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Perspectives on Clinical Outcomes of Studies of Products for Use in Cartilage Repair

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. Outline.

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Perspectives on Clinical Outcomes of Studies of Products for Use in Cartilage Repair

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  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 • FDA Guidance for Development of Products for the Treatment of OA • Newer methods for measuring symptomatic outcomes • State measures • KOOS • 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 • Symptomatic treatment of pain and function • Delay in structural progression • Prevention of the occurrence of OA

  5. Symptomatic Treatment of Pain and Function • 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 • Effects on non-signal joints and effects of potential confounders should be standardized in protocol and analysis

  6. Prevention of Occurrence of OA • 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

  7. Measurement of clinical outcomes • WOMAC Osteoarthritis Index • 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.

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

  9. OARSI Response Criteria • 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 Dougados et al: Osteoarthritis Cart 2000;8:395-403.

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

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

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

  13. OMERACT-OARSI Responder Index High improvement in pain or function > 50% and absolute change > 20 Yes No Responder • 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 Yes No Responder Non-responder Pham T et al: J Rheumatol 2003;30:1648-54

  14. 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

  15. Objective • To validate the OMERACT-OARSI Responder Index • 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.

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

  17. WOMAC Scores by OMERACT-OARSI Response

  18. HAQ Scores by OMERACT-OARSI Response

  19. EuroQoL Scores by OMERACT-OARSI Response

  20. SF-36 Scores by OMERACT-OARSI Response

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

  22. State Measures - 2 • 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

  23. State Measures - 2 • 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

  24. MCII Pain 177 (33%) Function 220 (41%) Global 136 (25%) PASS Pain 241 (44%) Function 221 (41%) Global 177 (33%) State Measures in OA Patients 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.

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

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

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

  28. KOOS • Reliable • 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

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

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

  31. Prevention of the Occurrence of Incident OA • Definition of incident OA • Structural • Arthroscopy • Radiography • MRI • Symptomatic

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

  33. Thank you for your time and attention.

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