Safety - PowerPoint PPT Presentation

Loading...

PPT – Safety PowerPoint presentation | free to view - id: 1e91e5-ZDc1Z



Loading


The Adobe Flash plugin is needed to view this content

Get the plugin now

View by Category
About This Presentation
Title:

Safety

Description:

Safety & Efficacy Update on Approved TNF-Blocking Agents. Jeffrey N. Siegel, M.D. ... Improving signs and symptoms. Inhibition of progression of structural damage ... – PowerPoint PPT presentation

Number of Views:30
Avg rating:3.0/5.0
Slides: 20
Provided by: cde43
Category:
Tags: safety | signs

less

Write a Comment
User Comments (0)
Transcript and Presenter's Notes

Title: Safety


1
Safety Efficacy Update on Approved TNF-Blocking
Agents
  • Jeffrey N. Siegel, M.D.
  • OTRR, CBER / FDA
  • Arthritis Advisory Committee
  • March 4, 2003

Center for Biologics Evaluation and Research
2
TNF BLOCKING AGENTS
  • Etanercept (Enbrel) first TNF blocker approved
    for RA 1998
  • Currently three approved
  • Each has demonstrated high ACR response rates
  • Each associated with uncommon, but serious
    adverse events

3
Indications Use Etanercept
  • Monotherapy or combination with MTX for
    moderately to severely active RA
  • Improving signs and symptoms
  • Inhibition of progression of structural damage
  • Polyarticular-course JRA
  • Psoriatic arthritis

4
Indications Use Infliximab
  • Combination with MTX for moderately to severely
    active RA
  • Improving signs symptoms
  • Inhibition of progression of structural damage
  • Improvement in physical function
  • Crohns Disease
  • Active disease (CDAI score gt 220)
  • Fistulizing disease

5
Adalimumab (Humira)
  • Monoclonal antibody to TNF-alpha
  • Sequence human-derived however studies
    demonstrate immunogenicity
  • Pivotal trials assessed safety and efficacy of
  • Monotherapy
  • Combination with methotrexate
  • Add on to standard of care
  • Licensed in December, 2002

6
Adalimumab Clinical Responses at 6 mo ( of
patients)
Study Adalimumab 40 mg q2w Adalimumab 40 mg q2w Placebo
Monotherapy (N544) ACR20 46 20
Monotherapy (N544) ACR50 22 8
Monotherapy (N544) ACR70 12 2
MTX combination (N619) ACR20 63 30
MTX combination (N619) ACR50 39 10
MTX combination (N619) ACR70 21 3
Add-on to standard of care (N636) ACR20 53 35
Add-on to standard of care (N636) ACR50 29 11
Add-on to standard of care (N636) ACR70 15 3
7
IndicationsHUMIRA (Adalimumab)
  • Monotherapy or combination with MTX or other
    DMARDs for RA
  • Improving signs and symptoms
  • Inhibition of progression of structural damage

8
Adalimumab Dosing Considerations
  • Recommended dose 40 mg SC q2wk
  • Optimal dose for MTX combination
  • With monotherapy, 40 q2wk effective, but higher
    response rates with 40 mg qwk
  • Monotherapy associated with higher rates of
    antibody formation than MTX combination
  • Immunogenicity associated with lower ACR response
    rates

9
Safety Update
  • Follow-up of August, 2001 AAC presentation
  • Present in depth discussion of new data on
    previously recognized serious adverse events and
    some newly recognized adverse events
  • TB experience with adalimumab
  • Lymphoma, malignancies with all agents
  • Liver injury with infliximab/etanercept
  • CHF

10
Analysis of Safety
  • Based on data from
  • Controlled clinical trials
  • Open-label extension studies
  • Postmarketing commitment for each product to
    assess 1000-2000 subjects x 5 years for
    malignancies and serious infections
  • Postmarketing registries
  • Spontaneous post-marketing reports

11
Serious Adverse Events AssociatedWith All 3
Approved TNF Blocking Agents
  • Serious infections
  • Tuberculosis
  • Opportunistic infections (e.g. histoplasmosis,
    listeriosis, coccidiodomycosis, PCP)
  • Non-opportunistic infections
  • Demyelinating events
  • Autoantibodies Autoimmune disease

12
Safety Concerns With TNF Blockers
  • For etanercept and infliximab, observed mostly in
    postmarketing reports some controlled trials in
    other diseases
  • For adalimumab
  • Much larger safety database at time of approval
  • SAEs observed pre-marketing
  • Many consistent with known mechanism of action,
    e.g. infections
  • Others unanticipated, e.g. CHF, demyelination

13
Agencys Communication of Risks
  • Stated in PI under
  • PRECAUTIONS section
  • WARNINGS section
  • BOX WARNING
  • Dear Healthcare Provider Letters
  • Peer-reviewed scientific publications
  • Presentations to Advisory Committee
  • Presentations at Medical Meetings

14
Considerations for Package Insert
  • Wording not identical for each product
  • Language dictated by data
  • Where data are similar, especially where there is
    a biologic rationale, class labeling may be
    warranted

15
TB Infliximab
  • TB seen in clinical trials
  • Cases of TB, some fatal and with unusual
    presentation, observed in post-marketing reports
  • Reporting rate several fold higher than incidence
    in US population
  • TB seen in patients not otherwise at risk
  • Boxed warning screening and prophylaxis
    recommended for all patients

16
TB Etanercept
  • Uncommon cases of TB seen in post-marketing
    experience
  • Reporting rate similar to US incidence
  • No cases in RA trials in US or EU (N3280)
  • Most US patients otherwise at high risk
  • Label Bold warning

17
Why Would AEs Differ Among Different TNF Blockers?
  • Potential explanations
  • Differing mechanisms of action soluble receptor,
    monoclonal antibodies
  • Differing affinity, avidity of binding
  • Differing ability to lyse TNF-bearing monocytes
  • Differing immunogenicity
  • Differences may contribute to unique efficacy and
    safety properties

18
Agenda
  • Update committee on known AEs and on newly
    documented AEs with TNF-blocking agents
  • TB
  • malignancies and lymphomas
  • Liver enzyme elevations/hepatic AEs
  • CHF
  • Challenges in interpreting open-label and
    post-marketing safety data

19
OVERVIEW
About PowerShow.com