Time required for study conduct

Parallel-group, placebo-controlled, randomized, double-blind ascending dose Phase I study design. Given this early stage of drug development, not all subjects from the same dose group or cohort are dosed on the same day. This practice of spacing the dosing of subjects in a given dose group minimizes the number of subjects who are exposed to a given escalating dose of the drug and who are potentially at risk for a dose-limiting or irreversible toxicity of the drug. Should...

Phase Iiiii Clinical Trials

Phase II III trials are designed to study the efficacy and safety of a test drug. Unlike Phase I studies, subjects recruited in Phase II III studies are patients with the disease for which the drug is developed. Response variables considered in Phase II III studies are mainly efficacy and safety variables. For example, in a trial for the evaluation of hypertension (high blood pressure), the efficacy variables are blood pressure measurements. For an anti-infective trial, the response variables...

Mixed Effects Emax Model

Equation 9.8 describes a mixed effects Fmax model as presented in Girard et al. (1995). This model is useful when there are multiple observations per patient as it accounts for the correlation of the within-patient responses and can be used to describe individual dose-response curves, patient indicator observation number for a patient response of patient i, observation j dose of the drug for patient i, observation j zero-dose response for patient i maximum attributable drug effect for patient i...

Linear in Log Dose Model

The linear in log-dose model is defined, for 9' (E0, 8) as where a value c > 0 is added to d to avoid problems with the placebo (d 0) arm. E0 is the basal effect and 8 is the slope associated with log(d + c). As with the Emax model, an increasing effect (8 > 0) model will be assumed. Clearly, the linear in log-dose model is a location-scale model which can be expressed as f (d, 9) E0 + 8f 0(d), with the standardized model being equal to so that the determination of the appropriate model...

Estimating the MED in Dose Finding Example

To illustrate the methods described in this section for estimating the MED from a dose-response model, we consider again the dose-finding study introduced in Section 10.1. The plot of mean responses per dose in Figure 10.1 suggests that an Emax model as described in Section 10.2 can be used to adequately describe the dose-response relationship and is the model that is used here to illustrate the MED estimation methods. Figure 10.1 can also be used to provide initial estimates for the ED50...

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...

Adjusting for Covariates 531 Model

In the previous section, the MTD was assumed to be the same for every member of the patient population no allowance is made for individual patient differences in susceptibility to treatment. Recent developments in our understanding of the genetics of drug-metabolizing enzymes and the importance of individual patient Figure 5.1. Posterior density of the MTD when the number of treated patients (from bottom to top) is 1,5,10,15,20,25,30,33. Thex-axis represents the MTD and the y-axis represents...

Preclinical Toxicology Studies

Before going into human trials, candidate drugs and biologic undergo extensive safety evaluation in several species of animal. The legal requirements in the United States are spelled out in regulations promulgated by the Food and Drug Administration for the filing of an Investigational Drug Exemption (IND U.S. Federal Register, 1988). The regulations call only for sufficient preclinical studies to assure the safety and rights of the human subjects who take part in Phase I, II, and III studies....

The Clinical Trial Simulation Project

The planning for the Phase II trial began prior to the candidate entering Phase I. Because the proposed dose-finding objectives were much more ambitious than those of a typical Phase IIa POC trial, we also began planning a clinical trial simulation (CTS) project to support the design process. A colleague who was not a regular clinical project team member led the CTS project. This administrative arrangement was necessary because the regular team members could not devote sufficient time, within...

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...

Frequency of Dosing

In designing dose-response clinical studies, we need to know how often should a patient take the test drug (e.g., once a day, twice a day, or dose every 4 hours during the day). This is a question about dosing frequency, and it is usually guided by the Phase I PK-PD findings. One of the PK parameters is the half-life of a drug. The estimated half-life helps to estimate how long the drug will stay in human body. Using this information, we can propose a dosing frequency to be used for...

Introduction

The primary goal of a cancer Phase I clinical trial is to determine the dose of a new drug or combination of drugs for subsequent use in Phase II trials to evaluate its efficacy. The dose sought is typically referred to as the maximally tolerated dose MTD and its definition depends on the treatment under investigation, the severity and reversibility of its side effects, and on clinical attributes of the target patient population. Since it is generally assumed that toxicity is a prerequisite 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...

Oral Artesunate Dose Response Analysis Example

Sas Dose Response Curve With Ed50 Line

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...

Introduction to the Emax Model

Response Curve

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 the...

Two Main Classes of Drug Effect

For any disease progress model, there are two distinct ways that a drug may affect the natural history of the disease. The first simply shifts the natural history curve producing an offset to the untreated time course of disease status. The second is to change the rate of progression of the disease. This is illustrated in Figure 6.5. The offset pattern of drug effect may also be called symptomatic because it is typically associated with responses that relieve a patient's symptoms e.g., pain...

Estimating the Starting Dose in Phase I

A strategy has been proposed to determine the highest recommended starting dose of new therapeutics in adult healthy volunteers FDA, 2002 . The draft guidance presents a fairly simple method of estimating the starting dose. The maximum recommended starting dose MRSD in adult healthy subjects is to be derived from the no-observed adverse effect levels NOAELs in toxicology studies of the most appropriate species, the NOAELs converted to human equivalent doses HED , and a safety factor is then...

References

Adelroth, E., Inman, M.D., Summers, E., Pace, D., Modi, M., and O'Byrne, P.M. 1997. Prolonged protection against exercise-induced bronchoconstriction by the leukotriene D4-receptor antagonist cinalukast. Journal of Allergy and Clinical Immunology 99 210-215. Andrews, E., and Dombeck, M. 2004. The role of scientific evidence of risks and benefits in determining risk management policies for medications. Pharmacoepidemiology and Drug Safety 13 599-608. Boxenbaum, H., and DiLea, C. 1995....

General Considerations for FIH Studies

Ascending dose studies are usually the first clinical trials in the drug development process. The upper limit of a compound's therapeutic window is partially characterized in Phase I as these ascending dose studies usually determine the dose-limiting AEs that prevent the titration to higher doses. The primary objectives of these ascending dose studies are to estimate a maximally tolerated dose MTD , to characterize the most frequently occurring AEs, and to gain a general understanding of the...

Schedule Dependence

There is no clearly recognized definition of what constitutes schedule dependence. One way it might be defined is if the same total dose is given with different dosing schedules and the cumulative response varies then this is schedule dependence. On the other hand if the time of peak drug effect changes with dose then this would not be usually called schedule dependence. Nevertheless, changes in the timing and magnitude of neutropenia with different dosing schedule of anticancer drugs have been...

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 the...