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There is often a knowledge gap between evidence generated on therapeutic products during clinical trials and the information needed for optimal use of the therapeutic products in clinical practice. This knowledge gap may partly be due to drug development programs primarily interested in obtaining marketing authorization or changes in drug labeling from regulatory authorities. Therefore, pre-market drug development is usually conducted in a limited number of selected individuals or groups that may not be representative of the intended patient population and the duration of drug exposure may be relatively shorter than the chronic use of many drugs in the post-approval period. Hence, approved therapeutic products may face uncertainty about appropriate use in clinical practice. This challenge is rarely addressed through acquisition of additional evidence in the post-approval period. Consequently, during the evaluation of benefit(s) and risk(s) of new therapeutic products, questions arise that relate to pre-market and post-market issues. Answering these questions typically require using the totality of evidence approach.
Totality of evidence is an approach in which all the available evidentiary sources are weighted for decision-making. Totality of evidence can also be an iterative process in which consecutive data build on existing evidence to provide the critical mass of reliable qualitative and quantitative knowledge needed for adequate assessment of the benefit(s) and risk(s) of therapeutic products.
The FDA applies totality of evidence in regulatory decision-making. Totality of evidence can permit regulatory flexibility because it may allow use of evidence in one discipline to reduce the uncertainty in another discipline. For example, clinical evidence may reduce pharmacological uncertainty, especially if the new product has an analog or belongs to an existing class with known effects. Also, statistical uncertainty may be tolerable if the epidemiological design of the study reduces bias as much as possible. Furthermore, totality of evidence considers changes in the therapeutic landscape.
In this presentation, I will discuss the utility and challenges encountered in the application of the totality of evidence approach for assessing therapeutic products intended for special populations. I focus on special populations because they frequently have limited data, appreciable uncertainties, and unmet medical needs that require flexibility in decision-making to reduce morbidity and mortality.