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) 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 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) 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 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%

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

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…

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 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) 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) 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 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 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 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 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 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 case Clinical trials showed increased risk of heart attacks for Vioxx when compared to naprosyn 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 Bombardier et al. suggested that the difference might be due to a protective effect of naprosyn

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 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 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

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

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