Trial Design Issues in SLE Joel Schiffenbauer FDA/CDER DAAODP

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

• Use of potentially toxic medications requires rigorous study design to demonstrate clear evidence of efficacy and safety (risk/benefit)

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

• Design will depend on claims sought

• Endpoints– Organ specific– Constitutional manifestations/ signs and

symptoms– Flare– Other: surrogates, steroid dose

Advantages and Disadvantages of Different Approaches

Endpoints Advantages Disadvantages

1) Disease activity indices

Sufficient power Imbalance in disease manifestations

2) Flare Sufficient power; reduces under treatment

Problematic if flares differ in treatment groups

3) Organ specific (single organ)

Homogeneous population; well defined outcomes

Decreased power

4) Organ specific (stratify by organ)

Improve power; maintain homogeneity

Increases complexity

Disease activity

• Active– treated vs untreated

• Inactive (or relatively inactive)– treated vs untreated

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

Endpoints

• What changes are considered clinically meaningful?

• What constitutes a successful outcome?

Outcome measures Active Inactive

Organ specific

Disease activity specific for organ; responder index; steroid dose

Flare; maintenance; steroid dose

Constitutional/signs and symptoms

Disease activity index; steroid dose

Flare; maintenance; Steroid dose

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– “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

• 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

• 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 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

• 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

• 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

• What data is needed for trials in CNS lupus?

• Other manifestations?

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 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

• 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

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

• 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

• 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

• 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?

• 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

• Definition of partial responders

• Toxicity of combination

• Consider factorial design

• See also Arth. Rheum. 2003; 48:1481-1483

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 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 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?

• 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

• 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 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

• 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

• By disease manifestation

• By dose of steroid

• Other

Covariate Analyses

• Anti-DNA at baseline

• Number of organs involved or disease activity at baseline

• By center

• Other- cytokine levels, complement

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

• 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• 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

• 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

• 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

• 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?

• No

• Multiple possibilities for “wins”

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

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