1 02/16/01 “Important Issues in Patient Reported “Important Issues in Patient Reported Outcomes (PRO) Research” Outcomes (PRO) Research” Feb. 16, 2001 Feb. 16, 2001 Organized by The Harmonization Coordination Committee Organized by The Harmonization Coordination Committee Representing Representing European Regulatory Issues on Quality European Regulatory Issues on Quality - - of of - - Life Assessment (ERIQA), International Life Assessment (ERIQA), International Society of Society of Pharmacoeconomic Pharmacoeconomic and Outcomes Research (ISPOR), Pharmaceutical and Outcomes Research (ISPOR), Pharmaceutical Research and Manufacturers of America ( Research and Manufacturers of America ( PhRMA PhRMA ) Health Outcomes Committee ) Health Outcomes Committee (HOC), and International Society of Quality of Life (ISOQOL) (HOC), and International Society of Quality of Life (ISOQOL)
Transcript
1 02/16/01
“Important Issues in Patient Reported “Important Issues in Patient Reported Outcomes (PRO) Research”Outcomes (PRO) Research”
Feb. 16, 2001Feb. 16, 2001
Organized by The Harmonization Coordination Committee Organized by The Harmonization Coordination Committee RepresentingRepresenting
European Regulatory Issues on QualityEuropean Regulatory Issues on Quality--ofof--Life Assessment (ERIQA), International Life Assessment (ERIQA), International Society of Society of PharmacoeconomicPharmacoeconomic and Outcomes Research (ISPOR), Pharmaceutical and Outcomes Research (ISPOR), Pharmaceutical Research and Manufacturers of America (Research and Manufacturers of America (PhRMAPhRMA) Health Outcomes Committee ) Health Outcomes Committee
(HOC), and International Society of Quality of Life (ISOQOL)(HOC), and International Society of Quality of Life (ISOQOL)
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HistoryHistory• Two Harmonization meetings held
!March 31, 2000!Sept. 14, 2000
• Representatives from ERIQA, ISOQOL, ISPOR, PhRMA HOC, and FDA observers
proposed by each organization • Discuss solutions when no
recommendations suggested• Proposed future steps to achieve
consensus on problematic issues
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First Meeting OutcomesFirst Meeting Outcomes• Consensus and areas of disagreement
were identified in four areas: Concept, Study Design, Interpretation and Conditions for Claims*
• Group agreed to continue discussion and form a coordination group with representatives from the four organizations to organize future meetings
*Report available on-line: www.mapi-research-inst/research/report.pdf
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22ndnd Meeting OutcomesMeeting Outcomes• Conceptual framework was broadened to
Patient Based Assessment (PBA) which was changed to Patient Reported Outcomes (PR0) for clarity
• Decision made to continue discussions and schedule meeting with FDA and EMEA representatives
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Today’s Meeting ObjectivesToday’s Meeting Objectives• Clarify aspects and components of PRO
evaluation • Discuss where PRO can add value to
clinical endpoints • Suggest use of this information within
labeling and promotional claims
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Meeting AgendaMeeting Agenda08:45 – 09:15 Group 1
09:15 - 10:00 Group 2
10:00 - 10:15 Break
10:15 - 10:45 Group 3
10:45 – 11:00 Group 4
11:00 – 11:15 Next Steps
11:15 – 11:45 Discussion
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Take Away PointsTake Away Points
• Patient has a unique voice and valuable perspective that should play a role in medical decision making
• PROs can be measured in reliable and valid ways
• PROs are increasingly used as efficacy endpoints in randomized controlled trials
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GROUP 1: Conceptual and GROUP 1: Conceptual and Definitional IssuesDefinitional Issues
Team Leader: Margaret Rothman, Ph.DMembers:
! Ivan Barofsky, Ph.D ! Pennifer Erickson, Ph.D! Paul Kind, M.Phil ! Donald Patrick, Ph.D, M.S.P.H.
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Patient - Reported Clinician - Reported
For example,
Functional statusSymptoms
HRQL
For example,
Global impressionsObservation & tests
of function
Caregiver - Reported
For example,
DependencyFunctional status
Physiological
For example,
FEV1HbA1c
Tumor size
Patient Outcomes Assessment Patient Outcomes Assessment Sources and ExamplesSources and Examples
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Patient - Reported Clinician- Reported
Global ImpressionFunctional status
Well-beingSymptoms
HRQLSatisfaction with TX
Treatment adherence
Caregiver - ReportedPhysiological
Patient Outcomes AssessmentPatient Outcomes AssessmentSources and ExamplesSources and Examples
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HealthHealth--Related Quality of Life: Related Quality of Life: One Type of PROOne Type of PRO
• Represents the patient’s evaluation of the impact of a health condition and its treatment on relevant aspects of life
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HealthHealth--Related Quality of Life: Related Quality of Life: Essential ElementsEssential Elements
Represents the patient’s evaluation of the impact of a health condition and its treatment on relevant aspects of life• The evaluative component can be measured by
HealthHealth--Related Quality of Life: Related Quality of Life: Essential ElementsEssential Elements
Represents the patient’s evaluation of the impact of a health condition and its treatment on relevant aspects of life• The relevant aspects of life are measured as
HealthHealth--Related Quality of Life: Related Quality of Life: Essential ElementsEssential Elements
Represents the patient’s evaluation of the impact of a health condition and its treatment on relevant aspects of life• Domains are selected to be relevant to patients
and their significant others, e.g.,◆ focus groups◆ cognitive interviews◆ literature reviews
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GROUP 2:The Value of GROUP 2:The Value of Patient Reported OutcomesPatient Reported OutcomesTeam Leader: Nancy Kline Leidy, Ph.DMembers:
! Asha Hareendarn, M.D.! Charlotte McMillan, Ph.D ! David Miller, Ph.D! Dennis Revicki, Ph.D! Pierre Sagnier, M.D.! Ingela Wiklund, Ph.D
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The Patient’s Perspective is ...The Patient’s Perspective is ...
• A unique indicator of the impact of disease• Essential for evaluating treatment efficacy• Useful for interpreting clinical outcomes• A key element in treatment decision-making
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PROsPROs May be the Sole Indicator May be the Sole Indicator of Disease Activityof Disease Activity
• PROs and traditional markers of disease activity are related, but not perfectly correlated• daily functioning & FEV-1
◆ r = 0.10 to 0.30◆ shared variance = 9%
• Thus, the two indicators are complementary
PROsPROs Supplement Traditional Supplement Traditional IndicatorsIndicators
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“Objective” “Subjective”Exercise test versus physical functioning, r = 0.40
Wiklund I et al.Clin Cardiol 1991;14
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The Patient’s Perspective is ...The Patient’s Perspective is ...
• A unique indicator of the impact of disease• Essential for evaluating treatment efficacy• Useful for interpreting clinical outcomes• A key element in treatment decision-making
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• the patient’s self-report is the primary or sole indicator of disease activity
• the treatment has a small impact on survival• it is important to ensure that treatments do not
adversely affect patients’ lives• the study is an equivalence trial where the drug
under study has PRO benefits
PROs PROs are essential endpoints in are essential endpoints in clinical trials when...clinical trials when...
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Dom
ain
Sco
re
WorkFunctioning
Social Energy/Vitality
MigraineSymptoms
Feelings/ConcernsFunctioning
21
3
9
12
15
Migraine-Specific Quality of Life QuestionnaireMean +/- S.E. Difference at 24 Hours
Note: Patients assigned to the placebo group had the option to take rizatriptan 10 mg at 2 hours.
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PROsPROs Provide Supplemental Provide Supplemental InformationInformation• In advanced breast cancer,
• continuous chemotherapy led to better HRQL than intermittent chemotherapy (Coates et al., 1987)
• standard-dose chemotherapy led to better HRQL than half-dose chemotherapy (Tannocket al., 1988)
• In soft tissue sarcoma of the limbs, • amputation of the affected limb led to better
HRQL than limb-sparing surgery plus adjuvant therapy (Sugarbaker et al., 1982)
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The Patient’s Perspective is ...The Patient’s Perspective is ...
• A unique indicator of the impact of disease• Essential for evaluating treatment efficacy• Useful for interpreting clinical outcomes• A key element in treatment decision-making
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Interpreting Clinical OutcomesInterpreting Clinical Outcomesin Terms of Patient Benefitin Terms of Patient Benefit
• Improvement in FEV-1• Effect on daily activity?
• Reduction in seizure frequency• Effect on social functioning & well-being?
HRQL Outcomes of Seizure HRQL Outcomes of Seizure Responders by Treatment GroupResponders by Treatment Group
-20
-10
0
10
20
30
Total Score SeizureWorry
CognitiveFunciton
MedicalEffects
SocialFunction
HealthStatus
Placebo LEV 1000 mg LEV 3000 mg
Cramer et al., Epilepsia, 41 (7): 868-74, 2000
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The Patient’s Perspective is ...The Patient’s Perspective is ...
• A unique indicator of the impact of disease• Essential for evaluating treatment efficacy• Useful for interpreting clinical outcomes• A key element in treatment decision-making
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PROsPROs in Clinicalin Clinical--Decision MakingDecision Making
• Are necessary for clinical decision-making• Must be communicated to decision makers
◆ clinicians, patients, payers◆ scientific dissemination is insufficient
Therefore..Therefore...• The FDA should not only allow, but encourage PRO
evidence in product labels and promotion
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The Patient’s Perspective is ...The Patient’s Perspective is ...
• A unique indicator of the impact of disease.• Essential for evaluating treatment efficacy.• Useful for interpreting clinical outcomes.• A key element in treatment decision-making.
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BreakBreak
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GROUP 3: Methodological GROUP 3: Methodological Considerations in Obtaining Considerations in Obtaining PROsPROs in Clinical Trialsin Clinical TrialsTeam Leader: Patrick Marquis, M.D. Members:
! Olivier Chassany, M.D.! Dominique Dubois, M.D.! Joseph Jackson, Ph.D! Nancy Santanello, M.D., M.S.! Rhys Williams, Ph.D
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Development and Validation of Development and Validation of PRO MeasuresPRO Measures• PROs are scientific measures that can evaluate
change in outcomes• Based on a recognized psychometric theory and
• Supported by empirical validation• Reliability, validity, responsiveness (Lohr
1996, Cronbach 1955, Goodwin 1997)
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Implementation, analysis and Implementation, analysis and reporting of PRO data reporting of PRO data -- 11• Endpoint specification (What is the claim you are
hoping to achieve? What are the measures and research questions that address that claim?)
• PRO selection and/or development (PRO demonstrates appropriate methods of measurement)
• PRO validation (Provide evidence of PRO validation)• Study design (Appropriately addresses issues that have
the potential to compromise the integrity of study - eg. randomization, administration methods, handling of missing data, etc.)
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Implementation, analysis and Implementation, analysis and reporting of PRO data reporting of PRO data -- 22• Data analysis (pre-specified PRO analytic
procedures for pre-specified claim)• Interpretation of results (What do the results
mean in the context of the clinical trial findings?)
• Reporting of results in approved labeling or promotion (full disclosure of all PRO results, PRO used, avoid implied terms)
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Patient Reported Outcome Patient Reported Outcome Measures Measures -- Conclusions Conclusions --• PROs are scientific measures that can evaluate
change in outcomes
• Handle like any other measures in clinical trials (physiologic, caregiver, clinician, … measures)
• Methods for selecting, developing, validating, measuring, reporting, PROs are the same as other clinical measures
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GROUP 4: Interest and Demand GROUP 4: Interest and Demand for PRO Informationfor PRO Information
Team Leader: Rick Berzon, Ph.DMembers:
! Joyce Cramer, Ph.D! Greg Boyer, Ph.D! Haim Erder, Ph.D! Albert Wu, M.D., Ph.D! Jean-Paul Gagnon, Ph.D! Richard Willke, Ph.D
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Current trends that drive Current trends that drive demand for PRO demand for PRO • Chronic Illness
• Increasing prevalence and greater longevity with chronic illnesses
• Cure often not achievable for chronic illness • Improving functioning and well-being are goals
for new therapies for chronic illnesses (e.g., epilepsy, HIV/AIDS, cancers)
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Patients want PRO Patients want PRO • Increases patient participation and voice in
health care decision-making• Patients’ decisions are based not on clinical
outcomes alone• More complete and relevant information for
patients• PROs have intuitive value to patients• PROs provide insights to patients regarding
treatment risks vs. benefits
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Clinicians want PROClinicians want PRO
• Willingness to allow patients to select among treatments based on potential for efficacy, adverse events and tolerability
• PRO assists in value-based, bottom line decisions for prescribers and payers, as well as for clinicians and patients
• Breast cancer patients:• Greater patient involvement in decision-
making leads to more limited surgery• (Curran et al. Eur J Ca 1998; 34:307-314.)
• Prostate cancer patients:• Greater patient awareness of treatment
options allows the patient to select and tailor individual treatment
• (Osoba et al. J Clin Oncol 1999; 17:1654-1663.)
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Example of Added Value from Example of Added Value from PRO: Alzheimer’s DiseasePRO: Alzheimer’s Disease
• Efficacy outcomes are patient memory, cognition• PROs are patient dignity, caregiver burden
• Medications slow progression and allow patients to remain home longer
◆ " caregiver burden ◆ " societal burden by delaying need for nursing home placement
• Patients and caregivers should know the impact of the treatment on outcomes in addition to measures of cognition (Shikiar et al. J Am Geriatr Soc 2000; 48:268-74.)
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Take Away PointsTake Away Points
• Patient has a unique voice and valuable perspective that should play a role in medical decision making
• PROs can be measured in reliable and valid ways
• PROs are increasingly used as efficacy endpoints in randomized controlled trials
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Next StepNext Step• Hold meetings with FDA and EMEA
representatives to expand discussions
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QuestionsQuestions• Does FDA accept that the validity,
reliability and sensitivity of PRO data can be established to a degree sufficient for use in labeling and promotion
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QuestionsQuestions• Does FDA accept that in general PRO
data may provide unique and valid information for use in product labels that is distinct from traditional clinical endpoints, or does its relevance have to be established on a case-by-case basis?
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QuestionsQuestions• What are FDA’s intentions toward
issuing a PRO guidance that is applicable across all reviewing divisions?
