Course Introduction & Background on Attorney Generals’ F.L.I.P. Grant and Neurontin Case

1. MODULE/LECTURE 1 Course Introduction & Background on Attorney Generals’ F.L.I.P. Grant and Neurontin Case Gordon Schiff MDDirector Clinical Quality Research & Improvement Dept of Medicine Cook County Professor of Medicine Rush University

2. OUTLINE of TODAY’S CLASS 1. Introduction: Description FLIP Project & Course • Why this course and our project is unique • Larger/current contexts: estrogen, vioxx 2. Neurontin Case Study • Patterns of use --Detailing example • Historical timeline ---Details of problems 3. Class Activity: • Annals Internal Med Article; Trigger questions 4. Orientation to Course; Syllabus • Topics, Projects, FLIP Tools, Grading Rules

4. Gabapentin (Neurontin) $430 Million Settlement • States Attorney Generals and Dept of Justice alleged Parke Davis (Warner-LambertPfizer) deceptively promoted Neurontin: • Conducted CME lacking balance, expensive “perks” to attending physicians. • “Publication strategies:” produced & distributed non-scientific, anecdotal reports for off-label uses. • ”Research payments” to prescribers, in effect, kickbacks for off-label prescribing. • Provided incomplete info to Drugdex reference, formulary committees

5. Neurontin- GabapentinManufactured Unproven Illegal Claims • Claims for un-approved uses • Bipolar disorder, migraine headaches, chronic pain • Metamorphosis of 2nd line epilepsy drug into blockbuster • Elaborately orchestrated by senior Parke Davis officials. • Total sales 2003- $2.7 billion • ~ 90% usage for indications lacking valid evidence • Neurontin costs to consumers >$200/month

6. http://www.ohsu.edu/cpgp/

7. Goal: • To improve prescribing practices by: • 1) educating health professionals at all levels of training about the drug development and approval process; • 2) making health professionals aware of pharmaceutical industry marketing practices and assisting them in developing the knowledge and skills to evaluate those marketing techniques; and 3) providing examples and strategies for evaluating existing sources of drug information, and for accessing unbiased sources of information about drugs. Atty Genl Consumer and Prescriber Grant Program RFP 8/05

8. Researchers at John H. Stroger Jr. Hospital of Cook County and the University of Illinois at Chicago have been awarded a two-year $400,000 grant to educate health professionals about the safety of prescribing prescription medications, according to a release from UIC. Gordon Schiff of the Department of Medicine at Stroger Hospital and associate professor of medicine at Rush Medical School, and Bruce Lambert, associate professor in the UIC College of Pharmacy, will collaborate on the project, designed to assist hospital formulary committees (a group that approves medications) evaluate the risks and benefits of new medications, and educate physicians and pharmacists about how to choose them, the release said ”

9. FLIP Project Team

11. Restoring Healthy Balance • How could #1 drug prescribed for women (HRT) turn out to not work for claimed benefits (incl lower heart risk) and cause more harm than good (breast, endometrial cancer, heart dis)?

12. Womens Health Initiative (WHI) Estrogen Rx

13. Restoring Healthy Balance • How could #1 drug prescribed for women (HRT) turn out to not work for claimed benefits (incl lower heart risk) and cause more harm than good (breast, endometrial cancer, heart dis)? • How could #1 drug prescribed for HBP (amlodipine (Norvasc)) turn out to be more harmful and less beneficial than inexpensive diuretic? • How could most commonly prescribed arthritis med (rofecoxib (Vioxx)) be so heavily promoted and prescribed (100 million scripts worldwide) despite evidence of 2 to 4 x risk of heart attacks?

14. U.S. Deaths from Vioxx More than Vietnam War • 1/1999--9/2004: 106.7 million rofecoxib prescriptions in US • 17·6% were high-dose, mostly to older patients • In 2 Merck-sponsored randomised trials: 2,25 relative risks for AMI • 5x for high-dose rofecoxib and 2x for the standard dose • Background rate AMI control NSAID users varied from 7·9 per 1000 person-years in CLASS1 to 12·4 per 1000 person-years in TennCare. • Using Merck studies relative risks w/ these background rates 88,000– 140,000 excess cases serious coronary disease in US • Using US national case-fatality rate-44%,suggests thousands of deaths attributable to rofecoxib use (~38,000-61,000) Graham Lancet 2005

15. Restoring Healthy Balance Modified from www.hcn.org

16. Restoring Healthy BalanceRe-balancing Overselling/Misrepresenting Benefits Minimizing/Hiding Risks Drug pricing

17. One-Sided Source of Education • In 2004, > $2 billion was spent on CME Pharmaceutical manufacturers paid for more than half • Firms that manufacture FDA-regulated products (primarily pharmaceuticals) provided 74.7% of the income of medical education and communication companies (MECCs). • CME provided by medical schools is almost equally reliant on the pharmaceutical industry, which 63.8% of CME income to medical schools • http://www.ama-assn.org/ama/pub/category/16260.html

18. Restoring Healthy Balance Approaches • Professional and Consumer Education • Reform of Medical and Pharmacy Education • Improved Evidence • Better Quality Critical Review Healthy Skepticism • Industry reforms/codes • Regulatory Oversight • Legislation • Litigation • Consumer and Professional Advocacy • New Forms Pharmacy-Medicine-Consumer Collaboration

19. Restoring Healthy Balance Approaches • Professional and Consumer Education • Reform of Medical and Pharmacy Education • Improved Evidence • Better Quality Critical Review Healthy Skepticism • Industry reforms/codes • Regulatory Oversight • Legislation • Litigation • Consumer and Professional Advocacy • New Forms Pharmacy-Medicine-Consumer Collaboration

20. Leveraging Formularies for Improved Prescribing Value-added role of formulary related to drug marketing • Venue for critical review new drug claims • Evaluation of comparative efficacy. • Less bias and conflict in decision-making • Cumulative expertise reviewing new drugs • Experience with pitfalls and biases • Identify/weigh potentials for overuse/misuse • Weigh of cost benefit  (for individual drug/indication). • Weigh institutional resource allocation (this drug vs. alternatives). • Raise/highlight safety concerns • Dissemination vehicles and tools (guidance and warnings). • More rational prescribingEnhanced: • Appropriateness • Safety • Cost Effectiveness

21. Case Study Gabapentin Neurontin®

22. Cold Call • Mr. Duhig calls on Dr. Schiff (unrehearsed)

23. Warner-Lambert buys Parke-Davis Patent for Gabapentin awarded to Warner-Lambert FDA approves Gabapentin for adjunctive treatment of partial complex seizures in adults Dr. David Franklin hired as Medical Science Liaison 1866 May 1996 1970 1977 1993 Parke-Davis Founded U.S. Gabapentin sales at $97.5m

24. Dr. Franklin files lawsuit against Warner-Lambert Dr. Franklin quits Warner-Lambert Pfizer buys Warner-Lambert/Parke-Davis and all patents (including pregabalin) Neurontin approved for adjunctive treatment of partial seizures in children Nov 2000 Aug 1996 July 2000 Oct 2000 Sept 1996 78% of Neurontin use is off-label (Pfizer documents)

25. Neurontin approved for Post Herpetic Neuralgia in adults Pfizer pleads guilty to charges of false marketing and settles for for $430m Patent on Neurontin expires Gabapentin marketed as generic Pregabalin campaign launched May 2002 May 2004 March 2005 June 2005 U.S. Neurontin sales at $2.5b Neurontin in top 10 U.S. drugs Sales at $2.6b Neurontin sales fall by 77% Lyrica captures 7% of anti-epileptic market

26. Bipolar disorder. Peripheral neuropathy, diabetic neuropathy and other pain syndromes. Epilepsy monotherapy. Reflex sympathetic dystrophy. Attention deficit disorder. Restless leg syndrome . Essential tremor and periodic limb movement disorder (ETPMLD) Migraines Drug and alcohol withdrawal Unapproved Indications for which Neurontin Illegally Promoted

27. Prescriptions for Gabapentin by Diagnostic Category Steinman, M. A. et. al. Ann Intern Med 2006;145:284-293

28. 44/115 (38%) Neurontin Detail Visits “Main Message” was Unapproved Uses Unapproved Uses Approved Uses Steinman et al SGIM 5/2006

31. 44/115 (38%) Neurontin Detail Visits “Main Message” was Unapproved Uses Unapproved Uses Approved Uses Steinman et al SGIM 5/2006

32. After receiving the detail visit, 46% (50/108) of physicians reported the intention to increase their prescribing or recommendation of gabapentin in the future Characteristics and impact of drug detailing for gabapentin. Steinman et al SGIM Abstract 5/2006

35. Framework for gabapentin marketing Steinman et al. Ann Intern Med 2006;

36. 1998 Promotion Budget for Gabapentin by Strategy and Tactical Category Steinman, M. A. et. al. Ann Intern Med 2006;145:284-293

37. Senior Marketing Executive John Ford 5/6/1996 Teleconference call

38. Debate on Neurontin Marketing Practices Trigger Questions/Statements • If the drug works, what’s wrong with it? • So, what, it didn’t hurt anybody • This is exceptional case, isolated problem that has now been fixed • Drug companies need to do this to make money, so they can develop needed new drugs • Everybody does it • They did show that pregabalin (Lyrica) works • This is only relevant to doctors (who do the prescribing), not to pharmacists • I want to work for industry, this ties my hands

39. Conclusion-Neurontin Promotion There is widespread agreement that commercial interests should not influence the clinical decisions that physicians make on behalf of their patients. As a result, a complex system has evolved to help manage these conflicts, focused primarily on disclosure and self-regulation by physicians, professional organizations, and the pharmaceutical industry. These efforts have been largely ineffective and the techniques used to promote gabapentin illustrate how commercial interests can intrude into the practice of medicine in both visible and hidden ways. Steinman, M. A. et. al. Ann Intern Med 2006;145:284-293

40. 1. Introduction- Neurontin 2. Formularies 3. Historical examples serious drug problems 4-5. Trial design Statistical biases 6. Surrogate vs. outcome end-points 7. Comparative efficacy 8. Promotion, advertising 9. Indications creep off label use 10. FDA; regulatory issues 11. Limited populations exposed pre-marketing 12. Cost effectiveness 13 Information sources 14. Principles of conservative prescribing Course Game Plan – Topics

41. Project • Pick a drug • Literature Search on Chosen DrugLook at Study DesignBegin to use FLIP Formulary Tools (2) • Engage Surrogate and Comparatives Efficacy Issues

42. Project (con’t) • Examine Promotional and Appropriate and Real life Use issue • Policy issues raised by this drugPrepare formal presentation • Presentations

43. FLIP Toolsfor next class • Formulary Culture Survey • Complete on Blackboard before class • Do before doing the reading • FLIP Formulary Checklist Tool • Levels of Understanding Tool