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. Thank you for your time and attention.