Data monitoring committees for clinical trials evaluating treatments of COVID-19.

The first cases of coronavirus disease 2019 (COVID-19) were reported in December 2019 and the outbreak of SARS-CoV-2 was declared a pandemic in March 2020 by the World Health Organization. This sparked a plethora of investigations into diagnostics and vaccination for SARS-CoV-2, as well as treatments for COVID-19. Since COVID-19 is a severe disease associated with a high mortality, clinical trials in this disease should be monitored by a data monitoring committee (DMC), also known as data safety monitoring board (DSMB). DMCs in this indication face a number of challenges including fast recruitment requiring an unusually high frequency of safety reviews, more frequent use of complex designs and virtually no prior experience with the disease. In this paper, we provide a perspective on the work of DMCs for clinical trials of treatments for COVID-19. More specifically, we discuss organizational aspects of setting up and running DMCs for COVID-19 trials, in particular for trials with more complex designs such as platform trials or adaptive designs. Furthermore, statistical aspects of monitoring clinical trials of treatments for COVID-19 are considered. Some recommendations are made regarding the presentation of the data, stopping rules for safety monitoring and the use of external data. The proposed stopping boundaries are assessed in a simulation study motivated by clinical trials in COVID-19.

Moving fast but going slow: coordination challenges for trials of COVID-19 post-exposure prophylaxis.

An unprecedented volume of research has been generated in response to the COVID-19 pandemic. However, there are risks of inefficient duplication and of important work being impeded if efforts are not synchronized. Excessive reliance on observational studies, which can be more rapidly conducted but are inevitably subject to measured and unmeasured confounders, can foil efforts to conduct rigorous randomized trials. These challenges are illustrated by recent global efforts to conduct clinical trials of post-exposure prophylaxis (PEP) as a strategy for preventing COVID-19. Innovative strategies are needed to help overcome these issues, including increasing communication between the Data Safety and Monitoring Committees (DSMCs) of similar trials. It is important to reinforce the primacy of high-quality trials in generating unbiased answers to pressing prevention and treatment questions about COVID-19.

International committee for monitoring assisted reproductive technologies: world report on assisted reproductive technologies, 2007.

OBJECTIVE: To analyze information on assisted reproductive technology (ART) performed worldwide, and trends in outcomes over successive years. DESIGN: Cross-sectional survey on access, efficiency, and safety of ART procedures performed in 55 countries during 2007. SETTING: Not applicable. PATIENT(S): Infertile women and men undergoing ART globally. INTERVENTION(S): Collection and analysis of international ART data. MAIN OUTCOME MEASURE(S): Number of cycles performed, by country and region, including pregnancies, single and multiple birth rates, and perinatal mortality. RESULT(S): Overall, >1,251,881 procedures with ART were reported, and resulted in 229,442 reported babies born. The availability of ART varied by country, from 12 to 4,140 treatments per million population. Of all aspiration cycles, 65.2% (400,617 of 614,540) were intracytoplasmic sperm injection. The overall delivery rate per fresh aspiration was 20.3%, and for frozen-embryo transfer (FET), 18.4%, with a cumulative delivery rate of 25.8%. With wide regional variations, single-embryo transfer represented 23.4% of fresh transfers, and the proportion of deliveries with twins and triplets from fresh transfers was 22.3% and 1.2%, respectively. The perinatal mortality rate was 19.9 per 1,000 births for fresh in vitro fertilization using intracytoplasmic sperm injection, and 9.6 per 1,000 for FET. The proportion of women aged ≥40 years increased to 19.8% from 15.5% in 2006. CONCLUSION(S): The international trend toward <3 transferred embryos continued, as did the wider uptake of FET. This was achieved without compromising delivery rates. The application of ART for women aged >40 years was a major component of ART services in some regions and countries.

Independent data monitoring committees: preparing a path for the future.

Independent data monitoring committees (IDMCs) were introduced to monitor patient safety and study conduct in randomized clinical trials (RCTs), but certain challenges regarding the utilization of IDMCs have developed. First, the roles and responsibilities of IDMCs are expanding, perhaps due to increasing trial complexity and heterogeneity regarding medical, ethical, legal, regulatory, and financial issues. Second, no standard for IDMC operating procedures exists, and there is uncertainty about who should determine standards and whether standards should vary with trial size and design. Third, considerable variability in communication pathways exist across IDMC interfaces with regulatory agencies, academic coordinating centers, and sponsors. Finally, there has been a substantial increase in the number of RCTs using IDMCs, yet there is no set of qualifications to help guide the training and development of the next generation of IDMC members. Recently, an expert panel of representatives from government, industry, and academia assembled at the Duke Clinical Research Institute to address these challenges and to develop recommendations for the future utilization of IDMCs in RCTs.

The future of monitoring in clinical research - a holistic approach: linking risk-based monitoring with quality management principles.

Since several years risk-based monitoring is the new "magic bullet" for improvement in clinical research. Lots of authors in clinical research ranging from industry and academia to authorities are keen on demonstrating better monitoring-efficiency by reducing monitoring visits, monitoring time on site, monitoring costs and so on, always arguing with the use of risk-based monitoring principles. Mostly forgotten is the fact, that the use of risk-based monitoring is only adequate if all mandatory prerequisites at site and for the monitor and the sponsor are fulfilled.Based on the relevant chapter in ICH GCP (International Conference on Harmonisation of technical requirements for registration of pharmaceuticals for human use - Good Clinical Practice) this publication takes a holistic approach by identifying and describing the requirements for future monitoring and the use of risk-based monitoring. As the authors are operational managers as well as QA (Quality Assurance) experts, both aspects are represented to come up with efficient and qualitative ways of future monitoring according to ICH GCP.

Reducing health care hazards: lessons from the commercial aviation safety team.

The movement to improve quality of care and patient safety has grown, but examples of measurable and sustained progress are rare. The slow progress made in health care contrasts with the success of aviation safety. After a tragic 1995 plane crash, the aviation industry and government created the Commercial Aviation Safety Team to reduce fatal accidents. This public-private partnership of safety officials and technical experts is responsible for the decreased average rate of fatal aviation accidents. We propose a similar partnership in the health care community to coordinate national efforts and move patient safety and quality forward.

Cell-based interventions for neurologic conditions: ethical challenges for early human trials.

BACKGROUND: Attempts to translate basic stem cell research into treatments for neurologic diseases and injury are well under way. With a clinical trial for one such treatment approved and in progress in the United States, and additional proposals under review, we must begin to address the ethical issues raised by such early forays into human clinical trials for cell-based interventions for neurologic conditions. METHODS: An interdisciplinary working group composed of experts in neuroscience, cell biology, bioethics, law, and transplantation, along with leading disease researchers, was convened twice over 2 years to identify and deliberate on the scientific and ethical issues raised by the transition from preclinical to clinical research of cell-based interventions for neurologic conditions. RESULTS: While the relevant ethical issues are in many respects standard challenges of human subjects research, they are heightened in complexity by the novelty of the science, the focus on the CNS, and the political climate in which the science is proceeding. CONCLUSIONS: Distinctive challenges confronting US scientists, administrators, institutional review boards, stem cell research oversight committees, and others who will need to make decisions about work involving stem cells and their derivatives and evaluate the ethics of early human trials include evaluating the risks, safety, and benefits of these trials, determining and evaluating cell line provenance, and determining inclusion criteria, informed consent, and the ethics of conducting early human trials in the public spotlight. Further study and deliberation by stakeholders is required to move toward professional and institutional policies and practices governing this research.

The role of the unblinded sponsor statistician.

In clinical trials sponsored by Merck the unblinded statistician is typically an employee of the company. From a pharmaceutical industry perspective, advantages of this approach include ensuring that the unblinded statistician is knowledgeable regarding the experimental treatments, therapeutic area and study objectives; that the quality of the analysis conforms to rigorous standards; and that the allocation schedule, database and interim results are kept confidential. These advantages are felt to outweigh any potential disadvantages.