1. The Role of Risk Information in Product Labeling Catherine Gray, PharmD Management Advisor Division of Drug Marketing, Advertising, and Communications Center for Drug Evaluation and Research IMMPACT Annual Meeting June 17, 2011

2. Objectives Explore FDA’s role in regulating prescription drug promotion and advertising. Explore FDA’s role in regulating prescription drug promotion and advertising. Discuss the impact of product labeling in advertising and promotion. Discuss the impact of product labeling in advertising and promotion. Review several examples of false or misleading promotion of prescription analgesic drug products. Review several examples of false or misleading promotion of prescription analgesic drug products.

3. Division of Drug Marketing, Advertising, and Communications (DDMAC) Protect the public health by assuring prescription drug information is truthful, balanced and accurately communicated. Protect the public health by assuring prescription drug information is truthful, balanced and accurately communicated. Accomplished through a comprehensive surveillance, enforcement and education program, and by fostering better communication of labeling and promotional information to both healthcare professionals and consumers. Accomplished through a comprehensive surveillance, enforcement and education program, and by fostering better communication of labeling and promotional information to both healthcare professionals and consumers.

4. FDA Structure

5. What Does DDMAC Regulate?  Written and printed prescription drug promotional materials made by the company which include:  TV and radio commercials  Sales aids, journal ads, and patient brochures  Drug websites, e-details, webinars, Epocrates, and email alerts  Oral Presentations made by representatives of the company which include:  Sales Reps  Hired Spokespeople  Medical Science Liaisons

6. Total # of Promotional Pieces

7. What does DDMAC do? Advice to industry Advice to industry Advice within FDA Advice within FDA Surveillance and Enforcement Surveillance and Enforcement Guidances and Policy Development Guidances and Policy Development Research Research

8. Advice to Industry Provide comments on DRAFT promotional materials (VOLUNTARY in most cases) Provide comments on DRAFT promotional materials (VOLUNTARY in most cases) Launch materials for new drugs or new indications Launch materials for new drugs or new indications Direct-to-consumer (DTC) broadcast ads Direct-to-consumer (DTC) broadcast ads Non-launch materials Non-launch materials Pre-submission required for certain drugs Pre-submission required for certain drugs (e.g., Subpart H “accelerated approval”)

9. Advice within FDA Provide consultation on: Provide consultation on: Draft labeling Draft labeling Cartons and product labels Cartons and product labels Medication Guides Medication Guides Patient Package Inserts (PPIs) Patient Package Inserts (PPIs) Dear Doctor letters Dear Doctor letters Pharmacoeconomics, health-related patient- reported outcome protocols Pharmacoeconomics, health-related patient- reported outcome protocols

10. Surveillance Review materials submitted to DDMAC at the time of initial dissemination Review materials submitted to DDMAC at the time of initial dissemination Conferences Conferences Complaints Complaints Healthcare professionals Healthcare professionals Consumers Consumers Lawyers Lawyers Competitors Competitors

11. Enforcement Action – Letters Pertain to pieces in the public domain Pertain to pieces in the public domain Public letter Public letter Untitled Letter versus Warning Letter Untitled Letter versus Warning Letter WL issued for more egregious or repeat violations WL issued for more egregious or repeat violations Impact Impact Expect immediate cessation of violative claims and presentations Expect immediate cessation of violative claims and presentations Corrective message expected for WL Corrective message expected for WL

12. How Does the PI Affect DDMAC? Primary reference for the evaluation of a promotional piece Primary reference for the evaluation of a promotional piece Content in the PI cannot be restricted from use in promotional materials Content in the PI cannot be restricted from use in promotional materials No role for promotion in the PI No role for promotion in the PI Consistency Consistency Within a single PI and across a drug category Within a single PI and across a drug category Language in Highlights, Warnings & Precautions, and Adverse Reactions Sections Language in Highlights, Warnings & Precautions, and Adverse Reactions Sections

13. Framing Risk Important not to minimize the data Important not to minimize the data “Is associated with…” “Is associated with…” “There were reports of…” “There were reports of…” “Causes…” “Causes…” Theoretical versus reported risks Theoretical versus reported risks Hierarchy of risk Hierarchy of risk Maintaining a risk to benefit balance Maintaining a risk to benefit balance

14. Conveying Risk in Broadcast Advertising Major Statement Major Statement Information relating to the major side effects and contraindication Information relating to the major side effects and contraindication Adequate Provision Adequate Provision Provides for dissemination of the PI Provides for dissemination of the PI Recognizes the inability of broadcast advertisements of reasonable length to present and communicate this information effectively Recognizes the inability of broadcast advertisements of reasonable length to present and communicate this information effectively Currently acceptable adequate provision Currently acceptable adequate provision

15. Conveying Risk in Professional and Consumer Directed Promotion Expect material context in direct conjunction with claims as necessary to qualify such claims Expect material context in direct conjunction with claims as necessary to qualify such claims Important safety information (ISI) section Important safety information (ISI) section Incorporating risk information throughout a promotional piece Incorporating risk information throughout a promotional piece

16. Common Violations Omission of Risk Omission of Risk Minimization of Risk Minimization of Risk Broadening of Indication Broadening of Indication Overstatement of Efficacy Overstatement of Efficacy Superiority Claims Superiority Claims

17. Omission of Risk Information Promotional materials that make product claims must also provide risk information Promotional materials that make product claims must also provide risk information Risk information should include Contraindications, Warnings, Precautions, pertinent Adverse Events Risk information should include Contraindications, Warnings, Precautions, pertinent Adverse Events Complete or partial omission of risk Complete or partial omission of risk

18. Minimization of Risk Information Omission of material information about a risk described in the approved labeling Omission of material information about a risk described in the approved labeling Inclusion of non-risk information in a risk section, or vice versa Inclusion of non-risk information in a risk section, or vice versa Risk information as a benefit Risk information as a benefit Framing Framing Layout/prominence Layout/prominence Sequence Sequence

19. Enforcement Example – Embeda™ (morphine sulfate and naltrexone HCl) Warning Letter Warning Letter Video news releases Video news releases Indication Indication Extended-release oral formulation of morphine sulfate and naltrexone HCl for the management of moderate to severe pain Extended-release oral formulation of morphine sulfate and naltrexone HCl for the management of moderate to severe pain REMS due to its potential for abuse, misuse, overdose and addiction REMS due to its potential for abuse, misuse, overdose and addiction

20. Embeda - Risks Number of serious risks, many of which are potentially fatal Number of serious risks, many of which are potentially fatal Risk profile mimics that of morphine and naltrexone, despite the unique PK characteristics Risk profile mimics that of morphine and naltrexone, despite the unique PK characteristics Boxed Warning – potentially fatal overdosing if capsules are chewed, crushed, dissolved, or co- ingested with alcoholic beverages Boxed Warning – potentially fatal overdosing if capsules are chewed, crushed, dissolved, or co- ingested with alcoholic beverages “Embeda can be abused in a manner similar to other opioid agonists, legal or illicit.” “Embeda can be abused in a manner similar to other opioid agonists, legal or illicit.”

21. Embeda – Risks (continued) Respiratory depression Respiratory depression Respiratory arrest Respiratory arrest Apnea Apnea Circulatory depression Circulatory depression Cardiac arrest Cardiac arrest Hypotension Hypotension Shock Shock

22. Embeda - Pharmacodynamics Clinical significance of the degree of reduction in drug liking and euphoria reported in clinical trials has not been established Clinical significance of the degree of reduction in drug liking and euphoria reported in clinical trials has not been established NO evidence that the naltrexone in Embeda reduces the abuse liability of Embeda NO evidence that the naltrexone in Embeda reduces the abuse liability of Embeda

25. Embeda – Violative Claims “EMBEDA™ is the first opioid approved by the FDA with pharmacological properties developed in response to the need for opioid analgesics that could reduce drug liking and euphoria when tampered with by crushing or chewing.” “EMBEDA™ is the first opioid approved by the FDA with pharmacological properties developed in response to the need for opioid analgesics that could reduce drug liking and euphoria when tampered with by crushing or chewing.” “If crushed or chewed, the naltrexone within EMBEDA™ is released and absorbed with the morphine. Naltrexone reverses the subjective and analgesic effects of morphine…” “If crushed or chewed, the naltrexone within EMBEDA™ is released and absorbed with the morphine. Naltrexone reverses the subjective and analgesic effects of morphine…”

26. Embeda’s ISI Each promotional piece contained a section of important safety information, but it failed to disclose the potential for FATAL risks associated with Embeda. Each promotional piece contained a section of important safety information, but it failed to disclose the potential for FATAL risks associated with Embeda. Stated that Embeda should not be crushed Stated that Embeda should not be crushed Failed to mention that such action results in a rapid release and absorption of a potentially fatal dose of morphine Failed to mention that such action results in a rapid release and absorption of a potentially fatal dose of morphine

27. Embeda - Outcome Given the acute public health hazard, rare action of calling the sponsor prior to issuing the letter Given the acute public health hazard, rare action of calling the sponsor prior to issuing the letter These and all promotional pieces with same or similar claims discontinued These and all promotional pieces with same or similar claims discontinued Press release removed from website Press release removed from website Corrective news release Corrective news release Distributed to similar number of media outlets and distribution lists Distributed to similar number of media outlets and distribution lists

28. Enforcement Example – Cymbalta (duloxetine HCl) Capsules Untitled Letter Untitled Letter Direct-to-consumer print advertisement Direct-to-consumer print advertisement Indicated for the management of fibromyalgia Indicated for the management of fibromyalgia Risks include a Boxed Warning for suicidality, contraindications for concomitant use with MAOI and patients with narrow-angle glaucoma Risks include a Boxed Warning for suicidality, contraindications for concomitant use with MAOI and patients with narrow-angle glaucoma

30. Does This Ad Have a Risk Problem? Numerous efficacy claims for Cymbalta Numerous efficacy claims for Cymbalta No risk in the main body of the ad No risk in the main body of the ad Risk presentation separated by magazine break Risk presentation separated by magazine break Paragraph format of risk presentation in reduced font size quite distinct from the efficacy claims Paragraph format of risk presentation in reduced font size quite distinct from the efficacy claims

31. What’s the Issue with Indocin ® ?

32. Indocin ® - The Fine Print

33. It’s in the Details… Omission of additional risks described in the approved labeling Omission of additional risks described in the approved labeling Includes information from the Boxed Warning, but fails to include any other risks Includes information from the Boxed Warning, but fails to include any other risks Other risks are serious and potentially FATAL Other risks are serious and potentially FATAL Material facts regarding dosing and administration to prevent serious, irreversible and potentially fatal adverse reactions Material facts regarding dosing and administration to prevent serious, irreversible and potentially fatal adverse reactions

34. Tools of the Trade in Evaluating Risk in Promotion Federal Food, Drug and Cosmetic Act Federal Food, Drug and Cosmetic Act Code of Federal Regulations Code of Federal Regulations Guidances Guidances The PI The PI The Competitor’s PI The Competitor’s PI

35. Contact Information DDMAC’s website DDMAC’s website http://www.fda.gov/AboutFDA/CentersOffices/ CDER/ucm090142.htm Phone and Fax Numbers Phone and Fax Numbers Phone: (301) 796-1200 Fax: (301) 847-8444 or (301) 847-8445

36. Questions