Title: Patient Selection Markers in Drug Development Programs
1Patient Selection Markers in Drug Development
Programs
- Michael Ostland
- Genentech
FDA/Industry Statistics Workshop Washington
D.C., September 14 16, 2005
2Outline
- Background
- Seven Questions from a Drug Development POV
- Concluding Remarks
3Background
- Most drugs benefit far less than 100 of the
patients who are treated. - Patients who get no efficacy from a drug
- Still run the risk of toxicity or side effects
- May miss out on a benefit they would have
received had they been treated with another drug
instead - Add costs to the health care system
- Dilute efficacy estimates in clinical trials
4Background (contd)
- In drug development patient selection may
- Enrich a population for patients who benefit,
thereby allowing a drugs efficacy to be detected
in a smaller phase III trial. (see Maitournam and
Simon) - Enrich a population for patients with a favorable
toxicity profile, thereby improving the
benefit/risk ratio.
Maitournam and Simon, Statist. Med. 2005
24329339
5Background (contd)
- 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.
6Seven Basic Questions
- What strategic imperative for patient selection?
- What is the desired outcome from the development
program (Target Product Profile)? - What could phase III look like?
- What should phase II look like?
- How do results from phase II lead to decisions
about the design in phase III? - How many patients are needed in phase II to
ensure adequate decision making? - What marker and what threshold for positive?
7Strategy for Patient Selection
- Patient selection for clinical drug development
can - proceed with one of several strategic
imperatives - Efficacy
- Include patients most likely to benefit
- Exclude patients least likely to benefit
- Safety
- Include patients least likely to experience
toxicity - Exclude patients most likely to experience
toxicity
8Target Product Profile
- 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.
9Phase III Designs with Patient Selection
- Option 1
- Standard design, except only enroll patients
- from marker selected population.
- Question
- What are the scientific and regulatory
- implications of not performing a definitive
- assessment of efficacy on unselected patients?
10Phase III Designs (contd)
- Option 2
- 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
- Question
- How does efficacy on marker unselected patients
impact inference when (1) is positive?
11Phase II Design
- Usually best to consider a randomized trial
- Allows assessment of whether the marker is truly
predictive of increased treatment benefit, rather
than simply prognostic for good outcome. - Assessment of safety with contemporaneous control
arm. - Ideally, one tests the marker prior to
randomization and stratifies, but this may not be
possible for logistic reasons.
12Phase II Design (contd)
- A randomized design with retrospective testing
A
Positive
assay
Negative
B
Treatment
Indeterminate
C
Enrolled Patients
randomize
D
E
F
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).
13Phase II to III Decision Making
- Broadly speaking, there are four possible
- decisions after a phase II trial with a patient
- selection marker
- Proceed to Ph III in marker subset only
- Proceed to Ph III in all patients and perform two
tests in all patients and in marker pts - Proceed to Ph III in all patients and ignore
marker - Do not proceed to Ph III at this time
14Decision making (Contd)
- Key efficacy comparisons
- A vs. D Treatment effect among known marker
positive - B vs. E Trt. effect among known marker negative
- (ABC) vs. (DEF) Overall treatment effect
- (A vs. D) vs. (B vs. E) Treatment effect by
marker interaction
A
Positive
Negative
B
Treatment
Indeterminate
C
Positive
D
Control
Negative
E
Indeterminate
F
15Decision making (Contd)
- Present the key efficacy and safety comparisons
along with reasonable estimates of uncertainty - Interpret results using Target Product Profile
- Take into account
- Asymmetry of the decision-making loss function
- Biologic plausibility
-
- Hard and fast rules for all possibilities are
hard (impossible?) to come by.
16Size of Phase II
- An area of great opportunity for statisticians
- Power is too rigid to be very useful
- Expected CI widths are hard to evaluate when
several parameters are of simultaneous interest - Probably want to approach it from a
decision-theory point of view. But this is not
trivial - The fore-mentioned lack of strictly defined
decision rules makes analysis impossible - Quickly approach the sort of mind-numbing
complexity that confirms clinicians worst
prejudices about statisticians.
17Marker Selection
- Best to have 1 3 candidate markers based on
biologic MOA and preclinical evidence. Then a
short phase II program can be used to
prospectively assess. - Sometimes need to use part of phase II to screen
for candidate markers, and then a subsequent
clinical study (prospective or retrospective?) to
validate. This is lengthier and requires care
(multiplicity, cross-validation at proper level,
etc.). Fortunately, a lot of smart statisticians
have made good progress on these matters.
Similar points apply to establishing positive
threshold
18Concluding Remarks
- Phase II is a critical part of clinical
development when patient selection markers are
considered - Knowledge of the assay is helpful
- A clear Target Product Profile is critical
- Statisticians have an important role in planning
and decision making in this complex, uncertain
environment - Planning for phase II in a way that can be
usefully communicated to decision makers is an
open question.
19Acknowledgements
Alex Bajamonde Cheryl Jones Lee Kaiser Gracie
Lieberman Ben Lyons Howard Mackey James
Reimann Julia Varshavsky Xiaolin Wang