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The POPPI 1 Example: Statistical Comments Thomas A. Louis, PhD Department of Biostatistics Johns Hopkins Bloomberg SPH tlouis@jhsph.edu Little nits regarding the testing setup ...transformed as log(mean C-peptide+ 1 ) . Why “ 1 ?”

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the poppi 1 example statistical comments
The POPPI 1 Example:Statistical Comments

Thomas A. Louis, PhD

Department of Biostatistics

Johns Hopkins Bloomberg SPH

tlouis@jhsph.edu

TrialNet Workshop

March 7, 2005

little nits regarding the testing setup
Little nits regarding the testing setup

...transformed as log(mean C-peptide+1).

  • Why “1?”
  • A formal, Bayesian approach would automatically (and implicitly) move away from log(0)

...Shapiro-Wilk test for normality of the residuals and the White test for homoscedasticity

  • How to choose level
  • These tests have low power
  • The alternative is always true
  • Properties of testitests can be poor

Either go with the Wilcoxon or use a

Bootstrap-based test (direct test or BCa CI-based)

TrialNet Workshop

March 7, 2005

bigger issues with the design
Bigger issues with the design

TrialNet Workshop

March 7, 2005

have you missed an important contrast
Have you missed an important contrast?
  • Size and power were determined for three pair-wise group comparisons:
    • Mycophenolate mofetil (MMF) vs control
    • MMF/DZB (Daclizumab) vs control
    • MMF versus MMF/DZB
  • If the contrast:

(MMF + MMF/DZB) –2*Control

is statistically and clinically significant, will you regret not having included it in your framework for controlling type I error?

TrialNet Workshop

March 7, 2005

fundamental issue

Fundamental Issue

Analysis plan should separate “evidence”

(the joint likelihood for the three

randomization groups) from decisions

based on the evidence

Multiplicity should be addressed by an

explicit loss function or a collection of loss

functions

TrialNet Workshop

March 7, 2005

sample size and power
Sample Size and Power
  • Sample size (and follow-up time) need to address uncertainty in the relation between the surrogate

(C-peptide) and clinical endpoints

  • “60 subjects per group”
    • “subjects”  “patients” (or participants)
    • Hard to imagine that with the current state of knowledge, 60/60/60 is sufficient
    • Is equal allocation efficient

(statistically and for recruiting?)

TrialNet Workshop

March 7, 2005

sample size and power accounting for uncertainties
Sample Size and PowerAccounting for uncertainties
  • A series of “what ifs” (e.g., what if  = 1, 2, ...) generally underestimates the necessary sample size
  • Need to account for uncertainty in , base rates, dropouts, biologically plausible clinical differences and other uncertainties

TrialNet Workshop

March 7, 2005

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TrialNet Workshop

March 7, 2005

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TrialNet Workshop

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TrialNet Workshop

March 7, 2005

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TrialNet Workshop

March 7, 2005

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TrialNet Workshop

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TrialNet Workshop

March 7, 2005

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(CV)2

TrialNet Workshop

March 7, 2005

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TrialNet Workshop

March 7, 2005

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0.0 0.8 1.3 1.9 2.5

CV

TrialNet Workshop

March 7, 2005

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0.0 0.8 1.3 1.9 2.5

CV

TrialNet Workshop

March 7, 2005

pre workshop questions
Pre-workshop Questions
  • How long should the treatment and follow-up period in trials be?

Sufficient to address the relevant treatment comparisons. If a surrogate endpoint is not sufficiently validated, follow-up must includ clinical endpoints, in part to produce meaningful comparisons and in part to gain information on the relation between the surrogate and clinical endpoints.

  • Can larger numbers of treatments be compared simultaneously with aggressive curtailment for futility?

Yes, but follow-up still must be sufficient to support dropping a treatment or declaring a winner.

TrialNet Workshop

March 7, 2005

pre workshop questions19
Pre-workshop Questions
  • Can short term trials be grafted onto long term trials – roll phase 2 patients into phase 3 studies? Yes!!
  • Should trials be powered for large effect sizes or for more moderate effect sizes with monitoring guidelines that could terminate early for an unexpected large effect?

Definitely power for clinically important and biologically viable effect sizes. Monitoring will temper what may be large, maximal sample sizes, but if the size needs to be big, it needs to be big.

  • Should trials be powered to rule out adverse effects?

Yes, to rule out relatively high-incidence (S)AEs. Whether to power to rule out small to moderate (S)AEs depends on the integrity of post-marketing surveillance and on external information.

TrialNet Workshop

March 7, 2005

a culture change
A culture change

Successfully addressing and implementing

the foregoing requires changes

in culture and bureaucracy,

plus some statistical developments

TrialNet Workshop

March 7, 2005