# Presentation: 826014

## 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

## 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

## 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 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)

## 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