[Federal Register: January 24, 2006 (Volume 71, Number 15)]
[Rules and Regulations]
[Page 3921-3997]
From the Federal Register Online via GPO Access [wais.access.gpo.gov]
[DOCID:fr24ja06-17]
[[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
[[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 http://frwebgate.access.gpo.gov/cgi-bin/leaving.cgi?from=leavingFR.html&log=linklog&to=http://www.fda.gov/cder/guidance/index.htm. The Center
for Biologics Evaluation and Research (CBER)-related information is
posted at http://frwebgate.access.gpo.gov/cgi-bin/leaving.cgi?from=leavingFR.html&log=linklog&to=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://frwebgate.access.gpo.gov/cgi-bin/leaving.cgi?from=leavingFR.html&log=linklog&to=http://www.fda.gov/cder/guidance/index.htm under ``Electronic Submissions'' and http://frwebgate.access.gpo.gov/cgi-bin/leaving.cgi?from=leavingFR.html&log=linklog&to=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://frwebgate.access.gpo.gov/cgi-bin/leaving.cgi?from=leavingFR.html&log=linklog&to=http://www.fda.gov/medwatch for drug products except vaccines and http://
http://frwebgate.access.gpo.gov/cgi-bin/leaving.cgi?from=leavingFR.html&log=linklog&to=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://frwebgate.access.gpo.gov/cgi-bin/leaving.cgi?from=leavingFR.html&log=linklog&to=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://frwebgate.access.gpo.gov/cgi-bin/leaving.cgi?from=leavingFR.html&log=linklog&to=http://www.fda.gov/cder/ddmac/y2ktable.htm http://frwebgate.access.gpo.gov/cgi-bin/leaving.cgi?from=leavingFR.html&log=linklog&to=http://www.fda.gov/cder/ddmac/y2kTITLE.htm.
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://frwebgate.access.gpo.gov/cgi-bin/leaving.cgi?from=leavingFR.html&log=linklog&to=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://frwebgate.access.gpo.gov/cgi-bin/leaving.cgi?from=leavingFR.html&log=linklog&to=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://frwebgate.access.gpo.gov/cgi-bin/leaving.cgi?from=leavingFR.html&log=linklog&to=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://frwebgate.access.gpo.gov/cgi-bin/leaving.cgi?from=leavingFR.html&log=linklog&to=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://frwebgate.access.gpo.gov/cgi-bin/leaving.cgi?from=leavingFR.html&log=linklog&to=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://frwebgate.access.gpo.gov/cgi-bin/leaving.cgi?from=leavingFR.html&log=linklog&to=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://frwebgate.access.gpo.gov/cgi-bin/leaving.cgi?from=leavingFR.html&log=linklog&to=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://frwebgate.access.gpo.gov/cgi-bin/leaving.cgi?from=leavingFR.html&log=linklog&to=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://frwebgate.access.gpo.gov/cgi-bin/leaving.cgi?from=leavingFR.html&log=linklog&to=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://frwebgate.access.gpo.gov/cgi-bin/leaving.cgi?from=leavingFR.html&log=linklog&to=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