a copy of the 2015 brochure here

Trends in OPDP Enforcement Letters
October 2012 – September 2013
September 17, 2013
Julie K. Tibbets
Partner, Alston & Bird LLP
(202) 239-3444
[email protected]
Overview of Activity:
October 2012-September 2013
§  CDER/Office of Prescription Drug Promotion (OPDP):
§  1 Warning Letter
§  18 Untitled Letters
§  2 letters noted offending materials were picked up by FDA personnel at
§  CBER Advertising and Promotional Labeling Branch (APLB)
§  1 Untitled Letter
§  OPDP oversees advertising/promotion of therapeutic biologics
§  2 of OPDP’s Untitled Letters were for BLAs
§  Compared to prior years, downward trend in letters, especially in warning letters
Trends & Emerging Trends
19 OPDP Letters
§  Risk information presentations (13)
§  Data from flawed study designs unable to provide substantial
evidence for claim (11)
§  Overstatement of efficacy
§  Unsubstantiated superiority
§  Investigational product promotion (3)
§  Press/news releases (3)
§  Composite data (1)
Presenting Risk Information: Legal Authorities
§  21 USC 352(a) – product is misbranded if its labeling is false or misleading
§  21 USC 352(n) – product is misbranded unless its advertising includes a
summary relating to side effects, contraindications, and effectiveness
§  21 USC 321(n) – misbranded labeling/advertising is determined not only
by representations made but also by representations not made – i.e., failing
to reveal material facts about representations made or material facts with
respect to consequences that may result from use as prescribed in product
labeling (or as customarily used)
§  21 CFR 1.21 – Labeling of a drug is misleading when it fails to reveal
material facts in light of representations made or material facts with respect
to consequences that may result from use as prescribed in product labeling
(or as customarily used)
Presenting Risk Information:
Advertising-Specific Legal Authorities
§  21 CFR 202.1(e)(5) – discusses when brief summary unsatisfactory
§  Lacks fair balance between risk/efficacy information such that efficacy information is presented
in “greater scope, depth, or detail”; however, brief summary is met when risk information is
“comparable in depth and detail” to efficacy/safety information
§  21 CFR 202.1(e)(6) – discusses when an advertisement lacks fair balance
§  Represents/suggests drug is safer or has less side effects/contraindications than demonstrated by
substantial evidence, including by way of comparison to another drug or presentation of studies
showing no or minimal side effects compared to approved label
§  21 CFR 202.1(e)(7) – discusses when an advertisement may lack fair balance
§  Fails to provide sufficient emphasis on side effects and contraindications
§  Fails to present side effects and contraindications with prominence and readability reasonably
comparable to efficacy information, taking into account typography, layout, contrast, headlines,
paragraphing, white space, and any other techniques apt to achieve emphasis.
§  Fails to provide adequate emphasis (e.g., by the use of color scheme, borders, headlines, or copy
that extends across the gutter) for the fact that two facing pages are part of the same
advertisement when one page contains risk information
Agency Guidance Activity
§  OPDP Director stated in October 2012 that OPDP planned on
revising its 2009 draft guidance on presenting risk information in
drug/device promotion
§  General, content, and format considerations
§  July 2013 CDER Guidance Agenda – no mention of planned
revision or finalization of draft guidance
§  Questions to consider:
§  Has the draft guidance become a vehicle for applying advertising-specific
regulations on fair balance/risk presentations to promotional labeling?
§  If so, has OPDP already been enforcing its draft guidance?
Examples from OPDP’s Letters (in Labeling)
Article Detailer
OPDP cited
Examples (in Labeling) (cont.)
§  Sigma-tau/Oncaspar® Sales Aid
OPDP cited 202.1(e)(7)(viii)
Presenting Data from Studies: Legal Authorities
Most frequently appearing in OPDP’s letters:
§  21 U.S.C. 352(a),(n) – misbranding authorities for labeling/advertising
§  21 CFR 202.1(e)(6) – advertising regulation providing an ad is lacking
fair balance where:
§  Contains a drug comparison that represents/suggests the drug is safer or more
effective than another drug when it has not been demonstrated to be safer or
more effective by substantial evidence or substantial clinical experience
§  Contains a representation or suggestion, not approved or permitted for use in
the labeling, that a drug is better, more effective, useful in a broader range of
conditions or patients, or is safer than demonstrated by substantial evidence
or substantial clinical experience
Presenting Data: Legal Authorities (cont.)
§  21 CFR 202.1(e)(7) – advertising regulation providing an ad “may”
lack fair balance where:
§  Contains favorable information or conclusions from a study that is
inadequate in design, scope, or conduct to furnish significant support for
such information or conclusions
§  Uses statistical analyses and techniques on a retrospective basis to discover
and cite findings not soundly supported by the study, or to suggest
scientific validity and rigor for data from studies the design or protocol of
which are not amenable to formal statistical evaluations
Study Designs ≠ Substantial Evidence
for Efficacy Claims
From OPDP’s October 2012-September 2013 letters:
§  Retrospective post hoc analyses
§  Retrospective single institution chart reviews
§  Retrospective sub-group analyses
§  Retrospective exploratory analyses
§  Retrospective analyses of different study populations
§  Post hoc analysis in a poster presentation
§  Open-label study with no control group
§  Comparative claims where not all competitors were studied
§  Meta-analyses based on a literature review
§  Lack of pre-specified endpoints for efficacy claims
§  Patient diaries to support adherence claims
Examples from OPDP’s Letters
§  Doxil® Website “In a
retrospective analysis”
§  Marplan® Website
“open-label” study
Investigational Drug Promotion
§  1 Warning Letter, 1 Untitled Letter in 2011
§  October 18, 2012 Untitled Letter to Burzynski Research Institute, Inc.
§  November 27, 2012 Untitled Letter to Salix Pharmaceuticals, Inc. and
Napo Pharmaceuticals, Inc.
§  April 25, 2013 Untitled Letter to CBA Research, Inc.
§  Materials OPDP reviewed included: company websites, online press
releases, web videos, booth brochures, and a podcast
Legal Authority
§  “Promotion of an investigational new drug is prohibited under FDA
regulations at 21 CFR 312.7(a), which states that ‘A sponsor or
investigator, or any person acting on behalf of a sponsor or investigator,
shall not represent in a promotional context that an investigational new
drug is safe or effective for the purposes for which it is under
investigation or otherwise promote the drug.’”
– FDA Untitled Letters/Warning Letter
Investigational Drug Promotion Examples
§  Salix/Napo:
ß Safety Claim
Investigational Drug Promotion Examples (cont.)
§  CBA Research:
§  Website presentation had a claim that CBT-1 “is” safe, well-tolerated
§  OPDP objected to positive/definitive conclusions – “achieves”, “is”
Press/News Releases
§  Form 2253 identifies “Print Press Release” and “Video News Release”
as two categories of advertising/promotional labeling materials
requiring submission
§  Some in industry still view these as non-promotional materials
§  3 Untitled Letters (1 for an investigational product):
§  October 18, 2012 Letter to Burzynski Research Institute – online
press releases
§  October 31, 2012 Letter to Cornerstone Therapeutics Inc. – HCP
letter with press release attached
§  February 21, 2013 Letter to ParaPRO, LLC – video news release
Legal Authorities
§  Burzynski investigational product Untitled Letter: 21 CFR 312.7(a)
§  Cornerstone/Curosurf® Untitled Letter:
§  21 USC 352(a) and 321(n) (misbranding authorities)
§  21 CFR 201.10(g)(1) (failing to include the established name where the
proprietary name was used in the press release headline)
§  Various 21 CFR 202.1(e)(5)-(7) advertising authorities (drug comparison
suggesting drug is safer/more effective than has been demonstrated)
§  ParaPRO/Natroba® Untitled Letter:
§  21 USC 352(a),(n) and 321(n) (misbranding authorities)
§  Various 21 CFR 202.1(e)(3), (5), (6) advertising authorities (failing to
adequately convey approved indication; drug comparison suggesting drug
is safer/more effective than has been demonstrated; no risk information)
Examples of Press Releases in OPDP Letters
ßNo established name
ßComparative claim
ßRetrospective design,
comparison of efficacy
of 3 products wasn’t
“The FDA has approved what could be a game changing medication in the war against head
lice; one that doesn’t require nit combing to be effective. It’s called Natroba. It is a topical
medicine whose active ingredient is derived from a naturally occurring soil microbe. It is
approved for kids 4 years and up and studies show it’s about twice as effective as permethrin
– the most commonly used over the counter product.” – Natroba® Video News Release
Composite Data Scores
§  April 26, 2012 – OPDP issues Untitled Letter to Meda Pharmaceuticals
Inc. for a telephone script
§  August 23, 2012 – FDA requested public comment on a proposed study
of consumer understanding of composite scores in DTC advertising
§  November 13, 2012 – OPDP issues Untitled Letter to Alcon Research,
Ltd. for a professional sales aid
§  May 14, 2013 – FDA submitted proposed study to OMB for review
§  August 13, 2013 – OMB announced approval of FDA’s planned study
of consumer understanding of benefit claims based on composite scores
in DTC advertising
FDA’s DTC Advertising Composite Score Study
§  FDA’s research will explore:
§  Whether consumers are aware of how efficacy is measured for specific drugs;
§  How well consumers comprehend the concept of composite scores;
§  Whether exposure to DTC ads with composite scores influences consumers’
perceptions of a drug’s efficacy and risk; and
§  Different methods for presenting composite scores in DTC ads to maximize
consumer comprehension and informed decision making
§  Phase 1: Internet survey of 1600 adults (review a print ad and provide
answers to questions)
§  Phase 2: Internet, randomized, controlled study of 1740 adults with
seasonal allergies reviewing a print ad for a fictitious seasonal allergy
drug testing different information presentations of composite score
benefit claims
OPDP’s Untitled Letters on Composite Scores
§  Alcon: Patanase® Overstatement of efficacy
§  PI Clinical Studies based on assessment of total nasal symptom score
(TNSS) – sum of the patient or caregiver’s scoring of nasal congestion,
rhinorrhea, itchy nose, and sneezing; OPDP said effect on score doesn’t
represent “a clear effect on any individual component of the TNSS”
§  Meda: “Also ASTEPRO 0.15% rapidly relieves allergic rhinitis
symptoms, including nasal congestion, without an added decongestant
within 30 to 45 minutes!”; OPDP said PI Clinical Studies based on
TNSS scores and this claim implied Astepro® is effective in the
treatment of the specific symptom of nasal congestion
Closing Takeaways
§  Focus legal and regulatory resources on risk and data presentations
§  Partner with marketing team members to ensure risk presentations
get equal time and attention in promotional materials during drafting
stage (including labeling)
§  Lean on medical reviewers to understand study designs/limitations
for supporting data
§  Few instances where OPDP issued letters in which risk and data
presentations did not warrant mention
Closing Takeaways (cont.)
§  Don’t overlook investigational product materials and websites
§  Beware of active verbs implying definitive conclusions
§  Ensure product-related press releases undergo multidisciplinary review
§  Ensure legal and regulatory review in particular
§  Same promotional rules and pitfalls apply
§  Inventory claims supported by composite score data for overstatement
of efficacy
§  Ensure benefit claims based on the score as a whole do not highlight
or imply efficacy in underlying components of the score
§  Keep an eye out for FDA’s DTC advertising composite score study
results to inform future benefit presentations of score-based claims