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