Module 2: Risk Assessment Tools

"All substances are poisons; there is none which is not a poison.
The right dose differentiates a poison and a remedy"
-Paracelsus

As the statement by Paracelsus indicates, the difference between a beneficial therapeutic effect and an adverse toxic effect often lies just in the dose of the drug. The US Food and Drug Administration definition of a safe drug is “one that has reasonable risks, given the magnitude of the benefit expected and the alternatives available”. The dose dependent response relationship between beneficial and toxic implies that even drugs that are considered ‘safe’ have a high potential for exerting toxic effects as the dose reaches a certain threshold. The FDA statement also implies that more adverse effects might be tolerated if no other alternatives are present and if there is a net benefit of using the drug.

The goal of pharmaceutical safety evaluation is to characterise the risk to humans exposed to the particular drug. Clearly, there has to be a process in which the risks (and benefits) of a new drug are determined. This process is called risk assessment. During this process the risk of adverse effects following exposure to a specific pharmaceutical compound is determined and quantified.

A pharmaceutical risk assessment procedure is often divided into four steps:

1) Hazard identification
2) Determination of the dose-response relationship
3) Exposure assessment
4) Integration of all data into a final assessment; risk characterization

The challenge throughout the risk assessment procedure is to extrapolate data obtained from a variety of sources, most importantly animal- and in vitro testing, into results that are meaningful in a human context and that ultimately provide safer drugs. Throughout this section, the reader should keep this in mind.