Clinical trials on trial: II Improving nonrandomized trials.
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Clinical Trials as Topic↗
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Recruitment for clinical trials: the Lipid Research Clinics Coronary Primary Prevention Trial experience. Its implications for future trials.
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Clinical Trials as Topic↗
Consistency of inter-trial activation using single-trial fMRI: assessment of regional differences.
Recently, the technique of single-trial fMRI was introduced, which allows the assessment of hemodynamic responses to single task executions (e.g. sensory, motor, or cognitive). In this study, single-trial fMRI was used to examine regional differences in the inter-trial consistency (ITC) of brain activity related to the processing of a dynamic visuo-spatial imagery task. For every single trial, a t-statistic assessing task-related activation was calculated and thresholded at a p-value of P < or =l0.05 (uncorrected). The percentage of trials with t-values above the threshold was used to assess differences in the consistency of brain activity in occipital, parietal, premotor and prefrontal regions of interest. While most of these regions showed activation which was highly consistent across trials, the consistency of activation was significantly reduced in the dorsolateral prefrontal cortex. We hypothesize that the consistency of activation across trials may be interpreted as an indicator of the functional relevance of a brain region for processing and solving a cognitive task. Thus, the analysis concept presented here has the potential to provide new insights into the neuro-cognitive mechanisms of human information processing. In addition, the results of this study confirm that averaging across trials might result in a significant loss of information about functional neuroanatomy. Regions which are active in some trials only, which show only weak activity increases, or whose activity is not constant and time-locked, might not show up in averaged activation maps and could thus erroneously be interpreted as irrelevant for task processing.
Adult↗
Impact of cyclooxygenase inhibitors in the Women's Health Initiative hormone trials: secondary analysis of a randomized trial.
OBJECTIVES: We evaluated the hypothesis that cyclooxygenase (COX) inhibitor use might have counteracted a beneficial effect of postmenopausal hormone therapy, and account for the absence of cardioprotection in the Women's Health Initiative hormone trials. Estrogen increases COX expression, and inhibitors of COX such as nonsteroidal anti-inflammatory agents appear to increase coronary risk, raising the possibility of a clinically important interaction in the trials. DESIGN: The hormone trials were randomized, double-blind, and placebo-controlled. Use of nonsteroidal anti-inflammatory drugs was assessed at baseline and at years 1, 3, and 6. SETTING: The Women's Health Initiative hormone trials were conducted at 40 clinical sites in the United States. PARTICIPANTS: The trials enrolled 27,347 postmenopausal women, aged 50-79 y. INTERVENTIONS: We randomized 16,608 women with intact uterus to conjugated estrogens 0.625 mg with medroxyprogesterone acetate 2.5 mg daily or to placebo, and 10,739 women with prior hysterectomy to conjugated estrogens 0.625 mg daily or placebo. OUTCOME MEASURES: Myocardial infarction, coronary death, and coronary revascularization were ascertained during 5.6 y of follow-up in the estrogen plus progestin trial and 6.8 y of follow-up in the estrogen alone trial. RESULTS: Hazard ratios with 95% confidence intervals were calculated from Cox proportional hazard models stratified by COX inhibitor use. The hazard ratio for myocardial infarction/coronary death with estrogen plus progestin was 1.13 (95% confidence interval 0.68-1.89) among non-users of COX inhibitors, and 1.35 (95% confidence interval 0.86-2.10) among continuous users. The hazard ratio with estrogen alone was 0.92 (95% confidence interval 0.57-1.48) among non-users of COX inhibitors, and 1.08 (95% confidence interval 0.69-1.70) among continuous users. In a second analytic approach, hazard ratios were calculated from Cox models that included hormone trial assignment as well as a time-dependent covariate for medication use, and an interaction term. No significant interaction was identified. CONCLUSIONS: Use of COX inhibitors did not significantly affect the Women's Health Initiative hormone trial results.
Journal Article↗
Clinical cooperative trials of the National Cancer Institute of Canada Clinical Trials Group Breast Cancer Site Group.
For more than 10 years, the National Cancer Institute of Canada Clinical Trials Group (NCIC CTG) Breast Cancer Site Group has focused primarily on trials of adjuvant therapy and of investigational new drugs (IND). Four trials of adjuvant therapy in node-positive women have been completed, are active, or are about to begin. Investigational new drug (IND) studies have included Phase II trials of intravenous and oral menagaril, 10-EDAM (edatrexate), taxotere, and mifepristone (RU-486) as well as a Phase I/II trial of 5-fluorouracil (5-FU), doxorubicin, and vinorelbine (FAN); a Phase I/II trial of 5-FU, leucovorin, doxorubicin, and vinorelbine (super-FAN), all as first-line therapy for metastatic disease; and a Phase III study of vinorelbine plus doxorubicin versus doxorubicin alone as first- or second-line metastatic therapy. A proposed study with the European Organization for Research and Treatment of Cancer in locally advanced breast cancer will compare a standard NCIC CTG regimen of cyclophosphamide, epirubicin, and 5-FU (CEF) with epirubicin and cyclophosphamide granulocyte colony-stimulating factor (G-CSF), a more dose-intensive regimen. In addition, NCIC CTG is preparing a pilot of CEF with G-CSF to examine whether a substantially more intensive dosage can be given without added toxicity. NCIC CTG will also enter patients into a currently active Cancer and Leukemia Group B/Southwest Oncology Group randomized trial of intensive therapy versus more intensive therapy with bone marrow support in women younger than age 60 with 10 or more positive nodes. It is believed that optimizing the combination and timing of adjuvant hormonal and chemotherapy, exploring dose intensive approaches, developing investigational new drugs, studying the role of biologics, and tumor banking in conjunction with clinical trials remain important approaches for the future.
Antineoplastic Combined Chemotherapy Protocols↗
Monitoring a randomized clinical trial for futility: the north-Norwegian lidocaine intervention trial.
Randomized clinical trials of acute disease are usually designed as single-look, fixed sample size trials. This methodological study compares the conventional approach with a multiple-look, group sequential design with stopping rules for both treatment efficacy and for an inconclusive trial outcome, called trial futility. An ongoing trial on pre-hospital prophylaxis of sudden death in acute myocardial infarction forms the basis of the analysis. The effects of introducing multiple looks (or interim analyses) and tests for futility were obtained by binomial simulation. The introduction of four looks (that is, three interim and a final analysis) resulted in a modest increase in the maximal number of patients required. This was, however, fully compensated for by the high probability of early termination in case of treatment efficacy. The addition of futility tests, enabling termination at half the maximum trial size when there is no treatment difference, resulted in only a negligible reduction of overall power. We conclude that multiple-look, group sequential designs testing for both treatment efficacy and trial futility may improve the cost-effectiveness of randomized trials of acute disease.
Binomial Distribution↗
Reappraisal of duplex criteria to assess significant carotid stenosis with special reference to reports from the North American Symptomatic Carotid Endarterectomy Trial and the European Carotid Surgery Trial.
PURPOSE: Duplex examination is today the principal initial method of assessing extracranial carotid or vertebral artery disease. However, varying haemodynamic criteria have been described to categorize the degree of internal carotid artery stenosis, and similarly the degree of stenosis detected with angiography has been assessed with different methods as highlighted in studies performed by the North American Symptomatic Carotid Endarterectomy Trial and the European Carotid Surgery Trial. This study looks at the correlation between two commonly used methods of assessing carotid artery stenosis with duplex criteria and the two methods of angiographic interpretation used in these trials. Duplex parameters are also identified to determine the greater than 70% stenosis group identified as at risk in these studies. METHODS: A total of 120 carotid bifurcations were studied in patients who underwent both carotid duplex and angiography. Correlations of duplex with angiography were assessed with duplex criteria described by Zwiebel and by Strandness and the angiographic methods used in studies performed by the North American Symptomatic Carotid Endarterectomy Trial and the European Carotid Surgery Trial. Receiver operator curves were constructed from the duplex data for the detection of stenosis greater than 70% based on the angiographic assessment used in the study performed by the North American Symptomatic Carotid Endarterectomy Trial. RESULTS: The duplex criteria described by Zwiebel and Strandness differed in their accuracy depending on which of the two methods was used to report the angiograms. Zwiebel's criteria agreed more with the angiographic method used in the study performed by the European Carotid Surgery Trial (sensitivity 98%, specificity 81%, accuracy 88%), whereas Strandness' criteria agreed more with the angiographic method used in the study performed by the North American Symptomatic Carotid Endarterectomy Trial (sensitivity 96%, specificity 85%, accuracy 89%). For the detection of a stenosis greater than 70%, a peak systolic velocity greater than 270 cm/sec and end diastolic velocity greater than 110 cm/sec provided a sensitivity of 96%, specificity of 91%, and accuracy of 93%. CONCLUSIONS: The accuracy of duplex studies compared with angiography in the assessment of extracranial vascular disease depends on the method of angiographic determination of carotid stenosis. Vascular laboratories should validate the duplex criteria they use against a standard method of angiographic assessment of carotid artery stenosis, with special reference to the recently reported studies noting the significance of a stenosis greater than 70% in patients with symptoms.
Blood Flow Velocity↗
Rationale, design, and organization of the PeriOperative ISchemic Evaluation (POISE) trial: a randomized controlled trial of metoprolol versus placebo in patients undergoing noncardiac surgery.
BACKGROUND: Noncardiac surgery is associated with significant cardiovascular mortality, morbidity, and cost. Small trials of beta-blockers suggest that they may prevent cardiovascular events in patients undergoing noncardiac surgery, but trial results are inconclusive. We have initiated the POISE trial to definitively establish the effects of beta-blocker therapy in patients undergoing noncardiac surgery. METHODS: The POISE trial is a blinded, randomized, and controlled trial of controlled-release metoprolol versus placebo in 10000 patients at risk for a perioperative cardiovascular event who are undergoing noncardiac surgery. Patients will receive the study drug 2 to 4 hours before surgery and subsequently for 30 days. The primary outcome is a composite of cardiovascular death, nonfatal myocardial infarction, and nonfatal cardiac arrest at 30 days. Patients will also be followed for events at 1 year. RESULTS: To date, the POISE trial has recruited >6300 patients in 182 centers in 21 countries. Currently, the patients' mean age is 69 years; 63% are males, 43% have a history of coronary artery disease, 43% have a history of peripheral arterial disease, and 30% have diabetes. Most participants have undergone vascular (42%), intraabdominal (23%), or orthopedic (19%) surgery. CONCLUSIONS: The POISE trial is a large international trial that will provide a reliable assessment of the effects of beta-blocker therapy in patients undergoing noncardiac surgery.
Adrenergic beta-Antagonists↗
Design of Physicians' Health Study II--a randomized trial of beta-carotene, vitamins E and C, and multivitamins, in prevention of cancer, cardiovascular disease, and eye disease, and review of results of completed trials.
PURPOSE: To assess the balance of benefits and risks of supplementation with beta-carotene, vitamin E, vitamin C, and multivitamins on cancer, cardiovascular (CVD), and eye diseases. DESIGN: Physicians' Health Study II (PHS II) is a randomized, double-blind, placebo-controlled trial enrolling 15,000 willing and eligible physicians aged 55 years and older. PHS II will utilize a 2 x 2 x 2 x 2 factorial design to test alternate day beta-carotene, alternate day vitamin E, daily vitamin C, and a daily multivitamin, in the prevention of total and prostate cancer, CVD, and the age-related eye diseases, cataract and macular degeneration. PRIOR RESULTS: The final results of the recently completed Physicians' Health Study I (PHS I), a randomized, double-blind, placebo-controlled trial in 22,071 healthy US male physicians, indicated that beta-carotene supplementation (50 mg on alternate days) had no significant benefit or harm on cancer or CVD during more than 12 years of treatment and follow-up. In regards to cancer, there were possible benefits on total and prostate cancer in those with low baseline levels assigned to beta-carotene, a finding compatible with the Chinese Cancer Prevention Study for combined treatment with beta-carotene, vitamin E, and selenium in a poorly nourished population. Further, with respect to CVD, there were apparent benefits of beta-carotene supplementation on subsequent vascular events among a small subgroup of 333 men with prior angina or revascularization. The currently available data from randomized trials of primary prevention are sparse and inconsistent for vitamin E and non-existent for vitamin C and multivitamins. For eye diseases, namely cataract and age-related macular degeneration, there are no completed large-scale randomized trials of antioxidant vitamins. CONCLUSIONS: PHS II is unique in several respects. PHS II is the only primary prevention trial in apparently healthy men testing the balance of benefits and risks of vitamin E on cancer and CVD. In addition, PHS II is the only primary prevention trial in apparently healthy men to test the balance of benefits and risks of vitamin C, multivitamins, as well as any single antioxidant vitamin, alone and in combination, on cancer, CVD, and eye diseases. Finally, PHS II is the only trial testing a priori the hypotheses that beta-carotene and vitamin E may reduce the risks of prostate cancer. Thus, PHS II will add unique as well as importantly relevant and complementary information to the totality of evidence from other completed and ongoing large-scale randomized trials on the balance of benefits and risks of beta-carotene, vitamin E, vitamin C, and multivitamins alone and in combination on prevention of cancer, CVD and eye diseases.
Aged↗
Direct comparison of characteristics, treatment, and outcomes of patients enrolled versus patients not enrolled in a clinical trial at centers participating in the TIMI 9 Trial and TIMI 9 Registry.
BACKGROUND: Questions about the generalizability of randomized trial results to clinical practice have arisen because the overall mortality rate is generally lower in trials, potentially because patients who are at lower risk are enrolled. However, little is known about the characteristics of patients included in clinical trials versus those who are not included. METHODS: The Thrombolysis In Myocardial Infarction (TIMI) 9 Registry prospectively evaluated patients with ST-elevation myocardial infarction at 20 hospitals during the TIMI 9 trial, which compared hirudin versus heparin with fibrinolysis. We compared the characteristics, treatment, and outcomes of patients enrolled in TIMI 9B (n = 3002) with other fibrinolytic-eligible patients not enrolled in TIMI 9B (n = 296) and with those not eligible for fibrinolysis by American College of Cardiology/American Heart Association criteria, at the same centers (n = 282), with the latter groups divided by use of reperfusion therapy. RESULTS: Across the groups, ranging from those in the TIMI 9 trial to those ineligible for fibrinolysis, we observed a gradient of higher-risk baseline characteristics, lower use of reperfusion therapy, and higher mortality rates (P <.001). In addition, comparing fibrinolytic-eligible patients in TIMI 9B versus those not enrolled in the trial, the use of aspirin, beta-blockers, and angiotensin-converting enzyme inhibitors was significantly higher in the TIMI 9B trial. Ineligible patients not treated with reperfusion therapy had much lower rates of use of these medications and the highest inhospital mortality rate (24%, adjusted odds ratio 2.8, P <.0001) CONCLUSIONS: In this prospective registry, patients not enrolled in a clinical trial had higher risk characteristics and worse outcomes; however, they also were treated less frequently with guideline-recommended medications, which may have contributed to their higher mortality rates.
Electrocardiography↗
Randomised clinical trials of fish oil supplementation in high risk pregnancies. Fish Oil Trials In Pregnancy (FOTIP) Team.
OBJECTIVE: To test the postulated preventive effects of dietary n-3 fatty acids on pre-term delivery, intrauterine growth retardation, and pregnancy induced hypertension. DESIGN: In six multicentre trials, women with high risk pregnancies were randomly assigned to receive fish oil (Pikasol) or olive oil in identically-looking capsules from around 20 weeks (prophylactic trials) or 33 weeks (therapeutic trials) until delivery. SETTING: Nineteen hospitals in Europe. SAMPLES: Four prophylactic trials enrolled 232, 280, and 386 women who had experienced previous pre-term delivery, intrauterine growth retardation, or pregnancy induced hypertension respectively, and 579 with twin pregnancies. Two therapeutic trials enrolled 79 women with threatening pre-eclampsia and 63 with suspected intrauterine growth retardation. INTERVENTIONS: The fish oil provided 2.7 g and 6.1 g n-3 fatty acids/day in the prophylactic and therapeutic trials, respectively. MAIN OUTCOME MEASURES: Preterm delivery, intrauterine growth retardation, pregnancy induced hypertension. RESULTS: Fish oil reduced recurrence risk of pre-term delivery from 33% to 21% (odds ratio 0.54 (95% CI 0.30 to 0.98)) but did not affect recurrence risks for the other outcomes (OR 1.26; 0.74 to 2.12 and 0.98; 0.63 to 1.53, respectively). In twin pregnancies, the risks for all three outcomes were similar in the two intervention arms (95% CI for the three odds ratios were 0.73 to 1.40, 0.90 to 1.52, and 0.83 to 2.32, respectively). The therapeutic trials detected no significant effects on pre-defined outcomes. In the combined trials, fish oil delayed spontaneous delivery (proportional hazards ratio 1.22; 1.07 to 1.39, P = 0.002). CONCLUSIONS: Fish oil supplementation reduced the recurrence risk of pre-term delivery, but had no effect on pre-term delivery in twin pregnancies. Fish oil had no effect on intrauterine growth retardation and pregnancy induced hypertension, affecting neither recurrence risk nor risk in twin pregnancies.
Delivery, Obstetric↗
EVALUATE hysterectomy trial: a multicentre randomised trial comparing abdominal, vaginal and laparoscopic methods of hysterectomy.
OBJECTIVES: To test the null hypothesis of no significant difference between laparoscopic hysterectomy (LH), abdominal hysterectomy (AH) and vaginal hysterectomy (VH) with regard to each of the outcome measures of the trial, and also to assess the cost-effectiveness of the alternatives. DESIGN: Patients were allocated to either the vaginal or abdominal trial by the individual surgeon according to their usual clinical practice. After allocation patients were then randomised to receive either LH or the default procedure in an unbalanced 2:1 manner. SETTING: Forty-three surgeons from 28 centres throughout the UK and two centres in South Africa took part in the study. PARTICIPANTS: Patients with gynaecological symptoms that, in the opinion of the gynaecologist and the patient, justified hysterectomy. INTERVENTIONS: Of 1380 patients recruited to the study, 876 were included in the AH trial and 504 in the VH trial. In the AH trial, 584 patients had a laparoscopic type of hysterectomy (designated ALH) and 292 had a standard AH. In the VH trial 336 had a VLH and 168 had a standard VH. A cost--utility analysis was undertaken based on a 1-year time horizon. Quality-adjusted life years (QALYs) were estimated using the EQ-5D. RESULTS: Compared with AH, LH was associated with a higher rate of major complications, less postoperative pain and shorter hospital stay, but took longer to perform. Securing the ovarian pedicles with laparoscopic sutures was used in only 7% of cases but was associated with 25% of the complications. At the 6 weeks postoperative point, ALH was associated with a significantly better physical component of the SF-12 (QoL questionnaire), better body image scale scores and a significantly increased frequency of sexual intercourse than AH. These differences were not observed at either 4 or 12 months after surgery. There were no significant differences in any measured outcome between LH and VH except that VLH took longer to perform and was associated with a higher rate of detecting unexpected pathology. Compared with VH, VLH had a higher mean cost per patient of GBP401 and higher mean QALYs of 0.0015, resulting in an incremental cost per QALY gained of GBP267,333. The probability that VLH is cost-effective was less than 50% for a large range of willingness to pay values for an additional QALY. Compared with AH, ALH had a higher mean cost per patient of GBP186 and higher mean QALYs of 0.007, resulting in an incremental cost per QALY gained of GBP26,571. CONCLUSIONS: ALH is associated with a significantly higher risk of major complications and takes longer to perform than AH. ALH is, however, associated with less pain, quicker recovery and better short-term QoL after surgery than AH. The cost-effectiveness of ALH is finely balanced and is also influenced by the choice of reusable versus disposable equipment. Individual surgeons must decide between patient-orientated benefits and the risk of severe complications. VLH was not cost-effective relative to VH. Recommendations for future research include the application and relevance of QoL measures following hysterectomy, and long-term follow-up; patient preferences; reducing complication rates; improving gynaecological surgical training; surgeon effect in surgery trials; care pathways for hysterectomy; additional pathology identification in LH and meta-analysis/further trial of VH versus LH.
Cost-Benefit Analysis↗
Prevention of esophageal cancer: the nutrition intervention trials in Linxian, China. Linxian Nutrition Intervention Trials Study Group.
In Linxian China, the esophageal/gastric cardia cancer mortality rates are among the highest in the world. There is suspicion that the population's chronic deficiencies of multiple micronutrients are etiologically involved. We conducted two randomized, placebo-controlled nutrition intervention trials to test the effects of vitamin and mineral supplements in lowering the rates of esophageal/gastric cancer. In the first trial, the dysplasia trial, 3318 adults with a cytological diagnosis of esophageal dysplasia received daily supplementation with 26 vitamins and minerals in doses typically 2-3 times the United States Recommended Daily Allowances, or placebos, for 6 years. The second trial, the general population trial, involved 29,584 adults and used a one-half replicate of a 2(4) factorial experimental design which tested the effects of four combinations of nutrients: A, retinol and zinc; B, riboflavin and niacin; C, vitamin C and molybdenum; and D, beta-carotene, vitamin E, and selenium. Doses for these daily supplements ranged from 1 to 2 times the United States Recommended Daily Allowances, and the different vitamin/mineral combinations or placebos were taken for a period of 5.25 years. As part of the general population trial, and end-of-intervention endoscopy survey was carried out in a small (1.3%) sample of subjects to see if supplementation affected the prevalence of dysplasia and early cancer. Herein we review the methods of these trials and the results of the endoscopic survey. Fifteen esophageal and 16 gastric cancers were identified in endoscopic biopsies from the 391 subjects evaluated from two villages, and nearly all were asymptomatic. No significant reductions in the prevalence of esophageal or gastric dysplasia or cancer were seen with any of the four supplement groups. However, the prevalence of gastric cancer among participants receiving retinol and zinc was 62% lower than those not receiving those supplements (P = 0.09), while participants receiving beta-carotene, vitamin E, and selenium had a 42% reduction in esophageal cancer prevalence (0.34). We have reported separately that cancer mortality over the entire 5.25-year period was significantly reduced among those receiving beta-carotene, vitamin E, and selenium. The findings from the overall trial and the endoscopic sample offer a hopeful sign and should encourage additional studies with these agents in larger numbers of subjects.
Adult↗
Prerandomization Surgical Training for the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-32 trial: a randomized phase III clinical trial to compare sentinel node resection to conventional axillary dissection in clinically node-negative breast cancer.
OBJECTIVE: To train surgeons in a standardized technique of sentinel lymph node biopsy and to prepare them for the requirements of a prospective randomized surgical trial. SUMMARY BACKGROUND DATA: The NSABP B32 trial opened to accrual in May 1999. A significant component of this trial was a prerandomization training phase of surgeons performed by a group of core surgical trainers. The goals of this training phase were to expeditiously instruct surgeons in a standardized technique of sentinel lymph node biopsy and to educate those same surgeons in complete and accurate data collection and source documentation for the trial. METHODS: This study is a description of the training data collected in a prospective fashion for the training component for surgeon entry into the B32 trial, evaluating the effectiveness of the training program in regards to surgical outcomes and protocol compliance. RESULTS: Two hundred twenty-six registered surgeons underwent site visit training by a core surgical trainer and 187 completed training and were approved to randomize patients on the trial. The results of 815 training (nontrial) cases demonstrated a technical success rate for identifying sentinel nodes at 96.2% with a false negative rate of 6.7%. A protocol compliance analysis, which included the evaluation of 94 separate fields, showed mean protocol compliance of 98.6% for procedural fields, 95.5% for source documentation fields and 95.0% for data entry fields. CONCLUSIONS: This training and quality control program has resulted in a large number of surgeons capable of performing sentinel lymph node biopsy in a standardized fashion with a high degree of protocol compliance and pathologic accuracy. This will ensure optimal results for procedures performed on the randomized phase of the trial.
Axilla↗
Effect of a clinical trial alert system on physician participation in trial recruitment.
BACKGROUND: Failure to recruit a sufficient number of eligible subjects in a timely manner represents a major impediment to the success of clinical trials. Physician participation is vital to trial recruitment but is often limited. METHODS: After 12 months of traditional recruitment to a clinical trial, we activated our electronic health record (EHR)-based clinical trial alert (CTA) system in selected outpatient clinics of a large, US academic health care system. When a patient's EHR data met selected trial criteria during the subsequent 4-month intervention period, the CTA prompted physician consideration of the patient's eligibility and facilitated secure messaging to the trial's coordinator. Subjects were the 114 physicians practicing at selected EHR-equipped clinics throughout our study. We compared differences in the number of physicians participating in recruitment and their recruitment rates before and after CTA activation. RESULTS: The CTA intervention was associated with significant increases in the number of physicians generating referrals (5 before and 42 after; P < .001) and enrollments (5 before and 11 after; P = .03), a 10-fold increase in those physicians' referral rate (5.7/mo before and 59.5/mo after; rate ratio, 10.44; 95% confidence interval, 7.98-13.68; P<.001), and a doubling of their enrollment rate (2.9/mo before and 6.0/mo after; rate ratio, 2.06; 95% confidence interval, 1.22-3.46; P = .007). CONCLUSIONS: Use of an EHR-based CTA led to significant increases in physicians' participation in and recruitment rates to an ongoing clinical trial. Given the trend toward the EHR implementation in health care centers engaged in clinical research, this approach may represent a much-needed solution to the common problem of inadequate trial recruitment.
Adult↗
The American College of Rheumatology preliminary core set of disease activity measures for rheumatoid arthritis clinical trials. The Committee on Outcome Measures in Rheumatoid Arthritis Clinical Trials.
OBJECTIVE: To develop a set of disease activity measures for use in rheumatoid arthritis (RA) clinical trials, as well as to recommend specific methods for assessing each outcome measure. This is not intended to be a restrictive list, but rather, a core set of measures that should be included in all trials. METHODS: We evaluated disease activity measures commonly used in RA trials, to determine which measures best met each of 5 types of validity: construct, face, content, criterion, and discriminant. The evaluation consisted of an initial structured review of the literature on the validity of measures, with an analysis of data obtained from clinical trials to fill in gaps in this literature. A committee of experts in clinical trials, health services research, and biostatistics reviewed the validity data. A nominal group process method was used to reach consensus on a core set of disease activity measures. This set was then reviewed and finalized at an international conference on outcome measures for RA clinical trials. The committee also selected specific ways to assess each outcome. RESULTS: The core set of disease activity measures consists of a tender joint count, swollen joint count, patient's assessment of pain, patient's and physician's global assessments of disease activity, patient's assessment of physical function, and laboratory evaluation of 1 acute-phase reactant. Together, these measures sample the broad range of improvement in RA (have content validity), and all are at least moderately sensitive to change (have discriminant validity). Many of them predict other important long-term outcomes in RA, including physical disability, radiographic damage, and death. Other disease activity measures frequently used in clinical trials were not chosen for any one of several reasons, including insensitivity to change or duplication of information provided by one of the core measures (e.g., tender joint score and tender joint count). The committee also proposes specific ways of measuring each outcome. CONCLUSION: We propose a core set of outcome measures for RA clinical trials. We hope this will decrease the number of outcomes assessed and standardize outcomes assessments. Further, we hope that these measures will be found useful in long-term studies.
Arthritis, Rheumatoid↗
Report from the panel on the Case for Registers of Clinical Trials at the Eighth Annual Meeting of the Society for Clinical Trials.
A plenary session at the Eighth Annual Meeting of the Society for Clinical Trials addressed "The Case for Registers of Clinical Trials." There are a number of reasons for having registers of clinical trials: to promote collaboration and communication among investigators regarding new and ongoing clinical trials, to provide a basis for methodologic research, and to facilitate meta-analysis by the availability of a system of trial identification that is independent of the published literature. The experience gleaned by those involved with two existing trial registers, the International Committee on Thrombosis and Haemostasis Registry and the Oxford Database of Perinatal Trials, can be used to provide insight into the issues generic to trial registration. The time perspective to be used, inclusion and exclusion criteria, the practicability of comprehensive prospective registration, and funding are central considerations for these and other registers.
Clinical Trials as Topic↗
Web-based decision support for clinical trial eligibility determination in an international clinical trials network.
Matching individuals to multisite cooperative clinical trials can be a complex and nonintuitive decision process that expends considerable time and may be prone to errors. We developed and tested a web-based decision support tool to aid investigators in matching patients to open clinical trials for children with rhabdomyosarcoma in the context of an international cooperative cancer clinical trials network. A decision tree for trial eligibility based on eight clinical variables representing major disease characteristics was translated into a web-based format. In a blinded fashion, we assessed the accuracy of the tool in assigning 100 randomly selected cases to the proper clinical trial. The web-based tool assigned patients to the proper clinical trial in all 100 randomly selected cases. The time needed to enter data and receive results using this tool is about 1 minute per patient entered. It is feasible to develop a web-based tool to help investigators in matching patients to clinical trials. When such decisions are complex and nonintuitive, such tools have the potential to improve the accuracy of clinical trial assignment and save time.
Child↗