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Medicina Clinica Jan 2021
Topics: Bibliometrics; Biomedical Research; COVID-19; Clinical Trials as Topic; Global Health; Humans; Pandemics; Publishing; Spain
PubMed: 33268132
DOI: 10.1016/j.medcli.2020.09.001 -
Cell Apr 2020Integrating precision diagnostics into personalized treatments requires understanding how biomarkers relate to clinical outcomes. Various clinical data collection...
Integrating precision diagnostics into personalized treatments requires understanding how biomarkers relate to clinical outcomes. Various clinical data collection methods exist, each with strengths and weaknesses. Interventional data are high quality but narrowly focused. Real-world data (RWD) provide broader information but with variable quality. Master protocols allow better efficiency in data collection. The master observational trial bridges the gap between interventional and retrospective RWD collection methods. To view this SnapShot, open or download the PDF.
Topics: Clinical Trials as Topic; Data Collection; Humans; Precision Medicine
PubMed: 32243791
DOI: 10.1016/j.cell.2020.02.032 -
Clinical Trials (London, England) Feb 2020The prevalence of type 2 diabetes is increasing in youths and differs from adult-onset type 2 diabetes in its characteristics and progression. Currently, only two drugs... (Review)
Review
BACKGROUND
The prevalence of type 2 diabetes is increasing in youths and differs from adult-onset type 2 diabetes in its characteristics and progression. Currently, only two drugs are approved for youth-onset type 2 diabetes and many patients are not meeting glycemic targets. Clearly, there is an urgent need to complete clinical trials in youths with type 2 diabetes to increase the therapeutic choice for these patients. However, factors such as limited patient numbers, unwillingness of patients to participate in trials, failure to meet strict inclusion and exclusion criteria, and poor clinic attendance have limited the size and number of trials in this complicated patient demographic.
RECOMMENDATIONS
This is a narrative opinion piece on the design of clinical trials in youth-onset type 2 diabetes prepared by researchers who undertake this type of study in different countries. The review addresses possible ways to enhance trial designs in youth-onset type 2 diabetes to meet regulatory requirements, while minimizing the barriers to patients' participation. The definition of adolescence, recruitment of sufficient patient numbers, increasing flexibility in selection criteria, improving convenience of trial visits, requirements of a control group, possible endpoints, and trial compliance are all considered. The authors recommend allowing extrapolation from adult data, using multiple interventional arms within future trials, broadening inclusion criteria, and focusing on endpoints beyond glucose control, among others, in order to improve the successful completion of more trials in this population.
CONCLUSIONS
Improvements in trial design will enable better recruitment and retention and thereby more evidence for treatment outcomes for youth-onset type 2 diabetes.
Topics: Adolescent; Clinical Trials as Topic; Diabetes Mellitus, Type 2; Health Services Needs and Demand; Humans; Hypoglycemic Agents; Patient Participation; Patient Selection; Research Design; Treatment Adherence and Compliance; Treatment Outcome
PubMed: 31450961
DOI: 10.1177/1740774519870190 -
Journal of Minimally Invasive Gynecology Mar 2021The objective of this article is to review the difficulties with the design and interpretation of surgical clinical trials. Few surgical procedures are evaluated in a... (Review)
Review
The objective of this article is to review the difficulties with the design and interpretation of surgical clinical trials. Few surgical procedures are evaluated in a randomized fashion. There are a number of factors that make the design of surgical trials diffiuclt, and many surgical questions cannot be answered with a clinical trial. Issues with standardization of the surgical procedure, variability of surgical skills, and changes in surgical expertise over time further complicate the design and implementation of surgical trials. Statistical methods for surgical trials often require a noninferiorty design and are more complicated to interpret than the more common superiority trial. Even when properly conducted, both superiority and noninferiority trials are often misinterpreted. Because of the relatively high success rate in surgery, trials require large numbers of patients and noninferiority trials are often inconclusive with respect to the primary outcome. Surgical trials are often misinterpreted or over interpreted, and there can be confusion in how the findings of these trials should be incorportated into clinical practice. The interpretation of the results of a surgical trial often differ significantly from the primary and secondary outcomes that were specified in the trial design.
Topics: Clinical Trials as Topic; Humans; Research Design; Surgical Procedures, Operative; Treatment Outcome
PubMed: 33190804
DOI: 10.1016/j.jmig.2020.10.011 -
PloS One 2022To assess the accuracy of principal investigators' (PIs) predictions about three events for their own clinical trials: positivity on trial primary outcomes, successful...
OBJECTIVE
To assess the accuracy of principal investigators' (PIs) predictions about three events for their own clinical trials: positivity on trial primary outcomes, successful recruitment and timely trial completion.
STUDY DESIGN AND SETTING
A short, electronic survey was used to elicit subjective probabilities within seven months of trial registration. When trial results became available, prediction skill was calculated using Brier scores (BS) and compared against uninformative prediction (i.e. predicting 50% all of the time).
RESULTS
740 PIs returned surveys (16.7% response rate). Predictions on all three events tended to exceed observed event frequency. Averaged PI skill did not surpass uninformative predictions (e.g., BS = 0.25) for primary outcomes (BS = 0.25, 95% CI 0.20, 0.30) and were significantly worse for recruitment and timeline predictions (BS 0.38, 95% CI 0.33, 0.42; BS = 0.52, 95% CI 0.50, 0.55, respectively). PIs showed poor calibration for primary outcome, recruitment, and timelines (calibration index = 0.064, 0.150 and 0.406, respectively), modest discrimination in primary outcome predictions (AUC = 0.76, 95% CI 0.65, 0.85) but minimal discrimination in the other two outcomes (AUC = 0.64, 95% CI 0.57, 0.70; and 0.55, 95% CI 0.47, 0.62, respectively).
CONCLUSION
PIs showed overconfidence in favorable outcomes and exhibited limited skill in predicting scientific or operational outcomes for their own trials. They nevertheless showed modest ability to discriminate between positive and non-positive trial outcomes. Low survey response rates may limit generalizability.
Topics: Clinical Trials as Topic; Forecasting; Research Personnel; Surveys and Questionnaires; Treatment Outcome
PubMed: 35134071
DOI: 10.1371/journal.pone.0262862 -
Genetics in Medicine : Official Journal... Nov 2021After decades of setbacks, gene therapy (GT) is experiencing major breakthroughs. Five GTs have received US regulatory approval since 2017, and over 900 others are... (Review)
Review
After decades of setbacks, gene therapy (GT) is experiencing major breakthroughs. Five GTs have received US regulatory approval since 2017, and over 900 others are currently in development. Many of these GTs target rare pediatric diseases that are severely life-limiting, given a lack of effective treatments. As these GTs enter early-phase clinical trials, specific ethical challenges remain unresolved in three domains: evaluating risks and potential benefits, selecting participants fairly, and engaging with patient communities. Drawing on our experience as clinical investigators, basic scientists, and bioethicists involved in a first-in-human GT trial for an ultrarare pediatric disease, we analyze these ethical challenges and offer points to consider for future GT trials.
Topics: Child; Clinical Trials as Topic; Genetic Therapy; Humans; Treatment Outcome
PubMed: 34234300
DOI: 10.1038/s41436-021-01245-3 -
Clinical Cancer Research : An Official... May 2021In clinical research, eligibility criteria promote patient safety and optimize the evidence generated from clinical trials. However, overly stringent eligibility... (Review)
Review
PURPOSE
In clinical research, eligibility criteria promote patient safety and optimize the evidence generated from clinical trials. However, overly stringent eligibility criteria, including laboratory requirements, may limit enrollment, resulting in delayed trial completion and potentially limiting applicability of trial results to a general practice population.
EXPERIMENTAL DESIGN
Starting in 2018, a working group consisting of experts in direct patient care, the FDA, industry, and patient advocacy developed recommendations to guide the optimal use of laboratory reference ranges and testing intervals in clinical trial eligibility criteria and study procedures. The working group evaluated current eligibility criteria across different clinical trial phases and performed a literature review to evaluate the impact of and justification for laboratory test eligibility requirements and testing intervals in clinical trials. Recommendations were developed on the basis of the goals of promoting safety and optimizing the evidence generated, while also expanding eligibility and applicability, and minimizing excess burden of trial participation.
RESULTS
In general, we found little variation over time and trial phase in laboratory test requirements, suggesting that these eligibility criteria are not refined according to ongoing clinical experience. We propose recommendations to optimize the use of laboratory tests when considering eligibility criteria.
CONCLUSIONS
Tailoring the use of laboratory test requirements and testing intervals may increase the number and diversity of patients in clinical trials and provide clinical data that more closely represent the general practice populations..
Topics: Biomedical Research; Clinical Decision-Making; Clinical Trials as Topic; Disease Management; Humans; Medical Oncology; Neoplasms; Research Design
PubMed: 33563636
DOI: 10.1158/1078-0432.CCR-20-3853 -
PloS One 2020While the epidemiologic burden of mental health disorders in the United States has been well described over the past decade, we know relatively little about trends in...
While the epidemiologic burden of mental health disorders in the United States has been well described over the past decade, we know relatively little about trends in how these disorders are being studied through clinical research. We examined all US interventional mental health trials submitted to ClinicalTrials.gov between October 1, 2007 and April 30, 2018 to identify trends in trial characteristics, comparisons with non-mental health trials, and trial attributes associated with discontinuation and results reporting. International data were excluded to minimize potential confounding. Over this period, mental health and non-mental health trials grew at similar rates, though Industry and US government-funded trials declined and academic medical center/hospital/other (AMC/Hosp/Oth) funded trials grew faster in mental health research. The proportion of trials with safeguards against bias, including blinding and oversight by data monitoring committees (DMCs), decreased. This occurred during growth in the proportion of trials studying behavioral and non-pharmacological interventions, which often cannot be blinded and do not require DMC oversight. There was concurrent decline in pharmaceutical trials. There was significant growth in trials studying Non-DSM (Diagnostic and Statistical Manual-5) conditions (e.g. suicidality and wellness), as well as substance use, anxiety, and neurocognitive disorders. One in 12 trials was discontinued. Trial discontinuation was associated with industry and AMC/Hosp/Oth funders, pharmaceutical interventions, and lack of DMC oversight. Only 29.9% of completed trials reported results to the registry. Decreased results reporting was associated with behavioral interventions, phase 1 trials, and industry and AMC/Hosp/Oth funders. The main implications of these data are that funding is shifting away from traditional government and industry sources, there is increasing interest in non-pharmacological treatments and Non-DSM conditions, and there are changing norms in trial design characteristics regarding safeguards against bias. These trends can guide researchers and funding bodies when considering the trajectory of future mental health research.
Topics: Bias; Biomedical Research; Clinical Trials Data Monitoring Committees; Clinical Trials as Topic; Humans; Mental Disorders; Mental Health; Patient Selection; Registries; Research Design; United States
PubMed: 32502181
DOI: 10.1371/journal.pone.0233996 -
Contemporary Clinical Trials Nov 2020The COVID-19 pandemic has substantially impacted the conduct of clinical trials. While initially preparing for a period of time, where it would likely be impossible to...
The COVID-19 pandemic has substantially impacted the conduct of clinical trials. While initially preparing for a period of time, where it would likely be impossible to supervise trials in the usual way and precautionary measures had to be implemented to care for medication supply and general safety of study participants it is now important to consider, how the impact of the pandemic on trial outcome can be assessed, which measures are needed to decide, how to proceed with the trial and what is needed to compensate to irregularity introduced by the pandemic situation. Obviously not all trials will suffer to the same degree: some trials may be close to finalizing recruitment, others may not yet have started. Similarly not all clinical trials investigate vulnerable patient populations, but some will and may in addition have recruited to an extent that beneficial effects achieved in the initial phase of the trial may be outweighed by an increase e.g. in mortality that impacts both treatment groups. The situation is further complicated by the fact that the pandemic reached different countries in the world and even cities in one country at different points in time with different severity. Our example is a randomized and double-blind clinical trial comparing digitoxin and placebo in patients with advanced chronic heart failure. This trial has recruited roughly 1/3 of the overall 2200 patients when the disease outbreak reached Germany. We discuss how simulations and theoretical considerations can be used to address questions about the need to increase the overall sample-size to be recruited to compensate for a potential shrinkage of the treatment effect caused by the COVID-19 pandemic and what role the degree of consistency could play when comparing pre-, during- and post- COVID-19 periods of trial conduct regarding the question, whether the treatment effect can be considered consistent and with this generalizable. This is dependent on the size of the treatment effect and the impact of the pandemic. We argue, that in case of doubt, it may be wise to proceed with the original study plan.
Topics: COVID-19; Clinical Trials as Topic; Early Termination of Clinical Trials; Germany; Global Health; Humans; Infection Control; Organizational Innovation; Outcome Assessment, Health Care; Randomized Controlled Trials as Topic; Research Design; SARS-CoV-2; Sample Size; Vulnerable Populations
PubMed: 32961360
DOI: 10.1016/j.cct.2020.106155 -
Annals of Hematology Jun 2020Ruxolitinib is a targeted drug to treat myelofibrosis (MF). Ruxolitinib has significant advantages in spleen reduction and increasing 5-year overall survival (OS), and... (Review)
Review
Ruxolitinib is a targeted drug to treat myelofibrosis (MF). Ruxolitinib has significant advantages in spleen reduction and increasing 5-year overall survival (OS), and ruxolitinib-based combinations might provide more benefits than ruxolitinib monotherapy. In this review, we focus on the data of ruxolitinib-based combinations therapies and treatment-related adverse events (AEs) and safety. We analyzed and summarized the data of ruxolitinib-based combinations. Ruxolitinib combined with prednisone + thalidomide + danazol (TPD), panobinostat, pracinostat, azacytidine, or hydroxyurea has well reduced spleen. Ruxolitinib combined with danazol or TPD had well therapies in improvement of hemoglobin (Hgb) and platelets (PLT). Most ruxolitinib-based combinations therapies showed a superior benefit on reduced treatment-related AEs than ruxolitinib monotherapy. Treatment-related AEs and dose modification affect the safety and tolerability of ruxolitinib-based combinations. Genetic testing before treatment is recommended. To provide better clinical guidance, comparisons of these randomized controlled trials with the trials of ruxolitinib alone are necessary. This review suggests that the clinical application of ruxolitinib-based combinations is worth waiting for.
Topics: Clinical Trials as Topic; Drug Therapy, Combination; Humans; Immunologic Factors; Nitriles; Primary Myelofibrosis; Pyrazoles; Pyrimidines; Treatment Outcome
PubMed: 32333155
DOI: 10.1007/s00277-020-04028-z