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

Hormone Refractory Prostate CancerHormone 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 drug

A benefit over available therapy

Post-approval studies Demonstrate 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

Docetaxel May 2004

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

Demonstration of efficacy Well controlled clinical trial Significant prolongation in OS

Docetaxel (TAX327) Docetaxel 75 mg/sqM IV q 3 weeks

10 cycles Cumulative dose = 750 mg/sqM

Docetaxel 30 mg/sqM q w for 5 of 6 weeks 5 cycles Cumulative dose = 750 mg/sqM

Mitoxantrone 12 mg/sqM q 3 weeks 10 cycles

Prednisone 5 mg PO bid in each study arm

Docetaxel (TAX327)

Patients=1,006

Primary efficacy end point Overall Survival Time from randomization to death

from any cause

Docetaxel OS was significantly superior in the

docetaxel q3w group compared with mitoxantrone q3w group

OS was also significantly superior for the combined docetaxel group compared with mitoxantrone group

OS for once weekly docetaxel arm was not statistically significantly different from that of mitoxantrone q 3 week group

Docetaxel

Docetaxel + P,q3w

Mitoxantrone + P, q3w

Number of patients

335 337

Median OS 95% CI

18.9 months(17.0-21.2)

16.5 months(14.4-18.6)

Hazard Ratio95% CI

0.761(0.619-0.936)

N/A

P value 0.0094 N/A

Demonstration of efficacyImprovement in symptoms and other

indices FDA accepted end points

Symptom measures Non-survival morbidity indices

Approvals based on non-survival end points Mitoxantrone Zoledronic acid

Mitoxantrone

November 1996

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

Mitoxantrone Pivotal trial- open label, Phase III

161 symptomatic patients

End point- Palliative Response Prospectively defined A 2-point improvement on a 6-point pain

intensity scale Accompanied by a stable analgesic score Duration- at least 6 weeks

Mitoxantrone

M+P P p valuePalliative response

29% 12% 0.011

Median duration of palliative response

229 days 53 days 0.0001

Median time to disease progression

301 days 133 days 0.0001

Median survival time

11.3 m 10.8 m 0.23 NS

Decrease of ≥ 75% in PSA

27% 5% 0.011

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 manifestations Increased power

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

Zoledronic acid SRE included in the composite end point

Pathological bone fractures Spinal cord compression Surgery to bone Radiation therapy to bone (including

Radioactive Isotopes)

A change in antineoplastic therapy due to increased pain

Added for prostate cancer trial

Demonstration of efficacySRE end point A decrease in the proportion of patients

with at least one SRE 33% vs. 44% Difference 11%, p 0.021

An increase in the median time to first SRE NR vs. 321 days HR 0.67, p 0.011

Evaluating Treatments for Advanced Prostate Cancer

Difficulties stem from several factors

Disease characteristics Patient population Prevalent clinical practice

Advanced HRPCDisease of heterogeneous natural history

Variable clinical course Diverse clinical manifestations Difficult treatment decisions

Traditional efficacy end points Limited utility

HRPCPSA only progression

Disease symptom None

Bone scan Negative

Survival Relatively long

HRPCSymptomatic progressive disease

Disease related symptoms Worsening of performance status Impaired quality of life

Survival Shortened

Clinical benefit of treatment Established

Patient Population

Competing causes of mortality

Advanced patient age Comorbid conditions

End points Problems confounding interpretation

PSA driven treatment changes

Missing clinical data

End points Problems confounding interpretation

PSA 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

Acknowledgements

Ramzi Dagher, MDDonna Griebel, MDJohn Johnson, MD

Richard Pazdur, MDDianne D SpillmanGrant Williams, MD