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…..

• 1 Allocation Schedule per Strata

• 1 stratification variable with 2 levels

• Increased potential for errors

Administrative Burden

Misclassification of Strata

• Multi-center variability

• Timing

0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.90%

10%

20%

30%

40%

50%

60%

% Reduction in Standard Error

Correlation

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.

• 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

0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.90%

10%

20%

30%

40%

50%

60%

% Reduction in Standard Error

Correlation

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

• 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

•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.

Conclusions

CLAIM: PRE-STRATIFIED RANDOMIZATION IS OFTEN NECESSARY FOR 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

• 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 MALARIA

79 CM

40 Immediate 39 Delayed

R

77 SMA

39 Immediate 38 Delayed

R

THIS NOT THIS

156 SEVERE MALARIA

78 Immediate?? SMA?? CM

78 Delayed?? SMA?? CM

R

Pre-stratified randomization Un-stratified randomization

BENEFITS OF PRE-STRATIFICATION

• Protection against Type 1 error1

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

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-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

TRIALS

Against1. Too many strata2. Challenge to

implement3. Not necessary

For1. Protection against

Type 1 error2. Reduced sample size

in equivalence trials3. Balanced interim

analyses4. Pre-specified

subgroup analyses5. Protection against

drop-out in multicenter studies