Sales and Marketing Standards in US and EU: speaking the same language

1. Sales and Marketing Standards in US and EU: speaking the same language? Paul Woods Paul.Woods@AstraZeneca.com Developed in conjunction with: Preeti Pinto � Executive Director of Medical Education and Regulatory Compliance; AstraZeneca USA Sharon Leighton � Global Medical Information Skills Leader; AstraZeneca

2. Sales and Marketing Standards in US and EU: speaking the same language? Emphasis on Prescription medicines Aspects relevant to Medical Information Environment What controls on promotion are there? EU directive MHRA guidance European Code ABPI code US regulation FDA/DDMAC; OIG PhRMA code Some relevant questions What can I claim for my product? What can I say to patients?

3. What�s the similarity between promotional regulations and elephants?

4. The environment for pharmaceutical company communications is changing Not just advertising but information and all relationships with HCPS We have a choice � sort ourselves out or be more restricted.Not just advertising but information and all relationships with HCPS We have a choice � sort ourselves out or be more restricted.

6. US: negative news coverage

7. Regulations and Codes are getting tougher Revised regulations or codes in practically every country Changed EU directive Revised and expanded EFPIA code Beyond FDA/DDMAC in the USA IFPMA code under revision Increased enthusiasm to enforce the rules Large fines and penalties Publicity

8. Marketing Codes of Practice Our sales representatives promote our products. They do this by providing information to doctors so they understand our products and the benefits they can deliver to patients. Our marketing policies and codes of practice give guidance to sales and marketing employees about the high ethical standards we require. Our codes stress that all marketing and promotion must be based on valid scientific evidence, be consistent with national prescribing documentation, and comply with the law. Inducements such as gifts or bribes are never acceptable under any circumstances. All GSK employees must also abide by our Code of Conduct and Employee Guide to Business Conduct. The Employee Guide contains a specific section covering our customers and marketplace. See Code of Conduct and Employee Guide to Business Conduct. Marketing Policies and Codes of Practice Our company-wide policy on Pharmaceutical Marketing and Promotional Activity applies to all employees and agents. It commits us to promotional practices that are ethical, responsible, principled and patient-centred. It prohibits bribery or other inducements to doctors. In December 2003 we introduced regional marketing practices codes in Europe, International and Japan (marketing codes were already in place in the US). These codes apply the same ethical standards in all regions but reflect differences in market structures, national healthcare systems and laws and regulations. We also adhere to international and regional industry codes of practice. These include the IFPMA, PhRMA, EFPIA and JPMA marketing codes. Progress During 2004 During 2004 GSK�s regional codes were translated into major local languages and rolled out across GSK. Sales and marketing employees now have access to them on the intranet and many have received printed copies. Area champions in each country have coordinated distribution and training on the new codes. The European code of practice includes a quarterly reporting mechanism where the markets confirm whether any breaches of the code of practice have occurred, the severity of any breaches and what actions have been taken to prevent recurrence. We also developed and distributed a new �Guide to US Healthcare Law� for our US Pharma employees. While this information was previously provided through training, the new guide provides a concise and easy-to-read overview of the complex legal requirements applicable to health care businesses in the US. The guide supports our commitment to an ethical culture in which employees have a good understanding of GSK�s sales and marketing policies and the legal framework behind them. Compliance with policies and procedures is a formal performance objective of sales and marketing employees in the US. This is evaluated as part of employee performance reviews. All US Pharma employees must include the following objective in 2005: "Consistently follow company policies and procedures, take and complete required compliance training in a timely manner, and report compliance issues to manager, Legal or Compliance." In addition, managers must include the following: "Ensure that supervised employees are trained on company policies and procedures and have taken all required training, and provide oversight and direction to supervised employees so that they are in compliance with company policies and procedures." Objectives for 2005 We plan to analyse the differences amongst the GSK International, European and US codes of practice and local requirements in an effort to consolidate and harmonise these codes as appropriate. The US will continue to enhance its compliance programme with the addition of resources to act as sales and marketing compliance advisers. These advisers will work with the business units to ensure that compliance and ethics policies are fully integrated and embedded. Marketing Codes of Practice Our sales representatives promote our products. They do this by providing information to doctors so they understand our products and the benefits they can deliver to patients. Our marketing policies and codes of practice give guidance to sales and marketing employees about the high ethical standards we require. Our codes stress that all marketing and promotion must be based on valid scientific evidence, be consistent with national prescribing documentation, and comply with the law. Inducements such as gifts or bribes are never acceptable under any circumstances. All GSK employees must also abide by our Code of Conduct and Employee Guide to Business Conduct. The Employee Guide contains a specific section covering our customers and marketplace. See Code of Conduct and Employee Guide to Business Conduct. Marketing Policies and Codes of Practice Our company-wide policy on Pharmaceutical Marketing and Promotional Activity applies to all employees and agents. It commits us to promotional practices that are ethical, responsible, principled and patient-centred. It prohibits bribery or other inducements to doctors. In December 2003 we introduced regional marketing practices codes in Europe, International and Japan (marketing codes were already in place in the US). These codes apply the same ethical standards in all regions but reflect differences in market structures, national healthcare systems and laws and regulations. We also adhere to international and regional industry codes of practice. These include the IFPMA, PhRMA, EFPIA and JPMA marketing codes. Progress During 2004 During 2004 GSK�s regional codes were translated into major local languages and rolled out across GSK. Sales and marketing employees now have access to them on the intranet and many have received printed copies. Area champions in each country have coordinated distribution and training on the new codes. The European code of practice includes a quarterly reporting mechanism where the markets confirm whether any breaches of the code of practice have occurred, the severity of any breaches and what actions have been taken to prevent recurrence. We also developed and distributed a new �Guide to US Healthcare Law� for our US Pharma employees. While this information was previously provided through training, the new guide provides a concise and easy-to-read overview of the complex legal requirements applicable to health care businesses in the US. The guide supports our commitment to an ethical culture in which employees have a good understanding of GSK�s sales and marketing policies and the legal framework behind them. Compliance with policies and procedures is a formal performance objective of sales and marketing employees in the US. This is evaluated as part of employee performance reviews. All US Pharma employees must include the following objective in 2005: "Consistently follow company policies and procedures, take and complete required compliance training in a timely manner, and report compliance issues to manager, Legal or Compliance." In addition, managers must include the following: "Ensure that supervised employees are trained on company policies and procedures and have taken all required training, and provide oversight and direction to supervised employees so that they are in compliance with company policies and procedures." Objectives for 2005 We plan to analyse the differences amongst the GSK International, European and US codes of practice and local requirements in an effort to consolidate and harmonise these codes as appropriate. The US will continue to enhance its compliance programme with the addition of resources to act as sales and marketing compliance advisers. These advisers will work with the business units to ensure that compliance and ethics policies are fully integrated and embedded.

10. Common Principles EMEA Mission Statement... To contribute to the protection and promotion of public health � The MHRA's primary objective � is to safeguard public health by ensuring that all medicines on the UK market meet appropriate standards of safety, quality and efficacy EFPIA Code of Practice: The Federation is conscious of the importance of providing accurate, fair and objective information about medicinal products so that rational decisions can be made as to their use. DDMAC Mission: �To protect the public health by assuring prescription drug information is truthful, balanced, and accurately communicated.� PhRMA code: we are committed to following the highest ethical standards as well as all legal requirements. This Code is to reinforce our intention that our interactions with healthcare professionals are to benefit patients and to enhance the practice of medicine.

11. Sales and Marketing Standards in US and EU: speaking the same language? Emphasis on Prescription medicines Aspects relevant to Medical Information Environment What controls on promotion are there? EU directive MHRA guidance European Code ABPI code US regulation FDA/DDMAC; OIG PhRMA code Some relevant questions What can I claim for my product? What can I say to patients?

12. A World of Pharmaceutical Advertising Controls

13. A World of Pharmaceutical Advertising Controls FD&C Federal Food Drug & Cosmetic ActFD&C Federal Food Drug & Cosmetic Act

14. What is Promotion ? Can Include: Advertisements, Mailings etc. Detail Aids, Brochures etc. Internet sites Exhibition Panels, Videos etc Gifts, Samples etc Reprints etc. Hospitality Representative�s Activities Meetings/Symposia Public Relations Any other communication Generally excludes: Medical Information ie responses to specific enquiries Shareholder/business communications Prescribing Information incl. Patient Information Leaflets Price Lists etc There�s no globally accepted definition of promotion � or �advertising�.. In essence though promotion, and promotional codes, covers a wide range of information and marketing activities which encourage product sales. It obviously includes advertisements in journals, Detail or Visual aids, Exhibition stands or booths, gifts or promotional aids and practically everything a representative says or does. Promotion CAN include Internet sites, reprints of papers, meetings & symposia and so on � sometimes these are promotional , sometimes they aren�t � it all depends! So a reprint from the BMJ isn�t in itself promotion, but when a company buys several hundred reprints, and they are distributed on a promotional booth or handed out by a representative this can bring them within the promotional codes. Note that hospitality is covered by promotional codes, even if it is offered in connection with non-promotional events eg an investigators meeting or an advisory board. PR activities relating to products or diseases also fall within the definition of promotion Generally excluded are responses to individual product queries � medical information and business information. In fact we are obliged by financial regulations to provide shareholders and financial analysts with significant business news. Prescribing information texts and catalogues and price lists are also generally not considered to be advertising or promotion. So there�s a wavy indistinct line between promotion and non-promotional communications � an item can be very educational � but still fall into the �promotional� classification .. And an item can be promotional in some circumstances � but non-promotional in others.There�s no globally accepted definition of promotion � or �advertising�.. In essence though promotion, and promotional codes, covers a wide range of information and marketing activities which encourage product sales. It obviously includes advertisements in journals, Detail or Visual aids, Exhibition stands or booths, gifts or promotional aids and practically everything a representative says or does. Promotion CAN include Internet sites, reprints of papers, meetings & symposia and so on � sometimes these are promotional , sometimes they aren�t � it all depends! So a reprint from the BMJ isn�t in itself promotion, but when a company buys several hundred reprints, and they are distributed on a promotional booth or handed out by a representative this can bring them within the promotional codes. Note that hospitality is covered by promotional codes, even if it is offered in connection with non-promotional events eg an investigators meeting or an advisory board. PR activities relating to products or diseases also fall within the definition of promotion Generally excluded are responses to individual product queries � medical information and business information. In fact we are obliged by financial regulations to provide shareholders and financial analysts with significant business news. Prescribing information texts and catalogues and price lists are also generally not considered to be advertising or promotion. So there�s a wavy indistinct line between promotion and non-promotional communications � an item can be very educational � but still fall into the �promotional� classification .. And an item can be promotional in some circumstances � but non-promotional in others.

15. Council Directive 2001/83 Member states shall prohibit: Advertising of a medicinal product before a marketing authorization has been granted. Advertising to the general public of prescription only medicinal products Advertising Shall encourage rational use Objective, not exaggerated or misleading Provisions on monitoring of advertising Powers to order cessation and prevent publication Enable publication of decision Require publication of corrective statement Acknowledges role of self-regulation Must establish a �scientific information service� Keep samples of all ads.

16. Information: Accurate, up-to-date, verifiable, �sufficiently complete .. to form opinion of the therapeutic value ..� Quotations, tables etc faithfully reproduced and sources indicated. Representatives: Adequate training and knowledge Have SmPC Report back ADRs etc. No gifts, pecuniary advantages etc. Unless inexpensive & relevant to practice HP* should not solicit or accept Hospitality: reasonable Secondary to main purpose HPs only Also: Regulations on Samples Essential information in Ads Council Directive 2001/83

17. MHRA Guidance Notes MHRA Guidance Note 23, The Blue Guide Also: MHRA Guidance Note 24 �Medicines which are promoted for use during pregnancy: Guidance for the pharmaceutical industry" MHRA Guidance Note 26 Disease Awareness Campaigns (DACs) guidelines

19. �Name and Shame� Press release when blue guide introduced & subsequent egPress release when blue guide introduced & subsequent eg

20. Outlines minimum standards for all 29 national codes Major expansion of provisions All national codes to be revised by end of 2005 Consistent with, but goes beyond, legislation Certification of promotional material in final form by doctor or pharmacist To be in compliance with applicable codes, laws and regulations Senior employee in each company responsible for supervision of standards Complaints processed through national associations Proportionate sanctions - fines recommended Publication of case reports in entirety encouraged Annual report to EFPIA board EFPIA European Code of Practice for the Promotion of Medicines 2005

21. EFPIA European Code of Practice for the Promotion of Medicines 2005Some Selected Key Points Claims (3) Accurate, balanced, fair, objective, �sufficiently complete�, up-to-date, ALL relevant evidence, clear, not mislead, capable of substantiation, encourage rational use, not exaggerated etc. etc. High ethical standards at all times; (5) not bring discredit upon, or reduce confidence in, the pharmaceutical industry No disguised promotion (7) Including studies Clear indication of sponsorship Events: appropriate venue and hospitality (9) Code of host and organising country apply International events only when justified delegate origin and logistics No entertainment; travel, meals, accommodation, fees only Not exceed what recipients would normally pay for themselves Inducements (10) No gifts etc as an inducement to prescribe Inexpensive and relevant to practice

22. ABPI Code of Practice: 2003 edition 22 clauses 109 sub-clauses Supplementary information on most clauses Case reports Up to 100+ annually Typically ~5000 words Publicly available Certification by 2 named responsible persons Doctor + 1 other 2 stage complaints process Code of practice panel 3 PMCPA employees + advisors Appeal Board Independent legally qualified chairman 3 independent doctors 1 independent pharmacist 1 patient representative 1 medicines information provider 4 industry medical directors 8 industry senior executives

23. Familiarisation Seminars on the Code of Practice for the Pharmaceutical Industry Venue:� London.� For dates and further details contact PMCPA +44 (0)207 930 9677 write to PMCPA 12 Whitehall, London, SW1A 2DY ABPI Code of Practice 

24. U.S.A. � Who�s involved? A Few Organizations: FDA Food and Drug Administration CDER Center for Drug Evaluation & Research CBER Center for Biologics Evaluation & Research DDMAC Division for Drug Marketing, Advertising and Communication FTC Federal Trade Commission WLF Washington Legal Foundation OIG Office of the Inspector General Corporate integrity agreements etc And some rules: FD&C Federal Food, Drug & Cosmetics Act, regulations and guidelines Prescription Drugs Marketing Act False Claims Act Fraud & Abuse legislation FDA Modernization Act ACCME guidance Independent education accreditation Product Liability Lanham Act Actions: Civil relief for party damaged by false advertising State legislation PhRMA code Hospitality and gifts AMA code Privacy regulations

25. Promotion Labeling �All labels and other written, printed or graphic matter upon any (drug) or any of its containers or wrappers or accompanying such article� e.g. calendars, price lists, letters, brochures, booklets, AV material, exhibits, reprints, oral statements. commercial presentations, commercial exhibits Accompany with Full Prescribing Information Advertising Promotional activities which aren�t labeling e.g. journal, newspaper, radio, TV advertisements, electronic media. Accompany with �Brief Summary� of Prescribing information

26. FDA / DDMAC enforcementDivision of Drug Marketing, Advertising and Communications Around 40 pharmacists, lawyers etc Requirement for routine clearance (2253s) Includes DTCA Not every item is actually reviewed Priority to launch campaigns, broadcast ads, �problem� drugs/companies Can request pre-clearance Mandatory for sub-part H approvals Screening of journals, Internet etc Processes complaints Notices of Violations (NOV) / untitled letters many each year Warning Letters for more serious violations Corrective advertising or �Dear Doctor� letter Seizures and Injunctions could include prohibition on distribution of product Criminal Prosecution generally only if fraud involved

28. Three major potential risk areas for pharmaceutical manufacturers: Integrity of data used by state and federal governments to establish payment; Kickbacks and other illegal remuneration Compliance with laws regulating drug samples. OIG could be concerned if an arrangement or practice: has a potential to interfere with, or skew, clinical decision-making? has a potential to undermine the clinical integrity of a formulary process? Involves information to decision-makers, prescribers or patients which is incomplete, inaccurate or misleading? Suppresses less positive research findings and researchers Involves bias toward newer drug therapies in CME The simple way to think about their concerns is to �Follow the Money.� The Guidance to Industry published several years agoThe simple way to think about their concerns is to �Follow the Money.� The Guidance to Industry published several years ago

31. Different �. And the same There are differences between countries: In implementation & interpretation of regulations and codes Even between EU countries In the balance between legal action, regulation and self-regulation Injunctions are common in Germany Regulatory Authority highly active in France and USA Self-Regulatory Codes are primary method in Nordic countries and UK In enthusiasm for taking action But world-wide the same principles apply Content is key

32. Sales and Marketing Standards in US and EU: speaking the same language? Emphasis on Prescription medicines Aspects relevant to Medical Information Environment What controls on promotion are there? EU directive MHRA guidance European Code ABPI code US regulation FDA/DDMAC; OIG PhRMA code Some relevant questions What can I claim for my product? What can I say to patients?

33. What can I claim? Common Principle Accurate, balanced, fair, not misleading etc USA specifics �Fair balance� Reveal all material facts about the product Present �fair balance� between information on side effects/ contraindications and effectiveness Similar prominence & in same place

34. Hard-Copy Location: Zeneca/ICI Adverts - 63 Title: Accolate - New in Asthma Product: Accolate - zafirlukast Company: Zeneca Subject: advert Year: 1998 Country:U.K Author: - General Practitioner Point illustrated: A tablet alternative to inhaled steroid introduction. First in new class of oral therapy Key words: Accolate, zafirlukast, GP, Asthma, Zeneca, UK, Advert Presentation: ABPI complaint from GW An advance in confident control - ? A claim for improved efficacy which could not be substantiated Hard-Copy Location: Zeneca/ICI Adverts - 63 Title: Accolate - New in Asthma Product: Accolate - zafirlukast Company: Zeneca Subject: advert Year: 1998 Country:U.K Author: - General Practitioner Point illustrated: A tablet alternative to inhaled steroid introduction. First in new class of oral therapy Key words: Accolate, zafirlukast, GP, Asthma, Zeneca, UK, Advert Presentation: ABPI complaint from GW An advance in confident control - ? A claim for improved efficacy which could not be substantiated

35. Placebo like tolerability:Amias (candesartan) leave piece Complaint: - Claims relating to the 'placebo-like tolerability' of candesartan were not in line with section 4.8 of its Summary of Product Characteristics. Complaint upheld by MHRA. 'placebo-like' in the context of safety claims, was not consistent with the SmPC as it implied that there were no drug associated side effects.The SmPC for Amias lists a number of such side effects. The claim was also considered to be misleading by suggesting that this product was 'safer� than alternative medicines. The MHRA has published advice on this type of claim in the March/April 2004 edition of its medicines updating service, 'MAIL'.

36. �Follistim� detail aidDDMAC untitled letter 2003 �Your detail aid is misleading because it minimizes the serious risks associated with the use of �Follistim� that are described in Warnings section of the PI.� �All of the risk information appearing in the detail aid is relegated to the last of the six pages and is presented in a single-spaced, paragraph format without additional emphasis.� �In contrast, effectiveness claims such as �recFSH: substantial benefits over uFSH,� .. (etc) .. are presented as large, colorful, bolded headers and other claims of effectiveness and benefits are presented throughout the detail aid with colorful charts, bolded headers, bullet points, and a significant amount of white space.�

37. What can I claim? Common Principles Supportable by substantial, up-to-date data Comparative claims must be based on head to head trials at appropriate doses Statistical and clinical significance important USA Specifics All product claims require data from �adequate and well-controlled trials� for substantiation Detailed FDA guidance on �substantial clinical evidence� Generally, two trials needed to support superiority claims One trial MAY be acceptable if backed by supportive evidence � at discretion of FDA Netherlands also usually requires 2 studies Comparative trials must be maximum approved doses FDA guidance requires at least two well controlled trials; however effectiveness of a new indication can be based on a single study. The Guidance for Industry: Providing Clinical Evidence of Effectiveness for Human Drug and Biological Products (Final), May-1998 (16166) describes the elements of the data to support single trial approval of a new indication a single study will generally be limited to situations in which a trial has demonstrated a clinically meaningful effect on mortality, irreversible morbidity, or prevention of a disease with potentially serious outcome and confirmation of the result in a second trial would be practically or ethically impossible. repetition of strongly positive trials that demonstrated a decrease in mortality would present significant ethical concerns. FDA guidance requires at least two well controlled trials; however effectiveness of a new indication can be based on a single study. The Guidance for Industry: Providing Clinical Evidence of Effectiveness for Human Drug and Biological Products (Final), May-1998 (16166) describes the elements of the data to support single trial approval of a new indication a single study will generally be limited to situations in which a trial has demonstrated a clinically meaningful effect on mortality, irreversible morbidity, or prevention of a disease with potentially serious outcome and confirmation of the result in a second trial would be practically or ethically impossible. repetition of strongly positive trials that demonstrated a decrease in mortality would present significant ethical concerns.

39. DDMAC Warning letter 2004 re: Risperdal Dear HCP letter �Hyperglycemia-related adverse events have infrequently been reported in patients receiving RISPERDAL. Although confirmatory research is still needed, a body of evidence from published peer-reviewed epidemiology research 1,2,3,4,5,6,7,8 suggests that RISPERDAL is not associated with an increased risk of diabetes when compared to untreated patients or patients treated with conventional antipsychotics. Evidence also suggests that RISPERDAL is associated with a lower risk of diabetes than some other studied atypical antipsychotics.� �This statement suggests that �Risperdal� does not increase the risk of diabetes, contradicting the Warning in the revised PI and minimizing the risks �.� �The references cited in the letter do not represent the weight of the pertinent scientific evidence�.. In addition, this statement does not accurately describe the results of the cited studies.� �FDA is not aware of substantial evidence or substantial clinical experience to support Janssen�s claim ��

40. DDMAC untitled letter 2005�Aggrenox� advertisement �Based on indirect comparisons, [Aggrenox] may be more effective than clopidogrel 75 mg�� The paper referenced as support for this claim is, in effect, a historically controlled trial that is inadequate to support a superiority claim. The main part of the ad fails to include information on the major risks associated with Aggrenox, including Warnings concerning alcohol consumption, coagulation abnormalities, peptic ulcer disease, and pregnancy. Additionally, the ad fails to disclose the Precaution concerning the risks of intracranial hemorrhage. DEPARTMENT OF HEALTH & HUMAN SERVICES Public Health Service Food and Drug Administration Rockville, MD 20857 TRANSMITTED BY FACSIMILE Daniel T. Coleman, Ph.D. Associate Director, Drug Regulatory Affairs Boehringer Ingelheim Pharmaceuticals, Inc. 900 Ridgebury Road P.O. Box 368 Ridgefield, CT 06877-0368 RE: NDA # 20-884 Aggrenox� (aspirin/extended-release dipyridamole) Capsules MACMIS ID # 12917 Dear Dr. Coleman: The Division of Drug Marketing, Advertising, and Communications (DDMAC) has reviewed a journal ad (AG-8951R) for Aggrenox� (aspirin/extended-release dipyridamole) Capsules submitted by Boehringer Ingelheim Pharmaceuticals, Inc. (Boehringer Ingelheim) under cover of Form FDA 2253 on September 19, 2004. The journal ad is false or misleading because it contains unsubstantiated superiority claims and fails to include pertinent information about risks associated with Aggrenox, and, therefore, misbrands the drug in violation of section 502(n) of the Federal Food, Drug, and Cosmetic Act (Act), 21 U.S.C. � 352(n), and FDA�s implementing regulations, 21 CFR 202.1(e)(3)(i); (e)(5)(ii); (e)(6)(ii). Background According to the FDA-approved product labeling (PI), Aggrenox is an oral combination antiplatelet agent indicated �to reduce the risk of stroke in patients who have had transient ischemia of the brain or completed ischemic stroke due to thrombosis.� The PI for Aggrenox contains several Contraindications, Warnings, Precautions, and Adverse Reactions, including Warnings regarding the consumption of alcohol, coagulation abnormalities, gastrointestinal (GI) side effects (including ulceration and bleeding), peptic ulcer disease, and pregnancy, as well as a Precaution regarding the risk of gastrointestinal bleeding and intracranial hemorrhage. Unsubstantiated Superiority Claim The journal ad claims that �Based on indirect comparisons, [Aggrenox] may be more effective than clopidogrel, 75 mg�� This claim, in the context of the other claims in the ad, suggests that Aggrenox is more effective than Plavix (clopidogrel). As the journal ad states, this claim is based on �indirect comparisons� (a review of studies directly comparing ticlopidine, clopidogrel, and dipyridamole/aspirin with aspirin alone). Drug comparisons that represent or suggest that a Daniel T. Coleman, Ph.D. Page 2 Boehringer Ingelheim NDA 20-884/MACMIS 12917 drug is safer or more effective than another drug are misleading if the representation or suggestion has not been demonstrated by substantial evidence obtained from adequate and wellcontrolled head-to-head clinical trial(s). See 21 CFR 202.1(e)(6)(ii). The paper referenced in the ad as support for this claim is, in effect, a historically controlled trial that is inadequate to support a superiority claim. We are not aware of substantial evidence or substantial clinical experience demonstrating that Aggrenox is superior to Plavix. Omission of Risk Information The main part of the ad contains various safety and effectiveness claims for Aggrenox. The headline, �People With Prior Stroke Or TIA Have The Greatest Need For BIG Protection Against Stroke Recurrence� is followed by: �Aggrenox Prevents Twice As Many Strokes As Aspirin� and other efficacy claims regarding Aggrenox�s ability to prevent strokes. The main part of the ad also includes a reference to the brief summary of prescribing information for Aggrenox on the adjacent page, and the following statement of risk information: �The most common adverse event with Aggrenox was headache (39.2% vs 32.9% for placebo), which was more frequent at the onset of therapy, but diminished over time. GI bleeding with Aggrenox was comparable to aspirin (4.1% vs 3.2%).� The main part of the ad fails to include information on the major risks associated with Aggrenox, including information about the Warnings concerning alcohol consumption, coagulation abnormalities, peptic ulcer disease, and pregnancy. Additionally, the ad fails to disclose the Precaution from the PI concerning the risks of intracranial hemorrhage. Although some of these risks relate to aspirin, this does not diminish the need to reflect them in promotion of Aggrenox, which contains aspirin as well as dipyridamole. See 21 CFR 202.1(e)(3)(i) and (e)(5)(ii). Conclusion and Requested Action The journal ad contains unsubstantiated superiority claims and omits information on the risks associated with Aggrenox, and, therefore, misbrands the drug in violation of section 502(n) of the Federal Food, Drug, and Cosmetic Act (Act), 21 U.S.C. � 352(n), and FDA�s implementing regulations, 21 CFR 202.1(e)(3)(i); (e)(5)(ii); (e)(6)(ii). DDMAC requests that Boehringer Ingelheim immediately cease the dissemination of promotional materials for Aggrenox the same as or similar to those described above. Please submit a written response to this letter on or before April 05, 2005, describing your intent to comply with this request, listing all promotional materials for Aggrenox the same as or similar to those described above, and explaining your plan for discontinuing use of such materials. Please direct your response to me at the Food and Drug Administration, Division of Drug Marketing, Advertising, and Communications, HFD-42, Rm. 8B-45, 5600 Fishers Lane, Rockville, MD 20857, facsimile at (301) 594-6771. In all future correspondence regarding this matter, please refer to MACMIS # 12917 in addition to the NDA numbers. We remind you that only written communications are considered official. If you choose to revise your promotional materials, DDMAC is willing to assist you with your revised materials by commenting on your revisions before you use them in promotion. Daniel T. Coleman, Ph.D. Page 3 Boehringer Ingelheim NDA 20-884/MACMIS 12917 The violations discussed in this letter do not necessarily constitute an exhaustive list. It is your responsibility to ensure that your promotional materials for Aggrenox comply with each applicable requirement of the Act and FDA implementing regulations. Sincerely, {See appended electronic signature page} Lance McLeroy, Pharm.D., M.S. Regulatory Review Officer Division of Drug Marketing, Advertising, and Communications --------------------------------------------------------------------------------------------------------------------- This is a representation of an electronic record that was signed electronically and this page is the manifestation of the electronic signature. --------------------------------------------------------------------------------------------------------------------- /s/ --------------------- Lance McLeroy 3/22/05 02:52:27 PM DEPARTMENT OF HEALTH & HUMAN SERVICES Public Health Service Food and Drug Administration Rockville, MD 20857 TRANSMITTED BY FACSIMILE Daniel T. Coleman, Ph.D. Associate Director, Drug Regulatory Affairs Boehringer Ingelheim Pharmaceuticals, Inc. 900 Ridgebury Road P.O. Box 368 Ridgefield, CT 06877-0368 RE: NDA # 20-884 Aggrenox� (aspirin/extended-release dipyridamole) Capsules MACMIS ID # 12917 Dear Dr. Coleman: The Division of Drug Marketing, Advertising, and Communications (DDMAC) has reviewed a journal ad (AG-8951R) for Aggrenox� (aspirin/extended-release dipyridamole) Capsules submitted by Boehringer Ingelheim Pharmaceuticals, Inc. (Boehringer Ingelheim) under cover of Form FDA 2253 on September 19, 2004. The journal ad is false or misleading because it contains unsubstantiated superiority claims and fails to include pertinent information about risks associated with Aggrenox, and, therefore, misbrands the drug in violation of section 502(n) of the Federal Food, Drug, and Cosmetic Act (Act), 21 U.S.C. � 352(n), and FDA�s implementing regulations, 21 CFR 202.1(e)(3)(i); (e)(5)(ii); (e)(6)(ii). Background According to the FDA-approved product labeling (PI), Aggrenox is an oral combination antiplatelet agent indicated �to reduce the risk of stroke in patients who have had transient ischemia of the brain or completed ischemic stroke due to thrombosis.� The PI for Aggrenox contains several Contraindications, Warnings, Precautions, and Adverse Reactions, including Warnings regarding the consumption of alcohol, coagulation abnormalities, gastrointestinal (GI) side effects (including ulceration and bleeding), peptic ulcer disease, and pregnancy, as well as a Precaution regarding the risk of gastrointestinal bleeding and intracranial hemorrhage. Unsubstantiated Superiority Claim The journal ad claims that �Based on indirect comparisons, [Aggrenox] may be more effective than clopidogrel, 75 mg�� This claim, in the context of the other claims in the ad, suggests that Aggrenox is more effective than Plavix (clopidogrel). As the journal ad states, this claim is based on �indirect comparisons� (a review of studies directly comparing ticlopidine, clopidogrel, and dipyridamole/aspirin with aspirin alone). Drug comparisons that represent or suggest that a Daniel T. Coleman, Ph.D. Page 2 Boehringer Ingelheim NDA 20-884/MACMIS 12917 drug is safer or more effective than another drug are misleading if the representation or suggestion has not been demonstrated by substantial evidence obtained from adequate and wellcontrolled head-to-head clinical trial(s). See 21 CFR 202.1(e)(6)(ii). The paper referenced in the ad as support for this claim is, in effect, a historically controlled trial that is inadequate to support a superiority claim. We are not aware of substantial evidence or substantial clinical experience demonstrating that Aggrenox is superior to Plavix. Omission of Risk Information The main part of the ad contains various safety and effectiveness claims for Aggrenox. The headline, �People With Prior Stroke Or TIA Have The Greatest Need For BIG Protection Against Stroke Recurrence� is followed by: �Aggrenox Prevents Twice As Many Strokes As Aspirin� and other efficacy claims regarding Aggrenox�s ability to prevent strokes. The main part of the ad also includes a reference to the brief summary of prescribing information for Aggrenox on the adjacent page, and the following statement of risk information: �The most common adverse event with Aggrenox was headache (39.2% vs 32.9% for placebo), which was more frequent at the onset of therapy, but diminished over time. GI bleeding with Aggrenox was comparable to aspirin (4.1% vs 3.2%).� The main part of the ad fails to include information on the major risks associated with Aggrenox, including information about the Warnings concerning alcohol consumption, coagulation abnormalities, peptic ulcer disease, and pregnancy. Additionally, the ad fails to disclose the Precaution from the PI concerning the risks of intracranial hemorrhage. Although some of these risks relate to aspirin, this does not diminish the need to reflect them in promotion of Aggrenox, which contains aspirin as well as dipyridamole. See 21 CFR 202.1(e)(3)(i) and (e)(5)(ii). Conclusion and Requested Action The journal ad contains unsubstantiated superiority claims and omits information on the risks associated with Aggrenox, and, therefore, misbrands the drug in violation of section 502(n) of the Federal Food, Drug, and Cosmetic Act (Act), 21 U.S.C. � 352(n), and FDA�s implementing regulations, 21 CFR 202.1(e)(3)(i); (e)(5)(ii); (e)(6)(ii). DDMAC requests that Boehringer Ingelheim immediately cease the dissemination of promotional materials for Aggrenox the same as or similar to those described above. Please submit a written response to this letter on or before April 05, 2005, describing your intent to comply with this request, listing all promotional materials for Aggrenox the same as or similar to those described above, and explaining your plan for discontinuing use of such materials. Please direct your response to me at the Food and Drug Administration, Division of Drug Marketing, Advertising, and Communications, HFD-42, Rm. 8B-45, 5600 Fishers Lane, Rockville, MD 20857, facsimile at (301) 594-6771. In all future correspondence regarding this matter, please refer to MACMIS # 12917 in addition to the NDA numbers. We remind you that only written communications are considered official. If you choose to revise your promotional materials, DDMAC is willing to assist you with your revised materials by commenting on your revisions before you use them in promotion. Daniel T. Coleman, Ph.D. Page 3 Boehringer Ingelheim NDA 20-884/MACMIS 12917 The violations discussed in this letter do not necessarily constitute an exhaustive list. It is your responsibility to ensure that your promotional materials for Aggrenox comply with each applicable requirement of the Act and FDA implementing regulations. Sincerely, {See appended electronic signature page} Lance McLeroy, Pharm.D., M.S. Regulatory Review Officer Division of Drug Marketing, Advertising, and Communications --------------------------------------------------------------------------------------------------------------------- This is a representation of an electronic record that was signed electronically and this page is the manifestation of the electronic signature. --------------------------------------------------------------------------------------------------------------------- /s/ --------------------- Lance McLeroy 3/22/05 02:52:27 PM

41. What can I claim? Common Principles Not inconsistent with the prescribing information Only promote approved products / indications Pack insert is basis for what can be claimed USA specifics Prescribing information (label) more closely linked to promotional claims Claims for safety or effectiveness outside approved prescription information need FDA prior approval (supplemental NDA) including new indications, uses in specific patient populations, conditions, routes of administration, or doses that are not reflected in FDA-approved labeling Claims considered �consistent� with approved PI can be made if supported by substantial evidence Full scientific exchange not restricted Restricted to presentations of results only � no conclusions

42. Promotion off label Although factually correct and in line with additional info in PIPromotion off label Although factually correct and in line with additional info in PI

44. DDMAC Warning Letter 2003: Pravachol Promotion of Unapproved Uses Not indicated to reduce risk of strokes in patients who do not have clinically evident CHD �These promotional materials are false or misleading in that they claim that Pravachol has been approved by the Food and Drug Administration (FDA) for conditions and patients for which it has not been approved.� .. �Your DTC and professional-directed promotional materials broaden the conditions and patient populations for which Pravachol is indicated.� �..

45. What can I say to patients? EU (and everywhere except US & NZ):No promotion of POMs to the public Non-promotional communications are permitted Uncertainty and different national interpretations on what constitutes advertising / promotion Press material Educational activities Disease awareness campaigns Compliance support Non-promotional answers to specific questions about specific products are not advertising USA: Promotion of prescription medicines to the public is allowed Subject to exactly the same regulations as promotion to HCPs Responses to unsolicited questions � not regulated if balanced and focused

46. Information for patients Title VIIIa: Information and Advertising Within three years: The Commission should deliver a report on the current practice with regard to information provision particularly on the Internet - and its risks and benefits for patients. following consultations with patients' and consumers' organisations, doctors' and pharmacists' organisations, Member States and other interested parties, Then .. if appropriate, put forward proposals for an information strategy to ensure good quality, objective, reliable and non-promotional information on medicinal products and other treatments address the question of the information source's liability.  Note � covers informationNote � covers information

47. Which means that �.. No advertising Quality of information is key Companies have until 2007 to convince politicians that they should be trusted sources of information for patients

48. Industry position Not seeking DTCA of POMs in Europenot appropriate now Are seeking agreement that pharmaceutical companies can make informed and objective information about the medicines that they research and manufacture available to the public

50. Leaflets available in storeLeaflets available in store

51. Occasionally our decisions are easy! Does the ad contain the approved name? Is the claim for 85% response rate accurate? I use to be indecisive but now I�m not sureOccasionally our decisions are easy! Does the ad contain the approved name? Is the claim for 85% response rate accurate? I use to be indecisive but now I�m not sure

52. And the answer is �