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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