FDA Labeling Overview FDA Seminar Denmark, April 23-24, 2013

1. FDA Labeling OverviewFDA Seminar Denmark, April 23-24, 2013 Theresa Finn, PhD Associate Director for Regulatory Policy Office of Vaccines Research and Review (OVRR) Center for Biologics Evaluation and Research (CBER) Food and Drug Administration (FDA)

2. Request to cover • An introduction to product labeling and labeling guidance • A label for the drug (vaccine) as a result of the review process

3. Outline • What is labeling • Regulations relevant to the prescribing information • PLR and PLR format • FDA application review and labeling • Examples: • Indications and Usage: Accelerated Approval Pathway • Pediatric Use section • Updating the package insert • Examples • Guidances

4. What is labeling?

5. “Labeling” • Package insert (PI), package circular, prescribing information (21 CFR 201.57) • Container label • Package label • Patient package insert • Medication guide • Instructions for use • Risk management materials • Promotional materials

6. Prescribing Information • Primary mechanism through which FDA and drug manufacturers communicate essential, science-based prescribing information to health care professionals • Reviewed by FDA

7. Labeling • Labeling must contain a summary of the essential scientific information needed for the safe and effective use of the drug • Labeling must be informative and accurate and neither misleading in tone nor false or misleading in any particular… 21 CFR 201.56(a)

8. Regulations relevant to prescribing information “PLR” and “PLR format”

9. Physician Labeling Rule (PLR) • The Physician Labeling Rule • FR Notice Vol. 71, No. 15, Jan 24, 2006 • Revised the regulations governing the format and content of labeling for prescription drugs and biologics (21 CFR 201.56 and 201.57) • Labeling that meets the content and format requirements of 201.56(d) and 201.57 is termed “PLR format”

10. Application of PLR format • New and recently approved drugs required to comply with PLR format [21 CFR 201.56(d) and 201.57] • Those products for which NDA, BLA or efficacy supplement was approved from June 30, 2001- or was pending on June 2006 there is a staged implementation schedule • Prescription drugs not subject to PLR format are subject to the labeling requirements [201.56(e) and 201.80], “old format”

11. PLR Format Overview • Approved labeling now has 3 parts: • Highlights • Contents • Full prescribing information (FPI) • Identifies and Dates “Recent Major Changes” • Captures Indications, D&A, Boxed Warning, CI and W&P • Referenced in Highlights; margin mark in FPI • Added date of initial US approval

12. PLR Format Overview cont’d • Reorders and reorganizes sections • Establishes format requirements • Warnings and Precautions consolidated • New sections • Drug Interactions • Dosage Forms and Strengths • Use in Specific Populations • Patient Counseling Information • Formerly optional, now required • Clinical Studies

13. Highlights Section • Sections in Highlights • Highlights limitation statement • Product Title (Drug name, dosage form, route of administration) • Initial U.S. approval date • Boxed Warning • Recent Major Changes • Indications and Usage • Dosage and Administration • Dosage Forms and Strengths • Contraindications • Warnings and Precautions • Adverse Reactions • Drug Interactions • Use in Specific Populations • Patient Counseling Information 21 CFR 201.57(a)

14. 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 * Indicates sections with specified numbering of subsections Contents and Full PrescribingInformation (FPI)

15. http://dailymed.nlm.gov...

16. Vaccine Label: “Snapshots” Highlights Warnings and Precautions

17. FDA Labeling Review

18. Labeling General Considerations • Labeling is based on review and analysis of information provided in an application (BLA, NDA) submitted by an applicant

19. FDA Review of Vaccine Labeling Responsibility of specific members of the review team: • Clinical Reviewer • Ensures accuracy of clinically relevant labeling • Statistician • Ensures accuracy of statistical clinical data • CMC reviewer • Ensures accuracy of chemistry and manufacturing information • Advertising and Promotional Labeling Branch Reviewer • Proprietary name review, consults on content for comprehension and promotional perspective, reviews for possible medication errors and promotional claims

20. Implied Indications and Usages Not Allowed in Labeling • Regulations: • Indications and Usage • For biological products, all indications listed in this section must be supported by substantial evidence of effectiveness. Indications or uses must not be implied or suggested in other sections of the labeling if not included in this section 201.57(c)(2)(iii)(v) • Dosage and Administration • Dosing regimens must not be implied or suggested in other sections of the labeling if not included in this section 201.57(c)(3)(ii) • Clinical Studies • For biological products, any clinical study that is discussed that relates to an indication of use of the biological product must constitute or contribute to substantial evidence and must not imply or suggest indications or uses or dosing regimens not stated in the “Indications and Usage” or Dosage and Administration” section 201.25(c)(14)(i)

21. Examples

22. Accelerated Approval • Products approved using the Accelerated Approval pathway • Regulations: • Indications and Usage section: • If the indication is approved based on a surrogate endpoint under [Accelerated Approval] a succinct description of the limitations of usefulness of the drug and any uncertainty about anticipated clinical benefits…” • 201.57(c)(2)(i)(B)

23. Accelerated Approval: Example • 1 INDICATIONS AND USAGE • FLULAVAL is indicated for active immunization against influenza disease caused by influenza virus subtypes A and type B contained in the vaccine. FLULAVAL is approved for use in persons 18 years of age and older. This indication is based on immune response elicited by FLULAVAL, and there have been no controlled trials adequately demonstrating a decrease in influenza disease after vaccination with FLULAVAL [see Clinical Studies (14)].

24. PREA • Pediatric Research Equity Act: FDAAA 2007 • Sec 505B(a)(4)(d): If the Secretary grants a full or partial waiver because there is evidence …the product would be ineffective or unsafe in pediatric populations, the information shall be included in the labeling for the drug or biological product.

25. Pediatric Use Section: Example • 8.4 Pediatric Use • The immune response to FLUARIX has been evaluated in children 6 months to <5 years of age. In a randomized, controlled study, serum hemagglutination-inhibition (HI) antibody titers were lower in children 6 months to <3 years of age compared to a US-licensed vaccine. Based on these data, FLUARIX is not approved for use in children younger than 3 years of age. …

26. Updating the package insert

27. Updating Labels • In general: • Review for implied indications and usages • Review for redundancies, outdated information • Review for general quality (format, organization, readability) and to make it a better communication tool • Old format to PLR format: • Develop highlights (should reflect the information in full prescribing) • Re-organize information in full prescribing as per PLR format

28. Previous version W/P Section Do not administer…. (implied contraindication) X should not be administered… (implied contraindication) Clinical studies section Transmission study Updated version W/P Section In clinical trials, risk of .. were increased in Children younger than .. with …may be at increased risk of … Clinical Pharmacology/ Pharmacodynamics section Transmission study Updating Labels: Examples

29. Selected Labeling Guidance • Guidance for Industry: Labeling for Human Prescription Drug and Biological Products – Implementing the PLR Content and Format Requirements, February 2013 • Guidance for Industry: Dosage and Administration Section of Labeling for Human Prescription Drug and Biological Products — Content and Format , March 2010 • Guidance for Industry: Warnings and Precautions, Contraindications, and Boxed Warning Sections of Labeling for Human Prescription Drug and Biological Products — Content and Format, October 2011 • Guidance for Industry: Adverse Reactions Section of Labeling for Human Prescription Drug and Biological Products-Content and Format, January 2006 • Guidance for Industry: Clinical Pharmacology Section of Labeling for Human Prescription Drug and Biological Products-Content and Format, Draft Guidance, February 2009 • Guidance for Industry: Clinical Studies Section of Labeling for Human Prescription Drug and Biological Products — Content and Format, January 2006 • Guidance for Industry: Content and Format for Geriatric Labeling, October 2001 http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm065010.htm

30. Summary • PLR format provides essential information in Highlights section • Facilitates finding information - consistency in content of sections and location of information (e.g. Pediatric Use is always in Section 8.4)