Upload
gwenda-adams
View
214
Download
0
Tags:
Embed Size (px)
Citation preview
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)