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

MODULE/LECTURE 1

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

OUTLINE of TODAY’S CLASS

Gabapentin (Neurontin) $430 Million Settlement

● States Attorney Generals and Dept of Justice alleged Parke Davis (Warner-LambertPfizer) 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

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

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

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

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

”

FLIP Project Team

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)?

Womens Health Initiative (WHI) Estrogen Rx

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?

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

Modified from www.hcn.org

Restoring Healthy Balance

Restoring Healthy BalanceRe-balancing

Overselling/Misrepresenting Benefits

Minimizing/Hiding Risks

Drug pricing

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

● 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

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

Restoring Healthy Balance Approaches

Leveraging Formularies for Improved Prescribing

1. Venue for critical review new drug claims 2. Evaluation of comparative efficacy.3. Less bias and conflict in decision-making4. Cumulative expertise reviewing new drugs5. Experience with pitfalls and biases6. Identify/weigh potentials for overuse/misuse7. Weigh of cost benefit  (for individual

drug/indication).8. Weigh institutional resource allocation (this

drug vs. alternatives).9. Raise/highlight safety concerns10. Dissemination vehicles and tools (guidance

and warnings).

More rational prescribing

Enhanced:1. Appropriateness 2. Safety3. Cost Effectiveness

Value-added role of formulary related to drug marketing

Case Study

Gabapentin Neurontin®

Cold Call

● Mr. Duhig calls on Dr. Schiff

(unrehearsed)

1866

Parke-Davis Founded

1970

Warner-Lambert buys Parke-Davis

1977

Patent for Gabapentin awarded to Warner-Lambert

1993

FDA approves Gabapentin for adjunctive treatment of partial complex seizures in adults

U.S. Gabapentin sales at $97.5m

May1996

Dr. David Franklin hired as Medical Science Liaison

Sept1996

Dr. Franklin files lawsuit against Warner-Lambert

Pfizer buys Warner-Lambert/Parke-Davis and all patents (including pregabalin)

July 2000

Oct2000

Aug1996

Dr. Franklin quits Warner-Lambert

Neurontin approved for adjunctive treatment of partial seizures in children

Nov2000

78% of Neurontin use is off-label (Pfizer documents)

U.S. Neurontin sales at $2.5b

Neurontin approved for Post Herpetic Neuralgia in adults

Pfizer pleads guilty to charges of false marketing and settles for for $430m

May 2002

May2004

Patent on Neurontin expiresGabapentin marketed as generic

March2005

June2005

Pregabalin campaign launched

Neurontin in top 10 U.S. drugsSales at $2.6b Neurontin sales

fall by 77%

Lyrica captures 7% of anti-epileptic market

Unapproved Indications for which Neurontin Illegally Promoted

• 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

Steinman, M. A. et. al. Ann Intern Med 2006;145:284-293

Prescriptions for Gabapentin by Diagnostic Category

0

10

20

30

40

50

60

70

80

Unapproved Uses

Approved Uses

44/115 (38%) Neurontin Detail Visits “Main Message” was Unapproved Uses

Steinman et al SGIM 5/2006

0

10

20

30

40

50

60

70

80

Unapproved Uses

Approved Uses

44/115 (38%) Neurontin Detail Visits “Main Message” was Unapproved Uses

Steinman et al SGIM 5/2006

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

Steinman et al. Ann Intern Med 2006;

Framework for gabapentin marketing

Steinman, M. A. et. al. Ann Intern Med 2006;145:284-293

1998 Promotion Budget for Gabapentin by Strategy and Tactical Category

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

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

There is widespread agreement that commercial interestsshould not influence the clinical decisions that physiciansmake on behalf of their patients. As a result, a complexsystem 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 thepractice of medicine in both visible and hidden ways.

Conclusion-Neurontin Promotion

Steinman, M. A. et. al. Ann Intern Med 2006;145:284-293

Course Game Plan – Topics

1. Introduction- Neurontin 2. Formularies 3. Historical examples

serious drug problems 4-5. Trial design

Statistical biases 6. Surrogate vs. outcome

end-points7. Comparative efficacy

8. Promotion, advertising 9. Indications creep

off label use10. FDA; regulatory issues11. Limited populations

exposed pre-marketing12. Cost effectiveness 13 Information sources 14. Principles of

conservative prescribing

Project

● Pick a drug● Literature Search on Chosen Drug

Look at Study DesignBegin to use FLIP Formulary Tools (2)

● Engage Surrogate and Comparatives Efficacy Issues

Project (con’t)

● Examine Promotional and Appropriate and Real life Use issue

● Policy issues raised by this drugPrepare formal presentation

● Presentations

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