Clinical Outcome Assessment to Demonstrate Treatment Benefit:
An FDA Perspective
Elektra Papadopoulos, MD, MPH Acting Associate Director
Clinical Outcome Assessment Staff Center for Drug Evaluation and Research (CDER), FDA
March 31, 2015
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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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Clinical Benefit
• Clinical benefit is demonstrated by evidence that the treatment has a positive impact on how a person with the condition or disease: – Survives – Feels or Functions in daily life
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Types of Outcome Assessments
• Survival • Clinical outcome assessments (COAs)
– Performance outcomes (PerfOs) – Clinician-reported outcomes (ClinROs) – Observer-reported outcomes (ObsROs) – Patient-reported outcomes (PROs)
• 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)
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*biomarker: 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
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Context of use Concept(s) of interest
Consider appropriateness of COA type
ClinRO ObsRO PRO PerfO
Observable concepts (e.g., signs, events, behaviors)
Unobservable concepts (e.g., feelings)
Self-report?
PRO
Functional performance
Clinical judgment needed
No clinical judgment needed
Selecting the COA type
FDA’s PRO Guidance for Industry (2009)
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• PRO is a measurement based on a report that comes from the patient (i.e., study subject) about the status of a patient’s health condition without amendment or interpretation of the patient’s report by a clinician or anyone else.
•Describes good measurement principles many of which are also applicable to other types of clinical outcome assessment tools
•Provides an optimal approach to PRO development; flexibility and judgment needed to meet practical demands
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Establishing Content Validity
• Begins after confirmation that the concept and the context of use are appropriate and the type of outcome assessment has been selected
• Evidence that the instrument measures the targeted concept in
the context of use – And that the score represents the concept – Supported by literature review, expert input and patient input
• Testing other measurement properties (e.g., test-retest reliability, construct validity and ability to detect change) will not replace or rectify problems with content validity.
Qualification of CLINICAL OUTCOME ASSESSMENTS (COAs)
CONCEPT OF INTEREST
= CLAIM
V. Modify Instrument
• Identify a new COU • Change wording of items, response options,
recall period, or mode/method of administration/data collection
• Translate and culturally adapt • Evaluate modifications using spokes I – IV • Document all changes Consider submitting to FDA for qualification of new COA, as appropriate.
II. Draft Instrument and Evaluate Content Validity
• Obtain patient or other reporter input • Generate new items • Select recall period, response options and format • Select mode/method of administration/data collection • Conduct cognitive interviewing • Pilot test draft instrument • Finalize instrument content, format and scoring rule • Document content validity
III. Cross-sectional Evaluation of Other Measurement Properties
• Assess score reliability (test-retest or inter-rater) and construct validity • Establish administration procedures & training materials • Document measure development • Prepare user manual Consider submitting to FDA for COA qualification for use in exploratory studies prior to longitudinal evaluation.
SPOKE III
IV. Longitudinal Evaluation of Measurement Properties/ Interpretation Methods
• Assess ability to detect change and construct validity • Identify responder definition(s) • Provide guidelines for interpretation of treatment benefit
and relationship to claim • Document all results • Update user manual Submit to FDA for COA qualification as effectiveness endpoint to support claims.
I. Identify Context of Use (COU) and Concept of Interest (COI)
• Outline hypothesized concepts and potential claims
• Determine intended population • Determine intended
application/characteristics (type of scores, mode and frequency of administration)
• Perform literature/expert review • Develop hypothesized conceptual
framework • Position COA within a preliminary
endpoint model • Document COU and COI
U.S. Food and Drug Administration Center for Drug Evaluation and Research Office of New Drugs http://www.fda.gov/Drugs
Measurement of Symptoms and Patient-reported signs
• Content validity considerations – What are the core signs/symptoms of a condition? – Which are most bothersome, important to patients? – Which signs/symptoms are expected to improve with the therapy? – How severe are the signs/symptoms at study entry? – Variability: Are signs/symptoms heterogeneous across patients/
within patients over time? – Do patients understand the questionnaire and respond as intended?
• Patient input in the form of qualitative research from the targeted patient population important
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Importance of defining the context of use
• Patient characteristics – Eligibility criteria: e.g., disease definition, other clinical
characteristics, baseline severity and age – Language, cultural considerations
• Endpoint definition
– E.g., Symptom-free days; mean symptom severity over a period of a week; time-to-worsening
• Analysis:
– E.g., Responder vs. comparison of mean change from baseline
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Clinician-reported outcomes • Content validity supported by clinician input, literature review • Similar considerations to evaluation of content validity of PROs,
such as: – Do rating clinicians interpret the instructions and items in the
instrument consistently and in the way intended? – Do clinicians agree that the points on the rating scale correspond to
clinically meaningful gradations of severity in the concept of interest?
– Are the appropriate aspects of the condition being captured as part of the measure?
– What are the conditions, in which the instrument is appropriate for use?
• Note: clinician-reported signs and patient-reported symptoms may not correlate highly
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Pediatric Measurement
• Self-report of symptoms and impacts provides direct evidence of treatment benefit and should be used when possible and appropriate
• Use verifiable report of observable concepts (e.g., signs, behaviors) when self-report not possible or appropriate (e.g., young children)
• Example: – A parent/caregiver should not be asked to rate unobservable
concepts such as pain – A parent/caregiver can validly report on observable signs (e.g.,
crying, holding a body part and so forth)
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Drug Development Tool Qualification Guidance (Final January 2014)
• Qualification process described for Biomarkers, Animal Models, and Clinical Outcome Assessments (COA)
• COA qualification: – a conclusion that within the
stated context of use, the results of measurement can be relied upon to represent a specific concept (i.e., outcome) with a specific interpretation when used in drug development and regulatory decision-making
http://www.fda.gov/downloads/Drugs/GuidanceComplicanceRegulatoryInformationi/Guidances/
UCM230597.pdf
Helpful Links
• FDA’s Patient-Reported Outcome (PRO) Guidance for Industry: – http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulato
ryInformation/Guidances/UCM071975.pdf • DDT Clinical Outcome Assessment Qualification Program webpage:
– http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DrugDevelopmentToolsQualificationProgram/ucm284077.htm • Includes Roadmap and Wheel and Spokes diagrams
• FDA’s DDT Qualification Program Guidance for Industry: – http://www.fda.gov/downloads/drugs/guidancecomplianceregulator
yinformation/guidances/ucm230597.pdf
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