Baseline assessment of pharmacovigilance activities in four sub-Saharan African countries: a perspective on tuberculosis

Background New medicines have become available for the treatment of drug-resistant tuberculosis (DR-TB) and are introduced in sub-Saharan Africa (SSA) by the national TB programs (NTPs) through special access schemes. Pharmacovigilance is typically the task of national medicines regulatory agencies (NMRAs), but the active drug safety monitoring and management (aDSM) recommended for the new TB medicines and regimens was introduced through the NTPs. We assessed the strengths and challenges of pharmacovigilance systems in Eswatini, Ethiopia, Nigeria and Tanzania, focusing on their capacity to monitor safety of medicines registered and not registered by the NMRAs for the treatment of DR-TB. Methods Assessment visits were conducted to all four countries by a multidisciplinary team. We used a pharmacovigilance indicator tool derived from existing tools, interviewed key stakeholders, and visited health facilities where DR-TB patients were treated with new medicines. Assessment results were verified with the local NMRAs and NTPs. Results Most countries have enabling laws, regulations and guidelines for the conduct of pharmacovigilance by the NMRAs. The relative success of NTP-NMRA collaboration is much influenced by interpersonal relationships between staff. Division of roles and responsibilities is not always clear and leads to duplication and unfulfilled tasks (e.g. causality assessment). The introduction of aDSM has increased awareness among DR-TB healthcare providers. Conclusion aDSM has created awareness about the importance of pharmacovigilance among NTPs. In the future, a push for conducting pharmacovigilance through public health programs seems useful, but this needs to coincide with increased collaboration with between public health programs and NMRAs with clear formulation of roles and responsibilities.

Pharmacovigilance- A drug safety monitoring tool

The objective of this narrative review is to converse about drug safety, global pharmacological authorities and their responsibility, the process of adverse event reporting, and the main functions of pharmacovigilance. Pharmacovigilance is a science that ensures patient safety against both newly launched and well-established medicinal products in the market. Pharmacovigilance is considered a specific tool used for observing and estimating Adverse Drug Reactions (ADRs) and is essential for successful drug management programs, clinical trials, and public health programs. In the few past years, the number of reported ADRs got increased as a result of which the volume of data got increased. To handle such huge data and the need to understand the pharmacovigilance, it requires highly skilled and proficient people for immediate detection of drug's side effects and protects the product from improper removal. The existing global network of pharmacovigilance centers will be strengthened through an independent review process in coordination with the Uppsala Monitoring Center. Its main role is to assess trials and crucial issues of drug safety that probably influence public health beyond national borders. In this global arena, Pharmacovigilance becomes an important and integral part of clinical research. Most of the countries set up pharmacovigilance centers to monitor drug safety; however, millennial pharmacovigilance faces major challenges for improved safety and drug monitoring.

Drug Safety Monitoring Information

Analysis of administrative decisions of foreign regulatory authorities on the recall of medicines and/or the need for changes in the instructions for their medical use due to changes in the safety profile, conducted by experts of the Scientific Centre for Expert Evaluation of Medicinal Products revealed 19 administrative decisions. These decisions contained information on the following medicines registered in Russia: amikacin, tobramycin, gentamicin, neomycin, ciprofloxacin, delafloxacin, levofloxacin, lomefloxacin, moxifloxacin, norfloxacin, ofloxacin, pefloxacin, prulifloxacin, rufloxacin, сeftriaxone, ceftaroline, rifapentine, tigecycline, bacitracin, ertapenem, daptomycin, erythromycin, fosfomycin, ampicillin+sulbactam, chloroquine, hydroxychloroquine.

Incidence rate and time to serious adverse events among rifampicin resistant tuberculosis patients in Georgia treated with new and repurposed anti-tuberculosis drugs, 2016-2018

Considering the complexity of second-line anti-tuberculosis (TB) treatment regimens, the management of drug-resistant TB (DR-TB) in Georgia remains a major challenge. Since the introduction of new and repurposed anti-TB medications, the implementation of active TB Drug Safety Monitoring (aDSM) was a critical program component to help establish safety and manage all treatment related Serious Adverse Events (SAEs). In our study, we aimed to describe the occurrence, characteristics and timing of SAE among patients with Rifampicin Resistant and Multi-Drug Resistant TB (RR/MDR-TB) receiving new and/or repurposed anti-TB medications (bedaquiline, delamanid, linezolid, clofazimine, imipenem) during the period of 2016-2018 in Georgia and identify predictors of SAE. The data were obtained from the medical charts, electronic database and standardized aDSM reports During 2016-2018 period in total 970 people with RR/MDR-TB were notified in Georgia and 388 of them received new and/or repurposed TB drugs as part of their treatment regimen and all were included into the study. The results showed a total of 73 SAEs registered among 49 (12.6%) patients receiving new and/or repurposed drugs. The overall SAE incidence rate per 100 person-months was 1.16. The severity of the majority of the SAEs (46.6%) was grade III and 21.9% were grade IV. The most common SAE reported was hepatotoxicity, with an incidence of 0.26 per 100 person-month (n=16, 21.9%) followed by cardiotoxicity with an incidence of 0.16 per 100 person-month (n=10, 13.7%). Median time to SAE occurrence was 183 days (IQR 84 – 334) after treatment initiation. Resistance profile was the only predictor associated with occurrence of a SAEs. There was increased hazard of SAEs among patients with XDR-TB (adjusted HR=2.18, 95% CI: 1.12-4.23). Our findings on SAEs among patients treated with new or repurposed anti-TB drugs are echoing the findings available in the literature. They highlight the need for close monitoring of patients and underlines the importance of the aDSM during the whole treatment. Safety profile of the medications and combinations used are yet to be established and larger datasets comprised of patients receiving same treatment regimens need to be utilized.

Drug Safety Monitoring—International Information

Experts of the Department for Evaluation of Medicinal Products’ Safety of the Scientific Centre for Expert Evaluation of Medicinal Products analysed administrative decisions of foreign regulatory authorities on limiting the use of some medicinal products and/or the need to introduce changes in patient information leaflets due to changes in the medicines’ safety profiles. The analysis helped to identify 16 administrative decisions that contain information on the following medicines registered in Russia: duloxetine, sertraline, paroxetine, сitalopram, desvenlafaxine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, venlafaxine, vortioxetine, mirtazapine, risperidone, clozapine, aripiprazole, quetiapine, olanzapine, lacosamide, gabapentin, pregabalin.

Analysis of adverse drug reactions reported to national pharmacovigilance center of Bhutan

Introduction: Medicines prescribed for diseases often causes adverse drug reactions in patients ranging from mere inconvenience to permanent disability and death. This is because, most of the adverse drug reactions especially the serious and latent ones may not have occurred during the clinical trials and vulnerable populations like children, pregnant women and the elderly are not all included in clinical trial studies considering the ethical and safety issues. Objectives: To study the demographic characteristics, types of adverse drug reactions and common drugs causing these reactions from the adverse drug reaction reports received by the national pharmacovigilance of Bhutan. Methods: A total of 222 adverse drug reactions were received at the national pharmacovigilance center from January 2016 to May 2018 were analyzed retrospectively. The Drug Regulatory Authority is the national pharmacovigilance center of Bhutan and is a member to the International Drug Monitoring Program since 2014. Results: 73% of adverse drug reactions occurred in adults while 13.5% occurred each in children and elderly. 48.7% of the total adverse drug reactions reports were caused by antibiotics out of which penicillin was the most common causal drug (32.4%). The most commonly reported adverse drug reactions was rashes (36.5%) followed by gastro-intestinal system disorder (14.9%). Conclusions: Antibiotics are common causal drugs for adverse drug reactions. All categories of health professional must be encouraged to report adverse drug reactions. Active surveillance for drug safety monitoring especially for those of patients who are on antibiotics is recommended.

Strengthened capacity of India´s bedaquiline Conditional Access Programme for introducing new drugs and regimens

BACKGROUND: Addressing TB in India is critical to meeting global targets. With the scale-up of diagnostic networks and the availability of new TB drugs, India had the opportunity to improve the detection and treatment outcomes in drug-resistant TB (DR-TB).OBJECTIVE: To document how the introduction of new drugs and regimens is helping India improve the care of DR-TB patients.DESIGN: In 2016, India´s National TB Programme (NTP) introduced bedaquiline (BDQ) under a Conditional Access Programme (BDQ-CAP) at six sites after providing extensive training and strengthening laboratory testing, pre-treatment evaluation, active drug safety monitoring and management (aDSM) and follow-up systems.RESULTS: An interim analysis reflected earlier and better culture conversion rates: 83% of the 620 patients converted within a median time of 60 days. However, 248 serious adverse events were reported, including 73 deaths (12%) and 100 cardiotoxicity events (16.3%). Encouraged by the evidence of safety and efficacy of BDQ, the NTP took steps to systematically expand its access to cover the entire population by 2018.CONCLUSION: The cautious yet focused approach used to introduce BDQ under BDQ-CAP paved the way for the rapid introduction of delamanid, as well as the shorter treatment regimen and the all-oral regimen for DR-TB.

Setting up pharmacovigilance based on available endTB Project data for bedaquiline

SETTING: Active pharmacovigilance (PV) is recommended for TB programmes, notably for multidrug-resistant TB (MDR-TB) patients treated with new drugs. Launched with the support of UNITAID in April 2015, endTB (Expand New Drug markets for TB) facilitated treatment with bedaquiline (BDQ) and/or delamanid of >2600 patients in 17 countries, and contributed to the creation of a central PV unit (PVU).OBJECTIVE: To explain the endTB PVU process by describing the serious adverse events (SAEs) experienced by patients who received BDQ-containing regimens.DESIGN: The overall PV strategy was in line with the ‘advanced´ WHO active TB drug safety monitoring and management (aDSM) system. All adverse events (AEs) of clinical significance were followed up; the PVU focused on signal detection from SAEs.RESULTS and CONCLUSION: Between 1 April 2015 and 31 March 2019, the PVU received and assessed 626 SAEs experienced by 417 BDQ patients. A board of MDR-TB/PV experts reviewed unexpected and possibly drug-related SAEs to detect safety signals. The experts communicated on clusters of risks factors, notably polypharmacy and off-label drug use, encouraging a patient-centred approach of care. Organising advanced PV in routine care is possible but demanding. It is reasonable to expect local/national programmes to focus on clinical management, and to limit reporting to aDSM systems to key data, such as the SAEs.

Comparative Analysis of International Databases of Adverse Drug Reactions

In 1968 the World Health Organisation initiated the development of an international programme for collection of data from the maximum number of sources about potential adverse effects of medicines. In order to implement this programme, a number of databases were created, such as the global database VigiBase, the European database EudraVigilance, and the database of the Eurasian Economic Union (EAEU). The aim of the present study was to compare approaches of the international spontaneous reports databases to collection, processing, and analysis of information on adverse drug reactions. It was demonstrated that the international databases VigiBase, EudraVigilance, and the EAEU database of adverse drug reactions contain different numbers of spontaneous reports, but serve the same objectives, namely to collect, process, and analyse information submitted as spontaneous reports. Unlike VigiBase that contains reports on authorised medicines coming from the national pharmacovigilance centres only, EudraVigilance also receives data from marketing authorisation holders and has reports on adverse drug reactions observed during clinical trials. The exchange of information between countries ensures rapid identification of safety signals concerning potential risks of medicines, and increases the likelihood of detecting rare and late-onset adverse reactions that may go unnoticed when analysing national data in a particular country. Spontaneous reports databases are an essential tool of the international drug safety monitoring community. Effective measures in this area will ultimately help to improve patients’ health and quality of life.