Have you ever wondered how biological drugs, such as antibodies, vaccines, and gene therapies, affect the development of embryos and fetuses? Unlike chemical drugs, biological drugs are not required to conduct animal studies to test their reproductive toxicity , which means their potential harm to the reproductive system and the offspring. Instead, they can use a method called WOE analysis to evaluate the risks and benefits of using these drugs during pregnancy.
WOE analysis is a way of weighing the evidence from different sources, such as the mechanism of action of the drug, the pharmacokinetic properties, the data from genetically modified animals, the human gene expression, and the effects of similar drugs. The purpose of WOE analysis is to identify the human risks based on all available data and information, and to avoid or reduce animal studies for developmental toxicity based on the 3R principle, which stands for replacement, reduction, and refinement.
The main factors considered in WOE analysis include:
- Whether the drug has systemic exposure and can cross the placental barrier to reach the fetus. This can affect the likelihood and severity of developmental toxicity.
- What are the biological effects of the target that the drug acts on. Some targets are involved in embryonic development, placental regulation, maternal tolerance, or uterine physiology, and may be affected by the drug.
- What are the effects of similar drugs that act on the same signaling pathway. This can provide clues to the potential risks of the drug.
- Whether there is a suitable pharmacological test system to evaluate the drug. This can help to select the relevant animal species for the study.
- What are the data from genetically modified animals and human gene expression. These can help to simulate the scenario of target inhibition or overexpression by the drug, and to observe the abnormality of pregnancy and embryo-fetus development.
- Whether there is an alternative molecule that can replace the drug. This can help to avoid the use of non-relevant animal species or to reduce the number of animals.
Based on the WOE analysis, a decision tree can be drawn to determine whether to conduct reproductive toxicity studies for biological drugs. The first step is to collect information from various sources. The next step is to consider the possible exposure of the embryo-fetus and the mother, and the off-target effects of the drug. The last step is to consider the patient population and the indication of the drug. If the WOE analysis can clearly indicate whether the drug will or will not cause developmental toxicity, no additional animal studies are needed. Otherwise, further developmental toxicity studies are recommended.
There are already many marketed biological products that did not conduct animal developmental toxicity studies based on WOE analysis.
- ADC products for cancer indications: These products are subject to ICH S9, which states that developmental toxicity studies are not required for drugs that target rapidly dividing cells or belong to a class of drugs that are known to cause developmental toxicity. Examples of such products are DS-8201, trastuzumab emtansine, and brentuximab vedotin.
- Immune checkpoint inhibitors for cancer indications: These products are also subject to ICH S9, and have a clear mechanism of action that could interfere with maternal-fetal immune tolerance and increase the risk of fetal loss. Examples of such products are nivolumab, pembrolizumab, and ipilimumab.
- Anti-infective product targeting an exogenous antigen: This product does not target an endogenous antigen and has no off-target binding, therefore it does not pose a developmental toxicity risk. An example of such product is bezlotoxumab, which targets Clostridium difficile toxin B.
WOE analysis is a useful tool for evaluating the reproductive toxicity of biological drugs, but it is not easy to conduct. It requires a comprehensive and critical review of the data and information, and a clear and logical presentation of the rationale and conclusion. It is also advisable to communicate with the regulatory authorities in advance, especially when animal studies are waived. WOE analysis can help to protect the safety of pregnant women and their offspring, and to promote the ethical and scientific development of biological drugs.
