Do drug companieshelp or hurt patients?

Gilbert Chu, MD, PhDProfessor of Medicine and Biochemistry

Down to a Science CafeDecember 2007

Gilbert Chu, MD, PhDProfessor of Medicine and Biochemistry

Down to a Science CafeDecember 2007

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 behavior1980 Bayh-Dole Act

Permits pharma to license NIH-funded research

1980 Bayh-Dole ActPermits pharma to license NIH-funded research

1984 Hatch-Waxman ActExempts 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 benefitProhibits Medicare from negotiating lower prices

Laws affect Pharma behavior

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

SLAC budget $150 M

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

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%

African black fly microfilariariver blindness

elephantiasiselephantiasis

Merck as a pharmaceutical leader

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…

Dorothy Hamill

The Vioxx case

Cyclo-oxygenase (COX) enzymes

prostaglandins ininflammatory cells contribute to:

• pain• heat• swelling

“housekeeping” substances in:• platelets (to make blood clots)• stomach mucosal cells

(for stomach protection)

Aspirin orNaprosyn

X

X

Cyclo-oxygenase (COX) enzymes

prostaglandins ininflammatory cells contribute to:

• pain• heat• swelling

“housekeeping” substances in:• platelets (to make blood clots)• stomach mucosal cells

(for stomach protection)

VioxxX

Cyclo-oxygenase (COX) enzymes

Annual sales: $3.5 billion

prostaglandins ininflammatory cells contribute to:

• pain• heat• swelling

“housekeeping” substances in:• platelets (to make blood clots)• stomach mucosal cells

(for stomach protection)

blood vessel endothelial cells (to prevent clots)

Cyclo-oxygenase (COX) enzymes

“housekeeping” substances in:• platelets (to make blood clots)• stomach mucosal cells

(for stomach protection)

prostaglandins ininflammatory cells contribute to:

• pain• heat• swelling

blood vessel endothelial cells (to prevent clots)

VioxxX

Cyclo-oxygenase (COX) enzymes

Could Vioxx cause

heart attacks?

“housekeeping” substances in:• platelets (to make blood clots)• stomach mucosal cells

(for stomach protection)

prostaglandins ininflammatory cells contribute to:

• pain• heat• swelling

Matthew & Martinez. “E-mails suggest that Merck knew Vioxx’s dangers at early stage.” Wall Street Journal, Nov. 1, 2004

The Vioxx case

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

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

1997: Alise Reicin, V.P. Clinical Research, Merck studies should be designed so “risks would not be evident”

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 case

Matthew & Martinez. “E-mails suggest that Merck knew Vioxx’s dangers at early stage.” Wall Street Journal, Nov. 1, 2004

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 case

Clinical trials showed increased risk of heart attacksfor Vioxx when compared to naprosyn

The Vioxx case

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=0.22p=0.04

Clinical trials showed increased risk of heart attacksfor Vioxx when compared to naprosyn

16 randomized trials, 1999-2003 Relative risk p value

All 16 trials 2.24Trial duration ≥ 6 months 2.17 0.82 < 6 months 2.33Independent endpoint committee? Yes (8 trials) 3.88 0.011 No or unclear (8 trials) 0.79

The Vioxx case

Bombardier et al. suggested that the difference might be due to a protective

effect of naprosyn

QuickTime™ and aTIFF (Uncompressed) decompressor

are needed to see this picture.

sponsored sponsored by Merckby Merck

p = 0.001p = 0.001

Favors naproxen Favors control

Combined 0.86 (95% CI 0.75-0.99)

Clinical trials failed to show protection from naproxen

The Vioxx case

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

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”

Alex Berenson, “Evidence in Vioxx suits shows intervention by Merck officials.” New York Times, Apr 24, 2005

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

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

Where were the problems?

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)

Can we fix the problem?Can we fix the problem?

Financial disclosure

ClinicalTrials.gov

Ban of pharma reps

Unbiased drug trials