The Impact of Variability in Patient Exposure During Premarket Clinical Development on Postmarket Safety Outcomes.
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ABSTRACT:
SUBMITTER: Cherkaoui S
PROVIDER: S-EPMC8595500 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundHealth Canada approves drugs on the basis of evidence from clinical trials using clinical or surrogate outcomes. This study compares the postmarket safety of these 2 groups of drugs.MethodsInformation about whether clinical or surrogate outcomes were used and the date of market approval were obtained from Health Canada's Summary Basis of Decision documents issued from Jan. 1, 2005, to Dec. 31, 2014. Safety warnings and the dates they were issued were identified through advisories on the MedEffect Canada website. Kaplan-Meier survival curves were calculated to determine the likelihood that drugs in the clinical and surrogate outcome groups would receive a serious safety warning. The time from market authorization to first serious safety warning was compared for the 2 groups of drugs.ResultsA total of 124 drugs were approved by Health Canada using clinical outcomes and 114 using surrogate outcomes. Kaplan-Meier curves did not differ between the 2 groups (p < 0.9). The median time from market authorization to first serious safety warning was 722 days in the clinical outcome group and 818 days in the surrogate outcome group (difference 96 days, 95% confidence interval -295 to 425).InterpretationWe found no statistically significant difference in postmarket safety between drugs approved using clinical outcomes and those approved using surrogate outcomes. Because drugs in the surrogate outcome group are approved before their benefit:harm ratio is fully established, these drugs should be used with caution until their clinical benefits are better understood.
| S-EPMC4593464 | biostudies-literature
Project description:Genome editing tools have already revolutionized biomedical research and are also expected to have an important impact in the clinic. However, their extensive use in research has revealed much unpredictability, both off and on target, in the outcome of their application. We discuss the challenges associated with this unpredictability, both for research and in the clinic. For the former, an extensive validation of the model is essential. For the latter, potential unpredicted activity does not preclude the use of these tools but requires that molecular evidence to underpin the relevant risk:benefit evaluation is available. Safe and successful clinical application will also depend on the mode of delivery and the cellular context.
| S-EPMC7264426 | biostudies-literature
Project description:IntroductionLong-term anticoagulation therapy using vitamin K antagonists (VKA) is used in millions of patients worldwide to reduce the risk of thrombotic or thromboembolic events. Control and monitoring of VKA therapy is improved by the regular self-measurement of international normalized ratio (INR) using a home monitoring device. This retrospective analysis of a large cohort of patients in the Netherlands seeks to determine whether the choice of INR monitor could have a clinical impact on patient outcomes.MethodsThe National Thrombosis Service provides medical supervision, training and support to anticoagulant patients eligible for home-monitoring of INR in the Netherlands. Two INR monitors (CoaguChek XS and INRatio2) have been distributed at random to patients since June 2011, and patient self-testing data (INR measurements and other clinical parameters) have been recorded to measure and improve treatment outcomes. The data have been retrospectively analyzed to determine any effect of the choice of monitor. Univariate and multivariate statistical tests are used to assess any differences between groups in terms of efficacy and safety parameters.ResultsData from 4,326 patients were collated, and 156,507 INR values were included in the analysis. Over half the patients (54.3%) were being treated for atrial fibrillation, and 77.6% were prescribed acenocoumarol. There were few differences between the patient populations using the two different monitors. Anticoagulant control overall was good, with high percentage of time (87.9%) in the appropriate INR range and low incidence of excessively high or low INR values (0.085/month). Minor clinical events related to safety were low (0.78 per patient-year) and showed few differences between monitors. Mortality rates were similar [hazard ratio (HR) 1.05, 95% confidence interval (CI) 0.65-1.70].ConclusionSelf-testing data from a large cohort of patients in the Netherlands suggest that there is no clinically relevant effect of the choice of coagulation monitor (CoaguChek XS or INRatio2) on the time in therapeutic range (TTR), minor or fatal outcomes of long-term anticoagulation management.
| S-EPMC4082646 | biostudies-literature
Project description:Attention-deficit hyperactivity disorder (ADHD) is a chronic condition and pharmacotherapy is the mainstay of treatment, with a variety of ADHD medications available to patients. However, it is unclear to what extent the long-term safety and efficacy of ADHD drugs have been evaluated prior to their market authorization. We aimed to quantify the number of participants studied and their length of exposure in ADHD drug trials prior to marketing.We identified all ADHD medications approved by the Food and Drug Administration (FDA) and extracted data on clinical trials performed by the sponsor and used by the FDA to evaluate the drug's clinical efficacy and safety. For each ADHD medication, we measured the total number of participants studied and the length of participant exposure and identified any FDA requests for post-marketing trials.A total of 32 clinical trials were conducted for the approval of 20 ADHD drugs. The median number of participants studied per drug was 75 (IQR 0, 419). Eleven drugs (55%) were approved after <100 participants were studied and 14 (70%) after <300 participants. The median trial length prior to approval was 4 weeks (IQR 2, 9), with 5 (38%) drugs approved after participants were studied <4 weeks and 10 (77%) after <6 months. Six drugs were approved with requests for specific additional post-marketing trials, of which 2 were performed.Clinical trials conducted for the approval of many ADHD drugs have not been designed to assess rare adverse events or long-term safety and efficacy. While post-marketing studies can fill in some of the gaps, better assurance is needed that the proper trials are conducted either before or after a new medication is approved.
| S-EPMC4090185 | biostudies-other
Project description:ObjectiveThe aim of this study was to determine the impact of all-cause inpatient harms on hospital finances and patient clinical outcomes.Research designA retrospective analysis of inpatient harm from 24 hospitals in a large multistate health system was conducted during 2009 to 2012 using the Institute of Healthcare Improvement Global Trigger Tool for Measuring Adverse Events. Inpatient harms were detected and categorized into harm (F-I), temporary harm (E), and no harm.ResultsOf the 21,007 inpatients in this study, 15,610 (74.3%) experienced no harm, 2818 (13.4%) experienced temporary harm, and 2579 (12.3%) experienced harm. A patient with harm was estimated to have higher total cost ($4617 [95% confidence interval (CI), $4364 to 4871]), higher variable cost ($1774 [95% CI, $1648 to $1900]), lower contribution margin (-$1112 [95% CI, -$1378 to -$847]), longer length of stay (2.6 d [95% CI, 2.5 to 2.8]), higher mortality probability (59%; odds ratio, 1.4 [95% CI, 1.0 to 2.0]), and higher 30-day readmission probability (74.4%; odds ratio, 2.9 [95% CI, 2.6 to 3.2]). A patient with temporary harm was estimated to have higher total cost ($2187 [95% CI, $2008 to $2366]), higher variable cost ($800 [95% CI, $709 to $892]), lower contribution margin (-$669 [95% CI, -$891 to -$446]), longer length of stay (1.3 d [95% CI, 1.2 to 1.4]), mortality probability not statistically different, and higher 30-day readmission probability (54.6%; odds ratio, 1.2 [95% CI, 1.1 to 1.4]). Total health system reduction of harm was associated with a decrease of $108 million in total cost, $48 million in variable cost, an increase of contribution margin by $18 million, and savings of 60,000 inpatient care days.ConclusionsThis all-cause harm safety study indicates that inpatient harm has negative financial outcomes for hospitals and negative clinical outcomes for patients.
| S-EPMC5965919 | biostudies-literature
Project description:ObjectivePhase IV trials are often used to investigate drug safety after approval. However, little is known about the characteristics of contemporary phase IV clinical trials and whether these studies are of sufficient quality to advance medical knowledge in pharmacovigilance. We aimed to determine the fundamental characteristics of phase IV clinical trials that evaluated drug safety using the ClinicalTrials.gov registry data.MethodsA data set of 19 359 phase IV clinical studies registered in ClinicalTrials.gov was downloaded. The characteristics of the phase IV trials focusing on safety only were compared with those evaluating both safety and efficacy. We also compared the characteristics of the phase IV trials in three major therapeutic areas (cardiovascular diseases, mental health and oncology). Multivariable logistic regression was used to evaluate factors associated with the use of blinding and randomisation.ResultsA total of 4772 phase IV trials were identified, including 330 focusing on drug safety alone and 4392 evaluating both safety and efficacy. Most of the phase IV trials evaluating drug safety (75.9%) had enrolment <300 with 96.5% <3000. Among these trials, 8.2% were terminated or withdrawn. Factors associated with the use of blinding and randomisation included the intervention model, clinical specialty and lead sponsor.ConclusionsPhase IV trials evaluating drug safety in the ClinicalTrials.gov registry were dominated by small trials that might not have sufficient power to detect less common adverse events. An adequate sample size should be emphasised for phase IV trials with safety surveillance as main task.
| S-EPMC5168517 | biostudies-literature
Project description:We improved a previous pharmacological target adverse-event (TAE) profile model to predict adverse events (AEs) on US Food and Drug Administration (FDA) drug labels at the time of approval. The new model uses more drugs and features for learning as well as a new algorithm. Comparator drugs sharing similar target activities to a drug of interest were evaluated by aggregating AEs from the FDA Adverse Event Reporting System (FAERS), FDA drug labels, and medical literature. An ensemble machine learning model was used to evaluate FAERS case count, disproportionality scores, percent of comparator drug labels with a specific AE, and percent of comparator drugs with the reports of the event in the literature. Overall classifier performance was F1 of 0.71, area under the precision-recall curve of 0.78, and area under the receiver operating characteristic curve of 0.87. TAE analysis continues to show promise as a method to predict adverse events at the time of approval.
| S-EPMC8246740 | biostudies-literature
Project description:Patient and public involvement (PPI) is recognized as a key component of clinical practice guideline development with important implications for guideline implementability. The impact of PPI on guidelines, however, has not been rigorously assessed. Better understanding of the impact of PPI must start with guideline question formation, which drives all subsequent development steps. The aim of this study was to investigate the effect of PPI on guideline question formation and validate a conceptual model of patient and public contributions to guidelines.For development of a clinical practice guideline on the topic of using amyloid positron emission tomography in the diagnosis of dementia, we convened two parallel guideline development groups, one with and one without patient representatives. Participating physicians were randomized to group assignment. Each group developed Population, Intervention, Comparator, Outcome, Time (PICOT) questions and identified key benefits and harms to incorporate in guideline development. Analysis included a descriptive comparison of proposed PICOT questions, benefits, and harms between groups and a qualitative analysis of discussion themes from audio recordings of the question development retreats.Proposed guideline questions, benefits, and harms were largely similar between groups, but only the experimental group proposed outcomes relating to development of cognitive impairment at specific time points and rate of progression. The qualitative analysis of the discussions occurring during guideline question development demonstrated key differences in group conduct and validated the proposed conceptual model of patient and public contributions to guidelines. PPI influenced the conduct of guideline development, scope, inclusion of patient-relevant topics, outcome selection, and planned approaches to recommendation development, implementation, and dissemination with implications for both guideline developers and the guideline development process.Evidence of how PPI impacts guideline development underscores the importance of engaging patient stakeholders in guideline development and highlights developer- and guideline-specific outcomes of PPI, both of which have implications for guideline implementation. It also raises the question of whether guidelines developed without such input are acceptable for use. PPI should be considered an essential element of trustworthy guideline development for purposes of development and funding.
| S-EPMC5902835 | biostudies-other
Project description:Clinical quality registries (CQRs) are playing an increasingly important role in improving health outcomes and reducing health care costs. CQRs are established with the purpose of monitoring quality of care, providing feedback, benchmarking performance, describing pattern of treatment, reducing variation and as a tool for conducting research.To synthesise the impact of clinical quality registries (CQRs) as an 'intervention' on (I) mortality/survival; (II) measures of outcome that reflect a process or outcome of health care; (III) health care utilisation; and (IV) healthcare-related costs.The following electronic databases were searched: MEDLINE, EMBASE, CENTRAL, CINAHL and Google Scholar. In addition, a review of the grey literature and a reference check of citations and reference lists within articles was undertaken to identify relevant studies in English covering the period January 1980 to December 2016. The PRISMA-P methodology, checklist and standard search strategy using pre-defined inclusion and exclusion criteria and structured data extraction tools were used. Data on study design and methods, participant characteristics attributes of included registries and impact of the registry on outcome measures and/or processes of care were extracted.We identified 30102 abstracts from which 75 full text articles were assessed and finally 17 articles were selected for synthesis. Out of 17 studies, six focused on diabetes care, two on cardiac diseases, two on lung diseases and others on organ transplantations, rheumatoid arthritis, ulcer healing, surgical complications and kidney disease. The majority of studies were "before after" design (#11) followed by cohort design (#2), randomised controlled trial (#2), experimental non randomised study and one cross sectional comparison. The measures of impact of registries were multifarious and included change in processes of care, quality of care, treatment outcomes, adherence to guidelines and survival. Sixteen of 17 studies demonstrated positive findings in their outcomes after implementation of the registry.Despite the large number of published articles using data derived from CQRs, few have rigorously evaluated the impact of the registry as an intervention on improving health outcomes. Those that have evaluated this impact have mostly found a positive impact on healthcare processes and outcomes.PROSPERO CRD42015017319.
| S-EPMC5591016 | biostudies-literature
Project description:AimsThe aim of this review was to synthesize the best available evidence on the impact of nurses' safety attitudes on patient outcomes in acute-care hospitals.DesignSystematic review with a narrative synthesis of the available data.Data sourcesData sources included MEDLINE, Cumulative Index of Nursing and Allied Health Literature, Scopus and Web of Science Core Collection. Studies published up to March 2021 were included.Review methodsThis review was conducted using guidance from the Joanna Briggs Institute for Systematic Reviews and reported as per the Preferred Reporting Items for Systematic Review and Meta-Analyses guidelines.ResultsA total of 3,452 studies were identified, and nine studies met the inclusion criteria. Nurses with positive safety attitudes reported fewer patient falls, medication errors, pressure injuries, healthcare-associated infections, mortality, physical restraints, vascular access device reactions and higher patient satisfaction. Effective teamwork led to a reduction in adverse patient outcomes. Most included studies (N = 6) used variants of the Hospital Survey on Patient Safety Culture to assess nurses' safety attitudes. Patient outcomes data were collected from four sources: coded medical records data, incident management systems, nurse perceptions of adverse events and patient perceptions of safety.ConclusionA positive safety culture in nursing units and across hospitals resulted in fewer reported adverse patient outcomes. Nurse managers can improve nurses' safety attitudes by promoting a non-punitive response to error reporting and promoting effective teamwork and good communication.
| S-EPMC8685891 | biostudies-literature