VI.B.6.1. Use of a medicinal product during pregnancy or breastfeeding

a. Pregnancy

Reports, where the embryo or foetus may have been exposed to medicinal products (either through maternal exposure and/or if the suspected medicinal product was taken by the father), should be followed-up in order to collect information on the outcome of the pregnancy and the development of the child after birth. The guidance provided in the Guideline on the Exposure to Medicinal Products during Pregnancy: Need for Post-Authorisation Data and (see GVP Annex III) and in GVP Product- or Population-Specific Considerations III. should be considered as regards the monitoring, collection and submission of information in these specific situations in order to facilitate the scientific evaluation. When an active substance (or one of its metabolites) has a long half-life, this should be taken into account when assessing the possibility of exposure of the embryo through the mother and/or the father if the medicinal product was taken before conception. Not infrequently, pregnant women or healthcare professionals will contact either competent authorities or marketing authorisation holders to request information on the teratogenicity of a medicinal product and/or on the experience of use during pregnancy. Reasonable attempts should be made to obtain information on any possible medicinal product exposure to an embryo or foetus and to follow-up on the outcome of the pregnancy (see VI.B.3. for follow-up guidance). Reports of exposure to medicinal products during pregnancy should contain as many detailed elements as possible in order to assess the causal relationships between any reported adverse reactions and the exposure to the suspected medicinal product. In this context the use of standard structured questionnaires is recommended. Individual cases with an abnormal outcome associated with a medicinal product following exposure during pregnancy are classified as serious reports and should be submitted in accordance with the requirements outlined in VI.B.7. and in line with the guidance provided in VI.C.6.2.3.1. for the electronic submission of those ICSRs in the EU. This especially refers to:  reports of congenital anomalies or developmental delay, in the foetus or the child,  reports of foetal death and spontaneous abortion, and  reports of suspected adverse reactions in the neonate that are classified as serious. Other cases, such as reports of induced termination of pregnancy without information on congenital malformation, reports of pregnancy exposure without outcome data, or reports which have a normal outcome should not be submitted as ICSRs since there is no suspected adverse reaction (see VI.B.2. for ICSR validation). These reports should however be collected and discussed in the periodic safety update reports (see GVP Module VII and VI.C.6.2.3.1. Subsection c for the management of the individual reports in the EU). In certain circumstances, reports of pregnancy exposure with no suspected reactions may necessitate to be submitted as ICSRs. This may be a condition of the marketing authorisation or stipulated in the risk management plan; for example pregnancy exposure to medicinal products contraindicated in pregnancy or medicinal products with a special need for surveillance because of a high teratogenic potential (e.g. thalidomide, isotretinoin). A signal of a possible teratogen effect (e.g. through a cluster of similar abnormal outcomes) should be notified immediately to the competent authorities in accordance with the guidance presented in GVP Module IX.

b. Breastfeeding

The guidance provided in GVP Product- or Population-Specific Considerations III. on the conduct of pharmacovigilance for medicines exposed via breastfeeding should be followed. Suspected adverse reactions which occur in infants following exposure to a medicinal product from breast milk should be submitted in accordance with the criteria outlined in VI.B.7. and in line with the guidance provided in VI.C.6.2.3.1. for the electronic submission of those ICSRs in the EU.

VI.B.6.2. Use of a medicinal product in a paediatric or elderly population

The collection of safety information in the paediatric or elderly population is important. Reasonable attempts should therefore be made to obtain and submit the age or age group of the patient when a case is reported by a healthcare professional, or consumer in order to be able to identify potential safety signals specific to a particular population. General guidance in VI.B.3. on reports follow-up should be applied.

Guidance provided in GVP Product- or Population-Specific Considerations IV. on the conduct of pharmacovigilance for medicines used in the paediatric population, and in GVP Product- or PopulationSpecific Considerations V. on the conduct of pharmacovigilance for medicines used in the geriatric population should be followed.

VI.B.6.3. Reports of overdose, abuse, misuse, medication error or occupational exposure

The definitions for overdose, abuse, misuse, medication error or occupational exposure provided in VI.A.1.2. should be applied.

Reports with no associated suspected adverse reaction should not be submitted as ICSRs. They should be recorded when becoming aware of them and considered in the periodic safety update reports as applicable (see GVP Module VII). When those reports constitute safety issues impacting on the riskbenefit balance of medicinal products authorised in the EU, they should be notified to the competent authorities in Member States and to the Agency in accordance with the guidance provided in VI.C.2.2.6.

Reports associated with suspected adverse reactions should be subject to submission in accordance with the modalities outlined in VI.B.7. and with the electronic submission requirements in the EU described in VI.C.6.2.3.3. They should be routinely followed-up to ensure that the information is as complete as possible with regard to the symptoms, suspected medicinal products name, outcomes, context of occurrence (e.g. error in prescription, administration, dispensing, dosage, unauthorised indication or population, etc.).

With regards to reports of medication errors, further guidance concerning their management and assessment, provided in the Good Practice Guide on Recording, Coding, Reporting and Assessment of Medication Errors12, should be followed.

Guidance is available in VI.C.2.2.12. with regard to the management in the EU of reported information on the off-label use of medicinal products.

VI.B.6.4. Lack of therapeutic efficacy

Reports of lack of therapeutic efficacy should be collected and recorded when notified and followed-up if incomplete. They should normally not be submitted as ICSRs if there is no associated suspected adverse reaction, but they should be discussed in periodic safety update reports as applicable (see GVP Module VII).

In certain circumstances, reports of lack of therapeutic efficacy with no suspected adverse reactions may require to be submitted within a 15-day time frame (see VI.C.6.2.3.4. for EU guidance on the management of these ICSRs). Medicinal products used in critical conditions or for the treatment of life-threatening diseases, vaccines, contraceptives are examples of such cases. This applies unless the reporter has specifically stated that the outcome was due to disease progression and was not related to the medicinal product. The requirement to submit these specific reports of lack of efficacy does not apply when the notification occurred in the frame of a non-interventional post-authorisation efficacy study. This is because they refer to the main end point of the study. EU guidance provided in VI.C.1.2.1. for non-interventional post-authorisation studies should be followed regarding the management of adverse events occurring in those efficacy studies.

Clinical judgement should be used when considering if cases of lack of therapeutic efficacy qualify for submission as ICSRs. For example, a report of lack of therapeutic efficacy with an antibiotic used in a life-threatening situation where the use of the medicinal product was not in fact appropriate for the infective agent should not be submitted. However, a report of lack of therapeutic efficacy for a lifethreatening infection, which appears to be due to the development of a newly resistant strain of a bacterium previously regarded as susceptible, should be submitted as ICSR within 15 days.

For vaccines, cases of lack of prophylactic efficacy should be submitted as ICSRs, in particular with the view to highlight potential signals of reduced immunogenicity in a sub-group of vaccinees, waning immunity, or strain replacement. With regard to the latter, it is considered that spontaneously reported cases of lack of prophylactic efficacy by a healthcare professional may constitute a signal of strain replacement. Such a signal may need prompt action and further investigation through postauthorisation safety studies as appropriate. General guidance regarding the monitoring of vaccines failure, provided in the Report of CIOMS/WHO Working Group on Vaccine Pharmacovigilance13, may be followed.