Which Benefits Can Justify Risks in Research?

Research ethics committees (RECs) evaluate whether the risk-benefit ratio of a study is acceptable. Decentralized clinical trials (DCTs) are a novel approach for conducting clinical trials that potentially bring important benefits for research, including several collateral benefits. The position of collateral benefits in risk-benefit assessments is currently unclear. DCTs raise therefore questions about how these benefits should be assessed. This paper aims to reconsider the different types of research benefits, and their position in risk-benefit assessments. We first propose a categorization of research benefits, based on the types of benefits that can be distinguished from the literature and ethical guidelines. Secondly, we will reconsider the position of collateral benefits. We argue that these benefits are not fundamentally different from other benefits of research and can therefore be included in risk-benefit assessments of DCTs.

Analytic and heuristic process for prudent antimicrobial use in animals: What are triggers and how do they work?

The over and misuse of antimicrobials in animal agriculture causes a prevailing crisis for humans, animals, and the environment. From the One Health approach perspective, the formation process of adopting prudent antimicrobial use (AMU), once established, can be used to mitigate this crisis. The study aimed to determine the analytic-based and heuristic-based process that evoked prudent AMU among animal farmers by synthesis of stimulus-organism-response framework and dual-system theory and to explore gender differences on risk-benefit trade-offs. A structural equation model was employed to test the proposed hypotheses with field survey data from 1100 small-scale farmers. The results reveal that for the analytic-based process, social influence, antimicrobial-related threats, and self-efficacy are all salient stimuli having indirect effects on intention via the two organisms of perceived risks and perceived benefits. For heuristic-based process, farmers' altruistic value orientations are positively associated with intention. An interesting fact is that threat awareness has two opposite effects on intention, namely, the suppression effect and the enhancement effect. Moreover, the negative effect of perceived risks on intention is greater among female farmers, compared to male counterparts. These findings provide valuable insights for the forming of theory-based intervention strategies to perfect China's national action plan.

Challenge Inoculum for Hepatitis C Virus Controlled Human Infection Model.

For any controlled human infection model (CHIM), a safe, standardized, and biologically relevant challenge inoculum is necessary. For hepatitis C virus (HCV) CHIM, we propose that human-derived high-titer inocula of several viral genotypes with extensive virologic, serologic, and molecular characterizations should be the most appropriate approach. These inocula should first be tested in human volunteers in a step-wise manner to ensure safety, reproducibility, and curability prior to using them for testing the efficacy of candidate vaccines.

Losing the balance in risk-benefit analysis.

The idea of a benefit-risk analysis has been used for decades, but no one has probably bothered to see if there is a ratio or even questioned the concept because it does give an intuitive sense. There are situations where the tendency to lose the balance between the risk and benefit has been observed to move either towards benefit alone or risk alone. This may happen in medicine for benefit alone and in the nuclear industry for risk alone when public perceptions are involved. For example, in medicine, when the risk is uncertain and/or may happen in the long term as against the benefit, which may be immediate, the tendency to ignore risk has been observed. On the other hand, accidents in the nuclear industry shadow the benefits of nuclear power, resulting in authorities abandoning nuclear power in some countries. Similarly, tissue reactions to patients in fluoroscopic guided interventions have been highlighted despite the fact that the stochastic risks in the same procedure may be tens of times higher. Attention has been drawn to the analogy of risks in pharmaceuticals as against radiation and better-developed system for drugs for us to learn from. This article describes situations of losing balance and provides motivation for the International Commission on Radiological Protection to develop solutions for situations that entail immediate benefits with long-term radiation risk, commonly encountered in medical exposure.

Apixaban Dosing Patterns Versus Warfarin in Patients With Nonvalvular Atrial Fibrillation Receiving Dialysis: A Retrospective Cohort Study.

BACKGROUND & OBJECTIVES: Comparison of clinical outcomes across anticoagulation regimens using different apixaban dosing or warfarin is not well-defined in patients with nonvalvular atrial fibrillation (AF) who are receiving dialysis. This study compared these outcomes in a US national cohort of patients with kidney failure receiving maintenance dialysis. STUDY DESIGN: Retrospective cohort study. SETTING & PARTICIPANTS: Patients receiving dialysis represented in the US Renal Data System database 2013-2018 who had AF and were treated with apixaban or warfarin. EXPOSURE: First prescribed treatment with apixaban dosed according to the label, apixaban dosed below the label, or warfarin. OUTCOME: Ischemic stroke/systemic embolism, major bleeding, and all-cause mortality. ANALYTICAL APPROACH: Cox proportional hazards models with inverse probability of treatment weighting. Analyses simulating an intention-to-treat (ITT) approach as well as those incorporating censoring at drug switch or discontinuation (CAS) were also implemented. Inverse probability of censoring weighting was used to account for possible informative censoring. RESULTS: Among 17,156 individuals, there was no difference in risk of stroke/systemic embolism among the label-concordant apixaban, below-label apixaban, and warfarin treatment groups. Both label-concordant (HR, 0.67 [95% CI, 0.55-0.81]) and below-label (HR, 0.68 [95% CI, 0.55-0.84]) apixaban dosing were associated with a lower risk of major bleeding compared with warfarin in ITT analyses. Compared with label-concordant apixaban, below-label apixaban was not associated with a lower bleeding risk (HR, 1.02 [95% CI, 0.78-1.34]). In the ITT analysis of mortality, label-concordant apixaban dosing was associated with a lower risk versus warfarin (HR, 0.85 [95% CI, 0.78-0.92]) while there was no significant difference in mortality between below-label dosing of apixaban and warfarin (HR, 0.97 [95% CI, 0.89-1.05]). Overall, results were similar for the CAS analyses. LIMITATIONS: Study limited to US Medicare beneficiaries; reliance on administrative claims to ascertain outcomes of AF, stroke, and bleeding; likely residual confounding. CONCLUSIONS: Among patients with nonvalvular AF undergoing dialysis, warfarin is associated with an increased risk of bleeding compared with apixaban. The risk of bleeding with below-label apixaban was not detectably less than with label-concordant dosing. Label-concordant apixaban dosing is associated with a mortality benefit compared to warfarin. Label-concordant dosing, rather than reduced-label dosing, may offer the most favorable benefit-risk trade-off for dialysis patients with nonvalvular AF.

Toward Informed User Decisions About Pharmacological Cognitive Enhancement.

Pharmacological cognitive enhancement (PCE) refers to the use of pharmaceuticals to improve cognitive function when that use is not intended to prevent or treat disease. Those who favour a liberal approach to PCE trust users to make informed decisions about whether enhancing is in their best interest. The author argues that making informed decisions about PCE requires a nuanced risk-benefit analysis that is not accessible to many users. Presently, the PCE use of prescription medications such as methylphenidate and modafinil is widespread but most commonly happens without medical supervision. Direct and indirect barriers generate a situation where the risks and benefits of PCE are inequitably distributed; as a result, PCE is sometimes not in the user's best interest. This is likely to also be the case for future pharmaceuticals. As a result, even if PCE pharmaceuticals were equitably distributed, its associated risks and benefits would not be. The article concludes with a discussion of the prospects of the clinical consultation on one hand, and e-health solutions on the other, in ameliorating the situation, arguing for cautious optimism.

Identification of information about adverse drug reactions in local medical journals using MEDLINE and Embase versus manual full text review.

INTRODUCTION: Collecting information about drugs in clinical practice is essential for ongoing riskbenefit analysis of the drug use. Medical literature is an important source of new information on drug safety, in particular for the signal assessment. A signal is an information about a new potentially causal association, or a new aspect of a known association (e.g. change in frequency or severity of the reaction) between a drug and an adverse event (AE). AIM OF THE STUDY: To verify the effectiveness of the identification of adverse drug reaction (ADR) reports published in the local medical literature using MEDLINE and Embase, versus manual full text review of journals. MATERIAL AND METHODS: The study was performed for 20 randomly selected drugs and 84 Polish medical journals and covers a review of 1,576 individual journal issues with 20,146 articles. Retrospective analysis of literature reports collected during manual full text review was performed and compared to the outcome of database search. RESULTS: ADRs for analyzed drugs were identified only in 17 out of 84 journals, as a result of which 66 reports were analyzed. The majority of reports (55%) were found in local non-indexed journals. Three reports originated from journals indexed in MEDLINE and 9 reports from journals indexed in Embase were not found in these databases because databases do not fully cover conference abstracts and journal supplements. Moreover, while using databases for ADR report search there is a risk of missing up to 30% of ADR reports. The average gap between article publication date and database entry was 119 days. CONCLUSIONS: We verified that the effectiveness of the identification of ADR reports published in the local medical literature is more accurate based on manual full text review than by searching in bibliographic databases.

Using a Composite Maternal-Infant Outcome Measure in Tuberculosis-Prevention Studies Among Pregnant Women.

BACKGROUND: Tuberculosis (TB-)-preventive therapy (TPT) among pregnant women reduces risk of TB in mothers and infants, but timing of initiation should consider potential adverse effects. We propose an analytical approach to evaluate the risk-benefit of interventions. METHODS: A novel outcome measure that prioritizes maternal and infant events was developed with a 2-stage Delphi survey, where a panel of stakeholders assigned scores from 0 (best) to 100 (worst) based on perceived desirability. Using data from TB APPRISE, a trial among pregnant women living with human immunodeficiency virus (WLWH) that randomized the timing of initiation of isoniazid, antepartum versus postpartum, was evaluated. RESULTS: The composite outcome scoring/ranking system categorized mother-infant paired outcomes into 8 groups assigned identical median scores by stakeholders. Maternal/infant TB and nonsevere adverse pregnancy outcomes were assigned similar scores. Mean (SD) composite outcome scores were 43.7 (33.0) and 41.2 (33.7) in the antepartum and postpartum TPT initiation arms, respectively. However, a modifying effect of baseline antiretroviral regimen was detected (P = .049). When women received nevirapine, composite scores were higher (worse outcomes) in the antepartum versus postpartum arms (adjusted difference, 14.3; 95% confidence interval [CI], 2.4-26.2; P = .02), whereas when women received efavirenz there was no difference by timing of TPT (adjusted difference, .62; 95% CI, -3.2-6.2; P = .53). CONCLUSIONS: For TPT, when used by otherwise healthy persons, preventing adverse events is paramount from the perspective of stakeholders. Among pregnant WLWH in high-TB-burden regions, it is important to consider the antepartum antiretroviral regimen taken when deciding when to initiate TPT. Clinical Trials Registration. NCT01494038 (IMPAACT P1078).

Applying a Risk-benefit Analysis to Outcomes in Tuberculosis Clinical Trials.

Although it is common to analyze efficacy and safety separately in clinical trials, this could yield a misleading study conclusion if an increase in efficacy is accompanied by a decrease in safety. A risk-benefit analysis is a systematic approach to examine safety and efficacy jointly. Both the "rank-based" and "partial-credit" methods described in this paper allow researchers to create a single, composite outcome incorporating efficacy, safety, and other factors. The first approach compares the distribution of rankings between arms. In the second approach, a score can be assigned to each outcome category, considering its severity and comparing the mean or median scores of arms. The methods were applied to the A5279/Brief Rifapentine-Isoniazid Efficacy for TB Prevention study, and design considerations for future clinical trials are discussed, including the challenge of arriving at a consensus on rankings/scorings. If well designed, a risk-benefit analysis may allow for a superiority comparison and, therefore, avoid setting a noninferiority margin. Clinical Trials Registration. NCT01404312 (A5279).

Use of Evidence-Based Herbal Medicines for Patients with Functional Gastrointestinal Disorders: A Conceptional Framework for Risk-Benefit Assessment and Regulatory Approaches.

BACKGROUND: Herbal or complementary medicines are frequently used for the treatment of patients with functional gastrointestinal disorders (FGID). Regulatory requirements for herbal therapies are inconsistent and, in many jurisdictions, herbal therapies are either self-, minimally- or unregulated. AIM: To provide guidance for the appropriate and safe use of herbal medicines in patients with FGID patients with special consideration of the regulatory frameworks. METHODS: A PubMed search of the literature was performed; relevant articles were included. RESULTS: Similar to chemically defined therapies herbal medicines can cause adverse events. Thus, a risk-benefit appraisal should be undertaken for these therapies. While there is no disease specific mortality in FGID patients, patients with FGID who fail to respond to "empiric" chemically defined therapies undergo diagnostic and therapeutic measures that can be associated with appreciable morbidity and mortality. Thus, effective herbal treatments that subsequently reduce health-care utilization, reduce risks related to diagnostic or therapeutic measures that are initiated if no improvement of symptoms occurs. This "protective" effect of effective treatments for FGID needs to be taken in consideration when the risks and benefits of treatments are determined. In addition, standards that mirror regulations for chemically defined treatments should apply and the components of the respective preparations should undergo ongoing toxicological testing and rigorous quality assurance measures (including pharmacovigilance) applied. CONCLUSIONS: Some herbal therapies offer significant benefits for patients with FGID. To ensure the safety of these treatments, the regulatory requirements should mirror requirements for chemically defined treatments.

Misrepresenting "Usual Care" in Research: An Ethical and Scientific Error.

Comparative effectiveness studies, referred to here as "usual-care" trials, seek to compare current medical practices for the same medical condition. Such studies are presumed to be safe and involve only minimal risks. However, that presumption may be flawed if the trial design contains "unusual" care, resulting in potential risks to subjects and inaccurately informed consent. Three case studies described here did not rely on clinical evidence to ascertain contemporaneous practice. As a result, the investigators drew inaccurate conclusions, misinformed research participants, and subjects' safety was compromised. Before approving usual-care protocols, IRBs and scientific review committees should evaluate the quality and completeness of information documenting usual-care practices. Guidance from governmental oversight agencies regarding evidence-based documentation of current clinical practice could prevent similar occurrences in future usual-care trials. Accurate information is necessary to ensure that trials comply with government regulations that require minimizing research risks to subjects and accurate informed consent documents.

Positive Public Health Ethics: Toward Flourishing and Resilient Communities and Individuals.

The COVID-19 pandemic is a global contagion of unprecedented proportions and health, economic, and social consequences. As with many health problems, its impact is uneven. This article argues the COVID-19 pandemic is a global health injustice due to moral failures of national governments and international organizations to prepare for, prevent and control it. Global and national health communities had a moral obligation to act in accordance with the current state of knowledge of pandemic preparedness. This obligation-a positive duty to develop and implement systems to reduce threats to and safeguard individuals' and, communities' abilities to flourish-stems from theories of global health justice and governance. The COVID-19 pandemic revealed and amplified the fragility and deficiencies in our global and domestic health institutions and systems. Moving forward, positive public health ethics is needed to set ethical standards for building and operating robust public health systems for resilient individuals and communities.

A simple tool for comparing benefits and 'costs' of COVID-19 exit strategies.

BACKGROUND: Governments and health policymakers are now looking for strategies to lift the COVID-19 lockdown, while reducing risk to the public. METHODS: We propose the population attributable risk (PAR) as an established epidemiological tool that could support decision-making through quickly estimating the main benefits and costs of various exit strategies. RESULTS: We demonstrate the feasibility of use of PAR using pandemic data, that were publicly available in mid-May 2020 from Scotland and the US, to estimate the proportion of COVID-19 hospital admissions which might be avoided, and the proportion of adverse labour market effects - for various scenarios - based on maintaining the lockdown for those of certain ages with and without comorbidities. CONCLUSION: These calculations could be refined and applied in different countries to inform important COVID-19 policy decisions, using routinely collected data.

[Studies on novel immune therapies: challenges from an ethical point of view]. / Studien zu neuen Immuntherapien: Herausforderungen aus Sicht der Ethik.

Novel immune therapies are more and more based on the molecular differentiation of disease patterns and related clinical studies are thus more often characterized by so-called adaptive study designs (umbrella or basket studies including platform studies), which are continuously adjusted based on novel results. This paper analyses new study designs beyond the often-postulated need for regulation in order to identify ethical problems based on typical structural features and to - whenever possible - suggest solutions. Additionally to the relationship between social and scientific values of a study as well as aspects of the scientific validity of new forms of evidence, the inclusion of study subjects under the condition of relative uncertainty, specific challenges in the process of ethical approval, as well as ethical and practical challenges in the process of informing patients and receiving informed consent will be addressed.

Deficiencies in Scientific Evidence for Medical Management of Gender Dysphoria.

Individuals who experience a gender identity that is discordant with biological sex are increasingly presenting to physicians for assistance in alleviating associated psychological distress. In contrast to prior efforts to identify and primarily address underlying psychiatric contributors to gender dysphoria, interventions that include uncritical social affirmation, use of gonadotropin-releasing hormone agonists to suppress normally timed puberty, and administration of cross-sex steroid hormones to induce desired secondary sex characteristics are now advocated by an emerging cohort of transgender medicine specialists. For patients with persistent gender dysphoria, surgery is offered to alter the appearance of breasts and genital organs. Efforts to address ethical concerns regarding this contentious treatment paradigm are dependent upon reliable evidence on immediate and long-term risks and benefits. Although strong recommendations have been made for invasive and potentially irreversible interventions, high-quality scientific data on the effects of this approach are generally lacking. Limitations of the existing transgender literature include general lack of randomized prospective trial design, small sample size, recruitment bias, short study duration, high subject dropout rates, and reliance on "expert" opinion. Existing data reveal significant intervention-associated morbidity and raise serious concern that the primary goal of suicide prevention is not achieved. In addition to substantial moral questions, adherence to established principles of evidence-based medicine necessitates a high degree of caution in accepting gender-affirming medical interventions as a preferred treatment approach. Continued consideration and rigorous investigation of alternate approaches to alleviating suffering in people with gender dysphoria are warranted. SUMMARY: This paper provides an overview of what is currently known about people who experience a gender identity that differs from their biological sex and the associated desire to engage the medical profession in alleviating associated discomfort and distress. The scientific evidence used to support current recommendations for affirming one's preferred gender, halting normally timed puberty, administering cross-sex hormones, and surgically altering primary and secondary sexual traits are summarized and critically evaluated. Serious deficits in understanding the cause of this condition, the reasons for the marked increase in people presenting for medical care, together with immediate and long-term risks relative to benefit of medical intervention are exposed.

Balancing Benefit vs Risk of Immunosuppressive Therapy for Individual Patients With Inflammatory Bowel Diseases.

Inflammatory bowel diseases (IBD) and their treatments, particularly immunosuppressive drugs, increase risk of infections and cancers. However, by promoting mucosal healing, these agents should reduce risks of infections related to intestinal lesions, malnutrition, intravenous devices, and IBD surgeries and reduce risk of cancers associated with chronic mucosal inflammation-although there are few data to support this concept. Corticosteroids increase the risk of vascular thromboembolic events, yet other immunosuppressive drugs that induce deep remission from IBD could decrease the incidence of cardiovascular events attributable to systemic inflammation and IBD-related hospitalizations and/or surgeries. The nature and magnitude of the risks of infections and cancers vary with immunosuppressive drug class and patient sex and age. For example, thiopurines increase risk of viral infections that might be fatal in young patients, whereas tumor necrosis factor antagonists increase risk of bacterial and intracellular infections that can be fatal in patients of any age, but particularly in older patients. The ability of drugs to prevent IBD-associated colorectal cancer varies with IBD location and duration. Models to assess the benefit:risk ratio of long-term use of immunosuppressive drugs for patients with IBD should be adapted based on patients' age, sex, and IBD phenotype, to properly guide patient management. The decision-making process should begin with a clear explanation of treatment risks and then integrate the patient's emotional perception of risks.

Quantitative risk reduction through peanut immunotherapy: Safety benefits of an increased threshold in Europe.

BACKGROUND: The clinical relevance of increasing an allergic individual's peanut sensitivity threshold by immunotherapy, that is, eliciting dose (ED) to 300 or 1000 mg peanut protein, has not been previously characterized in a European population. In this study, we quantify the clinical benefits of an increased threshold of reaction following immunotherapy for the peanut-allergic individual. METHODS: Quantitative risk assessments incorporated numerous inputs to predict the risk of an allergic reaction after exposure to residual peanut protein in packaged foods. The three primary inputs for the risk assessment were the peanut-allergic individual's clinical threshold value, the amount of food consumed per eating occasion of selected packaged foods, and the concentration of peanut protein in the consumed product. Individual risk reductions were calculated for both children and adolescents-adults. RESULTS: Using available consumption and packaged food contamination data, children reaching an ED of 300 mg (if initial ED ≤ 100 mg) or 1000 mg (if initial ED 300 mg) achieved >99.99% risk reduction. Adolescents-adults also achieved >99.99% risk reduction in all cases but one. Adolescents-adults who reached an ED of 300 mg (if initial ED ≤ 100 mg) achieved 99.3%-99.9% risk reduction when consuming ice cream. CONCLUSIONS: It is concluded that an increase in threshold following immunotherapy which achieves an eliciting dose of 300 or 1000 mg peanut protein is clinically relevant for the European peanut-allergic population. Benefits of an increased threshold include a significant reduction in risk due to traces of peanut protein.

When Parents Refuse: Resolving Entrenched Disagreements Between Parents and Clinicians in Situations of Uncertainty and Complexity.

When shared decision making breaks down and parents and medical providers have developed entrenched and conflicting views, ethical frameworks are needed to find a way forward. This article reviews the evolution of thought about the best interest standard and then discusses the advantages of the harm principle (HP) and the zone of parental discretion (ZPD). Applying these frameworks to parental refusals in situations of complexity and uncertainty presents challenges that necessitate concrete substeps to analyze the big picture and identify key questions. I outline and defend a new decision-making tool that includes three parts: identifying the nature of the disagreement, checklists for key elements of the HP and ZPD, and a "think list" of specific questions designed to enhance use of the HP and ZPD in clinical decision making. These tools together will assist those embroiled in complex disagreements to disentangle the issues to find a path to resolution.

Ethical Issues in Fecal Microbiota Transplantation in Practice.

Fecal microbiota transplantation (FMT) has demonstrated efficacy and is increasingly being used in the treatment of patients with recurrent Clostridium difficile infection. Despite a lack of high-quality trials to provide more information on the long-term effects of FMT, there has been great enthusiasm about the potential for expanding its applications. However, FMT presents many serious ethical and social challenges that must be addressed as part of a successful regulatory policy response. In this article, we draw on a sample of the scientific and bioethics literatures to examine clusters of ethical and social issues arising in five main areas: (1) informed consent and the vulnerability of patients; (2) determining what a "suitable healthy donor" is; (3) safety and risk; (4) commercialization and potential exploitation of vulnerable patients; and (5) public health implications. We find that these issues are complex and worthy of careful consideration by health care professionals. Desperation of a patient should not be the basis for selecting treatment with FMT, and the patient's interests should always be of paramount concern. Authorities must prioritize development of appropriate and effective regulation of FMT to safeguard patients and donors, promote further research into safety and efficacy, and avoid abuse of the treatment.