Institutional Foundations of Drug Disasters

Donald W. LightDonald W. Light

Professor of Social & Behavioral MedicineProfessor of Social & Behavioral MedicineUniversity of Medicine & Dentistry of New JerseyUniversity of Medicine & Dentistry of New Jersey

Leverhulme Trust Visiting Professor (UK) 2008Leverhulme Trust Visiting Professor (UK) 2008

Medical Sociology Session, ASA,Medical Sociology Session, ASA,Aug 3, 2008 BostonAug 3, 2008 Boston

Vioxx – worst drug disaster in historyVioxx – worst drug disaster in history

FDA estimated 32,000 heart attacks, stroke, FDA estimated 32,000 heart attacks, stroke, sudden deathsudden death

David Graham: 88,000-130,000 in USA. David Graham: 88,000-130,000 in USA.

30-40% died30-40% died

But rate was 16/ 1,000 in healthy pts But rate was 16/ 1,000 in healthy pts

44/ 1,000 in higher risk pts44/ 1,000 in higher risk pts

14 million higher risk pts took Vioxx in USA14 million higher risk pts took Vioxx in USA= 617,000 cardiac events= 617,000 cardiac events

21 million healthier pts took Vioxx21 million healthier pts took Vioxx= 336,000 cardiac events= 336,000 cardiac events

Total: 953,000 cardiac events in USA Total: 953,000 cardiac events in USA 1.9 million worldwide? 1.9 million worldwide?

Far worse than Vietnam, Chernobyl Far worse than Vietnam, Chernobyl - just a pain pill no one needed, - just a pain pill no one needed, not even patients with GI problems not even patients with GI problems

High cardiac risk known from beginning, High cardiac risk known from beginning, 1996 in development1996 in development

“…“…it is mechanism-based, as we worried it was” it is mechanism-based, as we worried it was” Merck’s chief scientist Merck’s chief scientist

[but] “We have a great drug… and we will do well.”[but] “We have a great drug… and we will do well.”

Hi risk documented in FDA review, Feb 2001Hi risk documented in FDA review, Feb 2001

““Do Not Use” by Public Citizen, others in 2001Do Not Use” by Public Citizen, others in 2001

One cardiac trauma for every gastro bleed One cardiac trauma for every gastro bleed prevented – prevented – NEJM editors, in 2006NEJM editors, in 2006

Risks do not start before 18months – Merck 2004Risks do not start before 18months – Merck 2004

Trial Evidence Feb 2001: risks start at 1 monthTrial Evidence Feb 2001: risks start at 1 month

Beyond Vioxx, a repeated pattern Beyond Vioxx, a repeated pattern

Drug companies knowingly expose patients to Drug companies knowingly expose patients to serious risks.serious risks.

a) Since 1950s, have discredited or denied a) Since 1950s, have discredited or denied severe reactions and kept selling. severe reactions and kept selling.

b) When banned in West, promoted without b) When banned in West, promoted without warnings in Africa, Asia, Latin Americawarnings in Africa, Asia, Latin America

c) Testing minimal, unsystematic, biased, c) Testing minimal, unsystematic, biased, unless required. unless required.

Thesis Thesis

The way drugs are tested, approved, The way drugs are tested, approved, marketed, and regulated routinely causes marketed, and regulated routinely causes widespread injury and death.widespread injury and death.

d) 4d) 4thth leading cause of death leading cause of death

e) 1.5 million hospitalizations/yr USAe) 1.5 million hospitalizations/yr USA4 million hospitalizations worldwide4 million hospitalizations worldwide

f) Adverse event reports to FDA tripled f) Adverse event reports to FDA tripled 1995-20051995-2005

8 Institutional Foundations:8 Institutional Foundations:1. Have companies design and run own 1. Have companies design and run own

trials at huge costtrials at huge cost

Intense pressure to prove drugs effective and safe.Intense pressure to prove drugs effective and safe.Hundreds of millions of costs. Hundreds of millions of costs.

Choose end points most likely to succeed, then Choose end points most likely to succeed, then market broadly after approvalmarket broadly after approval

Choose only selected safety indicators, don’t report Choose only selected safety indicators, don’t report othersothers

Randomly sample biased, healthy populationRandomly sample biased, healthy population

Short trials to detect benefits but not adverse Short trials to detect benefits but not adverse reactions.reactions.

Maximum dose for main effect w/o detecting adverse Maximum dose for main effect w/o detecting adverse effects. effects.

Do not count drop outs who suffer adverse effectsDo not count drop outs who suffer adverse effects

Companies analyze and write up results. Companies analyze and write up results.

Do not publish or make public negative results. Do not publish or make public negative results. Positive trials 5 x more likely to be publishedPositive trials 5 x more likely to be published

Cochrane Center analysis: Cochrane Center analysis:

company sponsorship itself is a major predictor of company sponsorship itself is a major predictor of positive effects positive effects

8 Institutional Foundations:8 Institutional Foundations:2. Efficacy = non-inferior or superior to 2. Efficacy = non-inferior or superior to

placebo placebo

-Rather than better than best existing therapyRather than better than best existing therapy

- Result: 6 of every 7 new drugs over past 25 years Result: 6 of every 7 new drugs over past 25 years not not therapeuticallytherapeutically superior superior

-Leads to synthetic models of path & treat. based on Leads to synthetic models of path & treat. based on surrogate end points, not clinically relevant:surrogate end points, not clinically relevant:

-Eg lower cholesterol prevents heart diseaseEg lower cholesterol prevents heart disease-Eg shrinking cancer tumors reduces deathEg shrinking cancer tumors reduces death-Eg serotonin SSRIs reduces major depressionEg serotonin SSRIs reduces major depression

2 in every 7 new drugs approved produces serious 2 in every 7 new drugs approved produces serious side effects that cause serious warnings or side effects that cause serious warnings or withdrawals or dosage reductionswithdrawals or dosage reductions

Thus Thus

new drugs are twice as likely to do more harm new drugs are twice as likely to do more harm than good compared to existing drugs or than good compared to existing drugs or therapy therapy

8 Institutional Foundations:8 Institutional Foundations:3. IP protections regardless of health benefit3. IP protections regardless of health benefit

Monopoly prices 40-100 times mfg costMonopoly prices 40-100 times mfg cost

esp for cancer, AIDS esp for cancer, AIDS

Strong incentive to develop follow-on Strong incentive to develop follow-on variants, me-too drugs, synthetic disease variants, me-too drugs, synthetic disease modelsmodels

Create demand far beyond proven benefitsCreate demand far beyond proven benefits

8 Institutional Foundations:8 Institutional Foundations:4. Medical journals drug dependent4. Medical journals drug dependent

Extensive, multi-pronged infusion of corporate Extensive, multi-pronged infusion of corporate influence on submissions & reviewing & publishing influence on submissions & reviewing & publishing

Journals Journals requirerequire all ads to be relevant to practice of all ads to be relevant to practice of medicine, rather than medicine, rather than prohibitprohibit such ads such ads

90% gross profit on reprints. Only positive results 90% gross profit on reprints. Only positive results sell. Merck paid NEJM $900,000 for reprints of Vioxx sell. Merck paid NEJM $900,000 for reprints of Vioxx article. article.

8 Institutional Foundations:8 Institutional Foundations:5. Industry controls education, information5. Industry controls education, information

Constructs accounts & narratives of our Constructs accounts & narratives of our bodies, pathology & treatmentbodies, pathology & treatment

Crafts discourses of fears & hopeCrafts discourses of fears & hope

Controls grand rounds, scientific meetings, Controls grand rounds, scientific meetings, CMECME

The major source of media articlesThe major source of media articlesdirect & indirectdirect & indirect

8 Institutional Foundations:8 Institutional Foundations:6. Industry allowed to swamp regulators6. Industry allowed to swamp regulators

US IG report 2003: FDA reviewers met US IG report 2003: FDA reviewers met

23 times with scientific advisory gps, 23 times with scientific advisory gps,

1,021 times with company officers. 1,021 times with company officers.

FDA officers repeatedly over-ride their own FDA officers repeatedly over-ride their own worried, critical reviewersworried, critical reviewers

do not admit themdo not admit them

ignore themignore them

exclude critical reviewers exclude critical reviewers

8 Institutional Foundations:8 Institutional Foundations:7. Companies fund FDA for speed-up 7. Companies fund FDA for speed-up

reviewsreviews

Congress cut, starved, then rescued the FDA with Congress cut, starved, then rescued the FDA with industry fundingindustry funding

Major study: time-crunch approvals 4 times more Major study: time-crunch approvals 4 times more likely to be withdrawn,likely to be withdrawn,

3 times more likely Black-boxed3 times more likely Black-boxed

NEJM 358:1354NEJM 358:1354

““When you’re getting paid directly from an industry you’re When you’re getting paid directly from an industry you’re supposed to be regulating, it takes quite a bit of edge out of the supposed to be regulating, it takes quite a bit of edge out of the regulating.” Sidney Wolfe, M.D. regulating.” Sidney Wolfe, M.D.

Institutional Foundations:Institutional Foundations:8. Maximum Harm Syndrome8. Maximum Harm Syndrome

Massive market launches, though safety Massive market launches, though safety evidence is incomplete & limitedevidence is incomplete & limited

Drs. can prescribe for any conditionDrs. can prescribe for any condition

Vs whole testing systemVs whole testing system

Making Drs into vehicles for proliferation, Making Drs into vehicles for proliferation,

and legal protectors fr liabilityand legal protectors fr liability

Maximum Harm Syndrome Maximum Harm Syndrome

Mgmt overrules, even suppresses, own expert Mgmt overrules, even suppresses, own expert reviewers. Approval division controls safety reviewers. Approval division controls safety decisions on drugs they approved decisions on drugs they approved

Lack staff to review marketing materials. Lack staff to review marketing materials. Months late. Little enforcement. Vioxx letter.Months late. Little enforcement. Vioxx letter.

Precautionary principle ignoredPrecautionary principle ignored

Only 14% agreed studies after approval done Only 14% agreed studies after approval done to detect safety problems to detect safety problems

Maximum Harm Syndrome Maximum Harm Syndrome

Companies largely control post-mkt Companies largely control post-mkt surveillance. Passive system surveillance. Passive system

Companies control responses to warnings – Companies control responses to warnings – label changes, letters to Drs.label changes, letters to Drs.

Routinely neutralize & bury, keep sellingRoutinely neutralize & bury, keep selling

E.g. Streptomycin in 50s, thalidomide… E.g. Streptomycin in 50s, thalidomide…

refocoxib (Vioxx), Zyprexa…refocoxib (Vioxx), Zyprexa…

Institutional ReformsInstitutional Reforms

2007 Act gives FDA important powers to 2007 Act gives FDA important powers to enforce post-mkt trials, take safety actions, enforce post-mkt trials, take safety actions, impose severe penalties, register all trials, impose severe penalties, register all trials, and post adverse events.and post adverse events.

Significant pro-active FDA reforms now on Significant pro-active FDA reforms now on several frontsseveral fronts

But safety officers & division organizationally But safety officers & division organizationally marginalized. Lack independence & budget.marginalized. Lack independence & budget.

Future Drug Disasters PredictableFuture Drug Disasters Predictable

So long as social contract with pharma So long as social contract with pharma rewards development of drugs with little rewards development of drugs with little advantage, advantage,

and has companies test and market to and has companies test and market to minimize evidence of serious harms and minimize evidence of serious harms and maximize use, maximize use,

the epidemic of toxic side effects will the epidemic of toxic side effects will continue and probably grow.continue and probably grow.

Institutional Reforms NeededInstitutional Reforms Needed

1. Regulator needs to be publicly funded to protect 1. Regulator needs to be publicly funded to protect public and patients . public and patients .

2. Benchmark for efficacy needs to be better than 2. Benchmark for efficacy needs to be better than existing treatments, using clinical end-points. existing treatments, using clinical end-points.

a) new drugs will be better drugsa) new drugs will be better drugs

3. Unauthorized uses must require patient consent 3. Unauthorized uses must require patient consent and monitoring to evaluate.and monitoring to evaluate.

Institutional Reforms Needed Institutional Reforms Needed

5. Major trials need to be publicly funded and run by 5. Major trials need to be publicly funded and run by NIH. Would cost much less and relieve companies of NIH. Would cost much less and relieve companies of much cost & risk. much cost & risk. A new deal.A new deal.

a) Save payers, patients billionsa) Save payers, patients billions

b) Save exposure to unnec risksb) Save exposure to unnec risks

6. Drs need to reaffirm their professionalism.6. Drs need to reaffirm their professionalism.

Real-time detailing fr independent sources, Real-time detailing fr independent sources,

like Kaiser, VHA. like Kaiser, VHA.

Institutional Reforms Needed Institutional Reforms Needed

7. “safe and effective” needs to be replaced by7. “safe and effective” needs to be replaced by

“ “apparently safe based on incomplete apparently safe based on incomplete information, and more effective than a information, and more effective than a placebo.” placebo.”

- a new public understanding- a new public understanding