Pharmacovigilance Planning Research Articles

Descriptive Analysis for the Trend of Pharmacovigilance Planning in Risk Management Plans on New Drugs Approved During 2016-2019.

Japanese pharmaceutical authorities have conducted regulatory renovations of pharmacovigilance planning (PVP) since implementing new procedures for developing post-marketing study plans in 2018 in order to promote more focused and scientific approaches. This study aimed to descriptively assess the effects of those regulatory renovations on PVP for new drugs in Japan. We identified PVP information (drug characteristics, efficacy and safety issues, and additional activities) from the first version of risk management plans for new drugs approved between 2016 and 2019. The following indicators were analyzed: (1) proportion of the number of drugs with at least one efficacy issue among all the drugs, (2) proportion of the number of safety issues with additional activity among all the safety issues, and (3) proportion of database studies among all additional activities. In total, 168 drugs, 1212 safety issues, and 301 additional activities were identified. The proportion of drugs with at least one efficacy issue decreased from 91.4% in 2016 to 27.3% in 2019, and the proportion of safety issues with additional activity also decreased from 93.9% in 2016 to 53.7% in 2019. In contrast, the proportion of database studies increased from 0 to 19.2%. The percentages of additional activities targeting important identified and potential risks also gradually decreased during the 4-year period. Notable changes in the three indicators during 2016-2019 were observed, which suggests that regulatory renovation has affected PVP in Japan.

From pharmacovigilance to pharmacovigilance planning - The system building for safe medication

The concept of pharmacovigilance planning (PVP) was initiated by the International Conference on Harmonization (ICH) in 2004 and followed by the publication of Topic ICH E2E Guideline. However, the implementation of PVP in societies like Taiwan where irrational medication or co-medication of conventional medicine with complementary/alternative medicine (CAM) is prevalent, became a challenge. This report aimed to (1) introduce the concept of PVP and the importance of evidence-based justification of medicinal products for risk prevention and minimization, (2) summarize the scientific evidence regarding the sites and mechanisms of drug-drug or drug-CAM interactions along the biological processing of xenobiotics and identify potential risks in relation to co-medication of conventional medicine with CAM by reviewing literatures, (3) employ public information to analyze potential risk underlying irrational medication of registered medicine, registered traditional Chinese medicine (TCM) and un-registered CAM in Taiwan, and (4) address the importance of conceptual change from individual product-oriented pharmacovigilance to a proactive system-based risk management of pharmacovigilance planning.

Strategy support for the Post‐Market Monitoring (PMM) of GM plants: Review of existing PMM strategies developed for the safety assessment of human and animal health

Strategy support for the Post‐Market Monitoring (PMM) of GM plants: Review of existing PMM strategies developed for the safety assessment of human and animal health

Risk management plans as a tool for proactive pharmacovigilance: a cohort study of newly approved drugs in Europe.

Risk Management Plans (RMPs) have become a cornerstone in the pharmacovigilance of new drugs in Europe. The RMP was introduced in 2005 to support a proactive approach in gaining knowledge on safety concerns through early planning of pharmacovigilance activities. However, the rate at which uncertainties in the safety profile are resolved through this proactive approach is unknown. We therefore examined the evolution of safety concerns in the RMP after initial approval for a selected cohort of 48 drugs, to provide insight into the knowledge gain over time. We found that 20.7% of the uncertainties existing at approval had been resolved 5 years after approval. Because new uncertainties were included in the RMP at a similar rate, the overall number of uncertainties remained approximately equal. The relatively modest accrual of knowledge, as demonstrated in this study through resolution of uncertainties, suggests that opportunities for optimization exist while ensuring feasible and risk-proportionate pharmacovigilance planning.

Scientists and the regulation of risk: standardising control

Contents: 1. Risk Regulation - From Controversies to Common Concepts 2. Communities, Networks and Colleges: Expert Collectives in Transnational Regulation 3. From Qualifying Products to Imputing Adverse Events: A Short History of Risk Regulation 4. Drawing Lessons. Medical Professionals and the Introduction of Pharmacovigilance Planning 5. Modelling Regulation. HACCP and the Ambitions of the Food Microbiology Elite 6. The Value of Abstraction. Food Scientists and the Invention of Post-Market Monitoring 7. Exploring Invisible Colleges: Sociology of the Standardising Scientist 8. Scientists, Standardisation and Regulatory Change. The Emergent Action of Invisible Colleges Appendix 1. Research Strategy and Methodology References

わが国の市販後の安全性監視の現状と今後のあるべき姿

Current pharmacovigilance activities may be captured by two important concepts, pharmacovigilance planning (PVP) and risk minimization action plan (risk MAP). PVP was advocated in E2E guideline of International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) in 2004. Risk MAP was proposed in 2005 in FDA's guidance as well as in EU risk management plan (EU-RMP). PVP requires a scientific approach where important safety issues unique to each product are specified and the conduct of the study with a design best for the specified problems. Similarly, risk MAP requires developing the best strategy to mitigate the specified problems. In Japan, drug use investigation (DUI) (shi-yo-sei-seki-cho-sa) was developed as early as in 1970s and became mandatory after the re-examination system for newly approved drugs was introduced in 1979. DUI is a stereotyped survey without control group where thousands of patients prescribed a new drug are followed typically for 3 to 6 months. Within 2012 risk management plan guidance will be implemented in Japan. This may promote a better practice of risk MAP. On the other hand, the real implementation of PVP is challenging because it requires various resources which do not currently exist in Japan. For example, it is important to establish the education system which can produce people who is capable of planning and conducting a good study. In addition, the system to achieve transparency, independence and standard like European Network of Centres for Pharmacoepidemiology and Pharmacovigilance (ENCePP) may be established.

A modified prescription‐event monitoring study to assess the introduction of Flixotide EvohalerTM into general practice in England: an example of pharmacovigilance planning and risk monitoring

A modified prescription-event monitoring (PEM) study was conducted to examine the safety of the introduction of the metered dose inhaler (MDI) Flixotide Evohaler (fluticasone with the propellant HFA 134a). Patients were identified from the first NHS prescriptions dispensed in England for Flixotide Evohaler. Postal questionnaires were sent to the prescribing doctor, requesting information including: demographic characteristics, severity of indication, concomitant medication, event data 3 months prior to and 3 months after the first prescription, and any reasons for stopping Flixotide. Pregnancies, deaths and selected events were followed up. Incidence density ratios (IDRs) were calculated to compare event rates 3 months before and 3 months after the introduction of Flixotide Evohaler. The cohort comprised 13 413 patients that were prescribed Flixotide Evohaler. The response rate was 64.0%. When the pre- and post-exposure periods were compared fewer patients had events in the post-exposure period, and there was no significant difference in the length of courses of oral steroid use. Eighteen patients experienced an event within 1 hour of using Flixotide Evohaler; these were minor with the exception of one case of angioneurotic facial oedema. Six of these events were assessed as possibly related to Flixotide Evohaler. During the study period there were an additional 13 patients with events assessed as possibly related to Flixotide Evohaler, including two reports of allergic reactions. The results suggest that the transition to Flixotide Evohaler was generally well tolerated. The modified methodology has contributed to the risk management of the introduction of this product.

Adverse drug events: counting is not enough, action is needed

estimate — that 10.4% of patients attending general practice experience an ADE — almost 2 million people have an ADE annually. Moreover, their findings show that these ADEs are not trivial, with about 1 million being moderate or severe and 138 000 requiring hospitalisation, a finding consistent with previous estimates. 3 Many of these ADEs are preventable, although the exact proportion of preventable events can be debated. There have now been more than 30 Australian studies estimating the number of ADEs in different settings. 3 It is clear that counting is not enough — it is time for action, but what can be done? Every developed country is trying to cope with the problem of ADEs. Australia has many structures and initiatives in place to reduce the occurrence of ADEs, and preventing ADEs necessarily involves them all. 3 Regulatory agencies, the medicines industry, quality use of medicines organisations and information providers, safety and quality organisations, professional bodies, health professionals and consumers can all assist. Prevention of ADEs cannot occur without better knowledge. It is noteworthy that the Therapeutic Goods Administration has adopted the European Medicines Agency guideline on pharmacovigilance planning. Increased pharmacovigilance, including observational studies, will require a substantial increase in resources. In Canada, less than 10% of the budget for drug regulation is allocated to issues concerning marketed products, including safety. Yet, in 50% of new drugs, serious adverse drug reactions are detected after market approval. 4 We need systems that can deal with the reality that only limited numbers of highly selected patients are studied before a drug is marketed. Regulators may have to consider restricting prescribing of new medications if they have limited safety information, particularly when equally efficacious therapy is available. New systems for detecting early signals of potential adverse drug reactions in expanded populations could complement the current reporting system for adverse drug reactions. An example is the Drug Safety Research Unit in the United Kingdom, which captures information on the first 10 000 patients using a newly marketed drug. 5 We need to capitalise on and expand the importance and significance of consumer reporting.

Use of the Dose, Time, Susceptibility (DoTS) Classification Scheme for Adverse Drug Reactions in Pharmacovigilance Planning

In the process of conceiving a pharmacovigilance plan, as proposed in the International Conference on Harmonisation E2E guideline, the challenge will be how to address possible safety issues with a set of appropriate pharmacovigilance methods. For successful planning, the various and sometimes complex dimensions of the adverse drug reaction in question have to be appropriately described. In order to accommodate these better, a 3-dimensional approach, based on dose, time and patient susceptibility, has recently been proposed (the DoTS model). This approach offers a way of presenting the various dimensions of the problem graphically. The aim of this article is to propose how an extended DoTS model, applied to three different scenarios, could give a better understanding of adverse drug reactions and assist in preparing a pharmacovigilance plan.

Better Awareness and Implementation of Pharmacovigilance and Risk Management Planning is Needed Within the European Pharmaceutical Industry

We should analyse risk much earlier (in clinical trials). We have clear leadership of our risk management planning efforts. Organisationally, lots of internal stakeholders must agree our strategic position on risks associated with brands. We require a governance mechanism to ensure consistent implementation monitoring and continuous improvement of our risk management programmes. We have the necessary cross functional processes to develop our strategic position on risk. We have experience in the assessment of the need for risk minimisation. We must develop skills in evaluating the effectiveness of risk minimisation tools. “In my experience, building a risk management function is less like applying a plaster to a wound and more like open heart surgery.”

市販後安全性研究に関するガイドラインの提案

The role of pharmacoepidemiology in drug surveillance is becoming more important as there has been an increasing number of social issues concerning post-marketing drug safety in accordance with the increasing number of swift approvals of innovative new drugs with high potency and efficacy due to the progress of medical and pharmaceutical sciences.The ICH E2E guideline for pharmacovigilance planning has been finalized as Step 4 and comprehensive risk management planning is being proposed in EU and US. Pharmacoepidemiology is thus an indispensable factor in safety surveillance.On the other hand, guidelines for conducting observational studies to investigate the potential safety issues do not exist in Japan. The guidelines for post-marketing safety surveillance observational studies presented here were drafted by referring to various observational studies and guidelines used by foreign companies for post-marketing surveillance and by taking into consideration, the feasibility of implementation in Japan.There are two parts in this report-the first part of the report describes goal, scope and principles such as standard matters, and the latter part illustrates the details of observational cohort study and nested case control study that are likely to be conducted by companies. Relevant groups will be requested to review the draft guideline to refine the contents for implementation and it is expected that pharmacoepidemiological studies would contribute to the post-marketing safety measures to be taken.

CIOMS and ICH Initiatives in Pharmacovigilance and Risk Management

In this article we review the current initiatives by the Council for International Organizations of Medical Sciences (CIOMS) and the International Conference on Harmonisation (ICH) on pharmacovigilance planning that are due for general release during 2004. These initiatives could form the basis for applying concepts of risk management to medicines throughout their life cycle, from preclinical and clinical development to marketed use. The CIOMS VI Working Group (with 28 senior scientists worldwide from drug regulatory authorities and pharmaceutical companies) is currently developing scientific guidance that relates to clinical trials for medicines during development. It recommends a developmental pharmacovigilance concept - a 'living' concept that would start early in drug development supporting the science and ethics of research leading up to licensing (marketing authorisation) and continuing to post-authorisation (postmarketing) pharmacovigilance. This approach is seen as complementary to current ICH initiatives called 'Pharmacovigilance Planning'. ICH will introduce two concepts in pharmacovigilance management of medicinal products: the 'Pharmacovigilance Specification' and the 'Pharmacovigilance Plan'. The 'Pharmacovigilance Specification' will summarise important knowns and unknowns about the medicine. It will include safety risks identified at the licensing stage, potential risks and any key missing information. These elements will be essential to the formulation of pharmacovigilance plans. Dialogue and common understanding between regulators and the pharmaceutical industry will be a key factor for developing pharmacovigilance plans during the life cycle of medicines. Appropriate interaction with health professionals and patients should also be planned for the future as regulatory systems become more transparent. Where no significant issues are apparent at the licensing (marketing authorisation) stage, routine pharmacovigilance practices will be followed during the marketing phase. Where issues do exist or the data are limited, further study, including epidemiological approaches can be planned. All types of medicines (new drugs, biological agents, orphan drugs) may be involved in these concepts, as would major extensions to existing medicines. Currently ongoing CIOMS and ICH initiatives are in line with emerging risk-management strategies in the US, the European Union and Japan aimed at early and proactive pharmacovigilance.

From E2A to E2E: new ICH topic on pharmacovigilance planning

From E2A to E2E: new ICH topic on pharmacovigilance planning