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.

Os desafios éticos da Razão Empreendedora / The ethical challenges of Entrepreneurial Logic

Resumo O texto apresenta e discute os novos personagens que têm crescente presença no ambiente de pesquisa, quais sejam o pesquisador empreendedor e a universidade empreendedora. Discute ainda o cenário atual da difusão de conhecimento científico que apresenta crescentes problemas, com dificuldade de publicação de resultados e dificuldades de acesso a resultados de pesquisa publicados. Discute também o significado da estratégia da pesquisa translacional e apresenta e discute alguns desafios éticos relevantes que resultam da reorganização das relações entre ciência e negócio. Em particular trata dos conflitos de interesse e dos resultados da supercompetição entre cientistas e instituições em um cenário de encurtamento de apoio financeiro público à ciência.

Abstract The paper introduces and discusses the new players that now have a growing presence on the research scene, namely the entrepreneurial researcher and the entrepreneurial university. It also discusses the current scenario of the diffusion of scientific knowledge that presents increasing problems, with difficulty in publishing results and difficulties in accessing the results of published research. It also discusses the implications of the strategy of translational research and presents and discusses some relevant ethical challenges that result from the reorganization of the relationship between science and business. In particular, it deals with conflicts of interest and the results of excessive competition between scientists and institutions in a scenario of diminished public financial support for science.

Biospecimens, Research Consent, and Distinguishing Cell Line Research.

Newly revised regulations for human research affecting translational oncology will become effective in January 2019. A substantial component of the debate leading to this revision was how to regulate biospecimen research; specifically, whether all biospecimens should be considered inherently "identifiable," thereby necessitating informed consent for use in research. The famous cases seminal to this discussion involve cancer cell lines, but the unique features of this kind of biospecimen research were largely missing from the regulatory deliberation. However, special aspects of cell line research-at the stages of procurement, generation, evolution, and sharing-alter how society should balance participant interests against the goals of research. Recommendations are offered to cancer researchers and policymakers going forward to enable ethically appropriate regulation of biospecimen research across its diverse spectrum.

Factors That Affect Chinese Parents' Willingness to Donate Children's Biospecimens in Pediatric Research.

Objective: To examine the factors that may influence Chinese parent's willingness to donate their children's biospecimens for use in pediatric research. Study Design: Parents or caregivers of the patients in the neurosurgery ward, oncological surgery ward, and internal medical wards at Shanghai Children's Medical Center were recruited during the period of March 1, 2016 to July 8, 2018. The questionnaire included the willingness to provide consent for donating their children's clinical biospecimens, their attitudes toward and motivations for donating their children's clinical biospecimens, opinions of contributing specimens, and an ethical consideration for their children's future willingness to donate biospecimens. Participants' demographic data and children's basic information were collected. Results: The majority of the participants agreed to donate the patients' biospecimens for research. Parents with pronounced religious beliefs, less education, who had only one child, child with a more severe disease, and living in an urban district were associated with negative attitudes toward biospecimen donation, but none of other parents' sociodemographic characteristics and some of the children's basic characteristics disclosed significant differences in donation attitudes. In five different types of biospecimens, parents were more reluctant to donate specific blood biospecimens. Physical pain and privacy protection were of most concern to parents when it came to donating their child's biospecimens. It was widely believed in parents that reconsent would be necessary for the 18-year-old adolescent. Conclusions: Our findings explored the factors that were of greatest worry to parents related to parents' willingness to donate their child's biospecimens in China. We recommend greater patient explanation to enhance the participant's engagement in the biospecimen donation, and the adolescent's attitude toward biospecimen donation needs further consideration.

Concise Review: A Comprehensive Analysis of Reported Adverse Events in Patients Receiving Unproven Stem Cell-Based Interventions.

The promise of stem cell (SC) therapies to restore functions of damaged tissues and organs brings enormous hope to patients, their families, loved ones, and caregivers. However, limits may exist for which indications SC therapies might be useful, efficacious, and safe. Applications of innovative therapies within regulatory boundaries and within the framework of controlled clinical trials are the norm in the scientific and medical community; such a system minimizes patient risk by setting a clear and acceptable safety and efficacy profile for new therapeutics before marketing authorization. This careful clinical validation approach often takes time, which patients suffering from terminal or debilitating diseases do not have. Not validated, unproven stem cell interventions (SCI) that promise a working treatment or cure for severe diseases have therefore found their way into the patient community, and providers of such treatments often take advantage of the public's willingness to pay large amounts of money for the misguided hope of a reliable recovery from their illnesses. We conducted a review of scientific publications, clinical case reports, and mass media publications to assess the reported cases and safety incidents associated with unproven SCI. The review also analyzes the main factors that were identified as contributing to the emergence and global rise of the "stem cell tourism" phenomenon. Stem Cells Translational Medicine 2018;1-10.

First-in-human Phase 1 CRISPR Gene Editing Cancer Trials: Are We Ready?

A prospective first-in-human Phase 1 CRISPR gene editing trial in the United States for patients with melanoma, synovial sarcoma, and multiple myeloma offers hope that gene editing tools may usefully treat human disease. An overarching ethical challenge with first-in-human Phase 1 clinical trials, however, is knowing when it is ethically acceptable to initiate such trials on the basis of safety and efficacy data obtained from pre-clinical studies. If the pre-clinical studies that inform trial design are themselves poorly designed - as a result of which the quality of pre-clinical evidence is deficient - then the ethical requirement of scientific validity for clinical research may not be satisfied. In turn, this could mean that the Phase 1 clinical trial will be unsafe and that trial participants will be exposed to risk for no potential benefit. To assist sponsors, researchers, clinical investigators and reviewers in deciding when it is ethically acceptable to initiate first-in-human Phase 1 CRISPR gene editing clinical trials, structured processes have been developed to assess and minimize translational distance between pre-clinical and clinical research. These processes draw attention to various features of internal validity, construct validity, and external validity. As well, the credibility of supporting evidence is to be critically assessed with particular attention to optimism bias, financial conflicts of interest and publication bias. We critically examine the pre-clinical evidence used to justify the first-inhuman Phase 1 CRISPR gene editing cancer trial in the United States using these tools. We conclude that the proposed trial cannot satisfy the ethical requirement of scientific validity because the supporting pre-clinical evidence used to inform trial design is deficient.

Current and emerging global themes in the bioethics of regenerative medicine: the tangled web of stem cell translation.

Probably the most serious problem facing the field of regenerative medicine today is the challenge of effective translation and development of viable stem cell-based therapies. Particular concerns have been raised over the growing market in unproven cell therapies. In this article, I explore recent developments in the stem cell therapy landscape and argue that while the sale of unproven therapies undoubtedly poses ethical concerns, it must be understood as part of a larger problem at the interface between biomedicine, healthcare, publics, policy and the market. Addressing this will require a broader perspective incorporating the shifting relationships between different stakeholder groups, the global politics of research and innovation, and the evolving role of publics and patients with respect to science.

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.

Adapting Preclinical Benchmarks for First-in-Human Trials of Human Embryonic Stem Cell-Based Therapies.

UNLABELLED: : As research on human embryonic stem cell (hESC)-based therapies is moving from the laboratory to the clinic, there is an urgent need to assess when it can be ethically justified to make the step from preclinical studies to the first protocols involving human subjects. We examined existing regulatory frameworks stating preclinical requirements relevant to the move to first-in-human (FIH) trials and assessed how they may be applied in the context of hESC-based interventions to best protect research participants. Our findings show that some preclinical benchmarks require rethinking (i.e., identity, purity), while others need to be specified (i.e., potency, viability), owing to the distinctive dynamic heterogeneity of hESC-based products, which increases uncertainty and persistence of safety risks and allows for limited predictions of effects in vivo. Rethinking or adaptation of how to apply preclinical benchmarks in specific cases will be required repeatedly for different hESC-based products. This process would benefit from mutual learning if researchers included these components in the description of their methods in publications. SIGNIFICANCE: To design translational research with an eye to protecting human participants in early trials, researchers and regulators need to start their efforts at the preclinical stage. Existing regulatory frameworks for preclinical research, however, are not really adapted to this in the case of stem cell translational medicine. This article reviews existing regulatory frameworks for preclinical requirements and assesses how their underlying principles may best be applied in the context of human embryonic stem cell-based interventions for the therapy of Parkinson's disease. This research will help to address the question of when it is ethically justified to start first-in-human trials in stem cell translational medicine.

Translational Research in Pediatrics IV: Solid Tissue Collection and Processing.

Solid tissues are critical for child-health research. Specimens are commonly obtained at the time of biopsy/surgery or postmortem. Research tissues can also be obtained at the time of organ retrieval for donation or from tissue that would otherwise have been discarded. Navigating the ethics of solid tissue collection from children is challenging, and optimal handling practices are imperative to maximize tissue quality. Fresh biopsy/surgical specimens can be affected by a variety of factors, including age, gender, BMI, relative humidity, freeze/thaw steps, and tissue fixation solutions. Postmortem tissues are also vulnerable to agonal factors, body storage temperature, and postmortem intervals. Nonoptimal tissue handling practices result in nucleotide degradation, decreased protein stability, artificial posttranslational protein modifications, and altered lipid concentrations. Tissue pH and tryptophan levels are 2 methods to judge the quality of solid tissue collected for research purposes; however, the RNA integrity number, together with analyses of housekeeping genes, is the new standard. A comprehensive clinical data set accompanying all tissue samples is imperative. In this review, we examined: the ethical standards relating to solid tissue procurement from children; potential sources of solid tissues; optimal practices for solid tissue processing, handling, and storage; and reliable markers of solid tissue quality.

Readability of Invasive Procedure Consent Forms.

BACKGROUND: Informed consent is a pillar of ethical medicine which requires patients to fully comprehend relevant issues including the risks, benefits, and alternatives of an intervention. Given the average reading skill of US adults is at the 8th grade level, the American Medical Association (AMA) and the National Institutes of Health (NIH) recommend patient information materials should not exceed a 6th grade reading level. We hypothesized that text provided in invasive procedure consent forms would exceed recommended readability guidelines for medical information. MATERIALS AND METHODS: To test this hypothesis, we gathered procedure consent forms from all surgical inpatient hospitals in the state of Rhode Island. For each consent form, readability analysis was measured with the following measures: Flesch Reading Ease Formula, Flesch-Kincaid Grade Level, Fog Scale, SMOG Index, Coleman-Liau Index, Automated Readability Index, and Linsear Write Formula. These readability scores were used to calculate a composite Text Readability Consensus Grade Level. RESULTS: Invasive procedure consent forms were found to be written at an average of 15th grade level (i.e., third year of college), which is significantly higher than the average US adult reading level of 8th grade (p < 0.0001) and the AMA/NIH recommended readability guidelines for patient materials of 6th grade (p < 0.0001). CONCLUSION: Invasive procedure consent forms have readability levels which makes comprehension difficult or impossible for many patients. Efforts to improve the readability of procedural consent forms should improve patient understanding regarding their healthcare decisions.

Using a Historical Lens to Envision the Next Generation of Genomic Translation Research.

BACKGROUND: The past 20 years have witnessed successive and exponential advances in genomic discovery and technology, with a broad scientific imperative pushing for continual advancements. The most consistent critique of these advances is that they have vastly outpaced translation of new knowledge into improvements in public health and medicine. METHODS: We employ a historical and epistemological analysis to characterize how prevailing scientific meta-narratives have shaped the pace and priorities of research applying genomics to health promotion. We use four 'pivotal events' - the genetic characterization of Down syndrome, the launch of the Human Genome Research Project, the discovery of BRCA1, and the emergence of direct-to- consumer genetic testing - to illustrate how these scientific meta-narratives have inhibited genomic translation research. RESULTS: The notion that discovery should precede translation research has over-focused translation research on the latest genetic testing platform. The idea that genetic-related research has an exceptional potential for public harm has encouraged research on worst case scenarios. The perceived competition between genetics and social determinants of health has discouraged a unified research agenda to move genomic translation forward. CONCLUSION: We make a case for creating new scientific meta-narratives in which discovery and translation research agendas are envisioned as an interdependent enterprise.

The structure of clinical translation: efficiency, information, and ethics.

The so-called drug pipeline is not really about drugs and not much like a pipeline. It is really about the production and dissemination of information, and it is much more like a web. The misunderstanding leads to a poor understanding of what's wrong with clinical translation and how it can be improved.

Consensus of clinical neurorestorative progress in patients with complete chronic spinal cord injury.

Currently, there is a lack of effective therapeutic methods to restore neurological function for chronic complete spinal cord injury (SCI) by conventional treatment. Neurorestorative strategies with positive preclinical results have been translated to the clinic, and some patients have gotten benefits and their quality of life has improved. These strategies include cell therapy, neurostimulation or neuromodulation, neuroprosthesis, neurotization or nerve bridging, and neurorehabilitation. The aim of this consensus by 31 experts from 20 countries is to show the objective evidence of clinical neurorestoration for chronic complete SCI by the mentioned neurorestorative strategies. Complete chronic SCI patients are no longer told, "nothing can be done." The clinical translation of more effective preclinical neurorestorative strategies should be encouraged as fast as possible in order to benefit patients with incurable CNS diseases. This manuscript is published as part of the International Association of Neurorestoratology (IANR) special issue of Cell Transplantation.

From patient to participant: enhancing the validity and ethics of cancer research through participatory research.

Participatory health research involves a wide spectrum of participation from the population of study. We describe the participatory research processes of a large mixed method study on the psychosocial impact of dragon boating in individuals with breast cancer. In particular, we discuss the involvement of a Community Advisory Group (consisting of five breast cancer patients/survivors) in the development of the research study, data collection and analysis, and dissemination of the study results. We also outline the elements of a research workshop, in which 13 breast cancer patients/survivors were involved in the development of a provincial survey for the study. The purpose of this article is to share our experience of engaging cancer patients/survivors in a participatory research study. We discuss the value-based elements of participatory research (power sharing, voice and respect, reciprocity, and mutual benefit), and provide a case-based example of how these participatory elements were employed to potentially increase the validity of the survey instrument, to enhance the ethics of working with a cancer population, and ultimately contributed to a high survey response rate.

Advancing neurosurgery through translational research.

Every year, the number of published research articles increases significantly. However, many potentially useful ideas are lost in this flood of data. Translational research provides a framework through which investigators or laboratories can maximize the likelihood that the product of their research will be adopted in medical practice. There are 2 recognizable models of translation appropriate for the majority of research: investigator driven and industry enabled. Investigator-driven research has more range because it does not have to consider the profit margin of research, but it is a slow process. The industry-enabled model accelerates the translational research process through the power of industry funding but is interested primarily in products with potential for profit. Two cases are examined to illustrate different methods of partnering with industry. IMRIS is a company founded by investigators to distribute intraoperative magnetic resonance imaging technology based on a movable high-field magnet. It took 7 years for IMRIS to make its first sale, but it is now a successful company. With neuroArm, a surgical robot, investigators decided to sell the intellectual property to an established company to ensure successful global commercialization. Translational research advances medicine by creating and distributing effective solutions to contemporary problems.

Uncertain translation, uncertain benefit and uncertain risk: ethical challenges facing first-in-human trials of induced pluripotent stem (ips) cells.

The discovery of induced pluripotent stem (iPS) cells in 2006 was heralded as a major breakthrough in stem cell research. Since then, progress in iPS cell technology has paved the way towards clinical application, particularly cell replacement therapy, which has refueled debate on the ethics of stem cell research. However, much of the discourse has focused on questions of moral status and potentiality, overlooking the ethical issues which are introduced by the clinical testing of iPS cell replacement therapy. First-in-human trials, in particular, raise a number of ethical concerns including informed consent, subject recruitment and harm minimisation as well as the inherent uncertainty and risks which are involved in testing medical procedures on humans for the first time. These issues, while a feature of any human research, become more complex in the case of iPS cell therapy, given the seriousness of the potential risks, the unreliability of available animal models, the vulnerability of the target patient group, and the high stakes of such an intensely public area of science. Our paper will present a detailed case study of iPS cell replacement therapy for Parkinson's disease to highlight these broader ethical and epistemological concerns. If we accept that iPS cell technology is fraught with challenges which go far beyond merely refuting the potentiality of the stem cell line, we conclude that iPS cell research should not replace, but proceed alongside embryonic and adult somatic stem cell research to promote cross-fertilisation of knowledge and better clinical outcomes.

Risks, benefits and ethical, legal, and societal considerations for translation of prenatal gene therapy to human application.

The still experimental nature of prenatal gene therapy carries a certain degree of risk, both for the pregnant mother as well as for the fetus. Some of the risks are procedural hazards already known from more conventional fetal medicine interventions. Others are more specific to gene therapy such as the potential for interference with normal fetal development, the possibility of inadvertent germ line gene transfer, and the danger of oncogenesis. This chapter reviews the potential risks in relation to the expected benefits of prenatal gene therapy. It discusses the scientific, ethical, legal, and social implications of this novel preventive approach to genetic disease and outlines preconditions to be met in preparation for a potential future clinical application.