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Seow, Hsien-Yeang, Patrick Whelan, Mark N. Levine, Kathryn Cowan, Barbara Lysakowski, Brenda Kowaleski, Anne Snider, Rebecca Y. Xu y Andrew Arnold. "Funding Oncology Clinical Trials: Are Cooperative Group Trials Sustainable?" Journal of Clinical Oncology 30, n.º 13 (1 de mayo de 2012): 1456–61. http://dx.doi.org/10.1200/jco.2011.37.2698.
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Purpose Many oncology clinical trials departments (CTDs) are in serious fiscal deficit and their sustainability is in jeopardy. This study investigates whether the payment models used to fund industry versus cooperative group trials contribute to the fiscal deficit of a CTD. Methods We examined the lifetime costs of all cooperative group and industry trials activated in the CTD of a cancer center between 2007 and 2011. A trial's lifetime is defined as being from the date the first patient was accrued until the last patient's actual or projected final follow-up visit. For each trial, we calculated the lifetime monthly net income, which was defined as monthly revenue minus monthly costs. Data sources included study protocols, trial budgets, and accrual data. Results Of the 97 trials analyzed, 64 (66%) were cooperative group trials. The pattern of lifetime net income for cooperative group trials has a positive peak during patient accrual followed by a negative trough during follow-up. In contrast, the pattern for industry trials resembled an “l” shape. The patterns reflect the differing payment models: upfront lump-sum payments (cooperative group) versus milestone payments (industry). Conclusion The negative trough in the lifetime net income of a cooperative group trial occurs because follow-up costs are typically not funded or are underfunded. CTDs accrue more patients in new trials to offset that deficit. The CTD uses revenue from accrual to existing trials to cross-subsidize past trials in follow-up. As the number of patients on follow-up increases, the fiscal deficit grows larger each year, perpetuating the cycle.
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Van Der Weyden, Martin B. "Trials on trial". Medical Journal of Australia 175, n.º 5 (septiembre de 2001): 241. http://dx.doi.org/10.5694/j.1326-5377.2001.tb143553.x.
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Nelson, Mark. "Trials on trial". New Scientist 209, n.º 2800 (febrero de 2011): 30. http://dx.doi.org/10.1016/s0262-4079(11)60384-9.
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Vulto, Arnold G. "Clinical trials on trial". European Journal of Hospital Pharmacy 19, n.º 4 (agosto de 2012): 347. http://dx.doi.org/10.1136/ejhpharm-2012-000180.
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Pimentel, Leonardo Duarte, Claudio Horst Bruckner, Candida Elisa Manfio, Sérgio Yoshimitsu Motoike y Hermínia Emília Prieto Martinez. "SUBSTRATE, LIME, PHOSPHORUS AND TOPDRESS FERTILIZATION IN MACAW PALM SEEDLING PRODUCTION". Revista Árvore 40, n.º 2 (abril de 2016): 235–44. http://dx.doi.org/10.1590/0100-67622016000200006.
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ABSTRACT The macaw palm [Acrocomia aculeata (Jacq.) Lood. ex Mart] has been domesticated to subsidize biodiesel production programs in Brazil. However, little is known about the seedling production of this species. This study aimed to evaluate substrate mixtures, limestone and phosphorus rates for substrate amendment and topdressing frequency in macaw palm seedlings. Three trials were conducted in a greenhouse up to six months of nursery cultivation. Trial 1: determination of percent mineral and organic fractions of seven substrate mixtures. Trial 2: evaluation of four limerates for soil amendment versus four phosphorus rates. Trial 3: evaluation of N, K and Mg topdressing frequency. Significant differences were found in the three trials for most of the variables (plant height, leaf number, shoot dry mass, root dry mass, vigor and bulb diameter). The main results obtained were as follow: Trial1 - the best seedling growth was observed in substrates with at least 25% organic matter. Trial2 -lime rates ranging from 0.50 to 1.25 kg associated with 3 to 4 kg of single superphosphate per m3 of substrate provided the best seedling growth. Trial 3 - topdressing fertilization provided better development of seedlings regardless of frequency.
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de Vries, Ymkje Anna, Annelieke M. Roest, Erick H. Turner y Peter de Jonge. "Hiding negative trials by pooling them: a secondary analysis of pooled-trials publication bias in FDA-registered antidepressant trials". Psychological Medicine 49, n.º 12 (28 de septiembre de 2018): 2020–26. http://dx.doi.org/10.1017/s0033291718002805.
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AbstractBackgroundPrevious studies on reporting bias generally examined whether trials were published in stand-alone publications. In this study, we investigated whether pooled-trials publications constitute a specific form of reporting bias. We assessed whether negative trials were more likely to be exclusively published in pooled-trials publications than positive trials and examined the research questions, individual trial results, and conclusions presented in these articles.MethodsData from a cohort of 105 randomized controlled trials of 16 antidepressants were extracted from earlier publications and the corresponding Food and Drug Administration (FDA) reviews. A systematic literature search was conducted to identify pooled-trials publications.ResultsWe found 107 pooled-trials publications that reported results of 23 (72%) of 32 trials not published in stand-alone publications. Only two (3.8%) of 54 positive trials were published exclusively in pooled-trials publications, compared with 21 (41.1%) of 51 negative trials (p < 0.001). Thirteen (12%) of 107 publications had as primary aim to present data on the trial's primary research question (drug efficacy compared with placebo). Only four of these publications, reporting on five (22%) trials, presented individual efficacy data for the primary research question. Additionally, only five (5%) of 107 pooled-trials publications had a negative conclusion.ConclusionsCompared with positive trials, negative trials of antidepressants for depression were much more likely to be reported exclusively in pooled-trials publications. Pooled-trials publications flood the evidence base with often-redundant articles that, instead of addressing the original primary research question, present (positive) results on secondary questions. Therefore, pooled-trials publications distort the apparent risk–benefit profile of antidepressants.
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Kim, Daniel J., Dan Otap, Nora Ruel, Naveen Gupta, Naveed Khan y Tanya Dorff. "NCI–Clinical Trial Accrual in a Community Network Affiliated with a Designated Cancer Center". Journal of Clinical Medicine 9, n.º 6 (24 de junio de 2020): 1970. http://dx.doi.org/10.3390/jcm9061970.
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Most cancer care is delivered in the community, while most clinical trials exist in academic centers. We analyzed clinical trial accrual of a tertiary care cancer center and its affiliated community sites to better understand what types of trials accrued at the community sites and whether community accrual increased ethnic diversity. The institutional clinical trial database was searched for solid tumor accruals during 2018–2019. Patient’s race was abstracted, and trial’s funding source, phase, and disease type/stage were tabulated. Of 3689 accruals, 133 were at community sites, representing 26 unique trials while the main campus accrued to 93 unique trials. Community site accruals were highest for breast and colorectal cancer, but patients with less common cancers such as renal, nasopharyngeal, and gastric cancer were also accrued at community sites. Accruals occurred to randomized trials, as well as phase Ib and translational biomarker studies. Minority patients constituted 20.0% and 32.5% of community site accruals for therapeutic and non-therapeutic trials respectively, compared to 20.6% and 29.8% of main campus accruals for therapeutic and non-therapeutic trials, respectively. We conclude that community sites affiliated with an academic cancer center can accrue to a broad spectrum of clinical trials while enhancing racial diversity in participation of clinical trials. Further expansion of access to clinical trials in community sites is necessary to broaden patient access to state-of-the-art and next-generation treatment options.
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Foster, Henry H. "TRIAL MARRIAGES AND DIVORCE TRIALS". Family Court Review 11, n.º 1 (15 de marzo de 2005): 1–7. http://dx.doi.org/10.1111/j.174-1617.1973.tb01183.x.
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Harman, Chloë. "Putting clinical trials on trial". Nature Reviews Nephrology 5, n.º 6 (junio de 2009): 301. http://dx.doi.org/10.1038/nrneph.2009.89.
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MIZUSHIMA, YUTAKA. "New trials of trial cases." Rinsho yakuri/Japanese Journal of Clinical Pharmacology and Therapeutics 29, n.º 1/2 (1998): 1–6. http://dx.doi.org/10.3999/jscpt.29.1.
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Palca, J. "Government ddI trials on trial". Science 246, n.º 4935 (8 de diciembre de 1989): 1244. http://dx.doi.org/10.1126/science.2511632.
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Renfro, Lindsay A., Axel M. Grothey, James Paul, Irene Floriani, Franck Bonnetain, Donna Niedzwiecki, Takeharu Yamanaka, Ioannis Souglakos, Greg Yothers y Daniel J. Sargent. "Projecting Event-Based Analysis Dates in Clinical Trials: An Illustration Based on the International Duration Evaluation of Adjuvant Chemotherapy (IDEA) Collaboration. Projecting Analysis Dates for the IDEA Collaboration". Forum of Clinical Oncology 5, n.º 2 (10 de diciembre de 2014): 1–7. http://dx.doi.org/10.2478/fco-2014-0006.
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Abstract Purpose: Clinical trials are expensive and lengthy, where success of a given trial depends on observing a prospectively defined number of patient events required to answer the clinical question. The point at which this analysis time occurs depends on both patient accrual and primary event rates, which typically vary throughout the trial's duration. We demonstrate real-time analysis date projections using data from a collection of six clinical trials that are part of the IDEA collaboration, an international preplanned pooling of data from six trials testing the duration of adjuvant chemotherapy in stage III colon cancer, and we additionally consider the hypothetical impact of one trial's early termination of follow-up. Patients and Methods: In the absence of outcome data from IDEA, monthly accrual rates for each of the six IDEA trials were used to project subsequent trial-specific accrual, while historical data from similar Adjuvant Colon Cancer Endpoints (ACCENT) Group trials were used to construct a parametric model for IDEA's primary endpoint, disease-free survival, under the same treatment regimen. With this information and using the planned total accrual from each IDEA trial protocol, individual patient accrual and event dates were simulated and the overall IDEA interim and final analysis times projected. Projections were then compared with actual (previously undisclosed) trial-specific event totals at a recent census time for validation. The change in projected final analysis date assuming early termination of follow-up for one IDEA trial was also calculated. Results: Trial-specific predicted event totals were close to the actual number of events per trial for the recent census date at which the number of events per trial was known, with the overall IDEA projected number of events only off by eight patients. Potential early termination of follow-up by one IDEA trial was estimated to postpone the overall IDEA final analysis date by 9 months. Conclusions: Real-time projection of the final analysis time during a trial, or the overall analysis time during a trial collaborative such as IDEA, has practical implications for trial feasibility when these projections are translated into additional time and resources required.
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Sydes, Matthew R., Yolanda Barbachano, Louise Bowman, Tom Denwood, Andrew Farmer, Steph Garfield-Birkbeck, Martin Gibson et al. "Realising the full potential of data-enabled trials in the UK: a call for action". BMJ Open 11, n.º 6 (junio de 2021): e043906. http://dx.doi.org/10.1136/bmjopen-2020-043906.
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RationaleClinical trials are the gold standard for testing interventions. COVID-19 has further raised their public profile and emphasised the need to deliver better, faster, more efficient trials for patient benefit. Considerable overlap exists between data required for trials and data already collected routinely in electronic healthcare records (EHRs). Opportunities exist to use these in innovative ways to decrease duplication of effort and speed trial recruitment, conduct and follow-up.ApproachThe National Institute of Health Research (NIHR), Health Data Research UK and Clinical Practice Research Datalink co-organised a national workshop to accelerate the agenda for ‘data-enabled clinical trials’. Showcasing successful examples and imagining future possibilities, the plenary talks, panel discussions, group discussions and case studies covered: design/feasibility; recruitment; conduct/follow-up; collecting benefits/harms; and analysis/interpretation.ReflectionSome notable studies have successfully accessed and used EHR to identify potential recruits, support randomised trials, deliver interventions and supplement/replace trial-specific follow-up. Some outcome measures are already reliably collected; others, like safety, need detailed work to meet regulatory reporting requirements. There is a clear need for system interoperability and a ‘route map’ to identify and access the necessary datasets. Researchers running regulatory-facing trials must carefully consider how data quality and integrity would be assessed. An experience-sharing forum could stimulate wider adoption of EHR-based methods in trial design and execution.DiscussionEHR offer opportunities to better plan clinical trials, assess patients and capture data more efficiently, reducing research waste and increasing focus on each trial’s specific challenges. The short-term emphasis should be on facilitating patient recruitment and for postmarketing authorisation trials where research-relevant outcome measures are readily collectable. Sharing of case studies is encouraged. The workshop directly informed NIHR’s funding call for ambitious data-enabled trials at scale. There is the opportunity for the UK to build upon existing data science capabilities to identify, recruit and monitor patients in trials at scale.
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Lebensburger, Jeffrey D., Lauren Pair, Lee Hilliard y Thomas H. Howard. "A Systematic Review Of All Interventional Sickle Cell Trials Registered At Clinicaltrials.Gov". Blood 122, n.º 21 (15 de noviembre de 2013): 2990. http://dx.doi.org/10.1182/blood.v122.21.2990.2990.
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Abstract Background Clinicaltrials.gov was created in 2000 to comply with the FDA Modernization Act of 1997 and since 2007, Federal law (Section 801 of the FDA Amendments Acts) mandates registration of all applicable, prospective clinical drug trials of health outcomes. ICMJE journals also require registration of all intervention trials prior to publication. Clinicaltrials.gov offers patients and clinicians a valuable tool to identify open sickle cell disease (SCD) clinical trials by disease and results of closed trials with links to manuscripts. Objective To conduct a systematic review of all completed interventional SCD trials registered at clinicaltrials.gov and identify enrollment rates and reporting of trial results. Methods We performed a search of “sickle” in www.clinicaltrials.gov to identify every registered SCD clinical trial. (Last update: August 5, 2013). Every “closed” “interventional” registered trial was recorded in a database to include: trial name, trial identifier, start/stop date, sponsor/collaborator, primary objectives, enrollment age, expected enrollment, type of trial, and manuscripts. For trials without a manuscript in the registry, we performed a Pubmed search by keywords from the trial title, intervention, and/or PI. All manuscripts identified were reviewed to confirm trial enrollment numbers. Results Three hundred and fifty three SCD trials were registered, of which 212 (60%) were closed or completed. We performed a systematic review of 147 “interventional”, closed trials. (1983-2012). The primary sponsor or collaborator listed for these trials included an academic center (n=72, 41 unique centers registered trials), industry or pharmaceutical company (n=47), and/or NIH (n=45). Ninety trials (61%) were registered as either phase I or II, 29 (20%) registered as phase III, 8 (5%) registered as phase 4, and 20 trials did not provide a phase. Fifty two percent of trials were randomized. For trials that listed inclusion criteria for age, 41% were pediatric trials, 50% were adult, and 9% were both pediatric and adult. The most frequent outcomes of interest for these trials were pain (22%), bone marrow transplant (12%), pulmonary hypertension (7.5%), and endothelial function/dysfunction (5.5%). The reporting of trial results and manuscripts to clinicaltrials.gov was low. Nineteen of 147 (13%) trials completed the “trial results” section in clinicaltrials.gov. Twenty six trials downloaded their primary manuscript to clinicaltrials.gov despite 51 trials having manuscripts published on Pubmed. Eighty seven closed clinical trials registered on clinicaltrials.gov have not reported their trial results to clinicaltrials.gov or published their manuscripts as searched in Pubmed. Barriers to successful enrollment in SCD trials were evident in this review. Thirty two (22%) trials updated their registry to reflect “study termination” or “withdrawal”. For the 27 trials that listed the reason for this early termination/withdrawal, 17 (63%) were closed for slow enrollment. Barriers to enrollment in phase III trials were identified as 45% of phase III trials enrolled < 60% of their expected participants. The reporting of phase III trials was also low as only 16 (55%) of the registered phase III trials results have published manuscripts. Conclusion Clinicaltrials.gov can be a valuable tool for clinicians to identify SCD clinical trials, but in practice is limited by investigator reporting of trial results. SCD clinical trials that are under-enrolled or not published place subjects at risk for participation in a trial without a scientific benefit to their disease community. Research should continue to focus on identifying and overcoming barriers to enrollment in clinical trials and publication of trial results. Disclosures: No relevant conflicts of interest to declare.
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Neel, Dylan, David Stephen Shulman y Steven G. DuBois. "Sponsorship of pediatric oncology interventional trials." Journal of Clinical Oncology 37, n.º 15_suppl (20 de mayo de 2019): 10044. http://dx.doi.org/10.1200/jco.2019.37.15_suppl.10044.
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10044 Background: The sponsor of a clinical trial is the single entity responsible for the overall conduct and oversight of the trial. Sponsors may be pharmaceutical/biotech companies (“industry”), government agencies (e.g. NIH), or other entities such as academic institutions. Trial sponsorship may have important regulatory and financial implications for the trial intervention under investigation. We sought to compare oncology trial sponsorship based upon age of eligibility. Methods: We used the clinicaltrials.gov database to evaluate all interventional trials from September 1, 2009 to December 1, 2018. We included all trials regardless of indication and then separately analyzed only oncology trials. We analyzed sponsor status as “industry”, “government”, or “other”. Results: Sponsorship data were available for 59,582 interventional trials across all disciplines (n = 15,564 oncology trials). Across all disciplines and ages of eligibility, lead trial sponsorship was 34% industry, 5% government, and 61% other. Across all oncology trials, sponsorship mix was similar: 31% industry; 6% government, and 62% other. Among adult oncology trials (age of eligibility starting at age 18 years), trial sponsorship was 33% industry, 6% government, and 61% other. Among pediatric-only oncology trials (age of eligibility capped < 18 years), trial sponsorship was 25% industry, 1% government, and 74% other. 5% of industry sponsored trials across all indications were pediatric-only compared to 0.63% of industry-sponsored trials in oncology. 95% of industry sponsored pediatric-only oncology trials were phase 1 or 2 trials, compared to 90% in adults. Conclusions: Pediatric-only interventional oncology trials are less likely to be industry sponsored compared to adult oncology trials or trials across all disciplines. Less than 1% of industry sponsored interventional trials in oncology focus on children < 18 years of age.
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Bansal, R., R. Khan, N. Gimpaya, M. A. Scaffidi, K. Elsolh, Y. Verma, J. Li y S. C. Grover. "A160 PREVALENCE OF OUTCOME SWITCHING AMONG PUBLISHED PHASE 3 INTERVENTIONAL TRIALS FOR INFLAMMATORY BOWEL DISEASE THERAPEUTICS". Journal of the Canadian Association of Gastroenterology 4, Supplement_1 (1 de marzo de 2021): 167–68. http://dx.doi.org/10.1093/jcag/gwab002.158.
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Abstract Background Outcome switching is a well-described form of inconsistent reporting in randomized clinical trials (RCTs), wherein pre-specified primary and/or secondary outcomes are changed between trial registration and the publication of results without explanation. This is of particular concern, as the selective publication of results that are favorable will insert bias into the trial’s results and may cast doubt on the veracity of its findings. While it has been investigated in other disciplines, the prevalence of outcome switching has yet to be described among RCTs for inflammatory bowel disease (IBD). Aims To determine the prevalence of correctly reported pre-specified primary and secondary outcomes in published phase 3 interventional RCTs for IBD. Methods We identified all phase 3 interventional trials for IBD with published results using clinicaltrials.gov. We included all results with an associated publication that detailed the results of the trial. We excluded registrations if: only an abstract of the results was available; trial results were only published as a pooled analysis; multiple trial segments were reported collectively; or a publication of the results could not be identified through clinicaltrials.gov or a custom search. Two reviewers extracted all pre-specified primary and secondary outcomes for each trial using the clinical trial registration page that was dated before the commencement of the trial. These outcomes were compared to the outcomes reported in the corresponding journal articles. Any discrepancies were noted, and additional outcomes were extracted. Results We identified a total of 88 phase 3 interventional RCTs for IBD, of which 57 were matched to independent publications of their results. All trials pre-specified a primary outcome, and 50 (87.7%) pre-specified secondary outcomes. 10 (17.5%) of trials did not report some or all primary outcomes, and 19 (33.3%) trials had a change or alteration to the primary outcome. Of the trials that pre-specified secondary outcomes, 16 (28.1%) did not report all pre-specified secondary outcomes. 49 (86.0%) trials added 6 (IQR: 2–8) unspecified secondary outcomes on average. Conclusions Many phase 3 interventional RCTs in IBD either did not report some or all primary outcomes, or altered the primary outcome. Trials routinely reported additional outcomes that were not pre-specified and failed to note that they were added post hoc. Based on these results, we recommend improvements in the reporting of pre-specified outcomes and higher fidelity in order to maintain confidence in trial results. Funding Agencies None
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Prasad, E. Maruthi y Shih-Ya Hung. "Current Therapies in Clinical Trials of Parkinson’s Disease: A 2021 Update". Pharmaceuticals 14, n.º 8 (25 de julio de 2021): 717. http://dx.doi.org/10.3390/ph14080717.
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Parkinson’s disease (PD) is a progressive neurodegenerative disorder that currently has no cure, but treatments are available to improve PD symptoms and maintain quality of life. In 2020, about 10 million people worldwide were living with PD. In 1970, the United States Food and Drug Administration approved the drug levodopa as a dopamine replacement to manage PD motor symptoms; levodopa-carbidopa combination became commercialized in 1975. After over 50 years of use, levodopa is still the gold standard for PD treatment. Unfortunately, levodopa therapy-induced dyskinesia and OFF symptoms remain unresolved. Therefore, we urgently need to analyze each current clinical trial’s status and therapeutic strategy to discover new therapeutic approaches for PD treatment. We surveyed 293 registered clinical trials on ClinicalTrials.gov from 2008 to 16 June 2021. After excluded levodopa/carbidopa derivative add-on therapies, we identified 47 trials as PD treatment drugs or therapies. Among them, 19 trials are in phase I (41%), 25 trials are in phase II (53%), and 3 trials are in phase III (6%). The three phase-III trials use embryonic dopamine cell implant, 5-HT1A receptor agonist (sarizotan), and adenosine A2A receptor antagonist (caffeine). The therapeutic strategy of each trial shows 29, 5, 1, 5, 5, and 2 trials use small molecules, monoclonal antibodies, plasma therapy, cell therapy, gene therapy, and herbal extract, respectively. Additionally, we discuss the most potent drug or therapy among these trials. By systematically updating the current trial status and analyzing the therapeutic strategies, we hope this review can provide new ideas and insights for PD therapy development.
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Cicchetti, Americo, Domenico Addesso, Filippo Elvino Leone, Antonino Amato, Luca Angerame, Angelo D'Aversa, Mario Fraticelli et al. "Valorization of clinical trials from the Italian National Health Service perspective: definition and first application of a model to estimate avoided costs". Global & Regional Health Technology Assessment 7, n.º 1 (16 de junio de 2020): 26–32. http://dx.doi.org/10.33393/grhta.2020.709.
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Introduction: From the perspective of healthcare organizations and public health care systems, the value of a clinical trial can be assessed from a clinical and economical perspective. However, to date, there is no standardized model for systematically capturing the economic value of clinical trials at organizational and system levels. The aim of this study was to develop and test a methodology for estimating the avoided costs deriving from the management of patients as part of a clinical trial.
Methods: Our methodology is based on the assumption that the economic value of a clinical trial derives from 1) the funding received by the experimental site from a trial’s sponsor, and from 2) the cost avoided by the experimental site with the treatment of patients within a study and not according to standard care by the experimental site.
Results: By applying the methodology to onco-hematological clinical trials conducted in two academic hospitals from 2011 to 2016, we demonstrate that savings between 2 million and 4 million euros were achieved over a five-year period. Thus, for every 1,000 euros invested by the pharmaceutical company into the clinical studies conducted at these hospitals, the hospitals saved on average 2,200 euros due to costs not incurred as a result of the trials.
Conclusions: The study has proposed and tested a methodology for estimating the economic value of clinical trials by taking into account avoided costs deriving from the treatment of patients enrolled in sponsored trials. The study has proposed a management tool for healthcare institutions to govern clinical trials.
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Moyé, Lemuel A. y Anita Deswal. "Trials within Trials". Controlled Clinical Trials 22, n.º 6 (diciembre de 2001): 605–19. http://dx.doi.org/10.1016/s0197-2456(01)00180-5.
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Hamm, Caroline M., Krista Naccarato, Stephen Sundquist, Suzana Kovacevic, Youshaa El-Abed y Janet Dancey. "Clinical trials navigator: Patient-centered access to clinical trials." Journal of Clinical Oncology 38, n.º 15_suppl (20 de mayo de 2020): e14024-e14024. http://dx.doi.org/10.1200/jco.2020.38.15_suppl.e14024.
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e14024 Background: Despite recommendations from premier institutions such as NCCN that all cancer patients should be entered on clinical trials, only 3 – 5 % of adult cancer patients are enrolled on clinical trials in North America. The reason for this is multi-factorial and includes poor trial design, inappropriate endpoints, inappropriate inclusion/exclusion factors, attitudes about trial participation held by patient and/or treating physician and lack of trial availability. Methods: To address issues of trial availability, in March 2019, we initiated a novel service to help Canadian patients find clinical trial options. The service compares patient demographic and health status information provided against potential opportunities sourced using clinicaltrials.gov and Canadian clinical trials websites. A report presenting outcomes of CTN review is developed for the requesting patient or physician. An interview is provided for the self-referring patient by supporting physicians. Results: To date 96 patients have used this service. Most (94%) were stage IV or refractory/ relapsed. Smaller disease sites represented 23% of our patient population (brain, sarcoma, pancreas). Our turn-around-time from request of services to delivery of report to patient or physician improved over time and is currently 24 hours during the working week. Of those eligible, 25% of patients died before referral, the median time from referral to the CTN to the patient’s death was 109 days (3 – 188 days). Conclusions: Significant interest from both physicians and patients for this service was identified. Strategies are being developed to encourage earlier referrals to clinical trials would improve number of patients entering clinical trials as 25% of our patients. [Table: see text]
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Grayling, Michael J., James MS Wason y Adrian P. Mander. "Group sequential designs for stepped-wedge cluster randomised trials". Clinical Trials 14, n.º 5 (27 de junio de 2017): 507–17. http://dx.doi.org/10.1177/1740774517716937.
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Background/Aims: The stepped-wedge cluster randomised trial design has received substantial attention in recent years. Although various extensions to the original design have been proposed, no guidance is available on the design of stepped-wedge cluster randomised trials with interim analyses. In an individually randomised trial setting, group sequential methods can provide notable efficiency gains and ethical benefits. We address this by discussing how established group sequential methodology can be adapted for stepped-wedge designs. Methods: Utilising the error spending approach to group sequential trial design, we detail the assumptions required for the determination of stepped-wedge cluster randomised trials with interim analyses. We consider early stopping for efficacy, futility, or efficacy and futility. We describe first how this can be done for any specified linear mixed model for data analysis. We then focus on one particular commonly utilised model and, using a recently completed stepped-wedge cluster randomised trial, compare the performance of several designs with interim analyses to the classical stepped-wedge design. Finally, the performance of a quantile substitution procedure for dealing with the case of unknown variance is explored. Results: We demonstrate that the incorporation of early stopping in stepped-wedge cluster randomised trial designs could reduce the expected sample size under the null and alternative hypotheses by up to 31% and 22%, respectively, with no cost to the trial’s type-I and type-II error rates. The use of restricted error maximum likelihood estimation was found to be more important than quantile substitution for controlling the type-I error rate. Conclusion: The addition of interim analyses into stepped-wedge cluster randomised trials could help guard against time-consuming trials conducted on poor performing treatments and also help expedite the implementation of efficacious treatments. In future, trialists should consider incorporating early stopping of some kind into stepped-wedge cluster randomised trials according to the needs of the particular trial.
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Nakamura, Kenichi y Taro Shibata. "Regulatory changes after the enforcement of the new Clinical Trials Act in Japan". Japanese Journal of Clinical Oncology 50, n.º 4 (27 de febrero de 2020): 399–404. http://dx.doi.org/10.1093/jjco/hyaa028.
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Abstract Objective To describe changes in Japanese clinical trial regulations after the implementation of the Clinical Trials Act in April 2018. Methods First, how to apply multiple regulations after the enforcement of Clinical Trials Act was described. Second, the changes in the number of clinical trials in the National Cancer Center Hospital under each regulation were compared before and after the implementation of Clinical Trials Act. Third, new requirements imposed by Clinical Trials Act and their influences were discussed. Results In April 2018, Clinical Trials Act was enacted and academic clinical trials were classified into the following three categories: (i) investigator-initiated registration-directed trial under the Pharmaceuticals and Medical Devices Act; (ii) clinical trial under Clinical Trials Act; and (iii) clinical trial under the Ethical Guidelines. While 90% (205/227) of interventional studies were conducted under the Ethical Guidelines before the implementation of Clinical Trials Act in 2018, 46% (94/204) were subject to Clinical Trials Act in 2019 at the National Cancer Center Hospital. Under the Clinical Trials Act, investigators receive a scientific/ethical review by a certified review board (CRB). The identification of investigators in charge is mandated and they are required to submit the conflict of interest management plan to CRB. After the CRB review, the principal investigator must submit the trial plan to the government, and the content is uploaded to the newly established clinical trial registry site, the Japan Registry of Clinical Trials. Conclusions The enforcement of the new Clinical Trials Act was supposed to improve the reliability of academic clinical trials in Japan; however, the financial and administrative burden may reduce clinical trial activity in the years to come.
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Shah, Harshal, Akash Mishra, Michael Gouzoulis, Netanel Ben-Shalom y Randy D'Amico. "QLTI-06. CHARACTERISTICS OF TERMINATED GLIOBLASTOMA-RELATED CLINICAL TRIALS: A REVIEW OF THE CLINICALTRIALS.GOV DATABASE". Neuro-Oncology 24, Supplement_7 (1 de noviembre de 2022): vii235. http://dx.doi.org/10.1093/neuonc/noac209.908.
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Abstract Glioblastoma multiforme (GBM) is a devastating primary central nervous system tumor. Although past clinical trials have incrementally improved prognosis overall survival remains poor, emphasizing a need for further successful clinical trials. Terminated clinical trials are an inefficient use of financial, medical, and administrative resources and fruitlessly expose patients to the risks of experimental treatments. Therefore, premature trial terminations should be minimized whenever possible. GBM-related clinical trials in particular are known to suffer several inefficiencies in study design resulting in premature termination, and a 2019 Think Tank held by the Society of Neuro-Oncology intended to address this issue, suggesting optimizing participant accrual and efficacy assessments. The primary aims of the present study are to quantify terminated and completed GBM-related clinical trials and analyze reasons for premature trial termination. Using univariate and multivariate analysis we demonstrate factors associated with greater odds of trial termination. ClinicalTrials.gov, a clinical trial registry maintained by the National Library of Medicine, was queried to identify all completed and terminated GBM-related clinical trials. Trial characteristics pertaining to study design were abstracted from reported information on ClinicalTrials.gov for all trials, and the reason for trial termination was determined for those trials that were terminated early. Univariate analysis by Pearson’s chi-square and a multivariate logistic regression were performed to identify independent predictors of early trial termination. We identified 886 completed and terminated GBM-related trials between 2003 and 2020. Of these, 175 (19.8%) were terminated prior to completion. The most common reason for termination was participant accrual difficulties, accounting for 63 (36.0%) terminated trials. Trial termination was associated with trials that reported a primary purpose of diagnosis relative to treatment (OR = 2.952, p = 0.001). The identified predictors of trial termination should be considered when designing GBM-related clinical trials to minimize the odds of early trial termination.
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Jones, Marcus, Marin Harbur y Ken J. Moore. "Automating Uniformity Trials to Optimize Precision of Agronomic Field Trials". Agronomy 11, n.º 6 (21 de junio de 2021): 1254. http://dx.doi.org/10.3390/agronomy11061254.
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Plot size has an important impact on variation among plots in agronomic field trials, but is rarely considered during the design process. Uniformity trials can inform a researcher about underlying variance, but are seldom used due to their laborious nature. The objective of this research was to describe variation in maize field trials among field plots of varying size and develop a tool to optimize field-trial design using uniformity-trial statistics. Six uniformity trials were conducted in 2015–2016 in conjunction with Iowa State University and WinField United. All six uniformity trials exhibited a negative asymptotic relationship between variance and plot size. Variance per unit area was reduced over 50% with plots 41.8 m2 in size and over 75% when using a plot size >111.5 m2 compared to a 13.9 m2 plot. Plot shape within a fixed plot size did not influence variance. The data illustrated fewer replicates were needed as plot size increased, since larger plots reduced variability. Use of a Shiny web application is demonstrated that allows a researcher to upload a yield map and consider uniformity-trial statistics to inform plot size and replicate decisions.
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Abbiss, Chris R., Kevin G. Thompson, Marcin Lipski, Tim Meyer y Sabrina Skorski. "Difference in Pacing Between Time- and Distance-Based Time Trials in Trained Cyclists". International Journal of Sports Physiology and Performance 11, n.º 8 (noviembre de 2016): 1018–23. http://dx.doi.org/10.1123/ijspp.2015-0613.
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The purpose of this study was to compare the pacing profiles between distance- and duration-based trials of short and long duration. Thirteen trained cyclists completed 2 time-based (6 and 30 min) and 2 distance-based (4 and 20 km) self-paced cycling time trials. Participants were instructed to complete each trial with the highest average power output. Ratings of perceived exertion (RPEs) were measured throughout the trials. Average power output was not different between the 4-km and 6-min trials (324 ± 46 vs 325 ± 45 W; P = .96) or between the 20-km and 30-min trials (271 ± 44 vs 267 ± 38 W; P = .24). Power output was greater on commencement of the distance-based trials when short and long trials were analyzed together. Furthermore, the rate of decline in power output over the 1st 40% of the trial was greater in the 20-km trial than in the 30-min trial (P = .01) but not different between the 4-km and the 6-min trials (P = .13). RPE was greater in the 4-km trial than in the 6-min trial but not different between the 20-km and 30-min trials. These findings indicate that athletes commenced distance-based time trials at relatively higher power outputs than a similar time-based trial. Such findings may result from discrete differences in our ability to judge or predict an exercise endpoint when performing time- and distance-based trials.
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Cooper, Cindy L., Amy Whitehead, Edward Pottrill, Steven A. Julious y Stephen J. Walters. "Are pilot trials useful for predicting randomisation and attrition rates in definitive studies: A review of publicly funded trials". Clinical Trials 15, n.º 2 (23 de enero de 2018): 189–96. http://dx.doi.org/10.1177/1740774517752113.
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Background/aims: External pilot trials are recommended for testing the feasibility of main or confirmatory trials. However, there is little evidence that progress in external pilot trials actually predicts randomisation and attrition rates in the main trial. To assess the use of external pilot trials in trial design, we compared randomisation and attrition rates in publicly funded randomised controlled trials with rates in their pilots. Methods: Randomised controlled trials for which there was an external pilot trial were identified from reports published between 2004 and 2013 in the Health Technology Assessment Journal. Data were extracted from published papers, protocols and reports. Bland–Altman plots and descriptive statistics were used to investigate the agreement of randomisation and attrition rates between the full and external pilot trials. Results: Of 561 reports, 41 were randomised controlled trials with pilot trials and 16 met criteria for a pilot trial with sufficient data. Mean attrition and randomisation rates were 21.1% and 50.4%, respectively, in the pilot trials and 16.8% and 65.2% in the main. There was minimal bias in the pilot trial when predicting the main trial attrition and randomisation rate. However, the variation was large: the mean difference in the attrition rate between the pilot and main trial was −4.4% with limits of agreement of −37.1% to 28.2%. Limits of agreement for randomisation rates were −47.8% to 77.5%. Conclusion: Results from external pilot trials to estimate randomisation and attrition rates should be used with caution as comparison of the difference in the rates between pilots and their associated full trial demonstrates high variability. We suggest using internal pilot trials wherever appropriate.
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Du, Jingcheng, Qing Wang, Jingqi Wang, Prerana Ramesh, Yang Xiang, Xiaoqian Jiang y Cui Tao. "COVID-19 trial graph: a linked graph for COVID-19 clinical trials". Journal of the American Medical Informatics Association 28, n.º 9 (24 de abril de 2021): 1964–69. http://dx.doi.org/10.1093/jamia/ocab078.
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Abstract Objective Clinical trials are an essential part of the effort to find safe and effective prevention and treatment for COVID-19. Given the rapid growth of COVID-19 clinical trials, there is an urgent need for a better clinical trial information retrieval tool that supports searching by specifying criteria, including both eligibility criteria and structured trial information. Materials and Methods We built a linked graph for registered COVID-19 clinical trials: the COVID-19 Trial Graph, to facilitate retrieval of clinical trials. Natural language processing tools were leveraged to extract and normalize the clinical trial information from both their eligibility criteria free texts and structured information from ClinicalTrials.gov. We linked the extracted data using the COVID-19 Trial Graph and imported it to a graph database, which supports both querying and visualization. We evaluated trial graph using case queries and graph embedding. Results The graph currently (as of October 5, 2020) contains 3392 registered COVID-19 clinical trials, with 17 480 nodes and 65 236 relationships. Manual evaluation of case queries found high precision and recall scores on retrieving relevant clinical trials searching from both eligibility criteria and trial-structured information. We observed clustering in clinical trials via graph embedding, which also showed superiority over the baseline (0.870 vs 0.820) in evaluating whether a trial can complete its recruitment successfully. Conclusions The COVID-19 Trial Graph is a novel representation of clinical trials that allows diverse search queries and provides a graph-based visualization of COVID-19 clinical trials. High-dimensional vectors mapped by graph embedding for clinical trials would be potentially beneficial for many downstream applications, such as trial end recruitment status prediction and trial similarity comparison. Our methodology also is generalizable to other clinical trials.
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Hao, Guo-Xiang, Xiao-Ling Wang, A.-Dong Shen, Evelyne Jacqz-Aigrain y Wei Zhao. "PEDIATRIC DRUG TRIALS IN CHINA". Archives of Disease in Childhood 101, n.º 1 (14 de diciembre de 2015): e1.12-e1. http://dx.doi.org/10.1136/archdischild-2015-310148.2.
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Background and objectiveThe introduction of the Pediatric Regulation by the European Union, together with the renewal of the Pediatric Rule by the US Food and Drug Administration on the requirements for pediatric labeling made it mandatory for sponsors to develop drugs for the pediatric population and promotes the pediatric drug trials in Europe and US. However, very little is known about the situation of pediatric drug trials in other countries, particularly in China, home to nearly 300 millions children. In order to support the global research in pediatric drug development and clarify the specific characteristics of pediatric drugs trials in China, we analyzed the drug trials registered in the Chinese Clincial Trial Registry database.MethodsThe pediatric drug trials registered in Chinese Clincial Trial Registry database between 2007 and 2014 were analyzed. The following information was extracted from the database by two authors: type of the trial, registered time, drug name, inclusion and exclusion criteria, population, number of patients, and sponsor.ResultsAmong all (4786) trials registered, 729 trials (15.2%) involved the pediatric population, and only 308 trials (6.4%) were pediatric drug trials. From 2007 to 2013 pediatric drug trials increased from 3 to 121. There were 66 pediatric drug trials including Chinese traditional medicine.ConclusionOur results demonstrated for the first time the situation of pediatric drug trials in China. Consistent with the initiatives of promoting pediatric drug development in Europe and US, the pediatric drug trial in China made a significant progress after 2012. The pediatric drug legislation is urgently needed in China.
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Weinberg, Jeffrey. "Clinical Trials in Progress: ROADS Trial". ONCOLOGY, n.º 3508 (agosto de 2021): 495. http://dx.doi.org/10.46883/onc.2021.3508.0495.
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Phase 3 Randomized Controlled Trial of Post-Surgical Stereotactic Radiotherapy (SRT) versus Surgically Targeted Radiation Therapy (STaRT) with GammaTile for Treatment of Newly Diagnosed Metastatic Brain Tumors (ROADS; NCT04365374).
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Dean, Rachel S. "Veterinary clinical trials are on trial". Veterinary Record 181, n.º 8 (18 de agosto de 2017): 193–94. http://dx.doi.org/10.1136/vr.j3867.
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Rokhsefat, Sana, Deanna E. Morra, Martin Offringa, Lisa M. Askie y Lauren E. Kelly. "Trial registration in pediatric surgery trials". Journal of Pediatric Surgery 53, n.º 7 (julio de 2018): 1273–79. http://dx.doi.org/10.1016/j.jpedsurg.2017.10.049.
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Curtis, John J. y Bruce Kaplan. "Transplant Immunosuppressive Drug Trials on Trial". American Journal of Transplantation 4, n.º 5 (mayo de 2004): 671–72. http://dx.doi.org/10.1111/j.1600-6143.2004.00474.x.
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Ludmir, Ethan B., Walker Mainwaring, Austin B. Miller, Timothy Lin, Amit Jethanandani, Andres F. Espinoza y Clifton David Fuller. "Age disparities among cancer clinical trial participants: The role of industry sponsorship." Journal of Clinical Oncology 37, n.º 15_suppl (20 de mayo de 2019): 11527. http://dx.doi.org/10.1200/jco.2019.37.15_suppl.11527.
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11527 Background: Randomized controlled trials (RCTs) in oncology, which often establish the standard of care for cancer patients, do not necessarily enroll trial participants representative of the broader patient population. We sought to characterize age disparities for cancer patients enrolled on RCTs, and asked whether certain trial-related factors (such as industry sponsorship) predispose trials to larger age disparities between trial enrollees and the general population. Methods: All phase 3 RCTs in clinical oncology with results available were identified through ClinicalTrials.gov. Only randomized multi-arm trials assessing a therapeutic intervention for cancer patients were included. The scope of trials was limited to breast, colorectal, lung, and prostate disease sites. Trial participant median ages were compared to national SEER data for population median ages by disease site. Results: Three-hundred and two trials met inclusion criteria. For all trials, the trial median age was an average 6.23 years younger than the population median age (95% CI: -5.55 to -6.91 years, p < 0.001). Trials with industry sponsorship had significantly younger trial patient populations compared with non-industry-sponsored trials (mean difference from population -6.57 vs -4.48 years, p = 0.02). Younger patients were enrolled on trials evaluating targeted agents (p = 0.04), superiority-design trials (p = 0.02), and trials utilizing a surrogate primary endpoint (p = 0.03). By disease site, lung cancer trials enrolled the youngest patients relative to the population median (-8.98 years), followed by breast (-7.76 years), colorectal (-6.96 years), and prostate (+2.66 years, p < 0.001). Conclusions: Industry-funded clinical trials are associated with larger age disparities among trial participants; we believe this represents a novel finding both in clinical oncology and academic medicine more broadly. Underrepresentation of older patients on RCTs has major ramifications for the generalizability of results as well as equity of access to care; future efforts to address trial participant age disparities may focus on those trials at greatest risk for disparities based on the identified risk factors, including industry sponsorship.
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Allan, C., A. Chapman, C. Parker, A. Boltong y J. Millar. "Missing Evidence: Exploring Unpublished Trials in Victoria, Australia". Journal of Global Oncology 4, Supplement 2 (1 de octubre de 2018): 96s. http://dx.doi.org/10.1200/jgo.18.28700.
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Background: Clinical trial registries were established to improve the transparency and completeness of clinical trial reporting and a number of policies have been introduced to encourage or mandate their use. While prospective trial registration has been endorsed in Australia, there is currently no legal requirement for researchers to register or communicate findings from clinical trials. There has also been, to the best of our knowledge, no analysis previously undertaken on publication rates for clinical trials performed in Australia. Aim: We aimed to determine the proportion of clinical trials that remain 'unpublished' in Victoria, Australia´s second most populous state, between 2009 and 2013. Methods: We used data reported to Cancer Council Victoria's Cancer Trials Management Scheme (CTMS) between 2009 and 2013, to identify trials that had recruited a new patient or recorded any follow-up patient activity in the specified time period. Using this data, we conducted a systematic search of ClinicalTrials.gov , the Australia and New Zealand Clinical Trials Registry (ANZCTR), PubMed and Google for records of the trial. Trial registration numbers, acronyms and scientific titles were used as primary search terms. Results were characterized by type of publication (i.e., whether it was an accredited scientific paper or other) and source location. Results: Of the trials reported to the CTMS between 2009 and 2013, 777 trials were included in this investigation; the majority (58.8%) were randomized controlled trials (RCTs). Compared with previously published findings, communication of trial results in this study was high; 70% of trials published results in an accredited scientific journal and a further 10% in alternate form, such as a conference abstract or media release. Publication rates were higher for trials with a commercial sponsor (85%) compared with trials sponsored by a cooperative group (77%). Nearly 8% of trials in this study had not been registered on an international clinical trials register. Only 39% of unregistered trials had published results. Of the registered trials, those registered on ClinicalTrials.gov were more likely to be published (86%) compared with trials listed on ANZCTR (68%). Between 2009 and 2013 , 8% of trials registered on ClinicalTrials.gov , in our data set, were terminated; 70% of these trials published results. Conclusion: Although the rate at which clinical trial findings were published in Victoria was higher in this investigation compared with equivalent overseas data, trials registered on ClinicalTrials.gov were more likely to publish results than unregistered trials or trials registered on ANZCTR. This suggests a potential need for trial registration and publication guidelines in Australia, similar to that of the United States where the requirements and procedures for submitting registration and summary result information for clinical trials on ClinicalTrials.gov have been compulsory for the last decade.
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Yao, Bin, Kathy Zhang, Yannis Jemiai y David D. Chang. "Interim decisions in oncology trials." Journal of Clinical Oncology 31, n.º 15_suppl (20 de mayo de 2013): e12530-e12530. http://dx.doi.org/10.1200/jco.2013.31.15_suppl.e12530.
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e12530 Background: Interim analyses are commonly performed in oncology clinical trials. For a phase III trial, interim monitoring rules are in general pre-specified for an independent data monitoring committee (DMC) to allow for the possibility of early stopping. Challenges and controversies exist when interim monitoring and subsequent decisions alter the course of the trial. Methods: Abstracts and primary publications of ASCO plenary session presentations for the last 10 years (2003-2012) were reviewed. Interim analyses related to the study design, conduct, endpoints, DMC decision, and reporting were reviewed. Mid-trial adaptations not limited to interim results were also summarized. Results: Fifty-two presentations were identified. Forty-one were randomized controlled trials; almost all were phase III trials. Interim monitoring and analyses were discussed in the primary manuscripts of 31 trials. The objectives of these interim analyses were safety monitoring, inference for superior efficacy, or futility. Fourteen trials crossed interim boundaries and were declared by the DMCs to have met the study objectives on efficacy endpoints such as progression-free survival and overall survival (OS). Mid-trial adaptations included dropping an arm or selecting a dose based on interim safety results. Other trial adaptations, motivated by issues such as slower accrual rate, change in treatment paradigm, or unexpected longer trial duration, included modifications of trial objectives, primary endpoints, sample sizes, and unplanned analyses. Conclusions: Interim monitoring is an important component of clinical trials but is not consistently reported. Decisions made after the primary endpoint has crossed the interim boundary have an impact on subsequent inferences of other endpoints (e.g. OS). Greater transparency and practical guidelines are needed to ensure continued trial integrity and valid inferences post interim.
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Knowles, Rachel L., Kam Pou Ha, Julia Mueller, Frances Rawle y Rosa Parker. "Challenges for funders in monitoring compliance with policies on clinical trials registration and reporting: analysis of funding and registry data in the UK". BMJ Open 10, n.º 2 (febrero de 2020): e035283. http://dx.doi.org/10.1136/bmjopen-2019-035283.
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ObjectivesTo evaluate compliance by researchers with funder requirements on clinical trial transparency, including identifying key areas for improvement; to assess the completeness, accuracy and suitability for annual compliance monitoring of the data routinely collected by a research funding body.DesignDescriptive analysis of clinical trials funded between February 2011 and January 2017 against funder policy requirements.SettingPublic medical research funding body in the UK.Data sourcesRelevant clinical trials were identified from grant application details, post-award grant monitoring systems and the International Standard Randomised Controlled Trial Number (ISRCTN) registry.Main outcome measureThe proportion of all Medical Research Council (MRC)-funded clinical trials that were (a) registered in a clinical trial registry and (b) publicly reported summary results within 2 years of completion.ResultsThere were 175 grants awarded that included a clinical trial and all trials were registered in a public trials registry. Of 62 trials completed for over 24 months, 42 (68%) had publicly reported the main findings by 24 months after trial completion; 18 of these achieved this within 12 months of completion. 11 (18%) trials took >24 months to report and 9 (15%) completed trials had not yet reported findings. Five datasets were shared with other researchers.ConclusionsCompliance with the funder policy requirements on trial registration was excellent. Reporting of the main findings was achieved for most trials within 24 months of completion; however, the number of unreported trials remains a concern and should be a focus for future funder policy initiatives. Identifying trials from grant management and grant monitoring systems was challenging therefore funders should ensure investigators reliably provide trial registries with information and regularly update entries with details of trial publications and protocols.
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Wong, Karen, Rachel Phelan, Eija Kalso, Imelda Galvin, David Goldstein, Srinivasa Raja y Ian Gilron. "Antidepressant Drugs for Prevention of Acute and Chronic Postsurgical Pain". Anesthesiology 121, n.º 3 (1 de septiembre de 2014): 591–608. http://dx.doi.org/10.1097/aln.0000000000000307.
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Abstract Background: This review evaluates trials of antidepressants for acute and chronic postsurgical pain. Methods: Trials were systematically identified using predefined inclusion and exclusion criteria. Extracted data included the following: pain at rest and with movement, adverse effects, and other outcomes. Results: Fifteen studies (985 participants) of early postoperative pain evaluated amitriptyline (three trials), bicifadine (two trials), desipramine (three trials), duloxetine (one trial), fluoxetine (one trial), fluradoline (one trial), tryptophan (four trials), and venlafaxine (one trial). Three studies (565 participants) of chronic postoperative pain prevention evaluated duloxetine (one trial), escitalopram (one trial), and venlafaxine (one trial). Heterogeneity because of differences in drug, dosing regimen, outcomes, and/or surgical procedure precluded any meta-analyses. Superiority to placebo was reported in 8 of 15 trials for early pain reduction and 1 of 3 trials for chronic pain reduction. The majority of positive trials did not report sufficient data to estimate treatment effect sizes. Many studies had inadequate size, safety evaluation/reporting, procedure specificity, and movement-evoked pain assessment. Conclusions: There is currently insufficient evidence to support the clinical use of antidepressants—beyond controlled investigations—for treatment of acute, or prevention of chronic, postoperative pain. Multiple positive trials suggest the therapeutic potential of antidepressants, which need to be replicated. Other nontrial evidence suggests potential safety concerns of perioperative antidepressant use. Future studies are needed to better define the risk–benefit ratio of antidepressants in postoperative pain management. Higher-quality trials should optimize dosing, timing and duration of antidepressant treatment, trial size, patient selection, safety evaluation and reporting, procedure specificity, and assessment of movement-evoked pain relevant to postoperative functional recovery.
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Bennette, Caroline Savage, Nathan Coleman Nussbaum, Melissa D. Curtis y Neal J. Meropol. "Using real-world cohorts to assess the generalizability and relevance of randomized clinical trials (RCTs)." Journal of Clinical Oncology 37, n.º 15_suppl (20 de mayo de 2019): 6540. http://dx.doi.org/10.1200/jco.2019.37.15_suppl.6540.
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6540 Background: RCTs are the gold standard for understanding the efficacy of new treatments, however, patients (pts) in RCTs often differ from those treated in the real-world. Further, selecting a standard of care (SOC) arm is challenging as treatment options may evolve during the course of a RCT. Our objective was to assess the generalizability and relevance of RCTs supporting recent FDA approvals of anticancer therapies. Methods: RCTs were identified that supported FDA approvals of anticancer therapies (1/1/2016 - 4/30/2018). Relevant pts were selected from the Flatiron Health longitudinal, EHR-derived database, where available. Two metrics were calculated: 1) a trial’s pt generalizability score (% of real-world pts receiving treatment consistent with the control arm therapy for the relevant indication who actually met the trial's eligibility criteria) and 2) a trial’s SOC relevance score (% of real-world pts with the relevant indication and meeting the trial's eligibility criteria who actually received treatment consistent with the control arm therapy). All analyses excluded real-world pts treated after the relevant trial’s enrollment ended. Results: 14 RCTs across 5 cancer types (metastatic breast, advanced non-small cell lung cancer, metastatic renal cell carcinoma, multiple myeloma, and advanced urothelial) were included. There was wide variation in the SOC relevance and pt generalizability scores. The median pt generalizability score was 63% (range 35% - 88%), indicating that most real-world pts would have met the RCT eligibility criteria. The median SOC relevance score was 37% (range 15% - 74%), indicating that most RCT control arms did not reflect the way trial-eligible real-world pts in the US were actually treated. Conclusions: There is great variability across recent RCTs in terms of pt generalizability and relevance of SOC arms. Real-world data can be used to inform selection of control arms, predict impact of inclusion/exclusion criteria, and also assess the generalizability of the results of completed trials. Incorporating real-world data in planning and interpretation of prospective clinical trials could improve accrual and enhance relevance of RCT outcomes.
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Ellaway-Barnard, Christopher, Hannah Killick, Guy Peryer, Jane L. Cross y Toby O. Smith. "The association between registration status and reported outcomes in physiotherapy randomised controlled trials". International Journal of Therapy and Rehabilitation 27, n.º 3 (2 de marzo de 2020): 1–15. http://dx.doi.org/10.12968/ijtr.2019.0023.
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Background/Aims Clinical trial registration has been proposed as a method of mitigating selective reporting in scientific research. It remains unknown whether trial registration is associated with reported outcomes in physiotherapy trials. This study aimed to analyse the association between registration status and outcome (the rejection or acceptance of a primary null hypothesis) for physiotherapy randomised controlled trials. Methods All randomised controlled trials reporting a physiotherapy intervention in publications listed in PubMed between 1 January 2017 and 30 June 2017 were included. Trial registration was determined based on the reporting of a registration number in the primary article or by identifying trials through trial registries. Results Of the 291 trials analysed, 176 (60.5%) were registered; 115 (39.5%) were not. There was no significant association between trial registration and outcome on multivariate analyses (Odds Ratio 1.65; 95% Confidence Interval (0.92–2.96); P=0.09). Only 22% of trials were prospectively registered. Conclusions Registration status and trial outcome are not associated in randomised controlled trials of physiotherapy interventions. The rate of physiotherapy trial registration remains low.
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Hoderlein, Xenia, Anne M. Moseley y Mark R. Elkins. "Citation of prior research has increased in introduction and discussion sections with time: A survey of clinical trials in physiotherapy". Clinical Trials 14, n.º 4 (19 de marzo de 2017): 372–80. http://dx.doi.org/10.1177/1740774517699821.
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Background/aims: Many clinical trials are reported without reference to the existing relevant high-quality research. This study aimed to investigate the extent to which authors of reports of clinical trials of physiotherapy interventions try to use high-quality clinical research to (1) help justify the need for the trial in the introduction and (2) help interpret the trial’s results in the discussion. Methods: Data were extracted from 221 clinical trials that were randomly selected from the Physiotherapy Evidence Database: 70 published in 2001 (10% sample) and 151 published in 2015 (10% sample). The Physiotherapy Evidence Database score (which rates methodological quality and completeness of reporting) for each trial was also downloaded. Results: Overall 41% of trial reports cited a systematic review or the results of a search for other evidence in the introduction section: 20% for 2001 and 50% for 2015 (relative risk = 2.3, 95% confidence interval = 1.5–3.8). For the discussion section, only 1 of 221 trials integrated the results of the trial into an existing meta-analysis, but citation of a relevant systematic review did increase from 17% in 2001 to 34% in 2015. There was no relationship between citation of existing research and the total Physiotherapy Evidence Database score. Conclusion: Published reports of clinical trials of physiotherapy interventions increasingly cite a systematic review or the results of a search for other evidence in the introduction, but integration with existing research in the discussion section is very rare. To encourage the use of existing research, stronger recommendations to refer to existing systematic reviews (where available) could be incorporated into reporting checklists and journal editorial guidelines.
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Goldenberg, Joshua Z. y Cynthia A. Wenner. "A Novel N of 1 Trial Design and Proposed Utility in Complementary and Alternative Medicine Research". Journal of Evidence-Based Complementary & Alternative Medicine 17, n.º 2 (22 de marzo de 2012): 126–30. http://dx.doi.org/10.1177/2156587212437556.
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An N of 1 trial is a multiple crossover study in a single participant. N of 1trials can combine the benefits of individualized patient practice and evidence-based medicine and are amenable to complementary and alternative medicine practice and research. This article will review the basic structure of N of 1trials, discuss how they are commonly used, and review their limitations and statistical considerations. The authors also propose a novel use of the N of 1 trial in the form of mixed-methodology add-on N of 1 trials targeted to a parent trial’s responders. This design can help uncover evidence of subgroup effects in small trials, address issues surrounding the small study effect, and explore the role of interparticipant variability and random chance in the parent trial.
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Levine, Deborah J. y Fernando Torres. "Clinical Trials Update". Advances in Pulmonary Hypertension 12, n.º 2 (1 de enero de 2013): 53–54. http://dx.doi.org/10.21693/1933-088x-12.2.53.
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The Clinical Trials Update highlights new and ongoing research trials that are evaluating therapies for PAH. In this issue, Deborah Levine, MD, examines the PATENT-1 study results, findings from CHEST-1, and outcomes of the SERAPHIN trial.
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Showell, Marian, Sam Buckman, Slavica Berber, Nada Ata Allah, Ben Patterson, Samantha Cole, Cynthia Farquhar y Vanessa Jordan. "Publication bias in trials registered in the Australian New Zealand Clinical Trials Registry: Is it a problem? A cross-sectional study". PLOS ONE 18, n.º 1 (5 de enero de 2023): e0279926. http://dx.doi.org/10.1371/journal.pone.0279926.
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Background Timely publication of clinical trials is critical to ensure the dissemination and implementation of high-quality healthcare evidence. This study investigates the publication rate and time to publication of randomized controlled trials (RCTs) registered in the Australian New Zealand Clinical Trials Registry (ANZCTR). Materials and methods We conducted a cross-sectional study of RCTs registered with the ANZCTR in 2007, 2009, and 2011. Multiple bibliographic databases were searched until October 2021 to identify trial publications. We then calculated publication rates, proportions, and the time to publish calculated from the date of first participation enrolment to publication date. Results Of 1,970 trial registrations, 541 (27%) remained unpublished 10 to 14 years later, and the proportion of trials published decreased by 7% from 2007 to 2011. The average time to publish was 4.63 years. The prospective trial registration rate for 2007, 2009 and 2011 was 48% (952 trials) and over this time there was an increase of 19% (280 prospective trials). Trials funded by non-Industry organizations were more likely to be published (74%, 1204/1625 trials) than the industry-funded trials (61%, 224/345 trials). Larger trials with at least 1000 participants were published at a rate of 88% (85/97 trials) and on average took 5.4 years to be published. Smaller trials with less than 100 participants were published at a lower rate with 67% (687/1024 trials) published and these trials took 4.31 years on average to publish. Conclusions Just over a quarter of all trials on the ANZCTR for 2007, 2009, and 2011 remain unpublished over a decade later. The average time to publication of nearly five years may reflect the larger trials which will have taken longer to recruit participants. Over half of study sample trials were retrospectively registered, but prospective registration improved over time, highlighting the role of mandating trial registration.
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Udayakumar, Suji, Sasha Thomson, Albiruni Ryan Abdul Razak y Kelvin K. Chan. "Do early phase trials predict clinical efficacy in subsequent phase III biomarker-enriched randomized trials?" Journal of Clinical Oncology 40, n.º 16_suppl (1 de junio de 2022): 3152. http://dx.doi.org/10.1200/jco.2022.40.16_suppl.3152.
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3152 Background: Efficacy endpoints of randomized controlled trials (RCT) are commonly used as the basis of regulatory drug approvals. Recently, promising results in early phase trials have resulted in approval of biomarker-targeted therapies. We examined if early phase trial results were associated with efficacy in subsequent biomarker-enriched RCTs. Methods: All cancer drug RCTs conducted between January 2006 and March 2021 were identified through Clinicaltrials.gov. Trials were eligible if a biomarker was used to select a patient population for treatment with a targeted agent. Associated early phase trials were included if they matched the RCT in treatment setting and patient population. Trials pairs were compared using objective response rate (ORR) and progression-free survival (PFS). We assessed difference in endpoints using summary measures (e.g., average, range). We examined whether early phase trials results were associated with RCT results using logistic regression. Results: The search yielded 2,157 unique phase III RCTs and 27 RCTs met eligibility criteria pairing with associated early phase trials, where 17 RCTs met their primary endpoint. The most common biomarkers were EGFR+ (n = 8), HER2+ (n = 5) and PD-L1 (n = 5). Based on average difference of trial pairs, ORR was similar between trials (1.59%, 95% CI = -2.5-5.6, p = 0.50) and median PFS was slightly higher in early phase trials (1.95 months, 95% CI = 0.91-2.99, p < 0.05). On an individual pair basis, there was large range of variability in the difference between early phase trials and RCTs for ORR (range = -23.9-20.2%) and median PFS (range = -0.8-7.4 months). The probability of the RCT meeting its primary endpoint is 50% or 95%, when the early phase trial ORR is 41.2% (95% CI = 35.2-47.1%) or 77.7% (95% CI = 71.7-83.6%), respectively. Conclusions: Through comparison of early phase trials and subsequent phase III RCT, we found that, overall, ORR has minimal bias in early phase trials, and median PFS appears to be slightly overestimated. Substantial variability in results for trial pairs suggests that, on an individual basis, results in early phase trial can be inconsistent with results in subsequent RCT. Early phase trial results may be associated with RCTs meeting their primary endpoint when ORR is very high; however, caution must be exercised when using early phase trials as representative of RCTs for decision-making as the predictive ability of early phase trials is limited.
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Unger, Joseph M., William E. Barlow, Catherine M. Tangen, Scott David Ramsey, Ian Murchie Thompson, Eric A. Klein, Michael Leo LeBlanc et al. "The scientific impact and value of large, NCI-sponsored randomized phase III cancer prevention trials." Journal of Clinical Oncology 35, n.º 15_suppl (20 de mayo de 2017): 1541. http://dx.doi.org/10.1200/jco.2017.35.15_suppl.1541.
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1541 Background: The cooperative cancer research groups of the National Cancer Institute’s National Clinical Trials Network have a history of successful conduct of large randomized phase III trials of prevention for cancer. An important question for funding agencies is whether the conduct of large prevention trials provides strong scientific return on investment. Methods: We used study data from a single NCI-sponsored cooperative group (SWOG) over a 20-year period (1990-2009, inclusive). During this time, SWOG conducted two large prevention trials (the Prostate Cancer Prevention Trial and the Selenium and Vitamin E Cancer Prevention Trial) and numerous treatment trials. Scientific impact for prevention and treatment trials was examined using citation analysis. Average annual citation counts were compared using t-tests. Scientific impact was also assessed as a function of trial costs. Results: Twenty-six treatment trials with 16,391 patients and two prevention trials with 54,415 patients were examined. The mean annual citation rate for primary articles was higher for prevention trials compared to treatment trials (173.6 vs. 41.7, p = .003). For both primary and secondary article publications, mean annual citations for articles associated with prevention trials were also higher (557.2 vs. 67.6, p < .0001). Large prevention trials were estimated to provide 70% greater scientific impact on a cost-adjusted basis. Conclusions: Based on these criteria, the scientific impact of large phase III cancer prevention trials was very high in absolute terms and after accounting for trial costs. For appropriate scientific questions, large prevention trials provide a strong scientific return on investment for federal funding agencies.
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Pinto, Rafael Zambelli, Mark R. Elkins, Anne M. Moseley, Catherine Sherrington, Robert D. Herbert, Christopher G. Maher, Paulo H. Ferreira y Manuela L. Ferreira. "Many Randomized Trials of Physical Therapy Interventions Are Not Adequately Registered: A Survey of 200 Published Trials". Physical Therapy 93, n.º 3 (1 de marzo de 2013): 299–309. http://dx.doi.org/10.2522/ptj.20120206.
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BackgroundClinical trial registration has several putative benefits: prevention of selective reporting, avoidance of duplication, encouragement of participation, and facilitation of reviews. Previous surveys suggest that most trials are registered. However, these surveys examined only trials in journals with high impact factors, which may bias the results.PurposeThis study examined the completeness of clinical trial registration and the extent of selective reporting of outcomes in a random sample of published randomized trials in physical therapy.Data SourcesThis was a retrospective cohort study in which 200 randomized trials of physical therapy interventions were randomly selected from those published in 2009 and indexed in the Physiotherapy Evidence Database (PEDro), regardless of the publishing journal.Data ExtractionEvidence of registration was sought for each trial in the study, on clinical trial registers, and by contacting authors.Data SynthesisThe proportion of randomized trials that were registered was 67/200 (34%). This proportion was significantly lower than among the trials in journals with high impact factors, where the proportion was 75% (odds ratio=7.4, 95% confidence interval=2.6–21.4). Unambiguous primary outcomes (ie, method and time points of measurement clearly defined in the trial registry entry) were registered for 32 trials, and registration was adequate (ie, prospective with unambiguous primary outcomes) for 5/200 (2.5%) trials. Selective outcome reporting occurred in 23 (47%) of the 49 trials in which selective reporting was assessable.LimitationsThe inclusion of only English-language trials prevents generalization of the results to non–English-language trials.ConclusionsRegistration of randomized trials of physical therapy interventions is rarely adequate. Consequently, the putative benefits of registration are not being fully realized.
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Moffitt, K., R. D. Marsh y C. Hudson. "The case for proactive, collaborative data-updating in a statewide cancer clinical trial matching service". Journal of Clinical Oncology 25, n.º 18_suppl (20 de junio de 2007): 6570. http://dx.doi.org/10.1200/jco.2007.25.18_suppl.6570.
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6570 Background Florida has the second highest cancer incidence of any state in the United States. To address Florida's growing cancer burden and the need for increased clinical trial participation, Florida Cancer Trials (FCT) launched a web-based and phone-based Clinical Trial Matching Service for the State of Florida on November 1, 2004 (operated by EmergingMed). After 2 years of monthly outreach to 96 trial sites, the FCT wanted to assess the outcome and ongoing need for intensive, grass-roots data verification activities in light of other publicly available cancer clinical trial databases. Methods On 10/23/06, FCT staff extracted all trials containing at least one Florida trial site from the PDQ and ClinicalTrials.gov (CT.gov) database. The same extraction was produced from the TrialCheck database on 11/10/06. Each database was compared to the list of active cancer clinical trials in the FCT/EmergingMed database on the same day. Every trial-site listed in the PDQ/CT.gov database, but missing from the FCT/EmergingMed database, was contacted by FCT staff to confirm the accuracy of each trial/site combination. Results PDQ/CT.gov contained 547 trials listed with Florida trial sites on 10/23/06 (the FCT/EmergingMed database contained 526 trials on the same day). On 11/10/06, the TrialCheck database listed 528 trials with Florida trial sites (the FCT/EmergingMed database contained 513 verified trials on the same day). The PDQ/CT.gov database was missing 25% of Florida's open trials, while the TrialCheck database was missing 36% of Florida's open trials. Moreover, 19% of PDQ/CT.gov's trial listings and 25% of TrialCheck's listings for Florida were erroneous. Conclusions With 25%–36% of Florida's trials missing from public databases, and 19%–25% of their current listings being false listings for Florida, the FCT continues to conclude that a grass-roots, monthly data verification schedule is necessary to maintain a cancer clinical trial database that is suitable for use in referring patients and physicians to Florida's cancer clinical trial sites. No significant financial relationships to disclose.
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Hsiue, Emily Han-Chung, Thomas J. Moore y G. Caleb Alexander. "Estimated costs of pivotal trials for U.S. Food and Drug Administration–approved cancer drugs, 2015–2017". Clinical Trials 17, n.º 2 (29 de febrero de 2020): 119–25. http://dx.doi.org/10.1177/1740774520907609.
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Background: Pivotal clinical trials provide critical evidence to regulators regarding a product’s suitability for marketing approval. The objectives of this study are (1) to characterize select features of trials for oncology products approved by the U.S. Food and Drug Administration between 2015 and 2017; and (2) to quantify the costs of these trials and how such costs varied based on trial characteristics. Methods: We identified novel oncology therapeutic drugs, and their respective pivotal trials, approved between 2015 and 2017 using annual summary reports from the Food and Drug Administration. Cost estimates for each pivotal trial were calculated using IQVIA’s CostPro, a clinical trial cost estimating tool based on executed contracts between pharmaceutical manufacturers and contract research organizations. Measures of drug and trial characteristics included trial design, end point, patient enrollment, and regulatory pathway. We also performed sensitivity analyses that varied assumptions regarding how efficiently each trial was conducted. Results: A total of 39 pivotal clinical trials provided the basis for Food and Drug Administration approval of 30 new oncology drugs from 2015 to 2017. Among these trials, primary end points were objective response rate in 20 (51.3%), progression-free survival in 13 (33.3%), and overall survival in 6 (15.4%). Twenty trials (51.3%) were single-arm studies. The median estimated cost of oncology pivotal trials was $31.7 million (interquartile range = $17.0–$60.4 million). Trials with objective response rate as primary end point had a median estimate of $17.7 million (interquartile range = $11.9–$27.1 million), compared with trials examining progression-free survival ($42.3 million, interquartile range = $34.6–$101.2 million) or overall survival ($79.4 million, interquartile range = $56.9–$97.7 million) (p < 0.001). Estimated costs for single-arm trials ($17.7 million, interquartile range = $11.9–$23.7 million) were less than for trials with a placebo-controlled ($56.7 million, interquartile range = $40.9–$103.9 million) or active control arm ($67.6 million, IQR = $35.5–$93.5 million) (p < 0.001). Conclusions: Relative to the estimated costs of drug development, the costs of these oncology pivotal trials were modest, with trials that produced more valuable scientific information costing more than their counterparts.
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Graham, H. Kerr. "The trials of trials". Developmental Medicine & Child Neurology 49, n.º 3 (marzo de 2007): 163. http://dx.doi.org/10.1111/j.1469-8749.2007.00163.x.
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Henegan, John Clark y Francis Garner Bell. "Variance of mean baseline health-related quality of life across phase III clinical trials in metastatic renal cell carcinoma." Journal of Clinical Oncology 40, n.º 6_suppl (20 de febrero de 2022): 329. http://dx.doi.org/10.1200/jco.2022.40.6_suppl.329.
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329 Background: Health-related quality of life (HRQoL) instruments in clinic trials provide insight into the impacts a disease and therapy have on a person’s well-being. Baseline measurements of global HRQoL reflect a trial population’s quality of life at the start of a trial. It is unknown how baseline mean HRQoL values vary across trials. Our hypothesis: The HRQoL for trials populations would decrease with later lines of therapy but would not be affected by chronological time. Methods: The year the first patient was enrolled in a trial, the number of prior lines of therapy, the HRQoL instrument(s) used, and the trial’s name was recorded along with the intervention arm’s global HRQoL summary statistics (i.e., mean value, standard deviation, and number of respondents). The intervention arm (as opposed to a combination of both arms of the study) was analyzed since the HRQoL at baseline was often balanced between the two arms but baseline HRQoL summary statistics for the entire trial population was not typically available. The baseline HRQoL means were compared across trials using common HRQoL instruments via one-way ANOVA (https://statpages.info/anova1sm.html). A p-value of less than 0.05 indicated there was a significant difference in mean HRQoL values somewhere among the various groups. The Tukey honestly significantly different post-hoc test was used to evaluate which groups were significantly different from others. Results: Mean baseline HRQoL varied significantly across trials for the FKSI-19 (p < 0.001) and the EQ-5D (p = 0.004) instruments. Conclusions: While HRQoL varied across trials for the FKSI-19 and the EQ-5D instruments, post-hoc tests indicated that only the FKDI-19 varied as hypothesized by line of therapy. The EQ-5D baseline HRQoL values variation correlated more by year of first participant. Future research should focus on the applicability of the EQ-5D and EQ-VAS HRQoL instruments in a modern population of patients with metastatic RCC.[Table: see text]