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In recent years, a number of therapeutic peptides have been authorized in the EU market, and several others are in the clinical development phase or under assessment for full dossier or generic applications. Quality and safety guidelines specific to peptides are limited, and some aspects have to be considered. In particular, concerns relate to the analytical investigation for impurities and the toxicological assessment of these substances. The guidelines and the compendial pharmacopoeias provide certain references but that may be questionable if interpreted according to whether therapeutic peptides are considered chemical or biological entities, large or small. The characterization of peptide-related impurities cannot follow the small molecule approach but should consider aspects closely linked to the complex mechanisms of action that these large molecules can exert in the human body. Although direct genotoxic mechanisms cannot be excluded, hazardous interactions on biological systems cannot be ruled out, as in the case of natural peptide toxins and their specific interactions with cellular or membrane targets. From a regulatory perspective, only after specific risk identification and characterization should an equally specific safety threshold in relation to potential toxicity be defined., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Cristiano Colalto reports writing assistance was provided by Italian Medicines Agency. Cristiano Colalto reports a relationship with Italian Medicines Agency that includes: employment. The author declares no dditional relationships or activities. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

The long-term investment in new approach methodologies (NAMs) within the EU and other parts of the world is beginning to result in an emerging consensus of how to use information from in silico, in vitro and targeted in vivo sources to assess the safety of chemicals. However, this methodology is being adopted very slowly for regulatory purposes. Here, we have developed a framework incorporating in silico, in vitro and in vivo methods designed to meet the requirements of REACH in which both hazard and exposure can be assessed using a tiered approach. The outputs from each tier are classification categories, safe doses, and risk assessments, and progress through the tiers depends on the output from previous tiers. We have exemplified the use of the framework with three examples. The outputs were the same or more conservative than parallel assessments based on conventional studies. The framework allows a transparent and phased introduction of NAMs in chemical safety assessment and enables science-based safety decisions which provide the same level of public health protection using fewer animals, taking less time, and using less financial and expert resource. Furthermore, it would also allow new methods to be incorporated as they develop through continuous selective evolution rather than periodic revolution., (© 2022. The Author(s).)

Mushrooms exhibit a high ability to accumulate potentially toxic elements. The legal regulations in force in the European Union countries do not define the maximum content of elements in dried wild-grown mushrooms. This study presents the content of mercury (Hg), lead (Pb), cadmium (Cd) and arsenic (As) determined in dried wild-grown mushrooms (Boletus edulis and Xerocomus badius) available for sale. Moreover, the health risk associated with their consumption is assessed. The inductively coupled plasma mass spectrometry (Cd, Pb, As) and atomic absorption spectrometry (Hg) were used. The mean Hg, Cd, Pb and As concentration in Boletus edulis was 3.039±1.092, 1.983±1.145, 1.156±1.049 and 0.897±0.469 mg/kg and in Xerocomus badius 0.102±0.020, 1.154±0.596, 0.928±1.810 and 0.278±0.108 mg/kg, respectively. The maximum value of the hazard index (HI) showed that the consumption of a standard portion of dried Boletus edulis may have negative consequences for health and corresponded to 76.2%, 34.1%, 33% and 4.3% of the maximum daily doses of Hg, Cd, Pb and As, respectively. The results indicate that the content of toxic elements in dried wild-grown mushrooms should be monitored. The issue constitutes a legal niche where unfavourable EU regulations may pose a threat to food safety and consumer health., Competing Interests: The authors have declared that no competing interests exist.

The EU Directive 2010/63/EU   on the protection of animals used for scientific purposes and other EU regulations, such as REACH and the Cosmetic Products Regulation advocate for a change in the way toxicity testing is conducted. Whilst the Cosmetic Products Regulation bans animal testing altogether, REACH aims for a progressive shift from in vivo testing towards quantitative in vitro and computational approaches. Several endpoints can already be addressed using non-animal approaches including skin corrosion and irritation, serious eye damage and irritation, skin sensitisation, and mutagenicity and genotoxicity. However, for systemic effects such as acute toxicity, repeated dose toxicity and reproductive and developmental toxicity, evaluation of chemicals under REACH still heavily relies on animal tests. Here we summarise current EU regulatory requirements for the human health assessment of chemicals under REACH and the Cosmetic Products Regulation, considering the more critical endpoints and identifying the main challenges in introducing alternative methods into regulatory testing practice. This supports a recent initiative taken by the International Cooperation on Alternative Test Methods (ICATM) to summarise current regulatory requirements specific for the assessment of chemicals and cosmetic products for several human health-related endpoints, with the aim of comparing different jurisdictions and coordinating the promotion and ultimately the implementation of non-animal approaches worldwide. Recent initiatives undertaken at European level to promote the 3Rs and the use of alternative methods in current regulatory practice are also discussed.

Background: Today, a growing number of individuals with mild cognitive impairment (MCI) wish to assess their risk of developing Alzheimer's disease (AD) dementia. The expectations as well as the effects on quality of life (QoL) in MCI patients and their close others through biomarker-based dementia risk estimation are not well studied., Objective: The PreDADQoL project aims at providing empirical data on effects of such prediction on QoL and at developing an ethical and legal framework of biomarker-based dementia risk estimation in MCI., Methods: In the empirical study, 100 MCI-patients and their close others will be recruited from two sites (Germany and Spain). They receive standardized counselling on cerebrospinal fluid (CSF) biomarker-based prediction of AD dementia and a risk disclosure based on their AD biomarker status. A mixed methods approach will be applied to assess outcomes., Results: The pilot-study yielded a specification of the research topics and newly developed questionnaires for the main assessment. Within this binational quantitative and qualitative study, data on attitudes and expectations toward AD risk prediction, QoL, risk communication, coping strategies, mental health, lifestyle changes, and healthcare resource utilization will be obtained. Together with the normative part of the project, an empirically informed ethical and legal framework for biomarker-based dementia risk estimation will be developed., Conclusion: The empirical research of the PreDADQoL study together with the ethical and legal considerations and implications will help to improve the process of counselling and risk disclosure and thereby positively affect QoL and health of MCI-patients and their close others in the context of biomarker-based dementia risk estimation.

All the cells in our bodies are derived from the germ cells of our parents, just as our own germ cells become the bodies of our children. The integrity of the genetic information inherited from these germ cells is of paramount importance in establishing the health of each generation and perpetuating our species into the future. There is a large and growing body of evidence strongly suggesting the existence of substances that may threaten this integrity by acting as human germ cell mutagens. However, there generally are no absolute regulatory requirements to test agents for germ cell effects. In addition, the current regulatory testing paradigms do not evaluate the impacts of epigenetically mediated intergenerational effects, and there is no regulatory framework to apply new and emerging tests in regulatory decision making. At the 50th annual meeting of the Environmental Mutagenesis and Genomics Society held in Washington, DC, in September 2019, a workshop took place that examined the heritable effects of hazardous exposures to germ cells, using tobacco smoke as the example hazard. This synopsis provides a summary of areas of concern regarding heritable hazards from tobacco smoke exposures identified at the workshop and the value of the Clean Sheet framework in organizing information to address knowledge and testing gaps., (© 2020 The Authors. Environmental and Molecular Mutagenesis published by Wiley Periodicals LLC on behalf of Environmental Mutagen Society.)

Introduction: Cardiovascular disease (CVD) is the commonest cause of death across the globe; incidence and prevalence rates are increasing. Together, CVD and diabetes mellitus are responsible for a quarter of the health gap observed between Aboriginal Australians and Torres Strait Islanders, and non-Indigenous Australians. Numerous programs have been proposed and implemented to Close the Gap; ideally, these should be evidence-based., Objective: The aim of this review is to evaluate primary prevention measures and programs that aim to reduce CVD risk in minority Indigenous populations around the world., Methods: A search of PubMed, the Cochrane Library and the Elsevier Scopus Database was initially conducted using the terms "cardiovascular disease", "population groups", "primary prevention", "health services, indigenous", "indigenous health", "risk assessment" and "risk management". Results were then assessed per inclusion/exclusion criteria. A second reviewer independently evaluated the publications and review process to ensure agreement., Results: The initial search produced 37 publications; 19 met the inclusion criteria and were incorporated into a comparative table. Most were descriptive, mixed-methods, audit or intervention studies. Heterogeneity of study design prevented statistical analysis., Conclusion: Addressing CVD risk in minority Indigenous populations is a multifactorial challenge; there is substantial room for improvement in routine risk assessment and management. Holistic approaches need to embrace local cultural perceptions of health and wellbeing. Validated risk reduction tools, individualised management plans, polypills and computer based decision support tools are promising to improve outcomes for those at risk., (Copyright © 2019 Australian and New Zealand Society of Cardiac and Thoracic Surgeons (ANZSCTS) and the Cardiac Society of Australia and New Zealand (CSANZ). Published by Elsevier B.V. All rights reserved.)

Objectives: Annual completion of a Valproate Risk Acknowledgement Form (RAF) is mandated in the United Kingdom due to neurodevelopmental risks of in utero valproate exposure. The number of women of childbearing potential taking valproate, the uptake of the RAF within this population and their clinical outcomes is not known or monitored. This study surveyed responses of clinicians administering the RAF to women of childbearing potential taking valproate medications., Materials and Methods: Study design-national online survey distributed to clinical specialists throughout the United Kingdom via their national organizations. Participants-clinicians qualified to counsel and administer the valproate RAF (as defined by the Medicines and Healthcare products Regulatory Agency). Main outcome measures-quantitative and qualitative responses regarding identification, uptake, effects and reactions to the RAF. Trial registration-registered at the Clinical Governance and Audit Committee at Royal Free London NHS Foundation Trust Hospital., Results: 215 respondents covering more than 4775 patient encounters were captured. Most patients continued on valproate, 90% with epilepsy as the indication. Respondents reported that seizure control deteriorated when switched to levetiracetam (33%) and lamotrigine (43%), compared to 7% when continuing valproate (P < .001)., Conclusions: 33%-43% of clinicians reported seizure control deterioration in women changed to alternatives to valproate. Informed consent requires women considering a change are given this information. Systematic capture of data automated through online RAFs and linked to patient outcomes is needed. There remains little data on valproate given for indications other than epilepsy., (© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

The Charlie Gard and Alfie Evans cases were high-profile cases involving disagreements between the parents of young infants and medical practitioners, which have given impetus to pre-existing calls for law reform that have been rebranded as 'Charlie's Law' and 'Alfie's Law'. I argue against the proposal to replace the best interest test, which is currently determinative in such contentious cases, with a significant harm test, as it would render UK law divergent from international law. I also employ critical theory to rebut the notion that parents are the best decision makers and refute criticisms of clinicians (who reflexively acknowledged the limits of medicine). I utilise theories of distributive justice to demonstrate that legal reform may exacerbate unfairness, and case law to show that it may be unworkable. Nonetheless, I apply critical and Foucauldian theory to critique the lack of patient and public empowerment within the NHS and I endorse the proposal to ensure that mediation is offered in contentious cases, as this may empower patients and their carers. I also aver that the best interests test should be informed by clearer criteria regarding the allocation of finite resources, which the public should influence via the democratisation of the NHS., (© The Author(s) 2019. Published by Oxford University Press; All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objective: The extent to which psychiatric diagnosis, treatment compliance, and violence risk influenced judges perceived benefits of Mental Health Court ("MHC") for defendants with psychiatric disorders was examined., Method: 81 judges completed one vignette in which psychiatric diagnosis (Schizophrenia, Major Depressive Disorder, Posttraumatic Stress Disorder), treatment compliance (yes/no), and violence risk (high/low) were randomized. The online survey was distributed via email and following the vignette, judges answered a question about the appropriateness of MHC., Results: Judges assessed defendants with severe psychiatric disorders (Schizophrenia and Major Depressive Disorder) - compared to defendants with PTSD - as more likely to benefit from MHCs. If deemed at low treatment compliance and/or high violence risk, judges were unlikely to appraise MHCs as beneficial, regardless of psychiatric diagnosis., Implications: Judges appear to consider relevant factors when determining whether MHC will benefit defendants with psychiatric disorders; however, future research should include more variables (e.g., addictions, history of violence) to examine the combined influence on judges' perception of MHC suitability., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

We discuss options to reform the EU genetically modified organism (GMO) regulatory framework, make risk assessment and decision-making more consistent with scientific principles, and lay the groundwork for international coherence. In this third of three articles, we focus on labeling and coexistence as well as discuss the political reality and potential ways forward., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Here, we discuss options to reform the EU genetically modified organism (GMO) regulatory framework, to make risk assessment and decision-making more consistent with scientific principles, and to lay the groundwork for international coherence. We discussed the scope and definitions in a previous article and, thus, here we focus on the procedures for risk assessment and risk management., (Copyright © 2019. Published by Elsevier Ltd.)

This study measured the exposure to different categories of medicinal products discussed by the European Union (EU) Pharmacovigilance Risk Assessment Committee from September to November 2018 in four electronic primary care health databases: IQVIA Medical Research Data-UK, IQVIA Medical Research Data-France, IQVIA Medical Research Data-Germany, and Clinical Practice Research Datalink Aurum, in the entire lifespan of each database until August 31, 2018. The assessment of 83 centrally authorized products and 45 nationally authorized products showed that coverage was better for products marketed for longer duration and worse for orphan drugs. The ability to detect associations against hypothetical comparators was better for more common events and for larger effect sizes. Coverage of advanced therapies was worse for those typically administered in a specialized rather than primary care setting. This study shows that to enable better informed regulatory decisions there is a need to access complementary data sources, particularly capturing secondary care prescribing., (© 2020 European Medicines Agency. Clinical Pharmacology & Therapeutics published by Wiley Periodicals, Inc. on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Coronary artery disease is the leading cause of morbidity and mortality. Tools have been developed to accurately diagnose and evaluate coronary artery disease. Coronary CT angiography (CCTA) provides detailed imaging to deliver precise analysis and prognostic information. We sought to compare the radiation dose from a 256-detector-row CT scanner with that from a 64-detector-row CT scanner across a similar profile of patients. Methods: Consecutive patients were screened for the Converge Registry study and, after consenting to be included, were enrolled in accordance with an Institutional Review Board-approved protocol. A control group who underwent 64-row CCTA were matched by age, sex, and body mass index (BMI) with a group who underwent 256-row CCTA. Results: We compared 110 patients in each group. We found that mean dose-length product (DLP) was significantly lower in the 256-row group than in the 64-row group ( P < 0.05). The radiation dose was reduced by 32% with use of the 256-row scanner for BMIs of 18.5-24.9 (DLP, 111.2 vs. 76.1 mGy-cm [1.56 vs. 1.07 mSv]; P < 0.05). For each BMI subgroup, there was a significant decrease in dose. Regression analysis found that with increasing BMIs, DLP significantly increased for both scanners. Conclusion: The 256-row scanner provided CCTA scans at significantly lower radiation doses than the 64-row scanner in different BMI groups, with all other variables accounted for. Lower radiation exposure along with lower contrast requirements can provide images with high diagnostic accuracy and less risk to the patient., (© 2020 by the Society of Nuclear Medicine and Molecular Imaging.)

The Risk Assessment Program (RAP) at Fox Chase Cancer Center (Philadelphia, PA) is a multi-generational prospective cohort, enhanced for personal and family history of cancer, consisting of over 10,000 individuals for whom data on personal and family history of cancer, risk factors, genetic and genomic data, health behaviors, and biospecimens are available. The RAP has a broad research agenda including the characterization of genes with known or potential relevance to cancer, gene-gene and gene-environment interactions, and their contribution to clinically useful risk assessment and risk reduction strategies. Increasingly, this body of research is identifying genetic changes which may have clinical significance for RAP research participants, leading us to confront the issue of whether to return genetic results emerging from research laboratories. This review will describe some of the important fundamental points that must be debated as we develop a paradigm for return of research results. The key issues to address as the scientific community moves toward adopting a policy of return of research results include the best criteria for determining which results to offer, the consent document components necessary to ensure that the participant makes a truly informed decision about receiving their results, and associated logistical and cost challenges. See all articles in this Special Collection Honoring Paul F. Engstrom, MD, Champion of Cancer Prevention ., (©2020 American Association for Cancer Research.)

Background: The Food Quality Protection Act of 1996, or FQPA, required the Environmental Protection Agency to set allowable levels for pesticides in a way that would "ensure that there is a reasonable certainty that no harm will result to infants and children from aggregate exposure to the pesticide chemical residue." The act stipulated that an additional tenfold margin of safety for pesticide risk assessments shall be applied to account for pre- and postnatal toxicity and for any data gaps regarding pesticide exposure and toxicity, unless there are reliable data to demonstrate that a different margin would be safe for infants and children., Discussion: To examine the implementation of the FQPA-mandated additional margin of safety, this analysis reviews 59 pesticide risk assessments published by the EPA between 2011 and 2019. The list includes 12 pesticides used in the largest amount in the U.S.; a group of 35 pesticides detected on fruits and vegetables; and 12 organophosphate pesticides. For the non-organophosphate pesticides reviewed here, the EPA applied an additional children's health safety factor in 13% of acute dietary exposure scenarios and 12% of chronic dietary exposure scenarios. For incidental oral, dermal and inhalation exposures, additional FQPA factors were applied for 15, 31, and 41%, respectively, of the non-organophosphate pesticides, primarily due to data uncertainties. For the organophosphate pesticides as a group, a tenfold children's health safety factor was proposed in 2015. Notably, in 2017 that decision was reversed for chlorpyrifos., Conclusions: For the majority of pesticides reviewed in this study, the EPA did not apply an additional FQPA safety factor, missing an opportunity to fully use the FQPA authority for protecting children's health.

Involuntary detention is used internationally to detain and treat people who are deemed to have a mental disorder. In England and Wales, approved mental health professionals (AMHPs) co-ordinate Mental Health Act assessments which allow for patients to be detained. AMHPs have legal duties to identify, inform and consult with a patient's nearest relative (NR), who are, in turn, given powers to initiate or challenge detention. Our study takes an original approach through examining how AMHPs interpret their duties towards nearest relatives. We adopted a two-stage design, which involved an online questionnaire with 55 AMHPs and focus group discussions with 33 AMHPs. The research was conducted in England between 2017 and 2018. Our questionnaire found that a high proportion of AMHPs reported that they had spoken to NRs for background information when assessing patients under the Mental Health Act. However, AMHPs were less likely to ask patients about their views of involving the NR prior to assessment. Focus group findings showed that AMHPs saw the NR role as offering an important 'safeguard' on the basis that NRs could provide information about the patient and advocate on their behalf. AMHPs identified practical difficulties in balancing their legal obligation towards NRs and patients; particularly where issues of potential abuse were raised or where patients had identified that they did not want NR involvement. While AMHPs stated that they sought to prioritise patient wishes regarding confidentiality, their accounts identified that patient consent about information sharing was sometimes implied rather than sought explicitly. Our findings reinforce conclusions by the recent Independent Review of the MHA, which states that current NR provisions are 'outdated, variable and insufficient'. We identify that current practice could be improved using advanced choice documents and outline implications for AMHP practice., (© 2019 John Wiley & Sons Ltd.)

Importance: Few gynecologic surgeons understand the mechanism by which surgical instruments are approved for human use and marketing or do they appreciate the central role they play in postmarket surveillance and reporting after instruments have come to market., Objective: Using the experience with the uterine morcellator, this review will detail the Food and Drug Administration (FDA) system for approving surgical instruments and the potential pitfalls of this process., Evidence Acquisition: Literature review and public documents from the FDA., Results: The FDA 510(k) approval process for surgical instruments relies largely on postmarket surveillance as exemplified by the uterine power morcellator, which was approved before sufficient evidence was available regarding its potential harms., Conclusions: The current system currently transfers the responsibility of ensuring safety and efficacy to the public, patients, and providers. To minimize potential harm, the FDA needs to incorporate a greater standard of evidence into its framework for the approval and regulation of medical devices. The burden of these requirements should be borne at least in part by the companies bringing equipment to market., Relevance: It is incumbent on all surgeons to be vigilant in their objective critical assessment of new instrumentation and report their outcomes after they come to market.

Recent guidance on safety monitoring during drug development, issued by regulatory authorities in the United States and European Union, indicate a shift in focus towards aggregate safety monitoring and scientific evaluation of integrated safety data. The call for program-level reviews of accumulating safety data, including from ongoing studies, provides an opportunity to leverage the scientific expertise and medical judgment of safety management teams with (a) a multidisciplinary approach, (b) quantitative frameworks to measure level of evidence, and (c) assessments that are product-specific and driven by medical judgment. A multidisciplinary team, regularly reviewing aggregate safety data throughout the development program, is vital not only for early signal detection but also for generating a better understanding of the accumulating data and context needed for decreasing false alarms., (© 2019 John Wiley & Sons, Ltd.)

Objective: In inpatient forensic settings, a psychiatrist is expected to wear 'Two Hats', as a treating physician and as an expert to provide risk assessments and expert advice to the judicial authorities for leave and release decisions. Although dual roles have long been accepted as an inevitable part of independent forensic practice, there are additional ethical challenges for the treating psychiatrist to provide an expert opinion. This paper examines the specific ethical ambiguities for a treating psychiatrist at the interface of legal process related to leave and release decisions in the treatment of forensic patients., Conclusions: While respect for justice is the prevailing ethical paradigm for court-related forensic work, the medical paradigm should remain the key ethical framework for psychiatrists in treatment settings. Thus, psychiatrist should be aware of possible adverse consequences in acting as forensic experts for their patients. A conscientious adherence to clinical facts and awareness of the 'Two Hats' ethical pitfall can serve as important reference points in framing the psychiatric evidence in the decision-making process and safeguard treating psychiatrist's role.

Background: This study compares standard regulatory methodology (fixed scenarios and models) to spatial modelling at a 1 km landscape resolution for the evaluation of predicted environmental concentrations of pesticides in groundwater. The use of spatial modelling in the decision-making processes is discussed and three options for the sub-national evaluation and restriction of substances based on spatial environmental fate modelling are examined. Wheat and sugar beet are tested with two modified FOCUS substances (A and D) in the PEARL and GeoPEARL models. The 80th percentile value in time and space, aggregated to three different sub-national divisions of interest to a regulator, is used as a regulatory relevant output., Results: Means and medians of predicted environmental concentrations at the national level are not useful summary statistics in the age of extensive and freely available geospatial data. A better statistic to use is the P80 (or other desired threshold/percentile combination) in time and space of predicted environmental concentration, combined with flexible and adaptable sub-divisions of the country based on the desired protective target., Conclusion: Tier 3b modelling is shown to provide an increase in localism and regulatory nuance over Tier 1 scenarios when combined with soil and aquifer type sub-national units. © 2019 Society of Chemical Industry., (© 2019 Society of Chemical Industry.)

Purpose: Recent public health safety issues involving medical devices have led to a growing demand to improve the current passive-reactive postmarket surveillance (PMS) system. Various European Union (EU) national competent authorities have started to focus on strengthening the postmarket risk evaluation. As a consequence, the new EU medical device regulation was published; it includes the concept of a PMS Plan., Methods: This publication reviewed Annex III Technical Documentation on PMS and Annex XIV Part B: Postmarket clinical follow-up from the new Regulation (EU) 2017/745 of the European Parliament and of the Council on medical devices., Results: The results of the PMS activities will be described in the PMS plan and will be used to update other related documents. A modular approach to structure the contents of the PMS plan will help to consistently update other PMS information. It is our suggestion that the PMS plan should consist of a PMS plan Core and a PMS plan Supplement. The PMS plan Core document will describe the PMS system, and the PMS plan Supplement will outline the specific activities performed by the manufacturer for a particular medical device., Conclusions: The PMS plan may serve as a thorough tool for the benefit-risk evaluation of medical devices. If properly developed and implemented, it will function as a key player in the establishment of a new framework for proactive safety evaluation of medical devices., (© 2019 The Authors. Pharmacoepidemiology and Drug Safety Published by John Wiley & Sons Ltd.)

This article summarizes historic developments, recent expert opinions, and (currently) unresolved challenges concerning the Biopharmaceutics Classification System (BCS)-based Biowaiver. An overview of approval statistics and application potential, case examples addressing the discriminatory power of the procedure, as well as an outlook on possible refinements in the future are provided and critically discussed. Over the last decade, regulatory guidance documents have been harmonized, for example, following scientific consent on allowing biowaivers for BCS class III drugs, making over 50% of orally administered drugs on the World Health Organization Essential Medicines List eligible for an abbreviated approval. Biowaiver monographs that present a complete risk-benefit evaluation for individual drugs have been issued by the International Pharmaceutical Federation for more than 25% of those drugs with the long-range aim of covering all essential drugs. Unresolved issues that have emerged from reported examples of false-negative and false-positive outcomes in the literature demand further adjustments to the regulatory requirements. Possible solutions for resolving these issues are the use of modeling and simulation and refined biorelevant in vitro tests that are better able to discriminate between dosage forms with unequal performance in vivo, potentially allowing biowaivers for selected BCS II drugs., (Copyright © 2019 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.)

Using the European Union's Registration, Evaluation, Authorisation and Restriction of Chemicals (REACH) ecotoxicity data, this paper compares 3 different approaches to calculate final substance toxicity hazard values using the USEtox approach (chronic EC50 + acute EC50/2), using only acute EC50 equivalent data (EC50 eq ), and using only chronic no observed effect concentration equivalent (NOEC eq) data. About 4008, 4853, and 5560 substance hazard values could be calculated for the USEtox model, acute only, and chronic only approaches, respectively. The USEtox model provides hazard values similar to the ones based on acute EC50 data only. Although there is a large amount of variability in the ratios, the data support acute EC50 eq to chronic NOEC eq ratios (calculated as geometric mean) of 10.64, 10.90, and 4.21 for fish, crustaceans, and algae respectively. Comparison of the calculated hazard values with the criteria used by the EU chemical Classification, Labelling, and Packaging regulation (CLP) shows the USEtox model underestimates the number of compounds categorized as very toxic to aquatic life and/or having long-lasting effects. In contrast, use of the chronic NOEC data shows a good agreement with CLP. It is therefore proposed that chronic NOEC eq are used to derive substance hazard values to be used in the EU Environmental Footprint. Due to poor data availability for some chemicals, the uncertainty of the final hazard values is expected to be high. Integr Environ Assess Manag 2019;15:796-807. © 2019 The Authors. Integrated Environmental Assessment and Management published by Wiley Periodicals, Inc. on behalf of Society of Environmental Toxicology & Chemistry (SETAC)., (© 2019 The Authors. Integrated Environmental Assessment and Management published by Wiley Periodicals, Inc. on behalf of Society of Environmental Toxicology & Chemistry (SETAC).)

Recent advances in Machine Learning (ML) have the potential to revolutionise psychosis prediction and psychiatric assessment. This article has two objectives. First, it clarifies which aspects of English Law are relevant in order to regulate the use of ML in clinical research on psychosis prediction. It is argued that its lawful implementation will depend upon the legal requirements regarding the balance between potential harms and benefits, particularly with reference to: (i) any additional risks introduced by the use of ML for data analysis and outcome prediction; and (ii) the inclusion of vulnerable research populations such as minors or incapacitated adults. Second, this article investigates how clinical prediction via ML might affect the practice of risk assessment under mental health legislation, with reference to English Law. It is argued that there is a potential for virtuous applications of clinical prediction in psychiatry. However, reaffirming the distinction between psychosis risk and risk of harm is paramount. Establishing psychosis risk and assessing a person's risk of harm are discrete practices, and so should remain when using artificial intelligence for psychiatric assessment. Evaluating whether clinical prediction via ML might benefit individuals with psychosis will depend on which risk we try to assess and on what we try to predict, whether this is psychosis transition, a psychotic relapse, self-harm and suicidality, or harm to others., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

The European Union Environmental Footprint (EU-EF) is a harmonized method to measure and communicate the life cycle environmental performance of products and organizations. Among 16 different impact categories included in the EU-EF, 1 focuses on the impact of substances on freshwater ecosystems and requires the use of toxicity data. This paper evaluates the use of the aquatic toxicity data submitted to the EU Registration, Evaluation, Authorisation and Restriction of Chemicals (REACH) regulation. It presents an automated computerized approach for selecting substance ecotoxicity values, building on a set of quality and reliability criteria to extract the most relevant data points for calculating the substance specific hazard values. A selected set of criteria led to the exclusion of approximately 82% of the original REACH ecotoxicological data available as of May 2015 due to incomplete initial encoding of the data by the REACH registrant, missing information such as duration of exposure, endpoint measured, species tested, and imprecise toxicity values (i.e., reported with greater than or less than signs). From an initial set of 305 068 ecotoxicity data records available in the REACH database, the final usable database contains 54 353 toxicity records (29 421 characterized as acute and 24 941 as chronic) covering 9 taxonomic groups, with algae, crustaceans, and fish representing 93% of the data. This data set is valuable for assessing the environmental toxicity of the substance contained whether through traditional substance risk assessment, product toxicity labeling, life cycle assessment (LCA) or environmental impact assessment approaches. However, the resulting loss of approximately 82% of the data suggests that changes in procedures used to generate, report, and document the data within REACH are needed to improve data utility for the various assessment approaches. The rules used to select the data to be used are the primary focus of this article. Integr Environ Assess Manag 2019;15:783-795. © 2019 The Authors. Integrated Environmental Assessment and Management published by Wiley Periodicals, Inc. on behalf of Society of Environmental Toxicology & Chemistry (SETAC)., (© 2019 The Authors. Integrated Environmental Assessment and Management published by Wiley Periodicals, Inc. on behalf of Society of Environmental Toxicology & Chemistry (SETAC).)

This paper presents a descriptive review of laws and regulations on the management of drugs and the residues thereof adopted by countries in Europe, the Americas and Australia. This review integrates relevant points of official documents of regulatory agencies in these countries, as well as important scientific works. All countries surveyed carry out drug management concomitant with the management of the residues thereof, ranging from awareness programs on the rational use and the risks of drugs through to the collection and safe disposal of such residues. Germany, the USA and Sweden demand a prior assessment of the environmental impact caused by a given drug as a criterion for its registration. Sweden is noteworthy in that it periodically updates a list of essential drugs based on risk assessment and the environmental risks posed by the residues thereof. In Brazil, the legal measures proposed including rational prescription and reverse logistics have not yet been effectively implemented. Prior environmental impact assessment safeguards the risks to human health and the wild biota caused by exposure to drug residues. Therefore, these international models could serve as a basis for discussion and/or legal and regulatory changes in Brazil.

The indication for MitraClip (Abbott Vascular, Santa Clara, CA, USA) in the USA is degenerative mitral regurgitation (DMR), but the Japanese indication includes both DMR and functional mitral regurgitation (FMR), in patients without severe left ventricular dysfunction. One of the reasons for this difference is that the Japanese Circulation Society submitted a formal request to the Japanese government for early approval of MitraClip for both DMR and FMR on the basis of unmet medical need for MR patients resistant to medical therapy, but at prohibitive risk for mitral valve surgery. Here, we describe the regulatory approval review process of MitraClip in Japan. Clinical data from outside Japan indicated that MitraClip provides significant improvements from baseline in New York Heart Association Class and hospitalizations for heart failure due to the reduction of MR grade without adversely affecting long-term prognosis in FMR patients as well as DMR patients. Also, a Japanese domestic trial showed a favorable acute procedural success rate without serious adverse events with MitraClip in both DMR and FMR patients. Further, it is considered in Japan that improvement of MR mechanically is clinically important in both DMR and FMR, in patients without severe left ventricular dysfunction. On the basis of these considerations, the MitraClip was approved in Japan for indications of both DMR and FMR with preserved cardiac function in patients at prohibitive risk for mitral valve surgery., (Copyright © 2019 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.)

Importance: Given high rates of opioid-related fatal overdoses, improving naloxone access has become a priority. States have implemented different types of naloxone access laws (NALs) and there is controversy over which of these policies, if any, can curb overdose deaths. We hypothesize that NALs granting direct authority to pharmacists to provide naloxone will have the greatest potential for reducing fatal overdoses., Objectives: To identify which types of NALs, if any, are associated with reductions in fatal overdoses involving opioids and examine possible implications for nonfatal overdoses., Design, Setting, and Participants: State-level changes in both fatal and nonfatal overdoses from 2005 to 2016 were examined across the 50 states and the District of Columbia after adoption of NALs using a difference-in-differences approach while estimating the magnitude of the association for each year relative to time of adoption. Policy environments across full state populations were represented in the primary data set. The association for 3 types of NALs was associated: NALs providing direct authority to pharmacists to prescribe, NALs providing indirect authority to prescribe, and other NALs. The study was conducted from January 2017 to January 2019., Exposures: Fatal and nonfatal overdoses in states that adopted NAL laws were compared with those in states that did not adopt NAL laws. Further consideration was given to the type of NAL passed in terms of its association with these outcomes. We hypothesize that NALs granting direct authority to pharmacists to provide naloxone will have the greatest potential for reducing fatal overdoses., Main Outcomes and Measures: Fatal overdoses involving opioids were the primary outcome. Secondary outcomes were nonfatal overdoses resulting in emergency department visits and Medicaid naloxone prescriptions., Results: In this evaluation of the dispensing of naloxone across the United States, NALs granting direct authority to pharmacists were associated with significant reductions in fatal overdoses, but they may also increase nonfatal overdoses seen in emergency department visits. The effect sizes for fatal overdoses grew over time relative to adoption of the NALs. These policies were estimated to reduce opioid-rated fatal overdoses by 0.387 (95% CI, 0.119-0.656; P = .007) per 100 000 people in 3 or more years after adoption. There was little evidence of an association for indirect authority to dispense (increase by 0.121; 95% CI, -0.014 to 0.257; P = .09) and other NALs (increase by 0.094; 95% CI, -0.040 to 0.227; P = .17)., Conclusions and Relevance: Although many states have passed some type of law affecting naloxone availability, only laws allowing direct dispensing by pharmacists appear to be useful. Communities in which access to naloxone is improved should prepare for increases in nonfatal overdoses and link these individuals to effective treatment.

Few clinical practices are as important for simultaneously augmenting patient safety and mitigating legal risk as the judicious evaluation and stratification of a patient's risk for suicide, proportionate clinical actions based thereon taken by the healthcare provider, and contemporaneous documentation of the foregoing. In this article, we draw from our combined decades of multidisciplinary experience as a clinical psychologist, forensic psychiatrist, medical malpractice attorney, and clinical psychology trainee to discuss the documentation of suicide risk assessment and management as a conduit to patient safety and legal risk mitigation. We additionally highlight documentation as a core clinical competency across disciplines and note areas of improvement, such as increased training, to bolster documentation practices., (© 2019 John Wiley & Sons, Ltd.)

For decades, our ability to predict suicide has remained at near-chance levels. Machine learning has recently emerged as a promising tool for advancing suicide science, particularly in the domain of suicide prediction. The present review provides an introduction to machine learning and its potential application to open questions in suicide research. Although only a few studies have implemented machine learning for suicide prediction, results to date indicate considerable improvement in accuracy and positive predictive value. Potential barriers to algorithm integration into clinical practice are discussed, as well as attendant ethical issues. Overall, machine learning approaches hold promise for accurate, scalable, and effective suicide risk detection; however, many critical questions and issues remain unexplored., (© 2019 John Wiley & Sons, Ltd.)

Custodial suicide is a foundational concern for correctional systems. The incarcerated population is at an increased risk for suicide as compared with people living in the community. Sufficient suicide prevention is a critical component of a constitutionally adequate system of correctional mental health care. The remedial phases of class action litigations have animated improvement in suicide prevention in many correctional systems across the United States. In the current climate, many legal obstacles make it more difficult for plaintiffs to prevail in such cases, but it is expected that advocates will find novel approaches in response to these legal hurdles, such as greater reliance on state law remedies, and will seek to expand the scope of potential actions in emerging areas such as immigration detention. Defendants and courts will, in turn, need to respond to these changes. This article explores the history of relevant litigations, and the legal obstacles currently faced by plaintiffs, as well as future directions the authors consider will likely be taken. Practical issues such as appropriate measurement of improvement in the area of suicide prevention are also explored., (© 2019 John Wiley & Sons, Ltd.)

The European Court of Justice's recent ruling that the new techniques for crop development are to be considered as genetically modified organisms under the European Union's regulations exacerbates the need for a critical evaluation of those regulations. The paper analyzes the regulation from the perspective of moral and political philosophy. It considers whether influential arguments for restrictions of genetically modified organisms provide cogent justifications for the policies that are in place, in particular a pre-release authorization requirement, mandatory labelling, and de facto bans (in the form of withholding or opting out of authorizations). It is argued that arguments pertaining to risk can justify some form of pre-release authorization scheme, although not necessarily the current one, but that neither de facto bans nor mandatory labelling can be justified by reference to common arguments concerning naturalness, agricultural policy (in particular the promotion of organic farming), socio-economic effects, or consumers' right to choose.

The United States Environmental Protection Agency (US EPA) has recently proposed changes to strengthen the transparency of its pivotal regulatory science policy and procedures. In this context, the US EPA aims to enhance the transparency of dose-response data and models, proposing to consider for the first time non-linear biphasic dose-response models. While the proposed changes have the potential to lead to markedly improved ecological risk assessment compared to past and current approaches, we believe there remain open issues for improving the quality of ecological risk assessment, such as the consideration of adaptive, dynamic and interactive effects. Improved risk assessment including adaptive and dynamic non-linear models (beyond classic threshold models) can enhance the quality of regulatory decisions and the protection of ecological health. We suggest that other countries consider adopting a similar scientific-regulatory posture with respect to dose-response modeling via the inclusion of non-linear biphasic models, that incorporate the dynamic potential of biological systems to adapt (i.e., enhancing positive biological endpoints) or maladapt to low levels of stressor agents., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Despite the importance of health vulnerability in disaster risk assessment, most of the existing disaster vulnerability indicators only emphasize economic and social vulnerability. Important underlying health risks such as non-communicable disease are not included in vulnerability measures. A three-phase methodology approach was used to construct a disaster risk model that includes a number of key health indicators which might be missing in global disaster risk analysis. This study describes the development of an integrated health vulnerability index and explains how the proposed vulnerability index may be incorporated into an all-hazard based disaster risk index in the Belt and Road Initiative (BRI), also known as the "Silk Road Economic Belt", region. Relevant indicators were identified and reviewed in the published literature in PubMed/Medline. A two-stage dimension reduction statistical method was used to determine the weightings of relevant dimensions to the construction of the overall vulnerability index. The proposed final health vulnerability index included nine indicators, including the proportion of the population below 15 and above 65 years, under-five mortality ratio, maternal mortality ratio, tuberculosis prevalence, age-standardized raised blood pressure, physician ratio, hospital bed ratio, and coverage of the measles-containing-vaccine first-dose (MCV1) and diphtheria tetanus toxoid and pertussis (DTP3) vaccines. This proposed index, which has a better reflection of the health vulnerability in communities, may serve as a policy and implementation tool to facilitate the capacity-building of Health-Emergency Disaster Risk management (Health-EDRM).

EU regulations call for the use of alternative methods to animal testing. During the last decade, an increasing number of alternative approaches have been formally adopted. In parallel, new 3Rs-relevant technologies and mechanistic approaches have increasingly contributed to hazard identification and risk assessment evolution. In this changing landscape, an EPAA meeting reviewed the challenges that different industry sectors face in the implementation of alternative methods following a science-driven approach. Although clear progress was acknowledged in animal testing reduction and refinement thanks to an integration of scientifically robust approaches, the following challenges were identified: i) further characterization of toxicity pathways; ii) development of assays covering current scientific gaps, iii) better characterization of links between in vitro readouts and outcome in the target species; iv) better definition of alternative method applicability domains, and v) appropriate implementation of the available approaches. For areas having regulatory adopted alternative methods (e.g., vaccine batch testing), harmonised acceptance across geographical regions was considered critical for broader application. Overall, the main constraints to the application of non-animal alternatives are the still existing gaps in scientific knowledge and technological limitations. The science-driven identification of most appropriate methods is key for furthering a multi-sectorial decrease in animal testing., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

Psychologists and other mental health clinicians are often called upon to assess violence and suicide risk. Access to firearms has important implications for client safety, but most psychologists report receiving little or no training on discussing firearms with clients in the context of delivering psychological services such as screening, assessment, or psychotherapy. Understanding the extent to which firearm legislation limits legal firearm ownership among people with mental illness can help clinicians identify and respond to situations in which people at high risk for violence may legally own or acquire a firearm. In this article, we discuss three clinical cases and review firearm legislation as it pertains to people with mental illness. (PsycINFO Database Record (c) 2018 APA, all rights reserved).

Aims: Additional risk minimization measures (aRMMs) may be needed to ensure that the benefits continue to outweigh the risks for medicines associated with serious risks. Prior research showed an increasing trend in medicines with aRMMs. We assessed whether the European pharmacovigilance legislation may have impacted the number and type of aRMMs., Methods: We included new active substances approved between 1 January 2010 and 31 December 2015. Information extracted from the summary of the Risk Management Plan at the time of licensing included date and type of marketing authorization, presence and type of aRMMs. We tested for differences using Pearson's Χ 2 test and segmented Poisson regression., Results: We identified 231 medicines approved during the study period, of which 30% had aRMMs at the time of licensing. ARMMs were in place for 38% of medicines before July 2012 and for 28% after (p = 0.16). Segmented Poisson regression did not show changes in trend or level of medicines with aRMMs., Discussion and Conclusion: During the study period, no significant differences in the proportion or trend of products with aRMMs at the time of licensing before and after the pharmacovigilance legislation were identified.

During the past four decades, a number of social science scholars have conceptualized technological disasters as a social problem. More specifically, research in this arena has identified individual and collective stress as a secondary trauma of processes intended to provide compensation and economic relief from disasters in general and, more specifically, technological disasters. Based on data from a 2013 household telephone survey of 1,216 residents of coastal Alabama, this article examines the relationship between psychosocial stress and compensation processes related to the 2010 BP Deepwater Horizon oil spill. We examine involvement with claims, settlement, and litigation activities; vulnerability and exposure to the spill; ties to resources; resource loss and gain; perceptions of risk and recreancy; and intrusive stress and avoidance behaviors as measured by the impact of event scale. Regression analysis reveals that the strongest contributors to intrusive stress were being part of the compensation process, resource loss, concerns about air quality, and income. Although being involved with compensation processes was a significant predictor of avoidance behaviors, the strongest contributors to avoidance behaviors were resource loss, air quality concern, income, being male, minority status, and community attachment. Beliefs that the compensation process was as distressing as the oil spill also significantly contributed to intrusive stress and avoidance behaviors. This research represents a step toward filling a gap in empirical evidence regarding the extent to which protracted compensation processes exacerbate adverse psychosocial impacts of disasters and hinder community recovery., (© 2018 Society for Risk Analysis.)

Over recent years, the psychiatric sector has endeavoured to develop community-based care. Paradoxically, the number of compulsory hospitalisations is increasing. At the same time, the legal framework is evolving and measures relating to the deprivation of liberty in the context of psychiatric care have given rise to extensive guidelines. The work of the French National Health Authority represents, in this context, a certain continuity, with regard to the legal, ethical and social discussions around restriction of liberty practices within psychiatric units. The main focus is on the prevention and management of violent outbursts., (Copyright © 2018 Elsevier Masson SAS. All rights reserved.)