Transcript Perspectives on Clinical Outcomes of Studies of Products

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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FDA Guidance for Development of
Products for the Treatment of OA
Newer methods for measuring
symptomatic outcomes
– State measures
– KOOS
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Newer methods for measuring
structural outcomes
Guidance for Industry:
Clinical Development Programs for
Products Intended for the Treatment
of Osteoarthritis
Food and Drug Administration
July 1999
Potential Claims for OA
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Symptomatic treatment of pain and
function
Delay in structural progression
Prevention of the occurrence of OA
Symptomatic Treatment of Pain
and Function
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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
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Effects on non-signal joints and effects of
potential confounders should be
standardized in protocol and analysis
Prevention of Occurrence of OA
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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
Measurement of clinical
outcomes
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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.
State Measures - 1
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OARSI Responder Criteria
– Dougados et al: Osteoarthritis Cart
2000;8:395-403.
OARSI Response Criteria
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Derived from analysis of data from 14
clinical trials of 1886 patients with either
hip or knee OA
– Randomized, double-blind, placebocontrolled parallel group trials
– Variety of interventions
• Oral NSAIDs
• Oral and IA OA specific drugs
Dougados et al: Osteoarthritis Cart 2000;8:395-403.
OARSI Response Criteria
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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
State Measures - 1
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OARSI Responder Criteria
– Dougados et al: Osteoarthritis Cart
2000;8:395-403.
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OMERACT-OARSI Responder Index
– Pham T et al: J Rheumatol 2003;30:164854
OMERACT-OARSI Responder
Index
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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)
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Expert opinion approach applied to results at
OMERACT 6 meeting
OMERACT-OARSI Responder Index
High improvement in pain or function > 50% and absolute change > 20
Yes
Responder
No
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
Responder
No
Non-responder
Pham T et al: J Rheumatol 2003;30:1648-54
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
Objective
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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.
Comparison of Outcomes by
OMERACT-OARSI Response
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236 (41.4%) of 570 patients randomized
achieved an OMERACT-OARSI
Response at the end of study
– 61% of 386 completers
WOMAC Scores by OMERACTOARSI Response
HAQ Scores by OMERACTOARSI Response
EuroQoL Scores by OMERACTOARSI Response
SF-36 Scores by OMERACTOARSI Response
Conclusion
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These data validate the OMERACTOARSI Responder Index.
– Results unchanged when analysis
performed only with completers (N = 386)
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OMERACT-OARSI Responder Index
should be considered as primary
outcome for clinical trials of
symptomatic therapies in patients with
OA.
State Measures - 2
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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
State Measures - 2
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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
State Measures in OA Patients
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MCII
– Pain
177 (33%)
– Function 220 (41%)
– Global 136 (25%)
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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.
Knee Rating Scales for Athletic
Patients
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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
KOOS
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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
KOOS
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Validated in several populations
– Surgical reconstruction of ACL
– Knee arthroscopy
– Meniscectomy 16 years previously
– Total knee arthroplasty
– Autologous cartilage transplantation
KOOS
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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
KOOS vs. WOMAC
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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
Summary
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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”
Prevention of the Occurrence of
Incident OA
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Definition of incident OA
– Structural
• Arthroscopy
• Radiography
• MRI
– Symptomatic
ACI Compared with
Microfracture in the Knee
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RCT: 80 patients followed for 2 years
Similar clinical outcomes
– Lysholm and VAS pain score
– Significant difference in SF-36 PCS
favoring microfracture group
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Similar structural outcomes
– Arthroscopy
– Histology of cartilage biopsies
Knutsen et al: J Bone Jt Surg 2004;86-A:455-64
Thank you for your time and
attention.