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Atrasentan For Men with Metastatic Hormone Refractory Prostate Cancer ODAC September 13 th , 2005. Clinical-Statistical Presentation Amna Ibrahim MD Shenghui Tang PhD DDOP, FDA. Outline of Presentation. 1- Past approvals 2- Phase III study Study design

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atrasentan for men with metastatic hormone refractory prostate cancer odac september 13 th 2005

Atrasentan For Men with Metastatic Hormone Refractory Prostate CancerODAC September 13th, 2005

Clinical-Statistical Presentation

Amna Ibrahim MD

Shenghui Tang PhD


outline of presentation
Outline of Presentation

1- Past approvals

2- Phase III study

  • Study design
  • Results of protocol-specified endpoints
  • Subgroup analyses
  • Reliability of results
  • Clinical relevance of results

3- Phase II study

Protocol, conduct and results

4- Major safety concerns- Phase III and II

past hrpc approvals
Past HRPC Approvals
  • Mitoxantrone + Prednisone (approved 1996)

- Primary endpoint: confirmed improvement in pain

- Interpretable pain severity scale

- Pre-specified analysis plan for pain evaluation

- Improved time to progression

  • Taxotere + Prednisone (approved 2004)

- Primary endpoint: Overall survival

For Both Approvals:

Primary endpoint: Pre-specified

Results: Persuasive- statistically & clinically

design of the atrasentan study phase iii study
Design of the Atrasentan StudyPhase III Study
  • Double blinded randomized study
  • Central independent review blinded to PSA
  • QoL was tertiary endpoint without detailed analysis plan
  • No mention of a specific measurement of pain submitted
disease progression definition phase iii study
Disease Progression Definition Phase III Study

Protocol-specified Primary Endpoint:

Time to Disease Progression- ITT

Events constituting Disease Progression (DP)

  • Radiographic Progression
  • Pain requiring intervention
  • Prostate Cancer complications requiring interventions
  • Skeletal Related Events (SREs)
events defining dp phase iii study applicant analyses
Events defining DPPhase III Study- applicant analyses

For both treatments arms combined (all progression events)

A- Radiographic Progression 74%

B- Pain 20%

C- Interventions 3%

D- SREs 2%

results of protocol specified endpoints phase iii study
Results of Protocol-Specified Endpoints Phase III Study
  • Failed primary endpoint TDP
  • Failed 4 of 5 secondary endpoints(-) OS, Time to PSA progression, change in bone scan index, & PFS (+) Mean change in ALP but difference of only 20 ng/ml, and missing data
  • Failed several tertiary endpoints(-) QoL adjusted TDP (QATDP), KPS and mean change in PSA.
phase ii study
Phase II Study
  • Randomized 3-arm, phase II study
  • Pretreated population
    • different from Ph III study
    • Any therapy (except hormones) 75% on placebo & 66% atrasentan 10 mg
    • prior chemo: 25% on placebo & 18% on Atrasentan 10 mg
  • Pts with prostate ca pain not excluded
  • Primary endpoint: TDP (defined differently from Ph III)
disease progression phase ii study
Disease ProgressionPhase II Study

Disease Progression Definition

  • intervention for cancer-related event
  • new symptoms related to tumor growth
  • New pain requiring opioids (evidence of disease and duration not required)
  • Other investigator defined measures not well-defined (incl. PSA rise, weakness, steroids use and deterioration)
conduct of studies applicant analyses for phase iii ii studies
Conduct of Studies (Applicant analyses for Phase III & II Studies)

Phase III study protocol violations:

Atrasentan 10 mg: 12%

Placebo: 18%

Phase II study protocol violations:

Atrasentan 10 mg: 58%

Placebo: 38%

Phase II missing data for imaging studies:

< 50% paired bone scans and CT scans available

fda statistical review

FDA Statistical Review

Shenghui Tang, PhD Mathematical StatisticianFDA/CDER/Division of Biometrics I

outline major statistical problems
Outline:Major Statistical Problems

• Early closure of the phase III study

• Failed primary efficacy (Phase II & III)

• Submitted analyses are post hoc:

  • subgroup & pooled analyses
  • QoL and pain analyses

• No adjustment for multiple comparisons

early closure of phase iii study
Early Closure of Phase III Study

• Independent Data Monitoring Committee recommended closure of the phase III study due to lack of efficacy

• The study closed on March 19, 2003

809 patients, 343 TDP events

failed primary efficacy phase ii iii
Failed primary efficacy Phase II & III

• No alpha left for further testing

• Any further analysis inflates

false positive rate

secondary efficacy analyses
Secondary Efficacy Analyses
  • Time to onset of PSA progression

unadjusted nominal p-value=0.344

  • Mean rate of change from baseline to final value in total bone scan index

unadjusted nominal p-value=0.051

  • Overall survival

unadjusted nominal p-value=0.791, HR=0.982

  • Mean change from baseline to final value in bone alkaline phosphatase (ALP)

unadjusted nominal p-value=0.001

secondary and tertiary efficacy analyses are exploratory
Secondary and Tertiary Efficacy Analyses are Exploratory

Per applicant’s specified protocol:

“…….If the primary efficacy analysis is

not statistically significant at the α=0.05 level, then statistical significance will not be declared for any of these secondary analyses, regardless of the observed p-values.”

subgroup analyses
Subgroup Analyses

Two main subgroup analyses in phase III study were submitted:

• Per-protocol patient population (12/04)

83% overall patient population

• Patients with bone metastases at baseline (BM) (12/04)

- Clinical Disease Progression analysis in

BM subgroup (First reported in the briefing


subgroup tdp analyses phase iii per protocol bone mets at baseline20
Subgroup TDP Analyses Phase III Per-Protocol & Bone Mets at Baseline

• Protocol stated that significance will not be declared for the per-protocol analysis

• Bone metastatic subgroup analysis is a post-hoc analysis

clinical disease progression analysis
Clinical Disease Progression Analysis
  • Not pre-specified

• Not adjusted for multiple comparisons

  • Informative censoring of radiological


  • >75% censored for progression
guidelines for statistical principles for clinical trials ich e9
Guidelines for Statistical Principles for Clinical Trials (ICH E9)

• ‘…, adjustment should always be considered and the details of any adjustment procedure… should be set out in the analysis plan.’

  • ‘ In most cases, however, subgroup and interaction analyses are exploratory and should be clearly identified as such; they should explore the uniformity of any treatment effects found overall.’
guidelines for structure and contents of clinical study reports ich e3
Guidelines for Structure and Contents of Clinical Study Reports (ICH E3)

Examination of Subgroups:

‘These analyses are not intended to "salvage" an otherwise non-supportive study but may suggest hypotheses worth examining in other studies or be helpful in refining labelling information, patient selection, dose selection etc.’

problems with subgroup analyses
Problems with Subgroup Analyses
  • High false positive or false negative rates.
  • False positive finding increases with number of significance tests
  • Not pre-specified = Post-hoc analysis
  • Primary failed → P-value not interpretable

Subgroup Analyses are Exploratory

pooled analysis of phase ii phase iii studies
Pooled Analysis of Phase II & Phase III Studies

Pooled analysis not acceptable:

  • Neither trial individually shows a statistically significant difference

2. Different Definitions of TDP

3. Different Patient populations

4. Atrasentan formulations not bioequivalent


pooled analysis phase ii phase iii studies cont d
Pooled Analysis Phase II & Phase III Studies (cont’d)

5. Post-hoc analysis

6. No independent review of progression

evaluation conducted in Phase II study

7. Pooling data causes imbalance in


8. Type I error not controlled

quality of life analysis
Quality of Life Analysis

• QoL tertiary endpoint

• Measured using FACT-P and EORTC-C30

• No hypothesis for QoL analysis

• Compare differences in mean scores

•No adjustment for multiple comparisons

quality of life analysis28
Quality of Life Analysis

Mean Change from Baseline to Final Assessment

for FACT-P and Subscores: ITT Subject Population

prostate cancer subscore pcs
Prostate Cancer Subscore (PCS)
  • I am losing weight
  • I have a good appetite
  • I have aches and pain that bother me
  • I have certain areas of my body where I experience significant pain
  • My pain keeps me from doing things I want to do
  • I am satisfied with my present comfort level
  • I am able to feel like a man
  • I have trouble moving my bowels
  • I have difficulty urinating
  • I urinate more frequently than usual
  • My problems with urinating limit my activities
  • I am able to have and maintain an erection
problems with qol analysis
Problems with QoL Analysis

• Clinical significance of the PCS mean

change of 1.02 on a scale of 0-48

• Recall Bias

• PCS score does not capture all the

patient perceived impact of atrasentan


• Missing data

pain analyses
Pain Analyses

• Change in pain-related scores (12/04)

• Time to 50% deterioration

(First reported in briefing package, 8/05)

pain related questions in pcs
Pain-related Questions in PCS
  • I have aches and pain that bother me
  • I have certain areas of my body where I experience significant pain
  • My pain keeps me from doing things I want to do
  • I am satisfied with my present comfort level

Not Specific to Bone or Prostate Cancer Pain

mean change in pain related scores in pcs
Mean Change in Pain-related Scores in PCS

• Not designed or validated for such use.

• Clinical significance of the PCS pain

score mean change of 0.7 on a scale of

0 to 16

• Each pain item measures a different

attribute of pain

• 7-day recall period.

• Questions not specific to bone pain.

Do not adequately measure pain

clinical review continued outline
Clinical Review ContinuedOutline
  • Clinical relevance of results (TDP)
  • Reliability of results (TDP)
  • Post hoc analyses (clinical aspects)
  • Safety
  • Conclusion
hazards of the hazard ratio
Hazards of the Hazard Ratio

Regarding Ratios (e.g. HR, proportions and odds ratios)

Meaningful only if also clinically relevant

  • Units of time not represented (improvement of 3 days to 6 days same as 3 years to 6 years)
  • For primary endpoint in the 3 populations, HR <1, but not clinically meaningful.
reliability of difference in rtdp hypothetical situation
Reliability of difference in rTDPhypothetical situation



Arm A



Arm B

Imaging Study

Months 3

Time Zero

TDP is 3 months on both arms

reliability of tdp results phase iii study
Reliability of TDP ResultsPhase III Study
  • Time to radiographic progression is time to imaging
  • Radiographic progressions drove study results (74% of DP events)
  • Imaging scheduled q 12 weeks per protocol (84 d)
  • Median TDP is ~ 89 days
  • No reliable effect of atrasentan was observed
  • Pain not primary endpoint for atrasentan studies unlike mitoxantrone study.

Mitoxantrone & Prednisone study

- 2 point improvement in 6 point scale of at least 6 weeks of duration

(29% vs 12%)

- Improved median time to progression (4.4 mo vs. 2.3 mo.)

Atrasentan study

- ~1 in 0-48 point scale (FACT-PCS)

- 0.2 in a 2-8 point scale (EORTC QLQ-C30, 2 items only)

& 0.7 in a 0-16 point scale (4 of 12 items from PCS)

  • Magnitude of effect on pain small and duration not considered in atrasentan study
retrospective pain analysis
Retrospective Pain Analysis

Time to 1st AE of bone pain - No requirement for routine assessment of bone pain in AE reporting

- for e.g. prostate cancer AE reporting was 12% on atrasentan and 16% on placebo arm

AE reporting not meant to be used as an endpoint

efficacy summary
Efficacy Summary

Phase II study is not acceptable.

Phase III Study:

  • Primary endpoint failed
  • Secondary endpoints failed or not clinically meaningful (includes bone markers, & QoL)
  • Bone markers & QoL endpoints pre-specified in the secondary and tertiary analyses failed
  • Marginal improvement of questionable clinical relevance and reliability in all 3 populations presented
  • Multiple post hoc analyses warrant further study
arrhythmias phase iii study
ArrhythmiasPhase III study

Arrhythmia Events:

Arrhythmia, Atrial fibrillation, Atrial flutter, Bradycardia,  Extrasystoles,  Palpitation, Supraventricular extrasystoles, Supraventricular tachycardia,  Tachycardia, Ventricular extrasystoles 

Number of patients:

Atrasentan (n=404): 20 (5%)

Placebo (n=397): 5 (1%)

arrhythmias phase ii study
ArrhythmiasPhase II study

Arrhythmia Events:

Arrhythmia, atrial fibrillation, AV block, bigeminy, electrocardiogram abnormal, palpitations, PR interval prolonged, sinus bradycardia, tachycardia, ventricular extrasystoles

Number of patients:

Atrasentan 10 mg (n=89): 9 patients (10%)

Atrasentan 2.5 mg (n=95): 8 patients (8%)

Placebo (n=104): 7 patients (7%)

  • Primary endpoint failed
  • Pre-specified stats plan: If Primary endpoint fails, study fails
  • Most secondary endpoints failed (including time to PSA change, PFS & OS)
  • Many tertiary endpoints failed (including bone markers and QoL-related endpoints)
  • Pain-related endpoints not prespecified
  • Safety concerns (CAD, CHF, Arrhythmias)
  • Atrasentan compared to placebo and not active control
  • Phase III study results not robust
  • Closed early by DSMB for futility
  • Failed pre-specified endpoints
  • Not persuasive- statistically or clinically
  • Signals for serious cardiac toxicity noted


  • Failed study in earlier stage of prostate cancer
  • Further studies in planning stage

Should this drug be studied further before consideration of widespread use?