Showing papers in "Clinical Trials in 2009"

Model calibration in the continual reassessment method

Abstract: Background The continual reassessment method (CRM) is an adaptive model-based design used to estimate the maximum tolerated dose in dose finding clinical trials. A way to evaluate the sensitivity of a given CRM model including the functional form of the dose-toxicity curve, the prior distribution on the model parameter, and the initial guesses of toxicity probability at each dose is using indifference intervals. While the indifference interval technique provides a succinct summary of model sensitivity, there are infinitely many possible ways to specify the initial guesses of toxicity probability. In practice, these are generally specified by trial and error through extensive simulations.Methods By using indifference intervals, the initial guesses used in the CRM can be selected by specifying a range of acceptable toxicity probabilities in addition to the target probability of toxicity. An algorithm is proposed for obtaining the indifference interval that maximizes the average percentage of correct selecti...

Meta-analysis of individual patient data versus aggregate data from longitudinal clinical trials

Abstract: Background In clinical trials following individuals over a period of time, the same assessment may be made at a number of time points during the course of the trial. Our review of current practice for handling longitudinal data in Cochrane systematic reviews shows that the most frequently used approach is to ignore the correlation between repeated observations and to conduct separate meta-analyses at each of a number of time points. Purpose The purpose of this paper is to show the link between repeated measurement models used with aggregate data and those used when individual patient data (IPD) are available, and provide guidance on the methods that practitioners might use for aggregate data meta-analyses, depending on the type of data available. Methods We discuss models for the meta-analysis of longitudinal continuous outcome data when IPD are available. In these models time is included either as a factor or as a continuous variable, and account is taken of the correlation between repeated observations. The meta-analysis of IPD can be conducted using either a one-step or a two-step approach: the latter involves analysing the IPD separately in each study and then combining the study estimates taking into account their covariance structure. We discuss the link between models for use with aggregate data and the two-step IPD approach, and the problems which arise when only aggregate data are available. The methods are applied to IPD from 5 trials in Alzheimer's disease. Results Two major issues for the meta-analysis of aggregate data are the lack of information about correlation coefficients and the effect of missing data at the patient-level. Application to the Alzheimer's disease data set shows that ignoring correlation can lead to different pooled estimates of the treatment difference and their standard errors. Furthermore, the amount of missing data at the patient level can affect these estimates. Limitations The models assume fixed treatment effects across studies, and that any missing data is missing at random, both at the patient-level and the study level. Conclusions It is preferable to obtain IPD from all studies to correctly account for the correlation between repeated observations. When IPD are not available, the ideal aggregate data are model-based estimates of treatment difference and their variance and covariance estimates. If covariance estimates are not available, sensitivity analyses should be undertaken to investigate the robustness of the results to different amounts of correlation.

Evaluating the benefit of event adjudication of cardiovascular outcomes in large simple RCTs.

Abstract: Background Event adjudication in randomized controlled trials is thought to be a necessary step to remove noise and potential bias from the results [1,2]. However, this hypothesis has not been wide...

Recommendations for safety planning, data collection, evaluation and reporting during drug, biologic and vaccine development: a report of the safety planning, evaluation, and reporting team

Abstract: Background The Safety Planning, Evaluation and Reporting Team (SPERT) was formed in 2006 by the Pharmaceutical Research and Manufacturers of America.Purpose SPERT’s goal was to propose a pharmaceutical industry standard for safety planning, data collection, evaluation, and reporting, beginning with planning first-in-human studies and continuing through the planning of the post-product-approval period.Methods SPERT’s recommendations are based on our review of relevant literature and on consensus reached in our discussions.Results An important recommendation is that sponsors create a Program Safety Analysis Plan early in development. We also give recommendations for the planning of repeated, cumulative meta-analyses of the safety data obtained from the studies conducted within the development program. These include clear definitions of adverse events of special interest and standardization of many aspects of data collection and study design. We describe a 3-tier system for signal detection and analysis of a...

Bayesian clinical trials at the University of Texas M. D. Anderson Cancer Center

Abstract: Background The Bayesian approach is being used increasingly in medical research. In particular, it has become a standard in designing clinical trials at the University of Texas M. D. Anderson Cancer Center.Purpose/Methods To address the extent and nature of Bayesian trials conducted at M. D. Anderson, we reviewed the protocols registered in the Protocol Document Online System between 2000 and early 2005. We summarize our findings and give details for three innovative trials that typify those in which a Bayesian approach has played a major role at the center.Results Of 964 protocols reviewed, 59% were conducted solely at M. D. Anderson and the rest were multicenter trials. Bayesian designs and analyses were used in about 20% (195/964) of the protocols that we reviewed. Of the 520 protocols identified as phase I or II drug trials, about 34% were Bayesian. Most of the 195 Bayesian trials were designed by M. D. Anderson statisticians. The Bayesian design features most commonly used were the continuous reasses...

Bayesian model averaging in meta-analysis: vitamin E supplementation and mortality.

Abstract: Context The strength and relevance of a meta-analysis depends on the validity of the statistical methods used. Of special importance is appropriately assessing different sources of variability. Many studies including meta-analyses have evaluated the efficacy and safety of vitamin E and have yielded varying results. Illuminating and resolving these disparities requires addressing study variability and model uncertainty.Objective To describe Bayesian meta-analysis methods for combining data from clinical trials, using recent studies that analyzed the relationship between vitamin E dose and all-cause mortality.Data Sources Studies used in a previously published meta-analysis appended by studies identified by a search of MEDLINE from August 2004 to December 2005 using the MeSH terms vitamin e and alpha tocopherol.Study Selection Inclusion criteria: men and nonpregnant women; use of vitamin E alone or in combination with other vitamins or minerals; random allocation of participants to either vitamin E or a pla...

Selection criteria and generalizability within the counterfactual framework: explaining the paradox of antidepressant-induced suicidality?

Abstract: Background Although the superior internal validity of the randomized clinical trial (RCT) is invaluable to establish causality, generalizability is far from guaranteed. In particular, strict select...

Confronting Challenges in Intervention Research with Ethnically Diverse Older Adults: The USC Well Elderly II Trial

Abstract: Background Community-dwelling older adults are at risk for declines in physical health, cognition, and psychosocial well-being. However, their enactment of active and health-promoting lifestyles can reduce such declines.Purpose The purpose of this article is to describe the USC Well Elderly II study, a randomized clinical trial designed to test the effectiveness of a healthy lifestyle program for elders, and document how various methodological challenges were addressed during the course of the trial.Methods In the study, 460 ethnically diverse elders recruited from a variety of sites in the urban Los Angeles area were enrolled in a randomized experiment involving a crossover design component. Within either the first or second 6-month phase of their study involvement, each elder received a lifestyle intervention designed to improve a variety of aging outcomes. At 4—5 time points over an 18—24 month interval, the research participants were assessed on measures of healthy activity, coping, social support, pe...

Risk analysis and risk adapted on-site monitoring in noncommercial clinical trials

Abstract: Background The concept of risk assessment for clinical trials has been discussed before, but no comprehensive structured procedure leading to risk-adapted quality management has been published so f...

Bayesian design using adult data to augment pediatric trials.

Abstract: Background It can be difficult to conduct pediatric clinical trials because there is often a low incidence of the disease in children, making accrual slow or infeasible. In addition, low mortality ...

Stopping clinical trials early for benefit: impact on estimation.

Abstract: Background It has been suggested in the literature that the well-known bias of treatment-effect estimators due to the possibility of early stopping for positive results is a major concern with inte...

Comparison of a phased experimental approach and a single randomized clinical trial for developing multicomponent behavioral interventions

Abstract: Background Many interventions in today's health sciences are multicomponent, and often one or more of the components are behavioral Two approaches to building behavioral interventions empirically

Involving American Indians and medically underserved rural populations in cancer clinical trials

Abstract: PURPOSE: To assess cancer clinical trial recruitment and reasons for nonaccrual among a rural, medically underserved population served by a community-based cancer care center. METHODS: We prospectively tracked clinical trial enrollment incidence among all new patients presenting at the Rapid City Regional Cancer Care Institute. Evaluating physicians completed questionnaires for each patient regarding clinical trial enrollment status and primary reasons for nonenrollment. Patients who identified as American Indian were referred to a program where patients were assisted in navigating the medical system by trained, culturally competent staff. RESULTS: Between September 2006 and January 2008, 891 new cancer patients were evaluated. Seventy-eight patients (9%; 95% confidence intervals, 7-11%) were enrolled on a clinical treatment trial. For 73% (95% confidence intervals, 69-75%) of patients (646 of 891) lack of relevant protocol availability or protocol inclusion criteria restrictiveness was the reason for nonenrollment. Only 45 (5%; 95% confidence intervals, 4-7%) patients refused enrollment on a trial. Of the 78 enrolled on a trial, 6 (8%; 95% confidence intervals, 3-16%) were American Indian. Three additional American Indian patients were enrolled under a nontreatment cancer control trial, bringing the total percentage enrolled of the 94 American Indians who presented to the clinic to 10% (95% confidence intervals, 5-17%). LIMITATIONS: Eligibility rates were unable to be calculated and cross validation of the number in the cohort via registries or ICD-9 codes was not performed. CONCLUSION: Clinical trial participation in this medically underserved population was low overall, but approximately 3-fold higher than reported national accrual rates. Lack of availability of protocols for common cancer sites as well as stringent protocol inclusion criteria were the primary obstacles to clinical trial enrollment. Targeted interventions using a Patient Navigation program were used to engage AI patients and may have resulted in higher clinical trial enrollment among this racial/ethnic group.

The calibration of treatment effects from clinical trials to target populations

Abstract: Standard practice teaches that randomized clinical trials should be preferred to observational studies if the aim is to obtain unbiased estimates of efficacy. It is often acknowledged that treatment efficacy might differ in the general population than in the clinical trial, but the source of those differences is often poorly understood or not regarded as important. Substantive differences between RCT and observational study results are typically ascribed to confounding of the latter. Recent literature [1,2] suggests that differences between the results seen in an RCT and in an observational study can be larger than expected not because of confounding, but because of differences between their respective patient populations. These efficacy estimates can differ enough to change treatment recommendations. The paper by Weisberg et al. in this issue [3] is a very clear and innovative example of such emerging literature. But there is another important message that one should derive from this work. That is, RCT results are useful only if we can calibrate their results to predict treatment efficacy in the target population of interest. This editorial makes the case for why calibration requires both clinical knowledge from observational studies, and new statistical insights.

Outcomes following vaginal prolapse repair and mid urethral sling (OPUS) trial - Design and methods

Abstract: Background The primary aims of this trial are to determine whether the use of a concomitant prophylactic anti-incontinence procedure may prevent stress urinary incontinence symptom development in w...

Caregiver-assisted coping skills training for patients with COPD: background, design, and methodological issues for the INSPIRE-II study

Abstract: Background Chronic Obstructive Pulmonary Disease (COPD) is a progressive illness characterized by airflow obstruction and dyspnea that afflicts over 12 million people and represents a leading cause...

Bayesian Design of Single-arm Phase II Clinical Trials with Continuous Monitoring

Abstract: Background Bayesian designs are increasingly used to conduct phase II clinical trials. However, stopping boundaries in most Bayesian designs are defined from posterior credible intervals. The use of designs based on posterior credible intervals results in a loss of efficiency when compared to formal stopping rules based on Bayesian hypothesis tests. Such designs also introduce an unnecessary element of subjectivity in the interpretation of trial results.Methods We derive a new class of Bayesian designs based on formal hypothesis tests. The prior densities used to define the alternative hypotheses in these tests assign no mass to parameter values that are consistent with the null hypotheses and are called nonlocal alternative prior densities.Results We show that Bayesian designs based on hypothesis tests and nonlocal alternative prior densities are more efficient than common Bayesian designs based on posterior credible intervals and common frequentist designs. In contrast to trial designs based on Bayesian...

Lithium treatment -- moderate dose use study (LiTMUS) for bipolar disorder: rationale and design.

Abstract: Background Recent data indicate that lithium use for bipolar disorder has declined over the last decade and that lithium largely has been replaced with alternate, commercially promoted medications that may or may not result in better outcomes.Purpose This article describes the rationale and study design of LiTMUS, a multi-site, prospective, randomized clinical trial of outpatients with bipolar disorder. LiTMUS seeks to address whether initiating therapy at lower doses of lithium as part of optimized treatment (OPT, guideline-informed, evidence-based, and personalized pharmacotherapy) improves outcomes and decreases the need for other medication changes across 6 months of therapy.Methods LiTMUS will randomize 284 adults with bipolar disorder (Type I or II) across 6 study sites. The co-primary outcomes are overall illness severity on clinical global improvement scale for bipolar disorder and a novel measure, necessary clinical adjustments. This metric provides a composite that reflects both clinical respons...

Scientific and political challenges in North America's first randomized controlled trial of heroin-assisted treatment for severe heroin addiction: Rationale and design of the NAOMI study:

Abstract: Background Heroin addiction is a chronic relapsing disease, best treated with opioid-agonist substitution therapy such as methadone maintenance. However, a subset of the most severely affected individuals do not benefit sufficiently from this treatment. The North American Opiate Medication Initiative (NAOMI) is a randomized clinical trial (RCT) to evaluate the hypothesis that pharmaceutical-grade heroin, diacetylmorphine (DAM) is more effective in retaining patients and improving their outcomes than Methadone Maintenance Treatment (MMT) among those with chronic, refractory injection opioid dependence.Purpose/Methods The study aimed at randomizing 253 participants to two intervention arms: (1) MMT alone or (2) injectable opioids (DAM or hydromorphone) plus adjunctive MMT if deemed appropriate. The planned study duration was 3 years, with a 1-year intake period, 1 year of treatment, and an additional year of follow-up. The NAOMI trial was initiated in March 2005 at two Canadian sites (Vancouver and Montreal...

Using factor analysis to confirm the validity of children's self-reported health-related quality of life across different modes of administration

Abstract: Background The measurement of pediatric health-related quality of life (HRQOL) in pediatric medicine and health services research has grown significantly over the past decade. While HRQOL instruments are often administered in clinic settings, alternative modes of administration are also utilized such as mail and telephone surveys. In order for comparisons across in-person, mail, and telephone administration to be valid, items on a HRQOL measure must have equivalent meaning across mode of administration. That is, they must demonstrate factorial invariance (stable factor structure) across mode of administration.Purpose The objective of the present study was to implement the multigroup confirmatory factor analysis (CFA) method for invariance testing across mode of administration for children's self-reported HRQOL.Methods Multigroup CFA was performed specifying a five-factor model across three modes of administration groups (in-person, mail, and telephone survey). The 23-item PedsQLTM 4.0 Generic Core Scales ...

Retention of Under-represented Minorities in Drug Abuse Treatment Studies:

Abstract: Background Differential attrition by minority participants can be as limiting to interpreting final results as poor initial recruitment of minority participants. This is especially important in drug abuse treatment studies, as minorities are over-represented in substance abuse clinical treatment programs.Purpose The specific aims of this secondary data analysis were to: (1) determine if there are differences in study retention rates by race/ethnicity and age, and (2) explore other client characteristics, as well as protocol and treatment program factors, that could account for differential retention rates.Methods We conducted a secondary analysis using data from 1737 participants in the first six clinical trials whose databases were locked in the NIDA Clinical Trials Network. Protocol level characteristics were also abstracted from these studies, and we used data from a study which assessed characteristics of community treatment programs that participated in these studies. Logistic regression was used to ...

Recruitment methods employed in the prostate, lung, colorectal, and ovarian cancer screening trial:

Abstract: Background The Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial (PLCO) is a US National Cancer Institute (NCI)-funded randomized controlled trial designed to evaluate whether certain s...

What can we learn from a decade of database audits? The Duke Clinical Research Institute experience, 1997—2006:

Abstract: Background Despite a pressing and well-documented need for better sharing of information on clinical trials data quality assurance methods, many research organizations remain reluctant to publish d...

Design, conduct, and analyses of Breast International Group (BIG) 1-98: A randomized, double-blind, phase-III study comparing letrozole and tamoxifen as adjuvant endocrine therapy for postmenopausal women with receptor-positive, early breast cancer

Abstract: Background Aromatase inhibitors provide superior disease control when compared with tamoxifen as adjuvant therapy for postmenopausal women with endocrine-responsive early breast cancer.Purpose To present the design, history, and analytic challenges of the Breast International Group (BIG) 1-98 trial: an international, multicenter, randomized, double-blind, phase-III study comparing the aromatase inhibitor letrozole with tamoxifen in this clinical setting.Methods From 1998—2003, BIG 1-98 enrolled 8028 women to receive monotherapy with either tamoxifen or letrozole for 5 years, or sequential therapy of 2 years of one agent followed by 3 years of the other. Randomization to one of four treatment groups permitted two complementary analyses to be conducted several years apart. The first, reported in 2005, provided a head-to-head comparison of letrozole versus tamoxifen. Statistical power was increased by an enriched design, which included patients who were assigned sequential treatments until the time of the tr...

Challenges in designing a pragmatic clinical trial: The mixed incontinence - Medical or surgical approach (MIMOSA) trial experience

Abstract: Background Mixed urinary incontinence (MUI) is a common, bothersome condition in women In MUI, the two subtypes of urinary incontinence that coexist are treated differently; stress urinary inconti

Sequential multiple-assignment randomized trial design of neurobehavioral treatment for patients with metastatic malignant melanoma undergoing high-dose interferon-alpha therapy

Abstract: Background Interferon-alpha therapy, which is used to treat metastatic malignant melanoma, can cause patients to develop two distinct neurobehavioral symptom complexes: a mood syndrome and a neurovegetative syndrome. Interferon-alpha effects on serotonin metabolism appear to contribute to the mood and anxiety syndrome, while the neurovegetative syndrome appears to be related to interferon-alpha effects on dopamine.Purpose Our goal is to propose a design for utilizing a sequential, multiple assignment, randomized trial design for patients with malignant melanoma to test the relative efficacy of drugs that target serotonin versus dopamine metabolism during 4 weeks of intravenous, then 8 weeks of subcutaneous, interferon-alpha therapy.Methods Patients will be offered participation in a double-blinded, randomized, controlled, 14-week trial involving two treatment phases. During the first month of intravenous interferon-alpha therapy, we will test the hypotheses that escitalopram will be more effective in redu...

Scientific and logistical challenges in designing the CONTROL trial: recombinant factor VIIa in severe trauma patients with refractory bleeding.

Abstract: Background Clinical research in trauma patients poses multiple challenges in study design. These reflect the heterogeneity of injury and treatment, the paucity of acceptable study endpoints aside from mortality, and the difficulties inherent in obtaining informed consent in acutely ill populations. A current example of this problem is the study of recombinant factor VIIa (rFVIIa), which has attracted considerable interest as a systemic procoagulant agent for use in trauma patients with exsanguinating hemorrhage.Purpose To report on the implementation of an international trial — CONTROL — intended to assess the efficacy and safety of rFVIIa in trauma, and discuss trauma research study design in light of this experience.Methods The CONTROL trial international steering committee confronted a number of barriers in the design of the CONTROL trial. They addressed methodologies for (1) standardizing entry criteria for trauma patients suffering inherently heterogeneous injuries, (2) obtaining informed consent in ...

A cost-effectiveness analysis of subject recruitment strategies in the HIPAA era: results from a colorectal cancer screening adherence trial.

Abstract: Background Changes in regulatory standards that restrict use of identifiable health information can reduce patient recruitment to clinical trials and increase recruitment costs.Purpose To compare subject accrual rates and costs of three recruitment strategies that comply with new regulatory standards within the context of a clinical trial evaluating the impact of shared decision-making on colorectal cancer screening adherence.Methods Sequential cohorts of English-speaking, average-risk patients due for colorectal cancer screening were allocated to one of three recruitment strategies: (1) a provider-initiated electronic ‘opt-in’ referral (Click) method; (2) a provider-mediated ‘opt-in’ referral letter (Letter) method; and (3) an investigator-initiated direct contact ‘opt-out’ (Call) method.Results During distinct 6-month recruitment periods between March 2005 and April 2006, 100 potential subjects were identified using the Click method, 847 by the Letter method, and 758 by the Call method. After excluding ...

Challenges in the design of a Home Telemanagement Trial for patients with ulcerative colitis

Abstract: Background Nonadherence, inadequate monitoring, and side-effects result in suboptimal outcomes in ulcerative colitis (UC). We hypothesize that telemanagement for UC will improve symptoms, quality of life, adherence, and decrease costs. Purpose This article describes the challenges encountered in the design of the home telemanagement in patients with UC trial.Methods In a randomized trial to assess the effectiveness of telemanagement for UC compared to best available care, 100 patients will be enrolled. Subjects in the intervention arm will complete self-testing with telemanagement weekly; best available care subjects will receive scheduled follow up, educational fact sheets, and written action plans. Telemanagement consists of a home-unit, decision support server, and web-based clinician portal. The home-unit includes a scale and laptop. Subjects will respond to questions about symptoms, side-effects, adherence, and knowledge weekly; subjects will receive action plans after self-testing. Outcome variables...

Redesigning a large-scale clinical trial in response to negative external trial results: the CAMUS study of Phytotherapy for Benign Prostatic Hyperplasia

Abstract: Background Benign prostatic hyperplasia (BPH), a common condition among older men, confers its morbidity through potentially bothersome lower urinary tract symptoms. Treatments for BPH include drugs such as alpha adrenergic receptor blockers and 5-alpha reductase inhibitors, minimally invasive therapies that use heat to damage or destroy prostate tissue, and surgery including transurethral resection of the prostate. Complementary and alternative medicines are gaining popularity in the U.S. Two phytotherapies commonly used for BPH are extracts of the fruit of Serenoa repens, the Saw palmetto dwarf palm that grows in the Southeastern U.S., and extracts of the bark of Pygeum africanum, the African plum tree.