1. Andrew Kotecki May 2 nd, 2005 A Vioxx a Day Won’t Keep the Doctor Away

3. Overview The biochemistry of pain relief The biochemistry of pain relief What exactly is Vioxx? What exactly is Vioxx? Pharmaceutical product development Pharmaceutical product development Does Vioxx work? Does Vioxx work? Evidence for health hazards, from release to recall Evidence for health hazards, from release to recall Who’s to blame? Who’s to blame?

4. How do you spell pain relief? NSAIDs - nonsteroidal antiinflammatory drugs NSAIDs - nonsteroidal antiinflammatory drugs Advil (not gumballs) IbuprofenAspirinAcetominophenNaproxen

5. Eicosanoids Paracrine hormones, acting locally rather than being transported in the bloodstream Paracrine hormones, acting locally rather than being transported in the bloodstream Derived from arachadonic acid (20-carbons) Derived from arachadonic acid (20-carbons) Catalyzed by COX Catalyzed by COX Three classes Three classes Leukotrienes Leukotrienes Thromboxanes (TBXs) Thromboxanes (TBXs) Prostaglandins (PGs) Prostaglandins (PGs) regulate cAMP synthesis regulate cAMP synthesis cause fever, inflammation, pain cause fever, inflammation, pain

6. COX Isozymes COX = cyclooxygenase (a.k.a. PGH 2 synthase) COX = cyclooxygenase (a.k.a. PGH 2 synthase) COX-1 COX-1 important for gastric cytoprotection, renal homeostasis, normal platelet functioning important for gastric cytoprotection, renal homeostasis, normal platelet functioning COX-2 COX-2 produces PGs responsible for fever, inflammation, pain produces PGs responsible for fever, inflammation, pain So, a drug that specifically inhibited COX-2 could relieve pain, swelling, without GI irritation! So, a drug that specifically inhibited COX-2 could relieve pain, swelling, without GI irritation!

7. How NSAIDs Work Non-specific COX inihibition Non-specific COX inihibition inhibit cycloogenase activity of both inhibit cycloogenase activity of both COX isozymes side effects side effects GI irritation, ulceration GI irritation, ulceration COX-1 inhibition reduces gastric protection COX-1 inhibition reduces gastric protection nonspecific COX inhibition is the problem nonspecific COX inhibition is the problem Duodenal ulcers in 15-30% of patients Duodenal ulcers in 15-30% of patients who regularly take NSAIDs ~16,500/yr die from associated GI effects ~16,500/yr die from associated GI effects

8. Vioxx (Rofecoxib) Oral anti-inflammatory, pain-reliever Oral anti-inflammatory, pain-reliever FDA approved May 21, 1999 FDA approved May 21, 1999 Perscribed to over 80 million patients Perscribed to over 80 million patients in 80 countries Over $2.5 billion in sales annually Over $2.5 billion in sales annually Highly specific inhibitor of COX-2 Highly specific inhibitor of COX-2 Reduces pain and inflammation, Reduces pain and inflammation, but without GI side effects

9. Pharmaceutical Product Development Average 12 years from beaker to medicine cabinet Average 12 years from beaker to medicine cabinet For every 5,000 compounds that enter preclinical testing, For every 5,000 compounds that enter preclinical testing, only 1 makes it to market Average $359 million spent for every successful drug Average $359 million spent for every successful drug

10. Clinical Trials Preclinical Testing File IND at FDA Phase IPhase IIPhase III File NDA at FDA FDA Phase IV Years3.51232.5 12 Total Additional Post marketing testing required by FDA Test Population Laboratory and animal studies 20 to 80 healthy volunteers 100 to 300 patient volunteers 1000 to 3000 patient volunteers Review process / Approval Purpose Assess safety and biological activity Determine safety and dosage Evaluate effectiveness, look for side effects Verify effectiveness, monitor adverse reactions from long- term use Success Rate 5,000 compounds evaluated 5 enter trials 1 approved IND = Investigational New Drug Application NDA = New Drug Application

11. Ethical Considerations Testing new drugs on humans? Testing new drugs on humans? Preceded by animal testing, to weed out the worst Preceded by animal testing, to weed out the worst Giving a placebo when effective treatment is available? Giving a placebo when effective treatment is available? Inform patients, volunteer basis Inform patients, volunteer basis If survival is threatened, known effective therapy is given If survival is threatened, known effective therapy is given Studies are sponsored by those who stand to make $$$ Studies are sponsored by those who stand to make $$$

12. Vioxx Works – Rat Studies Rofecoxib : Rofecoxib : ID 50 = 2.0 ± 0.2 mg/kg Indomethacin: ID 50 = 1.5 ± 0.1 mg/kg Effective anti-inflammatory Effective anti-inflammatory Rofecoxib : Rofecoxib : ID 50 = 0.24 ± 0.07 mg/kg Indomethacin: ID 50 = 1.07 ± 0.16 mg/kg Better fever-reducer Better fever-reducer

13. More than five times the selectivity of the next-best More than five times the selectivity of the next-best COX-2 inhibitor, Celebrex Vioxx Selectivity

14. Keeping GI Tract Happy Effects of chronic dosing for 5 days on GI integrity in squirrel monkeys. 100 mg/kg 1 mg/kg 5 mg/kg

15. Looking Good So Far… At least as effective as other NSAIDs At least as effective as other NSAIDs By far the most COX-2 selectivity (greater than 5-fold) By far the most COX-2 selectivity (greater than 5-fold) Significantly reduced GI irritation Significantly reduced GI irritation

16. VIGOR – March, 2000 Vioxx Gastrointestinal Outcomes Research Vioxx Gastrointestinal Outcomes Research Post-market study involving more than 28,000 patients Post-market study involving more than 28,000 patients Confirmed serious CV adverse events, including fatal and nonfatal MI and storke. Rofecoxib – 50 mg once daily (double dose). Naproxen – 500 mg twice daily. 1.7 % 0.7 %

17. Relative Incidence of Adverse CV Events Vioxx v. placebo – 0.84 Vioxx v. placebo – 0.84 Vioxx v. non-naproxen Vioxx v. non-naproxen NSAIDs – 0.79 Vioxx v. naproxen – 1.69 Vioxx v. naproxen – 1.69 However, similar mortality rates However, similar mortality rates No evidence for Vioxx causing CV problems No evidence for Vioxx causing CV problems Naproxen is cardioprotective Naproxen is cardioprotective

18. “Write That Down” “Until [further studies] are available, doctors should continue to prescribe all NSAIDs with caution.” – Br J Clin Pharmacol, 2003 “Until [further studies] are available, doctors should continue to prescribe all NSAIDs with caution.” – Br J Clin Pharmacol, 2003 “When [these data] became available, Merck notified all investigators in ongoing studies of a change in the exclusion criteria to allow patients to use low-dose aspirin.” – N Engl J Med 2000 “When [these data] became available, Merck notified all investigators in ongoing studies of a change in the exclusion criteria to allow patients to use low-dose aspirin.” – N Engl J Med 2000

19. Just a Thought Selective COX-2 inhibitors do not effect TBX-A 2 production Selective COX-2 inhibitors do not effect TBX-A 2 production TBX-A 2 is prothrombotic TBX-A 2 is prothrombotic They do decrease the production of PGI 2 They do decrease the production of PGI 2 PGI 2 is antithrombotic PGI 2 is antithrombotic Selective COX-2 action “may tip the neutral balance, leading to an increase in thrombotic CV events.” – JAMA 2001 Selective COX-2 action “may tip the neutral balance, leading to an increase in thrombotic CV events.” – JAMA 2001

20. From Bad to Worse APPROVe – adenamatous polyp prevention on VIOXX APPROVe – adenamatous polyp prevention on VIOXX Designed to assess Vioxx in prevention of colon cancer Designed to assess Vioxx in prevention of colon cancer Longer term study – CV effects past 18+ months Longer term study – CV effects past 18+ months Trial halted prematurely Trial halted prematurely Risk of MI and stroke – 3.5 per 100 patient years Risk of MI and stroke – 3.5 per 100 patient years Compare to 1.9 per 100 patient years in placebo group Compare to 1.9 per 100 patient years in placebo group September 30, 2004 – VIOXX recalled September 30, 2004 – VIOXX recalled The LARGEST prescription drug withdrawal in history The LARGEST prescription drug withdrawal in history

21. How bad is it, really? Ontario, Canada, in the year 2000 Ontario, Canada, in the year 2000 ~15,000 elderly filled Vioxx prescriptions ~15,000 elderly filled Vioxx prescriptions Extrapolating 3.5 events per 100 patient years Extrapolating 3.5 events per 100 patient years 240 patients experienced MI or stroke due to Vioxx 240 patients experienced MI or stroke due to Vioxx Over 80 million total patients, the impacts are huge Over 80 million total patients, the impacts are huge 1.28 million strokes or MIs due to Vioxx 1.28 million strokes or MIs due to Vioxx

22. Pointing Fingers Merck Merck Responsible for VIGOR and APPROVe studies Responsible for VIGOR and APPROVe studies FDA FDA Didn’t use authority to catch this sooner Didn’t use authority to catch this sooner Adverse Event Reporting (AER) Adverse Event Reporting (AER) Limited ability to identify a post-market problem Limited ability to identify a post-market problem

23. Merck VIGOR, APPROVe, and related studies done at Merck VIGOR, APPROVe, and related studies done at Merck March 9, 2000 March 9, 2000 “Merck’s research chief, Edward Scolnick, e-mailed colleagues that the CV events ‘are clearly there’ and stated ‘it is a shame but it is a low incidence and it is mechanism based as we worried it was.’” “Merck’s research chief, Edward Scolnick, e-mailed colleagues that the CV events ‘are clearly there’ and stated ‘it is a shame but it is a low incidence and it is mechanism based as we worried it was.’” February, 2001 February, 2001 “A letter was written by a Dr. James Fries, senior professor and medical director and Stanford University Medical School to Merck complaining about the intimidation by Merck’s investigators including the threatening of the loss of funding because of the school’s discussion of CV events associated with Vioxx.” “A letter was written by a Dr. James Fries, senior professor and medical director and Stanford University Medical School to Merck complaining about the intimidation by Merck’s investigators including the threatening of the loss of funding because of the school’s discussion of CV events associated with Vioxx.”

24. FDA Arthritis Advisory Committee meeting Feb 8, 2001 Arthritis Advisory Committee meeting Feb 8, 2001 Mtg. to discuss potential CV risks with Vioxx Mtg. to discuss potential CV risks with Vioxx Almost 1 year after VIGOR released Almost 1 year after VIGOR released Had authority to mandate a more specific trial Had authority to mandate a more specific trial Could have forced Merck to “get to the point” Could have forced Merck to “get to the point” Oct 6, 2001 Oct 6, 2001 Warning letter to Merck for misrepresenting the safety of Vioxx Warning letter to Merck for misrepresenting the safety of Vioxx April 11, 2002 April 11, 2002 Required package insert warning of CV precautions Required package insert warning of CV precautions Regulates direct-to-consumer advertising Regulates direct-to-consumer advertising Allowed Merck to spend $100 million/year Allowed Merck to spend $100 million/year

25. Adverse Event Reporting Post-marketing surveillance Post-marketing surveillance “Pharmacovigilance”: the process of monitoring and improving drug safety (WHO) “Pharmacovigilance”: the process of monitoring and improving drug safety (WHO) Standard form for physicians, pharmacists Standard form for physicians, pharmacists Two problems: Two problems: 1 – Providers may not voluntarily report 1 – Providers may not voluntarily report Too busy, fear of litigation Too busy, fear of litigation 2 – Some effects difficult to recognize 2 – Some effects difficult to recognize If a 70 year-old diabetic smoker had an MI, and also took Vioxx, a phsyician would not make the connection to Vioxx If a 70 year-old diabetic smoker had an MI, and also took Vioxx, a phsyician would not make the connection to Vioxx

26. Is Celebrex Next? Celecoxib is Pfizer’s Vioxx Celecoxib is Pfizer’s Vioxx ~5 times less selective – may reduce risks ~5 times less selective – may reduce risks CLASS (Celecoxib Longterm Arthritis Safety Study) CLASS (Celecoxib Longterm Arthritis Safety Study)

27. Key Points Vioxx was a selective inhibitor of COX-2 Vioxx was a selective inhibitor of COX-2 Effective pain and swelling relief without GI effects Effective pain and swelling relief without GI effects VIGOR study showed increased CV events VIGOR study showed increased CV events Explained by cardioprotective Naproxen Explained by cardioprotective Naproxen APPROVe showed significant CV effects over long-term usage of Vioxx largest drug recall ever APPROVe showed significant CV effects over long-term usage of Vioxx largest drug recall ever Liability uncertain Liability uncertain FDA, Merck, or post-market reporting FDA, Merck, or post-market reporting This will change the way drugs get to market This will change the way drugs get to market

28. References Cox, Michael M. and Nelson, David L. Principles of Biochemistry, 4th Edition. H. Freeman & Co. 2004. Cox, Michael M. and Nelson, David L. Principles of Biochemistry, 4th Edition. H. Freeman & Co. 2004. Chan C-C (1999) Rofecoxib: a potent and orally active cyclooxygenase-2 inhibitor. Pharmacological and biochemical profiles. J Pharamacol Exp Ther 290:551-560. Chan C-C (1999) Rofecoxib: a potent and orally active cyclooxygenase-2 inhibitor. Pharmacological and biochemical profiles. J Pharamacol Exp Ther 290:551-560. Layton D, Riley J, Wilton LV, and Shakir SA (2003) Safety profile of rofecoxib as used in general practice in England: results of a prescription-event monitoring study. Br J Clin Pharmacol 55:166- 174. Layton D, Riley J, Wilton LV, and Shakir SA (2003) Safety profile of rofecoxib as used in general practice in England: results of a prescription-event monitoring study. Br J Clin Pharmacol 55:166- 174. www.vioxx.com www.vioxx.com www.vioxx.com Wooltorton E (2002) What’s all the fuss? Safety concerns about COX-2 inhibitors rofecoxib (Vioxx) and celecoxib (Celebrex). CMAJ 166:1692-1693. Wooltorton E (2002) What’s all the fuss? Safety concerns about COX-2 inhibitors rofecoxib (Vioxx) and celecoxib (Celebrex). CMAJ 166:1692-1693. Konstam MA (2001) Cardiovascular thrombotic events in controlled clinical trials of rofecoxib. Circulation 104:15-23. Konstam MA (2001) Cardiovascular thrombotic events in controlled clinical trials of rofecoxib. Circulation 104:15-23. Bombardier C (2000) Comparison of upper gastrointestinal toxicity of rofecoxib abd naproxen in patients with rheumatoid arthritis. N Engl J Med 343:1520-1528. Bombardier C (2000) Comparison of upper gastrointestinal toxicity of rofecoxib abd naproxen in patients with rheumatoid arthritis. N Engl J Med 343:1520-1528. Forster AJ (2004) Rofecoxib announcement could have long-term implications. JAMA 137:9-10. Forster AJ (2004) Rofecoxib announcement could have long-term implications. JAMA 137:9-10. Mukherjee D (2001) Risk of cardiovascular events associated with selective COX-2 inhibitors. JAMA 286:954-959. Mukherjee D (2001) Risk of cardiovascular events associated with selective COX-2 inhibitors. JAMA 286:954-959. Flieger K (1995) FDA consumer special report: testing drugs in people. US FDA Online at www.fda.gov/fdac/special/newdrug/testing.html. Flieger K (1995) FDA consumer special report: testing drugs in people. US FDA Online at www.fda.gov/fdac/special/newdrug/testing.html. www.fda.gov/fdac/special/newdrug/testing.html Topol EJ (2004) Failing the public health – rofecoxib, Merck, and the FDA. N Engl J Med 351:1707-1709. Topol EJ (2004) Failing the public health – rofecoxib, Merck, and the FDA. N Engl J Med 351:1707-1709. www.yourlawyer.com www.yourlawyer.com www.yourlawyer.com

29. School’s Out (Forever)