Do drug companies help or hurt patients

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Do drug companieshelp or hurt patients
Gilbert Chu MD PhD Professor of Medicine and
Biochemistry Down to a Science Cafe December 2007
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New drugs for cancer patients

• Targeted attack of tumors
• Gleevec kinase inhibitor for chronic myeloid
  leukemia (Novartis)
• Avastin antibody vs. vascular endothelial growth
  factor (Genentech)
• Control of chemotherapy side effects
• Epogen red cell growth factor (Amgen)
• Neulasta neutrophil growth factor (Amgen)

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Laws affect Pharma behavior
1980 Bayh-Dole Act Permits pharma to license
NIH-funded research
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Laws affect Pharma behavior
1980 Bayh-Dole Act Permits pharma to license
NIH-funded research
1984 Hatch-Waxman Act Exempts generic companies
from repeating clinical trials delays approval
by 30 months if brand-name company sues to
protect patents
1992 Prescription Drug User Fee Act
(PDUFA) Charges 576000 for each FDA
application 1997 FDA guidelines on TV ads
2003 Medicare prescription drug
benefit Prohibits Medicare from negotiating
lower prices
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How much money is involved

• Colon cancer treatment Survival Cost 8 wks
• FL (fluorouracil leucovorin) 12 mo 63
• FL Eloxatin 21 mo 12000
• FL Eloxatin Avastin 27 mo 21000

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How much money is involved

• Net profits (Fortune 500)
• 10 pharma companies 36 B
• 490 non-pharma companies 34 B
• CEO salaries plus stock options
• Bristol-Myers Squibb 151 M
• Wyeth 82 M

SLAC budget
150 M
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How much money is involved

• Net profits (Fortune 500)
• 10 pharma companies 36 B
• 490 non-pharma companies 34 B
• CEO salaries plus stock options
• Bristol-Myers Squibb 151 M
• Wyeth 82 M
• Expenses vs. profits
• Marketing 35
• Research (mostly clinical trials) 11
• Profits 20

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Merck as a pharmaceutical leader
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Merck as a pharmaceutical leader

• 1985-1994 Roy Vagelos - Chairman/CEO
• Americas most admired corporation for 7 yrs
• 1987 ivermectin - anti-parasitic drug
• Used for heartworm in dogs
• Found to cure river blindness then elephantiasis
• Merck donated drug to patients without charge
• 1994 Ray Gilmartin takes over

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The Vioxx case
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Cyclo-oxygenase (COX) enzymes
prostaglandins in inflammatory cells

• contribute to
• pain
• heat
• swelling

• housekeeping substances in
• platelets (to make blood clots)
• stomach mucosal cells (for stomach
  protection)

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Cyclo-oxygenase (COX) enzymes
prostaglandins in inflammatory cells

• contribute to
• pain
• heat
• swelling

X
Aspirin or Naprosyn
X

• housekeeping substances in
• platelets (to make blood clots)
• stomach mucosal cells (for stomach
  protection)

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Cyclo-oxygenase (COX) enzymes
prostaglandins in inflammatory cells

• contribute to
• pain
• heat
• swelling

X
Vioxx
Annual sales 3.5 billion

• housekeeping substances in
• platelets (to make blood clots)
• stomach mucosal cells (for stomach
  protection)

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Cyclo-oxygenase (COX) enzymes
prostaglandins in inflammatory cells

• contribute to
• pain
• heat
• swelling

blood vessel endothelial cells (to prevent clots)

• housekeeping substances in
• platelets (to make blood clots)
• stomach mucosal cells (for stomach
  protection)

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Cyclo-oxygenase (COX) enzymes
prostaglandins in inflammatory cells

• contribute to
• pain
• heat
• swelling

X
Vioxx
blood vessel endothelial cells (to prevent clots)

• housekeeping substances in
• platelets (to make blood clots)
• stomach mucosal cells (for stomach
  protection)

Could Vioxx cause heart attacks
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The Vioxx case
Matthew Martinez. E-mails suggest that Merck
knew Vioxxs dangers at early stage. Wall
Street Journal Nov. 1 2004

• 1997 Alise Reicin V.P. Clinical Research Merck
• studies should be designed so risks would not be
  evident

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The Vioxx case
Matthew Martinez. E-mails suggest that Merck
knew Vioxxs dangers at early stage. Wall
Street Journal Nov. 1 2004

• 1997 Alise Reicin V.P. Clinical Research Merck
• studies should be designed so risks would not be
  evident

Bombardier C Laine L Reicin A Shapiro D
Burgos-Vargas R Davis B Day R Ferraz MB
Hawkey CJ Hochberg MC Kvien TK Schnitzer TJ
VIGOR Study Group Comparison of upper
gastrointestinal toxicity of rofecoxib and
naproxen in patients with rheumatoid
arthritis New England Journal of Medicine
November 2000
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The Vioxx case
Matthew Martinez. E-mails suggest that Merck
knew Vioxxs dangers at early stage. Wall
Street Journal Nov. 1 2004

• 1997 Alise Reicin V.P. Clinical Research Merck
• studies should be designed so risks would not be
  evident
• Merck 16 pages of instructions Dodge Ball
  Vioxx
• responses to physician queries were labeled as
  DODGE!
• Gurkirpal Singh Asst. Prof. speaker sponsored by
  Merck
• criticism of missing safety data led Merck to
  threaten Stanford

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The Vioxx case
Richard Horton Editor and Publisher The
Lancet In a recent Editorial we commended
Merck for acting promptly in the face of new
findings about the safety of Vioxx... Our praise
was premature... Merck and the FDA acted
out of ruthless short-sighted and irresponsible
self-interest.
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The Vioxx case
Clinical trials showed increased risk of heart
attacks for Vioxx when compared to naprosyn

• A crash course on statistics
• p-value is the probability that the result
  could have occurred by chance
• Physicians consider a result meaningful if p
• Example in a study of 1000 patients comparing
  Drug X to Drug Y heart attacks occurred in
• 8 patients on X 3 patients on Y
• 8 patients on X 1 patient on Y

p0.22
p0.04
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The Vioxx case
Clinical trials showed increased risk of heart
attacks for Vioxx when compared to naprosyn
Bombardier et al. suggested that the difference
might be due to a protective effect of naprosyn
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The Vioxx case
Clinical trials failed to show protection from
naproxen
Combined 0.86 (95 CI 0.75-0.99)
Favors naproxen
Favors control
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The Vioxx case
Lisse JR et al. for the ADVANTAGE Study
Group Gastrointestinal tolerability and
effectiveness of rofecoxib versus naproxen in the
treatment of osteoarthritis a
randomized controlled trial Annals Internal Med
October 2003
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The Vioxx case
Alex Berenson Evidence in Vioxx suits shows
intervention by Merck officials. New York
Times Apr 24 2005

• Lisse et al. reported heart attacks in 5 patients
  on Vioxx compared to 1 patient on naproxen p
  0.22
• Data originally filed at FDA documented heart
  attacks in 8 patients on Vioxx compared to 1 on
  naproxen p 0.04
• Dr. Alise Reicin asked for new diagnoses I
  would prefer unknown cause of death so we dont
  raise concerns
• Dr. Jeffrey Lisse (U. Arizona) claimed to be
  unaware of the altered diagnoses Merck designed
  the trial paid for the trial ran the trialThe
  initial paper was written at Merck and then sent
  to me for editing

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The Vioxx case
Deaths attributable to Vioxx 50000 American
deaths in Vietnam 58000 American deaths in Iraq
(12/1) 3882
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The Vioxx case
Where were the problems

• Merck officials
• altered the data
• designed the trials to conceal risks
• Academics physicians
• authored key papers
• delivered continuing medical education
• FDA
• failed to monitor the safety of Vioxx

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Is the medical literature biased

• Ghost writers in research papers
  (Flanagin et al. JAMA 1998)
• Annals of Internal Medicine (20)
• New England Journal of Medicine (26)
• Randomized myeloma trials favoring new drug
  (Djulbegovic et al. Lancet 2004)
• When NOT sponsored by industry 47 (p .608)
• When sponsored by industry 74 (p .004)

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Can we fix the problem

• Financial disclosure
• ClinicalTrials.gov
• Ban of pharma reps
• Unbiased drug trials

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