slide1
Download
Skip this Video
Download Presentation
Division of Oncology Drug Products Presentation NDA 21-649 Genasense (Oblimersen) for metastatic melanoma ODAC May 3, 2004

Loading in 2 Seconds...

play fullscreen
1 / 54

Division of Oncology Drug Products Presentation NDA 21-649 Genasense Oblimersen for metastatic melanoma ODAC May - PowerPoint PPT Presentation


  • 150 Views
  • Uploaded on

Division of Oncology Drug Products Presentation NDA 21-649 Genasense (Oblimersen) for metastatic melanoma ODAC May 3, 2004. Project Management Nicholette Hemingway, MPH Medical Review Robert Kane, MD Ann Farrell, MD Statistical Review Peiling Yang, Ph.D.

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 'Division of Oncology Drug Products Presentation NDA 21-649 Genasense Oblimersen for metastatic melanoma ODAC May ' - gilbert


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

Division of Oncology Drug Products Presentation NDA 21-649 Genasense (Oblimersen) for metastatic melanomaODAC May 3, 2004

fda review team for genasense g3139
Project Management

Nicholette Hemingway, MPH

Medical Review

Robert Kane, MD

Ann Farrell, MD

Statistical Review

Peiling Yang, Ph.D.

Rajeshwari Sridhara, Ph.D.

Pharmacology

Lilliam Rosario, Ph.D.

David E. Morse, Ph.D

Chemistry

Haripada Sarker, Ph.D.

Hasmukh Patel, Ph.D.

Clin. Pharm/Biopharm

Gene Williams, Ph.D.

Brian Booth, Ph.D.

FDA Review Team for Genasense (G3139)
presentation outline
Presentation Outline
  • Requirements for FDA approval
  • ODAC Review of Temozolomide
  • Genasense (Oblimersen) NDA 21-649
    • Trial Design (GM 301)
    • Primary Endpoint – Survival
    • Secondary Endpoints
  • Summary
requirements new drug approval
Requirements - New Drug Approval
  • FD&C Act 1962 - Substantial evidence of effectiveness required by Congress
    • Adequate & well-controlled investigations
    • Generally understood to mean evidence from at least 2 adequate and well-controlled studies
requirements new drug approval1
Requirements - New Drug Approval
  • FDAMA - 1997 One trial may suffice with other confirmatory evidence
  • Effectiveness Guidance Document - 1998 A single trial should be of excellent design, internally consistent, and demonstrate a compelling result – statistically strong evidence of an important clinical benefit such as survival.
new drug approval efficacy requirement
New Drug Approval Efficacy Requirement
  • Regular approval
    • clinical benefit or established surrogate
  • Accelerated Approval
    • uses a surrogate endpoint reasonably likely to predict clinical benefit
    • confirmation of clinical benefit required
approved drugs metastatic melanoma
Approved drugs - Metastatic Melanoma
  • Hydroxyurea (1967) - 10% response rate
  • Dacarbazine (1975) – DTIC single arm studies

Response Rate (RR) = 23% (6%CR)

Survival times range 5 – 9 months

    • To date, no evidence for Survival or

Progression-free Survival (PFS) benefit for DTIC

    • RR: 5% - 24% in other studies

No evidence for survival advantage for any combination over DTIC alone

  • Aldesleukin (1998) – IL-2
    • RR: 16% (6% CR with duration 2-5 yrs)
selected non approved drugs for metastatic melanoma
Selected Non-approved drugs for Metastatic Melanoma
  • Interferon
    • 1997 Interferon alfa-2b approval for adjuvant

therapy of melanoma

  • Temozolomide
    • ODAC 1999
temozolomide tmz
Temozolomide (TMZ)
  • One main study: open label, 305 patients with metastatic melanoma randomized to

DTIC IV each 3 weeks

versus TMZ p.o. each 4 weeks

  • Primary Endpoint – Survival (superiority) from median 6 mo-DTIC to 9 mo-TMZ
  • Secondary endpoints: PFS and RR
tmz was not approved
TMZ was not approved
  • Failed Primary Endpoint: No Survival benefit
  • PFS, a secondary endpoint, small magnitude
  • ODAC questioned the PFS difference
  • No symptomatic benefit demonstrated
  • A post-hoc survival analysis using a 6 month endpoint was not convincing
genasense gm301 trial regulatory history
Genasense GM301 TrialRegulatory History
  • July 2000 - Phase 3 protocol began
  • August 1, 2003 – Data Cutoff Date
  • December 8, 2003 - NDA submission
genasense gm301 trial design
Genasense GM301 Trial Design
  • Large, multicenter, unblinded study
  • Prolonged central venous access required for Genasense (G)
  • Protocol specified IRC for responders
  • Intellectual, emotional, and physical ability to maintain an ambulatory infusion pump

(for patients assigned to G + DTIC)

genasense gm301 trial design1
Genasense GM301 Trial Design
  • Primary Endpoint – Survival Improvement

Secondary endpoints:

      • Progression-free survival (PFS)
      • Response rate (RR)
      • Duration of response
      • Durable response rate (RR at 6 months)
      • Performance status (PS)
      • Tumor-related symptoms
      • Safety
genasense trial design gm301
Genasense Trial Design - GM301
  • Trial design - to show a 2 month median improvement in survival from 6 months with DTIC alone to 8 months with Genasense plus DTIC; 90% power
  • Trial Primary endpoint – survival
  • Trial Primary analysis – unadjusted log rank analysis of the intention-to-treat population
genasense study gm301
Genasense study GM301
  • Data cutoff date August 1, 2003
  • Analysis occurred at 535 deaths (70%)
  • Primary Endpoint Analysis:

Using the protocol specified analysis with the ITT population, no survival benefit was demonstrated by adding Genasense to DTIC treatment versus DTIC alone.

slide19

Statistical Review of Efficacy:

Progression-Free Survival (PFS)

(Secondary Endpoint)

results
Results
  • Failed to demonstrate efficacy in the primary endpoint, overall survival
    • at two-sided alpha level of 0.05
  • Strength of efficacy findings in the secondary endpoint, progression-free survival, is uncertain
outline
Outline
  • Review of Applicant’s Analyses and Results
  • Major FDA Concern: Lesion Assessment Times
  • Additional FDA Concerns
review of applicant s pfs analyses and results
Review of Applicant’s PFS Analyses and Results
  • PFS
    • Time from date of randomization to date of disease progression/death
  • Recorded Date of Disease Progression
    • The assessment date
    • Assessment date in each cycle:
      • The latest date among different lesion assessments in that cycle
review of applicant s pfs analyses and results1
Review of Applicant’s PFS Analyses and Results
  • Protocol-Specified Analysis:
    • Logrank: p-value = 0.0003
    • Median:74 (G3139 + DTIC) vs. 49 days (DTIC)
    • Cox Model (supportive): Hazard Ratio = 0.73
  • Alternative Approach:
    • Logrank: p-value = 0.0006
    • Median:61 (G3139 + DTIC) vs. 48 days (DTIC)
    • Cox model (supportive): Hazard Ratio = 0.75
review of applicant s pfs analyses and results2
Review of Applicant’s PFS Analyses and Results
  • Question:

Is this a true finding?

major fda concern lesion assessment times
Major FDA Concern: Lesion Assessment Times
  • Imbalance in Observed Lesion Assessment Times between Treatment Arms
lesion assessment times
Lesion Assessment Times
  • Planned Timing for Lesion Assessments
  • In Practice:
    • Not always as planned.
    • Even when assessed in planned cycles, there were differences in timing between arms.
slide27

Determining Event Dates

Survival Analysis

Survival Event Date

Randomization

Visit 1

Visit 2

PFS Analysis

PFS Event Date

Randomization

Visit 1

Visit 2

= Date of Death or actual tumor progression

lesion assessment times1
Lesion Assessment Times
  • Impact of Imbalance in Assessment Times on PFS Analysis:
    • Bias may be introduced in estimating PFS
    • Even a small imbalance may lead to incorrect conclusion
lesion assessment times3
Lesion Assessment Times

Impact of systematic bias:

Simulation study

  • Distribution identical in both arms (Median PFS = 50 days, 300 subjects in each arm)
  • Systematic increase by 2 days in assessment time in one arm
  • In 98% of the 5000 simulations p-values were < 0.05 (average p-value = 0.004)
additional fda concern
Additional FDA Concern
  • Missing data was observed
    • Missing assessments visits
    • Missing individual lesion measurements
  • In presence of missing data
    • Bias could be introduced, especially in an open-label study
summary of pfs finding
Summary of PFS Finding

The claimed PFS benefit may not be a true finding because of:

  • Difference in assessment intervals may explain observed PFS effect
  • Questions regarding reliability of data collected in an open-label study
summary of statistical review
Summary of Statistical Review
  • Study failed to achieve the primary objective of the study – No Overall Survival Benefit
  • Secondary endpoints – PFS analysis:
      • Existence of effect ?
      • Magnitude of effect ?
      • Multiplicity Issues
pfs analysis continued
PFS analysis - continued
  • Assessments done only at 6 week intervals, however PFS difference only 2-3 weeks
  • PFS difference is highly statistically significant, but may be fully accounted for by asymmetry in timing of assessments between arms
  • Magnitude of the effect size is uncertain
  • PFS: Real problem: what is the clinical relevance
primary endpoint survival no advantage for genasense
Primary Endpoint – Survival No Advantage for Genasense
  • Secondary endpoints:
      • Progression-free survival (PFS)
      • Response rate (RR)
      • Response duration
      • Durable response rate
      • Performance status (PS)
      • Tumor-related symptoms
      • Safety
response concordance
Response Concordance
  • 5 CRs identified by Genta/site investigators
    • 3 in G + DTIC arm and 2 in DTIC arm
  • None were adjudicated as CRs by Independent Review
  • 44% of responders (CR or PR) by Genta/site investigators were determined not assessable or unconfirmed by Independent Review.
  • 49% full concordance rate for response category between Genta and Independent Review.
genta new response data provided april 9 2004
Genta New Response Data provided April 9, 2004
  • New data is being examined
  • Problems with data developed outside of the study protocol:
    • Ascertainment bias between arms can occur when analysis is not prospectively planned
    • Subsequent therapies, e.g. surgery, not part of the protocol treatment may not be applied symmetrically
durable response rate genta analysis
Durable response rateGenta Analysis
  • Genta has pre-specified a response of

≥ 6 months as a durable response.

  • Durable response rate for G + D = 3.4%
  • Durable response rate for D = 1.3%
  • Difference - not significant
ecog performance status
ECOG Performance Status
  • There were no differences in performance status observed between study arms

during treatment

tumor related symptoms
Tumor-related symptoms
  • There were no differences in symptoms observed between study arms

during treatment

genasense summary
Genasense Summary
  • GM301Trial failed its primary protocol-specified endpoint
  • No Survival Benefit demonstrated with the addition of Genasense to DTIC
  • The efficacy of the control arm, DTIC alone, is consistent with other studies.
secondary endpoints pfs
Secondary Endpoints - PFS
  • PFS: No precedent for PFS as evidence of

clinical benefit for metastatic melanoma

    • May not be a true finding
    • PFS difference may be 13 or 25 days depending on censoring technique chosen for missing data
    • Clinical relevance ?
secondary endpoints response
Secondary Endpoints - Response

2. Response rate:

  • Difference from DTIC alone: 3 - 5%
  • No CRs Confirmed by IRC
  • Clinical relevance ?

3. Durable response rate: No sig. difference (3.4% (G+DTIC) vs. 1.3% (DTIC alone))

4. Response duration: 126 days (G+DTIC) versus 127.5 days (DTIC alone)

secondary endpoints genasense
Secondary endpoints- Genasense

5. Performance status:

- No benefit observed from Genasense

6. Symptomatic benefit: Not observed

7. Safety: Greater toxicity for the combination of G + DTIC

ad