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  • A Regulatory Perspective of End Points to Measure Safety and Efficacy of Drugs

    Hormone Refractory Prostate Cancer

    Bhupinder S. Mann, MBBSMedical OfficerDODP CDER FDA

  • Objectives

    End points utilized for granting approval

    Comments on difficulties encountered in measuring safety and efficacy of drugs for treatment of advanced HRPC

  • Approval of a New Drug

    Substantial evidence of effectiveness

    Adequate and well-controlled clinical investigations

  • End Points (Before 1992)Required to represent clinical benefit

    Direct measures of benefit, e.g.Improvement in survival Improvement of symptoms Accepted surrogates for benefit, e.g.Durable complete responses in acute leukemia

  • Accelerated Approval (1992)Surrogate endpoints that are reasonably likely to predict clinical benefit The drugA benefit over available therapy

    Post-approval studiesDemonstrate that the drug does provide clinical benefit

  • End pointsAccepted for drug approval Approved drugs for treatment of advanced HRPC

    Docetaxel (2004)Zoledronic acid (2003)Mitoxantrone(1996)

    Estramustine(1981)

  • Overall Survival (OS)Safety and efficacy

    Overall Survival

    A direct measure of efficacy

    A reassuring measure of safety

  • DocetaxelMay 2004Docetaxel in combination with prednisone is indicated for the treatment of patients with androgen independent (hormone refractory) metastatic prostate cancer

    Demonstration of efficacyWell controlled clinical trialSignificant prolongation in OS

  • Docetaxel (TAX327)Docetaxel 75 mg/sqM IV q 3 weeks10 cycles Cumulative dose = 750 mg/sqM Docetaxel 30 mg/sqM q w for 5 of 6 weeks5 cyclesCumulative dose = 750 mg/sqM Mitoxantrone 12 mg/sqM q 3 weeks10 cycles

    Prednisone 5 mg PO bid in each study arm

  • Docetaxel (TAX327)Patients=1,006

    Primary efficacy end point Overall SurvivalTime from randomization to death from any cause

  • Docetaxel OS was significantly superior in the docetaxel q3w group compared with mitoxantrone q3w groupOS was also significantly superior for the combined docetaxel group compared with mitoxantrone groupOS for once weekly docetaxel arm was not statistically significantly different from that of mitoxantrone q 3 week group

  • Docetaxel

  • Demonstration of efficacyImprovement in symptoms and other indices FDA accepted end pointsSymptom measuresNon-survival morbidity indices

    Approvals based on non-survival end pointsMitoxantrone Zoledronic acid

  • MitoxantroneNovember 1996

    For use in combination with corticosteroids as initial chemotherapy for treatment of patients with pain related to advanced hormone refractory prostate cancer

  • MitoxantronePivotal trial- open label, Phase III 161 symptomatic patients

    End point- Palliative Response Prospectively definedA 2-point improvement on a 6-point pain intensity scaleAccompanied by a stable analgesic scoreDuration- at least 6 weeks

  • Mitoxantrone

  • Zoledronic acid 2003

    Treatment of patients with progressive bone metastases from prostate cancer

  • Zoledronic acid End point used- Composite end point based on skeletal related events (SREs)Diverse disease manifestationsIncreased power

    Previously used in lytic bone disease in multiple myeloma and breast cancer

  • Zoledronic acid SRE included in the composite end point Pathological bone fracturesSpinal cord compressionSurgery to boneRadiation therapy to bone (including Radioactive Isotopes)

    A change in antineoplastic therapy due to increased painAdded for prostate cancer trial

  • Demonstration of efficacySRE end point A decrease in the proportion of patients with at least one SRE33% vs. 44%Difference 11%, p 0.021

    An increase in the median time to first SRENR vs. 321 daysHR 0.67, p 0.011

  • Evaluating Treatments for Advanced Prostate Cancer Difficulties stem from several factors

    Disease characteristicsPatient populationPrevalent clinical practice

  • Advanced HRPCDisease of heterogeneous natural historyVariable clinical courseDiverse clinical manifestationsDifficult treatment decisions

    Traditional efficacy end pointsLimited utility

  • HRPCPSA only progression Disease symptomNone

    Bone scanNegative

    Survival Relatively long

  • HRPCSymptomatic progressive diseaseDisease related symptomsWorsening of performance statusImpaired quality of life

    SurvivalShortened

    Clinical benefit of treatment Established

  • Patient Population

    Competing causes of mortality

    Advanced patient ageComorbid conditions

  • End points Problems confounding interpretation

    PSA driven treatment changes

    Missing clinical data

  • End points Problems confounding interpretationPSA based end points may be acceptable surrogates for anti-tumor activity, eg in Phase II clinical trials

    Reliable use of PSA based end points in Phase III comparative clinical trials remains to be defined

  • AcknowledgementsRamzi Dagher, MDDonna Griebel, MDJohn Johnson, MDRichard Pazdur, MDDianne D SpillmanGrant Williams, MD

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