1 FDA ODAC Meeting November 8, 2005 Celecoxib (CELEBREX ® ) Therapy for Familial Adenomatous Polyposis (FAP) Subpart H Phase IV Commitments.
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FDA ODAC MeetingNovember 8, 2005
Celecoxib (CELEBREX®) Therapy forFamilial Adenomatous Polyposis (FAP)
Subpart H Phase IV Commitments
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Agenda
Familial Adenomatous Polyposis (FAP) Basis for Celebrex approval in FAP
Subpart H commitments Status of Subpart H commitments
FAP Phenotype Suppression Study FAP Registry Study
Summary
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FAP Disease: Overview
Rare inherited disease
Annual incidence rate: 1-2 cases per 1 000 000
Prevalence rate: 2.6 to 4.7 per 100 000
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FAP Disease: Natural History
• Adenomas begin to develop in adolescence• 100-5000 colorectal adenomas• Cancer risk increases with number of adenomas• If untreated
100% colorectal cancer riskMedian life expectancy – 42 years
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FAP Disease: Management
Lifetime endoscopic surveillance Initial colon resection 18-20 years of age Repeated surgeries Surgical prophylaxis has dramatically reduced
this cancer risk, albeit with substantial morbidity Interest in developing medical treatment as an
adjunct to surgery
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Pivotal Registration TrialBasis for Approval
Description Double-blind, placebo-controlled study of celecoxib in patients with FAP
Sites U.T. M.D. Anderson, St. Mark’s (UK)
Treatment Groups Placebo
celecoxib (100, 400 mg po BID)
Primary Endpoint Percent change in the number of colorectal adenomas
Duration of Therapy 6 months
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Celebrex Efficacy in FAPDouble-blind, placebo-controlled Phase II Study
PlaceboCelecoxib 100 mg BIDCelecoxib 400 mg BID
-4.5
-11.9
-28
-35
-30
-25
-20
-15
-10
-5
0
-1.4-4.2
-14.5
-35
-30
-25
-20
-15
-10
-5
0
Patients: N = 81 (17 placebo, 32 100 mg BID, 32 400 mg BID)
Duration of Therapy: 6 months
RESULTS
Duodenal N = 50Duodenal N = 50ColorecColorectal tal N = 77 N = 77
% C
han
ge
Bas
elin
e%
Ch
ang
e B
asel
ine
****400 mg BID versus placebo400 mg BID versus placebo
P = 0.003P = 0.003****
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FAP Indication
Celecoxib (CELEBREX ®) in FAP approved December 1999 under 21 CFR Subpart H to reduce the number of adenomatous colorectal polyps in FAP as an adjunct to usual care (e.g., endoscopic surveillance, surgery) It is not known whether there is a clinical benefit from
a reduction in the number of colorectal polyps in FAP patients.
It is not known whether the effects of CELEBREX treatment will persist after treatment discontinuation
The efficacy and safety of CELEBREX treatment in patients with FAP beyond six months have not been studied
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Subpart H Phase IV Commitments
Post-approval Commitments under Subpart H Phase III placebo-controlled trial of celecoxib
in genotype positive, phenotype negative subjects with FAP
Registry-based observational study assessing clinical outcomes in FAP patients receiving celecoxib compared with control patients
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Genotype Positive StudyBrief Chronology of Events
FDA agrees with study concept
NCI/Pharmacia collaboration NCI issues request for proposals (RFP) Pharmacia to provide drug and monetary support
NCI contract awarded: MD Anderson - lead institution Creighton University Memorial Sloan Kettering Cancer Center Cleveland Clinic Texas Children Hospital University of California San Francisco Mt Sinai Hospital (Toronto) St Marks Hospital (England)
07/00
04/00
12/99
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Consideration of issues before Phase III Celecoxib dosing in children Pilot dose-ranging trial needed
Draft Phase I protocol developed
Phase I/III program submitted to FDA
Three Phase I Protocol revisions required Primary issue: need for placebo control in
Phase I setting
Phase I Protocol approved by NCI
08/00
01/01
02/01
01/02
Genotype Positive StudyBrief Chronology of Events (cont’d.)
10/00
13
MDACC IRB approval
Final Phase I protocol submitted to FDA
Use of investigational 50mg orally dispersible tablets not achieved
Protocol revised to use commercial capsule formulation
First patient enrolled in Phase I study
02/02
08/02
12/02
05/02
06/02
Genotype Positive StudyBrief Chronology of Events (cont’d.)
Expected completion of Phase I study Q3-4 2004
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Genotype Positive StudyPhase I Design
Description: Phase I Pilot Toxicity/Methods Validation Study of Celecoxib in Genotype or Phenotype-Positive Children with Familial Adenomatous Polyposis
Sites: U.T. M.D. Anderson and Cleveland Clinic
Patient population: Patients 10-14 years old with known polyp burden or confirmed APC mutation
Design: Dose escalation trial in successive cohorts of 6 patients (4 celecoxib, 2 placebo)
Treatment groups: Celecoxib (4, 8, 16 mg/kg/day po), Placebo
Sample size: N = 18 ( 3 cohorts of 6 patients)
Duration of therapy: 3 months
Primary endpoint: Safe dose in this patient population
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05/04
02/04
06/04
09/03
Pfizer assumes responsibility for the Phase IV commitments from Pharmacia
Phase III protocol design re-evaluated given updates on Phase I study
• Limitations of phenotype negative population identified
• Single center review of cases within age range
• Clinically meaningful endpoint: phenotype expression, define uniform threshold for endoscopic polyp removal
• Last subject enrolled in third cohort of the Phase I study
04/03
Genotype Positive StudyBrief Chronology of Events (cont’d.)
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Genotype Positive StudyBrief Chronology of Events (cont’d.)
Evaluate the consistency of measurement, number of possible patients per center, clinical practice standards & site feasibility globally for Phase III
DSMB of Phase I study meets Dec 16th for safety review: 16mg/kg/day dose was safe & appropriate for Phase III
09/04
12/04
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FAP Phase I – Adverse Events
Number of Events
Grade 1 AEs
Grade 2AEs
Total # of AEs
Placebo
n=624 0 24
4mg/kg
n=422 2 24
8mg/kg
n=45 2 7
16mg/kg
n=421 0 21
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Grade 1: 94.7 % of all reported AEs Grade 2: 5.3% of all reported AEs No CV AEs reported 21 (28%) events were gastrointestinal:
Abdominal Pain 28.5% (Placebo-3, 4mg/kg-2, 16mg/kg-1) Vomiting NOS 23.8% (4mg/kg-2, 8mg/kg-2, 16mg/kg-1) Nausea 14.3% (Placebo-1, 8mg/kg-1, 16mg/kg-1) Rectal Bleeding 4.8% (Placebo-1) Diarrhea 4.8% (4mg/kg-1) Others 23.8% (4mg/kg-2, 16mg/kg-3)
FAP Phase I – Adverse Events
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FAP Phase I: Polyp Count Difference
Celecoxib Dose
Co
un
t*
(N= 6) (N= 4) (N= 4) (N= 4)
Wilcoxon p-value=0.011
Placebo 4mg/kg 8mg/kg 16mg/kg
* Difference in polyp count between baseline & end of treatment
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Submission of briefing package to the FDA
Meeting with FDA to present Phase III protocol design
Special Protocol Assessment (SPA) for Phase III protocol submitted to FDA
Comments from FDA regarding SPA received
First patient to be enrolled in Phase III study
03/05
04/05
08/05
06/05
01/06
Genotype Positive StudyBrief Chronology of Events
• CV Safety Data (December 17th)12/04
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Genotype Positive StudyProposed Design
Description: Phase III study of celecoxib in genotype-positive, early phenotype positive or negative subjects with FAP
Treatment groups: PlaceboCelecoxib (16mg/kg/day, approximately 400mg BID)1:1 randomization
Sample size: N = 200
Duration of therapy: 5 years
Primary endpoint: Time to treatment failure defined as time from randomization to earliest occurrence of appearance of ≥ 20 polyps (>2mm, visible without dye enhancement) at any colonoscopy during the study or diagnosis of colorectal malignancy
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FAP Registry-based Study
Study Design: Observational Registry-based Study
Patient Population: Patients receiving celecoxib Historical/Concurrent controls
Participating Sites: Established FAP registries in Canada, US, Denmark, Germany and Australia
Objectives: - Describe patterns of celecoxib use in disease management
- Examine long-term benefits of celecoxib in prolonging time to FAP-related events- Evaluate long-term safety of celecoxib
Study Timelines Study Initiation: 3Q 2004 (US)
First Study Status Report: 4Q 2004
Finalization of Study: ~4Q 2010
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FAP Registry StudyBrief Chronology of Events
FDA grants accelerated approval for celecoxib in FAP
Discussion with experts initiated
Submission of alternative proposal to FDA
PHA meets with FDA to propose alternate controlled study of celecoxib vs. difluoromethylomithine (DFMO) FDA reiterates preference for a registry study
MDACC confirms interest in setting up Registry, with grant from PHA
MDACC sends copy of registry proposal written in June 2000, which is basis for current proposal
CGA Meeting, protocol concept endorsed by CGA members
12/99
04/01
06/01
08/01
02/00
12/00
10/01
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FAP Registry StudyBrief Chronology of Events (cont’d.)
02/03
03/03
MDACC confirms that CGA will enter patient on registry study
Protocol sent to CGA members to review
As a result of lack of enthusiasm from the CGA physicians, the registry protocol was modified to include patients entering their own data
Registry presented at CGA – patient questionnaire sent to PHA
Web-based Study prototype sent to PHA Submitted to MDACC IRB for approval
MDACC IRB rejects web-based registry protocol
Revised registry-based protocol under development
Draft Study protocol submitted to FDA for review
10/02
12/02
01/03
03/02
04/02
07/02
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10/04
11/04
09/04
Under preliminary review, FDA finds draft Study protocol acceptable
First investigator meeting FAP Registry Planning Meeting to review draft protocol and
finalize Study protocol for health authorities review
Pfizer and CRO Study Kick-off meeting
Final Study protocol submitted to FDA for review IRB approval from Cleveland Clinic
Site initiation visit performed at Cleveland Clinic, and site activated
Investigator Study Kick-off meeting
Registry-based observational study protocol was amended (Amendment #1)
First data transfer received from Cleveland Clinic Amendment #1 protocol submitted to FDA
02/04
05/04
09/03
04/03
FAP Registry StudyBrief Chronology of Events (cont’d.)
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FAP Registry StudyBrief Chronology of Events (cont’d.)
Study re-activated at Cleveland Clinic
Combined assessment and site initiation visit at Mount Sinai (Toronto), Canada
Second semi-annual report submitted to EMEA
05/05
Site initiation visit performed at Hvidovre Univ. Hospital, and site activated, first data transfer received
Information on the CV safety of Celebrex® based on results from two long-term cancer trials publicly released
Health Canada suspended FAP Indication Cleveland Clinic investigator withholds Study First Study semi-annual report submitted to EMEA
Pfizer agrees to a temporary suspension of launch of Celebrex® for the FAP indication in Europe until finalization of EMEA assessment
01/05
12/04
03/05
06/05
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Study Status*
Site / Investigator Country Current Site Status
The Cleveland Clinic Foundation / Dr. James Church
USAInitiated:
Sept 1, 2004
Mount Sinai Hospital / Dr. Steven Gallinger
CanadaInitiated:
May 10, 2005
Hvidovre Univ. Hospital / Dr. Steffen Bulow
DenmarkInitiated:
Dec 6, 2004
Heinrich-Heine-Universitat, Dusseldorf /Dr. Gabriela Moeslein
Germany Initiation Delayed
The Cancer Council of Victoria / Dr. Finlay Macrae
Australia Initiation Delayed
* Pfizer Protocol Nº NQ4-00-02-012 Study Status Report June 13, 2005
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Study Subjects in Activated Registries*Number of Study subjects by Registry Site
Paramater Celecoxib Matched Control All Subjects
Number of FAP Subjects Entered to Data
United States 4 1 5
Canada 0 0 0
Denmark 4 0 4
Germany 0 0 0
Australia 0 0 0
Total 8 1 9
Percentages are based on the number of FAP subjects entered in each study group through the current reporting period. Information in this table reflects data transfers through April 29, 2005 for the US Registry and December 16, 2004 for the Danish Registry. Additionally, information in this table reflects recent verbal confirmation from the Danish investigator pertaining to one (1) subject (#10030001) who discontinued participation due to rash (assessed as non-severe by the principal investigator).
* Pfizer Protocol Nº NQ4-00-02-012 Study Status Report June 13, 2005
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In Summary
FAP is a rare life-threatening genetic disease with few therapeutic options
Pfizer remains fully committed to compliance with subpart H requirements – significant activity since previous ODAC March 2003 Phase III FAP Pediatric Study FAP Registry Study initiated in 3Q 2004
Despite challenges encountered Confirmatory Phase III Study ready to begin Multi-institutional FAP registry Study undertaken and
in progress
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