Improving the trustworthiness, usefulness, and ethics of biomedical research through an innovative and comprehensive institutional initiative.

The reproducibility crisis triggered worldwide initiatives to improve rigor, reproducibility, and transparency in biomedical research. There are many examples of scientists, journals, and funding agencies adopting responsible research practices. The QUEST (Quality-Ethics-Open Science-Translation) Center offers a unique opportunity to examine the role of institutions. The Berlin Institute of Health founded QUEST to increase the likelihood that research conducted at this large academic medical center would be trustworthy, useful for scientists and society, and ethical. QUEST researchers perform "science of science" studies to understand problems with standard practices and develop targeted solutions. The staff work with institutional leadership and local scientists to incentivize and support responsible practices in research, funding, and hiring. Some activities described in this paper focus on the institution, whereas others may benefit the national and international scientific community. Our experience, approaches, and recommendations will be informative for faculty leadership, administrators, and researchers interested in improving scientific practice.

The bench is closer to the bedside than we think: Uncovering the ethical ties between preclinical researchers in translational neuroscience and patients in clinical trials.

Millions of people worldwide currently suffer from serious neurological diseases and injuries for which there are few, and often no, effective treatments. The paucity of effective interventions is, no doubt, due in large part to the complexity of the disorders, as well as our currently limited understanding of their pathophysiology. The bleak picture for patients, however, is also attributable to avoidable impediments stemming from quality concerns in preclinical research that often escape detection by research regulation efforts. In our essay, we connect the dots between these concerns about the quality of preclinical research and their potential ethical impact on the patients who volunteer for early trials of interventions informed by it. We do so in hopes that a greater appreciation among preclinical researchers of these serious ethical consequences can lead to a greater commitment within the research community to adopt widely available tools and measures that can help to improve the quality of research.

Surgical Translational Research May Be Forward or Reverse.

The classic concept of translational research can be described as a bench-to-bedside approach. Reverse translational research, bedside-to-benchtop, also may have a place. Under some circumstances, innovative clinicians may develop new techniques in advance of basic science research. A recent example of the success of reverse translational research is shoulder superior capsular reconstruction. Theoretically, new surgical techniques are ideally first tested ex vivo, but this does not guarantee clinical success, and in some cases, experienced, specialized surgeon-scientists can modify existing techniques and perform novel interventions with little risk to patients. Benefits of reverse translational research include a shorter time from innovation to application, and real, not theoretical, determination of clinical outcome. If a reverse approach is warranted, strict adherence to bioethical principles is required, including cooperation with ethics committees, institutional review boards, trial registration, and informed consent. Translational research can be bidirectional.

Ethical, Legal and Regulatory Issues of Paediatric Translational Research. Call for an Adequate Model of Governance.

The lack of paediatric medicines, including innovative and advanced ones, is a long-lasting and well-known problem at European and international levels. Despite the existing legal frameworks and incentives, children remain deprived of many kinds of therapy because of challenges faced in appropriately study and tailoring medicinal and other products for them. In this context, the necessity to foster paediatric research addressing unsolved and uncovered issues within a 'translational approach' has appeared. This article, after having clarified the concept of translational research in the perspective of the establishment of a European paediatric research infrastructure (RI), will identify and point out ethical, legal and regulatory issues particularly relevant in a children's rights perspective. It concludes asking for the setting up of an adequate model of governance within a future RI, including adequate and independent ethical oversight and a pluridisciplinary common service dealing with ethical, legal and societal issues relevant for children.

Towards medicine of excellence in Mexico: the "Código Infarto" protocol, a view from the perspective of translational bioethics.

INTRODUCTION: Mexico is the country with the highest mortality due to ST-elevation acute myocardial infarction (STEMI), and the IMSS has therefore developed the protocol of care for emergency departments called Código Infarto (Infarction Code). In this article, aspects of translational medicine are discussed with a bioethical and comprehensive perspective. OBJECTIVE: To analyze the Código Infarto protocol from the perspective of translational bioethics. METHOD: A problem-centered approach was carried out through reflective equilibrium (or Rawls' method), as well as by applying the integral method for ethical discernment. RESULTS: The protocol of care for emergency services Código Infarto is governed by evidence-based medicine and value-based medicine; it is guided by a principle of integrity that considers six dimensions of quality for the care of patients with STEMI. CONCLUSION: The protocol overcomes some adverse social determinants that affect STEMI medical care, reduces mortality and global economic disease burden, and develops medicine of excellence with high social reach.

INTRODUCCIÓN: México es el país con mayor mortalidad por infarto agudo de miocardio con elevación del segmento ST (IAM CEST), por lo que el Instituto Mexicano del Seguro Social desarrolló el protocolo de atención para los servicios de urgencias denominado Código Infarto. En este artículo se discuten aspectos de la medicina traslacional con una perspectiva bioética e integral. OBJETIVO: Analizar el protocolo Código Infarto desde la perspectiva de la bioética traslacional. MÉTODO: Se realizó una aproximación centrada en el problema a través del equilibrio reflexivo, así como la aplicación del método integral para el discernimiento ético. RESULTADOS: El protocolo de atención para los servicios de urgencias Código Infarto se rige por la medicina basada en la evidencia y la medicina basada en valores; se orienta por el principio de integridad que considera las seis dimensiones de la calidad para la atención de pacientes con IAM CEST. CONCLUSIÓN: El protocolo supera algunos determinantes sociales adversos que afectan la atención médica del IAM CEST, disminuye la mortalidad, la carga económica global de la enfermedad y desarrolla una medicina de excelencia de alto alcance social.

A few ethical issues in translational research for gene and cell therapy.

BACKGROUND: Although translational research for drug development can provide patients with valuable therapeutic resources it is not without risk, especially in the early-phase trials that present the highest degree of uncertainty. With the extraordinary evolution of biomedical technologies, a growing number of innovative products based on human cells and gene therapy are being tested and used as drugs. Their use on humans poses several challenges. METHODS: In this work, we discuss some ethical issues related to gene and cell therapies translational research. We focus on early-phase studies analysing the regulatory approach of Europe and the United States. We report the current recommendations and guidelines of international scientific societies and European and American regulatory authorities. RESULTS: The peculiarity of human cell- or tissue-based products and gene therapy has required the development of specific regulatory tools that must be continually updated in line with the progress of the research. The ethics of translational research for these products also requires further considerations, particularly with respect to the specificity of the associated risk profiles. CONCLUSIONS: An integrated ethical approach that aims for transparency and regulation of development processes, the support of independent judgment in clinical trials and the elimination of unregulated and uncontrolled grey areas of action are necessary to move gene and cell therapy forward.

When genomic medicine reveals misattributed genetic relationships-the debate about disclosure revisited.

PURPOSE: Accidental discovery of misattributed parentage is an age-old problem in clinical medicine, but the ability to detect it routinely has increased recently as a result of high-throughput DNA sequencing technologies coupled with family sequencing studies. Problems arise at the clinical-research boundary, where policies and consent forms guaranteeing nondisclosure may conflict with standard clinical care. METHODS: To examine the challenges of managing misattributed parentage within hybrid translational research studies, we used a case study of a developmentally delayed child with a candidate variant found through a large-scale trio genome sequencing study in which data from unrelated samples were routinely excluded. RESULTS: We discuss whether genetic parentage should be explicitly confirmed during clinical validation, thus giving greater weight to the diagnosis according to American College of Medical Genetics and Genomics variant interpretation guidelines, and what tensions this approach would create. CONCLUSION: We recommend that the possibility of finding and disclosing misattributed parentage should be addressed during the consent or pretest counseling process, and that clinical relevance should determine whether or not to disclose results in the clinic. This proposition has implications for research governance, and implies that it may not always be possible to uphold nondisclosure commitments as investigations move from research to clinical care.

Tensions in ethics and policy created by National Precision Medicine Programs.

Precision medicine promises to use genomics and other data-intensive approaches to improve diagnosis and develop new treatments for major diseases, but also raises a range of ethical and governance challenges. Implementation of precision medicine in "real world" healthcare systems blurs the boundary between research and care. This has implications for the meaning and validity of consent, and increased potential for discrimination, among other challenges. Increased sharing of personal information raises concerns about privacy, commercialization, and public trust. This paper considers national precision medicine schemes from the USA, the UK, and Japan, comparing how these challenges manifest in each national context and examining the range of approaches deployed to mitigate the potential undesirable social consequences. There is rarely a "one size" fits all solution to these complex problems, but the most viable approaches are those which take account of cultural preferences and attitudes, available resources, and the wider political landscape in which national healthcare systems are embedded.

Synthetic Biology and the Translational Imperative.

Advances at the interface between the biological sciences and engineering are giving rise to emerging research fields such as synthetic biology. Harnessing the potential of synthetic biology requires timely and adequate translation into clinical practice. However, the translational research enterprise is currently facing fundamental obstacles that slow down the transition of scientific discoveries from the laboratory to the patient bedside. These obstacles including scarce financial resources and deficiency of organizational and logistic settings are widely discussed as primary impediments to translational research. In addition, a number of socio-ethical considerations inherent in translational research need to be addressed. As the translational capacity of synthetic biology is tightly linked to its social acceptance and ethical approval, ethical limitations may-together with financial and organizational problems-be co-determinants of suboptimal translation. Therefore, an early assessment of such limitations will contribute to proactively favor successful translation and prevent the promising potential of synthetic biology from remaining under-expressed. Through the discussion of two case-specific inventions in synthetic biology and their associated ethical implications, we illustrate the socio-ethical challenges ahead in the process of implementing synthetic biology into clinical practice. Since reducing the translational lag is essential for delivering the benefits of basic biomedical research to society at large and promoting global health, we advocate a moral obligation to accelerating translational research: the "translational imperative."

The contribution of genomics in the medicine of tomorrow, clinical applications and issues.

Fifteen years after the completion of first human genome sequencing, the technique is almost a commodity but there is still little evidence of its usefulness as a diagnostic, prognostic or therapeutic tool. In France, the France genomics plan 2025 was launched in 2015 with the goal of integrating genomic tests into clinical practice and developing a National genomics network including industrial partnerships. Reflection on scientific applications and operational or societal issues is needed to make recommendations to help better associate Genomics and the medicine of tomorrow. In the perspective of personalized Evidence-based Medicine, studies with an appropriate methodological level to improve the definition of evidence should be promoted. The many operational challenges require the implementation of organisations and means to streamline the process of results reporting, and regulatory adaptations concerning the status of professions involved, the management of data generated, and the consent of patients. In parallel, genetic training for healthcare professionals and raising awareness on genetic tests for the public should be considered. The ethical stake should also be taken into account, especially on the participation of the patient in decisions concerning them and integrating the notion of uncertainty into the information given. The sociological effects on the experience and expectations of patients and the general population towards genomic medicine should also be evaluated to improve information, prevention and support for people. Finally, medico-economic studies must be conducted to inform policy-makers on the cost-effectiveness of complete genome sequencing for population health.

Spinning the Genome: Why Science Hype Matters.

There is a growing body of literature that describes both the degree to which science is hyped and how and why that hype happens. Hype can be described as an inappropriate exaggeration of the significance or potential value of a particular study or area of science. Evidence tells us that this spin happens throughout the science translation process. There is hype in research grants, peer-reviewed publications, scientific abstracts, institutional press releases, media representations, and, of course, in the associated marketing of a new product. There is also evidence that it has played a particularly significant role in the area of genetic research. Science hype is a complex phenomenon that involves many actors. And it is, at least to some degree, the result of systemic pressures imbedded in the current incentives associated with biomedical research. This article reviews what the evidence says about the sources of hype, the social and scientific harms, and what can be done to nudge us in the right direction.

An Epistemic Argument for Research-Practice Integration in Medicine.

Arguments in favor of greater research-practice integration in medicine have tended to be ethical, political, or pragmatic. There are good epistemic reasons to pursue greater integration, and it is important to think through these reasons in order to avoid inadvertently designing new systems in ways that replicate the epistemic elitism common within current systems. Meaningful transformation within health care is possible with close attention to all reasons in favor of greater research-practice integration, including epistemic reasons.

Research Translation and Emerging Health Technologies: Synthetic Biology and Beyond.

New health technologies are rapidly emerging from various areas of bioscience research, such as gene editing, regenerative medicine and synthetic biology. These technologies raise promising medical possibilities but also a range of ethical considerations. Apart from the issues involved in considering whether novel health technologies can or should become part of mainstream medical treatment once established, the process of research translation to develop such therapies itself entails particular ethical concerns. In this paper I use synthetic biology as an example of a new and largely unexplored area of health technology to consider the ways in which novel health technologies are likely to emerge and the ethical challenges these will present. I argue that such developments require us to rethink conventional attitudes towards clinical research, the roles of doctors/researchers and patients/participants with respect to research, and the relationship between science and society; and that a broader framework is required to address the plurality of stakeholder roles and interests involved in the development of treatments based on novel technologies.

Research on HIV cure: Mapping the ethics landscape.

In an essay, Karine Dubé and coauthors discuss the ethics of preclinical and clinical studies relevant to achieving an HIV cure.

Serving epigenetics before its time.

Society prizes the rapid translation of basic biological science into ways to prevent human illness. However, the premature rush to take murine epigenetic findings in these directions makes impossible demands on prospective parents and triggers serious social and ethical questions.

Partnering with patients in translational oncology research: ethical approach.

BACKGROUND: The research program CARPEM (cancer research and personalized medicine) brings together the expertise of researchers and hospital-based oncologists to develop translational research in the context of personalized or "precision" medicine for cancer. There is recognition that patient involvement can help to take into account their needs and priorities in the development of this emerging practice but there is currently no consensus about how this can be achieved. In this study, we developed an empirical ethical research action aiming to improve patient representatives' involvement in the development of the translational research program together with health professionals. The aim is to promote common understanding and sharing of knowledge between all parties and to establish a long-term partnership integrating patient's expectations. METHODS: Two distinct committees were settled in CARPEM: an "Expert Committee", gathering healthcare and research professionals, and a "Patient Committee", gathering patients and patient representatives. A multidisciplinary team trained in medical ethics research ensured communication between the two committees as well as analysis of discussions, minutes and outputs from all stakeholders. RESULTS: The results highlight the efficiency of the transfer of knowledge between interested parties. Patient representatives and professionals were able to identify new ethical challenges and co-elaborate new procedures to gather information and consent forms for adapting to practices and recommendations developed during the process. Moreover, included patient representatives became full partners and participated in the transfer of knowledge to the public via conferences and publications. CONCLUSIONS: Empirical ethical research based on a patient-centered approach could help in establishing a fair model for coordination and support actions during cancer research, striking a balance between the regulatory framework, researcher needs and patient expectations. Our approach addresses the concept of translational ethics as a way to handle the main remaining gap between combining care and research activities in the medical pathway and the existing framework.

Ethical considerations in tissue engineering research: Case studies in translation.

Tissue engineering research is a complex process that requires investigators to focus on the relationship between their research and anticipated gains in both knowledge and treatment improvements. The ethical considerations arising from tissue engineering research are similarly complex when addressing the translational progression from bench to bedside, and investigators in the field of tissue engineering act as moral agents at each step of their research along the translational pathway, from early benchwork and preclinical studies to clinical research. This review highlights the ethical considerations and challenges at each stage of research, by comparing issues surrounding two translational tissue engineering technologies: the bioartificial pancreas and a tissue engineered skeletal muscle construct. We present relevant ethical issues and questions to consider at each step along the translational pathway, from the basic science bench to preclinical research to first-in-human clinical trials. Topics at the bench level include maintaining data integrity, appropriate reporting and dissemination of results, and ensuring that studies are designed to yield results suitable for advancing research. Topics in preclinical research include the principle of "modest translational distance" and appropriate animal models. Topics in clinical research include key issues that arise in early-stage clinical trials, including selection of patient-subjects, disclosure of uncertainty, and defining success. The comparison of these two technologies and their ethical issues brings to light many challenges for translational tissue engineering research and provides guidance for investigators engaged in development of any tissue engineering technology.

Is knowledge translation without patient or community engagement flawed?

Background: The engagement of patients/individuals and/or communities has become increasingly important in all aspects of the research process. Objective: The aim of this manuscript is to begin the discussion about the use and implementation of authentic engagement in the development of presentations and manuscripts which evolve from research that has engaged patients/individuals and/or communities. Methods: Community-Based Participatory Research; Transformative Action Research. Results and Discussion: In Canada, the framework for engaging patients/individuals and/or communities is clearly outlined in Chapter 9 of the Tri-Council Policy Statement: Ethical Conduct for Research Involving Humans which indicates that when research projects involving First Nations, Inuit and Métis peoples, the peoples in these communities are to have a role in shaping/co-creating the research that affects them. It is increasingly important that presentations and manuscripts that evolve from results/findings which have engaged patients/individuals and/or communities be co-presented/co-published. Presentations are often done without patients/individuals and/or communities and manuscripts published with only academic authors. Frequently, grants submitted and subsequently funded do not consider this aspect of the process in the budget which makes integrated and outcome knowledge translation, dissemination and distribution by and with patients/individuals and/or communities difficult to facilitate. Conclusions: This manuscript was designed to begin the discussion at various levels related to authentic engagement in the development of presentations and manuscripts which evolve from research that has engaged patients/individuals and/or communities. How will you include patients/individuals and/or communities in your presentations and publications?

Can Neuroscience Contribute to Practical Ethics? A Critical Review and Discussion of the Methodological and Translational Challenges of the Neuroscience of Ethics.

Neuroethics is an interdisciplinary field that arose in response to novel ethical challenges posed by advances in neuroscience. Historically, neuroethics has provided an opportunity to synergize different disciplines, notably proposing a two-way dialogue between an 'ethics of neuroscience' and a 'neuroscience of ethics'. However, questions surface as to whether a 'neuroscience of ethics' is a useful and unified branch of research and whether it can actually inform or lead to theoretical insights and transferable practical knowledge to help resolve ethical questions. In this article, we examine why the neuroscience of ethics is a promising area of research and summarize what we have learned so far regarding its most promising goals and contributions. We then review some of the key methodological challenges which may have hindered the use of results generated thus far by the neuroscience of ethics. Strategies are suggested to address these challenges and improve the quality of research and increase neuroscience's usefulness for applied ethics and society at large. Finally, we reflect on potential outcomes of a neuroscience of ethics and discuss the different strategies that could be used to support knowledge transfer to help different stakeholders integrate knowledge from the neuroscience of ethics.