Development of the Crohn s Disease Patient-Reported Outcomes (CD-PRO) Questionnaire in Adults

Transcription

1 Development of the Crohn s Disease Patient-Reported Outcomes (CD-PRO) Questionnaire in Adults Peter D.R. Higgins Director, IBD Program University of Michigan 1

2 Disclosures Directly involved in developing CD-PRO and UC-PRO submitted to the FDA on 20 December, 2013 Funding for development of PROs from: CCFA Genentech Amgen 2

3 Why PROs? FDA mission: to advance safe and effective products Effective substantial evidence of achieving clinically meaningful endpoints Directly measure how a patient feels or functions Or increases survival 3

4 Endpoints Clinically Meaningful Endpoints Objective Survival, IBD flares, surgical resection Subjective: Symptom score (ClinRO), validated PRO Surrogate Endpoints In the therapeutic pathway between the drug and clinically meaningful endpoints Amazingmab Fewer Flares Improved PRO Active Crohn s Disease Mucosal Improvement 4

5 The Bar for Phase 3 Trials There must be substantial evidence of something that matters to patients. Primary endpoint of phase 3 trials should represent (directly or through a surrogate) something that matters to a patient. Patient reported outcome (PRO) instruments and composite endpoints may be used to establish a benefit that matters. 5

6 Preliminary Experience CCFA funded study of what matters to patients Focus groups Concept identification Developed conceptual framework, identified patient terms, initial concepts Limitations Single center Low diversity population 6

7 Preliminary Data In response to FDA PRO Guidance Plan to develop PROs for FDA submission Involvement of industry Formed IBD PRO Consortium 2011 Multiple centers Greater diversity Expanded documentation Preparation for FDA submissions 7

8 Initial Instrument Decisions Structure Modular not a single total score like CDAI Able to add/remove modules as needed Target population: patients with Crohn s disease Full range of disease activity All disease locations Full range of disease behavior, include B1/B2/ B3 Initially exclude Ostomy can t count BM or rely on consistency Fistula a distinct set of symptoms/issues Will need future specific modules 8

9 Conceptual Framework: Signs and Symptoms 9

10 Focus Groups Goals: Obtain a comprehensive list of the important aspects of their Crohn s disease experience Identify recurring concepts and patient vocabulary Identify the range and anchor terms Show consistency across populations in US Result: Long list of concepts, terms consistent across groups of patients 10

11 Focus Group Sites Ann Arbor Oakland Baltimore San Diego Chapel Hill 11

12 Concept Saturation 12

13 Sign and Symptom Concepts in Crohn s Disease Abdominal pain Consistency of BM Frequency of BM Blood in BM Need to have a BM right away Passing Gas Vomiting Weakness Tiredness Joint pain Loss of appetite Bloating Nausea Dehydration (thirst) 13

14 Input from Patients on Use Signs and symptoms are highly variable Record daily (FDA: 24 hour recall) Minimum of 3 days of data to get an accurate picture of current state It is hard to record daily data Reminders/alarms daily epro should be indestructible, waterproof, stool-proof, and too wide to flush down a toilet 14

15 Patient-Rated Concept Importance Importance Points Allocated by Patients Top 15 Most Important Concepts to CD Subjects 15

16 Problem (modifiable) Concepts Incontinence vs. experience Experienced patients prevent accidents # of stools vs. anti-diarrheals/not eating epro data on day of visit Consistently fewer BMs Modified for travel to visit 16

17 Additional Modules Not for Labeling Claims, but Important to Patients Slower to change, 1 week recall Completed only at study visits Schedule activities around BM Eat less to control BM Avoid foods to help control BM Only go where toilet nearby Carry change of clothes Stayed at home due to CD Coping Activities 17

18 Additional Modules Not for Labeling Claims, but Important to Patients Interfere with work/school Interfere with chores at home Interfere with activities for enjoyment Interfere with sleep Interfere with ability to concentrate Makes leaving home difficult Interferes with ability to travel Less interested in sex Difficult to plan several days ahead Impact on Daily Life 18

19 Additional Modules Not for Labeling Claims, but Important to Patients Feel alone Feel embarrassed Feel worried Feel scared Feel you have no control of your life Feel angry Feel frustrated Feel depressed Emotional Impact 19

20 epro format 20

21 epro in Practice Daily alarms, epro reminders Mean time 2.7 min (with 7 extra validation items) Rate of missing data: 0% missing (epro requires daily data) Rate of patient exit: 1% of patients dropped out before end of study No major complaints about epro burden Some would prefer as app on phone 21

22 Translation Translations available for 65 languages and cultures Performed by Oxford Outcomes with review by PDRH and iteration/back-translation 22

23 Languages and Cultures Country Language Country Language Country Language Argentina Spanish Israel* Arabic Singapore English Australia English Israel* Hebrew Singapore Malay Austria German Israel* Russian Singapore Chinese Belgium French Italy Italian Slovakia Slovak Belgium Dutch Latvia Latvian South Africa Afrikaans Brazil Portuguese Latvia Russian South Africa English Bulgaria Bulgarian Lithuania Lithuanian South Africa Zulu Canada English Malaysia English South Africa Xhosa Canada French Malaysia Chinese South Africa Sesotho Colombia Spanish Malaysia Tamil South Korea Korean Croatia Croatian Malaysia Malay Spain Spanish Czech Rep. Czech Mexico Spanish Sweden Swedish Denmark Danish Netherlands Dutch Switzerland French Estonia Russian New Zealand English Switzerland German Estonia Estonian Norway Norwegian Taiwan Chinese Finland Swedish Philippines English Turkey Turkish Finland Finnish Philippines Tagalog UK English France French Poland Polish Ukraine Russian Germany German Portugal Portuguese Ukraine Ukrainian Greece Greek Romania Romanian US Spanish Hong Kong Chinese Russia Russian Vietnam Vietnamese Hungary Hungarian Serbia Serbian 23

24 CD-PRO Qualification Timeline Milestone Jan-Mar Apr-Jun Jul-Sep Oct-Dec Jan-Mar Apr-Jun Jul-Sep Oct-Dec Jan-Mar Apr-Jun Jul-Sep Oct-Dec Jan-Mar Apr-Jun Jul-Sep Oct-Dec Letter of Intent (LOI) filed with FDA Received DDT # for CD-PRO/SS LOI finalized with FDA Completed qualitative studies Qualification submission (qualitative only) FDA acceptance of qualitative work 24

25 FDA Feedback on CD-PRO Qualitative Submission The qualitative research has been found adequate and no additional qualitative research has been requested. CDER has agreed that the appropriate patient population was studied. CDER has agreed that item content reflects the concepts and language from the qualitative studies. 25

26 CD-PRO Qualification Timeline 2 CDER has provided input on the CD quantitative validation study, which has been incorporated into the study design. Below are estimated dates for ongoing work: Milestone Jan-Mar Apr-Jun Jul-Sep Oct-Dec Jan-Mar Apr-Jun Jul-Sep Oct-Dec CD validation study Analysis of quantitative data Qualification submission (quantitative) 26

27 Endpoint Positioning for PRO Co-Primary Objective Measure of Inflammation - Endoscopy - Biomarkers? - MRE? PRO - CD-PRO - Temp PRO-2? 27

28 Next steps for CD-PRO Complete Quantitative Validation Study (phase 2 data) Item analysis, factor structure, Rasch, scoring, reliability and validity Endpoint Selection Response and Remission Cut points correlate with physician, patient definitions Cut points correlate with those used with prior instruments (CDAI 100, CDAI<150) Exploratory qualification by FDA for use in longitudinal studies Assess ability to detect change Identify responder definition(s) Provide guidelines for interpretation Pediatric validation Additional modules for: Patients with ostomies Patients with fistulizing disease 28

29 Summary CD-PRO (and UC-PRO) developed using FDA PRO guidance. Qualitative data accepted by FDA. Translated, in epro format. Quantitative data collection in progress. When qualified, available for wide use. 29

30 Thank you 30