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There is an urgent need for increased understanding of COVID-19 and strategies for its prevention, treatment, and mitigation. All participants in the research enterprise, including institutional review boards, have an ethical duty to protect participants and ensure that the benefits gained from such research do not conflict with the core principles that guided researchers prior to the pandemic. In this review, we discuss the ethical issues surrounding initiation and conduct of clinical trials, focusing on novel COVID-19 therapeutic, vaccine, or biospecimen research, using the principles of autonomy, beneficence, and justice. We discuss strategies to manage the practical challenges associated with the conduct of clinical trials, with an emphasis on maintaining the rights and welfare of research participants.

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The Blood and Marrow Transplant Clinical Trials Network (BMT CTN), funded by the National Heart, Lung, and Blood Institute and the National Cancer Institute for more than 2 decades, is focused on improving the outcomes of hematopoietic cell transplantation (HCT) and other cellular therapies. It answered critical questions about conditioning intensity, donor choice, graft-versus-host disease prevention and treatment, and relapse mitigation strategies in a manner made possible by an extensive network of centers that have enrolled more than 16,000 patients to more than 55 trials. Although the BMT CTN has engaged patients in a variety of ways since its establishment, there is a growing realization that increasing that engagement and including caregivers offers many additional benefits to patients and investigators alike. Bringing the voice of patients and caregivers to clinical trial design is likely to enhance trial participation and reduce barriers to recruitment/retention. Unless clinical trials are designed with unique considerations of patients who have socioeconomic and access challenges, these populations will remain under-represented in HCT trials with limited generalizability of results. The next main frontier in our field is patient and caregiver access to high-quality HCT facilities coupled with the opportunity to participate in relevant, meaningful clinical research. In 2021, the BMT CTN Executive Committee convened a Patient and Caregiver Advocacy Task Force with a diverse membership representing a variety of stakeholders. The charge to the Task Force was to provide achievable recommendations for incorporating patient input at all steps of clinical trial development from initial concept to dissemination of results. Four focus areas were identified: (1) patient and caregiver input in research portfolio; (2) patient engagement in informed consent, protocol development and trial conduct; (3) communication to patients about trial progress, primary outcomes and secondary analyses; and (4) increased awareness among patients who may be considering BMT or cell therapy about BMT CTN trials. Three specific initiatives were considered as high priority by the Task Force: Fostering patient and caregiver engagement in development of the research portfolio and protocols; Developing communication plans for ongoing studies; and Simplifying the process for informed consent to make it more patient friendly. The BMT CTN has established a patient and caregiver advocacy committee that is tasked with developing concrete steps to incorporate recommendations of the BMT CTN Task Force in its current and future work. The BMT CTN recognizes patient and caregivers are valuable partners whose voice will enhance the conduct of impactful trials in BMT and cell therapy.

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Clinical trials to address the COVID-19 public health emergency have broadly excluded pregnant people from participation, illustrating a long-standing trend of clinical trial exclusion that has led to a clear knowledge gap and unmet need in the treatment and prevention of medical conditions experienced during pregnancy and of pregnancy-related conditions. Drugs (includes products such as drugs, biologics, biosimilars and vaccines) approved for a certain medical condition in adults are also approved for use in pregnant adults with the same medical condition, unless contraindicated for use in pregnancy. However, there are limited pregnancy-specific data on risks and benefits of drugs in pregnant people, despite their approval for all adults. The United States Food and Drug Administration-approved medical products are used widely by pregnant people, 90% of whom take at least 1 medication during the course of their pregnancy despite there being sparse data from clinical trials on these products in pregnancy. This overall lack of clinical data precludes informed decision-making, causing clinicians and pregnant patients to have to decide whether to pursue treatment without an adequate understanding of potential effects. Although some United States Food and Drug Administration initiatives and other federal efforts have helped to promote the inclusion of pregnant people in clinical research, broader collaboration and reforms are needed to address challenges related to the design and conduct of trials that enroll pregnant people, and to forge a culture of widespread inclusion of pregnant people in clinical research. This article summarizes the scientific, ethical, and legal considerations governing research conducted during pregnancy, as discussed during a recent subject matter expert convening held by the Duke-Margolis Center for Health Policy and the United States Food and Drug Administration on this topic. This article also recommends strategies for overcoming impediments to inclusion and trial conduct.

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The Australian clinical trials sector has grown steadily over the past decade, particularly with respect to early phase trials where Australia's research capacity, capability and quality of research is revered. With an increase in the number of internationally sponsored clinical research projects being conducted in Australia, particularly in the early phase setting, there has been a corresponding growth in the number of clinical research sites conducting early phase clinical trials. Australian researchers are guided by a multitude of research codes, guidance and statements which govern the conduct of clinical trials. Although international guidance regarding the conduct of early phase clinical trials exists, there is currently no single source outlining best practice recommendations for the conduct of early phase clinical trials in Australia. In recognition of this Clinical Trials: Impact & Quality (CT:IQ), a collaborative of sector stakeholders, convened a project team with comprehensive knowledge of the Australian clinical trials sector and particularly early phase research, to evaluate and collate broadly applicable and implementable guidance for the conduct of early phase clinical trials. Although the initial intent was to create guidance specific to early phase, we recognize the project outcomes are more broadly implementable irrespective of the research phase and are intended to support all clinical research sites to conduct high-quality clinical trials in Australia.

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BACKGROUND: The Open Payments database represents a new, substantial source of information on the US clinical trial investigator landscape. METHODS: This paper draws upon the Open Payments database. This database, mandated by the US Sunshine Act, does help provide a vital missing element in understanding the commercial clinical trial landscape in the United States: comprehensive, detailed, clinical investigator and site information by specific clinical trial. Pharmaceutical companies are required to report all payment detail to US-based physicians, including their participation in US clinical trials. The data are available going back to the second half of 2013 and are updated each year. Data compliance is very high. RESULTS: Open Payments data demonstrate, consistent with ClinicalTrials.gov results, a constancy in the level of commercially sponsored clinical trial activity. The number of active clinical investigators for example has remained unchanged each year since 2013. The percentage of one-time investigators is substantially lower than has often been quoted. A strikingly large percentage of investigators in the United States though participate in a very limited number of clinical trials. A large majority of clinical investigators conduct clinical trials in their private practice. CONCLUSION: Following the US experience, other countries are instituting physician payment databases similar to Open Payments Open Payments provides critical management and operation data, including detailed investigator and site experience data. In addition, it is possible to estimate how investigators performed on each clinical trial.

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The estimated probability of progressing from phase 3 analgesic clinical trials to regulatory approval is approximately 57%, suggesting that a considerable number of treatments with phase 2 trial results deemed sufficiently successful to progress to phase 3 do not yield positive phase 3 results. Deficiencies in the quality of clinical trial conduct could account for some of this failure. An Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials meeting was convened to identify potential areas for improvement in trial conduct in order to improve assay sensitivity (ie, ability of trials to detect a true treatment effect). We present recommendations based on presentations and discussions at the meeting, literature reviews, and iterative revisions of this article. The recommendations relate to the following areas: 1) study design (ie, to promote feasibility), 2) site selection and staff training, 3) participant selection and training, 4) treatment adherence, 5) data collection, and 6) data and study monitoring. Implementation of these recommendations may improve the quality of clinical trial data and thus the validity and assay sensitivity of clinical trials. Future research regarding the effects of these strategies will help identify the most efficient use of resources for conducting high quality clinical trials. PERSPECTIVE: Every effort should be made to optimize the quality of clinical trial data. This manuscript discusses considerations to improve conduct of pain clinical trials based on research in multiple medical fields and the expert consensus of pain researchers and stakeholders from academia, regulatory agencies, and industry.

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As we enter the information age of health care, digital health technologies offer significant opportunities to optimize both clinical care delivery and clinical research. Despite their potential, the use of such information technologies in clinical care and research faces major data quality, privacy, and regulatory concerns. In hopes of addressing both the promise and challenges facing digital health technologies in the transformation of health care, we convened a think tank meeting with academic, industry, and regulatory representatives in December 2016 in Washington, DC. In this paper, we summarize the proceedings of the think tank meeting and aim to delineate a framework for appropriately using digital health technologies in healthcare delivery and research.

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Clinical trials that combine medical therapy and surgical treatment pose a number of challenges. The ANTHALYA trial investigated the efficacy and safety of adding bevacizumab to neoadjuvant carboplatin-paclitaxel chemotherapy prior to interval debulking surgery (IDS) in patients with ovarian cancer. The success of the trial depended on the efficacy and the safety of the combination and on the surgical effort. Furthermore, at the time of study design, neoadjuvant bevacizumab had not been investigated in ovarian cancer patients and it was unknown if neoadjuvant angiogenic therapy would be well tolerated or would negatively impact the success of IDS. Therefore, safety in the ANTHALYA trial was paramount. To overcome these challenges we conducted the trial in collaboration with French oncologists and surgeons who were experts in the multidisciplinary treatment of ovarian cancer. Toxicity was monitored during the neoadjuvant and IDS periods using a Bayesian approach which provided flexibility in the decision-making process regarding the continuation or rapid discontinuation of the trial in response to a safety signal. We implemented a stopping rule for safety based on a number of pre-defined bevacizumab-related complications of special interest. We also developed an electronic case report form, which greatly facilitated the collection and dissemination of safety information and other trial data. Here we describe how we used these tools to ensure the successful conduct of ANTHALYA and report how it is possible to mix a Bayesian approach for monitoring toxicity and a frequentist approach for evaluating efficacy within the same trial.

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Background According to Good Clinical Practice, clinical trials must protect rights and safety of patients and make sure that the trial results are valid and interpretable. Monitoring on-site has an important role in achieving these objectives; it controls trial conduct at trial sites and informs the sponsor on systematic problems. In the past, extensive on-site monitoring with a particular focus on formal source data verification often lost sight of systematic problems in study procedures that endanger Good Clinical Practice objectives. ADAMON is a prospective, stratified, cluster-randomised, controlled study comparing extensive on-site monitoring with risk-adapted monitoring according to a previously published approach. Methods In all, 213 sites from 11 academic trials were cluster-randomised between extensive on-site monitoring (104) and risk-adapted monitoring (109). Independent post-trial audits using structured manuals were performed to determine the frequency of major Good Clinical Practice findings at the patient level. The primary outcome measure is the proportion of audited patients with at least one major audit finding. Analysis relies on logistic regression incorporating trial and monitoring arm as fixed effects and site as random effect. The hypothesis was that risk-adapted monitoring is non-inferior to extensive on-site monitoring with a non-inferiority margin of 0.60 (logit scale). Results Average number of monitoring visits and time spent on-site was 2.1 and 2.7 times higher in extensive on-site monitoring than in risk-adapted monitoring, respectively. A total of 156 (extensive on-site monitoring: 76; risk-adapted monitoring: 80) sites were audited. In 996 of 1618 audited patients, a total of 2456 major audit findings were documented. Depending on the trial, findings were identified in 18%-99% of the audited patients, with no marked monitoring effect in any of the trials. The estimated monitoring effect is -0.04 on the logit scale with two-sided 95% confidence interval (-0.40; 0.33), demonstrating that risk-adapted monitoring is non-inferior to extensive on-site monitoring. At most, extensive on-site monitoring could reduce the frequency of major Good Clinical Practice findings by 8.2% compared with risk-adapted monitoring. Conclusion Compared with risk-adapted monitoring, the potential benefit of extensive on-site monitoring is small relative to overall finding rates, although risk-adapted monitoring requires less than 50% of extensive on-site monitoring resources. Clusters of findings within trials suggest that complicated, overly specific or not properly justified protocol requirements contributed to the overall frequency of findings. Risk-adapted monitoring in only a sample of patients appears sufficient to identify systematic problems in the conduct of clinical trials. Risk-adapted monitoring has a part to play in quality control. However, no monitoring strategy can remedy defects in quality of design. Monitoring should be embedded in a comprehensive quality management approach covering the entire trial lifecycle.

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BACKGROUND: In the last few decades, the number of trials using Bayesian methods has grown rapidly. Publications prior to 1990 included only three clinical trials that used Bayesian methods, but that number quickly jumped to 19 in the 1990s and to 99 from 2000 to 2012. While this literature provides many examples of Bayesian Adaptive Designs (BAD), none of the papers that are available walks the reader through the detailed process of conducting a BAD. This paper fills that gap by describing the BAD process used for one comparative effectiveness trial (Patient Assisted Intervention for Neuropathy: Comparison of Treatment in Real Life Situations) that can be generalized for use by others. A BAD was chosen with efficiency in mind. Response-adaptive randomization allows the potential for substantially smaller sample sizes, and can provide faster conclusions about which treatment or treatments are most effective. An Internet-based electronic data capture tool, which features a randomization module, facilitated data capture across study sites and an in-house computation software program was developed to implement the response-adaptive randomization. RESULTS: A process for adapting randomization with minimal interruption to study sites was developed. A new randomization table can be generated quickly and can be seamlessly integrated in the data capture tool with minimal interruption to study sites. CONCLUSION: This manuscript is the first to detail the technical process used to evaluate a multisite comparative effectiveness trial using adaptive randomization. An important opportunity for the application of Bayesian trials is in comparative effectiveness trials. The specific case study presented in this paper can be used as a model for conducting future clinical trials using a combination of statistical software and a web-based application. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02260388 , registered on 6 October 2014.

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