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


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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.

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

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Division of oncology drug products presentation nda 21 649 genasense oblimersen for metastatic melanoma odac may

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 results itt population

TMZ Results ITT population


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


Patient disposition gm301

Patient Disposition – GM301


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.


Gm 301 primary analysis survival time itt population

GM 301: Primary Analysis Survival Time ITT population


Division of oncology drug products presentation nda 21 649 genasense oblimersen for metastatic melanoma odac may

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.


Division of oncology drug products presentation nda 21 649 genasense oblimersen for metastatic melanoma odac may

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


Summary of time to first 3 observed lesion assessments actual trial data

Summary of Time to First 3 Observed Lesion Assessments (Actual Trial Data)


Time to 1 st assessment trial data

Time to 1st Assessment(Trial Data)


Time to 2 nd assessment trial data

Time to 2nd Assessment(Trial Data)


Time to 3 rd assessment trial data

Time to 3rd Assessment(Trial Data)


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 times2

Lesion Assessment Times


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


Comparison of rr data as of original nda submission 12 8 03

Comparison of RRdata as of original NDA submission (12/8/03)


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


Duration of response genta analysis

Duration of Response – Genta analysis


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


Adverse events toxicity

Adverse Events – Toxicity


Adverse events hematologic toxicity

Adverse Events Hematologic Toxicity


Adverse events 5 non hematologic toxicity

Adverse Events ≥5%Non-hematologic Toxicity


Adverse events 5 non hematologic toxicity1

Adverse Events ≥ 5%Non-hematologic Toxicity


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


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