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Patient Selection Markers in Drug Development Programs . Michael Ostland Genentech. FDA/Industry Statistics Workshop: Washington D.C., September 14 – 16, 2005. Outline. Background Seven Questions from a Drug Development POV Concluding Remarks . Background.
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FDA/Industry Statistics Workshop:
Washington D.C., September 14 – 16, 2005
In drug development patient selection may:
Maitournam and Simon, Statist. Med. 2005; 24:329–339
By “marker” we typically have a biomarker in mind. Namely,
a characteristic that is objectively measured and evaluated as an indicator of normal biologic processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention (Biomarkers Definitions Working Group 2001)
In principle, any objectively measured baseline characteristic (or completely specified combination of multiple characteristics) could form the basis for selecting patients to be candidates to receive treatment.
Patient selection for clinical drug development can
proceed with one of several strategic imperatives:
Establish relationship between target efficacy/safety
and proportion of patients selected for treatment.
e.g., How much more effective does a drug need to be if only 40% of the population can be treated?
Other useful metrics possible.
Standard design, except only enroll patients
from marker selected population.
What are the scientific and regulatory
implications of not performing a definitive
assessment of efficacy on unselected patients?
Enroll all patients and assay for marker. Perform
two primary efficacy analyses while controlling
overall type I error rate:
(1) Efficacy among all patients
(2) Efficacy on marker selected patients
How does efficacy on marker unselected patients impact inference when (1) is positive?
Usually best to consider a randomized trial:
Ideally, one tests the marker prior to randomization and stratifies, but this may not be possible for logistic reasons.
IndeterminatePhase II Design (cont’d)
A randomized design with retrospective testing
Whether patients who test “indeterminate” ultimately get treated depends on the selection strategy: exclude only those least likely to benefit (yes), or only include only those most likely to benefit (no).
Broadly speaking, there are four possible
decisions after a phase II trial with a patient
Key efficacy comparisons:
Hard and fast rules for all possibilities are hard (impossible?) to come by.
Similar points apply to establishing “positive” threshold