ABSTRACT
Adaptive platform trials (APTs) are often complex clinical trials that, ideally, are well suited to answer the motivating clinical questions effectively and efficiently, with the motivating clinical questions and associated treatment arms expected to evolve over time as evidence accumulates. Recently, APTs have played a pivotal role in informing public health policy by efficiently generating compelling evidence regarding the effectiveness of therapies for COVID-19. For APTs to be maximally effective in informing future public health policy, they must be carefully tailored to address the right clinical questions, with the right balance of size, scope, rigor, and flexibility. The design process requires input from clinical and statistical domain experts and often includes input from trial implementation personnel, ethicists, and patient representatives. The design process is inherently iterative, with proposed designs evaluated through trial simulation, the identification of strengths and weaknesses of the proposed design, and revision by the team to address weaknesses. This iterative design process requires effective communication and collaboration between the statistical and clinical domain experts. This session is intended to present a current best practice in facilitating and enhancing the collaborative design process for APTs, including how best to present simulation-based trial performance to the design team and ensure effective interdisciplinary communication. The speakers have extensive experience in leading the design of APTs across multiple therapeutic areas, in both academic and industry settings. The session will begin with a brief presentation by Dr. Lewis on the basic structure of an APT and the tasks and challenges associated with the multidisciplinary design process. The subsequent discussion will be organized by the following themes: (1) considerations in the selection of the study population and primary outcome metric;(2) selecting treatment domains and factors to be compared;(3) trial simulation and communication of performance metrics to both statistical and non-statistical team members;and (4) defining and calibrating interim decision rules. Each of the 4 panel members will outline a recommended approach to facilitating 1 of the 4 design tasks, with examples drawn from their experience. The remaining time (15 min) will be available for a panel question-and-answer period. At the end of the session, the audience will have an understanding of the general organization of, and a process for facilitating, the design process for an adaptive platform trial. Panel Members Roger J Lewis, MD, PhD, is a Senior Physician in the Los Angeles County Department of Health Services, Professor of Emergency Medicine at the David Geffen School of Medicine at UCLA, and the Senior Medical Scientist at Berry Consultants, LLC, a group that specializes in innovative clinical trial design. He is also the former Chair of the Department of Emergency Medicine at Harbor-UCLA Medical Center. Dr. Lewis' expertise centers on adaptive and Bayesian clinical trials, including platform trials;translational, clinical, health services and outcomes research methodology;data and safety monitoring boards, and the oversight of clinical trials. Dr. Lewis was elected to membership in the National Academy of Medicine in 2009. He has authored or coauthored over 270 original research publications, reviews, editorials, and chapters. Dr. Lewis is a Past President of the Society for Academic Emergency Medicine (SAEM) and served on the Board of Directors for the Society for Clinical Trials. He is a fellow of the American College of Emergency Physicians, the American Statistical Association, and the Society for Clinical Trials. Juliana Tolles, MD, MHS, is an Assistant Professor of Emergency Medicine at the Harbor-UCLA Medical Center and the David Geffen School of Medicine at UCLA, and a Medical and Statistical Scientist at Berry Consultants, LLC. Her academic research interests include emergency medical services, resuscitation medicine, and trau a care. She has authored several reviews for Journal of the American Medical Association (JAMA) on statistical methodology and has lectured nationally on research methodology for the Society for Academic Emergency Medicine Advanced Research Methodology Evaluation and Design (ARMED) course. She is also a co-investigator for the Strategies to Innovate Emergency Clinical Care Trials (SIREN) network Southern California site. Kert Viele, PhD, is a Director and Senior Statistical Scientist with Berry Consultants, where he leads Berry Consultants' research enterprise. He is a leader in clinical trial implementation of Bayesian hierarchical modeling, with expertise in platform and basket trials as well as clinical trials incorporating the use of historical information. Prior to joining Berry Consultants in 2010, he was a faculty member at the University of Kentucky, where he received the Provost's Award for Outstanding Teaching and was an investigator for NSF and NIH-funded research. He has developed over 100 custom Bayesian adaptive clinical trials for clients in industry, government, and academia, and currently serves on several data safety monitoring boards for randomized clinical trials. A former editor of the journal Bayesian Analysis, Dr. Viele is also an author of FACTS (Fixed and Adaptive Clinical Trial Simulator), clinical trial simulation software currently licensed to multiple pharmaceutical, academic, and government organizations. William Meurer, MD, MS, is an Associate Professor of Emergency Medicine and Neurology at the University of Michigan Health System. In addition, he serves as a Medical and Statistical Scientist for Berry Consultants, LLC. He works to improve the care of patients with acute neurological disease both through his work on the acute stroke team and as a researcher. His work in the field focuses on the design of clinical trials with adaptive and flexible components. In addition, he is a principal investigator of the National Institutes of Neurological Disorders and Stroke (NINDS) Clinical Trials Methodology Course (http:// neurotrials.training) and a co-investigator in the clinical coordinating center of the Strategies to Innovate Emergency Care Clinical Trials (SIREN) network- also funded by NIH). He was a co-investigator on the Adaptive Designs Accelerating Promising Treatments into Trials (ADAPT-IT) project, as part of the FDA Advancing Regulatory Science initiative with NIH.
ABSTRACT
The COVID-19 pandemic has exposed numerous unresolved research ethics challenges particularly for Data Monitoring Committees (DMCs). DMCs have worked to ensure the ongoing social value of research as rapid changes occur in health policy and epidemiology and there is substantial pressure to release early findings to the public. Unlike Institutional Review Boards, DMCs are charged with carefully monitoring ongoing research, but with limited ethical guidance and often without representation from all host countries. This article highlights ethical challenges for DMCs and lessons learned from the COVID-19 pandemic. DMCs have long faced high-stakes decisions in clinical trials including whether to continue, modify, or terminate a trial based on emerging trial data. Trial protocols, statistical analysis plans, and data monitoring charters establish principles for DMC decisionmaking;however, there has not been a great deal of systematic examination of the ethical issues faced by DMCs. For example, which ethical considerations should be addressed by DMCs as opposed to Institutional Review Boards or researchers is often unclear. Formal guidance rarely addresses whether DMCs should monitor the representativeness of trial participants as compared with the target population for the intervention. Furthermore, post-trial issues have received limited attention. Should DMCs ensure the accuracy of press releases and manuscripts detailing study findings? How should DMCs determine when to unblind participants after a study is over if it is relevant for their medical decision-making? In this presentation, we will report preliminary results of a qualitative study of DMC members (i.e. statisticians, clinicians, and ethicists). We will highlight persistent controversies, the range of roles DMCs are expected to play in monitoring clinical trials, and variation in formal guidance about the ethical obligations of DMCs. We will also examine the question of whether and when ethicists should serve on DMCs. We will conclude by identifying critical ethical issues facing DMCs that warrant further attention.
ABSTRACT
Clinically approved cell and gene therapies are opening up future possibilities to treat and prevent myriad diseases, which may include allergic diseases. In South Africa, this could help alleviate the high disease burden and economic cost of treating such diseases. However, even if viable gene-editing options to treat, cure and prevent allergic diseases become safe, effective and affordable for the South African market within the next few decades, the ethical implications and challenges of perceptions, regulation and oversight to ensure safety and equitable access remain. It would be important for all stakeholders involved, including the public and physicians, clinicians and ethicists on clinical and research ethics committees, to be informed about the possibilities, to engage in discussions with one another and to redress any gaps in knowledge. It would be especially important to determine whether cases for gene-editing aimed at allergy would be applied for therapeutic purposes or for enhancement. Much research and discussion remain to be embarked upon;however, it is imperative that research and engagement are expanded and prioritised.
ABSTRACT
Vaccine hesitancy has been presented as a great obstacle to the "end of COVID." The large groups of protestors and low compliance have created tensions between groups of individuals. Healthcare providers have expressed anger and frustration to have unvaccinated individuals arrive at the emergency department in deteriorating conditions when these severe conditions could have been prevented. However, patient-centered care advocates that the patient's voice and values are acknowledged. Vaccine hesitancy, vaccine defiance, and mistrust of the medical profession have been continuous and recurrent phenomena. There are many instances in which medical research and technology occurred at the exploitation of marginalized groups. The Tuskegee Syphilis experiment is well known but others have been obscured. Indeed, ethicists acknowledge that moral objections to questionable research methods can be overturned in cases of emergency. Patients do have their own reasons why they may be vaccine hesitant despite acknowledging that vaccination is necessary. This presentation will present an ethics methodology approach to encourage collaboration between opposing groups. Reasons for both vaccine hesitancy and vaccine support will be presented. The goal is to provide respiratory students and professionals with additional tools to approach vaccine-hesitant patients so that future confrontations are collaborative and proactive. Recommended methods on how to approach and challenging patients on their values can help guide difficult discussions around vaccinations and mistrust in healthcare.
ABSTRACT
Objective The political costs associated with healthcare priority- setting give decision-makers an incentive to shield from the consequences of unpopular decisions. This fact, together with the factual and normative complexity of priority-setting decisions, give politicians reason to delegate decision-making through arrangements such as consultative procedures and to seek the advice of moral and political philosophers. Not surprisingly, many countries made use of ethics expert panels to advice on priority setting of COVID-19 vaccines in the first phase of the pandemic. However, the authority of a distinctive expertise in ethical guidance was being questioned in the public debate on vaccine prioritisation. This sceptical stance regarding the role and expertise of the ethics expert is not new. If we are all equal as autonomous beings and autonomy is the source of normativity, then we all have equal capacity for moral decision-making. The aim of this paper is to examine if and how ethics expertise can contribute to policy making regarding the development and implementation of COVID-19 immunisation programmes: What kind of expertise can ethicists offer? Methods Theoretical discussion based on an illustrative case: Domestically prioritisation of COVID-19 vaccines. Results and Discussion We argue that ethicists have an epistemic authority in the sense of being in a privileged position to give ethical advice if a set of meta-principles for regulation of the ethical debate is followed. By using a methodology of 'engaged philosophy', the ethics experts should seek to identify relevant values in the context of a specific problem and work through a series of steps so that broad agreement can be made in a given case. While we may not necessarily converge on the deepest foundations for our normative beliefs, we may reach agreement particular outcomes and mid-level principles.
ABSTRACT
Introduction: Early in the COVID-19 pandemic, human challenge trials with SARS-CoV-2 were proposed as a way to develop a vaccine faster, and thereby save lives. But would such trials in fact speed vaccine development? Is it ethical to infect healthy volunteers with wildtype SARS-CoV-2? And going forward, what should be the role of human challenge trials in the development of SARS-CoV-2 vaccines? This 60-min panel session, chaired by Professor Seema Shah, will explore scientific and ethical issues in SARS-CoV-2 human challenge trials. The panel brings together key stakeholders, including scientists working with a variety of challenge models, research ethicists, and a member of the advocacy group 1Day Sooner who recently participated in a challenge trial. The panel comprises five talks followed by a 10- to 15-min discussion period. Background: The origins of human challenge trials can be traced back to efforts in the 1790s to determine whether cow pox inoculation protected against smallpox. In the last 50 years, human challenge trials have enrolled thousands of healthy volunteers to be exposed to dozens of diseases, from the common cold to cholera. Challenge trials are used to better understand how a pathogen causes disease, how it is transmitted (and how transmission may be mitigated), and whether a vaccine candidate confers protection against it. In vaccine challenge trials, healthy participants are randomized to receive either vaccine or placebo, and they are subsequently exposed to the infectious agent. If less people who received the vaccine, compared to those who received placebo, become infected, this provides evidence that the vaccine is efficacious. Challenge trials have played important roles in developing vaccines for cholera, typhoid, and malaria. To protect volunteers, in the modern era, scientists have generally restricted their use of such trials to diseases that are well-understood, or for which there is curative treatment. In the face of the global COVID-19 pandemic, human challenge trials with SARS-CoV-2 were proposed as a means to speed vaccine development and save lives. But are such trials ethical? There are risks associated with COVID-19, including in young people, such as myocarditis, stroke, long COVID, and death. Proponents argue ethical norms are too conservative and may be set aside in a pandemic, provided informed volunteers are willing to participate. What should be the role of challenge trials in the development of a SARS-CoV-2 vaccine? While challenge trials were initially proposed as a substitute for phase 3 efficacy trials for vaccines, challenge trials take time to set up and did not keep pace with dramatically accelerated vaccine development in the COVID-19 pandemic. They also have limitations, including generalizability to older adults or people with comorbidities, since they test vaccine efficacy in 15-150 healthy young adults. Nevertheless, challenge trials could test the second round of vaccine candidates, which is important if the first vaccine approved is not very efficacious or safe or to ensure widespread global access of vaccines. Our panel comprising a healthy volunteer, scientists working with a variety of challenge models, and research ethicists will explore and discuss these ethical and scientific issues. Talk 1: Human challenge trials with SARS-CoV-2 Meta Roestenberg (Leids Universitair Medisch Centrum, The Netherlands) will introduce human challenge trials and their use in vaccine development. She will discuss the development of a SARS-CoV-2 challenge model, and the role of challenge trials in the development of second-generation SARS-CoV-2 vaccines. Bio: https://www.lumc.nl/org/parasitologie/medewerkers/ metaroestenberg Talk 2: The volunteer experience in a SARS-CoV-2 challenge trial Alastair Fraser-Urquhart (1Day Sooner) participated in the UK SARS-CoV-2 challenge trial in Spring 2021, and he will describe his experience in the trial. 1Day Sooner is a grass roots organization that has gathered over 38,000 people globally who have expressed a willingness to participa e in SARS-CoV-2 challenge trials. Bio: https://1daysooner.org/ Talk 3: Developing ethical guidance for SARS-CoV- 2 challenge trials Seema Shah (Northwestern University Feinberg School of Medicine, USA;session co-chair) will describe the development of ethical guidance for SARS-CoV-2 challenge trials published in Science and Vaccine in 2020 and the World Health Organization's key criteria document. She will outline the main ethical considerations in such trials and explain the most compelling potential social value they could provide. Bio: https://www.feinberg.northwestern.edu/faculty-profiles/ az/profile.html?xid = 42926 Talk 4: A critical perspective on the ethics of SARSCoV- 2 challenge trials Charles Weijer (Western University, Canada;session co-chair) will examine critically the case for SARS-CoV-2 challenge trials. He will focus on the social value of challenge trials, whether benefits are justified by risks to volunteers, the use of high-risk groups in such trials, and their impact on public trust in a SARS-CoV-2 vaccine. Bio: https:// www.charlesweijer.com/about-me Talk 5: The future of challenge trials in SARS-CoV- 2 and future pandemics Gagandeep Kang (Christian Medical College, India) will consider the future of challenge trials in the future of SARS-CoV-2 vaccine development and, indeed, their role in future pandemics. The pace of vaccine development and clinical trials in the COVID-19 pandemic is unprecedented. Does this undermine the need for challenge trials? If not, what ought to be their role in vaccine development? Bio: https://en.wikipedia.org/wiki/Gagandeep-Kang Format: This 60-min panel session will be chaired by Professor Seema Shah. Each of the talks will be 8- to 10-min in duration and they will cover the volunteer experience, the science of challenge trials, and ethical issues. The five talks will be followed by a highly interactive 10- to 15-min discussion period. The discussion will be divided into two sections. The first half of the discussion will explore the ethics of SARS-CoV-2 challenge trials. The second half will discuss the future role of challenge trials in vaccine development.