in alphabetical order:

Transcription

1 FORUM 1

2 in alphabetical order: 2 Laurie B. Burke, RPh, MPH, Founder, Lora Group, LLC, Royal Oak, MD, USA and Affiliate Associate Professor, University of Maryland School of Pharmacy Stefan Cano, PhD, CPsychol, AFBPsS, Chief Science Officer, Modus Outcomes, Stotfold, England, UK Jeremy Hobart, PhD, FRCPJ, Professor of Clinical Neurology and Health Measurement, Peninsula College of Medicine and Dentistry, Plymouth, UK Maria Isaac, MASc, MD, PhD, Scientific Administrator, Science Advice & Orphan Drugs Sector (SAOD), European Medicines Agency (EMA), London, UK Patrick Marquis, MD, MBA, Chief Executive Officer, Modus Outcomes Boston, MA, USA

3 3 Elektra Papadopoulos, MD, MPH, Acting Associate Director for Study Endpoints Review, ONDIO, CDER, FDA, Silver Spring, MD, USA Donald Patrick, PhD, MSPH, Professor, Department of Health Services and Director, Seattle Quality of Life Group, University of Washington, Seattle, WA, USA John H. Powers, III, MD FACP FIDSA Associate Clinical Professor of Medicine, George Washington University School of Medicine, Washington, DC, USA Ashley Slagle, PhD, MS, Study Endpoints Reviewer, ONDIO, CDER, FDA, Silver Spring, MD, USA Marc K. Walton, MD, PhD, Senior Scientific Director, Janssen Research and Development, Titusville, NJ, USA

4 4 As of May 2015 More than 15% of ISPOR s 9,500 members in 114 countries around the world identify PROs as a primary research interest. ISPOR COA and ClinRO Task Force Reports will be #9 and #10 of ISPOR PRO & COA Good Research Practices Task Force Reports since 2009.

5 5 Clinical Outcomes Assessments: Conceptual Foundation (in development) Clinician-Reported Outcomes (ClinROs) Good Measurement Practices (in development) PRO Data Collection Using Mixed Modes in Clinical Trials (2014) Assessment of PROs in Children and Adolescents (2013) epro Systems Validation (2013) epro-changing Mode of Administration of PRO Instruments from Paper to Electronic (2009) Content Validity in Existing PRO Instruments & Their Modification (2009) Content Validity in Newly-developed PRO Instruments Part 1 - Eliciting Concepts for a New PRO Instrument (2011) Content Validity in Newly-Developed PRO Instruments Part 2 - Assessing Respondent Understanding (2011) Translation & Linguistic Validation of PRO Instruments (2009)

6 6 6 Develop an Emerging Good Research Practices Report to: Further improve development and use of clinical outcome assessments (COAs), including ClinROs in US and European clinical research and practice Improve patient outcomes and allow better assessments of benefits and harms through better measures

7 Biomarkers Performance Clinician-Reported Observer-Reported Signs Patient-Reported Cholesterol (coronary disease) C-reactive protein (inflammation ) Motor (timed 25 foot walk test) Sensory (visual acuity, test reading) Cognition (memory recall, or other cognitive testing (e.g., digit symbol substitution test). Global impression of severity/change Algorithmic ratings Radiographic readings with human interpretation Cough Activity level Sleep Symptoms Function Feelings Perceptions Survival

8 8 A COA is any assessment that depends on a patient s volition or a rater s judgment. COAs include: patient-reported outcome (PRO) measures, clinician-reported outcome (ClinRO) measures, observerreported outcome (ObsRO) measures, and performance outcome (PerfO) measures. COAs exclude: survival and biomarkers.

9 9 9 Rising costs require evidence of value to all stakeholders. Payers interested in technology assessment and evidence-based treatments. Consumer and patient voice rising in importance with patient-centeredness. Regulators like US Food and Drug Administration and European Medicines Agency require for approval.

10 : EMA Reflection Paper on the Regulatory Guidance for the Use of Health Related Quality of Life (HRQL) Measures in the Evaluation of Medicinal Products 2009: FDA PRO Guidance for Industry A PRO instrument, like physician-based instruments, should be shown to measure the concept it is intended to measure, and the FDA will review the evidence that a particular PRO instrument measures the concept claimed. 2011: Review and Qualification of Clinical Outcome Assessments; Public Workshop 2014: Qualification Process for Drug Development Tools Guidance 2014: Reflection Paper on the Use of Patient Reported Outcome (PRO) Measures in Oncology Studies

11 11 Treatment benefit Favorable effect on meaningful aspect of how patients feel or function in their lives, or how long patients survive Improved effectiveness Decreased harms

12 12 Measurement of the effects of an intervention (benefit or harm to a patient) = comparison between test and control group The purpose of conducting clinical investigations of a drug is to distinguish the effect of a drug from other influences, such as spontaneous change in the course of the disease, placebo effect, or biased observation. 21CFR

13 13 It is NOT a: Diagnostic tool used to define disease Predictor of outcome select person likely to experience an outcome independent of intervention Enrichment strategy selecting patients most likely to benefit from intervention for enrollment in trial

14 14 Survival COA: Clinical Outcome Assessment PRO Patient-Reported Outcome ClinRo Clinician-Reported Outcome ObsRO Observer-Reported Outcome PerfO - Performance Outcome Biomarkers

15 15 Observable* concepts Unobservable concepts (e.g., feelings, sensations) Performance of a task (patient cooperation and motivation required - Instructions provided by a health professional - e.g., cognitive testing, 6 min WT) Report by trained health professional not needed Report by trained health professional needed Self-report feasible and appropriate? No Yes ObsRO PRO ClinRO PRO PerfO

16 16 16 Foundational Topics Covered: Treatment Benefit The Relationship Between Patient Assessments and Study Endpoints The Intended Treatment Benefit The Measured Concept of Interest Context of Use: Important Clinical Trial Factors Attributes of an OA

17 17 17 A favorable effect on a meaningful aspect of how a patient feels or functions in their life, or on survival. Meaningful aspect means meaningful to the patient In their life means in the patient s usual (typical) life

18 18 18 Endpoint is a particular method for assessment of the patients at one or more times during the study and analyzed according to a specified statistical method to provide a comparison between groups NOT the assessment itself Outcome assessment is the measuring instrument that provides a rating or a score that is intended to represent some aspect of the patient s medical status

19 19 19 Even though many outcome assessments (biomarkers, PerfOs, most ClinROs and ObsROs, and some PROs) do not measure how patients feel, function or survive, the relationship between the outcome and treatment benefit needs to be established. In order to do this, the underlying intended treatment benefit needs to be identified so that the usefulness of the OA can be evaluated Ex: improved survival is the intended treatment benefit; reduction in LDL-C is the outcome assessment

20 20 20 The concept of interest is what is actually represented by the OA score May or may not be the same a the meaningful aspects of how patients feel, function or survive The same COI may be measured by multiple different OAs Ex: pain intensity can be measured using many different pain scales

21 21 21 The specifics of study design and other study features Disease or condition Patient subpopulation Culture, language, geography Standard clinical practice Endpoint positioning Manner of use within the endpoint Measurement setting Method of administration The context of use may alter the OA performance characteristics and interpretation

22 22 22 Influence the measurement properties and how the measurement properties are evaluated Whether the OA is dependent on patient active involvement or rater participation Whether the rater applies judgment to form the measurement Relationship between the OA and treatment benefit (feels, function, survives)

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24 24 24 Goals: Define ClinRO Outcome assessments and types of ClinROs Outline emerging good measurement practices to consider when deciding to use ClinRO Outcome Assessments as (part of) endpoint in clinical trial Little clinical research found specifically related to ClinRO assessments even though commonly used in clinical trials.

25 25 Clinician Reported Outcomes Report that comes from a trained health-care professional after observation of patient s health condition Involve a clinical judgment or interpretation of the observable signs, behaviors, or other physical manifestations thought to be related to a disease or condition ClinRO measures cannot directly assess symptoms that are known only to the patient (e.g., pain intensity)

26 26 When clinicians can form accurate assessments (that reflect feels, functions, survival) that becomes the measurement on which a study endpoint is based For example, Where patients are unable to self-report on their own health status due to mental or physical impairment or age (e.g., neonates) Or where patients cannot comment on a specific sign (e.g., Parkinson s disease)

27 27 Types of ClinROs: Readings dichotomous report: fracture on a radiography, absence of presence skin lesions, emetic episodes Ratings categorical/scoring report: spleen size, change in skin lesions, severity of schizophrenia (PANSS); improvement in vein appearance Globals Clinician Global Impressions (CGI): overall judgment on patient status; what is measured and how assessments made not clearly defined

28 28 Clinicians can be various types of trained members of an investigative team Physicians Nurses, nurse practitioners, physicians assistants Clinical research associates Various types of therapists Etc.

29 29 GMP 1: Define the context of use of the measure GMP 2: Define concept of interest GMP 3: Explain relationship of assessment to direct treatment benefit GMP 4: Documentation of content validity GMP 5: Documentation of other measurement properties GMP 6: Interpretation and analysis clinical trial results GMP 7: Implementation in clinical trials

30 30 30 Context of Use Treatment benefit (feels,function,survival) concept(s) of interest outcome assessment(s) endpoint(s)

31 31 31 COU patients with cystic fibrosis Treatment benefit patient functional disability and symptoms COI pulmonary exacerbation COA Clinician judged symptoms based on Fuchs criteria (check list of 12 sinopulmonary signs and symptoms) Endpoint comparison of proportions of patients in test and control groups on time to first exacerbation of CF (presence of at least 4 signs/symptoms resulting in administration of medication)

32 32 32 COU: Acute Bacterial Skin and Skin Structure Infections in adults who can self-report Treatment benefit: patient pain and decreased function in daily life COI: skin lesion size COA: scalar measurement (rating) of skin lesion size with paper ruler at baseline and during study by clinicians (judgment required to perform measurement) Endpoint: Proportion of patients in test and controls groups with >20% decrease in lesion size by hr post-randomization (PRO in development)

33 33 33 COU Hospital-acquired pneumonia in adult patients who can self-report Treatment benefit undefined; serious and life threatening disease so all-cause mortality key; symptoms and/or function in survivors not defined as part of ClinRO CG COI undefined COA clinical response variables undefined: clinician judgment of improvement in signs, symptoms, biomarkers (body temperature, WBC, CXR) such that no additional antimicrobial therapy is prescribed Endpoint difference of proportions between test and control group at various time points called clinical response

34 34 Same good measurement practices apply to all COAs PerfO, PRO, ObsRO, and ClinRO All clinical trials should include patientcentered outcomes that measure survival, function, and/or feelings (directly or indirectly) in endpoints. Live Longer or Live Better For indirect measures understanding of relationship between indirect measure and direct treatment benefit

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37 Q & A