[Federal Register: December 22, 2000 (Volume 65, Number 247)]
[Proposed Rules]
[Page 81081-81131]
From the Federal Register Online via GPO Access [wais.access.gpo.gov]
[DOCID:fr22de00-36]
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Part III
Department of Health and Human Services
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Food and Drug Administration
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21 CFR Part 201
Requirements on Content and Format of Labeling for Human Prescription
Drugs and Biologics; Requirements for Prescription Drug Product Labels;
Proposed Rule
[[Page 81082]]
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DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
21 CFR Part 201
[Docket No. 00N-1269]
RIN 0910-AA94
Requirements on Content and Format of Labeling for Human
Prescription Drugs and Biologics; Requirements for Prescription Drug
Product Labels
AGENCY: Food and Drug Administration, HHS.
ACTION: Proposed rule.
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SUMMARY: The Food and Drug Administration (FDA) is proposing to amend
its regulations governing the format and content of labeling for human
prescription drug and biologic products. This proposal would revise
current regulations to require that the labeling of new and recently
approved products include a section containing highlights of
prescribing information and a section containing an index to
prescribing information, reorder currently required information and
make minor changes to its content, and establish minimum graphical
requirements. These revisions would make it easier for health care
practitioners to access, read, and use information in prescription drug
labeling and would enhance the safe and effective use of prescription
drug products. This proposal would also amend prescription drug
labeling requirements for older drugs to require that certain types of
statements currently appearing in labeling be removed if they are not
sufficiently supported. Finally, the proposal would eliminate certain
unnecessary statements that are currently required to appear on
prescription drug product labels and move other, less important
information to labeling. These changes would simplify drug product
labels and reduce the possibility of medication errors.
DATES: Submit written comments by March 22, 2001. Submit written
comments on the information collection requirements by January 22,
2001.
ADDRESSES: Submit written comments to the Dockets Management Branch
(HFA-305), Food and Drug Administration, 5630 Fishers Lane, rm. 1061,
Rockville, MD 20857. Submit written comments on the information
collection requirements to the Office of Information and Regulatory
Affairs, Office of Management and Budget (OMB), New Executive Office
Bldg., 725 17th St. NW., rm. 10235, Washington, DC 20503, ATTN: Wendy
Taylor.
FOR FURTHER INFORMATION CONTACT: For information on drug product
labeling:
Nancy M. Ostrove, Center for Drug Evaluation and Research (HFD-42),
Food and Drug Administration, 5600 Fishers Lane, Rockville, MD 20857,
301-827-2828, e-mail:
Ostrove@CDER.FDA.GOV
or
Lee D. Korb, Center for Drug Evaluation and Research (HFD-7), Food and
Drug Administration, 5600 Fishers Lane, Rockville, MD 20857, 301-594-
2041, e-mail: Korbl@CDER.FDA.GOV
For information on biologics labeling: Toni M. Stifano, Center for
Biologics Evaluation and Research (HFM-600), Food and Drug
Administration, 1401 Rockville Pike, Rockville, MD 20856, 301-827-6190,
e-mail: Stifano@CBER.FDA.GOV
SUPPLEMENTARY INFORMATION:
Table of Contents
I. Background
II. The Need for Revised Prescription Drug Labeling
A. Initial Focus Groups
B. Physician Surveys
C. Initial Prototype Development
D. Qualitative Testing of Initial Prototypes
E. The Public Meeting
III. A Description of the Proposed Labeling Requirements
A. General Requirements of Content and Format of Labeling for
Human Prescription Drugs (Sec. 201.56)
B. Revised Format and Content Requirements Applicable to Newer
Drugs
C. Revisions to Labeling for Older Drugs
IV. Proposed Implementation Plan
A. General Implementation Scheme for the Revised Format and
Content Requirements
B. Implementation of Proposed Content and Format Revisions to
Products Approved or Submitted for Approval Under an ANDA
C. Implementation of Proposed Content Requirements Applicable to
Newer and Older Drugs
D. Implementation of Proposed Sec. 201.57(c)(17) and Proposed
Sec. 201.80(f)(2)
E. Voluntary Submission of Labeling Conforming to Proposed
Content and Format Requirements
F. Relationship of Proposed Requirements to Other Prescription
Drug Labeling Initiatives
V. Revisions to Prescription Drug Labels
VI. Revisions to Sections 201.58 and 201.100(d)(3), Rescission of
Section 201.59 (21 CFR 201.59)
VII. Paperwork Reduction Act of 1995
A. Summary of Provisions in Proposed Rule That Contain
Collections of Information
B. Estimates of Reporting Burden
C. Capital Costs
VIII. Environmental Impact
IX. Executive Order 13132: Federalism
X. Analysis of Economic Impacts
A. Purpose
B. Benefits of Regulation
C. Costs of Regulation
D. Impacts on Small Entities
XI. Request for Comments
XII. References
I. Background
The part of a prescription drug product's approved labeling
directed to health care practitioners (also known as its ``package
insert,'' ``direction circular,'' or ``package circular'') 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. The regulations governing the format and content of labeling
for prescription drugs and biologics appear at Secs. 201.56 and 201.57
(21 CFR 201.56 and 201.57).\1\ Under Sec. 201.100(d) (21 CFR
201.100(d)), any labeling, as defined in section 201(m) of the act (21
U.S.C. 321(m)), that is distributed by or on behalf of the
manufacturer, packer, or distributor of the drug, that furnishes or
purports to furnish information for use of the drug, or that
prescribes, recommends, or suggests a dosage for the use of the drug,
must meet the content and format requirements contained in Secs. 201.56
and 201.57. Thus, Secs. 201.56 and 201.57 apply to the labeling for all
prescription drugs approved under an NDA, abbreviated new drug
application (ANDA), or BLA, including labeling on or within the package
from which the drug is to be dispensed and ``promotional'' labeling
described in Sec. 202.1(l)(2) (21 CFR 202.1(l)(2)).
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\1\ Although current Secs. 201.56 and 201.57 do not specifically
refer to 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.
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Regulations proposing Secs. 201.56 and 201.57 were published in the
Federal Register of April 7, 1975 (40 FR 15392). At the time of the
proposal, agency regulations required that certain section headings
appear in prescription drug labeling, but did not, for the most part,
specify the type of information required under those headings. The
purpose of the proposal was to improve prescription drug labeling by
ensuring that it contained more specific, comprehensive, and accurate
information. The agency determined
[[Page 81083]]
that the 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, and that revision
of labeling requirements was necessary to achieve this objective for
all products. Among other things, the proposal set forth standards for
the content of labeling information required under the then-existing
section headings, provided for a new section in prescription drug
labeling entitled ``Clinical Pharmacology,'' revised the format and
expanded the content requirements for the ``Indications and Usage'' and
``Adverse Reactions'' sections of prescription drug labeling, and
reformatted and expanded required information related to possible
hazards of use in pregnant women and in children.
Regulations finalizing Secs. 201.56 and 201.57 were published in
the Federal Register of June 26, 1979 (44 FR 37434). These regulations
were revised in 1994 by amending the requirements relating to the
inclusion of data relevant to use in pediatric populations (59 FR
64240, December 13, 1994) and in 1997 by amending the requirements
relating to the inclusion of data relevant to use in geriatric
populations (62 FR 45313, August 27, 1997).
Current Sec. 201.56 requires that prescription drug labeling
contain the required information in the format specified in current
Sec. 201.57. Section 201.56 also sets forth general requirements for
prescription drug labeling, including the requirement that labeling
contain a summary of the essential scientific information needed for
the safe and effective use of the drug, that it be informative and
accurate and neither promotional in tone nor false or misleading, and
that labeling be based whenever possible on data derived from human
experience. In addition, Sec. 201.56 sets forth required and optional
section headings for prescription drug labeling and specifies the order
in which those headings must appear. Required section headings include:
``Description,'' ``Clinical Pharmacology,'' ``Indications and Usage,''
``Contraindications,'' ``Warnings,'' ``Precautions,'' ``Adverse
Reactions,'' ``Drug Abuse and Dependence,'' ``Overdosage,'' ``Dosage
and Administration,'' and ``How Supplied.'' Section headings that may
be included under certain circumstances include: ``Animal Pharmacology
and/or Animal Toxicology,'' ``Clinical Studies,'' and ``References.''
Current Sec. 201.57 specifies the kind of information that is
required to appear under each of the section headings set forth in
Sec. 201.56. This information is intended to help ensure that health
care practitioners are provided with a complete and accurate
explanation of prescription drugs to facilitate their safe and
effective prescribing. Thus, the regulations require prescription drug
labeling to contain detailed information on various topics that may be
important to practitioners.
In addition to these regulations, the National Childhood Vaccine
Injury Act (Public Law 103-66) requires FDA to monitor the adequacy of
labeling for children's vaccines.
In addition to the requirements for prescription drug labeling
discussed above, current Secs. 201.55 (21 CFR 201.55) and 201.100(b)
set forth certain requirements for prescription drug product labels. As
discussed in section V of this document, the agency is proposing
certain amendments to these requirements that would simplify
prescription drug product labels and reduce the possibility of
medication errors.
II. The Need for Revised Prescription Drug Labeling
Although the format and content requirements for prescription drug
labeling in Secs. 201.56 and 201.57 have enabled health care
practitioners to prescribe drugs more safely and effectively, the
requirements, together with various developments in recent years, have
contributed to an increase in the amount, detail, and complexity of
labeling information. This has made it harder for health care
practitioners to find specific information and to discern the most
critical information in product labeling.
Nonregulatory developments that have affected the length and
complexity of drug labeling include technological advances in the drug
products themselves and recognition of the importance of including new
or additional labeling information, such as information on drug/drug
interactions and information necessary to optimize use in various
subpopulations. In addition, the use of labeling in product liability
and medical malpractice lawsuits, together with increasing litigation
costs, has caused manufacturers to become more cautious and include
virtually all known adverse event information, regardless of its
importance or its plausible relationship to the drug. Finally,
accelerated approval of certain drugs for serious or life-threatening
illnesses has resulted in the rapid availability of products for which
expanded information about benefits and risks is necessary to help
ensure safe and effective prescribing.
In response to the resulting increase in the length and complexity
of prescription drug labeling and to anecdotal evidence suggesting that
current prescription drug labeling does not optimally communicate its
information (Ref. 1), FDA evaluated the usefulness of prescription drug
labeling for its principal audience to determine whether, and how, its
format and content can be improved. As discussed below, the agency
conducted two initial focus groups and a national physician survey to
ascertain how prescription drug labeling is used by health care
practitioners, what labeling information is most important to
practitioners, and how prescription drug labeling can be improved.
Based on the results of the physician survey, FDA developed two
prototype revisions to the format of prescription drug labeling
(``Prototypes 1 and 2'') and examined the value of these prototypes in
four physician focus groups. Based on these results, FDA developed a
third prototype (``Prototype 3'') and held a public meeting to solicit
public comments on Prototype 3. FDA revised the prototype (``Prototype
4'') based on the public meeting and written comments submitted to the
agency on Prototype 3. Prototype 4 serves as the model for this
proposal and is included as Appendix 1.\2\
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\2\ All prototypes may be seen at the Dockets Management Branch
(address above) between 9 a.m. and 4 p.m., Monday through Friday
(see Docket No. 95N-0314).
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A discussion follows of the agency's prescription drug labeling
development efforts, including the focus groups, physician surveys,
public meeting, and prototype development.
A. Initial Focus Groups
In February 1992, FDA conducted two physician focus groups (Ref. 2)
to ascertain how practitioners use prescription drug labeling, which
aspects of labeling are most important to practitioners, and how
current labeling can be improved. The focus groups indicated that the
Physicians' Desk Reference (PDR) was the most common source of labeling
information. The practitioners expressed concern about the lack of ease
in locating specific information among the extensive information
presented. They stated that the most important information needed to
make a confident decision about prescribing a particular drug for a
particular individual is contraindications (especially when the patient
is a member of a special population), side effects, drug interactions,
dosage, comparative efficacy, and cost information. The
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focus groups' recommendations with regard to improving the format
included: (1) Using graphical devices to highlight important
information; (2) adding an abstract of important information; (3)
placing packaging and dosing information earlier in labeling; (4)
enlarging the type size; and (5) reducing or eliminating anecdotal,
marginal information.
B. Physician Surveys
Between October 1993 and March 1994, FDA conducted a telephone
interview survey of a national probability sample of office-based
physicians to determine how physicians perceive and use drug product
labeling and to ascertain how labeling (the drug package insert) could
be made more useful (the DPI survey). FDA designed the DPI survey to
examine specific issues, including what is the perceived importance of
the various labeling sections and what formatting alterations could
make labeling more useful to practicing physicians.
Results of the DPI survey demonstrated that office-based physicians
use drug product labeling primarily to answer specific questions about
patient care rather than as a general educational tool and that
labeling (generally in its reprinted form in the PDR) is consulted
after the physician has made a tentative prescribing decision. The DPI
survey further demonstrated that:
(1) The labeling sections physicians read most often and perceive
as most important are: Dosage and Administration, Contraindications,
Warnings, Adverse Reactions, and Precautions;
(2) Overall, the Clinical Pharmacology section, and the Abuse and
Dependence and Overdosage sections, are referred to relatively
infrequently;
(3) Physicians are prompted to refer to labeling most often by
negative product experiences and newness of the product; and
(4) Physicians believe that labeling overly stresses the occurrence
of extremely rare events. They also asserted that although they can
generally find the information they need, the usefulness of labeling
could be improved by highlighting and providing an abstract of the most
important information.
In addition to the DPI survey that addressed drug package inserts
generally, the agency conducted a physician survey from October 1994 to
October 1995 to obtain information specifically regarding physicians'
use of and perceptions about vaccine package inserts (the VPI survey).
The VPI survey was conducted by the agency's Center for Biologics
Evaluation and Research (CBER) in an effort to improve the utility of
vaccine package inserts in communicating the nature and extent of risks
associated with vaccines. Among other things, the VPI survey was
designed to examine whether changes can be made to vaccine package
inserts to increase their usefulness.
Although the objectives of and the methodology used in the VPI
survey were different than those used in the DPI survey, the VPI survey
helped to confirm the findings of the DPI survey. For example, the VPI
survey found that, overall, the vaccine package insert sections that
are perceived as most useful by physicians include Dosage and
Administration, Indications and Usage, Contraindications, Warnings, and
Adverse Reactions. The Clinical Pharmacology and References sections
were found to be among the least useful sections. Of the physicians
surveyed, 71 percent indicated that they would increase their use of
vaccine package inserts if a summary of prescribing information were
used in the inserts. Eighty percent of physicians surveyed indicated
that the summary should be no more than one-half page in length, 64
percent wanted the summary to have large print, and 56 percent wanted
the summary to list serious reactions and be printed in bold type. The
physicians also indicated that the following information (listed in
order of preference) should be included in a summary: (1) Indications/
usage, contraindications, and warnings; (2) adverse reactions,
precautions, and dosage/administration; (3) a description of the
vaccine; and (4) storage.
C. Initial Prototype Development
Based on the results of the DPI survey, FDA developed two
prototypes of revised labeling formats for each of three prescription
drug products (Prototypes 1 and 2). Both prototypes incorporated three
major differences from the current labeling requirements. The first and
most visible difference was the addition of a short section, entitled
``Summary of Prescribing Information,'' inserted at the very beginning
of the labeling. It included brief excerpts from the content areas that
physicians felt included the most important labeling information. The
second major difference was the reordering and reorganization of the
presentation of information topics in the current labeling. For
example, one of the sections judged by survey participants to be most
important and most often used, ``Dosage and Administration,'' is
currently required to be placed toward the end of labeling. This
section was placed more toward the beginning of labeling in the
prototypes. The ``Clinical Pharmacology'' section, judged by physicians
as one of the least frequently used and least important, is currently
placed at the beginning of labeling. This section and other less highly
rated sections were moved toward the end of the labeling in the
prototypes.
The prototypes also combined the current ``Warnings'' and
``Precautions'' sections into a single section entitled ``Special
Considerations'' because of anecdotal information that physicians do
not make meaningful distinctions between these two categories. The
prototypes also included the subheadings ``Hypersensitivity Reactions''
and ``Major Toxicities'' to distinguish potentially serious reactions
from ``General Precautions,'' which included drug interactions.
Subsections currently required to be included under the ``Precautions''
section concerning use of a drug in special populations (e.g.,
``Pediatrics,'' ``Labor and Delivery,'' ``Nursing Mothers'') and the
section entitled ``Information for Patients'' were reorganized in the
prototype into separate headings entitled ``Use in Specific
Populations'' and ``Patient Counseling Information.''
The third major difference between the prototypes and current
labeling was the use of a paragraph identification system to make
detailed information more accessible. This system was designed to be
used together with a listing of the contents of the comprehensive
information, inserted immediately before the comprehensive section. The
system was also designed to provide ``pointers'' within the summary
section that would refer readers desiring additional information to the
proper place in the comprehensive section. The system is analogous to
the hypertext linkage systems currently used on the Internet in which a
user can select a particular word or phrase within other text to have
more detailed information about the selected word or phrase
automatically displayed.
The only difference between Prototypes 1 and 2 was the length of
their ``summary'' sections. Prototype 1 included a two-column page-
length summary while the summary of Prototype 2 was one and one-half
pages in length.
D. Qualitative Testing of Initial Prototypes
FDA conducted qualitative testing of the revised labeling format
prototypes (Prototypes 1 and 2) in four physician focus groups. The
focus group results
[[Page 81085]]
showed that the physicians preferred the prototype with the one-page
summary section (Prototype 1), but believed (consistent with the VPI
survey results) that it was still too lengthy, which might discourage
its use. The physicians stated that the availability of a short summary
would not decrease the likelihood of reading the detailed labeling
sections, but would direct them more efficiently to needed detailed
information in the comprehensive section. The physicians also found the
contents listing very helpful.
The focus group results confirmed the agency's belief that it is
important to include the following sections prominently in the summary
of prescription drug information: ``Indications and Usage,'' ``Dosage
and Administration,'' and ``How Supplied.'' It is also important that
the summary include information about the negative attributes of a drug
product--its contraindications, warnings, precautions, and adverse drug
reactions (ADR's), and that drug interactions be listed under a
separate major heading.
The focus groups also recommended that summary information be
presented in a short, bulleted format and include pointers indicating
where in the labeling they should go for additional information. Many
physicians preferred a table format, where possible, in place of
narrative descriptions, and preferred the placement of patient
counseling information toward the end of labeling.
E. The Public Meeting
Based on the results of the physician survey and focus group
testing, FDA developed a revised prototype (Prototype 3). This
prototype differed from the two initial prototypes in that it had a
shorter ``Summary'' section and the organization of sections was
changed. The paragraph identification system was modified such that the
major information headings would be assigned the same index number,
regardless of product, to help familiarize prescribers more rapidly
with the new indexing system and facilitate ease of access to specific
types of information across products. Finally, the combined warnings
and precautions section was renamed ``Warnings/Precautions'' and
information relating to drug interactions was removed from the combined
section and placed under its own separate heading.
In the Federal Register of October 5, 1995, FDA published a notice
(60 FR 52196) announcing an informal public meeting on October 30,
1995,\3\ to present background information and research concerning how
approved prescription drug product labeling could be revised to
communicate important information more effectively to health care
practitioners, and to solicit comments on Prototype 3. Several
panelists, including representatives from the American Medical
Association (AMA), United States Pharmacopeial Convention,
Pharmaceutical Research and Manufacturers of America, Biometric
Research Institute, Inc., American Pharmaceutical Association, American
Academy of Physician Assistants, and the American Academy of Nurse
Practitioners presented their comments on Prototype 3 at the meeting.
Many panelists supported the prototype, stating, for example, that it
would ``result in more useful and user-friendly professional labeling
for the prescribing physician.''
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\3\ A transcript of the meeting may be seen at the Dockets
Management Branch (address above) between 9 a.m. and 4 p.m., Monday
through Friday (see Docket No. 95N-0314).
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FDA also received 10 written comments on Prototype 3 in response to
the October 5, 1995, notice. Many of these comments supported the
labeling prototype, stating, for example, that ``the proposed
reorganization of the product labeling is a positive step that better
reflects the manner in which the information is actually employed at
the point of care.'' Another comment stated that ``[t]he prototype is
well organized, and the information seems to be positioned to be more
accessible and, therefore, more helpful to health-care practitioners.''
Other comments recommended that FDA conduct additional research on the
prototype and that ``FDA thoroughly study any reformatting with a broad
range of health care professionals who use labeling.''
The written comments submitted in response to the notice are
discussed below.
III. A Description of the Proposed Labeling Requirements
In its effort to develop prototypes of drug labeling and obtain
feedback on those prototypes, the agency has identified certain format
elements that it believes would enhance the ability of practitioners to
access, read, and use prescription drug labeling. The proposed rule
would revise current Secs. 201.56 and 201.57 to incorporate these
format elements as requirements for new and more recently approved
drugs. Older drugs would remain subject to the format requirements in
current Sec. 201.57, which would be redesignated as Sec. 201.80.
Certain requirements in current Sec. 201.57 also would be modified to
help ensure that statements appearing in the labeling of older drugs
relating to effectiveness or dosage and administration are sufficiently
supported. The categories of drugs that would be subject to the revised
labeling format and content requirements are discussed below in
conjunction with the description of proposed Sec. 201.56. The
implementation scheme for the proposed changes is discussed in detail
in section IV of this document. As discussed in section IV, the agency
believes that applying the revised format requirements only to more
recently approved products is appropriate because, among other factors,
physicians are more likely to refer to the labeling of recently
approved products than the labeling of older products.
The format changes that would be required under the proposal for
new and more recently approved drugs include the addition of an
introductory section of prescribing information, entitled ``Highlights
of Prescribing Information,'' to the comprehensive labeling information
required under current Sec. 201.57 (the comprehensive prescribing
information).\4\ The highlights section would consist of selected
information that practitioners most commonly refer to and view as most
important from specific sections in the comprehensive prescribing
information. As discussed further in this section and in section IV of
this document, sponsors would be responsible for proposing language to
be used in the highlights section in their product applications (i.e.,
NDA's, BLA's, or efficacy supplements). As with all approved
prescription drug labeling, review and approval of the language by FDA
would be required. The proposal would also add an index to, reorder,
and reorganize the comprehensive prescribing information to make it
easier to use and read, and make minor changes to its content. The
proposal would set minimum standards and requirements for certain
critical graphic elements of the format of prescription drug labeling.
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\4\ The highlights section (``Highlights of Prescribing
Information'') corresponds to the section entitled ``Summary of
Prescribing Information'' in earlier prototypes. As discussed below,
the agency has changed the title in response to industry comments
that the section does not represent a true summary. To avoid
confusion about which labeling section is being discussed, the term
``summary'' is used only in direct quotes of comments.
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A detailed description of each section of the proposed rule is
provided below. Comments received on those sections of Prototype 3
corresponding to the proposed requirements are also
[[Page 81086]]
summarized and addressed. \5\ In addition to requesting general
comments on the proposal, the agency is seeking comment on the
following specific issues (presented here for the convenience of the
reader):
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\5\ As discussed above, the proposed rule is based on Prototype
4, which is very similar to Prototype 3.
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(1) Whether, and under what circumstances, it may be inappropriate
to include the proposed ``Highlights of Prescribing Information''
section in the labeling of a particular drug or drug class;
(2) Does the inclusion of a highlights section have a significant
effect on manufacturers' product liability concerns and, if so, is this
concern adequately addressed by: (a) Titling this section
``highlights'' rather than ``summary,''; and (b) including the
following statement, in bold, at the end of the highlights section:
``These highlights do not include all the information needed to
prescribe (name of drug) safely and effectively. See (name of drug)'s
comprehensive prescribing information provided below.'' If these are
not sufficient, could the agency take different or additional measures
to alleviate product liability concerns without eliminating the
highlights section altogether or lengthening it to an extent that it
would no longer serve its intended purpose;
(3) Whether the full text of any boxed warnings should be included
in the proposed ``Highlights of Prescribing Information'' section,
regardless of length;
(4) What different types of icons could be used to signal a boxed
warning and what are their costs and benefits;
(5) Whether there should be a time limit by which the ``Recent
Labeling Changes'' section must be removed;
(6) Whether the information required under the ``Indications and
Usage'' subsection in the proposed ``Highlights of Prescribing
Information'' section should be presented verbatim from the
comprehensive labeling section or summarized in a bulleted format;
(7) Whether it is necessary to include the proposed requirement for
an index section given the proposed requirement for a highlights
section (i.e., do the additional purposes served by the index justify
its inclusion?);
(8) Whether not including standardized headings in the ``Warnings/
Precautions'' section is appropriate. If it is believed that specific
standardized headings should be included, FDA requests comment about
what they should be;
(9) Whether it is necessary to include a contact number for
reporting suspected serious adverse drug reactions in the proposed
``Comprehensive Prescribing Information'' section as well as the
proposed ``Highlights of Prescribing Information'' section;
(10) 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;
(11) Whether the proposed requirement to bold certain information
in proposed Sec. 201.57(d)(5) will serve its intended purpose of
ensuring the visual prominence of the bolded information or whether
different highlighting methods may be more effective;
(12) Whether the proposed one-half page limit on the ``Highlights
of Prescribing Information'' section (not including boxed warning(s) or
contraindication(s)) is adequate or whether there are alternatives that
would be more appropriate and under what circumstances such
alternatives should be considered;
(13) What means (other than the vertical line proposed in
Sec. 201.57(d)(9)) could be used to facilitate access to, and
identification of, new labeling information in the proposed
comprehensive prescribing information section;
(14) Whether the proposed minimum 8-point font size for labeling is
sufficient or whether a minimum 10-point font size would be more
appropriate; and
(15) Whether the revised format and content requirements should be
applied to drug products with an NDA, BLA, or efficacy supplement that
is pending at the effective date of the final rule, 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.
A. General Requirements on Content and Format of Labeling for Human
Prescription Drugs (Sec. 201.56)
The proposal would revise current Sec. 201.56 to set forth: (1)
General labeling requirements applicable to all prescription drugs; (2)
the categories of new and more recently approved prescription drugs
subject to the revised content and format requirements in proposed
Secs. 201.56(d) and 201.57; (3) the schedule for implementing the
revised content and format requirements in proposed Secs. 201.56(d) and
201.57; (4) the required and optional sections and subsections
associated with the revised format in proposed Sec. 201.57; and (5) the
required and optional sections and subsections for the labeling of
older prescription drugs not subject to the revised format and content
requirements.
Proposed Sec. 201.56(a) (``General Requirements'') would set forth
general labeling requirements applicable to all prescription drugs.
These are currently set forth at Sec. 201.56(a) through (c), and
include the requirements that labeling contain a summary of the
essential scientific information needed for the safe and effective use
of the drug, that labeling be informative and accurate and neither
promotional in tone nor false or misleading, and that labeling be based
whenever possible on data derived from human experience.
Proposed Sec. 201.56(b) sets forth the categories of new and more
recently approved prescription drugs and biologics subject to the
revised format and content requirements in proposed Secs. 201.56(d) and
201.57. These would include prescription drug products for which an
NDA, BLA, or efficacy supplement has been approved in the 5 years
before the effective date of the final rule, drug products for which an
NDA, BLA, or efficacy supplement is pending at the effective date of
the final rule, and drug products for which an NDA, BLA, or efficacy
supplement is submitted on or after the effective date of the final
rule. The revised content and format requirements in the proposed rule
would not apply to drug products approved more than 5 years before the
effective date of the final rule (provided that an efficacy supplement
was not approved for such products in the 5 years before the effective
date of the final rule, or submitted after the effective date of the
final rule). As mentioned above, these products would remain subject to
the labeling requirements in current Sec. 201.57, which under the
proposal would be redesignated as Sec. 201.80.
Proposed Sec. 201.56(c) sets forth the schedule for implementing
the revised format and content requirements in proposed Secs. 201.56(d)
and 201.57. The implementation schedule is discussed in detail in
section IV of this document. The implementation schedule would require
that for products with certain applications (i.e., NDA's, BLA's, and
efficacy supplements) submitted on or after the effective date of the
final rule, revised labeling must be submitted with the application.
For drugs and biological products approved in the 5 years before the
effective date of the final rule, revised labeling must be submitted on
a staggered basis beginning 3 years after the effective date of the
final rule. The implementation schedule would require that labeling for
the most recently
[[Page 81087]]
approved drugs (i.e., those approved in the year immediately preceding
the effective date of the final rule) be revised first.
Proposed Sec. 201.56(d) would require that labeling for new and
more recently approved prescription drugs contain the information
required under proposed Sec. 201.57 under specified headings and
subheadings. This section sets forth required and optional headings for
labeling under the revised format. Proposed Sec. 201.57(d)(1) through
(d)(4) is similar to current Sec. 201.56(d), but reflects the revised
headings and subheadings that are included under proposed
Sec. 201.57(a) (Highlights of Prescribing Information) and
Sec. 201.57(c) (Comprehensive Prescribing Information). The section
also reflects the proposed reorganization and revisions of the
comprehensive prescribing information. Proposed Sec. 201.56(d)(5) would
permit the use of additional subheadings where appropriate to emphasize
specific topics within the text of required sections. For example,
under the ``Warnings/Precautions'' section, additional subheadings
could be used to set off each warning or precaution. The use of
headings in this manner is consistent with current labeling formatting
practice and would provide sponsors with a valuable tool in designing
labeling that effectively communicates important information to
prescribers.
Proposed Sec. 201.56(e) would set forth the required section
headings and subheadings for older drugs (i.e., drugs approved more
than 5 years before the effective date of the final rule). The section
incorporates current Sec. 201.56(d) without change, except for the
references to Sec. 201.57, which would be changed to reflect the
redesignation of current Sec. 201.57 to Sec. 201.80.
B. Revised Format and Content Requirements Applicable to Newer Drugs
1. Highlights of Prescribing Information
Proposed Sec. 201.57(a) would require that the labeling of human
prescription drugs, specified in Sec. 201.56(b)(1), contain the heading
``Highlights of Prescribing Information'' followed by the specific
information and subheadings listed in proposed Sec. 201.57(a)(1)
through (a)(17). As discussed below, information under these sections
would be a concise extract of the most important information already
required under current Sec. 201.57, as well as certain additional
information that the agency believes is important to prescribers (e.g.,
recent labeling changes). The agency is proposing to add this
highlights section to prescription drug labeling because, based on the
information discussed in section II of this document, the agency
believes that the usefulness of labeling can be improved by
highlighting at the beginning of labeling the information that is most
often used and cited as most important by health care practitioners.
FDA is requesting comment, however, about whether and under what
circumstances it may be inappropriate to include a highlights section
for a particular drug or drug class.
Inclusion of only a limited amount of information in the highlights
section would not affect any of the regulations related to prescription
drug promotion. Manufacturers still would be responsible for ensuring
that claims in promotional labeling and advertisements are consistent
with the comprehensive prescribing information. Thus, for example, if
certain limitations of use contained in the comprehensive prescribing
information regarding a drug's effectiveness, contraindications, or
side effects is permitted to be excluded from the highlights section, a
manufacturer still would be required to include information about those
limitations in its promotional labeling and advertisements in
accordance with applicable regulations. It is essential that
promotional labeling and advertisements be consistent with the
comprehensive prescribing information because the highlights section
does not include all the information needed to prescribe a drug safely
and effectively, and is thus not intended to act as a substitute for
the comprehensive prescribing information. This responsibility is
described in the introductory paragraph of proposed Sec. 201.57(a)
which provides that, in order to comply with Secs. 202.1(e) and
201.100(d)(1), statements made in promotional labeling and
advertisements must be consistent with all information included in
labeling under proposed Sec. 201.57(c) (i.e., the comprehensive
prescribing information).
Several comments received on Prototype 3 strongly supported
inclusion of a highlights section in the labeling. One comment stated
that the section ``would impart key information of most common interest
to prescribers'' and ``would be a concise and clear means of displaying
information.'' Another comment stated that the highlights section
serves ``as an excellent vehicle for drawing the practitioner's
attention to the most important facts and precautions associated with a
product'' and that ``[c]ross-referencing each point in the summary to
the underlying complete prescribing information further enhanced the
summary's value.''
Other comments on Prototype 3 opposed inclusion of a highlights
section. Several comments contended that practitioners might rely
solely on this section and fail to read the comprehensive prescribing
information. One comment stated that ``it is difficult, if not
impossible, for summary information to adequately deliver the complete
message regarding complicated prescribing information'' and ``the mere
availability of a summary, even if it is followed by the complete
information, discourages a time-pressured human being from reviewing
the pertinent sections of the complete prescribing information.''
It is unrealistic to expect practitioners to read every word of
product labeling each time they reference it, regardless of how
desirable it may be for them to do so. Therefore, FDA is proposing to
add the highlights section to prescription drug labeling to draw
attention to those sections of the labeling that are most important,
and to do so in a way that readily facilitates and encourages more
detailed followup. For example, certain kinds of information that are
now potentially lost in a long list of topics under ``Precautions''
would be identified and described at least briefly in the highlights
section.
Other comments expressed concern about the inclusion of a
highlights section because of its potential effect on product
liability. The comments stated that including a highlights section
would force manufacturers to pick and choose only certain parts of the
warning information listed in the comprehensive information. One
comment stated that this ``would allow an expert witness testifying on
behalf of a patient who suffered an adverse reaction that was listed in
the full prescribing information to argue that a manufacturer's warning
was inadequate or ``buried'' because that specific adverse reaction was
not also highlighted in the Summary.''
The agency recognizes that prescription drug labeling may be used
as evidence in product liability cases and other types of civil actions
to determine, among other things, whether a manufacturer has adequately
disclosed information about risks associated with its drug. However,
the agency believes that it is highly speculative to assert that,
because certain risk information has been summarized in or omitted from
the highlights section of prescription drug labeling (but included in
its entirety in the comprehensive prescribing information), a
manufacturer may be found liable in a
[[Page 81088]]
product liability action based on a theory that the warning is
``buried.''
Moreover, although the highlights section would not include all
information about risks associated with a drug, the agency believes
that, as described in this proposal, the highlights section would
include the most important information regarding drug-related risks. As
discussed below in section III.B.1.j. of this document, the ``Warnings/
Precautions'' section of the highlights would include those ADR's that
are most relevant to clinical prescribing situations. This would
include both rare but life-threatening drug reactions and less serious
but more common reactions that may be important from a clinical
standpoint when prescribing a drug. Additionally, this section of the
highlights would include, under its own subheading, the most common or
frequently occurring ADR's that are reasonably associated with the use
of the drug, which for most drugs would be those ADR's with an
incidence of greater than 1 percent.
Nevertheless, the highlights section is not intended to act as a
substitute for the comprehensive prescribing information, and it is
extremely important for practitioners to be aware of this and to review
all relevant sections of the comprehensive prescribing information
before making prescribing decisions. Thus, in response to the comments'
concerns, to generally aid in avoiding misunderstandings about the
purpose of the highlights section by health care practitioners and
others, and to encourage practitioners to review the relevant sections
of the comprehensive prescribing information, the agency is proposing
two modifications to Prototype 3. First, FDA is proposing that the
introductory section be entitled ``Highlights of Prescribing
Information.'' This title more appropriately acknowledges that the
section does not comprehensively summarize all sections of product
labeling. Second, the following statement would be required to be
presented in bold print, at the end of the highlights section: ``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.'' The agency is seeking comment on whether the inclusion of a
highlights section would have a significant effect on manufacturers'
product liability concerns and, if so, whether this concern has been
adequately addressed in this proposal. If it is believed that product
liability concerns have not been adequately addressed, the agency seeks
comment on whether it could take different or additional measures to
alleviate product liability concerns without eliminating the highlights
section altogether, or lengthening it to an extent that it would no
longer serve its intended purpose.
a. Product names and other basic information. Proposed
Sec. 201.57(a)(1) would require that information necessary to identify
a drug product--the proprietary name and the established name or, for
biologics, the proper name (as defined in Sec. 600.3 (21 CFR 600.3))
and any informative descriptors--be the first information that appears
in the highlights section. This information would be followed by the
product's dosage form and route of administration. For drugs that are
controlled substances, the controlled substance symbol designating the
schedule in which the controlled substance is listed must also be
included in this section. In accordance with Sec. 1302.04 (21 CFR
1302.4), the symbol must be clear and large enough to afford prompt
identification of the controlled substance.
b. Inverted black triangle. Proposed Sec. 201.57(a)(2) would
require placement of the ``\'' symbol if the drug has been approved in
the United States for less than 3 years and contains a new molecular
entity (NME) or new biological product, a new combination of active
ingredients, is indicated for a new population, is administered by a
new route, or uses a novel drug delivery system. It is well recognized
that many important ADR's are not discovered until several years of
marketing have elapsed. FDA believes that providing an easily
recognizable symbol to serve as a signal for increased vigilance and
reporting of suspected adverse reactions will facilitate faster
recognition of rare but serious side effects that may be associated
with newly marketed products and help ensure that drugs are used with
particular care during their initial years of marketing. The inverted
black triangle symbol is currently used in the United Kingdom to alert
prescribers to the fact that a product contains a new active ingredient
or is indicated for a new route of administration, among other things.
FDA recognizes that U.S. prescribers' experience with the \ symbol is
limited and that it will take time and an educational program to
familiarize them with it. FDA believes that efforts to educate the
public about this symbol, as well as general education concerning
revisions to the labeling format, can be largely accomplished through
the agency's routine outreach and education programs.
c. Prescription drug symbol. Proposed Sec. 201.57(a)(3) would
require placement of the ``Rx '' symbol to indicate that the
drug is a prescription drug.
d. Highlighted boxed warning. Proposed Sec. 201.57(a)(4) would
require that the full text of boxed warning(s) or contraindication(s)
required by proposed Sec. 201.57(c)(1) be included in the highlights
section, provided that the text does not exceed 20 lines. For boxed
warnings longer than 20 lines, the proposed section would require a
statement, not to exceed 20 lines, summarizing the contents of the
boxed warning. The agency has tentatively concluded that the proposed
limit of 20 lines of text, together with a ``pointer'' to the full
boxed warning (discussed below) and any other pertinent information in
the comprehensive prescribing information, is sufficient to disclose
the most important aspects of the warning for the purposes of the
highlights section. However, because of the importance of the
information in the boxed warning, the agency requests comment on
whether the full text of any boxed warning should be included in the
highlights, regardless of the length of its text.
The agency is proposing to require that the text of all boxed
warnings in the highlights section be preceded by an appropriate
heading, in uppercase letters, that contains the signal word
``WARNING'' and describes the subject of the warning. For example, an
appropriate heading for a boxed warning regarding use of the drug
product during pregnancy could be entitled ``WARNING REGARDING USE IN
PREGNANCY'' or a warning about agranulocytosis could be entitled
``WARNING: AGRANULOCYTOSIS.'' When the agency determines that a
contraindication must be placed inside a box, the heading should
reflect that the information inside the box is a contraindication. For
example, an appropriate heading for a contraindication against use in
pregnant women could be ``WARNING: DO NOT USE IN PREGNANT WOMEN.''
Research on the effectiveness of warning labels has consistently shown
that the use of a signal word to attract attention increases the
effectiveness of warnings (Ref. 3). Both the text of the summary
statement and the heading would be required to be contained within a
box and bolded. The signal word and title would be required to be in
uppercase letters to provide for additional prominence.
In addition to the requirements discussed above, proposed
Sec. 201.57(a)(4) would require that, for boxed warning(s) or
contraindication(s)
[[Page 81089]]
that must be summarized because it exceeds 20 lines of text, a
statement be placed immediately under the heading that states: ``See
for full boxed warning.'' This statement would alert practitioners to
the fact that the boxed warning statement appearing in the
``Highlights'' section does not constitute the full boxed warning.
e. Recent labeling changes. Proposed Sec. 201.57(a)(5) would
require the subheading title ``Recent Labeling Changes'' (instead of
the title ``New Information'' in Prototype 3) to indicate that this
section of the labeling includes recent FDA approved or authorized
substantive labeling changes, not other kinds of new information, such
as information that is in the scientific literature, but not approved
or authorized by FDA for inclusion in labeling. Minor or nonsubstantive
changes, such as changes in an address, correction of typographical
errors, or grammatical changes, would not be required to be included
under this section. The agency is proposing to require that the
``Recent Labeling Changes'' section remain for at least 1 year after
the date of the labeling change. In response to the comments, the
section would be permitted to be retained, after the expiration of the
1-year period, until the next labeling revision. FDA is requesting
comments, however, concerning whether there should be a time limit by
which the section must be removed. To ensure that practitioners are
aware of the date of the most recent labeling revision, FDA is
proposing, under Sec. 201.57(a)(16), that the highlights section
prominently include the date of the most recent labeling revision.
f. Indications and usage. Proposed Sec. 201.57(a)(6) would require
the heading ``Indications and Usage,'' followed by a concise statement
of each of the product's indications, as specified in proposed
Sec. 201.57(c)(2), with any appropriate subheadings. This information
must include major limitations of use (e.g., particular subsets of the
population, second line therapy status, antimicrobials limited to
certain microorganisms). At the public meeting, the agency requested
public comment about whether the information required under this
heading should be presented verbatim from the comprehensive labeling
section or summarized in a bulleted format. Although FDA received
strong support for the latter, it remains interested in receiving
further comment on this subject.
g. Dosage and administration. Proposed Sec. 201.57(a)(7) would
require the heading ``Dosage and Administration,'' followed by
highlights of the comprehensive prescribing information proposed under
Sec. 201.57(c)(3), with any appropriate subheadings. Information under
this heading would consist of the most common dosage regimen(s) and the
most important moderating information, such as different doses for
population subsets, critical monitoring requirements, and other
therapeutically important information. If different dosage regimens are
associated with different indications or patient populations, this
information should be summarized as succinctly as possible. As
discussed above, many physicians in the initial focus groups stated
that tabular presentation of dosage and administration information is
useful. The agency encourages development of such a format and provides
in Prototype 4 one example of a tabular presentation of different
dosage regimens for different indications.
h. How supplied. Proposed Sec. 201.57(a)(8) would require the
heading ``How Supplied,'' followed by a concise summary of information
concerning the product's dosage form(s) under proposed
Sec. 201.57(c)(4). This would ordinarily include the metric strength or
strengths of the dosage form and whether the tablets are scored. If
appropriate, the information in this section heading could include
subheadings to specify different dosage forms (e.g., tablets, capsules,
suspension).
i. Contraindications. Proposed Sec. 201.57(a)(9) would require the
heading ``Contraindications,'' followed by a concise summary of the
comprehensive prescribing information in proposed Sec. 201.57(c)(5),
and any appropriate subheadings.
j. Warnings/precautions. Proposed Sec. 201.57(a)(10) would require
the heading ``Warnings/Precautions,'' followed by a concise summary of
the most clinically significant aspects of the comprehensive
prescribing information in proposed Sec. 201.57(c)(6), with any
appropriate subheadings. The cautionary information chosen from the
comprehensive prescribing information for inclusion in this section
should be that which is most relevant to clinical prescribing
situations. Rare but life-threatening drug reactions must be included,
especially when the likelihood of occurrence can be reduced by taking
recommended steps (e.g., by monitoring, by checking the patient's
history or current medication use, or through informing patients which
symptoms to look for and report immediately). However, seriousness of
reaction should not be the only criterion. It may be just as, if not
more, important from a clinical standpoint for a prescriber to know
about a less serious, but common and irritating adverse reaction likely
to reduce compliance with drug therapy in many patients. Thus, in
determining whether specific cautionary information should be included
in the highlights section, consideration should be given to a
combination of factors, including the seriousness of an adverse
reaction and its frequency of occurrence, whether steps can be taken to
avoid the adverse reaction or identify and treat it at an early stage,
and the likelihood that the reaction could affect patient compliance or
continuation of therapy. These factors should be assessed in light of
how they would affect a health care practitioner's decision to
prescribe the particular drug in a clinical setting and how the
practitioner would use and monitor the drug.
The agency is also proposing that the ``Warnings/Precautions''
heading in the highlights section include the subheading ``Most Common
Adverse Reactions ( n/100).'' This subheading would
typically list the most common or frequently occurring ADR's that are
reasonably associated with the use of the drug from the adverse
reactions section under proposed Sec. 201.57(c)(9). As stated in the
report of the Council for International Organizations of Medical
Sciences (CIOMS) Working Group III report entitled ``Guidelines for
Preparing Core Clinical-Safety Information on Drugs'' (Ref. 4), common
ADR's include those with an incidence of greater than 1 in 100 (i.e., 1
percent). Therefore, the agency believes that, for most drugs, it would
be appropriate to report ADR's with an incidence of greater than 1
percent. However, for those drugs that are associated with a very large
number of ADR's, and/or for which many of the ADR's occur at an
incidence rate of more than 1 percent, it may be appropriate to report
in the highlights section only those ADR's associated with incidences
of 2, 3, 4, or 5 percent, or more. The incidence rate that is used to
determine inclusion in this subsection would be required to be
disclosed in parentheses together with this subheading.
k. Contacts for ADR reporting. Proposed Sec. 201.57(a)(11) would
require, for drug products other than vaccines, the following statement
be placed in the highlights section following ``Warnings/Precautions'':
``To report SUSPECTED SERIOUS ADR's, 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
[[Page 81090]]
statement would be required: ``To report SUSPECTED SERIOUS ADR's, call
(insert name of manufacturer) at (insert manufacturer's phone number)
or VAERS at (insert the current VAERS number).'' In partnership with
many professional associations and private sector groups, FDA has
consistently encouraged the reporting of suspected serious adverse drug
reactions. The proposed section would alert practitioners to the
importance of reporting suspected serious ADR's and provide convenient
reporting contacts.
l. Drug interactions. Proposed Sec. 201.57(a)(12) would require the
heading ``Drug Interactions,'' followed by a concise summary from the
comprehensive prescribing information in proposed Sec. 201.57(c)(7) of
other prescription or over-the-counter drugs or foods that interact in
clinically significant ways with the product, with any appropriate
subheadings.
m. Use in specific populations. Proposed Sec. 201.57(a)(13) would
require the heading ``Use in Specific Populations,'' followed by a
concise listing of any clinically important differences in response to
or use of the drug in specific populations from the comprehensive
prescribing information in proposed Sec. 201.57(c)(8), with any
appropriate subheadings. With respect to pregnancy categories, the
agency does not believe that prescribers would find it helpful to
include in the highlights section the category for the drug or selected
animal data related to use of the drug during pregnancy. Thus,
manufacturers should include under this heading only that information
concerning use of the drug during pregnancy that is provided under the
``Contraindications'' or ``Warnings/Precautions'' sections of the
highlights. In the absence of such information, the availability of
human data regarding use during pregnancy should be briefly noted.
n. Referral to patient counseling information. Proposed
Sec. 201.57(a)(14) would require, where applicable, the verbatim
statement ``See P for Patient Counseling Information.'' This statement
would inform practitioners of the existence of patient counseling
information and allow them to easily access the information. As
discussed below in the description of Sec. 201.57(c)(17), patient
counseling information is intended to help practitioners communicate
important drug information to patients. For drugs that have approved
patient labeling or Medication Guides, the following statement would be
required: ``See P for Patient Counseling Information, followed by
(insert name of drug)'s (insert either approved patient labeling or
Medication Guide).''
o. Highlights reminder. Proposed Sec. 201.57(a)(15) would require
that the labeling 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.'' As discussed
previously, this statement would be a prominent reminder to
practitioners that the highlights section is not intended to be an all-
inclusive source of drug prescribing information.
p. Labeling revision date. As discussed previously, proposed
Sec. 201.57(a)(16) would require that the highlights section include
the date of the most recent labeling revision, identified as such. The
inclusion of this date in the highlights section would indicate to
practitioners precisely when the ``recent labeling changes'' identified
under Sec. 201.57(a)(5) were incorporated into the labeling.
q. Index numbers in the highlights section. Proposed
Sec. 201.57(a)(17) would require that any subheadings required by
paragraphs (a)(4) through (a)(10), (a)(12), and (a)(13), as well as
additional subheadings included in the highlights under
Sec. 201.56(d)(5), be followed in parentheses by their corresponding
index number (i.e., the number appearing before required subheadings
under Sec. 201.56(d)(1) or assigned to optional subheadings in
accordance with Sec. 201.56(d)(5)). The agency is proposing the use of
a numbering system to facilitate the cross-referencing of specific
topics between the highlights section, the index, and the comprehensive
prescribing information. As discussed in the following section III.B.2,
several comments supported this numbering system.
2. Comprehensive Prescribing Information: Index
Proposed Sec. 201.57(b) would require the heading ``Comprehensive
Prescribing Information: Index'' followed by a list that contains each
subheading required under Sec. 201.56(d)(1), if not omitted under
Sec. 201.56(d)(3), and each optional subheading included in the
comprehensive prescribing information under Sec. 201.56(d)(5). Each
subheading would be required to be preceded by its corresponding index
number or identifier. The agency is proposing to require this indexing
system to make it easier for practitioners to access specific topics
included in the comprehensive prescribing information and to facilitate
hypertext links in electronic labeling that will be available in the
near future.
In general, the comments on Prototype 3 supported the indexing
system. For example, one comment stated that when standardized across
all approved drug product labeling, this system will provide a useful
mechanism for facilitating electronic retrieval of information by
subject area and will enable practitioners to more quickly and easily
locate needed data. Some comments stated that the index should be used
in place of the highlights section because the index alone is
sufficient to direct the reader to the appropriate information. In
contrast, one comment asserted that the use of index numbers in the
highlights section that cross-reference the comprehensive prescribing
information would be sufficient without inclusion of an index.
As discussed above, the purpose of the highlights section is to
highlight only the labeling information that practitioners considered
to be most important. The index, in contrast, is intended to make it
easier for the practitioner to access any details in the comprehensive
prescribing information, regardless of the perceived importance of the
information. Although both sections contribute to enabling
practitioners to more easily access, read, and use prescription drug
labeling information, the highlights section and the index serve
separate and distinct purposes. Therefore, FDA is proposing to include
both sections in prescription drug labeling. However, FDA requests
comment on whether the additional purposes served by the index are
sufficient to justify its inclusion in labeling.
3. Comprehensive Prescribing Information
The agency is proposing to revise the content and format of the
comprehensive prescribing information contained in current Sec. 201.57
to make it easier for health care practitioners to access, read, and
use the labeling information. The proposal would reorder the
information to place more prominently those sections that the agency
found, based on the physician surveys, focus groups, public comments,
and its own experience, to be most important and most commonly
referenced by practitioners. In most cases, this would require moving
the information closer to the beginning of the comprehensive section.
The agency is also proposing to reorganize certain sections of the
labeling, to require standardized index numbers for each subheading,
and certain other format and content changes.
[[Page 81091]]
a. Proposed Sec. 201.57(c)(1)--boxed warning. Under the current
``Warnings'' section (Sec. 201.57(e)), labeling must describe serious
adverse reactions and potential safety hazards, limitations in use
imposed by them, and steps that should be taken if they occur. The
section provides that, ``Special problems, particularly those that may
lead to death or serious injury, may be required by the Food and Drug
Administration to be placed in a prominently displayed box.'' If a
boxed warning is required, ``its location will be specified by the Food
and Drug Administration.'' Under the current regulation, boxed warnings
have frequently been placed at or near the beginning of labeling to
increase their prominence and accessability. However, this has not
always been the case.
The proposal would move the language describing when boxed warnings
may be required from Sec. 201.57(e) to Sec. 201.57(c)(1). The agency is
proposing to move this requirement out of the ``Warnings'' section
because, in the past, information required to be placed within a box
has consisted of contraindications information as well as warnings
information. Proposed Sec. 201.57(c)(1) would revise the language in
current Sec. 201.57(e) to specify that a box is appropriate for
contraindications information as well as warnings information.
Additionally, because of the importance of the information contained in
boxed warnings, the agency believes that boxed warnings should always
be placed before other labeling information. Accordingly, proposed
Sec. 201.57(c)(1) would require that any boxed warning(s) be the first
substantive information to appear in the comprehensive prescribing
information section of prescription drug labeling. As with the boxed
warning in the highlights section, the agency is proposing to require
that the boxed warning in the comprehensive labeling section be
preceded by an appropriately descriptive heading, placed within the
box, that contains the signal word ``WARNING,'' and a brief descriptive
title in uppercase letters. The heading may be general (e.g.,
``WARNING: USE IN PREGNANCY'') or specific (e.g., ``WARNING:
INTERACTION WITH CYP3A4 INHIBITORS'').
The agency is proposing to require that, for indexing purposes, the
boxed warning be preceded by an exclamation point ``!'' instead of the
number ``1.'' This is appropriate because index numbers will be
standardized across all products, yet many products do not have a boxed
warning. Therefore, if the number ``1'' were to be used in conjunction
with boxed warnings for the relatively few products that have a boxed
warning, the highlights and comprehensive prescribing information for
the many products without a boxed warning would begin with the index
number ``2,'' which might be confusing. In addition, the agency
believes that the exclamation point is an appropriate icon to help
alert prescribers to the importance of the information contained in the
boxed warning. However, other icons could be considered, such as an
open hand that signals ``stop'' or, if labeling is in color, a red
octagon that signals ``stop.'' The agency requests comments on the
relative benefits and costs of different icons that could be associated
with a boxed warning.
b. Proposed Sec. 201.57(c)(2)--indications and usage. Under current
Sec. 201.57(c), a drug product's indications must be included after the
``Description'' and ``Clinical Pharmacology'' sections of labeling. The
section requires, among other things, that indications be supported by
substantial evidence of effectiveness based on adequate and well-
controlled studies, unless the requirement is waived under Sec. 201.58
(21 CFR 201.58) or Sec. 314.126(c) (21 CFR 314.126(c)). \6\
---------------------------------------------------------------------------
\6\ Current Secs. 201.57(c) and 201.58 inadvertently refer to
waiver under Sec. 314.126(b) instead of (c). The agency is proposing
to correct these references in the current rulemaking.
---------------------------------------------------------------------------
Under proposed Sec. 201.57(c)(2), the ``Indications and Usage''
section would be placed more prominently toward the beginning of the
comprehensive prescribing section than it is currently. Proposed
Sec. 201.57(c)(2)(i) would modify current Sec. 201.57(c)(1) to remove
certain examples of indications that have become outdated. Section
201.57(c)(2)(ii) would modify current Sec. 201.57(c)(2) to clarify that
indications or uses not included in the ``Indications and Usage''
section may not be implied or suggested in other sections of labeling.
Proposed Sec. 201.57(c)(2)(iii) would be added to address
biological drug products subject to licensing under section 351 of the
Public Health Service Act (the PHS Act) (42 U.S.C. 262). The proposed
section would make clear that substantial evidence of effectiveness
must support indications for biological drug products. Under section
351 of the PHS Act, FDA approves BLA's on, among other things, a
demonstration that the biological product that is the subject of the
application is safe, pure, and potent. Potency has long been
interpreted to include effectiveness (Sec. 600.3(s)).
In 1972, FDA initiated a review of the safety and effectiveness of
all previously licensed biologics. The agency stated then that proof of
effectiveness would consist of controlled clinical investigations as
defined in the provision for ``adequate and well controlled studies''
for new drugs, Sec. 314.126, unless waived as not applicable to the
biological product or essential to the validity of the study when an
alternative method is adequate to substantiate effectiveness
(Sec. 601.25(d)(2) (21 CFR 601.25(d)(2) (the biologics efficacy
review)). One example of such an adequate alternative was identified to
be serological response data where a previously accepted correlation
with clinical effectiveness exists.
Although the biologics efficacy review regulation, Sec. 601.25,
references Sec. 314.126, and the Food and Drug Administration
Modernization Act of 1997 (the Modernization Act) directs FDA to take
measures to minimize differences between the review and approval of
BLA's and NDA's, Sec. 314.126 does not expressly apply to BLA's.
However, FDA believes that it is appropriate to take the
characteristics of an adequate and well-controlled clinical
investigation, as described in Sec. 314.126, into account in evaluating
the sufficiency of evidence of effectiveness that sponsors submit in
BLA's to satisfy the licensure standards in section 351 of the PHS Act.
(See FDA's guidance for industry entitled ``Providing Clinical Evidence
of Effectiveness for Human Drugs and Biological Products,'' May 1998.)
Proposed Sec. 201.57(c)(2)(iv)(A) would modify current
Sec. 201.57(c)(3) to specify that if evidence is available to support
the safety and effectiveness of the drug or biologic only in selected
subgroups of the larger population with the disease or condition, or if
evidence to support the indication is based on surrogate endpoints, the
limitations in the usefulness of the drug (or, in the case of surrogate
endpoints, the limitations of the supporting efficacy data) must be
described succinctly. Reference should be made to the ``Clinical
Studies'' section (proposed Sec. 201.57(c)(15)) for a detailed
discussion of the specific methodology and clinical data relevant to
the limitation. The agency anticipates that this change would
facilitate a more focused ``Indications and Usage'' section for the
practitioner seeking basic information. For those practitioners seeking
more detailed information, the reference to the ``Clinical Studies''
section should be sufficient to signal that additional information is
available.
Current Sec. 201.57(c)(3)(iv) permits the agency to require a
statement that there is a lack of evidence supporting a drug's
[[Page 81092]]
effectiveness for a use or condition if there is a common belief that a
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 shows that
the drug is ineffective. Proposed Sec. 201.57(c)(2)(iv)(D) would modify
the current section to permit the agency to require a statement that
there is a lack of evidence that a drug is safe for a use or condition
when the preponderance of the evidence shows that the therapeutic
benefits of the product do not generally outweigh its risks. The agency
believes that the current language is too limiting in that it only
addresses products that are shown to be ineffective for a particular
use or condition. This fails to address products that may be effective,
but pose an unacceptable safety risk for the condition or use.
c. Proposed Sec. 201.57(c)(3)--dosage and administration; proposed
Sec. 201.57(c)(4)--how supplied/storage and handling. Under current
Sec. 201.57, the ``Dosage and Administration'' and ``How Supplied''
headings appear toward the end of prescription drug labeling. Under
``Dosage and Administration,'' labeling must state the usual dose and
dosage range, the recommended intervals between doses, duration of
treatment, and any modification of doses needed in special patient
populations, among other information. Under ``How Supplied,'' labeling
must include the strength of the dosage form, units in which the dosage
form is ordinarily available, information appropriate to the
identification of the dosage form, and special handling and storage
conditions.
Based on the DPI survey and focus groups conducted by FDA, the
agency has determined that the information contained in these sections
is important to practitioners and frequently referenced by them.
Accordingly, the agency is proposing to move both sections closer to
the beginning of the comprehensive prescribing section to facilitate
access to them. In addition, the agency is proposing that the current
heading ``How Supplied'' be changed to ``How Supplied/Storage and
Handling'' to emphasize the placement of storage and handling
information in the section, which may otherwise be overlooked by
practitioners. The proposal would add a provision to the current dosage
and administration section stating that, where established and when
clinically important, efficacious and/or toxic drug and/or metabolite
concentration ranges and therapeutic concentration windows for drug
and/or metabolite(s) must be stated in this section. The proposed
section would also require information on therapeutic drug
concentration monitoring (TDM) when TDM is clinically necessary.
Finally, the current dosage and administration section would be revised
to specify that dosing regimens must not be implied or suggested in
other sections of labeling if not included in this section.
d. Proposed Sec. 201.57(c)(5)--contraindications. Current
Sec. 201.57(d) requires contraindications to be placed immediately
following indications. The section requires labeling to describe those
situations in which a drug should not be used because the risk of use
clearly outweighs any possible benefit. Proposed Sec. 201.57(c)(5)
would incorporate the current section without substantive change.
e. Proposed Sec. 201.57(c)(6)--warnings/precautions. Warning and
precautionary information currently appears under two separate headings
in accordance with Sec. 201.57(e) and (f), respectively. Under
``Warnings,'' labeling must describe serious adverse reactions and
potential safety hazards, limitations in use imposed by them, and steps
that should be taken if they occur. Under the heading ``Precautions,''
labeling must contain, among other things, information regarding any
special care to be exercised by the practitioner for safe and effective
use of the drug (current Sec. 201.57(f)(1)) and information on
laboratory tests that may be helpful in following a patient's response
or in identifying possible adverse reactions (current
Sec. 201.57(f)(3)).
To make this information easier to use, the agency is proposing to
combine the ``Warnings'' information required by current Sec. 201.57(e)
with the ``Precautions'' information required by current
Sec. 201.57(f)(1) and (f)(3) into one heading entitled ``Warnings/
Precautions.'' As discussed below, the remaining information covered in
current Sec. 201.57(f) would be presented under new proposed section
headings.
Observations and suggestions from the physician focus groups
discussed in section II of this document, combined with FDA's
experience, have convinced the agency that the distinction between
warnings and precautions is perceived by prescribers as being
relatively arbitrary and frequently not clinically meaningful. FDA
first attempted to address these concerns by combining the Warnings and
Precautions sections in the labeling prototype presented at the public
hearing (i.e., Prototype 3). That prototype, however, continued to
account for differences in the types of information required in the
current Warnings and Precautions sections by creating subsections that
distinguished more specifically between ``Hypersensitivity Reactions,''
``Major Toxicities,'' and ``General Precautions.''
After further consideration, FDA believes that the clinical
relevance of an adverse reaction is not always related to the
seriousness of the reaction. For example, if a drug is associated with
two adverse reactions (one serious, but very rare, and another less
serious, but extremely common), it may be as important from a clinical
standpoint, if not more so, for a prescriber to know about the less
serious reaction as it is to know about the serious reaction. This is
especially true where the less serious reaction may affect compliance
with drug therapy for many patients. In addition, for certain products,
a warning about a serious but nonpredictable ADR may be less clinically
meaningful than the recommendation for routine monitoring to detect a
relatively less serious but predictable ADR. Accordingly, the proposed
``Warnings/Precautions'' section would substitute the terminology
``clinically significant adverse reaction'' for the terminology
``serious adverse reactions'' in the current ``Warnings'' section to
clarify that clinically significant adverse reactions must be included
under the section. In addition, the proposed rule would not require
adverse reactions selected for inclusion in the ``Warnings/
Precautions'' section to be distinguished by specific standardized
headings on the basis of seriousness or other criteria. However,
certain adverse reactions (including those that result in
contraindications) may be serious enough to warrant being placed inside
a box under proposed Sec. 201.57(c)(1). FDA requests comment about
whether the lack of standardized headings in the ``Warnings/
Precautions'' section is appropriate. If it is believed that specific
standardized headings are appropriate, FDA requests comment about what
they should be.
Proposed Sec. 201.57(c)(6)(iv) would require, where applicable, a
brief notation of the information that is currently required under
Sec. 201.57(f)(4)(ii) (i.e., information on known interference of a
drug with laboratory tests) and a reference to the detailed labeling
information. As discussed below, under the proposal the detailed
labeling information would be moved from its present location under
``Precautions'' to a separate ``Drug Interactions'' section. The agency
is proposing this requirement to alert practitioners to the existence
of important laboratory test interference information without making
the ``Warnings/Precautions'' section unnecessarily lengthy.
[[Page 81093]]
Proposed Sec. 201.57(c)(6)(v) would require, for drug products
other than vaccines, the inclusion of the statement ``To report
SUSPECTED SERIOUS ADR's, 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 SUSPECTED SERIOUS ADR's, call (insert name of
manufacturer) at (insert manufacturer's phone number) or VAERS at
(insert the current VAERS number).'' As discussed above, inclusion of
these statements would also be required in the highlights section. The
agency believes that inclusion of these statements in both places would
contribute to the communication of this important information. FDA is
requesting comments, however, concerning whether this additional
requirement constitutes unnecessary repetition.
As discussed in further detail below, the remaining information
currently required to appear under the ``Precautions'' section would be
reorganized into new section headings. The agency believes that this is
appropriate because some of the information currently included under
``Precautions'' is in fact not cautionary (e.g., a negative
carcinogenicity study or lack of drug interactions). Other information
currently included may be cautionary, but was deemed to be sufficiently
important to be included under its own section heading to provide
greater emphasis and ease of access. The proposal would move the
information required by current Sec. 201.57(f)(2) (``Information for
patients'') to proposed Sec. 201.57(c)(17); move the information
required by current Sec. 201.57(f)(4) (``Drug interactions'') to
proposed Sec. 201.57(c)(7); move the information required by current
Sec. 201.57(f)(5) (``Carcinogenesis, mutagenesis, impairment of
fertility'') to proposed Sec. 201.57(c)(14); and move the information
required by current Sec. 201.57(f)(6) through (f)(10) (``Pregnancy,''
``Labor and delivery,'' ``Nursing mothers,'' ``Pediatric use,'' and
``Geriatric use'') to proposed Sec. 201.57(c)(8).
f. Proposed Sec. 201.57(c)(7)--drug interactions. Under current
Sec. 201.57(f)(4), ``Drug interactions'' is a subsection under
``Precautions.'' The subsection requires the inclusion of practical
guidance for the practitioner on preventing clinically significant
drug/drug and drug/food interactions that may occur in patients taking
the drug. Specific drugs with which the labeled drug interacts in vivo
must be identified, and the mechanisms of action briefly noted.
Proposed Sec. 201.57(c)(7) would move ``Drug interactions'' from
current Sec. 201.57(f)(4) to create a separate section with the same
heading. The agency believes that placing this information in a
separate section under its own heading would draw attention to this
area of increasingly recognized importance. This change was supported
both by focus group participants and by comments received on the
prototype.
g. Proposed Sec. 201.57(c)(8)--use in specific populations. Under
current Sec. 201.57(f)(6) through (f)(10), information on specific
populations (i.e., ``Pregnancy,'' ``Labor and Delivery,'' ``Nursing
mothers,'' ``Pediatric use,'' and ``Geriatric use'') is placed under
``Precautions.'' The agency is proposing to move this information to
its own section entitled ``Use in Specific Populations.'' FDA believes
that by establishing a more descriptive heading for this information,
and separating the information from other types of information
currently required to appear under the precautions section, the
information would be easier to find and use.
Current Sec. 201.57(f)(6)(i)(d) and (f)(6)(i)(e) require the
labeling of drug products in Pregnancy Categories D and X to contain
the statement ``* * * 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 the fetus.'' Proposed
Sec. 201.57(c)(8)(i)(A)(4) and (c)(8)(i)(A)(5) would modify this
statement to read: ``If this drug is administered to a woman with
reproductive potential, the patient should be apprised of the potential
hazard to a fetus.'' The agency is proposing this revision to alert
practitioners to the risk of prescribing the drug to any woman of child
bearing age, since such a woman can be in the first trimester of
pregnancy and be unaware that she is pregnant. This caution would
highlight to prescribers the importance of considering the pregnancy-
related effects of drugs, especially those used on a chronic basis, for
women who may become pregnant as well as those who are already
pregnant. The agency is also currently considering other initiatives to
revise pregnancy labeling that may be proposed in the future. However,
because of the importance of the current revision, the agency believes
that it is appropriate to propose it immediately.
Proposed Sec. 201.57(c)(8)(iii) would change the subheading
``Nursing mothers'' to ``Lactating Women'' to recognize the role of
women who may nurse an infant but are not the mother, as well as women
who produce breast milk for others' use. Proposed
Sec. 201.57(c)(8)(iii)(B) and (c)(8)(iii)(C) would substitute the
terminology ``clinically significant adverse reactions'' for the
``serious adverse reaction'' terminology in current
Sec. 201.57(f)(8)(i) and (f)(8)(ii) to clarify that all clinically
significant adverse reactions, not just those that are classified as
serious, must be taken into consideration when placing the required
precautionary statements in labeling. Minor conforming changes would
also be made to the section.
Under proposed Sec. 201.57(c)(8)(vi), the agency would permit
additional subsections representing other types of patient
subpopulations to be included under the ``Use in Specific Populations''
section if sufficient data are available concerning the use of the drug
in the subpopulations (e.g., hepatically or renally impaired or
immunocompromised populations).
h. Proposed Sec. 201.57(c)(9)--adverse reactions. Current
Sec. 201.57(g) defines adverse reaction as an ``undesirable effect,
reasonably associated with the use of the drug, that may occur as part
of the pharmacological action of the drug or may be unpredictable in
its occurrence.'' Proposed Sec. 201.57(c)(9) would revise the
definition of adverse drug reaction to read: ``An adverse reaction is a
noxious and unintended response to any dose of a drug product for which
there is a reasonable possibility that the product caused the
response.''
The revised definition of ``adverse reaction'' in proposed
Sec. 201.57(c)(9) is consistent with the definition of ``adverse drug
reaction'' developed by the International Conference on Harmonisation
of Technical Requirements for Registration of Pharmaceuticals for Human
Use (ICH) in a final ICH guideline entitled ``Clinical Safety Data
Management: Definitions and Standards for Expedited Reporting'' (60 FR
11284, March 1, 1995) (the ICH E2A guideline). The ICH E2A guideline
defines an adverse drug reaction as follows:
All noxious and unintended responses to a medicinal product
related to any dose should be considered adverse drug reactions. The
phrase `response to medicinal products' means that a causal
relationship between a medicinal product and an adverse event is at
least a reasonable possibility, i.e., the relationship cannot be
ruled out.
ICH was formed to facilitate international consideration of issues,
particularly safety issues, concerning the use of global data in the
[[Page 81094]]
development and use of drugs and biological products. ICH has worked to
promote the harmonization of technical requirements for products among
three regions: The European Union (EU), Japan, and the United States.
As discussed in further detail below, FDA believes that adoption of the
proposed definition of ``adverse reaction'' will result in a more
focused ``Adverse Reactions'' section and will promote consistency in
labeling worldwide. Moreover, the agency is currently in the process of
developing a proposed rule revising its adverse event reporting
regulations for drugs and biological products, and the revised
definition of ``adverse reaction'' in proposed Sec. 201.57(c)(9) is
consistent with definitions being considered by the agency for
inclusion in that rulemaking. FDA will ensure that the term is
consistently defined in both regulations.
The definition of ``adverse reaction'' in proposed Sec. 201.57
would change the current definition in two respects. It would
substitute the terminology ``a noxious and unintended response to any
dose of a drug product'' for ``an undesirable effect.'' This change in
terminology would clarify that only those responses that are noxious
(i.e., injurious to health) and unintended, rather than all effects
that are undesirable (which does not necessarily imply either that the
effect is injurious or unintended) may be included in the ``Adverse
Reaction'' section of labeling. In addition, the proposed definition
would substitute the terminology ``for which there is a reasonable
possibility that the product caused the response'' for ``reasonably
associated with the use of the drug, that may occur as part of the
pharmacological action of the drug or may be unpredictable in its
occurrence.'' The agency is proposing this change in terminology
because the ``reasonably associated'' language in the current
definition can be and in many cases has been interpreted as meaning
that a reaction should be included merely if there is a temporal
association, rather than a reasonable causal association, between a
response and a drug. This has resulted in the inclusion of information
in the ``Adverse Reactions'' section of labeling that is not meaningful
to prescribers and which dilutes the usefulness of the clinically
meaningful information. The revised definition would clarify that at
least a reasonably plausible causal relationship must exist between a
drug and a noxious and unintended response for the response to be
included as an adverse reaction in the ``Adverse Reactions'' section of
labeling.
i. Proposed Sec. 201.57(c)(10)--drug abuse and dependence; proposed
Sec. 201.57(c)(11)--overdosage. Labeling sections ``Drug Abuse and
Dependence'' and ``Overdosage'' are currently required to appear in
labeling under Sec. 201.57(h) and (i), respectively. Proposed
Sec. 201.57(c)(10) and (c)(11) would incorporate the current sections
without change.
j. Proposed Sec. 201.57(c)(12)--description. Under current
Sec. 201.57(a), the ``Description'' section appears at the beginning of
prescription drug labeling and requires certain basic information about
the drug such as the proprietary and established name of the drug and
its dosage form and route of administration.
Under proposed Sec. 201.57(c)(12), the information would be moved
toward the end of product labeling, but retain its current placement in
relation to the ``Clinical Pharmacology'' section. Movement of the
description section reflects the findings of the focus group studies
and physician surveys that the information in the section is less
important than other labeling information that would be required under
proposed Sec. 201.57(c)(1) through (c)(11). In addition, the most
important information prescribers need from the description section,
the proprietary or established name of the drug (or, for biologics, the
proper name), is required to appear at the beginning of the highlights
section under proposed Sec. 201.57(a)(1).
k. Proposed Sec. 201.57(c)(13)--clinical pharmacology. Under
current Sec. 201.57(b), the ``Clinical Pharmacology'' section appears
near the beginning of prescription drug labeling, immediately following
the ``Description'' section. The section requires a concise factual
summary of the product's clinical pharmacology and actions. The section
includes absorption, distribution, metabolism, excretion, elimination,
pharmacokinetic, and pharmacodynamic (i.e., concentration in body
fluids associated with therapeutic and/or toxic effects) information
important for safe and effective use of the drug, if known. The section
may include information based on in vitro or animal data if the
information is essential to a description of the biochemical and/or
physiological mode of action of the drug or is otherwise pertinent to
human therapeutics. Under current Sec. 201.57(b)(2), in vitro or animal
data related to the activity or efficacy of a drug that have not been
shown to be pertinent to clinical use by adequate and well-controlled
clinical studies are generally prohibited except in two specific
circumstances: (1) 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''; and (2) in vitro and animal data for classes of drugs
other than anti-infectives may be included if a waiver is granted under
Sec. 201.58 or Sec. 314.126(c).
Under proposed Sec. 201.57(c)(13), the section would be moved
toward the end of product labeling. Movement of the section reflects
prescribing physicians' reports, as demonstrated in the physician
surveys, that the clinical pharmacology information appearing in this
section is used less often than other labeling information. In
addition, the current positioning of this sometimes lengthy section,
just before the ``Indications and Usage'' section, may make it more
difficult and time consuming to find the latter section, which is more
commonly referred to by practitioners. This revised placement of the
clinical pharmacology section would also be consistent with the
practice of the EU, which requires this information be placed toward
the end of its Summary of Product Characteristics (the EU's equivalent
of approved product labeling). Clinical pharmacology information that
is relevant to other labeling sections and affects practitioners'
prescribing concerns may be placed in other sections of the
comprehensive prescribing information and/or highlights. For example,
clinically important information related to special populations or drug
interactions may appear under ``Special Populations'' or ``Drug
Interactions.'' Similarly, clinically important information related to
efficacious and/or toxic drug concentration ranges may appear under
``Dosage and Administration.'' Therefore, the agency does not believe
that the placement toward the end of product labeling of clinical
pharmacology information that is less likely to be used is
objectionable to the majority of prescribers.
The proposal would revise current Sec. 201.57(b)(1) to require that
the information currently required under that section be presented
under three separate subsections entitled ``Mechanism of action,''
``Pharmacodynamics,'' and ``Pharmacokinetics.'' Where a category of
information is not available for a specific drug, the labeling would be
required to contain a statement about the lack of information. The
information required under these subsections is substantially similar
to currently required information. The changes are
[[Page 81095]]
intended primarily to enhance the clinical pharmacology section's
organization and clarity. In addition, an optional subsection entitled
``Other clinical pharmacology information'' has been added to permit
the presentation of information that is not covered by the three
required subsections but is helpful to optimal use and understanding of
the clinical pharmacology of the drug or biological product.
Information within this section could include information related to
the clinical pharmacology of drug/drug interactions or use in specific
populations. The agency also is proposing that, if specific data on
alternative dosing regimens (e.g., for hepatically or renally impaired
patients) appears in the ``Clinical Pharmacology'' section, it must
also appear in the ``Dosage and Administration'' section.
The proposal also would revise current Sec. 201.57(b)(2) such that
in vitro data related to the activity or efficacy for all drugs,
including anti-infective drugs, could be included only if a waiver is
granted under Sec. 201.58 or 314.126(c). Since issuing the current
regulations, extensive in vitro data has been included for nearly all
anti-infective drugs. The agency believes that, despite the disclaimer
concerning their lack of clinical relevance, inclusion of these data in
approved product labeling creates the misleading impression that a
product's in vitro action represents sufficient information to treat
infections with the listed pathogens in humans. In vitro data alone do
not provide information about factors critical to effective therapy,
including tissue levels of the product necessary to cure the treated
infection, and appropriate length of treatment. Such information is
often essential to help ensure safe and effective use and avoid the
development of antimicrobial resistance. More specifically, using anti-
infectives at subtherapeutic levels for the wrong time period
facilitates the development of antimicrobial resistance. Consequently,
FDA believes that ``in vitro only'' labeling information, in
contributing to the inappropriate prescribing of anti-infectives, may
also be contributing to the further development of antimicrobial
resistance for many drugs. Therefore, the proposal would treat the
inclusion of in vitro data for anti-infective drugs in labeling the
same as other data that have not been shown by adequate and well-
controlled clinical studies to be pertinent to clinical use (i.e., such
data may be included only if a waiver is granted under Sec. 201.58 or
Sec. 314.126(c)).
l. Proposed Sec. 201.57(c)(14)--nonclinical toxicology. Current
Sec. 201.57(f)(5) requires a subsection entitled ``Carcinogenesis,
mutagenesis, impairment of fertility'' to appear in the labeling under
``Precautions.'' The subsection must state whether long-term studies in
animals have been performed to evaluate carcinogenic potential and, if
so, the species and results of the studies. The section also requires a
description of reproduction studies or other animal data, if any,
revealing a problem or potential problem concerning mutagenesis or
impairment of fertility. Under current Sec. 201.57(l), a section
entitled ``Animal Pharmacology and/or Animal Toxicology'' may be placed
near the end of labeling to include animal data related to the safety
or efficacy of a drug, if the data cannot be appropriately incorporated
into other labeling sections.
Proposed Sec. 201.57(c)(14) would move current Sec. 201.57(f)(5)
and (l) under a new section heading entitled ``Nonclinical
Toxicology.'' The agency believes that the proposed title for the
section accurately describes the nature and purpose of the animal data
commonly included under both of these sections. Movement of the
information under current Sec. 201.57(f)(5) toward the end of the
comprehensive labeling section reflects the agency's findings that this
section is less important than other labeling information that would be
required before it.
m. Proposed Sec. 201.57(c)(15)--clinical studies. Current
Sec. 201.57(m) permits, but does not require, that a ``Clinical
Studies'' section appear near the end of prescription labeling in the
place of a detailed discussion of a subject that is of limited interest
but nonetheless important. The section also permits a reference to be
made to a clinical study in any labeling section if the study is
essential to understanding the available information.
Proposed Sec. 201.57(c)(15) would revise current Sec. 201.57(m) to
require a separate heading entitled ``Clinical Studies.'' The section
would be required to contain a discussion of clinical study results
that are important to a prescriber's understanding of the basis for
approval of the drug product, including the extent of the product's
benefits, how the drug was used in clinical trials, who was studied,
and critical parameters that were monitored. The agency is proposing to
require inclusion of this information to provide practitioners with
more accurate and specific information about a drug's efficacy that
could help them to make informed prescribing decisions. The proposed
section would revise current Sec. 201.57(m) to specify that a brief
reference to a specific important clinical study or studies may be
placed in any labeling section, but any detailed discussion of the
study's methodology and results must be included in the ``Clinical
Studies'' section, to which the reader would be directed. This change
is being proposed to make it easier for practitioners to find clinical
studies information, which has typically (although not invariably) been
included in either the ``Indications and Usage'' or ``Clinical
Pharmacology'' sections. Language has also been added to this section
to reinforce the prohibition in proposed Sec. 201.57(c)(2) against
implying or suggesting uses or dosing regimens for a product that are
not included in its ``Indications and Usage'' or ``Dosing and
Administration'' sections.
n. Proposed Sec. 201.57(c)(16)--references. Proposed
Sec. 201.57(c)(16)(i) would state that if the reference is cited in
labeling in the place of a detailed discussion of data and information
concerning an indication for or use of a drug or biological product,
the reference must be based upon an adequate and well-controlled
clinical investigation under Sec. 314.126(b) or, for a biological
product, upon substantial evidence of effectiveness. This section
incorporates current Sec. 201.57(m), as it relates to the use of
references, without substantive change except for the addition of the
language for biologics. The section would be assigned the letter ``R''
as an identifier for indexing purposes instead of the index number
``15.'' This would permit, where appropriate, the insertion of
nonstandardized headings between the ``Nonclinical Toxicology'' and
``References'' sections without affecting the standard index numbering
system (i.e., additional nonstandardized headings would be assigned the
index number ``15,'' ``16,'' and so on).
o. Proposed Sec. 201.57(c)(17)--patient counseling information.
Current Sec. 201.57(f)(2) requires a subsection entitled ``Information
for Patients'' to appear in labeling under ``Precautions.'' The
subsection requires labeling to include information to be given to
patients for the safe and effective use of a drug. In addition, the
subsection requires that any printed patient information required to be
distributed to a patient be referenced under the ``Precautions''
section and its full text printed at the end of labeling.
Based on the results of the physician survey and the comments
received on Prototype 3, proposed Sec. 201.57(c)(17) would retitle the
heading of the information required under current Sec. 201.57(f)(2)
from ``Information for Patients'' to ``Patient Counseling
Information.'' The proposed change would clarify that the information
under this section is not intended to be
[[Page 81096]]
distributed to patients, but is intended to facilitate practitioner
counseling of patients. To further clarify this, the phrase ``to be
given to patients'' in current Sec. 201.57(f)(2) would be changed to
``useful for patients to know.'' The agency is proposing to use the
letter ``P'' to identify the section for indexing purposes, rather than
an index number, for the same reasons that the letter ``R'' has been
used as an identifier for the references section (see the previous
discussion of the ``References'' section). Finally, the agency is
proposing that the section be moved from its current location under
``Precautions'' to a separate section at the end of the comprehensive
prescribing information. This would ensure that patient counseling
information would immediately precede any approved patient labeling or
Medication Guide, which would be required to be reprinted immediately
following it. Under the proposal, all approved printed patient
information or Medication Guides would be required to be referenced in
this section and reprinted following the ``Patient Counseling
Information'' section, regardless of whether the information is
required by regulation to be distributed to the patient.
4. Format Requirements
Although current Secs. 201.56 and 201.57 set forth required
headings and a required order for prescription drug labeling
information, they do not contain requirements for a minimum type size
or other graphical elements.
FDA has determined, based on the focus group and survey results
described in section II of this document, that the typically lengthy
and undifferentiated format of prescription drug labeling makes it
difficult to locate and read specific information. Proposed
Sec. 201.57(d) would set forth new minimum standards and requirements
for the format of prescription drug labeling to improve its legibility,
readability, and usability.
The agency believes that optimum labeling formats can be created
only by permitting the flexible application of graphical techniques.
However, the agency has also determined that it is necessary to
establish minimum standards and requirements for certain key graphic
elements to ensure an acceptable base level of readability for
prescription drug labeling. Type size, letter and line spacing,
contrast, print and background color, and type style are all factors
that may affect the readability of labeling information (Ref. 5).
Accordingly, the proposal would establish minimum standards and
requirements for many of these key graphic elements while leaving
manufacturers extensive flexibility to implement their own ideas in
labeling design.
Proposed Sec. 201.57(d)(1) would require that all headings and
subheadings be highlighted by bold type that prominently distinguishes
the headings and subheadings from other information.
Proposed Sec. 201.57(d)(2) would require that a horizontal line
separate the three major sections of information proposed in
Sec. 201.57(a), (b), and (c). The agency believes that horizontal lines
will distinctively separate each section of important information to
make it more conspicuous and easier to read.
The agency is proposing to require in Sec. 201.57(d)(3) that the
headings specified in paragraphs (a)(4) through (a)(10), (a)(12),
(a)(13), and (a)(14) of Sec. 201.57 be highlighted in two ways. First,
these headings must be presented in bold type. Second, these headings
must be presented in the center of a horizontal line that provides a
visual demarcation from the preceding section. For example, the heading
``Recent Labeling Changes'' could be presented as follows:
``-----Recent Labeling Changes-----''
To maintain flexibility in the application of graphical techniques,
the agency would permit the horizontal line to consist of a series of
horizontal icons (see, e.g., Prototype 4). The agency believes that a
visual separation of each section of important information would
facilitate search and readability.
Proposed Sec. 201.57(d)(4) would require the use of bullet points
to distinguish multiple subheadings listed under proposed
Sec. 201.56(d)(5) in paragraphs (a)(4) through (a)(10), (a)(12), and
(a)(13) of Sec. 201.57. For example, if there is more than one
subheading listed under the ``Indications and Usage'' heading, these
subheadings would be preceded by a bullet point. The agency is not
proposing to specify a graphical icon for bulleted points.
Proposed Sec. 201.57(d)(5) would require that the labeling
information required by paragraphs (a)(1) through (a)(4), (a)(11), and
(a)(15) of Sec. 201.57 be highlighted by bold print. The agency
requests comment on whether the proposed use of bolding in all of these
sections will serve its intended purpose of ensuring visual prominence,
or if different highlighting methods, such as the use of different
colors, may be equally or more effective.
Proposed Sec. 201.57(d)(6) would require that the letter height or
type size for all labeling information, headings, and subheadings set
forth in paragraphs (a), (b), and (c) of this section be a minimum of 8
points. FDA believes that this minimum type size would make it easier
for practitioners to read labeling information and thus help to ensure
the safe and effective use of prescription drug products. The rationale
for the use of 8-point type size is discussed below.
There are no clear recommendations in the literature with regard to
minimum type size for medical practitioners or other ``experts'' in a
field. Type size can affect visibility and reading speed (Ref. 6).
Early studies of how type size affects the speed of reading suggest
that 8-point type is read significantly more slowly than 10-point type
(Ref. 7). Newspapers, which are targeted to the general public, are
usually printed in 8-point type (Ref. 8). However, the smallest
recommended font size for the general public typically is 10-point,
while larger font sizes are recommended for populations where low-
literacy, age, or impaired vision are significant factors (Refs. 9, 10,
and 11). A recent guidance document issued by a national collaborative
group recommending format parameters for written patient prescription
medicine materials recommended that 10- or 12-point type be used for
this information, also noting that 12-point type is generally
recommended for older persons. Because many prescribers are older and
subject to the same limitations as others in reading print materials,
this would suggest the use of a minimum of 10- or perhaps even 12-point
type for prescription drug labeling. FDA performed a cost analysis,
discussed in section X of this document, comparing the cost of
requiring 10- versus 8-point type in prescription drug labeling. The
analysis shows that there would be significant additional costs
associated with producing and packaging 10-point type size labeling
versus 8-point. Thus, although 10-point type size would clearly be
better than 8-point with regard to its legibility, FDA is proposing to
require the use of 8-point type to minimize the economic impacts on
industry. However, the agency solicits
[[Page 81097]]
comments on minimum type size requirements, and in particular on
whether the benefits of 10-point type justify its additional costs and
should therefore be required.
Proposed Sec. 201.57(d)(7) would require that the index numbers
required by paragraphs (c)(1) through (c)(17) of Sec. 201.57 be
presented in bold print and 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).
Proposed Sec. 201.57(d)(8) would limit the length of the highlights
section by requiring that the information under proposed
Sec. 201.57(a), except for any boxed warning information required under
Sec. 201.57(a)(4), be limited in length to an amount that, if printed
in 2 columns on one side of a standard size 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. The length restriction is being proposed in response to certain
comments and the agency's concerns that, without setting a definitive
limit on the amount of information that may be included in the
highlights section, there will not be sufficient incentive to make the
difficult, but necessary decisions about inclusion of specific
information. As discussed above, the purpose of the highlights section
is to provide a concise extract of the most important information from
the comprehensive prescribing information. If too much information is
included, the section would no longer serve its intended purpose.
However, the agency recognizes that there may be circumstances under
which this limited amount of information may be inadequate to
communicate appropriately even the highlights of a product's labeling.
Therefore, the agency requests comments on whether the proposed space
limitation is adequate or whether there are alternatives that would be
more appropriate and under what circumstances such alternatives should
be considered.
Proposed Sec. 201.57(d)(9) would require that labeling sections in
the comprehensive prescribing information containing recent changes
identified in Sec. 201.57(a)(5) be highlighted by a vertical line on
the left edge of the new or modified text. Given the extensive amount
of information in the comprehensive prescribing information section,
this additional graphic emphasis should make it easier for
practitioners to identify modified labeling information. In addition,
this graphic device will allow those practitioners who are reading the
comprehensive information thoroughly to identify new labeling
information without referring back to the highlights section.
Nonetheless, FDA invites comments on other means that could be used to
facilitate access to, and identification of, new labeling information
for both casual and indepth readings.
C. Revisions to Labeling for Older Drugs
As discussed in sections II and IV of this document, older drugs
not subject to the revised labeling content and format requirements
would remain subject to the requirements in current Sec. 201.57. Under
the proposed rule, current Sec. 201.57 would be redesignated as
Sec. 201.80 to permit the revised content and format requirements for
new drugs to be designated as Sec. 201.57. In addition to the
redesignation of the current section, the proposed rule would make
certain revisions to the content of current Sec. 201.57. The content
revisions being proposed in redesignated Sec. 201.80 are consistent
with certain revisions in proposed Sec. 201.57 for newer drugs and
would help to ensure that statements currently appearing in the
labeling of older drugs relating to effectiveness or dosage and
administration are sufficiently supported. As discussed in section IV
of this document, these content changes would be required to be made
within 1 year of the effective date of the final rule.
Proposed Sec. 201.80(b)(2) would replace current Sec. 201.57(b)(2).
Under the proposed section, in vitro or animal data related to the
activity or efficacy for all drugs, including anti-infective drugs,
that have not been shown by adequate and well-controlled studies to be
pertinent to clinical use, could be included in the labeling only if a
waiver is granted under Sec. 201.58 or Sec. 314.126(c). The agency is
proposing this limitation because the inclusion of data showing that a
drug product is effective against certain pathogens in vitro may lead
practitioners to believe that the drug product is effective for
treatment of infections or other illnesses in humans involving those
pathogens. However, in vitro action alone is generally not sufficient
to demonstrate effectiveness in humans. Therefore, under the proposal,
in vitro data that does not meet the revised requirements would be
required to be removed from the ``Clinical Pharmacology'' labeling
section of older approved drug products.
Proposed Sec. 201.80(c)(2)(i) and (c)(2)(ii) would replace current
Sec. 201.57(c)(2). Proposed Sec. 201.80(c)(2)(i) would incorporate
current Sec. 201.57(c)(2) and modify it to include the requirement that
indications or uses must not be implied or suggested in sections of
labeling other than ``Indications and Usage'' if not included in that
section. This change is consistent with the change in proposed
Sec. 201.57(c)(2)(ii). Proposed Sec. 201.80(c)(2)(ii) is the same as
proposed Sec. 201.57(c)(2)(iii), and would be added to address
biological drug products subject to licensing under section 351 of the
PHS Act. As discussed in section III of this document, the proposed
section would make clear that substantial evidence of effectiveness
must support indications for biological drug products.
Proposed Sec. 201.80(f)(2) would replace the current ``Information
for Patients'' section. The proposed section would modify the current
section to require that any approved patient information or Medication
Guide, not just those that are required by regulation to be distributed
to patients, be referenced in the ``Precautions'' section and reprinted
immediately following the last section of labeling. The agency believes
that including this information in professional labeling will
facilitate practitioner access to the information and improve their
ability to communicate to patients information that the agency and
sponsor believe is important.
Proposed Sec. 201.80(j) would modify current Sec. 201.57(j)
(``Dosage and Administration'') to clarify that dosing regimens must
not be implied or suggested in other sections of labeling if not
included in this section.
Proposed Sec. 201.80(m)(1) would modify current Sec. 201.57(m)(1)
to state that, for biological products, references do not have to be
based upon, and clinical studies do not have to constitute, adequate
and well-controlled studies. This change is being made to address
biological products subject to licensing under section 351 of the PHS
Act. In addition, the section would be modified to clarify that
clinical studies and references must not imply or suggest indications,
uses, or dosing regimens not stated in the ``Indications and Usage'' or
``Dosage and Administration'' sections.
IV. Proposed Implementation Plan
A. General Implementation Scheme for the Revised Format and Content
Requirements
The proposed implementation plan for the revised labeling format
and content requirements in proposed Secs. 201.56(d) and 201.57 is
summarized in table 1.
[[Page 81098]]
Table 1.--Implementation Plan
------------------------------------------------------------------------
Time by Which Conforming
Applications (NDA's, BLA's, and Efficacy Labeling Must Be
Supplements) Required to Conform to New Submitted to the Agency
Labeling Requirements for Approval
------------------------------------------------------------------------
Applications submitted on or after the Time of submission
effective date of the final rule.
Applications pending at the time of the 3 years after the
effective date of the final rule and effective date of the
applications approved 0 to 1 year before the final rule.
effective date of the final rule.
Applications approved 1 to 2 years before the 4 years after the
effective date of the final rule. effective date of the
final rule.
Applications approved 2 to 3 years before the 5 years after the
effective date of the final rule. effective date of the
final rule.
Applications approved 3 to 4 years before the 6 years after the
effective date of the final rule. effective date of the
final rule.
Applications approved 4 to 5 years before the 7 years after the
effective date of the final rule. effective date of the
final rule.
------------------------------------------------------------------------
As discussed in section III of this document, the agency is
proposing that, with the exception of the requirements discussed in
section IV.C and IV.D of this document, the content and format
revisions apply only to products with applications (i.e., NDA's, BLA's,
and efficacy supplements) pending at the time of the effective date of
the final rule, products for which such applications are submitted on
or after the effective date of the final rule, and products with such
applications that were approved up to and including 5 years before the
effective date of the final rule. Thus, the proposed content and format
requirements would not apply to products with applications that were
approved more than 5 years before the effective date of the final rule,
unless an efficacy supplement was approved for such products in the 5
years before the effective date of the final rule or is submitted after
the effective date of the final rule. As discussed in section III of
this document, these older products would remain subject to the
labeling requirements in current Sec. 201.57, which under the proposal
would be redesignated as Sec. 201.80.
The agency believes that applying the requirements only to more
recently approved products is appropriate because, as discussed
previously in section II of this document, physicians are more likely
to refer to the labeling of recently approved products than the
labeling of older products. Additionally, the labeling of recently
approved products is likely to be longer and more complex than that of
older products and thus more in need of the proposed format revisions.
Finally, even though certain older products will remain subject to the
current format and content requirements (as revised by the proposal),
many products not initially covered by the revised format and content
requirements will at some point submit efficacy supplements, and thus
will be required to revise their labeling to conform to the revised
format and content requirements.
The agency intends to make the final rule based on this proposal
effective 120 days after the date of its publication in the Federal
Register. As indicated in table 1, the time by which revised labeling
for products with applications would be required to be submitted would
depend on when the application was approved. Applications (NDA's,
BLA's, and efficacy supplements) submitted for review on or after the
effective date of the final rule would be required to include labeling
in the new format as part of the application. Sponsors of products with
applications pending at the time the final rule becomes effective and
applications approved before the effective date of the final rule would
be required to submit labeling supplements for approval on a staggered
basis beginning 3 years after the effective date of the final rule. The
proposed implementation scheme would require revised labeling to be
submitted for newer products first, followed by older products. This
plan is intended to minimize the rule's economic impact by providing
manufacturers with sufficient time to design and print new labeling and
deplete existing stocks of products with old labeling. At the same
time, newer products for which revised labeling is most essential will
either have revised labeling or will revise labeling at the earliest
possible date.
B. Implementation of Proposed Content and Format Revisions to Products
Approved or Submitted for Approval Under an ANDA
Under section 505(j)(2) of the act (21 U.S.C. 355(j)(2)) and
Secs. 314.94(a)(8) and 314.127(a)(7) (21 CFR 314.94(a)(8) and
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
(see 21 CFR 314.93) or because the generic and innovator products are
manufactured by different manufacturers. Thus, whether a prescription
drug product that was approved under an ANDA before the effective date
of the final rule, or that is submitted for approval under an ANDA
after the effective date of the final rule, will be required to have
labeling that complies with the final rule will depend on the status of
the labeling of the listed drug referenced in the ANDA. Where a
reference listed product's labeling conforms to the requirements of the
final rule (i.e., where the NDA for the product was submitted after the
effective date of the final rule, the NDA for the product was pending
on or submitted within 5 years before the effective date of the final
rule and the labeling has been required to be revised under the
implementation scheme, or the labeling for the product was revised by
the sponsor to comply with the final rule voluntarily), the generic
product that references the listed drug in its ANDA would be required
to have labeling that is the same as the listed product and would
therefore be required to comply with the final rule. On the other hand,
where a reference listed product's labeling does not conform to the
requirements of the final rule (i.e., the product was approved more
than 5 years before the effective date of the final rule, or the final
rule applies to the product but the product's labeling is not yet
required to be revised under the implementation scheme), a generic
product that references the product in its ANDA would not be required
to have labeling that complies with the final rule.
C. Implementation of Proposed Content Requirements Applicable to Newer
and Older Drugs
The agency is proposing that the revised content requirements for
newer drugs in proposed Sec. 201.57(c)(2)(ii), (c)(2)(iii), (c)(3),
(c)(13)(ii), and (c)(15)(i), and the revised content requirements for
older drugs at proposed Sec. 201.80(b)(2), (c)(2)(i) and (c)(2)(ii),
(j), and (m)(1), be implemented no later than 1 year after the
effective date of the final rule. The agency believes that the changes
necessary for existing product labeling
[[Page 81099]]
to comply with these sections could be made without prior FDA approval,
that is, with a supplement explaining the changes at the time the
applicant makes them under Sec. 314.70(c) (21 CFR 314.70(c)) or
Sec. 601.12(f) (21 CFR 601.12(f)) (i.e., a ``Changes Being Effected''
supplement). FDA is proposing a broad and prompt implementation of
these sections because the agency believes that the requirements
proposed in the sections are necessary to help ensure that the
information in labeling regarding a drug product's indications or uses
is not misleading, and to help ensure that the staggered implementation
scheme does not give a marketing advantage to certain products.
In accordance with the discussion above, the proposed sections
would be implemented as follows. Proposed Sec. 201.57(c)(2)(ii) and
(c)(2)(iii) and proposed Sec. 201.80(c)(2)(i) and (c)(2)(ii) would
require that indications or uses not included in the ``Indications and
Usage'' section not be implied or suggested in other sections of
labeling. Thus, any implied or suggested indication or use for a drug
not included in the ``Indications and Usage'' section would have to be
removed from the labeling by 1 year after the effective date of the
final rule. Similarly, proposed Sec. 201.57(c)(3) and proposed
Sec. 201.80(j) would require that dosing regimens not included in the
``Dosage and Administration'' section be removed from other sections of
labeling. Proposed Sec. 201.57(c)(15)(i) and proposed Sec. 201.80(m)(1)
would require that any clinical study that is discussed that relates to
an indication for or use of a drug be adequate and well-controlled as
described in Sec. 314.126(b), except for biological products, and
relate only to indications, uses, or dosing regimens stated in the
``Indications and Usage'' or ``Dosage and Administration'' sections.
Thus, any discussion of a clinical study or studies related to
indications, uses, or dosing regimens not included in the ``Indications
and Usage'' or ``Dosage and Administration'' sections would have to be
removed. Finally, under proposed Sec. 201.57(c)(13)(ii) and proposed
Sec. 201.80(b)(2), in vitro or animal data related to the activity or
efficacy of a drug that have not been shown by adequate and well
controlled studies to be pertinent to clinical use would be required to
be removed by 1 year after the effective date of the final rule unless
a waiver is granted to permit inclusion of the data.
D. Implementation of Proposed Sec. 201.57(c)(17) and Proposed
Sec. 201.80(f)(2)
Proposed Sec. 201.57(c)(17) would require that any approved printed
patient information or Medication Guide be reprinted immediately
following ``Patient Counseling Information.'' Proposed
Sec. 201.80(f)(2) would require that any approved printed patient
information or Medication Guide be reprinted immediately following the
last section of labeling. The agency is proposing that these
requirements be implemented by 1 year after the effective date of the
final rule. Sponsors of newer products subject to the revised format
and content requirements in proposed Sec. 201.57 would have to comply
with the requirement in proposed Sec. 201.57(c)(17) before revising
other sections of labeling. These sponsors would be required to reprint
the approved patient labeling or Medication Guide following the last
section of labeling (e.g., generally after ``How Supplied'' or
``References''). The agency is proposing this broad and prompt
implementation to help ensure that practitioners have access to printed
patient information or Medication Guides.
E. Voluntary Submission of Labeling Conforming to Proposed Content and
Format Requirements
Sponsors of drug products that are not required under the proposed
rule to comply with the revised format and content requirements may
voluntarily submit revised labeling for approval by the agency.
F. Relationship of Proposed Requirements to Other Prescription Drug
Labeling Initiatives
The format and content revisions discussed in this proposal are the
most extensive of many prescription drug labeling revision initiatives
that are being considered by the agency. The agency will provide
information on additional labeling initiatives, and how the agency
intends to coordinate their implementation, at a later date.
V. Revisions to Prescription Drug Labels \7\
---------------------------------------------------------------------------
\7\ The proposed changes would not affect the label
requirements, set forth in parts 600 through 680 (21 CFR parts 600
through 680), for most biological products. As specified in
Sec. 601.2(c)(3), the label requirements described in Sec. 610.62 do
not apply to those biological products listed in Sec. 601.2(c)(1).
However, CBER is currently evaluating how it can best address the
concerns regarding drug product labels discussed under section V of
this document.
---------------------------------------------------------------------------
In addition to revising its regulations governing the format and
content of labeling for prescription drugs, the agency is proposing
minor revisions to the information required to appear on prescription
drug product labels.\8\ The proposed changes are intended to lessen
overcrowding of prescription drug product labels by eliminating
unnecessary statements and moving to the package insert less critical
information that is currently required to appear on the product label.
The agency believes that overcrowding of drug product labels makes
reading critical information on these labels more difficult and may be
one possible cause of medication errors by health care
practitioners.\9\ Thus, the agency hopes that by reducing the amount of
required information on product labels and simplifying them, the number
of medication errors will be reduced. It is estimated that at least one
death every day is attributable to a medication error (Ref. 12). From
January 1992 to May 1997, FDA's Center for Drug Evaluation and Research
(CDER) has received approximately 6,000 reports of errors (actual or
potential). Approximately 50 percent or 3,000 of these reports were
attributable to the labeling, packaging, and/or design of the drug
product.
---------------------------------------------------------------------------
\8\ Under section 201(k) of the act, the term label means a
display of written, printed, or graphic matter upon the immediate
container of an article.
\9\ The term ``medication error'' is a general term used to
refer to many types of errors associated with medication use
including improper dosage, wrong strength or concentration, wrong
drug or dosage form, use of the drug for an improper duration, or
use on the wrong patient.
---------------------------------------------------------------------------
The proposed changes are consistent with the recommendations of the
joint United States Pharmacopeia (USP)-FDA Advisory Panel on
Simplification and Improvement of Injection Labeling, which was formed
to explore ways to avoid medication errors associated with overcrowded
product labels.\10\ The proposed changes are also consistent with the
recommendations of an independent task force, the Committee to Reduce
Medication Errors, which studied ways to reduce medication errors by
improving label legibility.\11\ Although the recommendations of the
joint USP-FDA advisory panel and the committee were targeted primarily
at labels for injection products, the agency believes that they will
help to reduce medication errors for all dosage forms. Thus, the
proposed changes would apply to all types of drug products. A
[[Page 81100]]
detailed description of the proposed changes follows.
---------------------------------------------------------------------------
\10\ The recommendations were published in the Pharmacopeial
Forum (Ref. 13).
\11\ The Committee to Reduce Medication Errors was assembled by
the State of Washington and included individuals from pharmaceutical
associations, industry, and health care practitioners.
---------------------------------------------------------------------------
Current Sec. 201.100(b)(2) requires that the label of a
prescription drug bear a statement of the recommended or usual dosage.
Current Sec. 201.55 explains that, because the dosage may vary widely
for treatment of different conditions, it may not be possible to
present an informative or useful statement of the recommended or usual
dosage in the space available on the label. Section 201.55 states that,
in this case, the requirements of Sec. 201.100(b)(2) may be met by
including on the label a statement such as ``See package insert for
dosage information,'' provided that detailed dosage information is
contained in the package insert. The proposal would revise Secs. 201.55
and 201.100(b)(2) such that, if it is not possible to place an
informative and useful statement of the recommended or usual dosage on
the label, the statement on the label would not be required. In these
cases, the dosage information would appear in the comprehensive
prescribing information section of the labeling without a statement on
the label referencing the information.
Current Sec. 201.100(b)(5) states that the label of a prescription
drug for other than oral use must bear the names of all inactive
ingredients, with some exceptions. Under current Sec. 201.57(a)(iii),
this information must also appear under the ``Description'' section in
the package insert. The proposal would eliminate current
Sec. 201.100(b)(5) so that inactive ingredient information would not
have to appear on the label. Instead, proposed Sec. 201.57(c)(12)(i)(D)
would require the information to appear in the package insert under the
section entitled ``Description.''
Current Sec. 201.100(b)(7) requires that the label of a
prescription drug bear a statement directed to the pharmacist
specifying the type of container to be used in dispensing the drug
product to maintain its identity, strength, quality, and purity. The
proposal would eliminate the requirement that this information appear
on the label and instead under proposed Sec. 201.57(c)(4)(v) require
the information to appear in the package insert under the section
entitled ``How Supplied/Storage and Handling.''
In addition to these changes to drug product labels, the agency
recently proposed a change to Sec. 201.100(b)(1) to require that the
label of prescription drugs bear the ``Rx only'' symbol,
rather than the statement: ``Caution, Federal law prohibits dispensing
without prescription.'' (See 65 FR 18934, April 10, 2000.) This change
was proposed in accordance with section 126 of the Modernization Act,
which required that the ``Rx only'' symbol replace the
longer statement. The change, when finalized in the other rulemaking,
will eliminate unnecessary verbiage in the drug product label and thus
should also contribute to the reduction of medication errors.
The proposed changes described in this section V, if finalized,
would be implemented for all new NDA's as soon as the final rule takes
effect. For products with approved or pending NDA's at the time the
final rule takes effect, the changes would be implemented as follows.
Changes affecting the labeling of a prescription drug product (i.e.,
changes made to the package insert in accordance with proposed
Sec. 201.57(c)(12)(i)(D) and (c)(4)(v)) would not be required to be
made until the first time that labeling is revised for reasons other
than to comply with the proposed requirements or 7 years after the
final rule takes effect, whichever occurs first. The proposed changes
to the container label (i.e., changes made to remove currently required
statements from the container label) should not be made until the
changes to the package insert are made. This would ensure that the
information that currently is required to appear on the container label
appears on the package insert before it is removed from the label. Once
changes to the package insert are made, the changes to the container
label would not be required until the first time the label is revised
for reasons other than to comply with the proposed requirements. Thus,
no additional printing costs would be associated with the proposed
changes and, as discussed in section X of this document, economic
impacts associated with the proposed changes would be minimal.
VI. Revisions to Secs. 201.58 and 201.100(d)(3), Rescission of
Sec. 201.59 (21 CFR 201.59)
The agency is proposing to revise Secs. 201.58 and 201.100(d)(3) to
be consistent with revisions to proposed Sec. 201.57 and the addition
of proposed Sec. 201.80 (proposed redesignated Sec. 201.57).
The agency is also proposing to rescind Sec. 201.59. Section
201.59(a) sets forth the effective date, December 26, 1979, for current
Secs. 201.56, 201.57, and 201.100(d)(3). Section 201.59(b) sets forth
the effective date, April 10, 1981, for Sec. 201.100(e). Section
201.59(a)(1), (a)(2), and (a)(3) set forth exceptions to the December
26, 1979, effective date for current Secs. 201.56, 201.57, and
201.100(d)(3) for certain categories of drugs. Section 201.59(a)(1)
sets forth an effective date of April 10, 1981, for prescription drugs
that are not biologics and not subject to section 505 of the act and
that were not subject to former section 507 of the act (21 U.S.C. 357,
repealed 1997). Section 201.59(a)(2) sets forth different effective
dates, and a schedule for submitting revised labeling, for certain
classes of prescription drugs (e.g., anticonvulsants and progestins)
that as of December 26, 1979, were: (1) A licensed biologic, (2) a new
drug subject to an approved NDA or ANDA, or (3) an antibiotic drug
subject to an approved antibiotic form. Section 201.59(a)(3) applies
the same effective dates and schedule for submitting revised labeling
in Sec. 201.59(a)(2) to drugs that are approved after December 26,
1979, that are duplicates of drugs approved on or before December 26,
1979. Because all of the effective dates and dates for submission of
revised labeling set forth in Sec. 201.59 have passed and current
Secs. 201.56, 201.57, 201.100(d)(3), and 201.100(e) have been
implemented for all categories of drugs and drug classes identified in
Sec. 201.59, Sec. 201.59 is no longer necessary and the agency is
proposing that it be removed from the regulations.
VII. Paperwork Reduction Act of 1995
This proposed rule contains information collection provisions that
are subject to review by the Office of Management and Budget (OMB)
under the Paperwork Reduction Act of 1995 (44 U.S.C. 3501-3520). A
description of these provisions is given below with an estimate of the
annual reporting burden. Included in the estimate is the time for
reviewing instructions, searching existing data sources, gathering and
maintaining the data needed, and completing and reviewing each
collection of informaiton.
FDA invites comments on: (1) Whether the proposed collection of
information is necessary for proper performance of FDA's functions,
including whether the information will have practical utility; (2) the
accuracy of FDA's estimate of the burden of the proposed collection of
information, including the validity of the methodology and assumptions
used; (3) ways to enhance the quality, utility, and clarity of the
information to be collected; and (4) ways to minimize the burden of the
collection of information on respondents, including through the use of
automated collection techniques, when appropriate, and other forms of
information technology.
Title: Requirements on Content and Format of Labeling for Human
Prescription Drugs and Biologics;
[[Page 81101]]
Requirements for Prescription Drug Product Labels.
Description: FDA is proposing to amend its regulations governing
the format and content of labeling for human prescription drug and
biologic products. The proposal would revise current regulations to
require that the labeling of new and recently approved products include
a section containing highlights of prescribing information and a
section containing an index to prescribing information, reorder
currently required information and make minor changes to its content,
and establish minimum graphical requirements. These revisions would
make it easier for health care practitioners to access, read, and use
information in prescription drug labeling and would enhance the safe
and effective use of prescription drug products. The proposal would
also amend prescription drug labeling requirements for older drugs to
require that certain types of labeling statements currently appearing
in labeling be removed if they are not sufficiently supported. Finally,
the proposal would eliminate certain unnecessary statements that are
currently required to appear on prescription drug product labels and
move other, less important information to labeling. These changes would
simplify drug product labels and reduce the possibility of medication
errors.
FDA's legal authority to amend its regulations governing the
content and format of labeling for human prescription drug and biologic
products and to amend its regulations governing the requirements for
prescription drug product labels derives from sections 201, 301, 501,
502, 503, 505, and 701 of the act (21 U.S.C. 321, 331, 351, 352, 353,
355, and 371) and section 351 of the PHS Act (42 U.S.C. 262).
A. Summary of Provisions in Proposed Rule That Contain Collections of
Information
1. Requirements on Content and Format of Labeling for Human
Prescription Drugs and Biologics (Proposed Sec. 201.56)
Current FDA regulations at Sec. 201.56 require that prescription
drug labeling contain certain information in the format specified in
current Sec. 201.57. Current Sec. 201.56 also sets forth general
requirements for prescription drug labeling, including the requirement
that labeling contain a summary of the essential scientific information
needed for the safe and effective use of the drug, that it be
informative and accurate without being promotional in tone or false or
misleading, and that labeling be based whenever possible on data
derived from human experience. In addition, current Sec. 201.56 sets
forth required and optional section headings for prescription drug
labeling and specifies the order in which those headings must appear.
The proposal would revise current Sec. 201.56 to set forth: (1)
General labeling requirements applicable to all prescription drugs; (2)
the categories of new and more recently approved prescription drugs
subject to the revised content and format requirements in proposed
Secs. 201.56(d) and 201.57; (3) the schedule for implementing the
revised content and format requirements in proposed Secs. 201.56(d) and
201.57; (4) the required and optional sections and subsections
associated with the revised format in proposed Sec. 201.57; and (5) the
required and optional sections and subsections for the labeling of
older prescription drugs not subject to the revised format and content
requirements.
2. Specific Requirements on Content and Format (Proposed Sec. 201.57)
Current Sec. 201.57 specifies the kind of information that is
required to appear under each of the section headings set forth in
Sec. 201.56. This information is intended to help ensure that health
care practitioners are provided with a complete and accurate
explanation of prescription drugs to facilitate safe and effective
prescribing. Thus, current FDA regulations already require prescription
drug labeling to contain detailed information on various topics that
may be important to practitioners.
The proposed regulations would require that prescription drug
labeling for newer products include a new section entitled ``Highlights
of Prescribing Information'' (proposed Sec. 201.57(a)) and a new
section containing an index to prescribing information (entitled
``Comprehensive Prescribing Information: Index''; proposed
Sec. 201.57(b)). The proposal would also reorder currently required
information (current Sec. 201.57, proposed as Sec. 201.57(c)
``Comprehensive Prescribing Information''), make minor content changes,
and establish minimum graphical requirements.
Proposed Sec. 201.57(a) would require that the labeling of newer
human prescription drugs contain a new section entitled ``Highlights of
Prescribing Information.'' Information under this section would be a
concise extract of the most important information already required
under current Sec. 201.57, as well as certain additional information
that the agency believes is important to prescribers.
Proposed Sec. 201.57(b) would require that the labeling of newer
human prescription drugs contain a new section entitled ``Comprehensive
Prescribing Information: Index'' and would consist of a list of all the
sections of the labeling required in the Comprehensive Prescribing
Information (proposed Sec. 201.57(c); current Sec. 201.57), preceded by
a corresponding index number or identifier.
Proposed Sec. 201.57(c) would require that the labeling of newer
human prescription drugs contain a section entitled ``Comprehensive
Prescribing Information'' and would revise the content and format of
the labeling requirements contained in current Sec. 201.57 to make it
easier for health care practitioners to access, read, and use the
labeling information. The proposal would reorder the information to
place more prominently those sections found to be most important and
most commonly referenced by practitioners. In most cases, this would
require moving the information closer to the beginning of the
comprehensive section. The proposal would also reorganize sections of
the labeling, require standardized index numbers for each subheading,
and make certain other format and content changes.
Although current Secs. 201.56 and 201.57 set forth required
headings and a required order for prescription drug labeling
information, they do not contain requirements for a minimum type size
or other graphical elements. Proposed Sec. 201.57(d) would set forth
new minimum requirements for the format of prescription drug labeling
to improve its legibility, readability, and usability. The proposal
would establish minimum requirements for key graphic elements such as
bold type, bullet points, type size, spacing, and other highlighting
techniques.
Older drugs not subject to the revised labeling content and format
requirements in proposed Sec. 201.57 would remain subject to the
requirements in current Sec. 201.57 which would be redesignated as
Sec. 201.80. In addition to the redesignation of current Sec. 201.57,
the proposed rule would make certain revisions to its content. The
content revisions being proposed are consistent with certain revisions
for newer drugs in proposed Sec. 201.57. These revisions are designed
to help ensure that labeling statements related to effectiveness or
dosage and administration are sufficiently supported.
In addition to revising the regulations governing the format and
content of labeling for prescription drugs, proposed Sec. 201.100(b)
would make
[[Page 81102]]
minor revisions to the information required to appear on prescription
drug product labels. The proposed changes are intended to lessen
overcrowding of drug product labels by eliminating unnecessary
statements and moving to the package insert less critical information
that currently must appear on the product label.
B. Estimates of Reporting Burden
1. Labeling Design, Testing, and Submission to FDA for New Applications
(Secs. 201.56 and 201.57)
Current Sec. 201.56 requires that prescription drug labeling
contain certain information in the format specified in current
Sec. 201.57, and also sets forth general requirements for prescription
drug labeling. Current Sec. 201.57 specifies the kind of information
that is required to appear under each of the section headings set forth
in Sec. 201.56. As a result of these regulations, applicants must
design drug product labeling, test the designed labeling, and prepare
and submit the labeling to FDA for approval. Based on information
received from the pharmaceutical industry, FDA estimates that it takes
applicants approximately 3,200 hours to design, test (e.g., to ensure
that the redesigned labeling will still fit into carton-enclosed
products), and submit prescription drug product labeling to FDA as part
of a new drug application. Annually, FDA receives (on average) 137 new
applications containing such labeling from approximately 101
applicants.
2. The Reporting Burdens for the General Requirements (Proposed
Sec. 201.56)
The reporting burdens for the general requirements in proposed
Sec. 201.56(a) are the same as those for current Sec. 201.56(a) through
(c), and are estimated in table 2 under current Secs. 201.56 and
201.57. Proposed Sec. 201.56(b) and (c) set forth the categories of new
and more recently approved prescription drugs subject to the revised
content and format requirements in proposed Secs. 201.56(d) and 201.57
and the schedule for implementing the revised content and format
requirements. No reporting burdens are directly associated with these
requirements. Proposed Sec. 201.56(d) sets forth the required and
optional sections and subsections associated with the revised format in
proposed Sec. 201.57. The reporting burdens for this paragraph are
estimated in table 2 under the requirements for proposed Sec. 201.57.
Proposed Secs. 201.56(e) and 201.80 set forth the labeling
requirements for older prescription drugs. These are the same as the
requirements in current Secs. 201.56 and 201.57, with one exception.
The exception is that provisions have been added in proposed
Sec. 201.80(b), (c), (f), (j), and (m) that would require certain
statements to be removed from labeling or modified within 1 year of the
effective date of the final rule. Therefore, the reporting burden
associated with proposed Secs. 201.56(e) and 201.80 will generally be
the same as that for current Secs. 201.56 and 201.57, which has been
estimated in table 2. The reporting burden for proposed Sec. 201.80(b),
(c), (f), (j), and (m) is estimated in table 2 under proposed
Sec. 201.80, and has been combined with the reporting burden for the
corresponding requirements for newer drugs in proposed Sec. 201.57(c).
3. Labeling Redesign, Testing, and Submission to FDA for Approved
Applications (Proposed Sec. 201.57(a), (b), (c), and (d))
Proposed Sec. 201.57(a) would require a new section in prescription
drug product labeling entitled ``Highlights of Prescribing
Information''; proposed Sec. 201.57(b) would require a new section in
the labeling entitled ``Comprehensive Prescribing Information: Index'';
proposed Sec. 201.57(c) would require a revision of the content and
format requirements in current Sec. 201.57 and a new title
``Comprehensive Prescribing Information''; and proposed Sec. 201.57(d)
would establish new requirements for type size and other graphical
elements. For applications approved during the 5 years before the
effective date of these new prescription drug labeling requirements,
and for applications pending on the effective date, applicants must
redesign drug product labeling, test the redesigned labeling (e.g., to
ensure that the larger labeling will still fit in carton-enclosed
products), and prepare and submit that labeling to FDA for approval.
Based on the data and information provided in the ``Analysis of
Economic Impacts'' (section X of this document), approximately 366
labeling supplements would be submitted to FDA during the period 3 to 7
years after the effective date. Approximately 145 applicants would
submit these labeling supplements, and the time required for
redesigning, testing, and submitting the labeling to FDA would be
approximately 190 hours.
4. Labeling Revision and Submission to FDA Within 1 Year for Approved
Applications (Proposed Sec. 201.57(c) and Proposed Sec. 201.80(b), (c),
(f), (j), and (m))
Under the ``Proposed Implementation Plan'' (see section IV of this
document), certain provisions under proposed Sec. 201.57(c) and
proposed Sec. 201.80 would be implemented within 1 year after the
effective date. Based on the data and information provided in the
analysis of economic impacts, approximately 1,888 labeling supplements
would be submitted to FDA during the first year after the effective
date. Approximately 145 applicants would submit these labeling
supplements, and the time required for revising and submitting the
labeling for these supplements would be approximately 38 hours.
5. Labeling Design and Testing for New Applications (Proposed
Sec. 201.57(a), (b), (c), and (d))
Under the proposed implementation plan, prescription drug labeling
in new applications submitted after the effective date must include new
sections entitled ``Highlights of Prescribing Information'' and
``Comprehensive Prescribing Information: Index,'' as well as other new
information and features not currently required in prescription drug
labeling. Based on the data and information provided in the economic
analysis, approximately 1,421 new applications would be submitted to
FDA over a 10-year period after the effective date. Approximately 145
applicants would submit these applications, and the time required for
the new labeling design and testing for each application would be
approximately 149 hours.
6. Label Revisions (Proposed Sec. 201.100(b))
In addition to revising the regulations governing the format and
content of labeling for prescription drugs, the proposal, as explained
above, would make minor revisions to the information required to appear
on prescription drug product container labels. Neither the economic
analysis nor this Paper Reduction Act analysis include burden estimates
for these label revisions because, under the proposed rule, these
changes do not have to be made until the next label revision. Thus, no
new burdens would result from these proposed label revisions.
C. Capital Costs
A small number of carton-enclosed products may require new
packaging to accommodate the longer insert. The economic analysis
estimates that 1
[[Page 81103]]
percent of both the products with new efficacy supplement changes and
the products approved in the 5 years before the effective date of the
rule would incur costs of $200,000 each for needed packaging changes.
Products approved after the effective date of the final rule would not
incur added equipment costs because their labeling and packaging are
not yet established. The estimated present costs for equipment changes
over 10 years totals $1 million.
Description of Respondents: Persons and businesses, including small
businesses and manufacturers.
Table 2.--Estimated Reporting Burden 1
----------------------------------------------------------------------------------------------------------------
Number of
21 CFR section Number of responses per Total Hours per Total hours
respondents respondent responses response
----------------------------------------------------------------------------------------------------------------
Current 201.56 and 201.57: 101 1.36 137 3,200 438,400
Labeling design, testing, and
submission to FDA for new
applications...................
Proposed 201.57(a),(b),(c), (d): 145 2.52 366 190 69,540
Labeling redesign, testing, and
submission to FDA for approved
applications...................
Proposed 201.57(c) and 201.80: 145 13.02 1,888 38 71,744
Labeling revision and
submission to FDA within 1 year
for approved applications......
Proposed 201.57(a),(b),(c), (d): 145 9.80 1,421 149 211,729
Labeling design and testing for
new applications...............
-------------------------------------------------------------------------------
Total....................... .............. .............. .............. .............. 791,413
----------------------------------------------------------------------------------------------------------------
1 There is no capital costs or operating and maintenance costs associated with this collection of information.
In compliance with the Paperwork Reduction Act of 1995 (44 U.S.C.
3507)(d), the agency has submitted the information collection
provisions of this proposed rule to OMB for review. Interested persons
are requested to send comments regarding collection of information by
January 22, 2001, to the Office of Information and Regulatory Affairs,
OMB, New Executive Office Bldg., 725 17th St. NW., rm. 10235,
Washington, DC 20503, Attn: Wendy Taylor.
VIII. Environmental Impact
The agency has determined under 21 CFR 25.30(h) 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.
IX. Executive Order 13132: Federalism
FDA has analyzed this proposed rule in accordance with Executive
Order 13132: Federalism. The Order requires Federal agencies to
carefully examine actions to determine if they contain policies that
have federalism implications or that preempt State law. As defined in
the Order, ``policies that have federalism implications'' refers to
regulations, legislative comments or proposed legislation, and other
policy statements or actions that have substantial direct effects on
the States, on the relationship between the National Government and the
States, or on the distribution of power and responsibilities among the
various levels of government.
FDA is publishing this proposed rule to revise its regulations
governing the format and content of labeling for human prescription
drug products. The proposal would revise current regulations to require
that labeling include a section containing highlights of prescribing
information and a section containing an index to prescribing
information. The proposal would also reorder currently required
labeling information and make minor changes to its content. Finally,
the proposal would establish minimum graphical requirements for
labeling. This proposal would also eliminate certain unnecessary
statements on prescription drug product labels and move other, less
important information to labeling. Because enforcement of these
labeling provisions is a Federal responsibility, there should be
little, if any, impact from this rule, if finalized, on the States, on
the relationship between the National Government and the States, or on
the distribution of power and responsibilities among the various levels
of Government. In addition, this proposed rule does not preempt State
law.
Accordingly, FDA has determined that this proposed rule does not
contain policies that have federalism implications or that preempt
State law.
X. Analysis of Economic Impacts
FDA has examined the impacts of the proposed rule under Executive
Order 12866, the Regulatory Flexibility Act (5 U.S.C. 601-612), and the
Unfunded Mandates Reform Act (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, if a rule may have a significant economic impact on a
substantial number of small entities, an agency must consider
alternatives that would minimize the economic impact of the rule on
small entities. Section 202(a) of the Unfunded Mandates Reform Act of
1995 (Public Law 104-4) requires that agencies prepare a written
assessment 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 proposed rule is consistent with the
regulatory philosophy and principles identified in Executive Order
12866 and in these two statutes. The proposed rule would amend current
requirements for the format and content of labeling for human
prescription drug and biologic products.
Based on the analysis following, as summarized in table 3, FDA
projects that the present value of the quantifiable benefits of the
proposed rule could exceed $296 million over 10 years. Direct costs
resulting from the proposed changes are projected to range from
approximately $8 million to $16.9 million in any one year, for a total
present value of approximately $94.5 million over 10 years at 7
percent. The agency thus concludes that the benefits of this proposal
substantially outweigh
[[Page 81104]]
the costs. Furthermore, the agency has determined that the proposed
rule is not an economically significant rule as described in the
Executive Order, because annual impacts on the economy are
substantially below $100 million.
The Unfunded Mandates Reform Act does not require FDA to prepare a
statement of costs and benefits for the proposed rule because the
proposed rule is not expected to result in any one-year expenditure
that would exceed $100 million adjusted annually for inflation. The
current inflation-adjusted statutory threshold is $110 million.
This rule may affect a substantial number of small entities, as
defined by the Regulatory Flexibility Act. About half of the costs
associated with relabeling are directly proportional to sales volume;
thus, products with fewer sales would be associated with relatively
lower relabeling costs. Nonetheless, it is possible that some small
firms that produce small amounts of affected drugs, or small firms that
might be required to undertake packaging modifications, may be
significantly affected by this proposed rule. The following analysis
constitutes the agency's initial regulatory flexibility analysis as
required by the Regulatory Flexibility Act.
Table 3.--Summary of Projected Quantifiable Benefits and Costs Over 10
Years
------------------------------------------------------------------------
Present
Benefits and costs Total ($ value ($
million) million)
------------------------------------------------------------------------
Benefits:
Physician time saved...................... 102.09 62.76
Adverse drug events avoided............... 345.58 233.80
-------------------------
Total benefits........................ 447.67 296.56
=========================
Costs:
Reformatting, revising, and FDA approval.. 14.68 11.62
Producing prescription drug labeling...... 81.43 54.37
PDR costs................................. 43.96 28.54
-------------------------
Total costs........................... 140.07 94.53
------------------------------------------------------------------------
A. Purpose
The objective of the proposed rule is to make it easier for health
care practitioners to find, read, and use information important to the
safe and effective prescribing of prescription pharmaceuticals (drugs
and biologics) for patient treatment. The agency has found that the
current format, while effective, can be improved to more optimally
communicate important drug information. The proposed rule is designed
to achieve this objective by amending the current format for the
labeling of human prescription drug and biological products to, among
other things, highlight frequently accessed and new information,
include an indexing system, and reorder certain information.
B. Benefits of Regulation
The expected economic benefits of this proposed rule are the sum of
the present values of: (1) The reduced time needed by health
professionals to read or review prescription drug labeling for desired
information; (2) the increased effectiveness of treatment; and (3) the
decreased number of adverse events resulting from avoidable drug-
related errors.
1. Decreased Health Professional Time
The proposed new format for prescription drug labeling (i.e.,
package inserts or professional labeling) would reduce the time
physicians, pharmacists, and other health professionals must spend
reading prescription drug labeling by highlighting frequently used
information, by including an indexing system to direct readers to more
detailed material in other sections of the labeling, and by reordering
and reorganizing the detailed material to facilitate access to
information deemed to be most important to prescribers. Although FDA is
unaware of any data estimating the total time health professionals
spend reading the labeling of prescription drugs, a 1994 FDA survey of
physicians found that 42 percent referred to 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. Even if physicians spend, on
average, only 30 seconds referring to labeling (once the labeling is at
hand), these findings imply that the cumulative amount of time spent
referring to labeling by the nation's approximately 599,000 physicians
active in patient care equals about 1.1 million hours per year (Ref.
14). If the new format reduced by 15 seconds the amount of time
physicians needed to find information on prescription drug labeling,
implementing that format for all prescription drug products would save
approximately 525,000 hours per year.
Although the proposed rule initially applies to only a small
percentage of all prescription drug labeling, its focus on the most
recently approved products includes the labeling that health
professionals are most likely to consult 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. This analysis assumes that the rule will begin affecting
labeling consultations in the second year of implementation and that it
will affect 5 percent of all consultations in that year. The percentage
of reformatted 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, until reaching 50 percent in year 10. Thus, in year 10, the time
savings for physicians is projected to equal about 264,000 hours per
year. 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. Table 4 shows the annual value of physician
time saved and indicates that the present value over 10 years equals
approximately $62.8 million.\12\ Savings in pharmacist time
[[Page 81105]]
could also be substantial, although they were not estimated.
---------------------------------------------------------------------------
\12\ Hourly income for physicians was calculated using AMA data
for the 1996 average net income of all non-Federal physicians
(exclusing residents) and average weekly workload (Jacob, J., 1998,
``Income Data Spark Debate Among Delegates,'' American Medical News,
July 13, 1998, http://frwebgate.access.gpo.gov/cgi-bin/leaving.cgi?from=leavingFR.html&log=linklog&to=http://www.ama-assn.org/sci-pubs/amnews/pick_98/anna0713.htm.) FDA's analysis assumes, on average, that physicians
work 56 hours per week for 47 weeks per year and that physician
employee benefits are 20 percent of annual income. Thus, the hourly
income of about $75 was calculated as follows: ($166,000 x 1.2)
(47 x 56). A 7 percent discount rate was used to derive the
present value of the benefit stream.
Table 4.--Annual Benefits of Regulation
----------------------------------------------------------------------------------------------------------------
Physician time Saved ($ Adverse Drug Events Total Benefits ($
million) Avoided ($ million) million)
Year -----------------------------------------------------------------------------
Current Present Current Present Current Present
value value value value value value
----------------------------------------------------------------------------------------------------------------
1................................. $0.00 $0.00 $0.00 $0.00 $0.00 $0.00
2................................. 2.00 1.75 38.40 33.54 40.40 35.29
3................................. 4.00 3.27 38.40 31.34 42.40 34.61
4................................. 6.01 4.58 38.40 29.29 44.40 33.87
5................................. 10.01 7.14 38.40 27.38 48.41 34.51
6................................. 12.01 8.00 38.40 25.59 50.41 33.59
7................................. 14.01 8.73 38.40 23.91 52.41 32.64
8................................. 16.01 9.32 38.40 22.35 54.41 31.67
9................................. 18.02 9.80 38.40 20.89 56.41 30.69
10................................ 20.02 10.18 38.40 19.52 58.41 29.70
-----------------------------------------------------------------------------
Total......................... $102.09 $62.76 $345.60 $233.81 $447.66 $296.57
----------------------------------------------------------------------------------------------------------------
2. Improved Effectiveness of Treatment
Under the proposed rule, the highlights section would emphasize the
drug information that physicians report is the most important for
decisionmaking. In addition, any patient information or Medication
Guide approved by FDA would be printed at the end of the labeling
regardless of when the product was approved. Moreover, certain
information will be removed from existing professional labeling because
the rule only allows inclusion of data that are pertinent to the
clinical uses specified in the indications section. Consequently, this
proposed rule would improve the ability of physicians to select the
most safe and effective pharmaceutical treatments for their patients
and to administer those treatments in the most safe and effective
manner. In addition, the proposal may enhance the likelihood that
physicians will communicate important information to patients, which
could improve patient understanding and compliance with treatment. 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 Avoidable Adverse Events
Because it will highlight important information about dosage, side
effects, and contraindications, the proposed new prescription drug
labeling format would decrease the number of adverse drug events
(ADE's) caused by incorrect product use. Many ADE's result from poor or
incorrectly applied 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) and are potentially preventable. Studies
of hospitalized patients in the early 1990's suggest that the rate of
preventable ADE's that occur during hospitalization is approximately
1.2 to 1.8 ADE's per 100 patients admitted (Refs. 15 and 16). Moreover,
the latter study found that a majority of preventable ADE's (about 1
ADE 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. Given the
approximately 35 million hospitalizations annually in the United
States, \13\ these data suggest that about 350,000 ADE's among
hospitalized patients are potentially preventable with better labeling
for health professionals. Studies show that the occurrence of an ADE in
a hospitalized patient increased the costs of caring for the patient by
an average of $2,262 to $2,595 (Refs. 15 and 17). Costs associated with
preventable ADE's were even higher, averaging about $4,685 per patient
(Ref. 17). If other hospitals incur similar costs for preventable
ADE's, the potentially preventable annual costs from this source could
total $1.6 billion nationally.
In addition, many outpatients are hospitalized as a result of
preventable adverse events associated with outpatient drugs. FDA
previously estimated that the costs associated with these
hospitalizations total $4.4 billion per year \14\ (60 FR 44232, August
24, 1995). If half of these adverse events also are related to
physician ordering errors, about $2.2 billion per year additional
hospital costs result from this source of error. Thus, combining both
inpatient and outpatient adverse drug events, about $3.8 billion per
year in hospital costs may be potentially preventable through better
prescription drug labeling.
---------------------------------------------------------------------------
\13\ 1997 hospital discharges, Heathcare Cost and Utilization
Project (HCUP) Nationwide Inpatient Sample, 1997, Agency for
Healthcare Research and Quality (AURQ), April 2000. Http://
http://frwebgate.access.gpo.gov/cgi-bin/leaving.cgi?from=leavingFR.html&log=linklog&to=http://www.ahrq.gov/data/hcupnet.htm.
\14\ 60 FR 44232, August 24, 1995. An estimated 498, 750
patients are hospitalized annually for a preventable adverse drug
reaction to a prescription drug product, costing $4.4 billion in
hospital charges. ($4.4 billion = 498,750 patients x $8,890 average
hospiotal charges per patient; 498,740 patients = 35 million
discharges x 3% treated for adverse drug events x 95% of adverse
drug events from prescription drug products x 50% of adverse drug
events that are preventable.)
---------------------------------------------------------------------------
The actual proportion of the ADE costs that would be prevented
under the proposed rule cannot be predicted with certainty. If these
costs were reduced by even 1 percent, however, the proposed rule would
reduce hospitalization costs by $38.4 million per year. Over 10 years,
the present value of these benefits would total $233.8 million (table
4). Furthermore, if additional averted costs (e.g., physician visits,
additional outpatient costs, patient time, lost productivity) were
included, the savings from the ADE's avoided would be substantially
higher.
C. Costs of Regulation
The proposed rule mandates two broad types of changes to the
labeling of
[[Page 81106]]
prescription drug products. First, the professional labeling of
recently approved and future products must follow format and content
requirements proposed in the rule. Second, some labeling of products
already approved for marketing must be revised to: (1) Delete
information not pertinent to the approved indication, and (2) add
previously approved printed patient information or a Medication Guide.
Therefore, direct costs incurred to change professional labeling
include the costs of: (1) Designing or revising prescription drug
labeling and submitting the new labeling to FDA for approval, (2) the
costs of producing longer labeling, and (3) printing a longer PDR.
1. Labeling Changes for Recently Approved and Future Prescription Drug
Products
a. Affected products. The proposed rule would require that
prescription drug labeling conform to format and content requirements
for two categories of products: (1) All NDA's, BLA's, and efficacy
supplements submitted to FDA on or after the effective date of the
final rule: and (2) all NDA's, BLA's, and efficacy supplements pending
at the time of the effective date of the final rule or approved over
the 5 years preceding the effective date of the final rule. For the
first category of products, the labeling requirements would apply when
a sponsor files an NDA or BLA (new applications) or efficacy
supplement. Products in the second category must file supplemental
applications within 3 to 7 years after the effective date of the final
rule according to the implementation plan provided in table 1. Labeling
for nonprescription products (including nonprescription products
approved under NDA's) is not covered by this rule.
Estimates of the number of new applications that would be affected
by the rule over a 10-year period are shown in table 5 and are based on
the number of application approvals since 1990.
Table 5.--Number of Affected New Drug and Biological Applications and Estimated Labeling Design Costs
--------------------------------------------------------------------------------------------------------------------------------------------------------
Number of affected applications by type Cost for prescription drug labeling design ($ mil)
------------------------------------------------------------------------------------------------------
Year New NDA's/ New NDA's/ Present
BLA's ES's* Before--5** Total BLA's ES's* Before--5** Total value
--------------------------------------------------------------------------------------------------------------------------------------------------------
1................................................ 85 59 0 144 $0.43 $0.30 $0.00 $0.72 $0.67
2................................................ 134 73 0 207 0.67 0.37 0.00 1.04 0.90
3................................................ 121 57 74 252 0.61 0.29 0.56 1.45 1.18
4................................................ 113 38 74 225 0.57 0.19 0.56 1.31 1.00
5................................................ 113 20 73 206 0.57 0.10 0.55 1.21 0.86
6................................................ 113 14 73 200 0.57 0.07 0.55 1.18 0.79
7................................................ 113 10 72 195 0.57 0.05 0.54 1.16 0.72
8................................................ 113 8 0 121 0.57 0.04 0.00 0.61 0.35
9................................................ 113 6 0 119 0.57 0.03 0.00 0.60 0.32
10............................................... 113 5 0 118 0.57 0.03 0.00 0.59 0.30
Total...................................... 1,131 290 366 1,787 $5.66 1.47 2.76 9.87 7.09
--------------------------------------------------------------------------------------------------------------------------------------------------------
* Efficacy supplements
** Approvals 5 years before effective date.
For this analysis, January 1, 1995, was used as a proxy for the
effective date of the proposed rule. The number of covered application
approvals for the 3 consecutive years beginning in 1995 were 85, 134,
and 121, an average of 113 each year. FDA assumes that this average
rate will continue. During this same 3-year period, 59, 73, and 57
efficacy supplements were approved for applications that initially had
been approved prior to 1995. FDA estimates, therefore, that if this
rule had become effective on January 1, 1995, as many as 144 products
(i.e., 85 covered applications and 59 efficacy supplements) would have
incurred design costs in the first year. Most efficacy supplements are
filed and approved within 5 years of the approval date of their
original application. Therefore, beginning in 1997, an increasing
number of efficacy supplements would not have required changes to the
labeling format because these changes would have been made in the
original application. As the annual number of affected efficacy
supplements declined over time, the annual number of affected total
applications would likewise diminish, as projected in table 5.
Furthermore, between 1990 and 1994 (i.e., the 5-year period before the
proxy effective date), an additional 366 applications were approved.
Thus, an average of 73 additional applications would have been received
annually in years 3 through 7.
b. Prescription drug labeling design costs. The cost of designing
prescription drug labeling that conforms to the proposed 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 labeling that would otherwise 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
labeling changed to the new format. Costs for currently marketed
products undergoing relabeling for other reasons (e.g., related to an
efficacy supplement) will be intermediate between these extremes.
FDA has estimated the cost of designing novel patient labeling (for
the first prescription drug in a therapeutic class) at about
$12,000.\15\ The estimated costs of redesigning patient labeling for
products that could use previously developed prototypes (i.e., generic
drugs or innovator drugs in the same therapeutic class for which
patient labeling was already developed) ranged from $500 to $1,500 per
product. Although the design of prescription drug labeling under the
proposed rule will primarily follow a format specified by FDA, detailed
discussion and drug-specific decisions (e.g., regarding exactly which
adverse reactions should be listed in the highlights section) will be
necessary. Consequently, this analysis estimates $7,500 as the average
cost to a firm that needs to redesign the labeling of an existing
innovator drug, to
[[Page 81107]]
test the redesigned labeling (e.g., to ensure that the larger labeling
will still fit in carton-enclosed products), and to prepare and submit
that labeling to FDA for approval. Additional costs for the latter
task, however, would be incurred only for those drugs approved in the 5
years before the effective date of the rule. Although sponsors of new
applications and efficacy supplements would incur many of the same
design costs, they would experience no additional testing and
application costs. Thus, the design of labels for new applications and
efficacy supplements is estimated to cost $5,000 on average.
---------------------------------------------------------------------------
\15\ 60 FR 44232. $11,667 for 2 months full-time effort of
professional/technical employees with annual compensation, including
40 percent benefits of $70,000 ($11,667 = $50,000 x 1.4 x \2/12\).
---------------------------------------------------------------------------
In the first year after the final rule becomes effective, an
estimated 144 affected products would incur an additional cost per drug
of $5,000 to comply with the proposed rule. As shown in table 5, the
total first-year costs would amount to $720,000, increasing in the
second year to $1.04 million. Costs increase in year 3 to a high of
$1.45 million as sponsors of recently approved products begin
submitting FDA supplemental applications, at $7,500 per application, to
comply with the new labeling format and content. After the seventh
year, when all products approved within 5 years before the rule's
effective date or pending approval at that time have redesigned
labeling, the costs decline to about $0.6 million per year. As a
result, the estimated present value of the costs of redesigning
prescription drug labeling over 10 years is about $7.1 million.
c. Costs associated with producing labeling. Under the proposed
rule, labeling for each affected product would be expanded to include a
highlights section, an index, and additional formatting and font size
requirements (if the labeling does not already meet these
requirements). Consequently, all affected labeling will be longer than
at present, with current shorter labeling affected proportionately more
than current longer labeling (due to the fact that the highlights
section will add nearly the same amount of absolute length to every
affected product with prescription drug labeling). Longer labeling
increases the cost of paper, ink, and other ongoing incremental
printing costs. These costs apply both to the labeling that physically
accompanies the product and to the labeling that accompanies
promotional materials. Also, some products packaged in cartons
containing package inserts will require a product-by-product review to
assess whether the carton can still accommodate the longer labeling. It
is possible that a few products would require equipment changes (e.g.,
different insert-folding machinery).
i. Incremental printing costs. Based on quotes from industry
consultants, FDA estimates that the cost of printing larger
prescription drug labeling is approximately $0.0086 for each additional
100 square inches. The agency estimates that the proposed rule would
increase the average size of labeling by about 93 square inches \16\
adding $.008 to the per label printing cost, or $7,960 per million
package inserts printed. The new highlights and index sections account
for about 37 percent of the additional printing cost, whereas the
larger font size imposes the remaining 63 percent of the incremental
printing cost.
---------------------------------------------------------------------------
\16\ The length of professional labeling from a random sample of
approximately 5 percent of the listings printed in the PDR averaged
2.67 pages with a font size of 6.5 point. Twenty-four percent of the
sample had at least one boxed warning with an average length of
about 5.6 square inches in 6.5-point font or 6.25 square inches in
8-point font. Increasing the font size from 6.5 point to 8 point
(i.e., the minimum font size specified in the proposed rule) would
increase the average length by an estimated 59 percent, or
approximately 1.6 pages. Moreover, the agency estimates that the new
highlights section, including any boxed warnings, and indexing
system may add up to 90 percent of a page to professional labeling.
Therefore, the proposed rule would increase the length of the
average professional labeling by about 2.5 pages. Because package
inserts are printed on both sides, the average package insert would
increase in size by 92.6 square inches.
---------------------------------------------------------------------------
U.S. retail pharmacies dispense about 2.3 billion prescriptions per
year, of which an estimated 560 million are for unit-of-use products,
which often include labeling within the package.\17\ If the remaining
1.7 billion pharmacy-prepared prescriptions average one insert per 3.33
prescriptions (assumes an average of 100 units per container and 30
units dispensed per prescription), the total number of inserts
accompanying retail products equals roughly 1.1 billion. Adding
hospital pharmaceutical volume, estimated at approximately 38 percent
of retail volume, yields an annual total of 1.5 billion package inserts
accompanying prescribed products. Allowing 10 percent for wastage
indicates that pharmaceutical companies distribute roughly 1.65 billion
package inserts with prescribed products each year. Over time, an
increasing number of these inserts would have to be revised. Because
the rule initially affects only innovator products and about 60 percent
of all prescriptions are for branded products, FDA calculated that
about 1 billion of these inserts are currently provided with about
2,287 branded products.\18\ Thus, on average, about 435,000 inserts (1
billion 2,287) may be shipped annually for each affected
product. Table 6 shows the estimated number of revised inserts that
would accompany the prescribed products. Multiplying these numbers by
the estimated incremental printing cost of $.008 per label indicates
that the annual costs for package inserts would rise to about $6.2
million by the 10th year.
---------------------------------------------------------------------------
\17\ Unpublished FDA analysis based on survey results from nine
pharmacists and applied to IMS data.
\18\ Derived from the 1998 Approved Drug Products With
Therapeutic Equivalence Evaluations (Orange Book), CDER, FDA. The
estimate is a count of all branded products marketed under an NDA
and differentiated by active ingredient, dosage form, or
manufacturer, not including multiple dosage strengths. Although
biologics were not counted, adding biologics would not significantly
alter results.
Table 6.--Incremental Printing Costs for Reformatted Professional Labeling Year
----------------------------------------------------------------------------------------------------------------
Number printed per Incremental printing costs ($ million)
year (million) ---------------------------------------------
Year Number of ------------------------
approvals Package Promotional Package Promotional Total Present
inserts labeling inserts labeling value
----------------------------------------------------------------------------------------------------------------
1.............................. 144 62.6 250.5 $0.50 $1.99 $2.49 $2.33
2.............................. 207 152.7 416.1 1.22 3.31 4.53 3.95
3.............................. 252 262.3 616.0 2.09 4.90 6.99 5.71
4.............................. 225 360.2 677.8 2.87 5.40 8.26 6.30
5.............................. 206 449.8 675.9 3.58 5.38 8.96 6.39
6.............................. 200 536.8 634.9 4.27 5.05 9.33 6.21
[[Page 81108]]
7.............................. 195 621.6 611.1 4.95 4.86 9.81 6.11
8.............................. 121 674.3 540.3 5.37 4.30 9.67 5.63
9.............................. 119 726.0 476.8 5.78 3.80 9.57 5.21
10............................. 118 777.3 416.4 6.19 3.31 9.50 4.83
--------------------------------------------------------------------------------
Total.................... 1,787 4,623.6 5,315.8 $36.82 $42.30 $79.11 $52.67
----------------------------------------------------------------------------------------------------------------
To calculate the amount of labeling printed for promotional
purposes, FDA assumed that the 23.7 million office and hospital calls
per year made by pharmaceutical representatives \19\ involved an
average of 2 printed pieces of labeling per visit, or a total of 47.4
million per year. In addition, sales representatives made 8.2 million
sample calls, distributing an estimated 82 million package inserts per
year, or an average of 10 samples per call. Since most promotional
visits involve relatively new products--the products most affected by
this rule--FDA assumed that all of this labeling would incur additional
printing costs, amounting to about $1.0 million annually.
---------------------------------------------------------------------------
\19\ Data from IMS, 1997, as presented at FDA on June 3, 1998.
Data include an estimated 17.8 million office calls, 8.2 million
sample calls, and 5.9 million hospital calls made in 1997.
---------------------------------------------------------------------------
Finally, FDA estimated that about 800,000 pieces of labeling per
approval would be distributed each year by mail or at conferences to
physicians, other health care professionals, consumers, retail pharmacy
outlets and hospital pharmacies for 3 years following approval of a new
drug.\20\ As shown in table 6, annual total promotional labeling costs
peak at $5.4 million in year 4. Over 10 years, the present value of the
incremental printing costs for all types of longer prescription drug
labeling would be about $52.7 million.
---------------------------------------------------------------------------
\20\ For each approval, it was assumed that all physicians
involved in primary care and 25 percent of physicians practicing a
medical specialty would receive 2 mailings per year, or an estimated
711,535 pieces (i.e., = (274,726 x 2) + (0.25 x 324,198 x 2)),
for 3 years following product launch. An additional 10 percent or
71,153 pieces are estimated to be distributed annually for 3 years
to other health professionals or consumers. Furthermore, FDA assumes
that 50,829 retail pharmacy outlets and 7,120 hospital pharmacies
would receive one mailing to announce the launch of a new product in
the year of approval.
---------------------------------------------------------------------------
Some companies may incur additional costs associated with
maintaining the labeling posted on their web sites. The agency did not
estimate these related costs but believes they would be minimal and a
routine cost of doing business. Nonetheless, the agency requests
comment.
ii. Equipment costs. Agency consultants with expertise in
pharmaceutical labeling operations estimate that only a small number of
carton-enclosed products may require new packaging to accommodate the
longer insert. This analysis assumes that 1 percent of both the
products with new efficacy supplement changes and the products approved
in the 5 years before the effective date of the rule would incur costs
of $200,000 each for needed packaging changes. Products approved
subsequent to the effective date of the final rule would not incur
added equipment costs because their labeling and packaging are not yet
established. The estimated present value of equipment changes totals
$1.0 million over 10 years.
d. PDR costs. FDA estimates that the new highlights section,
including any boxed warnings, and index would add about one-half pages
to each affected labeling printed in the PDR.\21\
---------------------------------------------------------------------------
\21\ The new highlights section could add up to one-half page
when printed in 8-point size. Because the PDR is printed in a 6.5-
point New Century Schoolbook Roman font, the highlights section
would require less than one-half page in the PDR. The agency
estimates 37 percent less space is required to print information in
the smaller PDR font, reducing the size required for the new
highlights section to 0.3 pages (i.e., 0.5 x (1--0.37) = 0.315
pages). A sample of labeling printed in the PDR found that about 24
percent of the products may be required to print a boxed warning
averaging 5.6 square inches. Therefore, the agency estimates an
additional 0.02 pages for these warnings (i.e., 23.9 percent x 5.6
square inches / 75 square inches per page = 0.02 pages).
Furthermore, the new indexing system is estimated to add
approximately 60 column lines to a PDR listing, equaling
approximately 0.2 pages (i.e., (60 lines / 96 lines per column) / 3
columns per page = .21 pages). In total, up to .54 pages may be
added to the professional labeling printed in the PDR.
---------------------------------------------------------------------------
Conversations with Medical Economics (the publisher of the PDR) on
the cost per printed page imply that the annual publishing costs of the
extra space required for printing the expanded labeling would be about
$4,300 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). It
was further 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 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 labeling in the PDR would be about $0.75
million for year 1. These costs would continue to increase over time as
all drug approvals after the effective date of the rule would have
longer PDR listings. The estimated annual and total cost of printing
longer PDR listings are shown in table 7.
[[Page 81109]]
Table 7.--Cost for Longer Listings in the PDR
----------------------------------------------------------------------------------------------------------------
PDR printing costs ($ million)
Year ---------------------------------------------------------------
PDR bound Supplement Total Present value
----------------------------------------------------------------------------------------------------------------
1............................................... $0.47 $0.31 $0.78 $0.73
2............................................... 1.13 0.47 1.60 1.40
3............................................... 1.95 0.41 2.36 1.93
4............................................... 2.68 0.37 3.05 2.32
5............................................... 3.34 0.35 3.69 2.63
6............................................... 3.99 0.34 4.33 2.89
7............................................... 4.62 0.34 4.96 3.09
8............................................... 5.01 0.34 5.35 3.11
9............................................... 5.39 0.34 5.73 3.12
---------------------------------------------------------------
10.............................................. 5.78 0.33 6.11 3.11
---------------------------------------------------------------
Total....................................... $34.36 $3.60 $37.96 $24.33
----------------------------------------------------------------------------------------------------------------
2. Labeling Changes for All Approved Prescription Drug Products
The agency is also proposing several new retrictions for the
labeling of all prescription drug products. These changes can be made,
without prior FDA approval, upon submission of a ``changes being
effected'' supplement. Labeling for all prescription drug products must
comply with the proposed content requirements within 1 year after the
effective date of the final rule.
a. Affected products. The proposed rule will no longer allow
certain information that is sometimes now included in professional
labeling (e.g., discussion of studies not supporting approved
indications, suggestion of uses or indications not included in the
``Indications and Uses'' section, or discussion of in vitro and animal
studies on drug action or efficacy that have not been shown to be
pertinent to clinical use by adequate and well-controlled studies). FDA
does not know how much product labeling would be affected, but because
labeling of most antibiotics currently contains data from in vitro
studies, the agency estimates that the proposed rule could affect 90
percent of all antibiotics. Of the approximately 5,300 marketed
products in the United States, there are an estimated 789 antibiotics
products.\22\ Moreover, up to 25 percent of all other marketed products
could have labeling containing information that would be prohibited. In
the first year, therefore, as many as 1,838 products might have to
delete some material from their professional labeling.
---------------------------------------------------------------------------
\22\ Derived from the 1998 Approved Drug Products With
Therapeutic Equivalence Evalutaion (Orange Book), CDER, FDA.
Products with NDA numbers in the 50,000 or 60,000 series (i.e.,
antibiotics), with a distinct dosage form or manufacturer were
counted. This number, however, probably overestimates the number of
antibiotic products with distinct labeling.
---------------------------------------------------------------------------
In addition, any existing prescription drug product with approved
printed patient information or Medication Guide must reprint this
information following the last section of the professional labeling.
The agency estimates that about 50 approved products, or approximately
1 percent of the existing products, could be affected by this
requirement.
b. Professional labeling design costs. Industry consultants
estimate that, on average, prescription drug manufacturers would incur
about $2,000 per product in design and implementation costs for a major
revision in the content of professional labeling. Industry consultants
with expertise in pharmaceutical labeling estimate that professional
labeling inventories represent approximately 3 months worth of
production. If given an adequate lead time, companies should be able to
minimize inventory losses. This proposed rule would require changes
within 1 year of the effective date. Assuming that not all affected
firms would have sufficient time to deplete their inventories,
consultants estimate the per product professional labeling inventory
losses are $570 for a 12 month lead time. Thus, including excess
inventory losses, the cost to change professional labeling is estimated
at $2,600 per product. In the first year, therefore, firms may incur
one-time costs of $4.7 million and $0.1 million, respectively, to
remove prohibited material from labeling and to add printed patient
information to labeling for all affected products (table 8).
c. Incremental printing costs for professional labeling. FDA
estimates that an average of 310,000 package inserts may be printed
annually for each prescription drug product marketed in the United
States.\23\ The removal of prohibited information from professional
labeling may reduce the size of current packageinserts by about 3
percent or 3 square inches. With such a small change in the length of
professional labeling, it is unlikely that the package insert would
actually change size. Therefore, the agency assumed no cost savings for
shorter professional labeling.
---------------------------------------------------------------------------
\23\ 310,000 inserts per product = 1.65 billion inserts printed
annually/5,300 products.
---------------------------------------------------------------------------
In contrast, printed patient information would add an estimated 2
pages or about 75 square inches to the length of professional labeling.
For each of the affected products, manufacturers would incur additional
incremental printing costs of about $2,000 for longer labeling.\24\ For
all 50 affected products, annual incremental printing costs would
increase by $0.1 million (table 8).
---------------------------------------------------------------------------
\24\ $2,000 per product = 75 square inches/insert x 0.000086
square inches x 310,000 inserts per product.
[[Page 81110]]
Table 8.--Costs to Revise Professional Labeling of Existing Prescription Product
----------------------------------------------------------------------------------------------------------------
One-Time Annual
Number of labeling incremental Annual PDR
Changes to Labeling affected revision costs printing costs costs ($
products ($ million) ($ million) million)
----------------------------------------------------------------------------------------------------------------
Removal of prohibited material.................. 1,838 $4.70 $0.00 $0.00
Addition of approved printed patient information 50 0.13 0.10 0.60
or Medication Guide............................
Total....................................... 1,888 4.83 0.10 0.60
----------------------------------------------------------------------------------------------------------------
d. PDR costs. The agency assumes that 75 percent of prescription
drug products have labeling already printed in the PDR. In accord with
the rationale described above, the annual printing costs for the PDR
are estimated to be unchanged for products that remove information and
to increase for products that add patient information. The per product
annual cost to print two additional pages in the PDR is about
$16,000.\25\ For all affected products, the annual PDR costs would
increase by $0.6 million (table 8).
---------------------------------------------------------------------------
\25\ $16,000 per product = $8,000/page x 2 pages.
---------------------------------------------------------------------------
3. Changes to Drug Product Labels
The proposed rule also specifies minor changes to prescription drug
product labels to remove excess information from the label to help
reduce medication errors. To reduce the burden on industry, changes to
labels are not required until the first time labeling is revised after
the effective date of the final rule. Therefore, no additional
compliance costs are estimated for these changes.
Table 9 displays the estimated compliance costs for the three major
cost categories over a 10-year period.
Table 9.--Compliance Cost Over 10-Year Period
----------------------------------------------------------------------------------------------------------------
Cost Category ($ million)
---------------------------------------------------------------------------
Producing
Year professional
Labeling design labeling Printing PDR Total costs ($
and FDA approval (including million)
equipment costs)
----------------------------------------------------------------------------------------------------------------
1................................... $5.55 $2.71 $1.38 $9.64
2................................... 1.04 4.77 2.20 8.01
3................................... 1.45 7.35 2.96 11.76
4................................... 1.31 8.59 3.65 13.54
5................................... 1.21 9.25 4.29 14.75
6................................... 1.18 9.60 4.93 15.72
7................................... 1.16 10.08 5.56 16.79
8................................... 0.61 9.78 5.95 16.34
9................................... 0.60 9.69 6.33 16.61
10.................................. 0.59 9.61 6.71 16.91
---------------------------------------------------------------------------
Total current value............. 14.68 81.43 43.96 140.07
---------------------------------------------------------------------------
Total present value............. 11.62 54.37 28.54 94.52
----------------------------------------------------------------------------------------------------------------
D. Impacts on Small Entities
1. The Need for and the Objectives of the Rule
As discussed in detail in section II of this document, various
developments in recent years have contributed to an increase in the
length and complexity of prescription drug product labeling, and made
it more difficult for health care practitioners to find specific
information and discern the most critical information in labeling. The
objective of the proposed requirements is to enhance the safe and
effective use of prescription drug products by making it easier for
health care practitioners to access, read, and use information in
prescription drug product labeling.
As previously stated, FDA's legal authority to amend its
regulations governing the content and format of labeling for human
prescription drug and biologic products and to amend its regulations
governing the requirements for prescription drug product labels derives
from sections 201, 301, 501, 502, 503, 505, and 701 of the act (21
U.S.C. 321, 331, 351, 352, 353, 355, and 371) and section 351 of the
PHS Act (42 U.S.C. 262).
2. Description and Estimate of the Number of Small Entities Affected
This proposed rule would affect all small entities required to
design their prescription drug labeling to comply with this rule. The
Small Business Administration (SBA) considers firms in Standardized
Industrial Classification Code 2834, Pharmaceutical Preparations, with
fewer than 750 employees to be small entities. Although U.S. Census
size categories do not correspond to SBA size categories, of the
approximately 600 firms identified, over 90 percent have fewer than 500
employees.\26\ Thus, most of the firms in the pharmaceutical industry
are considered small entities for Regulatory Flexibility Act purposes.
In contrast, an agency review of NDA's received in FY 97, 98, and 99
found that about 19 small entities submit NDA's each year. In addition,
an equal number of small firms that submit BLA's, ES's and/or
reformatted professional labeling for approval would also be affected,
for a total of about 38.
---------------------------------------------------------------------------
\26\ U.S. Department of Commerce, Bureau of the Census, 1992
Census of Manufacturers, Industry Series, Drugs, MC92-1-28C.
---------------------------------------------------------------------------
[[Page 81111]]
Census of Manufactures data on revenues per firm apply to all
establishments classified in 2834, Pharmaceutical Preparations. As
noted above, only a subset of this industry is affected by this rule.
The agency does not know the average revenues for the affected sectors.
3. Description of the Compliance Requirements
The compliance requirements for small entities under this proposed
rule are the same as those described above for other affected entities.
Compliance primarily involves: (1) Designing labeling that conforms to
the format requirements as illustrated in the FDA-designed prototype;
and (2) once the labeling is approved by FDA, ensuring that all future
printed labeling (including labeling used for promotional purposes) is
in the new format. Because sponsors already submit labeling with NDA's
and supplements to FDA, no additional skills will be required to comply
with the proposed rule.
The group of small entities likely to bear the highest total costs
under this proposed rule are those firms that have: (1) Existing
products with 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 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 total costs of
compliance, but the incremental cost per unit sold would be higher.
To illustrate the impact on small entities with different
production volumes, the following examples estimate the professional
labeling costs 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 10
outlines the projected per-unit and total costs to the firm under three
different levels of production: 1,000, 10,000, and 100,000 units
produced per year.
Table 10.--Estimated Costs for Hypothetical Small Firm With a Single
Product, Under Three Alternative Levels of Production
------------------------------------------------------------------------
Number of units produced and sold
each year
Cost category -----------------------------------
100,000 10,000 1,000
------------------------------------------------------------------------
Example 1--Change labeling approved
less than 1 year before effective
date:
Professional labeling redesign/ $7,500 $7,500 $7,500
application....................
Printing package inserts \1\.... 87 88 9
Printing professional labeling 1,611 161 16
used for promotional purposes
\2\............................
-----------------------------------
Total....................... 9,987 7,749 7,525
Additional cost per unit sold... 0.10 0.77 7.53
Example 2--Add patient information
to labeling of an existing product:
Professional labeling redesign.. 2,600 2,600 2,600
Printing package inserts \3\.... 710 71 7
Printing longer PDR \4\......... 16,000 16,000 16,000
-----------------------------------
Total....................... 19,310 18,671 18,607
Additional cost per unit sold... 0.87 1.87 18.61
------------------------------------------------------------------------
\1\ Number of package inserts printed is calculated as units produced/
year plus 10 percent wastage factor, at an incremental printing cost
of $.00796 per label.
\2\ Incremental costs associated with printing labeling used for
promotional purposes are assumed to be 184% of the costs of printing
package inserts, based on the ratio of the average number of pieces
printed for mailings to the average number printed as package inserts.
\3\ Number of package inserts printed is calculated as units produced/
year plus 10 percent wastage factor, at an incremental printing cost
of $.00645 per package insert.
\4\ Assume that professional labeling is already being printed in the
PDR.
In addition to the costs identified in table 10, 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 finds
that the impact of this proposed rule would not be significant for most
small entities in this industry, but it is possible that more than a
few small firms may incur significant costs. The agency solicits public
comment on the potential impact of the proposed rule on small entities.
4. Alternatives Considered
a. Formatting alternatives. FDA has considered numerous alternative
formats, including a longer highlights section. The highlights section
was limited to about one-half page to respond to health professionals'
concerns about length as well as to reduce the incremental printing
costs to sponsors.
The agency also considered increasing the minimum required font
size from 8 point to 10 point. The larger font size would increase
labeling by approximately 196 square inches, whereas labeling printed
in 8-point font size is estimated to increase by only 93 square inches.
Furthermore, the incremental costs for labeling printed in 10 point
font size would be approximately $16,850 per million inserts, more than
double the incremental costs of labeling printed in 8-point font size.
Over 10 years, the total present value of producing longer labeling
would increase by $111.5 million with the larger font size, compared to
$52.7 million for the 8-point font size. Although the agency has
tentatively rejected the minimum 10-point font size requirement because
of the additional burden on industry, FDA solicits comment on minimum
font size requirements.
b. Alternative categories of affected products. Three alternative
categories of products to be covered by the
[[Page 81112]]
rulemaking were considered: (1) All drugs, (2) a proposed 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 drug
reactions. The agency has tentatively rejected these three alternatives
because it was uncertain whether the benefits would exceed the costs,
especially in the case of older drugs and generic drugs for which
physicians infrequently consult labeling. In addition, the ``top 200''
lists were excluded because the agency believed that the most important
subset of these products would be covered by the currently proposed
rule. However, FDA solicits comment on these alternative criteria for
selecting drugs to be affected by the rulemaking.
c. Alternative implementation schedule. FDA considered a shorter
implementation schedule, requiring that the labeling for all
applications and efficacy supplements approved 5 years prior to the
implementation date be revised 3 years after the effective date. The
more gradual implementation schedule has been proposed primarily to
reduce the impact of the rule on small entities as well as the
immediate impact of the rulemaking on the industry as a whole.
XI. Request for Comments
Interested persons may submit to the Dockets Management Branch
(address above) written comments regarding this proposal by March 22,
2001. Two copies of any comments are to be submitted, except that
individuals may submit one copy. Comments are to be identified with the
docket number found in brackets in the heading of this document.
Received comments may be seen in the office above between 9 a.m. and 4
p.m., Monday through Friday.
XII. References
The following references have been placed on display in the Dockets
Management Branch (address above) and may be seen by interested persons
between 9 a.m. and 4 p.m., Monday through Friday.
1. LittleJohn, J.K., ``Package Insert: View of a Rural Town
Practitioner,'' Drug Information Journal, vol. 21, pp. 63-65, 1987.
2. National BioSystems, Inc., ``Focus Group Report: Physician's
Perceptions of Prescription Drug Labeling Information,'' Contract
#223-91-3501, February 1992.
3. Wogalter, M.S., ``Factors Influencing the Effectiveness of
Warnings,'' in Visual Information for Everyday Use: Design and
Research Perspectives, edited by H.J.G. Zwaga, T. Boersema, and
H.C.M. Hoonhout, Taylor & Francis, 1999.
4. Council for International Organization of Medical Sciences,
``Guidelines for Preparing Core Clinical-Safety Information on
Drugs: Report of CIOMS Working Group III,'' 1995.
5. Wilkins, A.G., and M.I. Nimmo-Smith, ``The Clarity and
Comfort of Printed Text,'' Ergonomics, vol. 30, pp. 1705-1720, 1987.
6. Silver, N.C., and C.C. Braun, ``Perceived Readability of
Warning Labels with Varied Font Sizes and Styles,'' Safety Science,
vol. 16, pp. 615-625, 1993.
7. Tinker, M.A., Legibility of Print, Ames, IA, Iowa State
University Press, 1963.
8. Steering Committee for the Collaborative Development of a
Long-Range Action Plan for the Provision of Useful Prescription
Medicine Information, ``Action Plan for the Provision of Useful
Prescription Medicine Information,'' Washington, DC, 1996.
9. Kripalani, S., ``The Write Stuff: Simple Guidelines Can Help
You Write and Design Effective Patient Education Materials,'' Texas
Medicine, vol. 91, pp. 40-45, 1995.
10. 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.
11. 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.
12. Leape, L., ``Systems Analysis of Adverse Drug Events,''
Journal of the American Medical Association, vol. 274, pp. 35-41,
1995.
13. Pharmacopeial Forum, vol. 20, No. 4, pp. 7885-7887, July and
August 1994.
14. Randolph, L., Physician Characteristics and Distribution in
the United States, 1997/1998 ed., Chicago, IL, American Medical
Association, 1998.
15. 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, vol. 277,
pp. 301-306, 1997.
16. Bates, D.W. et al., ``Incidence of Adverse Drug Events and
Potential Adverse Drug Events,'' Journal of the American Medical
Association, vol. 274, pp. 29-34, 1995.
17. Bates, D.W. et al., ``The Costs of Adverse Drug Events in
Hospitalized Patients,'' Journal of the American Medical
Association, vol. 277, pp. 307-311, 1997.
List of Subjects in 21 CFR Part 201
Drugs, Labeling, Reporting and recordkeeping requirements.
Therefore, under the Federal Food, Drug, and Cosmetic Act and under
authority delegated to the Commissioner of Food and Drugs, it is
proposed that 21 CFR part 201 be amended as follows:
PART 201--LABELING
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.
Sec. 201.55 [Amended]
2. Section 201.55 Statement of dosage is amended by revising the
third sentence to read as follows: ``When this occurs, a statement of
the recommended or usual dosage is not required on the label or
carton.''
3. Section 201.56 is revised to read as follows:
Sec. 201.56 Requirements on content and format of labeling for human
prescription drugs and biologics.
(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.
(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 shall 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 Secs. 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), biological license application (BLA), or efficacy supplement has
been approved by the Food and Drug Administration (FDA) anytime from 0
up to and including 5 years before [effective date of final rule];
(ii) Prescription drug products for which an NDA, BLA, or efficacy
supplement is pending on [effective date of final rule]; or
(iii) Prescription drug products for which an NDA, BLA, or efficacy
supplement is submitted anytime on or after [insert effective date of
final rule].
(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
[[Page 81113]]
requirements in Secs. 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 [effective date of the final rule],
proposed conforming labeling must be submitted as part of the
application.
(2) For products for which an NDA, BLA, or efficacy supplement is
pending at [effective date of final rule], or that has been approved
any time from [effective date of final rule] up to and including 1 year
before [effective date of final rule], a supplement with proposed
conforming labeling must be submitted no later than 3 years after
[effective date of the final rule].
(3) For products for which an NDA, BLA, or efficacy supplement has
been approved from 1 year up to and including 2 years before [effective
date of final rule], a supplement with proposed conforming labeling
must be submitted no later than 4 years after [effective date of the
final rule].
(4) For products for which an NDA, BLA, or efficacy supplement has
been approved from 2 years up to and including 3 years before
[effective date of final rule], a supplement with proposed conforming
labeling must be submitted no later than 5 years after [effective date
of the final rule].
(5) For products for which an NDA, BLA, or efficacy supplement has
been approved from 3 years up to and including 4 years before
[effective date of final rule], a supplement with proposed conforming
labeling must be submitted no later than 6 years after [effective date
of the final rule].
(6) For products for which an NDA, BLA, or efficacy supplement has
been approved from 4 years up to and including 5 years before
[effective date of the final rule], a supplement with proposed
conforming labeling must be submitted no later than 7 years after
[effective date of the final rule].
(d) Labeling requirements for newly 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 section headings and subheadings and in the
following order:
Highlights of Prescribing Information
Product Names, Other Required and Optional Information
Boxed Warning
Recent Labeling Changes
Indications and Usage
Dosage and Administration
How Supplied
Contraindications
Warnings/Precautions
Drug Interactions
Use in Specific Populations
Comprehensive Prescribing Information: Index
Comprehensive Prescribing Information
!Boxed Warning
1 Indications and Usage
2 Dosage and Administration
3 How Supplied/Storage and Handling
4 Contraindications
5 Warnings/Precautions
6 Drug Interactions
7 Use in Specific Populations
7.1 Pregnancy
7.2 Labor and delivery
7.3 Lactating women
7.4 Pediatric use
7.5 Geriatric use
8 Adverse Reactions
9 Drug Abuse and Dependence
10 Overdosage
11 Description
12 Clinical Pharmacology
12.1 Mechanism of action
12.2 Pharmacodynamics
12.3 Pharmacokinetics
12.4 Other clinical pharmacology information
13 Nonclinical Toxicology
13.1 Carcinogenesis, mutagenesis, impairment of fertility
13.2 Animal toxicology and/or pharmacology
14 Clinical Studies
P Patient Counseling Information
(2) The labeling may contain an additional section entitled ``R
References'' if appropriate and if in compliance with
Sec. 201.57(c)(16).
(3) Sections or subsections of the labeling required under
Sec. 201.57(a), (b), or (c) may be omitted if clearly inapplicable.
(4) The labeling required under Sec. 201.57(c) may contain a
``Product Title'' section preceding any boxed warning as required in
Sec. 201.57(c)(1) or, in the absence of such warning, preceding the
``Indications and Usage'' section, and containing only the information
required by Secs. 201.57(c)(12)(i)(A) through (c)(12)(i)(D) and
201.100(e). The information required by Sec. 201.57(c)(12)(i)(A)
through (c)(12)(i)(D) must appear in the ``Description'' section of the
labeling, whether or not it also appears in a ``Product Title''
section.
(5) The labeling required under Sec. 201.57(c) may include
additional nonstandardized subheadings under the standardized
subheadings listed in paragraphs (d)(1) and (d)(2) of this section to
emphasize specific topics within the text of the required sections
where the use of additional subheadings will enhance labeling
organization, presentation, or ease of use (e.g., subheadings may be
used to set off individual warnings or precautions, or for each drug
interaction). If additional subheadings are used, they must be assigned
a decimal index number that corresponds to their placement in labeling
and is consistent with the standardized index numbers and identifiers
listed in paragraphs (d)(1) and (d)(2) of this section (e.g.,
subheadings added to the ``Warnings/Precautions'' subsection could be
numbered 5.1, 5.2, and so on; subheadings in the ``Patient Counseling
Information'' subsection could be numbered P.1, P.2, and so on).
(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) The labeling may omit any section or subsection of the labeling
format if clearly inapplicable.
(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) shall appear in the
[[Page 81114]]
``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 after the last
section of the labeling.
4. 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 drugs and biologic 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
requirements in paragraphs (c)(2)(ii), (c)(2)(iii), (c)(3),
(c)(13)(ii), (c)(15)(i), and (c)(17) of this section, which must be
implemented no later than 1 year after [effective date of the final
rule].
(a) Highlights of prescribing information. This section must appear
in all prescription drug labeling. Statements made in promotional
labeling and advertisements must be consistent with all information
included in labeling under paragraph (c) of this section in order to
comply with Sec. 202.1(e) and Sec. 201.100(d)(1) of this chapter. The
section must include the following information under the identified
subheading, if any, in the following order:
(1) 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.
(2) Inverted black triangle symbol. The ``\'' symbol if the drug
product has been approved for less than 3 years in the United States
and contains a new molecular entity or new biological product, a new
combination of active ingredients, is indicated for a new population,
is administered by a new route, or uses a novel drug delivery system.
This symbol must be placed on the same line as the proprietary name of
the product, or the established or proper name if there is no
proprietary name.
(3) Prescription drug symbol. The symbol to indicate that the
drug is a prescription drug. This symbol must be placed on the same
line as the proprietary name of the product, or the established or
proper name if there is no proprietary name, immediately following any
``\'' symbol.
(4) Boxed warnings or contraindications. The full text of any boxed
warning or contraindication required by paragraph (c)(1) of this
section, provided that the text does not exceed a length of 20 lines.
Where the text exceeds 20 lines, a statement summarizing the contents
of the boxed warning(s) or contraindication(s) must be included, also
not to exceed a length of 20 lines. The boxed warning or summary
statement of the boxed warning must be preceded by a heading, in upper-
case letters, containing the word ``WARNING(S)'' and other words that
are appropriate to identify the subject of the warning. Both the text
of the boxed warning or summary statement of the boxed warning and
heading must be contained within a box and bolded. For summary
statements of a boxed warning, the following statement shall be placed
immediately following the heading of the boxed warning: ``See ! for
full boxed warning.''
(5) Recent labeling changes. A listing of the section(s) of the
comprehensive prescribing information in paragraph (c) of this section
that contain(s) substantive labeling changes that have been approved by
FDA or authorized under Sec. 314.70(c)(2) or (d)(2) of this chapter, 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 index number
or identifier. This section must be retained in the labeling for at
least 1 year after the date of the labeling change, and may be retained
until such time that the labeling is reprinted for the first time
following the change.
(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., particular subsets of the population, second line therapy
status, or antimicrobials limited to certain microorganisms) must be
briefly noted.
(7) Dosage and administration. The most important aspects of the
comprehensive prescribing information required under paragraph (c)(3)
of this section, with any appropriate subheadings. This would include
the most common dosage regimen(s) and critical differences among
population subsets, monitoring requirements, and other therapeutically
important clinical pharmacologic information. The use of tables is
encouraged, where appropriate (e.g., when there are different dosage
regimens for different indications).
(8) How supplied. A concise summary of information concerning the
product's dosage form(s) that is required under paragraph (c)(4) of
this section. This would ordinarily include the metric strength or
strengths of the dosage form and whether the product is scored. If
appropriate, the information in this section of the labeling should
include subheadings to specify different dosage forms (e.g., tablets,
capsules, injectables, suspension).
(9) Contraindications. A concise summary of the comprehensive
prescribing information required under paragraph (c)(5) of this
section, with any appropriate subheadings.
(10) Warnings/precautions. A concise summary of the most clinically
significant aspects of the comprehensive prescribing information
required under paragraph (c)(6) of this section, with any appropriate
subheadings. Clinically significant warnings and precautions include
those that affect prescribing because of their severity and consequent
influence on the decision to use the drug, because it is critical to
safe use of the drug to monitor patients for them, or because measures
can be taken to prevent or mitigate harm. This section of the the
labeling must also include the subheading ``Most Common Adverse
Reactions ( n/100).'' Under this subheading, the most
frequently occurring adverse reactions (i.e., noxious and unintended
responses for which there is a reasonable causal association with the
use of the drug), as described in paragraph (c)(9) of this section,
must be listed along with the incidence rate used to determine
inclusion. Typically, the incidence rate for inclusion would be
expected to be 1/100. When appropriate, adverse reactions
important for other reasons (e.g., because they lead to discontinuation
or dosage adjustment) may be included.
(11) ADR reporting contacts. For drug products other than vaccines,
the verbatim statement ``To report SUSPECTED SERIOUS ADR's, call
(insert name of manufacturer) at (insert manufacturer's phone number)
or FDA's MedWatch at (insert current FDA MedWatch number).'' For
vaccines, the verbatim statement ``To report SUSPECTED SERIOUS ADR's,
call (insert name of manufacturer) at (insert manufacturer's phone
number) or
[[Page 81115]]
VAERS at (insert the current VAERS number).''
(12) Drug interactions. A concise summary of other prescription and
over-the-counter drugs or foods that interact in clinically significant
ways with the product, from the comprehensive prescribing information
required under paragraph (c)(7) of this section, with any appropriate
subheadings.
(13) Use in specific populations. A concise summary of any
clinically important differences in response or use of the drug in
specific populations, from the comprehensive prescribing information
required under paragraph (c)(8) of this section, with any appropriate
subheadings.
(14) Patient counseling information statement. When applicable, the
verbatim statement ``See P for Patient Counseling Information.'' If the
product has approved patient labeling or a Medication Guide, the
verbatim statement ``See P for Patient Counseling Information, followed
by (insert name of drug)'s (insert either approved patient labeling or
Medication Guide).''
(15) Highlights limitation statement. The verbatim 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.''
(16) Revision date. The date of the most recent revision of the
labeling, identified as such, placed at the end of the highlights
section.
(17) Index number placement. Any subheadings required by paragraphs
(a)(4) through (a)(10), (a)(12), and (a)(13) of this section, as well
as additional subheadings included in the highlights section of the
labeling under Sec. 201.56(d)(5), must be followed by their index
number in parentheses.
(b) Comprehensive prescribing information: Index. This section must
appear in all prescription drug labeling immediately following the
information required under paragraph (a) of this section and must
contain a list of each subheading required under Sec. 201.56(d)(1), if
not omitted under Sec. 201.56(d)(3), preceded by the index number or
identifier required under Sec. 201.56(d)(1) or (d)(2). The section must
also contain additional subheading(s) included in the comprehensive
prescribing information section of labeling under Sec. 201.56(d)(5),
preceded by the index number or identifier assigned under that section
of the labeling.
(c) Comprehensive prescribing information. This section must appear
in prescription drug labeling immediately following the information
required under paragraph (b) of this section. The section of the
labeling must contain the information in the order required under
paragraphs (c)(1) through (c)(17) of this section, together with the
subheadings and index numbers or identifiers required under
Sec. 201.56(d)(1), unless omitted under Sec. 201.56(d)(3). If
additional subheadings are used within a labeling subsection in
accordance with Sec. 201.56(d)(5), they must be preceded by the index
number assigned under that section.
(1) Boxed warnings and contraindications. Special problems,
particularly those that may lead to death or serious injury, may be
required by FDA to be placed in a prominently displayed box. The boxed
warning(s) or contraindication(s) ordinarily must be based on clinical
data, but serious animal toxicity may also be the basis of boxed
information in the absence of clinical data. If a box containing
warning(s) or contraindication(s) is required, it must be located
preceding the ``Indications and Usage'' section of the labeling. The
box must be preceded by an exclamation point (!) and must contain, in
uppercase letters, a heading inside the box that includes the word
``WARNING(S)'' and is appropriate to communicate the general focus of
the boxed information. If the information related to the boxed risk is
extensive, the detailed information must be included under a bolded
subheading in the appropriate section of the labeling (either
``Contraindications'' or ``Warnings/Precautions''). The brief
explanation of the risk(s) in the box must be followed by a reference
(i.e., the appropriate index number) to this more detailed information.
(2) 1 Indications and usage. (i) This section of the labeling must
state that:
(A) The drug is indicated in the treatment, prevention, mitigation,
cure, or diagnosis of a recognized disease or condition; and/or
(B) The drug is indicated for the treatment, prevention,
mitigation, cure, or diagnosis of an important manifestation of a
recognized disease or condition; and/or
(c) The drug is indicated for the relief of symptoms associated
with a recognized disease or syndrome; and/or
(D) The drug, if used for a particular indication only in
conjunction with a primary mode of therapy (e.g., diet, surgery,
behavior changes, or some other drug), is an adjunct to the mode of
therapy.
(ii) For drug products other than biologics, all indications listed
in this section of the labeling 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.
(iii) For biologics, all indications listed in this section of the
labeling 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 of the labeling.
(iv) This section of the labeling must also contain the following
additional information:
(A) If evidence is available to support the safety and
effectiveness of the drug or biologic only in selected subgroups of the
larger population with a disease, syndrome, manifestation, or symptom
under consideration (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 (e.g., CD4 cell counts or viral load), this
section of the labeling must succinctly describe the available evidence
and state the limitations of usefulness of the drug. In such cases,
reference should be made to the ``Clinical Studies'' section of the
labeling for a detailed discussion of the methodology and results of
clinical studies relevant to such limitation(s). The labeling must also
identify specific tests needed for selection or monitoring of the
patients who need the drug (e.g., microbe susceptibility tests).
Information on the approximate kind, degree, and duration of
improvement to be anticipated must be stated if available and for all
drugs except biological products must be based on substantial evidence
derived from 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. For biological
products, such information must be based upon substantial evidence. If
the information is relevant to the recommended intervals between doses,
the usual duration of treatment, or any modification of dosage, it must
be stated in the ``Dosage and Administration'' section of the labeling
and referenced in this section of the labeling.
(B) If safety considerations are such that the drug should be
reserved for certain situations (e.g., cases refractory to other
drugs), this information must be stated in this section of the
labeling.
(C) If there are specific conditions that should be met before the
drug is used on a long-term basis (e.g., demonstration
[[Page 81116]]
of responsiveness to the drug in a short-term trial in a given
patient), the labeling must identify the conditions; or, if the
indications for long-term use are different from those for short-term
use, the labeling must identify the specific indications for each use.
(D) 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 the
labeling state that there is a lack of evidence that the drug is
effective or safe for that use or condition.
(E) Any statements comparing the safety or effectiveness, either
greater or less, 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.
(3) 2 Dosage and administration. This section of the labeling must
state the recommended usual dose, the usual dosage range, and, if
appropriate, an upper limit beyond which safety and effectiveness have
not been established. Dosages must be stated for each indication and
subpopulation when appropriate. Dosing regimens must not be implied or
suggested in other sections of labeling if not included in this section
of the labeling. When established and clinically important, efficacious
and/or toxic drug and/or metabolite concentration ranges and
therapeutic concentration windows for drug and/or metabolites must be
stated in this section of the labeling. Information on therapeutic drug
concentration monitoring (TDM) must also be included in this section of
the labeling when TDM is clinically necessary. This section of the
labeling must also state the intervals recommended between doses, the
optimal method of titrating dosage, the usual duration of treatment,
and any modification of dosage needed in special patient populations
(e.g., in children, in geriatric age groups, or in patients with renal
or hepatic disease). Specific tables or monographs should be used when
they would clarify dosage schedules. Radiation dosimetry information
must be stated for both the patient receiving a radioactive drug and
the person administering it. This section of the labeling 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 drug or
reconstituted drug, when important; essential information on drug
incompatibilities if the drug is mixed in vitro with other drugs; and
the following 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 How supplied/storage and handling. This section of the
labeling 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 ordinarily include:
(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 must be placed 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, and National Drug
Code number; and
(iv) Special handling and storage conditions.
(v) A statement directed to the pharmacist specifying the type of
container to be used in dispensing the drug product to maintain its
identity, strength, quality, and purity. Where there are standards and
test procedures for determining that the container meets the
requirements for specified types of containers as defined in an
official compendium, such terms may be used. For example, ``Dispense in
tight, light-resistant container as defined in the National
Formulary.'' Where standards and test procedures for determining the
types of containers to be used in dispensing the drug product are not
included in an official compendium, the specific container or types of
containers known to be adequate to maintain the identity, strength,
quality, and purity of the drug products must be described. For
example, ``Dispense in containers that (statement of specifications
that clearly enable the dispensing pharmacist to select an adequate
container).''
(5) 4 Contraindications. This section of the labeling must
describe those situations in which the drug should not be used because
the risk of use clearly outweighs any possible therapeutic benefit.
These situations include administration of the drug to patients known
to have a severe hypersensitivity reaction to it; 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 it; or continued use of the drug in the face of an
unacceptably hazardous adverse reaction. 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 of the labeling must state ``None known.''
(6) 5 Warnings/precautions. (i) General. Under this section
heading, the labeling must describe clinically significant adverse
reactions and other potential safety hazards, including those resulting
from drug/drug interactions; limitations in use imposed by them; and
steps that should be taken if they occur. The labeling must be revised
to include a warning as soon as there is reasonable evidence of an
association of a clinically significant hazard 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 of the labeling may be required by FDA if the drug is
commonly prescribed for a disease or condition, and there is lack of
substantial evidence of effectiveness for that disease or condition,
and such usage is associated with clinically significant risk or
hazard. The frequency of all clinically significant adverse reactions
(including those that do not require a boxed warning) and, if known,
the approximate mortality and morbidity rates for patients sustaining
the reaction, which are important to safe and effective use of the
drug, must be expressed as provided under the ``Adverse Reactions''
section of the labeling.
(ii) Other special care precautions. This section of the labeling
must also 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
[[Page 81117]]
under any other specific section or subsection of the labeling).
(iii) Monitoring: Laboratory tests. This subsection of the labeling
must identify any laboratory tests that may be 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. If the product is known to
interfere with laboratory tests, this subsection of the labeling must
briefly note this interference and reference where the detailed
information is discussed (typically this will be under the ``Drug
Interactions'' section).
(v) ADR reporting contacts. This section of the labeling must
include the statement: ``To report SUSPECTED SERIOUS ADR's, call
(insert name of manufacturer) at (insert manufacturer's phone number)
or FDA's MedWatch at (insert current FDA MedWatch number).'' For
vaccines, this section of the labeling must include the statement: ``To
report SUSPECTED SERIOUS ADR's, call (insert name of manufacturer) at
(insert manufacturer's phone number) or VAERS at (insert the current
VAERS number).''
(7) 6 Drug interactions. (i) This section of the labeling must
contain specific practical guidance for the practitioner on preventing
clinically significant drug/drug interactions with other prescription
or over-the-counter drugs, and drug/food interactions (for example,
interactions with dietary supplements and such foods as grapefruit
juice) that may occur in patients taking the drug. Specific drugs or
classes of drugs with which the drug to which the labeling applies may
interact in vivo must be identified, and the mechanism(s) of the
interaction must be briefly described. Information in this section of
the labeling must be limited to that pertaining to clinical use of the
drug in patients. Drug interactions supported only by animal or in
vitro experiments should not ordinarily be included, but animal or in
vitro data may be used if shown to be clinically relevant. Interactions
that have particularly serious consequences may be described briefly in
the ``Contraindications'' or ``Warnings/Precautions'' sections of
labeling, as appropriate, with a more complete description under this
section of the labeling. Drug incompatibilities, i.e., drug
interactions that may occur when drugs are mixed in vitro, as in a
solution for intravenous administration, must be discussed under the
``Dosage and Administration'' section of the labeling rather than under
this section of the labeling.
(ii) This section of the labeling must also contain practical
guidance on known interference of the drug with laboratory tests.
(8) 7 Use in specific populations. This section of the labeling
must contain the following subsections:
(i) 7.1 Pregnancy. This subsection of the labeling 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 of the labeling 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
[[Page 81118]]
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/Precautions' section.'' Under the ``Warnings/
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 administered
to a woman with reproductive potential, 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 administered to a woman with reproductive potential, 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) 7.2 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 section of the labeling, this
subsection of the labeling 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 of the labeling is unknown, it must state that
the information is unknown.
(iii) 7.3 Lactating women. (A) If a drug is absorbed systemically,
this subsection of the labeling 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 of the labeling must contain one of the
following statements, as appropriate. If the drug is associated with
clinically significant 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 producing milk for consumption or to discontinue
the drug, taking into account the importance of the drug to the
lactating woman.'' If the drug is not associated with clinically
significant 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 lactating woman.''
(C) If a drug is absorbed systemically and information on excretion
in human milk is unknown, this subsection of the labeling must contain
one of the following statements, as appropriate. If the drug is
associated with clinically significant 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 clinically
significant 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 producing milk for consumption or to discontinue the
drug, taking into account the importance of the drug to the lactating
woman.'' If the drug is not associated with clinically significant
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 lactating
woman.''
(iv) 7.4 Pediatric use. (A) Pediatric population(s)/pediatric
patient(s): For the purposes of paragraphs (c)(8)(iv)(B) through
(c)(8)(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 (i.e., an
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 of the
labeling, and appropriate pediatric dosage information must be given
under the ``Dosage and Administration'' section of the labeling. The
``Pediatric use'' subsection of the labeling 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 of the labeling 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/Precautions'' section(s) of the labeling.
(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 of the labeling 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 of
the labeling. The ``Pediatric use'' subsection of the
[[Page 81119]]
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/Precautions'' section(s)
of the labeling.
(D) FDA may approve a drug for pediatric use based on adequate and
well-controlled studies in adults, with other information supporting
pediatric use. In such cases, the agency will have concluded that the
course of the disease and the effects of the drug, both beneficial and
adverse, are sufficiently similar in the pediatric and adult
populations to permit extrapolation from the adult efficacy data to
pediatric patients. The additional information supporting pediatric use
must ordinarily include data on the pharmacokinetics of the drug in the
pediatric population for determination of appropriate dosage. Other
information, such as data from pharmacodynamic studies of the drug in
the pediatric population, data from other studies supporting the safety
or effectiveness of the drug in pediatric patients, pertinent
premarketing or postmarketing studies or experience, may be necessary
to show that the drug can be used safely and effectively in pediatric
patients. 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).
Data summarized in the preceding prescribed statement in this
subsection of the labeling must be discussed in more detail, if
appropriate, under the ``Clinical Pharmacology'' or the ``Clinical
Studies'' section of the labeling. For example, pediatric
pharmacokinetic or pharmacodynamic studies and dose-response
information should be described in the ``Clinical Pharmacology''
section of the labeling. Pediatric dosing instructions must be included
in the ``Dosage and Administration'' section of the labeling. 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 of the labeling and, as
appropriate, in the ``Contraindications,'' ``Warnings/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 of the labeling 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 of the labeling, or, if
appropriate, the hazard must be stated in the ``Contraindications'' or
``Warnings/Precautions'' section of the labeling 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 of the labeling
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 of the labeling, or, if appropriate, the hazard must be
stated in the ``Contraindications'' or ``Warnings/Precautions'' section
of the labeling and this subsection must refer to it.
(G) If the sponsor believes that none of the statements described
in paragraphs (c)(8)(iv)(B) through (c)(8)(iv)(F) of this section is
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/Precautions''
section of the labeling.
(v) 7.5 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 of the labeling, and appropriate geriatric dosage must
be stated under the ``Dosage and Administration'' section of the
labeling. The ``Geriatric use'' subsection of the labeling 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 of the labeling must
pertain to use of the drug in persons 65 years of age and older. Data
summarized in this subsection of the labeling must be discussed in more
detail, if appropriate, under ``Clinical Pharmacology'' or the
``Clinical Studies'' section of the labeling. As appropriate, this
information must also be contained in the ``Warnings/Precautions'' or
``Contraindications'' section of the labeling.
(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 of the labeling 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
[[Page 81120]]
subjects respond differently from younger subjects, and other reported
clinical experience has not identified such differences, the
``Geriatric use'' subsection of the labeling 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 of the
labeling 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 of the labeling 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/Precautions,''
``Dosage and Administration,'' or other sections of the labeling.
(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 of the labeling and in detail under the
``Clinical Pharmacology'' section of the labeling. The ``Clinical
Pharmacology'' and ``Drug interactions'' section of the labelings
ordinarily contain 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 of the labeling must include the
statement:
This drug is known to be substantially excreted by the kidney,
and the risk of toxic 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 of the labeling, or, if appropriate, the hazard must be
stated in the ``Contraindications'' or ``Warnings/Precautions'' section
of the labeling, and the ``Geriatric use'' subsection must refer to
those sections of the labeling.
(E) Labeling under paragraphs (c)(8)(v)(A) through (c)(8)(v)(C) of
this may include statements, if they would be useful in enhancing safe
use of the drug, that 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)(8)(v)(A) through (c)(8)(v)(E) of this section is
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 of the labeling. Additional subsections
of the labeling 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).
(9) 8 Adverse reactions. An adverse reaction is a noxious and
unintended response to any dose of a drug product for which there is a
reasonable possibility that the product caused the response (i.e., the
relationship cannot be ruled out).
(i) Listing of adverse reactions. This section of the labeling must
list the adverse reactions (not all the adverse events) that occur with
the drug and with drugs in the same pharmacologically active and
chemically related class, if applicable.
(ii) Categorization of adverse reactions. 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. 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.
(iii) Potentially fatal adverse reactions. The ``Warnings/
Precautions'' section of the labeling or, if appropriate, the
``Contraindications'' section of the labeling must identify any
potentially fatal adverse reaction.
(iv) Comparisons of adverse reactions between drugs. For drug
products other than biologics, 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
[[Page 81121]]
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.
(10) 9 Drug abuse and dependence. This section of the labeling must
contain the following subsections, as appropriate for the specific
drug.
(i) Controlled substance. If the drug is controlled by the Drug
Enforcement Administration, the schedule in which it is controlled must
be stated.
(ii) Abuse. This subsection of the labeling must be based primarily
on human data and human experience, but pertinent animal data may also
be used. This subsection of the labeling must state the types of abuse
that can occur with the drug and the adverse reactions pertinent to
them. Particularly susceptible patient populations must be identified.
(iii) Dependence. This subsection of the labeling 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 must be provided, and the
principles of treating the effects of abrupt withdrawal must be
described.
(11) 10 Overdosage. This section of the labeling must describe the
signs, symptoms, and laboratory findings of acute overdosage and the
general principles of treatment. This section of the labeling must be
based on human data, when available. If human data are unavailable,
appropriate animal and in vitro data may be used. Specific information
must be provided about the following:
(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 and/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 of
the labeling 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, such as proven antidotes, induced
emesis, gastric lavage, and forced diuresis. Unqualified
recommendations for which data are lacking with the specific drug or
class of drugs, especially treatment using another drug (for example,
central nervous system stimulants, respiratory stimulants) may not be
stated unless specific data or scientific rationale exists to support
safe and effective use.
(12) 11 Description. (i) This section of the labeling 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 biologics,
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 Secs. 610.60 and
610.61 of this chapter for biologic labels;
(D) If the drug is for other than oral use, the names of all
inactive ingredients, except that:
(1) Flavorings and perfumes may be designated as such without
naming their components.
(2) Color additives may be designated as coloring without naming
specific color components unless the naming of such components is
required by a color additive regulation prescribed in subchapter A of
this chapter.
(3) Trace amounts of harmless substances added solely for
individual product identification need not be named. If the drug is
intended for administration by parenteral injection, the quantity or
proportion of all inactive ingredients must be listed, except that
ingredients added to adjust the pH or to make the drug isotonic may be
declared by name and a statement of their effect; and if the vehicle is
water for injection, it need not be named.
(E) If the product is sterile, a statement of that fact;
(F) The pharmacological or therapeutic class of the drug;
(G) For drug products other than biologics, the chemical name and
structural formula of the drug; and
(H) 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) Under this section, the
labeling must contain information relating to the human clinical
pharmacology and actions of the drug in humans. Information based on in
vitro data using human biomaterials (e.g., human liver slices) and/or
pharmacologic animal models or preparations may be included if it is
essential to a description of the biochemical and/or physiological mode
of action of the drug or drug/drug interactions or is otherwise
pertinent to human therapeutics. The section of the labeling must
include the following subheadings and information:
(A) 12.1 Mechanism of action. This section of the labeling 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). A brief description of disease
pathophysiology may be included to help facilitate an understanding of
the drug's action and impact on this process. If the mechanism of
action is not known, the labeling must contain a statement about the
lack of information.
(B) 12.2 Pharmacodynamics. This section of the labeling must
include a description of any biochemical or physiologic pharmacologic
effects of the drug or active metabolites thought to be related to
preventing, diagnosing, mitigating, curing, or treating disease, and/or
those related to adverse effects or toxicity. Dose and/or concentration
response relationship(s) and the time course of action must be included
if known. Information on activity of metabolites, if available, must
also be included in this section of the labeling. Recommendations based
on pharmacodynamic information regarding dosage titration, monitoring
of therapeutic effects, or drug concentration monitoring and dosage
adjustment should appear in other sections of the labeling such as the
``Warnings/Precautions'' and/or ``Dosage and Administration''sections.
If pharmacokinetic/pharmacodynamic relationships are not demonstrated
or are unknown, the labeling must contain a statement about the lack of
information.
(C) 12.3 Pharmacokinetics. This section of the labeling must
include clinically relevant pharmacokinetic information. In general,
the focus should be on factors that lead to and/or explain altered
critical measures (e.g.,
[[Page 81122]]
Cmax, AUC, half-life). Information about the
pharmacokinetics of a drug or active metabolites must include pertinent
absorption, distribution, metabolism (including metabolic pathways and
identification of the enzyme systems involved), and excretion
parameters. Information regarding bioavailability, the effect of food,
minimum concentration (Cmin), maximum concentration
(Cmax), time to maximum concentration (Tmax),
pertinent half-lives (t\1/2\), time to reach steady state, accumulation
route(s) of elimination, routes of clearance (e.g., CL-total, renal,
hepatic), and volume of distribution (Vd) for clinical doses
must be presented as appropriate. Information regarding nonlinearity in
pharmacokinetic parameters, metabolic induction or inhibition, and
clinically relevant binding (plasma protein, erythrocyte) parameters
must also be presented as appropriate. Qualitative and quantitative
assessment of metabolism must be presented in this section of the
labeling. The impact of age, gender, ethnicity, disease states, and
other factors on pharmacokinetic parameters must be noted and
referenced to other sections of the labeling as necessary (e.g., ``Use
in Specific Populations,'' ``Warnings/Precautions,'' ``Dosage and
Administration''). The clinical significance of any factors that change
the product's pharmacokinetics must be noted, and recommendations based
on this pharmacokinetic information must appear in other sections of
the labeling, such as the ``Warnings/Precautions'' and/or ``Dosage and
Administration'' sections, as necessary. If important pharmacokinetic
information is unavailable, the labeling must contain a statement about
the lack of information.
(D) 12.4 Other clinical pharmacology information. Under this
heading, information may be presented that is not required under other
sections of the labeling where such information is helpful to an
understanding of the clinical pharmacology of the product. Information
within this section of the labeling may include in vitro data related
to the clinical pharmacology of drug/drug interactions or use in
specific populations. If specific data on alternative dosing regimens
(e.g., for hepatically or renally impaired patients) is included in
this section of the labeling, it must also be included under
Sec. 201.57(c)(3) (i.e., the ``Dosage and Administration'' section of
the comprehensive prescribing information).
(ii) In vitro or animal data related to the activity or efficacy of
a drug that have not been shown by adequate and well-controlled studies
to be pertinent to clinical use may only be included in this section of
the labeling if a waiver is granted under Sec. 201.58 or
Sec. 314.126(c) of this chapter.
(14) 13 Nonclinical toxicology. Under this section heading, the
labeling must contain the following subsections as appropriate for the
drug:
(i) 13.1 Carcinogenesis, mutagenesis, impairment of fertility.
This subsection of the labeling must state whether long-term studies in
animals have been performed to evaluate carcinogenic potential and, if
so, the species and results. If reproduction studies or other data in
animals reveal a problem or potential problem concerning mutagenesis or
impairment of fertility in either males or females, the information
must be described. Any precautionary statement on these topics must
include practical, relevant advice to the prescriber on the
significance of these animal findings. If there is evidence from human
data that the drug may be carcinogenic or mutagenic or that it impairs
fertility, this information must be included under the ``Warnings/
Precautions'' section of the labeling.
(ii) 13.2 Animal toxicology and/or pharmacology. In many cases,
the labeling need not include this section. Significant animal data
necessary for safe and effective use of the drug in humans must
ordinarily be included in one or more of the other sections of the
labeling, as appropriate. Commonly for a drug that has been marketed
for a long time, and in rare cases for a new drug, chronic animal
toxicity studies have not been performed or completed for a drug that
is administered over prolonged periods or is implanted in the body. The
unavailability of such data must be stated in the appropriate section
of the labeling for the drug. If the pertinent animal data cannot be
appropriately incorporated into other sections of the labeling, this
section may be used.
(15) 14 Clinical studies. This section of the labeling generally
must contain a discussion of clinical study design and results that are
important to a prescriber's understanding of the basis for approval of
the drug. However, this section of the labeling must not include an
encyclopedic listing of all, or even most, studies performed as part of
the product's clinical development program. The section generally will
provide more specific information than contained elsewhere in labeling
on the effects of the drug in relevant clinical studies, and especially
on the extent of the product's demonstrated benefits (e.g., how the
drug was used in clinical trials, who was studied, and critical
parameters that were monitored). Although typically not needed, a brief
reference to a specific important clinical study may be made in any
section of the labeling required under Secs. 201.56 and 201.57 if the
study is essential to an understandable presentation of the information
in that section of the labeling. Following a succinct description of
the available evidence, reference must be made to ``Clinical Studies''
for presentation of more detailed discussion of the methodology and
results of relevant studies. A clinical study (including Phase I,
pharmacokinetic, etc.) may be discussed in prescription drug labeling
only under the following conditions:
(i) For drug products other than biologics, any clinical study that
is discussed 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 of the labeling. For biological products, any
clinical study that is discussed that relates to an indication for or
use of the biologic must contitute 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 of the labeling.
(ii) Any discussion of a clinical study that relates to a risk or
risks from the use of the drug must also reference the other sections
of the labeling for the drug where the risk or risks are identified or
discussed.
(16) R References. This section may appear in labeling in the place
of a detailed discussion of a subject that is of limited interest, but
nonetheless important. References may appear in sections of the
labeling format, other than the ``References'' section, in rare
circumstances only. A reference may be cited in prescription drug
labeling only under the following conditions:
(i) If the reference is cited in the labeling in the place of a
detailed discussion of data and information concerning an indication
for or use of a drug or biological product, the reference must be based
upon an adequate and well-controlled clinical investigation under
Sec. 314.126(b) of this chapter or for a biological product, upon
substantial evidence of effectiveness.
(ii) If the reference is cited in the labeling in the place of a
detailed discussion of data and information concerning a risk or risks
from the use of the drug, the risk or risks must also be identified or
discussed in the appropriate section of the labeling for the drug.
[[Page 81123]]
(17) P Patient counseling information. This section of the labeling
must contain information useful for patients to know for safe and
effective use of the drug (e.g., precautions concerning driving or the
concomitant use of other substances that may have harmful additive
effects). This section of the labeling must appear as the last section
of the comprehensive prescribing information. Any approved printed
patient information or Medication Guide must be referenced in this
section of the labeling and the full text of such patient information
or Medication Guide must be reprinted immediately following this
section of the labeling.
(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 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)(4) through (a)(10),
(a)(12), (a)(13), and (a)(14) of this section must be highlighted in
bold type and must be presented in the center of a horizontal line.
(4) If there are multiple subheadings listed under paragraphs
(a)(4) through (a)(10), (a)(12), or (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), and (a)(15) 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.
(7) The index numbers and identifiers (i.e., ``P'' and ``R'')
required by Sec. 201.56(d) and paragraphs (c)(1) through (c)(17) 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), 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 x 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) The comprehensive labeling sections or subsections identified
in paragraph (a)(5) of this section (i.e., those containing recent
labeling changes) must be highlighted by the inclusion of a vertical
line on the left edge of the new or modified text.
5. Section 201.58 is amended by revising the first sentence to read
as follows:
Sec. 201.58 Requests for waiver of requirement for adequate and well-
controlled studies to substantiate certain labeling statements.
A request under Sec. 201.57(c)(2)(ii), (c)(2)(iv)(A), and
(c)(9)(iv), or a request under Sec. 201.80(b)(2), (c)(2), (c)(3)(i),
(c)(3)(v), and (g)(4) for a waiver of the requirements of
Sec. 314.126(b) of this chapter must be submitted in writing as
provided in Sec. 314.126(c) of this chapter to the Director, Center for
Drug Evaluation and Research, Food and Drug Administration, 5600
Fishers Lane, Rockville, MD 20857, or, if applicable, the Director,
Center for Biologics Evaluation and Research, 8800 Rockville Pike,
Bethesda, MD 20892. * * *
Sec. 201.59 [Removed]
6. Section 201.59 Effective date of Secs. 201.56, 201.57,
201.100(d)(3), and 201.100(e) is removed.
7. Newly redesignated Sec. 201.80 is amended by revising paragraphs
(b)(2), (c)(2), (f)(2), and (m)(1) and by adding a new sentence after
the first sentence of paragraph (j) to read as follows:
Sec. 201.80 Specific requirements on content and format of labeling
for human prescription drugs and biologics; older drugs not described
in Sec. 201.56(b)(1).
* * * * *
(b) * * *
(2) Data that demonstrate activity or effectiveness in in vitro or
animal tests and that have not been shown by adequate and well-
controlled studies to be pertinent to clinical use may be included
under this section of the labeling only if a waiver is granted under
Sec. 201.58 or Sec. 314.126(c) of this chapter.
(c) * * *
(2)(i) For drug products other than biologics, all indications
listed in this section of the labeling 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 of the labeling.
(ii) For biologics, all indications listed in this section of the
labeling 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 of the labeling.
* * * * *
(f) * * *
(2) Information for patients. This section of the labeling must
contain information useful for patients to know for safe and effective
use of the drug (e.g., precautions concerning driving or the
concomitant use of other sustances that may have harmful additive
effects). Any approved printed patient information or Medication Guide
must be referenced in this section of the labeling and the full text of
such patient information or Medication Guide must be reprinted
immediately following the last section of labeling.
* * * * *
(j) Dosage and administration. * * * Dosing regimens must not be
implied or suggested in other sections of labeling if not included in
this section of the labeling. * * *
* * * * *
(m) * * *
(1) If the clinical study or reference is cited in the labeling in
place of a detailed discussion of data and information concerning an
indication for use of the drug, the reference must be based upon, or
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 of the labeling.
* * * * *
8. Section 201.100 is amended by removing paragraphs (b)(5) and
(b)(7), by redesignating paragraph (b)(6) as paragraph (b)(5), by
adding a new paragraph (b)(6), and by revising paragraphs (b)(2) and
(d)(3) and newly redesignated paragraph (b)(5) to read as follows:
Sec. 201.100 Prescription drugs for human use.
* * * * *
(b) * * *
(2) The recommended or usual dosage, unless not required under
Sec. 201.55; and
* * * * *
(5) An identifying lot or control number from which it is possible
to
[[Page 81124]]
determine the complete manufacturing history of the package of the
drug.
(6) In the case of containers too small or otherwise unable to
accommodate a label with sufficient space to bear all such information,
but which are packaged within an outer container from which they are
removed for dispensing or use, the information required by paragraphs
(b)(2) and (b)(3) of this section may be contained in other labeling on
or within the package from which it is to be dispensed; the information
referred to in paragraph (b)(1) of this section may be placed on such
outer container only; and the information required by this paragraph
(b)(6) may be on the crimp of the dispensing tube.
* * * * *
(d) * * *
(3) The information required, and in the format specified, by
Secs. 201.56, 201.57, and 201.80.
* * * * *
Dated: August 4, 2000.
Jane E. Henney,
Commissioner of Food and Drugs.
Donna E. Shalala,
Secretary of Health and Human Services.
Note: The following appendix will not appear in the Code of
Federal Regulations.
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