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Guidance on PRO Endpoints and Label Regulations Debra Silberg, MD PhD Senior Director, Clinical Medicine Shire Our purpose We enable people with life-altering conditions to lead better lives. Disclaimer • Debra Silberg is an employee and shareholder of Shire Pharmaceuticals. • The views and opinions expressed in the following PowerPoint slides are those of the individual presenter and should not be attributed to Shire, its directors, or officers. • These PowerPoint slides are the intellectual property of the individual presenter and are protected under the copyright laws of the United States of America and other countries. Used by permission. To be as brave as the people we help. © 2014 Shire Development LLC. All rights reserved 2 Endpoints Must Show Treatment Benefit The impact of a treatment on how a patient “survives, feels, or functions” • Same as the “clinical benefit” • Can be measured directly or indirectly • Survives • Feels • A patient’s physical sensations related to health • A patient’s perceived mental state related to health • Functions • A patient’s ability to perform an activity (e.g., walking 25 feet) • Not specific organ function or physiological processes (e.g. liver metabolism) To be as brave as the people we help. © 2014 Shire Development LLC. All rights reserved 3 Outcomes Assessments for Measuring Treatment Benefit in Clinical Trials • Clinical Outcome Assessments (COAs) There are four types of COA measures: • • • • Patient-reported outcome (PRO) measures Clinician-reported outcome (ClinRO) measures Observer-reported outcome (ObsRO) measures Performance outcome (PerfO) measures • Biomarkers •Results not influenced by humans; relies on a standardized, automated process (i.e. Blood pressure) • Survival To be as brave as the people we help. © 2014 Shire Development LLC. All rights reserved 4 Patient-Reported Outcome (PRO) • A PRO is any report of the status of a patient’s health condition that comes directly from the patient, without interpretation of the patient’s response by a clinician or anyone else. • Only PRO assessments can measure symptoms and patient experiences with a condition • Examples: • Self-report of daily number of incontinence episodes • Self-report of pain intensity on a 0 to 10 numerical rating scale (NRS) To be as brave as the people we help. © 2014 Shire Development LLC. All rights reserved 5 Observer-Reported Outcome (ObsRO) • An assessment that is determined by an observer who does not necessarily have a relevant background of professional training • Often used when the patient is unable to self-report (e.g., infants, young children, severely cognitively incapacitated persons) • Used to capture observable concepts only (e.g., signs or behaviors—NOT symptoms) • Not PROXY • Examples include: • Parent report of infant behavior (e.g., crying) • Caregiver report of patient task performance (e.g., ability to dress oneself without assistance) To be as brave as the people we help. © 2014 Shire Development LLC. All rights reserved 6 Clinician-Reported Outcome (ClinRO) • An assessment made by an observer with some recognized professional training that is relevant to the measure being taken • May include an evaluation and interpretation of the patient's condition based on clinical judgment. • Examples include: • Subjective impression following physical examination • Physical performance measures To be as brave as the people we help. © 2014 Shire Development LLC. All rights reserved 7 Performance outcome (PerfO) measures • A PerfO is a measurement based on a task(s) performed by a patient according to instructions that is administered by a health care professional. • Performance outcomes require patient cooperation and motivation. • Examples include: • measures of gait speed (e.g., timed 25 foot walk test), • memory recall (e.g., match names to faces after 10 minutes) • cognitive testing (e.g., digit symbol substitution test - matches symbols with their corresponding digit ) To be as brave as the people we help. © 2014 Shire Development LLC. All rights reserved 8 FDA Guidance Guidance for Industry Patient-Reported Outcome Measures: Use in Medical Product Development to Support Labeling Claims U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER) Center for Biologics Evaluation and Research (CBER) Center for Devices and Radiological Health (CDRH) December 2009 Clinical/Medical To be as brave as the people we help. © 2014 Shire Development LLC. All rights reserved 9 To be as brave as the people we help. 10 Column 1 To be as brave as the people we help. © 2014 Shire Development LLC. All rights reserved 11 Column 2 To be as brave as the people we help. © 2014 Shire Development LLC. All rights reserved 12 Column 3 To be as brave as the people we help. © 2014 Shire Development LLC. All rights reserved 13 To be as brave as the people we help. 14 Spoke 1 I. Identify Context of Use (COU) and Concept of Interest (COI) • Outline hypothesized concepts and potential claims • Determine intended population • Determine intended application/characteristics (type of scores, mode and frequency of administration) • Perform literature/expert review • Develop hypothesized conceptual framework • Position COA within a preliminary endpoint model • Document COU and COI To be as brave as the people we help. © 2014 Shire Development LLC. All rights reserved 15 Context of Use 1. What is your Clinical Outcome Assessment intended to be used for • What claims do you want to make 2. What disease are you interested in – do you have a definition of your disease? 3. What severity are you studying? 4. Is there a specific characteristic that you are interested in? • Drug mechanism of action • Symptom complex that is dominant • Particular feature of the disease To be as brave as the people we help. © 2014 Shire Development LLC. All rights reserved 16 Draft Conceptual Framework (example from seasonal allergies*) SASA-PRO (Seasonal Allergy Symptom Assessment-PRO) Item 1 (sneezing) Item 2 (coughing) Domain 1 Airway Item 3 (runny nose) Domain 2 Nose Item 4 (watery eyes) Item 5 (itchy eyes) Domain 3 Eyes General Concept Symptoms of Seasonal Allergies * This is not a real instrument, it is just an example To be as brave as the people we help. © 2014 Shire Development LLC. All rights reserved 17 Develop an Endpoint Model Concept Indication Treatment of Seasonal Allergies Supportive Concepts Adjuvant therapies Endpoints Primary Symptom Score using the 5 item SASA-PRO* (Seasonal Allergy Symptom Assessment-PRO) Secondary Antihistamine use Possible Claims: 50% reduction in symptom score and 80% less antihistamine use To be as brave as the people we help. * This is not a real instrument, it is just an © 2014 Shire Development LLC. All rights reserved 18 Spoke 2 II. Draft Instrument and Evaluate Content Validity • Obtain patient or other reporter input • Generate new items • Select recall period, response options and format • Select mode/method of administration/data collection • Conduct cognitive interviewing • Pilot test draft instrument • Finalize instrument content, format and scoring rule • Document content validity To be as brave as the people we help. © 2014 Shire Development LLC. All rights reserved 19 Signs and Symptoms - Endpoint Evaluation • Qualitative Work with Patients and/or Caregivers • Elicit the key symptoms and signs by patient (or caregiver) interviews, probe patients on what the literature and HCPs said • Individual or focus groups – obtain new items • Interview until saturation is reached – no new items/concepts are elicited during the interviews • Support findings from patients with further discussions with health care providers • Iterative process as you continue development • Validity – The instrument measures what it is intended to measure • Content Validity • Evidence that the instrument measures the concept of interest • ToQualitative evidence that the items and domains are be as brave as the people we help. appropriate © 2014 Shire Development LLC. All rights reserved 20 Spoke 3 III. Cross-sectional Evaluation of Other Measurement Properties • Assess score reliability (test-retest or inter-rater) and construct validity • Establish administration procedures & training materials • Document measure development • Prepare user manual To be as brave as the people we help. © 2014 Shire Development LLC. All rights reserved 21 Attributes of PROs • Reliability • Ability to yield consistent, reproducible estimates of the true treatment effect • Shows stability of scores overtime when no change is expected • Construct Validity • Extent that the items and domains of the instrument measure the construct/concept that they were intended to measure • Responsiveness – Ability to detect change • The PRO instrument can identify difference in scores over time in individuals or groups who have changed with respect to the measurement concept To be as brave as the people we help. Definitions from the FDA guidance document © 2014 Shire Development LLC. All rights reserved 22 Spoke 4 IV. Longitudinal Evaluation of Measurement Properties/ Interpretation Methods • Assess ability to detect change and construct validity • Identify responder definition(s) • Provide guidelines for interpretation of treatment benefit and relationship to claim • Document all results • Update user manual To be as brave as the people we help. © 2014 Shire Development LLC. All rights reserved 23 Quantitative Phase • Test the instrument in a setting in which change can be observed • Observational or Clinical Trial • Determine a Responder Definition or a Statistical Means of Measurement • Clinically meaningful change – minimally important difference (MID) • Composite vs. single symptom endpoint • Endpoint Evaluation • use anchors such as global health score to establish what would be considered a meaningful effect To be as brave as the people we help. © 2014 Shire Development LLC. All rights reserved 24 Deciding on Endpoints – What is your Claim? “Begin with the end in mind” • Must know the claim that you want to make regarding the therapy early in clinical development • Utilize the TPP (Target Product Profile) guidance from the FDA to assist in clinical development To be as brave as the people we help. © 2014 Shire Development LLC. All rights reserved 25 FDA-TPP Guidance Document Guidance for Industry and Review Staff Target Product Profile — A Strategic Development Process Tool U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER) To be as brave as the people we help. © 2014 Shire Development LLC. All rights reserved 26 TPP – from the guidance • “The TPP provides a statement of the overall intent of the drug development program, and gives information about the drug at a particular time in development” • “Use of a TPP can facilitate the efficiency of sponsorFDA interactions and communications. A TPP helps focus a sponsor’s drug development team and FDA review staff on the drug development goals in terms of drug labeling.” To be as brave as the people we help. © 2014 Shire Development LLC. All rights reserved 27 Case Study– Pediatric COA for Ulcerative Colitis Developing a PRO and ObsRO • Ulcerative Colitis is a chronic inflammatory disease of the colon (pediatric and adult) • Signs and Symptoms include: abdominal pain, blood in stool, frequent bowel movements, stool urgency and tiredness • Considerations: who is evaluating the disease state? • What age child can answer a questionnaire? • An observer can only report what they see, but not how a patient feels • What input should the physician have? To be as brave as the people we help. © 2014 Shire Development LLC. All rights reserved 28 Current instrument and why a new one was needed PUCAI (pediatric UC activity index) – Most commonly used in a clinically setting and has been used for clinical trials Items: • Abdominal pain • Rectal bleeding • Stool consistency • Number of stools per 24 hrs • Nocturnal stools • Activity level • • Physicians ask the questions and records answers Reflects a daily average of the last 2 days (unless conditions are changing rapidly, then the most recent 24 hours) • Issues: • The status of a patient’s health condition should come directly from the patient without interpretation by a clinician (FDA PRO guidance) • Recall of information over multiple days • Limited number of days considered To be as brave as the people we help. Turner et.al. Gastroenterology 2007 133:423 © 2014 Shire Development LLC. All rights reserved 29 Endpoint Model for Pediatric Ulcerative Colitis (UC) Concept Indication 1 Improvement in signs and symptoms among children and adolescence with mild to moderate UC Indication 2 Endpoints Primary *DUCS total sign and symptom score (PRO and ObsRO) Stability of signs and symptoms among children and adolescence with UC in remission Supportive Concept Improvement of the mucosal appearance of the colon Secondary Endoscopic appearance of the colon *DUCS=Daily Ulcerative Colitis Scale for Children and Caregivers To be as brave as the people we help. © 2014 Shire Development LLC. All rights reserved 30 Process for Developing DUCS* • Concept Elicitation • Literature Review • Interviews with patients with UC in active and remission stage (8-17 y.o.) and parents/caregivers • Reached information saturation (i.e., the criterion that no new information is presented in the last patient interview) • Supportive information and confirm consistency for 5-7 y.o. • Healthcare professional interviews • Patient/parent on-line blogs • • Establishment of the Conceptual Framework for patients and parents/caregivers Create the questions for the eDiary • Cognitive Debriefing • • Determine that the items will be uniformly interpreted among patients and parents/caregivers Assess the content validity (i.e., clarity, relevance, and comprehensiveness of the diaries.) To be as brave as the people we help. *Developed with Oxford Outcomes – An ICON plc company © 2014 Shire Development LLC. All rights reserved 31 Conceptual Framework for PRO for DUCS (8-17 y.o.) To be as brave as the people we help. © 2014 Shire Development LLC. All rights reserved 32 Conceptual Framework for ObsRO – DUCS (5-10 y.o.) To be as brave as the people we help. © 2014 Shire Development LLC. All rights reserved 33 Example of the DUCS for the patient (PRO) To be as brave as the people we help. © 2014 Shire Development LLC. All rights reserved 34 Example of DUCS for the Parent/Caregiver (ObsRO) To be as brave as the people we help. © 2014 Shire Development LLC. All rights reserved 35 Next Steps for DUCS • Quantitative Stage done during Clinical Trial • Psychometric evaluation • The validity and reliability of the DUCS measures • Test with anchors (current health and global change) • Determine a responder definition • score change experienced by a patient over a time period, that reflects a meaningful improvement from the patient perspective To be as brave as the people we help. © 2014 Shire Development LLC. All rights reserved 36 Successful Labeling Based on Symptoms Reported in a PRO using the FDA guidance from 2009 • Clinical trial for Myelofibrosis : • Pre-specified Secondary endpoint: the proportion of patients with a reduction in the total symptom score of 50% or more from baseline to week 24, as assessed with the modified Myelofibrosis Symptom Assessment Form (MFSAF) • Clinical trial for Varicose Veins: • Primary efficacy endpoint: improvement in patient symptoms, as measured by the change from baseline to Week 8 in the 7day average electronic daily diary VVSymQ® score. The VVSymQ® score is a patient-reported outcome measure based on daily patient assessment of the varicose vein symptoms determined to be most important to patients: heaviness, achiness, swelling, throbbing, and itching. To be as brave as the people we help. © 2014 Shire Development LLC. All rights reserved 37 Pitfalls in Study Design that Affect Label • Keep endpoints as primary or key secondary • Example from the medical reviewer: “Dyspnea Domain: While CRQ was defined as a secondary endpoint for other international sites, in the US this endpoint was designated as an “other endpoint”. There Is no regulatory precedent for a claim based on this questionnaire” • Numerical improvement, not clinically important: • The results showed numeric improvements, however the differences did not exceed the minimal clinical important difference that is reported in the literature. • Instrument not “validated” to use for regulatory purposes • Multiplicity and hierarchical testing • To account for multiplicity, a step-down testing procedure based upon statistical significance for the previous tests in the hierarchy was used. If the symptomatic endpoints were after other efficacy measures that did not meet statistical significance, even if the symptoms showed significance they can not be used in the label. To be as brave as the people we help. © 2014 Shire Development LLC. All rights reserved 38 Useful Reference • Clinical Outcome Assessment Qualification Program • Qualification of COAs from the FDA • http://www.fda.gov/Drugs/DevelopmentApprovalProcess/ DrugDevelopmentToolsQualificationProgram/ucm28407 7.htm To be as brave as the people we help. © 2014 Shire Development LLC. All rights reserved 39