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BLA 99-0884: Enbrel for Early RA
Jeffrey N. Siegel, M.D.
Division of Clinical Trials Design and Analysis
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Review committee Jeffrey Siegel, M.D. Chair, Clinical George Mills, M.D. Imaging Boguang Zhen, Ph.D. Biostatistics Susan Giuliani Project Manager Debra Bower Bioresearch Monitoring David Green, Ph.D. Pharm-tox Lisa Rider, M.D. Consultant
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Current indication
Enbrel is indicated for reduction in signs and symptoms of moderately to severely active rheumatoid arthritis in patients who have had an inadequate response to one or more disease-modifying antirheumatic drugs (DMARDs). Enbrel can be used in combination with methotrexate in patients who do not respond adequately to methotrexate alone.
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Indications sought in current BLA
Extend indication to signs & symptoms in early RA patients
Seek general claim of prevention of structural damage
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Outline of presentation
Trial design Modifications to protocol Background information on radiographic
endpoints Efficacy results Safety data
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Primary endpoints
Co-primary endpoints:– Clinical: ACR-N AUC at 6 mo– Radiographic: Improvement in erosion scores
at 12 mo– Hochberg method of assessing statistical
significance: both EPs must achieve statistical significance at 0.05 level OR either at 0.025 level
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Additional endpoints
Disability based on Health Assessment Questionnaire (HAQ)
Health-related quality of life (HRQL) Major clinical response
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Outline of presentation
Trial design Modifications to protocol Background information on radiographic
endpoints Efficacy results Safety data
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16.0012: Modifications During trial, the agency discussed with Immunex
evidence from recent reports that many patients with early RA treated with MTX developed few, if any, erosions
The agency asked Immunex if it would wish to seek an approval based on non-inferiority if the study did not demonstrate superiority to MTX.
The agency noted that the basis for a non-inferiority determination should be determined prospectively
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Modifications (cont.)
Immunex revised analysis of radiographic endpoint to a demonstration of non-inferiority
Changed variable from erosion score to total Sharp score (erosion score + joint space narrowing score)– Reason: Data unavailable to establish effect
size for erosion score
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Outline of presentation Trial design Modifications to protocol Background information on radiographic
endpoints Efficacy results Safety data
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Non-inferiority trials
In some clinical settings, efficacy may be demonstrated from a finding of non-inferiority in an active control trial: – Reproducible historical experience indicates
that in a trial with a given design that the active control will reliably give a result of a given size
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0
Progression Rate
Margin
active minus placebo (historical)
Efficacy of active control
New drug superior
New drug meets non-inferiority std.
No evidence ofefficacy
New drug minus Active
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Steps to Establish Non-Inferiority
Determine from historical trials that active control reliably has an effect of at least a certain size
Plan trial design to be similar to that of prior trials (stage of disease, concomitant therapy, endpoint, etc.)
Set a non-inferiority margin to be excluded (smaller than the total active control effect)
Ensure appropriate trial conduct (e.g., concomitant meds, study drug compliance)
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Historical control data
Sponsor derived effect size of active control from several studies, including:– A multi-year observational study of recent-
onset RA (Wolfe and Sharp, 1998)– A 3-arm, randomized, controlled study
comparing placebo, MTX and ARAVA (MN301/303)
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Non-inferiority: assumptions
Mean yearly progression rate ~6 u/year (Sharp score) in untreated patients
Mean progression rate on MTX ~2 u/yr Preserving 70% of MTX benefit means
ruling out a difference of 1.2 u [(4-1.20/4 = 0.70]
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Limitations of non-inferiority trial design
Historical controls do not provide reproducible data to establish effect size for MTX
Effect size for MTX based on different patient population from current study:– shorter duration of disease– different MTX regimen
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Non-inferiority design: conclusions
Because cannot formally establish a minimal effect size, non-inferiority cannot per se be taken as evidence of efficacy
Therefore, interpretation of the trial must be based on totality of the data, including additional analyses
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Outline of presentation Trial design Modifications to protocol Background information on radiographic
endpoints Efficacy results Safety data
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Disposition of subjectsPatients enrolled: 653
MTX Enbrel10 mg
Enbrel25 mg
Randomized, butnot treated 224 213 216
Rec’d 1 dose(mod ITT)
217(97%)
208(98%)
207(96%)
Completed 12mo evaluations
202(93%)
188(90%)
193(93%)
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Radiographic procedures
Hand, foot films obtained: baseline, 6, 12 mo Read: 6 trained readers, blinded, random
order Inter--reader correlation coefficient 0.8 Agency review of radiographs:
– Data complete, of uniformly good quality– Readings generally consistent and accurate
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Primary endpoint analysis
Primary analysis specified a mixed model estimating annual x-ray progression rates using 0, 6 & 12 month films and baseline covariates
Non-inferiority analysis to exclude margin of 1.2 u/year
Protocol specified sequential test of:– non-inferiority– if non-inferiority demonstrated, test superiority
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X-ray primary endpoint analysis
Mean 12-mo. Change in TSS(2-sided 95% CI)
MTX 1.33 (0.55, 2.12)
10 mg 1.4 (0.6, 2.2)
25 mg 0.8 (0.04, 1.64)
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X-ray primary endpoint analysis
Difference in mean progression rates (2-sided 90% CI)
25 mg – MTX -0.50 (-1.16, 0.16)(2-sided 95% CI)
25 mg – MTX -0.50 (-1.28, 0.29)
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Primary endpoint
Test of non-inferiority excluded margin of greater than 1.2 u/yr (max. outer bound 0.29)
Test of superiority of Enbrel 25 mg to MTX does not reach statistical significance (p=.21)
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Additional analyses
Prespecified stratification by disease duration
Components of Sharp score: erosion scores 6 month vs. 12 month data Subjects w/ no radiographic progression
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Analysis by disease duration: TSS
0
0.5
1
1.5
2
2.5
TSS
ann
ual c
hang
e (u
/yr)
< 18 mo > 18 mo
MTXEnbrel 10Enbrel 25
N=478 N=154
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Components of total Sharp score
Total Sharp score (TSS) is summation of:– erosion score– joint space narrowing
Enbrel 25 mg showed decrease in erosion score compared to MTX (0.9 vs. 0.4 u/yr, p = .047)
No difference in joint space narrowing (0.4 u/yr)
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Time course of x-ray changes
Analyze 0-6, 6-12 mo rate of change Agency observed substantial skewing of
data, violating assumptions of mixed model. Therefore non-parametric test more appropriate
For its analysis, agency used raw data for last observation and first observation adjusting for time interval
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0
0.2
0.4
0.6
0.8
1
1.2
1.4
1.6
Cha
nge
in e
rosi
on s
core
(u
/yr)
MTX Enbrel
MTXEnbrel
12 mo change in erosion scores
P=0.001
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Changes over time: erosions
0
0.2
0.4
0.6
0.8
1
1.2
Rad
iogr
aphi
c pr
ogre
ssio
n (u
)
0-6 mo 6-12 mo 0-12 mo
MTXEnbr 25
P = 0.0006 P = NS
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Changes over time: TSS
0
0.2
0.4
0.6
0.8
1
1.2
1.4
Rad
iogr
aphi
c pr
ogre
ssio
n (u
)
0-6 mo 6-12 mo 0-12 mo
MTXEnbr 25
P = 0.0006 P = NS
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Patients w/ no radiographic progression
0102030405060708090
100
Pro
port
ion
of s
ubje
cts
(%)
Erosions: 12 mo TSS: 12 mo
MTXEnbr 25
P = 0.004 P = 0.174
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Subset analysis
Based subset analysis on 12-month change in erosion scores
No important differences based on age, ethnicity, gender, duration of disease (0-18 mo vs. 18-36 mo)
Also assess baseline prognostic variables: ESR, erosions at baseline
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Erosion score/Baseline ESR > 30
0
0.2
0.4
0.6
0.8
1
1.2
1.4
1.6
12 m
o ch
ange
ero
sion
sco
re
<30 mm/h >30 mm/h
MTXEnbrelN=115
N=121
N=92N=96
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Erosions/baseline erosions
0
0.2
0.4
0.6
0.8
1
1.2
1.4
1.6
12 m
o ch
ange
ero
sion
sc
ore
< 2 >= 2
MTXEnbrel
N=137
N=145
N=69N=72
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Radiographic EP
Although the trial excluded pre-specified margin for non-inferiority, there are limitations to the interpretation of these data
Meaningful secondary endpoints showed a difference compared to active control, e.g. erosion scores, 6 month data, patients with no radiographic progression
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Clinical EP: Summary
10 endpoint of 6 month AUC showed statistically significant difference between Enbrel 25 mg and MTX
Landmark analysis of proportion of subjects achieving ACR20 and 50 at 6 and 12 months not statistically significant
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Additional endpoints
Disability (HAQ) Health-related quality of life Major clinical response
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Disability
0
0.2
0.4
0.6
0.8
1
1.2
1.4
1.6
HA
Q d
isab
ility
inde
x
MTX Enbrel 10 Enbrel 25
Baseline12 mo
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Health related Quality of life
Physical summary score:– Same across trial arms at baseline, ~ 2 SD below
US norms– Improved in all arms at 12 months
» Less improvement in 10 mg arm than 25 mg Enbrel arm
Mental health summary score:– Similar to US norms at baseline– Higher in all arms at 12 months
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Major Clinical Response (MCR)
Rationale for criteria of ACR70:– Represents a degree of improvement rarely
seen in placebo arms of controlled studies of DMARDs:
» Placebo (MTX vs. placebo): 0%
» Placebo (CsA vs pl/background MTX): 0%
Definition:– 6 consecutive months of an ACR70
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Major Clinical Response (MCR)
0
2
4
6
8
10
12
Pro
port
ion
of s
ubje
cts
(%)
MTX Enbr 10 Enbr 25
MCR
P = 0.06
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Safety
Serious AEs, deaths Drop-out for adverse events Other AEs Long-term safety Post-marketing reports
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Deaths in trial 16.0012
2 observed during 12 month study period– 10 mg: Lung ca, dx month 2 – 25 mg: non-infectious complications of an
aortic aneurysm repair
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SAEs
MTX 10 mg 25 mgInfections 4 4 5Malignancy (excl. skin) 1 2 3DVT, pulm. Embolus 0 2 2Interstitial pneumonitis 3 0 0Angina, MI 4 3 0Other 9 3 8Total events (patients): 21 (17) 14 (9) 18 (15)
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Infectious SAEsMTX Enbrel 10 Enbrel 25
Pneumonia (3) Pneumonia Pneumonia (3)
UTI Bacteremia (2) Sepsis
Septic arthritis
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Malignancies
25 mg– Prostate, carcinoid (lung), Hodgkin’s
10 mg– breast, lung
MTX– colon– 1 additional ca, at beginning of second year:
bladder
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Thrombotic SAEs
25 mg:– DVT (2):
» 3 mo on study. Risk factor: OCP
» 1 week on study. Risk factor: Baker’s cyst
10 mg:– DVT: 2 weeks on study. No risk factors– Massive PE associated with dx of lung ca
MTX: none
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Safety
Serious AEs, deaths Drop-out for adverse events Other AEs Long-term safety Post-marketing reports
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Subjects not completing 52 weeks dosing
MTX Enbrel 10mg
Enbrel25 mg
AEs 21 9 10
Abnl LFTs 3 3 1
LOE 7 15 9
Other 14 15 9
Total 45 42 29
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AEs causing dropoutsMTX Enbrel
10 mgEnbrel 25
mgAlopecia, oral/nasal
ulcers, vomiting9 0 0
Infection 3 3 1
Malignancy 1 2 2
MTX pneumonitis 3 0 0
ISR 0 0 1
Other AEs 5 4 6
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Safety
Serious AEs, deaths Drop-out for adverse events Other AEs Long-term safety Post-marketing reports
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Other adverse events
Overall adverse event rate higher in MTX arm than with Enbrel:– MTX 95% vs. Enbrel 90%
Rate of ISR (37% vs. 7%), bleeding at injection site (14% vs. 10%) higher in Enbrel arm than MTX
No other pattern of increased adverse events observed with Enbrel
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Safety
Serious AEs, deaths Drop-out for adverse events Other AEs Long-term safety Post-marketing reports
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Safety in other clinical trials
In previous controlled trials, saw higher incidence of:– injection site reactions– infections
Upper respiratory infections (URIs) were major contributor to higher rate of infection
Serious infections seen in long-term extension studies
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Phase 4 safety study: 16.0018
3-year, open-label study of 1200 subjects receiving Enbrel
638 enrolled at time of BLA submission Goals:
– Assess long-term safety, including mortality rate, incidence of malignancy and autoimmune disease compared to historical control databases
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Long-term safety in DMARD-refractory RA
Size of database– 782 patients overall (16.0018 and others)
» 2-3 years: 71 patients
» 1-2 years: 502 patients
AE rate:– None occurred with an incidence higher than in
controlled studies– No AE with pattern of increased incidence with
longer duration of exposure
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Long-term safety
Infections– Types of infection similar to that seen in
controlled trials– No infection with a higher incidence with long-
term treatment
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Long-term safety: serious infections
Infections assoc with hospitalization or IV antibiotics– Incidence of 5.5/100 patient-years– Types of infections expected for patients with
RA in their age group No increase in rate with longer duration of
exposure
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Safety
Serious AEs, deaths Drop-out for adverse events Other AEs Long-term safety Post-marketing reports
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Post-marketing reports
Post approval of Enbrel, there were reports of deaths from serious infection and sepsis– Associated risk factors: diabetes, active infection, h/o
recurrent infection Actions taken:
– Issue dear doctor letter with warning about use of Enbrel in patients with DM, active infections or a history of chronic infections
– Agency asked sponsor to initiate clinical trial to assess degree of risk
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Safety study of Enbrel in patients at risk of infection
Since clinical trials excluded patients at higher risk for infection, it is unknown whether Enbrel may predispose certain subgroups of patients to serious infection
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Safety study in at-risk patients
1000-patient, randomized, 4-month, double-blind, placebo-controlled trial of Enbrel
Inclusion criteria:– RA by ARA criteria– At increased risk for infection:
» DM requiring insulin or oral hypoglycemics» Chronic pulmonary disease (COPD or asthma)» h/o pneumonia in past year» Recurrent bronchitis, sinusitis or UTI (at least 2 episodes in
past year)
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Safety study in at-risk patients
Sample size calculations:– Assumes event rate of 10% in control– 94% power to exclude a 2x relative risk for
Enbrel (95% CI)– Power of study would be lower if event rate
below 10%
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Conclusions
For x-ray data, 95% CI excluded inferiority of 1.2 u/yr– Secondary endpoints suggest superiority of Enbrel in
preventing erosions Primary signs & symptoms endpoint showed
superiority for Enbrel 25 mg– Landmark 6, 12 month ACR 20/50 higher for Enbrel
25 mg, but not statistically significant Overall AE/SAE rate not higher with Enbrel