The Predictive Value of Non-Clinical Testing

There is a big concern for unintentionally exposing an embryo or foetus in women of childbearing potential. Such women should not be exposed without intent before data have become available that allow assessing potential benefits and risks. The women can be included in early clinical trials in some situations without non-clinical embryo-foetal developmental toxicity studies. Women do wish to become more involved and in order to do so safely, ways to minimise risks include:

1. Reproduction toxicity studies can characterise the risk of a medicine.
2. Risks can be limited if pregnancy is prevented during clinical trials. This can be done with pregnancy tests (e.g. based on human chorionic gonadotropin (hCG)) use of highly effective methods of birth control (failure <1%), orstudy entry only after a confirmed menstrual period.

In some cases, it might be difficult to conduct embryo-foetal development toxicity studies in an appropriate animal model (as in some medicines derived from biotechnology). Researchers therefore have more options to consider that can minimise the risks for teratogenicity (causing foetal malformations):

• Inform the participant of possible risks to the embryo or foetus.
• Educate the participant to ensure compliance.
• Test for pregnancy during the trial.
• Know the mechanism of action of the drug and how exposed the foetus will be. For example, for monoclonal antibodies embryo-foetal exposure is low in humans during organogenesis. Based on this, developmental toxicity studies can be done.

It is normal that preliminary data on reproduction toxicity are available from two animal species when women of childbearing potential (WOCBP) are included in clinical trials. In addition, when measures are taken to prevent pregnancy in clinical trials, up to 150 WOCBP may be included and receive the investigational treatment for a relatively short duration (up to 3 months) and before definitive reproduction toxicity testing. This procedure is acceptable because of the very low rate of pregnancy in controlled clinical trials of this size and duration. Also because preliminary studies that are carefully designed can detect most developmental toxicity that could slow or stop enrolment.

Despite the ICH harmonised guideline, different regions have different requirements for embryo-foetal development toxicity studies before WOCBPs can be included into clinical trials.

If pregnant women and children are included in clinical trials, it requires that all the relevant non-clinical data are available. It is also preferred that data on non-pregnant women have been assessed.