Risk-based Monitoring Research Articles

Investigation of the Factors Affecting Risk-Based Quality Management of Investigator-Initiated Investigational New-Drug Trials for Unapproved Anticancer Drugs in Japan.

With an increase in the complexity and cost of clinical trials and the advances in information technology, monitoring guidance issued by regulatory authorities recommends risk-adapted monitoring. To introduce the monitoring method for investigator-initiated investigational new drug (IND) trials using unapproved anticancer drugs, we performed exploratory retrospective analyses to identify risk factors for data quality. To select investigator-initiated IND trials using unapproved anticancer drugs, we set the trial selection criteria. Data collection was performed by using audit trails and monitoring reports. Collected data were analyzed by univariate and multivariate analyses to identify the independent risk factors related to error. By trial selection criteria, 5 investigator-initiated IND trials using unapproved anticancer drugs were selected. The error rates of the total data, critical data, and noncritical data were 7.4%, 9.7%, and 5.9%, respectively. There was no difference between clinical research core hospitals certified by the Ministry of Health, Labour and Welfare and other hospitals in univariate analysis (odds ratio [OR], 1.00; 99% confidence interval [CI], 0.96-1.05; P = .9179). As the main independent risk factors related to error, critical data in the importance of data (OR, 1.28; 99% CI, 1.24-1.33; P < .0001) and groups with ≤3 patients after registration (OR, 1.12; 99% CI, 1.10-1.15; P < .0001) were significantly related to errors in multivariate analysis. The results of this research suggest that the feasibility of risk-based monitoring and sampling source data verification was indicated for noncritical data and patients after the third case.

A paired training curriculum and internal monitoring program for clinical research regulatory compliance in the emerging era of the single Institutional Review Board

Academic health systems and their investigators are challenged to systematically assure clinical research regulatory compliance. This challenge is heightened in the emerging era of centralized single Institutional Review Boards for multicenter studies, which rely on monitoring programs at each participating site. To describe the development, implementation, and outcome measurement of an institution-wide paired training curriculum and internal monitoring program for clinical research regulatory compliance. Standard operating procedures (SOPs) were developed to facilitate investigator and research professional adherence to institutional policies, federal guidelines, and international standards. An SOP training curriculum was developed and implemented institution-wide. An internal monitoring program was launched, utilizing risk-based monitoring plans of pre-specified frequency and intensity, assessed upon Institutional Review Boards approval of each prospective study. Monitoring plans were executed according to an additional SOP on internal monitoring, with monitoring findings captured in a REDCap database. We observed few major violations across 3 key domains of clinical research conduct and demonstrated a meaningful decrease in the rates of nonmajor violations in each, over the course of 2 years. The paired training curriculum and monitoring program is a successful institution-wide clinical research regulatory compliance model that will continue to be refined.

Risk-based Monitoring Network Design for Geologic Carbon Storage Sites

A comprehensive risk-based monitoring assessment methodology is developed to (i) incorporate background data for thresholds and monitoring design, (ii) use stochastic leakage simulations and monitoring modeling for risk scenarios given uncertainty, (iii) apply statistical methods to combine multiple monitoring techniques and provide decision support for evaluating proposed monitoring plans, and (iv) facilitate implementation in the National Risk Assessment Partnership (NRAP) integrated assessment model (IAM) framework. This methodology is illustrated using a case representative of the High Plains aquifer, considering the stochastic leakage events simulated using reactive transport simulations. The resulting groundwater quality changes were reflected in three groundwater monitoring parameters (pH, TDS and benzene concentrations), which were used to calculate the corresponding detection probability for each simulation, based on the background distributions and the selected thresholds. The consequent detection probability was then used to evaluate the monitoring well density and the proposed network designs. Beyond the detectability, the earliest response time and spatial coverage constraints of a monitoring network design are considered, and the role of adaptive monitoring strategies for compliance monitoring and incorporation of expert judgment on likely leakage locations is considered.

Comparative costs and activity from a sample of UK clinical trials units

BackgroundThe costs of medical research are a concern. Clinical Trials Units (CTUs) need to better understand variations in the costs of their activities.MethodsRepresentatives of ten CTUs and two grant-awarding bodies pooled their experiences in discussions over 1.5 years. Five of the CTUs provided estimates of, and written justification for, costs associated with CTU activities required to implement an identical protocol. The protocol described a 5.5-year, nonpharmacological randomized controlled trial (RCT) conducted at 20 centres. Direct and indirect costs, the number of full time equivalents (FTEs) and the FTEs attracting overheads were compared and qualitative methods (unstructured interviews and thematic analysis) were used to interpret the results. Four members of the group (funding-body representatives or award panel members) reviewed the justification statements for transparency and information content. Separately, 163 activities common to trials were assigned to roles used by nine CTUs; the consistency of role delineation was assessed by Cohen’s κ.ResultsMedian full economic cost of CTU activities was £769,637 (range: £661,112 to £1,383,323). Indirect costs varied considerably, accounting for between 15% and 59% (median 35%) of the full economic cost of the grant. Excluding one CTU, which used external statisticians, the total number of FTEs ranged from 2.0 to 3.0; total FTEs attracting overheads ranged from 0.3 to 2.0. Variation in directly incurred staff costs depended on whether CTUs: supported particular roles from core funding rather than grants; opted not to cost certain activities into the grant; assigned clerical or data management tasks to research or administrative staff; employed extensive on-site monitoring strategies (also the main source of variation in non-staff costs). Funders preferred written justifications of costs that described both FTEs and indicative tasks for funded roles, with itemised non-staff costs. Consistency in role delineation was fair (κ = 0.21–0.40) for statisticians/data managers and poor for other roles (κ < 0.20).ConclusionsSome variation in costs is due to factors outside the control of CTUs such as access to core funding and levels of indirect costs levied by host institutions. Research is needed on strategies to control costs appropriately, especially the implementation of risk-based monitoring strategies.

A risk-based framework for Measurement, Monitoring and Verification (MMV) of the Goldeneye storage complex for the Peterhead CCS project, UK

CO2 emissions from the Peterhead CCS gas power plant were planned to be captured, compressed and transported offshore to be injected at a rate of 1 million tons per year for up to 20 years into the depleted Goldeneye hydrocarbon gas field. Although site selection, characterization and engineering designs are considered the prime means of ensuring confidence in the long-term security of CO2 storage, demonstration that they are performing is provided by a comprehensive risk-based Measurement, Monitoring and Verification (MMV) program. The Goldeneye MMV program was designed according to a systematic site-specific storage containment risk assessment to (1) demonstrate containment, (2) monitor for conformance, (3) provide data for emission accounting, and (4) support storage transfer of long-term liabilities. The MMV design process identified a set of appropriate monitoring tasks and candidate monitoring technologies needed to perform them based on comprehensive site-specific feasibility studies. This procedure reduced forty-five candidate monitoring technologies by half to result in a fit-for-purpose monitoring plan that satisfied UK and EU regulations while using less than fifteen different containment and environmental monitoring techniques.

Generating evidence on a risk-based monitoring approach in the academic setting \u2013 lessons learned

BackgroundIn spite of efforts to employ risk-based strategies to increase monitoring efficiency in the academic setting, empirical evidence on their effectiveness remains sparse. This mixed-methods study aimed to evaluate the risk-based on-site monitoring approach currently followed at our academic institution.MethodsWe selected all studies monitored by the Clinical Trial Unit (CTU) according to Risk ADApted MONitoring (ADAMON) at the University Hospital Basel, Switzerland, between 01.01.2012 and 31.12.2014. We extracted study characteristics and monitoring information from the CTU Enterprise Resource Management system and from monitoring reports of all selected studies. We summarized the data descriptively. Additionally, we conducted semi-structured interviews with the three current CTU monitors.ResultsDuring the observation period, a total of 214 monitoring visits were conducted in 43 studies resulting in 2961 documented monitoring findings. Our risk-based approach predominantly identified administrative (46.2%) and patient right findings (49.1%). We identified observational study design, high ADAMON risk category, industry sponsorship, the presence of an electronic database, experienced site staff, and inclusion of vulnerable study population to be factors associated with lower numbers of findings. The monitors understand the positive aspects of a risk-based approach but fear missing systematic errors due to the low frequency of visits.ConclusionsWe show that the factors mostly increasing the risk for on-site monitoring findings are underrepresented in the current risk analysis scheme. Our risk-based on-site approach should further be complemented by centralized data checks, allowing monitors to transform their role towards partners for overall trial quality, and success.

Abstract P2-11-02: A longitudinal look at toxicity management within a platform trial: Lessons from the I-SPY 2 TRIAL

Abstract Background: I-SPY 2 is a multicenter, phase 2 trial using response-adaptive randomization within biomarker subtypes to evaluate a series of investigational agents or regimens when added to standard neoadjuvant therapy for women with high-risk stage II/III breast cancer - investigational agent (I) +paclitaxel (T) qwk, doxorubicin &amp; cyclophosphamide (AC) q2-3 wk x 4 vs. T+/-HP/AC (control arm(s)). Although the primary endpoint is pathologic complete response (pCR) at surgery, a key secondary aim is to evaluate the toxicity profiles of these investigational agents. Distinct aspects of safety monitoring in a platform trial, as well as the specificities of safety management in a potentially curative population make the experiences from I-SPY 2 valuable to the community. Methods: Inclusion and exclusion criteria are uniformly applied to all women in I-SPY 2. When a new investigational agent/regimen is planned for the trial, agent specific laboratory/hematologic limits or additional required tests are added, as needed. Eligibility criteria remain in the trial for its duration and apply to all investigational and control arms. Laboratory and adverse event data are collected and monitored in real time. The lead investigator of the investigational agent/regimen who chaperones a specific agent/regimen through the trial (“Agent Chaperone”), Medical Monitor, I-SPY 2 Agents Committee, CRO safety group, and an active DSMB that meets monthly oversee the management of toxicities within each investigational agent/regimen of the trial. Toxicity profiles for an investigational agent/regimen are compared to their relevant control. Safety analyses are intention to treat. Results: From March 2010-May 2016, eleven (11) investigational agents/regimens have opened (and 6 have completed evaluation) and 973 women have been randomized. These agents/regimens span a variety of mechanisms of action including targeted therapies such as small molecule inhibitors and antibodies, as well as immunotherapies. Additions to the trial's eligibility criteria have been made with new investigational arms. Adverse events of special interest have been monitored for each investigational arm and specific toxicities treated uniformly when applicable. A risk-based monitoring plan has been implemented that focuses on the collection and review of the trial's most critical data elements including serious adverse events and drug specific safety issues, allowing for a more efficient and focused effort. Safety issues have been quickly addressed and requirements updated, when needed, given the importance of limiting (or avoiding) long-term safety complications within this neoadjuvant patient population. Accrual to the trial has (been) maintained over time and the safety of trial participants has been well managed. Conclusion: A platform trial requires an evolving, and focused safety-monitoring process that adapts as new investigational agents are included. I-SPY 2's infrastructure and team science approach has created a system to manage patients across multiple arms with different risk profiles. These practices will support the safe evaluation of additional new combinations and regimens and serves as a guide for safety management within standing platform trials. Citation Format: Paoloni M, Lyandres J, Buxton MB, Berry DA, Esserman LJ, DeMichele A, Yee D. A longitudinal look at toxicity management within a platform trial: Lessons from the I-SPY 2 TRIAL [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P2-11-02.

International Council for Harmonisation E6(R2) addendum: Challenges of implementation.

The International Council for Harmonisation (ICH) E6 – good clinical practice (GCP) (R2) addendum – was released in 2016 to encourage implementation of improved approaches for the management of clinical trials. The changes in different sections include new approaches – quality management system, risk-based monitoring with emphasis on human subject protection, and data integrity. The article discusses challenges in adoption and implementation of the changes in ICH GCP guideline for clinical trial stakeholders.

Policy Change to Adequately Address Monitoring Conduct in a Risk-Based Environment

In the new Risk-Based (RB) environment of clinical trials, policy to prevent and address misconduct and fraud by Clinical Research Associates (CRA) is virtually nonexistent. To date, misconduct of CRAs and its potential cost to patients and sponsors has not been studied, and thus, has not been addressed. Through strong policy change, it is time for regulators to voice a firm stance that misconduct and fraud will not be tolerated by any member of the scientific community. Traditionally, onsite monitoring has been the standard for quality control with its emphasis placed on Clinical Research Site (CRS) conduct. Quality Assurance (QA) audits retrospectively sample CRS work-product for any possible mistakes or misconduct missed during the monitoring process. There are no regulated standards for how onsite monitoring visits are conducted, during which there is very little oversight of CRAs. Misconduct and fraud by CRAs is not well documented in the literature or in FDA guidance, and with the adoption of Risk-Based Monitoring (RBM) methods, there will be far less oversight of CRAs creating room for their potential misconduct and fraud. The resulting financial cost to sponsors, and risk to patient safety and rights, cannot yet be estimated. Regulators must make confronting CRA misconduct a priority.

Риск-ориентированный мониторинг антропозоонозных цестодозов на основе геоинформационных систем

Objective of research: The target of the paper is to develop a model of GIS-based risk monitoring of zoonotic cestodiasis in human.&#x0D; Materials and methods: The use of geographic information systems (GIS) as an epizootiological and epidemiological method for the risk-based monitoring of human cestodiasis enables the development of a multi-level platform for solution of a wide range of tasks related to the control of this disease. The modern GIS tools use the methods of geoinformatics applying powerful software and hardware: open access geographic web servers, tools for multidimensional complex analysis, creating most accurate electronic and paper maps. Full-featured GIS contain a full set for processing geospatial data including acquisition of data, its integration and storage, automatic data processing, editing, creation and maintenance of topology, spatial analysis, access to the database management system (DBMS), visualization and creation of hard copies of any cartographic data.&#x0D; Results and discussion: The use of GIS enables to study more closely the regularities of epizootic process, geography of human cestodiasis and to improve the methodology both for short-term and long-term retrospective epizootiological analyses.

Epidemiological situation of bovine tuberculosis in the State of Mato Grosso, Brazil

In 2009, the epidemiological situation of bovine tuberculosis was studied in the state of Mato Grosso, which is a traditional beef exporter. The state was divided into four regions. In each region, properties were selected randomly. A predetermined random number of animals were chosen from these properties, and comparative cervical tuberculin tests were conducted. In total, 28,878 animals from 1,133 properties underwent examination. The animals with inconclusive results were reexamined with the same diagnostic procedure in a minimal interval of 60 days. In each sampled property, a questionnaire-based survey was conducted to identify possible risk factors for the disease. In the state, the prevalence of infected herds and animals was 1.3% [0.7; 2.4] and 0.12% [0.03; 0.44], respectively. Further, the prevalence of infected herds and animals were 0.0% [0.0; 2.0] and 0.0% [0.0; 0.08] in the Pantanal region, 1.3% [0.5; 3.1] and 0.04% [0.01; 0.17] in the dairy region, 0.7% [0.2; 2.7] and 0.01% [0.003; 0.04] in the fattening region, and 1.7% [0.7; 4.1] and 0.24% [0.06; 0.90] in the breeding region, respectively. It was observed that the condition of the herds infected with bovine tuberculosis was associated with milk production, European or mestizo breeds, degree of sophistication in the production mode, and herd size of up to 486 animals. Therefore, the implementation of a monitoring system for detection and elimination of the residual infected herds along with incorporation of risk-based monitoring elements is the best strategy for the state.

Transformation in site monitoring practices through risk based monitoring

&lt;p&gt;As the current trends in clinical trial industry, is evolving day by day and adopting upcoming technology to integrate data from different sources into risked based monitoring (RBM) Portal, to increase efficient tracking system in a way that help in understanding site characteristic and make on-site monitoring visit more focused and accurate. Transformation from traditional monitoring method to RBM solution will significantly improve quality of data and will also reduce study risk and time. RBM is a standardized, systematic approach to identify and assess potential risk.&lt;/p&gt;

Critical utility of e-solutions in risk based monitoring

&lt;p class="abstract"&gt;&lt;span lang="EN-IN"&gt;As the clinical trial industry is evolving from a traditional 100% SDV (source data verification) approach to reduced SDV &amp;amp; Centralized Monitoring by applying a risk based monitoring (RBM) approach, hence forth leveraging of e-Solutions and real time data integrations would be critical in RBM. Technological considerations are critical to collect data real time to assess, monitor and mitigate risk in compliance with Good Clinical Practices. This article will examine the importance of e-Solutions and real time analytics in alignment with various systems for developing an effective RBM strategy&lt;/span&gt;.&lt;/p&gt;

Risk based monitoring (RBM) tools for clinical trials: A systematic review

IntroductionIn November 2016, the Integrated Addendum to ICH-GCP E6 (R2) will advise trial sponsors to develop a risk-based approach to clinical trial monitoring. This new process is commonly known as risk based monitoring (RBM). To date, a variety of tools have been developed to guide RBM. However, a gold standard approach does not exist. This review aims to identify and examine RBM tools. MethodsReview of published and grey literature using a detailed search-strategy and cross-checking of reference lists. This review included academic and commercial instruments that met the Organisation for Economic Co-operation and Development (OECD) classification of RBM tools. ResultsNinety-one potential RBM tools were identified and 24 were eligible for inclusion. These tools were published between 2000 and 2015. Eight tools were paper based or electronic questionnaires and 16 operated as Service as a System (SaaS). Risk associated with the investigational medicinal product (IMP), phase of the clinical trial and study population were examined by all tools and suitable mitigation guidance through on-site and centralised monitoring was provided. ConclusionRBM tools for clinical trials are relatively new, their features and use varies widely and they continue to evolve. This makes it difficult to identify the “best” RBM technique or tool. For example, equivalence testing is required to determine if RBM strategies directed by paper based and SaaS based RBM tools are comparable. Such research could be embedded within multi-centre clinical trials and conducted as a SWAT (Study within a Trial).

Risk Based Monitoring (RBM): A global study focusing on perception and merits among clinical investigational sites.

BackgroundSeveral approaches to clinical trial monitoring, including the Risk Based Monitoring (RBM) are aimed at the protection of the human subjects (safety), improved data quality, and ultimately, reducing the cost of drug development and operations. There exists minimal evidence globally about the perceptions and the level of confidence among the clinical staff on the merits of RBM. The present study assessed the perception among clinical research staff globally (developed and emerging countries) on the applicability and adaptability of RBM.MethodsAn electronic questionnaire survey consisting of twelve items was developed, validated, and then circulated globally via email to three thousand clinical research staff members at various investigational sites. This survey collected information on the use of RBM and factors that relate to clinical trial cost, data quality, subject safety, and the readiness to adopt RBM practices. The survey responses were summarized and analyzed by using the information e.g. responder's age, sex, clinical research role, global location, and experience in clinical research trials.ResultsResponses were received from ten countries, six emerging and four developed. Of the 3000 surveys sent to emerging (1,000) and developed (2,000) countries, a total response of 595 (261 vs 334) participants was received, respectively. The emerging versus developed group had 100 vs 137 participants with complete responses (CR); 34 vs 35 participants with partial responses (PR); and 127 vs 162 participants were disqualified with no exposure (NE) responses. About 67% of the overall responders were investigators, followed by 23%, 10% coordinator and other staff respectively. There was not significant difference in feedback between the researchers in developing versus emerging countries (p = 0.20) with regards to their perception of RBM reducing the overall cost of conducting a clinical research. Responders from emerging countries had a more favorable response than in the developed countries. Similarly, when asked if RBM will be more effective in addressing data quality (p = 0.006), patient safety (p = 0.05) and findings fraud/fabrication (p = 0.01), researchers from emerging countries indicated more confidence than researchers from developed countries. There was also a significant difference in the readiness to adopt RBM between responders of emerging versus developed markets (p < 0.0001).ConclusionThis unique study performed across ten emerging and developed countries strongly supported the need for systematic global training, education, and implementation of RBM regulatory guidance, with an aim for better safety of subjects and improved quality of clinical trial data. Furthermore, studies with larger sample sizes are recommended to provide an evidence-based approach.

The analysis of specialists’ opinion on the implementation of concept of risk management in clinical trials of drugs

At the modern stage of the pharmaceutical industry development quality risk management becomes an integral part of all the processes of drug development and clinical trials (CT).Aim of paper is to study the opinion of competent experts in the field of CT of drugs and formation of strategic ways of risk management at the clinical site as well as to identify possible complications in the practical implementation of these approaches.Materials and methods: the survey of the expert group (17 people) to select the indicators and the parameters measuring the risks of CT at clinical site, as well as their acceptable levels. The assessment of survey results was done using non-parametric statistics methods. Results of research. There were established the differences of various stakeholders’ notion of conceptual content and practical importance of quality management and the application of risk-oriented approaches at the clinical site in relation to CT quality that can become an obstacle to their implementation. The introduction of risk-based monitoring into the system for CT management at the clinical site corresponds to the interests of all stakeholders involved in the study. General concernment of the customer’s representatives, regulatory authority and researchers should be an important basis for the implementation of the risk-based management at the clinical site. So, it is necessary to create a common understanding of the terminology, objectives and expected outcomes of risk management at the clinical site, as well as a clear allocation of the duties and responsibilities of each side.Conclusions. The expediency of the concept of risk management application at the clinical site, practical orientation, as well as the need to develop scientific and methodological approaches for its implementation, contributing to the formation of a common basis for action and coordinated interaction of stakeholders involved in the management of CT were proved.

Challenges to the Implementation of Risk-Based Monitoring

Regulatory agencies, multinational companies, and contract research organizations across the globe advocate implementation of risk-based monitoring (RBM) due to its perceived benefits, yet the pharmaceutical industry has yet to employ it on a full scale. Implementing the RBM strategy confidently and consistently among all stakeholders requires a shift in mindset from conducting 100% source data verification to a risk-based approach, cognizance of evolving roles, consistent understanding of RBM’s underlying principles and methodology, objective decision-making, and more regulatory guidance.

ESource and Risk-Based Monitoring

The growing cost of drug development paves the way for newer technologies in clinical research. Taking its cue from success stories of automation across industries, the pharmaceutical sector’s acceptance of the Cloud, Big Data, and analytics stands as a testimony to changing times. Risk-based monitoring (RBM) looks at study issues at the root level and uses technology to challenge the status quo. The need for 100% source data verification (SDV) is being challenged, and innovative ideas to reduce SDV are being explored. Electronic source (eSource) can catalyze clinical trials transformation via RBM.

Keeping Up with Clinical Research Technologies

The goal of this issue is to help readers keep pace with technological trends happening in the research enterprise. While it can be exciting to see how technology makes positive impacts professionally, in the clinical research line of work we also need to think about how technologies are regulated and how they can affect human subjects protections. Technologies may solve old problems, but the reality is that they create new ones, too, for example as paper case report forms (CRFs) turn into electronic CRFs (eCRFs) and, because of eCRFs, onsite monitoring segues into remote, risk-based monitoring.

A model for risk-based monitoring of contaminants in feed ingredients

A qualitative spreadsheet model has been developed for ranking feed ingredients on the basis of the potential risk of exceeding existing guidance or maximum levels in the EU for a certain contaminant, and the potential consequence of the presence of this contaminant on the health of animals and/or humans. The approach was based on the general concept of risk, being frequency times consequences of presence of the contaminant. Contamination of compound feeds due to presence of the contaminant in feed ingredients was estimated, per animal category, by: annual volumes of feed ingredients used for feed production, stratified per country of origin; the portion of each ingredient in compound feed formulations used for various animal categories; and the potential contamination of an ingredient per country of origin. The consequences of the contamination were accounted for by two consequence factors, both estimated per animal category: one for the potential impact of the contaminant on the health of the target animal, and one for the impact on human health, related to the possible formation of residues in animal derived food products.The use of the model was demonstrated by its application to the presence of dioxins and dl-PCBs in compound feed for farm animals produced in the Netherlands in 2013 and 2014. Model results include the relative contribution, based on relative ranking scores, of each feed ingredient to the chance of exceeding limits and potential consequences on animal and human health. Feed ingredients ranking highest were palm oil, other fats and oils, dried products like bakery products, sunflower expeller/extracted, maize, and fish meal.The model can be used by risk managers in feed industry and by governmental bodies for supporting decision making on the optimal allocation of resources for control of ingredients for compound feed production for presence of contaminants.