XVI.Add.III.2. Criteria for requiring a PPP or selecting pregnancy-specific risk minimisation measures

The decisive criteria for requiring a PPP (or selected pregnancy-specific RMM instead) should always be:

• Level of scientific evidence for the teratogenic potential of a medicinal product in humans, including the evidence on the magnitude and nature of the teratogenic effect; and
• Context of the likely use of the medicinal product (see also CHMP Guideline on Risk Assessment of Medicinal Products on Human Reproduction and Lactation: From Data to Labelling2).

Both these criteria should be re-assessed regularly. The need for a PPP (or selected pregnancy-specific RMM instead) should be risk-proportionate in relation to the magnitude and nature of the teratogenicity (e.g. frequency, type or outcome of malformation) and may change when new evidence emerges.

The Agency and competent authorities in Member States can propose further measures on a case by-case basis and as applicable.

Depending on the assessment of the two criteria, the following most typical scenarios and requirements are foreseen:

A) Proven or strongly suspected teratogenicity

If a medicinal product is proven or strongly suspected to be teratogenic in humans and is expected to be used in women of childbearing potential under the clinical conditions for which the product is authorised, and the magnitude and nature of the teratogenicity are significant, a PPP is considered necessary (see XVI.Add.III.3.).

Where the magnitude and nature of the teratogenicity do not justify a PPP (but the first two 51 criteria are fulfilled), additional pregnancy-specific RMM are considered necessary, in addition to advice in the summary of product characteristics (SmPC) and package leaflet (PL) as routine RMM (see CHMP Guideline on Risk Assessment of Medicinal Products on Human Reproduction and Lactation: From Data to Labelling3). As a minimum, these additional pregnancy-specific RMM should include, usually supported by educational materials for both patients and healthcare professionals, the following:

• Personal patient counselling by a healthcare professional;
• Pregnancy testing before the start of treatment and, as applicable, also during and after treatment; and
• Application of effective contraceptive measures.

If the use of the product by women of childbearing potential under the clinical conditions for which the product is authorised is considered unlikely (but the criterion of proven or strongly suspected teratogenicity in humans is fulfilled), routine RMM alone are usually considered appropriate.

If the likelihood of the use of the product in women of childbearing potential is difficult to predict, additional pregnancy-specific RMM may still be required, based on the assessment.

B) Possible but unconfirmed teratogenicity

If the available evidence suggests possible teratogenicity of a medicinal product, but a causal relationship between harm in children and the in-utero exposure to the product has not been confirmed or is not strongly suspected, the decision on whether to require additional pregnancy specific RMM in addition to advice in the product information as routine RMM (see CHMP Guideline on Risk Assessment of Medicinal Products on Human Reproduction and Lactation: From Data to Labelling4) should take into account the following considerations:

• Teratogenicity of the product is known or suspected from animals, but there is insufficient, inconclusive or no evidence in humans;
• Type or outcome of malformation in animals; and
• Use in women of childbearing potential is expected under the clinical conditions for which the product is authorised.

In principle, in most cases of possible but unconfirmed teratogenicity, it is expected that routine RMM will be sufficient.

Additional pregnancy-specific RMM may still be required, based on the assessment.

C) Unlikely teratogenicity

If teratogenicity of a medicinal product in humans is considered unlikely and if the use of a medicinal product in women of childbearing potential is considered unlikely under the clinical conditions for which the product is authorised (e.g. a product for treating prostate cancer), 85 additional pregnancy-specific RMM are not considered appropriate.

However, routine RMM are still considered appropriate, in particular if the use of the medicinal product in women of childbearing potential may occur, even if very rarely, or is difficult to predict.

Schematically, the considerations determining whether a PPP or selected pregnancy-specific RMM are necessary are depicted for the most typical scenarios in Figure XVI.Add.III.1.