Progress Report on the Patient Reported Outcomes Harmonization Team Jean Paul Gagnon, PhD Aventis Pharmaceuticals Inc.

Objectives Discuss Historical Development Describe Forum Outcomes Outline Future Activities

Objectives Discuss Historical Developments

Who started the PRO Harmonization Group? European Regulatory Issues on Quality-of-Life Assessment (ERIQA) International Society of Pharmacoeconomic and Outcomes Research (ISPOR) International Society of Quality of Life (ISOQOL) Pharmaceutical Research and Manufacturers of America (PhRMA) Health Outcomes Committee (HOC)

What is its mission? To harmonize Patient Reported Outcome issues used in drug development and Evaluation.

What are its objectives? Clarify areas of concern or confusion about PRO evaluation Explain the added value of PRO outcomes among all key players, i.e., academics, regulators, industry researchers, prescribers and patients Open and maintain communication between key players Disseminate meeting outcomes, i.e., to publish papers, to participate in conferences

Objectives Discuss Historical Development Describe Forum Outcomes

Forums Three Harmonization Forums held March 31, 2000 Sept. 14, 2000 February 16, 2001 Representatives from ERIQA, ISOQOL, ISPOR, PhRMA HOC and FDA observers

March 2000 Meeting Objectives Discuss problematic issues Harmonize recommendations proposed by each organization Recommend solutions when none exist Proposed future steps to achieve consensus on problematic issues

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 meeting Real issue “does outcomes research provide added value” *Report available on-line: www.mapi-research-inst/research/report.pdf

Impact of Outcomes Data Can the added-value of the outcome be demonstrated, i.e., what does the outcome provide beyond traditional measures? Does the subjective impact of treatment provide value over observer-based assessments or simple symptom scales? Does the measure capture information that is missed with traditional measures?

September 2000 Meeting Outcomes Conceptual framework was broadened to Patient Based Assessment (PBA) which was changed to Patient Reported Outcomes (PRO) for clarity Decision made to continue discussions and schedule meeting with FDA and EMEA representatives

February 2001 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

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

Patient Outcomes Assessment Sources and Examples Clinician - Reported Patient - Reported Physiological Caregiver - Reported For example, Global impressions Observation & tests of function For example, FEV1 HbA1c Tumor size For example, Dependency Functional status Global Impression Functional status Well-being Symptoms HRQL Satisfaction with TX Treatment adherence Assessment of outcome can be achieved in several ways, but most robust involves repeated application of a standardized measurement. Outcome can be defined as a change in this measurement parameter Locates outcome parameters within their primary setting. e.g. clinical or biological markers as tumor size are primarily located within the professional domain. However, parameters such as B/P may be measured by others (e.g. patients). Productivity not included as it is secondary to function

Areas of Agreement Patient Reported Outcomes (PRO) evaluation is a valid concept PRO can be operationalized PRO claims should conform with the evidence and be pre-specified PRO should be reported with fair balance in labeling and promotional claims

“Objective” “Subjective” This cartoon concludes what HRQOL stands for.. It is actually not the objective exercise test data in an hospital environment that we measure but the everyday activities at home or at work subjectively perceived by the patient himself Efficacy is often difficult to measure in disorders for which the patients subjective experience of symptoms and therapy and their impact is critical. “Objective” “Subjective” Exercise test versus physical functioning, r = 0.40 Wiklund I et al. Clin Cardiol 1991;14

Objectives Discuss Historical Development Describe Forum Outcomes Outline Future Activities

Future Plans for Pro Team Publish article on work to date, draft manuscript prepared Develop slide presentations for conferences, e.g., ISPOR, ISOQOL, DIA, others Supply content via website Continue to hold forums until deemed unnecessary Measure outcomes from Forums

February 2002 Forum Agenda Instrument development: what are the standards Instrument selection: demonstrating hypothesis, relationships to measurement Statistical issues: focus on handling missing data Interpretation: Interpreting changes that are not consistent between outcomes

Summary Discussed Historical Developments Described Meeting Outcomes Outlined Future Activities

QUESTIONS Jean Paul Gagnon jean. gagnon@aventis QUESTIONS Jean Paul Gagnon jean.gagnon@aventis.com 800-981-2491 Aventis Pharmaceuticals Inc.