Patient-Reported Outcomes Where are we and where are we heading?

Transcription

1 Patient-Reported Outcomes Where are we and where are we heading? Jane A. Scott, PhD Director Patient Reported Outcomes Janssen Global Services

2 Key Messages Patient-reported outcome (PRO) = method for assessing a patient s experience from the patient s perspective PROM (PRO Measure) = PRO FDA & EMA requirements for PRO use in product development research are having a wider affect on medical research PROs replacing expert rating of symptoms and some types of functioning PROs can be efficient way to collect many clinical signs Technological advances due to increased focus on PRO will affect what is expected for all subjective ratings and clinical study design in the future PRO (method) quality of life (endpoint concept) J Scott: PRO in Drug Development 04/10/2011 MRC Methodology Workshop 2

3 Overview A Review of PRO and other subjective assessments in medical product development research Key issues in measurement for clinical research Implications for MRC sponsored research and global clinical trials J Scott: PRO in Drug Development 04/10/2011 MRC Methodology Workshop 3

4 Basic Requirements for Endpoint Measurement Well-defined Assessment instrument is a valid measure of concept Includes all that is important about measurement concept Valid for study design Valid in population studied Valid procedures (administration, handling, scoring, analysis) Prespecification to limit bias Protocol specifies endpoint and how assessed SAP specifies scoring, analysis and interpretation Reliable same results if Same instrument used repeatedly (Test-Retest) Different instruments purporting to measure same concept are used (Parallel Test) Different assessors use same instrument (Inter-rater reliability) J Scott: PRO in Drug Development 04/10/2011 MRC Methodology Workshop 4

5 Record-based Assessments Death Medical resources used Biological & Anthropomorphic Assessments Analysis of tissue samples Data from Medical Devices Imaging studies Vital signs (weight, height, pulse, blood pressure, temperature) Machine-assessed functioning (e.g., FEV1, treadmill tests) Subjective Assessments Measurements based on patient self-report (PROs) Measurements based on observation of the patient by someone else Clinician-reported outcomes (ClinROs) Observers including technicians, family, friends, teachers of the patient (ObsRO) J Scott: PRO in Drug Development 04/10/2011 MRC Methodology Workshop 5

6 PRO is a measurement based on a report that comes directly from the patient (i.e. study subject) about the status of a patient s health condition without amendment or interpretation of the patient s response by a clinician or anyone else. The use of a PRO instrument is advised when measuring a concept that is best known by the patient or best measured from the patient s perspective US FDA Guidance for Industry: Patient Reported Outcomes: Use in Medical Product Claims, Dec 2009 J Scott: PRO in Drug Development 04/10/2011 MRC Methodology Workshop 6

7 How did we get here? J Scott: PRO in Drug Development 04/10/2011 MRC Methodology Workshop 7

8 Framingham Heart Study Karnofsky Performance Status (KPS) Karnofsy & Burchenal 1949 NHANES Spilker (ed) Quality of Life and Pharmacoeconomics in Clinical Trials Nottingham Health Profile (NHP) Hunt et al, s 1960 s 1970 s 1980 s Katz ADL Scale Katz et al Sickness Impact Profile Bergner et al Medical Outcomes Study Health Survey Short Form-36 (SF-36) Ware et al, 1989 J Scott: PRO in Drug Development 04/10/2011 MRC Methodology Workshop 8

9 Health Survey for England 0.57/litre Flonase claims QOL benefit using AQLQ fmri Zofran claims based on FLIE & FLIC FDA Guidance on DTC causes rise from $220 million/yr to $2.8 billion/yr for drug ads J Scott: PRO in Drug Development 04/10/2011 MRC Methodology Workshop 9

10 Draft map of Human Genome released Mayo QOL Clinical Significance Meeting FDA draft PRO Guidance Soliris QOL & fatigue claims FDA PRO Guidance finalized PRO term coined by PRO Harmonization Group EMA HRQL Reflection Paper Critical Path Institute (C-PATH) PRO Consortium 1 st public meeting FDA draft DDT Qualification Guidance UK PROMS initiative uses PRO to measure treatment satisfaction J Scott: PRO in Drug Development 04/10/2011 MRC Methodology Workshop 10

11 Why use PROs in Clinical Research? Way to document patients perspective on concepts that are Known only to patients Easier to assess by asking patients Important to patients and their families Rising treatment costs focus attention on whether the patient benefits from treatment Health care decision-makers expect clinical improvement in how patients survive, feel and function Patients pay some or all costs for treatments depending on the country Drug expenditures are wasted if patients do not adhere due to lack of symptom improvement, poor tolerability, or inconvenient treatments Patients and their advocates seek information about the condition and how different treatments affect patients lives J Scott: PRO in Drug Development 04/10/2011 MRC Methodology Workshop 11

12 FDA Labeling Endpoints Year #NMEs Evaluated #PROs (%) #ClinROs (%) (33%) 18 (67%) (36%) 23 (68%) (33%) 13 (72%) (32%) 16 (73%) (11%) 13 (72%) (42%) 16 (67%) Total (33%) 99 (70%) Source: Laurie Burke, 22 nd Annual DIA EuroMeeting, Monaco 2010 J Scott: PRO in Drug Development 04/10/2011 MRC Methodology Workshop 12

13 PRO Show Value of Most Expensive Drug Soliris, a monoclonal antibody developed for treatment of a very rare blood disorder (paroxysmal nocturnal hemoglobinuria, PNH) Approved as orphan drug in 2007 by EMA and FDA World s Most Expensive Drug $409,500/yr/patient J Scott: PRO in Drug Development 04/10/2011 MRC Methodology Workshop 13

14 Research Trends Since PRO Guidance PRO help document clinical validity of biologic assays Daily assessment of symptoms for symptom treatments epro encouraged for patient diaries Major research initiatives use PRO/PROMs in COPD (EXACT-PRO, IMI PROActive at 16million!!!) C-PATH PRO Consortium Journal articles focus on the development, validation, and interpretation endpoint measures Identifying clinical significance of observed differences a major challenge for any new assessment J Scott: PRO in Drug Development 04/10/2011 MRC Methodology Workshop 14

15 Cumulative Distribution Function Preferred to Evaluate Treatment Outcomes Experimental Treatment (solid line) Control Treatment (dash line --) J Scott: PRO in Drug Development 04/10/2011 MRC Methodology Workshop 15

16 The Future Electronic data capture will be the norm not the exception Enables faster completion of studies and less missing data Training and procedures used to assess all endpoints will be major topic of critiques by regulators and journals Efforts to identify the best available instrument for specific concepts will lead to a few qualified PRO, ClinRO, and ObsRO New endpoint measures based on composites of old and new measures (e.g., ACR-50, PROActive, PROMIS) New methods will be developed to reduce subjectivity of qualitative methods used in developing subjective assessments CONSORT standards for QOL reporting in development will ensure better understanding of QOL evidence and methods J Scott: PRO in Drug Development 04/10/2011 MRC Methodology Workshop 16

17 Final Thoughts All key study endpoints require rigorous measurement Well-established methods for developing/validating measures Content validity critical for subjective measures at FDA New tools for evaluating content validity are needed to reduce subjectivity Clinical meaning of observed changes must be documented Cumulative distribution analyses that give the most complete picture of how patients respond to a treatment are here to stay New methods still needed J Scott: PRO in Drug Development 04/10/2011 MRC Methodology Workshop 17

18 J Scott: PRO in Drug Development 04/10/2011 MRC Methodology Workshop 18

19 Why all this interest in PROs? Regulatory agencies acknowledge value of PRO EMA publishes reflection paper on Quality of Life in clinical development trials FDA publishes draft guidance on use of PRO for medical product labeling Guidances reflect State-of-the-art in survey, psychological, and cognitive research raise questions about the adequacy of PROs used in clinical trials Experience of regulators about common problems that occur when PRO are use, and especially when inadequately implemented in trials Focus: how to ensure PRO provide well-defined and reliable evidence of clinical benefit to the patient J Scott: PRO in Drug Development 04/10/2011 MRC Methodology Workshop 19

20 Example: Russell et al. Sleep Medicine 2009; 10: Reduced Sleep Disturbance Direct Effect (73%; p<0.01) Indirect Effect (27%; p=0.01) Decreased Pain Pregabalin 450 mg/day (vs Placebo) J Scott: PRO in Drug Development 04/10/2011 MRC Methodology Workshop 20 Total Effect = 12.7 reduction (improvement)