Recent progress in synthetic biology has enabled the development of novel therapeutic opportunities for the treatment of human disease. In the near future, first-in-human trials will be indicated. FIH trials mark a key milestone in the translation of medical SynBio applications into clinical practice. Fostered by uncertainty of possible adverse events for trial participants, a variety of ethical concerns emerge with regards to SynBio FIH trials, including ‘risk’ minimization. These concerns are associated with any FIH trial, however, due to the (...) novelty of the approach, they become more pronounced for medical applications of emerging technologies like SynBio. To minimize potential harm for trial participants, scholars, guidelines, regulations and policy makers alike suggest using ‘risk assessment’ as evaluation tool for such trials. Conversely, in the context of emTech FIH trials, we believe it to be at least questionable to contextualize uncertainty of potential adverse events as ‘risk’ and apply traditional risk assessment methods. Hence, this issue needs to be discussed to enable alterations of the evaluation process before the translational phase of SynBio applications begins. In this paper, we will take the opportunity to start the debate and highlight how a misunderstanding of the concept of risk, and the possibilities and limitations of risk assessment, respectively, might impair decision-making by the relevant regulatory authorities and research ethics committees, and discuss possible solutions to tackle the issue. (shrink)

Nanotechnology, which involves manipulation of matter on a ‘nano’ scale, is considered to be a key enabling technology. Medical applications of nanotechnology are expected to significantly improve disease diagnostic and therapeutic modalities and subsequently reduce health care costs. However, there is no consensus on the definition of nanotechnology or nanomedicine, and this stems from the underlying debate on defining ‘nano’. This paper aims to present the diversity in the definition of nanomedicine and its impact on the translation of basic science (...) research in nanotechnology into clinical applications. We present the insights obtained from exploratory qualitative interviews with 46 stakeholders involved in translational nanomedicine from Europe and North America. The definition of nanomedicine has implications for many aspects of translational research including: fund allocation, patents, drug regulatory review processes and approvals, ethical review processes, clinical trials and public acceptance. Given the interdisciplinary nature of the field and common interest in developing effective clinical applications, it is important to have honest and transparent communication about nanomedicine, its benefits and potential harm. A clear and consistent definition of nanomedicine would significantly facilitate trust among various stakeholders including the general public while minimizing the risk of miscommunication and undue fear of nanotechnology and nanomedicine. (shrink)

First-in-human research has several characteristics that require special attention with respect to ethics and human subjects protections. At least some nanomedical technologies may also have characteristics that merit special attention in clinical research, as other papers in this symposium show. This paper considers how to address these characteristics in the consent form and process for FIH nanomedicine research, focusing principally on experimental nanotherapeutic interventions but also considering nanodiagnostic interventions.It is essential, as a starting point, to recognize that the consent form (...) and process are by no means the primary protectors of human subjects. Instead, consideration of the form and content of informed consent becomes relevant only after a clinical trial has been reviewed and deemed scientifically and ethically acceptable.Two convergent types of challenges to informed consent are posed by nanomedicine FIH research. First, some issues appear generally applicable to FIH research, but have specific nanomedicine implications. (shrink)

Nanomedicine is yielding new and improved treatments and diagnostics for a range of diseases and disorders. Nanomedicine applications incorporate materials and components with nanoscale dimensions where novel physiochemical properties emerge as a result of size-dependent phenomena and high surface-to-mass ratio. Nanotherapeutics and in vivo nanodiagnostics are a subset of nanomedicine products that enter the human body. These include drugs, biological products, implantable medical devices, and combination products that are designed to function in the body in ways unachievable at larger scales. (...) Nanotherapeutics andin vivonanodiagnostics incorporate materials that are engineered at the nanoscale to express novel properties that are medicinally useful. These nanomedicine applications can also contain nanomaterials that are biologically active, producing interactions that depend on biological triggers. Examples include nanoscale formulations of insoluble drugs to improve bioavailability and pharmacokinetics, drugs encapsulated in hollow nanoparticles with the ability to target and cross cellular and tissue membranes and to release their payload at a specific time or location, imaging agents that demonstrate novel optical properties to aid in locating micrometastases, and antimicrobial and drug-eluting components or coatings of implantable medical devices such as stents. (shrink)

The label ‘Translational Research’ (TR) has become ever more popular in the biomedical domain in recent years. It is usually presented as an attempt to bridge a supposed gap between knowledge produced at the lab bench and its use at the clinical bedside. This is claimed to help society harvest the benefits of its investments in scientific research. The rhetorical as well as moral force of the label TR obscure, however, that it is actually used in very different ways. In (...) this paper, we analyse the scientific discourse on TR, with the aim to disentangle and critically evaluate the different meanings of the label. We start with a brief reconstruction of the history of the concept. Subsequently, we unravel how the label is actually used in a sample of scientific publications on TR and examine the presuppositions implied by different views of TR. We argue that it is useful to distinguish different views of TR on the basis of three dimensions, related to (1) the construction of the ‘translational gap’; (2) the model of the translational process; and (3) the cause of the perceived translational gap. We conclude that the motive to make society benefit from its investments in biomedical science may be laudable, but that it is doubtful whether the dominant views of TR will contribute to this end. (shrink)

To give substance to the rhetoric of ‘learning health systems’, a variety of novel trial designs are being explored to more seamlessly integrate research with medical practice, reduce study duration and reduce the number of participants allocated to ineffective interventions. Many of these designs rely on response adaptive randomisation. However, critics charge that RAR is unethical on the grounds that it violates the principle of equipoise. In this paper, I reconstruct critiques of RAR as holding that it is inconsistent with (...) five important ethical principles. I then argue that these criticisms rest on a faulty view of equipoise encouraged by the idea that a RAR study models the beliefs of a single rational agent about the relative merits of the interventions being studied. I outline a view in which RAR models an idealised health system in which diverse communities of fully informed experts shrink or grow as their constituent members update their expert opinions in light of reliable medical evidence. I show how a proper understanding of clinical equipoise can reconcile this conception of RAR with these five ethical principles. This analysis removes an in-principle objection to RAR and sheds important light on the relationship between clinical equipoise and transient diversity in the scientific community. (shrink)

The biomedical literature and popular media are full of upbeat reports about the health benefits we can expect from medical innovations using nanotechnology. Some particularly enthusiastic reports portray nanotechnology as one of the innovations that will lead to a significantly extended human life span. Extreme enthusiasts predict that nanotechnology “will ultimately enable us to redesign and rebuild, molecule by molecule, our bodies and brains….”Nanomaterials have special characteristics that could contribute to improved patient care. But the same characteristics that make nanotechnology (...) promising also present risks to humans exposed to nanomaterials. A failure to appreciate these risks could jeopardize the research effort. As others have pointed out, if nanomedical interventions produce unexpected human harm, a loss of public and government support for nanomedicine is likely to follow.Like other forms of medical innovation, novel nanomedical interventions require human testing to evaluate their safety and effectiveness. (shrink)

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. (shrink)

The last two decades have witnessed a crescendo of allegations that clinical translation is rife with waste and inefficiency. Patient advocates argue that excessively demanding regulations delay access to life‐saving drugs, research funders claim that too much basic science languishes in academic laboratories, journal editors allege that biased reporting squanders public investment in biomedical research, and drug companies (and their critics) argue that far too much is expended in pharmaceutical development.But how should stakeholders evaluate the efficiency of translation and proposed (...) reforms to drug development? Effective reforms require an accurate model of the systems they aspire to improve—their components, their proper functions, and their pathologies. However, there is currently no explicit and well‐developed model of translation for evaluating such criticisms.In what follows, we offer an explicit model of clinical translation. Many discussions of clinical translation and its pathologies presume that its main output is tangible: new drugs, vaccines, devices, and diagnostics. We disagree. We argue that the principal output of clinical translation is information—in particular, information about the coordinated set of materials, practices, and constraints needed to safely unlock the therapeutic or preventive activities of drugs, biologics, and diagnostics. To develop this information calls for a process far different from a simple linear progression of clinical trials; it requires exploratory sampling of many different elements in this set. Our model points to some limitations and liabilities of influential proposals for reforming research. It also reveals some underrecognized opportunities for improving the efficiency of clinical translation. (shrink)

The label ‘Translational Research’ (TR) has become ever more popular in the biomedical domain in recent years. It is usually presented as an attempt to bridge a supposed gap between knowledge produced at the lab bench and its use at the clinical bedside. This is claimed to help society harvest the benefits of its investments in scientific research. The rhetorical as well as moral force of the label TR obscure, however, that it is actually used in very different ways. In (...) this paper, we analyse the scientific discourse on TR, with the aim to disentangle and critically evaluate the different meanings of the label. We start with a brief reconstruction of the history of the concept. Subsequently, we unravel how the label is actually used in a sample of scientific publications on TR and examine the presuppositions implied by different views of TR. We argue that it is useful to distinguish different views of TR on the basis of three dimensions, related to (1) the construction of the ‘translational gap’; (2) the model of the translational process; and (3) the cause of the perceived translational gap. We conclude that the motive to make society benefit from its investments in biomedical science may be laudable, but that it is doubtful whether the dominant views of TR will contribute to this end. (shrink)

Launch of clinical investigation represents a substantial escalation in commitment to a particular clinical translation trajectory; it also exposes human subjects to poorly understood interventions. Despite these high stakes, there is little to guide decision-makers on the scientific and ethical evaluation of early phase trials. In this article, we review policies and consensus statements on human protections, drug regulation, and research design surrounding trial launch, and conclude that decision-making is largely left to the discretion of research teams and sponsors. We (...) then review what is currently understood about how research teams exercise this discretion, and close by laying out a research agenda for characterizing the way investigators, sponsors, and reviewers approach decision-making in early phase research. (shrink)

The innovative field of Regenerative Medicine (RM) is expected to extend the possibilities of prevention or early treatment in healthcare. Increasingly, clinical trials will be developed for people at risk of disease to investigate these RM interventions. These individuals at risk are characterised by their susceptibility for developing clinically manifest disease in future due to the existence of degenerative abnormalities. So far, there has been little debate about the ethical appropriateness of including such individuals at risk in clinical trials. We (...) discuss three main challenges of selecting this participant model for testing RM interventions: the challenge of achieving a proportional risk–benefit balance; complexities in the trial design in terms of follow-up and sample size; and the difficulty of obtaining informed consent due to the many uncertainties. We conclude that selecting the model is not ethically justifiable for first-in-man trials with RM interventions due to the high risks and uncertainties. However, the model can be ethically appropriate for testing the efficacy of RM interventions under the following conditions: interventions should be low risk; the degenerative abnormalities (and other risk factors) should be strongly related with disease within a short time frame; robust preclinical evidence of efficacy needs to be present; and the informed consent procedure should contain extra safeguards with regard to communication on uncertainties. (shrink)

The U.S. National Institute of Allergies and Infectious Diseases and the National Institute of Mental Health have a new research priority: inclusion of terminally ill persons living with HIV in HIV cure-related research. For example, the Last Gift is a clinical research study at the University of California San Diego for PLWHIV who have a terminal illness, with a prognosis of less than 6 months. As end-of-life HIV cure research is relatively new, the scientific community has a timely opportunity to (...) examine the related ethical challenges. Following an extensive review of the EOL and HIV cure research ethics literature, combined with deliberation from various stakeholders and our experience with the Last Gift study to date, we outline considerations to ensure that such research with terminally ill PLWHIV remains ethical, focusing on five topics: 1) protecting autonomy through informed consent, 2) avoiding exploitation and fostering altruism, 3) maintaining a favorable benefits/risks balance, 4) safeguarding against vulnerability through patient-participant centeredness, and 5) ensuring the acceptance of next-of-kin/loved ones and community stakeholders. EOL HIV cure-related research can be performed ethically and effectively by anticipating key issues that may arise. While not unique to the fields of EOL or HIV cure-related research, the considerations highlighted can help us support a new research approach. We must honor the lives of PLWHIV whose involvement in research can provide the knowledge needed to achieve the dream of making HIV infection curable. (shrink)

BackgroundCurrent policies regulating the use of animals for scientific purposes are based on balancing between potential gain of knowledge and suffering of animals used in experimentation. The balancing process is complicated, on the one hand by plurality of views on our duties towards animals, and on the other hand by more recent discussions on uncertainty in the probability of reaching the final aim of the research and problems of translational failure.MethodsThe study combines ethical analysis based on a literature review with (...) neuropsychiatry-related preclinical research as a case study.ResultsBased on the analysis and the case study we show that neuropsychiatry-related preclinical research is an especially interesting case from an ethical perspective. The 3R principles are used to minimize the negative consequences for the animals used in research. However, neuropsychiatric research is characterized by specific challenges in assessing the probability of success of reaching the final aim, due to our limited mechanistic knowledge of human neuropsychiatric illness. Consequently, the translational value of the currently used animal models may be difficult to prove, which undermines the validity of these models and complicated the ethical assessment.ConclusionsWe conclude that a combined approach that deals with both science and the ethical dimensions is necessary to address the problems of validity and translation in neuropsychiatry-related preclinical research. We suggest this approach to comprise first, improved experimental methods, e.g. by using systematic reviews, second, a more patients-based approach that leads to models that reflect interindividual variation better, and third, more interdisciplinary cooperation. (shrink)

Next SectionThe current focus on early intervention trials in Alzheimer's disease research raises particular ethical issues. These arise out of problems of validating study results and translating them into general practice for one thing and out of unwanted effects of an uncertain diagnosis for diagnosed people for another. The first addresses the demands of scientific research compared to those of medical practice, questioning how the medical value of clinical trials is evaluated. The second relates the scientific and medical value of (...) early intervention trials to the normative value of an uncertain diagnosis. Are people who are diagnosed with a potential early form of AD in clinical studies patients proper—although they would not have been diagnosed with the given “disease” in non-research-oriented medical settings? The very problem of framing this question in terms of diagnostic misconceptions connects conceptual with ethical issues of research into preclinical stages of neurodegenerative diseases. (shrink)