Risk-based centralized data monitoring of clinical trials at the time of COVID-19 pandemic.

OBJECTIVES: COVID-19 pandemic caused several alarming challenges for clinical trials. On-site source data verification (SDV) in the multicenter clinical trial became difficult due to travel ban and social distancing. For multicenter clinical trials, centralized data monitoring is an efficient and cost-effective method of data monitoring. Centralized data monitoring reduces the risk of COVID-19 infections and provides additional capabilities compared to on-site monitoring. The key steps for on-site monitoring include identifying key risk factors and thresholds for the risk factors, developing a monitoring plan, following up the risk factors, and providing a management plan to mitigate the risk. METHODS: For analysis purposes, we simulated data similar to our clinical trial data. We classified the data monitoring process into two groups, such as the Supervised analysis process, to follow each patient remotely by creating a dashboard and an Unsupervised analysis process to identify data discrepancy, data error, or data fraud. We conducted several risk-based statistical analysis techniques to avoid on-site source data verification to reduce time and cost, followed up with each patient remotely to maintain social distancing, and created a centralized data monitoring dashboard to ensure patient safety and maintain the data quality. CONCLUSION: Data monitoring in clinical trials is a mandatory process. A risk-based centralized data review process is cost-effective and helpful to ignore on-site data monitoring at the time of the pandemic. We summarized how different statistical methods could be implemented and explained in SAS to identify various data error or fabrication issues in multicenter clinical trials.

Creation of an institutional semi-independent data monitoring committee.

BACKGROUND: A major goal of the National Institutes of Health's Clinical and Translational Science Award program is to facilitate clinical research and enhance the transition of basic to clinical research. As such, a number of Clinical and Translational Science Award centers have developed services to facilitate the conduct of clinical research, including support with fulfilling regulatory requirements. METHODS: The University of Kentucky sought to establish an institutional semi-independent monitoring committee to provide oversight for clinical research studies per National Institutes of Health requirements and recommendations. Our semi-independent monitoring committee was initiated in 2010. RESULTS: Since the inception of our semi-independent monitoring committee we have restructured its operations and protocols to improve efficiency. This article discusses our experiences with semi-independent monitoring committee creation and growth. CONCLUSION: This article summarizes our experience in creating and maturing an institutional data monitoring committee.

Innovative approaches to investigator-initiated, multicentre paediatric clinical trials in Canada.

Data from clinical trials are needed to guide the safe and effective use of medicines in children. Clinical trials are challenging to design and implement in all populations, and children present additional considerations. Several regions including the UK, USA and Europe have established clinical trial infrastructure to capitalise on expertise and promote clinical trials enrolling children. Our objective is to describe the partnerships and operational considerations for the development of paediatric clinical trials infrastructure in Canada. We describe the design and conduct of four emergency room paediatric trials, with four separate sponsors, across four provinces in parallel. Operations discussed include multisite contract development, centralised risk-based data monitoring, ethical review and patient engagement. We conclude with lessons learnt, additional challenges and potential solutions to facilitate drug development for children in Canada.

The changing landscape of data monitoring committees-Perspectives from regulators, members, and sponsors.

Data Monitoring Committees (DMCs) are an integral part of clinical drug development. Their use has evolved along with changing study designs and regulatory expectations, which has associated statistical and ethical implications. Although there is guidance from the different regulatory agencies, there are opportunities to bring more consistency to address practical issues of establishing and operating a DMC. Challenging issues include defining the scope of DMC decisions, the regulatory requirements and expectations, the perceived independence of DMCs, the specific focus primarily on safety, etc. Wider use of adaptive clinical trial designs in recent years introduce additional challenges in terms of trial governance and the complexity of DMC activities. A panel comprised of clinical and statistical experts from across academia, industry, and regulatory agencies shared their experience and thoughts on the importance of these aspects and offered perspectives on the future of the DMCs. This paper documents the thinking from the panel session at the CEN-ISBS conference held in Vienna, Austria, 2017.

Learning from OCTET - exploring the acceptability of clinical trials management methods.

BACKGROUND: Conducting research can be time consuming, difficult and challenging. Guidance and pragmatic advice focussing on randomised controlled trial conduct are available but do not necessarily constitute comprehensive guidance. A successful trial is one that recruits to time and target and collects high-quality data within the originally agreed budget. Standardised trial management tools have outlined key project management elements for a successful trial as a method of ensuring good practice in research trials: initiation, planning, execution, monitoring and closure. Lessons are also frequently learnt during the development and conduct of trials but rarely shared for the benefit of others. For the wider research team, the key focus will always be on the execution and delivery of a study. The aim of this study was to evaluate the acceptability of clinical trials management methods, focussing on study execution and monitoring, as implemented in the National Institute for Health Research Health Technology Assessment Programme-funded Obsessive Compulsive Treatment Efficacy Trial (OCTET). METHODS: Workshops, questionnaires and semi-structured interviews were used to explore acceptability of trial management methods with members of the OCTET Trial research team. Nine members participated in the focus group, 10 completed a questionnaire and 20 were interviewed as part of qualitative work for the main OCTET study. Data was collected and analysed using thematic analysis. RESULTS: Six key themes were identified: support; communication; processes; resources; training and ethos. Clear and open communication, enthusiasm and accessibility of the trial managers and chief investigator were consistently noted as an important facet of the successful running of the trial. Clear resources and training materials were also found to be crucial in helping staff to work within the trial setting. Constructive suggestions were also made for improvement of these resources; for example, including both checklists and flowcharts within trial processes. CONCLUSION: Organisation, openness and positivity are crucial for executing a trial successfully, whilst clear and focussed processes and resources are essential in monitoring and controlling the trial progress. Although derived from a single study, these findings are likely to be applicable to the successful conduct of all trials. Trial managers should consider developing these elements when setting up a study. TRIAL REGISTRATION: Clinical Trial Registry, ID: ISRCTN73535163 . Registered prospectively on 5 April 2011.

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.

Could safety boards provide a valuable tool to enhance the safety of reproductive medicine?

Medicine and aviation have a striking number of similarities. Both are led by highly-trained individuals performing complex tasks that are critical to outcomes. They also integrate the efforts of other professionals to assure that the flight, procedures, or processes are completed successfully. Also in common, is the potential for errors to have catastrophic and even life-threatening consequences. Both aviation and medicine have responded to this complex operating environment by building safety programs. Unfortunately, those in medicine have not been optimal in reducing significant adverse outcomes, including deaths. It has been suggested that given the parallels, that aviation safety programs might be adapted to clinical medicine. One such measure would the formation of a Clinical Safety Board (CSB) modeled after the National Transportation Safety Board (NTSB). Such a board would collect data across the nation and determine root causes of errors. They may then provide recommendations to professional societies and regulatory agencies for consideration for implementation. Such programs would be dependent on accurate and thorough reporting. Indemnification, similar to that enacted by the federal government for aviation, would be critical. In the end, a CSB should empower better patient care with reduced liability to the providers and programs.

Multicenter clinical trials in sepsis: understanding the big picture and building a successful operation at your hospital.

Only through adequately designed and adequately conducted clinical trials can new treatments be found for the benefit of the septic patient. Over the past 20 years, tens of thousands of patients have been enrolled in sepsis clinical trials with little success. These efforts, however, have not been without worth. Much has been learned and the knowledge gained has changed our approach to trial design in this very difficult field. Animal studies are better designed to match the clinical picture of severe sepsis. Phase II studies are more carefully engineered to answer questions about the most suitable target population and end points. Trial conduct likely benefits from use of CROs and a CCC. The future of clinical trials may include more standardization of sepsis management across investigative sites. Before the decision is made to become an investigative site in a multicenter industry-sponsored clinical trial in sepsis or severe sepsis, it is important to recognize what is required to succeed. Once these key-to-success elements are in place, members of the investigative team are more likely to realize the satisfaction and career growth from becoming a successful site. The most professional satisfaction comes from the knowledge of contributing to original science in the field of the sepsis.

International Committee for Monitoring Assisted Reproductive Technology (ICMART) and the World Health Organization (WHO) revised glossary of ART terminology, 2009.

OBJECTIVE: Many definitions used in medically assisted reproduction (MAR) vary in different settings, making it difficult to standardize and compare procedures in different countries and regions. With the expansion of infertility interventions worldwide, including lower resource settings, the importance and value of a common nomenclature is critical. The objective is to develop an internationally accepted and continually updated set of definitions, which would be utilized to standardize and harmonize international data collection, and to assist in monitoring the availability, efficacy, and safety of assisted reproductive technology (ART) being practiced worldwide. METHOD: Seventy-two clinicians, basic scientists, epidemiologists and social scientists gathered together at the World Health Organization headquarters in Geneva, Switzerland, in December 2008. Several months before, three working groups were established as responsible for terminology in three specific areas: clinical conditions and procedures, laboratory procedures, and outcome measures. Each group reviewed the existing International Committee for Monitoring Assisted Reproductive Technology glossary, made recommendations for revisions and introduced new terms to be considered for glossary expansion. RESULT(S): A consensus was reached on 87 terms, expanding the original glossary by 34 terms, which included definitions for numerous clinical and laboratory procedures. Special emphasis was placed in describing outcome measures, such as cumulative delivery rates and other markers of safety and efficacy in ART. CONCLUSION(S): Standardized terminology should assist in analysis of worldwide trends in MAR interventions and in the comparison of ART outcomes across countries and regions. This glossary will contribute to a more standardized communication among professionals responsible for ART practice, as well as those responsible for national, regional, and international registries.

[The Coordinating Centres for Clinical Trials Network. Objectives and significance for research sites]. / Das KKS-Netzwerk. Ziele und Bedeutung für den Forschungsstandort.

In the late 1990s a funding program was set up by the federal German government to help keep stride with developments in the international research arena. Within this programme, Coordinating Centres for Clinical Trials ("Koordinierungszentren für Klinische Studien", KKS) were established at 12 German universities aiming at supporting all processes of academic clinical trials according to international standards. A close network infrastructure was chosen in order to reap maximum benefit from synergy effects and to promote the harmonisation of standards. Continuing to grow, the KKS Network currently has 16 research institutions as members. More than 400 employees within the KKS Network provide scientific services to clinical trials at universities, hospitals and in industry. In cooperation with study clinics, surgeries, study groups and competence networks in medicine within Europe and beyond, the KKS supports many different research projects covering all areas of medicine. The KKS Network contributes expertise to legislative processes within Germany and Europe through its work in professional committees and working groups. A wide range of education and training concepts supports clinical research as a scientific field in its own right. After nearly ten years the KKS Network has established itself as an indispensable partner in the field of clinical research.

[Mission and tasks of the Coordination Centres for Clinical Trials]. / Aufgaben der Koordinierungszentren für Klinische Studien.

Coordination Centres for Clinical Trials (Koordinierungszentren für Klinische Studien, KKS) were set up to increase the quality and number of clinical trials in Germany as well as to establish clinical trial training programs in order to improve international recognition of German clinical research. Over the past 6 years, 12 KKS have been set up at the respective universities with a public grant from the Federal Ministry of Education and Research (BMBF). Many non-clinical services have been established to ensure successful co-operation in clinical trials with clinical scientists and industry. KKS help researchers to efficiently conduct commercial and non-commercial clinical trials in various disease areas. Their expertise and infrastructure allow the university to assume sponsor responsibility in non-commercial drug trials. Because of their professional work and education activities KKS are well accepted by industry and the scientific community. Central professional trial organisations such as the KKS have been shown to be the pre-requisite for meeting the growing, manifold and complex requirements for clinical trials. Therefore they are considered essential for progress and success in clinical research.

[The German Clinical Trials Register: reasons, general and technical aspects, international integration]. / Das Deutsche Register Klinischer Studien: Begründung, technische und inhaltliche Aspekte, internationale Einbindung.

In order to provide a central portal for information on clinical research in Germany and thus to facilitate the search of planned, ongoing and completed clinical trials, the German Clinical Trials Register (GermanCTR) was implemented in cooperation with the WHO's registries network. It is an open access online register of clinical trials conducted in Germany, which allows all users to search for, register and share information on clinical trials. The project is funded by the Federal Ministry of Education and Research and is implemented at the Institute for Medical Biometry and Medical Informatics of the University Medical Center Freiburg as a joint project of the Clinical Trials Center Freiburg and the German Cochrane Center. Since October 2008 the GermanCTR is an approved WHO Primary Registry and allows clinical trial registration in Germany according to the requirements of the International Committee of Medical Journal Editors (ICMJE). Reasons for a national trials register, general and technical aspects of implementing the GermanCTR as well as the national and international integration are described here.

[Requirements to a medical and biologic assessment and the hygienic control of the food production received from recombinant-DNA microorganisms].

In work the characteristic of the created in the Russian Federation system of an estimation of safety of the foodstuff received from/or with use of genetically modified microorganisms (GMM) is given, at their admission to realization and the hygienic control of given production over a revolution. It is shown, that strategy of a safety at a stage of registration GMM, the established order and accepted control measures of the foodstuff received from/or with use GMM, in Russia their large-scale commercial use, and the normative-legal and methodical base based on the federal legislation on state regulation in the field of genetically engineering activity, about quality and effectively outstrip safety of foodstuff about protection of the rights of consumers, is harmonized with approaches of the international organizations.

[Risk assessment and chemical safety under REACH]. / Risikobewertung und Chemikaliensicherheit unter REACH.

Under the new European chemical legislation REACH (EG 1907/2006), dangerous properties of chemical substances will be evaluated and data gaps will be closed. This information is needed for other regulations, such as safety at the working place or for the safe handling of products. Existing knowledge on chemical compounds must be broadened because previous regulations have focused on high production volume compounds. The evaluation procedures needed too much time, and for the majority of non-evaluated substances a new strategy is needed. REACH places the duty for registration of substances with the producers and importers. Data gaps for risk evaluation will be closed. Competent authorities will be relieved from the primary risk evaluation of most substances. Alternative strategies of evaluation using previous information and non-animal testing approaches will be supported to avoid animal testing where appropriate. The new European chemical agency ECHA will use the provided information in order to identify very dangerous chemical substances which should be controlled by authorization of its use and the circumstances thereof.