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When Should a Clinical Trial Design with Pre-Stratification be Used?

When Should a Clinical Trial Design with Pre-Stratification be Used?. Group 1. Stratification. Why? Achieve balance between groups on factors associated with the response (prognostic variables) How? Strata created based on prognostic factors Pre-Stratification

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When Should a Clinical Trial Design with Pre-Stratification be Used?

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  1. When Should a Clinical Trial Design with Pre-Stratification be Used? Group 1

  2. Stratification • Why? • Achieve balance between groups on factors associated with the response (prognostic variables) • How? • Strata created based on prognostic factors • Pre-Stratification • Stratification before treatment allocation; accounted for in analysis • Post-Stratification • Treatment allocation without strata; stratification in analysis

  3. When to Pre-Stratify • Aims: • Reduction in variability (balance of prognostic factors between treatment groups) • Increase in power • Conditions: • Known salient prognostic variables • Ex: Multiple study sites • Allows for dropping or adding sites during trial (FDA.gov) • Ex: Gender, age groups, etc. • Focus on few prognostic variables • More important in smaller study size Kernan et al 1999

  4. Example: CARP Trial

  5. The Study • Study Question • Is coronary re-vascularization appropriate in patients with stable coronary artery disease prior to an elective major vascular surgery? • Study Design • Randomized, multi-center phase III trial • Intervention • Coronary re-vascularization prior to elective surgery • No coronary re-vascularization prior to elective surgery • Primary endpoint = long-term mortality • Pre-stratification: • Center (18 VA Medical Centers) • Prognostic factor: Type of elective vascular surgery (intraabdominal or infrainguinal)

  6. On Stratification Intervention: Re-vascularization Pre-Strata 2: Vascular Surgery Pre-Strata 1: Center Randomize Yes Infrainguinal Center 1 Vascular Intervention Planned No Yes Intrabdominal No Randomize

  7. Results of Stratification

  8. Why not post-stratify? • Higher risk for imbalance in vascular surgery type getting different study intervention • Could skew the primary outcome Post-Strata: Vascular Surgery Intervention: Re-vascularization Pre-Strata: Center Randomize Infrainguinal Outcome Yes Center 1 Intrabdominal No

  9. Problems with Pre-Stratification • Requires baseline values for prognostic variables prior to randomization • Precise stratum definition can be difficult • More administrative work • Small gain in power for large trial • Can diminish power if too many strata

  10. Summary • When Should a Clinical Trial Design with Pre-Stratification be Used? • Multi-center studies • Smaller sample size with known prognostic factors • Known prognostic factors that may be difficult to post-stratify

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