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Contemporary Clinical Trials Nov 2014Underrepresentation of racial and ethnic minorities in clinical trials remains a reality while they have disproportionately higher rates of health disparities. (Review)
Review
BACKGROUND
Underrepresentation of racial and ethnic minorities in clinical trials remains a reality while they have disproportionately higher rates of health disparities.
OBJECTIVE
The purpose of this study was to identify successful community-engaged interventions that included health care providers as a key strategy in addressing barriers to clinical trial enrollment of underrepresented patients.
DESIGN
A systematic review of the literature on interventions addressing enrollment barriers to clinical trials for racial and ethnic minorities was performed in Ovid MEDLINE, EBSCO Megafile, and EBSCO CINAHL. The systematic review identified 360 studies, and 20 were selected using the inclusion criteria. An iterative process extracted information from the eligible studies.
RESULTS
The 20 selected studies were analyzed and then grouped by first author, nature of the clinical research initiative, priority populations, key strategies, and study outcomes. Nine of the studies addressed cancer clinical trials and 11 related to chronic medical conditions, including diabetes, hypertension management, and chronic kidney disease. The key strategies employed were categorized according to their presumed impact on barriers incurred at distinct steps in study recruitment: clinical trial awareness, opportunity to participate, and acceptance of enrollment. The strategies were further categorized by whether they would address barriers associated with minority perceptions of the research process and barriers related to how studies were designed and implemented.
CONCLUSION
Multiple and flexible strategies targeting providers and participants at provider sites and within communities might be needed to enroll underrepresented populations into clinical trials.
Topics: Awareness; Clinical Trials as Topic; Ethnicity; Humans; Minority Groups; Patient Selection; Racial Groups
PubMed: 25131812
DOI: 10.1016/j.cct.2014.08.004 -
Journal of the National Cancer Institute Apr 2020The US Food and Drug Administration's accelerated approval and later withdrawal of bevacizumab in patients with metastatic breast cancer (mBC) is a seminal case for... (Meta-Analysis)
Meta-Analysis
BACKGROUND
The US Food and Drug Administration's accelerated approval and later withdrawal of bevacizumab in patients with metastatic breast cancer (mBC) is a seminal case for ongoing debates about the validity of using progression-free survival (PFS) as a surrogate measure for overall survival (OS) in cancer drug approvals. We systematically reviewed and meta-analyzed the evidence around bevacizumab's regulatory approval and withdrawal in mBC.
METHODS
We searched for all published phase II or III clinical trials testing bevacizumab as a first-line therapy for patients with mBC. Data were extracted on trial demographics, interventions, and outcomes. Descriptive analysis was stratified by whether the trial was initiated before, during, or after the accelerated approval. We used a cumulative random-effects meta-analysis to assess the evolution of evidence of the effect of bevacizumab on PFS and OS. We estimated the association between the trial-level PFS and OS effect using a nonlinear mixed-regression model.
RESULTS
Fifty-two studies were included. Trial activity dramatically dropped after the accelerated approval was withdrawn. Eight clinical trials reported hazard ratios (hazard ratios) and were meta-analyzed. The cumulative hazard ratio for PFS was 0.72 (95% CI = 0.65 to 0.79), and the cumulative hazard ratio for OS was 0.90 (95% CI = 0.80 to 1.01). The regression model showed a statistically nonsignificant association between PFS benefit and OS benefit (β = 0.43, SE = 0.81).
CONCLUSION
The US Food and Drug Administration's decision-making in this case was consistent with the evolving state of evidence. However, the fact that seven clinical trials are insufficient to conclude validity (or lack thereof) for a trial-level surrogate suggests that it would be more efficient to conduct trials using the more clinically meaningful endpoints.
Topics: Antineoplastic Agents, Immunological; Bevacizumab; Breast Neoplasms; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Decision Making; Drug Approval; Endpoint Determination; Female; Humans; Legislation, Drug; Neoplasm Metastasis; Nonlinear Dynamics; Progression-Free Survival; Randomized Controlled Trials as Topic; Regression Analysis; Survival Rate; United States; United States Food and Drug Administration
PubMed: 31651981
DOI: 10.1093/jnci/djz211 -
JAMA Mar 2010Theory and simulation suggest that randomized controlled trials (RCTs) stopped early for benefit (truncated RCTs) systematically overestimate treatment effects for the... (Comparative Study)
Comparative Study Meta-Analysis Review
CONTEXT
Theory and simulation suggest that randomized controlled trials (RCTs) stopped early for benefit (truncated RCTs) systematically overestimate treatment effects for the outcome that precipitated early stopping.
OBJECTIVE
To compare the treatment effect from truncated RCTs with that from meta-analyses of RCTs addressing the same question but not stopped early (nontruncated RCTs) and to explore factors associated with overestimates of effect.
DATA SOURCES
Search of MEDLINE, EMBASE, Current Contents, and full-text journal content databases to identify truncated RCTs up to January 2007; search of MEDLINE, Cochrane Database of Systematic Reviews, and Database of Abstracts of Reviews of Effects to identify systematic reviews from which individual RCTs were extracted up to January 2008.
STUDY SELECTION
Selected studies were RCTs reported as having stopped early for benefit and matching nontruncated RCTs from systematic reviews. Independent reviewers with medical content expertise, working blinded to trial results, judged the eligibility of the nontruncated RCTs based on their similarity to the truncated RCTs.
DATA EXTRACTION
Reviewers with methodological expertise conducted data extraction independently.
RESULTS
The analysis included 91 truncated RCTs asking 63 different questions and 424 matching nontruncated RCTs. The pooled ratio of relative risks in truncated RCTs vs matching nontruncated RCTs was 0.71 (95% confidence interval, 0.65-0.77). This difference was independent of the presence of a statistical stopping rule and the methodological quality of the studies as assessed by allocation concealment and blinding. Large differences in treatment effect size between truncated and nontruncated RCTs (ratio of relative risks <0.75) occurred with truncated RCTs having fewer than 500 events. In 39 of the 63 questions (62%), the pooled effects of the nontruncated RCTs failed to demonstrate significant benefit.
CONCLUSIONS
Truncated RCTs were associated with greater effect sizes than RCTs not stopped early. This difference was independent of the presence of statistical stopping rules and was greatest in smaller studies.
Topics: Bias; Clinical Trials Data Monitoring Committees; Data Collection; Randomized Controlled Trials as Topic; Treatment Outcome
PubMed: 20332404
DOI: 10.1001/jama.2010.310 -
Klinische Monatsblatter Fur... May 2017A systematic review was carried out of the reported therapeutic effects of complementary and alternative medicine methods as supplementary or primary treatments for... (Review)
Review
A systematic review was carried out of the reported therapeutic effects of complementary and alternative medicine methods as supplementary or primary treatments for patients suffering from glaucoma, cataract or age-related macular degeneration (AMD). For the years 1990 to 2013, the following databases were screened for reports of the application of complementary and alternative treatments: PubMed, Cochrane Library, EMBASE, CAMbase and AMED. Both randomised and prospective non-randomised patient trials were included in the review; results were evaluated in the following classes: "phytotherapy", "acupuncture/acupressure", "biofeedback" and "other alternative treatments". The studies were evaluated by measures of clinical effect, statistical significance (p value and/or confidence interval) and the underlying trial design. 30 clinical trials were included, including 13 on glaucoma, 5 on cataract and 12 on AMD patients. These trials were based on patient numbers of 6 - 332, 27 - 157 and 6 - 328 patients, respectively. Phytotherapy was applied in 14 trials, including 6 on glaucoma patients (all 6 with a controlled design, and 3 of which reporting statistically significant results); 5 trials were on cataract patients (3 with a controlled design and 2 with a significant result) and 3 on AMD patients (only 1 with a controlled design, with a significant result). Acupuncture/acupressure was investigated in 9 trials, 5 on glaucoma patients (3 with a controlled design, 1 with a significant result); no acupuncture/acupressure trial was found in cataract patients, but 4 trials in AMD patients (none with a controlled design). Biofeedback was studied in 4 trials, all on AMD patients (only one with a controlled design, without statistically significant findings). Despite its rigorous inclusion criteria, this review identified several clinical trials on complementary and alternative medicine in ophthalmological patients. Phytotherapeutic methods gave significant results in half of the reported controlled trials, whereas there were few significant benefits with acupuncture or acupressure.
Topics: Cataract; Clinical Trials as Topic; Complementary Therapies; Evidence-Based Medicine; Eye Diseases; Glaucoma; Humans; Macular Degeneration; Prevalence; Treatment Outcome
PubMed: 27459518
DOI: 10.1055/s-0042-106901 -
Epidemiologic Reviews Jan 2017Patient-reported outcomes (PROs) are increasingly used to monitor treatment-related symptoms and physical function decrements in cancer clinical trials. As more patients... (Review)
Review
Patient-reported outcomes (PROs) are increasingly used to monitor treatment-related symptoms and physical function decrements in cancer clinical trials. As more patients enter survivorship, it is important to capture PRO physical function throughout trials to help restore pretreatment levels of function. We completed a systematic review of PRO physical function measures used in cancer clinical trials and evaluated their psychometric properties on the basis of guidelines from the US Food and Drug Administration. Five databases were searched through October 2015: PubMed/MEDLINE, EMBASE, CINAHL (Cumulative Index of Nursing and Allied Health Literature), Health and Psychosocial Instruments, and Cochrane. From an initial total of 10,233 articles, we identified 108 trials that captured PRO physical function. Within these trials, approximately 67% used the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire and 25% used the Medical Outcomes Study Short Form 36. Both the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire and Medical Outcomes Study Short Form 36 instruments generically satisfy most Food and Drug Administration requirements, although neither sought direct patient input as part of item development. The newer Patient-Reported Outcomes Measurement Information System physical function short form may be a brief, viable alternative. Clinicians should carefully consider the psychometric properties of these measures when incorporating PRO instrumentation into clinical trial design to provide a more comprehensive understanding of patient function.
Topics: Activities of Daily Living; Clinical Trials as Topic; Health Status; Humans; Neoplasms; Patient Reported Outcome Measures; Quality of Life; Symptom Assessment
PubMed: 28453627
DOI: 10.1093/epirev/mxx008 -
Value in Health : the Journal of the... 2011Health technology assessments (HTAs) intend to inform real-world decisions. They often draw on data from explanatory trials and hence are not always applicable to the... (Review)
Review
OBJECTIVE
Health technology assessments (HTAs) intend to inform real-world decisions. They often draw on data from explanatory trials and hence are not always applicable to the decision problem. HTAs may therefore not meet the needs of decision makers. Our objective was to develop and apply a checklist to: 1) systematically frame HTAs in a way that they are applicable to the decision problem; and 2) assess if a decision problem can be informed by an available HTA.
METHODS
We reviewed published literature to identify factors that should be considered when framing HTAs for resource allocation decisions. The checklist was finalized in collaboration with clinicians and policy makers. We applied the checklist to the economic evaluation of trastuzumab in early breast cancer. We defined a reference case and for each study, retrieved through a systematic review, we examined if each factor was explicitly considered.
RESULTS
A checklist was developed with 11 factors (e.g., clinical practice, consequences, and patient use). In the case of trastuzumab, most factors were considered by the 11 retrieved economic evaluations. Two factors, being the inclusion of all relevant comparators and professional use, were considered by none of the studies.
CONCLUSIONS
We developed a comprehensive checklist with 11 factors to frame HTAs and to assess the applicability of HTAs to resource allocation decisions. Economic evaluations on trastuzumab considered some of these factors, but overlooked others. The proposed checklist assists in systematically considering all factors in developing the conceptual model of an HTA, to make HTAs better reflect the decision problem.
Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Breast Neoplasms; Checklist; Clinical Trials as Topic; Cost-Benefit Analysis; Decision Support Techniques; Evidence-Based Medicine; Female; Health Care Rationing; Health Services Research; Humans; Models, Economic; Outcome and Process Assessment, Health Care; Research Design; Technology Assessment, Biomedical; Trastuzumab; Treatment Outcome
PubMed: 21839418
DOI: 10.1016/j.jval.2011.01.005 -
The Cochrane Database of Systematic... Apr 2009Impaired mucociliary clearance characterises lung disease in cystic fibrosis (CF). Hypertonic saline (HS) enhances mucociliary clearance in vitro and may lessen the... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Impaired mucociliary clearance characterises lung disease in cystic fibrosis (CF). Hypertonic saline (HS) enhances mucociliary clearance in vitro and may lessen the destructive inflammatory process in the airways.
OBJECTIVES
To investigate the effects of nebulised HS in CF compared to placebo or other treatments for mucociliary clearance.
SEARCH STRATEGY
We searched the Cochrane CF and Genetic Disorders Group Trials Register, comprising references identified from comprehensive electronic database searches, handsearches of relevant journals and abstract books of conference proceedings.Most recent search: 31 July 2008.
SELECTION CRITERIA
Controlled trials assessing HS compared to placebo or other mucolytic therapy, for any duration or dose regimen in people with CF (any age or disease severity).
DATA COLLECTION AND ANALYSIS
Two authors independently reviewed all identified trials and data; and assessed trial quality.
MAIN RESULTS
Twelve trials (442 participants, aged 6 to 46 years) were included; five excluded and two await classification.In two placebo-controlled trials, HS (3% to 7%, 10 ml twice-a-day) significantly increased forced expiratory volume at one second (FEV1) at four weeks, mean difference (MD) 4.15 (95% CI 1.14 to 7.16); but not significantly after 48 weeks, MD 2.31 (95% CI -2.72 to 7.34). Two trials compared a similar dose of HS to recombinant deoxyribonuclease (RhDNAse). One three-week trial showed a non-significant difference, MD 1.60 (95% CI -7.96 to 11.16). However, in the second trial, after 12 weeks, RhDNAse led to a greater increase in FEV1 than HS (5 ml twice-daily), in participants with moderate to severe lung disease, MD 8.00 (95% CI 2.00 to 14.00).One 48-week placebo-controlled trial showed significant improvements in frequency of antibiotic use and quality of life; also that HS did not increase the concentration of Pseudomonas aeruginosa or Staphylococcus aureus.
AUTHORS' CONCLUSIONS
Treatment with 7% HS for 48 weeks showed a small improvement in FEV1 at four weeks; however, this was not sustained at 48 weeks (primary outcome measure of the only long-term trial). Unlike RhDNAse, HS can't, in the long term, be said to improve lung function. However, it did improve quality of life and reduce pulmonary exacerbations. Delivered following a bronchodilator, HS appears inexpensive and safe with no increased infection risk.We believe there is sufficient evidence to recommend using HS in CF; qualifying this we highlight that the only long-term trial failed to demonstrate a significant difference in its primary outcome (lung function) with improvements only in secondary outcomes.
Topics: Administration, Inhalation; Controlled Clinical Trials as Topic; Cystic Fibrosis; Humans; Mucociliary Clearance; Nebulizers and Vaporizers; Randomized Controlled Trials as Topic; Saline Solution, Hypertonic
PubMed: 19370568
DOI: 10.1002/14651858.CD001506.pub3 -
Acta Anaesthesiologica Scandinavica May 2012A sufficient plasma level of fibrinogen is critical for the formation of a fibrin clot and haemostasis in both the perioperative setting and in massive haemorrhage. We... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
A sufficient plasma level of fibrinogen is critical for the formation of a fibrin clot and haemostasis in both the perioperative setting and in massive haemorrhage. We assessed the efficacy and safety of fibrinogen concentrate substitution in the perioperative setting and in massive haemorrhage.
METHODS
We conducted a systematic literature search for studies conducted on humans and published in either English or German in several databases from 1985 to 2010. In addition, we screened several web sites for assessments on fibrinogen concentrate substitution and conducted a hand search using Scopus. In terms of efficacy, we included all prospective, controlled studies. Concerning safety, we included all prospective studies.
RESULTS
We identified two randomised controlled trials and two non-randomised controlled studies, which included a total of 74 patients. The studies indicate that the administration of fibrinogen concentrate is associated with improved clot firmness and reduction in the substitution of other blood products such as red blood cells, fresh frozen plasma and platelet concentrates, as well as decreased post-operative bleeding and drainage volume. In addition, fibrinogen concentrate administration has been reported to be safe with regard to thrombosis and thromboembolic complications, as well as mortality. However, the studies identified were of poor quality.
CONCLUSION
In conclusion, the results of the available controlled trials suggest that the administration of fibrinogen concentrate was effective and safe. However, because all studies identified were of inadequate quality, these findings need to be confirmed by randomised controlled trials of sufficient size and long-term follow-up.
Topics: Clinical Trials as Topic; Erythrocyte Transfusion; Fibrinogen; Follow-Up Studies; Humans; Perioperative Care; Plasma; Platelet Count; Postoperative Hemorrhage; Prospective Studies; Randomized Controlled Trials as Topic
PubMed: 22150561
DOI: 10.1111/j.1399-6576.2011.02586.x -
The Cochrane Database of Systematic... Oct 2004Laparoscopic surgery for acute appendicitis has been proposed to have advantages over conventional surgery. (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Laparoscopic surgery for acute appendicitis has been proposed to have advantages over conventional surgery.
OBJECTIVES
To compare the diagnostic and therapeutic effects of laparoscopic and conventional 'open' surgery.
SEARCH STRATEGY
We searched the Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE, SciSearch, the congress proceedings of endoscopic surgical societies.
SELECTION CRITERIA
We included randomized clinical trials comparing laparoscopic (LA) versus open appendectomy (OA) in adults or children. Studies comparing immediate OA versus diagnostic laparoscopy (followed by LA or OA if necessary) were separately identified.
DATA COLLECTION AND ANALYSIS
Two reviewers independently assessed trial quality. Missing information or data was requested from the authors. We used odds ratios (OR), relative risks (RR), and 95% confidence intervals (CI) for analysis.
MAIN RESULTS
We included 54 studies, of which 45 compared LA (with or without diagnostic laparoscopy) vs. OA in adults. Wound infections were less likely after LA than after OA (OR 0.45; CI 0.35 to 0.58), but the incidence of intraabdominal abscesses was increased (OR 2.48; CI 1.45 to 4.21). The duration of surgery was 12 minutes (CI 7 to 16) longer for LA. Pain on day 1 after surgery was reduced after LA by 9 mm (CI 5 to 13 mm) on a 100 mm visual analogue scale. Hospital stay was shortened by 1.1 day (CI 0.6 to 1.5). Return to normal activity, work, and sport occurred earlier after LA than after OA. While the operation costs of LA were significantly higher, the costs outside hospital were reduced. Five studies on children were included, but the result do not seem to be much different when compared to adults. Diagnostic laparoscopy reduced the risk of a negative appendectomy, but this effect was stronger in fertile women (RR 0.20; CI 0.11 to 0.34) as compared to unselected adults (RR 0.37; CI 0.13 to 1.01).
REVIEWERS' CONCLUSIONS
In those clinical settings where surgical expertise and equipment are available and affordable, diagnostic laparoscopy and LA (either in combination or separately) seem to have various advantages over OA. Some of the clinical effects of LA, however, are small and of limited clinical relevance. In spite of the mediocre quality of the available research data, we would generally recommend to use laparoscopy and LA in patients with suspected appendicitis unless laparoscopy itself is contraindicated or not feasible. Especially young female, obese, and employed patients seem to benefit from LA.
Topics: Acute Disease; Appendicitis; Humans; Laparoscopy; Randomized Controlled Trials as Topic
PubMed: 15495014
DOI: 10.1002/14651858.CD001546.pub2 -
Stereotactic and Functional Neurosurgery 2022Chronic pain is a debilitating condition that imposes a tremendous burden on health-care systems around the world. While frontline treatments for chronic pain involve... (Review)
Review
BACKGROUND
Chronic pain is a debilitating condition that imposes a tremendous burden on health-care systems around the world. While frontline treatments for chronic pain involve pharmacological and psychological approaches, neuromodulation can be considered for treatment-resistant cases. Neuromodulatory approaches for pain are diverse in both modality and target and their mechanism of action is incompletely understood.
OBJECTIVES
The objectives of this study were to (i) understand the current landscape of pain neuromodulation research through a comprehensive survey of past and current registered clinical trials (ii) investigate the network underpinnings of these neuromodulatory treatments by performing a connectomic mapping analysis of cortical and subcortical brain targets that have been stimulated for pain relief.
METHODS
A search for clinical trials involving pain neuromodulation was conducted using 2 major trial databases (ClinicalTrials.gov and the International Clinical Trials Registry Platform). Trials were categorized by variables and analyzed to gain an overview of the contemporary research landscape. Additionally, a connectomic mapping analysis was performed to investigate the network connectivity patterns of analgesic brain stimulation targets using a normative connectome based on a functional magnetic resonance imaging dataset.
RESULTS
In total, 487 relevant clinical trials were identified. Noninvasive cortical stimulation and spinal cord stimulation trials represented 49.3 and 43.7% of this count, respectively, while deep brain stimulation trials accounted for <3%. The mapping analysis revealed that superficial target connectomics overlapped with deep target connectomics, suggesting a common pain network across the targets.
CONCLUSIONS
Research for pain neuromodulation is a rapidly growing field. Our connectomic network analysis reinforced existing knowledge of the pain matrix, identifying both well-described hubs and more obscure structures. Further studies are needed to decode the circuits underlying pain relief and determine the most effective targets for neuromodulatory treatment.
Topics: Brain; Chronic Pain; Clinical Trials as Topic; Connectome; Humans; Magnetic Resonance Imaging; Spinal Cord Stimulation
PubMed: 34380132
DOI: 10.1159/000517873