CRISPR Ethics: Moral Considerations for Applications of a Powerful Tool

With the emergence of CRISPR technology, targeted editing of a wide variety of genomes is no longer an abstract hypothetical, but occurs regularly. As application areas of CRISPR are exceeding beyond research and biomedical therapies, new and existing ethical concerns abound throughout the global community about the appropriate scope of the systems' use. Here we review fundamental ethical issues including the following: 1) the extent to which CRISPR use should be permitted; 2) access to CRISPR applications; 3) whether a regulatory framework(s) for clinical research involving human subjects might accommodate all types of human genome editing, including editing of the germline; and 4) whether international regulations governing inappropriate CRISPR utilization should be crafted and publicized. We conclude that moral decision making should evolve as the science of genomic engineering advances and hold that it would be reasonable for national and supranational legislatures to consider evidence-based regulation of certain CRISPR applications for the betterment of human health and progress.     

Ethics and Epistemology in Big Data Research

Biomedical innovation and translation are increasingly emphasizing research using “big data.” The hope is that big data methods will both speed up research and make its results more applicable to “real-world” patients and health services. While big data research has been embraced by scientists, politicians, industry, and the public, numerous ethical, organizational, and technical/methodological concerns have also been raised. With respect to technical and methodological concerns, there is a view that these will be resolved through sophisticated information technologies, predictive algorithms, and data analysis techniques. While such advances will likely go some way towards resolving technical and methodological issues, we believe that the epistemological issues raised by big data research have important ethical implications and raise questions about the very possibility of big data research achieving its goals.     

The Brazilian legal framework on the scientific use of animals

Brazil has an exceptionally dynamic research sector in Latin America in health, biotechnology, and pharmacology, backed by defined government policies on science and technology and a health research agenda focusing on important neglected diseases: malaria, leishmaniasis, Chagas disease, turberculosis, leprosy, and dengue. The Brazilian health research policy promotes partnerships and networks among scientists in academic institutions in both wealthy industrialized and disease-endemic countries, and in these efforts the government's guidelines for animal use in biomedical research are considered fundamental to guarantee both animal welfare and the quality of research. Given international discussions of animal experimentation regulations and guidelines, in this article we describe current Brazilian legislation governing the use of animals in scientific investigations. We conclude that, despite advances in the implementation of the 3Rs (reduction, refinement, replacement), the new regulatory framework does not sufficiently incorporate ethical considerations, lacking explicit reference to the 3Rs as well as measures for their full application. The more humane use of animals in research will depend on the approach adopted by Brazil's National Council for the Control of Animal Experimentation to promote the 3Rs and to improve internal regulations as well as data collection and analysis in research institutions. In Brazil as elsewhere, one of the greatest challenges to policymakers is to harmonize the myriad and intertwined legal provisions without hindering biomedical research.     

Translational Informatics for Parkinson’s Disease: from Big Biomedical Data to Small Actionable Alterations

Parkinson's disease (PD) is a common neurological disease in elderly people, and its morbidity and mortality are increasing with the advent of global ageing. The traditional paradigm of moving from small data to big data in biomedical research is shifting toward big data-based identification of small actionable alterations. To highlight the use of big data for precision PD medicine, we review PD big data and informatics for the translation of basic PD research to clinical applications. We emphasize some key findings in clinically actionable changes, such as susceptibility genetic variations for PD risk population screening, biomarkers for the diagnosis and stratification of PD patients, risk factors for PD, and lifestyles for the prevention of PD. The challenges associated with the collection, storage, and modelling of diverse big data for PD precision medicine and healthcare are also summarized. Future perspectives on systems modelling and intelligent medicine for PD monitoring, diagnosis, treatment, and healthcare are discussed in the end.     

Ethics and biomedical research

Ethics in biomedical research took off from the 1947 Nuremberg Code to its own right in the wake of the Declaration of Helsinki in 1964. Since then, (inter)national regulations and guidelines providing a framework for clinical studies and protection for study participants have been drafted and implemented, while ethics committees and drug evaluation agencies have sprung up throughout the world. These two developments were crucial in bringing about the protection of rights and safety of the participants and harmonization of the conduct of biomedical research. Ethics committees and drug evaluation agencies deliver ethical and scientific assessments on the quality and safety of the projects submitted to them and issue respectively approvals and authorizations to carry out clinical trials, while ensuring that they comply with regulatory requirements, ethical principles, and scientific guidelines. The advent of biomedical ethics, together with the responsible commitment of clinical investigators and of the pharmaceutical industry, has guaranteed respect for the patient, for whom and with whom research is conducted. Just as importantly, it has also ensured that patients reap the benefit of what is the primary objective of biomedical research: greater life expectancy, well-being, and quality of life.     

Genetic databases and pharmacogenetics: introduction

Since the inception of the Human Genome Project, human genetics has frequently been conducted through big science projects, combining academic, state and industrial methods, interests and resources. The legitimacy of such projects has been linked to national prestige and images of the nation, the purity of scientific endeavour, the entrepreneurial spirit, medical progress and the public health. A key complication in these discourses is that large-scale genetic research has yet to show major results when considered in terms of the objectives used to legitimate investment and social support for these projects. The main area showing promise at present is the developing field of pharmacogenetics, which is now attracting major industry and government investment. Sociological, ethical and philosophical study of human genetic sample-based research and pharmacogenetics has developed in parallel with inquiry in the biological and biomedical sciences. This paper introduces a symposium on the ethical and social aspects of this field of biomedical research.     

A Brief History of Biomedical Research Ethics in Iran: Conflict of Paradigms

During the past two decades, Iran has experienced a noteworthy growth in its biomedical research sector. At the same time, ethical concerns and debates resulting from this burgeoning enterprise has led to increasing attention paid to biomedical ethics. In Iran, Biomedical research ethics and research oversight passed through major periods during the past decades, separated by a paradigm shift. Period 1, starting from the early 1970s, is characterized by research paternalism and complete reliance on researchers as virtuous and caring physicians. This approach was in concordance with the paternalistic clinical practice of physicians outside of research settings during the same period. Period 2, starting from the late 1990s, was partly due to revealing of ethical flaws that occurred in biomedical research in Iran. The regulatory and funding bodies concluded that it was not sufficient to rely solely on the personal and professional virtues of researchers to safeguard human subjects' rights and welfare. The necessity for independent oversight, emphasized by international declarations, became obvious and undeniable. This paradigm shift led to the establishment of research ethics committees throughout the country, the establishment of academic research centers focusing on medical ethics (MEHR) and the compilation of the first set of national ethical guidelines on biomedical research–one of the first and most important projects conducted by and in the MEHR. Although not yet arrived, ‘period 3’ is on its way. It is predictable from the obvious trends toward performance of high‐quality clinical research and the appearance of a highly educated new generation, especially among women.     

Cutting red tape to manage public health threats: An ethical dilemma of expediting antibiotic drug innovation

Antibiotic resistance, arising when bacteria develop defences against antibiotics, is creating a public health threat of massive proportions. This raises challenging questions for standard notions in bioethics when suitable policy is to be characterized and justified. We examine the particular proposal of expediting innovation of new antibiotics by cutting various forms of regulatory ‘red tape’ in the standard system for the clinical introduction of new drugs. We find strong principled reasons in favour of such a lowering of the ethical standards of research and the clinical introduction of new antibiotic formulas. However, this support is undermined by pragmatic challenges owing to expected responses from stakeholders, creating uncertainty about which policies could actually be effectively implemented. We describe an underlying dilemma on how to rationally justify compromises between ideal ethical justification and pragmatic risks that needs to be further addressed in this light. We suggest a solution to this dilemma related to proposals of expediting antibiotic drug innovation.     

Glocal Clinical Registries: Pacemaker Registry Design and Implementation for Global and Local Integration – Methodology and Case Study

Background

The ability to apply standard and interoperable solutions for implementing and managing medical registries as well as aggregate, reproduce, and access data sets from legacy formats and platforms to advanced standard formats and operating systems are crucial for both clinical healthcare and biomedical research settings.

Purpose

Our study describes a reproducible, highly scalable, standard framework for a device registry implementation addressing both local data quality components and global linking problems.

Methods and Results

We developed a device registry framework involving the following steps: (1) Data standards definition and representation of the research workflow, (2) Development of electronic case report forms using REDCap (Research Electronic Data Capture), (3) Data collection according to the clinical research workflow and, (4) Data augmentation by enriching the registry database with local electronic health records, governmental database and linked open data collections, (5) Data quality control and (6) Data dissemination through the registry Web site. Our registry adopted all applicable standardized data elements proposed by American College Cardiology / American Heart Association Clinical Data Standards, as well as variables derived from cardiac devices randomized trials and Clinical Data Interchange Standards Consortium. Local interoperability was performed between REDCap and data derived from Electronic Health Record system. The original data set was also augmented by incorporating the reimbursed values paid by the Brazilian government during a hospitalization for pacemaker implantation. By linking our registry to the open data collection repository Linked Clinical Trials (LinkedCT) we found 130 clinical trials which are potentially correlated with our pacemaker registry.

Conclusion

This study demonstrates how standard and reproducible solutions can be applied in the implementation of medical registries to constitute a re-usable framework. Such approach has the potential to facilitate data integration between healthcare and research settings, also being a useful framework to be used in other biomedical registries.     

Ethical tissue: a not-for-profit model for human tissue supply

Following legislative changes in 2004 and the establishment of the Human Tissue Authority, access to human tissues for biomedical research became a more onerous and tightly regulated process. Ethical Tissue was established to meet the growing demand for human tissues, using a process that provided ease of access by researchers whilst maintaining the highest ethical and regulatory standards. The establishment of a licensed research tissue bank entailed several key criteria covering ethical, legal, financial and logistical issues being met. A wide range of stakeholders, including the HTA, University of Bradford, flagged LREC, hospital trusts and clinical groups were also integral to the process.     

Social value,clinical equipoise,and research in a public health emergency

The 2016 CIOMS International ethical guidelines for health‐related research involving humans states that ‘health‐related research should form an integral part of disaster response’ and that, ‘widespread emergency use [of unproven interventions] with inadequate data collection about patient outcomes must therefore be avoided’ (Guideline 20). This position is defended against two lines of criticism that emerged during the 2014 Ebola outbreak. One holds that desperately ill patients have a moral right to try unvalidated medical interventions (UMIs) and that it is therefore unethical to restrict access to UMIs to the clinical trial context. The second holds that clinical trials in contexts of high‐mortality diseases are morally suspect because equipoise does not exist between a standard of care that offers little prospect of clinical benefit and a UMI that might offer some clinical advantage.     

什么是生命伦理学？——从历史发展的视角

生命伦理学是20世纪60年代兴起于美国的一门新兴学科,旨在应对生命科学和生物技术的发展或医疗保健的演变使人类面临的种种伦理难题。生命伦理学的兴起有着特殊的社会历史背景。它在发展过程中出现的一些里程碑式的案例,对生命伦理学的发展产生了深远的影响。从其发展特征上看,生命伦理学和医学伦理学紧密联系,有着更为广泛的研究内容和独特的专业特性。生命伦理学要有效回应现代医学和生命科学的发展给人类带来的伦理难题,既要准确地界定伦理问题,又要以适当的方式将伦理学基础理论应用到具体问题当中。对生命伦理学的基本理论进行概述。     

Biological Databases for Human Research

The completion of the Human Genome Project lays a foundation for systematically studying the human genome from evolutionary history to precision medicine against diseases.With the explosive growth of biological data, there is an increasing number of biological databases that have been developed in aid of human-related research. Here we present a collection of humanrelated biological databases and provide a mini-review by classifying them into different categories according to their data types. As human-related databases continue to grow not only in count but also in volume, challenges are ahead in big data storage, processing, exchange and curation.     

Adjusting the focus: A public health ethics approach to data research

This paper contends that a research ethics approach to the regulation of health data research is unhelpful in the era of population‐level research and big data because it results in a primary focus on consent (meta‐, broad, dynamic and/or specific consent). Two recent guidelines – the 2016 WMA Declaration of Taipei on ethical considerations regarding health databases and biobanks and the revised CIOMS International ethical guidelines for health‐related research involving humans – both focus on the growing reliance on health data for research. But as research ethics documents, they remain (to varying degrees) focused on consent and individual control of data use. Many current and future uses of health data make individual consent impractical, if not impossible. Many of the risks of secondary data use apply to communities and stakeholders rather than individual data subjects. Shifting from a research ethics perspective to a public health lens brings a different set of issues into view: how are the benefits and burdens of data use distributed, how can data research empower communities, who has legitimate decision‐making capacity? I propose that a public health ethics framework – based on public benefit, proportionality, equity, trust and accountability – provides more appropriate tools for assessing the ethical uses of health data. The main advantage of a public health approach for data research is that it is more likely to foster debate about power, justice and equity and to highlight the complexity of deciding when data use is in the public interest.     

Informed Consent in Cross-cultural Perspective: Clinical Research in the Tibetan Autonomous Region, PRC

Procedures of Informed Consent are considered a high priority for international biomedical research. However, informed consent protocols are not necessarily transferable across cultural, national or ethnic groups. Recent debates identify the need for balancing ethical universals with practical and local conditions and paying attention to questions of cultural competence when it comes to the Informed Consent process for clinical biomedical research. This article reports on the results of a two-year effort to establish a culturally appropriate Informed Consent process for biomedical research in the Tibet Autonomous Region in the People's Republic of China. A team of Tibetan and American researchers, physicians, health professionals and medical anthropologists conducted the research. The Informed Consent was specifically for undertaking a triple-blind, double placebo-controlled randomized clinical trial of a Tibetan medicine compared with Misoprostol for reducing postpartum blood loss. The findings suggest greater need for flexibility and cooperation in establishing Informed Consent protocols across cultures and nations.     

LINKING INTERNATIONAL RESEARCH TO GLOBAL HEALTH EQUITY: THE LIMITED CONTRIBUTION OF BIOETHICS

Health research has been identified as a vehicle for advancing global justice in health. However, in bioethics, issues of global justice are mainly discussed within an ongoing debate on the conditions under which international clinical research is permissible. As a result, current ethical guidance predominantly links one type of international research (biomedical) to advancing one aspect of health equity (access to new treatments). International guidelines largely fail to connect international research to promoting broader aspects of health equity – namely, healthier social environments and stronger health systems. Bioethical frameworks such as the human development approach do consider how international clinical research is connected to the social determinants of health but, again, do so to address the question of when international clinical research is permissible. It is suggested that the narrow focus of this debate is shaped by high‐income countries' economic strategies. The article further argues that the debate's focus obscures a stronger imperative to consider how other types of international research might advance justice in global health. Bioethics should consider the need for non‐clinical health research and its contribution to advancing global justice.     

Blood Collection Procedure of Laboratory Primates: A Neglected Variable in Biomedical Research

A survey of 75 biomedical articles dealing with stress-dependent blood parameters in caged primates revealed that the conditions under which blood collection occurred were in most cases described either not at all or so haphazardly that it would be impossible to determine if humane handling procedures were used and basic principles of scientific methodology applied. These findings were unexpected because there is ample scientific evidence not only that stress-sensitive research data are influenced by traditional blood sampling procedures, but also that those data-biasing effects can be avoided. If dependent variables of the blood collection procedure are not controlled, data variability will increase, automatically increasing the number of animals needed for statistical analysis. For ethical and scientific reasons, it was recommended that editors of biomedical journals require authors to provide sufficient information of the blood collection--and, when applicable, the sedative injection--procedure to ensure that the experiment was done with the smallest number of animals possible to achieve statistical significance and that the investigation can be replicated reliably in another laboratory and the research data interpreted with reasonable accuracy.     

DADOS-Prospective: an open source application for Web-based prospective data collection

Background  

Randomized, prospective trials involving multi-institutional collaboration have become a central part of clinical and translational research. However, data management and coordination of multi-center studies is a complex process that involves developing systems for data collection and quality control, tracking data queries and resolutions, as well as developing communication procedures. We describe DADOS-Prospective, an open-source Web-based application for collecting and managing prospective data on human subjects for clinical and translational trials. DADOS-Prospective not only permits users to create new clinical research forms (CRF) and supports electronic signatures, but also offers the advantage of containing, in a single environment, raw research data in downloadable spreadsheet format, source documentation and regulatory files stored in PDF format, and audit trails.     

A human rights approach to an international code of conduct for genomic and clinical data sharing

Fostering data sharing is a scientific and ethical imperative. Health gains can be achieved more comprehensively and quickly by combining large, information-rich datasets from across conventionally siloed disciplines and geographic areas. While collaboration for data sharing is increasingly embraced by policymakers and the international biomedical community, we lack a common ethical and legal framework to connect regulators, funders, consortia, and research projects so as to facilitate genomic and clinical data linkage, global science collaboration, and responsible research conduct. Governance tools can be used to responsibly steer the sharing of data for proper stewardship of research discovery, genomics research resources, and their clinical applications. In this article, we propose that an international code of conduct be designed to enable global genomic and clinical data sharing for biomedical research. To give this proposed code universal application and accountability, however, we propose to position it within a human rights framework. This proposition is not without precedent: international treaties have long recognized that everyone has a right to the benefits of scientific progress and its applications, and a right to the protection of the moral and material interests resulting from scientific productions. It is time to apply these twin rights to internationally collaborative genomic and clinical data sharing.     

Implementing shared decision making in routine mental health care

Shared decision making (SDM) in mental health care involves clinicians and patients working together to make decisions. The key elements of SDM have been identified, decision support tools have been developed, and SDM has been recommended in mental health at policy level. Yet implementation remains limited. Two justifications are typically advanced in support of SDM. The clinical justification is that SDM leads to improved outcome, yet the available empirical evidence base is inconclusive. The ethical justification is that SDM is a right, but clinicians need to balance the biomedical ethical principles of autonomy and justice with beneficence and non‐maleficence. It is argued that SDM is “polyvalent”, a sociological concept which describes an idea commanding superficial but not deep agreement between disparate stakeholders. Implementing SDM in routine mental health services is as much a cultural as a technical problem. Three challenges are identified: creating widespread access to high‐quality decision support tools; integrating SDM with other recovery‐supporting interventions; and responding to cultural changes as patients develop the normal expectations of citizenship. Two approaches which may inform responses in the mental health system to these cultural changes – social marketing and the hospitality industry – are identified.