Published on May 1, 2014
Avoiding Off-label Promotion Presented by Dale Cooke April 30, 2014
2 Agenda On label vs. off label Risk of off-label promotion Reprint distribution Unsolicited requests
On-label vs. Off-label
4 “Safe & Effective” Safe > 1938 Food, Drug, and Cosmetic Act > No regulatory definition, but gain must outweigh risks Effective > 1962 Kefauver-Harris Drug Amendments > Effective for what? > Establishes the notion of an indication > Two double-blind, placebo- controlled studies What is on label?
5 What is off label? Anything that is not in the approved label
6 A typology of off-label promotion Expansion to different disease entity > Similar symptoms of a different disease > Similar etiology of different disease Broadening of indication > Different patient populations > Different stage/severity of a condition Expansion of dosing schedule Different route of administration
7 A distinction Off-Label Use The use or direction to use an FDA-approved product in a manner that is not indicated in the FDA-approved label Off-Label Promotion The activity of encouraging the use or direction to use an FDA- approved product in a manner that is not indicated in the FDA approved label
8 The importance “healthcare professionals may lawfully use or prescribe [a] product for uses or treatment regimens that are not included in the product's approved labeling” FDA Guidance for Industry, Good Reprint Practices for the Distribution of Medical Journal Articles and Medical or Scientific Reference Publications on Unapproved New Uses of Approved Drugs and Approved or Cleared Medical Devices
9 Implications Off-label use is permissible In fact… off-label use accounts for 21% of all prescriptions.* * Stafford, Randall. “Regulating Off-Label Drug Use— Rethinking the Role of the FDA” NEJM 358; 14. April 3, 2008.
10 A Further Distinction Off-label promotion The activity of encouraging the use or direction to use an FDA- approved product in a manner that is not indicated in the FDA approved label Dissemination of off-label information Providing information about uses of an FDA-approved product that are not indicated in the FDA approved label
Risks of off-label promotion
12 Bad ad program
13 What’s at stake? $4.3 billion in False Claims Act recoveries in 2013 $19.2 billion in the past five years
14 Corporate Integrity Agreements Requirements of a CIA include: • Hiring additional employees and outside consultants to ensure compliance with a rigorous set of requirements • Establishing new procedures and extensive documentation that all of those procedures are followed precisely • Signed certifications from the President of the company down to senior brand leaders verifying that all procedures have been followed precisely
16 New guidance http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ UCM387652.pdf
17 Significant changes from previous guidance Recognition of the different nature of text books from journal articles Clinical Practice Guidelines (CPG) inclusion
18 Do’s & don’ts Materials should be: – Published by independent organization of experts with full disclosure policy for conflicts – Peer-reviewed – Independently available (via subscription or purchase) – Addressing adequate, well-controlled investigations – Current Materials should NOT be: – Specially funded by manufacturer of the product – Written, edited, or excerpted specifically for manufacturer – Edited or influenced by anyone with financial ties to manufacturer
19 Additional constraints Materials should NOT: – Be false and misleading – Pose a significant risk to public health Unacceptable materials include: – Letters to the editor – Abstracts of publications – Reports of healthy volunteer trials – Publications with conclusions but little or no data for them
20 How to disseminate Materials disseminated should be: – Unabridged – Clean from any marks or highlighting – Accompanied by approved product label – Accompanied by comprehensive bibliography – Disseminated with contrary results, where applicable – Distributed separately from any promotional content
21 How to disseminate (cont’d) Permanently affixed information: – Uses described are not FDA approved or cleared – Manufacturer’s connection to the product – Any author with a financial connection to manufacturer – Any funders of the studies – All risks and safety concerns related to the unapproved use
22 CPG considerations Disseminated CPGs should be trustworthy: – Be based on a systematic review of existing evidence – Knowledgeable, multidisciplinary panel of experts – Consider patient subgroups and preferences – Based on an explicit, transparent process minimizing distortion, biases, and conflicts of interest – Provide standardized recommendations, identifying strength of the recommendation & quality of evidence – Be reconsidered/revised as warranted by new evidence
24 2011 guidance http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ UCM387652.pdf
25 Solicited vs. unsolicited Requests “prompted in any way” by manufacturer are solicited and forbidden Examples of solicited requests: – Presenting off-label use data at promotional events – Distributing information about ongoing research and soliciting inquiries – Encouraging users to post videos about their experiences using YouTube – Announcing results of studies via Twitter suggesting safe and effective use – Sending information about off-label uses to people and encouraging them to write about the uses in public forums – Using URLs, phone numbers, etc., to imply off-label use – Making off-label information accessible online via pull-down menus that imply off-label use or searches that return results beyond the limited question being asked
26 Response process Seven-step process 1. Provide information “only to the individual making the request directly to the firm as a private, one-on-one communication.” 2. Information provided “should be tailored to answer only the specific question(s) asked.” 3. Information “should be truthful, non-misleading, accurate, and balanced.” 4. Information “should be scientific in nature.” 5. Information “should be generated by medical or scientific personnel independent from sales or marketing departments.”
27 Response process 6.Provide in addition to the specific off-label information requested: – Current Labeling – “A prominent statement notifying the recipient that FDA has not approved or cleared the product as safe and effective for the use addressed in the materials provided” – A “prominent statement” of the approved indication(s) – “A prominent statement providing all important safety information including, if applicable, any boxed warning for the product” – Complete references for the off-label information 7.Maintain records of the request including: – “The nature of the request for information, including the name, address, and affiliation of the requestor” – What information was provided – Any follow-up by the requestor
28 Common principles Division of Labor: – Science & Medicine responds to off-label requests – Sales & Marketing promote products Including the PI Statement of the approved use(s) Statement of the new use as unapproved Information should be truthful, non-misleading Always supply a balanced response including appropriate risk information Disclosure of all ties to manufacturer
Questions? Dale Cooke VP/GD, Regulatory Dale.Cooke@DigitasHealth.com @PhillyCooke on Twitter www.scribd.com/Dale_Cooke RegulatoryRx.blogspot.com
30 Dale Cooke VP/Group Director, Regulatory Dale Cooke is the head of the regulatory department for Digitas Health LifeBrands. He has worked with more than 30 pharmaceutical and medical device clients around the world from offices in Philadelphia, New York, Boston, San Francisco, and London. Dale advises clients on FDA enforcement actions and provides recommendations for compliance with FDA regulations, with a focus on issues involving the Internet and emerging technology. His insights have been featured in the Wall Street Journal’s Health blog, The Pink Sheet, MedAdNews, PharmExec, and others. Dale is an active member of the Regulatory Affairs Professionals Society (RAPS), Drug Information Association (DIA), Food and Drug Law Institute (FDLI), and the Alliance for a Stronger FDA. He also serves on the faculty of the University of California San Francisco’s American Course in Drug Development Regulatory Sciences program. Dale is the author of Effective Review and Approval of Digital Promotional Tactics, which is part of the FDLI’s primer series. He is regularly invited to speak at industry conferences on topics including FDA enforcement trends, best practices for review processes, global review practices, and life sciences use of social media. Dale earned his B.A. in Philosophy from Southern Methodist University and an M.A. in Analytical Philosophy from the University of Arizona and studied Epidemiology and Biostatistics at Drexel University’s School of Public Health and Healthcare Compliance at Seton Hall University’s School of Law.
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