Guidance for Industry:
Labeling for Human Prescription Drug and Biological Products — Implementing the New Content and Format Requirements

(PDF format of this document)

Guidance for Industry[1]
Labeling for Human Prescription Drug and Biological Products —Implementing the New Content and Format Requirements[2]

I.                   Introduction

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).[3]  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).[4]  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.[5]  

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.[6]  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.   

1.         Creating Hierarchy  

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. 

2.         Avoiding Redundancy

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.   

3.         Using Cross-References

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)).

4.         Illustrative Example 

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. 

IV.       Highlights

A.                 General Principles

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)). 

B.                 Information in Highlights

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. 

2.                  Boxed Warning (§ 201.57(a)(4))

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. 

3.                  Recent Major Changes (§  201.57(a)(5))

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)). 

4.                  Indications and Usage (§ 201.57(a)(6))

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.  

5.                  Dosage and Administration (§ 201.57(a)(7))

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). 

6.                  Dosage Forms and Strengths (§ 201.57(a)(8))

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.

7.                  Contraindications (§ 201.57(a)(9))

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.

8.                  Warnings and Precautions (§ 201.57(a)(10))

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. 

9.                  Adverse Reactions (§ 201.57(a)(11))

·        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),[7] 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[8]

10.       Drug Interactions (§ 201.57(a)(12))

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. 

11.       Use in Specific Populations (§ 201.57(a)(13))

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.   

V.        Procedural 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.   

1.         New NDAs, BLAs, and Efficacy Supplements

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[9] 

2.         Approved and Pending Applications

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.[10]  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)).[11]   

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).   

C.                 Submitting Electronic Versions of Labeling  

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.[12] 

D.                Applying for a Waiver from Highlights’ One-Half Page Requirement  

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.   

E.                 Class Labeling

1.         Mandated Statements

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