Prescription Drug Labeling

1. Prescription Drug Labeling “From Discovery to Approval” Distance-Course in Regulatory Affairs Lehigh University John J Spaltro, Ph.D. Director, Regulatory Affairs – Domestic Merck Research Laboratories

2. Disclosure/Disclaimer Dr. Spaltro is a employee of Merck & Co., this presentation includes his interpretation of US drug labeling regulations and he is solely responsible for its content. Information presented does not represent any interest or interpretation of Merck & Co..

3. Objectives • Event History leading to FDA regulation of drug labeling • Laws that regulate prescription drug labeling and promotional materials • Scope of labeling components and their content • Significance of promotional labeling and DTC Advertising and why FDA regulates these materials • Current topics in prescription drug labeling • Where to find current information related to prescription drug labeling

4. Prescription Drug Labeling • Essential scientific information needed for safe and effective use • Informative, accurate, not promotional or misleading • Based on human experience, whenever possible • Animal data when necessary for safe and effective use

5. Drug Labeling Law • Federal Register • Legal newspaper published daily, contains current federal agency regulations, proposed rules, and Executive orders. • Federal Register: Main Page • Code of Federal Regulations (CFR) • CFR codifies final rules published in Federal Register • Divided into titles an subparts representing broad areas subject to Federal regulation • Updated yearly and issued quarterly • Code of Federal Regulations: About • 21CFR201:Drug Labeling - Title 21-Drugs, Subpart 201-Labeling • Labeling Requirements for Prescription Drugs and Insulin • Laws • Laws Enforced by the FDA

6. Labeling Components • Professional Labeling • Immediate Container/ Outer package • Patient Product Information • Medication Guide • Promotional Labeling • DTC Advertising

7. Professional Label • Adverse Reactions • Drug Abuse and Dependence • Overdose • Dosage and Administration • How Supplied • Preparation for use (shaking) • Dose • Route or method of administration • Frequency of administration • Duration of administration • Time of administration (e.g., meals) • Description • name, dosage form, ingredients, sterility, class, structure) • Animal pharmacology • Clinical Pharmacology • Clinical Studies • Indications and Usage • Contraindications • Warnings • Precautions • General precautionary information • Drug interactions; carcinogenicity, mutagenesis, fertility; • Pregnancy/ nursing mothers; • Special Populations – pediatric, geriatrics

8. Example Professional Label Professional Labeling: Isotrentinoin

9. Container/Package Labels • Statement of identity • Established name, Ingredients • Net quantity of contents • Weight, measure, numerical count, combination • Statement of usual dosage • “See package insert” • Rx only • Replaces “Caution, Federal law prohibits dispensing without prescription” • Expiration date • Name and place of business of manufacturer, packer, or distributor

10. Patient Product Information (PPI) • Extension of professional labeling for the patient • Distributed to patients when dispensed and includes Important information in consumer-friendly language • May describe benefits, risks, how to recognize risks, dosage and administration • May Include Special Notices (Boxed Warnings) • Required for certain drugs • oral contraceptives (21 CFR 310.501) • estrogens (21 CFR 310.515) • progestational drug products (21 CFR 310.516) • Voluntary for other drugs

11. Example PPI Patient Product Information

12. Medication Guides • Serious and significant public health concern • Significant risk:benefit issue(s) that may affect patients’ decisions to use, or continue to use the product • Patient compliance (i.e., adherence to directions for use) is crucial to drugs safety/ effectiveness • Where additional information could help prevent serious adverse effects • Where drug would used primarily in an outpatient setting without supervision of health professional

13. Medication Guide(s) • Brand name • What is the most important information I should know about (name of drug)? • What is (name of drug)? • Who should not take (name of drug)? • How should I take (name of drug)? • What should I avoid while taking (name of drug)? • What are the possible or reasonably likely side effects of (name of drug)? • Additional headings

14. Example Medication Guide Accutane Medication Guide

15. FDAMA & Off-Label Use • The Food and Drug Modernization Act of 1997 (FDAMA) - FDAMA Homepage

16. Off-Label Use: Pre- & Post-FDAMA Post- • Firms may distribute information related to new (unapproved) use of approved drug, prior to FDA approval, if: • Reprint or copy of a peer-reviewed scientific or medical journal article, or reference publication, about a clinical investigation • Is not false or misleading and does not pose a significant risk to the public health • Manufacturer must submit copy to FDA (DDMAC) 60 days prior to dissemination Pre- • “On-Label” Indications are listed in FDA approved labeling, however, FDA does not dictate the medical practice • Drug sponsors may not discuss, promote or distribute materials that encourage “off-label” use • Promotion of “Off-label” use by sponsors would: • Diminish use of evidence-based medicine • Expose patients to unidentified risk or harm

17. Promotional Labeling • Direct-to Consumer (DTC) promotion for purpose to enhance patient awareness of disease states, available therapies, potential side effects • Includes magazines, newspapers, broadcast (TV/radio), internet dissemination/ advertising of drug information to physicians and patients • May be product-claim, reminder or help-seeking advertisements • New form of product labeling with specific regulation by DDMAC

18. DTC Regulation • Before 1980, No DTC promotion • 1983 – Voluntary Moratorium • 1985 – Policy Statement, Sufficient Safeguards • 1990’s – Promotional Message/ Brief Summary (AEs) • Mid 1990s – “Reminder Ads” • 1997 – FDA Draft Guidance

19. DDMAC • Division of Drug Marketing, Advertising and Communication (DDMAC) • Regulates DTC promotional labeling • Ensures truthful, balanced and accurate communication of drug information to the public • Post-Hoc evaluation, most recommendations to “Stop or Discontinue” due to false, misleading or unbalance representation

20. DDMAC Authority • Untitled Letters– notice of violation • Warning Letters – More serious violations • Injunctions and Consent Decrees • Criminal Investigation or Prosecution • Product Seizure

21. Case Studies • SSRI Class Labeling for Anti-Depressant Use in Pediatrics • Pregnancy Contraindication for Thalidomide Use in ENL • “Fen-Phen” Off-Label Use for Weight-Loss and Obesity

22. Case: SSRI Class Labeling • FDA Adverse Event Reporting (AERS) • MedWatch-ADHD • Antidepressant Use in ADHD • Public Health Advisory: Suicidality in Children and Adolescents Being Treated with Antidepressant Medications • Class Labeling for Selective Seratonin Uptake Receptor Inhibitors (SSRIs) - SSRI Class Labeling Notification • Black-box warning for all antidepressants used in pediatric indications • FDA Label Change Request to Manufacturers

23. Case: Thalidomide • Sold (1960s) in Europe for pain-relief and sleeping-aid, never tested for effects in pregnancy • Phocomelia (limb defects) associated with use • Resurgence (1990s) for beneficial side-effects in ENL (Leprosy) • Approved by FDA in 1998 for severe debilitating and disfiguring lesions associated with ENL • Unprecedented Regulatory Authority for Distribution • BLACK-BOX Pregnancy Labeling and Special Warnings to patients and prescribers • Tight control of Marketing for Thalidomid (ENL) • System for Thalidomide Education and Prescribing Safety (STEPS) CDER- Thalidomide Information Page

24. Case: “Fen-Phen” Off-Label Use • Off-Label combination use of two singly approved drugs (Fenfluramine-Phentermine) for treatment for obesity • Cardiac Valvular Abnormalities identified by FDA-MedWatch • July, 1997 FDA Public Health Advisory – “Fen-Pen” • Black-Box Warning for Fenfluramine in-combination for greater than 3 months can lead to valvulopathy • Wyeth-Ayerst Physician Advisory Letter • Physician Advisory Letter – Pondimin • FDA Announces Fenfluramine-Dexfenfluramine withdrawal from market • FDA ANNOUNCES FEN-PHEN WITHDRAWAL

25. Question 1: As a healthcare provider, you prescribe the administration of an approved drug and observe the occurrence of a serious adverse event, product problem or medication error associated with the prescribed therapy. Why and how should you report such an event?

26. Answer: Question 1 Why: FDA relies on the voluntary reporting of these events. FDA uses this data to maintain our safety surveillance of all FDA-regulated products. Your report may be the critical action that prompts safety investigation, advisory panel review, labeling modification, health advisory or even product recall. How: Healthcare professionals and consumers should voluntarily report all serious adverse events, product problems or medications errors noted spontaneously in the course of clinical care through FDA’s MED-WATCH program

27. Question 2: FDA has responsibility for assuring that regulated marketed medical products are safe and effective. Explain how the FDA communicates drug product information required for safe and effective use of a marketed medical product.

28. Answer: Question 2 FDA uses specialized approved labeling to clearly communicate drug product information to physicians (Professional Labeling) and consumers (Patient Product Information). Medication Guides and “Black-Box” warnings are used to notify prescribers and consumers of significant risk: benefit information.

29. Question 3: As a medical product consumer, what resources are available to assure that you safely and effectively administer drugs as prescribed by your physician? As caregiver to the elderly or children, which section(s) of the professional label or patient package insert contain especially important information?

30. Answer: Question 3 • Approved labeling (PL, PPI, MG), Drugs@FDA (Therapeutic Equivalents), FDA Med-Watch (AERS), as well as, doctor or pharmacist. • Indications for Use, Dosage and Administration, Use in Special Populations, Warnings and Precautions