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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 Gleevec kinase inhibitor for chronic myeloid leukemia (Novartis)

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do drug companies help or hurt patients
Do drug companieshelp or hurt patients?

Gilbert Chu, MD, PhD

Professor of Medicine and Biochemistry

Down to a Science Cafe

December 2007

new drugs for cancer patients
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)
laws affect pharma behavior
Laws affect Pharma behavior

1980 Bayh-Dole Act

Permits pharma to license NIH-funded research

laws affect pharma behavior4
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

Aventis: Eloxatin

Genentech: Avastin

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

how much money is involved6
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

how much money is involved7
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%
    • Profits20%
merck as a pharmaceutical leader

elephantiasis

river blindness

African black fly

microfilaria

Merck as a pharmaceutical leader
merck as a pharmaceutical leader9
Merck as a pharmaceutical leader
  • 1985-1994: 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…
cyclo oxygenase cox enzymes
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 enzymes12
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)
cyclo oxygenase cox enzymes13
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)
cyclo oxygenase cox enzymes14
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 enzymes15
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?

the vioxx case16
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 case17
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 case18
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”
  • 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
the vioxx case19
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.”

the vioxx case20
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

the vioxx case21

16 randomized trials, 1999-2003 Relative risk p value

All 16 trials 2.24

Trial duration

≥ 6 months 2.17 0.82

< 6 months 2.33

Independent endpoint committee?

Yes (8 trials) 3.88 0.011

No or unclear (8 trials) 0.79

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

the vioxx case22

sponsored

by Merck

p = 0.001

The Vioxx case

Clinical trials failed to show protection from naproxen

Combined 0.86 (95% CI 0.75-0.99)

Favors naproxen

Favors control

the vioxx case23
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 case24
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 8patients 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 case25
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 case26
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
is the medical literature biased
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)
slide29

Can we fix the problem?

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