Slides (Updated 9/13/13)
Slides (Updated 9/13/13)
Slides (Updated 9/13/13)
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Trends in OPDP Enforcement Letters<br />
October 2012 – September 20<strong>13</strong><br />
September 17, 20<strong>13</strong><br />
Julie K. Tibbets<br />
Partner, Alston & Bird LLP<br />
(202) 239-3444<br />
julie.tibbets@alston.com
Overview of Activity:<br />
October 2012-September 20<strong>13</strong><br />
§ CDER/Office of Prescription Drug Promotion (OPDP):<br />
§ 1 Warning Letter<br />
§ 18 Untitled Letters<br />
§ 2 letters noted offending materials were picked up by FDA personnel at<br />
conferences<br />
§ CBER Advertising and Promotional Labeling Branch (APLB)<br />
§ 1 Untitled Letter<br />
§ OPDP oversees advertising/promotion of therapeutic biologics<br />
§ 2 of OPDP’s Untitled Letters were for BLAs<br />
§<br />
Compared to prior years, downward trend in letters, especially in warning letters<br />
2
Trends & Emerging Trends<br />
19 OPDP Letters<br />
§ Risk information presentations (<strong>13</strong>)<br />
§ Data from flawed study designs unable to provide substantial<br />
evidence for claim (11)<br />
§ Overstatement of efficacy<br />
§ Unsubstantiated superiority<br />
§ Investigational product promotion (3)<br />
§ Press/news releases (3)<br />
§ Composite data (1)<br />
3
PART I<br />
TRENDS:<br />
- RISK INFORMATION<br />
- DATA PRESENTATIONS<br />
4
Presenting Risk Information: Legal Authorities<br />
§ 21 USC 352(a) – product is misbranded if its labeling is false or misleading<br />
§ 21 USC 352(n) – product is misbranded unless its advertising includes a<br />
summary relating to side effects, contraindications, and effectiveness<br />
§ 21 USC 321(n) – misbranded labeling/advertising is determined not only<br />
by representations made but also by representations not made – i.e., failing<br />
to reveal material facts about representations made or material facts with<br />
respect to consequences that may result from use as prescribed in product<br />
labeling (or as customarily used)<br />
§ 21 CFR 1.21 – Labeling of a drug is misleading when it fails to reveal<br />
material facts in light of representations made or material facts with respect<br />
to consequences that may result from use as prescribed in product labeling<br />
(or as customarily used)<br />
5
Presenting Risk Information:<br />
Advertising-Specific Legal Authorities<br />
§ 21 CFR 202.1(e)(5) – discusses when brief summary unsatisfactory<br />
§<br />
Lacks fair balance between risk/efficacy information such that efficacy information is presented<br />
in “greater scope, depth, or detail”; however, brief summary is met when risk information is<br />
“comparable in depth and detail” to efficacy/safety information<br />
§ 21 CFR 202.1(e)(6) – discusses when an advertisement lacks fair balance<br />
§<br />
Represents/suggests drug is safer or has less side effects/contraindications than demonstrated by<br />
substantial evidence, including by way of comparison to another drug or presentation of studies<br />
showing no or minimal side effects compared to approved label<br />
§ 21 CFR 202.1(e)(7) – discusses when an advertisement may lack fair balance<br />
§ Fails to provide sufficient emphasis on side effects and contraindications<br />
§<br />
§<br />
Fails to present side effects and contraindications with prominence and readability reasonably<br />
comparable to efficacy information, taking into account typography, layout, contrast, headlines,<br />
paragraphing, white space, and any other techniques apt to achieve emphasis.<br />
Fails to provide adequate emphasis (e.g., by the use of color scheme, borders, headlines, or copy<br />
that extends across the gutter) for the fact that two facing pages are part of the same<br />
advertisement when one page contains risk information<br />
6
Agency Guidance Activity<br />
§ OPDP Director stated in October 2012 that OPDP planned on<br />
revising its 2009 draft guidance on presenting risk information in<br />
drug/device promotion<br />
§ General, content, and format considerations<br />
§ July 20<strong>13</strong> CDER Guidance Agenda – no mention of planned<br />
revision or finalization of draft guidance<br />
§ Questions to consider:<br />
§ Has the draft guidance become a vehicle for applying advertising-specific<br />
regulations on fair balance/risk presentations to promotional labeling?<br />
§ If so, has OPDP already been enforcing its draft guidance?<br />
7
Examples from OPDP’s Letters (in Labeling)<br />
Teva/Clozapine<br />
Article Detailer<br />
OPDP cited<br />
202.1(e)(7)(viii)<br />
8
Examples (in Labeling) (cont.)<br />
§ Sigma-tau/Oncaspar ® Sales Aid<br />
9<br />
OPDP cited 202.1(e)(7)(viii)
Presenting Data from Studies: Legal Authorities<br />
Most frequently appearing in OPDP’s letters:<br />
§ 21 U.S.C. 352(a),(n) – misbranding authorities for labeling/advertising<br />
§ 21 CFR 202.1(e)(6) – advertising regulation providing an ad is lacking<br />
fair balance where:<br />
§ Contains a drug comparison that represents/suggests the drug is safer or more<br />
effective than another drug when it has not been demonstrated to be safer or<br />
more effective by substantial evidence or substantial clinical experience<br />
§ Contains a representation or suggestion, not approved or permitted for use in<br />
the labeling, that a drug is better, more effective, useful in a broader range of<br />
conditions or patients, or is safer than demonstrated by substantial evidence<br />
or substantial clinical experience<br />
10
Presenting Data: Legal Authorities (cont.)<br />
§ 21 CFR 202.1(e)(7) – advertising regulation providing an ad “may”<br />
lack fair balance where:<br />
§ Contains favorable information or conclusions from a study that is<br />
inadequate in design, scope, or conduct to furnish significant support for<br />
such information or conclusions<br />
§ Uses statistical analyses and techniques on a retrospective basis to discover<br />
and cite findings not soundly supported by the study, or to suggest<br />
scientific validity and rigor for data from studies the design or protocol of<br />
which are not amenable to formal statistical evaluations<br />
11
Study Designs ≠ Substantial Evidence<br />
for Efficacy Claims<br />
From OPDP’s October 2012-September 20<strong>13</strong> letters:<br />
§ Retrospective post hoc analyses<br />
§ Retrospective single institution chart reviews<br />
§ Retrospective sub-group analyses<br />
§ Retrospective exploratory analyses<br />
§ Retrospective analyses of different study populations<br />
§ Post hoc analysis in a poster presentation<br />
§ Open-label study with no control group<br />
§ Comparative claims where not all competitors were studied<br />
§ Meta-analyses based on a literature review<br />
§ Lack of pre-specified endpoints for efficacy claims<br />
§ Patient diaries to support adherence claims<br />
12
§ Doxil ® Website “In a<br />
retrospective analysis”<br />
Examples from OPDP’s Letters<br />
à<br />
§ Marplan ® Website<br />
“open-label” study<br />
<strong>13</strong>
PART II<br />
EMERGING TRENDS:<br />
- INVESTIGATIONAL DRUG PROMOTION<br />
- PRESS/NEWS RELEASES AS PROMOTIONAL MATERIALS<br />
- COMPOSITE SCORE BENEFIT CLAIMS<br />
14
Investigational Drug Promotion<br />
§ 1 Warning Letter, 1 Untitled Letter in 2011<br />
§ October 18, 2012 Untitled Letter to Burzynski Research Institute, Inc.<br />
§ November 27, 2012 Untitled Letter to Salix Pharmaceuticals, Inc. and<br />
Napo Pharmaceuticals, Inc.<br />
§ April 25, 20<strong>13</strong> Untitled Letter to CBA Research, Inc.<br />
§ Materials OPDP reviewed included: company websites, online press<br />
releases, web videos, booth brochures, and a podcast<br />
15
Legal Authority<br />
§ “Promotion of an investigational new drug is prohibited under FDA<br />
regulations at 21 CFR 312.7(a), which states that ‘A sponsor or<br />
investigator, or any person acting on behalf of a sponsor or investigator,<br />
shall not represent in a promotional context that an investigational new<br />
drug is safe or effective for the purposes for which it is under<br />
investigation or otherwise promote the drug.’”<br />
– FDA Untitled Letters/Warning Letter<br />
16
Investigational Drug Promotion Examples<br />
§ Salix/Napo:<br />
ß Safety Claim<br />
17
Investigational Drug Promotion Examples (cont.)<br />
§ CBA Research:<br />
§ Website presentation had a claim that CBT-1 “is” safe, well-tolerated<br />
§ OPDP objected to positive/definitive conclusions – “achieves”, “is”<br />
18
Press/News Releases<br />
§ Form 2253 identifies “Print Press Release” and “Video News Release”<br />
as two categories of advertising/promotional labeling materials<br />
requiring submission<br />
§ Some in industry still view these as non-promotional materials<br />
§ 3 Untitled Letters (1 for an investigational product):<br />
§ October 18, 2012 Letter to Burzynski Research Institute – online<br />
press releases<br />
§ October 31, 2012 Letter to Cornerstone Therapeutics Inc. – HCP<br />
letter with press release attached<br />
§ February 21, 20<strong>13</strong> Letter to ParaPRO, LLC – video news release<br />
19
Legal Authorities<br />
§<br />
§<br />
§<br />
Burzynski investigational product Untitled Letter: 21 CFR 312.7(a)<br />
Cornerstone/Curosurf ® Untitled Letter:<br />
§ 21 USC 352(a) and 321(n) (misbranding authorities)<br />
§ 21 CFR 201.10(g)(1) (failing to include the established name where the<br />
proprietary name was used in the press release headline)<br />
§ Various 21 CFR 202.1(e)(5)-(7) advertising authorities (drug comparison<br />
suggesting drug is safer/more effective than has been demonstrated)<br />
ParaPRO/Natroba ® Untitled Letter:<br />
§<br />
§<br />
21 USC 352(a),(n) and 321(n) (misbranding authorities)<br />
Various 21 CFR 202.1(e)(3), (5), (6) advertising authorities (failing to<br />
adequately convey approved indication; drug comparison suggesting drug<br />
is safer/more effective than has been demonstrated; no risk information)<br />
20
Examples of Press Releases in OPDP Letters<br />
ßNo established name<br />
ßComparative claim<br />
ßRetrospective design,<br />
comparison of efficacy<br />
of 3 products wasn’t<br />
pre-specified<br />
“The FDA has approved what could be a game changing medication in the war against head<br />
lice; one that doesn’t require nit combing to be effective. It’s called Natroba. It is a topical<br />
medicine whose active ingredient is derived from a naturally occurring soil microbe. It is<br />
approved for kids 4 years and up and studies show it’s about twice as effective as permethrin<br />
– the most commonly used over the counter product.” – Natroba ® Video News Release<br />
21
Composite Data Scores<br />
§ April 26, 2012 – OPDP issues Untitled Letter to Meda Pharmaceuticals<br />
Inc. for a telephone script<br />
§ August 23, 2012 – FDA requested public comment on a proposed study<br />
of consumer understanding of composite scores in DTC advertising<br />
§ November <strong>13</strong>, 2012 – OPDP issues Untitled Letter to Alcon Research,<br />
Ltd. for a professional sales aid<br />
§ May 14, 20<strong>13</strong> – FDA submitted proposed study to OMB for review<br />
§ August <strong>13</strong>, 20<strong>13</strong> – OMB announced approval of FDA’s planned study<br />
of consumer understanding of benefit claims based on composite scores<br />
in DTC advertising<br />
22
FDA’s DTC Advertising Composite Score Study<br />
§ FDA’s research will explore:<br />
§ Whether consumers are aware of how efficacy is measured for specific drugs;<br />
§ How well consumers comprehend the concept of composite scores;<br />
§ Whether exposure to DTC ads with composite scores influences consumers’<br />
perceptions of a drug’s efficacy and risk; and<br />
§ Different methods for presenting composite scores in DTC ads to maximize<br />
consumer comprehension and informed decision making<br />
§ Phase 1: Internet survey of 1600 adults (review a print ad and provide<br />
answers to questions)<br />
§ Phase 2: Internet, randomized, controlled study of 1740 adults with<br />
seasonal allergies reviewing a print ad for a fictitious seasonal allergy<br />
drug testing different information presentations of composite score<br />
benefit claims<br />
23
OPDP’s Untitled Letters on Composite Scores<br />
§ Alcon: Patanase ® Overstatement of efficacy<br />
§ PI Clinical Studies based on assessment of total nasal symptom score<br />
(TNSS) – sum of the patient or caregiver’s scoring of nasal congestion,<br />
rhinorrhea, itchy nose, and sneezing; OPDP said effect on score doesn’t<br />
represent “a clear effect on any individual component of the TNSS”<br />
§ Meda: “Also ASTEPRO 0.15% rapidly relieves allergic rhinitis<br />
symptoms, including nasal congestion, without an added decongestant<br />
within 30 to 45 minutes!”; OPDP said PI Clinical Studies based on<br />
TNSS scores and this claim implied Astepro ® is effective in the<br />
treatment of the specific symptom of nasal congestion<br />
24
25<br />
TAKEAWAYS
Closing Takeaways<br />
§ Focus legal and regulatory resources on risk and data presentations<br />
§ Partner with marketing team members to ensure risk presentations<br />
get equal time and attention in promotional materials during drafting<br />
stage (including labeling)<br />
§ Lean on medical reviewers to understand study designs/limitations<br />
for supporting data<br />
§ Few instances where OPDP issued letters in which risk and data<br />
presentations did not warrant mention<br />
26
Closing Takeaways (cont.)<br />
§ Don’t overlook investigational product materials and websites<br />
§ Beware of active verbs implying definitive conclusions<br />
§ Ensure product-related press releases undergo multidisciplinary review<br />
§ Ensure legal and regulatory review in particular<br />
§ Same promotional rules and pitfalls apply<br />
§ Inventory claims supported by composite score data for overstatement<br />
of efficacy<br />
§ Ensure benefit claims based on the score as a whole do not highlight<br />
or imply efficacy in underlying components of the score<br />
§ Keep an eye out for FDA’s DTC advertising composite score study<br />
results to inform future benefit presentations of score-based claims<br />
27
THANK YOU!<br />
NEXT:<br />
OPEN ISSUES<br />
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