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3.
Stroke ; 52(11): 3739-3747, 2021 11.
Article in English | MEDLINE | ID: covidwho-1443690

ABSTRACT

The coronavirus disease 2019 (COVID-19) pandemic has presented unique challenges to stroke care and research internationally. In particular, clinical trials in stroke are vulnerable to the impacts of the pandemic at multiple stages, including design, recruitment, intervention, follow-up, and interpretation of outcomes. A carefully considered approach is required to ensure the appropriate conduct of stroke trials during the pandemic and to maintain patient and participant safety. This has been recently addressed by the International Council for Harmonisation which, in November 2019, released an addendum to the Statistical Principles for Clinical Trials guidelines entitled Estimands and Sensitivity Analysis in Clinical Trials. In this article, we present the International Council for Harmonisation estimand framework for the design and conduct of clinical trials, with a specific focus on its application to stroke clinical trials. This framework aims to align the clinical and scientific objectives of a trial with its design and end points. It also encourages the prospective consideration of potential postrandomization intercurrent events which may occur during a trial and either impact the ability to measure an end point or its interpretation. We describe the different categories of such events and the proposed strategies for dealing with them, specifically focusing on the COVID-19 pandemic as a source of intercurrent events. We also describe potential practical impacts posed by the COVID-19 pandemic on trials, health systems, study groups, and participants, all of which should be carefully reviewed by investigators to ensure an adequate practical and statistical strategy is in place to protect trial integrity. We provide examples of the implementation of the estimand framework within hypothetical stroke trials in intracerebral hemorrhage and stroke recovery. While the focus of this article is on COVID-19 impacts, the strategies and principles proposed are well suited for other potential events or issues, which may impact clinical trials in the field of stroke.


Subject(s)
COVID-19 , Clinical Trials as Topic/methods , Data Interpretation, Statistical , Research Design , Stroke/therapy , Clinical Trials as Topic/standards , Guidelines as Topic , Humans , Implementation Science , SARS-CoV-2
5.
Clin Trials ; 18(5): 615-621, 2021 10.
Article in English | MEDLINE | ID: covidwho-1280563

ABSTRACT

The COVID-19 pandemic has resulted in unprecedented challenges for healthcare systems worldwide. It has also stimulated research in a wide range of areas including rapid diagnostics, novel therapeutics, use of technology to track patients and vaccine development. Here, we describe our experience of rapidly setting up and delivering a novel COVID-19 vaccine trial, using clinical and research staff and facilities in three National Health Service Trusts in Cambridgeshire, United Kingdom. We encountered and overcame a number of challenges including differences in organisational structures, research facilities available, staff experience and skills, information technology and communications infrastructure, and research training and assessment procedures. We overcame these by setting up a project team that included key members from all three organisations that met at least daily by teleconference. This group together worked to identify the best practices and procedures and to harmonise and cascade these to the wider trial team. This enabled us to set up the trial within 25 days and to recruit and vaccinate the participants within a further 23 days. The lessons learned from our experiences could be used to inform the conduct of clinical trials during a future infectious disease pandemic or public health emergency.


Subject(s)
COVID-19 Vaccines/therapeutic use , COVID-19 , Clinical Trials as Topic/standards , Pandemics , COVID-19/prevention & control , Clinical Trials as Topic/organization & administration , Humans , Pandemics/prevention & control , State Medicine , United Kingdom/epidemiology
6.
Can J Cardiol ; 37(9): 1353-1364, 2021 09.
Article in English | MEDLINE | ID: covidwho-1252583

ABSTRACT

The COVID-19 crisis led to a flurry of clinical trials activity. The COVID-evidence database shows 2814 COVID-19 randomized trials registered as of February 16, 2021. Most were small (only 18% have a planned sample size > 500) and the rare completed ones have not provided published results promptly (only 283 trial publications as of February 2021). Small randomized trials and observational, nonrandomized analyses have not had a successful track record and have generated misleading expectations. Different large trials on the same intervention have generally been far more efficient in producing timely and consistent evidence. The rapid generation of evidence and accelerated dissemination of results have led to new challenges for systematic reviews and meta-analyses (eg, rapid, living, and scoping reviews). Pressure to regulatory agencies has also mounted with massive emergency authorizations, but some of them have had to be revoked. Pandemic circumstances have disrupted the way trials are conducted; therefore, new methods have been developed and adopted more widely to facilitate recruitment, consent, and overall trial conduct. On the basis of the COVID-19 experience and its challenges, planning of several large, efficient trials, and wider use of adaptive designs might change the future of clinical research. Pragmatism, integration in clinical care, efficient administration, promotion of collaborative structures, and enhanced integration of existing data and facilities might be several of the legacies of COVID-19 on future randomized trials.


Subject(s)
COVID-19 , Pandemics , Randomized Controlled Trials as Topic , COVID-19/therapy , Clinical Trials as Topic/methods , Clinical Trials as Topic/standards , Clinical Trials as Topic/statistics & numerical data , Drug Repositioning , Humans , Randomized Controlled Trials as Topic/methods , Randomized Controlled Trials as Topic/standards , Randomized Controlled Trials as Topic/statistics & numerical data , Research Design/standards , SARS-CoV-2
7.
Contemp Clin Trials ; 106: 106438, 2021 07.
Article in English | MEDLINE | ID: covidwho-1230388

ABSTRACT

With billions of dollars in research and development (R&D) funding continuing to be invested, the novel coronavirus disease 2019 (COVID-19) has become into a singular focus for the scientific community. However, the collective response from the scientific communities have seen poor return on investment, particularly for therapeutic research for COVID-19, revealing the existing weaknesses and inefficiencies of the clinical trial enterprise. In this article, we argue for the importance of structural changes to existing research programs for clinical trials in light of the lessons learned from COVID-19.


Subject(s)
Biomedical Research/organization & administration , COVID-19/epidemiology , COVID-19/therapy , Clinical Protocols/standards , Clinical Trials as Topic/organization & administration , Biomedical Research/economics , Biomedical Research/standards , Clinical Trials as Topic/economics , Clinical Trials as Topic/standards , Humans , SARS-CoV-2
9.
Indian J Med Ethics ; VI(2): 1-10, 2021.
Article in English | MEDLINE | ID: covidwho-1206593

ABSTRACT

This article compares the current debate over the use of placebos in developing country clinical trials of second generation Covid-19 vaccines with the debates over previous paradigmatic cases raising similar issues. Compared to the earlier zidovudine and Surfaxin trials, Covid-19 vaccine trials are likely to confer lower risk to placebo groups and to offer a greater number and variety of alternative study designs. However, turning to the developing world to conduct studies that would be unacceptable in developed countries, simply on the ground that Covid-19 vaccines are generally unavailable in developing countries, is not ethically justifiable. This is so whether the justification is rooted in total absence of vaccine in a given country or in developing country vaccine prioritisation practices, because at root both derive from economic, not scientific conditions. However, the advent of variants that may create genuine uncertainty as to comparator vaccine effectiveness could justify a placebo control, depending on vaccine characteristics, variant prevalence, the degree of variant resistance, and the acceptability of immune-bridging studies. These factors must be considered together in the necessary case-by-case assessment of the ethical justification for any proposed trial.


Subject(s)
COVID-19 Vaccines/standards , COVID-19/prevention & control , Clinical Trials as Topic/ethics , Clinical Trials as Topic/standards , Ethics, Medical , Patient Rights/standards , Placebos/standards , Adult , Aged , Aged, 80 and over , Developing Countries , Female , Guidelines as Topic , Humans , Male , Middle Aged , Pandemics , Risk Factors , SARS-CoV-2
10.
Indian J Med Ethics ; VI(2): 1-7, 2021.
Article in English | MEDLINE | ID: covidwho-1206592

ABSTRACT

Vaccines preventing Covid-19 have been approved in several countries. Is it still ethically acceptable to use placebo controls during the development of other vaccine options? If two of the most influential international guidelines of biomedical research are consulted, the Declaration of Helsinki and the CIOMS-guidelines, the answer is "no". We discuss the implications for ongoing vaccine research, and how placebo controls might be justified nevertheless. However, the ethical conflict remains highly problematic. We suggest that such ethical dilemmas should be avoided in the future by the introduction of a new system of global governance. Once vaccines are approved, a global regulation should oblige producers to provide the necessary amount of vaccine doses for the control groups of ongoing vaccine research.


Subject(s)
COVID-19 Vaccines/standards , COVID-19/prevention & control , Clinical Trials as Topic/standards , Ethics, Medical , Guidelines as Topic , International Cooperation , Placebos/standards , Adult , Aged , Aged, 80 and over , Female , Humans , Male , Middle Aged , Pandemics , SARS-CoV-2
11.
Indian J Med Ethics ; VI(2): 1-7, 2021.
Article in English | MEDLINE | ID: covidwho-1206589

ABSTRACT

Recently the WHO Ad Hoc Expert Group proposed that it is ethical to continue placebo-controlled Covid-19 vaccine trials in countries where vaccines are not available even if this vaccine is marketed and being used elsewhere. The reason for this proposal is the usual scientific argument claiming that these trials are the most efficient method to obtain reliable results, and individuals in these countries will continue to get the local standard of care, meaning no vaccination, and thus participants are not being left worse off. We refute this argument on two counts. First the global equity and justice issue, that the scarcity of vaccines in most countries is created by the rich nations that have hoarded vaccines. Second, the science versus research ethics issue, that there are valid scientific methods like non-inferiority trials which can give reliable results, and that applying a standard of care imposed by rich nations is both unethical and possibly exploitative. Thus, we feel that the WHO Ad Hoc Expert Group is wrong in proposing to continue placebo-controlled Covid-19 vaccine trials.


Subject(s)
COVID-19 Vaccines/standards , COVID-19/prevention & control , Clinical Trials as Topic/ethics , Clinical Trials as Topic/standards , Ethics, Medical , Human Rights , Placebos/standards , Guidelines as Topic , Humans , Pandemics , SARS-CoV-2
12.
Indian J Med Ethics ; VI(2): 1-7, 2021.
Article in English | MEDLINE | ID: covidwho-1206586

ABSTRACT

Thanks to an impressive R&D effort, three vaccines for Covid-19 have been conditionally approved by stringent regulators as of February 2021, and sixteen have entered the WHO evaluation process. However, they all need to keep on being evaluated in clinical trials. The WHO Ad Hoc Expert Group on the Next Steps for Covid-19 Vaccine suggested that countries with limited or no access to an effective vaccine could ethically permit placebo-controlled trials, even if effective vaccines were already being marketed elsewhere. Here, I argue that inclusion in a placebo-controlled trial is ethically sound for those who would be in any case ineligible for vaccination outside the trial, and as long as the access to the vaccine outside the trial depends on a transparent and just allocation framework. Conversely, carrying out placebo-controlled studies in countries where vaccines are not (or are insufficiently) available because of unequal global allocation, would be unethical, as an ethical strategy cannot be built on an unethical premise.


Subject(s)
COVID-19 Vaccines/standards , COVID-19/prevention & control , Clinical Trials as Topic/ethics , Clinical Trials as Topic/standards , Ethics, Medical , Guidelines as Topic , Placebos/standards , Humans , Pandemics , SARS-CoV-2
18.
Lancet Glob Health ; 9(3): e366-e371, 2021 03.
Article in English | MEDLINE | ID: covidwho-1149597

ABSTRACT

Inclusion of pregnant women in COVID-19 clinical trials would allow evaluation of effective therapies that might improve maternal health, pregnancy, and birth outcomes, and avoid the delay of developing treatment recommendations for pregnant women. We explored the inclusion of pregnant women in treatment trials of COVID-19 by reviewing ten international clinical trial registries at two timepoints in 2020. We identified 155 COVID-19 treatment studies of non-biological drugs for the April 7-10, 2020 timepoint, of which 124 (80%) specifically excluded pregnant women. The same registry search for the July 10-15, 2020 timepoint, yielded 722 treatment studies, of which 538 (75%) specifically excluded pregnant women. We then focused on studies that included at least one of six drugs (remdesivir, lopinavir-ritonavir, interferon beta, corticosteroids, chloroquine and hydroxychloroquine, and ivermectin) under evaluation for COVID-19. Of 176 such studies, 130 (74%) listed pregnancy as an exclusion criterion. Of 35 studies that evaluated high-dose vitamin treatment for COVID-19, 27 (77%) excluded pregnant women. Despite the surge in treatment studies for COVID-19, the proportion excluding pregnant women remains consistent. Exclusion was not well justified as many of the treatments being evaluated have no or low safety concerns during pregnancy. Inclusion of pregnant women in clinical treatment trials is urgently needed to identify effective COVID-19 treatment for this population.


Subject(s)
COVID-19/drug therapy , Clinical Trials as Topic/standards , Patient Selection/ethics , Pregnancy Complications, Infectious/drug therapy , Clinical Trials as Topic/ethics , Eligibility Determination , Female , Humans , Pregnancy , SARS-CoV-2
19.
Clin Pharmacol Ther ; 109(6): 1517-1527, 2021 06.
Article in English | MEDLINE | ID: covidwho-1118136

ABSTRACT

The coronavirus disease 2019 (COVID-19) pandemic and the accompanying control measures have significantly affected clinical trial (CT) conduct, and sponsors have needed to make rapid changes to their CT operations. As a result, regulatory guidance was pivotal during the initial phases of the pandemic. This study aimed to evaluate the regulatory readiness and guidance related to COVID-19 in the European Union (EU). The European Medicines Agency (EMA) and national competent authorities' (NCAs') websites were searched in September and October 2020 for guidances on the management of CTs during the pandemic published from January 2020 onward. "Regulatory readiness" was defined as the number of days from the first European COVID-19 case (January 24, 2020) to the first published guidance by the respective NCA. "Regulatory guidance" was evaluated by coding the guidances for the following predefined operational trial activities important for ongoing CTs: obtaining informed consent, participant information, clinic visits, home health visits, telemedicine visits, self-monitoring, investigational medicinal product (IMP) supply, IMP adherence monitoring, CT monitoring, documentation management, regulatory management, and safety management. Twenty-four of the 27 EU NCAs published country-specific guidance. The time from the first European COVID-19 case to the first published EMA guidance was 56 days and ranged from 47 to 66 days for the first national guidances. Guidance was provided most frequently for regulatory management (24/24), safety management (23/24), documentation management (22/24), and CT monitoring (22/24). The regulatory guidance provided during the pandemic, ensuring participant safety and data integrity, may now be the starting point to innovate future CT conduct.


Subject(s)
COVID-19/drug therapy , COVID-19/epidemiology , Clinical Trials as Topic/organization & administration , Drug Approval/organization & administration , European Union/organization & administration , Clinical Trials as Topic/standards , Decision Making , Humans , Medication Adherence , Pandemics , Research Design , SARS-CoV-2 , Telemedicine , Time Factors
20.
Therapie ; 76(4): 347-358, 2021.
Article in French | MEDLINE | ID: covidwho-1111864

ABSTRACT

BACKGROUND: The Clinical Investigations Center of Saint-Louis Hospital (CIC-1427) is a structure dedicated to clinical trials and mainly early phase trials (first-in-man administration, phase 1 and 2). These trials are conducted in a French Regional Health Agency (ARS) authorized structure. In March 2020, faced to the global COVID-19 pandemic and the French national lockdown measures, the CIC-1427 had to rapidly adapt its operating procedures to ensure the safety of both patients and staff. STUDY OBJECTIVE: Ensuring optimal management of patients included in early phase clinical trials, while respecting the good clinical and professional practices (GCP/GPP) of the CICs protocol sponsors' requirements, patients' safety and clinical research multidisciplinary staff safety (nurses, caregivers' assistants (AS), clinical research assistants (CRA), clinical trial coordinators (CTC), project leaders, health executive and investigating physicians), in the context of the health crisis related to COVID-19. METHODS AND RESULTS: Due to their activity, requiring on-site presence, each staff member of the CIC-1427 clinical research team had to adapt their daily activity to the constraints of the health crisis. New specific procedures were quickly developed to deal with the pandemic. Most of the on-site medical visits were replaced by virtual consults with biological assessments in the local laboratories. "Remote monitoring" replaced on-site monitoring visits. Treatments were sent to each patient's home via couriers after agreement of the CPPs of each protocol (Committee for the Protection of Persons). The essential visits were maintained on site thanks to the unfailing involvement of our clinical care team, with implementation of a specific sanitary protocol. CONCLUSION: The involvement of our entire multidisciplinary research team ensured that each patient was able to benefit from a personalized follow-up and to continue the treatment on-trial. The newly introduced procedures also allowed collection of a maximum of safety and efficacy data for clinical trial sponsors while complying with good regulatory practices. This set of procedures developed during the first epidemic wave, fundamentally helped setting the frame for a better coping during the subsequent pandemic waves.


Subject(s)
COVID-19/epidemiology , Clinical Trials as Topic/organization & administration , Clinical Trials as Topic/standards , Communicable Disease Control , Pandemics , Clinical Trials as Topic/methods , France/epidemiology , Humans , SARS-CoV-2
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