Good Pharmacovigilance Practices Research Articles

An Overview on Good Pharmacovigilance Practices and New Operational Plan Milestones of Eudravigilance in European Union

This review article mainly focuses on Eudravigilance (EV) the pillar for pharmacovigilance activities in the European Economic Area (EEA) which launched new operational plan for development of operational activity with anticipated timelines and also focuses on the Good Pharmacovigilance Practices (GVP) deals with analysis of safety data from uninhibited reporting systems with proven value for detection of risks of marketed medicines and with more modules of effected guidelines. EV system describes key activities and developments that will impact on or relate to itself and its stakeholders during the next 3 years from 2018 to 2020. The main aim is to ensure sustainability of EV and associated activities in support of the EU pharmacovigilance activities and protection of public health. The operational plan will be updated regularly as regards timelines and new activities/developments. In addition system interaction with the stakeholders as a part of training and communication engagement are covered to ensure that a platform for learning, cooperation and alignment throughout the evolution and operation of EV. GVP covers maintenance of risk management activities and to increase the beneficial effects of drug in population and maintenance of good reporting practices to avoid adverse reactions and the guidelines are based on population or product specific considerations and major pharmacovigilance process.

Good Pharmacovigilance Practice in Paediatrics: An Overview of the Updated European Medicines Agency Guidelines.

Good Pharmacovigilance Practice in Paediatrics: An Overview of the Updated European Medicines Agency Guidelines.

Awareness of, and Compliance with, Domperidone Revised Labeling After a Risk-Minimization Activity in Europe.

Background and ObjectiveRisk-minimization measures (RMM), including label revisions were implemented in Europe for domperidone because of evidence of increased incidence of cardiac arrhythmia and sudden cardiac death. In accordance with the guideline on good pharmacovigilance practices, the European Medicines Agency Pharmacovigilance Risk Assessment Committee requested to conduct two studies to evaluate the effectiveness of these risk minimization measures.MethodsIn Belgium, France, Germany, Spain, and the UK, surveys were conducted to assess physicians’ knowledge on the updated domperidone labeling information, and a drug-utilization study (DUS) was conducted using healthcare databases to assess domperidone prescribing patterns before and after the RMM. Four DUS sensitivity analyses (scenarios) evaluated uncertainty regarding domperidone treatment duration and indication.ResultsAmong 1805 physicians participating in the survey, most were aware of the approved indication (nausea and vomiting, 80%), treatment duration (≤ 7 days, 70%), and maximum adult daily dose (10 mg three times daily, 84%). Only 33% selected the on-label indication from a list of indications for which they would prescribe domperidone. Awareness was low for medications contraindicated for concomitant use (26%) and contraindicated conditions (4%). In the DUS, under the optimistic scenario, a large improvement in labeling compliance from pre- to post-implementation period was observed in France (27% vs. 69%), while Belgium, Germany, Spain, and the UK showed small improvements (< 10%). In the other scenarios, there was little to no improvement in compliance with the revised labeling from the pre- to post-implementation periods in most countries.ConclusionsThe survey findings documented that most physicians in all five countries were aware of the main aspects of the revised labeling. Results of the DUS were inconclusive regarding the effect of the RMM and compliance with the revised labeling for all countries except France.Electronic supplementary materialThe online version of this article (10.1007/s40261-019-00831-3) contains supplementary material, which is available to authorized users.

Recent changes in the pharmacovigilance system in the Russian Federation and the EAEU

The Eurasian Economic Union (EAEU) is an international organization for regional economic integration, established by the Treaty on the Eurasian Economic Union, which currently includes 5 countries - Russia, Kazakhstan, Belarus, Armenia and Kyrgyzstan. The EAEU ensures the freedom of goods movement, as well as services, capital and labor, conducting a coordinated, agreed/unified economic policy. The current practice of pharmacovigilance in the EAEU is of interest to potential foreign investors and market players. The aim of this study was to analyze the recent changes in pharmacovigilance in the EAEU countries in order to adopt the strategy of the pharmaceutical industry players. Materials and methods . The regulatory base of pharmacovigilance in the EAEU countries and the unified EAEU provisions on adverse reactions (ADR) were analyzed. A critical analysis of the current periodic safety update reports (PSUR) and risk management plans (RMP) was also carried out. Results. The united EAEU drug market is a complex system that incorporates 35 regulations, including the variety of good practice guidelines regarding the circulation of medicinal products (GMP, GCP, GLP, GDP, and GVP). This group of regulations contains basic documents on the inspection of production lines, the assessment of generic equivalence, the development of biological drugs, and the pharmacovigilance (PV). Currently, the ADR reporting in the EAEU countries is at a level lower than that in Russia. The common EAEU database of identified ADRs has been already initiated, but the number of incoming signals is quite small. The most common flaws of the PSUR are the late reports, the incorrect format and contents of those; the inconsistent information about the product, different from that of Roszdravnadzor, the discrepancy between the Patients information leaflet (“Instruction for medical use”) and the Summary of Product Characteristics (SmPC), and the lack of important and relevant scientific and clinical information. In the EAEU, the submission of Risk Management Plan (RMP) as part of the registration dossier is required for any new medication (New Chemical Entity), including a new combination of drugs. The present article also covers other updates in the Pharmacovigilance system, regulated by the Good Pharmacovigilance practice, which entered into effect on 01.01.2017, as well as the updated tasks for harmonization within the EAEU. Conclusions. The medicinal products circulating in the EAEU have to be checked for their efficacy and safety in order to identify possible negative consequences and/or individual patient intolerance. This information will serve to warn the medical staff and patients, veterinary specialists and animal owners about potential hazards of using these products. In the near future, the Eurasian Union plans to launch a “sanitation” campaign in the pharmaceutical market and get rid of low-effective and unsafe drugs. In this respect, the issues of pharmacovigilance become particularly relevant.

Study design, process and outcome indicators of post‐authorization studies aimed at evaluating the effectiveness of risk minimization measures in the EU PAS Register

Risk minimization measures (RMMs) represent an essential tool for preventing the occurrence of safety-related outcomes. The evaluation of RMMs effectiveness is essential to prove their success and ensure protection of public health. The aim of this qualitative review was to assess the design, process and outcome indicators used for attesting successful implementation of RMMs. We searched the EU Post-Authorization Studies Register up to 30 June 2018 for studies having the scope defined as 'effectiveness evaluation'. Study titles and objectives were screened to select the ones evaluating the effectiveness of RMMs. We described and assessed the extent to which these studies aligned with Good Pharmacovigilance Practices guidelines recommendations. Out of 360 registered studies, we identified 35 studies on evaluation of RMMs effectiveness, 29 being eligible for review. Twenty-six studies evaluated additional RMMs, employed in case routine interventions are considered insufficient. All studies assessed process indicators, five also assessing outcome indicators, thus using a dual-evidence approach as recommended by the guidelines. However, none of the latter used a pre-post design, comparing the frequency of the adverse outcome before and after the implementation of RMMs. Behaviour and knowledge were the most often assessed process indicators. Outcome indicators included occurrence of adverse reactions, pregnancy, off-label use and medication errors. Only four studies had an established threshold, all for process indicators. Stricter adherence to existing recommendations would allow for a more robust design for reaching established endpoints for RMM effectiveness evaluation. It would also infer harmonization, facilitate review and further more detailed guidance on conducting these studies.

SIGNAL AS A TOOL OF THE PHARMACOVIGILANCE

The European Medical Agency (EMA) in 2012 formulated modern legislation defining the procedure for pharmacovigilance — the Good Pharmacovigilance Practices (GVP), which replaced the earlier provisions of the Pharmacovigilance Guidelines for Human Medicines. The signal management position is included in one of the GVP EMA modules and became part of the EAEC GVP Rules. EMA in 2017 published a regulatory guide for detecting a signal in spontaneous reporting databases, which became an Annex to Module IX of the GVP Rules «Signal Management». The approach proposed in the Appendix supplements the classical analysis of disproportionality with other data, based on both statistical and clinical judgments. The article deals with the problem of detecting signals about the safety of medicines. The main parameters that determine the effectiveness of methods for detecting signals on disproportionality and allowing to compare the productivity of different statistical methods with respect to each other are considered. Priority directions are considered when evaluating the signal, and key elements of a qualitative method for detecting signals are drawn up, taking into account the expert opinion.

Strengthening standards, transparency, and collaboration to support medicine evaluation: Ten years of the European Network of Centres for Pharmacoepidemiology and Pharmacovigilance (ENCePP).

Strengthening standards, transparency, and collaboration to support medicine evaluation: Ten years of the European Network of Centres for Pharmacoepidemiology and Pharmacovigilance (ENCePP).

Непрерывный мониторинг электронных ресурсов в работе уполномоченного лица по фармаконадзору

The regular monitoring of medicinal product (MP) safety is one of the requirements of the Good Pharmacovigilance Practices (GVP) for marketing authorization holders. The search and study of information about adverse reactions (AR) of medicinal products by pharmaceutical manufacturers allow us to constantly update the AR database, identify changes in the benefit-risk ratio when using MPs, and conduct the qualitative assessment of the safety profile.

Social Media Monitoring and Adverse Drug Reaction Reporting in Pharmacovigilance: An Overview of the Regulatory Landscape.

In the context of the European Union's Innovative Medicines Initiative (IMI) project titled Web-Recognizing Adverse Drug Reactions (WEB-RADR; http://web-radr.eu ), which focuses on the assessment of new data sources and the optimization of the collection of information on suspected adverse reactions in pharmacovigilance, a survey was performed in 182 countries/jurisdictions in 2014 to 2015. The goal was to gather information on existing practices, guidance, and legal requirements on social media monitoring to identify potential safety issues related to medicines. The survey response rate was 100%. The results revealed that 80% of the surveyed countries do not have such necessities despite the fact that 63% of these countries have an established national pharmacovigilance system. Among the countries having an established pharmacovigilance system, only 29% have specific requirements, most countries do have similar provisions as set out in the EU guidelines on Good Pharmacovigilance Practices (GVP). A small subset of countries within the European Economic Area (EEA) have requirements that exceed those stated in GVP, namely, Italy, France, Sweden, and the UK. Outside the EEA, Turkey and the United States have also developed further guidance. The outcome of the survey will inform the development of a future policy framework on the further use of social media as new pharmacovigilance data source in the EEA. In addition, this paper elaborates on some current practical case management issues encountered by companies based on the existing regulatory guidance.

Good Pharmacovigilance Practice: Accountability of Ayurvedic Pharmaceutical Companies.

Good Pharmacovigilance Practice: Accountability of Ayurvedic Pharmaceutical Companies.

Pharmacovigilance in the Russian Federation: Construction, Development and Reforms of PV System

The review outlines the current issues of Pharmacovigilance System in the Russian Federation, namely present state of regulatory aspects of PV system in Russia, regulatory requirements in Russia and in Eurasian Economic Union, review of the causes of under-reporting of ADRs. Specific focus has been made on topical issues such as a harmonization of the requirements to the Pharmacovigilance System, currently underway in Russia, the issue of Guidelines on Good Pharmacovigilance Practice (GVP) in the Eurasian Economic Union. These actions are aimed at improving and harmonizing the rules governing the main aspects of the Pharmacovigilance System in the Russian Federation. Also the review analyses one of the most important aspects in development of a new Pharmacovigilance System-the attitude towards pharmacovigilance in patients and healthcare professionals.

The “Fluad Case” in Italy: Could it have been dealt differently?

ABSTRACTDuring the influenza vaccination campaign 2014–2015, the reporting of 3 deaths within 48 hours of vaccination with Fluad brought the Italian Medicines Agency (AIFA) to pronounce the withdrawal of 2 batches of vaccine, based on the precautionary principle. Investigations by the Italian National Institute of Health, and by the Pharmacovigilance Risk Assessment Committee (PRAC), the committee at the European Medicines Agency (EMA) responsible for monitoring and assessing the safety profiles of human drugs, concluded that there was a lack of causality between the reported deaths and the vaccines administered. However, the media impact of the decision taken by AIFA, resulted in a lower influenza vaccination coverage compared with the previous years. The aim of our study was to identify possible critical points that may have led to a non-perfect management of the event. A review of the regulatory framework in place was performed, with a particular focus on the Guidelines on Good Pharmacovigilance Practices developed by the EMA to facilitate the signal management process. The management of reports involves the following steps: signal detection, its validation and confirmation, analysis and prioritization, assessment, recommendations for action and the exchange of information. In our opinion, both the signal detection phase and the phase of validation have been critical: the withdrawal of vaccine batches is possible even in case of a single suspected serious adverse reaction. However, aspects such as the biological plausibility, the presence of potential alternative causes and previous awareness should also be considered. Furthermore, the number of reported deaths was consistent with the expected background mortality rate in the vaccinated cohort. The disproportionate media coverage given to the AIFA decision resulted in a reduced vaccine confidence in the general population and in a decreased immunization coverage. Improving the communication on vaccine safety issues is crucial at this stage to restore a climate of trust in this powerful tool for primary prevention.

Effectiveness of a risk-minimization activity involving physician education on metabolic monitoring of patients receiving quetiapine: results from two postauthorization safety studies.

Following Good Pharmacovigilance Practices Module XVI, two complementary studies were performed that included process and outcome measurements of the effectiveness of physician education on metabolic monitoring of patients receiving quetiapine. A multinational survey of 800 European Union physicians was utilized to assess the receipt of educational materials and also to assess the degree of monitoring as reported by physicians. Recall of receipt of educational materials ranged from 16.0 to 69.0% across the participating countries; however, physicians reported that 64.5% of patients were being monitored, with the majority reporting performance of three or more of four key metabolic-monitoring activities. Higher rates of monitoring were reported by those who reported receiving materials. Assessment of outcomes in a separate retrospective analysis of electronic medical record data showed lower levels of monitoring performed by specialist physicians. The monitoring activities observed were assessed as acceptable on the basis of the established performance of UK physicians, who are incentivized to deliver preventive screening.

English

Risk communication associated with drug use is a critical point in post-marketing surveillance. Therefore, validation of strategies to minimize under-reporting of adverse drug events (ADE) are needed in order to contribute towards good pharmacovigilance practices. The present study aims to validate a multi-faceted educational intervention (MEI) in pharmacovigilance for Mercosur countries and assess its impact on particular attitudes, knowledge, and skills to correctly complete the ADE form to ensure quality of reports. The MEI was developed during four one-hour meetings. The following activities were carried out: a lecture regarding landscape; importance and concepts related to pharmacovigilance; classroom practice for elucidating the correct completion of ADE reports; distribution of an educational manual and completion of a questionnaire to assess knowledge, attitudes, and skills in pharmacovigilance. The answers of the questionnaire were analyzed using a content analysis technique. Definitions from the World Health Organization and the minimum and desired criteria to fill the ADE form, according to the Pan American Health Organization, were considered gold-standard answers. The impact of the MEI was analyzed by a Wilcoxon statistical test. 82 subjects were enrolled and sixteen returned questionnaires. Since after the methodology there were also fifteen reports of medication error, the MEI did contribute to the improvement of knowledge (p<0.002), skills (p=0.002) and attitude in pharmacovigilance. The proposed MEI may contribute to risk management, as it enhanced the quantity and quality of the reports. Furthermore, it can be used to effectively harmonize pharmacovigilance practices in Latin American countries. Key words: Adverse drug reaction reporting systems, drug-related side effects and adverse reactions, pharmacovigilance, attitude of health personnel, risk management.

Regulatory Definitions and Good Pharmacovigilance Practices in Social Media: Challenges and Recommendations.

Social media presents new challenges to the biopharmaceutical industry for conducting pharmacovigilance activities. The authors reviewed worldwide regulatory guidance documents related to monitoring of adverse events posted on social media sites and identified gaps in current regulatory definitions for pharmacovigilance. Points to consider for addressing these gaps are made to offer standards for industry consideration and a potential framework for guidance from global health authorities.

PRM229 - Do We Need to Strengthen Study Design in Observational Studies?

Guidance and standards are made available by the European Network of Centres for Pharmacoepidemiology and Pharmacovigilance (ENCePP) as reference tools for methodology and transparency of post-authorization studies. They are cited by the Guideline on good pharmacovigilance practices (GVP) Module VIII as relevant scientific guidances. Here we report an analysis conducted on Pharmacovigilance Risk Assessment Committee (PRAC) minutes regarding methodological issues. All publicly available minutes of PRAC meetings from July 2012 to March 2015 were considered. The number of submitted post-authorization safety study (PASS) protocols requiring endorsement was recorded (excluding advices), as well as endorsement/ refusal and reason. ENCePP documentation was consulted. From July 2012 to March 2015, 33 PASS protocols submitted to PRAC requiring endorsement were considered, increasing with years: 2 in 2012, 8 (17 considering resubmissions) in 2013, 18 (24 considering resubmissions) in 2014. The total number of evaluations was 54. Thirteen were endorsed at the first step (including endorsement with changes requested), while 20 required at least one amendment reaching approval up to 15 months after submission. The most common reasons for refusal concerned study design (20 cases), mainly reporting designs not allowing to fulfil study objectives (N=14). Furthermore, PRAC review asked for alternatives to reduce bias and confounding (N=2), simplifications aiming at reinforcing the observational nature of the study (N=1), further justification of sample size (N=1) and considerations on feasibility (N=1). From 2013 to 2014 an increasing number of endorsed PASS protocols was observed (7/17 and 12/24 respectively). During the same years ENCePP Checklist for Study Protocols and ENCePP Guide on Methodological Standards in Pharmacoepidemiology were reviewed, and the number of studies included in the ENCePP e-register increased. An increasing use of guidance and standards will allow strengthening robustness of design and results of observational studies.

Global Implications of the EU’s Pharmacovigilance System Master File Requirements: Newly Developed Decision Trees to Distinguish Different Study Types

In Europe, a new guideline on good pharmacovigilance practices–Module II: Pharmacovigilance system master file (PSMF)—was issued, and initially came into effect on 2 July 2012, with revision on 12 April 2013. The guideline describes the PSMF, which is a detailed description of the pharmacovigilance system and supports/documents its compliance with the requirements. Establishing and maintaining a PSMF is a global activity. However, because of differences or absence of regulations, legislation or guidance documents (soft laws) across the globe, definitions of studies may be different. However, as part of the PSMF, the marketing authorisation holder in Europe should be able to produce and make available a list including data arising from all study sources (the so-called ‘study list’) for inspection, audit and Qualified Person responsible for Pharmacovigilance oversight. For medicinal products authorised in Europe, this study list should describe, on a worldwide basis, the status of each study/programme, the applicable country(ies), the product(s) and the main objective. Most importantly, it should distinguish between non-interventional and interventional studies (clinical trials) and should be organised by active substance. The study list should include all ongoing studies/programmes as well as all studies/programmes completed in the last 2 years and may be provided as an annex to the PSMF or separately. This article analyses the global impact of the new European PSMF requirements, with special focus on the mandatory global study list. There are distinct differences between biomedical research, market research, patient support programmes and non-interventional and interventional studies, and a decision tree to support classification is proposed. This decision tree should improve harmonisation of study assessment and minimise inter-country variability in the presentation of studies/programmes for the PSMF.

A Business Intelligence Solution to Pharmacovigilance Signal Tracking and Management: One Mid-Size Pharma’s Experience

In 2012, the European Medicines Agency published guidelines for good pharmacovigilance practices. Within these guidelines, the Agency advised that marketing authorization holders (MAHs) establish safety signal tracking systems that capture outcomes related to signals that have been validated. Historically, MAHs have collected data and information to document signal detection and evaluation activities, and now many are developing robust approaches, to meet the guidelines, that systematically track and manage signals. Given the requirements, these systems could become highly reliant on business intelligence (BI) solutions. Expectations for these systems include the ability to document and track safety signals electronically through each step of the signal detection process, save source documents, and collect key performance indicators. They also include the ability to extract this information programmatically for regulatory or senior management reporting as well as for monitoring of compliance metrics. In addition, this type of systems-based approach facilitates resource management and assists MAHs to be regulatory inspection and audit ready. This article shares an experience of one mid-size pharmaceutical company.

Editorial: Risk management

The thalidomide tragedy of the early 1960s cost several thousand lives, but it ultimately led to changes that will undoubtedly save many thousands more: it triggered a chain of events involving the WHO and the ICH that resulted in the pharmacovigilance systems we have today. A key aspect of pharmacovigilance – the safety monitoring of drugs after their licensing – is risk management, which aims to better understand the benefit-risk profiles of drugs and minimise their risks to patients. A rapidly evolving area, risk management is the theme of both this issue of Medical Writing and the 3rd EMWA Symposium in Dublin. In December 2008 the European Commission unveiled the so-called ‘EU Pharma Package’, a set of proposals to give EU citizens better access to information on medicines and better protection from the harms caused by genuine and fake medicines. This package was followed by new pharmacovigilance legislation – Directive 2010/84/EU and Regulation (EU) 1235/2010 – which came into force in July 2012, and a revised good pharmacovigilance practices (GVP) guideline from the EMA, published in April 2014: Module V – Risk management systems (Rev 1). Writing in this issue ofMedicalWriting,Tizianavon Bruchhausen andKerstin Prechtel explore how these recent changes have affected safety medical writing, increasing document complexity and helping to create a new role: the pharmacovigilance medical writer. They identify some of the personal qualities pharmacovigilance writers require and outline the processes by which they can prepare Risk Management Plans (RMPs) for different purposes. In Europe, an RMPmust be submitted to the EMA with each new marketing authorisation application. Since July 2012, the EMA’s RMP has had a modular format. Sandra Gotsch guides us through its seven parts (I–VII) and eight modules (SI–SVIII), providing insights, tips, and – for those of us who are new to RMPs – reassurance! RMPs are further covered in a feature article by Lesley Wise, who describes how the risk management of approved medicines has seen an increasing focus on continued benefit-risk activities throughout a medicine’s lifecycle. Lesley examines the historical background to benefit-risk assessment, changes to the content and format of RMPs in the EMA’s revised GVP guideline (see above), and the new ICH standard for periodic benefit-risk evaluation: the Periodic Benefit-Risk Evaluation Report (PBRER). Looking to the future (perhaps the not-so-distant future), Massoud Toussi, Lisa Chamberlain James, andAlasdair Breckenridge explore the possible role of social media in adverse event (AE) reporting. They explain the value of AE data from social media and highlight technological and other developments that are needed for such data to be properly captured and used, potentially revolutionising pharma’s pharmacovigilance activities.

The changing face of (benefit-)risk management

Over the last 20 years the focus of post-approval management of medicines has changed from risk management to the assessment and management of benefit-risk. In the EU this has been reinforced by changes in the legislation underpinning pharmacovigilance and the introduction of Good Pharmacovigilance Practice (GVP) modules. The documents used by companies to present and manage the benefits and risks of a product to regulators changed in 2012, requiring a change in focus for companies and regulators which needs to be reflected in increased cross-functional working and continued benefit-risk assessments.