TNF Blocker Safety: Lymphoma and Liver Failure

1
TNF Blocker SafetyLymphoma andLiver Failure

• Tim Coté MD MPH, Chief, Therapeutics Blood
  Safety Branch, DE/OBE/CBER/FDA
• March 4, 2003

2
Postmarketing Surveillance

• Clinicians and others can report adverse events
  associated with drugs
• Passive surveillance
• Greatest strength is as a means of signal
  generation

3
Characteristics of Postmarketing Reports

• Voluntary for clinicians but mandatory for
  companies
• Often incomplete
• -Unreported cases and
• -Sketchy narratives
• Coded into MedDRA terminology with high
  sensitivity
• Causality assessments are tenuous by design
• Cannot generate incidence rates

4
Lymphomas with TNF Blockers

• Rich body of medical literature associating
  immunodisregulation and lymphoma biologically
  plausible that TNF blockers might cause lymphoma
• Hundreds of thousands of patients on these drugs,
  increasing the public health importance of this
  Committees consideration.
• We have published a series of 26 lymphomas
  arising among people on TNF Blockers, but
  causality unclear.

5
Lymphomas and TNF Blockers Current Understanding

• RA and NHL are associated this complicates the
  problem.
• Placebo-controlled studies have been small.
• Manufacturers pre- and post-marketing cohort
  studies have short follow-up times relative to
  carcinogenesis.

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Update Lymphomas Reported to FDA following TNF
blockers, 1/99-12/02
7
Reports of 158 Lymphomas Reported Among Persons
Taking TNF Blockers, 1/99-12/02
Source Reports to FDA MedWatch program
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Patient Characteristics Lymphoma among patients
treated with TNF blockers
9
Histology of 158 Lymphomasamong Patients with
TNF Blockers, Reported to FDA 1/99-12/02

• 78 (49) Lymphoma NOS
• 26 (16) non-Hodgkins Lymphoma, NOS
• 23 (15) B-cell lymphoma, NOS
• 20 (13) Hodgkins Disease
• 6 (4) T-cell Lymphoma
• 3 (2) Mantle cell lymphoma
• 1 (1) Plasmacytoma
• 1 (1) Burkitts Lymphoma

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Conclusions Lymphoma among TNF blocker recipients

• They are poorly characterized. It has not been
  established if they are the same grade as the
  general population. Histologically, they may be
  consistent with lymphoma secondary to
  immunodeficiency.
• Clinical trials found increased NHL risk, but
  based on few observations.
• Assessment is complicated by RA-confounded
  increases.
• The number of cases of lymphoma among persons
  taking TNF Blockers is growing.
• FDA needs input from the AAC to assess causality
  and/or propose means to better evaluate causality.

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Liver Failure

• Signal for Leflunomide, thus of interest for TNF
  Blockers
• In clinical trials, some patients on Infliximab
  showed elevated increased liver enzymes.

12
Infliximab-mediated ALT Increases

• Increased ALT was predominately lt2x ULN
• -No clinical sequelae

13
Analysis of Liver Failure Reports to FDA
14
Extraneous causes of hepatic impairment among 43
pts on TNF Blockers.
15
Conclusion Liver Failure with TNF blockers

• Liver Failure with TNF Blockers appears to be a
  rare event
• While there are a large number of people on TNF
  blockers, chance occurrence is unlikely (1/106 in
  general pop) causality cannot be ruled out.
  Some concern remains warranted
• Further clinical data on remaining cases are
  pending.