Combining colonoscopy with FIT can improve current familial colorectal cancer colonoscopy surveillance - a modelling study.

BACKGROUND: We assessed whether familial colorectal cancer (FCRC) surveillance in individuals without hereditary CRC can be optimized METHODS: The ASCCA-FCRC model simulates CRC development in individuals with a family history of CRC at 2-fold and 4-fold increased CRC risk compared to the general population. We simulated a strategy without surveillance, the current Dutch guideline (5-yearly colonoscopy between 45-75), and three sets of alternative strategies; colonoscopy surveillance, surveillance combining colonoscopy and fecal immunochemical test (FIT) and FIT-based surveillance. Each set included a range of strategies differing in age range and test interval. The optimal strategy was defined as the strategy with highest quality-adjusted life years (QALYs) satisfying all criteria: 1) in the (near-)efficiency area of the cost-effectiveness frontier, and compared to current surveillance 2) non-inferior effectiveness, 3) no substantial increase in colonoscopy burden and, 4) not more expensive. RESULTS: The optimal strategy was 10-yearly colonoscopy with 2-yearly FIT between colonoscopies from age 40 to 80 for both 2- and 4-fold increased CRC risk. At 2-fold risk, this strategy prevented 0.8 more CRC deaths, gained 15.8 more QALYs at 731 fewer colonoscopies and saved €98k over the lifetime of 1,000 individuals compared to current surveillance. At 4-fold risk, figures were 2.1 more CRC deaths prevented, 37.0 more QALYs gained at 567 fewer colonoscopies and €127k lower costs. Current surveillance was not (near-)efficient. CONCLUSION: FIT could play an important role in FCRC surveillance. Surveillance with 10-yearly colonoscopy and 2-yearly FIT between colonoscopies from age 40 to 80 increases QALYs and reduces colonoscopy burden and costs compared to current FCRC surveillance.

Risk-based lung cancer screening in heavy smokers: a benefit-harm and cost-effectiveness modeling study.

BACKGROUND: Annual screening through low-dose computed tomography (LDCT) is recommended for heavy smokers. However, it is questionable whether all individuals require annual screening given the potential harms of LDCT screening. This study examines the benefit-harm and cost-effectiveness of risk-based screening in heavy smokers and determines the optimal risk threshold for screening and risk-stratified screening intervals. METHODS: We conducted a comparative cost-effectiveness analysis in China, using a cohort-based Markov model which simulated a lung cancer screening cohort of 19,146 heavy smokers aged 50 ~ 74 years old, who had a smoking history of at least 30 pack-years and were either current smokers or had quit for < 15 years. A total of 34 risk-based screening strategies, varying by different risk groups for screening eligibility and screening intervals (1-year, 2-year, 3-year, one-off, non-screening), were evaluated and were compared with annual screening for all heavy smokers (the status quo strategy). The analysis was undertaken from the health service perspective with a 30-year time horizon. The willingness-to-pay (WTP) threshold was adopted as three times the gross domestic product (GDP) of China in 2021 (CNY 242,928) per quality-adjusted life year (QALY) gained. RESULTS: Compared with the status quo strategy, nine risk-based screening strategies were found to be cost-effective, with two of them even resulting in cost-saving. The most cost-effective strategy was the risk-based approach of annual screening for individuals with a 5-year risk threshold of ≥ 1.70%, biennial screening for individuals with a 5-year risk threshold of 1.03 ~ 1.69%, and triennial screening for individuals with a 5-year risk threshold of < 1.03%. This strategy had the highest incremental net monetary benefit (iNMB) of CNY 1032. All risk-based screening strategies were more efficient than the status quo strategy, requiring 129 ~ 656 fewer screenings per lung cancer death avoided, and 0.5 ~ 28 fewer screenings per life-year gained. The cost-effectiveness of risk-based screening was further improved when individual adherence to screening improved and individuals quit smoking after being screened. CONCLUSIONS: Risk-based screening strategies are more efficient in reducing lung cancer deaths and gaining life years compared to the status quo strategy. Risk-stratified screening intervals can potentially balance long-term benefit-harm trade-offs and improve the cost-effectiveness of lung cancer screenings.

Acceptability of de-intensified screening for women at low risk of breast cancer: a randomised online experimental survey.

BACKGROUND: Risk-stratified approaches to breast screening show promise for increasing benefits and reducing harms. But the successful implementation of such an approach will rely on public acceptability. To date, research suggests that while increased screening for women at high risk will be acceptable, any de-intensification of screening for low-risk groups may be met with less enthusiasm. We report findings from a population-based survey of women in England, approaching the age of eligibility for breast screening, to compare the acceptability of current age-based screening with two hypothetical risk-adapted approaches for women at low risk of breast cancer. METHODS: An online survey of 1,579 women aged 40-49 with no personal experience of breast cancer or mammography. Participants were recruited via a market research panel, using target quotas for educational attainment and ethnic group, and were randomised to view information about (1) standard NHS age-based screening; (2) a later screening start age for low-risk women; or (3) a longer screening interval for low-risk women. Primary outcomes were cognitive, emotional, and global acceptability. ANOVAs and multiple regression were used to compare acceptability between groups and explore demographic and psychosocial factors associated with acceptability. RESULTS: All three screening approaches were judged to be acceptable on the single-item measure of global acceptability (mean score > 3 on a 5-point scale). Scores for all three measures of acceptability were significantly lower for the risk-adapted scenarios than for age-based screening. There were no differences between the two risk-adapted scenarios. In multivariable analysis, higher breast cancer knowledge was positively associated with cognitive and emotional acceptability of screening approach. Willingness to undergo personal risk assessment was not associated with experimental group. CONCLUSION: We found no difference in the acceptability of later start age vs. longer screening intervals for women at low risk of breast cancer in a large sample of women who were screening naïve. Although acceptability of both risk-adapted scenarios was lower than for standard age-based screening, overall acceptability was reasonable. The positive associations between knowledge and both cognitive and emotional acceptability suggests clear and reassuring communication about the rationale for de-intensified screening may enhance acceptability.

Determining the extent and frequency of on-site monitoring: a bayesian risk-based approach.

BACKGROUND: On-site monitoring is a crucial component of quality control in clinical trials. However, many cast doubt on its cost-effectiveness due to various issues, such as a lack of monitoring focus that could assist in prioritizing limited resources during a site visit. Consequently, an increasing number of trial sponsors are implementing a hybrid monitoring strategy that combines on-site monitoring with centralised monitoring. One of the primary objectives of centralised monitoring, as stated in the clinical trial guidelines, is to guide and adjust the extent and frequency of on-site monitoring. Quality tolerance limits (QTLs) introduced in ICH E6(R2) and thresholds proposed by TransCelerate Biopharma are two existing approaches for achieving this objective at the trial- and site-levels, respectively. The funnel plot, as another threshold-based site-level method, overcomes the limitation of TransCelerate's method by adjusting thresholds flexibly based on site sizes. Nonetheless, both methods do not transparently explain the reason for choosing the thresholds that they used or whether their choices are optimal in any certain sense. Additionally, related Bayesian monitoring methods are also lacking. METHODS: We propose a simple, transparent, and user-friendly Bayesian-based risk boundary for determining the extent and frequency of on-site monitoring both at the trial- and site-levels. We developed a four-step approach, including: 1) establishing risk levels for key risk indicators (KRIs) along with their corresponding monitoring actions and estimates; 2) calculating the optimal risk boundaries; 3) comparing the outcomes of KRIs against the optimal risk boundaries; and 4) providing recommendations based on the comparison results. Our method can be used to identify the optimal risk boundaries within an established risk level range and is applicable to continuous, discrete, and time-to-event endpoints. RESULTS: We evaluate the performance of the proposed risk boundaries via simulations that mimic various realistic clinical trial scenarios. The performance of the proposed risk boundaries is compared against the funnel plot using real clinical trial data. The results demonstrate the applicability and flexibility of the proposed method for clinical trial monitoring. Moreover, we identify key factors that affect the optimality and performance of the proposed risk boundaries, respectively. CONCLUSION: Given the aforementioned advantages of the proposed risk boundaries, we expect that they will benefit the clinical trial community at large, in particular in the realm of risk-based monitoring.

QC Constellation: a cutting-edge solution for risk and patient-based quality control in clinical laboratories.

OBJECTIVES: Clinical laboratories face limitations in implementing advanced quality control (QC) methods with existing systems. This study aimed to develop a web-based application to addresses this gap, and improve QC practices. METHODS: QC Constellation, a web application built using Python 3.11, integrates various statistical QC modules. These include Levey-Jennings charts with Westgard rules, sigma-metric calculations, exponentially weighted moving average (EWMA) and cumulative sum (CUSUM) charts, and method decision charts. Additionally, it offers a risk-based QC section and a patient-based QC module aligning with modern QC practices. The codes and the web application links for QC Constellation were shared at https://github.com/hikmetc/QC_Constellation, and http://qcconstellation.com, respectively. RESULTS: Using synthetic data, QC Constellation demonstrated effective implementation of Levey-Jennings charts with user-friendly features like checkboxes for Westgard rules and customizable moving averages graphs. Sigma-metric calculations for hypothetical performance values of serum total cholesterol were successfully performed using allowable total error and maximum allowable measurement uncertainty goals, and displayed on method decision charts. The utility of the risk-based QC module was exemplified by assessing QC plans for serum total cholesterol, showcasing the application's capability in calculating risk-based QC parameters including maximum unreliable final patient results, risk management index, and maximum run size and offering risk-based QC recommendations. Similarly, the patient-based QC and optimization modules were demonstrated using simulated sodium results. CONCLUSIONS: In conclusion, QC Constellation emerges as a pivotal tool for laboratory professionals, streamlining the management of quality control and analytical performance monitoring, while enhancing patient safety through optimized QC processes.

Determining a risk-proportionate approach to the validation of statistical programming for clinical trials.

BACKGROUND: The contribution of the statistician to the design and analysis of a clinical trial is acknowledged as essential. Ability to reconstruct the statistical contribution to a trial requires rigorous and transparent documentation as evidenced by the reproducibility of results. The process of validating statistical programmes is a key requirement. While guidance relating to software development and life cycle methodologies details steps for validation by information systems developers, there is no guidance applicable to programmes written by statisticians. We aimed to develop a risk-based approach to the validation of statistical programming that would support scientific integrity and efficient resource use within clinical trials units. METHODS: The project was embedded within the Information Systems Operational Group and the Statistics Operational Group of the UK Clinical Research Collaboration Registered Clinical Trials Unit network. Members were asked to share materials relevant to validation of statistical programming. A review of the published literature, regulatory guidance and knowledge of relevant working groups was undertaken. Surveys targeting the Information Systems Operational Group and Statistics Operational Group were developed to determine current practices across the Registered Clinical Trials Unit network. A risk-based approach was drafted and used as a basis for a workshop with representation from statisticians, information systems developers and quality assurance managers (n = 15). The approach was subsequently modified and presented at a second, larger scale workshop (n = 47) to gain a wider perspective, with discussion of content and implications for delivery. The approach was revised based on the discussions and suggestions made. The workshop was attended by a member of the Medicines for Healthcare products Regulatory Agency Inspectorate who also provided comments on the revised draft. RESULTS: Types of statistical programming were identified and categorised into six areas: generation of randomisation lists; programmes to explore/understand the data; data cleaning, including complex checks; derivations including data transformations; data monitoring; or interim and final analysis. The risk-based approach considers each category of statistical programme against the impact of an error and its likelihood, whether the programming can be fully prespecified, the need for repeated use and the need for reproducibility. Approaches to the validation of programming within each category are proposed. CONCLUSION: We have developed a risk-based approach to the validation of statistical programming. It endeavours to facilitate the implementation of targeted quality assurance measures while making efficient use of limited resources.

Assessing the impact of risk-based data monitoring on outcomes for a paediatric multicentre randomised controlled trial.

BACKGROUND/AIMS: Regulatory guidelines recommend that sponsors develop a risk-based approach to monitoring clinical trials. However, there is a lack of evidence to guide the effective implementation of monitoring activities encompassed in this approach. The aim of this study was to assess the efficiency and impact of the risk-based monitoring approach used for a multicentre randomised controlled trial comparing treatments in paediatric patients undergoing cardiac bypass surgery. METHODS: This is a secondary analysis of data from a randomised controlled trial that implemented targeted source data verification as part of the risk-based monitoring approach. Monitoring duration and source to database error rates were calculated across the monitored trial dataset. The monitored and unmonitored trial dataset, and simulated trial datasets with differing degrees of source data verification and cohort sizes were compared for their effect on trial outcomes. RESULTS: In total, 106,749 critical data points across 1,282 participants were verified from source data either remotely or on-site during the trial. The total time spent monitoring was 365 hours, with a median (interquartile range) of 10 (7, 16) minutes per participant. An overall source to database error rate of 3.1% was found, and this did not differ between treatment groups. A low rate of error was found for all outcomes undergoing 100% source data verification, with the exception of two secondary outcomes with error rates >10%. Minimal variation in trial outcomes were found between the unmonitored and monitored datasets. Reduced degrees of source data verification and reduced cohort sizes assessed using simulated trial datasets had minimal impact on trial outcomes. CONCLUSIONS: Targeted source data verification of data critical to trial outcomes, which carried with it a substantial time investment, did not have an impact on study outcomes in this trial. This evaluation of the cost-effectiveness of targeted source data verification contributes to the evidence-base regarding the context where reduced emphasis should be placed on source data verification as the foremost monitoring activity.

Perspectives of refugee parents and unaccompanied minors on initial health assessment and access to care.

To explore the needs, expectations, and experiences of asylum-seeking parents and unaccompanied minors under the age of 18 years on the initial health assessment for children and adolescents and access to care upon entry in the Netherlands, We conducted five semi-structured focus group discussions with asylum-seeking parents and unaccompanied minors, from Syria, Eritrea, Afghanistan, and other Middle-East and African countries, supported by professional interpreters. To triangulate findings, semi-structured interviews with health care professionals involved in care for refugee children were conducted. Transcripts of focus group discussions were inductively and deductively coded and content analyzed; transcripts of interviews were deductively coded and content analyzed. In total, 31 asylum-seeking participants: 23 parents of 101 children (between 0 and 18 years old), 8 unaccompanied minors (between 15 and 17 years), and 6 healthcare professionals participated. Parents and minors expressed that upon entry, their needs were met for vaccinations, but not for screening or care for physical and mental health problems. Parents, minors, and health professionals emphasized the necessity of appropriate information and education about health, diseases, and the health system. Cultural change was mentioned as stressful for the parent-child interaction and parental well-being.     Conclusion: The perspectives of refugee parents and unaccompanied minors revealed opportunities to improve the experience of and access to health care of refugees entering the Netherlands, especially risk-specific screening and more adequate education about health, diseases, and the Dutch health care system. What is Known: •  Refugees have specific health needs due to pre-flight, flight, and resettlement conditions. Health assessment upon entry was non-obligatory in the Netherlands, except for the tuberculosis screening. Health needs were not always met, and refugees experienced barriers in access to care. What is New: • The initial health assessment met the needs concerning vaccinations but mismatched the needs regarding physical and mental health assessment. Screening for specific risk-related diseases and mental health could enable refugee parents and minors to engage better with the health system.

Regulatory Aspects for Approval of Advanced Therapy Medicinal Products in the EU.

In the European Union (EU), advanced therapy medicinal products (ATMPs) undergo evaluation by the European Medicines Agency's (EMA) Committee for Advanced Therapies (CAT) to obtain marketing authorization under the centralized procedure. Because of the diversity and complexity of ATMPs, a tailored approach to the regulatory process is required that needs to ensure the safety and efficacy of each product. Since ATMPs often target serious diseases with unmet medical need, the industry and authorities are interested in providing treatment to patients in a timely manner through optimized and expedited regulatory pathways. EU legislators and regulators have implemented various instruments to support the development and authorization of innovative medicines by offering scientific guidance at early stages, incentives for small developers and products for rare diseases, accelerated evaluation of marketing authorization applications, different types of marketing authorizations, and tailored programs for medicinal products with the orphan drug designation (ODD) and the Priority Medicines (PRIME) scheme. Since the regulatory framework for ATMPs was established, 20 products have been licenced, 15 with orphan drug designation, and 7 supported by PRIME. This chapter discusses the specific regulatory framework for ATMPs in the EU and highlights previous successes and remaining challenges.

Communicating the results of risk-based breast cancer screening through visualizations of risk: a participatory design approach.

BACKGROUND: Risk-based breast cancer (BC) screening raises new questions regarding information provision and risk communication. This study aimed to: 1) investigate women's beliefs and knowledge (i.e., mental models) regarding BC risk and (risk-based) BC screening in view of implications for information development; 2) develop novel informational materials to communicate the screening result in risk-based BC screening, including risk visualizations of both quantitative and qualitative information, from a Human-Centered Design perspective. METHODS: Phase 1: Interviews were conducted (n = 15, 40-50 years, 5 lower health literate) on women's beliefs about BC risk and (risk-based) BC screening. Phase 2: In three participatory design sessions, women (n = 4-6 across sessions, 40-50 years, 2-3 lower health literate) made assignments and created and evaluated visualizations of risk information central to the screening result. Prototypes were evaluated in two additional sessions (n = 2, 54-62 years, 0-1 lower health literate). Phase 3: Experts (n = 5) and women (n = 9, 40-74 years) evaluated the resulting materials. Two other experts were consulted throughout the development process to ensure that the content of the information materials was accurate. Interviews were transcribed literally and analysed using qualitative thematic analysis, focusing on implications for information development. Notes, assignments and materials from the participatory design sessions were summarized and main themes were identified. RESULTS: Women in both interviews and design sessions were positive about risk-based BC screening, especially because personal risk factors would be taken into account. However, they emphasized that the rationale of risk-based screening and classification into a risk category should be clearly stated and visualized, especially for higher- and lower-risk categories (which may cause anxiety or feelings of unfairness due to a lower screening frequency). Women wanted to know their personal risk, preferably visualized in an icon array, and wanted advice on risk reduction and breast self-examination. However, most risk factors were considered modifiable by women, and the risk factor breast density was not known, implying that information should emphasize that BC risk depends on multiple factors, including breast density. CONCLUSIONS: The information materials, including risk visualizations of both quantitative and qualitative information, developed from a Human-Centered Design perspective and a mental model approach, were positively evaluated by the target group.

Early-onset group B streptococcal infections in five Nordic countries with different prevention policies, 1995 to 2019.

BackgroundNeonatal early-onset disease caused by group B Streptococcus (GBS) is a leading cause of infant morbidity. Intrapartum antibiotic prophylaxis (IAP) is effective in preventing early-onset GBS disease, but there is no agreement on the optimal strategy for identifying the pregnant women requiring this treatment, and both risk-based prophylaxis (RBP) and GBS screening-based prophylaxis (SBP) are used.AimThe aim of this study was to evaluate the effect of SBP as a public health intervention on the epidemiology of early-onset GBS infections.MethodsIn 2012, Finland started the universal SBP, while Denmark, Iceland, Norway and Sweden continued with RBP. We conducted an interrupted time series analysis taking 2012 as the intervention point to evaluate the impact of this intervention. The incidences of early- and late-onset GBS infections during Period I (1995-2011) and Period II (2012-2019) were collected from each national register, covering 6,605,564 live births.ResultsIn Finland, a reduction of 58% in the incidence of early-onset GBS disease, corresponding to an incidence rate ratio (IRR) of 0.42 (95% CI: 0.34-0.52), was observed after 2012. At the same time, the pooled IRR of other Nordic countries was 0.89 (95% CI: 0.80-1.0), specifically 0.89 (95% CI: 0.70-1.5) in Denmark, 0.34 (95% CI: 0.15-0.81) in Iceland, 0.72 (95% CI: 0.59-0.88) in Norway and 0.97 (95% CI: 0.85-1.1) in Sweden.ConclusionsIn this ecological study of five Nordic countries, early-onset GBS infections were approximately halved following introduction of the SBP approach as compared with RBP.

Bayesian Methods for Quality Tolerance Limit (QTL) Monitoring.

In alignment with the ICH guideline for Good Clinical Practice [ICH E6(R2)], quality tolerance limit (QTL) monitoring has become a standard component of risk-based monitoring of clinical trials by sponsor companies. Parameters that are candidates for QTL monitoring are critical to participant safety and quality of trial results. Breaching the QTL of a given parameter could indicate systematic issues with the trial that could impact participant safety or compromise the reliability of trial results. Methods for QTL monitoring should detect potential QTL breaches as early as possible while limiting the rate of false alarms. Early detection allows for the implementation of remedial actions that can prevent a QTL breach at the end of the trial. We demonstrate that statistically based methods that account for the expected value and variability of the data generating process outperform simple methods based on fixed thresholds with respect to important operating characteristics. We also propose a Bayesian method for QTL monitoring and an extension that allows for the incorporation of partial information, demonstrating its potential to outperform frequentist methods originating from the statistical process control literature.

Prototyping a Secure and Usable User Authentication Mechanism for Mobile Passenger ID Devices for Land/Sea Border Control.

As the number of European Union (EU) visitors grows, implementing novel border control solutions, such as mobile devices for passenger identification for land and sea border control, becomes paramount to ensure the convenience and safety of passengers and officers. However, these devices, handling sensitive personal data, become attractive targets for malicious actors seeking to misuse or steal such data. Therefore, to increase the level of security of such devices without interrupting border control activities, robust user authentication mechanisms are essential. Toward this direction, we propose a risk-based adaptive user authentication mechanism for mobile passenger identification devices for land and sea border control, aiming to enhance device security without hindering usability. In this work, we present a comprehensive assessment of novelty and outlier detection algorithms and discern OneClassSVM, Local Outlier Factor (LOF), and Bayesian_GaussianMixtureModel (B_GMM) novelty detection algorithms as the most effective ones for risk estimation in the proposed mechanism. Furthermore, in this work, we develop the proposed risk-based adaptive user authentication mechanism as an application on a Raspberry Pi 4 Model B device (i.e., playing the role of the mobile device for passenger identification), where we evaluate the detection performance of the three best performing novelty detection algorithms (i.e., OneClassSVM, LOF, and B_GMM), with B_GMM surpassing the others in performance when deployed on the Raspberry Pi 4 device. Finally, we evaluate the risk estimation overhead of the proposed mechanism when the best performing B_GMM novelty detection algorithm is used for risk estimation, indicating efficient operation with minimal additional latency.

Risk factors affecting the food safety risk in food business operations for risk-based inspection: A systematic review.

Foodborne illnesses result in a high disease burden worldwide, making food safety control of food business operations (FBOs) an urgent issue. With public agencies and FBOs facing challenges in monitoring the complex food supply chain with limited resources, scientific and objective insights into those factors that are related to food safety at FBOs are needed. These factors can be used as input for risk-based inspection. We conducted a systematic review to identify and analyze risk factors affecting the FBOs' food safety risk. We used a set of predefined search strings in Scopus and Web of Science to search for scientific manuscripts published in the English language between January 1 2003 and February 1 2023. The review identified 53 relevant studies and 43 risk factors. The presence of certified personnel turned out to be the most cited factor. Nearly half of the extracted factors had only been investigated in one study. Additional challenges were identified for developing a universal ready-to-use list of factors for the building of a risk-based inspection method, such as the limitation in the applicability of identified factors in different types of FBOs, and the variability in conclusions between publications for certain factors (e.g., FBO location and inspection history), stressing the need for additional research. Future studies should also prioritize standardizing definitions and measurements, particularly regarding compliance factors. In general, the current list of factors brought forward in our review lays the groundwork for building a transparent, objective, and risk-based method for food safety inspections of FBOs.

Evaluation and comparison of risk-based and universal prenatal HCV screening programs in Alberta, Canada.

BACKGROUND & AIMS: Canadian clinical practice guidelines currently recommend risk-based screening for HCV in pregnant individuals. However, no provinces or territories have ever compared the effectiveness of risk-based vs. universal screening for the prenatal diagnosis of HCV. We aimed to evaluate and compare HCV screening programs after implementing a universal population-level pilot program among prenatal patients in Alberta, Canada. METHODS: The Alberta Prenatal Screening Program for Select Communicable Diseases was amended to include universal HCV antibody screening. Cohorts of pregnant individuals screened for HCV through risk-based or universal programs were generated over 1-year periods. HCV screening rates and prevalence were analyzed and compared between cohorts to evaluate the effectiveness of screening methods. Social and demographic risk factors for HCV-positive individuals were compared between screening cohorts to identify which populations may be overlooked with risk-based guidelines. RESULTS: HCV antibody screening rates were 11.9% and 99.9% among pregnant individuals in the risk-based and universal cohorts, respectively. HCV prevalence among the cohorts was 0.07% and 0.11% (difference = 0.04%, p = 0.032), with an average of 21 additional HCV-positive pregnant individuals identified annually with universal screening. HCV-positive pregnant patients diagnosed through universal screening were more likely to engage in high-risk sexual behaviours/sex work compared to those diagnosed through risk-based screening (47.6% vs. 12.5%, respectively p = 0.035), suggesting that these high-risk cases are being missed by risk-based screening. CONCLUSIONS: Universal HCV screening diagnoses significantly higher numbers of pregnant individuals infected with HCV compared to risk-based screening. Universal HCV screening or amending risk-based guidelines to incorporate more proxy variables for risk factors should be considered to improve prenatal HCV screening guidelines in Canada and help achieve HCV elimination in the next decade. IMPACT AND IMPLICATIONS: HCV is a bloodborne pathogen that can cause severe liver disease and be vertically transmitted from a mother to her baby during pregnancy. Pregnant individuals in Alberta are currently only tested for HCV if they disclose engaging in activities that put them at risk of acquiring the infection (risk-based screening). Using a population-wide universal prenatal HCV screening program, our work shows that testing based on patient disclosed risk alone leads to the significant underdiagnosis of HCV in pregnant individuals and suggests individuals engaging in sex work or risky sexual behaviours are being overlooked by the current risk-based program. Our outcomes represent the first province-wide study to evaluate and compare prenatal HCV risk-based and universal screening programs in Canada and provide evidence to support the update of prenatal HCV screening policies across the country and in similar jurisdictions.

Impact of monitoring approaches on data quality in clinical trials.

AIMS: Source data verification (SDV) has been reported to account for up to 25% of the budget in clinical trials (CT) and cost-benefit of SDV has been questioned. Guidelines for risk-based monitoring (RBM) were published in 2013 by agencies and in 2016, ICH-GCP-E6-(R2) added a requirement for risk-based approaches. This report will perform a comparison of the impact of RBM vs classic monitoring (CM) on data quality (defined as accuracy of data reporting from source data to final trial data) and expected impact on costs of CTs. METHODS: Data on residual errors from four, large comparable randomised CTs were examined by post-trial SDV. Observed discrepancies were analysed in the categories of "overall" data, "major efficacy" and "major safety". In each category, the residual error rate was calculated as the number of discrepancies divided by the number of data-fields verified. RESULTS: A total of 1 716 087 data points were verified using CM and 323 174 using RBM. The overall error rate was 0.40% for RBM and 0.37% for CM (P < 0.01). For major efficacy, defined by risk assessment, the error rate was 0.15% and 0.28% (P < 0.0001); in major safety, defined by risk assessment, the error rate was 0.49% and 0.67% (P = 0.15), both in favour of the RBM approach. CONCLUSION: These empirical data, directly comparing RBM with CM, suggest that RBM improves data quality regarding data-points of major importance to trial outcomes, efficacy and major safety. Overall, the RBM approach showed a correlation to reduced amount of data collection errors with major relevance for interpretation of study results and subject safety as well as reducing on-site monitoring and data cleaning resources.

Diagnostic accuracy of extended HPV DNA genotyping and its application for risk-based cervical cancer screening strategy.

OBJECTIVES: To evaluate the consistency of 14 high-risk HPVs (hr-HPVs) detection between extended HPV DNA genotyping and a well-validated partial HPV genotyping kit, and to explore the diagnostic accuracy of risk stratification strategy based on extended HPV genotyping for cervical cancer (CC) screening. METHODS: Baseline data from a clinical trial of recombinant HPV 9-valent vaccine in China was analyzed. All enrolled women aged 20-45 years received cervical cytology, HPV detection by extended and partial HPV genotyping kits. Those who met the indications would further receive colposcopy. The primary endpoints were cervical intraepithelial neoplasia 2/3 or worse (CIN2+/CIN3+). RESULTS: A total of 8,000 women were enrolled between April 2020 and July 2020 and 83/33 cases were diagnosed as CIN2+/CIN3+. The overall agreement between the extended and partial HPV genotyping was 92.66 %. And the agreement further increased with the progression of lesions, which lead to similarly high sensitivity and negative predictive value of these kits. A stratified triage strategy of CC screening was constructed based on the immediate CIN2+/CIN3+ risk of specific HPV. Compared with the conventional HPV primary CC screening strategy, the risk-based strategy had higher specificity for CIN (CIN2+: 94.84 vs. 92.46 %, CIN3+: 96.05 vs. 91.92 %), and needed fewer colposcopies for detecting one cervical disease. CONCLUSIONS: Extended HPV genotyping had good agreement with a well-validated partial HPV genotyping CC primary screening kit in hr-HPV detection. Extended HPV genotyping could facilitate risk-based stratified management strategy and improve the diagnostic accuracy of primary CC screening.

Lack of transparent reporting of trial monitoring approaches in randomised controlled trials: A systematic review of contemporary protocol papers.

BACKGROUND: Monitoring is essential to ensure patient safety and data integrity in clinical trials as per Good Clinical Practice. The Standard Protocol Items: Recommendations for Interventional Trials Statement and its checklist guides authors to include monitoring in their protocols. We investigated how well monitoring was reported in published 'protocol papers' for contemporary randomised controlled trials. METHODS: A systematic search was conducted in PubMed to identify eligible protocol papers published in selected journals between 1 January 2020 and 31 May 2020. Protocol papers were classified by whether they reported monitoring and, if so, by the details of monitoring. Data were summarised descriptively. RESULTS: Of 811 protocol papers for randomised controlled trials, 386 (48%; 95% CI: 44%-51%) explicitly reported some monitoring information. Of these, 20% (77/386) reported monitoring information consistent with an on-site monitoring approach, and 39% (152/386) with central monitoring, 26% (101/386) with a mixed approach, while 14% (54/386) did not provide sufficient information to specify an approach. Only 8% (30/386) of randomised controlled trials reported complete details about all of scope, frequency and organisation of monitoring; frequency of monitoring was the least reported. However, 6% (25/386) of papers used the term 'audit' to describe 'monitoring'. DISCUSSION: Monitoring information was reported in only approximately half of the protocol papers. Suboptimal reporting of monitoring hinders the clinical community from having the full information on which to judge the validity of a trial and jeopardises the value of protocol papers and the credibility of the trial itself. Greater efforts are needed to promote the transparent reporting of monitoring to journal editors and authors.

Marketing Regulatory Oversight of Advanced Therapy Medicinal Products in Europe.

Advanced therapy medicinal products (ATMP) in the European Union (EU) are regulated by Regulation 1394/2007 and comprise gene and cell therapy and tissue-engineered products. Under this framework, ATMP are authorised by the centralised procedure, coordinated by the European Medicines Agency (EMA), whereas clinical trial authorisations remain at the remit of each National Competent Authority. The Committee for Advanced Therapies is responsible for the scientific evaluation of the marketing authorisation applications and for generating a draft opinion that goes to the Committee for Human Medicinal Products for a final opinion. For every application, data and information relating to manufacturing processes and quality control of the active substance and final product have to be submitted for assessment together with data from non-clinical and clinical safety and efficacy studies. Technical requirements for ATMP are defined in the legislation, and guidance for different products is available through several EMA/CAT guidelines.Due to the diverse and complex nature of ATMP, a need for some regulatory flexibility was recognised. Thus, a risk-based approach was introduced in Regulation 1394/2007 allowing adapted regulatory requirements. This has led, for instance, to the development of good manufacturing practice (GMP) guidelines specific for ATMP. This, together with enhanced regulatory support, has allowed an increasing number of successful marketing authorisation applications resulting in 25 licensed ATMP in the EU, mainly gene therapy medicinal products. The promise of messenger RNA and genome editing technologies as therapeutic tools make the future for these innovative medicinal products look even brighter.This chapter reviews the regulatory landscape together with some of the support initiatives developed for ATMP in the EU.

Regulatory Oversight of Cell, Tissue, and Gene Therapy Products in Singapore.

The Health Sciences Authority of Singapore has implemented a fit-for-purpose regulatory framework for Cell, Tissue, and Gene Therapy Products (CTGTPs) on 1 March 2021. A total of 11 pieces of subsidiary legislation for CTGTP are gazetted under the Health Products Act as Health Products (CTGTP) Regulations 2021. The CTGTPs are stratified into lower-risk Class 1 CTGTP or moderate- to higher-risk Class 2 CTGTP based on their degree of manipulation, intended use, and if they are combined or used with therapeutic products or medical devices. The regulatory controls are calibrated to the different risk profiles of the products. This risk-based regulatory approach aims to facilitate successful product development and registration in Singapore for innovative CTGTP with a least burdensome regulatory framework while ensuring reasonable safeguards on the safety, quality, and efficacy of the products. This chapter describes the regulatory oversight of CTGTP in Singapore.