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Trial Design Issues in SLE. Joel Schiffenbauer FDA/CDER DAAODP. SLE. SLE may wax and wane with and without therapy making determination of the efficacy and safety of new therapies difficult

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trial design issues in sle

Trial Design Issues in SLE

Joel Schiffenbauer

FDA/CDER

DAAODP

slide2
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)
trial design issues
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
efficacy trial considerations
Efficacy Trial Considerations
  • Design will depend on claims sought
  • Endpoints
    • Organ specific
    • Constitutional manifestations/ signs and symptoms
    • Flare
    • Other: surrogates, steroid dose
disease activity
Disease activity
  • Active
    • treated vs untreated
  • Inactive (or relatively inactive)
    • treated vs untreated
endpoints
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
endpoints8
Endpoints
  • What changes are considered clinically meaningful?
  • What constitutes a successful outcome?
flares
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?
advantages and disadvantages of flare design
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)
examples of organ specific flare definition
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?)
general flare definition
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
trial design issues14
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
domains omeract lupus 2000 9 322
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
data for lupus nephritis
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
data for other manifestations
Data For Other Manifestations
  • What data is needed for trials in CNS lupus?
  • Other manifestations?
trial design issues18
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
trial design information http www fda gov cder guidance
Trial Design Informationhttp://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)
controls
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
controls21
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
other designs
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?
randomized withdrawal
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
replacement study
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
is there a soc
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
add on trials
“Add-on” Trials
  • Definition of partial responders
  • Toxicity of combination
  • Consider factorial design
  • See also Arth. Rheum. 2003; 48:1481-1483
equivalence or non inferiority trials
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)
trial design issues28
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
blinding
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
why blind
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
blinding cont d
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
trial design issues32
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
itt imputation of missing data
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
stratification
Stratification
  • By disease manifestation
  • By dose of steroid
  • Other
covariate analyses
Covariate Analyses
  • Anti-DNA at baseline
  • Number of organs involved or disease activity at baseline
  • By center
  • Other- cytokine levels, complement
concomitant medications
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?
concomitant medications cont d
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
duration of studies
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)
practical considerations
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
extension studies
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
safety database
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?
one size fits all
One Size Fits All?
  • No
  • Multiple possibilities for “wins”
factors to consider in sle trial design
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
acknowledgements
Acknowledgements
  • Lee Simon
  • Jeff Siegel
  • Douglas Throckmorton
  • James Witter
  • Lourdes Villalba
  • Tatiana Oussova
  • Carolyn Yancey
  • Members of DAAODP
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