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Repeated Measurements and Cross-Over Designs by Damaraju Raghavarao, Lakshmi Padgett

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Chapter 7Two-Period Cross-Over Designs with Residual Effects

7.1 INTRODUCTION

Two-period CODWR using two treatments introduced by Grizzle were extensively used in pharmaceutical studies until the early 1970s. These designs consist of using two sequences of treatments (A, B) and (B, A) on n1 and n2 experimental units.

This design has an intuitive appeal to the clinicians in that each patient acts as his or her own control, resulting in

  • Elimination of between-patient variation
  • Reduction in sample size
  • Reduction in cost due to fewer patients

However, several anomalies and controversies surround these designs. These designs are severely criticized for not accounting for the interaction between the periods and sequences of treatments used in the experiment or the carryover effect. The carryover effect may exist due to an inadequate washout period. In the presence of a carryover effect, the estimated treatment effect may be biased. However, if we can assume the carryover effect to be negligible in size, then one can proceed using this design (Huitson et al., 1982; Jones and Kenward, 2003). Brown (1980), Hills and Armitage (1979) and Grizzle (1965) recommend that if carryover effects are not negligible, a parallel design should be used, or if a cross-over design has been used, then the analysis should only be based on the first-period data. However, (Willan and Pater, 1986) disagree with this advice. Their view is that ‘the amount of carryover effect required to make a parallel group ...

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