1. Trial Design Issues in SLE Joel Schiffenbauer FDA/CDER DAAODP

2. SLE SLE may wax and wane with and without therapy making determination of the efficacy and safety of new therapies difficult Use of potentially toxic medications requires rigorous study design to demonstrate clear evidence of efficacy and safety (risk/benefit)

3. Trial Design Issues Choice of endpoints Data to collect Controls and trial designs/SOC issues Blinding ITT analysis/Imputation of missing data Stratification Covariates Concomitant medications

4. Efficacy Trial Considerations Design will depend on claims sought Endpoints –Organ specific –Constitutional manifestations/ signs and symptoms –Flare –Other: surrogates, steroid dose

5. Advantages and Disadvantages of Different Approaches

6. Disease activity Active –treated vs untreated Inactive (or relatively inactive) –treated vs untreated

7. Endpoints Active disease –disease activity measures (indices; organ specific) –responder index (eg disease activity measure+HRQOL+damage+steroid dose etc) –steroid dose/concomitant medications dose Inactive disease –flare (time to, number of, rate of) –steroid dose/concomitant medications

8. Endpoints What changes are considered clinically meaningful? What constitutes a successful outcome?

9. Outcome measures

10. Flares What reduction in flare rate is clinically meaningful in the context of adverse events? Are all flares equal (renal vs joints)? Should a new therapy be asked to address the treatment of active disease in addition to preventing flares?

11. Advantages and Disadvantages of Flare Design Advantages –“Responder analysis” takes into account individual responses –Reduces time of partial treatment Disadvantages –“Heterogeneous” outcomes –Does not demonstrate treatment of active disease –Impractical (few flares)

12. Examples of Organ Specific Flare Definition Renal flare: attributed to SLE by treating physician (one or more criteria?) – reproducible increase in serum creatinine greater than 20% accompanied by proteinuria, hematuria and/or RBC casts and /or WBC casts; –Reproducible increase in 24 hour protein (how much?)

13. General Flare Definition Defined as at least one of the following: –increase in prednisone (>5mg/day) for at least 14 days since the previous visit –SLE manifestation requiring hospitalization –addition of new medication or an increase in the dose of an existing medication to specifically treat a manifestation of increased SLE activity

14. Trial Design Issues Choice of endpoints Data to collect Controls and trial designs/SOC issues Blinding ITT analysis/Imputation of missing data Stratification Covariates Concomitant medications Randomization/Allocation concealment

15. Domains (OMERACT) Lupus 2000; 9:322 Disease activity measures –SLEDAI, SLAM, BILAG, ECLAM, SELENA SLEDAI, SLAM-R – Definitions of Active Nephritis by U/A, 24 hour CCr, proteinuria –Renal flare Damage: ACR/SLICC Damage Index – Deterioration of Renal Function: End Stage Renal Disease [ESRD] Doubling of Serum Creatinine Chronicity Index on Biopsy Health status/HRQOL: SF-36 Should also include: – Economic costs – Adverse events

16. Data for Lupus Nephritis Renal pathology; does everyone need a biopsy? Urine protein- what is a clinically meaningful change in proteinura? Urine sediment-what is a clinically meaningful change in hematuria? Renal function –Serum creatinine –An appropriate measure of GFR-does a change in GFR (vs doubling of serum creatinine) represent an important benefit? Other: adverse events

17. Data For Other Manifestations What data is needed for trials in CNS lupus? Other manifestations?

18. Trial Design Issues Choice of endpoints Data to collect Controls and trial designs/SOC issues Blinding ITT analysis/Imputation of missing data Stratification Covariates Concomitant medications

19. Trial Design Information http://www.fda.gov/cder/guidance ICH E9: Statistical principles for clinical trials ICH E10: Choice of control group and related issues in clinical trials RA guidance SLE guidance (future) CONSORT (Consolidated Standards of Reporting Trials) recommendations (Lancet 2001; 357:1191)

20. Controls Ideally a study would have placebo (eg SOC plus placebo vs true placebo) plus active control plus dose response Allows for measure of absolute effect size Shows existence of effect Shows dose response Allows comparison of therapies

21. Controls Superiority trial –SOC (eg steroids plus cyclo) plus new drug vs SOC plus placebo (“add-on” trial) See Arth. Rheum. 2003; 48:1481 –SOC (eg steroids) plus new drug vs SOC plus cyclo Equivalence (non-inferiority) –SOC plus new drug vs SOC plus comparator

22. Other Designs Limited placebo (steroids only?) period –depends on organ studied –at the beginning of an active control trial (to establish assay sensitivity) –Are there instances where steroids only are an acceptable treatment in lupus nephritis?

23. Randomized Withdrawal Subjects receive test treatment for specified time are randomly assigned to continued treatment with the test treatment or placebo See NEJM 1991; 324:150

24. Replacement Study New drug or placebo added by random assignment – conventional treatment given at an effective dose –and the conventional treatment is then withdrawn usually by tapering Ability to maintain patients baseline status (preventing flares) Steroid sparing agents

25. Is There a SOC? Depends on the organ studied For lupus nephritis –Are there instances where steroids only are acceptable? For CNS For other organ involvement If cyclophosphamide is used, it may be difficult to demonstrate an effect of the new therapy especially if mechanisms of actions are similar

26. “Add-on” Trials Definition of partial responders Toxicity of combination Consider factorial design See also Arth. Rheum. 2003; 48:1481-1483

27. Equivalence or Non-inferiority Trials Historical evidence of sensitivity to drug effects based on prior placebo controlled trials Appropriate trial conduct –setting a margin of difference (cannot be greater than the smallest effect size that the active drug would be reliably expected to have compared with placebo)

28. Trial Design Issues Choice of endpoints Data to collect Controls and trial designs/SOC issues Blinding ITT analysis/Imputation of missing data Stratification Covariates Concomitant medications

29. Blinding Blinding is intended to minimize the potential biases resulting from differences in management of patients or interpretation of results Can trials with IV cyclophosphamide be adequately blinded? Changes in labs, hair loss, nausea Ann. Int. Med 1971; 75: 165- “therapist” and “observer” (do not know WBC, clinical status); pharmacist to prepare meds; wigs for patients

30. Why Blind? Subjects on active drug might report more favorable outcomes because they expect a benefit or might be more likely to stay in a study Knowledge of treatment could affect the vigor of attempts to obtain on-study follow up

31. Blinding cont’d Knowledge of treatment could affect decisions about whether a subject should remain on treatment or receive concomitant medication Knowledge of treatment could affect decisions as to whether a given subject’s results should be included in analysis

32. Trial Design Issues Choice of endpoints Data to collect Controls and trial designs/SOC issues Blinding ITT analysis/Imputation of missing data Stratification Covariates Concomitant medications

33. ITT/Imputation of Missing Data Important to pre-specify how missing data will be handled especially in relatively small trials (LOCF, WOCF etc); other conservative methods of imputation Use of responder index: respond at any time, respond at last visit, respond at each visit. Use may maintain power and reduce sample size

34. Stratification By disease manifestation By dose of steroid Other

35. Covariate Analyses Anti-DNA at baseline Number of organs involved or disease activity at baseline By center Other- cytokine levels, complement

36. Concomitant Medications Need to define allowable medications at baseline Other medications such as ACE inhibitors Rescue medication –Do patients stay in trial? –How much is allowed?

37. Concomitant Medications cont’d Steroids – Subtle changes in steroid dose could influence outcomes; –Consider a run-in period to standardize steroid dose; –Dose adjustment specified in protocol; – Change in steroid dose (steroid sparing) must be clinically meaningful

38. Duration of Studies May depend on claims sought –could a trial for “treats constitutional changes” be 3 months in duration? Inactive disease: –time to collect adequate number of flares Active disease –Acute (induction) weeks to months? –Chronic (maintenance) months to year(s)? Extension studies vs phase IV studies (need to consider economic costs)

39. Practical considerations May be difficult to perform chronic well controlled trial secondary to flares, changing medications, dropouts, changes in medical practice In disease that waxes and wanes, short trials may not provide adequate demonstration of efficacy, safety, and durability

40. Extension Studies Need to demonstrate maintenance of effect (durability) and safety Comparator(s): are they needed? Blinded or open label? Phase IV commitments –how long? Depends on what needs to be demonstrated

41. Safety Database ICH: 300-600 patients for 6 months and 100 for one year (for chronic non-life threatening disorders) What is standard for a disorder as varied as lupus in which some manifestations are chronic and others acute and life- threatening?

42. One Size Fits All? No Multiple possibilities for “wins”

43. Factors to Consider in SLE Trial Design Organ specific vs non-organ specific Active vs inactive disease Activity measure vs flare vs other Superiority vs equivalence Induction vs maintenance Short term and long term safety Data to collect

44. Acknowledgements Lee Simon Jeff Siegel Douglas Throckmorton James Witter Lourdes Villalba Tatiana Oussova Carolyn Yancey Members of DAAODP