Introduction

Identifying the correct dose is one of the most important and difficult goals in drug development. Selecting too high a dose can result in an unacceptable toxicity profile, while selecting too low a dose decreases the chance of it showing effectiveness in Phase III trials and thus getting regulatory approval. Typically decisions derived from dose-response studies can be divided into two main components establishing that the treatment has some effect on the outcome under consideration, the so...

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...

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

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

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...

Escalation and A B Designs

In this section, we describe two types of designs that are used in dose-finding studies in oncology and other areas. Both designs do not need specification of the total sample size, since, ideally, experimentation is continued until the MTD is exceeded by one dose level. The escalation design is defined as follows. Subjects are assigned in groups of size m starting with the lowest dose. Let CU be an integer such that 0 lt CU lt m. Let X dj be the number of toxicities in a cohort of subjects...

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...