Important Issues in Patient Reported Outcomes (PRO) Research

Important Issues in Patient Reported Outcomes (PRO) Research Feb. 16, 2001 Organized by The Harmonization Coordination Committee Representing European Regulatory Issues on Quality-of of-life Assessment (ERIQA), International Society of Pharmacoeconomic and Outcomes Research (ISPOR), Pharmaceutical Research and Manufacturers of America (PhRMA( PhRMA) ) Health Outcomes Committee (HOC), and International Society of Quality of Life (ISOQOL) 1 02/16/01

History Two Harmonization meetings held!march 31, 2000!Sept. 14, 2000 Representatives from ERIQA, ISOQOL, ISPOR, PhRMA HOC, and FDA observers 2 02/16/01

Objectives Discuss problematic issues Harmonize recommendations proposed by each organization Discuss solutions when no recommendations suggested Proposed future steps to achieve consensus on problematic issues 3 02/16/01

First 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 4 02/16/01

2 nd Meeting 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 5 02/16/01

Today 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 6 02/16/01

Meeting Agenda 08:45 09:15 Group 1 09:15-10:00 Group 2 10:00-10:15 Break 10:45 11:00 Group 4 11:00 11:15 Next Steps 11:15 11:45 Discussion 10:15-10:45 Group 3 7 02/16/01

Take 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 8 02/16/01

GROUP 1: Conceptual and Definitional Issues Team Leader: Margaret Rothman, Ph.D Members:! Ivan Barofsky, Ph.D! Pennifer Erickson, Ph.D! Paul Kind, M.Phil! Donald Patrick, Ph.D, M.S.P.H. 9 02/16/01

Patient Outcomes Assessment Sources and Examples Clinician - Reported Physiological Caregiver - Reported Patient - Reported For example, Global impressions Observation & tests of function For example, FEV 1 HbA1c Tumor size For example, Dependency Functional status For example, Functional status Symptoms HRQL 10 02/16/01

Patient Outcomes Assessment Sources and Examples Clinician- Reported Physiological Caregiver - Reported Patient - Reported Global Impression Functional status Well-being Symptoms HRQL Satisfaction with TX Treatment adherence 11 02/16/01

Health-Related Quality of Life: One Type of PRO Represents the patient s evaluation of the impact of a health condition and its treatment on relevant aspects of life 12 02/16/01

Health-Related Quality of Life: Essential 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 severity bothersomeness importance or satisfaction 13 02/16/01

Health-Related Quality of Life: Essential 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 domains, e.g., physical psychological social symptoms 14 02/16/01

Health-Related Quality of Life: Essential 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 15 02/16/01

GROUP 2:The Value of Patient Reported Outcomes Team Leader: Nancy Kline Leidy, Ph.D Members:! Asha Hareendarn, M.D.! Charlotte McMillan, Ph.D! David Miller, Ph.D! Dennis Revicki, Ph.D! Pierre Sagnier, M.D.! Ingela Wiklund, Ph.D 17 02/16/01

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 18 02/16/01

PROs May be the Sole Indicator of Disease Activity Patient-reported symptoms rhinitis, migraine, functional gastrointestinal disorders, menopause, pain Patient-reported functioning sexual dysfunction, insomnia 19 02/16/01

PROs is Key Indicator of Disease Activity Patient-reported symptoms COPD, asthma, psoriasis, atopic dermatitis, benign prostatic hypertrophy Patient-reported functioning Parkinson s disease, MS, arthritis, cancer, stroke, traumatic brain injury 20 02/16/01

PROs Supplement Traditional Indicators 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 21 02/16/01

Objective Subjective Exercise test versus physical functioning, r = 0.40 22 02/16/01 Wiklund I et al. Clin Cardiol 1991;14

PROs are essential endpoints in clinical trials when... 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 24 02/16/01

Migraine-Specific Quality of Life Questionnaire 21 Mean +/- S.E. Difference at 24 Hours Domain Score 15 12 9 3 Placebo rizatr iptan 2.5 mg Work Functioning Social Functioning Energy/ Vitality Migraine Symptoms Feelings/ Concerns rizatr iptan 5 mg 25 02/16/01 rizatr iptan 10 mg Note: Patients assigned to the placebo group had the option to take rizatriptan 10 mg at 2 hours.

PROs Provide Supplemental Information 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 (Tannock et 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) 26 02/16/01

Interpreting Clinical Outcomes in Terms of Patient Benefit Improvement in FEV-1 Effect on daily activity? Reduction in seizure frequency Effect on social functioning & well-being? 28 02/16/01

HRQL Outcomes of Seizure Responders by Treatment Group 30 20 10 0-10 -20 Total Score Seizure Worry Cognitive Funciton Medical Effects Social Function Health Status Placebo LEV 1000 mg LEV 3000 mg Cramer et al., Epilepsia, 41 (7): 868-74, 2000

PROs in Clinical-Decision Making Treatment Guidelines Oncology - ASCO Respiratory Disease Practice Guidelines - COPD, Asthma Gastrointestinal Disease - IBS Practice Guidelines - GERD Cardiovascular Disease Vascular Surgeons; Atrial Fibrillation Urology - BPH, urinary incontinence HIV- DHHS Panel Guidelines 31 02/16/01

PRO Data... Are necessary for clinical decision-making Must be communicated to decision makers clinicians, patients, payers scientific dissemination is insufficient Therefore... The FDA should not only allow, but encourage PRO evidence in product labels and promotion 32 02/16/01

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. 33 02/16/01

Break 35 02/16/01

GROUP 3: Methodological Considerations in Obtaining PROs in Clinical Trials Team 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 36 02/16/01

Development and Validation of PRO Measures PROs are scientific measures that can evaluate change in outcomes Based on a recognized psychometric theory and methods (Likert 1932, Murphy 1937, McIver 1981, Nunnally 1994, 3rd edition) Supported by empirical validation Reliability, validity, responsiveness (Lohr 1996, Cronbach 1955, Goodwin 1997) 37 02/16/01

Implementation, analysis and reporting of PRO data - 1 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.) 38 02/16/01

Implementation, analysis and reporting of PRO data - 2 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) 39 02/16/01

Patient Reported Outcome Measures - 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 40 02/16/01 clinical measures

GROUP 4: Interest and Demand for PRO Information Team Leader: Rick Berzon, Ph.D Members:! 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 42 02/16/01

Current trends that drive 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) 43 02/16/01

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 44 02/16/01

Clinicians 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 45 02/16/01

Patient Empowerment: Cancer Breast cancer patients: Greater patient involvement in decisionmaking 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.) 46 02/16/01

Example of Added Value from PRO: 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.) 47 02/16/01

Next Step Hold meetings with FDA and EMEA representatives to expand discussions 50 02/16/01

Questions 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 51 02/16/01

Questions 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? 52 02/16/01

Questions What are FDA s intentions toward issuing a PRO guidance that is applicable across all reviewing divisions? 53 02/16/01

QUESTIONS AND DISCUSSION 54 02/16/01