Transcript FDA Approach to Outcome Measure Development

Approach to Outcome Measure
Development or Selection: A
Regulatory Perspective
Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials
(IMMPACT)
April 17-18, 2014
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
• Treatment benefit can be demonstrated as
either:
– A comparative advantage in how patients survive, feel
or function
– A comparative reduction in treatment-related toxicity
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Purpose of Outcome Assessment
• To determine whether or not a drug has been
demonstrated to provide treatment benefit
• A conclusion of treatment benefit is described
in labeling in terms of the concept of interest
(COI), the thing measured by the outcome
assessment
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Types of Outcome Assessments
• Survival
• Biomarkers
– A physiologic, pathologic, or anatomic characteristic that is objectively
measured and evaluated as an indicator of some normal or abnormal
biologic function, process or response to a therapeutic intervention
• Clinical outcome assessments (COAs)
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–
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Performance outcomes (PerfOs)
Clinician-reported outcomes (ClinROs)
Observer-reported outcomes (ObsROs)
Patient-reported outcomes (PROs)
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Choice of COA Type
• Determine the most appropriate reporter for the COI in the
COU
– If symptom intensity is the concept of interest in a patient population
that can respond themselves, a PRO is most appropriate.
– If clinical judgment is required to interpret an observation, a ClinRO is
chosen.
– If the COI can only be adequately captured by observation in daily life
(outside of a healthcare setting), and the patient cannot report for
him or herself, then an ObsRO is chosen.
– When it would be useful to observe an actual demonstration of
defined tasks demonstrating functional performance in the clinical
setting, a PerfO may be appropriate.
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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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Treatment Benefit: What To Measure?
All are important, but interpretation of trial results depends on knowing how
treatment impacts the core disease-defining concepts first.
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
S/Ss
Additional
functioning
Additional
S/Ss
Productivity
Health status
General
physical
functioning
Social
functioning
Health-related
quality of life
Satisfaction
with
health
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Adequate and well-controlled
efficacy (A&WC) studies
• Studies that provide:
– Evidence to support drug marketing authorization
– Substantial evidence of effectiveness
• Required by law to support a conclusion that a drug is effective
– See 21 CFR 314.126
• Deemed A&WC based on multiple features of a
clinical study design including:
– Nature of the primary endpoint
• Well-defined and reliable
– Rigor of control of the Type I error rate
– Prospectively planned analyses designed with rigor
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When is a COA adequate for use in
adequate and well-controlled studies?
• 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
• 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
http://www.fda.gov/downlo
ads/Drugs/GuidanceComplia
nceRegulatoryInformation/G
uidances/UCM205269.pdf
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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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Review of ClinRO, ObsRO, PRO, and PerfO
Measures: Any Differences?
SAME:
I.
II.
III.
IV.
V.
VI.
VII.
VIII.
IX.
X.
XI.
XII.
Instrument
Targeted Claims
Endpoint Model
Conceptual Framework
Content Validity
Other Measurement Properties
Interpretation of Scores
Language Translation and Cultural
Adaptation
Data Collection Method
Modifications
Clinical Trial Design and Data
Analysis Issues
Key References
DIFFERENT:
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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
– May be useful for other purposes:
•
•
•
•
•
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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Seeking Advice from FDA
• Discuss plans early!
• 2 pathways:
– In the context of an Investigational New Drug (IND)
program
– Drug Development Tool (DDT) Qualification
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DDT Guidance (Final January 2014)
• Describe a process NOT
evidentiary standards
http://www.fda.gov/downloads/
Drugs/GuidanceComplicanceReg
ulatoryInformationi/Guidances/
UCM230597.pdf
• Qualification process
described for Biomarkers,
Animal Models, and Clinical
Outcome Assessments
(COA)
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CDER Qualification of
Clinical Outcome Assessments
• DDT Qualification Guidance: COA qualification is a conclusion
that within the stated context of use (COU), the results of
measurement can be relied upon to represent a specific
concept (COI) with a specific interpretation when used in drug
development and regulatory decision-making
– Plain language: Within a specific clinical context, we’re measuring the
right thing, in the right way, and we can rely upon the results of the
qualified assessment across clinical trials within that clinical context
• CDER qualification is currently reserved for those COAs that
are ultimately intended to support primary or secondary
endpoints in clinical trials
• Qualified instruments shall be made available publically
available
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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.
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Roadmap to PATIENT-FOCUSED OUTCOME MEASUREMENT in Clinical Trials
Understanding the
Disease or Condition
Natural history of the disease or
condition
• Onset/Duration/Resolution
• Diagnosis
• Pathophysiology
• Range of manifestations
Patient subpopulations
• By severity
• By onset
• By comorbidities
• By phenotype
Health care environment
• Treatment alternatives
• Clinical care standards
• Health care system perspective
Patient/caregiver perspectives
• Definition of treatment benefit
• Benefit-risk tradeoffs
• Impact of disease
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Conceptualizing
Treatment Benefit
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A. Identify the meaningful health aspect
that is the intended benefit to patients in
their daily lives
• Survives (e.g., length of survival)
• Feels (e.g., symptom severity)
• Functions (e.g., walking ability)
B. Identify the measureable concept of
interest that represents the meaningful
health aspect, which can be:
• Equivalent to the meaningful health aspect
(e.g., patients’ self-reported ambulatory
activities in daily life) OR
• Distinct from, but related to the meaningful
health aspect (e.g., 6-minute walk test)
C. Define context of use for clinical
trials, e.g.:
• Disease/Condition entry criteria
• Clinical trial design
• Endpoint positioning
D. Consider appropriate clinical outcome
assessment type(s):
• Patient-Reported Outcome (PRO)
• Observer-Reported Outcome (ObsRO)
• Clinician-Reported Outcome (ClinRO)
• Performance Outcome
(motor, sensory, cognition)
Selecting/Developing
the Outcome Measure
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A.
•
•
•
•
Search for existing clinical outcome
assessment measuring the concept(s) of
interest in the context of use :
Measure exists
Measure exists but needs to be modified
No measure exists
Measure under development
B. Begin clinical outcome assessment development
• Document content validity
(qualitative or mixed methods research)
• Evaluate cross-sectional measurement properties
(reliability and construct validity)
• Create user manual
• Consider submitting to FDA for qualification
for use in exploratory studies
C. Complete clinical outcome
assessment development:
• Document longitudinal measurement properties
(construct validity, ability to detect change)
• Document guidelines for interpretation of
treatment benefit and relationship to claim
• Update user manual
• Submit to FDA for qualification as
effectiveness endpoint to support claims
Updated on March 14, 2014
U.S. Food and Drug Administration
Center for Drug Evaluation and Research
Office of New Drugs
http://www.fda.gov/Drugs
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Understanding the Disease or
Condition
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Understanding the Disease or
Condition
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Understanding the
Disease or Condition
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Understanding the Disease or
Condition
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FDA’s Patient Focused
Drug Development Initiative
• Systematically gather patients’ perspectives on their
condition and available therapies to treat their
condition
• 20 public meetings over the course of PDUFA V, each
focused on a specific disease area
• http://www.fda.gov/ForIndustry/UserFees/Prescripti
onDrugUserFee/ucm368342.htm
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Conceptualizing Treatment Benefit
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Conceptualizing Treatment Benefit
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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
•
Patient subpopulations
– Patient demographics
– Reporting ability
– Culture and language
•
Clinical trial design and objectives
–
–
–
–
–
•
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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Conceptualizing Treatment Benefit
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Selecting/Developing the Measure
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Selecting/Developing the Measure
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Selecting/Developing the Measure
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COA Wheel and Spokes
• This diagram identifies the key components of
the documentation submitted to CDER to
support COA qualification
• The Wheel and Spokes diagram also
represents the general iterative process used
in developing a COA for qualification.
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Spoke I
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Spoke II
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What Is Content Validity?
•
Content validity is the extent to which the content of an
instrument represents important aspects of a given concept
for an intended use and for a defined target population
•
Establishing content for a new instrument may involve both
qualitative and quantitative research methods. Qualitative
data are essential for establishing content validity of a COA
•
Input from the target population is essential
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Conceptual Framework
• An explicit description or diagram of the
relationships between the questionnaire or
items in an assessment and the concepts
measured
• Describes how the individual items contribute
to the total score that will be analyzed and
ultimately described in labeling
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Conceptual Framework
Item 1
Item 2
Item 3
Score of Domain A
Domain
Concept
A
Total Score
Score of Domain B
Overall
Concept
Item 4
Item 5
Item 6
Domain
Concept
B
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Spoke III
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Qualification for Use in Exploratory
Studies / as Exploratory Endpoints
• At this point in time, submitters may
consider the option of submitting
evidence for COA qualification.
Qualification at this point in development
will be for use in exploratory analyses for
purposes of testing other measurement
properties.
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Spoke IV
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COA Qualification for Use as
Primary or Secondary Endpoint
• When all measurement properties are
tested, evidence will be reviewed to
support COA qualification for use in
adequate and well-controlled studies as a
primary or secondary endpoint measure
of effectiveness.
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Spoke V
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Conclusion
• The roadmap to a well-defined and reliable
outcome assessment begins with a full
understanding of the disease or condition to be
tested
• An assessment cannot be chosen or developed
without a well-defined context of use,
understanding of the meaningful health aspect,
and targeted concept of interest to be assessed
• The science of measurement continues to evolve
with new tools and methods for efficient
development and modification of assessments
• There is no one size fits all approach to measure
development, we all must endeavor to be flexible,
while applying good measurement principles as
appropriate for each unique situation
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