Bioequivalence and Bioavailability Forum

❝ Astonishing enough this is already mentioned in the 1997 FDA guidance:

July 1992

Note that the carryover effect is, essentially, the sequence effect, which can be tested against the sum of squares within sequence. If this carryover effect exists, then it confounds the test on formulations. [...] My own experience with a large number of comparative bioavailability trials has led me to believe that significant carryover effects (at the 0.05 level) tend to occur in about 5% of the trials; in other words, I believe that carryover effects do not normally exist. There are several reasons why this assumption is a reasonable one. First sub­jects in bioavailability trials are usually normal human volunteers whose physi­cal condition is unlikely to change radically from one period of a crossover trial to another, unlike patients whose disease state may progress during the course of even a short trial. Second, the trial usually involves only single doses of the drug formulations and is thus unlikely to result in a marked change in a sub­ject's physical condition. Third, a washout period is scheduled between the periods of the crossover trial which allows for elimination of all drug from the system; and a direct check of the presence of drug is, of course, obtained from the zero-hour blood level. Wagner (1974)^[2] has, however, raised the possibility that an unmeasured metabolite might still be present in the body and affect the biotransformation at the succeeding administration.

1. WJ Westlake
   Bioavailability and Bioequivalence of Pharmaceutical Formulation
   In: KE Peace (Ed.), Biopharmaceutical Statistics for Drug Development
   Marcel Dekker, New York, p337 (1988)
   
2. JG Wagner
   Use of a Clinical Pharmacokinetics Laboratory for Bioavailability Assessment
   In: G Levy (Ed.), Clinical Pharmacokinetics: A Symposium
   American Pharmaceutical Association, Academy of Pharmaceutical Sciences, Washington, D.C., p154 (1974)