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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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FDA Review Team for Genasense (G3139)

• Project ManagementNicholette Hemingway, MPH

• Medical ReviewRobert Kane, MD

Ann Farrell, MD

• Statistical ReviewPeiling Yang, Ph.D.

Rajeshwari Sridhara, Ph.D.

• PharmacologyLilliam Rosario, Ph.D.

David E. Morse, Ph.D

• Chemistry Haripada Sarker, Ph.D.

Hasmukh Patel, Ph.D.

• Clin. Pharm/BiopharmGene Williams, Ph.D.

Brian Booth, Ph.D.

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Presentation Outline 1. Requirements for FDA approval

2. ODAC Review of Temozolomide

3. Genasense (Oblimersen) NDA 21-649• Trial Design (GM 301)• Primary Endpoint – Survival • Secondary Endpoints

4. Summary

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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

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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.

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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

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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 studiesNo evidence for survival advantage for any

combination over DTIC alone • Aldesleukin (1998) – IL-2

– RR: 16% (6% CR with duration 2-5 yrs)

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Selected Non-approved drugs for Metastatic Melanoma

• Interferon– 1997 Interferon alfa-2b approval for adjuvant

therapy of melanoma

• Temozolomide– ODAC 1999

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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

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TMZ Results ITT population

TMZN=156

DTICN=149

Hazard Ratio

p value

Median Survival

7.7 mo 6.4 mo 0.85 0.20 *

Median PFS

53days

42days 0.67 0.002 *

Overall Response Rate

12.2 % 9.4 % 0.43 **

* log rank ** Chi square

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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

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Genasense GM301 TrialRegulatory History

• July 2000 - Phase 3 protocol began

• August 1, 2003 – Data Cutoff Date

• December 8, 2003 - NDA submission

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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)

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Genasense GM301 Trial Design

• Primary Endpoint – Survival Improvement Secondary endpoints:

1. Progression-free survival (PFS)

2. Response rate (RR)

3. Duration of response

4. Durable response rate (RR at 6 months)

5. Performance status (PS)

6. Tumor-related symptoms

7. Safety

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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

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ITT G + D D Total

Number of Patients Randomized

386 385 771

Less number not treated 15 25 40

Still on study after day 42 (1st assessment)

186(48%)

151(39%)

337 (44%)

Discontinued early -

( < 8 cycles)

326

(84%)

328 (85%)

654 (85%)

Patient Disposition – GM301

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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.

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GM 301: Primary Analysis Survival Time ITT population

Number ( %)

died

Median Survival Time

HR *

Log rank

p

G + DTIC

n = 386

266 (69%)

274 days 9.0 mo 0.89 0.18

DTIC

n = 385

269 (70%)

238 days 7.8 mo

* 95% C.I. (0.75, 1.06)

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Statistical Review of Statistical Review of Efficacy:Efficacy:

Progression-Free Survival (PFS) Progression-Free Survival (PFS) (Secondary Endpoint)(Secondary Endpoint)

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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

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Outline

• Review of Applicant’s Analyses and Results

• Major FDA Concern: Lesion Assessment Times

• Additional FDA Concerns

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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

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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

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Review of Applicant’s PFS Analyses and Results

• Question:Is this a true finding?

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Major FDA Concern: Lesion Assessment Times

• Imbalance in Observed Lesion Assessment Times between Treatment Arms

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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.

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Visit 1 Visit 2Randomization

= Date of Death or actual tumor progression

Survival Event Date

Visit 1 Visit 2Randomization

PFS Event Date

Survival Analysis

PFS Analysis

Determining Event Dates

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Summary of Time to First 3 Observed Lesion Assessments

(Actual Trial Data)

AssessmentNumber

Median in days Logrank p-valueG3139 +

DTICDTIC

1 48 43 <0.001

2 94 87 <0.001

3 137 129 <0.001

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Time to 1st Assessment (Trial Data)

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Time to 2nd Assessment (Trial Data)

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Time to 3rd Assessment (Trial Data)

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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

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Lesion Assessment Times

How Bias May Be Introduced: A Hypothetical Example

Patient 001Control

Patient 002Experiment

al

Actual day of DP Day 35

1st time of assessment

Day 42 Day 48

Recorded day of DP Day 42 Day 48

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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)

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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

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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

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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

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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

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Primary Endpoint – Survival No Advantage for Genasense

• Secondary endpoints:1. Progression-free survival (PFS)

2. Response rate (RR)

3. Response duration

4. Durable response rate

5. Performance status (PS)

6. Tumor-related symptoms

7. Safety

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G + DTIC

(N=386)

DTIC

(N=385)

difference

P value

Genta / Investigator

45

(11.7%)

26

(6.8%) 4.9%

0.018

Blinded Independent

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(6.7%)

14 (3.6%) 3.1%

0.056

Comparison of RR data as of original NDA

submission (12/8/03)

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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.

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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

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Duration of Response – Genta analysis

Intent-to-Treat Population

G + DTIC DTIC Alone

Number of patients N = 45 N = 26

Mean (SD) Days 175.7 (136.0) 153.5 ( 99.2)

Median Days 126.0 127.5

Range (Days) (41 , 565) (42 , 390)

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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

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ECOG Performance Status

• There were no differences in performance status observed between study arms

during treatment

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Tumor-related symptoms

• There were no differences in symptoms observed between study arms

during treatment

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Category G + DTICN (%)

DTICN (%)

Number of patients receiving any therapy

371 360

At least 1 Grade 3 or 4 adverse event (AE)

249 (67%)

154 (43%)

At least 1 serious adverse event (SAE)

149 (40%)

97 (27%)

At least 1 adverse event and discontinued permanently

69 (19%)

39 (11%)

Adverse Events – Toxicity

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G + DTIC (N = 371)

n (%)

DTIC (N = 360)

n (%)

Grade 3 - 4 Neutropenia 79 (21%) 45 (12%)

Grade 3 - 4 Thrombocytopenia 58 (16%) 23 (6%)

Adverse Events Hematologic Toxicity

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Adverse Events ≥ 5%Non-hematologic Toxicity

AE G + DTIC DTICNausea 231 (62%) 169 (47%)

Pyrexia 197 (53%) 63 (18%)

Fatigue 170 (46%) 142 (39%)

Vomiting 139 (38%) 75 (21%)

Infections 123 (33%) 65 (18%)

Anorexia 114 (31%) 56 (16%)

Headache 97 (26%) 47 (13%)

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AE G + DTIC DTICRigors 76 (21%) 16 (4%)

Pruritus and Rash 57 (15% ) 18 (5%)

Injection site infection 24 (7%) 4 (1%)

Injection-site Reactions 21 (6%) 5 (1%)

Influenza-like Illness 19 (5%) 3 (0.8%)

Upper extremity thrombosis

18 (5%) 3 (0.8%)

*Axillary vein, Subclavian vein, Jugular vein, injection site thrombosis and superior vena caval syndrome

Adverse Events ≥ 5%Non-hematologic Toxicity

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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.

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Secondary Endpoints - PFS

1. 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 ?

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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)

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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