The Role of Risk Information in Product Labeling

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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

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Objectives

• Explore FDAs role in regulating prescription
  drug promotion and advertising.
• Discuss the impact of product labeling in
  advertising and promotion.
• Review several examples of false or misleading
  promotion of prescription analgesic drug products.

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Division of Drug Marketing, Advertising, and
Communications (DDMAC)

• 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.

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FDA Structure
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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

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Total of Promotional Pieces
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What does DDMAC do?

• Advice to industry
• Advice within FDA
• Surveillance and Enforcement
• Guidances and Policy Development
• Research

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Advice to Industry

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

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Advice within FDA

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

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Surveillance

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

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Enforcement Action Letters

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

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How Does the PI Affect DDMAC?

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

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Framing Risk

• Important not to minimize the data
• Is associated with
• There were reports of
• Causes
• Theoretical versus reported risks
• Hierarchy of risk
• Maintaining a risk to benefit balance

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Conveying Risk in Broadcast Advertising

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

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Conveying Risk in Professional and Consumer
Directed Promotion

• Expect material context in direct conjunction
  with claims as necessary to qualify such claims
• Important safety information (ISI) section
• Incorporating risk information throughout a
  promotional piece

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Common Violations

• Omission of Risk
• Minimization of Risk
• Broadening of Indication
• Overstatement of Efficacy
• Superiority Claims

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Omission of Risk Information

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

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Minimization of Risk Information

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

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Enforcement Example Embeda (morphine sulfate
and naltrexone HCl)

• Warning Letter
• Video news releases
• Indication
• 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

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Embeda - Risks

• Number of serious risks, many of which are
  potentially fatal
• 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
• Embeda can be abused in a manner similar to
  other opioid agonists, legal or illicit.

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Embeda Risks (continued)

• Respiratory depression
• Respiratory arrest
• Apnea
• Circulatory depression
• Cardiac arrest
• Hypotension
• Shock

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Embeda - Pharmacodynamics

• 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

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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.
• If crushed or chewed, the naltrexone within
  EMBEDA is released and absorbed with the
  morphine. Naltrexone reverses the subjective and
  analgesic effects of morphine

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Embedas ISI

• 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
• Failed to mention that such action results in a
  rapid release and absorption of a potentially
  fatal dose of morphine

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Embeda - Outcome

• 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
• Press release removed from website
• Corrective news release
• Distributed to similar number of media outlets
  and distribution lists

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Enforcement Example Cymbalta (duloxetine HCl)
Capsules

• Untitled Letter
• Direct-to-consumer print advertisement
• 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

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Does This Ad Have a Risk Problem?

• Numerous efficacy claims for Cymbalta
• No risk in the main body of the ad
• Risk presentation separated by magazine break
• Paragraph format of risk presentation in reduced
  font size quite distinct from the efficacy claims

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Whats the Issue with Indocin?
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Indocin - The Fine Print
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Its in the Details

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

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Tools of the Trade in Evaluating Risk in Promotion

• Federal Food, Drug and Cosmetic Act
• Code of Federal Regulations
• Guidances
• The PI
• The Competitors PI

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Contact Information

• DDMACs website
• http//www.fda.gov/AboutFDA/CentersOffices/
  CDER/ucm090142.htm
• Phone and Fax Numbers
• Phone [phone]
• Fax [phone] or [phone]

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Questions