Pharmacology
    Indications and Usage
    Contraindications
    Warnings
    Precautions
    Adverse Reactions
    Drug Abuse and Dependence
    Overdosage
    Dosage and Administration
    How Supplied
    (2) The labeling may contain the following additional section 
headings if appropriate and if in compliance with Sec.  201.80(l) and 
(m):
    Animal Pharmacology and/or Animal Toxicology
    Clinical Studies
    References
    (3) Omit clearly inapplicable sections, subsections, or specific 
information.
    (4) The labeling may contain a ``Product Title'' section preceding 
the ``Description'' section and containing only the information 
required by Sec.  201.80(a)(1)(i), (a)(1)(ii), (a)(1)(iii), and 
(a)(1)(iv) and Sec.  201.100(e). The information required by Sec.  
201.80(a)(1)(i) through (a)(1)(iv) must appear in the

[[Page 3988]]

``Description'' section of the labeling, whether or not it also appears 
in a ``Product Title.''
    (5) The labeling must contain the date of the most recent revision 
of the labeling, identified as such, placed prominently immediately 
after the last section of the labeling.
    (6) The requirement in Sec.  201.80(f)(2) to reprint any FDA-
approved patient labeling at the end of prescription drug labeling or 
accompany the prescription drug labeling must be implemented no later 
than June 30, 2007.

0
3. Section 201.57 is redesignated as Sec.  201.80 and new Sec.  201.57 
is added 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).

    The requirements in this section apply only to prescription drug 
products described in Sec.  201.56(b)(1) and must be implemented 
according to the schedule specified in Sec.  201.56(c), except for the 
requirement in paragraph (c)(18) of this section to reprint any FDA-
approved patient labeling at the end of prescription drug labeling or 
accompany the prescription drug labeling, which must be implemented no 
later than June 30, 2007.
    (a) Highlights of prescribing information. The following 
information must appear in all prescription drug labeling:
    (1) Highlights limitation statement. The verbatim statement ``These 
highlights do not include all the information needed to use (insert 
name of drug product) safely and effectively. See full prescribing 
information for (insert name of drug product).''
    (2) Drug names, dosage form, route of administration, and 
controlled substance symbol. The proprietary name and the established 
name of the drug, if any, as defined in section 502(e)(3) of the 
Federal Food, Drug, and Cosmetic Act (the act) or, for biological 
products, the proper name (as defined in Sec.  600.3 of this chapter) 
including any appropriate descriptors. This information must be 
followed by the drug's dosage form and route of administration. For 
controlled substances, the controlled substance symbol designating the 
schedule in which the controlled substance is listed must be included 
as required by Sec.  1302.04 of this chapter.
    (3) Initial U.S. approval. The verbatim statement ``Initial U.S. 
Approval'' followed by the four-digit year in which FDA initially 
approved a new molecular entity, new biological product, or new 
combination of active ingredients. The statement must be placed on the 
line immediately beneath the established name or, for biological 
products, proper name of the product.
    (4) Boxed warning. A concise summary of any boxed warning required 
by paragraph (c)(1) of this section, not to exceed a length of 20 
lines. The summary must be preceded by a heading, in upper-case 
letters, containing the word ``WARNING'' and other words that are 
appropriate to identify the subject of the warning. The heading and the 
summary must be contained within a box and bolded. The following 
verbatim statement must be placed immediately following the heading of 
the boxed warning: ``See full prescribing information for complete 
boxed warning.''
    (5) Recent major changes. A list of the section(s) of the full 
prescribing information, limited to the labeling sections described in 
paragraphs (c)(1), (c)(2), (c)(3), (c)(5), and (c)(6) of this section, 
that contain(s) substantive labeling changes that have been approved by 
FDA or authorized under Sec.  314.70(c)(6) or (d)(2), or Sec.  
601.12(f)(1) through (f)(3) of this chapter. The heading(s) and, if 
appropriate, the subheading(s) of the labeling section(s) affected by 
the change must be listed together with each section's identifying 
number and the date (month/year) on which the change was incorporated 
in labeling. These labeling sections must be listed in the order in 
which they appear in the full prescribing information. A changed 
section must be listed under this heading in Highlights for at least 1 
year after the date of the labeling change and must be removed at the 
first printing subsequent to the 1 year period.
    (6) Indications and usage. A concise statement of each of the 
product's indications, as required under paragraph (c)(2) of this 
section, with any appropriate subheadings. Major limitations of use 
(e.g., lack of effect in particular subsets of the population, or 
second line therapy status) must be briefly noted. If the product is a 
member of an established pharmacologic class, the concise statement 
under this heading in Highlights must identify the class in the 
following manner: ``(Drug) is a (name of class) indicated for 
(indication(s)).''
    (7) Dosage and administration. A concise summary of the information 
required under paragraph (c)(3) of this section, with any appropriate 
subheadings, including the recommended dosage regimen, starting dose, 
dose range, critical differences among population subsets, monitoring 
recommendations, and other clinically significant clinical 
pharmacologic information.
    (8) Dosage forms and strengths. A concise summary of the 
information required under paragraph (c)(4) of this section, with any 
appropriate subheadings (e.g., tablets, capsules, injectable, 
suspension), including the strength or potency of the dosage form in 
metric system (e.g., 10-milligram tablets) and whether the product is 
scored.
    (9) Contraindications. A concise statement of each of the product's 
contraindications, as required under paragraph (c)(5) of this section, 
with any appropriate subheadings.
    (10) Warnings and precautions. A concise summary of the most 
clinically significant information required under paragraph (c)(6) of 
this section, with any appropriate subheadings, including information 
that would affect decisions about whether to prescribe a drug, 
recommendations for patient monitoring that are critical to safe use of 
the drug, and measures that can be taken to prevent or mitigate harm.
    (11) Adverse reactions. (i) A list of the most frequently occurring 
adverse reactions, as described in paragraph (c)(7) of this section, 
along with the criteria used to determine inclusion (e.g., incidence 
rate). Adverse reactions important for other reasons (e.g., because 
they are serious or frequently lead to discontinuation or dosage 
adjustment) must not be repeated under this heading in Highlights if 
they are included elsewhere in Highlights (e.g., Warnings and 
Precautions, Contraindications).
    (ii) For drug products other than vaccines, the verbatim statement 
``To report SUSPECTED ADVERSE REACTIONS, contact (insert name of 
manufacturer) at (insert manufacturer's phone number) or FDA at (insert 
current FDA phone number and Web address for voluntary reporting of 
adverse reactions).''
    (iii) For vaccines, the verbatim statement ``To report SUSPECTED 
ADVERSE REACTIONS, contact (insert name of manufacturer) at (insert 
manufacturer's phone number) or VAERS at (insert the current VAERS 
phone number and Web address for voluntary reporting of adverse 
reactions).''
    (iv) For manufacturers with a Web site for voluntary reporting of 
adverse reactions, the Web address of the direct link to the site.
    (12) Drug interactions. A concise summary of the information 
required under paragraph (c)(8) of this section, with any appropriate 
subheadings.

[[Page 3989]]

    (13) Use in specific populations. A concise summary of the 
information required under paragraph (c)(9) of this section, with any 
appropriate subheadings.
    (14) Patient counseling information statement. The verbatim 
statement ``See 17 for Patient Counseling Information'' or, if the 
product has FDA-approved patient labeling, the verbatim statement ``See 
17 for Patient Counseling Information and (insert either FDA-approved 
patient labeling or Medication Guide).''
    (15) Revision date. The date of the most recent revision of the 
labeling, identified as such, placed at the end of Highlights.
    (b) Full prescribing information: Contents. Contents must contain a 
list of each heading and subheading required in the full prescribing 
information under Sec.  201.56(d)(1), if not omitted under Sec.  
201.56(d)(4), preceded by the identifying number required under Sec.  
201.56(d)(1). Contents must also contain any additional subheading(s) 
included in the full prescribing information preceded by the 
identifying number assigned in accordance with Sec.  201.56(d)(2).
    (c) Full prescribing information. The full prescribing information 
must contain the information in the order required under paragraphs 
(c)(1) through (c)(18) of this section, together with the headings, 
subheadings, and identifying numbers required under Sec.  201.56(d)(1), 
unless omitted under Sec.  201.56(d)(4). If additional subheadings are 
used within a labeling section, they must be preceded by the 
identifying number assigned in accordance with Sec.  201.56(d)(2).
    (1) Boxed warning. Certain contraindications or serious warnings, 
particularly those that may lead to death or serious injury, may be 
required by the FDA to be presented in a box. The boxed warning 
ordinarily must be based on clinical data, but serious animal toxicity 
may also be the basis of a boxed warning in the absence of clinical 
data. The box must contain, in uppercase letters, a heading inside the 
box that includes the word ``WARNING'' and conveys the general focus of 
the information in the box. The box must briefly explain the risk and 
refer to more detailed information in the ``Contraindications'' or 
``Warnings and Precautions'' section, accompanied by the identifying 
number for the section or subsection containing the detailed 
information.
    (2) 1 Indications and usage. This section must state that the drug 
is indicated for the treatment, prevention, mitigation, cure, or 
diagnosis of a recognized disease or condition, or of a manifestation 
of a recognized disease or condition, or for the relief of symptoms 
associated with a recognized disease or condition.
    (i) This section must include the following information when the 
conditions listed are applicable:
    (A) If the drug is used for an indication only in conjunction with 
a primary mode of therapy (e.g., diet, surgery, behavior changes, or 
some other drug), a statement that the drug is indicated as an adjunct 
to that mode of therapy.
    (B) If evidence is available to support the safety and 
effectiveness of the drug or biological product only in selected 
subgroups of the larger population (e.g., patients with mild disease or 
patients in a special age group), or if the indication is approved 
based on a surrogate endpoint under Sec.  314.510 or Sec.  601.41 of 
this chapter, a succinct description of the limitations of usefulness 
of the drug and any uncertainty about anticipated clinical benefits, 
with reference to the ``Clinical Studies'' section for a discussion of 
the available evidence.
    (C) If specific tests are necessary for selection or monitoring of 
the patients who need the drug (e.g., microbe susceptibility tests), 
the identity of such tests.
    (D) If information on limitations of use or uncertainty about 
anticipated clinical benefits is relevant to the recommended intervals 
between doses, to the appropriate duration of treatment when such 
treatment should be limited, or to any modification of dosage, a 
concise description of the information with reference to the more 
detailed information in the ``Dosage and Administration'' section.
    (E) If safety considerations are such that the drug should be 
reserved for specific situations (e.g., cases refractory to other 
drugs), a statement of the information.
    (F) If there are specific conditions that should be met before the 
drug is used on a long term basis (e.g., demonstration of 
responsiveness to the drug in a short term trial in a given patient), a 
statement of the conditions; or, if the indications for long term use 
are different from those for short term use, a statement of the 
specific indications for each use.
    (ii) If there is a common belief that the drug may be effective for 
a certain use or if there is a common use of the drug for a condition, 
but the preponderance of evidence related to the use or condition shows 
that the drug is ineffective or that the therapeutic benefits of the 
product do not generally outweigh its risks, FDA may require that this 
section state that there is a lack of evidence that the drug is 
effective or safe for that use or condition.
    (iii) Any statements comparing the safety or effectiveness of the 
drug with other agents for the same indication must, except for 
biological products, be supported by substantial evidence derived from 
adequate and well-controlled studies as defined in Sec.  314.126(b) of 
this chapter unless this requirement is waived under Sec.  201.58 or 
Sec.  314.126(c) of this chapter. For biological products, such 
statements must be supported by substantial evidence.
    (iv) For drug products other than biological products, all 
indications listed in this section must be supported by substantial 
evidence of effectiveness based on adequate and well-controlled studies 
as defined in Sec.  314.126(b) of this chapter unless the requirement 
is waived under Sec.  201.58 or Sec.  314.126(c) of this chapter. 
Indications or uses must not be implied or suggested in other sections 
of the labeling if not included in this section.
    (v) For biological products, all indications listed in this section 
must be supported by substantial evidence of effectiveness. Indications 
or uses must not be implied or suggested in other sections of the 
labeling if not included in this section.
    (3) 2 Dosage and administration. (i) This section must state the 
recommended dose and, as appropriate:
    (A) The dosage range,
    (B) An upper limit beyond which safety and effectiveness have not 
been established, or beyond which increasing the dose does not result 
in increasing effectiveness,
    (C) Dosages for each indication and subpopulation,
    (D) The intervals recommended between doses,
    (E) The optimal method of titrating dosage,
    (F) The usual duration of treatment when treatment duration should 
be limited,
    (G) Dosing recommendations based on clinical pharmacologic data 
(e.g., clinically significant food effects),
    (H) Modification of dosage needed because of drug interactions or 
in special patient populations (e.g., in children, in geriatric age 
groups, in groups defined by genetic characteristics, or in patients 
with renal or hepatic disease),
    (I) Important considerations concerning compliance with the dosage 
regimen,
    (J) Efficacious or toxic concentration ranges and therapeutic 
concentration windows of the drug or its metabolites, if established 
and clinically significant.

[[Page 3990]]

 Information on therapeutic drug concentration monitoring (TDM) must 
also be included in this section when TDM is necessary.
    (ii) Dosing regimens must not be implied or suggested in other 
sections of the labeling if not included in this section.
    (iii) Radiation dosimetry information must be stated for both the 
patient receiving a radioactive drug and the person administering it.
    (iv) This section must also contain specific direction on dilution, 
preparation (including the strength of the final dosage solution, when 
prepared according to instructions, in terms of milligrams of active 
ingredient per milliliter of reconstituted solution, unless another 
measure of the strength is more appropriate), and administration of the 
dosage form, if needed (e.g., the rate of administration of parenteral 
drug in milligrams per minute; storage conditions for stability of the 
reconstituted drug, when important; essential information on drug 
incompatibilities if the drug is mixed in vitro with other drugs or 
diluents; and the following verbatim statement for parenterals: 
``Parenteral drug products should be inspected visually for particulate 
matter and discoloration prior to administration, whenever solution and 
container permit.'')
    (4) 3 Dosage forms and strengths. This section must contain 
information on the available dosage forms to which the labeling applies 
and for which the manufacturer or distributor is responsible, 
including:
    (i) The strength or potency of the dosage form in metric system 
(e.g., 10 milligram tablets), and, if the apothecary system is used, a 
statement of the strength in parentheses after the metric designation; 
and
    (ii) A description of the identifying characteristics of the dosage 
forms, including shape, color, coating, scoring, and imprinting, when 
applicable. The National Drug Code number(s) for the drug product must 
not be included in this section.
    (5) 4 Contraindications. This section must describe any situations 
in which the drug should not be used because the risk of use (e.g., 
certain potentially fatal adverse reactions) clearly outweighs any 
possible therapeutic benefit. Those situations include use of the drug 
in patients who, because of their particular age, sex, concomitant 
therapy, disease state, or other condition, have a substantial risk of 
being harmed by the drug and for whom no potential benefit makes the 
risk acceptable. Known hazards and not theoretical possibilities must 
be listed (e.g., if severe hypersensitivity to the drug has not been 
demonstrated, it should not be listed as a contraindication). If no 
contraindications are known, this section must state ``None.''
    (6) 5 Warnings and precautions. (i) General. This section must 
describe clinically significant adverse reactions (including any that 
are potentially fatal, are serious even if infrequent, or can be 
prevented or mitigated through appropriate use of the drug), other 
potential safety hazards (including those that are expected for the 
pharmacological class or those resulting from drug/drug interactions), 
limitations in use imposed by them (e.g., avoiding certain concomitant 
therapy), and steps that should be taken if they occur (e.g., dosage 
modification). The frequency of all clinically significant adverse 
reactions and the approximate mortality and morbidity rates for 
patients experiencing the reaction, if known and necessary for the safe 
and effective use of the drug, must be expressed as provided under 
paragraph (c)(7) of this section. In accordance with Sec. Sec.  314.70 
and 601.12 of this chapter, the labeling must be revised to include a 
warning about a clinically significant hazard as soon as there is 
reasonable evidence of a causal association with a drug; a causal 
relationship need not have been definitely established. A specific 
warning relating to a use not provided for under the ``Indications and 
Usage'' section may be required by FDA in accordance with sections 
201(n) and 502(a) of the act if the drug is commonly prescribed for a 
disease or condition and such usage is associated with a clinically 
significant risk or hazard.
    (ii) Other special care precautions. This section must contain 
information regarding any special care to be exercised by the 
practitioner for safe and effective use of the drug (e.g., precautions 
not required under any other specific section or subsection).
    (iii) Monitoring: Laboratory tests. This section must identify any 
laboratory tests helpful in following the patient's response or in 
identifying possible adverse reactions. If appropriate, information 
must be provided on such factors as the range of normal and abnormal 
values expected in the particular situation and the recommended 
frequency with which tests should be performed before, during, and 
after therapy.
    (iv) Interference with laboratory tests. This section must briefly 
note information on any known interference by the product with 
laboratory tests and reference the section where the detailed 
information is presented (e.g., ``Drug Interactions'' section).
    (7) 6 Adverse reactions. This section must describe the overall 
adverse reaction profile of the drug based on the entire safety 
database. For purposes of prescription drug labeling, an adverse 
reaction is an undesirable effect, reasonably associated with use of a 
drug, that may occur as part of the pharmacological action of the drug 
or may be unpredictable in its occurrence. This definition does not 
include all adverse events observed during use of a drug, only those 
adverse events for which there is some basis to believe there is a 
causal relationship between the drug and the occurrence of the adverse 
event.
    (i) Listing of adverse reactions. This section must list the 
adverse reactions that occur with the drug and with drugs in the same 
pharmacologically active and chemically related class, if applicable. 
The list or lists must be preceded by the information necessary to 
interpret the adverse reactions (e.g., for clinical trials, total 
number exposed, extent and nature of exposure).
    (ii) Categorization of adverse reactions. Within a listing, adverse 
reactions must be categorized by body system, by severity of the 
reaction, or in order of decreasing frequency, or by a combination of 
these, as appropriate. Within a category, adverse reactions must be 
listed in decreasing order of frequency. If frequency information 
cannot be reliably determined, adverse reactions must be listed in 
decreasing order of severity.
    (A) Clinical trials experience. This section must list the adverse 
reactions identified in clinical trials that occurred at or above a 
specified rate appropriate to the safety database. The rate of 
occurrence of an adverse reaction for the drug and comparators (e.g., 
placebo) must be presented, unless such data cannot be determined or 
presentation of comparator rates would be misleading. If adverse 
reactions that occurred below the specified rate are included, they 
must be included in a separate listing. If comparative rates of 
occurrence cannot be reliably determined (e.g., adverse reactions were 
observed only in the uncontrolled trial portion of the overall safety 
database), adverse reactions must be grouped within specified frequency 
ranges as appropriate to the safety database for the drug (e.g., 
adverse reactions occurring at a rate of less than 1/100, adverse 
reactions occurring at a rate of less than 1/500) or descriptively 
identified, if frequency ranges cannot be determined. For adverse 
reactions with significant clinical implications, the listings must be 
supplemented with additional detail about the nature, frequency, and

[[Page 3991]]

severity of the adverse reaction and the relationship of the adverse 
reaction to drug dose and demographic characteristics, if data are 
available and important.
    (B) Postmarketing experience. This section of the labeling must 
list the adverse reactions, as defined in paragraph (c)(7) of this 
section, that are identified from domestic and foreign spontaneous 
reports. This listing must be separate from the listing of adverse 
reactions identified in clinical trials.
    (iii) Comparisons of adverse reactions between drugs. For drug 
products other than biological products, any claim comparing the drug 
to which the labeling applies with other drugs in terms of frequency, 
severity, or character of adverse reactions must be based on adequate 
and well-controlled studies as defined in Sec.  314.126(b) of this 
chapter unless this requirement is waived under Sec.  201.58 or Sec.  
314.126(c) of this chapter. For biological products, any such claim 
must be based on substantial evidence.
    (8) 7 Drug interactions. (i) This section must contain a 
description of clinically significant interactions, either observed or 
predicted, with other prescription or over-the-counter drugs, classes 
of drugs, or foods (e.g., dietary supplements, grapefruit juice), and 
specific practical instructions for preventing or managing them. The 
mechanism(s) of the interaction, if known, must be briefly described. 
Interactions that are described in the ``Contraindications'' or 
``Warnings and Precautions'' sections must be discussed in more detail 
under this section. Details of drug interaction pharmacokinetic studies 
that are included in the ``Clinical Pharmacology'' section that are 
pertinent to clinical use of the drug must not be repeated in this 
section.
    (ii) This section must also contain practical guidance on known 
interference of the drug with laboratory tests.
    (9) 8 Use in specific populations. This section must contain the 
following subsections:
    (i) 8.1 Pregnancy. This subsection may be omitted only if the drug 
is not absorbed systemically and the drug is not known to have a 
potential for indirect harm to the fetus. For all other drugs, this 
subsection must contain the following information:
    (A) Teratogenic effects. Under this subheading, the labeling must 
identify one of the following categories that applies to the drug, and 
the labeling must bear the statement required under the category:
    (1) Pregnancy category A. If adequate and well-controlled studies 
in pregnant women have failed to demonstrate a risk to the fetus in the 
first trimester of pregnancy (and there is no evidence of a risk in 
later trimesters), the labeling must state: ``Pregnancy Category A. 
Studies in pregnant women have not shown that (name of drug) increases 
the risk of fetal abnormalities if administered during the first 
(second, third, or all) trimester(s) of pregnancy. If this drug is used 
during pregnancy, the possibility of fetal harm appears remote. Because 
studies cannot rule out the possibility of harm, however, (name of 
drug) should be used during pregnancy only if clearly needed.'' The 
labeling must also contain a description of the human studies. If 
animal reproduction studies are also available and they fail to 
demonstrate a risk to the fetus, the labeling must also state: 
``Reproduction studies have been performed in (kinds of animal(s)) at 
doses up to (x) times the human dose and have revealed no evidence of 
impaired fertility or harm to the fetus due to (name of drug).'' The 
labeling must also contain a description of available data on the 
effect of the drug on the later growth, development, and functional 
maturation of the child.
    (2) Pregnancy category B. If animal reproduction studies have 
failed to demonstrate a risk to the fetus and there are no adequate and 
well-controlled studies in pregnant women, the labeling must state: 
``Pregnancy Category B. Reproduction studies have been performed in 
(kind(s) of animal(s)) at doses up to (x) times the human dose and have 
revealed no evidence of impaired fertility or harm to the fetus due to 
(name of drug). There are, however, no adequate and well-controlled 
studies in pregnant women. Because animal reproduction studies are not 
always predictive of human response, this drug should be used during 
pregnancy only if clearly needed.'' If animal reproduction studies have 
shown an adverse effect (other than decrease in fertility), but 
adequate and well-controlled studies in pregnant women have failed to 
demonstrate a risk to the fetus during the first trimester of pregnancy 
(and there is no evidence of a risk in later trimesters), the labeling 
must state: ``Pregnancy Category B. Reproduction studies in (kind(s) of 
animal(s)) have shown (describe findings) at (x) times the human dose. 
Studies in pregnant women, however, have not shown that (name of drug) 
increases the risk of abnormalities when administered during the first 
(second, third, or all) trimester(s) of pregnancy. Despite the animal 
findings, it would appear that the possibility of fetal harm is remote, 
if the drug is used during pregnancy. Nevertheless, because the studies 
in humans cannot rule out the possibility of harm, (name of drug) 
should be used during pregnancy only if clearly needed.'' The labeling 
must also contain a description of the human studies and a description 
of available data on the effect of the drug on the later growth, 
development, and functional maturation of the child.
    (3) Pregnancy category C. If animal reproduction studies have shown 
an adverse effect on the fetus, if there are no adequate and well-
controlled studies in humans, and if the benefits from the use of the 
drug in pregnant women may be acceptable despite its potential risks, 
the labeling must state: ``Pregnancy Category C. (Name of drug) has 
been shown to be teratogenic (or to have an embryocidal effect or other 
adverse effect) in (name(s) of species) when given in doses (x) times 
the human dose. There are no adequate and well-controlled studies in 
pregnant women. (Name of drug) should be used during pregnancy only if 
the potential benefit justifies the potential risk to the fetus.'' The 
labeling must contain a description of the animal studies. If there are 
no animal reproduction studies and no adequate and well-controlled 
studies in humans, the labeling must state: ``Pregnancy Category C. 
Animal reproduction studies have not been conducted with (name of 
drug). It is also not known whether (name of drug) can cause fetal harm 
when administered to a pregnant woman or can affect reproduction 
capacity. (Name of drug) should be given to a pregnant woman only if 
clearly needed.'' The labeling must contain a description of any 
available data on the effect of the drug on the later growth, 
development, and functional maturation of the child.
    (4) Pregnancy category D. If there is positive evidence of human 
fetal risk based on adverse reaction data from investigational or 
marketing experience or studies in humans, but the potential benefits 
from the use of the drug in pregnant women may be acceptable despite 
its potential risks (for example, if the drug is needed in a life-
threatening situation or serious disease for which safer drugs cannot 
be used or are ineffective), the labeling must state: ``Pregnancy 
Category D. See `Warnings and Precautions' section.'' Under the 
``Warnings and Precautions'' section, the labeling must state: ``(Name 
of drug) can cause fetal harm when administered to a pregnant woman. 
(Describe the human data and any pertinent animal data.) If this drug 
is used during pregnancy, or if the patient becomes

[[Page 3992]]

pregnant while taking this drug, the patient should be apprised of the 
potential hazard to a fetus.''
    (5) Pregnancy category X. If studies in animals or humans have 
demonstrated fetal abnormalities or if there is positive evidence of 
fetal risk based on adverse reaction reports from investigational or 
marketing experience, or both, and the risk of the use of the drug in a 
pregnant woman clearly outweighs any possible benefit (for example, 
safer drugs or other forms of therapy are available), the labeling must 
state: ``Pregnancy Category X. See `Contraindications' section.'' Under 
``Contraindications,'' the labeling must state: ``(Name of drug) may 
(can) cause fetal harm when administered to a pregnant woman. (Describe 
the human data and any pertinent animal data.) (Name of drug) is 
contraindicated in women who are or may become pregnant. If this drug 
is used during pregnancy, or if the patient becomes pregnant while 
taking this drug, the patient should be apprised of the potential 
hazard to a fetus.''
    (B) Nonteratogenic effects. Under this subheading the labeling must 
contain other information on the drug's effects on reproduction and the 
drug's use during pregnancy that is not required specifically by one of 
the pregnancy categories, if the information is relevant to the safe 
and effective use of the drug. Information required under this heading 
must include nonteratogenic effects in the fetus or newborn infant (for 
example, withdrawal symptoms or hypoglycemia) that may occur because of 
a pregnant woman's chronic use of the drug for a preexisting condition 
or disease.
    (ii) 8.2 Labor and delivery. If the drug has a recognized use 
during labor or delivery (vaginal or abdominal delivery), whether or 
not the use is stated in the Indications and Usage section, this 
subsection must describe the available information about the effect of 
the drug on the mother and the fetus, on the duration of labor or 
delivery, on the possibility that forceps delivery or other 
intervention or resuscitation of the newborn will be necessary, and the 
effect of the drug on the later growth, development, and functional 
maturation of the child. If any information required under this 
subsection is unknown, it must state that the information is unknown.
    (iii) 8.3 Nursing mothers. (A) If a drug is absorbed systemically, 
this subsection must contain, if known, information about excretion of 
the drug in human milk and effects on the nursing infant. Pertinent 
adverse effects observed in animal offspring must be described.
    (B) If a drug is absorbed systemically and is known to be excreted 
in human milk, this subsection must contain one of the following 
statements, as appropriate. If the drug is associated with serious 
adverse reactions or if the drug has a known tumorigenic potential, the 
labeling must state: ``Because of the potential for serious adverse 
reactions in nursing infants from (name of drug) (or, ``Because of the 
potential for tumorigenicity shown for (name of drug) in (animal or 
human) studies), a decision should be made whether to discontinue 
nursing or to discontinue the drug, taking into account the importance 
of the drug to the mother.'' If the drug is not associated with serious 
adverse reactions and does not have a known tumorigenic potential, the 
labeling must state: ``Caution should be exercised when (name of drug) 
is administered to a nursing woman.''
    (C) If a drug is absorbed systemically and information on excretion 
in human milk is unknown, this subsection must contain one of the 
following statements, as appropriate. If the drug is associated with 
serious adverse reactions or has a known tumorigenic potential, the 
labeling must state: ``It is not known whether this drug is excreted in 
human milk. Because many drugs are excreted in human milk and because 
of the potential for serious adverse reactions in nursing infants from 
(name of drug) (or, ``Because of the potential for tumorigenicity shown 
for (name of drug) in (animal or human) studies), a decision should be 
made whether to discontinue nursing or to discontinue the drug, taking 
into account the importance of the drug to the mother.'' If the drug is 
not associated with serious adverse reactions and does not have a known 
tumorigenic potential, the labeling must state: ``It is not known 
whether this drug is excreted in human milk. Because many drugs are 
excreted in human milk, caution should be exercised when (name of drug) 
is administered to a nursing woman.''
    (iv) 8.4 Pediatric use. (A) Pediatric population(s)/pediatric 
patient(s): For the purposes of paragraphs (c)(9)(iv)(B) through 
(c)(9)(iv)(H) of this section, the terms pediatric population(s) and 
pediatric patient(s) are defined as the pediatric age group, from birth 
to 16 years, including age groups often called neonates, infants, 
children, and adolescents.
    (B) If there is a specific pediatric indication different from 
those approved for adults that is supported by adequate and well-
controlled studies in the pediatric population, it must be described 
under the ``Indications and Usage'' section, and appropriate pediatric 
dosage information must be given under the ``Dosage and 
Administration'' section. The ``Pediatric use'' subsection must cite 
any limitations on the pediatric indication, need for specific 
monitoring, specific hazards associated with use of the drug in any 
subsets of the pediatric population (e.g., neonates), differences 
between pediatric and adult responses to the drug, and other 
information related to the safe and effective pediatric use of the 
drug. Data summarized in this subsection should be discussed in more 
detail, if appropriate, under the ``Clinical Pharmacology'' or 
``Clinical Studies'' section. As appropriate, this information must 
also be contained in the ``Contraindications'' and/or ``Warnings and 
Precautions'' section(s).
    (C) If there are specific statements on pediatric use of the drug 
for an indication also approved for adults that are based on adequate 
and well-controlled studies in the pediatric population, they must be 
summarized in the ``Pediatric use'' subsection and discussed in more 
detail, if appropriate, under the ``Clinical Pharmacology'' and 
``Clinical Studies'' sections. Appropriate pediatric dosage must be 
given under the ``Dosage and Administration'' section. The ``Pediatric 
use'' subsection of the labeling must also cite any limitations on the 
pediatric use statement, need for specific monitoring, specific hazards 
associated with use of the drug in any subsets of the pediatric 
population (e.g., neonates), differences between pediatric and adult 
responses to the drug, and other information related to the safe and 
effective pediatric use of the drug. As appropriate, this information 
must also be contained in the ``Contraindications'' and/or ``Warnings 
and Precautions'' section(s).
    (D)(1) When a drug is approved for pediatric use based on adequate 
and well-controlled studies in adults with other information supporting 
pediatric use, the ``Pediatric use'' subsection of the labeling must 
contain either the following statement or a reasonable alternative:
    The safety and effectiveness of (drug name) have been 
established in the age groups ------ to ------ (note any 
limitations, e.g., no data for pediatric patients under 2, or only 
applicable to certain indications approved in adults). Use of (drug 
name) in these age groups is supported by evidence from adequate and 
well-controlled studies of (drug name) in adults with additional 
data (insert wording that accurately describes the data submitted to 
support a finding of substantial evidence of effectiveness in the 
pediatric population).
    (2) Data summarized in the preceding prescribed statement in this 
subsection must be discussed in more detail, if appropriate, under the 
``Clinical

[[Page 3993]]

Pharmacology'' or the ``Clinical Studies'' section. For example, 
pediatric pharmacokinetic or pharmacodynamic studies and dose response 
information should be described in the ``Clinical Pharmacology'' 
section. Pediatric dosing instructions must be included in the ``Dosage 
and Administration'' section. Any differences between pediatric and 
adult responses, need for specific monitoring, dosing adjustments, and 
any other information related to safe and effective use of the drug in 
pediatric patients must be cited briefly in the ``Pediatric use'' 
subsection and, as appropriate, in the ``Contraindications,'' 
``Warnings and Precautions,'' and ``Dosage and Administration'' 
sections.
    (E) If the requirements for a finding of substantial evidence to 
support a pediatric indication or a pediatric use statement have not 
been met for a particular pediatric population, the ``Pediatric use'' 
subsection must contain an appropriate statement such as ``Safety and 
effectiveness in pediatric patients below the age of (----) have not 
been established.'' If use of the drug in this pediatric population is 
associated with a specific hazard, the hazard must be described in this 
subsection, or, if appropriate, the hazard must be stated in the 
``Contraindications'' or ``Warnings and Precautions'' section and this 
subsection must refer to it.
    (F) If the requirements for a finding of substantial evidence to 
support a pediatric indication or a pediatric use statement have not 
been met for any pediatric population, this subsection must contain the 
following statement: ``Safety and effectiveness in pediatric patients 
have not been established.'' If use of the drug in premature or 
neonatal infants, or other pediatric subgroups, is associated with a 
specific hazard, the hazard must be described in this subsection, or, 
if appropriate, the hazard must be stated in the ``Contraindications'' 
or ``Warnings and Precautions'' section and this subsection must refer 
to it.
    (G) If the sponsor believes that none of the statements described 
in paragraphs (c)(9)(iv)(B) through (c)(9)(iv)(F) of this section are 
appropriate or relevant to the labeling of a particular drug, the 
sponsor must provide reasons for omission of the statements and may 
propose alternative statement(s). FDA may permit use of an alternative 
statement if FDA determines that no statement described in those 
paragraphs is appropriate or relevant to the drug's labeling and that 
the alternative statement is accurate and appropriate.
    (H) If the drug product contains one or more inactive ingredients 
that present an increased risk of toxic effects to neonates or other 
pediatric subgroups, a special note of this risk must be made, 
generally in the ``Contraindications'' or ``Warnings and Precautions'' 
section.
    (v) 8.5 Geriatric use. (A) A specific geriatric indication, if any, 
that is supported by adequate and well-controlled studies in the 
geriatric population must be described under the ``Indications and 
Usage'' section, and appropriate geriatric dosage must be stated under 
the ``Dosage and Administration'' section. The ``Geriatric use'' 
subsection must cite any limitations on the geriatric indication, need 
for specific monitoring, specific hazards associated with the geriatric 
indication, and other information related to the safe and effective use 
of the drug in the geriatric population. Unless otherwise noted, 
information contained in the ``Geriatric use'' subsection must pertain 
to use of the drug in persons 65 years of age and older. Data 
summarized in this subsection must be discussed in more detail, if 
appropriate, under ``Clinical Pharmacology'' or the ``Clinical 
Studies'' section. As appropriate, this information must also be 
contained in the ``Warnings and Precautions'' and/or 
``Contraindications'' section(s).
    (B) Specific statements on geriatric use of the drug for an 
indication approved for adults generally, as distinguished from a 
specific geriatric indication, must be contained in the ``Geriatric 
use'' subsection and must reflect all information available to the 
sponsor that is relevant to the appropriate use of the drug in elderly 
patients. This information includes detailed results from controlled 
studies that are available to the sponsor and pertinent information 
from well-documented studies obtained from a literature search. 
Controlled studies include those that are part of the marketing 
application and other relevant studies available to the sponsor that 
have not been previously submitted in the investigational new drug 
application, new drug application, biologics license application, or a 
supplement or amendment to one of these applications (e.g., 
postmarketing studies or adverse drug reaction reports). The 
``Geriatric use'' subsection must contain the following statement(s) or 
reasonable alternative, as applicable, taking into account available 
information:
    (1) If clinical studies did not include sufficient numbers of 
subjects aged 65 and over to determine whether elderly subjects respond 
differently from younger subjects, and other reported clinical 
experience has not identified such differences, the ``Geriatric use'' 
subsection must include the following statement:
    Clinical studies of (name of drug) did not include sufficient 
numbers of subjects aged 65 and over to determine whether they respond 
differently from younger subjects. Other reported clinical experience 
has not identified differences in responses between the elderly and 
younger patients. In general, dose selection for an elderly patient 
should be cautious, usually starting at the low end of the dosing 
range, reflecting the greater frequency of decreased hepatic, renal, or 
cardiac function, and of concomitant disease or other drug therapy.
    (2) If clinical studies (including studies that are part of 
marketing applications and other relevant studies available to the 
sponsor that have not been submitted in the sponsor's applications) 
included enough elderly subjects to make it likely that differences in 
safety or effectiveness between elderly and younger subjects would have 
been detected, but no such differences (in safety or effectiveness) 
were observed, and other reported clinical experience has not 
identified such differences, the ``Geriatric use'' subsection must 
contain the following statement:
    Of the total number of subjects in clinical studies of (name of 
drug), ---- percent were 65 and over, while ---- percent were 75 and 
over. (Alternatively, the labeling may state the total number of 
subjects included in the studies who were 65 and over and 75 and 
over.) No overall differences in safety or effectiveness were 
observed between these subjects and younger subjects, and other 
reported clinical experience has not identified differences in 
responses between the elderly and younger patients, but greater 
sensitivity of some older individuals cannot be ruled out.
    (3) If evidence from clinical studies and other reported clinical 
experience available to the sponsor indicates that use of the drug in 
elderly patients is associated with differences in safety or 
effectiveness, or requires specific monitoring or dosage adjustment, 
the ``Geriatric use'' subsection must contain a brief description of 
observed differences or specific monitoring or dosage requirements and, 
as appropriate, must refer to more detailed discussions in the 
``Contraindications,'' ``Warnings and Precautions,'' ``Dosage and 
Administration,'' or other sections.
    (C)(1) If specific pharmacokinetic or pharmacodynamic studies have 
been carried out in the elderly, they must be described briefly in the 
``Geriatric use'' subsection and in detail under the ``Clinical 
Pharmacology'' section. The ``Clinical Pharmacology'' and ``Drug 
Interactions'' sections ordinarily contain

[[Page 3994]]

information on drug/disease and drug/drug interactions that is 
particularly relevant to the elderly, who are more likely to have 
concomitant illness and to use concomitant drugs.
    (2) If a drug is known to be substantially excreted by the kidney, 
the ``Geriatric use'' subsection must include the statement:
    This drug is known to be substantially excreted by the kidney, 
and the risk of adverse reactions to this drug may be greater in 
patients with impaired renal function. Because elderly patients are 
more likely to have decreased renal function, care should be taken 
in dose selection, and it may be useful to monitor renal function.
    (D) If use of the drug in the elderly appears to cause a specific 
hazard, the hazard must be described in the ``Geriatric use'' 
subsection, or, if appropriate, the hazard must be stated in the 
``Contraindications'' or ``Warnings and Precautions'' section, and the 
``Geriatric use'' subsection must refer to those sections.
    (E) Labeling under paragraphs (c)(9)(v)(A) through (c)(9)(v)(C) of 
this section may include statements, if they are necessary for safe and 
effective use of the drug, and reflect good clinical practice or past 
experience in a particular situation, e.g., for a sedating drug, it 
could be stated that:
    Sedating drugs may cause confusion and over-sedation in the 
elderly; elderly patients generally should be started on low doses 
of (name of drug) and observed closely.
    (F) If the sponsor believes that none of the requirements described 
in paragraphs (c)(9)(v)(A) through (c)(9)(v)(E) of this section are 
appropriate or relevant to the labeling of a particular drug, the 
sponsor must provide reasons for omission of the statements and may 
propose an alternative statement. FDA may permit omission of the 
statements if FDA determines that no statement described in those 
paragraphs is appropriate or relevant to the drug's labeling. FDA may 
permit use of an alternative statement if the agency determines that 
such statement is accurate and appropriate.
    (vi) Additional subsections. Additional subsections may be 
included, as appropriate, if sufficient data are available concerning 
the use of the drug in other specified subpopulations (e.g., renal or 
hepatic impairment).
    (10) 9 Drug abuse and dependence. This section must contain the 
following information, as appropriate:
    (i) 9.1 Controlled substance. If the drug is controlled by the Drug 
Enforcement Administration, the schedule in which it is controlled must 
be stated.
    (ii) 9.2 Abuse. This subsection must state the types of abuse that 
can occur with the drug and the adverse reactions pertinent to them, 
and must identify particularly susceptible patient populations. This 
subsection must be based primarily on human data and human experience, 
but pertinent animal data may also be used.
    (iii) 9.3 Dependence. This subsection must describe characteristic 
effects resulting from both psychological and physical dependence that 
occur with the drug and must identify the quantity of the drug over a 
period of time that may lead to tolerance or dependence, or both. 
Details must be provided on the adverse effects of chronic abuse and 
the effects of abrupt withdrawal. Procedures necessary to diagnose the 
dependent state and the principles of treating the effects of abrupt 
withdrawal must be described.
    (11) 10 Overdosage. This section must be based on human data. If 
human data are unavailable, appropriate animal and in vitro data may be 
used. The following specific information must be provided:
    (i) Signs, symptoms, and laboratory findings associated with an 
overdosage of the drug;
    (ii) Complications that can occur with the drug (for example, organ 
toxicity or delayed acidosis);
    (iii) Concentrations of the drug in biologic fluids associated with 
toxicity or death; physiologic variables influencing excretion of the 
drug, such as urine pH; and factors that influence the dose response 
relationship of the drug, such as tolerance. The pharmacokinetic data 
given in the ``Clinical Pharmacology'' section also may be referenced 
here, if applicable to overdoses;
    (iv) The amount of the drug in a single dose that is ordinarily 
associated with symptoms of overdosage and the amount of the drug in a 
single dose that is likely to be life threatening;
    (v) Whether the drug is dialyzable; and
    (vi) Recommended general treatment procedures and specific measures 
for support of vital functions (e.g., proven antidotes, gastric lavage, 
forced diuresis, or as per Poison Control Center). Such recommendations 
must be based on data available for the specific drug or experience 
with pharmacologically related drugs. Unqualified recommendations for 
which data are lacking for the specific drug or class of drugs must not 
be stated.
    (12) 11 Description. (i) This section must contain:
    (A) The proprietary name and the established name, if any, as 
defined in section 502(e)(2) of the act, of the drug or, for biological 
products, the proper name (as defined in Sec.  600.3 of this chapter) 
and any appropriate descriptors;
    (B) The type of dosage form(s) and the route(s) of administration 
to which the labeling applies;
    (C) The same qualitative and/or quantitative ingredient information 
as required under Sec.  201.100(b) for drug labels or Sec. Sec.  610.60 
and 610.61 of this chapter for biological product labels;
    (D) If the product is sterile, a statement of that fact;
    (E) The pharmacological or therapeutic class of the drug;
    (F) For drug products other than biological products, the chemical 
name and structural formula of the drug; and
    (G) If the product is radioactive, a statement of the important 
nuclear physical characteristics, such as the principal radiation 
emission data, external radiation, and physical decay characteristics.
    (ii) If appropriate, other important chemical or physical 
information, such as physical constants or pH, must be stated.
    (13) 12 Clinical pharmacology. (i) This section must contain 
information relating to the human clinical pharmacology and actions of 
the drug in humans. Pharmacologic information based on in vitro data 
using human biomaterials or pharmacologic animal models, or relevant 
details about in vivo study designs or results (e.g., drug interaction 
studies), may be included in this section if essential to understand 
dosing or drug interaction information presented in other sections of 
the labeling. This section must include the following subsections:
    (A) 12.1 Mechanism of action. This subsection must summarize what 
is known about the established mechanism(s) of the drug's action in 
humans at various levels (e.g., receptor, membrane, tissue, organ, 
whole body). If the mechanism of action is not known, this subsection 
must contain a statement about the lack of information.
    (B) 12.2 Pharmacodynamics. This subsection must include a 
description of any biochemical or physiologic pharmacologic effects of 
the drug or active metabolites related to the drug's clinical effect in 
preventing, diagnosing, mitigating, curing, or treating disease, or 
those related to adverse effects or toxicity. Exposure-response 
relationships (e.g., concentration-response, dose-response) and time 
course of pharmacodynamic response (including short-term clinical 
response) must be included if known. If this information is unknown, 
this subsection must contain a statement about the lack

[[Page 3995]]

of information. Detailed dosing or monitoring recommendations based on 
pharmacodynamic information that appear in other sections (e.g., 
``Warnings and Precautions'' or ``Dosage and Administration'') must not 
be repeated in this subsection, but the location of such 
recommendations must be referenced.
    (C) 12.3 Pharmacokinetics. This subsection must describe the 
clinically significant pharmacokinetics of a drug or active 
metabolites, (i.e., pertinent absorption, distribution, metabolism, and 
excretion parameters). Information regarding bioavailability, the 
effect of food, minimum concentration (Cmin), maximum 
concentration (Cmax), time to maximum concentration 
(Tmax), area under the curve (AUC), pertinent half-lives 
(t1/2), time to reach steady state, extent of accumulation, 
route(s) of elimination, clearance (renal, hepatic, total), mechanisms 
of clearance (e.g., specific enzyme systems), drug/drug and drug/food 
(e.g., dietary supplements, grapefruit juice) pharmacokinetic 
interactions (including inhibition, induction, and genetic 
characteristics), and volume of distribution (Vd) must be 
presented if clinically significant. Information regarding nonlinearity 
in pharmacokinetic parameters, changes in pharmacokinetics over time, 
and binding (plasma protein, erythrocyte) parameters must also be 
presented if clinically significant. This section must also include the 
results of pharmacokinetic studies (e.g., of metabolism or interaction) 
that establish the absence of an effect, including pertinent human 
studies and in vitro data. Dosing recommendations based on clinically 
significant factors that change the product's pharmacokinetics (e.g., 
age, gender, race, hepatic or renal dysfunction, concomitant therapy) 
that appear in other sections (e.g., ``Warnings and Precautions,'' 
``Dosage and Administration'' or ``Use in Specific Populations'') must 
not be repeated in this subsection, but the location of such 
recommendations must be referenced.
    (ii) Data that demonstrate activity or effectiveness in in vitro or 
animal tests and that have not been shown by adequate and well-
controlled clinical studies to be pertinent to clinical use may be 
included under this section only under the following circumstances:
    (A) In vitro data for anti-infective drugs may be included if the 
data are immediately preceded by the statement ``The following in vitro 
data are available but their clinical significance is unknown.''
    (B) For other classes of drugs, in vitro and animal data that have 
not been shown by adequate and well-controlled studies, as defined in 
Sec.  314.126(b) of this chapter, to be necessary for the safe and 
effective use may be included in this section only if a waiver is 
granted under Sec.  201.58 or Sec.  314.126(c) of this chapter.
    (14) 13 Nonclinical toxicology. This section must contain the 
following subsections as appropriate:
    (i) 13.1 Carcinogenesis, mutagenesis, impairment of fertility. This 
subsection must state whether long term studies in animals have been 
performed to evaluate carcinogenic potential and, if so, the species 
and results. If results from reproduction studies or other data in 
animals raise concern about mutagenesis or impairment of fertility in 
either males or females, this must be described. Any precautionary 
statement on these topics must include practical, relevant advice to 
the prescriber on the significance of these animal findings. Human data 
suggesting that the drug may be carcinogenic or mutagenic, or 
suggesting that it impairs fertility, as described in the ``Warnings 
and Precautions'' section, must not be included in this subsection of 
the labeling.
    (ii) 13.2 Animal toxicology and/or pharmacology. Significant animal 
data necessary for safe and effective use of the drug in humans that is 
not incorporated in other sections of labeling must be included in this 
section (e.g., specifics about studies used to support approval under 
Sec.  314.600 or Sec.  601.90 of this chapter, the absence of chronic 
animal toxicity data for a drug that is administered over prolonged 
periods or is implanted in the body).
    (15) 14 Clinical studies. This section must discuss those clinical 
studies that facilitate an understanding of how to use the drug safely 
and effectively. Ordinarily, this section will describe the studies 
that support effectiveness for the labeled indication(s), including 
discussion of study design, population, endpoints, and results, but 
must not include an encyclopedic listing of all, or even most, studies 
performed as part of the product's clinical development program. If a 
specific important clinical study is mentioned in any section of the 
labeling required under Sec. Sec.  201.56 and 201.57 because the study 
is essential to an understandable presentation of the information in 
that section of the labeling, any detailed discussion of the study must 
appear in this section.
    (i) For drug products other than biological products, any clinical 
study that is discussed in prescription drug labeling that relates to 
an indication for or use of the drug must be adequate and well-
controlled as described in Sec.  314.126(b) of this chapter and must 
not imply or suggest indications or uses or dosing regimens not stated 
in the ``Indications and Usage'' or ``Dosage and Administration'' 
section. For biological products, any clinical study that is discussed 
that relates to an indication for or use of the biological product must 
constitute or contribute to substantial evidence and must not imply or 
suggest indications or uses or dosing regimens not stated in the 
``Indications and Usage'' or ``Dosage and Administration'' section.
    (ii) Any discussion of a clinical study that relates to a risk from 
the use of the drug must also refer to the other sections of the 
labeling where the risk is identified or discussed.
    (16) 15 References. When prescription drug labeling must summarize 
or otherwise rely on a recommendation by an authoritative scientific 
body, or on a standardized methodology, scale, or technique, because 
the information is important to prescribing decisions, the labeling may 
include a reference to the source of the information.
    (17) 16 How supplied/storage and handling. This section must 
contain information on the available dosage forms to which the labeling 
applies and for which the manufacturer or distributor is responsible. 
The information must include, as appropriate:
    (i) The strength or potency of the dosage form in metric system 
(e.g., 10 milligram tablets) and, if the apothecary system is used, a 
statement of the strength in parentheses after the metric designation;
    (ii) The units in which the dosage form is ordinarily available for 
prescribing by practitioners (e.g., bottles of 100);
    (iii) Appropriate information to facilitate identification of the 
dosage forms, such as shape, color, coating, scoring, imprinting, and 
National Drug Code number; and
    (iv) Special handling and storage conditions.
    (18) 17 Patient counseling information. This section must contain 
information necessary for patients to use the drug safely and 
effectively (e.g., precautions concerning driving or the concomitant 
use of other substances that may have harmful additive effects). Any 
FDA-approved patient labeling must be referenced in this section and 
the full text of such patient labeling must be reprinted immediately 
following this section or, alternatively, accompany the prescription 
drug labeling. Any FDA-approved patient labeling printed immediately 
following this section or

[[Page 3996]]

accompanying the labeling is subject to the type size requirements in 
paragraph (d)(6) of this section, except for a Medication Guide to be 
detached and distributed to patients in compliance with Sec.  208.24 of 
this chapter. Medication Guides for distribution to patients are 
subject to the type size requirements set forth in Sec.  208.20 of this 
chapter.
    (d) Format requirements. All labeling information required under 
paragraphs (a), (b), and (c) of this section must be printed in 
accordance with the following specifications:
    (1) All headings and subheadings required by paragraphs (a) and (c) 
of this section must be highlighted by bold type that prominently 
distinguishes the headings and subheadings from other labeling 
information. Reverse type is not permitted as a form of highlighting.
    (2) A horizontal line must separate the information required by 
paragraphs (a), (b), and (c) of this section.
    (3) The headings listed in paragraphs (a)(5) through (a)(13) of 
this section must be presented in the center of a horizontal line.
    (4) If there are multiple subheadings listed under paragraphs 
(a)(4) through (a)(13) of this section, each subheading must be 
preceded by a bullet point.
    (5) The labeling information required by paragraphs (a)(1) through 
(a)(4), (a)(11)(ii) through (a)(11)(iv), and (a)(14) of this section 
must be in bold print.
    (6) The letter height or type size for all labeling information, 
headings, and subheadings set forth in paragraphs (a), (b), and (c) of 
this section must be a minimum of 8 points, except for labeling 
information that is on or within the package from which the drug is to 
be dispensed, which must be a minimum of 6 points.
    (7) The identifying numbers required by Sec.  201.56(d) and 
paragraphs (c)(1) through (c)(18) of this section must be presented in 
bold print and must precede the heading or subheading by at least two 
square em's (i.e., two squares of the size of the letter ``m'' in 8 
point type).
    (8) The information required by paragraph (a) of this section, not 
including the information required under paragraph (a)(4) of this 
section, must be limited in length to an amount that, if printed in 2 
columns on a standard sized piece of typing paper (8 1/2 by 11 inches), 
single spaced, in 8 point type with 1/2-inch margins on all sides and 
between columns, would fit on one-half of the page.
    (9) Sections or subsections of labeling that are identified as 
containing recent major changes under paragraph (a)(5) of this section 
must be highlighted in the full prescribing information by the 
inclusion of a vertical line on the left edge of the new or modified 
text.
    (10) For the information required by paragraph (b) of this section, 
each section heading must be in bold print. Each subheading within a 
section must be indented and not bolded.

0
4. Section 201.58 is revised to read as follows:


Sec.  201.58  Waiver of labeling requirements.

    An applicant may ask the Food and Drug Administration to waive any 
requirement under Sec. Sec.  201.56, 201.57, and 201.80. A waiver 
request must be submitted in writing to the Director (or the Director's 
designee), Center for Drug Evaluation and Research, Food and Drug 
Administration, 5600 Fishers Lane, Rockville, MD 20857, or, if 
applicable, the Director (or the Director's designee), Center for 
Biologics Evaluation and Research, Food and Drug Administration, 1401 
Rockville Pike, suite 200 North, Rockville, MD 20852-1448. The waiver 
must be granted or denied in writing by the Director or the Director's 
designee.


Sec.  201.59  [Removed]

0
5. Section 201.59 is removed.

0
6. Newly redesignated Sec.  201.80 is amended by:
    a. Revising the section heading;
    b. Amending paragraphs (b)(2)(ii), (c)(3)(i), (c)(3)(v), and (g)(4) 
by removing the phrase ``Sec.  314.126(b)'' the second time it appears 
and by adding in its place the phrase ``Sec.  314.126(c)'';
    c. Removing the phrase ``induced emesis,'' in paragraph (i)(6);
    d. Revising paragraphs (c)(2), (f)(2), and (m)(1); and
    e. Adding a new sentence after the first sentence of paragraph (j).
    The additions and revisions 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).

* * * * *
    (c) * * *
    (2)(i) For drug products other than biological products, all 
indications listed in this section must be supported by substantial 
evidence of effectiveness based on adequate and well-controlled studies 
as defined in Sec.  314.126(b) of this chapter unless the requirement 
is waived under Sec.  201.58 or Sec.  314.126(c) of this chapter. 
Indications or uses must not be implied or suggested in other sections 
of labeling if not included in this section.
    (ii) For biological products, all indications listed in this 
section must be supported by substantial evidence of effectiveness. 
Indications or uses must not be implied or suggested in other sections 
of labeling if not included in this section.
* * * * *
    (f) * * *
    (2) Information for patients. This subsection must contain 
information necessary for patients to use the drug safely and 
effectively (e.g., precautions concerning driving or the concomitant 
use of other substances that may have harmful additive effects). 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, alternatively, accompany the 
prescription drug labeling. The type size requirement for the 
Medication Guide set forth in Sec.  208.20 of this chapter does not 
apply to the Medication Guide that is reprinted in or accompanying the 
prescription drug labeling unless such Medication Guide is to be 
detached and distributed to patients in compliance with Sec.  208.24 of 
this chapter.
* * * * *
    (j) Dosage and administration. * * * Dosing regimens must not be 
implied or suggested in other sections of labeling if not included in 
this section. * * *
* * * * *
    (m) * * *
    (1)(i) If the clinical study is cited in the labeling in place of a 
detailed discussion of data and information concerning an indication 
for use of the drug, the clinical study must constitute an adequate and 
well-controlled study as described in Sec.  314.126(b) of this chapter, 
except for biological products, and must not imply or suggest 
indications or uses or dosing regimens not stated in the ``Indications 
and Usage'' or ``Dosage and Administration'' section.
    (ii) When prescription drug labeling must summarize or otherwise 
rely on a recommendation by an authoritative scientific body, or on a 
standardized methodology, scale, or technique, because the information 
is important to prescribing decisions, the labeling may include a 
reference to the source of the information.
* * * * *

0
7. Section 201.100 is amended by revising paragraph (d)(3) to read as 
follows:


Sec.  201.100  Prescription drugs for human use.

* * * * *
    (d) * * *

[[Page 3997]]

    (3) The information required, and in the format specified, by 
Sec. Sec.  201.56, 201.57, and 201.80.
* * * * *

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

0
8. The authority citation for 21 CFR part 314 continues to read as 
follows:

    Authority: 21 U.S.C. 321, 331, 351, 352, 353, 355, 355a, 356, 
356a, 356b, 356c, 371, 374, 379e.

0
9. Section 314.70 is amended by:
    a. Removing from paragraph (b)(2)(v)(B) the phrase ``(b)(8)(iv) of 
this chapter.'' and adding in its place the phrase ``(b)(8)(iv) of this 
chapter; and'';
    b. Adding paragraph (b)(2)(v)(C);
    c. Revising the introductory text of paragraph (c)(6)(iii); and
    d. Revising paragraph (d)(2)(x).
    The additions and revisions read as follows:


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

* * * * *
    (b) * * *
    (2) * * *
    (v) * * *
    (C) Any change to the information required by Sec.  201.57(a) of 
this chapter, with the following exceptions that may be reported in an 
annual report under paragraph (d)(2)(x) of this section:
    (1) Removal of a listed section(s) specified in Sec.  201.57(a)(5) 
of this chapter; and
    (2) Changes to the most recent revision date of the labeling as 
specified in Sec.  201.57(a)(15) of this chapter.
* * * * *
    (c) * * *
    (6) * * *
    (iii) Changes in the labeling, except for changes to the 
information required in Sec.  201.57(a) of this chapter (which must be 
made pursuant to paragraph (b)(2)(v)(C) of this section), to accomplish 
any of the following:
* * * * *
    (d) * * *
    (2) * * *
    (x) An editorial or similar minor change in labeling, including a 
change to the information allowed by paragraphs (b)(2)(v)(C)(1) and (2) 
of this section.
* * * * *

PART 601--LICENSING

0
10. The authority cite for 21 CFR part 601 continues to read as 
follows:

    Authority: 15 U.S.C. 1451-1561; 21 U.S.C. 321, 351, 352, 353, 
355, 356b, 360, 360c-360f, 360h-360j, 371, 374, 379e, 381; 42 U.S.C. 
216, 241, 262, 263, 264; sec 122, Pub. L. 105-115, 111 Stat. 2322 
(21 U.S.C. 355 note).

0
11. Section 601.12 is amended by:
    a. Adding two sentences after the second sentence and before the 
third sentence in paragraph (f)(1);
    b. Revising the introductory text of paragraph (f)(2)(i);
    c. Removing from paragraph (f)(3)(i)(B) the word ``and'';
    d. Removing from paragraph (f)(3)(i)(C) the phrase ``Medication 
Guide.'' and adding in its place the phrase ``Medication Guide; and''; 
and
    e. Adding paragraph (f)(3)(i)(D).
    The additions and revisions read as follows:


Sec.  601.12  Changes to an approved application.

* * * * *
    (f) * * *
    (1) * * * An applicant cannot use paragraph (f)(2) of this section 
to make any change to the information required in Sec.  201.57(a) of 
this chapter. An applicant may report the minor changes to the 
information specified in paragraph (f)(3)(i)(D) of this section in an 
annual report. * * *
    (2) * * *
    (i) An applicant shall submit, at the time such change is made, a 
supplement for any change in the package insert, package label, or 
container label, except for changes to the package insert required in 
Sec.  201.57(a) of this chapter (which must be made pursuant to 
paragraph (f)(1) of this section), to accomplish any of the following:
* * * * *
    (f) * * *
    (3) * * *
    (i) * * *
    (D) A change to the information required in Sec.  201.57(a) of this 
chapter as follows:
    (1) Removal of a listed section(s) specified in Sec.  201.57(a)(5) 
of this chapter; and
    (2) Changes to the most recent revision date of the labeling as 
specified in Sec.  201.57(a)(15) of this chapter.
* * * * *

    Dated: December 7, 2005.
Andrew C. von Eschenbach,
Acting Commissioner of Food and Drugs.

    Dated: December 7, 2005.
Michael O. Leavitt,
Secretary of Health and Human Services.
[FR Doc. 06-545 Filed 1-18-06; 10:28 am]
BILLING CODE 4160-01-C