1. 1 Non-inferiority designs for relapse prevention of schizophrenia Gene Laska Ph.D. Department of Psychiatry NYU School of Medicine Nathan Kline Institute for Psychiatric Research

2. 2 The problem of relapse in schizophrenia Montero’s review of the literature estimated that 42 percent of patients with schizophrenia relapsed over the course of a year 1 For patients who discontinued antipsychotic therapy, relapse was an almost certain at one year 2 1. Montero, I., Pérez, I. Ruiz, & Gómez-Beneyto, M. (1998). Social adjustment in schizophrenia: Factors predictive of short-term social adjustment in a sample of schizophrenic patients. Acta Psychiatrica Scandinavica, 97, 116-121 2. Weiden, P.J., and Olfson, M. (1995). Cost of relapse in schizophrenia. Schizophrenia Bulletin, 24, 419-429.

3. 3 Framing the issue Comparisons to placebo in a RCT provide the most persuasive evidence It may be unethical to use placebo when better treatments exist Are active controlled trials using non- inferiority designs a valid alternative?

4. 4 Logic of non-inferiority trials If a standard S is consistently superior to placebo, then To show that a test treatment T is superior to placebo… It suffices to show that the test treatment is as good as (not inferior) to the standard

5. 5 The formal concept of non-inferiority: definition If T’s effect is not worse than C’s effect by more than δ, it is said to be non-inferior δ is a pre-specified non-inferiority margin

6. 6 Equivalence, non-inferiority and superiority: graphically Control better Test better -  0  equivalent non-inferior test superior control superior uninformative Test - Control

7. 7 Setting the non-inferiority margin Subjective – often contentious –If too large: inferior treatments may be called non-inferior –If too small: huge sample sizes are required Usually a fraction of the historical difference between control and placebo

8. 8 Assay sensitivity The ability of a RCT to find a difference between treatments if there truly is a difference- a property of one trial Sensitivity is a property for a class of RCTs Statisticians call this “power” – the probability of detecting a true difference of size 

9. 9 Assay sensitivity in a three armed RCT with T,C and P If T>P or S>P then the trial has demonstrated assay sensitivity If T=S=P then the trial is a failure –It has no assay sensitivity because it is known that S>P –No inference regarding the equivalence of S and T is possible

10. 10 Assay sensitivity in a two armed RCT with T and S A trial that finds T>S or S>T has ipso facto demonstrated assay sensitivity Problem: A two armed trial that does not distinguish treatments (S=T) has not demonstrated assay sensitivity Differentiating a failed trial from a trial that correctly finds no difference is not possible

11. 11 Therefore The conclusion that a test drug is non inferior to a standard is only valid if the standard would have been superior to placebo had one been included in the trial This possibility can only be appraised by comparing the results with historical RCTs

12. 12 Randomized controlled relapse prevention studies in the literature Leucht et al - AJP 2003 numerous studies* Schooler et al - AJP 2005 risperidone/haloperidol Pigott et al J - Clin Psych 2003 aripiprazole /placebo *Trials needed to have estimated relapse rates using Kaplan Meier and have reasonable sample sizes

13. 13 Probability of relapsing in 6 months based on KM Estimates-Aty vs Pl atypicalplacebo

14. 14 Probability of relapsing in 6 months based on KM Estimates-Aty vs Conv atypicalconventional

15. 15 Six month relapse rates for eleven prevention studies placeboatypical conventional

16. 16 Implications of the historical RCTs Six-month relapse rates RangeMean vs P vs Con –Atypicals 3 - 3919.1 21.6 17.0 –Conventionals 3 - 47 26.6 –Placebo 53 – 6356.0 There is no overlap of active vs placebo Reasonable to set  = 10 -15% test vs a conventional 15 - 20% test vs an atypical

17. 17 Powering the trial: example Assume P C = P T is about.35 Suppose  =.15 Let the two groups have equal sample sizes What sample size will reject H 0 with 80% power? Approximate sample size is 183 per group (based on Fisher’s exact test)

18. 18 Conclusion Regulatory Concern: Just as in an acute trial, the major concern is concluding that an ineffective drug works The historical record suggests that in active controlled relapse preventions studies in schizophrenia this risk is small