Why Do I Choose an Animal Model or an Alternative Method in Basic and Preclinical Biomedical Research? A Spectrum of Ethically Relevant Reasons and Their Evaluation.

BACKGROUND: Research model selection decisions in basic and preclinical biomedical research have not yet been the subject of an ethical investigation. Therefore, this paper aims, (1) to identify a spectrum of reasons for choosing between animal and alternative research models (e.g., based on in vitro or in silico models) and (2) provides an ethical analysis of the selected reasons. METHODS: In total, 13 researchers were interviewed; the interviews were analyzed qualitatively. The ethical analysis was based on the principlism approach and a value judgement model. RESULTS: This paper presents 66 reasons underlying the choice of researchers using animal (27 reasons) or alternative models (39). Most of the reasons were assigned to the work environment (29) and scientific standards (22). Other reasons were assigned to personal attitudes (11) and animal welfare (4). Qualitative relevant normative differences are presented in the ethical analysis. Even if few reasons can be rejected outright from an ethical point of view, there are good reasons to give some more weight than others. CONCLUSIONS: The spectrum of reasons and their ethical assessment provide a framework for reflection for researchers who may have to choose between animal models and (investing in) alternatives. This can help to reflect on and ethically justify decisions.

Transformative medical ethics: A framework for changing practice according to normative-ethical requirements.

We propose a step-by-step methodological framework of translational bioethics that aims at changing medical practice according to normative-ethical requirements, which we will thus call "transformative medical ethics." The framework becomes especially important when there is a gap between widely acknowledged, ethically justified normative claims and their realization in the practice of biomedicine and technology (ought-is gap). Building on prior work on translational bioethics, the framework maps a process with six different phases and 12 distinct translational steps. The steps involve various research activities including conceptual philosophical inquiry and (socio-)empirical research. On the one hand, the framework can be used as a heuristic tool to identify barriers to the transformation process. On the other hand, it can provide guidance for researchers and practitioners to develop appropriate (conceptual action and practice) models, which are then implemented and evaluated in specific practice contexts. We use the example of realizing the norm of respect for autonomy in the practice of medical decision-making to illustrate the framework. Further research is required, for example, to theoretically underpin the framework, to apply it to other ought-is gaps, and to evaluate its feasibility and effectiveness in various practice areas. Overall, the framework of transformative medical ethics suggests a strategic process to investigate and promote practice change that is ethically informed in all phases.

From book to bedside? A critical perspective on the debate about "translational bioethics".

The concept of "translational bioethics" has received considerable attention in recent years. Most publications draw an analogy to translational medicine and describe bioethical research that aims at implementing and evaluating ethical interventions. However, current accounts of translational bioethics are often rather vague and seem to differ with regard to conceptual and methodological assumptions. It is not clear and scarcely analyzed what exactly "translation" in the field of bioethics means, in particular regarding goals and processes so that it is justified to appeal to translational medicine. In this article, we thus explore possible analogies and disanalogies between translational medicine and translational bioethics to establish whether the often occurring reference to concepts of translational medicine in the field of bioethics can be justified by substantial analogies. We will first provide an account of different models of translational medicine. In a second step, we will propose an analytic definition that explicitly articulates the essential characteristics of "translational research" irrespective of the research field (i.e., biomedicine, bioethics). Subsequently, we will explore whether and in how far general characteristics and phases of translational research in medicine can be applied to translational research in bioethics. Based on our analyses, we will come to the skeptical conclusion that at present there are considerable conceptual disanalogies and unsolved conceptual problems that disallow using "translational bioethics" in a meaningful analogy to respective accounts in biomedicine. Nevertheless, we will demonstrate that some insights gained by the conceptual accounts of translational medicine can contribute to advance current research activities in bioethics.

Ethical Requirements for Human Challenge Studies: A Systematic Review of Reasons.

Human challenge studies (HCS) are controlled clinical trials in which participants are deliberately infected with a pathogen. Such trials are being developed for an increasing number of diseases. Partly as a result of the coronavirus disease 2019 (COVID-19) pandemic, there has been a recent ethical debate about the reasons for and against HCS in general, or rather, about the requirements that individual HCS must fulfill to be ethically acceptable. A systematic review was conducted to categorize and summarize such requirements and the reasons given for them. Ethics literature was searched in PubMed, Google Scholar, BELIT, and PhilPapers; eligibility criteria were articles published in a scientific/scholarly journal (original research, reviews, editorials, opinion pieces, and conference/meeting reports). Of 1,322 records identified, 161 publications were included, with 183 requirements (with associated reasons) in 10 thematic categories extracted via qualitative content analysis. In synthesizing and interpreting the requirements and their reasons, three issues emerge as particularly sensitive in the case of HCS: the meaning of the right to withdraw from research procedures, communication of researchers with the public and various stakeholders, and the conditions of informed consent. However, four other issues, not specific to HCS, stand out as the most controversial: the acceptable level of risk to participants, payment of participants, protection of vulnerable groups, and standards for international collaborations. Controversies in these areas indicate that further debate is warranted, possibly leading to more specific instructions in ethics guidance documents.

Values, decision-making and empirical bioethics: a conceptual model for empirically identifying and analyzing value judgements.

It can be assumed that value judgements, which are needed to judge what is 'good' or 'better' and what is 'bad' or 'worse', are involved in every decision-making process. The theoretical understanding and analysis of value judgements is, therefore, important in the context of bioethics, for example, to be able to ethically assess real decision-making processes in biomedical practice and make recommendations for improvements. However, real decision-making processes and the value judgements inherent in them must first be investigated empirically ('empirical bioethics'). For this to succeed, what exactly a 'value judgement' is and of what components it might consist must initially be theoretically clarified. A corresponding conceptual model can then support or even enable empirical data collection and analysis and, above all, subsequent ethical analysis and evaluation. This paper, therefore, presents a value judgement model with its theoretical derivation. It also illustrates its application in an interview study of decision-making between animal experimentation and alternative methods in the context of biomedical research. Though the model itself can be theoretically deepened and extended, the application of the model works in general and helps to uncover what value judgements can enter into decision-making. However, the empirical methods, for example, qualitative interviews, can also be better oriented towards eliciting value judgements (as understood according to the model). Further applications of the model to other topics or by means of other empirical methods are conceivable.

A systematic review documenting reasons whether physicians should provide treatment to their family and friends.

BACKGROUND: Physicians are likely to be asked to provide medical care to relatives or friends. Evidence suggests that most physicians treat loved ones during their active years. However, in the academic literature, critical approaches to the matter are dominating. Ethical guidelines often discourage physicians from treating family members and friends outside of exceptional circumstances. OBJECTIVE: This systematic review aims to identify reasons for and against treating family and friends as portrayed in the literature published. METHODS: A search string designed for the database "PubMed," snowball sampling, and hand searching was used to identify possibly eligible publications. Seventy-six publications were screened for all reasons presented in favour of and against physicians treating loved ones. Qualitative content analysis was used for data extraction. Combining a deductive and inductive approach, a coding system was developed. RESULTS: Many publications analysed represent articles portraying personal experiences; fewer show original research. Reasons against and in favour of treating family and friends were identified. Several publications specify conditions under which the treatment of loved ones may be legitimate. The reasons identified can be assigned to a micro or macro level of human interaction. CONCLUSIONS: This systematic review shows that the discourse of physicians treating loved ones is held predominantly in the context of personal experiences. The majority of authors seem to have a rather pragmatic interest in the topic, and systematic or analytic approaches are rare. While most authors mention various codes of ethics, several publications criticize these or consider them insufficient.

Ethical guidelines, such as the Code of Medical Ethics of the American Medical Association, ask physicians not to treat their family members and friends. However, studies show that most physicians are confronted with loved ones asking for medical interventions during their careers. The divide between the ethical guidelines and the physicians' actual practice demonstrates the ethical dilemma at hand. In this systematic review, literature addressing the topic of physicians treating family and friends (PTFF) is analysed. The majority of publications voice concerns about PTFF. A common reason against PTFF is the risk of losing objectivity. Other publications endorse PTFF, mentioning, for example, the possibility of saving costs. Specific situations in which PTFF is justified are presented as well. The analysis of publications on the topic indicates a rather clinical approach, less of a philosophical one. Several authors criticize too little assistance in this matter of the ethical guidelines. The examination of the existing literature on the topic of PTFF suggests that, as the circumstances are very context-specific, a universal answer applying to each case of PTFF will hardly be found.

How to derive ethically appropriate recommendations for action? A methodology for applied ethics.

Researchers in applied ethics, and some areas of bioethics particularly, aim to develop concrete and appropriate recommendations for action in morally relevant real-world situations. When proceeding from more abstract levels of ethical reasoning to such concrete recommendations, however, even with regard to the very same normative principle or norm, it seems possible to develop divergent or even contradictory recommendations for action regarding a certain situation. This may give the impression that such recommendations would be arbitrary and, hence, not well justified. Against this background, we, first, aim at showing that ethical recommendations for action, although being contingent in some sense, are not arbitrary if developed appropriately. For this purpose, we examine two types of contingencies arising in applied ethics reasoning based on recent examples of recommendations for action in the context of the COVID-19 pandemic. In doing so, we refer to a three-step model of ethical reasoning towards recommendations for actions. This, however, leaves open the question of how applied ethics may cope with contingent recommendations for action. Therefore, in a second step, we analyze the role of bridge principles for developing ethically appropriate recommendations for action, i.e., principles which connect normative claims with relevant empirical information to justify certain recommendations for action in a given morally relevant situation. Finally, we discuss some implications for reasoning and reporting in empirically informed ethics.

States of Uncertainty, Risk-Benefit Assessment and Early Clinical Research: A Conceptual Investigation.

It can be argued that there is an ethical requirement to classify correctly what is known and what is unknown in decision situations, especially in the context of biomedicine when risks and benefits have to be assessed. This is because other methods for assessing potential harms and benefits, decision logics and/or ethical principles may apply depending on the kind or degree of uncertainty. However, it is necessary to identify and describe the various epistemic states of uncertainty relevant to such estimates in the first place. Therefore, this paper aims to develop a category system of different epistemic states of uncertainty which, although not exclusively, is primarily intended to be applied to early clinical trials. It is formed on the basis-and various combinations-of three dimensions of uncertainty that represent certain parts of incomplete knowledge: outcome (type of event), probability (of outcome) and evaluation (assessment of outcome). Furthermore, it is argued that uncertainty can arise from three different sources (the structure of the object of research, the state of the evidence, or individual handling of the research and already existing knowledge). The categories developed are applied to actual examples from gene therapy and genome editing to illustrate that they can be helpful for a more precise definition of the respective uncertainties, especially in the context of risk-benefit assessment. The categories allow a differentiated perspective of decision-making situations from the point of view of incomplete knowledge in general, but particularly, for example, in early clinical research, and may thereby support a more acceptable ethical assessment of potential harms and benefits.

Additional treatment with mistletoe extracts for patients with breast cancer compared to conventional cancer therapy alone - efficacy and safety, costs and cost-effectiveness, patients and social aspects, and ethical assessment.

Background: Chemotherapy is often used in the treatment of breast cancer in women. Side effects such as diarrhea, fatigue, hair loss, fever or disturbances in blood formation impair the women's quality of life. An essential treatment goal of the accompanying mistletoe therapy (MT) used in complementary medicine is to improve the health-related quality of life during cancer therapy. Aim and methods: The HTA report on which this article is based examines the medical efficacy and safety, costs and cost-effectiveness, patient and social aspects, and ethical aspects of MT in women with breast cancer. Systematic reviews were conducted for this purpose. The search period of the literature search ranged from 2004 to October 2020. Results: A total of 2 evidence-based medical guidelines, 3 randomized trials assessing efficacy and 1 additional non-randomized intervention trial, as well as 3 observational studies assessing safety, a cost analysis, 12 cross-sectional studies on patient aspects and 17 articles on ethical evaluation were included. Improvements in health-related quality of life compared to the control group were small to moderate. Due to the high risk of bias in the studies, it is possible that the difference is not caused by MT. One study with a small sample size showed no effect on progression-free survival after 5 years. Studies on the effect of MT on overall survival are lacking. In seven studies, local skin reactions of low and moderate severity were reported in a median of 25% (range 5 to 94%) of patients, and mild to moderate systemic reactions in a median of 2% (range 0 to 8%) of patients. A comparative cost analysis from Germany reported significantly lower medical costs within 5 years after surgery for patients with MT than for patients without MT, but the underlying observational study did not control for systematic bias. With regard to patient aspects, the frequency of use and the reasons for use from the patient's or practitioner's point of view were mainly investigated. A median of 25% (range 7 to 46%) of patients with breast cancer and 29% (range 29 to 79%) of treatment providers use MT. The main motivations of patients for use were to reduce side effects, strengthen the immune system and take an active role in the treatment process. Patients felt insufficiently advised. Studies on other aspects are lacking. The ethical evaluation was able to identify 6 overarching themes; the central challenge is the insufficient evidence on efficacy and safety.

"Same same but different"? On the questionable but crucial differentiation between ethical and social aspects in health technology assessment.

INTRODUCTION: In health technology assessment (HTA), the demarcation of ethical and social aspects in two separate domains is a given fact. While an overlapping of ethical and social aspects is possible, this also raises theoretical and methodological questions, such as why overlaps happen (on the basis of which understanding of ethical and social aspects), or whether they are legitimate from a methodological point of view. METHODS: We analyzed, on a basis of purposive sampling, a) two well-known HTA frameworks (HTA Core Model, INTEGRATE-HTA), b) methodological literature about ethical and/or social aspects in HTA, and c) published HTA reports from the German DAHTA database and the international CRD database regarding statements on the understanding (definition/characterization) and relationship between ethical and social aspects. RESULTS: The frameworks use identical definitions for ethical aspects but deviate when it comes to social aspects. Methodological papers do not always provide a definition of social and ethical aspects. In the context of ethical aspects, they often refer back to ethics as a base discipline that deals with the motives and consequences of good and bad actions for ethical aspects, while for social aspects, there is orientation towards already existing checklists and methods, without reference to a base discipline such as sociology. The analyzed HTA reports barely offered details on their understanding of ethical or social aspects (7% of n = 33). DISCUSSION: The problem of defining/characterizing and differentiating ethical and social aspects exists in both theory and practice. The impression is that little attention is paid to demarcations and overlaps, and that also the methodological literature has not yet thoroughly addressed the issue. While there are also pragmatic reasons for the possible ambiguity between the ethical and the social domains, deeper epistemological issues related to the multi-/interdisciplinarity nature of HTA will have to be considered, too, such as the danger of "disciplinary capture" (pressure on some domains and their basic disciplines, e.g., ethics, to adopt the concepts and standards of other domains that are more dominant in HTA, e.g., efficacy assessment/evidenced-based medicine). CONCLUSION: The domains in HTA reports should be better described epistemologically and brought into a coherent relationship with each other. This is important to avoid unreasonable overlapping and possible problematic redundancy. Further, this could help with questions of adequate expertise and methods for the processing of all relevant information for solid technology assessment.

Systematic reviews of empirical literature on bioethical topics: Results from a meta-review.

BACKGROUND: In bioethics, especially nursing ethics, systematic reviews are increasingly popular. The overall aim of a systematic review is to provide an overview of the published discussions on a specific topic. While a meta-review on systematic reviews on normative bioethical literature has already been performed, there is no equivalent for systematic reviews of empirical literature on ethical topics. OBJECTIVE: This meta-review aims to present the general trends and characteristics of systematic reviews of empirical bioethical literature and to evaluate their reporting quality. RESEARCH DESIGN: Literature search was performed on PubMed and Google Scholar. Qualitative content analysis and quantitative approaches were used to evaluate the systematic reviews. Characteristics of systematic reviews were extracted and quantitatively analyzed. The reporting quality was measured using an adapted PRISMA checklist. FINDINGS: Seventy-six reviews were selected for analysis. Most reviews came from the field of nursing (next to bioethics and medicine). Selected systematic reviews investigated issues related to clinical ethics (50%), followed by research ethics (36%) and public health ethics or organizational ethics (14%). In all, 72% of the systematic reviews included authors' ethical reflections on the findings and 59% provided ethical recommendations. Despite the heterogeneous reporting of the reviews, reviews using PRISMA tended to score better regarding reporting quality. DISCUSSION: The heterogeneity currently observed is due both to the interdisciplinary nature of nursing ethics and bioethics, and to the emerging nature of systematic review methods in these fields. These results confirm the findings of our previous review of systematic reviews on normative literature, thereby highlighting a recurring methodological gap in systematic reviews of bioethical literature. This also indicates the need to develop more robust methodological standards. CONCLUSION: Through its extensive overview of the characteristics of systematic reviews of empirical literature on ethical topics, this meta-review is expected to inform further discussions on minimal standards and reporting guidelines.

How to tackle the conundrum of quality appraisal in systematic reviews of normative literature/information? Analysing the problems of three possible strategies (translation of a German paper).

BACKGROUND: In the last years, there has been an increase in publication of systematic reviews of normative ("argument-based") literature or of normative information (such as ethical issues) in bioethics. The aim of a systematic review is to search, select, analyse and synthesise literature in a transparent and systematic way in order to provide a comprehensive and unbiased overview of the information sought, predominantly as a basis for informed decision-making in health care. Traditionally, one part of the procedure when conducting a systematic review is an appraisal of the quality of the literature that could be included. MAIN TEXT: However, while there are established methods and standards for appraising e.g. clinical studies or other empirical research, quality appraisal of normative literature (or normative information) in the context of a systematic review is still rather a conundrum - not only is it unclear how it could or should be done, but also the question whether it necessarily must be done is not settled yet. Based on a pragmatic definition of "normative literature" as well as on a typology of different types of systematic reviews of normative literature/information, this paper identifies and critically discusses three possible strategies of conducting quality appraisal. CONCLUSIONS: The paper will argue that none of the three strategies is able to provide a general and satisfying solution to the problems associated with quality appraisal of normative literature/information. Still, the discussion of the three strategies allows outlining minimal conditions that elaborated strategies have to meet in future, and facilitates sketching a theoretically and practically promising strategy.

The value of bioethical research: A qualitative literature analysis of researchers' statements.

INTRODUCTION: Value and waste in preclinical and clinical research projects are intensively debated in biomedicine at present. Such different aspects as the need for setting objectives and priorities, improving study design, quality of reporting, and problematic incentives of the academic reward system are addressed. While this debate is also fueled by ethical considerations and thus informed by bioethical research, up to now, the field of bioethics lacks a similar extensive debate. Nonetheless, bioethical research should not go unquestioned regarding its scientific or social value. What exactly constitutes the value of bioethical research, however, remains widely unclear so far. METHODS: This explorative study investigated possible value dimensions for bioethical research by conducting a qualitative literature analysis of researchers' statements about the value of their studies. 40 bioethics articles published 2015 in four relevant journals (The American Journal of Bioethics, Bioethics, BMC Medical Ethics and Journal of Medical Ethics) were analyzed. The value dimensions of "advancing knowledge" (e.g. research results that are relevant for science itself and for further research) and "application" (e.g. increasing applicability of research results in practice) were used as main deductive categories for the analysis. Further subcategories were inductively generated. RESULTS: The analysis resulted in 62 subcategories representing a wide range of value dimensions for bioethical research. Of these, 45 were subcategories of "advancing knowledge" and 17 of "application". In 21 articles, no value dimensions related to "application" was found; the remaining 19 articles mentioned "advancing knowledge" as well as "application". The value dimensions related to "advancing knowledge" were, in general, more fine-grained. CONCLUSIONS: Even though limitations arise regarding the sample, the study revealed a plethora of value dimensions that can inform further debates about what makes bioethical research valuable for science and society. Besides theoretical reflections on the value of bioethics more meta-research in bioethics is needed.

Standards of practice in empirical bioethics research: towards a consensus.

BACKGROUND: This paper reports the process and outcome of a consensus finding project, which began with a meeting at the Brocher Foundation in May 2015. The project sought to generate and reach consensus on standards of practice for Empirical Bioethics research. The project involved 16 academics from 5 different European Countries, with a range of disciplinary backgrounds. METHODS: The consensus process used a modified Delphi approach. RESULTS: Consensus was reached on 15 standards of practice, organised into 6 domains of research practice (Aims, Questions, Integration, Conduct of Empirical Work, Conduct of Normative Work; Training & Expertise). CONCLUSIONS: Through articulating these standards we outline a position that encourages responses, and through those responses we will be able to identify points of agreement and contestation that will drive the conversation forward. In that vein, we would encourage researchers, funders and journals to engage with what we have proposed, and respond to us, so that our community of practice of empirical bioethics research can develop and evolve further.

Beyond integrating social sciences: Reflecting on the place of life sciences in empirical bioethics methodologies.

Empirical bioethics is commonly understood as integrating empirical research with normative-ethical research in order to address an ethical issue. Methodological analyses in empirical bioethics mainly focus on the integration of socio-empirical sciences (e.g. sociology or psychology) and normative ethics. But while there are numerous multidisciplinary research projects combining life sciences and normative ethics, there is few explicit methodological reflection on how to integrate both fields, or about the goals and rationales of such interdisciplinary cooperation. In this paper we will review some drivers for the tendency of empirical bioethics methodologies to focus on the collaboration of normative ethics with particularly social sciences. Subsequently, we argue that the ends of empirical bioethics, not the empirical methods, are decisive for the question of which empirical disciplines can contribute to empirical bioethics in a meaningful way. Using already existing types of research integration as a springboard, five possible types of research which encompass life sciences and normative analysis will illustrate how such cooperation can be conceptualized from a methodological perspective within empirical bioethics. We will conclude with a reflection on the limitations and challenges of empirical bioethics research that integrates life sciences.

What methods do reviews of normative ethics literature use for search, selection, analysis, and synthesis? In-depth results from a systematic review of reviews.

BACKGROUND: (Semi-)systematic approaches to finding, analysing, and synthesising ethics literature on medical topics are still in their infancy. However, our recent systematic review showed that the rate of publication of such (semi-)systematic reviews has increased in the last two decades. This is not only true for reviews of empirical ethics literature, but also for reviews of normative ethics literature. In the latter case, there is currently little in the way of standards and guidance available. Therefore, the methods and reporting strategies of such reviews vary greatly. The purpose of the follow-up study we present was to obtain deeper methodological insight into the ways reviews of normative literature are actually conducted and to analyse the methods used. METHOD: Our search in the PubMed, PhilPapers, and Google Scholar databases led to the identification of 183 reviews of ethics literature published between 1997 and 2015, of which 84 were identified as reviews of normative and mixed literature. Qualitative content analysis was used to extract and synthesise descriptions of search, selection, quality appraisal, analysis, and synthesis methods. We further assessed quantitatively how often certain methods (e.g. search strategies, data analysis procedures) were used by the reviews. RESULTS: The overall reporting quality varies among the analysed reviews and was generally poor even for major criteria regarding the search and selection of literature. For example, only 24 (29%) used a PRISMA flowchart. Also, only 55 (66%) reviews mentioned the information unit they sought to extract, and 12 (14%) stated an ethical approach as the theoretical basis for the analysis. Interpretable information on the synthesis method was given by 47 (60%); the most common methods applied were qualitative methods commonly used in social science research (83%). CONCLUSION: Reviews which fail to provide sufficient relevant information to readers have reduced methodological transparency regardless of actual methodological quality. In order to increase the internal validity (i.e. reproducibility) as well as the external validity (i.e. utility for the intended audience) of future reviews of normative literature, we suggest more accurate reporting regarding the goal of the review, the definition of the information unit, the ethical approach used, and technical aspects.

[Quality appraisal in systematic reviews of normative literature. A problem analysis]. / Qualitätsbewertung in systematischen Übersichtsarbeiten normativer Literatur. Eine Problemanalyse.

Systematic reviews aim at searching, selecting, analyzing and synthesizing scientific literature in a transparent and systematic way in order to inform decision-making in the health care system on the basis of the best available evidence. In recent years, such reviews have also gained importance also in bio-, public health- and research ethics, as well as in health technology assessment. Such reviews do not only analyze ethically relevant empirical literature (e.g. on risk and benefit), but normative literature as well, i.e. literature consisting of ethical arguments. As the appraisal of the literature that should be included is paramount for a systematic review, the problem of how to appraise the quality of normative literature arises. This problem has not yet been solved satisfactorily. After developing a pragmatic definition for "normative literature", a typology of different types of systematic reviews of normative literature is presented. Based on existing approaches for quality appraisal, this paper identifies three possible strategies for solving the problem of quality appraisal of normative literature, and discusses their respective strength and weaknesses relative to the different types of systematic reviews. It becomes apparent that none of the existing approaches is able to solve the problem of quality appraisal in a general and convincing way. The paper concludes with stating minimal conditions regarding the elaboration of future strategies, and outlines a promising strategy that is theoretically acceptable and practically feasible.