1. Do drug companies help or hurt patients?
Gilbert Chu, MD, PhD
Professor of Medicine and Biochemistry
Down to a Science Cafe
December 2007

2. 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)

3. Laws affect Pharma behavior
1980 Bayh-Dole Act
Permits pharma to license NIH-funded research

4. 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

5. 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

6. 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

7. 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%

8. Merck as a pharmaceutical leader
river blindness
elephantiasis
African black fly
microfilaria

9. Merck as a pharmaceutical leader
: Roy Vagelos - Chairman/CEO
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…

10. The Vioxx case
Dorothy Hamill

11. 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)

12. 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)

13. 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)

14. 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)

15. 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?

16. The Vioxx case
Matthew & Martinez. “ s 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”

17. The Vioxx case
Matthew & Martinez. “ s 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

18. The Vioxx case
Matthew & Martinez. “ s 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”
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

19. 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.”

20. 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
8 patients on X, 1 patient on Y
p=0.22
p=0.04

21. The Vioxx case Clinical trials showed increased risk of heart attacks
for Vioxx when compared to naprosyn
16 randomized trials, Relative risk p value
All 16 trials
Trial duration
≥ 6 months
< 6 months
Independent endpoint committee?
Yes (8 trials)
No or unclear (8 trials)
Bombardier et al. suggested that the difference might be due to a protective effect of naprosyn

22. Clinical trials failed to show protection from naproxen
The Vioxx case
Clinical trials failed to show protection from naproxen
sponsored
by Merck
p = 0.001
Combined 0.86 (95% CI )
Favors naproxen
Favors control

23. 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

24. 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 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”

25. The Vioxx case Deaths attributable to Vioxx 50,000
American deaths in Vietnam 58,000
American deaths in Iraq (12/1) 3,882

26. Where were the problems?
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

27. 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)

29. Can we fix the problem? Financial disclosure ClinicalTrials.gov
Ban of pharma reps
Unbiased drug trials