covance: does your pro have sufficient validation for your clinical study goals?

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Ensuring Product Success:Does your PRO have sufficient validation for

your clinical study goals?

March 22, 2012March 22, 2012WebcastWebcast

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IntroductionsIntroductions

Background: PROsBackground: PROs

Summary and QuestionsSummary and Questions

PRO considerations based on clinical study goals PRO considerations based on clinical study goals

AgendaAgenda

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IntroductionIntroduction

Felicia Bergstrom, MSPHAssociate Director

Covance Market Access Services, Inc.

Jason Cole, Ph.D.Director

Covance Market Access Services, Inc.

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AgendaAgenda


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PROs: What is it and why do we care?PROs: What is it and why do we care?

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Health is a state of complete physical, mental and social well‐being and not

merely the absence of disease or infirmityWHO, 1948

How can we possibly assume we are improving health care without considering

the voice of the patient? John E. Ware, Jr., PhD

A patient‐reported outcome is any report coming directly from patients about a health condition or its treatment

FDA, 2009

Validity DriversValidity Drivers

Working Groups

Regulatory Agencies

Terminology

ISPORISPORPRO ConsortiumPRO Consortium

COACOA• PRO• ClinRO• ObsRODDTDDT

BackgroundBackground

EMA: HRQoL Reflection Paper

ISPOR: Translation and cultural adaptation

ISPOR: Translation and cultural adaptation

FDA: Drug Development Tool

(DDT)*

FDA: Drug Development Tool

(DDT)*

2005 - 2008 2009 2010 2011

FDA: PRO Label Claims - Final

FDA: PRO Label Claims - Final

ISPOR: Concepts for new PRO instruments

ISPOR: Concepts for new PRO instruments

ISPOR(Content validity,

ePRO, & Translation)

ISPOR(Content validity,

ePRO, & Translation)

EMA: Qualification of novel technologies

EMA: Qualification of novel technologies

* Draft

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FDA Guidance on PRO Label ClaimFDA Guidance on PRO Label Claim

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The same basic evidence is needed to evaluate any type of endpoint

The appropriate endpoint depends on the context of use

Describes the level of evidence required to support “well-defined and reliable” endpoints

Evidentiary basis to demonstrate appropriate for context of use

Endpoint model: Defines the role of the PRO in the context of all non-exploratory endpoints in a clinical trialConceptual framework: Blueprint showing the relationship between items and domains (concepts)

Content validity: Evidence to support the conclusion that the PRO measures the claimed concept

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CONCEPTCONCEPTDOMAINSDOMAINSITEMSITEMS

Hypothetical Conceptual Framework: AsthmaHypothetical Conceptual Framework: Asthma

Waken by symptoms Waken by symptoms

Reduced sleep quality Reduced sleep quality

Reduced work hoursReduced work hours

Accomplish less Accomplish less

Tardiness Tardiness

Limited strenuous activitiesLimited strenuous activities

Limited in playing sports Limited in playing sports

Having trouble walking uphillHaving trouble walking uphill

AbsenteeismAbsenteeism

Limited sleep Limited sleep

Sleep DisturbanceSleep Disturbance

Limitation in productivityLimitation in productivity

Limitation in physical activities

Limitation in physical activities

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Content Validity and PRO Label ClaimsContent Validity and PRO Label Claims

The subjective impact of asthma on patients’ health-related quality of life was evaluated by the Asthma Quality of Life Questionnaire (AQLQ(S)) (based on a 7-point scale where 1 = maximum impairment and 7 = no impairment). A change from baseline ≥0.5 points is considered a clinically meaningful improvement.

The mean difference in AQLQ between patients receiving DULERA 100 mcg/5 mcg and placebo was 0.5 [95% CI 0.32, 0.68].

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http://www.spfiles.com/pidulera.pdf (page 18)

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Most Common PRO Uses In Clinical StudiesMost Common PRO Uses In Clinical Studies

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Publication Only

Most common use by far

Results limited to dissemination via publication

Moderate validation required

Requires the least prep time ahead of use in study

Product-Specific Label Claim

Much less common, but growing in use since guidance release

Results disseminated in product label, advertising, and publications

Strong validation required

PRO label claim can provide a competitive advantage over similar products in the marketplace

Universal Label Claim (DDT)

Evolving; described in 2010 DDT draft guidance

Results disseminated in product label, advertising, and publications

Strong validation required

No further validation required when using a qualified DDT, which may accelerate trial and approval timelines

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Validation Demands Per PRO Use Validation Demands Per PRO Use

Publication Only Label Claim

Task Existing New Existing New

Literature review to determine next steps

Receive KOL input on conceptual model

Elicit concept

Item generation

Cognitive debriefing

Psychometric evaluation

Validation of responder definition

Validate mode of administration

Translation and cultural adaptation

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PRO Process: Literature ReviewPRO Process: Literature Review

Task Publication Label Claim DDT

Identify relevant items and concepts XXX XXX XXX

Select measure(s) to satisfy evidence needs XXX XXX N/A

Determine if a qualitative study is required to confirm content validity and/or mode of administration X XXX N/A*

* Qualitative study is required for DDT, thus there is no need to determine whether required

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If a validated measure exists:Align PRO concepts and messages and select PRO measure to satisfy evidence needs Evaluate whether content validity of measure is sufficient based on study goal and regulatory requirements

Determine if a qualitative study is required to confirm content validity and/or mode of administration

If no validated measure exists:Initiate steps required to develop a new measure

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PRO Process: Qualitative ValidationPRO Process: Qualitative Validation


Elicit concepts N/A XX XXX

Item generation N/A XX XXX

Cognitive debriefing N/A XX XXX

Finalize measure N/A X XXX

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Elicit concepts: Focus groups and qualitative interviews

Item generation: Creation of items used to develop preliminary measure Instruments based on sampling of universe of items covering domain (construct) Cognitive debriefing (Qualitative Interviews): Test the items order to determine if patients can appropriately understand, interpret and utilize the questionnaire Finalize measure: Integrate patient feedback to develop a finalized instrument (ready for validation testing)

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PRO Process: Modality and TranslationsPRO Process: Modality and Translations

Task Publication Label Claim DDTValidate mode of administration X XXX XXX

Translation and cultural validation XXX XXX XXX

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Modality: Regulatory agencies require documentation of proper validation of existing PRO in an ePRO modality

Follow FDA PRO Guidance for Label Claim study Follow ISPOR recommendations for publication study (less stringent)

Translations: PROs must be culturally adapted and linguistically validated to be used as valid research measures in internationalclinical trials.

Applies regardless of intended use of these dataBegin translations immediately following selection (and/or validation, if required) of selected PRO measure(s)

Include question in site selection survey to identify common languages spoken by patients at each site

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PublicationN/A

X

X

X

N/A

N/A

X

N/A*

X

X

X

N/A

Label ClaimX

X

X

X

N/A*

N/A*

X

N/A*

X

X

X

N/A*

DDTX†

X†

N/A

N/A

X

X

N/A

N/A

N/A

N/A

N/A

X**

Timeline for Integration of a Validated PRO Measure Timeline for Integration of a Validated PRO Measure

TaskDevelop draft conceptual/ endpoint model

Conduct lit review, select PRO measure

Obtain PRO licensing

Confirm PRO content validity for intended population

Qualitative validation

Conduct cognitive debriefs/ finalize measure

Confirm PRO administration mode validated

Conduct study to validate mode of administration

Determine linguistic validation requirements

Conduct PRO translations

Conduct cognitive debriefs following translations

Quantitative validation (cross-sectional)

Total Time: (7 months – 40+ months)

Timeline assumes: (1) Value messages previously developed, and (2) PRO analysis, preparation of regulatory briefing documents, development of PRO publications will occur following study.

† Includes literature review and development of scoping stage summary document* If required**Longitudinal validation study can be integrated in to clinical study

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PRO Process: Quantitative ValidationPRO Process: Quantitative Validation


Cross-sectional validation N/A XX XXX

Longitudinal validation N/A XX XXX

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Quantitative validation: begins upon completion of the qualitative validation

Involves a larger group of patients

Cross-sectional validation study: Establish the draft PRO measure’s psychometric properties and update and finalize the measure

Longitudinal validation study: Validate the “final version” by removing poor or superfluous items, measure test-retest reliability, and determine criteria for responder analyses

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Summary

Q&AQ&A

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www.covance.com/marketaccess

Felicia Bergstrom, MSPHAssociate Director

Covance Market Access Services Inc.Phone: 240-632-3682

Email: [email protected]

Jason Cole, Ph.D.Director

Covance Market Access Services Inc.Phone: 805-403-7095

Email: [email protected]

LINK to Feedback SurveyLINK to Feedback Survey

covance: does your pro have sufficient validation for your clinical study goals?

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