# Presentation: 930974

## Prescription Drug Labeling:  Implementation of FDA’s New Regulation for the Content and Format of the USPI and Accompanying Documents

**Steven W. Bass, PhD**
**Group Director, Global Labeling and Promotion Compliance**
**Bristol-Myers Squibb Company **
**Laurie Burke, RPh, MPH**
**Director, Study Endpoints and Labeling Development**
**Office of New Drugs, CDER, FDA**
**Jamie M. Fava, PharmD**
**Manager, Global Labeling**
**Bristol-Myers Squibb Company **

**June 19, 2006**

## Introduction to the New Content and Format of Labeling: “Physician’s Labeling Rule (PLR)”

**Steven W. Bass, PhD**
**Group Director, Global Labeling and Promotion Compliance**
**Bristol-Myers Squibb Company **

## Learning objectives At the conclusion of this session, participants should be able to: 

- Gain familiarity with the Physician’s Labeling Rule (PLR) and accompanying guidance documents
- Understand the major changes and improvements to the USPI and general principles for converting to new format
- Identify products affected by the PLR and corresponding implementation schedules
- Understand how PLR in SPL format will facilitate various e-labeling initiatives
- Gain insight into FDA’s interpretation of the new regulations and guidance documents through the Q & A

## Session Overview

**Regulatory History **
**PLR Overview**
**Q and A**
**DIA Labeling SIAC Discussions**
**DIA Webinar (March 21) **
**FDA/DIA Hands-on Workshop (May 4-5)**
**CDER Live (May 9)**
**Audience Questions **

## Regulatory History

**The Current Rule:**
- 44 FR 37462, **June 26, 1979** (201.56, 201.57, 201,100)
**FR Dec. 13, 1994 –** **Pediatric Final Rule** - **Effective December 13,** **1996**
**FR Aug. 27, 1997** – **Geriatric Final Rule** - **Implement based on**** ****NDA app. Date - **_**by 8/27/2003**_** all labeling must have Geriatric Section**
**CFR 201.24 – Final Rule: FR Feb 6, 2003 – Effective**** ****Feb 6, 2004:**** ****Labeling Requirements for Systemic Antibiotic Drug**
**FDA Sponsored Public Meeting – October 30, 1995**
**FR December 22, 2000 – Proposed Rule**
**FR January 24, 2006 – Final Rule**

## PLR - fully integrated with the Guidance Documents

**Still to come:**
**Clinical Pharmacology Section**
**Dosage and Administration Section**

***PLR - fully integrated with the Guidance****** ******Documents***

## Implementation of FDA’s New Regulation for the Content and Format of the USPI and Accompanying Documents

**Laurie Burke, RPh, MPH**
**Director, Study Endpoints and Labeling Development**
**Office of New Drugs, CDER, FDA**

## Agenda

**PLR Overview****	****	****	****	**
**PLR process issues ****	****	**
**Integration of PLR with SPL****	****	**
**Q and A**

## 21 CFR Sections

| § 201.56 | General labeling requirements  |
| --- | --- |
| § 201.57 | Specific requirements for “newer” drugs (HL, Contents, FPI) |
| § 201.58 | Waiver provision |
| § 201.80 | Specific requirements for “older” drugs
(formerly § 201.57) |
| 314.70 | Supplements and other changes to an approved application |

## Goals for new labeling rule

**More informative labeling**
**More accessible labeling**
**More memorable labeling**
**Better risk communication**
**Fewer medication errors**

## Overview of format changes to labeling

**Highlights**
- High level summary (half page max)
- Links to appropriate section of Full Prescribing Information (FPI)
**Contents (table of)**
- Consistent order and numbering of sections
- Links to FPI
**FPI**
- Frequently referenced info moved forward (except for Patient Counseling Info, now required and appears last)
- Safety info consolidated (Warnings and Precautions)

## New Sections of Labeling

**Formerly in *****Precautions***
***Drug Interactions***
***Use in Specific Populations***
***Patient Counseling Information***
**Formerly optional**
***Clinical Studies***
***Nonclinical Toxicology***
**Formerly in *****How Supplied***
***Dosage Forms and Strengths***

## Established Pharmacologic Class

***Highlights Indications***** section:**
**“****This drug is a ________ indicated for....”**
**Important for prescribing decisions (e.g., avoid drug interactions) **
**Pharmacologic class may be defined by 1 or more types of terms**
**Mechanism of action**
**Physiologic effect**
**Structural class**
**If not “established,” exclude the term**
**Guidance under development**
**Pharmacology Class Coordinating Committee also under development**

## Revisions to Safety Requirements

***Boxed Warning***
- Appears in* Highlights *in bulleted format, limited to 20 lines
- Repeated in full text at beginning of* FPI*
***Contraindications***
- Include only known hazards
- Only list patient groups where risk clearly outweighs any possible benefit
***Warnings and Precautions***
- Expanded to include clinically significant adverse reactions
***Adverse Reactions***
- Include only reactions with some basis for causal relationship to drug
- Separate listings of ARs from clinical trials and ARs from spontaneous reports
- Pool AR profile using data from all trials

## Other New Requirements

**Dosing regimens and indications/uses implied in any other sections must be listed in D&A and I&U.**
**I&U includes limitations of use and conditions of use**
- Uncertainty about anticipated benefit (e.g., approval based on a surrogate)
- Approved as adjunct treatment only
- Limited info in an important patient group
**Explicit requirement to update labeling when new information becomes available**

## Recent Major Changes

**Identified and dated in HL**
**Margin mark in FPI**
**Required for changes to:**
- Boxed Warning
- Indications and Usage
- Dosage and Administration
- Contraindications
- Warnings and Precautions
**Remain for 1 year**

## Other improvements	

**Emphasizes “Patient Counseling Information”**
**Encourages AR reporting**
- FDA contact information (phone and internet address) for reporting AEs
- Industry phone/internet address if dedicated to AE reporting
**Adds initial US approval date**
**Adds date of labeling revision**

## Example of Contents for a Fictitious Drug 

## Example of Highlights for a Fictitious Drug

**Example of Highlights for a Fictitious Drug**

## Affected Products

**New NDAs, BLAs and efficacy supplements**
**Applications approved up to 5 years prior to 6/30/06**
**Encouraged voluntary compliance by older products**
**ALL products must append ALL FDA-approved patient labeling by June 30, 2007**
- Applies to “older” products
- Can be submitted in the Annual Report

## Implementation Schedule

| New NDA/BLA or efficacy supplement submitted: | Label must conform: |
| --- | --- |
| 6/30/06 or after | At time of submission |
| Pending on 6/30/06 
Approved 6/30/05-6/30/06 | 6/30/09 (3 years) |
| Approved 6/30/04-6/29/05 | 6/30/10 (4 years) |
| Approved 6/30/03-6/29/04 | 6/30/11 (5 years) |
| Approved 6/30/02-6/29/03 | 6/30/12 (6 years) |
| Approved 6/30/01-6/29/02 | 6/30/13 (7 years) |
| Approved Pre-6/30/01 | Voluntary at any time 
(encouraged to conform) |

## Prior-approval labeling supplements required

**For revision to new requirements adding *****Highlights***
**For future changes to *****Highlights***
- Exceptions that may be submitted with Annual Report:
*Removal of a listed section from “Recent Major Changes” after 1 year*
*Changes to the revision date*

## Waivers

**Expanded over previous requirements**
**May be requested to waive any requirement under 201.56, 201.57, or 201.80.**

## 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, missing sections must be developed**
**Labeling info may**
- Transfer in its entirety to a new section
- Be divided between sections
- Be repeated in different sections in varying levels of detail, avoiding redundancy
**Combine and consolidate info about similar issues under one subheading, if possible**
**Use cross-referencing**

## Electronic Labeling Initiatives

**Structured Product Labeling (SPL) is the content of labeling in a standardized electronic file format with tagged blocks of text and coded data elements**
- Use of this common format will enable all parties to create, send, and receive product labeling content
- Coded data elements will enable Decision Support Systems to develop query functions
**PLR facilitates eLabeling initiatives**
- eHealth records
- ePrescribing
- Daily Med
- Electronic repository populated by current FDA labeling managed by NLM

## SPL PLR format submissions

**SPL PLR implementation guide available in draft**
**Additional data element requirements**
- Highlights data elements
- Data Council website provides “stylesheet” for PLR data elements
- Additional guidance pending