marketing tactics of the pharmaceutical industry gundy sweet, pharmd, fashp director, drug...

Marketing Tactics of the Pharmaceutical Industry

Gundy Sweet, PharmD, FASHPDirector, Drug Information Service

Clinical Associate ProfessorUniversity of Michigan

May 2009

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Disclosure

Gundy Sweet discloses no relevant financial relationships with commercial interests

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Objectives At the conclusion of this program, you

will be able to: Name 5 marketing tactics used by the

pharmaceutical industry Define 2 ways in which industry can

influence the published data State 2 reasons why the industry moved

towards physicians as speakers

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Overarching Questions Why may doctors prescribe drugs that

are marginally effective?

Why are patients given drugs that have risky side effects when safer agents may be available?

Why are prescriptions written for costly agents when less costly agents are available?

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Marginally Effective Drugs Lyrica for fibromyalgia

Placebo-controlled trials (2) 1-week Pb wash-in; 13*- or 14^-week DB treatment Outcomes

Change in pain score from baseline >30% improvement from baseline

Results Both studies showed a significant decrease in

pain score with L vs Pb Only the second trial showed a significant

difference in percent of patients who achieved >30% improvement

42-50% of those receiving L compared to 30% of those receiving Pb

16-33% of L discontinued due to adverse event

*Mease P et al. J Pain. 2008;9:792-805.^Arnold L et al. J Rheumatol. 2008;35:502-14.

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Marginally Effective Drugs Lyrica for fibromyalgia

Durability trial 6 weeks of Lyrica to all to identify

optimum dose Responders (54%) randomized to

placebo (Pb) or Lyrica (L) for 26 weeks Primary outcome: loss tx response

(<30% decrease pain score) 60% receiving Pb and 30% receiving L 17% receiving L dropped out due to

adverse events

Crofford L et al. Pain. 2008;136:419-31.

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Drugs with Safety Concerns Darvon (Lilly): came to market in 1957

Data Propoxyphene no better than aspirin or

acetaminophen for pain control Known problems with addiction/risk of death from

overdose Lilly continued to market the drug which

brought them $100 million/yr 1979 Natl Insti Drug Abuse – 1100

deaths/yr FDA then mandated educational campaign,

but it was too late for MDs and patients

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Drugs with Cost Concerns Numerous drug classes have seen “new

and improved” versions of older drugs Non-sedating antihistamines PPIs

The newer agents typically come at an increased cost, some of which are sizeable

What do we get for our money? Increased efficacy? Increased safety? Nothing?

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The journey of drug therapy…

MD prescribes

drug

Insurance/ patient pays

for drug

Patient consumes/ uses drug

Data sources include:- Drug reps- Published data- Colleagues

May end up paying for a higher cost drug when it was not needed.

May end up taking a drug for which safety data are not well known.

Pharmaceutical industry has

influence in all of these avenues

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MD prescribes

drug


for drug





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History of Pharmaceutical Marketing Pharmaceutical marketing is not a

new industry practice Reps started calling on MDs in the mid-

1800s Building relationships with MDs with the

goal of selling product

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Effects of Reps Starts Early

Pharmaceutical industry influence starts early in MD training:* first stethoscope free lunches during educational programs textbooks weekend trips to ideal locations to

hear talks about new drugs financial incentives to attend educational

programs (fancy dinner and an honorarium)

*Note that 2009 PhRMA Guidelines will stop some of this

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Power of the Sales Force Sales force increased

1995: 38,000 reps 2005: 100,000 reps

2.6 fold increase in 10 years 1 rep: 6 MDs (1 rep: 2.5 targeted MDs)

MDs were swamped by reps and began to feel justified in accepting gifts for lost time with patients

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Power of the Sales Force New generation reps evolved in 1990s

“Older” reps needed to be savvy and resourceful to get prescribing data

New reps had electronic prescribing data handed to them

Marketing firms (eg, IMS) collect the data on prescriptions written in pharmacies and sell the data to pharmaceutical industry

Sale of data sent $44 million to AMA in 2005 Reps now knew exactly who prescribed

what products, how much, and how often

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Techniques Used Prescribing incentive programs (e.g.,

Inderal LA) Unrestricted educational grants Samples or vouchers

Only provided for most promoted, usually most costly drugs

Allows rep to gain access to MDs Research money

Pharmaceutical industry funds >70% of research (vs 30% 30 years ago)

Power of funding influences prescribing

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MD prescribes

drug


for drug





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Industry Effect on Published Data For FDA-approved drugs, public disclosure

of trials is available through: FDA Summary Basis of Approval document Study summaries in the package insert Published literature in peer-reviewed journals

37% of clinical trial abstracts never get published

Clinicians need full access to data to make informed decisions for patient care

But does that happen?

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Industry Control of Journal Content Betty Dong and levothyroxine

1986: Synthroid (Knoll Pharmaceuticals) and

UCSF investigators (Betty Dong/Francis Greenspan)

Study to compare Synthroid to other forms of levothyroxine (4 products studied)

Dong signed a contract with Knoll Included a clause stating that results were

confidential and could not be released without consent from the manufacturer

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Industry Control of Journal Content

1990: Results: 4 products were equivalent Manuscript accepted by JAMA Knoll threatened lawsuit if published

1995: Modified report published by Knoll - products

not equivalent - Dong not an author 1997:

Dong article was published (JAMA. 1997;277:1205) Suppression of findings by Knoll impacted clinical

practice and cost of treatment for many years

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Selective Publication Selective publication of trials

Evaluated 12 antidepressants All phase II and III studies registered with

FDA between 1987-2004 Compared outcomes in FDA analysis to

matching publications 74 studies were identified in the FDA

database 51 (69%) studies were published

Turner et al. N Engl J Med 2008;358:252-60.

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Selective Publication

Study Outcome by FDA Analysis

Published agrees with FDA decision

Published conflicts with FDA decision

Study not published

Positive (n=38)

37 (97%) 1 (3%)

Questionable (n=12)

6 (50%) 6 (50%)

Negative (n=24)

3 (12%) 5 (21%) 16 (67%)

N Engl J Med 2008;358:252-60.

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Selective Publication Does selective publication happen across the

board? All 90 new molecular entities approved, 1998-

2000 Purpose: how often trials are published 909 studies in the FDA Summary Documents 43% of these studies were published

32% published prior to FDA approval 92% published within 3 years of approval

Characteristics of published studies larger sample size, good study design (randomized,

blinded), and favorable study outcomes

Lee K. PLoS Medicine. 2008;5:1348-56.

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Selective Publication Does selective publication happen across the

board? All 90 new molecular entities approved, 1998-2000 909 studies in the FDA Summary Documents 43% of these studies were published

32% published prior to FDA approval 92% published within 3 years of approval

Characteristics of published studies larger sample size, good study design (randomized,

blinded), and favorable study outcomes Conclusions

Publication of favorable outcomes consistent with findings seen for select reviews

Concern – healthcare professionals do not have access to the true risks/benefits of new drugs without seeing all available data

Lee K. PLoS Medicine. 2008;5:1348-56.

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Controlling Content of Journals

UCSF investigators assessed: Extent of publication Whether or not concurrence with FDA

analysis Outcomes and conclusions

All NME approved in 2001-2002 (n=33) All trials submitted to FDA that had a

comparator group (n=164)

Rising K et al. PLoS Medicine. 2008;5:1561-70.

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Controlling Content of JournalsExtent of publication 128 (78%) of trials in NDA were published

Active controls & favorable outcomes 80% had 1 author & 15% had all authors with ties to

industry

Concurrence with FDA analysis 43 outcomes in FDA documents did not favor NME

20 (47%) not included in published report 5 of remaining 23 changed in published data

10 conclusions in FDA documents did not favor NME

9 of these conclusions changed in publication to favor test drug

Rising K et al. PLoS Medicine. 2008;5:1561-70.

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Controlling the Journal

Australasian Journal of Bone and Joint Medicine

•Published by Elsevier (credible)

•2003-2005

Elsevier•No disclosure of Merck funding in journal•Printed excerpts of peer-reviewed articles or summarized articles•Emphasis on studies favorable for Vioxx and Fosamax

Advisory Brd

•“Honorary”•Australian rheumatologist •Never rec’d single paper for peer review

Merck•Phony journal that resembled peer-reviewed journal•Used as a marketing piece

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MD prescribes

drug


for drug





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Colleagues as Educators Industry has many different

relationships with healthcare providers: Advisory board memberships Involvement with speakers programs Paid to be thought leaders for ghost written

articles Industry is major source of funding for

CME Accreditation Council for CME - in 2003,

90% of the $1 billion spent on CME came from industry

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Colleagues as Educators 2005: industry profits leveled off

Pharmaceutical sales force saw cuts Industry hired more MDs as speakers

Thought leaders or key opinion leaders Purpose – to persuade colleagues to use the new

drugs Result….

Industry paid MD to give a talk

Audience of MDs, sometimes paid to listen

And sometimes, also a great meal for all

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Colleagues as Educators Relationships with industry became

lucrative for MDs Some MDs were found to have

incredible incomes from industry Estimated that 25% of MDs participate in

speakers bureaus Reports of earning >$300K/yr

Recent report of a world-renown psychiatrist receiving $1.6 million in consulting fees over 7 yearsAre disclosure laws

needed?

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Increased Transparency

Several states have implemented laws mandating disclosure of payments to healthcare professionals by the pharmaceutical industry

Disclosures are publicly available in some states……..……….or are they?

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Increased Transparency Study to determine:

Magnitude of payments (>$100) in Vermont and Minnesota

Accessibility and quality of data available to the public

Ross JS et al. JAMA. 2007;297:1216-23.Ross JS et al. JAMA. 2008;300:1998-2000.

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Ease of access to the data Vermont

Payment disclosures available from Office of Attorney General

Web-based annual summaries, aggregate data

Drug companies can declare payments as trade secrets

61% of reports had missing data Only 10% of original reports had usable MD data

Freedom of Information Act request (took 1 year) and Public Citizen lawsuit against Attorney General (took 2 years) to get full disclosure

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Ease of access to the data Minnesota

Payment disclosures from Board of Pharmacy

Only available in original paper submission forms, filed by year

Data were not available as a public report

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So is transparency working? The laws in place are a start, but they

are inadequate Incomplete disclosure and insufficient

access Changes are needed to improve the

system Disallow trade secret exception Require state agency enforcement Appoint responsible party for collecting

and providing data in a usable format

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Why Colleagues as Educators?

Benefits of using MDs Talks by MDs generate 4x more

prescriptions than those by reps ROI was 2x

Lucrative marketing tactic for off-label uses (which is illegal for reps)

But it all came to a head in 2004…………..

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The Neurontin Story Neurontin (gabapentin, Warner-

Lambert) was approved in 1993 for seizures

Allegations of off-label use began in 1996 by a whistle-blower (Dr. Franklin, MSL)

Aggressive, elaborate, complex, organized, $40M marketing strategy Extensive off-label promotion for multiple

indications pain, migraine, bipolar disorder, ADD,

monotherapy for epilepsy, restless leg syndrome

•For many of these indications, there were no data to support the use•For some indications, there were data showing that Neurontin was no better than placebo

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The Neurontin Story Tactics

Targeted key MDs Used MD-champions for peer-to-peer selling Paid MDs to attend ‘consultant meetings’ or

‘advisory boards’ Paid MDs to moderate teleconferences Sponsored ‘independent’ CME through

unrestricted educational grants Paid MDs to allow rep-preceptorships Created speakers bureaus using influential

MDs Provided ‘grant’ money for ‘research’

•Frequent RXers of anticonvulsants•MDs with potential to influence others

“One of the most effective ways” for off-label marketing

•…but they weren’t providing any advice•Received generous honorarium, expensive meals, paid trip•Heard talks on off-label use

Rep spent the day with the MD, seeing patients, and ‘offering advice’

•STEPS trial – Neurontin titration to effectiveness•Uncontrolled, open-label design•MDs told to increase dose until seizure free, up to 3600 mg/d•Over 700 MDs participated, ave of 3 patients per MD, rec’d $300/pt•Published paper said evaluated effectiveness•Internal documents said goal was to teach MDs to push the dose higher to clinical effect

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The Neurontin Story Did the plan work?

1995 sales – $97.5 million 2003 sales - $2.5 billion 2000 – 78% of sales were for off-label

indication In 2004, 8 years after the suit was

initially filed, Pfizer pleaded guilty to fraudulent marketing and violating FDCA

Coincidentally, the patent on Neurontin expired in 2004

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The Neurontin Story Settlement with Pfizer was for $430

million Criminal fine, civil liabilities for fraud,

fines to consumer protection agencies, and $27 million to whistle blower

But was it worth it? Neurontin generated $2.5 billion in

2003 alone compared to $98 million in 1995

Steinman MA et al. Ann Intern Med. 2006;145:284-93.

…and in January 2009 Eli Lilly agreed to pay $1.42 billion for off-label promotion of Zyprexa….and recently, Pfizer settled for $2.3 billion to stop an investigation into their off-label promotion of Bextra and other drugs

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Lessons Learned The Neurontin case greatly increased

awareness of MDs and the public to the marketing tactics and deceit being used by the industry….

…. led to changes that we are still seeing today.

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What can you do???????

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Ways to Regulate Influence Realize that the pharmaceutical

industry is a business They have a fiduciary responsibility to

their shareholders

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Ways to Regulate Influence Understand that the information which comes

from reps/industry is often biased or distorted Know how to sort through the data Realize that published reports tend to favor

studies with positive outcomes Be familiar with guidelines on ethical interactions

from AMA, ACCP and PhRMA New push for tighter controls between

Professional Medical Associations and PhRMA funding (JAMA. 2009;301:1367)

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On An Institutional Level Consider policies that restrict access

of pharmaceutical reps in health systems: Require an appointment to conduct

business Don’t allow food for meetings Don’t allow gifts of any sort Don’t allow samples and require approval

of vouchers

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When reviewing new drugs Require disclosure of potential conflict

of interest for those involved with drug selection/purchasing decisions

Review published literature carefully Pull FDA Summary Document to

identify data that may be missing Review clinicaltrials.gov to see all

hypothesis-testing studies conducted and a synopsis of the results

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On A Personal Level Be aware of the realities of the

business world Don’t cave in to marketing pressures Maintain high ethical and moral

standards Know and understand the limitations

of the published literature and educate others accordingly

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And remember, the industry will always come out with something new……..

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