# Presentation: 739827

## Update on the Safety ofTNF Blockers

- Li-ching Liang,  M.D.
**FDA / CBER/ OTRR**
**Arthritis Advisory Committee**
**March 4, 2003**

## Update on Safety Outline

- 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

## AdalimumabSafety 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

## Adalimumab and TB: Early Clinical 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

## TB:  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

## Adalimumab: 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
**            **

## Malignancies

- 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

## Malignancies & 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.**

## Malignancies with AdalimumabControlled Portions 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 |

## Lymphomas with Adalimumab Controlled Portions of Controlled Trials

|  | 
Lymphomas Observed | 
Number of Patients | Mean Duration of Treatment |
| --- | --- | --- | --- |
| Adalimumab-treated |  2 (0.1%) |  1380 | 0.6 yr |
| Placebo-treated | 0 (0%) |  690 | 0.5 yr |

## Observed vs. Expected Cancer Rates   Adalimumab Clinical Development Program (thru 8/02)                                                * Based on SEER database

| Cancer Site | Observed  | Expected  | 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**

## Summary of 10 Lymphoma Cases By TypeAmong Adalimumab-Treated Patients (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

## Etanercept

**Malignancies and Lymphomas**

## Etanercept  Malignancies in Placebo-Controlled Portions of Clinical Trials  (6 month trials)Etanercept:  Malignancies in Controlled Portions of 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) |

## Etanercept:  Types of Malignancies in Controlled Portions of RA Trials

| Placebo-treated subjects
(N=5) | Etanercept-treated subjects
(N= 12) |
| --- | --- |
| Bladder
Colon
Cervix
Prostate
Metastatic adenoCA | Breast (3)
Prostate (3)
Lung (2)
Colorectal
Leukemia
Lymphoma (Hodgkin’s)
Melanoma

 |

## Etanercept: Lymphomas 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**

## Infliximab

**Malignancies and Lymphomas**

## Infliximab:  All malignancies in controlled portions of controlled trials (includes ASPIRE data)

| 
Population | 
n | Mean Duration of Treatment | Observed No.
 Cases of All Malignancies | 
% of Pts.
 | 
95% CI |
| --- | --- | --- | --- | --- | --- |
| Infliximab- treated subjects |  |  |  |  |  |
| RA 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 subjects |  |  |  |  |  |
| RA 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% |

## Infliximab:  All malignancies seen in the controlled portions of controlled 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

**Rectal adenoCA****	**
**Bladder CA****	****	**
**Hypernephroma****	**
**Pancreatic CA****	**
**Endometrial CA**

## Infliximab:  Lymphomas in controlled portions of controlled trials 

| 
Population | 
n | Mean Duration 
of Treatment | Observed No.
 Cases of
Lymphomas | 
% of Pts. |
| --- | --- | --- | --- | --- |
| Infliximab- treated subjects |  |  |  |  |
| RA Studies | 1298 | 1.1 yr | 1 | 0.1% |
| All Studies | 2421 | 1.0 yr | 3 | 0.1% |
| Placebo-treated subjects |  |  |  |  |
| RA Studies | 430 | 1.0 yr | 0 | - |
| All Studies | 489 | 0.9 yr | 0 | - |

## Infliximab:  All malignancies in all clinical trial experience

| 
Population | 
N | Median Subj-Yrs Follow-up | Obsv’d
No. 
Cases | Expt’d
No. Cases | 
SIR
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) |

## Infliximab:  Lymphomas in all clinical trial experience

| Population | N | Median Subj-Yrs Follow-up | Obsv’d
No. 
Cases | Expt’d
No. Cases | SIR
95%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

 | 6.98
2.56, 15.19 |
| Placebo-treated subjects |  |  |  |  |  |
| All RA Studies | 430 | 1.4 | 0
 | 0.14
 | [NC]
 |
| All Studies | 489 | 1.4 | 0

 | 0.15

 | [NC]
 |

## Lymphoma with TNF BlockersConclusions

**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**

## Lymphoma with TNF BlockersConclusions

**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**