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Quo vadis (where are you going) pharmacovigilance?

2022; Wiley; Volume: 89; Issue: 2 Linguagem: Inglês

10.1111/bcp.15584

1365-2125

Spoorthy Kulkarni, Michael Rieder, Robert Likić,

Biosimilars and Bioanalytical Methods

The goal of pharmacovigilance is to ensure that therapies are safe to use. The Hippocratic principle of do no harm (primum non nocere) forms the very foundation of pharmacovigilance. Pharmacovigilance systems are processes designed to identify potential adverse drug reactions (ADRs) in a timely manner, to evaluate causality and to translate this information into risk mitigation strategies. They span the complete life cycle of a therapy beginning from preclinical studies to real-world use. These processes include scrupulous risk assessments and constant surveillance by all stake holders and require significant support and funding to achieve the shared goal of safety. Despite efforts to date, ADRs continue to lead to significant burden on health services. A recently reported retrospective study utilizing VigiBase, the World Health Organization's (WHO) pharmacovigilance database, found that 23 million ADRs were recorded in the last decade, among which 1.34% were fatal.1 By 2010, 134 countries had joined the WHO pharmacovigilance programme. It was not until the 1960s thalidomide disaster that the formal system of modern pharmacovigilance took shape in the form of the WHO Programme for International Drug Monitoring. By the 1990s, the inception of the International Council for Harmonization, an organization created by the joint efforts of regulatory authorities (RA) and pharmaceuticals, came together with a mission to align pharmaceutical regulatory requirements globally. History is testimony to numerous drug withdrawals based on spontaneous reporting of ADRs, and >75 drugs were withdrawn by 2003,2 including phenformin, terfenadine, astemizole, troglitazone and cisapride. Overall, drugs are withdrawn due to organ or system toxicities such as hepatotoxicity, cardiotoxicity (mainly QT prolongation) and myelotoxicity. However, until a decade ago, there was very little progress in the technical processes of pharmacovigilance; a number of flaws exist in the process of spontaneous reporting including: under-reporting of ADRs by physicians and patient groups,3 issues germane to clinical trials methodology, including inadequate techniques for evaluation of safety signals,4 limited critical thinking, little or no audit trail, poor quality of reports, and underuse of technology and data mining applications. Additionally, specific considerations and guidelines to gather safety data in certain populations such as the elderly, children, pregnant women and socio-economically disadvantaged groups may be needed as these groups generally tend to be poorly represented in clinical trials. Fortunately, the landscape of pharmacovigilance regulation is changing, and more countries are now harmonizing their efforts towards having a centralized system of surveillance of therapy-related harms. One such example is the white paper published in a recent themed issue, providing practical considerations for paediatric pharmacovigilance, throughout the life cycle of medicinal products.5 Clinical trials are designed to frame the benefit vs. risk of harm for a therapy in a well-defined setting, typically for a relatively brief period of time and in well-defined, small sample of the population with robust monitoring. Thus, there is a compelling need for postmarketing (Phase 4) surveillance studies to assess the efficacy and safety of newly marketed compounds in the real world. Phase 4 studies can evaluate the effectiveness of therapies in the original indications, but importantly, they offer opportunities for identifying long-term and/or rare serious or non-serious ADRs. In addition, 2020 saw emergency use authorization and rapid approvals of new therapies and vaccines for the global pandemic of COVID-19, caused by the novel coronavirus SARS-CoV-2, based on new therapeutic platforms such as mRNA, which brought global pharmacovigilance activities into focus. Rapid detection of signals and transparency on safety monitoring in the real-world setting saw growth collaboration among key stakeholders while the communication resulting from these activities acted as a medium for educating the authorities in order to address the disparities between various countries, and healthcare professionals (HCPs) especially where the pharmacovigilance systems were weaker and failed to fulfil the International Council for Harmonization guidelines.6 The unprecedented and rapid growth of next-generation therapeutics such as RNA-based therapies may need further increased, longer and novel methods of surveillance, which in turn may lead to emergence of novel risk management plans. The therapeutic revolution in biological, genetic and cellular therapies will present many challenges but also many opportunities. Outside the context of clinical trials, HCPs, such as physicians, nurses and pharmacists, and patients can typically engage in spontaneous reporting of suspected ADRs using local pharmacovigilance monitoring systems such as the Yellow Card system in the UK (https://yellowcard.mhra.gov.uk/information). In the UK, > 1/3 of the reports come directly from patients, and the value of patient engagement is undeniable as, ultimately, the patient remains at the centre of the exercise of pharmacovigilance. Overall, several reports are unchanged, and this probably means that the reports from HCP are now reduced. This may partly be the result of robust labelling regulation from RA. HCPs are probably motivated to report novel potential ADRs, ADRs related to newly marketed drugs or severe ADRs.7 There are significant advantages and disadvantages to spontaneous reporting alone as a primary source of ADR reporting and contribution towards a signal in real-world setting. The Internet and social media as a source of safety signals need further research8 but may be particularly important in the less studied population groups. In the past, every new ADR report was individually assessed to decide if it led to a safety signal. Over the past decade, the creation of large pharmacovigilance databases such as EudraVigilance and statistical programs utilizing methods such as disproportionality scoring have allowed faster analysis of ADR reports to identify specific drug–reaction combinations, leading to better use of the resource time. Access to de-identified real-world electronic health record databases along with these pharmacovigilance databases and newer statistical methodology in addition has enabled researchers to assess false-positive rates of ADRs attributable to specific drugs or drug classes. Alkabbani et al. highlight the advantages of active-comparator restricted disproportionality analysis use on a drug–disease–ADR case example of sodium glucose transporter inhibitor in diabetes mellitus.9 Whether the ADRs detected turn into a signal is dependent on many factors, and as such, the criteria to meet the requirement of a signal are constantly refined and validated. All ADRs affecting children and any that result in death are further evaluated. Once the pharmacovigilance signal is detected, it is assessed if it is a true adverse effect and then RA proceed with a full investigation. The analysis generally leads to risk-based management, implying specific monitoring assigned to certain therapies based on the anticipated and observed risk. An example of risk-based management is designation of a black triangle to medicines that require additional oversight. Other examples include labelling changes, revising dosage recommendations and contraindications in some circumstances. Generally, these changes are communicated to prescribers through various channels. Furthermore, many developed countries now rely on automated processes using artificial intelligence to identify drug safety signals, making pharmacovigilance operations scalable, sustainable and agile. The advances in computational power enabled management of massive quantities of data, with the focus on end case processing, aggregate reporting and signal detection/evaluation automation.10 As global clinical trials and drug development become the norm, more data become available from more sources, and more global production is undertaken, leading to global governance, monitoring and assessment. As such, the awareness of pharmacovigilance can be well discerned by the increasing numbers of PubMed-indexed publications dealing with pharmacovigilance (Figure 1) over the decades. Digitization is hoped to lead to improvement in the quality of the reports, enhancing the reach of the judgement and expertise of the person behind the screen to regulators and companies, and it is eventually expected to increase the engagement of patients in shared care and decision making. Keeping up with the boom of digitization, RA now also engage in virtual and/or hybrid monitoring visits and real-time surveillance upholding medical and scientific excellence. The same platforms continue to enable global training of the future workforce in pharmacovigilance principles. Source: PubMed As noted in this themed issue, a major challenge in the near future will be to ensure that the heterogeneity in the partnership and regulatory framework alignment between the national RAs, pharmacovigilance systems and pharmaceutical companies achieves sustainable improvement in public health goals while ensuring pragmatism and proper utilization of resources and hazards of futile automation. Addressing country-specific prerequisites for pharmacovigilance that are practical and beneficial to patients and HCPs should be a focus.11 Heterogeneity in prescribing practices, for example, self-prescribing trends as occurring in some low- and middle-income countries,12 and intake of alternative medicines must guide the different regulations needed while keeping safe medicines accessible.13 This is highlighted in this themed issue by the Kiguba et al. who highlight the problems and areas of progress in low- and middle-income countries with a focus on Africa.14 Consistent efforts towards achieving the pharmacovigilance goal can be seen in many countries with increased awareness by national RA. Again, in this themed issue, Song et al. map the various changes implemented to bridge gaps and address the challenges with adverse event reporting system in China.15 The WHO also supports the development of national pharmacovigilance systems by providing a Global Benchmarking Tool.16 In this themed issue, manuscripts describing pharmacovigilance in diverse geographic populations and in special populations as well as studies describing methodological issues in ADR signal detection analyses make for interesting reading. We would like to invite our readers to submit articles in other broader aspects of pharmacovigilance such as comparing practices in the largest pharmacovigilance databases and RA including the Food and Drug Administration, European Medicines Agency, and the Japanese Pharmaceuticals and Medical Devices Agency. In our view, a comprehensive overview of methodological approaches would make an interesting read and would be welcome. In summary, the journey of pharmacovigilance has been arduous, yet of sustained systematic steps towards refinement. The hope is that the global and local systems continue to underscore the goal of safer medicines for all. Sharing of best practices and training of future workforce including medical students and increased awareness and public health education are the key to building pharmacovigilance systems that are sustainable in the long term. S.K. is funded by UKRI-MRC Secondment Award (MR/W003538/1). The authors declare no conflicts of interest. Spoorthy Kulkarni wrote the first draft of the manuscript. Michael Rieder and Robert Likic performed a critical revision. All authors approved the final version of the manuscript.