[Federal Register Volume 65, Number 247 (Friday, December 22, 2000)]
[Proposed Rules]
[Pages 81082-81131]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 00-32375]



[[Page 81081]]

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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

  Federal Register / Vol. 65 , No. 247 / Friday, December 22, 2000 / 
Proposed Rules  

[[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:
    [email protected]

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: [email protected]
    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: [email protected]

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

[[Page 81084]]

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://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://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.

BILLING CODE 4160-01-P

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[FR Doc. 00-32375 Filed 12-21-00; 8:45 am]
BILLING CODE 4160-01-C