Guidance for Industry:
Labeling for Human Prescription Drug and Biological Products —
Implementing the New Content and Format Requirements
(PDF format of this document)
DRAFT GUIDANCE
This guidance document is being
distributed for comment purposes only.
Comments and suggestions regarding this draft
document should be submitted within 90 days of publication in the
Federal Register of the notice announcing the availability
of the draft guidance. Submit comments to the Division of Dockets
Management (HFA-305), Food and Drug Administration, 5630 Fishers
Lane, rm. 1061, Rockville, MD 20852. All comments should be
identified with the docket number listed in the notice of
availability that publishes in the Federal Register.
For questions regarding this draft document
contact (CDER) Janet Norden at 301-796-2270, or (CBER) Toni
Stifano at 301-827-6190.
U.S. Department of Health and Human Services
Food and Drug Administration
Center for Drug Evaluation and Research (CDER)
Center for Biologics Evaluation and Research (CBER)
January 2006
Labeling
Guidance for
Industry
Labeling for Human Prescription Drug and Biological Products —
Implementing the New Content and Format Requirements
Additional copies are available
from:
Office of Training and
Communications
Division of Drug Information, HFD-210
5600 Fishers Lane
Rockville, MD 20857
(Tel) 301-827-4573
(Internet)
http://www.fda.gov/cder/guidance/index.htm
or
Office of Communication, Training
and
Manufacturers Assistance, HFM-40
Center for Biologics Evaluation and Research
Food and Drug Administration
1401 Rockville Pike, Rockville, MD 20852-1448
(Tel) 800-835-4709 or 301-827-1800
(Internet)
http://www.fda.gov/cber/guidelines.htm
U.S. Department of Health and Human Services
Food and Drug Administration
Center for Drug Evaluation and Research (CDER)
Center for Biologics Evaluation and Research (CBER)
January 2006
Labeling
Guidance for Industry
Labeling for Human Prescription Drug
and Biological Products —Implementing the New Content and Format
Requirements
This
draft guidance, when finalized, will represent the Food and Drug
Administration's (FDA's) current thinking on this topic. It does
not create or confer any rights for or on any person and does not
operate to bind FDA or the public. You can use an alternative
approach if it satisfies the requirements of the applicable
statutes and regulations. If you want to discuss an alternative
approach, contact the FDA staff responsible for implementing this
guidance. If you cannot identify the appropriate FDA staff, call
the appropriate number listed on the title page of this guidance.
This guidance is intended to
assist applicants in complying with the new content and format
requirements of labeling for human prescription drug and biological
products (21 CFR 201.56(d) and 201.57).
FDA recognizes the broad scope and complexity of these new
regulations and is issuing this guidance to provide recommendations
for applicants revising labeling of already approved products and
for applicants drafting labeling for new products to be submitted
with a new drug application (NDA) or biologics license application (BLA).
FDA also recognizes that, as both applicants and the Agency become
more familiar with writing labeling that complies with these new
regulations, good examples and practices will emerge. FDA has
appended a list of Frequently Asked Questions (FAQs) (Appendix A)
and has posted illustrative examples of labeling in the new format
at
www.fda.gov/cder/regulatory/physLabel/default.htm. The
information at this Web site will be updated with new examples, if
needed, as they become available.
This
guidance provides recommendations on the following subjects:
-
Issues to consider when
revising labeling for approved products to meet the new content
and format requirements, including:
·
how to distribute
information among newly created sections
·
when it is
important to repeat information in varying levels of detail in
different sections
·
how to minimize
redundancy
·
when to
cross-reference
-
Issues to consider when
developing “Highlights of Prescribing Information” (Highlights)
-
Procedural information,
including:
·
how to determine
which applications are covered
·
how to submit
labeling
·
how to apply for a
waiver
·
information about
class labeling
·
information about
abbreviated new drug applications (ANDAs)
-
How to format labeling,
including the use of subheadings, cross-references, type size, and
how to address omitted sections
FDA has
also made minor amendments to the regulations for labeling of
prescription drug and biological products not subject to the new
content and format requirements (see 21 CFR 201.56(e) and 201.80 and
sections V.A and V.B of this document).
FDA's guidance
documents, including this guidance, do not establish legally
enforceable responsibilities. Instead, guidances describe the
Agency's current thinking on a topic and should be viewed only as
recommendations, unless specific regulatory or statutory
requirements are cited. The use of the word should in Agency
guidances means that something is suggested or recommended, but not
required.
II. BACKGROUND
In January 2006, the Agency published a final
rule that amended the requirements for the content and format of
labeling for human prescription drug and biological products. The
new regulations are designed to make information in prescription
drug labeling easier for health care practitioners to access, read,
and use, thereby facilitating practitioners’ use of labeling to make
prescribing decisions. Changes to the labeling format include the
addition of introductory prescribing information, entitled
“Highlights of Prescribing Information” (Highlights), and a “Table
of Contents” (Contents) for the “Full Prescribing Information” (FPI).
Highlights contains selected information from the FPI that health
care practitioners most commonly reference and consider most
important. The Contents lists the sections and subsections of the
FPI. The final rule also reorders and reorganizes the FPI, makes
minor changes to the content of the FPI, and sets minimum graphical
requirements for the format of the labeling. For the purpose of
this guidance, the term new format refers to labeling that
meets the content and format requirements at §§ 201.56(d) and
201.57. The term old format refers to labeling formatted to
meet the requirements of the 1979 final rule (former §§ 201.56 and
201.57).
See Appendix B for a listing of prescription drug labeling sections
in the old and new formats.
This
guidance focuses on the major issues applicants may face when
developing new labeling or when revising labeling to meet the new
requirements and provides procedural information important for
implementation. FDA expects that
the most challenging aspects of this new regulation will be
developing Highlights and distributing information among sections
that have been substantially affected by this rule, particularly
when the information must be culled from the labeling in the old
format. Therefore, the guidance focuses primarily on these issues
and not on developing sections that have not been changed by this
rule. Additional guidance documents that address content and format
for specific FPI sections are available and should be consulted when
developing labeling.
III.
considerations for REVIsing LABELING
A. General
Principles
The FPI in the new format
contains substantially the same information as labeling in the old
format, typically with reordering and reorganization of the
information. For example, new labeling sections (e.g.,
Drug Interactions,
Use in Specific Populations,
Patient Counseling
Information) contain information formerly included in the
PRECAUTIONS section. Certain sections (e.g.,
Clinical Studies,
Nonclinical Toxicology)
that were previously optional are now required (§ 201.56(d)).
Therefore, although labeling in the old format for approved products
does not contain the new section headings, most of the content
already is included in the labeling under different headings or
subheadings. For example, information from the old
Warnings section and
old Precautions
section is consolidated into a single new section (Warnings
and Precautions) and information in certain old
Precautions subsections (e.g., Information for Patients,
Drug Interactions, Pregnancy, Labor and Delivery,
Nursing Mothers, Pediatric Use, Geriatric Use)
is relocated to new labeling sections (e.g.,
Patient Counseling
Information, Drug
Interactions, Use in
Specific Populations).
FDA recommends following these
general principles when revising labeling in the old format.
1. Developing
New Sections
FDA expects that most sections
or subsections from labeling in the old format can be moved, with
little or no modification, to corresponding sections in the new
format. See Appendix C for information on how to reorganize
labeling sections and subsections within the new format.
In some cases, however, the
labeling in the old format may not include the information specified
by the new regulations or the content of a section may be
inadequate. If the information or section in the old format is
inadequate, it must be revised (§ 201.56(a)).
If the labeling in the old
format lacks an entire section that is required in the new format,
then the section must be developed unless it is clearly inapplicable
(§ 201.56(d)). For example, if the labeling in the old format does
not contain an Information for Patients subsection in the
Precautions section,
the applicant must develop a
Patient Counseling Information section unless the section is
clearly inapplicable to use of the drug.
2.
Data Analyses
FDA recognizes that revising
labeling to comply with the new regulations is an excellent
opportunity to update labeling content to ensure that it accurately
reflects current knowledge. FDA expects that, in most cases, the
revisions will involve limited rewriting aimed at clarifying text,
eliminating redundancies, and updating outdated terminology. FDA
emphasizes that no new data analyses of the information in the old
format are required as long as the labeling that is developed is
truthful and accurate. However, if new information is available
that causes the labeling to be inaccurate, the labeling must be
updated to incorporate the new information (§ 201.56(a)(2)). In some cases, new data analyses may be necessary.
3. Updating
Claims
Although the content of
information in labeling in the old format will not significantly
change when converted to the new format, the process of updating
labeling provides a unique opportunity for the applicant to
systematically evaluate information in labeling to identify
unsubstantiated claims or outdated information and revise it
accordingly. By regulation, all express or implied claims in
labeling must be supported by substantial evidence.
If unsubstantiated claims currently exist in labeling, the applicant
must revise the labeling to remove such claims (§
201.56(a)(3)).
B. Distributing Information
Among Sections
When revising labeling in the
old format to comply with the new regulations, applicants will face
many decisions about where to put information and whether to repeat
information in more than one section. Often sections or subsections
can be moved with little or no modification (see Appendix C). In
some cases, it will be more appropriate to move certain information
from a labeling section in the old format to a different labeling
section in the new format or to consolidate similar issues under a
new subheading. In other cases, it will be appropriate to divide
portions of information in a single labeling section among two or
more sections. The following general principles and examples are
offered to help applicants make decisions about where to locate
information in the new format.
It is often important to repeat
information in varying levels of detail in different labeling
sections, based on the type and clinical relevance of the
information. Important clinical information relevant to prescribing
decisions should be identified, prioritized, and located in the
labeling section that most appropriately communicates the type of
information being considered.
Detailed information
about a particular topic should be consolidated in a single labeling
section. Often, other sections of labeling should more briefly
describe or refer to the topic, but not repeat the same level of
detail. For example, clinically relevant information about a drug
interaction that rises to the level of a warning will typically be
described in the Warnings and
Precautions section, with supporting detail in the
Drug Interactions
section and other sections as appropriate (e.g.,
Dosage and Administration
section if a dosage modification is necessary).
In some instances,
information repeated in different sections of labeling in the old
format can be combined in the new format.
For example, the old Warnings
and old Precautions
sections sometimes each contained information about a similar issue;
this information can now be consolidated under one subheading in the
new Warnings and Precautions section. When moving and
consolidating information in labeling, optional subheadings can be
ordered to reflect the importance and relative public health
significance of the information.
When information about
the same topic is contained in more than one section, the section
with greatest clinical relevance (i.e., containing the most
important information relevant to prescribing) will typically
include a succinct description and will cross-reference the related
sections that contain additional detail. If the detailed
information is appropriately divided into more than one section,
those sections should cross-reference each other. In some cases,
cross-references are required (e.g., § 201.57(c)(1), (c)(6)(iv), and
(c)(15)(ii)).
The Agency expects that
distributing information among certain sections may present special
challenges. Based on our experience in developing mock labeling, we
have identified several basic principles. The following discussion
of distributing information among labeling sections illustrates
these principles. Although drug interaction information has been
selected for this example, these principles also apply to other
labeling sections.
·
Drug interaction
information typically appears in the
Clinical Pharmacology and
Drug Interactions
sections. Frequently, there is a subset of information that is
clinically relevant and essential for prescribing decisions. That
subset of information may be distributed among several sections,
including the Boxed Warning,
Contraindications,
Warnings and Precautions, and
Dosage and Administration
(§ 201.57(c)(3)(i)(H) and (c)(8)). FDA recommends using a
descriptive header of summary concepts preceding a discussion of
specific information (e.g., “CYP3A inhibitor”).
·
When drug
interaction information rises to the level of a warning, precaution,
or contraindication or necessitates a dosage adjustment, this
information should be discussed briefly in the applicable section(s),
with details in the Drug
InteractionS section (§ 201.57(c)(8)).
·
The
Drug Interactions
section contains clinically relevant information, such as the need
to modify a dose or regimen. It can include information about the
observed absence of a drug interaction if that interaction would
otherwise be anticipated or is of special concern (e.g., other drugs
in the class need a dosage adjustment or if the drugs are commonly
coadministered).
·
More detail about drug interaction studies, including
negative results of drug interaction studies, and any clinically
relevant, nonclinical data should be included in the
Clinical Pharmacology section.
The purpose of
Highlights is to provide immediate access to the information that
practitioners most commonly refer to and view as most important.
Highlights is intended to serve as an information tool, drawing
attention to this information and guiding the practitioner to the
section in the FPI where detailed information can be obtained.
Highlights is not a verbatim repetition of selected information from
the FPI, or simply a repetition of the Contents, but a concise,
informative summary of crucial prescribing information. Rarely, it
may be appropriate to repeat information verbatim from the FPI
(e.g., a succinct boxed warning statement or short indication
statement), but in most cases, the information should be summarized
and presented in an easily accessible format (e.g., bulleted,
tabular).
It is critical that
the summarized content of Highlights be consistent with the more
detailed information in the FPI, but not all of that information
will be included in Highlights. Selecting the information to
include in Highlights requires judgment about the data in relation
to the clinical setting in which the drug is used. The information
considered of greatest importance will vary, depending on factors
such as differences in safety profiles or dosing considerations for
different indications or populations.
Information about a
topic, or similar topics, extracted from the FPI should be grouped
together and summarized with a brief, clear statement. For example,
several warnings from the FPI about a similar issue could be
condensed into one bulleted item under the Warnings and Precautions
heading in Highlights.
Summarized information
should be presented in direct language that is succinct and imparts
a complete piece of information (e.g., for a warning: a description
of the risk, its consequences, and the actions to take to prevent
or mitigate it). In some cases, the information can be summarized
in a few words, while in others, a few short phrases or sentences
are more appropriate. Each summarized statement should be located
under the appropriate Highlights heading and must cross-reference
the section(s) or subsection(s) of the FPI that contains more
detailed information (§ 201.56(d)(3)).
1.
Initial U.S.
Approval (§ 201.57(a)(3))
On the line
immediately beneath the established name (or for biologics, the
proper name of the product), the verbatim statement “Initial U.S.
Approval” must be presented, followed by the four-digit year in
which FDA initially approved the new molecular entity, the new
biological product, or the new combination of active ingredients
(e.g., Initial U.S. Approval: 2004).
Multiple dates should
not be listed for products with multiple formulations approved or
licensed in different years. For these products, list the initial
approval date of the new molecular entity, new biologic product, or
new combination of active ingredients.
The Boxed Warning in
Highlights must contain a concise summary of the information from
the Boxed Warning in
the FPI, and is limited in length to 20 lines. Because the
Boxed Warning in the
FPI is an abbreviated description of the drug’s most important
warnings and contraindications, the Boxed Warning in Highlights
serves to emphasize such information, as well as to direct attention
to the complete box and to the sections in the FPI that contain more
detailed information.
FDA recommends that
the information under the Boxed Warning heading in Highlights be
summarized in a bulleted format, with each bullet communicating a
discrete warning or contraindication. In rare instances, the
Boxed Warning in the
FPI may be sufficiently concise to warrant repeating the statement
verbatim in the Boxed Warning in Highlights.
When substantive
labeling changes are made to any of the following sections of the
FPI, the heading(s) of the changed section(s) must be listed in
Highlights under the heading Recent Major Changes:
·
Boxed Warning
·
Indications and Usage
·
Dosage and Administration
·
Contraindications
·
Warnings and Precautions
Minor corrections,
such as typographical errors or grammatical changes, are not
considered substantive labeling changes.
·
What must be included
— At
a minimum, the section heading, identifying number, and the date on
which the change was incorporated in the labeling in month/year
format (e.g., 6/2005 or June 2005)
— If
appropriate, the section subheading (e.g., when there are multiple
subheading listings for a section)
·
Multiple labeling changes
— If
there are changes in more than one section of the labeling, the
sections in Recent Major Changes should be listed in the same order
as they appear in the FPI.
— If
there is more than one change in the same labeling section during
the 1-year period listed and the change is to the content under the
same subheading, the date that supersedes the previous one should be
listed. For example, if a new indication (hypertension) was added
to the labeling in March 2005, and a limitation to the hypertension
indication was added in June 2005, the change under the Recent Major
Changes heading should be listed as:
Indications and
Usage, Hypertension (1.2) 6/2005
— If
there is more than one change in the same labeling section during
the 1-year period listed, but the change is to the content under
different subheadings, each section heading, subheading, identifying
number, and date should be listed separately. For example:
Indications and
Usage, Hypertension (1.2) 6/2005
Indications and Usage, Heart Failure (1.3)
9/2005
·
Listing related information from different FPI sections
When a drug product
is approved for a new indication, new information is often added to
other sections of labeling (e.g.,
Dosage and Administration,
Warnings and Precautions,
Clinical Studies). If
there are changes in any of the five applicable sections, each
changed section should be listed under the Recent Major Changes
heading. For example:
Indications and
Usage, Hypertension (1.2) June 2005
Dosage and
Administration, Hypertension (2.2) June 2005
Warnings and
Precautions, Hyperkalemia (5.6) June 2005
·
Marking text in the FPI with a vertical line
The corresponding new
or modified text in the FPI sections listed under Recent Major
Changes must be marked with a vertical line on the left edge (§
201.57(d)(9)). It is unusual for information to be
completely deleted from labeling (e.g., removing a warning as
opposed to moving the warning to a different section), but if this
occurs, the review division will determine how best to identify this
change.
·
Initial submission of revised labeling in the new
format
The Agency
acknowledges that whether to include the Recent Major Changes
heading when converting labeling to the new format may be unclear
because it is difficult to anticipate if the 1-year time period for
listing the changed labeling section will elapse before the labeling
in the new format is approved. Therefore, applicants should include
any substantive labeling changes under the Recent Major Changes
heading in the draft labeling submitted for review. At the time of
approval, the review division will determine whether the section is
still applicable.
·
Removing a listing from Recent Major Changes
A changed section
must be listed under Recent Major Changes for at least 1 year after
the date the labeling change was approved and can continue to be
listed until the labeling is reprinted for the first time after the
1-year period. When the 1-year time period expires, the applicant
can choose (1) to reprint labeling immediately to remove the listing
or (2) to wait until the next reprinting to remove the listing. FDA
recommends that applicants notify the Agency in their Annual Report
about removal of a listing from Recent Major Changes and the
corresponding vertical line in the FPI (see 21 CFR 314.70(b)(2)(v)(C)(1)
and 601.12(f)(3)(i)(D)(1)).
Information under the
Indications and Usage heading must include a concise statement of
each of the drug’s indications, briefly noting any major
limitations. FDA recommends that the information be presented in a
bulleted format. In unusual circumstances, it may be appropriate to
present the indications verbatim from the FPI (e.g., when a product
has one indication and the statement in the FPI is sufficiently
concise). For a product with limitations of use that are applicable
to all of the product’s indications or with a major safety concern
associated with all its uses, it is appropriate to list those
limitations or concerns together, under an appropriately titled
subheading (e.g., Important Limitations).
If the drug is a
member of an established pharmacologic class, the information under
Indications and Usage must include the statement “(Drug) is a
(name of class) indicated for (indication(s)).” If
the drug is not a member of an established pharmacologic class, the
statement should be omitted.
Information under the
Dosage and Administration heading must contain a concise summary of
the recommended dosage regimen, starting dose, dose range, critical
differences among population subsets, monitoring recommendations, if
any, and other clinically significant clinical pharmacology
information that affects dosing recommendations (e.g., dosing
adjustments recommended for concomitant therapy, specific
populations with coexisting conditions, clinically relevant food
effects). FDA recommends a tabular format to enhance accessibility
of information (e.g., when there are different dosing regimens for
different indications). When applicable and important, special
storage or handling information can be mentioned under this heading
(e.g., special handling of chemotherapeutic agents, need for
refrigeration, reconstitution prior to administration of the drug).
Information under the
Dosage Forms and Strengths heading must include a concise summary of
the dosage form and strength and whether the drug product is
scored. If a drug product has numerous dosage forms, bulleted
subheadings (e.g., capsules, tablets, injectable, suspension) or
tabular presentations are recommended.
Information under the
Contraindications heading must include either a concise summary of
the situations in which the drug should not be used because the risk
clearly outweighs any possible therapeutic benefit or the statement
“none” if no contraindicated situations have been identified.
“Relative contraindications” (i.e., circumstances under which the
drug may be used with caution) are not true contraindications and
are not appropriate for inclusion under this heading.
Information under the
Warnings and Precautions heading must include a concise summary of
the most clinically significant safety concerns that affect
decisions about whether to prescribe the drug, recommendations for
patient monitoring to ensure safe use of the drug, and measures that
can be taken to prevent or mitigate harm. Thus, although it is
unlikely that all of the safety information listed in the FPI will
be included in Highlights, the most clinically significant safety
concerns should be addressed.
·
Most frequently occurring adverse reactions
Information under the
Adverse Reactions heading must include a listing of the most
frequently occurring adverse
reactions, even if they are included elsewhere in Highlights, and the
criteria used to determine inclusion (e.g., incidence rate). The
listing should be concise, not lengthy or comprehensive. This
listing may include adverse reactions that are important for reasons
other than frequency (e.g., leading to discontinuation or dosage
adjustments) unless they are included elsewhere in Highlights (e.g.,
under Warnings and Precautions or Contraindications).
The adverse reactions
listed as most frequently occurring or most common should be
selected from the table of adverse reactions from clinical trials in
the FPI. Rates of most common adverse reactions vary, but should be
appropriate to the nature of a drug’s adverse reactions profile and
the size and composition of the safety database. The criteria for
determining inclusion must be identified along with the listing
(e.g., >2%). If adverse reaction profiles vary significantly for
different indications, list the most common adverse reactions by
indication. Also note if different criteria for determining
inclusion are used for different indications.
·
Adverse reaction reporting contact information
Highlights must also
contain adverse reaction reporting contact information that
includes:
1.
The verbatim statement “To report SUSPECTED ADVERSE REACTIONS,
contact” followed by the manufacturer’s name and phone number for
adverse reaction reporting,
2.
the manufacturer’s Web address of the direct link to its Web site
for voluntary reporting of adverse reactions (if available),
and
3.
FDA’s phone number and Web address for voluntary reporting of
adverse reactions (see below).
FDA’s phone numbers and Web
addresses for voluntary reporting of adverse reactions:
MedWatch (for drug products
other than vaccines)
Phone number –
1-800-FDA-1088
Web address –
www.fda.gov/medwatch
VAERS (for vaccines)
Phone number –
1-800-822-7967
Web address –
www.fda.gov/vaers
Information under the
Drug Interactions heading includes a concise summary of:
·
a list of other drugs (or classes of drugs) or foods
that interact or are predicted to interact in clinically significant
ways with the drug
·
practical instructions for preventing or decreasing
the likelihood of the interaction
Descriptive
subheadings of summary concepts (e.g., CYP3A inhibitor) may precede
specific information. In general, drugs that were found not to
interact or to interact in a nonclinically relevant way should not
be included under this heading, nor should details of drug
interaction studies. However, it may be appropriate to include
pertinent negative findings of drug interaction studies under this
heading if the interaction
would otherwise be anticipated or is of special concern (e.g., other
drugs in the class need a dosage adjustment or if the drugs are
commonly coadministered). A tabular format is recommended
for presentation of drug interaction information for drugs with
numerous clinically significant interactions.
Interactions with
particularly serious clinical consequences that are summarized under
the Contraindications or Warnings and Precautions heading in
Highlights would be described in greater detail in the
Drug Interactions
section in the FPI.
Because some drugs are
associated with a large number of clinically significant drug
interactions, it may not be possible to concisely summarize all the
critical information in Highlights. In these instances, include a
statement under the Drug Interactions heading in Highlights that
alerts the prescriber to the presence and significance of the drug
interaction information in the FPI.
Information under the
Use in Specific Populations heading includes a concise summary of
any clinically important differences in response or recommendations
for use of the drug in specific populations (e.g., differences
between adult and pediatric responses, need for specific monitoring
in patients with hepatic impairment, need for dosing adjustments in
patients with renal impairment). Typically, information under this
heading includes limitations or precautions for specific populations
or established differences in response.
Ordinarily, the
absence of information about the safety and effectiveness of a drug
in a specific population (e.g., pregnant women, children) should not
be included under this heading. It may be appropriate to include
some information about use in specific populations under other
headings in Highlights (e.g., Contraindications, Warnings and
Precautions, Dosage and Administration) based on the type and
clinical relevance of the information.
A.
Applications Covered by the Final Rule
Section 201.56(b)(1)
provides that the final rule applies to prescription drug products
with an NDA, BLA, or efficacy supplement that:
·
is submitted on or after the effective date of the
final rule,
·
is pending on the effective date of the final rule, or
·
has been approved in the 5 years prior to the
effective date of the final rule.
Although FDA
recognizes the effort involved in revising labeling, the Agency
strongly believes that the new format is a significant advance in
communicating drug information. Therefore, we encourage applicants
with products to which the final rule does not apply to voluntarily
revise the labeling of their products to comply with the new content
and format requirements.
After the effective date of the
final rule, draft labeling submitted with new NDAs, BLAs, and
efficacy supplements must be in the new format. Consistent with
current practice, the labeling will be reviewed with the application
or supplement.
The following efficacy
supplements trigger the requirement to revise labeling to the new
format:
·
A new indication
or a significant modification of an existing indication, including
removal of a major limitation of use
·
A new dosage
regimen, including an increase or decrease in daily dosage or a
change in frequency of administration
·
A comparative
efficacy or comparative pharmacokinetics claim naming another drug
·
A change expected
to significantly affect the size of the patient population to be
given the drug, either broadening or narrowing the population (e.g.,
pediatrics, geriatrics)
·
Clinical data to
verify and describe the clinical benefit for a drug approved based
on a surrogate endpoint or on an effect on a clinical endpoint other
than survival or irreversible morbidity (see 21 CFR 314.510 and
601.41)
·
A labeling
supplement with clinical data
The timing for submitting
labeling in the new format is based on the implementation plan (see
§ 201.56(c) and Appendix D), but an applicant can voluntarily
convert product labeling to the new format prior to the date
specified in the implementation plan. For an approved application,
the labeling would be submitted as a prior approval labeling
supplement.
Applicants voluntarily revising older labeling would also submit
draft labeling as a prior approval labeling supplement. Under §
201.56(c)(2), for applications pending when the rule becomes
effective, FDA would approve labeling in the old format and the
applicant then would have the implementation period to submit a
prior approval labeling supplement. When more than one approval for
the same product occurred in the 5 years prior to the effective date
of the final rule (e.g., NDA and efficacy supplement), the date of
the most recent approval determines the timing of submission of
labeling in the new format according to the implementation plan.
After labeling is approved in the new format, any subsequent changes
to Highlights, other than identified minor exceptions, require
submission of a prior approval supplement (§§ 314.70(b) and
(c) and 601.12(f)).
B. Appending
FDA-Approved Patient Labeling
The final rule
requires that, 1 year after the effective date, any FDA-approved
patient labeling either accompany the labeling or be reprinted
immediately following the last section of the labeling (§§
201.57(c)(18) and 201.80(f)(2)).
Prior to the final rule, the
regulations required that any printed patient information or
Medication Guide required to be distributed to patients be reprinted
at the end of labeling. The final rule changes these requirements as
follows:
·
Any FDA-approved patient labeling, and not just labeling
required by regulation to be distributed to patients, must be
reprinted in or accompany the labeling. Because distribution of
Medication Guides to patients has always been required (see 21 CFR
part 208), the final rule does not change this requirement.
·
This requirement applies to the labeling of all drugs, not
just those subject to the new format requirements.
·
The final rule provides the option of either reprinting the
FDA-approved patient labeling (including Medication Guides)
immediately following the last section of labeling or having the
FDA-approved patient labeling accompany the labeling as a separate
document.
When the only change to the
labeling is the addition of FDA-approved patient labeling (either
reprinted in or accompanying the labeling as a separate document), a
labeling supplement is unnecessary. The Agency recommends notifying
FDA of this change in the annual report (see §§ 314.81 and 601.12).
If there are changes to the labeling other than those listed in the
annual report, submit the appropriate labeling supplement (e.g.,
changes being effected (CBE) or prior approval).
For information about submitting
labeling electronically, applicants should consult the guidances for
industry on Providing Regulatory Submissions in Electronic Format
— Human Pharmaceutical Product Applications and Related Submissions
Using the eCTD Specifications and Providing Regulatory
Submissions in Electronic Format — Content of Labeling.
The new regulations require that
Highlights, excluding the boxed warning, be limited in length to
one-half page (§ 201.57(d)(8)). FDA recognizes that under certain
circumstances, particularly when a product has many indications or
many serious warnings that merit inclusion in Highlights, it may not
be possible to accommodate all the required information within
one-half page. In this case, the applicant can submit a waiver
request with the submission (e.g., NDA, BLA, efficacy supplement, or
labeling supplement). (See 21 CFR 201.58.) The applicant should
prominently identify the submission as one that includes a waiver
request. In the waiver request, the applicant should explain why
the one-half page requirement could not be met. The Agency will
discuss the waiver request with the applicant during labeling
negotiations and will formally document its decision in an action
letter.
In some instances, a
statement(s) for a drug or class of drugs is required by regulation
to be included in a particular section of the labeling. For
example, 21 CFR 310.517 requires that labeling for oral
hypoglycemics of the sulfonylurea class include a statement in the
WARNINGS section. When converting labeling to the new format, the
statement must be included in the corresponding section in the new
format (e.g., a statement required to be included in the
Boxed Warning in the
old format must be included in the
Boxed Warning in the
new format). For sections that have been altered or eliminated, see
Table 1 for the location of the statement in the new format.
Table 1 — Location of Statements Required To Be Included in Labeling
Location in Old Format
|
|
Warnings |
Warnings and Precautions
|
Precautions (General) |
Warnings and Precautions
|
Precautions (Drug Interactions) |
Drug
Interactions
|
Precautions (Special Populations) |
Use
in Specific Populations
|
Precautions (Information for Patients) |
Patient Counseling Information
|
How
Supplied (or after
How Supplied) |
How
Supplied/Storage and Handling
|
The Agency will
consider, on a case-by-case basis, those instances where statements
are required to be included in labeling in the new format, but not
in a specific labeling section. Whether a specific statement
required by regulation must appear in Highlights will be determined
by the Agency.
In some cases, the
labeling of all members of a class of drugs includes identical
statements, even though they are not mandated by regulation. These
class labeling statements describe a risk or effect that is
typically associated with members of the class, based on what is
known about the pharmacology or chemistry of the drugs. For
example, the boxed warning about the risk of using an ACE inhibitor
during the second and third trimesters of pregnancy is uniformly
presented in all labeling for this class of drugs.
To ensure consistent
presentation of class labeling statements within drug classes, the
Agency will determine during the labeling review and approval
process: (1) the appropriate location of a class labeling statement
in the FPI, (2) whether the information merits inclusion in
Highlights, and (3) the content and location of the summarized
statement in Highlights. Applicants should propose content and
location of class labeling statements in the new format in the draft
labeling submitted with their applications or supplements.
Under 21 CFR
314.94(a)(8), the labeling of a drug product submitted for approval
under an ANDA must be the same as the labeling of the listed drug
referenced in the ANDA, except for changes required because:
1.
differences have been approved under a suitability petition filed
under 21 CFR 314.93
2.
the ANDA product and the reference listed drug are produced or
distributed by different manufacturers
3.
aspects of the listed drug’s labeling are protected by patent or
exclusivity
Thus, if the labeling
of the reference listed drug is revised to comply with the final
rule, the labeling of the ANDA product must also be revised in
accordance with 21 CFR 314.127(a)(7).
ANDA applicants are
encouraged to consult the guidance for industry on revising ANDA
labeling following revision of the reference listed drug labeling
for information about when and how to submit labeling supplements.
The final rule includes certain formatting
requirements (e.g., ordering, numbering, type size) that were
designed to enhance readability and accessibility of labeling
information (§ 201.57(d)). Beyond these requirements, the Agency expects that
some flexibility in formatting will be necessary because of
variability in the type and quantity of labeling information for
different drugs. The Agency recommends the use of a two-column
format for Highlights and Contents because this format enhances
effective communication of the labeling information. Other general
recommendations for specific formatting issues are described below.
The use of subheadings, in
addition to those required by the final rule to help organize
information in the FPI, is encouraged (e.g., to identify individual
warnings). Each subheading that is used must be assigned a decimal
number that corresponds to its placement and order in the FPI (§§
201.56(d)(2) and 201.57(c)).
Any required section,
subsection, or specific information that is clearly inapplicable
must be omitted from Highlights and the FPI. For example, if a drug
is indicated for use only in males, and there are no preclinical or
clinical data relevant to women of childbearing potential, the
Pregnancy, Labor and Delivery, and Nursing Mothers
subsections would be omitted because they are not applicable.
When a section or subsection is
omitted from the FPI, the section must also be omitted from the
Contents (§ 201.56(d)(4)). The heading “Full Prescribing
Information: Contents” must be followed by an asterisk and the
following statement must appear at the end of the Contents:
“*Sections or subsections omitted from the Full Prescribing
Information are not listed” (§ 201.56(d)(4)).
In the example of a drug
indicated for use only in males, the Contents heading appears as
follows:
FULL PRESCRIBING INFORMATION: CONTENTS*
The numbering in the Contents
and FPI appears as follows:
8 USE IN SPECIFIC POPULATIONS
8.4 Pediatric Use
8.5 Geriatric Use
9 DRUG ABUSE AND DEPENDENCE
At the end of the Contents, the
following statement appears:
*Sections or subsections omitted from the Full Prescribing
Information
are not listed.
In most cases when clinically
relevant information about a drug is not available, the section or
subsection should be omitted. Infrequently, describing the absence
of data will provide important information for the prescriber and,
therefore, the section or subsection should be included. For
example, if a drug has not been adequately studied in a specific
patient population (e.g., hepatically impaired), the labeling should
include a Hepatic Impairment subsection that describes the
lack of information.
Cross-referencing is
encouraged, and in some cases required (e.g., § 201.57(c)(1),
(c)(6)(iv), and (c)(15)(ii)),
because it reduces the need to repeat detailed information about a
similar issue in several different sections (see III.B.3 of this
guidance for more information). The preferred presentation of
cross-references in Highlights is the numerical identifier in
parentheses following the summarized labeling information (e.g.,
(1.1)). The preferred presentation of cross-references in the FPI
is the section heading followed by the numerical identifier (e.g.,
see Indications and Usage (1.1)). Because cross-references
are embedded in the text in the FPI, the use of italics to achieve
emphasis is encouraged.
The final rule
requires different minimum type sizes for trade labeling (i.e.,
labeling on or within the package from which the drug is to be
dispensed) and for labeling disseminated in other settings (e.g.,
labeling that accompanies prescription drug promotional materials).
(See § 201.57(d)(6).) Appendix E shows minimum type size requirements
for labeling in the new format (§
201.57) and in the old format (§
201.80), including requirements for FDA-approved patient
labeling. The Agency encourages a minimum type size of 10 points
for FDA-approved patient labeling.
APPENDIX A —
Frequently Asked Questions
Where to Locate Information
Q1. Where should microbiology data be
presented in the CLINICAL PHARMACOLOGY section?
A1. A subsection in the CLINICAL
PHARMACOLOGY section can be created (e.g., 12.4 Microbiology)
and all of the microbiology information for antimicrobial products
consolidated into that subsection.
Q2. Labeling for some products includes disease-specific
pathophysiology or epidemiology information. In the new format,
where should this information be presented?
A2. In rare cases when a brief description of disease
pathophysiology may facilitate understanding of a drug’s
pharmacology, the information may be included in the Mechanism of
Action subsection of the CLINICAL PHARMACOLOGY section
(§ 201.57(c)(13)(i)(A)). Epidemiologic information is discouraged
because it is quickly outdated and will therefore require the
applicant to frequently update the product’s labeling.
Q3. What section of the labeling should contain animal
efficacy data when a drug is approved based on effectiveness data
from studies in animals (§§ 314.610 and 601.91)?
A3. In general, the specifics about animal efficacy study
results should be presented in the Animal Toxicology and/or
Pharmacology subsection of the NONCLINICAL TOXICOLOGY section of
labeling. However, other sections should disclose that
effectiveness was derived solely from animal studies and explain why
(e.g., INDICATIONS AND USAGE, CLINICAL STUDIES). For example, the
CLINICAL STUDIES section should make it clear that no human efficacy
studies were conducted due to ethical considerations and that
approval was based solely on evidence of effectiveness in animals.
This section should also include a cross-reference to the Animal
Toxicology and/or Pharmacology subsection. In addition,
the labeling provided to patients must explain that the drug’s
approval was based on efficacy studies conducted in animals alone
(§§ 314.610(b)(3) and 601.91(b)(3)).
Q4. Can the proprietary (or proper) and established names be
repeated at the beginning of the FPI?
A4. The proprietary and established names, as well as other
product identification information must be presented in Highlights
(§ 201.57(a)(2)). The proprietary and established names can be
repeated at the beginning of the FPI, or at the beginning of each
page of the FPI (e.g., as a header), if this enhances product
identification on subsequent pages of labeling.
Scope
Q5. Are combination products subject
to this new labeling rule?
A5.
Combination products that are comprised of a prescription drug and
biologic, a prescription drug and device, or a biologic and device
that were reviewed under a BLA or NDA are subject to the new
labeling rule, if the prescription drug component is subject to the
new labeling rule (see § 201.56(b)). Applicants with these products
must submit revised labeling to conform with the new requirements to
the original NDA or BLA. In addition, applicants with combination
products reviewed under device authorities should contact the Office
of Combination Products regarding whether the drug or biological
product component is subject to the prescription drug labeling
rule. (See 21 CFR part 3.)
Procedural
Q6. How should a
labeling supplement be submitted for a product reviewed in more than
one division?
A6. For a product with marketing applications in more than one
review division, the applicant should continue to follow the
procedures established with the divisions for submitting labeling
supplements. If the applicant is uncertain about where to submit a
supplement that converts labeling to the new format, the division
where the original NDA or BLA was approved should be contacted for
assistance.
Q7. Does the adverse reaction reporting contact information
have to be presented as part of the “fair balance” information in
promotional materials?
A7. There is no requirement to include the adverse reaction
reporting contact information in promotional materials.
Formatting
Q8. Can the proprietary and established (or proper) names be
presented on the same line in Highlights?
A8. To conserve space in Highlights, the proprietary and
established names should be presented on the same line, unless they
are too long. In that case, the established name should be
presented on the line underneath the proprietary name.
Q9. Is there a preferred format for
the revision date?
A9. The date of the most recent revision must be presented at
the end of Highlights (§ 201.57(a)(15)). The preferred format is
“Revised: Month Year” or “Revised: Month/Year” (i.e., Revised: June
2003 or Revised: 6/2003).
Q10. Should Latin abbreviations be used in the DOSAGE AND
ADMINISTRATION section (e.g., qd versus once daily)?
A10. The Agency recommends that Latin abbreviations be avoided
because of the greater potential for medication errors should an
abbreviation be misread.
APPENDIX b — Prescription Drug
Labeling Sections
Old Format* |
New Format** |
Description
Clinical Pharmacology
Indications and Usage
Contraindications
Warnings
Precautions
Adverse Reactions
Drug Abuse and Dependence
Overdosage
Dosage and Administration
How Supplied
Optional sections:
Animal Pharmacology
and/or Animal Toxicology
Clinical Studies
References
|
Highlights of Prescribing Information
Product Names, Other Required
Information
Boxed Warning
Recent Major Changes
Indications and Usage
Dosage and Administration
Dosage Forms and Strengths
Contraindications
Warnings and Precautions
Adverse Reactions
Drug Interactions
Use in Specific Populations
FULL PRESCRIBING INFORMATION: CONTENTS
FULL Prescribing Information
Boxed Warning
1 Indications and Usage
2 Dosage and Administration
3 Dosage Forms and Strengths
4 Contraindications
5 Warnings and Precautions
6 Adverse Reactions
7 Drug Interactions
8 Use in Specific Populations
9 Drug Abuse and Dependence
10 Overdosage
11 Description
12 Clinical Pharmacology
13 Nonclinical Toxicology
14 Clinical Studies
15 References
16 How Supplied/Storage and Handling
17 Patient Counseling Information
|
* As required by 21 CFR 201.56(e) and 201.80.
**As required by 21
CFR 201.56(d) and 201.57
APPENDIX c —
Reorganizing Labeling Sections
Location in Old Format |
→ |
Location in FPI in New Format |
Boxed Warning | → | Boxed Warning |
Description | → | Description |
Clinical Pharmacology | → | Clinical Pharmacology |
Indications and Usage | → | Indications and Usage |
Contraindications | → | Contraindications |
Warnings | → | Warnings and Precautions |
Precautions | | |
General | → | Warnings and Precautions |
Information for Patients | → | Patient Counseling Information |
Laboratory Tests | → | Warnings and Precautions |
Drug Interactions | → | Drug Interactions |
Drug/Laboratory Test Interactions | → | Warnings and Precautions |
Carcinogenesis, Mutagenesis, Impairment of Fertility | → | Nonclinical Toxicology (Carcinogenesis, Mutagenesis, Impairment of Fertility) |
Pregnancy | → | Use in Specific Populations (Pregnancy) |
Labor and Delivery | → | Use in Specific Populations (Labor and Delivery) |
Nursing Mothers | → | Use in Specific Populations (Nursing Mothers) |
Pediatric Use | → | Use in Specific Populations (Pediatric Use) |
Geriatric Use | → | Use in Specific Populations (Geriatric Use) |
Adverse Reactions | → | Adverse Reactions |
Drug Abuse and Dependence | → | Drug Abuse and Dependence |
Overdosage | → | Overdosage |
Dosage and Administration | → | Dosage and Administration |
How Supplied | → | Dosage Forms and Strengths |
| → | How Supplied/Storage and Handling |
Animal Pharmacology and/or Animal Toxicology | → | Nonclinical Toxicology (Animal Toxicology and/or Pharmacology) |
Clinical Studies | → | Clinical Studies |
References | → | References |
Applications (NDAs, BLAs, and Efficacy Supplements) Required
to Conform to New Labeling Requirements |
Time by Which Conforming Labeling Must Be Submitted to the
Agency for Approval |
Applications submitted on or after June
30, 2006
Applications pending on June 30, 2006 and
applications approved any time from June 30, 2005, up to and
including June 30, 2006
Applications approved any time from June
30, 2004, up to and including June 29, 2005
Applications approved any time from June
30, 2003, up to and including June 29, 2004
Applications approved any time from June
30, 2002, up to and including June 29, 2003
Applications approved any time from June
30, 2001, up to and including June 29, 2002
Applications approved prior to June 30,
2001 |
Time of submission
June 30, 2009
June 30, 2010
June 30, 2011
June 30, 2012
June 30, 2013
Voluntarily at any time
|
|
Type Size Requirements
for Labeling |
FDA-Approved Patient Labeling Included
with Labeling |
Type Size Requirements
for FDA-Approved Patient Labeling |
New Format (21 CFR 201.57) |
Trade Labeling (i.e., labeling on or within
the package from which the drug is to be dispensed) |
Minimum 6-point type |
FDA-approved patient labeling that is not
for distribution to patients
|
Minimum 6-point type |
Any FDA-approved patient labeling (except a
Medication Guide) that is for distribution to patients
|
Minimum 6-point type |
Medication Guide that is for distribution
to patients
|
Minimum 10-point type |
Other Labeling
(e.g., labeling accompanying promotional
materials) |
Minimum 8-point type
|
FDA-approved patient labeling that is not
for distribution to patients
|
Minimum 8-point type |
Any FDA-approved patient labeling (except a
Medication Guide) that is for distribution to patients
|
Minimum 8-point type* |
Medication Guide that is for distribution
to patients
|
Minimum 10-point type |
Old Format (21 CFR 201.80) |
Trade Labeling and
Other Labeling |
No
minimum requirement |
FDA-approved patient labeling that is not
for distribution to patients
|
No
minimum requirement |
Any FDA-approved patient labeling (except a
Medication Guide) that is for distribution to patients
|
No
minimum requirement |
Medication Guide that is for distribution
to patients
|
Minimum 10-point type |
If a manufacturer does not have a Web site for voluntary
reporting of adverse reactions, the manufacturer is not required
to create one.
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Date created: January 18, 2006 |