1. The New Content and Format Requirements for Prescription Drug Labeling Leaner, Cleaner, More Precise Rachel E. Behrman, MD, MPH Office of Medical Policy Center for Drug Evaluation and Research Food and Drug Administration

2. 2 Learning objectives At the conclusion of this session, participants should be able to: 1.Describe the major content and format changes to prescription drug labeling and the rationale for the changes 2.Summarize the essential concepts for developing specific labeling sections from the new final and draft labeling guidances 3.Describe general principles for developing and converting labeling as described in the draft “Implementation” guidance

3. 3 Impetus and Rationale Increasing length, detail and complexity of prescription drug labeling Research demonstrated that prescribers: –Use labeling primarily to find a specific item of information or answer a specific question –Found existing format difficult to use when looking for specific information –Wanted easy access to certain labeling sections that they find more useful or important –Would use labeling more if it included a short (maximum length one-half page) synopsis Result is more informative, accessible and memorable labeling, resulting in a better risk communication and management tool that will decrease errors due to misunderstood or incorrectly applied drug information

4. Overview Highlights –High level ½ page summary –Cited or concisely summarized information accompanied by identifying numbers indicating where to find more detail Contents –Allows easy reference to full prescribing information –Allows hyperlinks in electronic formats Reorders and reorganizes sections –Frequently referenced information moved forward –Safety information remains consolidated Establishes format requirements –Minimum 8-point font (trade labeling that accompanies drug product will have minimum 6-point font) –Standardized bolding and “white space” Clarifies and updates requirements

5. Example of Highlights for a Fictitious Drug

6. Example of Contents for a Fictitious Drug

7. Improvements Emphasizes “Patient Counseling Information” –Referenced in Highlights –New section in Full Prescribing Information (FPI) –Approved patient labeling, if available, is reprinted at end Encourages AR reporting by including contact information (toll-free number and Internet address) for reporting both serious and nonserious ARs Identifies and Dates “Recent Major Changes” –Captures Boxed Warning, Indications, D&A, Contraindications and W&P –Referenced in Highlights; margin mark in FPI Adds the established pharmacologic class, if known, to Highlights Adds initial U.S. approval date

8. Format Changes Warnings and Precautions consolidated Formerly in Precautions, now new sections –Drug Interactions –Use in Specific Populations –Patient Counseling Information Formerly optional, now required –Clinical Studies –Nonclinical Toxicology Created Dosage Forms and Strengths and moved How Supplied to near end

9. Revision of Safety Requirements Contraindications –Risk of use clearly outweighs any possible benefit –Includes only known hazards (e.g., eliminate “allergic to any component of drug”) Warnings and Precautions Expanded to include clinically significant adverse reactions Adverse Reactions –Retains, and clarifies, existing definition of what to include (reasonable association = some basis for causal relationship) –Separates ARs from clinical trials and postmarketing spontaneous reports –Revises requirements on how to classify and categorize ARs and how to describe AR rates –Requires a description of AR profile based on entire database

10. Adverse Reaction Definition Previous § 201.57Revised § 201.57 An adverse reaction is an undesirable effect, reasonably associated with the use of the drug, that may occur as part of the pharmacological action of the drug or may be unpredictable in its occurrence. For the purposes of prescription drug labeling, an adverse reaction is an undesirable effect, reasonably associated with use of a drug, that may occur as part of the pharmacological action of the drug or may be unpredictable in its occurrence. This definition does not include all adverse events observed during use of a drug, only those adverse events for which there is some basis to believe there is a causal relationship between the drug and the occurrence of the adverse event.

11. Other Clarifications D&A and I&U Dosing regimens and indications or uses not included in these sections must not be implied or suggested in other sections For approval based on a surrogate, I&U must –Include a succinct description of the limitation of use –Describe any uncertainty about the anticipated benefit –Refer to a description of available evidence in Clinical Studies Clinical Studies –Include detail about AWC studies pertinent to S&E use –Not an encyclopedic listing References – include only when labeling must rely on either –Recommendation by authoritative body –Standardized methodology, scale or technique

12. Affected Products New NDAs, BLAs and efficacy supplements (e.g., new indication, new dosage regimen, new route of administration) Applications and efficacy supplements approved up to 5 years prior to final rule Encourage voluntary compliance by older products All products must append FDA-approved patient labeling within 1 year

13. Implementation Schedule NDA, BLA or efficacy supplement Labeling must conform Submitted on or after 6/30/06At time of submission Pending on 6/30/06 Approved 6/30/05-6/30/06 6/30/09 (3 years) Approved 6/30/04-6/29/056/30/10 (4 years) Approved 6/30/03-6/29/046/30/11 (5 years) Approved 6/30/02-6/29/036/30/12 (6 years) Approved 6/30/01-6/29/026/30/13 (7 years) Approved Pre-6/30/01 Voluntary at any time (encouraged to conform)

14. Appending Patient Labeling FDA-approved patient labeling must be reprinted at end of labeling or accompany labeling by June 30, 2007 –Includes MedGuides, approved “PPIs,” instructions for use, etc. –Applies to all drugs, including “older” products that are not subject to the new requirements –Can be submitted in the Annual Report

15. Labeling Supplement Regulations (§§ 314.70 and 601.12) Changes to Highlights require submission of a prior-approval labeling supplement Exceptions – changes to Highlights that may be submitted in the Annual Report –Removal of a listed section from “Recent Major Changes” after 1 year –Changes to the revision date

16. Older Prescription Drug Products § 201.57 redesignated § 201.80 Modifications –Ensure that statements currently appearing in labeling related to effectiveness or dosage and administration are sufficiently supported –Require that FDA-approved patient labeling be attached or accompany prescription drug labeling (within 1 year of effective date) –Limit References to cited authoritative report, methodology, scale or technique

17. 21 CFR Changes § 201.56General labeling requirements § 201.57Specific requirements for “newer” drugs § 201.58Waiver provision § 201.80Specific requirements for “older” drugs (formerly § 201.57) §§ 314.70 and 601.12Supplements – changes to Highlights require prior- approval

18. Related Regulatory Initiatives Electronic Labeling Rule required sponsors to submit e-labeling to FDA beginning 6/2004 Barcoding rule requires bar codes on labels of prescription drugs and OTC drugs The Drug Listing Proposed Rule will require the electronic submission to FDA of drug registration and listing information for all marketed human and animal medical products Modernizing MedWatch –Expanding communications –Unified AE reporting systems Paperless labeling will eliminate requirement for insert

19. § 201.56 General Requirements Labeling must: –Contain a summary of essential scientific information for the safe and effective use of the drug –Be informative and accurate and neither promotional in tone nor false or misleading –Be based whenever possible on data derived from human experience. No implied claims or suggestions of drug use may be made if there is inadequate evidence of safety or lack of substantial evidence of effectiveness –Be updated when new information becomes available that causes the labeling to become inaccurate, false, or misleading