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Pulmonary Circulation Jul 2023Selection of endpoints for clinical trials in pulmonary arterial hypertension (PAH) is challenging because of the small numbers of patients and the changing expectations... (Review)
Review
Selection of endpoints for clinical trials in pulmonary arterial hypertension (PAH) is challenging because of the small numbers of patients and the changing expectations of patients, clinicians, and regulators in this evolving therapy area. The most commonly used primary endpoint in PAH trials has been 6-min walk distance (6MWD), leading to the approval of several targeted therapies. However, single surrogate endpoints such as 6MWD or hemodynamic parameters may not correlate with clinical outcomes. Composite endpoints of clinical worsening have been developed to reflect patients' overall condition more accurately, although there is no standard definition of worsening. Recently there has been a shift to composite endpoints assessing clinical improvement, and risk scores developed from registry data are increasingly being used. Biomarkers are another area of interest, although brain natriuretic peptide and its -terminal prohormone are the only markers used for risk assessment or as endpoints in PAH. A range of other genetic, metabolic, and immunologic markers is currently under investigation, along with conventional and novel imaging modalities. Patient-reported outcomes are an increasingly important part of evaluating new therapies, and several PAH-specific tools are now available. In the future, alternative statistical techniques and trial designs, such as patient enrichment strategies, will play a role in evaluating PAH-targeted therapies. In addition, modern sequencing techniques, imaging analyses, and high-dimensional statistical modeling/machine learning may reveal novel markers that can play a role in the diagnosis and monitoring of PAH.
PubMed: 37554146
DOI: 10.1002/pul2.12271 -
The Journal of Extra-corporeal... Mar 2014The most common cardiac surgical procedures are coronary artery bypass graft surgery and aortic or mitral valve repair or replacement. Underlying conditions include... (Review)
Review
The most common cardiac surgical procedures are coronary artery bypass graft surgery and aortic or mitral valve repair or replacement. Underlying conditions include coronary artery disease and heart failure, manifesting as exertional angina, dyspnea, and poor exercise tolerance. The major goals of surgery are to alleviate symptoms and improve patient survival. These, therefore, should inform the choice of primary outcome measures in clinical studies enrolling patients undergoing cardiac surgery. Studies focusing on surrogate outcome measures are relied on all too often. Many are of questionable significance and often have no convincing relationship with patient outcome. Traditional "hard endpoint" outcome measures include serious complications and death with the former including myocardial infarction (MI) and stroke. Such serious adverse outcomes are commonly collected in registries, but because they occur infrequently, they need to be large to reliably detect true associations and treatment effects. For this reason, some investigators combine several outcomes into a single composite endpoint. Cardiovascular trials commonly use major adverse cardiac events (MACEs) as a composite primary endpoint. However, there is no standard definition for MACE. Most include MI, stroke, and death; others include rehospitalization for heart failure, revascularization, cardiac arrest, or bleeding complications. An influential trial in noncardiac surgery found that perioperative beta-blockers reduced the risk of MI but increased the risk of stroke and death. Such conflicting findings challenge the veracity of such composite endpoints and raise a far more important question: which of these endpoints, or even others that were unmeasured, are most important to a patient recovering from surgery? Given the primary aims of cardiac surgery are to relieve symptoms and improve good quality survival, it is disability-free survival that is the ultimate outcome measure. The question then becomes: what is disability and how should it be quantified after cardiac surgery?
Topics: Cardiac Surgical Procedures; Disease-Free Survival; Heart Diseases; Heart Function Tests; Humans; Outcome Assessment, Health Care; Prognosis; Quality of Life; Recovery of Function; Risk Assessment
PubMed: 24779115
DOI: No ID Found -
Journal of Clinical Pharmacology Jul 2018The selection of appropriate endpoints in pediatric drug development trials is a critical aspect of trial design. Given the high pediatric trial failure rate, selecting...
The selection of appropriate endpoints in pediatric drug development trials is a critical aspect of trial design. Given the high pediatric trial failure rate, selecting optimal trial design elements, such as the primary efficacy endpoint, is essential to ensuring increased potential for trial success. The objectives of this study were to identify the primary efficacy endpoints measured in pediatric drug development trials submitted to the US Food and Drug Administration and to relate endpoint attributes to trial and label outcome. The analysis included pediatric pivotal efficacy studies submitted from September 2007 to July 2016 for which there was a corresponding adult trial for the same indication. Two hundred and thirty-four efficacy trials on 138 unique products studied in pediatric patients were assessed. The adult and pediatric endpoints were the same in 141 of the 234 trials (60.3%), and these trials succeeded in meeting their primary endpoint more often (122 of 141 [86.5%]) than when the adult and pediatric endpoints differed (57 of 93 [61.3%]; odds ratio, 4.03; 95%CI, 2.10-7.80). Trials that included both pediatric and adult patients succeeded more frequently than those trials that did not combine pediatric and adult patients (85 of 95 versus 94 of 139, respectively; odds ratio, 4.05; 95%CI, 1.94-9.31). No differences were observed in pediatric trial success between those using subjective and objective endpoints. Using the same endpoint in the pediatric trial as was measured in the corresponding adult trial and enrolling pediatric and adult patients in the same trial were attributes associated with trial success.
Topics: Adult; Child; Clinical Trials as Topic; Drug Development; Endpoint Determination; Humans; Pediatrics; Treatment Outcome; United States; United States Food and Drug Administration
PubMed: 29663424
DOI: 10.1002/jcph.1109 -
American Journal of Ophthalmology Mar 2019To assess the impact of a masked Endpoint Committee on estimates of the incidence of primary open-angle glaucoma (POAG) treatment efficacy and statistical power of the... (Randomized Controlled Trial)
Randomized Controlled Trial
PURPOSE
To assess the impact of a masked Endpoint Committee on estimates of the incidence of primary open-angle glaucoma (POAG) treatment efficacy and statistical power of the Ocular Hypertension Treatment Study-Phase 1, 1994-2002 (OHTS-1).
DESIGN
Retrospective interrater reliability analysis of endpoint attribution by the Endpoint Committee.
METHODS
After study closeout, we recalculated estimates of endpoint incidence, treatment efficacy, and statistical power using all-cause endpoints and POAG endpoints. To avoid bias, only the first endpoint per participant is included in this report.
RESULTS
The Endpoint Committee reviewed 267 first endpoints from 1636 participants. The Endpoint Committee attributed 58% (155 of 267) of the endpoints to POAG. The incidence of all-cause endpoints vs POAG endpoints was 19.5% and 13.2%, respectively, in the observation group and 13.1% and 5.8%, respectively, in the medication group. Treatment effect for all-cause endpoints was a 33% reduction in risk (relative risk = 0.67, 95% confidence interval [CI] of 0.54-0.84) and a 56% reduction in risk for POAG endpoints (relative risk = 0.44, 95% CI of 0.31-0.61). Post hoc statistical power for detecting treatment effect was 0.94 for all-cause endpoints and 0.99 for POAG endpoints.
CONCLUSION
Endpoint Committee adjudication of endpoints improved POAG incidence estimates, increased statistical power, and increased calculated treatment effect by 23%. An Endpoint Committee should be considered in therapeutic trials when common ocular and systemic comorbidities, other than the target condition, could compromise study results.
Topics: Adult; Antihypertensive Agents; Endpoint Determination; Female; Glaucoma, Open-Angle; Humans; Intraocular Pressure; Male; Middle Aged; Ocular Hypertension; Optic Disk; Optic Nerve Diseases; Reproducibility of Results; Retrospective Studies; Risk Factors; Tonometry, Ocular; Treatment Outcome; Vision Disorders; Visual Field Tests; Visual Fields
PubMed: 30471242
DOI: 10.1016/j.ajo.2018.11.006 -
The American Journal of Cardiology Jun 2016Surrogate endpoints facilitate trial efficiency but are variably linked to clinical outcomes, and limited data are available exploring their utilization in... (Review)
Review
Surrogate endpoints facilitate trial efficiency but are variably linked to clinical outcomes, and limited data are available exploring their utilization in cardiovascular clinical trials over time. We abstracted data regarding primary clinical, intermediate, and surrogate endpoints from all phase II to IV cardiovascular clinical trials from 2001 to 2012 published in the 8 highest Web of Science impact factor journals. Two investigators independently classified the type of primary endpoint. Of the 1,224 trials evaluated, 677 (55.3%) primary endpoints were clinical, 165 (13.5%) intermediate, and 382 (31.2%) surrogate. The relative proportions of these endpoints remained constant over time (p = 0.98). Trials using surrogate endpoints were smaller (187 vs 1,028 patients) and enrolled patients more expeditiously (1.4 vs 0.9 patients per site per month) compared with trials using clinical endpoints (p <0.001 for both comparisons). Surrogate endpoint trials were independently more likely to meet their primary endpoint compared to trials with clinical endpoints (adjusted odds ratio 1.56, 95% CI 1.05 to 2.34; p = 0.03). Rates of positive results in clinical endpoint trials have decreased over time from 66.1% in 2001 to 2003 to 47.2% in 2010 to 2012 (p = 0.001), whereas these rates have remained stable over the same period for surrogate (72.0% to 69.3%, p = 0.27) and intermediate endpoints (74.4% to 71.4%, p = 0.98). In conclusion, approximately a third of contemporary cardiovascular trials use surrogate endpoints. These trials are completed more expeditiously and are more likely to meet their primary outcomes. The overall scientific contribution of these surrogate endpoint trials requires further attention given their variable association with definitive outcomes.
Topics: Biomarkers; Cardiovascular Diseases; Clinical Trials as Topic; Endpoint Determination; Humans; Journal Impact Factor
PubMed: 27085935
DOI: 10.1016/j.amjcard.2016.03.021 -
Journal of Clinical Periodontology May 1995Endpoints are conditions or events that are associated with individual study subjects and that are used to assess treatment efficacy. 2 types of endpoints can be... (Review)
Review
Endpoints are conditions or events that are associated with individual study subjects and that are used to assess treatment efficacy. 2 types of endpoints can be distinguished: "true" endpoints (reflect unequivocal evidence of tangible benefit to the patient) and "surrogate" endpoints (usually a measure of disease process). The purpose of this study was to survey four aspects of endpoint usage in randomized controlled trials (RCT's) on the treatment of periodontitis: (1) the typical number of endpoints per RCT, (2) the proportion of RCTs using the same endpoint, (3) the proportion of RCTs using true endpoints, and (4) whether treatment choice influenced endpoint choice. 92 publications (1988-1992) reporting on 82 RCT's were identified. The typical number of endpoints per RCT was 6 (range: 1-28). The 3 most frequently used endpoints were mean probing depth (78% of the trials), mean probing attachment level (66%), and the plaque index (37%). In total, 153 distinct surrogate endpoints were defined. Most of these were used infrequently; over 80% of the 153 endpoints were used in fewer than 5 of the 82 trials. No trials used tooth loss as a true endpoint. In the design of an RCT, treatment choice influenced surrogate endpoint choice. Surrogate endpoints based on re-entry surgery were exclusively used for regenerative procedures and microbiological surrogate endpoints were mostly used for RCT's on anti-microbials. The conclusion is that the typical RCT used multiple surrogate endpoints, some of which were used infrequently by other trials. Such endpoint usage characteristics are suitable for exploratory RCTs (designed to identify active treatments or to elucidate treatment mechanisms). The question is raised as to whether periodontal research has reached the point of needing properly designed definitive studies, whose purpose it would be to provide unequivocal evidence of tangible benefits to the patient by the various treatments. If a need for definitive randomized controlled trials is perceived, then the use of (multiple) surrogate endpoints as primary outcomes should be questioned. Surrogate endpoint usage has led to both false positive and false negative conclusions in other chronic disease studies. Endpoint selection and validation in RCTs may be an important element in resolving controversies about periodontal treatments.
Topics: Humans; Outcome Assessment, Health Care; Periodontal Index; Periodontitis; Randomized Controlled Trials as Topic; Reproducibility of Results
PubMed: 7601922
DOI: 10.1111/j.1600-051x.1995.tb00167.x -
Statistical Methods in Medical Research May 2024When the primary endpoints in randomized clinical trials require long term follow-up or are costly to measure, it is often desirable to assess treatment effects on...
When the primary endpoints in randomized clinical trials require long term follow-up or are costly to measure, it is often desirable to assess treatment effects on surrogate instead of clinical endpoints. Prior to adopting a surrogate endpoint for such purposes, the extent of its surrogacy on the primary endpoint must be assessed. There is a rich statistical literature on assessing surrogacy in the overall population, much of which is based on quantifying the proportion of treatment effect on the primary endpoint that is explained by the treatment effect on the surrogate endpoint. However, the surrogacy of an endpoint may vary across different patient subgroups according to baseline demographic characteristics, and limited methods are currently available to assess overall surrogacy in the presence of potential surrogacy heterogeneity. In this paper, we propose methods that incorporate covariates for baseline information, such as age, to improve overall surrogacy assessment. We use flexible semi-non-parametric modeling strategies to adjust for covariate effects and derive a robust estimate for the proportion of treatment effect of the covariate-adjusted surrogate endpoint. Simulation results suggest that the adjusted surrogate endpoint has greater proportion of treatment effect compared to the unadjusted surrogate endpoint. We apply the proposed method to data from a clinical trial of infliximab and assess the adequacy of the surrogate endpoint in the presence of age heterogeneity.
PubMed: 38717356
DOI: 10.1177/09622802241247719 -
Journal of Biopharmaceutical Statistics 2018We review the design, data monitoring, and analyses of clinical trials with co-primary endpoints. Recently developed methods for fixed-sample and group-sequential... (Review)
Review
We review the design, data monitoring, and analyses of clinical trials with co-primary endpoints. Recently developed methods for fixed-sample and group-sequential settings are described. Practical considerations are discussed, and guidance for the application of these methods is provided.
Topics: Clinical Trials as Topic; Data Interpretation, Statistical; Endpoint Determination; Guidelines as Topic; Humans; Models, Statistical; Research Design; Sample Size
PubMed: 29083951
DOI: 10.1080/10543406.2017.1378668 -
Journal of Neurosurgery Aug 2019Randomized controlled trials (RCTs) form the basis of today's evidence-based approach to medicine, and play a critical role in guidelines and the drug and device... (Review)
Review
OBJECTIVE
Randomized controlled trials (RCTs) form the basis of today's evidence-based approach to medicine, and play a critical role in guidelines and the drug and device approval process. Conflicts of interest (COIs) are commonplace in medical research, but little is known about their influence. The authors aimed to evaluate the extent and influence of COIs in recent RCTs published in core neurosurgical journals using a cross-sectional analysis.
METHODS
Through review of 6 general neurosurgical journals, all interventional RCTs published from January 2009 to January 2019 were identified. Because it is difficult to objectively assess study outcome, the authors opted for a strict rating approach based on the statistical significance of unambiguously reported primary endpoints, and the reported statistical protocol.
RESULTS
A total of 129 RCTs met the inclusion criteria. During the study period, the Journal of Neurosurgery published the largest number of RCTs (n = 40, 31%). Any potential COI was disclosed by 57%, and a mean of 12% of authors had a personal COI. Nonfinancial industry involvement was reported in 10%, while 31% and 20% received external support and sponsoring, respectively. Study registration was reported by 56%, while 51% of studies were blinded. Registration showed an increasing trend from 17% to 76% (p < 0.001). The median randomized sample size was 92 (interquartile range 50-153), and 8% were designed to investigate noninferiority or equality. Sixty-three RCTs (49%) unambiguously reported a primary endpoint, of which 13% were composite primary endpoints. In 43%, study outcome was positive, which was associated with a noninferiority design (31% vs 3%, p = 0.007) and a composite primary endpoint (46% vs 9%, p = 0.002). Potential COIs were not significantly associated with study positivity (69% vs 59%, p = 0.433). In the multivariate analysis, only a composite primary endpoint remained predictive of a positive study outcome (odds ratio 6.34, 95% confidence interval 1.51-33.61, p = 0.017).
CONCLUSIONS
This analysis provides an overview of COIs and their potential influence on recent trials published in core neurosurgical journals. Reporting of primary endpoints, study registration, and uniform disclosure of COIs are crucial to ensure the quality of future neurosurgical randomized trials. COIs do not appear to significantly influence the outcome of randomized neurosurgical trials.
PubMed: 31419788
DOI: 10.3171/2019.5.JNS183560 -
Allergy Sep 2014The goal of asthma treatment is to control the disease according to guidelines issued by bodies such as the Global Initiative for Asthma. Effective control is dependent... (Review)
Review
The goal of asthma treatment is to control the disease according to guidelines issued by bodies such as the Global Initiative for Asthma. Effective control is dependent upon evaluation of symptoms, initiation of appropriate treatment and minimization of the progressive adverse effects of the disease and its therapies. Although individual outcome measures have been shown to correlate with asthma control, composite endpoints are preferred to enable more accurate and robust monitoring of the health of the individual patient. A number of validated instruments are utilized to capture these component endpoints; however, there is no consensus on the optimal instrument for use in clinical trials. The Asthma Control Questionnaire (ACQ) has been shown to be a valid, reliable instrument that allows accurate and reproducible assessment of asthma control that compares favourably with other commonly used instruments. This analysis provides a summary of the use of ACQ in phase II, III and IV asthma trials. Comparisons between the ACQ and other instruments are also presented. Our analysis suggests that the ACQ is a valid and robust measure for use as a primary or secondary endpoint in future clinical trials.
Topics: Asthma; Clinical Trials as Topic; Endpoint Determination; Humans; Surveys and Questionnaires; Treatment Outcome
PubMed: 25039248
DOI: 10.1111/all.12415