Requirements on Content and Format of Labeling for Human Prescription Drug and Biological Products, 3922-3997 [06-545]

Agencies

• Food and Drug Administration
• DEPARTMENT OF HEALTH AND HUMAN SERVICES

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



[[Page 3921]]

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

Part II





Department of Health and Human Services





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



Food and Drug Administration



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



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

[[Page 3922]]


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

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.

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

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, nordenj@CDER.FDA.GOV, or Elizabeth Sadove, Center 
for Drug Evaluation and Research (HFD-7), Food and Drug Administration, 
5600 Fishers Lane, Rockville, MD 20857, 301-594-2041, 
sadovee@CDER.FDA.GOV.
    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, 
stifano@CBER.FDA.GOV, 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.
---------------------------------------------------------------------------

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)
----------------------------------------------------------------------------------------------------------------

[[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)
----------------------------------------------------------------------------------------------------------------
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)
----------------------------------------------------------------------------------------------------------------
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)
----------------------------------------------------------------------------------------------------------------
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)
----------------------------------------------------------------------------------------------------------------
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)
----------------------------------------------------------------------------------------------------------------
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)
----------------------------------------------------------------------------------------------------------------
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 https://www.fda.gov/cder/guidance/index.htm. The Center 
for Biologics Evaluation and Research (CBER)-related information is 
posted at https://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 https://www.fda.gov/cder/guidance/index.htm under 
``Electronic Submissions'' and https://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 co