trends in warning and nov letters 2013

Alan BergstromSenior Director, Commercial Regulatory Affairs

CBI Promotional ComplianceOctober 7, 2013

Trends in Recent Warning and NOV Letters Issued by OPDP

The content, views, and opinions in this presentation are my own and do not in anyway represent the views or opinions of Daiichi Sankyo, Inc.

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OPDP Letters 2000 – 2013

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Professional versus Consumer Violations 2013

8 Professional – 4 websites, 1 e-mail, 2 sales aids, 1 reprint carrier

5 Consumer – 2 print ads, 2 patient brochure, 1 VNR

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Category of Violations for 2013

Omission/Minimization of Risk – 11Unsubstantiated Superiority – 5Omission of Material Fact – 5Overstatement of Efficacy – 3Unsubstantiated Claim – 2Unsubstantiated Efficacy – 2Misleading Claim – 2Promotion of Investigational Agent – 1Inadequate Communication of Indication – 1Unsubstantiated MOA – 1Failure to Submit - 1

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Is There an Evident Trend?

•Unsubstantiated Claims?•Promotion of Investigational Agents?•Press releases/VNRs?

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Unsubstantiated Claims

2010 2011 2012 2013

25/48 14/31 13/28 8/13

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What is substantial evidence?

•Evidence consisting of adequate and well-controlled investigations

•21 CFR 314.126 describes the characteristics of adequate and well-controlled trials

•21 CFR 202.1(e)(6) and (e)(7) describes multiple ways materials are or may be false and misleading

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What are some red flags to OPDP?

•Open-label studies•Post-hoc subgroup analyses•Meta-analyses•Comparative studies

From: Substantial Evidence and Other Standards, by Elaine Hu Cunningham, Senior Regulatory Review Officer ,OPDP, at DIA Marketing Pharmaceuticals 2012.

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Examples of letters for 2013

•Retrospective• Doxil website NOV dated May 22, 2013

•Meta-analysis• Marplan website NOV dated May 6, 2013

•Retrospective (in support of a Comparative Claim)• Clozapine article detailer NOV dated April 8, 2013

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Retrospective study

“The references cited to support claims onthe website concerning CA-125 consist ofretrospective evaluations of primary dataperformed in a post-hoc manner,retrospective single institution chart reviews,a retrospective sub-group analysis, andexploratory studies that cite sponsor’s dataon file. Retrospective studies and institutionalchart reviews do not constitute substantialevidence or substantial clinical experienceto support the claims and presentations…”

Unsubstantiated claim

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Meta-analysis

“The reference cited to support these claims is a publication which describes a literature review and meta-analyses examining the efficacy of several MAOIs, including isocarboxazid (Marplan). The meta-analyses …may have produced a biased sample of studies since failed or negative clinical trials are often not published in the medical literature.”

Overstatement of Efficacy

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Retrospective study

“…claims of superiority must be supportedby two adequate and well-controlled head-to-head clinical trials…”

“The study…presents the results of aretrospective Positive and NegativeSyndrome Scale (PANSS)-derived five-factor analysis of data…”“…a single, retrospective, PANSS-derivedfive-factor analysis…does not constitute substantial evidence or substantial clinical experience…”

Unsubstantiated Superiority

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Promotion of Investigational Agents

2010 2011 2012 2013

0/48 3/31 2/28 1/13

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Promotion of Investigational Agents

21 CFR 312.7 “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…”

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Promotion of Investigational Agents

CBA Research Inc.

“The above referenced claims make numerous positive and definitive conclusions about CBT-1, such as its ability to reverse multi-drug resistance in cancer cells and to improve patient outcomes, while reducing the toxic side effects of chemotherapy and decreasing treatment failures.”

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Press Releases/VNRs

2010 2011 2012 2013

0/48 0/31 2/28 1/13

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Video News Release

ParaPRO LLCNatroba (spinosad) topical suspension, 0.9%•Omits ALL risk information including warnings and precautions, and the most frequently reported AEs•Unsubstantiated superiority claims – “game changing medication, one that doesn’t require nit combing to be effective”.•Fails to adequately communicate the full indication

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Key Takeaways

•Omission/minimization of risk still leads the list of violations•Unsubstantiated claims/efficacy/superiority a close second•Increased focus on investigational agents and Press Releases/VNRs (?)•Important to read the letters issued by OPDP

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Thank You

Questions?