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Drug safety relates to the potential for adverse effects related to the administration of drugs. Efforts to establish the safely profile of drugs begin early in their development, with in vitro and in vivo toxicity testing, and continue through clinical trials leading up to drug approval and following approval in specific post-marketing studies or general pharmacovigilance efforts.

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FIELD GRAND CHALLENGE article

A new era of pharmacovigilance: future challenges and opportunities.

• 1 Department of Diagnostics and Public Health, University of Verona, Verona, Italy
• 2 Department of Medicine, University of Verona, Verona, Italy

Introduction

Medicines safety monitoring is a continuous and dynamic process throughout all the phases of the life cycle of a drug. During the drug development, safety is investigated in different phases. In pre-clinical studies, the primary goal of safety evaluation is the identification of a safe dose in humans and of safety parameters for clinical monitoring. In clinical phase, phase I studies are designed to estimate the tolerability of the dose range expected to be needed for later clinical studies in healthy volunteers; phase II studies are focused on determining appropriate range of drug doses in patients with a disease or condition of interest, while phase III clinical trials are the most important studies to refine understanding of benefit-risk profile of the drug and to identify less common adverse drug reactions. Although drug safety evaluation is very rigorous and thorough, pre-marketing clinical trials have however intrinsic limitations that do not allow to exhaustively evaluate drug safety profile ( Singh and Loke, 2012 ). These studies are conducted on limited numbers of patients that are selected based on strict eligibility criteria and not fully representing real-world populations and have limited duration, thus preventing detection of rare and long-term adverse reactions.

Therefore, the post-marketing assessment of medicines plays a key role for better defining drugs’ safety profile in real-world setting and filling the evidence gap of pre-marketing studies.

In the field of drug safety and regulation, a number of challenges have to be faced in the near future. First of all, COVID-19 pandemic highlighted how relevant pharmacovigilance and proper risk communication during public health emergency are. Second, the development of advanced methodologies including machine learning techniques and the availability of large amount of electronic healthcare data offer opportunity for optimizing drug benefit-risk profile evaluation in real world setting. Finally, innovative therapeutics, such as advanced therapy medicinal products, digital therapeutics, vaccines developed based on advanced technologies, requiring special pharmacovigilance monitoring have been increasingly marketed in recent years, often upon accelerated pathway approval. Some of the challenges and future opportunities in this field are briefly discussed below.

Pharmacovigilance in Healthcare Emergency

During the first waves of the pandemic, the absence of vaccines and drugs for treatment/prevention of COVID-19 led to a rush to repurpose drugs already approved for other indications. As a consequence, a large number of drugs (e.g., hydroxychloroquine, ivermectin and azithromycin) has been off-label used for the treatment of COVID-19 patients, even if underlying scientific evidence on benefits was of low quality and mostly based on in vitro studies ( Sultana et al., 2020a ).

Pharmacovigilance monitoring in this context has been crucial for identifying the risks associated to drugs off-label used, thus reminding the “do not harm first” principle, especially if no or weak evidence on benefits is available. This is the case of azithromycin, a macrolide antibiotic that has been widely used, for the treatment of COVID-19 patients ( Crisafulli et al., 2021 ). Its known proarrhythmogenic activity, which can be exacerbated when used in combination with other drugs proposed for COVID-19 treatment (e.g., hydroxychloroquine), led regulatory agencies to issue warnings against the use of this drug, unless in case of bacterial superinfection occurrence ( Sultana et al., 2020b ).

Accelerated approvals of drugs and vaccines to tackle the COVID-19 pandemic emphasized also the need to expeditely generate safety data in post-marketing setting by identifying and preventing serious risks and ultimately ensuring patients’ safety.

Another lesson learned from COVID-19 pandemic is the importance of drug- and vaccine-related risk communication to healthcare providers as well as patients for informed therapeutic choice and ease of appropriate use of medicines/vaccines. On the contrary, failure to effectively communicate to public and healthcare professionals can lead to a loss of trust and reputation of regulators and other stakeholders, as well as loss of lives ( World Health Organization, 2020 ). It is the case of hydroxychloroquine, one of the drugs that gained much attention to be repurposed for COVID-19 treatment. Despite its efficacy was not proven, it has been praised by numerous public figures, such as the United States past President Donald J. Trump. As a consequence, several observational studies documented a substantial increase in purchases and internet searches for hydroxychloroquine and chloroquine after being promoted by Donald J Trump ( Liu et al., 2020 ; Niburski and Niburski, 2020 ), showing how misleading information, especially if coming from individuals in positions of power, may increase inappropriate drug use and the risk of serious adverse reactions.

Database Networks for Post-Marketing Surveillance for Vaccines and Medicines

The increased access to large scale distributed database networks provides new ways and opportunities to monitor the post-marketing safety of vaccines and medicines and to generate real-world evidence to support decision-making. With this aim, in May 2008 the FDA launched the Sentinel Initiative, an infrastructure analyzing electronic healthcare data to assess the safety of approved medical products. To date, Sentinel has developed one of the largest distributed database networks for the assessment of medical product safety, comprising the Sentinel System, which uses common data models and analytic tools to analyze pre-existing real-world data, and the FDA-Catalyst, which uses routine queries, interventions and interactions with health plan members and/or providers ( Food and Drug Administration, 2019 ).

Conducting pharmacoepidemiological studies combining multiple databases is particularly useful when outcomes or exposure of interest are rare, or when evidence is needed from different countries, to generate evidence rapidly and with stronger external validity ( Gini et al., 2020 ). The combination of several claims databases may provide the statistical power needed to investigate the association between clinically relevant safety outcomes and specific drug exposure. In this regard, the Italian VALORE project is a good example of how the creation of a distributed network of administrative databases can have a great potential for conducting post-marketing surveillance of biological drugs, including biosimilars, in Italian patients affected by immune-mediated inflammatory diseases ( Trifirò et al., 2021 ).

One of the lessons learned from COVID-19 is that the potential of distributed networks of administrative databases to promptly generate robust real-world evidence is particularly high in conditions of public health emergency. This is the example of the ITA-COVID19 network, an Italian multiregional network established for the conduction of pharmacoepidemiological studies to evaluate the association between drugs, vaccines and COVID-19 through the linkage of claims databases to COVID-19 registries ( Spila-Alegiani et al., 2021 ; Trifirò et al., 2020 ). Other examples of distributed networks of real-world data sources being widely used to support COVID-19 research are OpenSAFELY, an English analytics platform for analysis of electronic health records data ( Williamson et al., 2020 ) and the Observational Health Data Sciences and Informatics (OHDSI) program, an interdisciplinary collaborative aiming at generating real-world evidence through large-scale analytics ( Lane et al., 2020 ).

Artificial Intelligence in Pharmacovigilance

The availability of healthcare data has been tremendously increasing over the last years and will further increase in the near future thanks to massive marketing of digital tools collecting patient-derived data.

Huge amounts of electronic data present an opportunity to apply artificial intelligence (AI) techniques to improve drug safety assessment. Information extraction, using natural language processing (NLP) techniques and text mining to gather relevant insights from available, largely unstructured sources, has been gaining importance within the field of clinical research. As regards pharmacovigilance, text mining and NLP methods can be very useful to gather information on adverse drug reactions (ADRs) and drug-drug interactions from various textual sources, supporting researchers and clinicians in monitoring drug safety ( Wong et al., 2018 ). Indeed, both public and private entities are currently trying to develop AI tools that can allow to automatically process ADRs ( Basile et al., 2019 ).

Artificial intelligence and machine learning may also be useful in pharmacovigilance for 1) the automatic execution of tasks associated with case report entry and processing, 2) the identification of clusters of adverse events representing symptoms of syndromes, 3) the conduction of pharmacoepidemiological studies, 4) data linkage, through the conduction of probabilistic matching within datasets and 5) the prediction and prevention of adverse events through specific models using real-world data ( Bate and Hobbiger, 2021 ).

Safety Monitoring of Digital Therapeutics

Digital therapeutics (DTx) one of the most recent frontiers of medicine and can be defined as “technologies that deliver medical interventions directly to patients using evidence-based, clinically evaluated software to treat, manage, and prevent a broad spectrum of diseases and disorders” ( Digital Therapeutics Alliance, 2021 ).

As for conventional medicines, with the increasing uptake of DTx into clinical practice, a proper post-marketing surveillance of DTx has to be implemented to rapidly identify potential safety signals and establish the safety profile of these technologies. Side effects associated with DTx may be generally less severe and easier to manage than those caused by conventional drugs. However, based on findings from pivotal trials, adverse effects of DTx may still occur to a greater extent than in respective control arms, thus requiring careful post-marketing monitoring.

Another important aspect of DTx is that they allow to collect a massive quantity of post-marketing patient-level data that can be harnessed to re-assess their safety and effectiveness in real-world setting. However, the increase in individual patient-related data poses concerns about data privacy and quality, thus highlighting the need to define a legal framework that allows on the one hand to guarantee individual privacy and on the other hand to transparently share data for research purposes.

Pharmacovigilance of Advanced Therapy Medicinal Products

Advanced therapy medicinal products (ATMPs) are medicines for human use that are based on genes, cells or tissue engineering ( European Medicines Agency, 2021 ). ATMPs provide new opportunities to restore, correct or modify physiological functions or make a medical diagnosis. Due to their high innovativeness, these medicines usually benefit from accelerated assessment and accelerated approval pathways, thus highlighting the need to generate post-marketing evidence about their benefit-risk profile. However, uncertainties concerning the safety profile of new ATMPs cannot be ascribed only to regulatory pathways. As these medicines often target rare diseases, pre-marketing evidence is generally weak because of inherent limitations of clinical trials due to small number of recruited patients, use of surrogate endpoints and single-arm design ( Augustine et al., 2013 ). Therefore, post-marketing studies play a key role in generating long term evidence about the safety of these medicines and to fill the knowledge gap of pre-marketing studies. The detection of safety issues should start early and continue throughout the development of the ATMP in order to prevent or minimize the risk when possible. In some cases, the use of ATMPs is expected to be a once in a life-time treatment, therefore the sustainability of efficacy over time is a question that can only be answered by long-term efficacy follow-up. The objectives of the safety and efficacy follow-up will depend on the characteristics of the product ( European Medicines Agency, 2018a ). In the case of chimeric antigenic therapies (CAR-T) routine risk minimization measures have to be supplemented with additional risk minimization measures under relevant important risks (e.g., cytokine release syndrome, infections and serious neurological adverse reactions) ( European Medicines Agency, 2018b ; European Medicines Agency, 2018c ).

Ecopharmacovigilance

Ecopharmacovigilance is “the science and activities concerning detection, assessment, understanding and prevention of adverse effects or other problems related to the presence of pharmaceuticals in the environment, which affect both human and the other animal species” ( Velo and Moretti, 2010 ), ecopharmacovigilance is a very important issue nowadays and it plays a crucial role to reduce the environmental risk of pharmaceutical pollutants. Indeed, pharmaceuticals are widespread environmental pollutants that may be excreted into the environment through different routes, such as the excretion by the patient as parent compound or active metabolites via the sewer system and the release into the waste waters by manufacturers or hospitals and the terrestrial depositions ( Holm et al., 2013 ). Several studies documented the effects of pharmaceutical pollution on various animal species, such as vultures and fish ( Wang et al., 2017 ). The role of ecopharmacovigilance is becoming more and more important to control and minimize the sources of pharmaceutical pollution through the detection, assessment and prevention of adverse effects related to the presence of pharmaceuticals in the environment.

Although the detected concentrations of pharmaceuticals in the environment were mainly low (ng/L to μg/L) potential direct and indirect risks for humans exist and should be carefully monitored. Indeed, it is known that sex hormones exert their pharmacological activity at very low concentrations and that exposure to antibiotics may contribute to bacterial resistance ( Velo and Moretti, 2010 ). Furthermore, special populations like pregnant women, children and older patients may be more vulnerable also to low concentrations of medicines. Addressing issues related to pharmaceutical pollution is therefore one of the main current aims of pharmacovigilance.

At Frontiers in Drug Safety and Regulation , we are interested in promoting research concerning the disciplines of pharmacovigilance, pharmacoepidemiology, regulatory science and public health to elevate regulatory sciences with patient-oriented approaches addressing emerging issues concerning drug safety.

Author Contributions

GT and SC conceived the study and wrote the paper.

Conflict of Interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Publisher’s Note

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

Augustine, E. F., Adams, H. R., and Mink, J. W. (2013). Clinical Trials in Rare Disease: Challenges and Opportunities. J. Child. Neurol. 28 (9), 1142–1150. doi:10.1177/0883073813495959

CrossRef Full Text | Google Scholar

Basile, A. O., Yahi, A., and Tatonetti, N. P. (2019). Artificial Intelligence for Drug Toxicity and Safety. Trends Pharmacol. Sci. 40 (9), 624–635. doi:10.1016/j.tips.2019.07.005

PubMed Abstract | CrossRef Full Text | Google Scholar

Bate, A., and Hobbiger, S. F. (2021). Artificial Intelligence, Real-World Automation and the Safety of Medicines. Drug Saf. 44 (2), 125–132. doi:10.1007/s40264-020-01001-7

Crisafulli, S., Ientile, V., L’Abbate, L., Fontana, A., Linguiti, C., Manna, S., et al. (2021). COVID-19 Patient Management in Outpatient Setting: A Population-Based Study from Southern Italy. Jcm 11 (1), 51. doi:10.3390/jcm11010051

Digital Therapeutics Alliance (2021). Understanding DTx: A New Category of Medicine. Available at: https://dtxalliance.org/understanding-dtx/ . (Accessed January 30, 2022).

Google Scholar

European Medicines Agency (2021). Advanced Therapy Medicinal Products: Overview. Available at: https://www.ema.europa.eu/en/human-regulatory/overview/advanced-therapy-medicinal-products-overview .

European Medicines Agency (2018a). Guideline on Safety and Efficacy Follow-Up and Risk Management of Advanced Therapy Medicinal Products . Available at: https://www.ema.europa.eu/en/documents/scientific-guideline/draft-guideline-safety-efficacy-follow-risk-management-advanced-therapy-medicinal-products-revision_en.pdf (Accessed January 30, 2022).

European Medicines Agency (2018c). Summary of Risk Management Plan for Yescarta (Axicabtagene Ciloleucel). Available at: https://www.ema.europa.eu/en/documents/rmp-summary/yescarta-epar-risk-management-plan-summary_en.pdf . (Accessed January 30, 2022).

European Medicines Agency (2018b). Summary of the Risk Management Plan for Kymriah (Tisagenlecleucel). Available at: https://www.ema.europa.eu/en/documents/rmp-summary/kymriah-epar-risk-management-plan-summary_en.pdf . (Accessed January 30, 2022).

Food and Drug Administration (2019). FDA's Sentinel Initiative. Available at: https://www.fda.gov/safety/fdas-sentinel-initiative . (Accessed January 30, 2022).

Gini, R., Sturkenboom, M. C. J., Sultana, J., Cave, A., Landi, A., Pacurariu, A., et al. (2020). Different Strategies to Execute Multi‐Database Studies for Medicines Surveillance in Real‐World Setting: A Reflection on the European Model. Clin. Pharmacol. Ther. 108 (2), 228–235. doi:10.1002/cpt.1833

Holm, G., Snape, J. R., Murray-Smith, R., Talbot, J., Taylor, D., and Sörme, P. (2013). Implementing Ecopharmacovigilance in Practice: Challenges and Potential Opportunities. Drug Saf. 36 (7), 533–546. doi:10.1007/s40264-013-0049-3

Lane, J. C. E., Weaver, J., Kostka, K., Duarte-Salles, T., Abrahao, M. T. F., Alghoul, H., et al. (2020). Risk of Hydroxychloroquine Alone and in Combination with Azithromycin in the Treatment of Rheumatoid Arthritis: a Multinational, Retrospective studyThe Lancet. Lancet Rheumatol. 2 (11), e698–e711. doi:10.1016/S2665-9913(20)30276-9

Liu, M., Caputi, T. L., Dredze, M., Kesselheim, A. S., and Ayers, J. W. (2020). Internet Searches for Unproven COVID-19 Therapies in the United States. JAMA Intern. Med. 180 (8), 1116–1118. doi:10.1001/jamainternmed.2020.1764

Niburski, K., and Niburski, O. (2020). Impact of Trump's Promotion of Unproven COVID-19 Treatments on Social Media and Subsequent Internet Trends: Observational Study. J. Med. Internet Res. 22 (11), e20044. doi:10.2196/20044

Singh, S., and Loke, Y. K. (2012). Drug Safety Assessment in Clinical Trials: Methodological Challenges and Opportunities. Trials 13, 138. doi:10.1186/1745-6215-13-138

Spila Alegiani, S., Crisafulli, S., Giorgi Rossi, P., Mancuso, P., Salvarani, C., Atzeni, F., et al. (2021). Risk of Coronavirus Disease 2019 Hospitalization and Mortality in Rheumatic Patients Treated with Hydroxychloroquine or Other Conventional Disease-Modifying Anti-rheumatic Drugs in Italy. Rheumatology 60 (SI), SI25–SI36. doi:10.1093/rheumatology/keab348

Sultana, J., Crisafulli, S., Gabbay, F., Lynn, E., Shakir, S., and Trifirò, G. (2020a). Challenges for Drug Repurposing in the COVID-19 Pandemic Era. Front. Pharmacol. 11, 588654. doi:10.3389/fphar.2020.588654

Sultana, J., Cutroneo, P. M., Crisafulli, S., Puglisi, G., Caramori, G., and Trifirò, G. (2020b). Azithromycin in COVID-19 Patients: Pharmacological Mechanism, Clinical Evidence and Prescribing Guidelines. Drug Saf. 43 (8), 691–698. doi:10.1007/s40264-020-00976-7

Trifirò, G., Isgrò, V., Ingrasciotta, Y., Ientile, V., L’Abbate, L., Foti, S. S., et al. (2021). Large-Scale Postmarketing Surveillance of Biological Drugs for Immune-Mediated Inflammatory Diseases through an Italian Distributed Multi-Database Healthcare Network: The VALORE Project. BioDrugs 35 (6), 749–764. doi:10.1007/s40259-021-00498-3

Trifirò, G., Massari, M., Da Cas, R., Menniti Ippolito, F., Sultana, J., Crisafulli, S., et al. (2020). Renin-Angiotensin-Aldosterone System Inhibitors and Risk of Death in Patients Hospitalised with COVID-19: A Retrospective Italian Cohort Study of 43,000 Patients. Drug Saf. 43 (12), 1297–1308. doi:10.1007/s40264-020-00994-5

Velo, G., and Moretti, U. (2010). Ecopharmacovigilance for Better Health. Drug Saf. 33 (11), 963–968. doi:10.2165/11539380-000000000-00000

Wang, J., He, B., Yan, D., and Hu, X. (2017). Implementing Ecopharmacovigilance (EPV) from a Pharmacy Perspective: A Focus on Non-steroidal Anti-inflammatory Drugs. Sci. Total Environ. 603-604, 772–784. doi:10.1016/j.scitotenv.2017.02.209

Williamson, E. J., Walker, A. J., Bhaskaran, K., Bacon, S., Bates, C., Morton, C. E., et al. (2020). Factors Associated with COVID-19-Related Death Using OpenSAFELY. Nature 584 (7821), 430–436. doi:10.1038/s41586-020-2521-4

Wong, A., Plasek, J. M., Montecalvo, S. P., and Zhou, L. (2018). Natural Language Processing and its Implications for the Future of Medication Safety: A Narrative Review of Recent Advances and Challenges. Pharmacotherapy 38 (8), 822–841. doi:10.1002/phar.2151

World Health Organization (2020). Risk Communication and Community Engagement Readiness and Response to Coronavirus Disease (COVID-19). Available at: file:///C:/Users/Farmacologia/Downloads/WHO-2019-nCoV-RCCE-2020.2-eng.pdf . (Accessed January 30, 2022).

Keywords: pharmacovigilance, pharmacoepidemiology, real-world data, drug safety, regulatory science

Citation: Trifirò G and Crisafulli S (2022) A New Era of Pharmacovigilance: Future Challenges and Opportunities. Front. Drug. Saf. Regul. 2:866898. doi: 10.3389/fdsfr.2022.866898

Received: 31 January 2022; Accepted: 10 February 2022; Published: 25 February 2022.

Edited and reviewed by:

Copyright © 2022 Trifirò and Crisafulli. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

*Correspondence: Gianluca Trifirò, [email protected]

Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.

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The COVID-19 pandemic showed, once again, how drug safety and proper communication in the field of pharmacovigilance play key roles in public health, especially in times of emergency.Although randomized clinical trials aim to assess drug efficacy and safety before its approval, some intrinsic limitations may be detected, such as the limited number of eligible patients and short follow-up periods, which consequently do not reflect the real-world population. Real-world data collection from electronic health databases and the adoption of automated tools with the integration of advanced methodologies have radically changed scientific evidence by improving drug benefit–risk profile assessment in real-world settings. For this reason, pharmacovigilance and pharmacoepidemiology studies are essential to further establish the appropriate prescribing, effectiveness, drug–drug interactions, short- and long-term drug safety, and all risk minimization measures of pharmacological treatments, especially for innovative therapies.Authors are invited to submit original articles as well as systematic reviews, meta-analyses, and review articles in this Special Issue to contribute to the implementation of real-world data for public health. We look forward to receiving your contributions on drug safety.

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Donaldson L, Ricciardi W, Sheridan S, et al., editors. Textbook of Patient Safety and Clinical Risk Management [Internet]. Cham (CH): Springer; 2021. doi: 10.1007/978-3-030-59403-9_31

Textbook of Patient Safety and Clinical Risk Management [Internet].

Chapter 31 medication safety.

Hooi Cheng Soon , Pierangelo Geppetti , Chiara Lupi , and Boon Phiaw Kho .

Affiliations

Published online: December 15, 2020.

Pharmacotherapy is the most common therapeutic intervention in healthcare to improve health outcomes of patients. However, there are many instances where prescribed medications resulted in patient morbidity and mortality instead. Medication errors can happen at any step of the medication use process, but a substantial burden of medication-related harm is focused primarily on three priority areas of healthcare delivery: transitions of care, polypharmacy and high-risk situations. This chapter highlights prevalence of issues concerning these three core areas and describes common medication errors as well as risk mitigation strategies to improve service delivery. An appreciation of these inherent risks will enable healthcare providers to navigate the pitfalls better and make efforts to ensure medication safety while providing health services.

31.1. Introduction

Ensuring patient safety during health services delivery is fundamental for an efficient healthcare system [ 1 ]. A strong organisational culture of patient safety and quality enables service providers to be better prepared for health emergencies, promote healthier populations and contribute to the achievement of universal health coverage [ 2 ].

Pharmacotherapy is the most common therapeutic intervention in healthcare to improve health outcomes of patients. Despite the intent to benefit patients, there are many instances where effectiveness of medications is undermined by poor medication use process and practices that could promote avoidable medication errors, thus putting patients’ health in jeopardy [ 2 ]. Safe care requires that all individuals, patients and care providers are protected from medication-related harm when using the essential health services they need. A medication error is defined by the United States National Coordinating Council for Medication Error Reporting and Prevention as “ Any preventable event that may cause or lead to inappropriate medication use or patient harm while the medication is in the control of the health care professional, patient, or consumer. Such events may be related to professional practice, health care products, procedures, and systems, including prescribing, order communication, product labelling, packaging, and nomenclature, compounding, dispensing, distribution, administration, education, monitoring and use ” [ 3 ].

Unsafe medication practices leading to medication errors are among the leading causes of morbidity and mortality in health services delivery. A medication safety fact file released by the World Health Organization (WHO) in 2019 shows that medication errors harm millions of patients yearly [ 4 ]. The resultant financial burden of harm was estimated at USD42 billion each year, representing approximately 1% of global expenditure on health [ 5 ]. More importantly, these errors are preventable . Identifying the causes of errors and building safeguards in the healthcare system are key steps towards providing safe, quality, people-centred, timely, equitable, efficient and integrated health services.

31.1.1. A Focus on Transitions of Care, Polypharmacy and High-Risk Situations

Medication errors often occur as a result of gap in medication use process and practice, from prescribing and ordering to transcribing and/or documenting, and from preparing and dispensing to administering and monitoring. Transition points of care, such as admissions to hospital from a community or primary care setting, transfer from one area within the hospital to another or discharge from hospital to another care setting, are particularly vulnerable to medication errors [ 2 ]. Moreover, medications prescribed can be contraindicated for a particular patient, or in combination with his or her concomitant medications. The risk of harm is further heightened in high-risk situations associated with the use of high-risk medications.

The available evidence indicates that a substantial amount of medication-related harm is focused on transitions of care, polypharmacy and high-risk situations. In March 2017, the WHO launched the third Global Patient Safety Challenge: Medication Without Harm with the goal of reducing the risk of severe avoidable medication-related harm by 50%, over 5 years, globally [ 2 ]. It was envisioned that when these areas are appropriately managed, the risk of avoidable harm to many patients could be reduced, leading to improved patients’ trust towards the healthcare system, as well as healthcare workers’ job satisfaction, ultimately achieving safer hospital and primary care.

31.1.2. Learning Objectives

This chapter aims to highlight inherent risks and weaknesses in the medication use process in healthcare facilities, focusing on the three main areas identified as having the greatest burden of harm, as well as on the strategies that can be applied to mitigate them. After completing this chapter, readers will be able to appreciate the prevalence and incidence of common medication safety issues, as well as approaches that can be employed to reduce avoidable medication-related harm associated with transitions of care, polypharmacy and high-risk situations. As health service delivery requires inter-disciplinary involvement, this chapter also aims to engage and empower young or experienced students or residents from different specialties to work together in ensuring medication safety while delivering health services.

31.1.3. Learning Outcomes: Knowledge and Performance

31.1.3.1. knowledge requirements.

• The relationship between medication errors and adverse drug events (ADEs).
• The scale of medication errors at three priority areas of medication safety.
• Common points in the medication use process where errors can take place.
• Ways to ensure medication safety at three priority medication safety areas.
• The benefits of inter-professional approach.

31.1.3.2. Performance Requirements

• Improve quality and availability of information during transitions of care.
• Engage with and educate patients, families and caregivers.
• Carry out medication reconciliations.
• Perform medication reviews.
• Practice deprescribing.
• Use generic names.
• Be extra vigilant during high-risk situations or treating high-risk patients with high-risk medications.
• Understand and practice drug calculations, e.g. adjustments of dosage based on clinical parameters.
• Be familiar with the medications prescribed, prepared, dispensed, and/or administered.
• Develop double-check habits.
• Appreciate human limitations and human factors as contributing factor of errors.
• Communicate clearly and be an effective team player.
• Report and learn from errors.

31.2. Medication Safety in Transitions of Care

Transitions of care involve movement of patients between different levels of care within the same setting or across settings, and consultations with different healthcare providers (see Fig. 31.1 ). Transitions of care may also involve other care providers, such as palliative care or social care. During transitions of care, changes to the current medication list of patients are very likely to occur. Therefore, ensuring medication safety involves implementation of safe medication practices to bridge critical communication gaps in medication use process. These could include appropriate prescription and risk assessment, medication review, patient engagement and communication, as well as medication reconciliation [ 6 ]. Figure 31.1 shows the medication use process for a patient within the same setting or across different levels of care, specifically at the interface between hospital and primary care.

Medication use process and communication during transitions of care

31.2.1. Prevalence of Medication Discrepancies

For patients who receive multiple medications from varied prescribers across different settings, obtaining a single medication list or a “gold standard” on what they should be taking can pose a significant challenge [ 7 ]. This invariably predisposes patients to a “mismatch” of the medications they take on a regular basis and what is prescribed to them at points of care, such as upon admission or at discharge. Technically, the use of the term “medication discrepancy” will be more appropriate than the term “error” when referring to the “mismatch”, in efforts to capture potential medication errors that occur during transitions of care [ 7 ]. Medication discrepancy is, therefore, defined as “ Any difference between the medication use history and the medication orders. Discrepancies may be intentional, undocumented intentional or unintentional discrepancies ” [ 6 ].

The prescribing process, from starting a new medication, adding, withholding or stopping a medication, to alteration of dosages by prescribers when patient receives outpatient care or inpatient care, could lead to confusion among subsequent care providers (e.g. primary care counterparts and pharmacists). For instance, when reasons for changes in the preadmission medication list are not reported in the patient’s discharge medication list, the next care providers have to conjecture to determine the rationale of these alternations, and whether the change is temporary or permanent [ 8 ]. Medication discrepancies owing to changes in medications during hospital admission can be intentional, attributed to the condition which caused the admission or unrelated to the reason for hospitalisation, such as to improve the management of existing chronic illnesses. Importantly, any undocumented intentional or unintentional medication discrepancy is a safety risk to patients. Studies indicate that more than half of patients experienced at least one unintended medication discrepancy during admission [ 9 , 10 ]. One national multi-site audit found that nearly half of the patients with at least one new medication started had undocumented reason, while more than half of the cases with medication discontinued or withheld had undocumented reason. In addition, three out of ten patients had unintentional omissions of preadmission medication [ 11 ].

31.2.2. Medication-Related Harm During Transitions of Care

Any injury resulting from medical interventions related to a drug. This includes both adverse drug reactions that are not preventable and complications resulting from medication errors, which are preventable [ 6 , 14 ].

31.2.3. Making Medication Use Safer During Transitions of Care

• Medication reconciliation
• Information clarity and availability at all transition of care points
• Patients and family engagement and education

31.2.3.1. Medication Reconciliation

Medication reconciliation is a risk mitigation strategy for preventing ADEs. It is defined as “ The formal structured process in which healthcare professionals partner with patients to ensure accurate and complete medication information transfer at interfaces of care ” [ 6 ]. Medication reconciliation is an important component in health services delivery especially for patients during hospitalisation. The best possible medication history (BPMH) is obtained when information about all medications taken by a patient is recorded accurately. This is often carried out via interview of patients, their families or caregivers using a structured format. Obtaining BPMH followed by reconciliating the medication lists during transitions of care is essential to ensure medication safety and continuity of care, with the goal of communicating accurate and complete medication information to patients and subsequent care providers (Table 31.1 ).

Steps in the medication reconciliation process to ensure medication safety during transitions of care [6]

Obtaining BPMH and carrying out medication reconciliation can take up to 30 min per patient [ 13 ]. Implementation of formal and structured medication reconciliation processes requires education and training of all healthcare professionals involved, including prescribers, nurses, pharmacists, and pharmacy technicians. Roles and responsibilities of each team member should be clearly elucidated and agreed upon. Targeting high-risk patients has the highest impact in contributing to the success of intervention, whereas having technologies and appropriate tools that aid standardisation could force completion of these processes [ 15 ]. The High 5s Project is a WHO initiative to standardise medication reconciliation processes to improve patient safety. Apart from reducing potential medication-related harm, one of the lessons shared in the High 5s Project on implementing medication reconciliation is that discrepancies that are resolved soon after admission will reduce delays in discharge and risk of human factor-related medication error [ 13 ].

31.2.3.2. Information Clarity and Availability at All Transition of Care Points

As mentioned earlier, BPMH is an important patient document for transitions of care. Hospitals and primary care teams should work together in a complementary manner to build the BPMH, and both patients and healthcare professionals should have access to an up-to-date medication list to ensure continuity of care [ 16 ]. Various facilitating tools and technologies described below are now available to ensure information availability and clarity during transitions of care.

Appropriate Tools and Technology

Having a checklist and form to standardise each stage of medication reconciliation processes can be helpful in improving medication safety, and an added benefit of this intervention is that it is feasible also in low resource settings. The form (either in paper format or a simple electronic format) should be designed to enable listing of all current medications and have a space to communicate changes in therapy, whether addition or discontinuation, temporary or permanent, with rationale clearly stated [ 16 , 17 ].

Electronic Health Records (EHRs)

EHRs are electronic versions of paper charts, which record patient information. A well-functioning EHR system improves the clarity and timeliness of medication information during transitions of care. While there has been steady growth in the adoption of EHRs globally, many are not integrated across or within settings, complicating the seamless transfer of information. Apart from sufficient funding, other major barriers include poorly developed infrastructures and communication technologies to support EHR systems, as well as the lack of human resources and capacity to develop and maintain such complex systems [ 18 ]. The discharge summary records should reflect the medication usage of the patient across transitions, as well as be accessible and editable by appropriate healthcare personnel [ 6 ]. When EHR and well-designed tools are available, up to a 45% reduction in unintentional discrepancies, improved patient-provider communication, optimisation of medication regimen and better patient medication adherence to treatment are achievable [ 19 , 20 ].

Information to Support Safe Use of Medications

Promoting the use of the generic name (international non-proprietary name) of medicines in the prescribing and labelling process will help to improve clarity for both patients and healthcare professionals alike and minimise reconciliation errors. In addition, national pharmacovigilance centres, pharmacies or medication information services can improve understanding as well as support safe and effective use of medication by providing readily accessible information on medications and potential ADE for both patients and healthcare professionals.

31.2.3.3. Patient Engagement and Education

Navigating the complicated processes in transitions of care, especially across settings, requires high level of health literacy and active involvement from patients and their families or caregivers [ 21 – 23 ]. This is essential as they are the only constant in their respective healthcare journeys, and those with low health literacy will face challenges to identify and voice discrepancies in their medication list during care transitions.

As being inadequately educated regarding their medications increases the risk of ADEs or suboptimal therapy, various actions can be taken by healthcare professionals to engage and educate patients. For starters, healthcare professionals should ensure that all patients as well as their immediate families or caregivers are made aware of changes in their medication, the monitoring needs and whom to contact should problems arise during transitions of care [ 13 ]. This can be done by properly engaging and counselling them, especially during discharge from hospitals, including asking whether they understand what is being communicated.

Other strategies include developing standardised discharge instructions for patients, creating or updating patient-held medication list with rationale for changes in therapy stated and follow-up needs specified. This comprehensive medication list can also increase their understanding about their medical conditions as well as the indication of each medications, how to take them, what side effects to expect and when they should seek help.

31.2.3.4. Monitoring and Measurement

Successful implementation of transitions of care interventions requires extensive coordination and communication between healthcare providers from different institutions. Various interventions can be put to trial to improve transitions of care, but they have to be adequately monitored and measured to determine their efficacy in reducing medication discrepancies and avoidable patient harm. Various standardised outcome measures are available, for instance process measures for the quality and effectiveness of medication reconciliation such as outstanding unintentional medication discrepancies and percentage of patients receiving medication reconciliation [ 13 ]. In addition, validated survey instruments for patient-centred measures, such as patient experience and understanding of medications, are also recommended to achieve a well-rounded evaluation [ 16 , 24 , 25 ].

31.3. Medication Safety in Polypharmacy

In order to have a rough estimate of the prevalence of polypharmacy, it is necessary to understand the definition of polypharmacy first. In its most simplistic definition, polypharmacy means “an individual on multiple medications” [ 26 , 27 ]. This usually afflicts those with numerous chronic health conditions, and is highly prevalent in the elderly as the number of co-morbidities increases in tandem with age [ 28 , 29 ]. Individuals with polypharmacy often consult more than one medical specialist and have prescription medications filled at multiple pharmacies, making their medication regimen complex. This is further complicated by usage of non-prescription as well as traditional and/or complementary medications [ 28 ].

There is however no exact definition for polypharmacy. It is often defined as taking five or more medications, but other numbers were also used as the cut-off point [ 30 ]. This numerical definition is criticised as being arbitrary, as the number of medications taken lacks correlation with patients’ clinical outcome. In fact, the use of multiple medications is warranted and rational in some health conditions, for example, heart or renal failure. This rational polypharmacy is contrary to the negative connotation associated with the term, where it is used to describe duplication of therapy, presence of drug interaction, non-indicated or excessive use of medicines [ 31 , 32 ]. Hence, proponents now advocate for a distinction to be made between appropriate and inappropriate polypharmacy [ 31 , 32 ].

For polypharmacy to be appropriate, the combination of medicines prescribed has to be optimised based on available best evidence and incorporates the patient’s wishes to achieve the intended clinical outcomes [ 26 , 33 ]. Failure to do so will result in inappropriate or problematic polypharmacy, where the risk of therapy outweigh the intended benefit, resulting in suboptimal treatment or patient harm. This includes potential prescribing omissions, where polypharmacy paradoxically results in under-prescribing of indicated medications due to an aversion towards potential ADR and non-adherence [ 33 ].

31.3.1. Prevalence of Polypharmacy

Most prevalence studies focused on the number of medicines, as well as frequency of potentially inappropriate medications (PIM) [ 34 , 35 ]. Polypharmacy is usually defined as ≥5 medications, while the term excessive polypharmacy is used for ≥10 medications. Most of the research on polypharmacy focuses on the elderly (aged ≥65 years old), those living in managed care facilities and cancer patients, as these populations are more prone and vulnerable to the consequences of inappropriate polypharmacy. In the elderly population, a systematic review noted that those in primary care recorded a lower prevalence of patients having ≥5 medications at 27–59% compared to those who are hospitalised at 46–84% [ 35 ]. A study conducted across Europe established that one-third of community dwelling patients were on polypharmacy [ 36 ]. Rates of excessive polypharmacy were also reported, with around 10% of patients falling within this group [ 35 , 37 ]. In long-term care facilities, 38–91% were on ≥5 medications, whereas 11–65% were on ≥10 medications [ 38 ].

31.3.2. Medication-Related Harm in Polypharmacy

The concern with polypharmacy that makes it a medication safety priority is that it increases the risk of adverse drug reactions (ADRs) due to drug-drug interactions and duplicity of therapy. These unwanted effects are a major source of iatrogenic medication-related harm for patients, and the elderly are more susceptible due to age-related physiologic decline [ 31 , 39 ]. An adverse reaction can also result in a prescription cascade, where it is mistaken for an emerging medical condition and treated with new medicines [ 29 ]. These situations contribute to the incidence of intentional or non-intentional non-adherence among patients, as well as physical harm such as falls, fractures, cognitive impairments and dementia [ 29 , 40 ]. In terms of economic implications, polypharmacy increases avoidable healthcare costs such as emergency department visits and hospitalisations [ 40 , 41 ].

The main cause of polypharmacy is the emergence of multiple morbidities in an ageing population. The prevalence of having two or more chronic conditions increases with age, afflicting two-thirds of those aged more than 65 years old [ 42 ]. Multiple morbidity is a major confounder of the relationship between number of medications and health outcomes [ 43 ]. Other patient factors affecting polypharmacy include gender, with females having a greater preponderance to take more medications, ethnicity, and socioeconomic status, with those of poorer background and less education more prone to polypharmacy [ 34 , 37 , 44 ].

Health system changes causing an increase in polypharmacy include improved patient awareness and availability of treatment, wider insurance coverage, as well as pharmaceutical promotions [ 45 , 46 ]. The rise of preventative medicine also contributes to polypharmacy, as patients are prescribed medicines to reduce their probability of being inflicted with stroke or acute myocardial infarctions [ 26 ]. Emphasis on evidence-based practice also results in the routine application of clinical guidelines in prescriptions. Unfortunately, these guidelines are often single condition specific and do not cater to potential medication-related problems due to treatment of multiple morbidities, further increasing the number of medications and potentially inappropriate medications being prescribed [ 26 , 29 , 40 ].

The number of medicines itself, regardless of appropriateness, also constitutes a risk for ADR as it increases the odds of drug interaction and inappropriate prescription [ 37 , 40 ]. For example, the combined use of diuretics and blood pressure medications in a patient with heart failure can lead to postural hypotension and hyponatremia. Interactions can also occur with non-prescription medicines, complementary and alternative medicines as well as food [ 34 ]. In fact, the addition of a new medication in a patient with polypharmacy was found to elevate the risk of prescribing or monitoring error by 16% [ 27 ]. Prevalence of potential inappropriate medications meanwhile was found to range from 27% to 56% among the elderly in clinical care [ 35 ].

31.3.3. Approaches for Addressing Polypharmacy

Ensuring medication safety in polypharmacy entails the optimisation of medicines use, in which medicines prescribed for a patient are indicated and well considered in terms of their risk and benefit profiles, potential interactions and patient acceptability. Various interventions aimed at improving the appropriate use of polypharmacy had been carried out, but systematic reviews concluded that these interventions had yet to demonstrate significant clinical outcomes [ 33 , 47 ]. However, this is more likely caused by deficiencies in the research designs rather than actual ineffectiveness of the interventions in the trials. Most of the studies also follow-up their subjects for less than 1 year, which may not be enough to detect significant changes in clinical outcomes.

Interventions were led by doctors, pharmacists or multidisciplinary endeavours, and involved structured pharmaceutical care programme, educational intervention and training, medication review, medication screening, prescription review, electronic medical record-based intervention, comprehensive geriatric assessment and multidisciplinary case conference [ 33 , 47 ]. Some of the more established strategies are further discussed below.

For patients living in nursing homes or aged care facilities, similar multifaceted interventions were employed to optimise medications use. Medication review was the main recurring component along with multidisciplinary case discussion, education for staff, and utilisation of clinical decision support system [ 48 ]. Other interventions suggested include (1) implementing a medication reconciliation service by pharmacists, (2) conducting audits on high-risk medication use, (3) developing deprescribing scripts, (4) developing prescribing guidelines for geriatric patients with multiple co-morbidities, (5) making electronic medication charts and records accessible to all healthcare professionals, and (6) empowering facility level Medication Advisory Committee to determine medication appropriateness [ 49 ].

31.3.3.1. Measuring Appropriateness of Medications

In order to ensure medication safety in polypharmacy, medications taken by a patient, especially those with multiple morbidities, should always be assessed by physicians before the start of a new medication, or routinely by pharmacists during medication review and reconciliation [ 50 ]. The aim of this assessment is to increase medication appropriateness and decrease inappropriately prescribed medication and prescribing omissions.

Among the elderly, the Beers criteria is often used to determine appropriateness of medicines use [ 51 ]. Medicines that should generally be avoided in this population or in certain specific medical conditions are considered. A total of 48 medicines are deemed inappropriate to be used among the elderly, including benzodiazepines, anticholinergics and antihistamines, long-term non-steroidal anti-inflammatory drugs and stimulation laxatives. Other validated screening tools include Medication Appropriateness Index (MSI) and Screening Tool of Older Persons’ Prescriptions and Screening Tool to Alert Doctors to Right Treatment (STOPP/START) [ 26 ]. Burt et al. developed a 12-item measure of polypharmacy appropriateness based on a systematic review and expert panel consensus, adding in measures on determinants of patient adherence, medication regimen complexity and non-pharmacological treatments [ 52 ].

31.3.3.2. Medication Reviews

Medication review is the foremost strategy to reduce polypharmacy. In medication reviews, patients’ medications are evaluated by a trained healthcare professional and discussed together to identify drug-related problems. Interventional recommendations are then made to optimise treatment [ 41 , 53 , 54 ]. In 2018, the Scottish National Health Services published a comprehensive seven-step review process to serve as guidance in managing polypharmacy in a patient-centred manner. It involves (1) establishing treatment objectives with the patient, before working through the whole list of medications to determine drug therapies that are (2) essential as well as (3) potentially unnecessary. The current treatment is then assessed to determine its (4) effectiveness, (5) safety, (6) cost-effectiveness and (7) patient acceptance [ 50 ].

Medication reviews are often led by pharmacists, where other issues such as medication adherence, device use technique and monitoring of treatment are also considered [ 53 , 54 ]. This service is available in most Western countries, including the United States, United Kingdom, Australia, Canada and New Zealand, and is often conducted in community pharmacies and reimbursable by the respective governments [ 54 ]. Outcome wise, medication reviews that are more comprehensive and conducted in the context of patients’ clinical condition were found to significantly reduce hospitalisation [ 53 ]. Medication reviews with follow-up were also found to improve patients’ quality of life, reduce medication-related hospitalisations and to be cost-effective [ 55 , 56 ]. In the United States, medication reviews known as Medication Therapy Management (MTM) were found to improve medication appropriateness, adherence and hospitalisation for diseases such as heart failure and diabetes [ 57 ].

For a patient with polypharmacy, there is an increased risk of discrepancies during transition of care between different institutions. Hence conducting medication reviews and reconciliations during hospital admission and upon discharge are likely to have a high impact on medication safety. A mechanism has to be in place to ensure changes in medication are properly documented and conveyed to the receiving care team, as this vital information is often inaccurate or lacking [ 26 , 27 ].

31.3.3.3. Rational Prescribing

Several guidelines on prescribing for the elderly exist, especially for conditions often affecting them such as management of constipation, chronic pain and rational usage of benzodiazepines, anticholinergics and anti-psychotics [ 50 ]. Guidelines for the management of patients with multiple chronic conditions are also being developed and this is the way forward for the management of polypharmacy [ 27 ]. Such guidelines are currently lacking, with only eight being identified by a systematic review [ 58 ]. Tools to assist in decision-making on polypharmacy are also available, for example, the Medicines Effectiveness Summary, where the annualised numbers needed to treat (NNT) to achieve a beneficial outcome for high-risk medications were calculated based on available trial evidence [ 50 ].

Computerised decision support systems are also increasingly being adopted to tackle polypharmacy. This includes assisted detection of inappropriate medicines and doses, which are then conveyed to prescribers via an alert system. This intervention has been found to modestly reduce ADEs [ 37 ]. PRIMA-eDS, a recently developed European-based electronic decision support system, is able to recommend medication discontinuation or modification based on patients’ data and latest guidelines [ 59 ].

31.3.3.4. Deprescribing

Deprescribing entails going through a patient’s medication list systematically to identify items that can be safely discontinued. It includes identifying the rationale of each previously prescribed medication, weighing the benefit of the regimen against risk of ADEs, assessing their potential to be discontinued, prioritising the discontinuation sequence, as well as monitoring the effect on patient care [ 60 ]. Due diligence is important in deprescribing, as inappropriately stopping a medication can lead to adverse drug withdrawal events. For these medications, a gradual tapering of doses is recommended [ 44 ]. Research findings suggested that deprescribing saves cost, reduces waste of medications and does not result in patient harm; however definitive impact on clinical outcomes as well as patients’ medication adherence cannot be determined due to paucity of high quality, long-term trials [ 61 , 62 ].

31.3.3.5. Health System Changes

In order to develop polypharmacy management programmes that are sustainable, change management principles such as Kotter’s Eight step process for leading change, as well as implementation strategies that are grounded in established theories are recommended [ 41 ]. Multidisciplinary and multinational projects, engaging varied stakeholders including politicians, healthcare commissioners, educators, regulators, providers, and patients, such as the European Union’s SIMPATHY consortium are also essential to spur innovation and drive change management [ 63 ].

31.3.3.6. Practical Tips

In addition to institutional changes, healthcare professionals can also address polypharmacy according to their individual capacities. The King’s Fund (2013) suggested practical tips on polypharmacy management that can be carried out by all healthcare providers [ 26 ]. Tips include ensuring that medication regimens are as simple as possible for patients in terms of frequency and pill burden, for example, substituting rather than adding medications to the regimen. Making things easier is also recommended, such as providing clear and specific written instructions, dosing schedules, compliance aids as well as assessing their level of understanding.

31.3.3.7. Practicing Patient-Centred Care

The involvement of patients and their family members in shared decision-making on their treatment regimen is important to ensure medication safety in polypharmacy. Prescribers should always communicate with patients to ensure that their needs are met and concerns addressed. Involvement of patients is essential to ensure that they understand the medication regimen and will adhere to the medicines prescribed [ 26 , 50 , 52 ]. Tools to facilitate patient involvement can be used, including patient-held medication records, explanation materials for illnesses and medications as well as empowerment support materials such as WHO’s 5 Moments for Medication Safety [ 41 ].

31.4. High-Risk Situations in Medication Safety

Regarding medication safety, high-risk situations are circumstances which are associated with significant harm due to unsafe medication practices or medication errors [ 64 ]. The inherent risk of use of certain drugs, defined as high-risk or high-alert medications, as well as certain work environments (e.g. hospital healthcare) and clinical scenarios (e.g. emergency and anaesthesia settings), which involve particular difficulties for healthcare professionals in complying with safe medication practices, represent some examples of high-risk situations. Similarly, there are also some conditions inherent to the individual, such as childhood and old age, and medical conditions, such as hepatic or renal impairment and cardiac failure, which predispose patients to an increased risk of medication errors and ADRs [ 64 ]. Pregnant women can even be included among high-risk patients due to the limited information about the safety of most medications in this population, because of a lack of randomised clinical trials [ 65 ]. High-risk situations, as a whole, require mechanisms to prevent medication errors and, in case they occur, should cover means of identification before they result in harm to the patient. In a recent consensus prioritisation exercise, a group of leading researchers in patient and medication safety, including experts from the WHO Global Patient Safety Network, identified development of guidelines and standard operating procedures for high-risk medications, patients and contexts, as well as the production of score-based approaches to predict high-risk situations as top priority research areas [ 66 ].

31.4.1. Medication Errors and Related Harm in High-Risk Situations

31.4.1.1. high-risk medications.

High-risk medications are drugs that are more likely to cause harm to a patient when they are used in error or taken inappropriately. Although mistakes may or may not be more common with these drugs, the consequences of an error at any level of their management (i.e. prescription, storage, dispensing, preparation, administration and monitoring) are more devastating to patients compared to non-high-risk medications [ 67 ]. These medicines require particular attention in the medication use process, mainly because of their potential toxicity, low therapeutic index or high possibility of pharmacological interactions.

A recent systematic review, which focused on the epidemiology of prescribing errors with high-risk medications in the inpatient setting, highlighted that the prevalence of these errors was highly variable, ranging from 0.24 to 89.6 errors per 100 orders. This wide range reflected the lack of uniqueness on definitions of both prescribing errors and high-risk medications. Dosage errors, incorrect date of prescription, and omissions of required medications were the most common prescribing errors. Opioids and sedatives were the most frequent pharmacological categories associated with these errors [ 68 ]. In another systematic literature review aimed at defining high-risk drug classes, methotrexate and warfarin were the top two drugs resulting in fatal medication errors [ 69 ].

While the drugs identified as high-risk may vary between countries and healthcare settings in light of the types of molecules used and patients treated, analysis of incident data and review of the literature identified a group of medicines that should universally be considered as high-risk. In 2015, the New South Wales Clinical Excellence Commission summarised these drugs by the mnemonic acronym “A PINCH” (anti-infective agents, potassium and other electrolytes, insulin, narcotics and other sedatives, chemotherapeutic and immunosuppressive agents, and heparin and anticoagulants) [ 70 ]. The most frequent medication errors and ADRs associated with the use of the high-risk medication categories considered in “A PINCH” are reported in Table 31.2 [ 64 , 70 ].

High-risk medication list [64]

This list is not intended to be exhaustive, and tables should be developed locally in order to reflect the specificities of drugs used in different work environments. A wider list has been drawn up and is periodically updated by the Institute for Safe Medication Practices (ISMP), based on error reports submitted to the ISMP National Medication Errors Reporting Program, evidences from the literature and inputs from practitioners and safety experts. High-risk medications have been classified according to their different use in acute care, ambulatory healthcare and long-term care settings [ 71 ].

31.4.1.2. High-Risk Patients

Data from observational studies indicate that 5–27% of all paediatric medication orders resulted in error [ 72 ]. Children, especially neonates and infants, are particularly vulnerable to patient safety concerns, including the use of weight-based dosing, the need for stock medicine dilution to administer small amounts of medication, immature hepatic and renal systems and the inability to self-administer medications or communicate side effects [ 73 ].

In the elderly, as discussed in the previous section, long-term polypharmacy due to the emergence of multiple chronic morbidities and high probability of drug-drug interactions are the most critical factors in the medication safety field. It is also noteworthy that the elderly are generally poorly compliant to therapy and less likely to tolerate drugs. Indeed, age-related physiological changes, including the reduction of glomerular filtration rate, the decreasing liver volume and blood flow, as well as an increase of gastric acidity, affect pharmacokinetic processes, thus exposing older people to an increased risk of ADRs [ 74 ].

Recent studies have reported that medication use is common among pregnant women. In a multinational web-based European study conducted in pregnant women and new mothers with a child less than 1-year-old, 28% of the women used medications classified as risky to the foetus or child. Having a chronic disorder was the factor with the strongest association with the use of risky medications during pregnancy [ 75 ]. Even fragile patient groups, such as those with chronic pain conditions, diabetes, cancer or major psychiatric disorders, need to be included among patients at increased risk of ADRs.

31.4.1.3. High-Risk Contexts

Two systematic reviews reported that prescribing errors are common in general practice and hospital inpatients [ 76 , 77 ]. The hospital environment is particularly prone to error-provoking conditions. Hospital wards may be busy or understaffed, and clinicians may inadequately supervise the medication use process or fail to check important information. Tiredness and the need to multitask often interrupt critical processes, such as administration of medicines, cause adverse ramifications for patient safety [ 78 ]. For example, a study conducted in a Spanish tertiary-care hospital emergency department noted that medication errors occurred most frequently when medication were administered, especially during the afternoon or evening shift when staff were more tired [ 79 ].

Certain hospital specialties are associated with increased risk of medication administration error. In a prospective incident monitoring study conducted at a large Chinese tertiary hospital, the frequency of administration error during anaesthesia was 1.1%. The largest categories of errors were omissions, incorrect doses and substitutions. Even then, substantially more respondents who claimed that they were not fully rested reported inattention as a contributing factor to errors compared to those who were fully rested [ 80 ].

31.4.2. Some Ways to Ensure Medication Safety in High-Risk Situations

31.4.2.1. high-risk medications.

Both at local and global level, the purpose of identifying a list of high-alert medications is to determine which drugs require special safeguards to reduce the risk of errors and minimise harm that can occur in the different phases of the medication use process [ 71 ]. Simplifying and standardising the ordering, storage, preparation, and dispensing of high-risk medications is the main strategy to reduce the risk of errors from high-risk medicines. In the fifth edition of the Accreditation Standards for Hospitals, the Joint Commission International identified improving the safety of high-risk medications in hospitals as a key objective, paying particular attention on the development and implementation of processes to manage the safe use of concentrated electrolytes [ 81 ]. Concentrated electrolyte solutions should always be stored in a controlled environment to prevent selection error and inadvertent administration of undiluted solutions, which have contributed to fatal outcomes.

Healthcare professionals are also involved in ensuring safe prescription, administration and monitoring of high-risk medications. In this regard, drugs with a narrow therapeutic index, such as chemotherapeutics and orally active vitamin K antagonists, should be carefully dosed and monitored by clinicians, in order to perform dose adjustments when necessary. Indeed, even small increases in the concentration of these medications at their site of action, for example, due to pharmacological interaction or concomitant disease, may cause a significant increase in their effect, resulting in patient harm [ 64 ]. Therapeutic guidelines should be followed for drugs where dosing is complex and duration of therapy substantially increases the risk of toxicity, for example, aminoglycosides and opioids [ 70 ]. “Navigating opioids for chronic pain” is a tool that provides guidance on different opioids based on morphine equivalence to compare the relative potency of the different molecules [ 82 ]. The use of shelf reminders, auxiliary labels, checklists and automated alerts, better if built into information technology systems, is intended to improve information and stimulate the attention of the clinicians regarding high-risk medicines. A regular review of local and broader system incidents and near-misses and the use of prospective analysis and re-design of systems is fundamental to prevent reoccurrence of the same errors with these drugs [ 70 ].

31.4.2.2. High-Risk Patients

All patients should be supported by a prescribing team working in close partnership with other healthcare providers, to ensure that they are aware of the therapeutic objectives of the medications taken, their likely benefits and potential side effects [ 83 ]. Self-empowerment among patients is essential to promote medication safety, as they serve as the final barrier in preventing medication errors. For this purpose, the use of aide-memoire tools, such as WHO 5 Moments for Medication Safety, should be promoted especially among high-risk patients, their families and caregivers, at all levels of care and across all settings [ 84 ].

Among the paediatric population, improving medication safety across the spectrum of their medication use process remains an area of critical focus. In a prospective cohort study on prioritising strategies for preventing medication errors and ADEs in paediatric inpatients, computerised physician order entry with clinical decision support systems, ward-based clinical pharmacists and improved communication among physicians, nurses, and pharmacists were identified as having the greatest potential to reduce medication errors [ 85 ]. While some advanced technologies, such as computerised physician order entry with clinical decision support systems, are increasingly adopted worldwide, others, including barcode administration systems and “SMART pumps” (i.e. infusion delivery systems that provide decision support for users), are only mainstream in the United States [ 86 ]. Technologies to improve medication safety that are still in the pipeline include mobile apps to assist each step of the medication management process from ordering to delivery in real time and workflow management systems.

In outpatient paediatrics, focus of interventions should be on the administration stage considering that parents, rather than patients or trained nurses, administer most medications. This process is error-prone, including parental confusion regarding the correct use of teaspoons, tablespoons, and dose cups. Supplementing the often-rushed information from physicians and pharmacists regarding drug administration with accurate Internet-based information on drugs or a personal consultation with an office-based pharmacist could be helpful [ 73 ].

In the elderly population, rational prescribing is a crucial step to avoid ADRs resulting from unnecessary drug use, incorrect drug choices, inappropriate dosing regimens and therapeutic duplications [ 74 ]. Lists have been derived from consensus opinion to guide clinicians, and primarily general practitioners, about appropriate prescriptions for older people, including the Beers Criteria and STOPP/START tool [ 87 , 88 ]. While the use of such criteria would reduce the risk of wrong prescription in older people, it is most effective if supplemented with periodic medication reviews, as reduction in the absolute number of prescribed medications, particularly non-indicated items, can minimise the risk of ADRs [ 74 ]. Multidisciplinary cooperation between nurses, physicists and pharmacists is essential in this aspect. By making medical care plans together, errors associated with incorrect doses and noncompliance with regulations and laws can be prevented more effectively [ 89 ].

There is a paucity of information on medication safety during pregnancy. This underscores the important role healthcare providers play as trusted sources of information for women during this vital stage of their life. Interactions between women of childbearing age and their physicians and pharmacists will influence the decisions they make about medication use. Strategic messaging and improved informational resources could help maximise the effectiveness of these interactions by ensuring that women receive the clear, credible, and comprehensive information about medication risks during pregnancy at the right time [ 90 ].

31.4.2.3. High-Risk Contexts

The working environment in healthcare facilities, primarily hospital settings, are often suboptimal with fluctuations in workload, staffing absences, missing medical records, distractions, and time pressures. Thus, prescribers should be equipped with the knowledge, skills and resilience to cope with these eventualities [ 91 ]. Various strategies can be taken to mitigate inherent risks in high-risk situations. As an example, in the hospital setting, preparing and administering intravenous medications is particularly complex, error prone and dangerous. Mitigation of this risk entails conduct of error checking at each stage of the preparation. The use of pre-prepared injections may also help by eliminating errors in the reconstitution of drug and diluent [ 92 ]. Another risk reduction strategy is the implementation of electronic prescription. A recent systematic review and meta-analysis of 38 prospective interventional studies found that hospital-based electronic prescription strategies reduced medication errors, dosing errors and ADEs. Although the available evidence was heterogeneous and mainly represented by non-randomised studies, it provides early data to justify implementation and further evaluation of computerised strategies [ 93 ].

31.5. Final Recommendations and Conclusions

The complexity and vastness of the healthcare system as well as the rapid advancement in pharmacotherapy render medication safety challenging to achieve. A patient can now be seen by multiple prescribers in multiple facilities and started on multiple medications, some of which are high-risk. Healthcare workers are also working in an increasingly siloed environment, focusing on the specialisation of their unit, resulting in fragmented information exchange and lack of inter-departmental cooperation. All these factors increase the probability and propensity for unintentional medication errors to occur. Therefore, it is now vital for the next generation of healthcare professionals to appreciate the magnitude of the challenges faced in ensuring medication safety, using the current strategies as a reference to devise their own innovative solutions.

As a recap of the chapter, transitions of care is a major contributor to medication discrepancies. A lack of information sharing among healthcare professionals detailing medication changes when patients transfer from one hospital to another or between different setting of care, and inadequate patient health literacy are the main causes for this lapse in medication safety. Focusing on medication reconciliation, information clarity during care transition, as well as patient engagement and empowerment are keys to alleviate this issue.

The use of multiple medications or polypharmacy is a rising trend. This will inevitably increase medication-related adverse events leading to patient harm. Various measures have been taken to promote rationale prescribing, especially among elderly patients as well as to reduce inappropriate polypharmacy. Conducting robust research in this area is a priority, as there is insufficient evidences that current polypharmacy-related interventions significantly improve patients’ clinical outcomes. Multifaceted interventions involving multiple stakeholders and health system changes should be the focus of future research to ensure medication safety in this aspect of care.

Some situations, including patients, specific medications and contexts of care, are associated with higher inherent safety risks. High-risk medications are often those with narrow therapeutic index and high potency, whereas some patient segments, especially children, geriatrics and pregnant women, are physiologically more vulnerable to errors. Chaotic and understaffed institutions, including poorly trained staff, also increase medication error risk. Use of alert systems, checklists and computerised technologies are strategies that can reduce the risk level. Safer hospital and primary care will be achievable when safety strategies and risk management skills are built into healthcare systems and practices of medication, safety and risk management is built into healthcare systems and processes.

Open Access This chapter is licensed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/ ), which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license and indicate if changes were made.

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• Cite this Page Soon HC, Geppetti P, Lupi C, et al. Medication Safety. 2020 Dec 15. In: Donaldson L, Ricciardi W, Sheridan S, et al., editors. Textbook of Patient Safety and Clinical Risk Management [Internet]. Cham (CH): Springer; 2021. Chapter 31. doi: 10.1007/978-3-030-59403-9_31
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• Introduction
• Medication Safety in Transitions of Care
• Medication Safety in Polypharmacy
• High-Risk Situations in Medication Safety
• Final Recommendations and Conclusions

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• Improving patient safety through a pharmacist-led medication reconciliation programme in nursing homes for the elderly in Spain. [Int J Clin Pharm. 2020] Improving patient safety through a pharmacist-led medication reconciliation programme in nursing homes for the elderly in Spain. Koprivnik S, Albiñana-Pérez MS, López-Sandomingo L, Taboada-López RJ, Rodríguez-Penín I. Int J Clin Pharm. 2020 Apr; 42(2):805-812. Epub 2020 Jan 28.
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Pharmacovigilance Safety Monitoring in Clinical Trials

Pharmacovigilance is that the science and activities associated with the gathering, detection and assessment of adverse event data. Major purpose of pharmacovigilance is to gauge the benefit- risk profile of drug for better efficacy and safety to be used in patients. Pharmacovigilance plays a major role in rationale use of drug which provides the information about the adverse drug reactions which seen in patients. In terms of volume Indian Pharma industry is third largest in world and in terms of value id thirteen largest in world. India is also known as a hub for clinical research and drug development. There is a requirement of a global and standardized pharmacovigilance system in India for better safety assessment in India. In drug development process the only priority of clinical trials is to make sure patient safety during and after the trials. A critical component throughout the drug development life-cycle is monitoring patient safety. Patient must be treated consistent with the requirements and illness of patient therefore the utmost value is given to monitoring of patient safety in the least levels of drug development. Such monitoring may be a dynamic process so to approach safety monitoring. To ensure a systematic approach to safety monitoring pharmaceutical sponsor must work proactively and collaboratively with all stakeholders. We have to focus upon all the aspects of drug safety in clinical trials including basics of drug safety, regulatory aspects of drug safety, patient suitability for safety in trials, post marketing safety and causality risk assessment of the drug products.

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Effects of Drug Policy Liberalization on Public Safety: A Review of the Literature

Ohio State Legal Studies Research Paper No. 746

Drug Enforcement and Policy Center, December 2022

15 Pages Posted: 6 Dec 2022

Maria M. Orsini

Ohio State University (OSU) - Department of Sociology

Date Written: December 5, 2022

After decades of criminalization, cannabis policy has liberalized rapidly throughout the U.S. in the 21st century. Following cannabis legalization in Colorado and Washington, legalization has gained momentum in many other U.S. states. While some states have fully legalized recreational cannabis for adult use, others have only decriminalized or legalized medical use. These reforms may have significant effects on public safety and public health, and therefore have become a topic of considerable academic interest. This review summarizes extant literature on the effect of drug policy liberalization on crime, traffic safety, law enforcement, and racial disparities. Overall, the literature suggests that cannabis legalization has resulted in some benefits to public health and public safety, even while some studies have produced mixed findings with regard to particular outcomes. Much of the literature regarding the impact of marijuana legalization on crime shows promising effects, including decreases in violent and property crime, reductions in drug-related arrests, and an improvement in crime clearance rates. Research on the relationship between cannabis policy liberalization and changes in traffic safety has produced mixed results, and while drug policy liberalization has the potential to reduce racial disparities, further changes are needed for those benefits to be achieved. Finally, all-drug decriminalization is associated with reductions in problematic drug use and criminal justice overcrowding, declines in youth drug use, and other health and social benefits, as evidenced by evaluations of Portugal’s policy and preliminary evidence in Oregon following decriminalization in 2020.

Keywords: Cannabis policy, public safety, drug decriminalization, crime rates, traffic safety, law enforcement, drug policy reform, racial disparities, criminal justice reform, marijuana legalization

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Maria M. Orsini (Contact Author)

Ohio state university (osu) - department of sociology ( email ).

Columbus, OH

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• Footnotes to tables should be indicated by superscript lower-case letters (or asterisks for significance values and other statistical data) and included beneath the table body.

Electronic Figure Submission

• Supply all figures electronically.
• Indicate what graphics program was used to create the artwork.
• For vector graphics, the preferred format is EPS; for halftones, please use TIFF format. MS Office files are also acceptable.
• Vector graphics containing fonts must have the fonts embedded in the files.
• Name your figure files with "Fig" and the figure number, e.g., Fig1.eps.
• Definition: Black and white graphic with no shading.
• Do not use faint lines and/or lettering and check that all lines and lettering within the figures are legible at final size.
• All lines should be at least 0.1 mm (0.3 pt) wide.
• Scanned line drawings and line drawings in bitmap format should have a minimum resolution of 1200 dpi.

Halftone Art

• Definition: Photographs, drawings, or paintings with fine shading, etc.
• If any magnification is used in the photographs, indicate this by using scale bars within the figures themselves.
• Halftones should have a minimum resolution of 300 dpi.

Combination Art

• Definition: a combination of halftone and line art, e.g., halftones containing line drawing, extensive lettering, color diagrams, etc.
• Combination artwork should have a minimum resolution of 600 dpi.
• Color art is free of charge for print and online publication.
• Color illustrations should be submitted as RGB.

Figure Lettering

• To add lettering, it is best to use Helvetica or Arial (sans serif fonts).
• Keep lettering consistently sized throughout your final-sized artwork, usually about 2–3 mm (8–12 pt).
• Variance of type size within an illustration should be minimal, e.g., do not use 8-pt type on an axis and 20-pt type for the axis label.
• Avoid effects such as shading, outline letters, etc.
• Do not include titles or captions within your illustrations.

Figure Numbering

• All figures are to be numbered using Arabic numerals.
• Figures should always be cited in text in consecutive numerical order.
• Figure parts should be denoted by lowercase letters (a, b, c, etc.).
• If an appendix appears in your article and it contains one or more figures, continue the consecutive numbering of the main text. Do not number the appendix figures, "A1, A2, A3, etc." Figures in online appendices [Supplementary Information (SI)] should, however, be numbered separately.

Figure Captions

• Each figure should have a concise caption describing accurately what the figure depicts. Include the captions in the text file of the manuscript, not in the figure file.
• Figure captions begin with the term Fig. in bold type, followed by the figure number, also in bold type.
• No punctuation is to be included after the number, nor is any punctuation to be placed at the end of the caption.
• Identify all elements found in the figure in the figure caption; and use boxes, circles, etc., as coordinate points in graphs.
• Identify previously published material by giving the original source in the form of a reference citation at the end of the figure caption.

Figure Placement and Size

• Figures should be submitted within the body of the text. Only if the file size of the manuscript causes problems in uploading it, the large figures should be submitted separately from the text.
• When preparing your figures, size figures to fit in the column width.
• For large-sized journals the figures should be 84 mm (for double-column text areas), or 174 mm (for single-column text areas) wide and not higher than 234 mm.
• For small-sized journals, the figures should be 119 mm wide and not higher than 195 mm.

If you include figures that have already been published elsewhere, you must obtain permission from the copyright owner(s) for both the print and online format. Please be aware that some publishers do not grant electronic rights for free and that Springer will not be able to refund any costs that may have occurred to receive these permissions. In such cases, material from other sources should be used.

Accessibility

In order to give people of all abilities and disabilities access to the content of your figures, please make sure that

• All figures have descriptive captions (blind users could then use a text-to-speech software or a text-to-Braille hardware)
• Patterns are used instead of or in addition to colors for conveying information (color-blind users would then be able to distinguish the visual elements)
• Any figure lettering has a contrast ratio of at least 4.5:1

Generative AI Images

Please check Springer’s policy on generative AI images and make sure your work adheres to the principles described therein.

Springer accepts electronic multimedia files (animations, movies, audio, etc.) and other supplementary files to be published online along with an article or a book chapter. This feature can add dimension to the author's article, as certain information cannot be printed or is more convenient in electronic form.

Before submitting research datasets as Supplementary Information, authors should read the journal’s Research data policy. We encourage research data to be archived in data repositories wherever possible.

• Supply all supplementary material in standard file formats.
• Please include in each file the following information: article title, journal name, author names; affiliation and e-mail address of the corresponding author.
• To accommodate user downloads, please keep in mind that larger-sized files may require very long download times and that some users may experience other problems during downloading.
• High resolution (streamable quality) videos can be submitted up to a maximum of 25GB; low resolution videos should not be larger than 5GB.

Audio, Video, and Animations

• Aspect ratio: 16:9 or 4:3
• Maximum file size: 25 GB for high resolution files; 5 GB for low resolution files
• Minimum video duration: 1 sec
• Supported file formats: avi, wmv, mp4, mov, m2p, mp2, mpg, mpeg, flv, mxf, mts, m4v, 3gp

Text and Presentations

• Submit your material in PDF format; .doc or .ppt files are not suitable for long-term viability.
• A collection of figures may also be combined in a PDF file.

Spreadsheets

• Spreadsheets should be submitted as .csv or .xlsx files (MS Excel).

Specialized Formats

• Specialized format such as .pdb (chemical), .wrl (VRML), .nb (Mathematica notebook), and .tex can also be supplied.

Collecting Multiple Files

• It is possible to collect multiple files in a .zip or .gz file.
• If supplying any supplementary material, the text must make specific mention of the material as a citation, similar to that of figures and tables.
• Refer to the supplementary files as “Online Resource”, e.g., "... as shown in the animation (Online Resource 3)", “... additional data are given in Online Resource 4”.
• Name the files consecutively, e.g. “ESM_3.mpg”, “ESM_4.pdf”.
• For each supplementary material, please supply a concise caption describing the content of the file.

Processing of supplementary files

• Supplementary Information (SI) will be published as received from the author without any conversion, editing, or reformatting.

In order to give people of all abilities and disabilities access to the content of your supplementary files, please make sure that

• The manuscript contains a descriptive caption for each supplementary material
• Video files do not contain anything that flashes more than three times per second (so that users prone to seizures caused by such effects are not put at risk)

This journal follows Springer Nature research data policy . Sharing of all relevant research data is strongly encouraged and authors must add a Data Availability Statement to original research articles.

Research data includes a wide range of types, including spreadsheets, images, textual extracts, archival documents, video or audio, interview notes or any specialist formats generated during research.

Data availability statements

All original research must include a data availability statement. This statement should explain how to access data supporting the results and analysis in the article, including links/citations to publicly archived datasets analysed or generated during the study. Please see our full policy here .

If it is not possible to share research data publicly, for instance when individual privacy could be compromised, this statement should describe how data can be accessed and any conditions for reuse. Participant consent should be obtained and documented prior to data collection. See our guidance on sensitive data for more information.

When creating a data availability statement, authors are encouraged to consider the minimal dataset that would be necessary to interpret, replicate and build upon the findings reported in the article.

Further guidance on writing a data availability statement, including examples, is available at:

Data repositories

Authors are strongly encouraged to deposit their supporting data in a publicly available repository. Sharing your data in a repository promotes the integrity, discovery and reuse of your research, making it easier for the research community to build on and credit your work.

See our data repository guidance for information on finding a suitable repository.

We recommend the use of discipline-specific repositories where available. For a number of data types, submission to specific public repositories is mandatory.

See our list of mandated data types .

The journal encourages making research data available under open licences that permit reuse. The journal does not enforce use of particular licences in third party repositories. You should ensure you have necessary rights to share any data that you deposit in a repository.

Data citation

The journal recommends that authors cite any publicly available data on which the conclusions of the paper rely. This includes data the authors are sharing alongside their publication and any secondary data the authors have reused. Data citations should include a persistent identifier (such as a DOI), should be included in the reference list using the minimum information recommended by DataCite (Dataset Creator, Dataset Title, Publisher [repository], Publication Year, Identifier [e.g. DOI, Handle, Accession or ARK]) and follow journal style.

See our further guidance on citing datasets.

Research data and peer review

If the journal that you are submitting to uses double-anonymous peer review and you are providing reviewers with access to your data (for example via a repository link, supplementary information or data on request), it is strongly suggested that the authorship in the data is also anonymised. There are data repositories that can assist with this and/or will create a link to mask the authorship of your data.

Support with research data policy

Authors who need help understanding our data sharing policy, finding a suitable data repository, or organising and sharing research data can consult our Research Data Helpdesk for guidance.

See our FAQ page for more information on Springer Nature's research data policy.

Upon acceptance, your article will be exported to Production to undergo typesetting. Shortly after this you will receive two e-mails. One contains a request to confirm your affiliation, choose the publishing model for your article, as well as to arrange rights and payment of any associated publication cost. A second e-mail containing a link to your article’s proofs will be sent once typesetting is completed.

Article publishing agreement

Depending on the ownership of the journal and its policies, you will either grant the Publisher an exclusive licence to publish the article or will be asked to transfer copyright of the article to the Publisher.

Offprints can be ordered by the corresponding author.

Color illustrations

Publication of color illustrations is free of charge.

Proof reading

The purpose of the proof is to check for typesetting or conversion errors and the completeness and accuracy of the text, tables and figures. Substantial changes in content, e.g., new results, corrected values, title and authorship, are not allowed without the approval of the Editor.

After online publication, further changes can only be made in the form of an Erratum, which will be hyperlinked to the article.

Online First

The article will be published online after receipt of the corrected proofs. This is the official first publication citable with the DOI. After release of the printed version, the paper can also be cited by issue and page numbers.

In addition to the normal publication process (whereby an article is submitted to the journal and access to that article is granted to customers who have purchased a subscription), Springer provides an alternative publishing option: Springer Open Choice. A Springer Open Choice article receives all the benefits of a regular subscription-based article, but in addition is made available publicly through Springer’s online platform SpringerLink.

Copyright and license term – CC BY-NC

Open Choice articles do not require transfer of copyright as the copyright remains with the author. In opting for open access, the author(s) agree to publish the article under the Creative Commons Attribution-NonCommercial 4.0 International License

Find more about the license agreement

• Please always use internationally accepted signs and symbols for units ( SI units ).
• Nomenclature: Insofar as possible, authors should use systematic names similar to those used by IUPAC .
• Genus and species names should be in italics.
• Generic names of drugs and pesticides are preferred; if trade names are used, the generic name should be given at first mention.
• Please use the standard mathematical notation for formulae, symbols, etc.: Italic for single letters that denote mathematical constants, variables, and unknown quantities; Roman/upright for numerals, operators, and punctuation, and commonly defined functions or abbreviations, e.g., cos, det, e or exp, lim, log, max, min, sin, tan, d (for derivative); Bold for vectors, tensors, and matrices.

This journal is committed to upholding the integrity of the scientific record. As a member of the Committee on Publication Ethics ( COPE ) the journal will follow the COPE guidelines on how to deal with potential acts of misconduct.

Authors should refrain from misrepresenting research results which could damage the trust in the journal, the professionalism of scientific authorship, and ultimately the entire scientific endeavour. Maintaining integrity of the research and its presentation is helped by following the rules of good scientific practice, which include*:

• The manuscript should not be submitted to more than one journal for simultaneous consideration.
• The submitted work should be original and should not have been published elsewhere in any form or language (partially or in full), unless the new work concerns an expansion of previous work. (Please provide transparency on the re-use of material to avoid the concerns about text-recycling (‘self-plagiarism’).
• A single study should not be split up into several parts to increase the quantity of submissions and submitted to various journals or to one journal over time (i.e. ‘salami-slicing/publishing’).
• Concurrent or secondary publication is sometimes justifiable, provided certain conditions are met. Examples include: translations or a manuscript that is intended for a different group of readers.
• Results should be presented clearly, honestly, and without fabrication, falsification or inappropriate data manipulation (including image based manipulation). Authors should adhere to discipline-specific rules for acquiring, selecting and processing data.
• No data, text, or theories by others are presented as if they were the author’s own (‘plagiarism’). Proper acknowledgements to other works must be given (this includes material that is closely copied (near verbatim), summarized and/or paraphrased), quotation marks (to indicate words taken from another source) are used for verbatim copying of material, and permissions secured for material that is copyrighted.

Important note: the journal may use software to screen for plagiarism.

• Authors should make sure they have permissions for the use of software, questionnaires/(web) surveys and scales in their studies (if appropriate).
• Research articles and non-research articles (e.g. Opinion, Review, and Commentary articles) must cite appropriate and relevant literature in support of the claims made. Excessive and inappropriate self-citation or coordinated efforts among several authors to collectively self-cite is strongly discouraged.
• Authors should avoid untrue statements about an entity (who can be an individual person or a company) or descriptions of their behavior or actions that could potentially be seen as personal attacks or allegations about that person.
• Research that may be misapplied to pose a threat to public health or national security should be clearly identified in the manuscript (e.g. dual use of research). Examples include creation of harmful consequences of biological agents or toxins, disruption of immunity of vaccines, unusual hazards in the use of chemicals, weaponization of research/technology (amongst others).
• Authors are strongly advised to ensure the author group, the Corresponding Author, and the order of authors are all correct at submission. Adding and/or deleting authors during the revision stages is generally not permitted, but in some cases may be warranted. Reasons for changes in authorship should be explained in detail. Please note that changes to authorship cannot be made after acceptance of a manuscript.

*All of the above are guidelines and authors need to make sure to respect third parties rights such as copyright and/or moral rights.

Upon request authors should be prepared to send relevant documentation or data in order to verify the validity of the results presented. This could be in the form of raw data, samples, records, etc. Sensitive information in the form of confidential or proprietary data is excluded.

If there is suspicion of misbehavior or alleged fraud the Journal and/or Publisher will carry out an investigation following COPE guidelines. If, after investigation, there are valid concerns, the author(s) concerned will be contacted under their given e-mail address and given an opportunity to address the issue. Depending on the situation, this may result in the Journal’s and/or Publisher’s implementation of the following measures, including, but not limited to:

• If the manuscript is still under consideration, it may be rejected and returned to the author.

- an erratum/correction may be placed with the article

- an expression of concern may be placed with the article

- or in severe cases retraction of the article may occur.

The reason will be given in the published erratum/correction, expression of concern or retraction note. Please note that retraction means that the article is maintained on the platform , watermarked “retracted” and the explanation for the retraction is provided in a note linked to the watermarked article.

• The author’s institution may be informed
• A notice of suspected transgression of ethical standards in the peer review system may be included as part of the author’s and article’s bibliographic record.

Fundamental errors

Authors have an obligation to correct mistakes once they discover a significant error or inaccuracy in their published article. The author(s) is/are requested to contact the journal and explain in what sense the error is impacting the article. A decision on how to correct the literature will depend on the nature of the error. This may be a correction or retraction. The retraction note should provide transparency which parts of the article are impacted by the error.

Suggesting / excluding reviewers

Authors are welcome to suggest suitable reviewers and/or request the exclusion of certain individuals when they submit their manuscripts. When suggesting reviewers, authors should make sure they are totally independent and not connected to the work in any way. It is strongly recommended to suggest a mix of reviewers from different countries and different institutions. When suggesting reviewers, the Corresponding Author must provide an institutional email address for each suggested reviewer, or, if this is not possible to include other means of verifying the identity such as a link to a personal homepage, a link to the publication record or a researcher or author ID in the submission letter. Please note that the Journal may not use the suggestions, but suggestions are appreciated and may help facilitate the peer review process.

These guidelines describe authorship principles and good authorship practices to which prospective authors should adhere to.

Authorship clarified

The Journal and Publisher assume all authors agreed with the content and that all gave explicit consent to submit and that they obtained consent from the responsible authorities at the institute/organization where the work has been carried out, before the work is submitted.

The Publisher does not prescribe the kinds of contributions that warrant authorship. It is recommended that authors adhere to the guidelines for authorship that are applicable in their specific research field. In absence of specific guidelines it is recommended to adhere to the following guidelines*:

All authors whose names appear on the submission

1) made substantial contributions to the conception or design of the work; or the acquisition, analysis, or interpretation of data; or the creation of new software used in the work;

2) drafted the work or revised it critically for important intellectual content;

3) approved the version to be published; and

4) agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

* Based on/adapted from:

ICMJE, Defining the Role of Authors and Contributors,

Transparency in authors’ contributions and responsibilities to promote integrity in scientific publication, McNutt at all, PNAS February 27, 2018

Disclosures and declarations

All authors are requested to include information regarding sources of funding, financial or non-financial interests, study-specific approval by the appropriate ethics committee for research involving humans and/or animals, informed consent if the research involved human participants, and a statement on welfare of animals if the research involved animals (as appropriate).

The decision whether such information should be included is not only dependent on the scope of the journal, but also the scope of the article. Work submitted for publication may have implications for public health or general welfare and in those cases it is the responsibility of all authors to include the appropriate disclosures and declarations.

Data transparency

All authors are requested to make sure that all data and materials as well as software application or custom code support their published claims and comply with field standards. Please note that journals may have individual policies on (sharing) research data in concordance with disciplinary norms and expectations.

Role of the Corresponding Author

One author is assigned as Corresponding Author and acts on behalf of all co-authors and ensures that questions related to the accuracy or integrity of any part of the work are appropriately addressed.

The Corresponding Author is responsible for the following requirements:

• ensuring that all listed authors have approved the manuscript before submission, including the names and order of authors;
• managing all communication between the Journal and all co-authors, before and after publication;*
• providing transparency on re-use of material and mention any unpublished material (for example manuscripts in press) included in the manuscript in a cover letter to the Editor;
• making sure disclosures, declarations and transparency on data statements from all authors are included in the manuscript as appropriate (see above).

* The requirement of managing all communication between the journal and all co-authors during submission and proofing may be delegated to a Contact or Submitting Author. In this case please make sure the Corresponding Author is clearly indicated in the manuscript.

Author contributions

In absence of specific instructions and in research fields where it is possible to describe discrete efforts, the Publisher recommends authors to include contribution statements in the work that specifies the contribution of every author in order to promote transparency. These contributions should be listed at the separate title page.

Examples of such statement(s) are shown below:

• Free text:

All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by [full name], [full name] and [full name]. The first draft of the manuscript was written by [full name] and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

Example: CRediT taxonomy:

• Conceptualization: [full name], …; Methodology: [full name], …; Formal analysis and investigation: [full name], …; Writing - original draft preparation: [full name, …]; Writing - review and editing: [full name], …; Funding acquisition: [full name], …; Resources: [full name], …; Supervision: [full name],….

For review articles where discrete statements are less applicable a statement should be included who had the idea for the article, who performed the literature search and data analysis, and who drafted and/or critically revised the work.

For articles that are based primarily on the student’s dissertation or thesis , it is recommended that the student is usually listed as principal author:

A Graduate Student’s Guide to Determining Authorship Credit and Authorship Order, APA Science Student Council 2006

Affiliation

The primary affiliation for each author should be the institution where the majority of their work was done. If an author has subsequently moved, the current address may additionally be stated. Addresses will not be updated or changed after publication of the article.

Changes to authorship

Authors are strongly advised to ensure the correct author group, the Corresponding Author, and the order of authors at submission. Changes of authorship by adding or deleting authors, and/or changes in Corresponding Author, and/or changes in the sequence of authors are not accepted after acceptance of a manuscript.

• Please note that author names will be published exactly as they appear on the accepted submission!

Please make sure that the names of all authors are present and correctly spelled, and that addresses and affiliations are current.

Adding and/or deleting authors at revision stage are generally not permitted, but in some cases it may be warranted. Reasons for these changes in authorship should be explained. Approval of the change during revision is at the discretion of the Editor-in-Chief. Please note that journals may have individual policies on adding and/or deleting authors during revision stage.

Author identification

Authors are recommended to use their ORCID ID when submitting an article for consideration or acquire an ORCID ID via the submission process.

Deceased or incapacitated authors

For cases in which a co-author dies or is incapacitated during the writing, submission, or peer-review process, and the co-authors feel it is appropriate to include the author, co-authors should obtain approval from a (legal) representative which could be a direct relative.

Authorship issues or disputes

In the case of an authorship dispute during peer review or after acceptance and publication, the Journal will not be in a position to investigate or adjudicate. Authors will be asked to resolve the dispute themselves. If they are unable the Journal reserves the right to withdraw a manuscript from the editorial process or in case of a published paper raise the issue with the authors’ institution(s) and abide by its guidelines.

Confidentiality

Authors should treat all communication with the Journal as confidential which includes correspondence with direct representatives from the Journal such as Editors-in-Chief and/or Handling Editors and reviewers’ reports unless explicit consent has been received to share information.

Authors are requested to disclose interests that are directly or indirectly related to the work submitted for publication. Interests within the last 3 years of beginning the work (conducting the research and preparing the work for submission) should be reported. Interests outside the 3-year time frame must be disclosed if they could reasonably be perceived as influencing the submitted work. Disclosure of interests provides a complete and transparent process and helps readers form their own judgments of potential bias. This is not meant to imply that a financial relationship with an organization that sponsored the research or compensation received for consultancy work is inappropriate.

Editorial Board Members and Editors are required to declare any competing interests and may be excluded from the peer review process if a competing interest exists. In addition, they should exclude themselves from handling manuscripts in cases where there is a competing interest. This may include – but is not limited to – having previously published with one or more of the authors, and sharing the same institution as one or more of the authors. Where an Editor or Editorial Board Member is on the author list we recommend they declare this in the competing interests section on the submitted manuscript. If they are an author or have any other competing interest regarding a specific manuscript, another Editor or member of the Editorial Board will be assigned to assume responsibility for overseeing peer review. These submissions are subject to the exact same review process as any other manuscript. Editorial Board Members are welcome to submit papers to the journal. These submissions are not given any priority over other manuscripts, and Editorial Board Member status has no bearing on editorial consideration.

Interests that should be considered and disclosed but are not limited to the following:

Funding: Research grants from funding agencies (please give the research funder and the grant number) and/or research support (including salaries, equipment, supplies, reimbursement for attending symposia, and other expenses) by organizations that may gain or lose financially through publication of this manuscript.

Employment: Recent (while engaged in the research project), present or anticipated employment by any organization that may gain or lose financially through publication of this manuscript. This includes multiple affiliations (if applicable).

Financial interests: Stocks or shares in companies (including holdings of spouse and/or children) that may gain or lose financially through publication of this manuscript; consultation fees or other forms of remuneration from organizations that may gain or lose financially; patents or patent applications whose value may be affected by publication of this manuscript.

It is difficult to specify a threshold at which a financial interest becomes significant, any such figure is necessarily arbitrary, so one possible practical guideline is the following: "Any undeclared financial interest that could embarrass the author were it to become publicly known after the work was published."

Non-financial interests: In addition, authors are requested to disclose interests that go beyond financial interests that could impart bias on the work submitted for publication such as professional interests, personal relationships or personal beliefs (amongst others). Examples include, but are not limited to: position on editorial board, advisory board or board of directors or other type of management relationships; writing and/or consulting for educational purposes; expert witness; mentoring relations; and so forth.

Primary research articles require a disclosure statement. Review articles present an expert synthesis of evidence and may be treated as an authoritative work on a subject. Review articles therefore require a disclosure statement. Other article types such as editorials, book reviews, comments (amongst others) may, dependent on their content, require a disclosure statement. If you are unclear whether your article type requires a disclosure statement, please contact the Editor-in-Chief.

Please note that, in addition to the above requirements, funding information (given that funding is a potential competing interest (as mentioned above)) needs to be disclosed upon submission of the manuscript in the peer review system. This information will automatically be added to the Record of CrossMark, however it is not added to the manuscript itself. Under ‘summary of requirements’ (see below) funding information should be included in the ‘ Declarations ’ section.

Summary of requirements

The above should be summarized in a statement and placed in a ‘Declarations’ section before the reference list under a heading of ‘Funding’ and/or ‘Competing interests’. Other declarations include Ethics approval, Consent, Data, Material and/or Code availability and Authors’ contribution statements.

Please see the various examples of wording below and revise/customize the sample statements according to your own needs.

When all authors have the same (or no) conflicts and/or funding it is sufficient to use one blanket statement.

Examples of statements to be used when funding has been received:

• Partial financial support was received from [...]
• The research leading to these results received funding from […] under Grant Agreement No[…].
• This study was funded by […]
• This work was supported by […] (Grant numbers […] and […]

Examples of statements to be used when there is no funding:

• The authors did not receive support from any organization for the submitted work.
• No funding was received to assist with the preparation of this manuscript.
• No funding was received for conducting this study.
• No funds, grants, or other support was received.

Examples of statements to be used when there are interests to declare:

Non-financial interests: Author C is an unpaid member of committee Z.

Non-financial interests: Author A is on the board of directors of Y and receives no compensation as member of the board of directors.

Non-financial interests: none.

Non-financial interests: Author D has served on advisory boards for Company M, Company N and Company O.

Examples of statements to be used when authors have nothing to declare:

• The authors have no relevant financial or non-financial interests to disclose.
• The authors have no competing interests to declare that are relevant to the content of this article.
• All authors certify that they have no affiliations with or involvement in any organization or entity with any financial interest or non-financial interest in the subject matter or materials discussed in this manuscript.
• The authors have no financial or proprietary interests in any material discussed in this article.

Authors are responsible for correctness of the statements provided in the manuscript. See also Authorship Principles. The Editor-in-Chief reserves the right to reject submissions that do not meet the guidelines described in this section.

Ethics approval

When reporting a study that involved human participants, their data or biological material, authors should include a statement that confirms that the study was approved (or granted exemption) by the appropriate institutional and/or national research ethics committee (including the name of the ethics committee) and certify that the study was performed in accordance with the ethical standards as laid down in the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards. If doubt exists whether the research was conducted in accordance with the 1964 Helsinki Declaration or comparable standards, the authors must explain the reasons for their approach, and demonstrate that an independent ethics committee or institutional review board explicitly approved the doubtful aspects of the study. If a study was granted exemption from requiring ethics approval, this should also be detailed in the manuscript (including the reasons for the exemption).

Retrospective ethics approval

If a study has not been granted ethics committee approval prior to commencing, retrospective ethics approval usually cannot be obtained and it may not be possible to consider the manuscript for peer review. The decision on whether to proceed to peer review in such cases is at the Editor's discretion.

Ethics approval for retrospective studies

Although retrospective studies are conducted on already available data or biological material (for which formal consent may not be needed or is difficult to obtain) ethics approval may be required dependent on the law and the national ethical guidelines of a country. Authors should check with their institution to make sure they are complying with the specific requirements of their country.

Ethics approval for case studies

Case reports require ethics approval. Most institutions will have specific policies on this subject. Authors should check with their institution to make sure they are complying with the specific requirements of their institution and seek ethics approval where needed. Authors should be aware to secure informed consent from the individual (or parent or guardian if the participant is a minor or incapable) See also section on Informed Consent .

If human cells are used, authors must declare in the manuscript: what cell lines were used by describing the source of the cell line, including when and from where it was obtained, whether the cell line has recently been authenticated and by what method. If cells were bought from a life science company the following need to be given in the manuscript: name of company (that provided the cells), cell type, number of cell line, and batch of cells.

It is recommended that authors check the NCBI database for misidentification and contamination of human cell lines. This step will alert authors to possible problems with the cell line and may save considerable time and effort.

Further information is available from the International Cell Line Authentication Committee (ICLAC).

Authors should include a statement that confirms that an institutional or independent ethics committee (including the name of the ethics committee) approved the study and that informed consent was obtained from the donor or next of kin.

Research Resource Identifiers (RRID)

Research Resource Identifiers (RRID) are persistent unique identifiers (effectively similar to a DOI) for research resources. This journal encourages authors to adopt RRIDs when reporting key biological resources (antibodies, cell lines, model organisms and tools) in their manuscripts.

Organism: Filip1 tm1a(KOMP)Wtsi RRID:MMRRC_055641-UCD

Cell Line: RST307 cell line RRID:CVCL_C321

Antibody: Luciferase antibody DSHB Cat# LUC-3, RRID:AB_2722109

Plasmid: mRuby3 plasmid RRID:Addgene_104005

Software: ImageJ Version 1.2.4 RRID:SCR_003070

RRIDs are provided by the Resource Identification Portal . Many commonly used research resources already have designated RRIDs. The portal also provides authors links so that they can quickly register a new resource and obtain an RRID.

Clinical Trial Registration

The World Health Organization (WHO) definition of a clinical trial is "any research study that prospectively assigns human participants or groups of humans to one or more health-related interventions to evaluate the effects on health outcomes". The WHO defines health interventions as “A health intervention is an act performed for, with or on behalf of a person or population whose purpose is to assess, improve, maintain, promote or modify health, functioning or health conditions” and a health-related outcome is generally defined as a change in the health of a person or population as a result of an intervention.

To ensure the integrity of the reporting of patient-centered trials, authors must register prospective clinical trials (phase II to IV trials) in suitable publicly available repositories. For example www.clinicaltrials.gov or any of the primary registries that participate in the WHO International Clinical Trials Registry Platform .

The trial registration number (TRN) and date of registration should be included as the last line of the manuscript abstract.

For clinical trials that have not been registered prospectively, authors are encouraged to register retrospectively to ensure the complete publication of all results. The trial registration number (TRN), date of registration and the words 'retrospectively registered’ should be included as the last line of the manuscript abstract.

Standards of reporting

Springer Nature advocates complete and transparent reporting of biomedical and biological research and research with biological applications. Authors are recommended to adhere to the minimum reporting guidelines hosted by the EQUATOR Network when preparing their manuscript.

Exact requirements may vary depending on the journal; please refer to the journal’s Instructions for Authors.

Checklists are available for a number of study designs, including:

Randomised trials (CONSORT) and Study protocols (SPIRIT)

Observational studies (STROBE)

Systematic reviews and meta-analyses (PRISMA) and protocols (Prisma-P)

Diagnostic/prognostic studies (STARD) and (TRIPOD)

Case reports (CARE)

Clinical practice guidelines (AGREE) and (RIGHT)

Qualitative research (SRQR) and (COREQ)

Animal pre-clinical studies (ARRIVE)

Quality improvement studies (SQUIRE)

Economic evaluations (CHEERS)

The above should be summarized in a statement and placed in a ‘Declarations’ section before the reference list under a heading of ‘Ethics approval’.

Examples of statements to be used when ethics approval has been obtained:

• All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. The study was approved by the Bioethics Committee of the Medical University of A (No. ...).

• This study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by the Ethics Committee of University B (Date.../No. ...).

• Approval was obtained from the ethics committee of University C. The procedures used in this study adhere to the tenets of the Declaration of Helsinki.

• The questionnaire and methodology for this study was approved by the Human Research Ethics committee of the University of D (Ethics approval number: ...).

Examples of statements to be used for a retrospective study:

• Ethical approval was waived by the local Ethics Committee of University A in view of the retrospective nature of the study and all the procedures being performed were part of the routine care.

• This research study was conducted retrospectively from data obtained for clinical purposes. We consulted extensively with the IRB of XYZ who determined that our study did not need ethical approval. An IRB official waiver of ethical approval was granted from the IRB of XYZ.

• This retrospective chart review study involving human participants was in accordance with the ethical standards of the institutional and national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. The Human Investigation Committee (IRB) of University B approved this study.

Examples of statements to be used when no ethical approval is required/exemption granted:

• This is an observational study. The XYZ Research Ethics Committee has confirmed that no ethical approval is required.

• The data reproduced from Article X utilized human tissue that was procured via our Biobank AB, which provides de-identified samples. This study was reviewed and deemed exempt by our XYZ Institutional Review Board. The BioBank protocols are in accordance with the ethical standards of our institution and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

All individuals have individual rights that are not to be infringed. Individual participants in studies have, for example, the right to decide what happens to the (identifiable) personal data gathered, to what they have said during a study or an interview, as well as to any photograph that was taken. This is especially true concerning images of vulnerable people (e.g. minors, patients, refugees, etc) or the use of images in sensitive contexts. In many instances authors will need to secure written consent before including images.

Identifying details (names, dates of birth, identity numbers, biometrical characteristics (such as facial features, fingerprint, writing style, voice pattern, DNA or other distinguishing characteristic) and other information) of the participants that were studied should not be published in written descriptions, photographs, and genetic profiles unless the information is essential for scholarly purposes and the participant (or parent/guardian if the participant is a minor or incapable or legal representative) gave written informed consent for publication. Complete anonymity is difficult to achieve in some cases. Detailed descriptions of individual participants, whether of their whole bodies or of body sections, may lead to disclosure of their identity. Under certain circumstances consent is not required as long as information is anonymized and the submission does not include images that may identify the person.

Informed consent for publication should be obtained if there is any doubt. For example, masking the eye region in photographs of participants is inadequate protection of anonymity. If identifying characteristics are altered to protect anonymity, such as in genetic profiles, authors should provide assurance that alterations do not distort meaning.

Exceptions where it is not necessary to obtain consent:

• Images such as x rays, laparoscopic images, ultrasound images, brain scans, pathology slides unless there is a concern about identifying information in which case, authors should ensure that consent is obtained.

• Reuse of images: If images are being reused from prior publications, the Publisher will assume that the prior publication obtained the relevant information regarding consent. Authors should provide the appropriate attribution for republished images.

Consent and already available data and/or biologic material

Regardless of whether material is collected from living or dead patients, they (family or guardian if the deceased has not made a pre-mortem decision) must have given prior written consent. The aspect of confidentiality as well as any wishes from the deceased should be respected.

Data protection, confidentiality and privacy

When biological material is donated for or data is generated as part of a research project authors should ensure, as part of the informed consent procedure, that the participants are made aware what kind of (personal) data will be processed, how it will be used and for what purpose. In case of data acquired via a biobank/biorepository, it is possible they apply a broad consent which allows research participants to consent to a broad range of uses of their data and samples which is regarded by research ethics committees as specific enough to be considered “informed”. However, authors should always check the specific biobank/biorepository policies or any other type of data provider policies (in case of non-bio research) to be sure that this is the case.

Consent to Participate

For all research involving human subjects, freely-given, informed consent to participate in the study must be obtained from participants (or their parent or legal guardian in the case of children under 16) and a statement to this effect should appear in the manuscript. In the case of articles describing human transplantation studies, authors must include a statement declaring that no organs/tissues were obtained from prisoners and must also name the institution(s)/clinic(s)/department(s) via which organs/tissues were obtained. For manuscripts reporting studies involving vulnerable groups where there is the potential for coercion or where consent may not have been fully informed, extra care will be taken by the editor and may be referred to the Springer Nature Research Integrity Group.

Consent to Publish

Individuals may consent to participate in a study, but object to having their data published in a journal article. Authors should make sure to also seek consent from individuals to publish their data prior to submitting their paper to a journal. This is in particular applicable to case studies. A consent to publish form can be found

here. (Download docx, 36 kB)

The above should be summarized in a statement and placed in a ‘Declarations’ section before the reference list under a heading of ‘Consent to participate’ and/or ‘Consent to publish’. Other declarations include Funding, Competing interests, Ethics approval, Consent, Data and/or Code availability and Authors’ contribution statements.

Sample statements for "Consent to participate" :

Informed consent was obtained from all individual participants included in the study.

Informed consent was obtained from legal guardians.

Written informed consent was obtained from the parents.

Verbal informed consent was obtained prior to the interview.

Sample statements for “Consent to publish” :

The authors affirm that human research participants provided informed consent for publication of the images in Figure(s) 1a, 1b and 1c.

The participant has consented to the submission of the case report to the journal.

Patients signed informed consent regarding publishing their data and photographs.

Sample statements if identifying information about participants is available in the article:

Additional informed consent was obtained from all individual participants for whom identifying information is included in this article.

Images will be removed from publication if authors have not obtained informed consent or the paper may be removed and replaced with a notice explaining the reason for removal.

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