Risk-based Quality Management Research Articles

Good Statistical Monitoring: A Flexible Open-Source Tool to Detect Risks in Clinical Trials

Abstract Background Risk-based quality management is a regulatory-recommended approach to manage risk in a clinical trial. A key element of this strategy is to conduct risk-based monitoring to detect potential risks to critical data and processes earlier. However, there are limited publicly available tools to perform the analytics required for this purpose. Good Statistical Monitoring is a new open-source solution developed to help address this need. Methods A team of statisticians, data scientists, clinicians, data managers, clinical operations, regulatory, and quality compliance staff collaborated to design Good Statistical Monitoring, an R package, to flexibly and efficiently implement end-to-end analyses of key risks. The package currently supports the mapping of clinical trial data from a variety of formats, evaluation of 12 key risk indicators, interactive visualization of analysis results, and creation of standardized reports. Results The Good Statistical Monitoring package is freely available on GitHub and empowers clinical study teams to proactively monitor key risks. It employs a modular workflow to perform risk assessments that can be customized by replacing any workflow component with a study-specific alternative. Results can be exported to other clinical systems or can be viewed as an interactive report to facilitate follow-up risk mitigation. Rigorous testing and qualification are performed as part of each release to ensure package quality. Conclusions Good Statistical Monitoring is an open-source solution designed to enable clinical study teams to implement statistical monitoring of critical risks, as part of a comprehensive risk-based quality management strategy.

QC constellation: A cutting-edge solution for risk-based quality management in laboratories

QC constellation: A cutting-edge solution for risk-based quality management in laboratories

Risk based quality management: the way forward to improve quality in medical laboratories

Risk based quality management: the way forward to improve quality in medical laboratories Risk based quality management is not new. Many different standards including CLSI standard EP23-A, ISO 14971, ISO 31000, and ISO 22367 address risk management in laboratories. Risk and safety are addressed in quality management systems, introduced to provide accreditation and recog-nition of health care institutions. Laboratory quality is different from other quality targets as quality of a test report begins and ends with the same indi-vidual; the patient. Therefore, it is a closed loop having direct repercussions to the patient. In addition, medical laboratories are unique in safety as there are biohazards and chemical hazards. When managing laboratories, we should ensure patient safety as the top priority while ensuring safety of the employees and the environment. The latest version of ISO15189:2022 standard emphasises more on safety and risks. The pro-bability of hazards occurring should be under-stood, and the repercussions of a risk should be given consideration. Combining probability of occurrence and repercussions of risks will enable laboratories to prioritise and plan actions. This

Comprehensive Assessment of Risk-Based Quality Management Adoption in Clinical Trials

BackgroundRisk-based monitoring (RBM) and risk-based quality management (RBQM) offer a compelling approach to increase efficiency, speed and quality in clinical trials by prioritizing and mitigating risks related to essential safety and efficacy data. Since 2013, the FDA and EMA have encouraged the use of RBM/RBQM, however adoption has been slow with limited understanding of the barriers to adoption.MethodsThe Tufts Center for the Study of Drug Development conducted an online survey among pharmaceutical, biotechnology, and contract research organizations and gathered 206 responses on 32 distinct RBQM practices.ResultsOn average, companies implemented RBQM in 57% of their clinical trials. Lower levels of adoption were observed among companies conducting fewer than 25 trials annually (48%) compared to those conducting more than 100 trials annually (63%). Primary barriers to adoption include lack of organizational knowledge and awareness, mixed perceptions of the value proposition of RBQM, and poor change management planning and execution. Insights into improving the level of adoption are discussed.

Drinking water quality management progress in Ontario, two decades after Walkerton.

Following the waterborne disease outbreak in Walkerton, Ontario, the province made significant efforts to implement recommendations of the public inquiry that resulted. As Ontario reformed its drinking water sector, other jurisdictions were advancing risk-based quality management frameworks for drinking water, including the World Health Organization (WHO) through its water safety plan (WSP) framework. Two decades after the Walkerton tragedy, this paper seeks to: (i) evaluate alignment of Ontario's Drinking Water Quality Management Standard (DWQMS) with the WSP framework (ii) review readily available data for evidence that Ontario's DWQMS implementation has improved drinking water safety and promoted a preventive approach through risk-based quality management. Our study found strong alignment between the Ontario DWQMS and WSP frameworks, with supporting programmes and risk assessment procedures present. Analysis of available regulatory data revealed abundant reporting of water quality and adverse incidents in municipal water systems. However, performance data were publicly available, the use of percentage scores for water quality testing obscures the details of system performance and water safety. Reports describing the DWQMS plan and audit results were difficult to obtain and not standardized. There is a need to develop mechanisms to ensure continual improvement of the DWQMS.

SA29 Adopting Clinical Trial Best practices of Hybrid Decentralized and Risk Based Quality Management (RBQM), to Help Optimize Prospective Observational (Real-World Evidence) Studies in Compliance, Cost and Time Criteria

RWE contribution in FDA approvals has increased by 70% from 2019 to 2020. RWE continues to offer evidence demonstrating safety and/or effectiveness in growing number of regulatory decisions1. During 2020, about 100% of FDA approvals in infectious and 75 % in Oncology disease area utilized RWE along with trial evidence2. The industry is expected to enhance focus on prospective real world evidence studies to generate safety and/or effectiveness to support trial evidence.

Risk-based Quality Management in CDM An inquiry into the value of generalized query-based data cleaning

INTRODUCTION: The essence of Risk-based Quality Management is to focus on what matters most. Sponsor companies are annually spending many billions of dollars on automated and manual data cleaning, utilizing internal and site resources to create the illusion of an error-free data base. However, over the last 15 years, a robust data acquisition process was developed, and much of the current query-based data cleaning approach is a self-imposed remnant of the error-prone processes of the past. OBJECTIVE: Motivated by previously reported insights regarding the limited value of generalized source data verification (SDV), seven pharmaceutical companies and a clinical trials solution vendor teamed up to answer the question “How efficient is the query-based data cleaning process?” METHODS: Twenty completed Phase III studies representing different sponsors and therapeutic areas (TAs) were randomly selected from a collective data pool. Query data was aggregated across studies and classified by query type (automatic/manual) and initiator role. Form types were standardized using a semi-supervised machine learning model. Each query record was classified as to whether the query resulted in a change (query efficacy) and whether a change was direct or indirect. Query efficacy was characterized by TA, query type, initiator role and form type and graphically represented using bar charts, histograms, heat maps and waffle plots. RESULTS: Combined, the studies represented more than 20,000 study participants, comprising nearly 50 million data points and over 1.9 million queries. While the overall query rate was 3.9%, even including indirect and non-informative modifications, fewer than half of these queries actually resulted in a data change, affecting less than 1.7% of entered data. CONCLUSION: While clear differences between the type of query, type of form, and query initiator provide important insights on approaches for further improving the Clinical Data Management (CDM) process, our data show that overall the current acquisition process is very robust. Considering the tremendous efforts that go into the generalized query-based data cleaning process, and the limited impact it has, it is concluded that this process does not contribute proportionally to the quality of the final database used for analysis. We recommend ending the current query process to correct errors of non-critical data in Phase 3 studies, and placing more emphasis on tools and techniques that help identify systemic issues in the data collection process. This would be a great leap forward for CDM towards a risk-based approach to quality management as described in ICH E6 (R2).

Central statistical monitoring of investigator-led clinical trials in oncology.

Investigator-led clinical trials are pragmatic trials that aim to investigate the benefits and harms of treatments in routine clinical practice. These much-needed trials represent the majority of all trials currently conducted. They are however threatened by the rising costs of clinical research, which are in part due to extensive trial monitoring processes that focus on unimportant details. Risk-based quality management focuses, instead, on “things that really matter”. We discuss the role of central statistical monitoring as part of risk-based quality management. We describe the principles of central statistical monitoring, provide examples of its use, and argue that it could help drive down the cost of randomized clinical trials, especially investigator-led trials, whilst improving their quality.

The analysis of the current state of quality management tools implementation in clinical trials of drugs in Ukraine

The specificity of the processes of organizing and conducting clinical trials (CT) determines the particular requirements for quality management systems (QMS) and their improvement. That is why there is a constant need to assess the effectiveness of CT quality management and determine the need to develop new QMS optimization tools that have been already implemented in the work.Аim. To study the state of the implementation of quality management tools in CT of drugs and assess their use in practice.Materials and methods. To identify problems and determine the need to create the ways to improve CT QMS we conducted a survey of 217 Ukrainian specialists working in the field of organizing and conducting CT.Results. According to the respondents, the most used QT quality management tools to ensure the proper level of quality in organizing and conducting CT are monitoring / audit, and routine internal quality control. The assessment of the knowledge level about risk-based quality management tools has shown that the personnel carrying out the processes of organizing and conducting CT does not fully possess even basic knowledge about the proper use of CT quality management tools. The analysis of the QMS implementation in the practical work of the respondents’ organizations has shown an insufficient level of implementation of such systems and their certification.Conclusions. Thus, it is advisable to perform work on the development of methods for the active implementation of risk-based tools into practice; it is necessary to train specialists in the field of CT according to the specialized professional and educational programs, as well as to use the wider implementation of QMS in organizations and their certification.

Survey of Risk-Based Quality Management Status and Establishment of Operational Model in Clinical Trials.

PurposeWith the release of the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use E6 addendum, it is very important to establish risk-based quality management systems which meet good clinical practice. The aim of this research was to propose for risk-based quality management practices in the organizations that conduct clinical trials in South Korea.Materials and MethodsThe survey participant pool consisted of domestic or multinational pharmaceutical companies and fullservice clinical research organizations operating in South Korea that had one or more clinical trials approved by the Korean Ministry of Food and Drug Safety in 2018.ResultsOf the 97 selected companies, a total of 61 companies completed the survey. A total of 42 companies (68.9%) had employees designated to quality management activities. The minimum and maximum numbers of dedicated personnel for quality management were one and 12, respectively, and the average was three. Regarding the role of quality management personnel in companies, standard operating procedure management, issue/corrective action and preventive action (CAPA) management, and preparing inspection were selected the most (81%). The system considered to be the most important for risk management was monitoring system (41 companies, 67.2%), followed by both vendor management and CAPA management systems (17 companies, 27.9%).ConclusionIn the future, organizations conducting clinical and subsequent pilot studies trials in South Korea should follow these quality management practice to share information with each other.

Identification of the risks in CAR T-cell therapy clinical trials in China: a Delphi study

Aims:Within the past few years, there has been tremendous growth in clinical trials of chimeric antigen receptor (CAR) T-cell therapies. Unlike those of many small-molecule pharmaceuticals, CAR T-cell therapy clinical trials are fraught with risks due to the use of live cell products. The aim of this study is to reach a consensus with experts on the most relevant set of risks that practically occur in CAR T-cell therapy clinical trials.Methods:A Delphi method of consensus development was used to identify the risks in CAR T-cell therapy clinical trials, comprising three survey rounds. The expert panel consisted of principal investigators, clinical research physicians, members of institutional ethics committees, and Good Clinical Practice managers.Results:Of the 24 experts invited to participate in this Delphi study, 20 participants completed Round 1, Round 2, and Round 3. Finally, consensus (defined as >80% agreement) was achieved for 54 risks relating to CAR T-cell clinical trials. Effective interventions related to these risks are needed to ensure the proper protection of subject health and safety.Conclusion:The Delphi method was successful in gaining a consensus on risks relevant to CAR T-cell clinical trials in a geographically diverse expert association. It is hoped that this work can benefit future risk-based quality management in clinical trials and can potentially promote the better development of CAR T-cell therapy products.

A Pilot Study to Understand the Acceptance of Clinical Research Industry in Application of Risk-Based Quality Management System to Clinical Trials

A Pilot Study to Understand the Acceptance of Clinical Research Industry in Application of Risk-Based Quality Management System to Clinical Trials

Risk-Based Quality and Compliance Management in Clinical Trials with Combination Products in Changing Global Regulatory Environment.

Newly emerging products which combine drugs, devices, and biologics are expected to provide new opportunities in bridging device and drug capabilities and establish synergies while bringing sophisticated combination products to consumers. The emergence of these novel products has triggered new regulatory, strategic, and technological challenges. While progress has been made at clarifying the issues that arise most frequently, regulatory authorities and product developers continue to struggle with complex regulatory and technical issues encompassing the development programs for combination products. A risk-based approach requires not only a strategy but also tools to define key indicators to measure specific risks. Key risk indicators (KRIs) and risk-based quality management systems should focus on safety of research subjects and data integrity. We analyzed current regulatory guidelines throughout the life cycle of combination products and compared old and new approaches to risk-based quality and compliance management for current good manufacturing practices and during pre-clinical and clinical phases of combination products development. Cause-effect analysis for two major risk categories in clinical trials with combination products was performed. The results of our analysis are based on observations from 15 clinical trials, which were conducted with combination products. Based on our findings, we proposed practical recommendations for the development of KRIs to improve conduct and ensure safety of research subjects in trials with combination products by utilizing risk-based quality management approach. Combination products, due to their specific nature, can increase risks while being tested in clinical trials. Metrics critical to risks and quality management should be linked to particular processes within development program for combination products. Ongoing collaboration between regulators, industry, and other stakeholders is essential to streamlining of the global combination entities development and approval process in a way that will produce safe and effective products for consumers.

The development of quality management systems in maintenance and monitoring the process of risk-based repair work in government buildings

Buildings exemplify the social and economic aspects of an environment and provide shelters, space and facilities for human activity. A decent maintenance system is a vital component of all buildings. However, a good maintenance system is not always present in the government buildings of Indonesia. Government buildings require maintenance to extend sustainability, indirectly accomplishing services to the community. Financial planning is issued annually by the government to maintain their buildings, but there is no underlined Quality Management System in this plan. This study aims to develop a Quality Management System in maintenance and monitor the process of repair work in Government Buildings. The methods used in this research are: The Delphi method and risk questionnaire surveys. The risks found in each activity have been analysed descriptively and qualitatively, resulting in responses reflecting the highest of risk. The result was that the risk-based quality management system in maintenance and monitoring process of repair work was successfully applied to improve the performance in the environment of governmental buildings.

Failure modes and effects analysis (FMEA) for Gamma Knife radiosurgery.

PurposeGamma Knife radiosurgery is a highly precise and accurate treatment technique for treating brain diseases with low risk of serious error that nevertheless could potentially be reduced. We applied the AAPM Task Group 100 recommended failure modes and effects analysis (FMEA) tool to develop a risk‐based quality management program for Gamma Knife radiosurgery.MethodsA team consisting of medical physicists, radiation oncologists, neurosurgeons, radiation safety officers, nurses, operating room technologists, and schedulers at our institution and an external physicist expert on Gamma Knife was formed for the FMEA study. A process tree and a failure mode table were created for the Gamma Knife radiosurgery procedures using the Leksell Gamma Knife Perfexion and 4C units. Three scores for the probability of occurrence (O), the severity (S), and the probability of no detection for failure mode (D) were assigned to each failure mode by 8 professionals on a scale from 1 to 10. An overall risk priority number (RPN) for each failure mode was then calculated from the averaged O, S, and D scores. The coefficient of variation for each O, S, or D score was also calculated. The failure modes identified were prioritized in terms of both the RPN scores and the severity scores.ResultsThe established process tree for Gamma Knife radiosurgery consists of 10 subprocesses and 53 steps, including a subprocess for frame placement and 11 steps that are directly related to the frame‐based nature of the Gamma Knife radiosurgery. Out of the 86 failure modes identified, 40 Gamma Knife specific failure modes were caused by the potential for inappropriate use of the radiosurgery head frame, the imaging fiducial boxes, the Gamma Knife helmets and plugs, the skull definition tools as well as other features of the GammaPlan treatment planning system. The other 46 failure modes are associated with the registration, imaging, image transfer, contouring processes that are common for all external beam radiation therapy techniques. The failure modes with the highest hazard scores are related to imperfect frame adaptor attachment, bad fiducial box assembly, unsecured plugs/inserts, overlooked target areas, and undetected machine mechanical failure during the morning QA process.ConclusionsThe implementation of the FMEA approach for Gamma Knife radiosurgery enabled deeper understanding of the overall process among all professionals involved in the care of the patient and helped identify potential weaknesses in the overall process. The results of the present study give us a basis for the development of a risk based quality management program for Gamma Knife radiosurgery.

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.

The comparative analysis of the ISO 9001:2015 standard and Good Clinical Practice guidelines: the framework for improving management of clinical trials

The comparative analysis of the iso 9001:2015 standard and Good Clinical Practice guidelines: the framework for improving management of clinical trialsThe principal concept of the ICH Q8, Q9 and Q10 guidelines is to encourage implementation of scientific and systematic approaches for quality assurance of pharmaceutical products. Clinical trials, which are the crucially important part of the pharmaceutical research and development process, are outside of these guidelines, and it actualizes the issue on introducing quality management into clinical trials.Aim. To analyze the ISO 9001 quality management methodology and the Addendum to GCP requirements in order to elaborate the methodical background for its combined use that will provide the effective work of the quality management system while achieving GCP compliance. Materials and methods. The methods of the comparative analysis, synthesis, generalization, abstraction and content analysis were used to determine the possibility of ISO 9001:2015 and ICH GCP integration.Results. The Addendum to GCPdemonstrates the conformity of its provisions with prominent trends of quality management confirmed by the ISO 9001:2015 standard. The Addendum to GCP declares that the quality management system should use a risk-based approach, which allows conducting clinical trials more efficiently.Conclusions. The ICH GCP framework can be easily and effectively integrated into the ISO 9001 quality management system of a particular clinical study, as well as in the entire system of quality assurance during the drug lifecycle. Further studies should be focused on development of the practical approaches and methods for implementation of the risk-based quality management in clinical trials.

Development of a conceptual model for risk-based quality management system

In this study, it is shown the attitudes and approaches behind the two important function-specific management system standards developed by International Organization for Standardization, namely quality management system (QMS) based on ISO 9001:2008 and risk management system (RMS) based on ISO 31000:2009, are largely similar and complementary. Also, both these management systems (MSs) are essential elements of organisational performance management system. Thus, as the key result, integration of the above MSs is suggested and a conceptual model to support this integration is introduced. The integration model is called risk-based quality management system. The main driver for such integration are: to reduce the number of MSs in an organisation and hence to decrease the number of resources employed and to enhance the organisation performance as both RMS and QMS are two sides of the same coin. The proposed risk-based conceptual model is built upon a review and analysis of authoritative journal papers in the field which shows there are some gaps. The risk-based conceptual model is developed on the basis of total quality integration model and the process approach. Finally, to implement the proposed model, an implementation methodology is suggested.

Risk assessment of fungal spoilage: A case study of Aspergillus niger on yogurt

A quantitative risk assessment model of yogurt spoilage by Aspergillus niger was developed based on a stochastic modeling approach for mycelium growth by taking into account the important sources of variability such as time-temperature conditions during the different stages of chill chain and individual spore behavior. Input parameters were fitted to the appropriate distributions and A. niger colony’s diameter at each stage of the chill chain was estimated using Monte Carlo simulation. By combining the output of the growth model with the fungus prevalence, that can be estimated by the industry using challenge tests, the risk of spoilage translated to number of yogurt cups in which a visible mycelium of A. niger is being formed at the time of consumption was assessed. The risk assessment output showed that for a batch of 100,000 cups in which the percentage of contaminated cups with A. niger was 1% the predicted numbers (median (5th, 95th percentiles)) of the cups with a visible mycelium at consumption time were 8 (5, 14). For higher percentages of 3, 5 and 10 the predicted numbers (median (5th, 95th percentiles)) of the spoiled cups at consumption time were estimated to be 24 (16, 35), 39 (29, 52) and 80 (64, 94), respectively. The developed model can lead to a more effective risk-based quality management of yogurt and support the decision making in yogurt production.

Failure Modes and Effects Analysis (FMEA): Based Quality Management Program for Stereotactic Radiosurgery

Stereotactic radiosurgery is a highly precise and accurate treatment technique for treating brain diseases with low serious error risks that nevertheless could potentially be reduced. We applied the AAPM Task Group 100 recommended failure modes and effects analysis (FMEA) tool to develop a risk-based quality management program for Gamma Knife radiosurgery. A team consisting of medical physicists, radiation oncologists, neurosurgeons, radiation safety officers, nurses, operating room technologists, and schedulers at our institution and an external physicist expert was formed for the FMEA study. A process tree and a failure mode table were created for the Gamma Knife radiosurgery procedures using the Leksell Gamma Knife Perfexion and 4C units. Three scores for the probability of occurrence, the severity, and the probability of no detection for failure modes were assigned to each failure mode by each professional on a scale from 1 to 10. Members of the team only contributed to the scoring for the steps with which they were familiar. The risk priority number (RPN) for each failure mode was then calculated as the average scores from all data sets collected. The established process tree for Gamma Knife radiosurgery consists of 10 sub-processes and 53 steps, including a sub-process for frame placement and 11 steps that are directly related to the frame-based nature of the Gamma Knife radiosurgery. Out of the 86 failure modes identified, 40 failure modes are Gamma Knife-specific, caused by the potential for inappropriate use of the radiosurgery head frame, the imaging fiducial boxes, the Gamma Knife helmets and plugs, the skull definition tools as well as other features of the GammaPlan treatment planning system. The other 46 failure modes are associated with the registration, imaging, image transfer, contouring processes that are common for all external beam radiation therapy techniques. The failure modes with the highest hazard scores are related to imperfect frame adaptor attachment, bad fiducial box assembly, overlooked target areas, inaccurate previous treatment information, and excessive patient movement during MRI scan. The implementation of the FMEA approach for Gamma Knife radiosurgery enabled deeper understanding of the overall process among all professionals involved in the care of the patient and helped identify potential weaknesses in the overall process. Some process steps were redesigned and controls put in place to address the identified potential weaknesses. A review of the impact of the redesign and controls on the process outcome will be performed in six months.