1. DIVISION OF REPRODUCTIVE AND UROLOGIC PRODUCTS Physician Labeling Rule Lisa Soule, M.D.

2. 2  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 § 201.56 General Labeling Requirements

3. 3  Health care providers:  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  Physician Labeling Rule (PLR) enacted to address these needs Research shows…

4. 4  Emphasizes “Patient Counseling Information”  Encourages adverse reaction (AR) reporting by including contact information (toll-free number and Internet address)  Identifies and Dates “Recent Major Changes”  Captures Boxed Warning, Indications, Dosage & Administration, Contraindications, and Warnings & Precautions  Referenced in Highlights; margin mark in Full Prescribing Information (FPI)  Adds initial U.S. approval date PLR Improvements

5. 5  Highlights  High level ½ page summary  Cited or concisely summarized information, accompanied by location in FPI to find more detail  Table of Contents  Reorders and reorganizes sections  Frequently referenced information moved forward  Safety information remains consolidated Overview of PLR

6. 6  Concise summary of information in FPI  Boxed Warning  Indications and Usage  Dosage and Administration  Dosage Forms and Strengths  Contraindications  Warnings and Precautions  Adverse Reactions  Drug Interactions  Use in Specific Populations Highlights

7. 7 Boxed Warning 1 Indications & Usage 2 Dosage & Administration 3 Dosage Forms & Strengths 4 Contraindications 5 Warnings & Precautions 6 Adverse Reactions 7 Drug Interactions 8 Use in Specific Populations 9 Drug Abuse & Dependence 10 Overdosage 11 Description 12 Clinical Pharmacology 13 Nonclinical Toxicology 14 Clinical Studies 15 References 16 How Supplied/Storage & Handling Handling 17 Patient Counseling Information Contents and FPI

8. 8  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 Format Changes

9. 9 Contraindications and Boxed Warning Sections  Contraindications  Risk from use clearly outweighs any possible therapeutic benefit  Known hazards only  Hormonal contraceptive labels list about 15 contraindications  Boxed Warning  AR so serious that it must be considered in assessing the risks and benefits of using a drug  AR can be prevented or reduced in frequency or severity by appropriate use of the drug  Currently, only boxed warning on hormonal contraceptives concerns smoking and increased risk of cardiovascular events  Other, bolded warnings, appear variably in labels

10. 10  Definition of adverse reaction: “reasonably associated with use of a drug” means that there is some basis to believe there is a causal relationship between the drug and occurrence of the AR  Identify most important ARs  Most common (>10% and 2x placebo)  ARs leading to intervention (discontinuation, dose change)  Avoid “laundry lists” (low frequency ARs without clear association with drug)  Currently, hormonal contraceptive labels usually list both “class” ARs and those noted in trials for the specific drug Adverse Reaction Section

11. 11 The AR section is intended to be updated as new information is obtained. Sources of information include  Controlled trials or epidemiological studies after marketing approval  Analyses of postmarketing adverse events Adverse Reaction Section

12. 12  A newly required section  Description of study design – may facilitate translation of results  Major design characteristics (e.g., blinding, controls, duration, randomization, etc.)  Treatment arms (if applicable), extent of exposure  Study population (e.g., inclusion/exclusion criteria, demographic characteristics, clinically relevant baseline values)  Methods that may have facilitated compliance (e.g., daily diaries, frequent contact with investigators) Clinical Studies Section

13. 13  The PLR initiative offers new opportunities to provide more informative labeling  New Patient Counseling Information section  Newly required Clinical Studies section may help in translation into the “real world”  New rules for safety sections may help focus on most relevant safety issues and allow for timely updating as new information is obtained Opportunities