Enrollment Of Randomized Controlled Trials Research Articles

Accelerating patient recruitment using social media: Early adopter experience from a good clinical practice-monitored randomized controlled phase I/IIa clinical trial on actinic keratosis

BackgroundPatient recruitment is a major cause of delays in randomized controlled trials (RCT). Online recruitment is evolving into an alternative to conventional in-clinic recruitment for RCT. The objective of this study was to test the effectiveness of online patient recruitment for an RCT on actinic keratosis (AK). MethodsIn this proof-of-concept study, adults with AK were recruited for a Phase I/IIa RCT (NCT05164393) via social media using targeted advertising Interested users were directed to a landing page to learn about the study, respond to questionnaires, and upload self-obtained smartphone pictures of potential AK. Facebook Analytics was used to track the number of advertisement views, individual users exposed to the advertisement, and advertisement clicks. Following eligibility-review by remote dermatologists, candidates were contacted for an in-clinic visit. A review of pertinent RCTs on AK (2012–2022) was conducted to compare recruitment metrics. ResultsThe online campaign served 886,670 views, reached 309,000 users, and generated 27,814 clicks. A total of 556 users underwent eligibility review, leading to 140 pre-evaluated potential study subjects. The RCT's enrollment target of 60 patients (68.8 ± 7.1 years, 43.3 % female) was reached in 53 days after screening 90 participants in-clinic, corresponding to a screen failure rate of 33.3 %. The total cost of this online recruitment campaign was 14,285 USD i.e. 238 USD per randomized patient. Compared to the existing literature (44 RCTs), our online approach resulted in 9 times more time-efficient recruitment per site. ConclusionUsing targeted advertisements, 60 patients with AK were recruited for a single-center Phase I/IIa RCT in 53 days. Social media appears to be an efficient platform for online recruitment of patients with low-grade AK for RCT.

Trends in U.S and global patient enrollment from 2014 to 2022 in lung cancer clinical trials supporting marketing applications: An FDA analysis.

1576 Background: Oncology drug development is an increasingly global endeavor, however it is unclear how enrollment in registrational clinical trials for lung cancer have been impacted. Clinical trial data must be reflective of the intended population in order to be considered applicable to U.S patients and medical practice, and for FDA review. Methods: Registrational clinical trials supporting lung cancer indications submitted to FDA from 2014 to 2022 were included. Patient enrollment per country was extracted for each trial, and countries were grouped into 9 global regions. The proportion of patients enrolled in the U.S and global regions were calculated for each trial. For the purpose of this analysis, MRCTs were defined as trials that enrolled at least 5% of patients from each of ≥ 3 global regions with no region accounting for ≥ 70% of patient enrollment. Trial-level patient enrollment was aggregated into 3 triennia: 2014-2016, 2017-2019, and 2020-2022. Results: A total of 66 pivotal trials supporting 59 applications submitted to FDA were evaluated during the study period. Of these, 91% ( n=60) were for non-small cell lung cancer while 9% ( n=6) were for small cell lung cancer; 59% ( n=39) were randomized controlled trials (RCTs) while 41% ( n=27) were single-arm trials; 53% ( n=35) were for biologics while 47% ( n=31) were for non-biologics; and 86% ( n=30) of the biologics-based regimens were anti-programmed death (ligand)-1 antibody-containing regimens. The proportion of trials with no U.S patient enrollment increased from 4.8% in 2014-2016 to 19.0% in 2020-2022 while those with ≥ 10% U.S patient enrollment declined from 71.4% in 2014-2016 to 52.3% in 2020-2022. There was a decline in the proportion of trials conducted as MRCTs since 2014 from 85.7% in 2014-2016 to 66.7% in 2020-2022. Conclusions: This exploratory analysis suggests that there may be declining U.S patient enrollment in lung cancer pivotal trials, and the proportion of these trials conducted as MRCTs may also be declining. These patterns of decline appear to be driven by the countries selected for patient enrollment in RCTs rather than in single-arm trials. Pivotal trials that do not enroll U.S patients and are not conducted as true MRCTs may have limited applicability to U.S patients.[Table: see text]

Is Inhaler Technique Adequately Assessed and Reported in Clinical Trials of Asthma and Chronic Obstructive Pulmonary Disease Therapy? A Systematic Review and Suggested Best Practice Checklist

Inhaled medications are central to treating asthma and chronic obstructive pulmonary disease (COPD), yet critical inhaler technique errors are made by up to 90% of patients. In the clinical research setting, recruitment of subjects with poor inhaler technique may give a false impression of both the benefits and the necessity of add-on treatments such as biologic therapies. To assess the frequency with which inhaler technique is assessed and reliably optimized before and during patient enrollment into randomized controlled trials (RCTs) addressing the efficacy of topical therapy, and the escalation of therapy for asthma and COPD. Systematic searches were conducted of PubMed and Embase for RCTs published in the past 10 years involving patients with a diagnosis of asthma or COPD undergoing escalation of baseline inhaled therapy (stepping up, changing, adding, switching, increasing, etc) or the introduction of biologic agents. Searches highlighted 1,014 studies, 118 of which were eligible after the removal of duplicates as well as screening and full text review. Of these, only 14 (11.9%) included accessible information in the methods section or referred to such information in online supplements or protocols concerning assessment of participants' inhaler technique. We therefore developed the proposed Best Practice Inhaler Technique Assessment and Reporting Checklist. Our study identifies a concerning lack of checking and correcting inhaler technique, or at least reporting that this was undertaken, before enrollment in asthma and COPD RCTs, which may affect the conclusions drawn. Mandating the use of a standardized checklist in RCT protocols and ensuring all published RCTs report checking and correcting inhaler technique before enrollment are important next steps.

Participation in a Heart Failure Clinical Trial: Perspectives and Opportunities From the VICTORIA Trial and VICTORIA Simultaneous Registry.

Randomized controlled trials (RCTs) often target enrollment of patients with demographics and outcomes less representative of the broader population of interest. To provide context for the VICTORIA trial (Vericiguat Global Study in Subjects With Heart Failure With Reduced Ejection Fraction), we designed a registry of hospitalized patients with worsening heart failure to characterize their clinical profile, outcomes, and reasons for their nonparticipation in a RCT. Fifty-one RCT sites in Canada and the United States participated. Eligible patients included those with chronic heart failure, hospitalized for heart failure, and an ejection fraction <45%; no other exclusions were applied. Sites identified patients between 2017 and 2019 during the RCT enrollment period. RCT eligibility criteria were applied, and non-mutually exclusive reasons for nonenrollment were captured. Mortality at 1 year was estimated via the Meta-Analysis Global Group in Chronic Heart Failure risk score or as observed in the RCT. Overall, 2056 patients were enrolled in the registry; 61% (n=1256) were ineligible for the RCT, 37% (n=766) were eligible but not enrolled, and 2% (n=34) were also enrolled in the RCT. Registry participants had a median age of 70, 33% were women, and 63% were White. The median risk score predicted a 20.9% 1-year mortality, higher than in the RCT (predicted 14.7% and observed 11.5%). Major reasons for ineligibility in the RCT included the use of nitrates (23%), systolic blood pressure <100 mm Hg (12%), and substance use (11%) with other exclusion criteria <10%. For eligible patients, reasons for nonparticipation in the RCT included lack of interest in participating (28%), poor compliance (25%), inability to complete follow-up (23%), too sick (20%), unable to provide consent (17%), and distance from site (15%). Patients with worsening heart failure in routine clinical practice exhibit high-risk features, and approximately one-third were eligible for an RCT but excluded. The majority of these nonparticipating patients had modifiable reasons. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02861534.

Xuefu Zhuyu decoction for nonalcoholic fatty liver disease: A protocol for systematic review and meta-analysis.

Background:Nonalcoholic fatty liver disease (NAFLD) includes nonalcoholic fatty liver (NAFL) and nonalcoholic steatohepatitis (NASH), which ranks only second to viral hepatitis and poses an increasingly serious challenge to global public health and economy. NAFLD has attracted more and more attention, but there is no drugs with exact curative effects are available. The commonly used drugs for the treatment of NAFLD in clinical practice are statins, such drugs, inevitably increase the burden on the live. Compared to statins, traditional Chinese medicines are believed to be “all natural” with fewer side effects, are associated with strong patient compliance. Accordingly, a great deal of clinical studies have shown that Xuefu Zhuyu decoction (XFZYD) can significantly improve the clinical symptoms and enhance the therapeutic effect. Meanwhile, a system review and meta-analysis are conducted by us to further clarify the effectiveness and safety of XFZYD for NAFLD.Methods:We will apply to database mainly range from the English literature searches Cochrane Library, PubMed, excerpt medica database, and Web of Science to the Chinese literature China national knowledge infrastructure, Chinese biomedical literature database, VIP, and Wanfang database, randomized controlled trials (RCTs) are enrolled to evaluate the effectiveness and safety of XFZYD in the treatment of NAFLD, the enrollment of RCTs is from the establishment of the database to February 01, 2021. Simultaneously we will retrieval clinical registration tests and grey literatures. The 2 researchers worked independently on literature selection, data extraction, and quality assessment. The dichotomous data is expressed in terms of relative risk, the continuous is represented by mean difference or standard mean difference, whether there is heterogeneity is the factor that determines the synthesis of data in fixed effect model or random effect model. Alanine aminotransferase (ALT) or Aspartic acid aminotransferase (AST) coupled with Glutamyltransferase (GGT) is considered as one of the main indicators of the NAFLD, while the pathology, imaging and diagnosis of metabolic syndrome are also auxiliary results. The last, meta-analysis was conducted by RevMan software version 5.3.Results:This study will provide evidence for treatment of NAFLD with XFZYD in terms of effectiveness and safety.Conclusion:This systematic review aims to confirm the efficacy and safety of XFZYD in the treatment of NAFLD.OSF registration number:DOI 10.17605/OSF.IO/7CWRK.

Xiaochaihu decoction for nonalcoholic fatty liver disease: A protocol for a systematic review and meta-analysis.

Background:Nonalcoholic fatty liver disease (NAFLD) is a clinicopathologic syndrome characterized by excessive deposition of fat in hepatocytes except for alcohol and other specific hepatic factors. Xiaochaihu decoction (XD) has been widely used to treat NAFLD in China. However, there is no systematic review found. In order to evaluate the efficacy and safety of XD in the treatment of NAFLS, we need to conduct a meta-analysis and systematic evaluation.Methods:There are enrolled randomized controlled trials (RCTs) evaluating the effectiveness and safety of XD in the treatment of NAFLD. Data come mainly from 4 Chinese databases (CNKI, CBM, Wanfang, and VIP Database) and 4 English databases (Pubmed, Embase, Cochrane Library, and Web of science). The enrollment of RCTs is from the starting date of database establishment till September 30, 2021. The work such as selection of literature, data collection, quality evaluation of included literature, and assessment of publication bias will be conducted by 2 independent researchers. Meta-analysis will be performed by RevMan 5.0 software.Results:This study will provide high-quality evidence for the effectiveness and safety of XD in the treatment of NAFLD.Conclusion:The results of the study will help us determine whether XD can effectively treat NAFLD.Ethics and dissemination:This study does not require ethical approval. We will disseminate our findings by publishing results in a peer-reviewed journal.OSF registration number:DOI 10.17605/OSF.IO/A5XEM

Huangyusang decoction for Type 2 diabetes: A protocol for systematic review and meta analysis.

Background:Diabetes is a chronic metabolic disease characterized by elevated blood glucose levels due to insulin resistance and β-cell dysfunction. In China, Huangyusang decoction (HYS) has been widely used to treat Type 2 diabetes. However, there is no systematic review found. In order to evaluate the efficacy and safety of HYS in the treatment of Type 2 diabetes, we need to conduct a meta-analysis and systematic evaluation.Methods:We will enroll the randomized controlled trials (RCTs) evaluating the effectiveness and safety of HYS in the treatment of Type 2 diabetes. Data come mainly from 4 Chinese databases (CNKI, Wanfang, CBM, and VIP Database) and 4 English databases (PubMed, Embase, Cochrane Library, and Web of science). The enrollment of RCTs is from the starting date of database establishment till January 30, 2021. Fasting blood glucose is considered as the main indicator of the dyslipidemia, while the body mass index, glycated hemoglobin, fasting insulin, triglycerides, and cholesterol are regarded as the secondary indicators. There are safety indicators including liver enzyme and kidney function. The work such as selection of literature, data collection, quality evaluation of included literature, and assessment of publication bias will be conducted by 2 independent researchers. Meta-analysis will be performed by RevMan 5.0 software.Results:This study will provide high-quality evidence for the effectiveness and safety of HYS in the treatment of type 2 diabetes.Conclusion:The results of the study will help us determine whether HYS can effectively treat type 2 diabetes.Ethics and dissemination:This study does not require ethical approval. We will disseminate our findings by publishing results in a peer-reviewed journal.OSF registration number:DOI 10.17605/OSF.IO/AXBRV.

Abstract 14171: Association of Women Authors With Women Enrollment in the Clinical Trials of Atrial Fibrillation

Introduction: Women with atrial fibrillation (AF) are more symptomatic, have poorer quality of life and carry a higher risk of stroke than men. Despite this woman have been underrepresented in randomized controlled trials (RCTs) of AF. Hypothesis: Women representation in the author panel might influence enrollment of women in RCTs of AF. Methods: We performed a systematic literature search from 1989 through December 2019 to identify RCTs of AF with a follow-up duration of ≥3 months. The multivariate linear regression model was constructed with the proportion of women enrollment in the RCTs as the dependent variable and the proportion of women in the author panel as a key independent variable. The model was adjusted for publication year, region, sponsor, and type of RCTs (invasive or medical treatment). Results: A total of 134 RCTs (n=149,162) were included. The median number of participants per trial was 205 (IQR, 74-676). The median number of women per trial was 71 (IQR, 27-218). The overall representation of women was 35.1% (95% CI, 32.6-37.6%), which did not improve between 1989 to 2019 (from 27.3% to 29.6%; P=0.10). RCTs of AF were authored by 1,568 authors. The median number of authors per trial publication was 10 (IQR, 7-10). The median number of women authors was 1 (IQR, 0-3). First (93%) and senior (92%) authors were predominantly men. Only 13.3% (n=18) of publications had women as first or senior authors, which did not improve over time (P=0.07). Multivariate model showed that each 1% increase in women in the author panel was associated with 19% increase in women enrollment in RCTs (P=0.02) (Table). Conclusions: Women remained underrepresented both as participants and as authors of RCTs of AF. Higher representation of women in the author panel was associated with higher enrollment of women in RCTs of AF. Efforts to recruitment and retain women AF investigators may be a critical mechanism to help lessen the disparities in both areas.

Erchen decoction for hyperlipemia: Protocol for a systematic review and meta-analysis.

Background:Hyperlipidemia is a metabolic disease characterized by elevated levels of blood lipids and lipoproteins and a major pathogenic factor of atherosclerosis. In China, Erchen decoction (ECD) has been widely used to treat hyperlipidemia. However, there is no systematic review found. In order to evaluate the efficacy and safety of ECD in the treatment of hyperlipidemia, we need to conduct a meta-analysis and systematic evaluation.Methods:We will enroll the randomized controlled trials (RCTs) evaluating the effectiveness and safety of ECD in the treatment of hyperlipidemia. Data come mainly from 4 Chinese databases (China national knowledge infrastructure, Wanfang, Chinese biomedical literature database, and VIP Database) and 4 English databases (Pubmed, Embase excerpt medica database, Cochrane Library, and Web of science). The enrollment of RCTs is from the starting date of database establishment till September 30, 2020. Low density lipoprotein cholesterol is considered as the main indicator of the dyslipidemia, while the serum concentrations of total cholesterol, triglyceride, high density lipoprotein cholesterol, apolipoprotein A, and apolipoprotein B are regarded as the secondary indicators. There are Safety indicators including liver enzyme, kidney function and fasting blood glucose. The work such as selection of literature, data collection, quality evaluation of included literature, and assessment of publication bias will be conducted by 2 independent researchers. Meta-analysis will be performed by RevMan 5.0 software.Results:This study will provide high-quality evidence for the effectiveness and safety of ECD in the treatment of hyperlipidemia.Conclusion:The results of the study will help us determine whether ECD can effectively treat hyperlipidemia.Ethics and dissemination:This study does not require ethical approval. We will disseminate our findings by publishing results in a peer-reviewed journal.OSF registration number:DOI 10.17605/OSF.IO/GZ69F

Enrollment Obstacles in a Randomized Controlled Trial: A Performance Survey of Enrollment in BEST-CLI Sites

Although randomized controlled trials (RCTs) provide the most reliable form of scientific evidence, they are challenging to complete because of a variety of enrollment obstacles. We evaluated obstacles in a large RCT by comparing survey results at high-performing sites (HPS) and low-performing sites (LPS). The Best Endovascular versus Best Surgical Therapy in Patients with Critical Limb Ischemia (BEST-CLI) trial is a prospective, pragmatic, multicenter, and multispecialty RCT that will compare clinical outcomes, quality of life, and cost in patients with CLI randomized to surgical bypass or endovascular therapy. BEST-CLI aims to enroll 2100 patients at 160 sites in North America, Europe, and New Zealand. We surveyed the 30 HPS and 30 LPS to assess perceptions of enrollment obstacles. HPS were defined by enrollment of 0.5 subjects or more per month or more than 8 total subjects enrolled. LPS were defined by enrollment of 0.1 subjects per month or only 1 subject total. Responses were compared by site performance status. There were 22 of 30 (73%) HPS and 14 of 30 (47%) LPS that answered the survey (P=0.06), including 17 investigators and 31 coordinators. The mean total enrollment and rate of enrollment at HPS and LPS were 12.5 subjects at 1.5 subjects/month and 1.0 subject at 0.1 subjects/month, respectively. The most common barrier to enrollment at HPS was difficulty convincing patients and their families to participate (36%), whereas at LPS both difficulty convincing patients and difficulty motivating investigators to enroll (29% each) were most frequently cited. At HPS, the most common obstacle to consenting patients for the trial was patient/family having strong preference toward revascularization strategy (32%) and at LPS it was patient/family not wanting to have treatment chosen at random (36%). At 55% of HPS and 43% of LPS, the trial team was reported as extremely collaborative (P=0.73), whereas 68% of HPS and 64% of LPS reported having identified a trial champion on their team (P=1). The most restrictive perceived enrollment criterion at HPS was prior index limb stenting with significant restenosis (32%), whereas at LPS it was excessive risk for surgical bypass (43%). Materials to aid enrollment were used equally at HPS and LPS: patient brochures at 59% HPS and 64% LPS (P=1); investigator talking points at 45% of HPS and 36% of LPS (P=0.73). Patient perceptions and investigator biases are significant challenges to enrollment in large RCTs. In the BEST-CLI trial, difficulty convincing patients and families to allow treatment randomization and difficulty in motivating investigators were major enrollment obstacles.

Wendan decoction for dyslipidemia: Protocol for a systematic review and meta-analysis.

Dyslipidemia is one of the most popular metabolic diseases and an important risk factor for arteriosclerotic cardiovascular diseases. In China, Wendan decoction (WDD) has been widely used to treat hyperlipidemia. However, no systematic review has been found. In order to evaluate the efficacy and safety of WDD in the treatment of dyslipidemia, a meta-analysis and systematic evaluation are conducted. The randomized controlled trials (RCTs) evaluating the effectiveness and safety of WDD in the treatment of dyslipidemia will be enrolled. Data are mainly from 4 English databases (Pubmed, Embase, Cochrane Library, and Web of science) and 4 Chinese databases (Wanfang, CBM, CNKI, and VIP Database). The enrollment of RCTs is from the starting date of database establishment till December 15, 2018. Low density lipoprotein cholesterol is considered as the main outcome, while the serum concentrations of total cholesterol, triglyceride, high density lipoprotein cholesterol, apolipoprotein A, and apolipoprotein B are regarded as the secondary outcome. Safety indicators include liver enzyme, fasting blood glucose, and kidney function. The work such as selection of literature, data collection, quality evaluation of included literature, and assessment of publication bias will be conducted by 2 independent researchers. Meta-analysis will be performed by RevMan 5.0 software. This study will provide high-quality evidence for the treatment of dyslipidemia with WDD in terms of effectiveness and safety. The results of the study will help us determine whether WDD can effectively treat hyperlipidemia. PROSPERO CRD 42018114957.

Pediatric Nephrologists’ Beliefs Regarding Randomized Controlled Trials

BackgroundPediatrics and pediatric nephrology lag behind adult medicine in producing randomized controlled trials (RCTs). Physician attitudes have been shown to play a significant role in RCT enrollment.MethodsWe surveyed members of...

New treatments compared to established treatments in randomized trials

The proportion of proposed new treatments that are 'successful' is of ethical, scientific, and public importance. We investigated how often new, experimental treatments evaluated in randomized controlled trials (RCTs) are superior to established treatments. Our main question was: "On average how often are new treatments more effective, equally effective or less effective than established treatments?" Additionally, we wanted to explain the observed results, i.e. whether the observed distribution of outcomes is consistent with the 'uncertainty requirement' for enrollment in RCTs. We also investigated the effect of choice of comparator (active versus no treatment/placebo) on the observed results. We searched the Cochrane Methodology Register (CMR) 2010, Issue 1 in The Cochrane Library (searched 31 March 2010); MEDLINE Ovid 1950 to March Week 2 2010 (searched 24 March 2010); and EMBASE Ovid 1980 to 2010 Week 11 (searched 24 March 2010). Cohorts of studies were eligible for the analysis if they met all of the following criteria: (i) consecutive series of RCTs, (ii) registered at or before study onset, and (iii) compared new against established treatments in humans. RCTs from four cohorts of RCTs met all inclusion criteria and provided data from 743 RCTs involving 297,744 patients. All four cohorts consisted of publicly funded trials. Two cohorts involved evaluations of new treatments in cancer, one in neurological disorders, and one for mixed types of diseases. We employed kernel density estimation, meta-analysis and meta-regression to assess the probability of new treatments being superior to established treatments in their effect on primary outcomes and overall survival. The distribution of effects seen was generally symmetrical in the size of difference between new versus established treatments. Meta-analytic pooling indicated that, on average, new treatments were slightly more favorable both in terms of their effect on reducing the primary outcomes (hazard ratio (HR)/odds ratio (OR) 0.91, 99% confidence interval (CI) 0.88 to 0.95) and improving overall survival (HR 0.95, 99% CI 0.92 to 0.98). No heterogeneity was observed in the analysis based on primary outcomes or overall survival (I(2) = 0%). Kernel density analysis was consistent with the meta-analysis, but showed a fairly symmetrical distribution of new versus established treatments indicating unpredictability in the results. This was consistent with the interpretation that new treatments are only slightly superior to established treatments when tested in RCTs. Additionally, meta-regression demonstrated that results have remained stable over time and that the success rate of new treatments has not changed over the last half century of clinical trials. The results were not significantly affected by the choice of comparator (active versus placebo/no therapy). Society can expect that slightly more than half of new experimental treatments will prove to be better than established treatments when tested in RCTs, but few will be substantially better. This is an important finding for patients (as they contemplate participation in RCTs), researchers (as they plan design of the new trials), and funders (as they assess the 'return on investment'). Although we provide the current best evidence on the question of expected 'success rate' of new versus established treatments consistent with a priori theoretical predictions reflective of 'uncertainty or equipoise hypothesis', it should be noted that our sample represents less than 1% of all available randomized trials; therefore, one should exercise the appropriate caution in interpretation of our findings. In addition, our conclusion applies to publicly funded trials only, as we did not include studies funded by commercial sponsors in our analysis.

An assessment of the collective efforts of clinical trials to provide evidence-based practice guidelines in cancer care.

6019 Background: It is unclear how many of the recommendations in the National Comprehensive Cancer Network (NCCN) guidelines are based Category 1 (C1: “high level evidence”), or whether current cancer research efforts are focusing on the knowledge gap between guidelines and supporting evidence. We defined the knowledge gap as the percent of NCCN recommendations based on lower levels of evidence, and assessed the relation between the knowledge gap and cancer research efforts in terms of clinical trial enrollment. Methods: We examined the active, phase 3 randomized controlled trials (RCTs) listed on clinicaltrials.gov for the 17 most prevalent solid tumors. We used the NCCN guidelines to tally the percentage of C1 recommendations. We used the Pearson coefficient and linear regression to examine whether enrollment in active phase 3 RCTs is associated with 1) the knowledge gap and 2) measures of burden to society including prevalence, incidence, person years life lost (PYLL) and disability adjusted life years (DALY). Results: We identified 834 treatment recommendations for the 17 included cancer types. Overall, 15% of the NCCN recommendations were rated as C1, varying from 40% for hepatobiliary to 0% for endometrial cancer. There was no association between RCT enrollment and the proportion of C1 recommendations in univariate or multivariate analyses. RCT enrollment positively correlated with measures of burden to society including prevalence (p-value &lt; 0.001), incidence (p-value 0.001), and DALY (p-value 0.038). Breast and prostate cancers have a large amount of RCT enrollment per PYLL and a relatively small knowledge gap. Melanoma, ovarian, and endometrial cancers have a moderate amount of RCT enrollment per PYLL and a relatively large knowledge gap. Lung, esophagus, bladder and CNS cancers have a low amount of RCT enrollment per PYLL and a moderate to large knowledge gap. Conclusions: RCT enrollment is not correlated to the knowledge gap. Current planned enrollment in RCTs is partially predicted by burden to society, with the strongest correlation to incidence and prevalence. Most recommendations in the NCCN guidelines are not based on C1 evidence.

Patients Enrolled in Randomized Controlled Trials Do Not Represent the Inflammatory Bowel Disease Patient Population

Multiple randomized controlled trials (RCTs) have been conducted to determine therapeutic efficacy of the biological agents for the inflammatory bowel diseases (IBD). However, the external validity of findings from RCTs might be compromised by their stringent selection criteria. We investigated the proportion of patients encountered during routine clinical practice who would qualify for enrollment into a pivotal RCT of biological agents for IBD. We performed a retrospective cohort study of adult patients with moderate-severe IBD who presented to a tertiary referral center. Inclusion and exclusion criteria were extracted from published RCTs of biologics approved by the Food and Drug Administration and applied to the study population. Only 31.1% of 206 patients with IBD (34% with Crohn's disease [CD], 26% with ulcerative colitis) would have been eligible to participate in any of the selected RCTs. Patients would have been excluded because they had stricturing or penetrating CD, took high doses of steroids, had comorbidities or prior exposure to biologics, or received topical therapies. Of the trial-ineligible patients with ulcerative colitis, 23.3% had colectomies, and 31.7% received infliximab, with a 63.2% response rate. Approximately half (49.4%) of the 82 trial-ineligible patients with CD received biological therapies, with lower response rates (60%) than trial-eligible patients (89%; P = .03). Most patients with moderate-severe IBD evaluated in an outpatient practice would not qualify for enrollment in a pivotal RCT of biological reagents; this finding raises important questions about their therapeutic efficacy beyond the clinical trial populations. Additional evaluation of the transparency of RCT design and selection criteria is needed to determine whether trial results can be generalized to the population.

International Participation in Cardiovascular Randomized Controlled Trials Sponsored by the National Heart, Lung, and Blood Institute

The aim of this study was to describe international enrollment and participation in National Institutes of Health (NIH)-sponsored cardiovascular randomized controlled trials (RCTs). RCTs provide the evidence base for major societal guidelines and profoundly influence patient care in the United States. Increased international involvement in clinical trials has been observed, but the rate of international enrollment in NIH-sponsored cardiovascular RCTs has not been described. The NIH registry of clinical trials was searched for phase III or IV cardiovascular RCTs funded by the National Heart, Lung, and Blood Institute. Studies with outcomes of myocardial infarction, stroke, or death published between 1997 and 2009 were included. Rates of international enrollment were obtained from published data or personal communication with corresponding authors. Twenty-four studies met all inclusion criteria. Nineteen trials including 151,682 patients had international participation (IP), with median IP of 9.5% (range 0% to 100%). Coronary artery disease trials (11 studies) had nearly 50% international enrollment. High-risk trials and trials testing acute interventions tended to have higher rates of IP. Cardiovascular RCTs sponsored by the National Heart, Lung, and Blood Institute have substantial rates of international enrollment, particularly coronary artery disease trials. Given questions of applicability and ethical and financial considerations, IP in U.S. clinical trials deserves further scrutiny.

Patterns of patient enrollment in randomized controlled trials

We aimed to describe enrollment patterns in a large cohort of randomized controlled trials (RCTs) and evaluate whether early recruitment predicts the ability of RCTs to reach their target enrollment. We considered all 77 efficacy RCTs initiated by the AIDS Clinical Trials Group between 1986 and 1996 (28,992 patients enrolled until November 1999). Thirteen RCTs (17%) failed to reach half their target recruitment. Enrollment trajectories showed that the initial rate of accrual determined the subsequent rates of enrollment. The target sample size was attained by 7/8, 11/14, 15/35 and 4/20 of trials with very rapid, rapid, moderate and slow enrollment during the first 3 months, respectively (P < 0.001). Enrollment during the first month or two strongly correlated with subsequent accrual (P < 0.001). The patient pool, the eligibility criteria, the attractiveness of a trial and adequacy of the network of clinical sites may influence RCT enrollment. Early enrollment offers strong evidence on the feasibility of a trial and is indicative of its future pace of recruitment.