Perspectives on Clinical Outcomes of Studies of Products

for Use in Cartilage Repair

Marc C. Hochberg, MD, MPHProfessor of Medicine

Head, Division of Rheumatology

University of Maryland School of Medicine

Baltimore, MD, USA

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

Guidance for Industry:Clinical Development Programs for Products Intended for the Treatment

of Osteoarthritis

Food and Drug Administration

July 1999

Potential Claims for OA

Symptomatic treatment of pain and function

Delay in structural progression Prevention of the occurrence of OA

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

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

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.

State Measures - 1

OARSI Responder Criteria– Dougados et al: Osteoarthritis Cart

2000;8:395-403.

Dougados et al: Osteoarthritis Cart 2000;8:395-403.

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

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

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

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

High improvement in pain or function > 50% and absolute change > 20

Responder

Yes 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

Responder Non-responder

Yes No

Pham T et al: J Rheumatol 2003;30:1648-54

OMERACT-OARSI Responder Index

Thank you for your time and attention.