Safety Monitoring In Clinical Trials Research Articles

Interactive medical and safety monitoring in clinical trials with clinDataReview: a validated and open-source reporting tool.

Continuous medical and safety monitoring of subject data during a clinical trial is a critical part of evaluating the safety of trial participants and as such is governed by protocol procedures and regulatory guidelines to meet the trial's intended objectives. We present an open-source validated graphical tool (clinDataReview R package) which provides access to the trial data with drill-down to individual patient profiles. The tool incorporates functionalities that facilitate detection of error and data inconsistencies requiring follow-up. It supports regular medical monitoring and oversight as well as safety monitoring committees with interactive tables and listings alongside graphical visualizations of the primary safety data in reports. An implementation example is given where the tool is used to deliver validated outputs following FDA/EMA guidelines. As such, this tool enables a more efficient, interactive, and reproducible review of safety data collected during an ongoing clinical trial.

Statistical rules for safety monitoring in clinical trials.

Protecting patient safety is an essential component of the conduct of clinical trials. Rigorous safety monitoring schemes are implemented for these studies to guard against excess toxicity risk from study therapies. They often include protocol-specified stopping rules dictating that an excessive number of safety events will trigger a halt of the study. Statistical methods are useful for constructing rules that protect patients from exposure to excessive toxicity while also maintaining the chance of a false safety signal at a low level. Several statistical techniques have been proposed for this purpose, but the current literature lacks a rigorous comparison to determine which method may be best suitable for a given trial design. The aims of this article are (1) to describe a general framework for repeated monitoring of safety events in clinical trials; (2) to survey common statistical techniques for creating safety stopping criteria; and (3) to provide investigators with a software tool for constructing and assessing these stopping rules. The properties and operating characteristics of stopping rules produced by Pocock and O'Brien-Fleming tests, Bayesian Beta-Binomial models, and sequential probability ratio tests (SPRTs) are studied and compared for common scenarios that may arise in phase II and III trials. We developed the R package "stoppingrule" for constructing and evaluating stopping rules from these methods. Its usage is demonstrated through a redesign of a stopping rule for BMT CTN 0601 (registered at Clinicaltrials.gov as NCT00745420), a phase II, single-arm clinical trial that evaluated outcomes in pediatric sickle cell disease patients treated by bone marrow transplant. Methods with aggressive stopping criteria early in the trial, such as the Pocock test and Bayesian Beta-Binomial models with weak priors, have permissive stopping criteria at late stages. This results in a trade-off where rules with aggressive early monitoring generally will have a smaller number of expected toxicities but also lower power than rules with more conservative early stopping, such as the O-Brien-Fleming test and Beta-Binomial models with strong priors. The modified SPRT method is sensitive to the choice of alternative toxicity rate. The maximized SPRT generally has a higher number of expected toxicities and/or worse power than other methods. Because the goal is to minimize the number of patients exposed to and experiencing toxicities from an unsafe therapy, we recommend using the Pocock or Beta-Binomial, weak prior methods for constructing safety stopping rules. At the design stage, the operating characteristics of candidate rules should be evaluated under various possible toxicity rates in order to guide the choice of rule(s) for a given trial; our R package facilitates this evaluation.

Clinical Assessment of Fetal Well-Being and Fetal Safety Indicators.

Delivering safe clinical trials of novel therapeutics is central to enable pregnant women and their babies to access medicines for better outcomes. This review describes clinical monitoring of fetal well‐being and safety. Current pregnancy surveillance includes regular antenatal checks of blood pressure and urine for signs of gestational hypertension. Fetal and placental development is assessed routinely using the first‐trimester “dating” and mid‐trimester “anomaly” ultrasound scans, but the detection of fetal anomalies can continue throughout pregnancy using targeted sonography or magnetic resonance imaging (MRI). Serial sonography can be used to assess fetal size, well‐being, and placental function. Carefully defined reproducible imaging parameters, such as the head circumference (HC), abdominal circumference (AC), and femur length (FL), are combined to calculate an estimate of the fetal weight. Doppler analysis of maternal uterine blood flow predicts placental insufficiency, which is associated with poor fetal growth. Fetal doppler analysis can indicate circulatory decompensation and fetal hypoxia, requiring delivery to be expedited. Novel ways to assess fetal well‐being and placental function using MRI, computerized cardiotocography (CTG), serum circulating fetoplacental proteins, and mRNA may improve the assessment of the safety and efficacy of maternal and fetal interventions. Progress has been made in how to define and grade clinical trial safety in pregnant women, the fetus, and neonate. A new system for improved safety monitoring for clinical trials in pregnancy, Maternal and Fetal Adverse Event Terminology (MFAET), describes 12 maternal and 18 fetal adverse event (AE) definitions and severity grading criteria developed through an international modified Delphi consensus process. This fills a vital gap in maternal and fetal translational medicine research.

Quantitative Safety Monitoring in Clinical Trials: Application of Multiple Statistical Methodologies for Infrequent Events.

There are limited quantitative approaches for evaluating rare safety outcomes from controlled clinical trials in either a blinded or unblinded setting. This manuscript demonstrates an application of three statistical methods for quantitative safety monitoring that can be implemented during any phase of a clinical trial, including open-label extension studies. An interactive safety monitoring (iSM) tool was developed using R language in the publicly available R-Shiny app and was implemented for three statistical methods of quantitative safety monitoring. These methods are sequential probability ratio test (SPRT), maximized SPRT (MaxSPRT), and Bayesian posterior probability threshold (BPPT). The iSM tool evaluated specific safety signals that incorporated pre-specified background rates or reference risk ratios. Two sets of blinded clinical trial data were used for case studies to demonstrate the use the iSM tool. Two particular adverse events, myocardial infarction (MI) and serious infection, were monitored. Monte Carlo simulation was conducted to evaluate the operating characteristics of pre-specified parameters. It showed that after adjusting for exposure, the BPPT and MaxSPRT yielded similar results in identifying a pre-specified signals while the SPRT method failed to detect such signals. Statistical methods shown for the case studies, as well as the application of the user-friendly iSM tool, greatly enhance the quantitative monitoring of safety events of interest in ongoing clinical trials The BPPT and MaxSPRT methods seem more sensitive in picking-up early signals than the SPRT method when the number of safety events is small.

Introduction to Pharmacovigilance and Monitoring

Pharmacovigilance has its own unique terminology that is important to understand. Pharmacovigilance also known as drug safety, is the pharmacological science relating to the collection, detection, assessment, monitoring, and prevention of adverse effects with pharmaceutical products. As such, pharmacovigilance heavily focuses on adverse drug reactions, or ADRs, which are defined as any response to a drug which is noxious and unintended, including lack of efficacy (the condition that this definition only applies with the doses normally used for the prophylaxis, diagnosis or therapy of disease, or for the modification of physiological disorder function was excluded with the latest amendment of the applicable legislation). Hence, need of pharmacovigilance arises which include, securing the early detection of new adverse reactions or patients subgroups of exceptional sensitivity; and introducing certain measures in order to manage such risks. Moreover, it is essential that new and medically still evolving treatments are monitored for their effectiveness and safety under real-life conditions after being marketed. The role of pharmacovigilance is to check the safety monitoring in clinical trials involves collecting adverse events, laboratory investigations and details of the clinical examination of patients. Pharmacovigilance staff may be involved to varying degrees in all phases of clinical trials, including the planning, execution, data analysis and reporting of safety.

The Safety Explorer Suite: Interactive Safety Monitoring for Clinical Trials.

Frequent and thorough monitoring of patient safety is a requirement of clinical trials research. Safety data are traditionally reported in a tabular or listing format, which often translates into many pages of static displays. This poses the risk that clinically relevant signals will be obscured by the sheer volume of data reported. Interactive graphics enable the delivery of the vast scope of information found in traditional reports, but allow the user to interact with the charts in real time, focusing on signals of interest. Clinical research staff, including biostatisticians, project managers, and a medical monitor, were consulted to guide the development of a set of interactive data visualizations that enable key safety assessments for participants. The resulting "Safety Explorer" is a set of 6 interactive, web-based, open source tools designed to address the shortcomings of traditional, static reports for safety monitoring. The Safety Explorer is freely available on GitHub as individual JavaScript libraries: Adverse Event Explorer, Adverse Event Timelines, Safety Histogram, Safety Outlier Explorer, Safety Results Over Time, and Safety Shift Plot; or in a single combined framework: Safety Explorer Suite. The suite can also be utilized through its R interface, the safetyexploreR package. The Safety Explorer provides interactive charts that contain the same information available in standard displays, but the interactive interface allows for improved exploration of patterns and comparisons. Medical Monitors, Safety Review Boards, and Project Teams can use these tools to effectively track and analyze key safety variables and study endpoints.

Haematological and immunological reference intervals for adult population in the state of Amhara, Ethiopia.

Reference intervals (RIs) currently being used in Ethiopia are derived from western populations. Thus, this study aimed to establish locally derived haematological and immunological RIs. The study was conducted in Amhara State, Ethiopia with a total of 967 (55.2% males) participants. 56.9% of males and 43.1% of females were eligible for haematological and immunological RI determination. A non-parametric test was used for the determination of upper (97.5th percentile) and lower (2.5th percentile) reference interval limits with 95% CI. The Harris and Boyd Rule was used to determine the need of partitioning of reference intervals based on gender. The established 95% reference intervals (2.5th-97.5th percentile) were: for WBC: 3-11.2 × 109 /l; for platelet: 90-399 × 109 /l; for RBC: 4-6 × 1012 /l for males and 3.5-5.6 × 1012 /l for females; for haemoglobin: (Hgb) 12-18.9 g/dl for males and 10.7-17.5 g/dl for females; for PCV: 35.7-55.3% for males and 32.2-50.1% for females; for CD4: 400-1430 × 109 /l for males and 466-1523 × 109 /l for females; for CD4 percentage: 18-49.1% for males and 21.3-52.9% for females; for MCV: 81-100 fl; for MCH: 25.3-34.6 pg; MCHC: 28.8-36.9%; for RDW: 11.6-15.4% and for MPV: 8-12.3 fl. Males had significantly higher RBC, Hgb and PCV than females. CD4 counts and CD4 percentage were significantly higher in females. The reference intervals established in this study differ from others and thus should be used for the interpretation of laboratory results in diagnosis and safety monitoring in clinical trials in Amhara.

Understanding of safety monitoring in clinical trials by individuals with CF or their parents: A qualitative analysis

BackgroundRecruiting both pediatric and adult participants for clinical trials in CF is currently of paramount importance as numerous new therapies are being developed. However, recruitment is challenging as parents of children with CF and adults with CF cite safety concerns as a principal barrier to enrollment. In conjunction with the CF Foundation (CFF) Data Safety Monitoring Board (DSMB), a pilot brochure was developed to inform patients and parents of the multiple levels of safety monitoring; the CFF simultaneously created an infographic representing the safety monitoring process. This study explores the attitudes and beliefs of CF patients and families regarding safety monitoring and clinical trial participation, and elicits feedback regarding the educational materials. MethodsSemi-structured interviews were conducted using a pre-tested interview guide and audio-recorded during routine CF clinic visits. Participants included 5 parents of children with CF <16years old; 5 adolescents and young adults with CF 16–21years old; and 5 adults with CF ≥22years old from pediatric and adult CF centers. The study team performed systematic text condensation analysis of the recorded interviews using an iterative process. ResultsFour major thematic categories with subthemes emerged as supported by exemplar quotations: attitudes toward clinical trials, safety values, conceptualizing the safety monitoring process, and priorities for delivery of patient education. Participant feedback was used to revise the pilot brochure; text was shortened, unfamiliar words clarified (e.g., “pipeline”), abbreviations eliminated, and redundancy avoided. ConclusionsQualitative analysis of CF patient and family interviews provided insights into barriers to participation in clinical trials, safety concerns, perspectives on safety monitoring and educational priorities. We plan a multicenter study to determine if the revised brochure reduces knowledge, attitude and practice barriers regarding participation in CF clinical trials.

Guidance for the collection of case report form variables to assess safety in clinical trials of vaccines in pregnancy

Vaccination in pregnancy is an effective strategy to prevent serious infections in mothers and their infants. Safety of this strategy is of principal importance to all stakeholders. As the number of studies assessing safety of vaccines in pregnancy increases, the need to ensure consistent collection and reporting of critical data to allow comparisons and data pooling becomes more important. The Global Alignment of Immunization Safety Assessment in Pregnancy (GAIA) project aims to improve data collection and create a shared understanding of maternal, fetal and neonatal outcomes in order to progress the global agenda for vaccination in pregnancy.The guidance in this document has been developed to harmonize the data collected in case report forms used for safety monitoring in clinical trials of vaccination in pregnant women. Data to be collected is prioritized to allow applicability in diverse research settings, including low and middle-income countries. Standardized data will enable the research community to have a common base upon which to conduct meta-analyses, strengthening the applicability of outcomes to different settings.

Reporting adverse events in a large community-based public health trial (building blocks): what gets reported and how does it vary?

Background Adverse event (AE) reporting is an integral part of safety monitoring for clinical trials and standard definitions for medical AEs exist under GCP. However, public health trials in community settings present challenges for consistent safety monitoring. For studies of complex behaviour change interventions, what should be recorded may not be self-evident. Building Blocks is such a trial and is evaluating the effectiveness of a home visiting intervention (Family Nurse Partnership programme). This presentation aims to assess variability in safety reporting, and explore factors associated with nature, level and quality of reporting.

Participants’ perspectives on safety monitoring in clinical trials

Minimizing the risk to study participants is an essential requirement of ethical research. Respecting the rights of subjects is also paramount, which includes respecting their autonomy by making available important information about the evolving safety profile of an investigational product as the trial progresses. Little is known about what trial participants understand and expect regarding monitoring and communication of serious adverse events during the conduct of a trial in which they have agreed to participate. To explore understanding and expectations of potential trial participants concerning monitoring and communication of serious adverse events during a clinical trial. A professional moderator led four 90-min, in-person focus groups: two groups with individuals who had never participated in a clinical trial and two groups with people who had. After relevant research terms were defined and existing regulations were explained, discussion focused on how participants expected safety to be monitored and communicated during the conduct of a clinical trial. Group comments were video-recorded and transcribed and then analyzed by the investigators. The 27 racially diverse focus group members were largely unaware of existing safeguards and regulations to manage risk in clinical trials. Many people expressed a desire for increased transparency about serious adverse events during the trial as well as shortened reporting deadlines. Focus group members also spontaneously expressed concerns about potential financial conflicts of interest in monitoring and reporting serious adverse events. This was a single-site, qualitative study and is not meant to establish the prevalence of beliefs. Potential trial participants have limited understanding and a wide range of expectations about how safety monitoring in clinical trials should be managed and communicated. The overall tenor of opinion suggests unease about participant safety and a desire to have more information conveyed by sponsors to investigators and, in some cases, by investigators to participants. Additional study in other regions and settings may be useful to more broadly explore the range of participants' beliefs and expectations. In the meantime, engaging patient advocates in the design of clinical trials and clearly communicating to trial participants the plan for oversight of their safety may help ease the types of concerns expressed in this study.

Safety Monitoring in Clinical Trials

Monitoring patient safety during clinical trials is a critical component throughout the drug development life-cycle. Pharmaceutical sponsors must work proactively and collaboratively with all stakeholders to ensure a systematic approach to safety monitoring. The regulatory landscape has evolved with increased requirements for risk management plans, risk evaluation and minimization strategies. As the industry transitions from passive to active safety surveillance activities, there will be greater demand for more comprehensive and innovative approaches that apply quantitative methods to accumulating data from all sources, ranging from the discovery and preclinical through clinical and post-approval stages. Statistical methods, especially those based on the Bayesian framework, are important tools to help provide objectivity and rigor to the safety monitoring process.

Changing regulation of clinical trials in Europe

The lack of harmonization of legislation, guidance and procedures for conducting clinical trials in Europe is generally considered unsatisfactory, despite the implementation of the Clinical Trials Directive in 2004. This article outlines the measures being taken by the Clinical Trials Facilitation Group of the Heads of Medicines Agencies and the Ad Hoc Clinical Trials Group of the European Commission to improve authorization, amendment and safety monitoring for clinical trials. It also comments, from a UK perspective, on the current status of the Commission’s consultation and impact assessment on potential changes to the Clinical Trials Directive, and anticipates the likely changes in the next 5 years.

Guidelines for data and safety monitoring for clinical trials not requiring traditional data monitoring committees

This is a commissioned report by a writing committee formed by the Society for Clinical Trials. The committee was formed with the objectives of 1) reviewing data monitoring guidelines for confirmatory (phase III) trials published by the National Institutes of Health, US Food and Drug Administration, Veterans Administration, and the International Conference on Harmonisation and 2) proposing corresponding guidelines for exploratory clinical trials (ie, most phase I and phase II trials and others not requiring a fully independent data monitoring committee). These trials typically involve fewer subjects and are of shorter duration than phase III trials. Nevertheless there are safety concerns, especially because these are often the first human trials for a new intervention. Recommendations are given for appropriate elements of a data monitoring plan, decision criteria for institution of a data monitoring committee (DMC), and critical elements for a DMC to consider in exploratory trials. Review and approval of data monitoring plans are suggested to fall under Institutional Review Board purview. Forming a committee with all the characteristics of a traditional phase III trial monitoring committee may be warranted for a small fraction of exploratory trials. Such a panel could consist of both trial investigators and outside members. The paper concludes with examples of data and safety monitoring practice from the University of Wisconsin Comprehensive Cancer Center and the AIDS Clinical Trials Groups.