Slides (Updated 9/13/13)

Slides (Updated 9/13/13)

Trends in OPDP Enforcement Letters

October 2012 – September 2013

September 17, 2013

Julie K. Tibbets

Partner, Alston & Bird LLP

(202) 239-3444

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


§ Doxil ® Website “In a

retrospective analysis”

Examples from OPDP’s Letters


§ 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

ßNo established name

ßComparative claim

ßRetrospective 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






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