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Time limits on organ viability from retrieval to implantation shape the US system for human organ transplantation. Preclinical research has demonstrated that emerging biopreservation technologies can prolong organ viability, perhaps indefinitely. These technologies could transform transplantation into a scheduled procedure without geographic or time constraints, permitting organ assessment and potential preconditioning of the recipients. However, the safety and efficacy of advanced biopreservation with prolonged storage of vascularized organs followed by reanimation will require new regulatory oversight, as clinicians and transplant centers are not trained in the engineering techniques involved or equipped to assess the manipulated organs. Although the Food and Drug Administration is best situated to provide that process oversight, the agency has until now declined to oversee organ quality and has excluded vascularized organs from the oversight framework of human cells, tissues, and cellular-based and tissue-based products. Integration of advanced biopreservation technologies will require new facilities for organ preservation, storage, and reanimation plus ethical guidance on immediate organ use versus preservation, national allocation, and governance of centralized organ banks. Realization of the long-term benefit of advanced biopreservation requires anticipation of the necessary legal and ethical oversight tools and that process should begin now., Competing Interests: Declaration of competing interests The authors of this manuscript have conflicts of interest to disclose as described by the American Journal of Transplantation: J. Bischof is co-founder of Vitristor and discloses “Cryopreservation compositions and methods” pending U.S. Patent Applications 14/775,998 and 17/579,369. K. Uygun is co-founder of Organ Solutions LLC. He and M. Toner are co-founders of Sylvatica Biotech Inc. All other authors have no disclosures., (Copyright © 2024 American Society of Transplantation & American Society of Transplant Surgeons. Published by Elsevier Inc. All rights reserved.)

Clinicians and patients often try a treatment for an initial period to inform longer-term therapeutic decisions. A more rigorous approach involves N-of-1 trials. In these single-patient crossover trials, typically conducted in patients with chronic conditions, individual patients are given candidate treatments in a double-blinded, random sequence of alternating periods to determine the most effective treatment for that patient. However, to date, these trials are rarely done outside of research settings and have not been integrated into general care where they could offer substantial benefit. Designating this classical, N-of-1 trial design as type 1, there also are new and evolving uses of N-of-1 trials that we designate as type 2. In these, rather than focusing on optimizing treatment for chronic diseases when multiple approved choices are available, as is typical of type 1, a type 2 N-of-1 trial tests treatments designed specifically for a patient with a rare disease, to facilitate personalized medicine. While the aims differ, both types face the challenge of collecting individual-patient evidence using standard, trusted, widely accepted methods. To fulfill their potential for producing both clinical and research benefits, and to be available for wide use, N-of-1 trials will have to fit into the current healthcare ecosystem. This will require generalizable and accepted processes, platforms, methods, and standards. This also will require sustainable value-based arrangements among key stakeholders. In this article, we review opportunities, stakeholders, issues, and possible approaches that could support general use of N-of-1 trials and deliver benefit to patients and the healthcare enterprise. To assess and expand the benefits of N-of-1 trials, we propose multistakeholder meetings, workshops, and the generation of methods, standards, and platforms that would support wider availability and the value of N-of-1 trials., (© 2021 The Authors. Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Efficacy trials, designed to gain regulatory marketing approval, evaluate drugs in optimally selected patients under advantageous conditions for relatively short time periods. Effectiveness trials, designed to evaluate use in usual practice, assess treatments among more typical patients in real-world conditions with longer follow-up periods. In "efficacy-to-effectiveness (E2E) trials," if the initial efficacy trial component is positive, the trial seamlessly transitions to an effectiveness trial component to efficiently yield both types of evidence. Yet more time could be saved by simultaneously addressing efficacy and effectiveness in an "efficacy and effectiveness too (EE2) trial." Additionally, hybrids of the E2E and EE2 approaches with differing degrees of overlap of the two components could allow flexibility for specific drug development needs. In planning EE2 trials, each stakeholder's current and future needs, incentives, and perspective must be considered. Although challenging, the ultimate benefits to stakeholders, the health system, and the public should justify this effort., (© 2019 The Authors Clinical Pharmacology & Therapeutics published by Wiley Periodicals, Inc. on behalf of American Society for Clinical Pharmacology and Therapeutics.)

We propose an "efficacy-to-effectiveness" (E2E) clinical trial design, in which an effectiveness trial would commence seamlessly upon completion of the efficacy trial. Efficacy trials use inclusion/exclusion criteria to produce relatively homogeneous samples of participants with the target condition, conducted in settings that foster adherence to rigorous clinical protocols. Effectiveness trials use inclusion/exclusion criteria that generate heterogeneous samples that are more similar to the general patient spectrum, conducted in more varied settings, with protocols that approximate typical clinical care. In E2E trials, results from the efficacy trial component would be used to design the effectiveness trial component, to confirm and/or discern associations between clinical characteristics and treatment effects in typical care, and potentially to test new hypotheses. An E2E approach may improve the evidentiary basis for selecting treatments, expand understanding of the effectiveness of treatments in subgroups with particular clinical features, and foster incorporation of effectiveness information into regulatory processes.

Synthetic biology seeks to create modular biological parts that can be assembled into useful devices, allowing the modification of biological systems with greater reliability, at lower cost, with greater speed, and by a larger pool of people than has been the case with traditional genetic engineering. We assess the offensive and defensive security implications of synthetic biology based on the insights of leading synthetic biologists into how the technology may develop, the projections of practicing biosecurity authorities on changes in the security context and potential security applications of synthetic biology, and joint appraisals of policy relevant sources of uncertainty. Synthetic biology appears to have minimal security implications in the near term, create modest offensive advantages in the medium term, and strengthen defensive capabilities against natural and engineered biological threats and enable novel potential offensive uses in the long term. To maximize defensive and minimize offensive effects of synthetic biology despite uncertainty, this essay suggests a combination of policy approaches, including community-based efforts, regulation and surveillance, further research, and the deliberate design of security and safety features into the technology.

Disputes over invocation of precaution in the presence of uncertainty are building. This essay finds: (1) analysis of past WTO panel decisions and current EU-US regulatory conflicts suggests that appeals to scientific risk assessment will not resolve emerging conflicts; (2) Bayesian updating strategies, with commitments to modify policies as information emerges, may ameliorate conflicts over precaution in environmental and security affairs.