1. Update on Current FDA Labeling Initiatives Iris P. Masucci, PharmD, BCPS Center for Drug Evaluation and Research FDA November 16, 2006 Pediatric Advisory Committee

2. 1 Outline l Overview of new labeling requirements l Discussion on incorporating pediatric information in labeling

3. 2 New Labeling Requirements

4. 3 Background l Previous labeling regulations from 1979 l Increase in amount and complexity of drug information l Goal – more informative and accessible labeling, resulting in a better risk communication and management tool

5. 4 Background l Physician Labeling Rule published on January 24, 2006 l Implementation date June 30, 2006

6. 5 Prior Labeling Requirements l Description l Clinical Pharmacology l Indications and Usage l Contraindications l Warnings l Precautions l Adverse Reactions l Drug Abuse and Dependence l Overdosage l Dosage and Administration l How Supplied l May contain: n Animal Pharmacology &/or Toxicology n Clinical Studies n References

7. 6 Revised Labeling Requirements l Highlights l Contents l Full prescribing information (FPI)

8. 7 Major Content Innovations l Highlights n High-level ½ page summary n Easily accessible format (e.g., bullets, tables) l Contents n Allows easy reference to FPI n Facilitates hyperlinks in electronic formats l “Recent Major Changes” with date n Captures changes occurring in Boxed Warning, Indications, Dosage and Administration, Contraindications, and Warnings & Precautions n Referenced in Highlights; margin mark in FPI

9. 8 Format Changes l Warnings and Precautions consolidated l Formerly in Precautions, now new required sections: n Drug Interactions n Use in Specific Populations n Patient Counseling Information l Formerly optional, now required: n Clinical Studies n Nonclinical Toxicology l New Dosage Forms and Strengths section

10. 9 Other Changes l Adds initial U.S. approval date and labeling revision date to Highlights l Adds established pharmacologic class to Indications section of Highlights l Requires adverse reaction reporting contact information in Highlights l Requires that approved patient labeling be reprinted at the end

11. 10 Highlights l Limitations Statement l Product Names and Date of Initial US Approval l Boxed Warning l Major Recent Changes l Indications and Usage l Dosage & Administration l Dosage Forms & Strengths l Contraindications l Warnings & Precautions l Adverse Reactions l Drug Interactions l Use in Specific Populations l Patient Counseling Information Statement l Revision Date

12. Example of Highlights for a Fictitious Drug

13. 12 Contents 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 17 Patient Counseling Information

14. Example of Contents for a Fictitious Drug

15. New NDA, BLA, or efficacy supplement: Label must conform: Submitted 6/30/06 or after At time of submission Pending on 6/30/06 or 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) Implementation Schedule

16. 15 FDA Web Page http://www.fda.gov/cder/regulatory/physLabel/ n Final Rule n Labeling guidances n Fictitious labeling examples n Templates n FAQs for healthcare professionals and consumers

17. 16 Incorporating Pediatric Information into Labeling

18. 17 CDER Labeling Initiatives l Seize opportunity for improving labels l Strive for consistency across CDER l Evaluate current labeling practices n e.g., incorporating pediatric information into approved labeling

19. 18 Important Question l Are the new data sufficient to warrant a pediatric indication?

20. 19 If yes, … l Information would be incorporated into label in applicable sections: n Indications and Usage n Dosage and Administration n Adverse Reactions n Use in Specific Populations – Pediatric Use n Pharmacokinetics/Pharmacodynamics n Clinical Studies

21. 20 If no, … l All information should appear in Use in Specific Populations – Pediatric Use l Will avoid implication of “approval” n Contextual language may be needed to explain this

22. 21 Categories of Pediatric Data 1.Substantial evidence in adults and children 2.Substantial evidence in children only 3.Studied in children, but evidence is not substantial 4.Substantial evidence not available in any population

23. 22 1. Substantial evidence in adults & children A. Based on adequate and well- controlled trials in adults and children atorvastatin, simvastatin atorvastatin, simvastatin B. Based on adequate and well- controlled trials in adults with other information supporting use in children ritonavir ritonavir

24. 23 2. Substantial evidence in children only l Condition unique to children or drug studied only in children meloxicam for JRA meloxicam for JRA oncologic agents for childhood leukemias oncologic agents for childhood leukemias

25. 24 3. Studied in children, but evidence is not substantial A.Efficacy not established, so do not use linezolid for CNS infections, gemcitabine linezolid for CNS infections, gemcitabine B.Safety not established, so do not use benzyl alcohol-containing products benzyl alcohol-containing products C.Data inconclusive to warrant approval citalopram, rosiglitazone citalopram, rosiglitazone

26. 25 4. Substantial evidence not available in any population l Studied in condition unique to children, but evidence does not support an approved indication tamoxifen for McCune-Albright Syndrome tamoxifen for McCune-Albright Syndrome

27. 26 Feedback? l Does the Committee think it will be helpful to have pediatric information for approved indications placed in the label in the usual places and information related to an unapproved use in the Pediatrics Use section?

28. 27 Feedback? l Does the Committee think that language explaining the lack of evidence to support approval in the Pediatric Use Section will be useful?

29. 28 Feedback? l Does the Committee think the Indications and Usage section should explicitly state the approved patient population n e.g, “in patients ages X and older" or "for adults with…”?