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
Objectives

Explore FDA’s 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.
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.
FDA Structure
Food and Drug
Administration
CDER
Center for
Drug
Evaluation
and
Research
CBER
Center for
Biologics
Evaluation
and
Research
CDRH
Center for
Devices
and
Radiological
Health
CFSAN
Center for
Food
Safety
and Applied
Nutrition
CVM
Center for
Veterinary
Medicine
CTP
Center for
Tobacco
Products
ORA
Office of
Regulatory
Affairs
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
Total # of Promotional Pieces
100000
80000
61,013
60000
47,040
43,235
71085
68,288
45712
78466
76631
45663
45571
40000
20000
10,901
6877
12,616
8,632
2006
2007
15998
14456
6223
14970
15930
16965
0
Mixed
2008
Consumer
2009
Professional
2010
Total
What does DDMAC do?





Advice to industry
Advice within FDA
Surveillance and Enforcement
Guidances and Policy Development
Research
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”)
Advice within FDA

Provide consultation on:






Draft labeling
Cartons and product labels
Medication Guides
Patient Package Inserts (PPIs)
Dear Doctor letters
Pharmacoeconomics, health-related patientreported outcome protocols
Surveillance



Review materials submitted to DDMAC
at the time of initial dissemination
Conferences
Complaints




Healthcare professionals
Consumers
Lawyers
Competitors
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

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
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
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
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
Common Violations





Omission of Risk
Minimization of Risk
Broadening of Indication
Overstatement of Efficacy
Superiority Claims
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
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
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
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 coingested with alcoholic beverages
“Embeda can be abused in a manner similar to
other opioid agonists, legal or illicit.”
Embeda – Risks (continued)







Respiratory depression
Respiratory arrest
Apnea
Circulatory depression
Cardiac arrest
Hypotension
Shock
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
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…”
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.
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
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
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
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
What’s the Issue with Indocin®?
Indocin® - The Fine Print
It’s 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
Tools of the Trade in Evaluating
Risk in Promotion





Federal Food, Drug and Cosmetic Act
Code of Federal Regulations
Guidances
The PI
The Competitor’s PI
Contact Information

DDMAC’s website
http://www.fda.gov/AboutFDA/CentersOffices/
CDER/ucm090142.htm

Phone and Fax Numbers
Phone: (301) 796-1200
Fax: (301) 847-8444 or (301) 847-8445
Questions