1. Value Based and Patient Reported Outcomes David N. Assis, MD Assistant Professor of Medicine Yale University

2. I have no disclosures relevant to this presentation.

3. Outline Value Based Medicine in PSC Patient Reported Outcomes (PRO) in PSC

4. Unmet Needs in PSC Surrogates Natural History Diagnostics Therapy Screening Surveillance Disease Mechanisms

5. Need for improved evidence! AASLD GuidelinesPBCPSC Year of latest guideline20092010 Recommendations (#)1536 Grade I33%17% Grade II33%61% Grade III33%22% Koh C, et al. Hepatology 2013;58:2142-2152.

6. Value

7. Value Based Medicine Healthcare Value = Outcome Cost Porter. N Engl J Med 2010; 363:2477-2481.

8. Value Based Medicine in PSC? How to define Value in PSC? – Rare disease – Heterogeneous phenotype – No proven effective therapy – Unclear Natural History – No current clinical trial endpoint Fabris et al. EASL 2015 [Abstract #1169].

9. Value Based Medicine in PSC? Collaboration of Italian Centers –University of Milan-Bicocca Selection of Outcome Indicators – Expert Consensus by Delphi Method Fabris et al. EASL 2015 [Abstract #1169].

10. Value Based Medicine in PSC? Proposed Outcome Indicators: –Mortality rate Those not yet listed for transplant –Death from cancer Bile duct, colon –Worsening of Osteoporosis –Rate of Cholangitis –Improvement in Quality of Life Fabris et al. EASL 2015 [Abstract #1169].

11. Value Based Medicine in PSC? Proposed Outcome Indicators: –Mortality rate Those not yet listed for transplant –Death from cancer Bile duct, colon –Worsening of Osteoporosis –Rate of Cholangitis –Improvement in Quality of Life Fabris et al. EASL 2015 [Abstract #1169].

12. –Short form 36 (SF-36) –Chronic liver disease questionnaire (CLDQ) –Fatigue impact scale –Hospital anxiety and depression scale –Patient health questionnaire –Mayo score –Psychological general well-being index –Fatigue impact scale Quality of Life in PSC

13. Learn from PBC! PBC-40 Tool –Patient-derived –Qualitative research –Item saturation –6 Domains Symptoms, Itch, Fatigue, Cognition, Social, Emotional Jacoby, et al. Gut 2005;54:1622–1629.

14. Patient Reported Outcome (PRO) A tool developed to directly measure the patient’s view of their health Iterative Process (takes time!) Development specific to the disease Allows for assessment of the effect of a medical intervention –Must show change over measurable time! FDA Guidance on PRO development

15. Patient Reported Outcome in PSC PSC is Heterogeneous –Multiple PSC Categories Large-Duct Small Duct IBD vs. no IBD –Early vs. late stage –Episodic nature of some symptoms –Age, gender, ethnic and cultural groups

16. Patient Reported Outcome in PSC A PRO in PSC will be useful if developed and tested on the demographic of interest North America Ethnically diverse Age range Disease range

17. Patient Reported Outcome in PSC Areas of Partnership between Patient Organizations and IPSCSG –Promotion of Patient Oriented Research –Development of a novel PRO Tool

18. Quality of Life in PSC PSC Partners Patient Registry (N=607) –Pruritus: 61% Average Intensity of 3.7 + 2.7 (1-10) –Abdominal Pain: 64% Average intensity of 1.7 + 0.9 (1-4) Safer, et al. Hepatology; 2015 AASLD Abstract #630.

19. Patient Reported Outcome in PSC Survey of PSC Partners Registry Patients Facebook comments (qualitative) March 2016 –Survey shared with FDA

20. Patient Reported Outcome in PSC April – May 2016 –Quantification of key symptoms via ATLAS Utilization of PROMIS ® tool format NIH Patient-Reported Outcomes Measurement Information System June 2016 –Follow up Survey to Registry Patients

21. 450 participants 381 participants 69 participants excluded (incomplete data) PSC Partners Patient Registry: 850+

24. Questions With regard to your PSC, over the past month… Pain, Fever/Chills, Quality of Life, Isolation and Depression, Sleep, Anxiety and Worry, Itching, Fatigue

25. Pain With 0 being no abdominal pain and 10 being the worst abdominal pain imaginable, in the past month, I would rate my abdominal pain on average to be...

26. Fever and Chills In the past month I have felt chills and fevers... 0- Never 1- Rarely 2- Sometimes 3- Often 4- Always

27. Quality of Life In the past month, I would say my quality of life is... 1- Poor 2- Fair 3- Good 4- Very Good 5- Excellent

28. Isolation and Depression In the past month I found that things in my life were overwhelming... In the past month I felt emotionally exhausted... 1- Never 2- Rarely 3- Sometimes 4- Often 5- Always

29. Sleep In the past month my sleep was restful... In the past month stress disturbed my sleep... 1- Never 2- Rarely 3- Sometimes 4- Often 5- Always

30. Anxiety and Worry In the past month I felt anxious... In the past month I felt worried... 1- Never 2- Rarely 3- Sometimes 4- Often 5- Always

31. Pruritus In the past month, on a scale of 0-10 with 0 being no itch and 10 being maximum itching I would rate my itching right now as...

32. Pruritus Itching disturbed my sleep in the past month... I felt embarrassed because of the itching in the past month… 0- Never 1- Rarely 2- Sometimes 3- Often 4- Always 5- N/A

33. Fatigue In the past month my level of fatigue on most days was.... 0- None 1- Mild 2- Moderate 3- Severe 4-Very severe

34. Fatigue In the past month I often felt run down... In the past month I often felt tired even when I have not done anything... In the past month I often was bothered by my fatigue... 1- Never 3- Rarely 3- Sometimes 4- Often 5- Always

35. PSC: with vs. without IBD 96 patients without IBD Patients with IBD reported more pain (p=0.0134)

36. PSC: Male vs. Female Female participants (N=190): Higher level of pain (p=0.001) More isolated (p=0.008) More helpless (p=0.0391) More emotionally exhausted (p=0.029) More upset (p=0.03) More itching interrupting sleep (p=0.017) More embarrassed itching (p=0.005) More run down (p=0.001) More fatigue (p=0.0241)

37. PSC: Caucasian vs. other races Other races (n=24): –More helpless (p=0.04) –More overwhelmed (p=0.01) –More emotionally exhausted (p=0.031) –More anxious (p=0.041) –More fatigue (p=0.04)

38. We need a PRO in PSC! –Understand and validate patient symptoms –Promote development of new Treatments that include Patient-Oriented Outcomes –Collaborative Process Patients and Patient Organizations International Centers Industry Partners FDA

39. Thank you Yale Liver Center Dr. Kim To Dr. Mario Strazzabosco Dr. James Boyer PSC Partners Seeking a Cure Rachel Gomel Ricky Safer Meegan Carey

40. Every Wall is a Door Ralph Waldo Emerson