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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, MD Biopharmaceutical Consultant Adjunct Clinical Professor, Division of Immunology, Stanford University. Abbott Alexion Amgen Corporation Aventis Pharmaceuticals Celltech Centocor

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FDA AAC: Discussion of SLE Concept Paper State of the Art: HRQOL, Fatigue and Function

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  1. 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

  2. Abbott Alexion Amgen Corporation Aventis Pharmaceuticals Celltech Centocor Genelabs Genentech Genzyme Hoffman LaRoche IDEC Incyte La Jolla Pharmaceuticals Novartis Pfizer Procter and Gamble Scios SKK SumitomoXoma Corporation Abgenix Affymax Alza Corporation Astra Zeneca Becton Dickinson Biogen Boeringher Ingelheim Entelos Geron, Inc. Glaxo SmithKline Immune Response Corp RWJohnson PRI Eli Lilly and Co Medarex Organon Otsuka Schering Plough Targeted Genetics Disclosures Current Clients Previous Clients

  3. 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

  4. OMERACT 4 SLE Module 1998Goal 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: 490-497 Smolen et al: J Rheum 1999; 26: 504-507

  5. Outcome Domains Recommended by OMERACT 4 Disease activity: Damage: HRQOL: Should also include: Adverse events Economic costs including health utilities Strand et al: J Rheum 1999; 26: 490-497 Smolen et al: J Rheum 1999; 26: 504-507

  6. 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

  7. SF-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

  8. Physicalfunction Rolephysical Generalhealth Roleemotion Socialfunction Bodilypain Vitality Mentalhealth Mentalcomponent SF-36 Domains and Summary Scores Physicalcomponent

  9. 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 reported mental health • Organ damage less associated with reported HRQOL than 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

  10. 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: 20:972-6 Gladman et al: Lupus 1996; 5:190-5

  11. 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

  12. HRQOL in SLE Compared with RA • Prospective study of 82 patients with RA, 82 with SLE matched for age, gender, disease duration and 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 assessment accumulated damage index Gilboe et al JRheum 1999; 26:1694-700

  13. SF-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 Gladman et al: J Rheum 1995; 23:1953-5 Gordon et al: A+R 1997; 40:487 Gladman et al: Clin Exp Rheum 1995; 14:305-8 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 Wang et al: J Rheum 2001; 28: 525-32

  14. SF-36 is Sensitive to Change in SLE 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; 26:2352-6Strand 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 • 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; 26:306-9 Thumboo et al J Rheum 1999; 26:97-102Thumboo et al J Rheum 2000; 27:1414-20 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

  15. 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 Thumboo et al J Rheum 1999; 26:97-102Thumboo et al J Rheum 2000; 27:1414-20

  16. Minimum Clinically Important Differences[MCID] • Degree of improvement in various outcome measures • Perceptible to patients • Considered clinically important / meaningful • Defined by patient query, delphi technique HAQ 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

  17. Minimum Clinically Important Differences [MCID] Score DirectionMCID Range of Scoring 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 • Redelmeier et al. Arch Intern Med. 1993; 153:1337-42 • Wells et al. J Rheumatol. 1993; 20:557-60 • Guzman et al. Arth Rheum. 1996; 39:5208 • Kosinski et al. Arth Rheum. 2000; 43:1478-87 • Samsa et al. Pharmacoeconomics. 1999; 15:141-155 • Thumboo et al. J Rheumatol. 1999; 26:97-102. • Zhao et al: Pharmacotherapy 1999; 19:1269-78 • Angst et al: Arth Care Res 2001; 45:384-91

  18. 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 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

  19. 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 et al: Ann Rh Ds 1986; 45:359-66 TerBorg et al: A+R 1990; 33:634-43 Bootsma et al: Lancet 1995; 345:1595-9 Bijl et al: Ann Rh Ds 2003: 62:534-9

  20. anti-dsDNA Changes in dsDNA Ab; Complement 3 Levels 100 mg 50 mg 50 mg LJP 394 % change in C3 % change 0 10 20 30 40 50 Placebo % change in C3 % change 0 10 20 30 40 50 C3 Study week

  21. 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] Strand et al: Lupus 2003; 12:677-86

  22. SF-36 Scores at Baseline Compared with Age, Gender Matched US Norms Strand et al: Lupus 2003; 12:677-86

  23. Mean Changes in SF-36 Domain Scores from Baseline to 16 Weeks [ITT] Strand et al: Lupus 2003; 12:677-86

  24. Mean Changes in SF-36 Domain Scores Pre and Post Renal Flare Strand et al: Lupus 2003; 12:677-86

  25. Conclusions • 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

  26. Longitudinal Changes in anti dsDNA Abs in2 RCTs, Regardless of Treatment Group Responder: ≥10% reduction in anti-dsDNA antibodies in ≥2/3 of all determinations 30% 20% 10% 0 -10% -20% -30% Non - responder % change from BL Responder Time (months)

  27. HRQOL Scores at Month 4 in «Responders» in 230 Patients with SLE Mean change scores PFI ROLP PAIN GHP VITAL SOC ROLE MHI

  28. HRQOL Scores at Month 6 in «Responders» in 298 Patients with SLE Mean change scores PFI ROLP PAIN GHP VITAL SOC ROLE MHI

  29. HRQOL Scores at Month 12 in «Responders» in 298 Patients with SLE Mean change scores PFI ROLP PAIN GHP VITAL SOC ROLE MHI

  30. 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”

  31. 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

  32. 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

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