Clinical development program examples

The ICH S7A guidance states that "supplemental" studies are meant to evaluate potential adverse pharmacodynamic effects on organ systems functions that are not acutely essential for the maintenance of human life and not addressed by the "core battery" or repeated dose toxicity studies when there is a cause for concern.25 Examples of physiological functions that fall into that category include, but are not limited to, the renal/urinary, immune, GI, endocrine and autonomic nervous systems. This section focuses on the renal and GI systems based on their potential impact on the clinical development program. 

This example suffers from an oversimplification that we have to deal with in the real world, namely that study participants do not always complete the study for the full length of the follow-up period. Participants may drop out of studies for a number of reasons, some of which reflect their experience with the drug (for example, it may be poorly tolerated). Therefore, the "time at risk" differs from individual to individual within the same trial, and it can differ to a considerable degree from trial to trial throughout a clinical development program. 

Examples of the application of strategies based on increasing LLE or LipE and optimizing physicochemical properties as key components of medicinal chemistry programs that delivered clinical development candidates have begun to be described in the last year or so. It remains to be seen whether the hoped for reduction in compound attrition that this approach seeks to achieve will be realized, as it is early days. 

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. 

Failed Clinical Drug Development Programs as Teaching Examples... 

Should an early decision be made to develop the eutomer, then the drug development program would be the same as for conventional NCEs, with the possible exception that assessment of in vitro and/or in vivo chiral inversion may be desirable. However, if development continues with the racemate, time, cost, and staff resource commitments become magnified. For example, a very important variable to consider is spedes differences in enantiomer exposure. Appropriate toxicokinetic studies are advisable in order to assure that, at toxicological doses, the animal species tested have attained suffident plasma concentrations of each enantiomer to support clinical evaluation at therapeutic doses in humans. The enantiomeric ratio (based on maximum drug concentrations fCmax] and/or area under the plasma drug concentration-time curve [ALJC]) should be evaluated, and... 

---