Introduction: In 2010, the European Union (EU) introduced new pharmacovigilance legislation that established an additional monitoring (AM) measure for certain medicines following their marketing authorization. Since 2013, a black inverted triangle (▼), accompanied by a brief explanatory sentence, has been displayed on their leaflet and in the summary of product characteristics. This symbol is uniformly used across all EU member states to indicate medicines subject to AM.

Aim: To analyze the medicines under AM listed by the European Medicines Agency (EMA) and compare them with those available on the pharmaceutical market in Bulgaria.

Material and methods: A descriptive analysis was performed on the EMA’s list of medicines under AM as of February 23, 2024 (EMA/245297/2013 Rev. 119). Additionally, the study assessed the market access and affordability of these medicines in Bulgaria by examining their inclusion in the Positive Drug List (PDL). Public electronic registers of the National Council on Prices and Reimbursement of Medicinal Products in Bulgaria were used for this analysis.

Results: The EMA’s list comprised a total of 358 medicines, of which 90 were available on the Bulgarian pharmaceutical market as of February 2024. The analysis revealed that the majority of these medicines were new active substances (n=27, 30%), new biologicals (n=12, 13.3%), and medicines requiring post-authorization safety studies, PASS (n=21, 23.3%).

Conclusion: Notably, only 25% of medicines under AM authorized in the EU were marketed in Bulgaria, with a significant proportion of these being new active substances, particularly in therapeutic areas such as oncology, hematology, and neurology.

additional monitoring, EMA, inverted black triangle, pharmacovigilance

After receiving marketing authorization, some medicinal products in the European Union (EU) are subject to additional monitoring (AM). Their package leaflet and Summary of Product Characteristics (SmPC) are labelled with a black inverted triangle (▼), accompanied by a short sentence explaining the meaning of the symbol, which reads, “This medicinal product is subject to additional monitoring.”^[1,2]

The concept of AM for medicinal products was introduced with changes to the EU pharmacovigilance legislation in 2010 and came into effect in 2012.^[1,2] The black inverted triangle, previously used in the United Kingdom (UK) to identify new active substances, has been adopted by the European Medicines Agency (EMA) to identify medicinal products under AM.^[3,4] Similarly, after the adoption of Regulation (EC) No. 1027/2012 (which came into effect in 2013), Spain discontinued the use of the yellow triangle, which had previously been used to indicate new active substances.^[3]

The black inverted triangle is now used across all EU member states to denote medicines subject to AM. Since autumn 2013, this symbol has been printed on the package leaflets of these medicines, but it is not displayed on the outer packaging.^[5] In addition to the EU and the UK, the Black Triangle Scheme has also been introduced in Australia since 2018.^[6]

When a medicinal product is placed under AM, healthcare providers (HCPs) and patients are encouraged to report any suspected adverse drug reactions (ADRs) to the competent authorities. The AM concept serves as an example of a regulatory risk-minimization measure undertaken at the EU level.^[7] It aims to reduce the risk associated with medicinal products that are not well-studied and for which the available drug utilization data is not sufficiently comprehensive and conclusive.^[5] However, only limited data regarding the impact of the black triangle symbol on reporting levels of ADRs is published in the scientific literature.^[8]

Although the concept was introduced 13 years ago, only a few studies have assessed the awareness of HCPs and patients regarding the black triangle symbol and AM process.^[9–12] All medicinal products undergo monitoring after receiving marketing authorization, but the black inverted triangle indicates that a medicine is subject to enhanced surveillance. This is typically due to the lack of sufficient information, for example, when the medicine is new to the pharmaceutical market or when evidence on its long-term use remains limited.^[5]

The assignment of black triangle status is mandatory in the cases presented in Fig. 1.^[1]

Figure 1.

Medicinal products with a mandatory black triangle status.^[1]

In addition to the cases presented in Fig. 1, other medicinal products may also be placed under AM based on an opinion from the Pharmacovigilance Risk Assessment Committee (PRAC) of the EMA.^[1]

EMA maintains a list of medicines under AM, which was first published in 2013 and has since been reviewed monthly by PRAC. Medicinal products can be added to the EMA’s list either after their initial marketing authorization or at any time during their lifecycle.^[5,13] These medicines remain under AM for five years or until PRAC decides to exclude them from the list. The up-to-date list of medicines subject to AM is publicly available on the EMA’s website. The list contains the following information: product name, active substance(s), reason(s) on the list, marketing authorization holder, link to product information (European public assessment report, EPAR), and date of inclusion on list.^[14]

The national competent authorities of EU member states (for Bulgaria – the Bulgarian Drug Agency) are required to provide a link to the EMA’s list of medicines under AM on their official websites.

Our primary objective was to analyze the medicines under AM listed by the EMA and compare them with those available on the pharmaceutical market in Bulgaria. Additionally, we evaluated the access to these medicines at the national level by examining data on their inclusion in the Positive Drug List (PDL), as well as their reimbursement status and payment levels.

A retrospective documentary analysis was conducted on the EMA’s list of medicines under AM as of February 23, 2024 (EMA/245297/2013 Rev. 119), published on the official website of the Agency. The availability and affordability of these medicines in Bulgaria were evaluated through a descriptive analysis of data from the Ceiling Prices Register and the PDL.

For this study, public electronic registries of the National Council on Prices and Reimbursement of Medicinal Products (NCPR) were searched, along with the EMA’s list of medicines under AM, available at www.ema.europa.eu.

The analyzed medicinal products were classified into the following groups:

• New active substances;
• New biological products;
• New active substances that are also new biological products;
• Medicinal products subject to post-authorization safety studies (PASS);
• Medicinal products authorized under exceptional circumstances;
• Medicinal products authorized under conditional approval;
• New active substances that are also new biological products and are authorized under conditional approval;
• Medicinal products that are new active substances, new biological products, and are subject to PASS;
• Medicinal products that are new active substances and are authorized under conditional approval;
• Medicinal products authorized under exceptional circumstances and subject to PASS;
• Medicinal products subject to restrictions regarding safety and efficacy.

Additionally, medicinal products under AM available on the Bulgarian pharmaceutical market were classified by therapeutic areas in which they are applied.

SmPCs and EPARs of the medicinal products under AM that were included in the EMA’s list in 2023 and the first two months of 2024, as well as those available on the Bulgarian pharmaceutical market as of February 2024, were comprehensively analyzed.

Medicinal products under AM with orphan designation, biosimilars, and those used in the treatment and prevention of COVID-19 available to Bulgarian patients were reviewed and classified by reason for inclusion in the EMA’s list, therapeutic area/indication for use, and data about inclusion in PDL, as well as reimbursement status/payment level. The study utilized publicly available datasets, eliminating the requirement for ethical approval.

As of February 2024, the EMA’s list of medicinal products under AM (EMA/245297/2013 Rev. 119) included 358 medicines. Among these, 90 medicinal products were available on the Bulgarian pharmaceutical market as of 29 February 2024. Price registration is a mandatory requirement for the placement of a medicinal product, authorized under the EU centralized procedure in accordance with Regulation (EC) No 726/2004, on the national market in Bulgaria.

Based on the criteria for inclusion in the EMA list for AM, the medicinal products available in Bulgaria were classified into several groups (Table 1).

The available medicinal products under AM on the Bulgarian pharmaceutical market were classified according to their therapeutic areas of application. The majority of medicines under AM belonged to the therapeutic areas of oncology (n=25, 27.8%), hematology (n=12, 13.3%), and neurology (n=11, 12.2%) (Fig. 2).

Only 25% of AM medicines authorized in the EU were marketed in Bulgaria. In contrast, a similar study conducted in Spain revealed that more than 60% of medicines under AM authorized between 2017 and 2019 in the EU were available on the national level, primarily antineoplastic and immunomodulatory drugs.^[15]

Financial accessibility of medicinal products under AM

The analysis of financial accessibility reveals that, as of February 29, 2024, eighty-four medicines under AM (considering valproates separately, n=11) were included in the PDL (Supplementary Table). Forty-five medicines under AM were added in both Annex 1 and Annex 2 of the PDL (Fig. 3).

Annex 1 includes medicines that are either fully reimbursed (100%) or partially reimbursed (up to 50% or 75%) by the National Health Insurance Fund (NHIF). Medicinal products included in Annex 2 are paid by the hospital budgets and are reimbursed at a 100% rate.

For 14 medicines under AM, only a limit price was registered, without reimbursement status (Fig. 3). Consequently, these medicines must be paid for out-of-pocket by patients, as they are not reimbursed by the NHIF.

Figure 2.

Distribution of analyzed medicinal products under АМ according to the therapeutic area in which they are applied, n=90 (Created with BioRender.com). Note: One annex of EMA’s list is counted as 1 product (e.g., valproates).

Figure 3.

Reimbursed medicines under AM in Bulgaria (valid for February 2024); (a) absolute frequency; (b) relative frequency. Note: Medicinal products containing sodium valproate or valproic acid are evaluated separately rather than as one product, as outlined in the EMA list of AM (n=11).

Orphan medicines under AM

Our analysis shows that, as of February 2024, 18 medicinal products under AM available on the Bulgarian pharmaceutical market had an orphan designation, representing 20% of the total AM medicines. Most of these products (n=7) belong to ATC code L: Antineoplastic and immunomodulating agents, followed by ATC code A: Alimentary tract and metabolism (n=5). (Fig. 4).

Figure 4.

Orphan medicines under AM available in Bulgaria classified according to the ATC system.

Our analysis revealed that as of February 2024, only 25% of the medicines under AM authorized at the EU level were marketed in Bulgaria. The majority of these medicines were classified as new active substances, followed by those requiring PASS and new biologics. Notably, most of these medicines were associated with therapeutic areas such as oncology, hematology, and neurology. Since medicines under AM continue to be authorized in the EU each year, it is essential to raise awareness among both HCPs and the general public regarding the inverted black triangle symbol. Increased understanding of its significance could help improve ADR reporting, thereby strengthening pharmacovigilance and ensuring better patient safety.

Conceptualization: R.S.: methodology: R.S.; investigation: R.S. and D.A.; recourses: R.S. and D.A., software: R.S.; writing—original draft preparation: R.S.; writing—review and editing: R.S. and D.A; visualization: R.S.; supervision: R.S.

We do confirm that the manuscript has been read and approved by all the authors, that the requirements for authorship as stated above in this document have been met, and that each author believes that the manuscript represents honest work.

We have no conflicts of interest to disclose.

There has been no financial support for this work, which could have influenced its outcomes.