ASENT 13th Annual Meeting
Outcome Measures to Support Labeling
Claims: What is new FDA Guidance?
Elektra J. Papadopoulos, M.D., M.P.H.
Study Endpoints and Labeling Development
CDER/FDA
February 24, 2011
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Disclosures
• No conflicts
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Presentation Outline
•
FDA review of rating scales
•
Drug development tool qualification process
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FDA Review of Rating Scales
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Characteristics of an Adequate and
Well-Controlled Study
•
21 CFR 314.126 (b)
(1) Clear statement of objectives
(2) Study design permits valid comparison (appropriate control)
(3) Select patients with disease/condition (treatment) or at risk of
disease (prevention)
(4) Baseline comparability (randomization)
(5) Minimize bias (blinding, etc.)
(6) Appropriate methods for assessment of outcome
(7) Appropriate methods of analysis
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21 CFR 314.126(b)(6)
“The methods of assessment of subjects’ response
are well-defined and reliable. The protocol for the
study and the report of results should explain the
variables measured, the methods of observation,
and the criteria used to assess response.”
• A well-defined and reliable endpoint measure is needed as
part of an adequate and well-controlled study to support
labeling claims
• Consideration of context of use is needed in this
assessment
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Endpoint Measure
• The measurement that will be statistically
compared among treatment groups to assess
the effect of treatment and corresponds with the
clinical trial’s objectives, design, and data
analysis plan
• Clinical Endpoint: A characteristic or variable
that reflects how a patient feels, functions, or
survives
– Biomarkers Definitions Working Group.
Clin Pharmacol Ther 2001; 69:89-95
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Claim
• Any statement of treatment benefit
• Can be found anywhere in FDA-approved
labeling or in advertising
• Must be supported by substantial evidence
• Must not be false or misleading
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Goal of Measurement: “Concept”
• Concept: The specific goal of measurement
(i.e., the thing or event that is to be measured)
– Forms the basis for describing claims in labeling
• Examples:
– Asthma Symptoms
– Cognitive Functioning
– Congestive Heart Failure Signs and Symptoms
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Types of Endpoint Measures
• Patient-reported outcomes
• Observer-reported outcomes (e.g., caregiverreported)
• Clinician-reported outcomes
• Objective tests (e.g., lab or device measurements)
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Patient Reported Outcome (PRO)
• Any report of the status of a patient’s health
condition coming directly from the patient,
without interpretation by physicians or anyone,
about how the patient functions or feels in
relation to a health condition and its treatment
Examples:
• Pain intensity
• Symptoms of community acquired pneumonia
• Physical functioning in chronic heart failure
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Clinician Reported Outcome (ClinRO)
• Clinician can be any type of trained professional
(e.g., physician, study nurse) rating study
participants at a study site
• Generally rate concepts that require clinical
judgment
• Cannot validly be used to measure patient
symptoms (e.g., pain, dyspnea) or other
unobservable concepts
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Observer Reported Outcome (ObsRO) (1)
• The observer is typically the person who takes
care of the patient (e.g., caregiver, parent) or
another observer (e.g., teacher)
– Should not rate concepts that require clinical judgment
• Useful when the patient is unable to report for
themselves (e.g., infants, young children,
cognitive impairment)
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Observer Reported Outcome (ObsRO) (2)
• Provides observations, but not interpretations, of
the patient’s health condition from the observer
• Cannot validly be used to measure patient
symptoms (e.g., pain) or other unobservable
concepts
– Ratings of unobservable concepts are proxy reports
– Proxy reports of unobservable concepts are NOT
well-defined and reliable endpoint measure capable
of supporting labeling claims
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FDA PRO Guidance
The adequacy of a PRO
instrument as a measure to
support medical product
labeling claims depends on its
documented measurement
properties that demonstrate
the instrument is “fit for
purpose”
http://www.fda.gov/downloads/Drugs/GuidanceCo
mplianceRegulatoryInformation/Guidances/UCM19
3282.pdf
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Measurement Properties
• Content Validity
– Critical for interpretation and labeling
– Should be established prior to evaluating other measurement
properties
• Construct Validity:
– Evidence that the PRO concepts measured conform to a priori
hypotheses concerning expected relationships with other measures or
characteristics of patients/patient groups
• Reliability
– Test-retest: Stability of scores over time when not change expected in
the concept of interest
– Internal Consistency: Intercorrelation of items that contribute to a score
• Ability to detect change
– Evidence that the PRO instrument can identify differences in scores
over time (individual or group) who have changed with respect to
measurement concept
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Content Validity
• Evidence that the instrument measures the concept of
interest including evidence that the items and domains of
an instrument are meaningful, comprehensive,
appropriate, and interpretable, relative to its intended
measurement concept, population, and use
• Established by:
– Literature review
– Expert opinion
– Responder input in form of qualitative research in the
target patient population
• Content validity cannot be evaluated independent of
the context of use
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FDA Review Considerations:
PRO Measures and Other Rating Scales
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•
•
•
•
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•
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General context of use within the trial
Items
Response options
Recall period
Structure (e.g., subscales)
Scoring
Instructions for use
Guidelines for interpretation of change
Translation and cultural adaptation
Measurement property documentation
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Drug Development Tool (DDT)
Qualification Process
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DDT Guidance (Draft)
• Qualification process for drug
development tools (DDTs):
– Biomarkers
– PRO tools and other rating
scales
• New and existing DDTs
http://www.fda.gov/downloads/Drugs/Guidance
ComplianceRegulatoryInformation/Guidances/
UCM230597.pdf
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DDT Qualification: What is it?
• Regulatory conclusion that within the stated context of
use, the results of the drug development tool (DDT)
measurement can be relied upon to have a stated
interpretation and utility- “fit for purpose”
• Context of use
– Target population
– Targeted labeling claims
– Endpoint model
• Endpoint assessment tools (primary or key secondary)
– Well-defined and reliable
– Clinically meaningful within a specified context of use
– Adequate to support a claim of treatment benefit
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Rationale for DDT Qualification
• Multidisciplinary, formal review of scale
development data
• Allows a scientifically well-supported
statement by CDER of qualification
• Efficient use of resources for industry and FDA
• Publicly available DDTs
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DDT Qualification: Framework
• A Critical Path Initiative
• Voluntary process
• Builds on developing public-private partnerships
between FDA and consortia representing medical
product industry, instrument developers, NIH, academia
• Collaboration allows FDA to work with multiple partners
to leverage expertise and resources
• Examples of collaborative efforts
– Critical Path Institute: PRO Consortium
– FDA-NIH Interagency Outcomes Assessment Working Group
(IOAWG)
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DDT Qualification: A New Process
• The qualification process provides an additional option for
submission of DDT development and validation data that is
outside of a specific medical product development program
FDA
Consultation
& Advice
Planning
Phase
Define
scope &
context of
use

Methods &
Results
Sharing
FDA
Review

Dossier
Submission;
FDA Review
Statement of
Qualification

DDT
Publicly
Available
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Conclusions
• Endpoint measures need to be well-defined and reliable
• FDA PRO Guidance document (2009) provides the
standard of evidence for FDA evaluation of PRO
measures to support labeling claims; many principles
also applicable to other types of rating scales
• PRO measures and other rating scales should be “fit for
purpose” within the proposed context of use
• Draft FDA Qualification Guidance (2010) for DDTs
provides a path for qualification of both new and existing
instruments
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