FDA Advisory Committee on FDA Advisory Committee on COX-2 Inhibitors & NSAIDs COX-2 Inhibitors & NSAIDs Gaithersburg, Maryland Gaithersburg, Maryland

February 16-18, 2005 February 16-18, 2005

Ernest Hawk, MD, MPHErnest Hawk, MD, MPHOffice of Centers, Training, & ResourcesOffice of Centers, Training, & Resources

DHHS/NIH/NCIDHHS/NIH/NCI

FDA Advisory Committee on FDA Advisory Committee on COX-2 Inhibitors & NSAIDs COX-2 Inhibitors & NSAIDs Gaithersburg, Maryland Gaithersburg, Maryland

February 16-18, 2005 February 16-18, 2005

Ernest Hawk, MD, MPHErnest Hawk, MD, MPHOffice of Centers, Training, & ResourcesOffice of Centers, Training, & Resources

DHHS/NIH/NCIDHHS/NIH/NCI

Celecoxib in Adenoma Prevention - The APC Trial

Celecoxib in Adenoma Prevention - The APC Trial

Colorectal Cancer - Global StatisticsColorectal Cancer - Global Statistics

Worldwide(2000)

Worldwide(2000)

USA(2005)USA

(2005)

Incidence

Mortality

Incidence

Mortality

895,000

489,000

895,000

489,000

145,290

56,290

145,290

56,2907.9 % of cancer deaths

(3rd leading cause)7.9 % of cancer deaths

(3rd leading cause)9.9% of cancer deaths

(2nd leading cause)9.9% of cancer deaths

(2nd leading cause)

Parkin M: Lancet Oncology 2:533-543, 2002

Jemal A, et al. CA Cancer J Clin 55:10-30, 2005

Parkin M: Lancet Oncology 2:533-543, 2002

Jemal A, et al. CA Cancer J Clin 55:10-30, 2005

5-20 yrs5-20 yrs 5-15 yrs5-15 yrsADENOMAADENOMA

NormalNormalNormalNormal MildMildMildMild ModerateModerateModerateModerate SevereSevereSevereSevere CancerCancerCancerCancer

APC, bcl-2, c-mycHypomethylation

COX-2COX-2

APC, bcl-2, c-mycHypomethylation

COX-2COX-2

K-rasK-ras SMAD 2SMAD 4

DCC

SMAD 2SMAD 4

DCC

P53E-Cadherin

P53E-Cadherin

Carcinogenesis is a Chronic Disease - From Molecular Defect to Dysplasia to Cancer

Carcinogenesis is a Chronic Disease - From Molecular Defect to Dysplasia to Cancer

Focus of Screening & Surgical CareFocus of Screening & Surgical CareFocus of Screening & Surgical CareFocus of Screening & Surgical Care

Focus of Molecularly-targeted InterventionFocus of Molecularly-targeted InterventionFocus of Molecularly-targeted InterventionFocus of Molecularly-targeted Intervention

Adapted from Ilyas et al. Eur. J. Cancer 1999; 35:335-351 Adapted from Ilyas et al. Eur. J. Cancer 1999; 35:335-351

Evidence for NSAID Efficacy in Reducing Colorectal Cancer RiskEvidence for NSAID Efficacy in

Reducing Colorectal Cancer Risk• Mechanistic:Mechanistic:

– Induce apoptosis, rInduce apoptosis, reduce angiogenesis & peduce angiogenesis & proliferationroliferation

– Stimulate immune surveillance Stimulate immune surveillance

• In vivo: > 100 studies in intestinal carcinogenesisIn vivo: > 100 studies in intestinal carcinogenesis

• Epidemiologic: > 30 studies suggesting 30-40% reductions in Epidemiologic: > 30 studies suggesting 30-40% reductions in

– Adenoma & cAdenoma & colorectal cancer incidenceolorectal cancer incidence

– Colorectal cancer mortalityColorectal cancer mortality

• Randomized trials of aspirin: Randomized trials of aspirin:

– 3 placebo-controlled trials showing 20-30% reductions in adenoma recurrence3 placebo-controlled trials showing 20-30% reductions in adenoma recurrence

• Evidence extends to other organsEvidence extends to other organs

– Breast, prostate, lung, head & neck, esophagus, bladder, skin, plasma cellsBreast, prostate, lung, head & neck, esophagus, bladder, skin, plasma cells

• Mechanistic:Mechanistic:

– Induce apoptosis, rInduce apoptosis, reduce angiogenesis & peduce angiogenesis & proliferationroliferation

– Stimulate immune surveillance Stimulate immune surveillance

• In vivo: > 100 studies in intestinal carcinogenesisIn vivo: > 100 studies in intestinal carcinogenesis

• Epidemiologic: > 30 studies suggesting 30-40% reductions in Epidemiologic: > 30 studies suggesting 30-40% reductions in

– Adenoma & cAdenoma & colorectal cancer incidenceolorectal cancer incidence

– Colorectal cancer mortalityColorectal cancer mortality

• Randomized trials of aspirin: Randomized trials of aspirin:

– 3 placebo-controlled trials showing 20-30% reductions in adenoma recurrence3 placebo-controlled trials showing 20-30% reductions in adenoma recurrence

• Evidence extends to other organsEvidence extends to other organs

– Breast, prostate, lung, head & neck, esophagus, bladder, skin, plasma cellsBreast, prostate, lung, head & neck, esophagus, bladder, skin, plasma cells

Established Safety Concerns of Nonselective COX Inhibitors (NSAIDs)

Established Safety Concerns of Nonselective COX Inhibitors (NSAIDs)

• 13 million chronic 13 million chronic users (U.S.)users (U.S.)

• Dyspepsia in 10-20%Dyspepsia in 10-20%

• Serious GI Serious GI complications in 1.3%complications in 1.3%

– Fatalities in 5-10% of Fatalities in 5-10% of these these

• Total direct cost/year Total direct cost/year > $2 billion> $2 billion

• ~ 15~ 15thth most common most common cause of death (U.S.)cause of death (U.S.)

• 13 million chronic 13 million chronic users (U.S.)users (U.S.)

• Dyspepsia in 10-20%Dyspepsia in 10-20%

• Serious GI Serious GI complications in 1.3%complications in 1.3%

– Fatalities in 5-10% of Fatalities in 5-10% of these these

• Total direct cost/year Total direct cost/year > $2 billion> $2 billion

• ~ 15~ 15thth most common most common cause of death (U.S.)cause of death (U.S.)

Wolfe, et al: NEJM 1999Wolfe, et al: NEJM 1999

Mortality for 7 Selected Mortality for 7 Selected Disorders (1997)Disorders (1997)

Mortality for 7 Selected Mortality for 7 Selected Disorders (1997)Disorders (1997)

FAP PATHOPHYSIOLOGYFAP PATHOPHYSIOLOGYFAP PATHOPHYSIOLOGYFAP PATHOPHYSIOLOGY

FAP PATIENTSFAP PATIENTSFAP PATIENTSFAP PATIENTS

NSAID CANCER PREVENTIONNSAID CANCER PREVENTIONNSAID CANCER PREVENTIONNSAID CANCER PREVENTION

– Genetic basis of disease– Adenoma-carcinoma sequence– Serial endoscopic surveillance– COX-2 overexpression– Established preclinical models

– Genetic basis of disease– Adenoma-carcinoma sequence– Serial endoscopic surveillance– COX-2 overexpression– Established preclinical models

– Preclinical data– Observational data– Intervention data– Safety concerns

– Preclinical data– Observational data– Intervention data– Safety concerns

– Unmet clinical need– Limited cohort – MDACC & St. Mark’s registries

– Unmet clinical need– Limited cohort – MDACC & St. Mark’s registries

NCI - PHARMACIA COLLABORATIVE NCI - PHARMACIA COLLABORATIVE TRIAL OF CELECOXIB IN FAPTRIAL OF CELECOXIB IN FAP

NCI - PHARMACIA COLLABORATIVE NCI - PHARMACIA COLLABORATIVE TRIAL OF CELECOXIB IN FAPTRIAL OF CELECOXIB IN FAP

SEARLE/PHARMACIASEARLE/PHARMACIASEARLE/PHARMACIASEARLE/PHARMACIA

– COX-2 technology– Celecoxib safety database– Celecoxib preclinical data

– COX-2 technology– Celecoxib safety database– Celecoxib preclinical data

Phenotype & Natural History of Familial Adenomatous Polyposis (FAP)

Phenotype & Natural History of Familial Adenomatous Polyposis (FAP)

• Germline APC gene defect• Autosomal dominant transmission• Frequency = 1/10,000 live births• ~ 20-30% of cases may be due to spontaneous mutations• ~ 100% lifetime cancer risk• Average age at death = 42 years

• Germline APC gene defect• Autosomal dominant transmission• Frequency = 1/10,000 live births• ~ 20-30% of cases may be due to spontaneous mutations• ~ 100% lifetime cancer risk• Average age at death = 42 years

• Extracolonic manifestationsExtracolonic manifestations• Duodenal adenomas/cancerDuodenal adenomas/cancer• DesmoidsDesmoids

• Despite standard careDespite standard care• RR of death = 3.35 (n = 222)RR of death = 3.35 (n = 222)

• Celecoxib is the only approved Celecoxib is the only approved pharmacologic adjunctive therapypharmacologic adjunctive therapy

Nugent, KP et al. Dis Colon Rectum, 1993Nugent, KP et al. Dis Colon Rectum, 1993

Percent Change in Number of

Colorectal Polyps with Celecoxib (Individual Patients; Median Results)

Percent Change in Number of Percent Change in Number of Colorectal Polyps with Celecoxib Colorectal Polyps with Celecoxib

(Individual Patients; Median Results)(Individual Patients; Median Results)

Per

cen

t C

han

ge

fro

m B

asel

ine

Per

cen

t C

han

ge

fro

m B

asel

ine

PlaceboPlaceboN=15N=15

100 mg BID100 mg BIDN=32N=32

400 mg BID*400 mg BID*N=30N=30

--8080

--6060

--4040

--2020

00

2020

4040

6060

8080

0%0% --7%7%

--32%32%

* P = 0.003 versus placebo* P = 0.003 versus placebo Steinbach, et al. NEJM, 2000

Colorectal Efficacy of Celecoxib in

Patients with FAP

Colorectal Efficacy of Celecoxib in

Patients with FAP

Patient 5120400 mg BIDPatient 5120400 mg BID

Baseline polyp number = 41Baseline polyp number = 41 6 Month polyp number = 216 Month polyp number = 21Percent change = Percent change = --48.8%48.8%

2

2,035 patients with prior sporadic adenomas

2,035 patients with prior sporadic adenomas

Randomized1:1:1

• Colonoscopy after 12 & 36 months evaluating

recurrence; collection of all adenomas

NCI/Pfizer’s APC TrialNCI/Pfizer’s APC Trial

Celecoxib 200 mg BID x 36 mos.

Stratified by aspirin use & clinical center

Stratified by aspirin use & clinical center

Celecoxib 400 mg BID x 36 mos.

Placebo x 36 mos.

91 Clinical Sites - 72 US, 10 Canada, 8 Australia, 1 UKAccrual - November 1999 to March 2002

91 Clinical Sites - 72 US, 10 Canada, 8 Australia, 1 UKAccrual - November 1999 to March 2002

Adjudication & Analysis of Serious CV Adverse Events in the APC & PreSAP Trials

Adjudication & Analysis of Serious CV Adverse Events in the APC & PreSAP Trials

• Recommended by DSMBsRecommended by DSMBs

• Independent Cardiovascular Safety CommitteeIndependent Cardiovascular Safety Committee

– Clinical Endpoint Committee (blinded)Clinical Endpoint Committee (blinded)

• Scott Solomon, MDScott Solomon, MD

• Peter Finn, MDPeter Finn, MD

– Cardiovascular Review CommitteeCardiovascular Review Committee

• Marc Pfeffer, MD, PhDMarc Pfeffer, MD, PhD

• John McMurray, MDJohn McMurray, MD

• Janet Wittes, PhDJanet Wittes, PhD

• Recommended by DSMBsRecommended by DSMBs

• Independent Cardiovascular Safety CommitteeIndependent Cardiovascular Safety Committee

– Clinical Endpoint Committee (blinded)Clinical Endpoint Committee (blinded)

• Scott Solomon, MDScott Solomon, MD

• Peter Finn, MDPeter Finn, MD

– Cardiovascular Review CommitteeCardiovascular Review Committee

• Marc Pfeffer, MD, PhDMarc Pfeffer, MD, PhD

• John McMurray, MDJohn McMurray, MD

• Janet Wittes, PhDJanet Wittes, PhD

CV Safety Adjudication & Analysis in the APC & PreSAP Trials - A 3-Step Process

CV Safety Adjudication & Analysis in the APC & PreSAP Trials - A 3-Step Process• PlanningPlanning

– Developed standard definitions, heirarchical categorization scheme & statistical Developed standard definitions, heirarchical categorization scheme & statistical analysis plananalysis plan

• Data Compilation, Verification, & AdjudicationData Compilation, Verification, & Adjudication

– Reviewed SAE forms & source documentsReviewed SAE forms & source documents

– Queried sites to supplement study dataQueried sites to supplement study data

– Adjudicated events Adjudicated events

– Created an ACCESS database of adjudicated CV SAEsCreated an ACCESS database of adjudicated CV SAEs

• AnalysisAnalysis

– Obtained randomization codes & relevant baseline dataObtained randomization codes & relevant baseline data

– Analyzed data according to intent-to-treat principlesAnalyzed data according to intent-to-treat principles

– Presented data to DSMBPresented data to DSMB

• PlanningPlanning

– Developed standard definitions, heirarchical categorization scheme & statistical Developed standard definitions, heirarchical categorization scheme & statistical analysis plananalysis plan

• Data Compilation, Verification, & AdjudicationData Compilation, Verification, & Adjudication

– Reviewed SAE forms & source documentsReviewed SAE forms & source documents

– Queried sites to supplement study dataQueried sites to supplement study data

– Adjudicated events Adjudicated events

– Created an ACCESS database of adjudicated CV SAEsCreated an ACCESS database of adjudicated CV SAEs

• AnalysisAnalysis

– Obtained randomization codes & relevant baseline dataObtained randomization codes & relevant baseline data

– Analyzed data according to intent-to-treat principlesAnalyzed data according to intent-to-treat principles

– Presented data to DSMBPresented data to DSMB

APC Trial - Patient Characteristics at BaselineAPC Trial - Patient Characteristics at Baseline

Baselinecharacteristic

Placebo

N =  679

Celecoxib200 mg BID

N =  685

Celecoxib400 mg BID

N =  671

Age in years 59.7  9.7 59.7  9.4 59.9  9.4

% % %

Male 69.7 67.2 67.7

History of cardiovascular events  47.3 48.9 45.8

    Myocardial infarction (MI) 4.3 3.2 4.6

   Cerebrovascular disease  2.1 2.9 1.9

   Congestive heart failure (CHF) 2.1 0.9 1.6

   Angina 7.5 7.3 6.3

   Hypertension 40.8 41.9 38.7

Diabetes† 9.0 9.6 9.5

Current smoker 18.0 17.4 14.3

Aspirin use 31.4 29.3 29.8

Lipid-lowering drug use 27.1 27.4 28.5

Note:  Plus-minus values are means ±SD. There were no significant differences among the groups. †Data were missing for one patient in the placebo group.

Solomon SD, et al: N Engl J Med 352, 2005

Incidence of Hierarchical Cardiovascular Composite Endpoints in the APC Trial

Incidence of Hierarchical Cardiovascular Composite Endpoints in the APC Trial

Endpoint Number of patients (%) Rate/1000 patient-years

Placebo 200 mg BID

400 mg BID

Placebo 200 mg BID

400 mg BID

Death from CV causes 1 (0.1) 3 (0.4) 6 (0.9) 0.5 1.4 2.9

Death from CV causes or MI 4 (0.6) 12 (1.8) 15 (2.2) 1.9 5.8 7.4

Death from CV causes, MI, or stroke

6 (0.9) 15 (2.2) 20 (3.0) 2.9 7.3 9.9

Death from CV causes, MI, stroke, or heart failure

7 (1.0) 16 (2.3) 23 (3.4) 3.4 7.8 11.4

Death from CV causes, MI, stroke, heart failure, or angina

11 (1.6) 18 (2.6) 25 (3.7) 5.4 8.7 12.5

Death from CV causes, MI, stroke, heart failure, angina, or need for a cv procedure

17 (2.5) 26 (3.8) 31 (4.6) 8.4 12.7 15.5

Solomon SD, et al: N Engl J Med 352, 2005

Hazard Ratios for Hierarchical Cardiovascular Composite Endpoints in the APC Trial

Hazard Ratios for Hierarchical Cardiovascular Composite Endpoints in the APC Trial

Solomon SD, et al: N Engl J Med 352, 2005

Endpoint Hazard Ratio with 95% Confidence Interval*

200 mg BID 400 mg BID

Death from CV causes 3.0 (0.3-28.6) 6.1 (0.7-50.3)

Death from CV causes or MI 3.0 (1.0-9.3) 3.8 (1.3-11.5)

Death from CV causes, MI, or stroke 2.5 (1.0-6.4) 3.4 (1.4-8.5)

Death from CV causes, MI, stroke, or heart failure

2.3 (0.9-5.5) 3.4 (1.4-7.8)

Death from CV causes, MI, stroke, heart failure, or angina

1.6 (0.8-3.4) 2.3 (1.1-4.7)

Death from CV causes, MI, stroke, heart failure, angina, or need for a cv procedure

1.5 (0.8-2.8) 1.9 (1.0-3.3)

*Relative to placebo

Number & Percentage of Patients with Individual CV Events in the APC Trial

Number & Percentage of Patients with Individual CV Events in the APC Trial

Endpoint

PlaceboN = 679n (%)

Celecoxib200 mg BID

N = 685n (%)

Celecoxib400 mg BID

N = 671n (%)

Death from CV causes 1 (0.1) 3 (0.4) 6 (0.9)

Death from non-CV causes 5 (0.7) 3 (0.4) 3 (0.4)

Death from any cause 6 (0.9) 6 (0.9) 9 (1.3)

Solomon SD, et al: N Engl J Med 352, 2005

APC Trial - CV Events by Baseline Subgroup

APC Trial - CV Events by Baseline Subgroup

• Examined cardiovascular risk in various risk Examined cardiovascular risk in various risk subgroupssubgroups

– Age, gender, cv risk factors, diabetes, aspirin Age, gender, cv risk factors, diabetes, aspirin use, use of lipid-lowering druguse, use of lipid-lowering drug

• No statistical evidence of a differential hazard by No statistical evidence of a differential hazard by baseline risk factorsbaseline risk factors

• Few events Few events

• Limited power Limited power

• Examined cardiovascular risk in various risk Examined cardiovascular risk in various risk subgroupssubgroups

– Age, gender, cv risk factors, diabetes, aspirin Age, gender, cv risk factors, diabetes, aspirin use, use of lipid-lowering druguse, use of lipid-lowering drug

• No statistical evidence of a differential hazard by No statistical evidence of a differential hazard by baseline risk factorsbaseline risk factors

• Few events Few events

• Limited power Limited power

Solomon SD, et al: N Engl J Med 352, 2005

681 676 675 673 670 611669 665 655 651 648 594677 675 672 668 667 612

Months sincefirst dose

Sample size

C 200 BIDC 400 BIDPlacebo

Log-rank statistic 8.74 (p= 0.013)

E:\Proj\APC Cox2\Programs\f_KMplot.sas v.010 death_MI_stroke_CHF_005_01.cgm (last run: 02/14/2005, 10:46)CEC adjudication data (received 02/03/2005) RAND data (received 11/23/2004) CRF data (received 02/03/2005)

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Kaplan-Meier Estimates of the Risk of Serious CV Events in the APC Trial by Treatment Arm*Kaplan-Meier Estimates of the Risk of Serious CV Events in the APC Trial by Treatment Arm*

Kaplan-Meier Estimates of the Risk of Serious CV Events in the APC Trial by Treatment Arm*

Kaplan-Meier Estimates of the Risk of Serious CV Events in the APC Trial by Treatment Arm*

Solomon SD, et al: N Engl J Med 352, 2005*In this analysis, “serious CV events” include death from CV causes, MI, stroke, or heart failure

671

Cross-trial Cardiovascular Safety Meta-analysis of Celecoxib

Cross-trial Cardiovascular Safety Meta-analysis of Celecoxib

Trial Planned Cohort Dosing Regimen Planned Duration

APC ~ 2,035 pts with prior adenomas

200 or 400 mg BID 3-5 years

PreSAP ~1,560 pts with prior adenomas

400 mg QD 3-5 years

Selcel ~1,600 pts with prior adenomas

400 mg QD 3 years

ADAPT ~2,625 pts at risk for Alzheimer’s dementia

200 mg BID 3 years

MA27 ~6,830 post-menopausal pts with ER+ breast cancer

400 mg BID 3 years

NEI ~86 pts with diabetic retinopathy

200 mg BID 2 years

Long-term NSAID Use May Increase Risks of Cardiovascular Death - A Norwegian Study, 2005

Long-term NSAID Use May Increase Risks of Cardiovascular Death - A Norwegian Study, 2005

• Population-based, nested case-control study of 454 Scandinavian Population-based, nested case-control study of 454 Scandinavian patients diagnosed with oral cancer between 1975 and 2003, and 454 patients diagnosed with oral cancer between 1975 and 2003, and 454 gender- and age-matched controls. gender- and age-matched controls. (Sudbo J, et al. 2005 - Manuscript submitted)(Sudbo J, et al. 2005 - Manuscript submitted)

• Population-based, nested case-control study of 454 Scandinavian Population-based, nested case-control study of 454 Scandinavian patients diagnosed with oral cancer between 1975 and 2003, and 454 patients diagnosed with oral cancer between 1975 and 2003, and 454 gender- and age-matched controls. gender- and age-matched controls. (Sudbo J, et al. 2005 - Manuscript submitted)(Sudbo J, et al. 2005 - Manuscript submitted)

00 11 22Hazard Ratio for CV Death in Long-term NSAID Users Compared to Non-users Hazard Ratio for CV Death in Long-term NSAID Users Compared to Non-users

(with 95% Confidence Intervals)(with 95% Confidence Intervals)Hazard Ratio for CV Death in Long-term NSAID Users Compared to Non-users Hazard Ratio for CV Death in Long-term NSAID Users Compared to Non-users

(with 95% Confidence Intervals)(with 95% Confidence Intervals)

2.06 2.06

33 5544 66

KetoprofenKetoprofen

PiroxicamPiroxicam

IndomethacinIndomethacin

NaproxenNaproxen

IbuprofenIbuprofen

1.16 1.16

2.86 2.86

1.70 1.70

2.26 2.26

1.84 1.84

1.901.90

AspirinAspirin

Any NSAIDAny NSAID

CV deathsCV deaths

4242

22

77

1010

77

44

1212

Issues Arising from the CV Safety Data with Celecoxib in the APC & PreSAP Trials

Issues Arising from the CV Safety Data with Celecoxib in the APC & PreSAP Trials

• ContextContext– EfficacyEfficacy

– Risk:benefit assessmentsRisk:benefit assessments

– Relative GI and CV safety Relative GI and CV safety compared to other compared to other NSAIDsNSAIDs

• SafetySafety– Overall safetyOverall safety

• GI ulcerationGI ulceration

– Accuracy & precisionAccuracy & precision

• Cross-trials meta-Cross-trials meta-analysisanalysis

• ContextContext– EfficacyEfficacy

– Risk:benefit assessmentsRisk:benefit assessments

– Relative GI and CV safety Relative GI and CV safety compared to other compared to other NSAIDsNSAIDs

• SafetySafety– Overall safetyOverall safety

• GI ulcerationGI ulceration

– Accuracy & precisionAccuracy & precision

• Cross-trials meta-Cross-trials meta-analysisanalysis

– Mechanism(s)Mechanism(s)

• DoseDose

• FrequencyFrequency

• DurationDuration

• PharmacokineticsPharmacokinetics

– Mitigation or risk Mitigation or risk managementmanagement

– Risk segregationRisk segregation

• Baseline risksBaseline risks

• Metabolic Metabolic polymorphismspolymorphisms

• Future ResearchFuture Research

– Mechanism(s)Mechanism(s)

• DoseDose

• FrequencyFrequency

• DurationDuration

• PharmacokineticsPharmacokinetics

– Mitigation or risk Mitigation or risk managementmanagement

– Risk segregationRisk segregation

• Baseline risksBaseline risks

• Metabolic Metabolic polymorphismspolymorphisms

• Future ResearchFuture Research