INTRODUCTION:

When a medicine is first licensed for the use in clinical practice only a number of patients are exposed compared to the number that will eventually receive it. Therefore relatively uncommon reactions may not be detected. It is primarily for this reason that the Yellow Card Scheme was set up. New medicines are marked in the British National Formulary (BNF) and all publicity material with a Black Triangle. Special reporting advice also applies to these medicines and they are generally described as being intensively monitored products by the Medicines and Healthcare products Regulatory Agency (MHRA).

Medicines that are being monitored particularly closely by regulatory authorities in the European Union (EU) are described as being under 'additional monitoring'. Medicines under additional monitoring will have an inverted Black Triangle displayed in their patient information leaflet and in the information for healthcare professionals called the summary of product characteristics, together with a short sentence “This medicinal product is subject to additional monitoring”. ^[1]

BLACK TRIANGLE MEDICINES:

Medicines regulatory authorities such as the MHRA license medicines after rigorous assessment of evidence including clinical trial data to ensure medicines meet required standards of safety, quality and efficacy. Clinical trials involve a relatively small number of patients for a limited period of time. Patients in clinical trials are carefully selected and followed up very closely under controlled conditions. In a real-life setting, a larger and more diverse group of patients will use the medicine, they may have other diseases and they may be taking other medicines. Some less common side effects may only occur once a medicine has been used for a long time by a large number of people. It is therefore vital that the safety of all medicines continues to be monitored while they are in use.^[1]

Information is continuously collected after a medicine is placed on the market to monitor real-life experience with the product. The MHRA closely monitors this information, alongside other regulators, to make sure that the benefits of medicines continue to outweigh their risks. The same monitoring methods are used across the EU so that information gathered in individual countries can be shared. This provides a wealth of knowledge for regulators to rely upon when making decisions, and enables them to act quickly to ensure patient safety when required, such as providing warnings to patients and healthcare professionals or restricting the way a medicine is used.

In the UK the Commission on Human Medicines (CHM) and the MHRA encourages the reporting of all suspected adverse reactions to newer drugs and vaccines, which are denoted by the Black Triangle symbol. This symbol appears next to the name of a relevant product:

· In the British National Formulary (BNF)

· In the British National Formulary for Children (BNFC)

· In Monthly Index of Medical Specialties (MIMS)

· In the Association of the British Pharmaceutical Industry (ABPI) Medicines Compendium

· On advertising material

· In Drug Safety Update

· Summaries of Product Characteristics and Patient Information Leaflets [1,2]

REASON FOR ASSIGNING BLACK TRIANGLE:

All medicines have been carefully monitored after they are placed on the market. If a medicine carried the Black Triangle symbol, this means that it is subject to intensive monitoring. This is because we have relatively limited information about their safety from clinical trials as these trials generally involve only small numbers of eligible patients who take the medicine for a relatively short period of time. Patients in clinical trials may not completely represent the population who will use the medicine when it is marketed. The Black Triangle symbol does not mean that the medicine is unsafe. ^[1]

A Black Triangle is always assigned to a medicine if:

· It contains a new active substance like new medicines or vaccines.

· It is a biological medicine, such as a vaccine or a medicine derived from plasma (blood).

· It has been given a conditional approval (where the company that markets the medicine must provide more data about it) or approved under exceptional circumstances (where there are specific reasons why the company cannot provide a comprehensive set of data)

· The company that markets the medicine is required to carry out additional studies for instance, to provide more data on long-term use of the medicine, or on a rare side effect seen during clinical trials.

Other medicines can also be placed under additional monitoring, on request from the MHRA or other regulators if the request is then approved by the European Medicines Agency’s Pharmacovigilance Risk Assessment Committee (PRAC). Medicines will be typically assigned a Black Triangle for a period of five years. Medicines may continue to have a Black Triangle if this is requested by regulators taking into account the time needed to complete the obligations place on a medicine marketing authorisation. A medicine previously removed from the list may be reinstated if new conditions related to monitoring of risks and benefits of a medicine are imposed after the granting of the marketing authorisation.^[1,3]

BLACK TRIANGLE MEDICINES LIST:

A European list of medicines under additional monitoring has been published by the European Medicines Agency. It was first published in April 2013, and will be reviewed every month by the PRAC. A medicine can be included on this list when it is approved for the first time or at any time during its lifecycle. A medicine remains under additional monitoring usually for five years or until the PRAC are satisfied that it can be removed from the list. Fremanezumab, adlimumab and bacomitinib are some of the medicines included in this list in April 2019.

There may be a delay between the decision to add or remove a medicine from this list and the time when its updated package leaflet comes into circulation. This is because it takes some time for the updated package leaflet to gradually replace older stock already on the EU market. The up-to-date list of medicines under additional monitoring is published each month on the MHRA website.

BLACK TRIANGLE TO EUROPEAN UNION:

All medicines subject to additional monitoring in Europe will have to carry a black inverted triangle warning in line with new pharmacovigilance rules published by the European Medicines Agency (EMA).

The Black Triangle Scheme for intensive monitoring of medicines has been used for many years in the UK by UK's Medicines and Healthcare products Regulatory Agency (MHRA) but the concept of additional monitoring and the black symbol were introduced EU-wide by new EU laws on the safety-monitoring of medicines, called the pharmacovigilance legislation, which came into effect in 2012. From 25 April 2013 medicines under additional monitoring indicated by the Black Triangle will be published in an EU-wide list. There will be requirements for Patient Information Leaflets and Summaries of Product Characteristics to include information about the Black Triangle and reporting of adverse drug reactions. ^[1]

Any new medicine authorised after 1 September 2013 which is subjected to additional monitoring will include the black symbol in the package leaflet and the summary of product characteristics when it is placed on the EU market. The legislation affects medicines authorised in the EU after 1 January 2011. Therefore, there will be a transition period for medicines authorised between January 2011 and August 2013 while their updated package leaflets gradually replace older stock. Any materials distributed to patients and healthcare professionals about a medicine subject to additional monitoring, will contain information on its additional monitoring status. ^[1]

REPORTING SIDE EFFECTS:

Reporting suspected side effects is an important way to gather more information on medicines on the market. Regulatory authorities look at reports of side effects alongside all the information they already have to make sure that the benefits of medicines remain greater than their risks and to take any necessary action. ^[1]

Patients and healthcare professionals are encouraged to report suspected side effects seen with any medicine. Under the new pharmacovigilance legislation, patients have the right to report suspected side effects directly to the national medicines regulatory authorities in their country if they wish. Information on how to do this must be given in each medicine's package leaflet and summary of product characteristics. ^[4]

The black triangle makes it possible to quickly identify medicines that are subject to additional monitoring. Patients and healthcare professionals are strongly encouraged to report any suspected side effects with medicines displaying the black triangle, so that any new emerging information can be analysed efficiently.

ADVANTAGES:

Updated product information will encourage patients and healthcare professionals to report adverse reactions, with new label requirements to identify the different ways to report an adverse event, including electronic reporting and the appropriate postal address.

These changes will allow easy identification of human medicines that are subject to additional monitoring and to encourage adverse-reaction reporting for all medicines.

Other plans include the introduction of an automatic urgent procedure for review at EU level and greater transparency for pharma companies that withdraw a medicine from the market.[4]

CONCLUSION:

Black triangle drugs are that need additional monitoring after marketing and denoted by inverted black triangle according to new pharmacovigilance rules published by the European Medicines Agency. A Black Triangle symbol is assigned to any drug or vaccine that have a new active substance or a biosimilar medicine or a new combination of medicines or active substances or a new route of administration or drug-delivery system etc. This help to encourage reporting of adverse reactions and promote safe drug use as a part of post marketing surveillance.

REFERENCES:

1. Black Triangle Scheme - new medicines and vaccines subject to EU-wide additional monitoring [Internet]Medical and healthcare products regulatory agency Available from: https://assets publishing.service.gov.uk/government/uploads/system/uploads/ attachment_data/file/396808/Black_Triangle_Scheme

2. The yellow card scheme: guidance for healthcare professionals, patients and public[internet].2015Gov. UK [updated 2018 oct 30] Available from: https: //www.gov.uk/guidance/the-yellow-card-scheme-guidance-for-healthcare-professionals&ved

3. Black triangle medicine part of an EU-wide scheme [Internet].2014Gov.UK[updated2014dec11] Availablefrom: https:// www.gov.uk/drug-safety-update/black-triangle-medicines-part-of-an-eu-wide -scheme&ved

4. What does black triangle drugs mean[pdf].2013European medicine agency [update 2013 oct 1] Available from: https:// www.ema.europa.eu/documents/other/what-does-black-triangle-mean_en.pdf

5. Martin RM, Kapoor KV, Wilton LV, Mann RD. Underreporting of suspected adverse drug reactions to newly marketed (“black triangle”) drugs in general practice: observational study. Bmj. 1998 Jul 11;317(7151):119-20. Available from: URL: https://www.ncbi.nih.gov/pmc/articles/PMC28603.

Received on 15.05.2019 Accepted on 16.06.2019

Asian J. Pharm. Res. 2019; 9(3):203-205.

DOI: 10.5958/2231-5691.2019.00033.9