Clinical Trials

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❘❙❚■ Chapter 10 | Crossover Trialsdifferences due to different patients) due to the effect of being in the trial itself.If this period effect is large, it can be minimized by allocating equal numbers ofsubjects to different sequences and some form of statistical adjustment might thenbe required [4–6].Where are crossover trials useful?Crossover trials are most commonly used in early drug development, especiallyin Phase I pharmacokinetic, bioequivalence, dose-proportionality, and doseescalationstudies (for investigating the maximum–tolerated dose), and in PhaseII pharmacodynamic studies. In later phases of drug development, as well as inother clinical studies, a crossover design is suitable for trials that involve relativelystable conditions such as asthma, rheumatism, migraine, mild-to-moderatehypertension, and angina.Treatments with a quickly reversible effect (eg, bronchodilators) are more suitedfor investigation under crossover design than those with a more persistent effect(eg, steroids). Furthermore, this design is more applicable to single-dose studiesthan to long-term repeat-administration studies.ConclusionThe crossover design for trials is a valuable tool in clinical research when appliedin the correct setting. Its main advantage is that it evaluates within-subjecttreatment comparisons rather than between-subject comparisons, as in studieswith a parallel design. Consequently, the data variability in crossover trials islower, which is reflected in there being more robust data with narrowerconfidence intervals, and which reduces the number of study subjects needed totest hypotheses in clinical settings. The main limitation of the crossover design isthe possibility that a carryover effect could occur, but this can be avoided byensuring that there is a sufficient washout interval between the differenttreatment periods.Crossover trials are widely used in the earlier phases of clinical drug development(pharmacokinetic, bioequivalence, and pharmacodynamic Phase I studies) andare clinically useful in studies involving stable chronic conditions and/or drugswith short-lived effects.98
Clinical Trials: A Practical Guide ■❚❙❘References1. Al-Said MS, Al-Khamis KI, Niazy EM, et al. Bioequivalence evaluation of two brands ofcefuroxime 500 mg tablets (Cefuzime ® and Zinnat ® in healthy volunteers). Biopharm Drug Dispos2000;21:205–10.2. Rosing J, Middeldorp S, Curvers J, et al. Low-dose oral contraceptives and acquired resistanceto activated protein C: a randomised crossover study. Lancet 1999;354:2036–40.3. Chow SC, Liu JP. Design and Analysis of Clinical Trials: Concepts and Methodologies.New York: John Wiley & Sons, 1998.4. Senn S. Crossover Trials in Clinical Research, 2nd edition. Chichester: John Wiley & Sons, 2002.5. Senn S. Crossover design. In: Chow SC, editor. Encyclopedia of Biopharmaceutical Statistics.New York: Marcel Dekker, 2000:142–9.6. Jones B, Kenward MG. Design and Analysis of Cross–over Trials, 2nd edition. London: Chapmanand Hall/CRC, 2003.99
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❘❙❚■ ContributorsStephen L
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Clinical Trials: A Practical Guide
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■■❚❙❘Chapter 19Comparison
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■■❚❙❘Part IVSpecial Trial
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■■❚❙❘Chapter 23Subgroup A
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■■❚❙❘Chapter 25Adjustment
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■■❚❙❘GlossaryGlossary453
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■■❚❙❘IndexIndex467
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Clinical Trials

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