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PubMed1997

Participants strengthen clinical trial research: the vital role of participant advisors in the Breast Cancer Prevention Trial.

Views regarding the rights and roles of participants in clinical trial research have changed extensively over the past several decades. Such changes have included moving from paternalistic views, in which human subjects often were totally uninformed of research participation, to a perspective that recognized certain rights of human subjects. In recent years, the consumer rights movement, a growing customer service perspective in health care, and the growth of a variety of advocacy groups have brought further change in attitudes and efforts to include consumer representatives and research participants in a variety of advisory roles. The BCPT PAB is a model for a way to involve research study participants in an expanded role. Members of the board initiate efforts to promote participation and inform potential participants about the trial. They help establish outreach efforts to recruit individuals from underrepresented populations. They serve as effective spokespersons for the trial to the media at both local and national levels, and they give highly useful guidance to the NSABP and the NCI regarding a variety of aspects of clinical trials. Beyond the formal responsibilities that were outlined when the board was established, the trial participants serving on the advisory board also have provided inspiration and motivation for other participants as well as for the clinicians, researchers, and administrators conducting the BCPT. The extensive contributions of the advisory board members confirm and add to the understanding of the variety of ways that clinical research participants can play a role in strengthening such research efforts. Further, the BCPT PAB may serve as a model strategy for drawing on the unique resource represented by the participants in clinical trial studies.

Breast Neoplasms↗
PubMed2000

Readiness for HIV vaccine trials: changes in willingness and knowledge among high-risk populations in the HIV network for prevention trials. The HIVNET Vaccine Preparedness Study Protocol Team.

Longitudinal data were analyzed to determine changes in willingness to participate in HIV vaccine efficacy trials and knowledge of vaccine trial concepts among populations at high risk of HIV-1 infection. Gay men (MSM), male and female injection drug users, and non-injecting women at heterosexual risk were recruited (n = 4892). Follow-up visits occurred every 6 months up to 18 months. Willingness was significantly lower at follow-up visits compared with at baseline. Knowledge levels increased for all study populations. Problematic concepts were possible effects of the vaccine on the immune system and lack of knowledge about efficacy of a vaccine before the start of a trial. For concepts concerning safety, blinding, and guarantees of future participation in trials, MSM men had significant increases in knowledge, but little to no change occurred for the other populations. An increase in knowledge was associated with becoming not willing, particularly among MSM with low knowledge levels. At least half of high-risk participants were consistently willing to participate in future vaccine efficacy trials and with basic vaccine education, knowledge levels increased. Continued educational efforts at the community and individual level are needed to address certain vaccine trial concepts and to increase knowledge levels in all potential study populations.

AIDS Vaccines↗
PubMed2026

Higher versus Routine Intraoperative Blood Pressure Targets in Noncardiac Surgery: A Systematic Review and Meta-analysis with Trial Sequential Analysis of Randomized Trials.

BACKGROUND: Observational studies consistently link intraoperative hypotension to adverse postoperative outcomes, leading guidelines to recommend maintaining mean arterial pressure 60 to 65 mmHg or greater during noncardiac surgery. Whether targeting higher intraoperative blood pressure values improves clinical outcomes remains uncertain. METHODS: The authors conducted a Preferred Reporting Items for Systematic Reviews and Meta-analyses-guided search on PubMed, Cochrane Central Register of Controlled Trials, Scopus, and Embase from inception to April 2026. Randomized trials comparing higher intraoperative blood pressure targets, either as fixed absolute thresholds or personalized to preoperative baseline, versus routine blood pressure management in adults undergoing elective noncardiac surgery with general anesthesia were included. Outcomes included in-hospital or 30-day mortality, postoperative delirium, acute kidney injury (AKI), 30-day major cardiovascular events, acute myocardial injury, stroke, length of stay, and intraoperative hypotension. RESULTS: Fifteen trials (15,603 patients) were included. Higher targets did not reduce AKI (risk ratio [RR], 0.95; 95% CI, 0.85 to 1.06; P = 0.36; I 2 = 16%) or acute myocardial injury (RR, 1.02; 95% CI, 0.94 to 1.12; P = 0.59; I 2 = 0%) compared with routine targets, with firm evidence from trial sequential analysis. Higher targets were associated with a significant reduction in postoperative delirium (RR, 0.73; 95% CI, 0.54 to 0.98; P = 0.04; I 2 = 26%), although trial sequential analysis indicated the cumulative evidence remained insufficient to draw firm conclusions. No significant effect was observed on in-hospital or 30-day mortality (RR, 1.00; 95% CI, 0.75 to 1.34; P = 1.00; I 2 = 0%); evidence on 30-day major cardiovascular events, stroke, and length of stay was similarly insufficient to draw firm conclusions. CONCLUSION: In adults undergoing elective noncardiac surgery, targeting higher intraoperative blood pressure values does not improve major postoperative outcomes compared with routine management. A potential reduction in postoperative delirium warrants confirmation in adequately powered trials.

Humans↗
PubMed1995

New developments in the conduct and management of multi-center trials: an international review of clinical trial units.

There is an urgent need for the performance of more, better designed, and better managed randomized clinical trials. After visits to 43 leading organizations and units involved in clinical trials in Europe and North America during 1993, the way of conducting randomized clinical trials was analyzed. By using a structured questionnaire, information on recent improvements in the way randomized clinical trials are performed was identified. These developments encompass human aspects (better information, collaboration, and communication) as well as non-human aspects (press button phone randomization and data management systems). By employing such developments, randomized clinical trials can run much more efficiently. This facilitates faster and better answers to the questions addressed by randomized clinical trials, thereby also making them more ethical.

Computer Communication Networks↗
PubMed2005

Generalizability of antidepressant efficacy trials: differences between depressed psychiatric outpatients who would or would not qualify for an efficacy trial.

OBJECTIVE: In recent years the generalizability of antidepressant efficacy trials has been questioned. Central to the question of generalizability is whether there are differences in clinical, demographic, and psychosocial characteristics between patients who would qualify for an antidepressant efficacy trial and those who would not qualify. METHOD: The authors compared three groups: 123 depressed patients who would qualify for an antidepressant efficacy trial, 289 whose symptom severity was too mild to qualify for an antidepressant efficacy trial, and 187 who would be excluded because they were suicidal or had a comorbid anxiety or substance use disorder. RESULTS: Compared with patients who would qualify for an antidepressant efficacy trial, patients who would be excluded because of comorbidity or suicidality were a more chronically ill group with more previous episodes, greater psychosocial impairment, and more personality pathology. CONCLUSIONS: These findings support further caution in generalizing the results from antidepressant efficacy trials to clinical populations.

Adult↗
PubMed2006

Prospective comparison of autologous stem cell transplantation followed by dose-reduced allograft (IFM99-03 trial) with tandem autologous stem cell transplantation (IFM99-04 trial) in high-risk de novo multiple myeloma.

The Intergroupe Francophone du Myélome (IFM) initiated 2 trials in 1999 to study patients with high-risk (beta2-microglobulin level greater than 3 mg/L and chromosome 13 deletion at diagnosis) de novo multiple myeloma. In both protocols, the induction regimen consisted of vincristine, doxorubicin, and dexamethasone (VAD) followed by first autologous stem cell transplantation (ASCT) prepared by melphalan 200 mg/m(2). Patients with an HLA-identical sibling donor were subsequently treated with dose-reduced allogeneic stem cell transplantation (IFM99-03 trial), and patients without an HLA-identical sibling donor were randomly assigned to undergo second ASCT prepared by melphalan 220 mg/m(2) and 160 mg dexamethasone with or without anti-IL-6 monoclonal antibody (IFM99-04 protocol). Two hundred eighty-four patients-65 in the IFM99-03 trial and 219 in the IFM99-04 trial-were prospectively treated and received at least one course of VAD. On an intent-to-treat basis, overall survival (OS) and event-free survival (EFS) did not differ significantly in the studies (medians 35 and 25 months in the IFM99-03 trial vs 41 and 30 months in the IFM99-04 trial, respectively). With a median follow-up time of 24 months, the EFS of the 166 patients randomly assigned in the tandem ASCT protocol was similar to the EFS of the 46 patients who underwent the entire IFM99-03 program (median, 35 vs 31.7 months), with a trend for a better OS in patients treated with tandem ASCT (median, 47.2 vs 35 months; P = .07). In patients with high-risk de novo MM, the combination of ASCT followed by dose-reduced allogeneic transplantation was not superior to tandem dose-intensified, melphalan-based ASCT.

Adult↗
PubMed2005

The DiGEM trial protocol--a randomised controlled trial to determine the effect on glycaemic control of different strategies of blood glucose self-monitoring in people with type 2 diabetes [ISRCTN47464659].

BACKGROUND: We do not yet know how to use blood glucose self-monitoring (BGSM) most effectively in the self-management of type 2 diabetes treated with oral medication. Training in monitoring may be most effective in improving glycaemic control and well being when results are linked to behavioural change. METHODS/DESIGN: DiGEM is a three arm randomised parallel group trial set in UK general practices. A total of 450 patients with type 2 diabetes managed with lifestyle or oral glucose lowering medication are included. The trial compares effectiveness of three strategies for monitoring glycaemic control over 12 months (1) a control group with three monthly HbA1c measurements; interpreted with nurse-practitioner; (2) A self-testing of blood glucose group; interpreted with nurse- practitioner to inform adjustment of medication in addition to 1; (3) A self-monitoring of blood glucose group with personal use of results to interpret results in relation to lifestyle changes in addition to 1 and 2. The trial has an 80% power at a 5% level of significance to detect a difference in change in the primary outcome, HbA1c of 0.5% between groups, allowing for an attrition rate of 10%. Secondary outcome measures include health service costs, well-being, and the intervention effect in sub-groups defined by duration of diabetes, current management, health status at baseline and co-morbidity. A mediation analysis will explore the extent to which changes in beliefs about self-management of diabetes between experimental groups leads to changes in outcomes in accordance with the Common Sense Model of illness. The study is open and has recruited more than half the target sample. The trial is expected to report in 2007. DISCUSSION: The DiGEM intervention and trial design address weaknesses of previous research by use of a sample size with power to detect a clinically significant change in HbA1c, recruitment from a well-characterised primary care population, definition of feasible monitoring and behaviour change strategies based on psychological theory and evidence, and measures along the hypothesised causal path from cognitions to behaviours and disease and well being related outcomes. The trial will provide evidence to support, focus or discourage use of specific BGSM strategies.

Adult↗
PubMed2005

Tolerability and adverse events in clinical trials of celecoxib in osteoarthritis and rheumatoid arthritis: systematic review and meta-analysis of information from company clinical trial reports.

The objective was to improve understanding of adverse events occurring with celecoxib in the treatment of osteoarthritis and rheumatoid arthritis. Data were extracted from company clinical trial reports of randomised trials of celecoxib in osteoarthritis or rheumatoid arthritis lasting 2 weeks or more. Outcomes were discontinuations (all cause, lack of efficacy, adverse event, gastrointestinal adverse event), endoscopically detected ulcers, gastrointestinal or cardio-renal events, and major changes in haematological parameters. The main comparisons were celecoxib (all doses) versus placebo, paracetamol (acetaminophen) 4,000 mg daily, rofecoxib 25 mg daily, or nonsteroidal anti-inflammatory drugs (NSAIDs) (naproxen, diclofenac, ibuprofen, and loxoprofen). For NSAIDs, celecoxib was compared both at all doses and at licensed doses (200 to 400 mg daily). Thirty-one trials included 39,605 randomised patients. Most patients had osteoarthritis and were women of average age 60 years or above. Most trials lasted 12 weeks or more. Doses of celecoxib were 50 to 800 mg/day. Compared with placebo, celecoxib had fewer discontinuations for any cause or for lack of efficacy, fewer serious adverse events, and less nausea. It had more patients with dyspepsia, diarrhoea, oedema, more adverse events that were gastrointestinal or treatment related, and more patients experiencing an adverse event. There were no differences for hypertension, gastrointestinal tolerability, or discontinuations for adverse events. Compared with paracetamol, celecoxib had fewer discontinuations for any cause, for lack of efficacy, or diarrhoea, but no other differences. Compared with rofecoxib, celecoxib had fewer patients with abdominal pain and oedema, but no other differences. Compared with NSAIDs, celecoxib had fewer symptomatic ulcers and bleeds, endoscopically detected ulcers, and discontinuations for adverse events or gastrointestinal adverse events. Fewer patients had any, or a gastrointestinal, or a treatment-related adverse event, or vomiting, abdominal pain, dyspepsia, or reduced haemoglobin or haematocrit. Discontinuations for lack of efficacy were higher. No differences were found for all-cause discontinuations, serious adverse events, hypertension, diarrhoea, nausea, oedema, myocardial infarction, cardiac failure, or raised creatinine. Company clinical trial reports present much more information than published papers. Adverse event information is clearly presented in company clinical trial reports, which are an ideal source of information for systematic review and meta-analysis.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed2004

Methodology of neuropsychological research in multicentre randomized clinical trials: a model derived from the International Subarachnoid Aneurysm Trial.

As advances in medicine and surgery lead to reductions in mortality rates for life-threatening conditions, it has become increasingly important to refine the methodology of auditing long-term morbidity. The inclusion of appropriate neuropsychological outcomes in a large multicentre randomized clinical trial poses considerable methodological and logistical difficulties. This paper presents a model developed to implement such a multicentre neuropsychological and quality of life audit for a subset of patients within the International Subarachnoid Aneurysm Trial (ISAT), the largest ever randomized trial in the treatment of subarachnoid haemorrhage. Based on our experience of collecting quality of life and neuropsychological outcomes from more than 550 patients, data are presented on the relative cost and efficacy of different organizational strategies, methods of canvassing patients and associated response rates. On the basis of this experience, we estimate a potential recruitment pool of 135 cases would be required to obtain some neuropsychological data on 100 cases. The design of any similar trial would therefore need to accommodate a loss to follow-up of approximately one third of the sample. In addition, our experience suggests that for a trial of this size and complexity, the deployment of centrally-based co-ordinators travelling to satellite centres is more cost-effective than employing co-ordinators based at those centres. Extrapolations from the observations and calculations reported here can be employed as an evidence base to inform the design of neuropsychological outcome studies in large multicentre trials.

Humans↗
PubMed2005

Power and sample size for clinical trials when efficacy is required in multiple endpoints: application to an Alzheimer's treatment trial.

BACKGROUND: When the efficacy of a treatment in a randomized controlled trial is required for multiple primary endpoints, trial design and analysis differ from trial requiring efficacy in only one of the multiple endpoints. METHODS: We consider a two-arm clinical trial requiring efficacy analysis for multiple primary endpoints, formulating the appropriate null and alternative hypotheses for the test of treatment efficacy. We study the significance level/statistical power of an intersection-union test (IUT) in this situation. We compare IUT with the intuitive approach (selecting the maximum sample size over those obtained from testing individual primary endpoints one by one) for determination of sample size. RESULTS: The proposed IUT reserves the same Type I error rate as shared by all endpoint-specific tests. The statistical power of the proposed IUT is no more than the minimum from the individual tests. The maximum sample size from multiple endpoint-specific tests is often inadequate for the test of treatment efficacy, especially when the standardized effect sizes are similar. Finally, the IUT can be applied to Alzheimer's disease treatment trials in which two primary endpoints are typically used. CONCLUSIONS: The IUT is a valid method for use in the design and analysis of clinical trials requiring efficacy at multiple primary endpoints.

Alzheimer Disease↗
PubMed2005

Clinical trial designs for predictive marker validation in cancer treatment trials.

Current staging and risk-stratification methods in oncology, while helpful, fail to adequately predict malignancy aggressiveness and/or response to specific treatment. Increased knowledge of cancer biology is generating promising marker candidates for more accurate diagnosis, prognosis assessment, and therapeutic targeting. To apply these exciting results to maximize patient benefit, a disciplined application of well-designed clinical trials for assessing the utility of markers should be used. In this article, we first review the major issues to consider when designing a clinical trial assessing the usefulness of a predictive marker. We then present two classes of clinical trial designs: the Marker by Treatment Interaction Design and the Marker-Based Strategy Design. In the first design, we assume that the marker splits the population into groups in which the efficacy of a particular treatment will differ. This design can be viewed as a classical randomized clinical trial with upfront stratification for the marker. In the second design, after the marker status is known, each patient is randomly assigned either to have therapy determined by their marker status or to receive therapy independent of marker status. The predictive value of the marker is assessed by comparing the outcome of all patients in the marker-based arm to that of all of the patients in the non-marker-based arm. We present detailed sample size calculations for a specific clinical scenario. We discuss the advantages and disadvantages of the two trial designs and their appropriateness to specific clinical situations to assist investigators seeking to design rigorous, marker-based clinical trials.

Biomarkers, Tumor↗
PubMed2006

Impact of a multi-disciplinary patient education session on accrual to a difficult clinical trial: the Toronto experience with the surgical prostatectomy versus interstitial radiation intervention trial.

PURPOSE: Random assignment to clinical trials involving different treatment modalities can be difficult. We describe our experience with the Surgical Prostatectomy Versus Interstitial Radiation Intervention Trial (SPIRIT; ACOSOG Z0070 NCIC PR10), a randomized trial for early-stage prostate cancer comparing radical prostatectomy (RP), and brachytherapy (BT). A multidisciplinary educational session was developed to improve patient understanding of treatment options and to facilitate accrual. PATIENTS AND METHODS: Prostate cancer referrals were screened and men who met favorable risk criteria (T1c/T2a, prostate-specific antigen [PSA] < 10 ng/mL, Gleason < or = 6) were invited to a structured education session before a specialty consultation. Men and their partners viewed the SPIRIT informed-consent video and heard from a cancer patient who described his participation in a randomized trial. Then, a urologist and radiation oncologist together compared and contrasted RP and BT to establish the rationale for the trial. RESULTS: In May 2002, SPIRIT opened for accrual and was endorsed by the University Health Network urologists and radiation oncologists. The first 27 eligible patients were approached about SPIRIT, consulted both specialties, and viewed an educational video. No patients consented. The multidisciplinary education session was then introduced. Forty-seven education sessions with 263 patients resulted in 34 consents. Of 203 patients who were suitable for the study but declined random assignment, 62 chose surgery, 94 chose brachytherapy, three patients chose external radiotherapy, and 11 chose no treatment. Consent rates for eligible and suitable patients were one in six. CONCLUSION: Men who understand their treatment options and trial rationale as presented jointly by representative specialists from competing treatment modalities may be better equipped to make an informed decision and are more likely to consent to random assignment.

Aged↗
PubMed2000

Placebo-controlled trials and active-control trials in the evaluation of new treatments. Part 1: ethical and scientific issues.

In recent years, several authors have argued that placebo-controlled trials are invariably unethical when known effective therapy is available for the condition being studied, regardless of the condition or the consequences of deferring treatment. Some have also disputed the value of placebo-controlled trials in such a setting, asserting that the comparison of new treatment with old treatment is sufficient to establish efficacy and is all that should be of interest. This article considers the ethical concerns about use of placebo controls and describes the limited ability of active-control equivalence (also known as noninferiority) trials to establish efficacy of new therapies in many medical contexts. The authors conclude that placebo-controlled trials are not uniformly unethical when known effective therapies are available; rather, their acceptability is determined by whether the patient will be harmed by deferral of therapy. If patients are not harmed, such trials can ethically be carried out. Furthermore, active-control trials, although valuable, informative, and appropriate in many circumstances, often cannot provide reliable evidence of the effectiveness of a new therapy.

Controlled Clinical Trials as Topic↗
PubMed2005

Medicare reimbursement for clinical trial services: understanding Medicare coverage in establishing a clinical trial budget.

In designing and setting up a clinical trial, investigators and private sponsors must take into account what costs will or will not be covered by third-party insurers and government payment programs like Medicare and Medicaid. Failure to "cost out" the clinical trials accurately can yield one of two results: either third-party payors are billed improperly, or even illegally, for experimental care, or significant research-related care is not billed, with either the investigating institution, or the research subjects themselves, shouldering the cost. Unfortunately, because Medicare has established different coverage principles to be applied depending on the type of trial being conducted, costing out the trial is not an easy task. This Article looks at the various Medicare coverage principles as they apply to clinical trials, including the 2000 National Coverage Decision and the recent expansion in coverage for Class A Investigational Devices created by the Medicare Prescription Drug, Improvement, and Modernization Act of 2003. The Article then examines how the Medicare secondary payor rule, which states that providers may not bill Medicare for items or services when another party has primary responsibility for those services, relates to clinical trails in light of recent commentary. The Article concludes with the presentation of a general framework that investigators can use to establish a clinical trial budgeting and billing system.

Budgets↗
PubMed2006

Conducting randomised controlled trials in primary care: lessons from an obesity management trial.

BACKGROUND: A UK trial ending in 2002 reported that a training intervention to improve the management of obesity in primary care had no impact. Process analysis showed that the intervention was taken up by very few of the practitioners in the participating practices. AIM: The aim of the current study was to explore both the reasons behind low levels of implementation and the context in which the trial was delivered. DESIGN: In-depth qualitative interviews. SETTING: General practices in the North East of England. METHOD: Interviews with 13 practitioners (GPs and practice nurses) and 10 patients, representing seven of the eight intervention practices in the largest centre of the original trial. RESULTS: While patients were clear that they had participated in a trial few of those interviewed had any recollection of the intervention. Most staff were positive about the training, resources to use with patients and the weight management model, but not all training needs were met. High initial expectations of the trial gave way to disillusionment, exacerbated by significant misunderstanding by some practice staff of their role in implementation. CONCLUSIONS: Frustration among practitioners managing obesity in primary care combined with unrealistic expectations of and misunderstanding about an intervention designed to improve care in the field, appeared to have resulted in disillusionment with and consequent disengagement from the trial.

Attitude of Health Personnel↗
PubMed1991

Carboplatin in non-small cell lung cancer: review of the Eastern Cooperative Oncology Group trial and comparison with other carboplatin trials.

Clinical trials evaluating carboplatin as a single agent or as a component of combination regimens in the treatment of non-small cell lung cancer (NSCLC) patients are reviewed in this report. Response rates for carboplatin varied from 9% to 20% in four trials testing carboplatin 400 mg/m2 as a single daily dose or given over 3 days. In one of these trials carboplatin treatment was associated with a modest but significant survival benefit, and in all of the trials severe toxicity was minimal. In a randomized trial comparing carboplatin/etoposide to cisplatin/etoposide, no significant differences were observed in response rates or survival duration, but there was a trend for less toxicity with carboplatin/etoposide. Other investigators have evaluated carboplatin in two-drug combination therapy with vinblastine, cisplatin, or etoposide in phase II trials. Response rates have ranged from 9% to 17%, suggesting that these particular combinations were not more effective than carboplatin alone. Providing palliation for stage IV NSCLC patients continues to be a major challenge. The low toxicity and modest activity observed with carboplatin suggest that further evaluation of carboplatin is warranted in stage IV NSCLC patients.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1989

Biostatistics in clinical trials: Part 2. Determining sample sizes for clinical trials.

The appropriate sample size for a clinical trial depends on the objectives of the trial. For Phase II trials, the recommended sample size is generally in the neighborhood of 25-40 patients, regardless of the choice of design. Sample sizes for Phase III trials are much more variable, ranging from less than a hundred to thousands of patients. The methodology of sample size determination for Phase III trials depends on the type of endpoint that is to be the primary focus of analysis. Tables of sample sizes for a variety of situations are presented. Use of sequential designs may reduce the required sample size by permitting early termination of trials whose results become definitive prior to completion of patient entry.

Clinical Trials as Topic↗
PubMed1996

[Early clinical trials in ECTG. Early Clinical Trial Group].

Methodology to conduct phase I trials in the Early Clinical Trial Group (ECTG) in Europe was reviewed and compared with current status of the trials in Japan. Single dose acute toxicity studies and repeated dose toxicity studies were required in order to enter phase I trials in Europe, while in Japan those results and various other toxicity studies such as mutagenecity, carcinogenecity and reproductive toxicity were required. Since significant numbers of new anticancer drugs are dropped in the early stage of clinical investigations, it is recommended that unnecessary toxicological studies be avoided. Repeated administration and dose escalations in the same patients are allowed during phase I trials in ECTG, partly in consideration of the patient's desire to obtain antitumor effects. Dose intensity and quality of life are considered in order to decide the optimal dose and schedule in phase II trials.

Antineoplastic Agents↗