slide1
Download
Skip this Video
Download Presentation
Evolving Safety Issues Associated With Erythropoietin Products Oncology Drugs Advisory Committee May 4, 2004

Loading in 2 Seconds...

play fullscreen
1 / 89

fda team - PowerPoint PPT Presentation


  • 227 Views
  • Uploaded on

Evolving Safety Issues Associated With Erythropoietin Products Oncology Drugs Advisory Committee May 4, 2004 Harvey Luksenburg, M.D. Division of Therapeutic Biological Oncology Products, ODE 6/OND/CDER. FDA Team. Harvey Luksenburg, M.D., Clinical Kaushik Shastri, M.D., Clinical

loader
I am the owner, or an agent authorized to act on behalf of the owner, of the copyrighted work described.
capcha
Download Presentation

PowerPoint Slideshow about 'fda team' - lotus


An Image/Link below is provided (as is) to download presentation

Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author.While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server.


- - - - - - - - - - - - - - - - - - - - - - - - - - E N D - - - - - - - - - - - - - - - - - - - - - - - - - -
Presentation Transcript
slide1

Evolving Safety Issues Associated With Erythropoietin Products Oncology Drugs Advisory CommitteeMay 4, 2004

Harvey Luksenburg, M.D. Division of Therapeutic Biological Oncology Products,ODE 6/OND/CDER

fda team
FDA Team

Harvey Luksenburg, M.D., Clinical

Kaushik Shastri, M.D., Clinical

Ellis Unger, M.D., Clinical

Andrea Weir, Ph.D., Pharm/Tox

Clare Gnecco, Ph.D., Statistics

Mark Rothmann, Ph.D., Statistics

Ruth Wager, Ph.D., Product

Emily Shacter, Ph.D., Product

background
Background
  • Two large randomized studies in cancer patients on chemotherapy ± EPO have shown
    • Shorter OS
    • Shorter PFS
    •  incidence of thrombotic/cardiovascular events

in the groups assigned to EPO

slide4

Background

  • The EPO products used in these two studies are not licensed in U.S.
  • Used a treatment strategy to achieve hemoglobin  12 gm/dL [higher than recommended in the labeling for U.S. licensed products]
background5
Background
  • Clinical trials for U.S. licensed EPO products were not designed to assess impact on
    • Response rate

(except N93-004)

    • TTP/PFS
    • OS
goals 1
Goals (1)
  • Safety issues observed with EPREX and NeoRecormon may also apply to U.S. licensed products
  • Review results of trials with EPREX and NeoRecormon (non-U.S. licensed) regarding safety concerns
goals 2
Goals (2)
  • Review data available regarding safety from trials of EPOGEN / Procrit and Aranesp (U.S. licensed)
  • To come to agreement on design of future studies regarding safety
safety issues with recombinant erythropoietins
Safety Issues With Recombinant Erythropoietins
  • Thrombotic and cardiovascular adverse events
  • Tumor progression
  • Survival
recombinant epo products u s licensed
Recombinant EPO Products (U.S. Licensed)
  • Epoetin alfa manufactured by Amgen
    • EPOGEN (marketed by Amgen Inc.)
    • Procrit (marketed by Ortho BioTech L.P.)
  • Darbepoetin alfa

(Aranesp; Amgen, Inc.)

recombinant epo products not licensed in u s
Recombinant EPO Products(Not Licensed in U.S.)
  • Epoetin alfa (EPREX, Ortho Biologics)
  • Epoetin beta (NeoRecormon; Hoffmann-La Roche)
epos as a class
EPOs as a Class
  • FDA considers all of these products members of the same product class
  • These evolving safety issues are assumed to apply to all products unless adequate and well-controlled trials demonstrate otherwise
differences
Differences
  • Epoetin alfa and beta have same amino acid sequence but differ in glycosylation
  • Aranesp differs in amino acid sequence (5) and degree of glycosylation
similarities
Similarities
  • All exert principal clinical effect by binding to the EPO receptor
  • All have similar pharmacodynamic effects when used at recommended dosages
  • Similar toxicity profile across products (except PRCA)
slide14

Target Hemoglobin: Background

  • Labels for EPOGEN/Procrit and Aranesp have dosage guidelines based on safety data from registration studies performed in patients with chronic renal failure (CRF)
recommended hgb hct
Recommended Hgb/Hct
  • EPOGEN/Procrit
    • “Suggested Target Hct. Range: 30% to 36%”
  • Aranesp
    • “The dose should be adjusted for each patient to achieve and maintain a target hemoglobin not to exceed 12 g/dL”
dosing recommendations
Dosing Recommendations
  • For rapid increase in Hgb greater than 1.0 g/dL (or 4 points in Hct) in any 2 week period dose should be reduced
  • Hold if Hgb > 13 g/dL, until Hgb falls < 12 g/dL, and restart dose at 25% belowprevious dose.
thrombotic events with epo
Thrombotic Events with EPO
  • Licensing studies for EPOGEN

/ Procrit and Aranesp demonstrated baseline risk of thrombotic & cardiovascular adverse events at labeled target Hgb (10-12 g/dL)

normal hematocrit study besarab et al nejm 1998
“Normal Hematocrit Study” (Besarab et al, NEJM 1998)
  • 1,233 patients with chronic renal failure on dialysis with clinical evidence of CHF or ischemic heart disease
  • EPOGEN at baseline in order to achieve/maintain Hct 27-33%
normal hematocrit study
“Normal Hematocrit Study”
  • Both arms received EPOGEN but randomized to different treatment strategies
    • Achieve Hct of 42% (±3) (“normal Hct”)
    • Maintain Hct of 30% (±3)

(“low Hct”)

breast cancer erythropoietin trial best eprex epoetin alfa
Breast Cancer Erythropoietin Trial (BEST) (EPREX [Epoetin alfa])
  • Randomized, DB, Placebo controlled
  • 939 women w/ metastatic breast cancer
    • 1st line therapy
    • +/- EPREX for 12 mos
    • Therapy started Hgb < 13 g/dL
best trial
BEST Trial
  • Primary objective to demonstrate superior survival at 12 months.
  • Target Hgb 12-14 g/dL
  • Stopped by IDMC based on first 4 mos safety data
best trial27
BEST Trial

At 4 months

  •  incidence of fatal thrombotic and cardiovascular events

EPREX 2.3%

Placebo 0.4%

henke et al lancet 2003 neorecormon epoetin beta
Henke et al (Lancet 2003) (NeoRecormon [Epoetin beta])
  • Randomized, DB, PC
    • 351 patients w/ head and neck cancer
    • Concurrent radiotherapy
    • Anemic < 12 g/dL women

< 13 g/dL men

henke et al
Henke et al
  • Primary Objective

To demonstrate superior locoregional PFS

  • Target Hgb ≤14 g/dL women

≤15 g/dL men

henke et al30
Henke et al
  • Hypertension, hemorrhage, venous thrombosis, pulmonary embolism, CVA

Epoetin beta 11%

Placebo 5%

  • Patients who died of “cardiac disorders”

Epoetin beta 5.5%

Placebo 3%

registration studies procrit
Registration Studies-Procrit
  • Pooled analyses of six multicenter, randomized, DB, placebo-controlled studies
  • 131 patients

– Various primary cancers

    • Platinum (n=59) & non-platinum (n=72)
    • Anemic
    • Primary endpoint: Proportion patients tranfused
registration studies procrit33
Registration Studies-Procrit
  • Incidence of thrombotic & cardiovascular events (pooled data)
  • Placebo 12% (8/68)
  • Procrit 3% (2/63)
study n93 004 procrit epoetin alfa
Study N93-004 (Procrit [Epoetin alfa])
  • Post-marketing commitment
  • Randomized, DB, PC, non-inferiority study
  • Intended to enroll 400 patients with SCLC
    • First line therapy
    • Baseline Hgb < 14 g/dL
study n93 004
Study N93-004
  • Primary Endpoint: Objective RR after 3 cycles chemo to rule out decrement of 15% in ORR with Procrit
  • No target Hgb, Procrit dose reduced for Hgb > 16 g/dL
  • Study terminated for poor accrual at 224 patients
study n93 00436
Study N93-004

Incidence of Thrombotic Vascular Events

  • Procrit 22% (24/109)
  • Placebo 23% (27/115)
  • Includes “chest pain”, MI, angina, stroke, cardiac arrest, peripheral ischemia, cardiovascular disorder, thrombosis, DVT, PE, phlebitis
aranesp 980297
Aranesp 980297
  • Randomized, DB, PC
  • 320 pts with lung cancer
    • Platinum-containing chemotherapy
    • Anemic (< 11 g/dL)
aranesp 98029739
Aranesp 980297
  • Primary endpoint: Proportion transfused between week 5 and week 12 or end of treatment period (EOTP)
  • Aranesp held for Hgb > 14 g/dL women & Hgb > 15 g/dL men
aranesp 98029740
Aranesp 980297

Thrombotic events

  • Aranesp 5% (7/155)
  • Placebo 3% (5/159)
slide42

Thrombotic/Vascular Events

Studies w/o Signal

slide43

Higher Target Hemoglobin

  • In September 2003 three placebo controlled clinical trials in oncology patients in which one arm received EPO to target a higher hemoglobin were terminated because of unexpected rates of thrombotic events in the EPO arm
preclinical studies
Preclinical Studies
  • EPO receptors (EPO-R) are present on some tumor cell lines & tumor vasculature (endothelial cells)
preclinical studies47
Preclinical Studies

EPO is reported to

  • Inhibit apoptosis
  • Stimulate angiogenesis; endothelial cell growth, migration, and proliferation
  • Reduce survival in tumor xenograft models
tumor stimulation
Tumor Stimulation
  • Studies supporting approval of Procrit and Aranesp for the treatment of anemia in cancer patients on chemotherapy not designed to assess impact on
    • Tumor response
    • Tumor progression
    • Survival
breast cancer erythropoietin trial best eprex epoetin alfa50
Breast Cancer Erythropoietin Trial (BEST) (EPREX [Epoetin alfa])
  • Randomized, DB, Placebo controlled
  • 939 women w/ metastatic breast cancer
    • 1st line therapy
    • +/- 12 mo EPREX
    • Therapy started Hgb < 13 g/dL
breast cancer erythropoietin trial best eprex epoetin alfa51
Breast Cancer Erythropoietin Trial (BEST) (EPREX [Epoetin alfa])
  • Primary objective to demonstrate superior survival at 12 months.
  • Target Hgb 12-14 g/dL
  • Stopped by IDMC based on first 4 mos safety data
best trial52
BEST Trial

At 4 months

  • 2-fold increase in disease progression

EPREX 6% (28/469)

Placebo 3% (13/470)

best trial eprex epoetin alfa
BEST Trial (EPREX [Epoetin alfa])

At 4 months

  • 2.5-fold increase in early mortality

EPREX 8.7% (41/469)

Placebo 3.4% (16/470)

henke et al lancet 2003 neorecormon epoetin beta54
Henke et al (Lancet 2003) (NeoRecormon [Epoetin beta])
  • Randomized, DB, PC
    • 351 patients w/ head & neck cancer
    • Concurrent radiotherapy
    • Anemic: Hgb < 12 g/dL women

Hgb < 13 g/dL men

henke et al55
Henke et al
  • Primary Objective to demonstrate superior locoregional PFS
  • Target Hgb ≤ 14 g/dL women

≤ 15 g/dL men

henke et al56
Henke et al

For Locoregional PFS

NeoRecormon vs. Placebo

RR 1.62

(95% CI 1.22, 2.14, p=0.0008)

henke et al57
Henke et al

For Locoregional progression

NeoRecormon vs. Placebo

RR 1.69

(95% CI 1.16-2.47; p=0.007)

study n93 004 procrit epoetin alfa58
Study N93-004 (Procrit [Epoetin alfa])
  • Post-marketing commitment
  • Randomized, DB, PC, non-inferiority study
  • Intended to enroll 400 patients with SCLC
    • First line therapy
    • Baseline Hgb < 14 g/dL
study n93 00459
Study N93-004
  • Primary Endpoint: Objective RR after 3 cycles chemo to rule out 15% decrement in ORR in Procrit arm
  • No target Hgb, Procrit dose reduced for Hgb > 16 g/dL
  • Study terminated at 225/400 for poor accrual
procrit n93 004
Procrit N93-004
  • Not designed to assess impact on TTP
  • Survival a secondary endpoint - no formal hypothesis testing
aranesp 98029762
Aranesp 980297
  • Randomized, DB, PC
  • 320 pts with lung cancer
    • Platinum-containing chemotherapy
    • Anemic (Hgb < 11 g/dL)
aranesp 98029763
Aranesp 980297
  • Primary endpoint: Proportion transfused between week 5 and week 12 (or EOTP)
  • Aranesp held for Hgb > 14 g/dL women & > 15 g/dL men
aranesp 98029764
Aranesp 980297

Median PFS (95% CI)

Aranesp 5 months (4, 7 mos)

Placebo 4 months (4, 5 mos)

Not designed to assess impact on PFS

slide66

Tumor Stimulation

Studies w/ Signal

slide67

Tumor Stimulation

Studies w/o Signal

breast cancer erythropoietin trial best eprex epoetin alfa70
Breast Cancer Erythropoietin Trial (BEST) (EPREX [Epoetin alfa])
  • Randomized, DB, Placebo controlled
  • 939 women w/ metastatic breast cancer
    • 1st line therapy
    • +/- EPREX for 12 mos
    • Study drug started at Hgb < 13 g/dL
best trial71
BEST Trial
  • Primary objective: To demonstrate superior survival at 12 months.
  • Target Hgb 12-14 g/dL
  • Stopped by IDMC based on 4 mo safety data
best trial72
BEST Trial

Estimated 12-month survival

EPREX: 70% (148 deaths/469)

Placebo: 76% (115 deaths/470)

RR of death=1.4

(95% CI 1.07,1.74; p=0.012)

henke et al lancet 2003 neorecormon epoetin beta74
Henke et al (Lancet 2003) (NeoRecormon [Epoetin beta])
  • Randomized, DB, PC
    • 351 patients w/ head and neck cancer
    • Concurrent radiotherapy
    • Anemic < 12 Hgb g/dL women

< 13 Hgb g/dL men

henke et al75
Henke et al
  • RR of death: 1.4

(95% CI 1.05-1.84, p=0.02 Cox)

  • Median overall survival

NeoRecormon 605 days

Placebo 928 days

(p=0.09, logrank)

study n93 004 procrit epoetin alfa76
Study N93-004 (Procrit [Epoetin alfa])
  • Randomized, DB, PC, non-inferiority study
  • Intended to enroll 400 patients with SCLC
    • First line therapy
    • Baseline Hgb < 14 g/dL
  • Not designed to assess impact on survival
study n93 004 procrit epoetin alfa77
Study N93-004 (Procrit [Epoetin alfa])

Median survival

Procrit 10.5 months (95% CI: 9, 13)

Placebo 10.4 months (95% CI: 8, 13)

Overall mortality rate

Procrit 92% (100/109)

Placebo 88% (101/115)

aranesp 98029779
Aranesp 980297

Randomized, DB, PC

  • 320 pts with lung cancer
    • Platinum-containing chemotherapy
    • Anemic (< 11 g/dL)
  • Not designed to address impact on survival
aranesp 98029780
Aranesp 980297

Median overall survival

Aranesp 10 mos (95% CI: 9, 12 mos)

Placebo 8 mos (95% CI: 7, 9 mos)

Overall mortality rate

Aranesp 14% (22/155)

Placebo 12% (19/159)

summary
Summary
  • Two large, multicenter studies (BEST & Henke) designed to show superior survival or PFS demonstrated
    • Increased thrombotic events
    • Shorter PFS
    • Shorter OS
  • Used a treatment strategy to achieve hemoglobin levels > 12 g/dL
summary85
Summary
  • Multicenter, placebo-controlled trials

Procrit (N93-004) and Aranesp (980297)

    • Smaller in size
    • Not designed to assess impact on PFS or OS
    • Treatment strategy varied – Procrit held > Hgb 14 g/dL

(label recommends 12 g/dL)

conclusions
Conclusions
  • Evolving safety concerns
  • Current dosing recommendations adequate to minimize risks of thrombotic events
  • Insufficient information for OS and PFS for U.S. licensed products at approved doses to assess risks
  • Amgen, Ortho Biotech and FDA agree on need for further studies
fda recommended elements
FDA Recommended Elements
  • Homogenous primary tumor type
  • Homogenous chemotherapy or radiotherapy regimens
  • Study designed to detect clinically meaningful decrements in response rate, PFS, and survival
fda recommended elements88
FDA Recommended Elements
  • Prespecified definitions of cardiovascular and thrombotic events
  • DSMB oversight
fda recommended elements89
FDA Recommended Elements

Determination of expression and

ligand affinity of EPO-R on

specific primary tumor types

  • Preferably through analysis of clinical tissue specimens or
  • Pre-existing tissue repositories representing common tumor types
ad