Clinical Trials

Clinical Trials: A Practical Guide ■❚❙❘In bioequivalence studies, C maxand AUC are often used as primary endpoints toassess bioequivalence between test and standard drug formulations, with respectto the rate of, and extent of, absorption of a study drug. Like the mean, the AUCdoes not take variability in response for a particular subject into consideration.When calculating an AUC by the trapezoidal rule, missing values areconventionally treated in the following ways. If missing values occur before thefirst or after the last observed response value, they do not contribute to theAUC calculation – in Figure 3, the plasma concentration is non-quantifiablebefore 0.25 hours and after 8 hours. If the missing value occurs between twoobserved data points, it is assumed that the outcome variable lies on a straight linebetween these points. For example, in Figure 3 the drug concentration between4 and 6 hours is assumed to be linearly distributed. Various other methods can beused to extrapolate missing values for different types of data, such as lastobservation carried forward. Each method has its advantages in different settings:for detailed information see Reference [9].Percentage of time/number of occasions that a response variableis above/below a certain valueThe use of percentage or number of follow-up measurements that are larger orsmaller (depending on the clinical relevance) than a prespecified value specificallytakes into account fluctuations in the response variable during the course of astudy. The former gives the fraction of time that an outcome variable is above orbelow a clinically meaningful value, whereas the latter reflects the frequency offluctuation around this selected value during the observation period. Thesesummary measures are useful when there are many peaks and troughs in aresponse profile with a very large number of time points. They are frequently usedin pharmacodynamic studies in which pH values or vital signs (eg, blood pressure,heart rate, respiration rate) are recorded at small time intervals.For example, a blinded trial was conducted in healthy volunteers to determinewhether drug A was comparable to drug B in the suppression of gastroesophagealreflux provoked by a standard meal, by using ambulatory esophageal pHmonitoring. The primary efficacy parameter was the percentage of time for whichthe esophageal pH fell below 4, and the second efficacy parameter was thenumber of occasions on which esophageal pH fell below 4. Figure 4 shows a pHprofile for a subject, in which the pH was recorded every 6 seconds over 4 hours.For this subject, the percentage of time and number of occasions for which the pHfalls below 4 are 0.75% and 5, respectively.325