Pharmacovigilance

Medicines under additional monitoring have a black inverted tringle displayed in their Summary of product characteristics (SPC) and the package leaflet (PIL), with the appropriate sentence:

▼This medicine is under additional monitoring.

After a marketing authorization is obtained for a medicinal product, it continues to be carefully monitored within the so-called post-market surveillance. However, if a medicine has the inverted black triangle symbol, it means that it is monitored more intensively than other medicines. The most common reason for additional monitoring of medicines is that less information is available about it compared to other medicines, e.g. because the medicine is new on the market or because there are limited data on its long-term use. If a medicine is marked with an inverted black triangle, it does not mean that the medicine is not safe.
The symbol of the inverted black triangle indicated at the very beginning of SPC/PIL should increase the attention of healthcare professionals and/or patients or users of such medicine, when monitoring the therapeutic use of the medicine. When they see an inverted black triangle, healthcare professionals and patients should know that it is extremely important to report any suspected adverse reactions to that medicine. For more detailed information on how to report a suspected adverse drug reaction click here.

What medicines are additionally monitored?

In accordance with the EU principles, the status of additional monitoring in the Republic of Serbia is always assigned to the following categories of medicines:

• medicines containing a new active substance that was approved in the EU after 01/01./2011;
• biological medicines, such as vaccines or drugs from human plasma (blood), approved after 01/01/2011;
• medicines for which the marketing authorization holder is obliged to conduct post-authorization safety studies (PASS), e.g. in order to provide more data on long-term use of the medicine or on rare side effects observed during clinical studies;
• medicines that received a conditional marketing authorization (when the marketing authorization holder must provide more data on the medicine over a certain period of time) or medicines approved under special circumstances (when there are specific reasons why the marketing authorization holder cannot provide comprehensive data on the medicine).

Other medicines can also receive additional monitoring status based on the decision of the Pharmacovigilance Risk Assessment Committee (PRAC) of the European Medicines Agency (EMA).
Also, the Medicines and Medical Devices Agency of Serbia (ALIMS) can determine the status of additional monitoring of a medicine in accordance with an expert assessment of its safety profile.
Medicines that are additionally monitored in the Republic of Serbia are all medicines approved by ALIMS with an active substance that is in the EU List of Medicines under Additional Monitoring (updated every month after the PRAC meeting), as well as Medicines outside the EU List for which the expert ALIMS assessment determined the status of additional monitoring in the Republic of Serbia.

When does a medicine get additional monitoring status?

A medicine can be included in the list of medicines under additional monitoring during its first registration, but also at any other stage of its lifecycle. Once included in the list, the medicine usually retains the additional monitoring status for five years or until the decision of the relevant regulatory authorities (EMA, ALIMS) is changed.

The release of the packaging of a medicine with the updated PIL text may be delayed in relation to the decision to add the medicine to the list for additional monitoring or to delete it from the list. This can happen because it takes a certain amount of time (prescribed by the applicable regulations) to replace the existing inventory of the packaging of medicines with the new one.

What are the obligations of the marketing authorization holder?

Marketing authorization holders in the Republic of Serbia should implement the decision by which their medicine is included in the list of medicines under additional monitoring by indicating the symbol of the inverted black triangle and the corresponding information in the draft SPC and PIL, or more specifically:

1. attached to the the marketing authorization application;
2. for medicines that already have a marketing authorization issued in the Republic of Serbia with a corresponding request for a variation that changes the SPC/PIL. If the marking of information on additional monitoring of medicines is the only change to SPC/PIL, a request for approval of variation C.I z) type IA is submitted;
3. attached to the marketing authorization renewal application.

You can download the method of specifying information about additional monitoring of medicines and reporting suspected adverse drug reactions in the information about medicines HERE.

Why is a list of medicines under intensive monitoring required?

Issuance of a marketing authorization is based on a positive assessment of the benefit-risk ratio in its therapeutic application for a clearly defined indication area. However, at the time of submitting a request for registration of a new medicine, not all possible risks of a new therapy are known, that is, information on the safety of a specific medicine is relatively limited. This is conditioned by numerous factors, which are the consequences of the usual way of conducting clinical trials, such as: small number of subjects, insufficient diversity of the studied population (in terms of age, gender and ethnicity), limited representation of comorbidities and concomitant therapy in the studied population, relatively short study duration, statistical flaws. In order to identify possible rare adverse reactions and complete the information on the safety profile of the medicine, it is very important to continue monitoring the medicine once it is marketed and to report suspicions of its adverse reactions. The information collected in this way is regularly evaluated by regulatory agencies that try to determine whether new data change the benefit-risk ratio of the medicine, that is, whether it is still positive.

Regulatory framework for additional monitoring of medicines

The list of medicines under additional monitoring is defined in accordance with Article 38 of the Rulebook on the manner of reporting, collecting and monitoring adverse reactions to medicines (Official Gazette of RS No. 64/2011), which stipulates that the Medicines and Medical Devices Agency of Serbia (ALIMS) determines the list of medicines that are marked with special labels for intensive monitoring of their safety profile.

EU legislation related to pharmacovigilance (Directive 2010/84/EU, Regulation (EU) No 1235/2010) defines the concept of “medicines under additional monitoring” which refers to medicines that are intensively monitored due to their safety profile, which is additionally regulated by the guidelines of Good Pharmacovigilance Practice (GVP) – Module X – Additional monitoring.