Assessment Methodology: Lessons from OMERACT Meetings Vibeke Strand, MD Biopharmaceutical Consultant...

Assessment Methodology:

Lessons from

OMERACT Meetings

Vibeke Strand, MDBiopharmaceutical Consultant

Adjunct Clinical Professor, Division of Immunology, Stanford University

OMERACT: Outcome Measures in

Rheumatology Clinical Trials• I: 1992: Rheumatoid Arthritis Clinical Trials

• II: 1994: Adverse Events → Establishment of Registries

Health Related Quality of LifeEconomic Evaluations

• III: 1996: OsteoarthritisOsteoporosisPsychosocial Measures

• IV: 1998: Longitudinal Observational StudiesRA Response Criteria / Imaging Ankylosing Spondylitis → ASASSystemic Lupus Erythematosus

• 5: 2000: MCIDEconomics: Cost EffectivenessImaging: Radiography and MRI

• 6: 2002: Economic EvaluationsImaging

What is OMERACT?

• Data driven process to define outcome measures to be used in RCTs and LOS for each clinical indication

• Domains derived from the “Ds”: DiscomfortDisabilityDollar costDeath

• Literature reviews, data available from LOS and RCTs:

• Validity of currently defined instruments to assess outcome

• “Data mining” to better understand clinical response

• Correlation of patient reported responses with other outcome measures

• Definition of “minimally clinically important improvement”= MCID

What is OMERACT?

• Presentation of evidence and development of consensus at each conference: Representatives from: Academia, Clinical Investigators,

Regulatory Agencies, Sponsors, Clinical Rheumatologists

• Goal: To Develop Recommendations for:

• “Core Set” of minimum number of domains / outcome measures assessed in RCTs and LOS

• Working agenda identifying ‘need’ to focus future work

• Previous OMERACT Recommendations have been ratified by WHO / ILAR in RA, OA, SLE, including HRQOL and

Economic evaluations

The OMERACT ‘Umbrella’

OSTEOARTHRITIS: OARSI

ANKYLOSING SPONDYLITIS: ASAS

PAIN:

IMMPACT

RHEUMATOID ARTHRITIS:EULARACR

JRA:PRCSG

SLE: SLICC EULAR

The OMERACT Filter

• TRUTH: Face, content, construct and criterion validityIs the measure truthful?Does it measure what is intended?

• DISCRIMINATION: Reliability and sensitivity to changeDoes the measure discriminate between situations

[states] of interest?

• FEASIBILITY: Can the outcome easily be measured given

constraints of time, money and interpretability?

Boers et al: JRheum 1998: 25: 198-9

Rheumatoid Arthritis: OMERACT I, 1992

• RCTs available, but data limited• Only a few included a measure of physical function• General ‘belief’ that none had demonstrated convincing

efficacy

• “Paper patients” derived from actual RCT data

• → [healthy] arguments regarding changes reported• Clear disagreement about importance of MD

Global assessments• Participants ranked patient reported physical

function and SJC highest when assessing efficacy

• Facilitated recognition that ‘perception’ of benefit variable

ACR Response CriteriaACR Response Criteria

• Defined and Ratified after OMERACT IData driven nominal group process

• Based on Paulus criteria and statistical analyses of CSSRD and MTX RCTsbest differentiating active therapy from placebo

• Require ≥20% improvement in 5 of 7 measures:

• Tender Joint Count and Swollen Joint Count

• and 3 of the following 5: MD Global Physical function: HAQ

Pain by VASPatient GlobalESR and/or CRP

• Defined and Ratified after OMERACT IData driven nominal group process

• Based on Paulus criteria and statistical analyses of CSSRD and MTX RCTsbest differentiating active therapy from placebo

• Require ≥20% improvement in 5 of 7 measures:

• Tender Joint Count and Swollen Joint Count

• and 3 of the following 5: MD Global Physical function: HAQ

Pain by VASPatient GlobalESR and/or CRP

EULAR Response Definition

>3.2 and ≤5.1

>5.1

≤3.2

DAS28 Score>1.2 ≤0.6>0.6 to ≤1.2

Decrease in DAS28

Good

Moderate

None

Van Gestel et al. Arth Rheum 1996; 26:705-11

DIscriminant function analysis of patients w/active; inactive RADisease activity state determined by treatment changes

As Demonstrated in RA, Responder Analyses

Have Face and Content Validity

As Demonstrated in RA, Responder Analyses

Have Face and Content Validity

• Allow assessment of multiple domains

• Facilitate comparison of efficacy across:• Products• Heterogeneous populations, and• Disease indications

• May lead to tiered approach to label indications

• Precedent: ACR Responder Index in RA DAS28 both confirms active disease

at baseline and ‘clinical responses’ Additional data by x-ray and HRQOL

• Allow assessment of multiple domains

• Facilitate comparison of efficacy across:• Products• Heterogeneous populations, and• Disease indications

• May lead to tiered approach to label indications

• Precedent: ACR Responder Index in RA DAS28 both confirms active disease

at baseline and ‘clinical responses’ Additional data by x-ray and HRQOL

Rheumatoid Arthritis: Later Efforts

• Demonstrated that ‘generic’ measures of HRQOL sensitive to change in RA RCTs

• Identified ‘MCID’ for HAQ and SF-36……facilitating:

• Comparisons across products, disease populations

• Economic evaluations

• Helped to show impact of ‘Rheumatic Diseases’ to WHO

• In this Bone and Joint Decade

• Identified importance of Rheumatic Diseases relative to CV, DM, HTN, OP….

• [Hopefully] → allocation of more resources toidentify and treat Rheumatic Diseases…..

Minimum Clinically Important Differences

[MCID]

Minimum Clinically Important Differences

[MCID]

• Degree of improvement

• Perceptible to patients = clinically important/ meaningful

• Defined by patient query, delphi techniqueOMERACT: 33-36% improvement;18% > placebo

• Confirmed by statistical correlations with patient global assessments in RCTs in RA and OA

• Determination of proportion of patients with clinically important improvement provides a more interpretable result with direct clinical implications

• Degree of improvement

• Perceptible to patients = clinically important/ meaningful

• Defined by patient query, delphi techniqueOMERACT: 33-36% improvement;18% > placebo

• Confirmed by statistical correlations with patient global assessments in RCTs in RA and OA

• Determination of proportion of patients with clinically important improvement provides a more interpretable result with direct clinical implications

1 Guzman et al. Arth Rheum. 1996; 39:5208 2 Kosinski et al. Arth Rheum. 2000; 43:1478-873 Redelmeier et al. Arch Intern Med. 1993; 153:1337-424 Wells et al. J Rheumatol. 1993; 20:557-605 Kosinski et al. Arth Rheum. 2000; 43:S140 6 Samsa et al. Pharmacoeconomics. 1999; 15:141-155 7 Thumboo et al. J Rheumatol. 1999; 26:97-102.

Minimum Clinically Important Differences

[MCID]

HAQ DI 1-4 0 - 3 – 0.22

SF-36 2, 5-7 0 - 100 + 5 - 10 points

PCS/MCS mean 50 ± 10 + 2.5 - 5 points

HAQ DI 1-4 0 - 3 – 0.22

SF-36 2, 5-7 0 - 100 + 5 - 10 points

PCS/MCS mean 50 ± 10 + 2.5 - 5 points

Score Direction MCIDRange of Scoring Literature

Score Direction MCIDRange of Scoring Literature

Health Assessment Questionnaire (HAQ)Health Assessment Questionnaire (HAQ)

• Widely accepted, validated, rheumatology-specific

instrument to assess physical function in RA

• Gold Standard: OMERACT/FDA Guidance

• 20 questions covering 8 types of activities

Dressing + Grooming; Arising; Eating; Walking;

Hygiene; Reaching; Gripping, Activities of Daily Living

• HAQ Disability Index (HAQ DI)

• Scores the worst items within each of the eight scales

• Based on use of aids and devices

• Widely accepted, validated, rheumatology-specific

instrument to assess physical function in RA

• Gold Standard: OMERACT/FDA Guidance

• 20 questions covering 8 types of activities

Dressing + Grooming; Arising; Eating; Walking;

Hygiene; Reaching; Gripping, Activities of Daily Living

• HAQ Disability Index (HAQ DI)

• Scores the worst items within each of the eight scales

• Based on use of aids and devices

Mean Improvement in HAQ Disability Index

Year-2 Cohorts at 24 Months

Improvement

Worsening

Mea

n C

han

ge

fro

m B

asel

ine

LEF MTX

US301 MN302/304

SSZ

MN301/303/305

*LEF vs MTX; p=0.01

-1

-0.5

0

-0.22

-0.73

-0.56

-0.6

-0.37

-0.48 -0.56

*

(248) (273)(51) (46)(97) (101)

% Achieving MCID 84% 69% 86% 82% 74% 78%

ATTRACT: HAQ Disability Index

Mean Improvement through Week 102Mean Improvement through Week 102

MTX + PlaceboMTX + Placebo 3 mg/kgq8w

3 mg/kgq8w

3 mg/kgq4w

3 mg/kgq4w

10 mg/kgq8w

10 mg/kgq8w

10 mg/kgq4w

10 mg/kgq4w

< 0.001< 0.001 < 0.001< 0.001 < 0.001< 0.001 < 0.001< 0.001p-value vs. MTX + Placebop-value vs. MTX + Placebo

0.2

0.4

0.5 0.5

0.40.45

0

0.1

0.2

0.3

0.4

0.5

Allinfliximab

Allinfliximab

Mea

n i

mp

rove

men

tM

ean

im

pro

vem

ent

ERA: Mean Change in HAQ DI at Month 12

-0.80Me

an

Ch

an

ge

fro

m B

L

MTX

ETN

-0.70-0.8

-0.7

-0.6

-0.5

-0.4

-0.3

-0.2

-0.1

MCID

Baseline HAQ DI: 1.6 1.6

Kosinski et al. AJMC. 2002;8:231-240

Mean Changes in HAQ DI at Weeks 24 and 52

Anakinra+MTX

-0.18 -0.15

-0.29 -0.28

-0.8

-0.7

-0.6

-0.5

-0.4

-0.3

-0.2

-0.1

0.0

Me

an

Ch

an

ge

fro

m B

ase

line

Placebo+MTX

Anakinra+MTX

24 weeks 52 weeks

MCID

Baseline: 1.38 Placebo 1.43 Active

Fleishman et al. Arth Rheum. 2002;46:S574.

Mean Changes in HAQ DI at Weeks 24 and 52

DE019: Adalimumab+MTX

-0.24 -0.25

-0.6 -0.61-0.56 -0.59

-0.8

-0.7

-0.6

-0.5

-0.4

-0.3

-0.2

-0.1

0.0

Me

an

Ch

an

ge

fro

m B

ase

line

Placebo BL 1.48

Adalimumab 20 mg weekly BL 1.45

Adalimumab 40 mg eow BL 1.44

24 weeks 52 weeks

MCID

Keystone E. Arthritis & Rheum 2002; 46(9) suppl.

Mean Changes in HAQ DI from Weeks 30 to 54

ASPIRE RCT

-0.79-0.75M

ea

n C

ha

ng

e fr

om

BL

; W

ks

30

-54

MTX

MTX+INF 3 mg/kg

MTX+INF 6mg/kg

-0.78

-0.8

-0.7

-0.6

-0.5

-0.4

-0.3

-0.2

-0.1

MCID

Baseline HAQ DI: 1.5 1.5 1.5

% Achieving MCID: 65 76 76Smolen et al. Ann Rheum Ds 2003;62:S64

Mean Changes in HAQ DI at Weeks 52

TEMPO RCT

-0.97

-0.61

Me

an

Ch

an

ge

fro

m B

L

MTX

ETNMTX+ETN

-0.66

-0.8

-0.7

-0.6

-0.5

-0.4

-0.3

-0.2

-0.1

MCID

Baseline HAQ DI: 1.7 1.7 1.8

-0.9

-1.0

SF-36: Short Form 36 Health Survey

• Validated, widely used generic measure of HRQOL• 8 Domains:

• Scored 0 - 100; age, sex adjusted rates• 2 Summary Scores

• Physical Component: PCS– Measures how decrements in physical function

affect day to day activities– Impact of physical impairment/disability on

HRQOL• Mental Component: MCS

– Impact of mental affect, symptoms of pain on HRQOL

• Normative based scoring (Mean: 50, SD: 10)

• Validated, widely used generic measure of HRQOL• 8 Domains:

• Scored 0 - 100; age, sex adjusted rates• 2 Summary Scores

• Physical Component: PCS– Measures how decrements in physical function

affect day to day activities– Impact of physical impairment/disability on

HRQOL• Mental Component: MCS

– Impact of mental affect, symptoms of pain on HRQOL

• Normative based scoring (Mean: 50, SD: 10)

SF-36 Two-Component ModelSF-36 Two-Component Model

PhysicalComponent

MentalComponent

PhysicalFunction

RolePhysical

BodilyPain

GeneralHealth

VitalitySocial

FunctionRole

EmotionMentalHealth

US 301: Baseline SF-36 Scores

US Norms vs US301 Population

US 301: Baseline SF-36 Scores

US Norms vs US301 Population

0PhysicalFunction

RolePhysical

BodilyPain

GeneralHealth

Perception

Vitality SocialFunction

RoleEmotion

MentalHealth

Study US301 PopulationUS Norms (A/S Adjusted)

10

20

30

40

50

60

70

80

90

100

US301: Mean Improvement in SF-36: Year-2

Cohorts Leflunomide and Methotrexate

US301: Mean Improvement in SF-36: Year-2

Cohorts Leflunomide and Methotrexate

BetterBetter

Mea

n S

core

s

Physical Role Bodily General Vitality Social Role MentalFunction Physical Pain Health Function Emotion Health

Perception

Physical Role Bodily General Vitality Social Role MentalFunction Physical Pain Health Function Emotion Health

Perception

0

10

20

30

40

50

60

70

80

90

LEF 24 Months (n = 93)LEF 24 Months (n = 93)

MTX 24 Months (n = 89)MTX 24 Months (n = 89)US Norms (A/S Adjusted)US Norms (A/S Adjusted)

Baseline Year-2 CohortBaseline Year-2 Cohort

35 PlaceboAdalimumab (40 mg) QOW

5.2

13.5

8.2

14.6

28.1

23.3

0

5

10

15

20

25

30

Me

an

Ch

an

ge

Fro

m B

as

elin

e

3.5

8.7 9.0

16.9

7.5

13.4

5.2

15.5

2.3

6.7

Mean Changes in SF-36 Scores

DE019: Adalimumab+MTX

MCID

Vitality

Physical Functio

ning

Physical Role

Bodily Pain

General Health

Social Functio

ning

Emotional H

ealth

Mental Health

Keystone E. Arthritis & Rheum 2002; 46 suppl.

Leflunomide and Methotrexate: Mean

Changes in SF-36 PCS Year-2 Cohort (US301)

60

US Norm

2 SDs below

US Norm

LEF (93) MTX (97)

BL 12 M 24 M BL 12 M 24 M

Impr

oved

Mea

n S

core

s

0

10

20

30

40

50

30.9

42.7 41.7

30.2

38.6 38.8

Etanercept and Methotrexate: Mean Changes

SF-36 PCS at 12 Months (ERA)

60

US Norm

2 SDs below

US Norm

Impr

oved

Mea

n S

core

s

0

10

20

30

40

50

BLBL 12M12M

Kosinski et al. AJMC. 2002;8:231-240.

ETN 25mg (193) MTX (199)

28.0

38.7

29.2

38.8

Infliximab: Median Improvement in SF-36 PCS

at Month 24 (ATTRACT)

Baseline: 23.9 –30.8

Kavanaugh et al. Arth Rheum. 2000;43:S147.

p-value vs. placebo

MTX + Placebo(n=88)

3 mg/kgq 8 wks

(n=86) 0.011

3 mg/kgq 4 wks

(n=86) <0.001

10 mg/kgq 8 wks(n=87)

<0.001

10 mg/kgq 4 wks

(n=81)<0.001

Med

ian

(IQ

R)

0

4

8

12

16

2.8

4.6

6.8 6.9 6.7

Anakinra+MTX: Mean Improvement in SF-36

PCS at Month 12

Baseline: 29.9 PL28.8 Active

Fleishman et al. Arth Rheum. 2002;46:S574.

Correlation Between HAQ and SF-36

Reference Study Scales Correlation

Ruta 1 — PCS -0.77

Talamo 2 — PF -0.72

Kavanaugh 3 Infliximab/ATTRACT PCS -0.51PF -0.54

Kosinski 4 Etanercept/ERA PCS -0.60PF -0.61

Lubeck 5 Etanercept/RAPOLO PCS -0.79PF -0.82

Strand 6 Leflunomide/US301 PCS -0.60PF -0.74

1 Ruta et al. Br J Rheum. 1998;37:425-436.2 Talamo et al. Br J Rheum. 1997;36:463-469.3 Kavanaugh et al. A&R. 2000;43:S147.4 Kosinski et al. Medical Care. 1999;37:MS23-39.5 Lubeck et al. Value in Health. 2001;4:MS2,163.6 Strand et al. A&R. 2001;44:S187.

MCID Values Are Consistent in RCTs in RA

• Improvements in HAQ DI and SF-36 in RA

with newly approved therapies are statistically

significant; more importantly, CLINICALLY

MEANINGFUL

• MCID values are consistent across agents and patient

populations

• Disease specific [‘relevant’] measure: HAQ

• Generic measure: SF-36

• Improvements in disease specific highly correlated

with generic measures

• Improvements in HAQ DI and SF-36 in RA

with newly approved therapies are statistically

significant; more importantly, CLINICALLY

MEANINGFUL

• MCID values are consistent across agents and patient

populations

• Disease specific [‘relevant’] measure: HAQ

• Generic measure: SF-36

• Improvements in disease specific highly correlated

with generic measures

MCID Workshop: Identifying Candidate Measures

to Define ‘Low Disease Activity State’

• Pain

• Function

• Inflammation

• Health Related Quality of life

• Structure damage

• Toxicity

• Co-morbidity

• Fatigue

Osteoarthritis

• OMERACT III: 1996

• Candidate instruments to assess:• Pain• Stiffness• Physical Function

• Limited data from RCTs; treatments offering only symptomatic benefit

• Identification of a ‘Core Set’ of 4 Domains as a foundation for future work

• Research Agenda: Identification of ‘Disease Control’, ‘Biologic Markers’ of Response

Western Ontario and McMaster Universities

(WOMAC) Osteoarthritis Index

• Self-administered questionnaire

• Developed querying patients with hip or knee OA

• Reflects physical activities most affected by symptoms, disease manifestations

• Composite score based on 24 questions; subscores:

• Pain (5 questions)

• Joint stiffness (2 questions)

• Physical function (17 questions)

• Scored by 0 - 4 Likert or 0 - 10 cm VAS scales

• Improvement = negative change

• Self-administered questionnaire

• Developed querying patients with hip or knee OA

• Reflects physical activities most affected by symptoms, disease manifestations

• Composite score based on 24 questions; subscores:

• Pain (5 questions)

• Joint stiffness (2 questions)

• Physical function (17 questions)

• Scored by 0 - 4 Likert or 0 - 10 cm VAS scales

• Improvement = negative change

BIOLOGIC MARKERS

HRQOL / UTILITY

PAINPAINPHYSICAL PHYSICAL FUNCTIONFUNCTION

PATIENT GLOBALPATIENT GLOBALIMAGING (≥1YR)IMAGING (≥1YR)

INFLAM-MATION

Placement Consequence

INNER Core CORE SET

MIDDLE Core HRQOL/ Utility (Strongly Recommended)

OUTER Core OPTIONAL

Placement Consequence

INNER Core CORE SET

MIDDLE Core HRQOL/ Utility (Strongly Recommended)

OUTER Core OPTIONAL

≥ 90%

≥30% - <90%

0% - <30%

≥ 90%

≥30% - <90%

0% - <30%

% Voting for inclusion% Voting for inclusion

8%8%36%36%90%90%

OTHER Eg, Performance based Flares Time to Surgery Analgesic Count

MD GLOBALMD GLOBAL

STIFFNESS

Pain: WOMAC pain / stiffness subscalesDifferentiating pain from stiffness

Physical function: WOMAC physical function subscale

Patient Global Assessment: How to phrase question?Signal jointIn all the ways arthritis affects you, how are you

doing today?Transition question

HRQOL/Utilities: WOMAC Composite ScoreSF-36EQ5D / Utilities

MD Global Assessment

Pain: WOMAC pain / stiffness subscalesDifferentiating pain from stiffness

Physical function: WOMAC physical function subscale

Patient Global Assessment: How to phrase question?Signal jointIn all the ways arthritis affects you, how are you

doing today?Transition question

HRQOL/Utilities: WOMAC Composite ScoreSF-36EQ5D / Utilities

MD Global Assessment

Outcome Measures in OA: OARSI GuidelinesOMERACT Core Set and ‘Strongly Recommended’

WOMAC Scores in OA RCTs: Identifying MCID

• MCID in WOMAC composite score, Likert scale:

• Anchored to Patient Global Assessment

• 12 wk pivotal OA RCTs with Celecoxib: 10.1 [0 – 89]

• Pain, Stiffness, Physical Fxn: 2.1, 1.2, 6.5[0 – 20] [0 – 8] [0 – 61]

• MCID in WOMAC VAS:

• Anchored to Patient Response to Rx [0-4 Likert scale]

• 6 wk RCTs OA hip, knee; Rofecoxib v Ibuprofen v PL:

• Pain, Stiffness, Physical Fxn: 9.7, 10, 9.3 mm, VAS

• 11 mm VAS for Patient Global Assessment

• MCID in WOMAC composite score, Likert scale:

• Anchored to Patient Global Assessment

• 12 wk pivotal OA RCTs with Celecoxib: 10.1 [0 – 89]

• Pain, Stiffness, Physical Fxn: 2.1, 1.2, 6.5[0 – 20] [0 – 8] [0 – 61]

• MCID in WOMAC VAS:

• Anchored to Patient Response to Rx [0-4 Likert scale]

• 6 wk RCTs OA hip, knee; Rofecoxib v Ibuprofen v PL:

• Pain, Stiffness, Physical Fxn: 9.7, 10, 9.3 mm, VAS

• 11 mm VAS for Patient Global Assessment

Ehrich et al: JRheum 2000;27: 2635-2641

Zhao et al. Pharmacother 1999;19:1269-78

0

2

4

6

8

10

12

14

CT20: knee CT21: knee CT54: hip

Placebo Cel 50 Cel 100 Cel 200 Nap 500

Improvement in WOMAC Composite Scores at

Week 12 : Pivotal OA RCTs, Celecoxib

Imp

rove

d S

core

s

* P <.05 v placebo

*

**

*

*

*

*

*

*

*

*

*

MCID = 10.1 (SE=0.4)

Zhao et al Pharmacother 1999;19:1269-78

WOMAC Physical Function Subscale, knee or

hip OA at 12 months: Pivotal RCT, Rofecoxib

R = randomizationP < 0.05 for all groups; treatment response compared with baseline Cannon GW, et al. Arthritis Rheum. 2000;43:978–987.

R = randomizationP < 0.05 for all groups; treatment response compared with baseline Cannon GW, et al. Arthritis Rheum. 2000;43:978–987.

Mea

n C

han

ge

(mm

)M

ean

Ch

ang

e (m

m)

-30-30

-35-35

-25-25

-20-20

-15-15

-10-10

-5-5

00

RR 22 44 88 1212 2626 3939 5252

WeekWeek

Rofecoxib 12.5 mg

Rofecoxib 25 mg

Diclofenac 150 mg

Rofecoxib 12.5 mg

Rofecoxib 25 mg

Diclofenac 150 mg

Mean baseline = 69.6 mmMean baseline = 69.6 mm

MCID = 9.3

SF-36 in Osteoarthritis RCTsSF-36 in Osteoarthritis RCTs• Truth or Validity

• Domains, especially Bodily Pain discriminated differences/ changes in symptoms over time

• Closer correlation with patient assessed outcomes

• Feasibility or Reliability

• Ceiling effects minimal; floor effects for RP and RE domains

• Able to detect effects of arthritis in community sample

• Discrimination or Responsiveness

• In longitudinal tests, BP domain and PCS summary score most responsive, even within 2-6 weeks

• Valid and responsive measure of TKR, esp long term

• Short term treatment → significant improvement in MCS

• Truth or Validity

• Domains, especially Bodily Pain discriminated differences/ changes in symptoms over time

• Closer correlation with patient assessed outcomes

• Feasibility or Reliability

• Ceiling effects minimal; floor effects for RP and RE domains

• Able to detect effects of arthritis in community sample

• Discrimination or Responsiveness

• In longitudinal tests, BP domain and PCS summary score most responsive, even within 2-6 weeks

• Valid and responsive measure of TKR, esp long term

• Short term treatment → significant improvement in MCSBrooks et al, A+R 1997; 40:S110

Ehrich et al: JRheum 2000;27: 2635-2641

Ware et al: A+R 1996; 39:S90

Bellamy et al, A+R 2000; S221

Ware et al: A+R 1996; 39:S90

Hill et al: JRheum 1999; 26:2029-35

0

5

10

15

20

25

US Norms Rofecoxib

PF RP PAIN GHP VITAL SOC RE MH

Mean Improvement in SF-36: All Rofecoxib

v Normative Data US Population

Mean Improvement in SF-36: All Rofecoxib

v Normative Data US Population

Imp

rove

me

nt

Difference between ages 45-54 and 55-64

US population. Ware et al 1993

-1

4

9

14

19

24

PF RP BP GH VT SF RE MH

Placebo Cel 50 Cel 100 Cel 200 Nap 500

Change in SF-36 Scores at Week 12: OA of knee

Pivotal Trial with Celecoxib

*

**

*

**

*

**

* *

*

* * **

*

*

*

* p < .05 v placebo

Use of WOMAC and SF-36 in RCTs of OA

Conclusions Based on the COX-2 Experience

Use of WOMAC and SF-36 in RCTs of OA

Conclusions Based on the COX-2 Experience

• WOMAC Questionnaire reflects clinical improvement consistent with other patient assessed measures

• Proved valid, reliable and sensitive to change• Pain and stiffness subscales reflect symptoms• Physical function subscale dominates composite score• WOMAC Composite score is a disease specific measure

of HRQOL• Correlates closely with improvements reported by

generic SF-36

• Based on MCID calculations, Likert and VAS versions similarly sensitive to change

• WOMAC Questionnaire reflects clinical improvement consistent with other patient assessed measures

• Proved valid, reliable and sensitive to change• Pain and stiffness subscales reflect symptoms• Physical function subscale dominates composite score• WOMAC Composite score is a disease specific measure

of HRQOL• Correlates closely with improvements reported by

generic SF-36

• Based on MCID calculations, Likert and VAS versions similarly sensitive to change

OMERACT 4 SLE Module 1998: Goal

• To develop consensus on required outcome domains

to be assessed in clinical trials in SLE

• Paucity of data from Randomized Controlled Trials [RCTs];

Most evidence derived from Longitudinal Observational

Studies [LOS]

• To develop consensus on required outcome domains

to be assessed in clinical trials in SLE

• Paucity of data from Randomized Controlled Trials [RCTs];

Most evidence derived from Longitudinal Observational

Studies [LOS]

Strand et al: J Rheum 1999; 26: 490-497Smolen et al: J Rheum 1999; 26: 504-507

Disease Activity Indices

BILAG, ECLAM, LAI, SLAM, SLEDAI

• Good evidence for validity, discrimination, feasibility in published cohort [LOS] studies

• Changes in one index correlated with others

• Recommendation to use index of choice– Computer generation of all 5 indices facilitates:

• Clinical research efforts: SLICCESCICITEURO-LUPUS

• Exchange of information: interested partiesbiotech / pharma

• Some limitations when used as primary outcome measures in RCTs; ongoing efforts to improve

• Good evidence for validity, discrimination, feasibility in published cohort [LOS] studies

• Changes in one index correlated with others

• Recommendation to use index of choice– Computer generation of all 5 indices facilitates:

• Clinical research efforts: SLICCESCICITEURO-LUPUS

• Exchange of information: interested partiesbiotech / pharma

• Some limitations when used as primary outcome measures in RCTs; ongoing efforts to improve

• Baseline domain scores low in SLE

– v. age/gender matched norms for Canada, Norway, UK, US

– v. serious medical problems (IDDM, CAD)

• In cohort studies reflects changes in disease activity measures

–   disease activity in PF, BP, GHP

– disease activity SF-36 domain scores, esp. PF

• Decrements in multiple domains correlate with increased disease activity and damage

– Immunosuppressive use

– ESRD

• Baseline domain scores low in SLE

– v. age/gender matched norms for Canada, Norway, UK, US

– v. serious medical problems (IDDM, CAD)

• In cohort studies reflects changes in disease activity measures

–   disease activity in PF, BP, GHP

– disease activity SF-36 domain scores, esp. PF

• Decrements in multiple domains correlate with increased disease activity and damage

– Immunosuppressive use

– ESRD

SF-36: Sensitive to Change in LOS in SLESF-36: Sensitive to Change in LOS in SLE

Gladman et al: J Rheum 1995; 23:1953-5

Gordon et al: A+R 1997; 40:S112 Gladman et al: Clin Exp Rheum 1995; 14:305-8Stoll et al: J Rheum 1997; 24:309-13 and 1608-14 Fortin et al: Lupus 1998; 7:101-7

Abu-Shakra et al J Rheum 1999; 26:306-9Thumboo et al J Rheum 1999; 26:97-102

Wang et al J Rheum 2001; 28:525-32

Rood et al J Rheum 2000; 27:2057-9

Vu, Escalante J Rheum 1999; 26:2595-2601

Domains Recommended by OMERACT 4

Disease activity: Disease Activity Scores: SLEDAI, BILAG, ECLAM, SELENA SLEDAI, SLAM-R

Definitions of Active Nephritis by U/A, 24 hour CCr,

proteinuria, «Renal flare» «Major SLE Flare»

Damage: ACR/SLICC Damage Index End Stage Renal Disease [ESRD] Doubling of Serum Creatinine Chronicity Index on Biopsy Bone loss due to disease activity and/or corticosteroids

HRQOL: SF-36

[Should also include: Adverse events Economic costs including health utilities]

Disease activity: Disease Activity Scores: SLEDAI, BILAG, ECLAM, SELENA SLEDAI, SLAM-R

Definitions of Active Nephritis by U/A, 24 hour CCr,

proteinuria, «Renal flare» «Major SLE Flare»

Damage: ACR/SLICC Damage Index End Stage Renal Disease [ESRD] Doubling of Serum Creatinine Chronicity Index on Biopsy Bone loss due to disease activity and/or corticosteroids

HRQOL: SF-36

[Should also include: Adverse events Economic costs including health utilities]As reviewed in Schiffenbauer et al: EBM Treatment of SLE; BJR: in press

Ankylosing Spondylitis: ASAS

• A successful and relevant example

• To be discussed by Robert LandeweJuergen Braun

Systemic Sclerosis Workshop: OMERACT 6

Absence of data: Few ‘failed’ RCTs

Limited information from LOS

Assessment by organ system involvement

• Renal

• Cardio-pulmonary

• Muscle

• HRQOL

• Skin

• GI

OMERACT 7

May 12-16, 2004 Asilomar, California

• Module: RA: Definition of Low Disease Activity

• Module Updates:

Imaging in Ankylosing Spondylitis [ASAS]

Working Group on Safety

• Workshops:

Outcome Measures in Psoriatic Arthritis

Outcome Measures in Fibromyalgia

Outcome Measures in Gout

The Patient Perspective in Outcome Measures