Experimental design, preclinical

Experimental Design Experimental design for both in vitro and in vivo translational studies is influenced by the endpoints that will be evaluated in clinical studies. The experimental design should also recognize that new endpoints may need to be evaluated in clinical trials. An example of a preclinical development program for a combined cell-based neo-organ product is presented in Table 35.10. 

The developability experiments in six scientific disciplines shown in Figure 4 more fully characterize a lead discovery candidate before the compound enters the definitive preclinical, then the nonclinical and clinical drug development processes. The experimental designs could also be used, with minor modifications, to evaluate a class of compounds and thus to select the candidate with the best characteristics for further development. With appropriate planning and commitment of resources, these studies can usually be completed in 3 to 6 months if major problems are not encountered in one or more of the scientific areas. 

Ette, E.I. Howie, C.A. Kelman, A.W. Whiting, B. Experimental design and efficient parameter estimation in preclinical pharmacokinetic studies. Pharm. Res. 1995, 12, 729-737. 

E. I. Ette, A. W. Kehnan, C. A. Howie, and B. Whiting, Efficient experimental design and estimation of population pharmacokinetic parameters in preclinical animal studies. Pharm Res 12 729-737 (1995). 

A clear understanding of the clinical indication is the first step this should drive preclinical experimental design. In addition, the nature of the gene and the delivery vector can dramatically alter the methodological approach to risk assessment. Similarly, the species used for conventional toxicological testing may not be... 

The goals of preclinical toxicity studies include identifying potential human toxicities, designing tests to further define the toxic mechanisms, and predicting the specific and the most relevant toxicities to be monitored in clinical trials. In addition to the studies shown in Table 5-1, several quantitative estimates are desirable. These include the no-effect dose—the maximum dose at which a specified toxic effect is not seen the minimum lethal dose—the smallest dose that is observed to kill any experimental animal and, if necessary, the median lethal dose (LD50)—the dose that kills... 

In vitro assays to determine the action of human cytochromes and other DMEs have been developed in the last 10 years. In more recent times, their use in preclinical testing has increased rapidly in response to the pressures of prioritizing drug candidates and the ethical drive to reduce animal experimentation. As drug metabolism is better understood at the molecular level, it is proving possible to design assays to look at particular aspects of this complex process. There are still limitations which reflect the discrete nature of the tests with respect to each other, whereas the in vivo... 

Guidelines for clinical trials have been established by the Food and Drug Administration (FDA) [6]. The classie model of clinical trial design takes pharmaceutical compounds that have shown some promise in preclinical experimentation through several levels of testing prior to implementation in clinical practice (Fig. 1). In general, preclinical studies in vitro and in animals... 

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