General information on safety signals
Information arising from one or multiple sources, including observations and experiments, which suggests a new potentially causal association, or a new aspect of a known association between an intervention and an event or set of related events, either adverse or beneficial, that is judged to be of sufficient likelihood to justify verificatory action [IR 520/2012 Art 19(1)].
Safety signals can be detected from a wide range of sources, such as spontaneous reports, clinical studies and scientific literature. The EudraVigilance database is an important source of information on suspected adverse reactions and signals.
The presence of a safety signal does not directly mean that a medicine has caused the reported adverse event. An illness or another medicine taken by the patient could also be the cause.
The assessment of safety signals establishes whether or not there is a causal relationship between the medicine and the reported adverse event.
The signal management process shall include the following activities: signal detection, signal validation, signal confirmation, signal analysis and prioritisation, signal assessment and recommendation for action.
This set of activities is performed in order to determine whether there are new risks associated with an active substance or a medicinal product or whether known risks have changed.
The signal detection process is carried out by EMA, by Member States and also by marketing authorization holders.
At European level, each EU Member State, including Romania, is assigned a list of active substances for signal management. The EMA list of active substances allocated to Member States for the management of safety signals is available here.
A safety signal that has been detected subsequently goes through successive validation and confirmation processes. Confirmed signals are evaluated at PRAC level and discussed in the plenary of the Committee. Subsequently, PRAC adopts the assessment conclusions and issues a recommendation.
PRAC recommendations on safety signals for medicinal products for human use are published on the EMA website on a monthly basis and are available here. These include recommendations for product information updates, translated into all official EU languages, including Romanian language.
Marketing authorization holders in Romania can use these translations to update their medicines information.
PRAC recommendations refer to authorized through centralized procedure and also to medicinal products authorized through national procedure (DCP, MRP, Repeat-Use or purely national procedure).
MAH should periodically monitor EMA website on safety signals in order to be kept up to date with PRAC recommendations on safety signals for their portfolio medicinal products and also to take the necessary actions in line with these recommendations.
For procedural aspects related to the handling of PRAC recommendations on signals (e.g. submission requirements, contact points, etc.) please refer to Questions and Answers on signal management.
The timeline recommended by PRAC for submission of variations following signal assessment is applicable to both innovator and generic medicinal products, unless otherwise specified.
Marketing-authorisation holders are expected to take action according to the recommendations. They should monitor the information on this page regularly to keep informed about the PRAC recommendations concerning their products.
In accordance with Art. 736, paragraph (3) of Law no. 95/2006 on healthcare reform, as republished, the MAH must update the product information whenever necessary:
”The marketing authorisation holder shall ensure that the product information is kept up to date with the current scientific knowledge, including the conclusions of the assessment and recommendations made public by means of the European medicines web-portal established in accordance with Article 26 of Regulation (EC) No 726/2004.”
List of safety signals discussed at PRAC
A list of all safety signals discussed since September 2012 at PRAC is available on the EMA website and is continuously updated. The list is available here.
The list contains useful information on the discussed signal, the active substance involved, whether MAH action for product information updates is needed and also a link to the minutes of the PRAC meeting that discussed the signal.
Reference legislation (available on NAMMDR website):
- Law no. 95/2006 on healthcare reform, as republished, TITLE XVIII- The Medicinal Product;
- GVP Module IX – Signal management;
- DIRECTIVE 2001/83/EC OF THE EUROPEAN PARLIAMENT AND OF THE COUNCIL of 6 November 2001 on the Community code relating to medicinal products for human use;
- DIRECTIVE 2010/84/EU OF THE EUROPEAN PARLIAMENT AND OF THE COUNCIL of 15 December 2010;
- Directive 2012/26/EU of the European Parliament and of the Council of 25 October 2012 amending Directive 2001/83/EC as regards pharmacovigilance Text with EEA relevance;
- REGULATION (EU) No 520/2012 of 19 June 2012 on the performance of pharmacovigilance activities provided for in Regulation (EC) No 726/2004 of the European Parliament and of the Council and Directive 2001/83/EC of the European Parliament and of the Council;
- REGULATION (EU) No 726/2004- Community procedures for the authorisation and supervision of medicinal products for human and veterinary use and establishing a European Medicines Agency;
- REGULATION (EU) No 1235/2010 OF THE EUROPEAN PARLIAMENT AND OF THE COUNCIL of 15 December 2010.