First-in-man (FIM) Phase I clinical trials are part of the critical path in the development of a new compound entity (NCE). Since FIM clinical trials are the first time that an NCE is dosed in human subjects, the designs used in these trials are unique and geared toward patient safety. We develop a method for obtaining the desired response using an adaptive non-linear approach. This method is applicable for studies in which MTD, NOEL,NOAEL, PK, PD effects or other such endpoints are evaluated to determine the desired dose. The method has application whenever a measurable PD marker is an indicator of potential efficacy and could be particularly useful for dose finding studies. The advantages in the adaptive non-linear methodology is that the actual range of dose response and lowest non-effective dose levels are more quickly and accurately determined using fewer subjects than typically needed for a conventional early phase clinical trial. Using the nonlinear logistic model, we demonstrate, with simulations, that the DOSEFIND approach has better asymptotic relative efficiency than a fixed-dose approach. Further, we demonstrate that, on average, this method is consistent in reproducing .the target dose, that it has very little bias. This is an indicator of reproducibility of the method, showing that the long-run average error is quite small. Additionally, DOSEFIND is more cost effective because the sample size needed to obtain the desired target dose is much smaller than that needed in the fixed dose approach.

In this project we review the developments of several variations of the up-and-down design utilized in Phase I clinical trials to estimate the maximum tolerated dose (MTD) of a drug which corresponds to a fixed probability of response or the pre-specified toxicity rate in the target population. In these designs selection of dose levels is restricted to one level higher, one level lower or the same. Several methods of estimation of the MTD are investigated. Some comparison of the designs by Monte Carlo simulation are carried out by the quality of the estimator of the target dose using the isotonic estimator. The designs are investigated under the generalized logistic (for different values of the power) and the gamma distributions. The NR is found to perform best on the basis of the quality of estimator under these distributions. The BCD is found to perform best on the basis of the average proportion of toxicity for a pre-specified toxicity rate of 0.2 whereas the KROW performs best for a toxicity rate of 0.3. / Thesis / Master of Science (MS)