# Presentation: 347929

## Labeling for Human Prescription Drug and Biological Products – Implementing the New Content and Format Requirements (“Implementation Guidance”)

- Colleen LoCicero, RPh
- Associate Director for Regulatory Affairs
- Office of Drug Evaluation I
- Center for Drug Evaluation and Research

## Content of Implementation Guidance

- Considerations for converting labeling
- Developing Highlights
- Formatting
- Procedural information

## General Principles for Converting Labeling

- No additional data analyses unless recent information causes labeling to be inaccurate
- Unique opportunity to evaluate and update claims in labeling
- Unless inapplicable (e.g., Drug Abuse and Dependence), missing sections must be developed (e.g., Patient Counseling Information)

## Considerations for Distributing Information in Labeling

- Labeling information may:
- Transfer in its entirety to a new section
- Be divided between sections
- Be repeated in different sections in varying levels of detail

##          Example

| Location in Old Format |  | Location in FPI in New Format |
| --- | --- | --- |
| 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 |

## Distributing Information

- Create a hierarchy
- Order information to reflect its importance and significance
- Locate information in the section that appropriately communicates the information
- Avoid redundancy
- Repeat information in varying levels of detail in different sections (generally, one section contains the detail; other sections contain a brief description with a cross-reference)
- Combine and consolidate information about similar issues under one subheading, if possible
- Create subsection headings that identify the content (avoid “General”)
- Use cross-referencing

## Issues to Consider When Developing Highlights

- It is a:
- Concise, informative summary of the most important and frequently referenced prescribing information
- Presented in an easily accessible format (e.g., bullets, tables)
- Guide to detailed information in FPI
- It is not a verbatim repetition of FPI or Contents

## General Principles for Developing Highlights

- Each bullet should impart a complete piece of information (e.g., describe the risk, its consequences, and how to prevent it).
- Concise summary is consistent with FPI, but not all information is included.  Selecting the most important prescribing information requires judgment.
- Group together similar topics (e.g., combine related Warnings and Precautions into one bullet)
- Use active voice; be direct. Condense repeated words or phrases.
- Omit sections that are not applicable or do not contain information that merits inclusion in Highlights. (Do not use “none” with the exception of Contraindications.)
- Consider using a table instead of bullets, when appropriate and feasible.
- Cross-reference to more detailed sections or subsections of FPI

## Highlights

- Concise summary of information in FPI
- Boxed Warning
- Indications and Usage (include established pharmacological class statement, if applicable)
- Dosage and Administration
- Dosage Forms and Strengths
- Contraindications
- Warnings and Precautions
- Adverse Reactions (listing of most common ARs)
- Drug Interactions
- Use in Specific Populations

## Boxed Warning

- What to include
- Heading: “WARNING” followed by subject of warning
- Statement:  “*See full prescribing information for complete boxed warning*.”
- Concise summary of information from the Boxed Warning in the FPI
- Limited to 20 lines
- Bulleted format with references to FPI

## Information Specific to Highlights

- Highlights Limitation Statement
- Product Name, Dosage Form, Route of Administration, and Controlled Substance Symbol
- Initial US Approval
- Recent Major Changes
- Adverse Reaction Reporting Contact Information
- Patient Counseling Information Statement
- Revision Date

## Initial US Approval

- Initial US Approval:  2006
- Year of initial approval of new molecular entity, new biological product, or new combination of active ingredients
- Do not list multiple dates for different formulations approved in different years

## Examples

- If a single product and combination product share the same labeling and are
- Approved in the same year
- Drug X
- Drug X and Drug Y
- Initial US Approval:  2002
- Approved in different years
- Drug X
- Initial US Approval:  2002
- Drug X and Drug Y
- Initial US Approval:  2004

## Recent Major Changes

- What to include
- Heading, subheading, numerical identifier, and date (mo/year) of changed section
- Only include changes to the following:
- Boxed Warning
- Indications and Usage
- Dosage and Administration
- Contraindications
- Warnings and Precautions
- Retain listing for one year – may notify FDA of removal of RMC listing in Annual Report
- Margin mark in FPI _only_ (not Highlights)
- Omit section if there are no recent major changes

## Recent Major Changes 

- Multiple labeling changes in one year
- If change is to same subsection, latest date supersedes previous one
- If change is to different subsection, list separately
- Initial submission in the new format
- List changes under RMC in draft labeling.  Review division will decide if section is still applicable at time of approval
- To remove a listing from RMC after one year
- Reprint labeling immediately to remove listing
- Wait until next printing to remove listing

## Adverse Reactions Reporting Contact Information

- Required statement:
- 	To report SUSPECTED ADVERSE REACTIONS, contact (insert name of manufacturer) at (insert manufacturer’s phone number) or FDA at (insert current FDA phone number and Web address for voluntary reporting of ARs).
- Include manufacturer’s direct link to its web site for voluntary reporting of ARs (if available).
- Current FDA phone numbers and web addresses:
- For drugs:  1-800-FDA-1088, _[www.fda.gov/medwatch](http://www.fda.gov/medwatch)_
- For vaccines:  1-800-822-7967, _[www.fd.gov/vaers](http://www.fd.gov/vaers)_

## Revision Date

- Type of labeling submission
- Original NDAs and BLAs, efficacy supplements, and PA labeling supplements:  approval date
- CBE labeling supplements:  generally, receipt date

## Formatting Information

- Subheadings
- Describe the content of the subsection
- Assign a decimal number
- Omitted sections
- Omit clearly inapplicable sections or subsections
- Maintain required order and numbers for sections
- Identify in Contents that a section is omitted with asterisk following heading and required statement (Sections or subsections omitted from the FPI are not listed) at end
- Cross references
- In FPI, use section heading, followed by numerical identifier (e.g., *see Indications and Usage (1.1)*)
- Use italics for emphasis

## Type Size Requirements for 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 |
| Other Labeling (e.g., labeling accompanying promotional materials) | Minimum 8-point type |
| Old Format (21 CFR 201.80) |  |
| Trade Labeling and Other Labeling | No minimum requirement |

## Procedural Information Included in the Implementation Guidance

- Implementation schedule
- Affected products
- Appending FDA-approved patient labeling
- Applying for a waiver from Highlights’     half page requirement
- Class labeling
- ANDA products

## Efficacy supplements that Trigger the New Requirements

- A new indication or 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 change in frequency of administration
- A new route 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, etc.)
- 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

## Applying for a Waiver from Highlights’ Half Page Requirement

- Submit waiver request with NDA, BLA, efficacy supplement or labeling supplement submission
- Prominently identify that the submission includes a waiver request
- Explain why the half page requirement cannot be met
- FDA will discuss the waiver request during labeling negotiations and document its decision in an action letter

## Class Labeling Statements

- Place the class labeling statement in the corresponding section of the FPI in the new format
- Propose content and location in Highlights
- FDA will determine whether a specific statement must appear in Highlights and determine its content and location

## ANDA Products

- Must convert labeling to the new format AFTER the reference listed drug does so
- Submit as a prior approval supplement