## Subject Population and Endpoints

Every clinical trial starts with a clinical question. Based on this question, clinical trial team members work together to draft a clinical trial protocol. This protocol serves as the design document for the trial. The results obtained from a clinical trial will help address the key clinical question. Hence, the most important study design consideration is to understand the objective(s) of the given study, and the trial is designed to collect the necessary clinical data to help answer these...

## Gate Keeping Procedure

This procedure is also known as predetermined step-down or the hierarchy procedure (Bauer and Budde, 1994 Bauer et al., 1998). In short, this procedure follows a prespecified sequence. Testing will be conducted at the 0.05 level at each stage and it will continue as long as the p-value is significant at the 0.05 level. Testing will stop at the first instance when a p-value is above 0.05. This procedure is used very frequently when there is a prior belief of a monotone dose-response relationship...

## Review of Multiple Test Procedures

Various procedures based on different contrasts of the dose means have been proposed in the literature (Ruberg, 1989, Tamhane et al., 1996, Dunnett and Tamhane, 1998). Here we will only consider step-down procedures based on pairwise contrasts because (1) as shown by Bauer (1997), only pairwise contrasts yield procedures that control the FWE even when the dose response is not monotone, (2) they are simple to use, and (3) they can be easily extended to nonnormal data by using appropriate...

## Sensitivity of the N Parameter

The slope factor (Hill factor), determines the steepness of the dose-response curve. As the slope factor N increases, the dose range, defined as the ratio of ED90 to ED 10 tightens. Hence, the larger the value of N, the more sensitive the response is to changes in the dose of the drug. Figure 9.4 illustrates the effect of a change in the slope parameter N from 1 to 3 on the Emax model dose-response curve. Figure 9.5 illustrates the dose range (ED90 ED10) as a function of the slope factor based...

## Two Main Mechanism Classes for Delayed Effects

There are two qualitatively different mechanisms linking plasma concentration time course to subsequent actions, effects, and responses. First, the drug molecule must be distributed to the site of action, e.g., at the cell surface in the extracellular fluid adjacent to a receptor. Second, a chain of events involving turnover of physiological mediators such as cyclic AMP, gene transcription factors, and proteins is required before the action is translated into an effect or clinical response. In...

## Introduction to the Emax Model

The Emax model is a nonlinear model frequently used in dose-response analyses. The model is shown in Eq. (9.1) Ri The value of the response for patient i Di The level of the drug for patient i, the concentration may also be used in many settings E0 The basal effect, corresponding to the response when the dose of the drug is zero Emax The maximum effect attributable to the drug ED50 The dose, which produces half of Emax N The slope factor (Hill factor), measures sensitivity of the response to...

## Dose Escalation

It is not always necessary to escalate to doses as high as the MTD in the FIH studies. The highest single dose tested can also be defined as the pharmacologically active dose (PAD) giving the maximal effect in the absence of toxicity (Figure 3.3). However, the estimation of the PAD from preclinical pharmacology studies may not be possible if animal models of the disease are not available or the understanding of the fundamental biochemical or physiological aspects of the mechanism of action of...

## References

Patient specific dosing in a cancer Phase I clinical trial. Statistics in Medicine 20 2079-2090. Babb, J.S., Rogatko, A., and Zacks, S. 1998. Cancer Phase I clinical Trials efficient dose escalation with overdose control. Statistics in Medicine 17 1103-1120. Cheng, J., Langer, C., Aamdal, S., Robert, F., Engelhardt, L.R., Fernberg, O., Schiller, J. et al. (2004). Individualized patient dosing in Phase I clinical trials The role of EWOC in PNU-214936. Journal of...

## Clinical Development Plan

In the early stage of drug development, as early as in the nonclinical stage, a clinical development plan (CDP) should be drafted. This plan should include clinical studies to be conducted in Phases I, II and III. The CDP should be guided by the draft drug label. The drug label provides detailed information on how the drug should be used. Hence, a draft label at the early stage of drug development lays out the target profile for the drug candidate. Clinical studies should be designed to help...

## Hochbergs Stepup Procedure

This is also a sample-determined stepwise procedure, similar to that in Section 12.3.2. While Holm's step-down testing is a shortcut version of thepartition testing based on Bonferroni methods, Huang and Hsu 2005 show that Hochberg's step-up testing is also a special case, or shortcut version, of a partition testing based on Simes' test. Although more powerful than Bonferroni method Holm's procedure, Simes' test Hochberg's procedure control the Type I error rate familywise error rate at a only...

## Traditional or 3 3 Design

The most widely used design in oncology is the traditional design also known as the standard or 3 3 design. According to the 3 3 design, subjects are assigned in groups of three starting with the lowest dose with the following provisions If only three patients have been assigned to the current dose so far, then If no toxicities are observed in a cohort of three, the next three patients are assigned to the next higher dose level If one toxicity is observed in a cohort of three, the next three...

## Logistic Model

The logistic model is a four-parameter model, 9' E0, Emax, ED50, 5 , defined as f d, 9 E0 Emax 1 exp ED50 - d 5 10.10 E0 is the left-asymptote parameter, corresponding to a basal effect level not the placebo effect, though , Emax is the maximum change in effect from the basal level, and ED50 is the dose that gives half of the maximum change in effect. Finally, 5 is a parameter controlling the rate of change with dose in the effect and which has a graphical interpretation as the increment over...

## Core SAS Code for the Emax Model Analysis of the Oral Artesunate Example Data in Section

Proc nlin data malaria method marquardt hougaard parms e0 70 ed50 1.4 emax -30 n 8.61 if dose 0 then model pct e0 else model pct e0 doseft Smax ed50n dosen ods output parameterestimates ests run malaria was the name of the SAS data set used, containing dose mg kg and parasite clearance time. The method option specifies the iterative technique NLIN uses to estimate the parameters method marquardt was used. pct is the dependent variable, the parameters in the model are e0, emax, ed50 and n. The...

## Model Uncertainty and Model Selection

In the previous sections we have described a variety of commonly used dose-response models and given some possibilities of deriving initial parameter estimates for constructing model contrasts. We have not yet discussed the problem of selecting a model for the final analysis. This is a particularly important issue in the regulated environment of pharmaceutical drug development, since it is required to prespecify completely the statistical analysis and thus also the dose-response model used for...

## Initial Parameter Values for the Oral Artesunate Dose Response Analysis Example

As discussed in Section 9.5.2, starting values for the parameters are required for Proc NLIN. Figures 9.9 and 9.10 illustrate fitting a smoothing spline to the data to provide initial estimates of Emax model parameters. Figure 9.10. Estimation of starting value for N using a smoothing spline. Figure 9.10. Estimation of starting value for N using a smoothing spline. Figure 9.10 illustrates the use of Eq. 9.5 in estimating a starting value for the slope parameter N. Based on Figures 9.9. and...

## Escalation with Overdose Control Design

The main attribute underlying EWOC is that it is designed to approach the MTD as fast as possible subject to the ethical constraint that the predicted proportion of patients who receive an overdose does not exceed a specified value. The design has many advantages over some competing schemes such as up-and-down designs and continual reassessment method see Babb et al. 1998 . In this section, we describe the methodology in details and give a real-life example illustrating this technique. Let Xmin...

## Oral Artesunate Dose Response Analysis Example

The following example is based on a study by Angus 2002 . The objective of the study was to characterize the dose-response of oral artesunate on falciparum malaria. Forty-seven adult patients were randomized to a single dose of oral artesunate varying from 0 to 250 mg together with a curative dose of oral mefloquine. A patient could receive a dose of either 0, 25, 50, 75, 100, 150, 200, or 250 mg. Figure 9.7 illustrates patients' parasite clearance time the time required for a patient to reach...