Do drug companies
help or hurt patients?
Gilbert Chu, MD, PhD
Professor of Medicine and Biochemistry
Down to a Science Cafe
December 2007
New drugs for cancer patients

Targeted attack of tumors


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Gleevec kinase inhibitor for chronic
myeloid leukemia (Novartis)
Avastin antibody vs. vascular endothelial
growth factor (Genentech)
Control of chemotherapy side effects

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Epogen red cell growth factor (Amgen)
Neulasta neutrophil growth factor (Amgen)
Laws affect Pharma behavior
1980 Bayh-Dole Act
Permits pharma to license NIH-funded research
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 $576,000 for each FDA application
1997 FDA guidelines on TV ads
2003 Medicare prescription drug benefit
Prohibits Medicare from negotiating lower prices
How much money is involved?
Colon cancer treatment
Survival
Cost 8 wks
FL (fluorouracil, leucovorin)
12 mo
$63
FL, Eloxatin
21 mo
$12,000
FL, Eloxatin, Avastin
27 mo
$21,000
Aventis: Eloxatin
Genentech: Avastin
How much money is involved?

Net profits (Fortune 500)

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10 pharma companies
490 non-pharma companies
$36 B
$34 B
CEO salaries plus stock options
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Bristol-Myers Squibb
Wyeth
$151 M
$82 M
SLAC budget
$150 M
How much money is involved?

Net profits (Fortune 500)



$36 B
$34 B
CEO salaries plus stock options


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10 pharma companies
490 non-pharma companies
Bristol-Myers Squibb
Wyeth
$151 M
$82 M
Expenses vs. profits



Marketing
Research (mostly clinical trials)
Profits
35%
11%
20%
Merck as a pharmaceutical leader
river blindness
African black fly
microfilaria
elephantiasis
Merck as a pharmaceutical leader

1985-1994: Roy Vagelos - Chairman/CEO

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America’s 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…
The Vioxx case
Dorothy Hamill
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)
Cyclo-oxygenase (COX) enzymes
X
Aspirin or
Naprosyn
X
prostaglandins in
inflammatory cells
contribute to:
• pain
• heat
• swelling
“housekeeping” substances in:
• platelets (to make blood clots)
• stomach mucosal cells
(for stomach protection)
Cyclo-oxygenase (COX) enzymes
X
Vioxx
prostaglandins in
inflammatory cells
contribute to:
• pain
• heat
• swelling
Annual sales: $3.5 billion
“housekeeping” substances in:
• platelets (to make blood clots)
• stomach mucosal cells
(for stomach protection)
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)
Cyclo-oxygenase (COX) enzymes
X
Vioxx
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)
Could Vioxx cause
heart attacks?
The Vioxx case
Matthew & Martinez. “E-mails suggest that Merck knew Vioxx’s
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”
The Vioxx case
Matthew & Martinez. “E-mails suggest that Merck knew Vioxx’s
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
The Vioxx case
Matthew & Martinez. “E-mails suggest that Merck knew Vioxx’s
dangers at early stage.” Wall Street Journal, Nov. 1, 2004

1997: Alise Reicin, V.P. Clinical Research, Merck

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Merck: 16 pages of instructions, “Dodge Ball Vioxx”

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studies should be designed so “risks would not be evident”
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
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, shortsighted, and irresponsible self-interest.”
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<0.05
• 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 p=0.22
p=0.04
• 8 patients on X, 1 patient on Y
The Vioxx case
Clinical trials showed increased risk of heart attacks
for Vioxx when compared to naprosyn
16 randomized trials, 1999-2003
All 16 trials
Trial duration
≥ 6 months
< 6 months
Independent endpoint committee?
Yes (8 trials)
No or unclear (8 trials)
Relative risk
p value
2.24
2.17
2.33
0.82
3.88
0.79
0.011
Bombardier et al. suggested that the difference
might be due to a protective effect of naprosyn
The Vioxx case
Clinical trials failed to show protection from naproxen
sponsored
by Merck
p = 0.001
QuickTime™ and a
TIFF (Uncompressed) decompressor
are needed to see this picture.
Combined 0.86 (95% CI 0.75-0.99)
Favors naproxen
Favors control
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
The Vioxx case
Alex Berenson, “Evidence in Vioxx suits shows
intervention by Merck officials.” New York Times, Apr 24, 2005

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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 don’t 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 trial…The initial paper was written at Merck
and then sent to me for editing”
The Vioxx case
Deaths attributable to Vioxx
50,000
American deaths in Vietnam
58,000
American deaths in Iraq (12/1)
3,882
The Vioxx case
Where were the problems?


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Merck officials
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altered the data
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designed the trials to conceal risks
Academics physicians
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“authored” key papers
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delivered continuing medical “education”
FDA
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failed to monitor the safety of Vioxx
Is the medical literature biased?

Ghost writers in research papers
(Flanagin et al. JAMA 1998)
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Annals of Internal Medicine (20%)
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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)
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When sponsored by industry: 74% (p = .004)
Can we fix the problem?
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Financial disclosure
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ClinicalTrials.gov
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Ban of pharma reps
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Unbiased drug trials