Arthritis Advisory Committee Arthritis Advisory Committee March 4, 2003 Update on the Safety of Update on the Safety of TNF Blockers TNF Blockers Li-ching Liang, M.D. FDA / CBER/ OTRR Arthritis Advisory Committee March 4, 2003
Arthritis Advisory Committee Arthritis Advisory Committee March 4, 2003
Update on the Safety ofUpdate on the Safety ofTNF BlockersTNF Blockers
Update on the Safety ofUpdate on the Safety ofTNF BlockersTNF Blockers
Li-ching Liang, M.D.FDA / CBER/ OTRR
Arthritis Advisory CommitteeMarch 4, 2003
Li-ching Liang, M.D.FDA / CBER/ OTRR
Arthritis Advisory CommitteeMarch 4, 2003
2Arthritis Advisory Committee Arthritis Advisory Committee March 4, 2003
Update on Safety Update on Safety OutlineOutline
Update on Safety Update on Safety OutlineOutline
• Update safety data from clinical trials and post-marketing reports
• Focus on several issues with new data– Adalimumab and Tuberculosis– Malignancies/Lymphoma with all
approved TNF blockers
• Update safety data from clinical trials and post-marketing reports
• Focus on several issues with new data– Adalimumab and Tuberculosis– Malignancies/Lymphoma with all
approved TNF blockers
3Arthritis Advisory Committee Arthritis Advisory Committee March 4, 2003
AdalimumabAdalimumabSafety DatabaseSafety Database
AdalimumabAdalimumabSafety DatabaseSafety Database
• At end of Phase 2 meeting, Agency recommended large safety database
• Abbott studied for safety:– 2070 pts. in controlled trials (mean
exposure 7 mo.)– >2400 pts. in open-label studies
(median exposure 24 mo.)• Interpretation of open label data difficult
due to lack of concurrent control group though larger experience and duration of such trials are beneficial
• At end of Phase 2 meeting, Agency recommended large safety database
• Abbott studied for safety:– 2070 pts. in controlled trials (mean
exposure 7 mo.)– >2400 pts. in open-label studies
(median exposure 24 mo.)• Interpretation of open label data difficult
due to lack of concurrent control group though larger experience and duration of such trials are beneficial
4Arthritis Advisory Committee Arthritis Advisory Committee March 4, 2003
Adalimumab and TB: Early Adalimumab and TB: Early Clinical Trial ExperienceClinical Trial Experience
Adalimumab and TB: Early Adalimumab and TB: Early Clinical Trial ExperienceClinical Trial Experience
• 8 cases seen of initial ~542 pts. treated (1.5%)
• After discussions with FDA, screening and prophylaxis measures begun:– Europe -> chest x-ray– USA -> PPD– For PPD+ patients, prophylactic anti-
TB treatment per CDC Guidelines
• 8 cases seen of initial ~542 pts. treated (1.5%)
• After discussions with FDA, screening and prophylaxis measures begun:– Europe -> chest x-ray– USA -> PPD– For PPD+ patients, prophylactic anti-
TB treatment per CDC Guidelines
5Arthritis Advisory Committee Arthritis Advisory Committee March 4, 2003
TB: Later ExperienceTB: Later ExperienceTB: Later ExperienceTB: Later Experience
• Reduction but not elimination of TB following screening:– 5 cases in subsequent 1900 patients
• Other factors may have reduced the TB rate:– lower doses used– fewer patients from highly endemic
areas
• Reduction but not elimination of TB following screening:– 5 cases in subsequent 1900 patients
• Other factors may have reduced the TB rate:– lower doses used– fewer patients from highly endemic
areas
Arthritis Advisory Committee Arthritis Advisory Committee March 4, 2003
Adalimumab: TuberculosisAdalimumab: TuberculosisAdalimumab: TuberculosisAdalimumab: Tuberculosis• Most reported TB cases from Europe• More frequent in patients receiving higher than licensed dose (40 mg q2wk)• Most cases extrapulmonary• Most occurred in first 8 months of therapy in controlled trials
– May reflect reactivation of latent infection
• Box Warning
• Most reported TB cases from Europe• More frequent in patients receiving higher than licensed dose (40 mg q2wk)• Most cases extrapulmonary• Most occurred in first 8 months of therapy in controlled trials
– May reflect reactivation of latent infection
• Box Warning
7Arthritis Advisory Committee Arthritis Advisory Committee March 4, 2003
MalignanciesMalignanciesMalignanciesMalignancies• Because of immunomodulatory properties of
TNF-blockers, concerned about malignancies with long-term treatment.
• Assessment difficult because hard to maintain a comparator control arm in long-term studies– One approach: Compare observed
malignancy rates to the expected rate in general population (e.g. using 1995-99 SEER Database adjusted for age, gender, race, geography) to calculate SIR - Standardized Incidence Ratio
• Because of immunomodulatory properties of TNF-blockers, concerned about malignancies with long-term treatment.
• Assessment difficult because hard to maintain a comparator control arm in long-term studies– One approach: Compare observed
malignancy rates to the expected rate in general population (e.g. using 1995-99 SEER Database adjusted for age, gender, race, geography) to calculate SIR - Standardized Incidence Ratio
Arthritis Advisory Committee Arthritis Advisory Committee March 4, 2003
Malignancies & RAMalignancies & RAMalignancies & RAMalignancies & RA
• Interpretation of data is complicated:– Lymphoma incidence reported to be
several fold higher among RA patients, especially those with higher levels of disease activity and inflammation*
– Most patients enrolled in trials have highly active disease
– Most receive concomitant DMARDs with immunosuppressive properties
*Baecklund E. et al. BMJ 1998; 317:180-1.
*Wolfe, F. Arthritis Rheum 1998; 41 (9): S188.
• Interpretation of data is complicated:– Lymphoma incidence reported to be
several fold higher among RA patients, especially those with higher levels of disease activity and inflammation*
– Most patients enrolled in trials have highly active disease
– Most receive concomitant DMARDs with immunosuppressive properties
*Baecklund E. et al. BMJ 1998; 317:180-1.
*Wolfe, F. Arthritis Rheum 1998; 41 (9): S188.
9Arthritis Advisory Committee Arthritis Advisory Committee March 4, 2003
Malignancies with AdalimumabMalignancies with AdalimumabControlled PortionsControlled Portions of Controlled Trials of Controlled TrialsMalignancies with AdalimumabMalignancies with Adalimumab
Controlled PortionsControlled Portions of Controlled Trials of Controlled Trials
Malignancies
Observed
Number of Patients
Mean Duration of Treatment
Adalimumab-treated
8 (0.58%) 1380 0.6 yr
Placebo-treated 0 (0%) 690 0.5 yr
10Arthritis Advisory Committee Arthritis Advisory Committee March 4, 2003
Lymphomas with AdalimumabLymphomas with Adalimumab Controlled PortionsControlled Portions of Controlled Trials of Controlled Trials
Lymphomas with AdalimumabLymphomas with Adalimumab Controlled PortionsControlled Portions of Controlled Trials of Controlled Trials
Lymphomas Observed
Number of Patients
Mean Duration
of Treatmen
t
Adalimumab-treated
2 (0.1%) 1380 0.6 yr
Placebo-treated
0 (0%) 690 0.5 yr
11Arthritis Advisory Committee Arthritis Advisory Committee March 4, 2003
Observed vs. Expected Cancer Rates Observed vs. Expected Cancer Rates Adalimumab Clinical Development Program Adalimumab Clinical Development Program
(thru 8/02)(thru 8/02)
* Based on SEER * Based on SEER databasedatabase
Observed vs. Expected Cancer Rates Observed vs. Expected Cancer Rates Adalimumab Clinical Development Program Adalimumab Clinical Development Program
(thru 8/02)(thru 8/02)
* Based on SEER * Based on SEER databasedatabase
Cancer SiteObserve
d Expecte
d SIR* 95% CI
All lymphomas 10 1.85 5.42 (2.6-10.0)
NHL 9 1.70 5.28 (2.4-10.0)
Hodgkin’s Dis
1 0.14 7.09 (0.1-39.5)
Breast 7 11.15 0.63 (0.3-1.3)
Colon – rectum 5 4.75 1.05 (0.3-2.5)
Lung 1 6.67 0.15 (0.0-0.8)
Melanoma 3 1.53 1.97 (0.4-5.7)
Prostate 5 4.45 1.12 (0.4-2.26)
Cervix – Uteri 4 2.30 1.74 (0.5-4.4)
Other sites 11 13.12 0.84 (0.4-1.15)
Total 46 45.82 1.00 (0.7-1.3)
* T
12Arthritis Advisory Committee Arthritis Advisory Committee March 4, 2003
Summary of 10 Lymphoma Cases By TypeSummary of 10 Lymphoma Cases By TypeAmong Adalimumab-Treated Patients Among Adalimumab-Treated Patients
(REAL Classification)(REAL Classification)
Summary of 10 Lymphoma Cases By TypeSummary of 10 Lymphoma Cases By TypeAmong Adalimumab-Treated Patients Among Adalimumab-Treated Patients
(REAL Classification)(REAL Classification)
• B cell lymphoma: Diffuse Large B-cell lymphoma (5)• B cell lymphoma: Mantle cell lymphoma• B cell lymphoma: Marginal Zone lymphoma• B cell lymphoma: Follicular center lymphoma• T cell lymphoma: Peripheral T cell lymphoma• Hodgkin’s Lymphoma
• B cell lymphoma: Diffuse Large B-cell lymphoma (5)• B cell lymphoma: Mantle cell lymphoma• B cell lymphoma: Marginal Zone lymphoma• B cell lymphoma: Follicular center lymphoma• T cell lymphoma: Peripheral T cell lymphoma• Hodgkin’s Lymphoma
Arthritis Advisory Committee Arthritis Advisory Committee March 4, 2003
EtanerceptEtanerceptEtanerceptEtanercept
Malignancies and LymphomasMalignancies and Lymphomas
14Arthritis Advisory Committee Arthritis Advisory Committee March 4, 2003
Etanercept Etanercept Malignancies in Placebo-Controlled Malignancies in Placebo-Controlled
Portions of Clinical Trials (6 month trials)Portions of Clinical Trials (6 month trials)
EtanerceptEtanercept: : Malignancies in Malignancies in Controlled PortionsControlled Portions
of Clinical Trialsof Clinical Trials
Etanercept Etanercept Malignancies in Placebo-Controlled Malignancies in Placebo-Controlled
Portions of Clinical Trials (6 month trials)Portions of Clinical Trials (6 month trials)
EtanerceptEtanercept: : Malignancies in Malignancies in Controlled PortionsControlled Portions
of Clinical Trialsof Clinical Trials
Placebo-treated
Etanercept-treated
No. Patients 921 2502
Mean Duration of Treatment 0.5 yr 0.5 yr
Observed No. of Malignancies
5 (0.5%) 12 (0.5%)
Observed No. of Lymphomas 0 1(Hodgkin’s)
15Arthritis Advisory Committee Arthritis Advisory Committee March 4, 2003
Etanercept:Etanercept: Types of Malignancies in Types of Malignancies in Controlled Portions of RA TrialsControlled Portions of RA Trials
Etanercept:Etanercept: Types of Malignancies in Types of Malignancies in Controlled Portions of RA TrialsControlled Portions of RA Trials
Placebo-treated subjects(N=5)
Etanercept-treated subjects(N= 12)
BladderColonCervixProstateMetastatic adenoCA
Breast (3)Prostate (3)Lung (2)ColorectalLeukemiaLymphoma (Hodgkin’s)Melanoma
16Arthritis Advisory Committee Arthritis Advisory Committee March 4, 2003
Etanercept:Etanercept: Lymphomas in Clinical Trial DatabaseLymphomas in Clinical Trial Database
Etanercept:Etanercept: Lymphomas in Clinical Trial DatabaseLymphomas in Clinical Trial Database
• 3389 patients representing 7364 pt-yrs of data• Median exposure of 2.2 yrs.• 6 lymphoma cases reported in all clinical trials
– additional 3 cases reported after f/u period• 2.6 cases expected*
– SIR 2.31 (95%CI 0.85, 5.03)
* Based on SEER database
• 3389 patients representing 7364 pt-yrs of data• Median exposure of 2.2 yrs.• 6 lymphoma cases reported in all clinical trials
– additional 3 cases reported after f/u period• 2.6 cases expected*
– SIR 2.31 (95%CI 0.85, 5.03)
* Based on SEER database
Arthritis Advisory Committee Arthritis Advisory Committee March 4, 2003
InfliximabInfliximabInfliximabInfliximab
Malignancies and LymphomasMalignancies and Lymphomas
18Arthritis Advisory Committee Arthritis Advisory Committee March 4, 2003
Infliximab: All malignancies in Infliximab: All malignancies in controlledcontrolled portionsportions of controlled trials of controlled trials (includes (includes ASPIREASPIRE
data)data)
Infliximab: All malignancies in Infliximab: All malignancies in controlledcontrolled portionsportions of controlled trials of controlled trials (includes (includes ASPIREASPIRE
data)data)
Population nMean
Duration of Treatment
Observed No.
Cases of All Malignancies
% of Pts.
95% CI
Infliximab- treated subjectsRA Studies 1298 1.1 yr 15 1.2% 0.9, 1.4%
All Studies 2421 1.0 yr 22 0.9% 0.7, 1.1%
Placebo-treated subjectsRA Studies 430 1.0 yr 1 0.2% 0.1, 0.3%
All Studies 489 0.9 yr 1 0.2% 0.02, 0.7%
19Arthritis Advisory Committee Arthritis Advisory Committee March 4, 2003
Infliximab: All malignancies seen in Infliximab: All malignancies seen in the the controlledcontrolled portionsportions of controlled of controlled
trials (including ASPIRE)trials (including ASPIRE)**
Infliximab: All malignancies seen in Infliximab: All malignancies seen in the the controlledcontrolled portionsportions of controlled of controlled
trials (including ASPIRE)trials (including ASPIRE)**
• Basal cell CA (6) • Squamous cell CA (4)• Breast CA (3)• Lymphoma (3)
– Follicular cell center – NK lymphoma– (IG) Angiocentric
• Melanoma (2)
*Total of 23 malignancies in 22 patients
• 1blinded data where all malignancies counted as if observed in infliximab-treated subjects
• Basal cell CA (6) • Squamous cell CA (4)• Breast CA (3)• Lymphoma (3)
– Follicular cell center – NK lymphoma– (IG) Angiocentric
• Melanoma (2)
*Total of 23 malignancies in 22 patients
• 1blinded data where all malignancies counted as if observed in infliximab-treated subjects
• Rectal adenoCA• Bladder CA• Hypernephroma• Pancreatic CA• Endometrial CA
• Rectal adenoCA• Bladder CA• Hypernephroma• Pancreatic CA• Endometrial CA
20Arthritis Advisory Committee Arthritis Advisory Committee March 4, 2003
Infliximab: Lymphomas in Infliximab: Lymphomas in controlled controlled portionsportions of controlled trials of controlled trials
Infliximab: Lymphomas in Infliximab: Lymphomas in controlled controlled portionsportions of controlled trials of controlled trials
Population
nMean
Duration of
Treatment
Observed No.
Cases ofLymphom
as
% of Pts.
Infliximab- treated subjectsRA Studies
1298 1.1 yr 1 0.1%
All Studies
2421 1.0 yr 3 0.1%
Placebo-treated subjectsRA Studies
430 1.0 yr 0 -
All Studies
489 0.9 yr 0 -
21Arthritis Advisory Committee Arthritis Advisory Committee March 4, 2003
Infliximab: All malignancies in Infliximab: All malignancies in all clinical trial experienceall clinical trial experience
Infliximab: All malignancies in Infliximab: All malignancies in all clinical trial experienceall clinical trial experience
Population NMedian Subj-Yrs Follow-
up
Obsv’dNo.
Cases
Expt’dNo.
CasesSIR
95%CI
Infliximab-treated subjects
RA Studies 1298 1.9 17 18.62 0.91(0.53, 1.46)
All Studies 2421 1.7 27 23.55 1.15(0.76, 1.67)
Placebo-treated subjects
RA Studies 430 1.4 2 4.10 0.49(0.06,1.76)
All Studies 489 1.4 4 4.31 0.93(0.25,2.38)
22Arthritis Advisory Committee Arthritis Advisory Committee March 4, 2003
Infliximab: Infliximab: Lymphomas in all clinical trial experience Lymphomas in all clinical trial experience
Infliximab: Infliximab: Lymphomas in all clinical trial experience Lymphomas in all clinical trial experience
Population N Median Subj-Yrs Follow-
up
Obsv’dNo.
Cases
Expt’dNo.
Cases
SIR95%CI
Infliximab-treated subjects RA Studies 1298 1.9 4 0.63 6.35
1.73, 16.26
All Studies 2421 1.7 6 0.86 6.982.56, 15.19
Placebo-treated subjectsAll RA
Studies430 1.4 0 0.14 [NC]
All Studies 489 1.4 0 0.15 [NC]
23Arthritis Advisory Committee Arthritis Advisory Committee March 4, 2003
Lymphoma with TNF BlockersLymphoma with TNF BlockersConclusionsConclusions
Lymphoma with TNF BlockersLymphoma with TNF BlockersConclusionsConclusions
• Lymphomas observed with all 3 TNF blockers– Small numbers/short exposure in
controlled portions of clinical trials– For entire database, calculated SIRs are
between ~2 and 7 compared to SEER database
– A more appropriate comparison would be to RA population but accurate incidence rates unavailable
• Lymphomas observed with all 3 TNF blockers– Small numbers/short exposure in
controlled portions of clinical trials– For entire database, calculated SIRs are
between ~2 and 7 compared to SEER database
– A more appropriate comparison would be to RA population but accurate incidence rates unavailable
24Arthritis Advisory Committee Arthritis Advisory Committee March 4, 2003
Lymphoma with TNF BlockersLymphoma with TNF BlockersConclusionsConclusions
Lymphoma with TNF BlockersLymphoma with TNF BlockersConclusionsConclusions
• 1-3 cases of lymphomas are diagnosed in treated groups for each TNF product, vs. 0 in control groups (6 lymphomas vs. 0 across all controlled studies)
• Biological plausibility of lymphomas associated with immunomodulatory agents, along with these data presented, raise concern about causality
• 1-3 cases of lymphomas are diagnosed in treated groups for each TNF product, vs. 0 in control groups (6 lymphomas vs. 0 across all controlled studies)
• Biological plausibility of lymphomas associated with immunomodulatory agents, along with these data presented, raise concern about causality