1. Perspectives on Clinical Outcomes of Studies of Products for Use in Cartilage Repair Marc C. Hochberg, MD, MPH Professor of Medicine Head, Division of Rheumatology University of Maryland School of Medicine Baltimore, MD, USA

2. Outline n FDA Guidance for Development of Products for the Treatment of OA n Newer methods for measuring symptomatic outcomes –State measures –KOOS n Newer methods for measuring structural outcomes

3. Guidance for Industry: Clinical Development Programs for Products Intended for the Treatment of Osteoarthritis Food and Drug Administration July 1999

4. Potential Claims for OA n Symptomatic treatment of pain and function n Delay in structural progression n Prevention of the occurrence of OA

5. Symptomatic Treatment of Pain and Function n Efficacy endpoints as specified in OARSI Recommendations and at OMERACT 3 –Pain and function should be disaggregated –Patient global assessment –Measurement of structure (x-ray) if trial lasts a year or more for risk-benefit assessment n Effects on non-signal joints and effects of potential confounders should be standardized in protocol and analysis

6. Delay in Structural Progression n Slowing in the loss of knee or hip joint space narrowing (JSN) using x-ray n Heirarchy of potential claims –Normalize the x-ray (theoretical) –Improve the x-ray –Slow [rate of] JSN by a prespecified amount The clinically relevant amount remains unknown –See diacerein trial (Dougados et al) for hip OA

7. Delay in Structural Progression n Does one need to demonstrate evidence of parallel symptom improvement? –No, if the x-ray normalizes or improves –Yes, if the rate of JSN is slowed relative to control (placebo) n Conclusion: –collect symptom endpoint regardless of the outcome anticipated

8. Prevention of Occurrence of OA n Defined as incident symptomatic OA using clinical and radiographic criteria –Additional joints in patients with prevalent OA –New joints in persons at risk for OA

9. Overall Risk-Benefit Assessment n Focus on safety database –ICH recommendations –Phase IV safety monitoring program may be needed

10. Measurement of clinical outcomes n WOMAC Osteoarthritis Index n Lequesne Algofunctional Index –GREES: Ann Rheum Dis 1996;55:552-7. –Altman et al: OA Cart 1996;4:217-26. –Bellamy et al: J Rheumatol 1997;24:799-802.

11. State Measures - 1 n OARSI Responder Criteria –Dougados et al: Osteoarthritis Cart 2000;8:395-403.

12. Dougados et al: Osteoarthritis Cart 2000;8:395-403. OARSI Response Criteria n Derived from analysis of data from 14 clinical trials of 1886 patients with either hip or knee OA –Randomized, double-blind, placebo- controlled parallel group trials –Variety of interventions Oral NSAIDs Oral and IA OA specific drugs

13. OARSI Response Criteria n Two sets of criteria (Propositions A and B) n Optimal cut-points differed by proposition, joint group, type of intervention, and “high” or “moderate” improvement n Requirement for both absolute and percent change n Limitations –62% of screened studies not included –Lack of simplicity –Increase in precision questionable –Not validated in other datasets

14. State Measures - 1 n OARSI Responder Criteria –Dougados et al: Osteoarthritis Cart 2000;8:395-403. n OMERACT-OARSI Responder Index –Pham T et al: J Rheumatol 2003;30:1648- 54

15. OMERACT-OARSI Responder Index n Objective: Development of a simplified set of criteria n Procedure: Compare performance of 6 different scenarios using two databases –Original database (14 studies with 1886 patients) –Revisit database (15 studies with 8164 patients) n Expert opinion approach applied to results at OMERACT 6 meeting

16. High improvement in pain or function > 50% and absolute change > 20 Responder YesNo Improvement in > 2 of the following 3 Pain > 20% with absolute change > 10 Function > 20% and absolute change > 10 PGA > 20% and absolute change > 10 ResponderNon-responder YesNo Pham T et al: J Rheumatol 2003;30:1648-54 OMERACT-OARSI Responder Index

17. Validation of the OMERACT-OARSI Responder Index: Responders Have Better Overall Health Status than Non-responders Marc C. Hochberg, Barker Bausell, Kevin Frick, Donald Steinwachs and Brian Berman University of Maryland School of Medicine and The Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA

18. Objective n To validate the OMERACT-OARSI Responder Index n Test the hypothesis that patients with knee OA participating in a clinical trial who fulfil the OMERACT-OARSI Responder Index will have better overall health status as measured by both arthritis-specific and general measures.

19. Patient Cohort n 570 patients with symptomatic knee OA enrolled in a randomized, 3-arm, 6- month, parallel group trial –Traditional Chinese acupuncture –“Sham” acupuncture –Education/attention control

20. Outcome Measures n WOMAC Osteoarthritis Index –Likert format n Patient Global Assessment n Health Assessment Questionnaire (HAQ) n Medical Outcomes Study (MOS) SF-36 n European Quality of Life (EuroQoL)

21. Data Analysis n Data from all 3 treatment groups pooled for this analysis n Responders identified using OMERACT- OARSI Responder Index –Pham T et al: J Rheumatol 2003;30:1648-54 n Outcomes in responders compared to those in non-responders using Students’ t-test n Analysis conducted on ITT population –Sensitivity analysis on completers only

22. Baseline Characteristics (N=570) n Age –Mean (SD) = 65.5 (8.6) years n Sex –Men (36%), Women (64%) n Race –White (69%), Black (29%), Other (2%) n Marital status: Married (60%) n Education: High-school graduates (91%)

23. Baseline Data (N=570) n WOMAC OA Index –Pain 43.5 (17.0) –Function 45.3 (17.6) –Total 45.6 (16.6) n HAQ –Pain 1.4 (0.7) –Disability 0.62 (0.41) n EuroQoL –EQ-5D 0.63 (0.22) –EQ-VAS 75.9 (16.7) n MOS SF-36 –Phys Funct 40.3 (22.3) –Role Phys 44.3 (40.1) –Bodily Pain 45.2 (19.9) –Gen Health 70.6 (17.9) –Role Emot 73.3 (37.5) –Vitality 54.2 (20.8) –Ment Heal 79.4 (14.2) –Social Act 79.3 (23.0)

24. Comparison of Outcomes by OMERACT-OARSI Response n 236 (41.4%) of 570 patients randomized achieved an OMERACT-OARSI Response at the end of study –61% of 386 completers

25. WOMAC Scores by OMERACT- OARSI Response

26. HAQ Scores by OMERACT- OARSI Response

27. EuroQoL Scores by OMERACT- OARSI Response

28. SF-36 Scores by OMERACT- OARSI Response

29. Comparison of Outcomes by OMERACT-OARSI Response n 234 (43%) patients randomized achieved an OMERACT-OARSI Response at the end of study –61% of patients completing the study n Responders had significantly better arthritis- specific and general health status than non- responders based on the WOMAC, HAQ, SF- 36 and EuroQoL instruments (P < 0.001 for all comparisons)

30. Conclusion n These data validate the OMERACT- OARSI Responder Index. –Results unchanged when analysis performed only with completers (N = 386) n OMERACT-OARSI Responder Index should be considered as primary outcome for clinical trials of symptomatic therapies in patients with OA.

31. State Measures - 2 n Minimal Clinically Important Improvement (MCII) –Smallest change in measurement that signifies an important improvement in a patient’s symptom –75%ile of distribution of change score among those who had good or excellent improvement with therapy Tubach F et al: Ann Rheum Dis 2005;64:29-33

32. State Measures - 2 n Patient Acceptable Symptom State (PASS) –Value in a measurement of a patient’s symptom beyond which the patient considers herself well –75%ile of distribution of absolute score among those who are satisfied with their current state after therapy Tubach F et al: Ann Rheum Dis 2005;64:34-7

33. State Measures in OA Patients n MCII –Pain 177 (33%) –Function 220 (41%) –Global 136 (25%) n PASS –Pain 241 (44%) –Function 221 (41%) –Global 177 (33%) Highly significant association between achieving an OMERACT-OARSI Response and having either an MCII or a PASS for each of the 3 domains, especially pain and function.

34. Measurement of clinical outcomes n WOMAC Osteoarthritis Index n Lequesne Algofunctional Index n Knee Injury and Osteoarthritis Outcome Score (KOOS) –Roos EM, Lohmander LS: HQLO 2003;I:64 http://www.hqlo.com/content/1/1/64

35. Knee Rating Scales for Athletic Patients n Modified Lysholm Scale n Cincinnati Knee Rating System n AAOS Sports Knee Rating Scale n ADL Scale of the Knee Outcome Survey n Single Assessment Numeric Evaluation n Knee Injury and OA Outcome Score n QoL Outcome Measure for Chronic ACL Def n International Knee Documentation Committee Marx RG: Arthroscopy 2003;19:1103-8

36. KOOS n Evaluates both short- and long-term consequences of knee injury n 42 items in 5 separately scored domains –Pain –Other symptoms –Function in daily living –Function in sport and recreation –Knee-related quality of life

37. KOOS n Validated in several populations –Surgical reconstruction of ACL –Knee arthroscopy –Meniscectomy 16 years previously –Total knee arthroplasty –Autologous cartilage transplantation

38. KOOS n Reliable n Responsive –Effect sizes > 1.0 for all 5 subscales in patients undergoing arthroplasty and tibial osteotomy –Effect sizes > 0.5 for all 5 subscales in patients undergoing ACL reconstruction and meniscectomy

39. KOOS vs. WOMAC n KOOS contains WOMAC pain, function and stiffness subscales (Likert v3.0) n KOOS adds 18 questions covering sport and recreational function, knee-related quality of life and other symptoms n Larger effect sizes with KOOS –Younger subjects with knee injury –Older subjects with total knee arthroplasty

40. Summary n There are numerous options for assessing clinically relevant outcomes in trials of products used for cartilage repair n KOOS is the recommended self-report measure of pain, function and QoL –“http://www.koos.nu”

41. Other Potential Clinical Outcomes n Time to joint replacement surgery n Time to indication for joint replacement surgery n Time to fulfil criteria for joint replacement surgery n Time to failure of therapy n Proportion of patients with success on Rx

42. Clinically relevant outcomes n Time to TJR –TJR is a cost-effective procedure –Recommended after failure of medical Rx –Limitations Variability in decision to perform TJR Length of surgical waiting lists (queue) Patient related factors, including willingness Racial/ethnic and gender disparities

43. Clinically relevant outcomes n Time to decision to perform TJR –Same limitations re: surgeon’s variability n Time to fulfil criteria to perform TJR –Objective scoring based on pain, loss of function and health-related QoL –Appropriateness criteria –Subject of a SIG during OMERACT 7 Maillefert JF et al: J Rheumatol; in press. Follow-up meeting was held in Paris 17/12/04

44. Clinically relevant outcomes n Time to treatment failure –Prespecified amount of joint space loss –Significant worsening of pain and/or function n Proportion of patients with success –Lack of loss of joint space by a prespecified amount –Clinically relevant improvement in pain and/or function

45. Prevention of the Occurrence of Incident OA n Definition of incident OA –Structural Arthroscopy Radiography MRI –Symptomatic

46. ACI Compared with Microfracture in the Knee n RCT: 80 patients followed for 2 years n Similar clinical outcomes –Lysholm and VAS pain score –Significant difference in SF-36 PCS favoring microfracture group n Similar structural outcomes –Arthroscopy –Histology of cartilage biopsies Knutsen et al: J Bone Jt Surg 2004;86-A:455-64

47. Thank you for your time and attention.