FDA AAC: Discussion of

SLE Concept Paper

State of the Art: HRQOL, Fatigue and

Function

FDA AAC: Discussion of

SLE Concept Paper

State of the Art: HRQOL, Fatigue and

Function

Vibeke Strand, MDBiopharmaceutical Consultant

Adjunct Clinical Professor, Division of Immunology, Stanford University

Vibeke Strand, MDBiopharmaceutical Consultant

Adjunct Clinical Professor, Division of Immunology, Stanford University

Disclosures

AbbottAlexionAmgen CorporationAventis PharmaceuticalsCelltechCentocorGenelabsGenentechGenzymeHoffman LaRocheIDECIncyteLa Jolla PharmaceuticalsNovartisPfizerProcter and GambleSciosSKKSumitomoXoma Corporation

AbbottAlexionAmgen CorporationAventis PharmaceuticalsCelltechCentocorGenelabsGenentechGenzymeHoffman LaRocheIDECIncyteLa Jolla PharmaceuticalsNovartisPfizerProcter and GambleSciosSKKSumitomoXoma Corporation

Abgenix AffymaxAlza CorporationAstra ZenecaBecton DickinsonBiogenBoeringher IngelheimEntelos Geron, Inc.Glaxo SmithKlineImmune Response CorpRWJohnson PRIEli Lilly and CoMedarexOrganonOtsukaSchering PloughTargeted Genetics

Abgenix AffymaxAlza CorporationAstra ZenecaBecton DickinsonBiogenBoeringher IngelheimEntelos Geron, Inc.Glaxo SmithKlineImmune Response CorpRWJohnson PRIEli Lilly and CoMedarexOrganonOtsukaSchering PloughTargeted Genetics

Current Clients Previous Clients

Lessons Learned: It is Difficult to Assess

Outcome in SLE RCTs

• Disease Activity Indices do NOT necessarily reflect OUTCOME

• Disease activity ≠ Disease severity

• Variability in weighting different organ manifestations

• Variability in scoring and scoring items [eg, fatigue]

• Only BILAG designed to reflect need for change in treatment

• Few have been used / validated in RCTs

• Poor correlation between patient and physician assessments of disease activity

• Responder analyses do NOT function well if they are proposed in absence of data from RCTs

• Changes in medical practice may confound treatment effects

• Disease Activity Indices do NOT necessarily reflect OUTCOME

• Disease activity ≠ Disease severity

• Variability in weighting different organ manifestations

• Variability in scoring and scoring items [eg, fatigue]

• Only BILAG designed to reflect need for change in treatment

• Few have been used / validated in RCTs

• Poor correlation between patient and physician assessments of disease activity

• Responder analyses do NOT function well if they are proposed in absence of data from RCTs

• Changes in medical practice may confound treatment effects

OMERACT 4 SLE Module 1998

Goal

To develop consensus on required outcome domains

to be assessed in clinical trials in SLE:

Randomized Controlled Trials [RCTs] and/or

Longitudinal Observational Studies [LOS]

Organizing Committee: D. Gladman

D. Isenberg

M. Petri

J. Smolen

V. Strand

To develop consensus on required outcome domains

to be assessed in clinical trials in SLE:

Randomized Controlled Trials [RCTs] and/or

Longitudinal Observational Studies [LOS]

Organizing Committee: D. Gladman

D. Isenberg

M. Petri

J. Smolen

V. Strand

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

Outcome Domains Recommended by

OMERACT 4

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

Disease activity:

Damage:

HRQOL:

Should also include:

Adverse events

Economic costs including health utilities

Disease activity:

Damage:

HRQOL:

Should also include:

Adverse events

Economic costs including health utilities

What is Health Related Quality of Life?

• NOT the economy…

• NOT the geopolitical situation…

• NOT status or access to resources…

• “In all the ways your disease affects you, how are you doing today?”

• SLE affects all domains of health related quality of life

• Patients complain of fatigue, inability to plan ahead, and changes in appearance

• NOT the economy…

• NOT the geopolitical situation…

• NOT status or access to resources…

• “In all the ways your disease affects you, how are you doing today?”

• SLE affects all domains of health related quality of life

• Patients complain of fatigue, inability to plan ahead, and changes in appearance

SF-36: Short Form 36 Health SurveySF-36: Short Form 36 Health Survey

Validated, widely used generic measure of HRQOL

• 8 Domains:

• Scored 0 - 100; age, gender adjusted norms

• 2 Summary Scores: Normative based scoring

• Mean: 50, SD: 10

• 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

• Facilitates comparison with other disease states

Validated, widely used generic measure of HRQOL

• 8 Domains:

• Scored 0 - 100; age, gender adjusted norms

• 2 Summary Scores: Normative based scoring

• Mean: 50, SD: 10

• 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

• Facilitates comparison with other disease states

Physicalcomponent

Mentalcomponent

Physicalfunction

Rolephysical

Bodilypain

Generalhealth

Vitality Socialfunction

Roleemotion

Mentalhealth

SF-36 Domains and Summary Scores

SLE Impacts all Domains of HRQOL

• Coping mechanisms most consistently associated with HRQOL, but not morbidity– Ethnicity and socioeconomic status are important – Variable

• Social support consistently associated with reportedmental health

• Organ damage less associated with reported HRQOLthan disease activity

• Data in patients receiving care from rheumatologists:

• In cohort studies or enrolled in RCTs

• May underestimate influences of access to care and treatment adherence

Sutcliffe et al: Rheumatol 1999; 38:1130-7Ward: Arth Rheum 2001; 44:2711-4

Disability in SLE Encompasses all Domains

of HRQOL• Fatigue and Depression important —

and are quantifiable

• Disease activity, damage ± health related quality of life

• Disability ± Impairment in physical function:

• 106 SLE pts in Baltimore: mean HAQ DI = 0.66

• > 25% had HAQ DI scores of 0

• <10% required assistance or assistive aids

• 120 SLE pts in Cleveland: mean HAQ DI = 0.83

• 125 in Canada: mean HAQ DI = 0.61

Hochberg et al JRheum 1988; 15:959-964

Milligan et al JRheum 1993: 20:972-6Gladman et al: Lupus 1996; 5:190-5

HRQOL in SLE compared with RA

• RA and SLE patients complain of: loss of energy, unpredictable course of disease

• SLE patients complain of fatigue; ‘inability to plan ahead’

• SLE patients have more dissatisfaction with perceived control of their bodies, and body image

• SLE patients dissatisfied with understanding about their condition on the part of MDs and other individuals

«Handicap invisible to others»

Burckhardt et al JRheum 1993; 20:997-81Archenholtz et al: Qual Life Res 1999; 8:411-6

HRQOL in SLE Compared with RA

• Prospective study of 82 patients with RA, 82 with SLEmatched for age, gender, disease durationand 74 age and gender controls

• Both diseases impact all dimensions of health status

• Less disability in RA, and lower VAS pain scores– but no difference in bodily pain domain scores

• SF-36 correlated best with:patient global assessmentaccumulated damage index

Gilboe et al JRheum 1999; 26:1694-700

SF-36: Short Form 36 Health SurveySF-36: Short Form 36 Health Survey

• Baseline domain scores low in SLE

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

– v. serious medical problems (IDDM, CAD)

• In cohort studies reflects changes in disease activity

(SLAM, BILAG, SLEDAI):

–   disease activity in PF, BP, GHP

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

– damage in PF, GHP

• Baseline domain scores low in SLE

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

– v. serious medical problems (IDDM, CAD)

• In cohort studies reflects changes in disease activity

(SLAM, BILAG, SLEDAI):

–   disease activity in PF, BP, GHP

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

– damage in PF, GHP

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

Gordon et al: A+R 1997; 40:487 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

Sutcliffe et al: J Rheum 1999; 26:2352-6 Wang et al: J Rheum 2001; 28: 525-32

SF-36 is Sensitive to Change in SLE

• Demonstrated valid and sensitive to change in RCTs and LOS in SLE

• Decrements in multiple domains correlate with increases in disease activity and damage – although generally weak correlations

• Immunosuppressive use

• Reflect ESRD

• Demonstrated valid and sensitive to change in RCTs and LOS in SLE

• Decrements in multiple domains correlate with increases in disease activity and damage – although generally weak correlations

• Immunosuppressive use

• Reflect ESRD

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

Thumboo et al J Rheum 2000; 27:1414-20Wang et al J Rheum 2001; 28:525-32

Stoll et al: J Rheum 1997; 24: 309-13 and 1608-14 Fortin et al: Lupus 1998; 7:101-7

Sutcliffe et al: J Rheum 1999; 26:2352-6 Strand et al: J Rheum 1999; 26:495-503 Thumboo et al: J Rheum 2000; 27:1414-1420

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

SF-36 is Sensitive to Change in SLE

• Changes in domain scores in general best correlated with changes in disease activity, higher glucocorticoid doses, use of cytotoxic agents

• Greatest variability in Role Physical and Role Emotional domains

• Taking the mean of the 4 physical domains = PHSand 4 mental domains = MHS

• PHS negatively correlated with ↑ steroid doses ↑ BILAG score

• MHS negatively correlated with ↑ steroid doses use of

cytotoxics ↑ BILAG scores

• Changes in domain scores in general best correlated with changes in disease activity, higher glucocorticoid doses, use of cytotoxic agents

• Greatest variability in Role Physical and Role Emotional domains

• Taking the mean of the 4 physical domains = PHSand 4 mental domains = MHS

• PHS negatively correlated with ↑ steroid doses ↑ BILAG score

• MHS negatively correlated with ↑ steroid doses use of

cytotoxics ↑ BILAG scoresThumboo et al J Rheum 1999; 26:97-102

Thumboo et al J Rheum 2000; 27:1414-20

Minimum Clinically Important Differences

[MCID]

Minimum Clinically Important Differences

[MCID]

• Degree of improvement in various outcome measures

• Perceptible to patients

• Considered clinically important / meaningful

• Defined by patient query, delphi techniqueHAQ DI: 0.22 improvement

• Confirmed by statistical correlations with clinical responses in placebo RCTs, using patient global assessments

• When group median (and mean) changes well exceed MCID, it can be expected that a majority of

patients will attain clinically meaningful improvement

• Degree of improvement in various outcome measures

• Perceptible to patients

• Considered clinically important / meaningful

• Defined by patient query, delphi techniqueHAQ DI: 0.22 improvement

• Confirmed by statistical correlations with clinical responses in placebo RCTs, using patient global assessments

• When group median (and mean) changes well exceed MCID, it can be expected that a majority of

patients will attain clinically meaningful improvement

1. Redelmeier et al. Arch Intern Med. 1993; 153:1337-422. Wells et al. J Rheumatol. 1993; 20:557-60 3. Guzman et al. Arth Rheum. 1996; 39:5208 4. Kosinski et al. Arth Rheum. 2000; 43:1478-875. Samsa et al. Pharmacoeconomics. 1999; 15:141-155 6. Thumboo et al. J Rheumatol. 1999; 26:97-102.7. Zhao et al: Pharmacotherapy 1999; 19:1269-788. Angst et al: Arth Care Res 2001; 45:384-91

Minimum Clinically Important Differences

[MCID]

HAQ DI 1-4 0 - 3 – 0.22

SF-36 2, 4-8 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, 4-8 0 - 100 + 5 - 10 points

PCS/MCS mean 50 ± 10 + 2.5 - 5 points

Score Direction MCIDRange of Scoring

Score Direction MCIDRange of Scoring

Other Points: Confounding Issue of Fatigue

• 2° to active SLE or fibromyalgia?

• Associated fibromyalgia in cohort series:• Petri: 25 - 30%• Gladman: 20%• Gordon, Isenberg: <10%

• Capable of treatment independent of SLE?

• Significantly impacts SF-36, • Other patient reported measures?• Fatigue assessed by MD included in SLAM; SLAM-R

• Krupp Fatigue Severity Score reflects alterations • NOT 2° to psychological stress• Different than reported in other ds states, eg MS

• 2° to active SLE or fibromyalgia?

• Associated fibromyalgia in cohort series:• Petri: 25 - 30%• Gladman: 20%• Gordon, Isenberg: <10%

• Capable of treatment independent of SLE?

• Significantly impacts SF-36, • Other patient reported measures?• Fatigue assessed by MD included in SLAM; SLAM-R

• Krupp Fatigue Severity Score reflects alterations • NOT 2° to psychological stress• Different than reported in other ds states, eg MS

Gladman et al J Rheum 1997; 24:2145-8Taylor et al A+R 1998: 41: 1797-85

Krupp et al Arch Neurol 1989: 46: 1121-3

Αnti dsDNA Ab levels Predict Disease Flares

• Swaak: in 143 SLE patients followed for up to 6 years:• 2x ↑ αdsDNA Ab levels within 10 weeks predicted 33 major

‘exacerbations’: 21 renal; 12 non-renal• 80% renal ‘flares’ predicted by ↓ C4 levels

• Ter Borg: in 17/72 SLE patients followed over mean 18.5 months • 24/33 ‘exacerbations’ predicted by ↑ αdsDNA Ab levels • 13 renal; 20 non-renal flares

• Bootsma: 156 patients; αdsDNA Ab levels measured monthly• When ↑↑: randomized to conventional Rx or addn 30 mg

prednisone• In 46: relapses in 20/24 v 2/22 p<0.001

• Bijl: in 36 patients: αdsDNA Ab levels measured monthly• When ↑↑ in 10: MMF 2000 QD → no clinical relapses in 6

months

• Swaak: in 143 SLE patients followed for up to 6 years:• 2x ↑ αdsDNA Ab levels within 10 weeks predicted 33 major

‘exacerbations’: 21 renal; 12 non-renal• 80% renal ‘flares’ predicted by ↓ C4 levels

• Ter Borg: in 17/72 SLE patients followed over mean 18.5 months • 24/33 ‘exacerbations’ predicted by ↑ αdsDNA Ab levels • 13 renal; 20 non-renal flares

• Bootsma: 156 patients; αdsDNA Ab levels measured monthly• When ↑↑: randomized to conventional Rx or addn 30 mg

prednisone• In 46: relapses in 20/24 v 2/22 p<0.001

• Bijl: in 36 patients: αdsDNA Ab levels measured monthly• When ↑↑ in 10: MMF 2000 QD → no clinical relapses in 6

months

TerBorg et al: A+R 1990; 33:634-43

Bootsma et al: Lancet 1995; 345:1595-9

Swaak et al: Ann Rh Ds 1986; 45:359-66

Bijl et al: Ann Rh Ds 2003: 62:534-9

-40

-30

-20

-10

0

10

20

30

40

-9

-7

-5

-3

-1

1

3

5

7

9-40

-30

-20

-10

0

10

20

30

40

-9

-7

-5

-3

-1

1

3

5

7

9

LJP 394

Placebo

anti-dsDNA C3

% c

han

ge

% c

han

ge

% ch

ang

e in C3

% ch

ang

e in C3

100 mg 50 mg 50 mg

0 10 20 30 40 50

0 10 20 30 40 50

Changes in dsDNA Ab; Complement 3 Levels

Study week

HRQOL Analysis

• All patients enrolled in LJP 394 phase 2/3 clinical trial who completed one baseline and follow-up SF-36

• Mean scores at endpoint and change scores in SF-36 domains; PCS and MCS summary scores

compared between active and placebo

• End of Induction [week 16] vs baseline (BL): ITT [n=179] and ‘high affinity’ populations

[n=157]

• Post vs Pre documented renal flare values; +/- patients receiving high dose steroids and/or cytotoxics [HDCC] prior to flare [n=37; n=30]

• All patients enrolled in LJP 394 phase 2/3 clinical trial who completed one baseline and follow-up SF-36

• Mean scores at endpoint and change scores in SF-36 domains; PCS and MCS summary scores

compared between active and placebo

• End of Induction [week 16] vs baseline (BL): ITT [n=179] and ‘high affinity’ populations

[n=157]

• Post vs Pre documented renal flare values; +/- patients receiving high dose steroids and/or cytotoxics [HDCC] prior to flare [n=37; n=30]Strand et al: Lupus 2003; 12:677-86

0102030405060708090

100

Do

main

Score

PFI ROLP PAIN GHP VITAL SOC ROLE MHI

US Norms SLE Patients at Baseline (n=179)

SF-36 Scores at Baseline Compared with

Age, Gender Matched US Norms

Strand et al: Lupus 2003; 12:677-86

2.2

4.7 6.0

11.3

5.1

3.0

4.85.7

4.9

2.3

0.7

4.3

-8.2

7.3

1.6 1.2

-15

-10

-5

0

5

10

15

PFI ROLP PAIN GHP VITAL SOC ROLE MHI

Placebo (n=92)

LJP 394 (n=87)

Mean Changes in SF-36 Domain Scores from

Baseline to 16 Weeks [ITT]

Strand et al: Lupus 2003; 12:677-86

Mean Changes in SF-36 Domain Scores Pre and

Post Renal Flare

Mean Changes in SF-36 Domain Scores Pre and

Post Renal Flare

-1.2

2.5

-3.6

1.6

-0.1

12.3

-5.3

-0.4-1.3

3.3

-10.7

2.3

-20.6

2.1

-5.2

0.0

-25

-20

-15

-10

-5

0

5

10

15

PFI ROLP PAIN GHP VITAL SOC ROLE MHI

Placebo (n=21)

LJP 394 (n=16)

Strand et al: Lupus 2003; 12:677-86

ConclusionsConclusions

• Patients with clinically stable SLE reported impaired HRQOL compared with age and gender matched US norms.

• During induction [16 weeks], SF-36 scores improved with active treatment, despite stable disease activity.

• Following a renal flare, patients receiving active treatment reported maintenance or improvement in HRQOL compared with deterioration in placebo; omitting patients who received HDCC prior to flare did not alter results.

• Differences in change scores in Role Emotional between treatment groups were replicated in all populations analyzed; are clinically meaningful, and may reflect changes in anti-dsDNA Ab levels.

• Patients with clinically stable SLE reported impaired HRQOL compared with age and gender matched US norms.

• During induction [16 weeks], SF-36 scores improved with active treatment, despite stable disease activity.

• Following a renal flare, patients receiving active treatment reported maintenance or improvement in HRQOL compared with deterioration in placebo; omitting patients who received HDCC prior to flare did not alter results.

• Differences in change scores in Role Emotional between treatment groups were replicated in all populations analyzed; are clinically meaningful, and may reflect changes in anti-dsDNA Ab levels.

Strand et al: Lupus 2003; 12:677-86

Longitudinal Changes in anti dsDNA Abs in

2 RCTs, Regardless of Treatment GroupResponder: Responder: ≥≥10% reduction in anti-dsDNA antibodies 10% reduction in anti-dsDNA antibodies

in in ≥≥2/3 of all determinations2/3 of all determinations

Non -Non -responderresponder

30%30%

20%20%

10%10%

00

-10%-10%

-20%-20%

-30%-30%

% c

han

ge

fro

m B

L%

ch

ang

e fr

om

BL

ResponderResponder

Time (months)Time (months)

HRQOL Scores at Month 4 in «Responders»

in 230 Patients with SLE

2.5

5.24.0 3.8

3.0

0.2

-2.9

0.2

5.2

15.3

4.2

8.1

4.9

6.9

3.9 3.6

-10

-5

0

5

10

15

20

Non-responder (n = 118) Responder (n=56)

PFI ROLP PAIN GHP VITAL SOC ROLE MHI

Me

an

ch

an

ge

sc

ore

s

HRQOL Scores at Month 6 in «Responders»

in 298 Patients with SLE

-0.1

-4.7-3.4

0.6

-1.9 -2.0-0.6

0.7

4.1 3.6

7.26.4

7.8

2.3 1.72.5

-10

-5

0

5

10

15

20

Non-responder (n = 162) Responder (n = 112)

Me

an

ch

an

ge

sc

ore

s

PFI ROLP PAIN GHP VITAL SOC ROLE MHI

HRQOL Scores at Month 12 in «Responders»

in 298 Patients with SLE

-3.2

-8.0

-5.1

1.2

-0.8

0.7

-0.3 -1.0

4.9

11.3

7.08.7

9.7

4.12.3

4.9

-15

-10

-5

0

5

10

15

20

Non-Responder (N=110) Responder (N=80)

Me

an

ch

an

ge

sc

ore

s

PFI ROLP PAIN GHP VITAL SOC ROLE MHI

HRQOL Scores at Months 6 and 12 in

«Responders» in 298 Patients with SLE

• Excluding 14 patients with renal flares ≤ 6 months do not change these results

• Excluding 41 patients with renal flares ≤ 12 months do not change these results

• Excludes use of high dose glucocorticoids and/or cyclophosphamide

• Are they clinically meaningful?

→ Analysis of “minimally clinically important differences”

• Excluding 14 patients with renal flares ≤ 6 months do not change these results

• Excluding 41 patients with renal flares ≤ 12 months do not change these results

• Excludes use of high dose glucocorticoids and/or cyclophosphamide

• Are they clinically meaningful?

→ Analysis of “minimally clinically important differences”

MCID in SF-36 Domains, PCS and MCS

• Correlation of change in 15 point scale by Guyatt et al:“In the past 3 months, has there been any change in your overall quality of life related to your lupus?”

• “a little better” = 6 on 15 point scale• “a little worse” = 10

• Improvements → mean change scores • Domains of SF-36: 6.7 – 11.4• PCS and MCS: 3.4 – 3.9

• Worsening → mean change scores • Domains of SF-36: +1.7 – -14.7• PCS and MCS: -0.8 – -2.0

• Correlation of change in 15 point scale by Guyatt et al:“In the past 3 months, has there been any change in your overall quality of life related to your lupus?”

• “a little better” = 6 on 15 point scale• “a little worse” = 10

• Improvements → mean change scores • Domains of SF-36: 6.7 – 11.4• PCS and MCS: 3.4 – 3.9

• Worsening → mean change scores • Domains of SF-36: +1.7 – -14.7• PCS and MCS: -0.8 – -2.0

Conclusions:

Yes, it IS difficult to assess Outcomes in SLE

Limited data derived from RCTs ― Yet to result in an ‘approved therapy’― Over a broad variety of promising interventions

Patient Reported HRQOL is an IMPORTANT OUTCOME

• Reflects improvements in disease activity

• Deterioration due to use of high dose glucocorticoids and/or immunosuppressives

• Has correlated with longer term clinical outcomes

• May improve w/ sustained reductions in α dsDNA Abs

• Which are clinically meaningful

Yes, it IS difficult to assess Outcomes in SLE

Limited data derived from RCTs ― Yet to result in an ‘approved therapy’― Over a broad variety of promising interventions

Patient Reported HRQOL is an IMPORTANT OUTCOME

• Reflects improvements in disease activity

• Deterioration due to use of high dose glucocorticoids and/or immunosuppressives

• Has correlated with longer term clinical outcomes

• May improve w/ sustained reductions in α dsDNA Abs

• Which are clinically meaningful