pre stratified randomization is not necessary for large clinical trials n.
Download
Skip this Video
Loading SlideShow in 5 Seconds..
PRE-STRATIFIED RANDOMIZATION IS NOT NECESSARY FOR LARGE CLINICAL TRIALS PowerPoint Presentation
Download Presentation
PRE-STRATIFIED RANDOMIZATION IS NOT NECESSARY FOR LARGE CLINICAL TRIALS

Loading in 2 Seconds...

play fullscreen
1 / 18

PRE-STRATIFIED RANDOMIZATION IS NOT NECESSARY FOR LARGE CLINICAL TRIALS - PowerPoint PPT Presentation


  • 127 Views
  • Uploaded on

PRE-STRATIFIED RANDOMIZATION IS NOT NECESSARY FOR LARGE CLINICAL TRIALS. Brent Leininger , Patrick Kurkiewicz , Lifeng Lin, Xiang Li, Bryan Trottier Jr , Yuanyuan Wang. Pre-stratification is Insurance. Risk of Chance Imbalance. As Sample Size Increases…. Administrative Burden.

loader
I am the owner, or an agent authorized to act on behalf of the owner, of the copyrighted work described.
capcha
Download Presentation

PowerPoint Slideshow about 'PRE-STRATIFIED RANDOMIZATION IS NOT NECESSARY FOR LARGE CLINICAL TRIALS' - vince


An Image/Link below is provided (as is) to download presentation

Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author.While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server.


- - - - - - - - - - - - - - - - - - - - - - - - - - E N D - - - - - - - - - - - - - - - - - - - - - - - - - -
Presentation Transcript
pre stratified randomization is not necessary for large clinical trials

PRE-STRATIFIED RANDOMIZATION IS NOT NECESSARY FOR LARGE CLINICAL TRIALS

Brent Leininger, Patrick Kurkiewicz,

Lifeng Lin, Xiang Li, Bryan TrottierJr, Yuanyuan Wang

risk of chance imbalance
Risk of Chance Imbalance

As Sample Size Increases…..

administrative burden
Administrative Burden
  • 1 Allocation Schedule per Strata
  • 1 stratification variable with 2 levels
  • Increased potential for errors
misclassification of strata
Misclassification of Strata
  • Multi-center variability
  • Timing
slide6

Pocock SJ, Assmann SE, Enos LE, Kasten LE. Subgroup analysis, covariate adjustment and baseline comparisons in clinical trial reporting: current practice and problems. Stat Med. 2002 Oct 15;21(19):2917-30.

slide7
111 of 258 trials balanced on prognostic factors (other than center)
  • 36% of trials accounted for stratification in the analysis
  • Accounting for stratification variables in the analysis is recommended by both ICH and CONSORT guidelines
slide8

Pocock SJ, Assmann SE, Enos LE, Kasten LE. Subgroup analysis, covariate adjustment and baseline comparisons in clinical trial reporting: current practice and problems. Stat Med. 2002 Oct 15;21(19):2917-30.

alternatives
Alternatives
  • Post-stratification (i.e. adjusted analysis)
    • Efficiency Loss vs. Pre-Stratification?
  • 4 strata, 80 patients per strata
  • Efficiency loss is <4%

McHugh R, Matts J. Post-stratification in the randomized clinical trial. Biometrics. 1983 Mar;39(1):217-25.

post stratification criticism
Post-Stratification Criticism
  • Define covariates ‘a priori’ OR…..
  • Define plan for covariate selection ‘a priori’

Pocock SJ, Assmann SE, Enos LE, Kasten LE. Subgroup analysis, covariate adjustment and baseline comparisons in clinical trial reporting: current practice and problems. Stat Med. 2002 Oct 15;21(19):2917-30.

claim pre stratified randomization is often necessary for large n 100 per group clinical trials
Claim: Pre-stratified randomization is Often necessaryfor large (N > 100 per group) clinical trials
  • Helps ensure that compared groups are similar with respect to known important prognostic factors
  • Potential benefits, even in large clinical trials1
    • Protection against Type 1 Error
    • Reduction of sample size in equivalence trials
    • Facilitation of interim analyses
    • Identification of subgroups prior to analysis
    • Protection against treatment assignment imbalance with recruitment-center dropout in multicenter trial

1 Kernan et al. J Clin Epidemiol (1999)

uganda study immediate vs delayed iron in severe malaria
UGANDA STUDY:IMMEDIATE VS. DELAYED IRON IN SEVERE MALARIA
  • Children with severe malaria randomized to immediate or delayed iron
  • Primary outcome = frequency of hospital admissions in next 12 months
  • Severe malaria includes cerebral malaria and severe malarial anemia
  • Children with severe malarial anemia have greater risk of readmission to hospital
uganda study immediate vs delayed iron in severe malaria1
UGANDA STUDY:IMMEDIATE VS. DELAYED IRON IN SEVERE MALARIA

THIS

NOT THIS

156 SEVERE MALARIA

79 CM

77 SMA

Pre-stratified randomization

Un-stratified randomization

R

R

R

39 Immediate

40 Immediate

78 Immediate

?? SMA

?? CM

78 Delayed

?? SMA

?? CM

39 Delayed

38 Delayed

benefits of pre stratification
Benefits of Pre-stratification
  • Protection against Type 1 error1

1 Feinstein and Landis in Kernan et al. J Clin Epidemiol (1999)

benefits of pre stratification1
Benefits of Pre-stratification
  • Smaller sample size in equivalence trials
    • Reduction in sample size by 12-42% over a range of assumptions (Nam, Stat Med 1995)
    • Significant savings in both cost and time
  • Facilitation of interim analyses
    • Interim DSMB meeting for iron/malaria study March 2013 (!)
      • 79 CM (40 I, 39 D) ; 78 SMA (39 I, 38 D)
      • Frequency of serious adverse events in I vs. D.
      • If not balanced, potential safety concern undetected
benefits of pre stratification2
Benefits of Pre-stratification
  • Subgroup analysis
    • Strata identified before start of study
    • Protects against multiple comparisons
    • Strengthens a finding of treatment effectiveness within subgroups
  • Multicenter study—protection against drop-out
    • Because patients in each center are balanced for treatment assignment, withdrawal of a center will not result in imbalance among remainder of patients.
claim pre stratified randomization is often necessary for large n 100 per group clinical trials1
Claim: Pre-stratified randomization is often necessaryfor large (N > 100 per group) clinical trials

Against

  • Too many strata
  • Challenge to implement
  • Not necessary

For

  • Protection against Type 1 error
  • Reduced sample size in equivalence trials
  • Balanced interim analyses
  • Pre-specified subgroup analyses
  • Protection against drop-out in multicenter studies