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ProjTitle.icon P.II.B.4. Post-authorization safety studies

The requirements for the design and conduct of post-authorization safety studies (PASS) in GVP Module VIII should be followed. For medicines where safety data relating to use of a medicine in pregnancy and breastfeeding are limited, additional pharmacovigilance activities may be warranted (see P.II.B.1.) to better characterize potential risk with use of the product in pregnancy and breastfeeding. Marketing authorization holders and SFDA are required to consider whether a PASS would be an appropriate tool for this purpose. A PASS may constitute a drug utilization study or it may investigate specific risks to the embryo, foetus or child. Potential study designs for the latter include all epidemiological designs in principle, including but not limited to pregnancy registries (see P.II.B.4.2.1.).

As per general guidance, the decision on whether or not to include additional pharmacovigilance activities in the RMP should be taken in a risk-proportionate manner. Considerations regarding risk proportionality will differ between the populations of pregnant women and breastfeeding women because the consequences of harm differ between these populations. In situations where a medicine is harmful to the child but use for the mother is imperative, it is relatively uncomplicated to avoid harm to the child during breastfeeding whereas avoidance of harm during pregnancy is not as straightforward.

Carrying out a PASS may be of particular value when use of a medicine is expected in pregnancy or breastfeeding, such as in the following situations:

•  when use of the product cannot be discontinued during pregnancy due to the disease being treated, when a disorder arises during pregnancy that needs treatment, or where changes in treatment during pregnancy are associated with risks for the pregnant woman and/or the foetus;  

•  if a potential risk to the child has been suggested by non-clinical data, a signal (see P.II.B.5.) or based on the chemical or pharmacological properties of the medicine; 

•  where the medicine is used to treat conditions that occur commonly in women of child-bearing potential; or  

•  if measuring compliance with RMM in place regarding pregnancy or breastfeeding (e.g. in the product information, educational material or a pregnancy prevention program) (see P.II.B.7.) is needed. 

•  If adverse events are reported in pregnant women taking a drug 

•  Changes in dosing or administration of drug in pregnant women

•  If a drug is approved for new indication in pregnant women. 

If a PASS is considered warranted, it should be designed considering the issue of competing endpoints (see P.II.A.1.3.) as well as the fact that exposure at different gestational ages may be associated with different adverse outcomes. The evaluation should consider all relevant outcomes throughout the human developmental lifecycle, therefore, and capture data on exposure in utero as well as any additive adverse events of medicine exposure through breast milk. The child should be followed up for a long enough period to capture the relevant information on health or developmental impact.

Possible ethical and feasibility aspects specific to the use of medicines in pregnancy or breastfeeding should be adequately anticipated and managed in the study protocol. Inclusion of pregnant women in a PASS should be solely subject to the clinical decision to treat the woman for her medical condition.​

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