Andrew KoteckiAndrew Kotecki

May 2May 2ndnd, 2005, 2005

A A Vioxx Vioxx a Day a Day Won’t Keep the Won’t Keep the

Doctor AwayDoctor Away

OverviewOverview

The biochemistry of pain reliefThe biochemistry of pain relief

What exactly is What exactly is VioxxVioxx??

Pharmaceutical product developmentPharmaceutical product development

Does Does VioxxVioxx work? work?

Evidence for health hazards, from release to recallEvidence for health hazards, from release to recall

Who’s to blame?Who’s to blame?

How do How do youyou spell pain relief? spell pain relief?

NSAIDs - NSAIDs - nnononssteroidal teroidal aantintiiinflammatory nflammatory ddrugsrugs

Advil(not gumballs)

Ibuprofen Aspirin Acetominophen Naproxen

EicosanoidsEicosanoids

Paracrine hormones, acting locally rather than Paracrine hormones, acting locally rather than being transported in the bloodstreambeing transported in the bloodstream

Derived from arachadonic acid (20-carbons)Derived from arachadonic acid (20-carbons) Catalyzed by COXCatalyzed by COX

Three classesThree classes LeukotrienesLeukotrienes Thromboxanes (TBXs)Thromboxanes (TBXs) Prostaglandins (PGs)Prostaglandins (PGs)

regulate cAMP synthesisregulate cAMP synthesis cause fever, inflammation, paincause fever, inflammation, pain

COX IsozymesCOX Isozymes

COX = cyclooxygenase (a.k.a. PGHCOX = cyclooxygenase (a.k.a. PGH22 synthase) synthase)

COX-1COX-1 important for gastric cytoprotection, renal homeostasis, normal important for gastric cytoprotection, renal homeostasis, normal

platelet functioningplatelet functioning

COX-2COX-2 produces PGs responsible for fever, inflammation, painproduces PGs responsible for fever, inflammation, pain

So, a drug that specifically inhibited COX-2 could relieve So, a drug that specifically inhibited COX-2 could relieve pain, swelling, without GI irritation!pain, swelling, without GI irritation!

How NSAIDs WorkHow NSAIDs Work

Non-specific COX inihibitionNon-specific COX inihibition inhibit cycloogenase activity of inhibit cycloogenase activity of bothboth

COX isozymesCOX isozymes side effects side effects

GI irritation, ulcerationGI irritation, ulceration COX-1 inhibition reduces gastric protectionCOX-1 inhibition reduces gastric protection nonspecificnonspecific COX inhibition is the problem COX inhibition is the problem Duodenal Duodenal ulcers in 15-30% of patientsulcers in 15-30% of patients

who regularly take NSAIDswho regularly take NSAIDs ~16,500/yr die from associated GI effects~16,500/yr die from associated GI effects

Vioxx Vioxx (Rofecoxib)(Rofecoxib)

Oral anti-inflammatory, pain-relieverOral anti-inflammatory, pain-reliever

FDA approved May 21, 1999FDA approved May 21, 1999

Perscribed to over 80 million patientsPerscribed to over 80 million patientsin 80 countriesin 80 countries

Over $2.5 billion in sales annuallyOver $2.5 billion in sales annually

Highly specific inhibitor of COX-2Highly specific inhibitor of COX-2

Reduces pain and inflammation,Reduces pain and inflammation,but without GI side effectsbut without GI side effects

Pharmaceutical Product DevelopmentPharmaceutical Product Development

Average 12 years from beaker to medicine cabinetAverage 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 marketonly 1 makes it to market

Average $359 million spent for every successful drugAverage $359 million spent for every successful drug

Clinical TrialsClinical Trials

 Preclinical

Testing

File IND

at FDA

Phase I Phase II Phase III

File NDA

at FDA

FDA   Phase IV

Years 3.5 1 2 3 2.512

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 trials1

approved

IND = Investigational New Drug ApplicationNDA = New Drug Application

Ethical ConsiderationsEthical Considerations

Testing new drugs on humans?Testing new drugs on humans? Preceded by animal testing, to weed out the worstPreceded 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 basisInform patients, volunteer basis If survival is threatened, known effective therapy is givenIf survival is threatened, known effective therapy is given

Studies are sponsored by those who stand to make $$$Studies are sponsored by those who stand to make $$$

VioxxVioxx Works – Rat Studies Works – Rat Studies

Rofecoxib : Rofecoxib : ID50 = 2.0 ± 0.2 mg/kg

Indomethacin: ID50 = 1.5 ± 0.1 mg/kg

Effective anti-inflammatoryEffective anti-inflammatory

Rofecoxib : Rofecoxib : ID50 = 0.24 ± 0.07 mg/kg

Indomethacin: ID50 = 1.07 ± 0.16 mg/kg

Better fever-reducerBetter fever-reducer

More than five times the selectivity of the next-bestMore than five times the selectivity of the next-best

COX-2 inhibitor, COX-2 inhibitor, CelebrexCelebrex

VioxxVioxx Selectivity Selectivity

Keeping GI Tract HappyKeeping GI Tract Happy

Effects of chronic dosing for 5 days onGI integrity in squirrel monkeys.

100

mg/k

g

1 m

g/kg

5 m

g/kg

Looking Good So Far…Looking Good So Far…

At least as effective as other NSAIDsAt 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 irritationSignificantly reduced GI irritation

VIGOR – March, 2000VIGOR – March, 2000 ViVioxxoxx GGastrointestinal astrointestinal OOutcomes utcomes RResearchesearch

Post-market study involving more than 28,000 patientsPost-market study involving more than 28,000 patients

Confirmed serious CV adverse events, including fatal andnonfatal MI and storke. Rofecoxib – 50 mg once daily(double dose). Naproxen – 500 mg twice daily.

1.7 %

0.7 %

Relative Incidence of Adverse CV EventsRelative Incidence of Adverse CV Events

VioxxVioxx v. placebo – 0.84 v. placebo – 0.84 Vioxx Vioxx v. non-naproxenv. non-naproxen

NSAIDs – 0.79NSAIDs – 0.79 Vioxx Vioxx v. naproxen – 1.69v. naproxen – 1.69

However, similar mortality ratesHowever, similar mortality rates

No evidence for No evidence for Vioxx Vioxx causing CV problemscausing CV problems Naproxen is cardioprotectiveNaproxen is cardioprotective

““Write That Down”Write That Down”

““Until [further studies] are available, doctors should Until [further studies] are available, doctors should continue to prescribecontinue to prescribe all NSAIDs with caution.” – all NSAIDs with caution.” – Br J Br J Clin PharmacolClin Pharmacol, 2003, 2003

““When [these data] became available, Merck notified all When [these data] became available, Merck notified all investigators in ongoing studies of a change in the investigators in ongoing studies of a change in the exclusion criteria to allow patients to use low-dose exclusion criteria to allow patients to use low-dose aspirin.” – aspirin.” – N Engl J MedN Engl J Med 2000 2000

Just a ThoughtJust a Thought

Selective COX-2 inhibitors do not effect TBX-ASelective COX-2 inhibitors do not effect TBX-A22

productionproduction TBX-ATBX-A22 is prothrombotic is prothrombotic

They They dodo decrease the production of PGI decrease the production of PGI22

PGIPGI22 is antithrombotic is antithrombotic

Selective COX-2 action “may tip the neutral balance, Selective COX-2 action “may tip the neutral balance, leading to an increase in thrombotic CV events.” – leading to an increase in thrombotic CV events.” – JAMA JAMA 20012001

From Bad to WorseFrom Bad to Worse

APPROVe – APPROVe – aadenamatous denamatous ppolyp olyp prprevention evention oon n VVIOXXIOXX Designed to assess Designed to assess VioxxVioxx in prevention of colon cancer in prevention of colon cancer Longer term study – CV effects past 18+ monthsLonger term study – CV effects past 18+ months

Trial halted prematurelyTrial halted prematurely Risk of MI and stroke – 3.5 per 100 patient yearsRisk of MI and stroke – 3.5 per 100 patient years Compare to 1.9 per 100 patient years in placebo groupCompare to 1.9 per 100 patient years in placebo group

September 30, 2004 – September 30, 2004 – VIOXXVIOXX recalled recalled The LARGEST prescription drug withdrawal in historyThe LARGEST prescription drug withdrawal in history

How bad is it, really?How bad is it, really?

Ontario, Canada, in the year 2000Ontario, Canada, in the year 2000 ~15,000 elderly filled ~15,000 elderly filled VioxxVioxx prescriptions prescriptions Extrapolating 3.5 events per 100 patient yearsExtrapolating 3.5 events per 100 patient years

240 patients experienced MI or stroke due to 240 patients experienced MI or stroke due to VioxxVioxx Over 80 million total patients, the impacts are hugeOver 80 million total patients, the impacts are huge

1.28 1.28 millionmillion strokes or MIs due to strokes or MIs due to VioxxVioxx

Pointing FingersPointing Fingers

MerckMerck Responsible for VIGOR and APPROVe studiesResponsible for VIGOR and APPROVe studies

FDAFDA Didn’t use authority to catch this soonerDidn’t use authority to catch this sooner

Adverse Event Reporting (AER)Adverse Event Reporting (AER) Limited ability to identify a post-market problemLimited ability to identify a post-market problem

MerckMerck

VIGOR, APPROVe, and related studies done at MerckVIGOR, APPROVe, and related studies done at Merck

March 9, 2000March 9, 2000 ““Merck’s research chief, Edward Scolnick, e-mailed colleagues that the 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 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.’”incidence and it is mechanism based as we worried it was.’”

February, 2001February, 2001 ““A letter was written by a Dr. James Fries, senior professor and medical A letter was written by a Dr. James Fries, senior professor and medical

director and Stanford University Medical School to Merck complaining director and Stanford University Medical School to Merck complaining about the intimidation by Merck’s investigators including the threatening about the intimidation by Merck’s investigators including the threatening of the loss of funding because of the school’s discussion of CV events of the loss of funding because of the school’s discussion of CV events associated with Vioxx.”associated with Vioxx.”

FDAFDA

Arthritis Advisory Committee meeting Feb 8, 2001Arthritis Advisory Committee meeting Feb 8, 2001 Mtg. to discuss potential CV risks with Mtg. to discuss potential CV risks with VioxxVioxx Almost 1 year after VIGOR releasedAlmost 1 year after VIGOR released

Had authority to mandate a more specific trialHad 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, 2001Oct 6, 2001 Warning letter to Merck for misrepresenting the safety of Warning letter to Merck for misrepresenting the safety of Vioxx Vioxx

April 11, 2002April 11, 2002 Required package insert warning of CV precautionsRequired package insert warning of CV precautions

Regulates direct-to-consumer advertisingRegulates direct-to-consumer advertising Allowed Merck to spend $100 million/yearAllowed Merck to spend $100 million/year

Adverse Event ReportingAdverse Event Reporting

Post-marketing surveillancePost-marketing surveillance ““Pharmacovigilance”: the process of monitoring and improving Pharmacovigilance”: the process of monitoring and improving

drug safety (WHO)drug safety (WHO)

Standard form for physicians, pharmacistsStandard form for physicians, pharmacists

Two problems:Two problems: 1 – Providers may not voluntarily report1 – Providers may not voluntarily report

Too busy, fear of litigationToo busy, fear of litigation 2 – Some effects difficult to recognize2 – Some effects difficult to recognize

If a 70 year-old diabetic smoker had an MI, and also took If a 70 year-old diabetic smoker had an MI, and also took VioxxVioxx, a , a phsyician would not make the connection to phsyician would not make the connection to VioxxVioxx

Is Is CelebrexCelebrex Next? Next?

Celecoxib is Pfizer’s Celecoxib is Pfizer’s VioxxVioxx ~5 times less selective – may reduce risks~5 times less selective – may reduce risks

CLASS (CLASS (CCelecoxib elecoxib LLongterm ongterm AArthritis rthritis SSafety afety SStudy)tudy)

Key PointsKey Points

Vioxx was a selective inhibitor of COX-2Vioxx was a selective inhibitor of COX-2 Effective pain and swelling relief without GI effectsEffective pain and swelling relief without GI effects

VIGOR study showed increased CV eventsVIGOR study showed increased CV events Explained by cardioprotective NaproxenExplained by cardioprotective Naproxen

APPROVe showed significant CV effects over long-term usage of APPROVe showed significant CV effects over long-term usage of Vioxx Vioxx largest drug recall everlargest drug recall ever

Liability uncertainLiability uncertain FDA, Merck, or post-market reportingFDA, Merck, or post-market reporting This will change the way drugs get to marketThis will change the way drugs get to market

ReferencesReferences

Cox, Michael M. and Nelson, David L. Principles of Biochemistry, 4th Edition. H. Freeman & Co. Cox, Michael M. and Nelson, David L. Principles of Biochemistry, 4th Edition. H. Freeman & Co. 2004. 2004.

Chan C-C (1999) Rofecoxib: a potent and orally active cyclooxygenase-2 inhibitor. Chan C-C (1999) Rofecoxib: a potent and orally active cyclooxygenase-2 inhibitor. Pharmacological and biochemical profiles. Pharmacological and biochemical profiles. J Pharamacol Exp TherJ Pharamacol Exp Ther 290290:551-560.:551-560.

Layton D, Riley J, Wilton LV, and Shakir SA (2003) Safety profile of rofecoxib as used in general 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. practice in England: results of a prescription-event monitoring study. Br J Clin PharmacolBr J Clin Pharmacol 5555:166-:166-174.174.

www.vioxx.comwww.vioxx.com Wooltorton E (2002) What’s all the fuss? Safety concerns about COX-2 inhibitors rofecoxib Wooltorton E (2002) What’s all the fuss? Safety concerns about COX-2 inhibitors rofecoxib

(Vioxx) and celecoxib (Celebrex). (Vioxx) and celecoxib (Celebrex). CMAJCMAJ 166166:1692-1693.:1692-1693. Konstam MA (2001) Cardiovascular thrombotic events in controlled clinical trials of rofecoxib. Konstam MA (2001) Cardiovascular thrombotic events in controlled clinical trials of rofecoxib.

CirculationCirculation 104104:15-23.:15-23. Bombardier C (2000) Comparison of upper gastrointestinal toxicity of rofecoxib abd naproxen in Bombardier C (2000) Comparison of upper gastrointestinal toxicity of rofecoxib abd naproxen in

patients with rheumatoid arthritis. patients with rheumatoid arthritis. N Engl J MedN Engl J Med 343343:1520-1528.:1520-1528. Forster AJ (2004) Rofecoxib announcement could have long-term implications. Forster AJ (2004) Rofecoxib announcement could have long-term implications. JAMAJAMA 137137:9-10.:9-10. Mukherjee D (2001) Risk of cardiovascular events associated with selective COX-2 inhibitors. Mukherjee D (2001) Risk of cardiovascular events associated with selective COX-2 inhibitors.

JAMAJAMA 286286:954-959.:954-959. Flieger K (1995) FDA consumer special report: testing drugs in people. Flieger K (1995) FDA consumer special report: testing drugs in people. US FDA US FDA Online at Online at

www.fda.gov/fdac/special/newdrug/testing.htmlwww.fda.gov/fdac/special/newdrug/testing.html.. Topol EJ (2004) Failing the public health – rofecoxib, Merck, and the FDA. Topol EJ (2004) Failing the public health – rofecoxib, Merck, and the FDA. N Engl J MedN Engl J Med

351351:1707-1709.:1707-1709. www.yourlawyer.comwww.yourlawyer.com

School’s Out (Forever)School’s Out (Forever)