Pharmacovigilance activities are of vital importance for ensuring effective and safe medicinal products. In order to clarify to which extent marketing authorisation holders (MAHs) meet the requirements of the Law and the Directives related to this activities, we conducted a systematic search among the procedures submitted to the Bulgarian Drug Agency (BDA) related to the implementation of the decisions of the Pharmacovigilance Committee and the Co-ordination Group for Mutual Recognition and Decentralised Procedures – Human (CMDh) for a period of 6 years. The results of the study showed significant discrepancies between regulatory requirements and the behavior of the MAH at the national level. This could be a serious problem, as inadequate or late implementations of the PRAC (Pharmacovigilance Risk Assessment Committee)/CMDh/EC recommendations can lead to untimely informing of healthcare professionals and patients about potential safety concerns and risks related to the use of medicinal products.

NSAIDs, opioids, regulatory requirements discrepancies

Pharmacovigilance issues increasingly require serious monitoring and standardized standard procedures for assessing patients‘ risk levels. There are accumulating evidence that in many cases the treatment of adverse drug reactions is extremely detrimental to patients and health care budgets and could have serious consequences. The data presented here clearly show that analgesics and some antidepressants are widely used in society, which often has serious consequences. The development and implementation of modern unified standards for safety assessment, as well as their timely implementation in EU countries, is of great importance.

According to the current European pharmaceutical legislation, all periodic safety update reports (PSUR) are subject to a centralized assessment, the so-called Periodic Safety Update Report Single Assessment (PSUSA). PSURs are submitted in accordance with the timetable described in the Guidelines for Good Pharmacovigilance Practice (2011) (GVP), Module VII, effective July 2, 2012, and replaced Volume 9A.

According to the Official Journal of the European Union (2010), the generic medicinal products as well as homeopathic medicinal products, and herbal products of traditional use do not fall within the scope of these requirements and no PSUR submission is required unless a specific requirement is included in the marketing authorisation or the Product is included in the so-called European Union reference dates (EURD) list. This list is updated by the European Medicines Agency and is available on the EMA’s website.

The procedures for a single assessment of periodic safety update reports shall be performed by EMA and affect all medicinal products containing the same active substance or combination of substances, even if they are subject to various authorisations or authorised by different countries. A Pharmacovigilance Risk Assessment Committee (2012) (PRAC) has been set up for this purpose. The assessment shall be carried out by the members of the PRAC or a Member State, following a nomination by the Co-ordination Group for Mutual Recognition and Decentralised Procedures – Human (CMDh), and usually ends with a single assessment report, which is circulated to all marketing authorisation holders (MAH) whose products are included in that assessment. It should be noted that MAH is fully responsible for the quality of the documentation submitted and is essential for the overall assessment. The Pharmacovigilance Committee evaluates the safety data for centrally authorised medicinal products, PSURs on a group of products, some of which are centrally authorised and those that have received marketing authorisation (MA) under purely national procedures (including decentralized or mutual recognition), as well as for products that are authorised in one Member State (MS) only. The assessment of the periodic safety update reports is a national responsibility in case of certain specific medicinal products that are of national interest or contain active substances that are not included in the EURD list.

Following the publication of the PRAC recommendations, the European Commission (EC) issues a decision that is sent to all Member States and should be implemented by the national competent authorities within 30 days of notification of medicinal products under a national procedure. The concerned medicinal products are usually described in an annex to the EC decision. By analogy with the referral procedures, the variations in the marketing authorisations must be submitted to the Bulgarian Drug Agency (BDA) within 10 days after the publication of the EC decision. CMDh’ s position includes a timetable for submission of Variation Applications, which is applicable to all affected products, including those not described in the Annex to the EC Decision. Changes in the product information after PSUSA procedures can be implemented using a Type IA with immediate notification variation, category C.I.3.a, provided they are available harmonized national translations and there is no need for additional assessment. If proposed by the Committee, resp. Commission text needs to be further adapted to the specific product information, a change may be submitted as a type IB, C.I.3.z. (Q 3.3 of CMDh/CMDv /132/2009, Rev.55, February 2020). Generic medicinal products, or those not directly affected by the PSUR procedure, have to comply with the deadlines (May 2020) showed in Table 1.

According to Art. 23 (3) Directive 2001/83 / EC, marketing authorisation holders must take the necessary action to actualize the product information – Summary of Product Characteristic (SPC) and Patient Leaflet, in accordance with current scientific knowledge, including the conclusions following an assessment by national and European regulatory authorities and the recommendations published on the website of the European Medicines Agency.

The Guideline on the classification of variations to the marketing authorisation specifies that if the variation does not meet any of the conditions for type IA/IA _IN and/or no documentation is available, the same variation may be submitted as type IB.

The purpose of the current analysis is to establish how marketing authorisation holders comply with European legislation in the field of pharmaceutical regulation at national level and to identify potential regulatory gaps. And on this basis to find answers to some key questions such as:

• What are the regulatory activities related to pharmacovigilance recommended by the Pharmacovigilance Committee for active substances belonging to the group of Nonsteroidal anti-inflammatory drugs (NSAIDs) and opioid analgesics?
• What are the recommended deadlines for implementing the new safety data in the product information and how the PRAC recommendations are implemented?

The materials are related to variation documentation for concerned medicinal products submitted at national level. It is regulated by the Law on Medicinal Products in Human Medicine Act and related regulations. A systematic review was carried out using the scientific conclusions published on the EMA website after each PSUSA, the data available in the register of authorised medicinal products and the published summary of product characteristics.

In the present research, we included a study of the submitted to the BDA and approved changes in the marketing authorisations of the cited groups of products, the terms in which they were submitted, and the types of changes used by the MAH.

The methodological approach that was chosen includes five successive stages:

1. Identification of PSUSA procedures that have resulted in recommendations for changes in the marketing authorisations for the indicated groups of active substances.
2. Clarification of the registration status of medicinal products.
3. Monitoring of the regulatory activities for each separate, authorised for use LP in Bulgaria, compliance of the applications for change received by the BDA with the recommendations of PRAC, resp. CMD (h) or EC.
4. Deadline for submission of applications and type of change, according to the classifier of changes.
5. Analysis of the results.

In connection with the above, data analysis was performed for all medicinal products containing NSAIDs and opioid analgesics and regulatory activity in connection with the completed PSUSA procedures over the past five years (2015–2019).

For the period 2015–2019 year out of all PSUSA concerning NSAIDs and opioid analgesics, nine completed with a recommendation by the PRAC changes in marketing authorisations (of which two of diclofenac for systemic use). For the others, the Committee did not identify any changes in the safety profile of the active substances and did not recommend any changes to the product information.

The systematic review of the marketing authorisations described above and their history during their life cycle identified significant inconsistencies with the established regulatory framework.

The most common discrepancies are:

• Submission of applications for type IB variation, in the presence of unified and approved national texts, which does not require an additional assessment.
• Incorrect classification of the variations, which implies different conditions and documentation.
• Failure to comply with the specified deadlines for implementation of the change.
• Failure to submit variation applications and, accordingly, lack of relevant safety information in the summary of product characteristics and/or package leaflet

Fig. 1 and Fig. 2 show the distribution of discrepancies by type of active substance, as well as a percentage of all active substances/products affected by the PSUR evaluation procedures.

Lack of understanding of modern pharmaceutical regulation or attempts to circumvent it is a possible reason for the identified discrepancies. In the practice of BDA, we often meet with ignorance of certain details of the procedures for variation of the MAs, such as the fact that the type IA and IA _IN variations are retrospect and are presumed to have already been implemented by the marketing authorisation holders before notifying the Agency thereof. Numerous meetings, training, and seminars were held to explain both the registration principles and those of drug safety.

Figure 1. 

Distribution of discrepancies by type of active substance for all active substances/products affected by the PSUR evaluation procedures. Legend: I: Total number of products by active substances; II: The change has not been implemented; III: The change is implemented by an appropriate procedure; IV: The change is implemented outside the specified deadlines.

Figure 2. 

A percentage of all active substances/products affected by the PSUR evaluation procedures. Legend: 1: The change is not implemented; 2: The change is implemented with an appropriate procedure; 3: The change is implemented outside the specified deadlines.