P.II.B.2 Management and reporting of adverse reactions.

P.II.B.2.1 Content of reports

It is essential that marketing authorization holders collect and provide as many elements as possible for all cases, irrespective of whether or not a product is authorized for use in pregnancy or breastfeeding, to facilitate the evaluation. The initial report should be submitted in ICH E2B message format.

The requirements for the management and reporting of suspected adverse reactions from spontaneous reporting or other sources, including specific, detailed guidance regarding the way of ICSR reporting, such as for the items listed below:

• Coding of reports of use a medicinal product during pregnancy or breastfeeding as follows:

− For the suspected adverse reaction, comply with the latest version of guidance for MedDRA Users, MedDRA Term Selection: Points to Consider (see GVP VI.B.7 – MedDRA support documentation);

− For the route of administration, code, in the case of exposure in pregnancy leading to pregnancy loss or other adverse pregnancy outcomes, the route of administration as 'transplacental' and use the MedDRA term 'exposure in utero' in the Reaction/event section; and in the case of exposure during breastfeeding, code the route of administration as 'transmammary' and use the MedDRA term 'Drug exposure via breast milk' in the Reaction/event section. The route of administration for the mother should be coded in the data elements, parent section of the parent-child report;

• Coding outcomes of exposure during pregnancy is open to ambiguity as a record of 'exposure during pregnancy, resolved' may mean that there is a prospective report of pregnancy exposure and either exposure discontinued, or the pregnancy has ended. Without reporting any further information regarding the pregnancy outcome this is not helpful. Efforts must be made to report the pregnancy outcome, even if this is not known until long after the exposure occurred and irrespective of whether or not the exposure was discontinued during the pregnancy;

• If a birth defect is the indication for using a particular medicine, this should be reflected in the data element for indication (or medical history of the child) and not result in a pa​rent-child report;

• Collecting and assessing information on off-label use and potential harm.

As many specific data elements as are possible to be obtained should be included in the structured ICH-E2B data elements of the ICSR (see GVP Module VI.www.sfda.gov.sa) as well as the narrative. In addition, to evaluate a possible causal relationship between the exposure to the medicinal product and the adverse events reported, the following guidance should be adhered to:

• The type of report on use of a medicinal product during pregnancy or breastfeeding, which may be retrospective or prospective, needs to be specified in the narrative. Prospective data of pregnancy exposure are data acquired prior to the knowledge of the pregnancy outcome or prior to the detection of a congenital anomaly at prenatal examination (e.g. foetal ultrasound, serum markers). For prospective cases, the gestational age at first contact with a reporter should be reported in the narrative. Prospective reports should be followed up upon first reporting as well as upon the expected date of delivery for details of pregnancy outcome as well as for any follow-up information for the reported maternal adverse reactions. Retrospective data of pregnancy exposure are data acquired after the outcome of the pregnancy is known or after the detection of a birth defect on prenatal test.

• Gestational age when the suspected adverse reaction was observed in the foetus and the gestational age at time of exposure need to be reported as accurately as possible. Both may be provided in months, weeks, days or trimester. Gestational age should be preferably calculated from early foetal ultrasound. The method used to assess gestational age should be specified in the narrative. Information on the exposure to any medicinal product should be included in the ICH-E2B section 'Drug information' of the ICSR. Information on the exposure to other teratogens (e.g. infections, occupational exposures) and on other potential causes for the adverse pregnancy outcome (e.g. familial history of congenital anomaly, maternal disease, lifestyle factors) should be included in the 'relevant medical history and concurrent conditions of parent' for so called parent-child reports, or in the patient's 'relevant medical history and concurrent conditions' in the report containing information on using drug during pregnancy.

• The results of examinations performed (e.g. foetal ultrasound, amniocentesis, laboratory tests) should be included in the section 'Results of tests and procedures relevant to the investigation of the patient' (see GVP Module VI). Specific requirements for the submission of ICSRs with pregnancy exposure are outlined in GVP Module VI and are summarized in Table 3 as follows:

Table 2:  Requirements for the submission of individual case safety reports with pregnancy exposure