Transcript Slagle presentation

Approach to Outcome Measure
Development or Selection: A
Regulatory Perspective
Measures of Outcome for Stimulant Trials (MOST)
March 25-26, 2015
Ashley F. Slagle, MS, PhD
Study Endpoints and Labeling Development (SEALD)
Office of New Drugs (OND)
Center for Drug Evaluation and Research (CDER)
Disclaimer
The views expressed in this presentation are those
of the speaker, and do not necessarily represent
an official FDA position.
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Treatment Benefit
• Treatment benefit is demonstrated by evidence
that the treatment has a positive impact on a
concept of interest:
– How long a patient lives
– How a patient feels or functions in daily life
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Purpose of Outcome Assessment
• To determine whether or not a drug has been
demonstrated to provide benefit to patients
• A conclusion of treatment benefit is described
in labeling in terms of the concept of interest,
or the thing measured by the outcome
assessment
• One of the most important aspects of drug
development is how that benefit is measured
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Types of Outcome Assessments
• Survival
• Clinical outcome assessments (COAs)
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Patient-reported outcomes (PROs)
Clinician-reported outcomes (ClinROs)
Observer-reported outcomes (ObsROs)
Performance outcomes (PerfOs)
• Surrogates
– Often a biomarker* that is intended as a substitute for how a
patient feels, functions, or survives
– Two types for use in clinical trials to support product approval:
• Established Surrogates (for regular approval)
• Reasonably likely to predict clinical benefit (for accelerated
approval; require post-marketing studies to confirm clinical
benefit)
*biomarker:
a physiologic, pathologic, or anatomic characteristic that is objectively measured and evaluated as an
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indicator of some normal or abnormal biologic function, process or response to a therapeutic intervention
Evidence of Treatment Benefit
• Direct evidence of treatment benefit is
derived from studies with endpoints that
measure survival, or how patients feel and
function in daily life
• Indirect evidence of treatment benefit is
derived from studies with endpoints that
measure other things that are related to how
patients survive, feel or function
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Direct Verses Indirect Evidence of
Treatment Benefit
Survival
Pain
Breathlessness
6MWT
Blood Pressure
PSA
Indirect
Evidence
Direct
Evidence
Evidence Continuum
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Evidence of Treatment Benefit
(Proximal to Distal)
Disease-defining
concepts
Core signs,
symptoms
or
decrements in
functioning
Proximal disease
Impact concepts
Distal disease
Impact concepts
Disease impact on
general life concepts
General
psychological
functioning
Related
functioning
Related
Signs/
symptoms
Productivity
Additional
functioning
Health status
General
physical
functioning
Additional
Signs/
Symptoms
Health-related
quality of life
Social
functioning
Satisfaction
with
health
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Evidentiary Standards to Document
Treatment Benefit
• Documented by “Substantial evidence” (21 CFR
201.56(a)(3))
• Evidence from “Adequate and well-controlled clinical
trials”
• The methods of assessment are “well-defined and
reliable” (21 CFR 314.126)
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When is a Clinical Outcome Assessment
Adequate for use?
• Regulatory standard: measures are well-defined and
reliable
– Empiric evidence demonstrates that the score quantifies
the concept of interest in the targeted context of use
• What does this mean?
– This means measuring the right thing (concept of interest),
in the right way in a defined population (targeted context
of use), and the score that quantifies that ‘thing’ does so
accurately and reliably, so that the effects seen in the
outcome assessment can be interpreted as a clear
treatment benefit.
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Good Measurement Principles
http://www.fda.gov/downlo
ads/Drugs/GuidanceComplia
nceRegulatoryInformation/G
uidances/UCM205269.pdf
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• Defines good measurement
principles to consider for “welldefined and reliable” (21 CFR
314.126) PRO measures intended
to provide evidence of treatment
benefit
• All COAs can benefit from the
good measurement principles
described within the guidance
• Provides optimal approach to
PRO development; flexibility and
judgment needed to meet
practical demands
Well-defined and Reliable
• The tool adequately measures the concept of interest
in the context or clinical setting of interest
• To assess this, we review the tool’s measurement
properties:
– Content validity
– Construct validity
– Reliability
– Ability to detect change
• Information to support interpretation of change
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What is Content Validity
• Are we asking the right questions in
our assessments?
• Do clinical trial participants
consistently interpret and
understand the questions on the
PRO assessment?
• What does the score of the
questionnaire represent?
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Thinking about Meaningful Change
• How much change is meaningful?
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Roadmap to Patient-Focused Outcome
Measurement in Clinical Trials
• Intended to illustrate how one might embark upon a
sound, orderly, instrument selection or development
pathway, beginning with the clinical context in which the
instrument is intended to be used.
• The graphic here is meant to help identify the types of
things that might be considered in order to improve the
ability of an outcome assessment to accurately measure
treatment benefit.
– Most assessment tools are a bit less orderly in their
development
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Defining Context of Use
Each of the following variables can impact the adequacy of a COA to
support a claim:
• Disease definition including, if appropriate
– Disease subtype
– Disease severity
– History of previous treatment
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Patient subpopulations
– Patient demographics
– Reporting ability
– Culture and language
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Clinical trial design and objectives
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Endpoint positioning
Endpoint definitions
Analysis plan
Methods for interpretation of study results
Targeted labeling claim
Clinical practice and study setting
– Inpatient vs. outpatient
– Geographic location
– Clinical practice variation
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Endpoint Definition and Positioning
• Create study objectives based on the COI in the COU
• Position the outcomes as trial endpoints that will be
interpretable in comparison with a control group
• Define endpoints using COA scores
• Plan analysis
– Measurement of change over time in individual patients
that are combined for a means of assessing a group score
• Analysis of means
• Analysis of proportions
– Hierarchy for testing multiple assessments
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Wheel and Spokes Diagram
• This diagram identifies the key components of
the documentation submitted to CDER to
support the use of a clinical outcome
assessment
• The Wheel and Spokes diagram also represents
the general iterative process used in
developing a clinical outcome assessment
• This type of work has been going on in the
social sciences for decades and we are now
bringing it to the world of drug development
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Clinical Outcome Assessment
Considerations
• Not all patient reported, clinical-reported, observer-reported, or
performance outcome assessments are appropriate Clinical Outcome
Assessments for use in clinical trials to support approval and labeling
– May be useful for other purposes:
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Diagnostic
Prognostic
Trial eligibility and trial enrichment
Epidemiologic or population studies
Clinical practice decision-making
– Measures used successfully for these other purposes will not necessarily be
appropriate outcomes assessments (i.e., they may not be able to reliably detect
treatment benefit in clinical trials or support labeling claims in a non-misleading
way)
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How FDA Can Help: Providing
Advice on Clinical Outcome Assessments
• Provide advice and recommendations on clinical
outcome assessments, including PROs:
– For individual drug development programs (within an IND)
– Through the Drug Development Tool (DDT) Clinical Outcome
Assessment Qualification Program
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DDT Qualification Guidance
http://www.fda.gov/downlo
ads/Drugs/GuidanceComplia
nceRegulatoryInformation/G
uidances/UCM230597.pdf
• Describe a process NOT
evidentiary standards
• Qualification process
described for Biomarkers,
Animal Models, and Clinical
Outcome Assessments
(COA)
• Final Guidance January 2014
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COA DDT Qualification Website
http://www.fda.gov/Drugs/DevelopmentApproval
Process/DrugDevelopmentToolsQualificationProgra
m/ucm284077.htm
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