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PubMed1999

On being the statistician on a Data and Safety Monitoring Board.

Data and Safety Monitoring Boards (DSMBs) are commonly appointed to monitor emerging data from major clinical trials. This paper describes their organization and remit, and their relationship with other trial committees and structures. The operation of formal stopping rules for safety and efficacy by a DSMB is discussed. The duties of a DSMB, from pre-trial planning through to stopping a study are described in detail, with emphasis on the reporting of information to the DSMB and the reporting of conclusions by the DSMB. The issue of blindness is given prominence and the role of the statistician on the DSMB is explored in detail.

Adverse Drug Reaction Reporting Systems↗

PubMed1994

Data management for large community trials in Nepal.

The current accessibility and sophistication of hardware and software has made it possible to design high-quality data management systems for community-based trials in resource-poor environments. We designed, implemented, and operated an effective data management system for the Nepal Nutrition Intervention Project Sarlahi (NNIPS), a placebo-controlled community trial to assess the impact of vitamin A supplementation on the preschool mortality of 38,000 children in the Sarlahi district of Nepal. A data center was established in Kathmandu, approximately 8 hr drive from the study area. The trial is now completed and over 200,000 forms have been processed. The majority of potential data discrepancies were identified and corrected by field workers during the interviews. Supervisors and forms editors located at the field office corrected most data errors. Once forms reach Kathmandu, the average number of data entry errors was 3.1 per 10,000 keystrokes for the eight data entry operators employed during the study. Extensive computerized checking of data during data entry found out-of-range, missing, or inconsistent data in only 1% of forms. Timely analysis of field worker performance provided ongoing feedback to supervisors and analysis for the Data Safety and Monitoring Committee, and for publication of results.

Bias↗

PubMed1994

The implications of surgical quality assurance in cancer clinical trials.

Prospective clinical trials are used to evaluate therapeutic interventions. Because surgery is involved in the diagnosis, staging, and therapy of solid malignancies, active surgical leadership in these cancer studies is important. There are currently barriers to widespread surgical participation in clinical trials. This report defines the obstacles as well as documents efforts to overcome them and improve surgical quality assurance in cooperative group research. The surgical leadership of several clinical cooperative groups sponsored by the National Cancer Institute (NCI) were interviewed. Cooperative group reports were analyzed with respect to internal audits, quality assurance and activities of surgical monitoring committees. Minutes from meetings of the NCI's workshops on "Surgeons in Clinical Trials" were reviewed. Six concerns present impediments to surgical quality in clinical trials. To address these, substantive surgical leadership is being developed throughout the cooperative group system. Surgical co-principal investigators for institutions and protocols are being appointed. Uniform surgical standards and operative guidelines are being developed. Surgical data review occur at the local institution as well as through central audits and surgical monitoring committees. Coordinators in surgical data management are being trained. Surgical education is organized at cooperative group meetings and disseminated to the surgical community by seminars, workshops, audiovisual teaching sessions, and scientific publications. Surgeons are playing increasing leadership roles in the cancer trials performed by cooperative groups. Surgical leaders are dedicated to a broad-scale quality assurance effort. Enhanced surgical commitment, widespread clinical participation, and focused leadership should affect a high level of surgical quality care in clinical trials research.

Clinical Trials as Topic↗

PubMed2000

Results of the low-dose (20 mg) pravastatin GISSI Prevenzione trial in 4271 patients with recent myocardial infarction: do stopped trials contribute to overall knowledge? GISSI Prevenzione Investigators (Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto Miocardico).

BACKGROUND: The aim of this study was to test the efficacy of a low-dose pravastatin regimen (20 mg daily) in patients with myocardial infarction. METHODS: GISSI Prevenzione (GISSI-P) is an open trial on secondary coronary heart disease prevention: 4271 recent acute myocardial infarction patients (< or = 6 months) with total blood cholesterol > or = 200 mg/dl were randomized to low-dose cholesterol-lowering treatment (pravastatin 20 mg daily) or no treatment. GISSI-P was started in 1993 and its story was crossed by the publication of the results of similarly designed clinical trials. The publication of 4S results in 1994 prompted the Data Safety and Monitoring Board (DSMB) and the Steering Committee (SC) to change the protocol so that only patients whose total blood cholesterol was < 250 mg/dl could be randomized whilst patients with total blood cholesterol > 250 mg/dl who had already been enrolled in the study had to be re-evaluated and, if appropriate, pharmacologically treated. The DSMB and the SC agreed to stop randomization prematurely in late 1996 after the publication of CARE results. RESULTS: Mean follow-up time was 23.0 +/- 6.7 months (median 24.3 months). The two treatment groups were well matched at baseline. Pharmacological interventions recommended by the protocol were widely prescribed (antiplatelet agents > 90%, beta-blockers 42.7%, and ACE-inhibitors 40.2%). Mainly because of the on-course modification of the study protocol, 402/2133 (18.8%) patients in the control group started a cholesterol-lowering treatment during follow-up. Conversely, 296/2138 (13.8%) patients permanently stopped taking their tablets. Side effects, however, were the reason for discontinuing therapy in 57 (2.7%) patients in the pravastatin group, and patient reluctance to continue accounted for most of the remainder. After excluding control patients who had started a cholesterol-lowering treatment during follow-up, the following changes of median lipid concentrations in the control group over the whole course were observed: total cholesterol -1.9%; LDL cholesterol -2.9%; triglycerides -2.0%; HDL cholesterol +1.4%. The analysis carried out excluding patients randomized to pravastatin treatment and actually not assuming the drug clearly indicated the cholesterol-lowering efficacy of low-dose pravastatin (total cholesterol -12.5%; LDL cholesterol -18.8%; triglycerides -7.9%; HDL cholesterol +3.4%). During the study 256 (6.0%) patients either died or had a non-fatal stroke or a myocardial infarction, 136 (6.4%) in the control group and 120 (5.6%) in the pravastatin group (relative risk 0.90, 95% confidence interval 0.71-1.15, p = 0.41); 160 patients died, 88 (4.1%) in the control group and 72 (3.4%) in the pravastatin group (relative risk 0.84, 94% confidence interval 0.61-1.14, p = 0.26). The few (n = 28) non-cardiovascular deaths were balanced: 16 (0.8%) in the control group and 15 (0.6%) in the pravastatin group. The reduction of cardiovascular events was more evident in the by-treatment analysis, with coronary heart disease deaths being significantly decreased (relative risk 0.60, 95% confidence interval 0.38-0.96, p = 0.04). The overall frequency of adverse events was similar in the two groups. No significant difference between treatment groups was found for total cases of cancer or at any particular site. CONCLUSIONS: Despite the decreased statistical power due to its premature stopping, the results of the GISSI-P suggest that a low-dose treatment with pravastatin (20 mg daily) is effective in reducing blood lipids, and underline the importance of long-term compliance with treatments in the search for a maximal effective dosage. Furthermore, the effects of a statin on total and coronary mortality quantified for the first time in a population exposed to Mediterranean dietary and lifestyle habits are markedly consistent with those obtained in different settings.

Aged↗

PubMedDate not supplied

Co-trimoxazole as prophylaxis against opportunistic infections in HIV-infected Zambian children (CHAP): a double-blind randomised placebo-controlled trial.

BACKGROUND: No trials of co-trimoxazole (trimethoprim-sulfamethoxazole) prophylaxis for HIV-infected adults or children have been done in areas with high levels of bacterial resistance to this antibiotic. We aimed to assess the efficacy of daily co-trimoxazole in such an area. METHODS: We did a double-blind randomised placebo-controlled trial in children aged 1-14 years with clinical features of HIV infection in Zambia. Primary outcomes were mortality and adverse events possibly related to treatment. Analysis was by intention to treat. FINDINGS: In October, 2003, the data and safety monitoring committee recommended early stopping of the trial. 541 children had been randomly assigned; seven were subsequently identified as HIV negative and excluded. After median follow-up of 19 months, 74 (28%) children in the co-trimoxazole group and 112 (42%) in the placebo group had died (hazard ratio [HR] 0.57 [95% CI 0.43-0.77], p=0.0002). This benefit applied in children followed up beyond 12 months (n=320, HR 0.48 [0.27-0.84], test for heterogeneity p=0.60) and across all ages (test for heterogeneity p=0.82) and baseline CD4 counts (test for heterogeneity p=0.36). 16 (6%) children in the co-trimoxazole group had grade 3 or 4 adverse events compared with 18 (7%) in the placebo group. These events included rash (one placebo), and a neutrophil count on one occasion less than 0.5x10(9)/L (16 [6%] co-trimoxazole vs seven [3%] placebo, p=0.06). Pneumocystis carinii was identified by immunofluorescence in only one (placebo) of 73 nasopharyngeal aspirates from children with pneumonia. INTERPRETATION: Our results suggest that children of all ages with clinical features of HIV infection should receive co-trimoxazole prophylaxis in resource-poor settings, irrespective of local resistance to this drug.

AIDS-Related Opportunistic Infections↗

PubMed2005

Coordinating and monitoring multisite clinical trials that combine pharmacological and behavioral treatments.

OBJECTIVE: Coordination of a large, multicenter Phase 3 clinical trial is critical to the success of the trial. The focus of this article is to describe the special challenges involved in the coordination of the 11 clinical centers conducting the COMBINE clinical trial and to discuss the challenges of monitoring the information collected on the 1,383 participants enrolled in this trial. METHOD: The role of the coordinating center in working with the clinical sites is to ensure both high data quality and that the intervention protocol is conducted with appropriate attention paid to patient safety and consistency across sites. To satisfy those goals, a research committee of investigators and coordinating center staff was formed. The committee monitored adverse event reporting, participant safety, recruitment, delivery of the interventions, collection of assessments and completeness and timeliness of transfer of data to the coordinating center. Objective measures of performance were determined for each criterion to provide the principal investigators, study sponsor and Data and Safety Monitoring Board with feedback on conduct of the trial. Site performance as defined by these criteria was evaluated periodically, with both detailed written and verbal feedback provided to each investigator and study coordinator. RESULTS: The system was successful in detecting sites with performance issues, providing feedback to site personnel and measuring improvement. Study leadership, clinical center staff and coordinating center staff felt that the procedures for identifying and solving performance issues worked well and improved overall performance. CONCLUSIONS: Establishing an organizational structure that provided (1) leadership, (2) a venue for communication, (3) performance criteria and (4) a process for monitoring performance goals and providing feedback has enabled COMBINE to achieve success in reaching these markers of clinical trial practice.

Alcoholism↗

PubMed2006

The prostate cancer prevention trial: design, biases and interpretation of study results.

PURPOSE: We describe the complexities of the study design of the PCPT and how they influenced the end point chosen, trial implementation, analysis and interpretation of the results. MATERIALS AND METHODS: Data from the PCPT are provided to evaluate and quantify the potential biases of this trial design. RESULTS: Six potential sources of bias, including prostate specific antigen, digital rectal examination, prostate biopsy technique, study medication nonadherence and contamination, and transurethral prostate resection are presented. These biases resulted in the need for the end of study biopsy to evaluate the trial objectives. CONCLUSIONS: There were a large number of known and potential biases that worked for and against finasteride. Because of the trial design and inherent biases, it is imperative that interim biopsy results should be interpreted with caution. While the period prevalence end point that relied on an end of study biopsy was perhaps not the most clinically relevant, it was the only way to remove as much bias as possible and meet the study objective of determining if finasteride could decrease the risk of prostate cancer. The success of the PCPT depended on constant scrutiny by the Data and Safety Monitoring Committee to monitor these biases. The design and biopsy assumptions outlined at the inception of the trial were met, including adherence and contamination rates, the for-cause biopsy rate and the final percent of men with study end points.

Bias↗

PubMed2001

Predicting analysis times in randomized clinical trials.

Randomized clinical trial designs commonly include one or more planned interim analyses. At these times an external monitoring committee reviews the accumulated data and determines whether it is scientifically and ethically appropriate for the study to continue. With failure-time endpoints, it is common to schedule analyses at the times of occurrence of specified landmark events, such as the 50th event, the 100th event, and so on. Because interim analyses can impose considerable logistical burdens, it is worthwhile predicting their timing as accurately as possible. We describe two model-based methods for making such predictions during the course of a trial. First, we obtain a point prediction by extrapolating the cumulative mortality into the future and selecting the date when the expected number of deaths is equal to the landmark number. Second, we use a Bayesian simulation scheme to generate a predictive distribution of milestone times; prediction intervals are quantiles of this distribution. We illustrate our method with an analysis of data from a trial of immunotherapy in the treatment of chronic granulomatous disease.

Bayes Theorem↗

PubMed2001

Prospective application of Bayesian monitoring and analysis in an "open" randomized clinical trial.

We describe the prospective application of Bayesian monitoring and analysis in an ongoing large multi-centre, randomized trial in which interim results are released to investigators. Substantial variability in prior opinion led us to reject the use of elicited clinical priors for monitoring, in favour of archetypal prior distributions representing reasonable scepticism and enthusiasm. Likelihoods for odds ratios for different covariate values are derived from a logistic regression model, which allows us to incorporate information from prognostic factors without resorting to specialized software. Priors, likelihoods and posterior distributions are regularly reported to both an independent Data Monitoring Committee and the trial investigators.

Bayes Theorem↗

PubMed1982

A case report of data monitoring experience: the nocturnal oxygen therapy trial.

The monitoring of accumulating data in a clinical trial is a challenging endeavor, yet one that must be undertaken to fulfill the ethical responsibility to the participating subject. This paper, using the Nocturnal Oxygen Therapy Trial as an example, discusses three issues often faced by data monitoring committees. These are (1) the multiplicity of outcomes, (2) decisions about extension of the patient recruitment period in order to achieve specified sample size goals, and (3) problems in monitoring survival data with a lag in the reporting of events. The decision process can be quite complex and existing statistical methodology can at best serve as a guide in this decision process.

Clinical Trials as Topic↗

PubMed1992

Trials and tribulations: the ISIS experience.

The ISIS trials group has grown slowly over the last ten years and now includes about 1000 collaborating hospitals worldwide. The original stimulus came from the thesis of a research student, Salim Yusuf, a newly qualified Rhodes Scholar from India. Yusuf's thesis (begun in 1976) examined methods of measuring infarct size quantitatively and paved the way to a preliminary trial of i.v. atenolol in 477 patients in Manchester and Oxford. Richard Peto was consulted about the statistical aspects of a trial design and pointed out that most clinical trials at that time were hopelessly inadequate in size to have the power reliably to ascertain the value of moderate but medically worthwhile treatments in many common conditions. We thus developed much larger collaboration, which still continues to grow. Dr Rory Collins joined the Oxford Cardiac Department and the CTSU in 1981 and now is the coordinator of the ISIS trials, and co-director with Richard Peto of the CTSU. Simple trials answer the questions rapidly and effectively. The mechanics of the trial do not hinder patient entry by participating doctors and nurses. The trials are mainly funded by industry, with 'priming' grants from the British Heart Foundation. Once the protocol is agreed the funding companies have no further input. The trials are planned and supervised by an international steering committee. Sir Richard Doll chairs the data monitoring committees. A brief overview of the three completed trials will be given, together with some peeps behind the scenes.

Clinical Trials as Topic↗

PubMed1991

Interim analysis in clinical trials.

The early development of experimental design discouraged a sequential approach to the analysis of data, yet this seems a natural form of scientific enquiry. Clinical trial investigators should continuously monitor the quality of their techniques, but will often wish to delegate data monitoring to an independent group. The history and functions of data monitoring committees (DMCs) are reviewed. DMCs come in many shapes and sizes. They will need to consider many aspects of the data before making recommendations to the investigators, who have ultimate responsibility for early termination or protocol changes. Statistical issues form part of the assessment, and will involve management, safety and efficacy. Two broad approaches to early stopping are (i) the demonstration of strong evidence that a treatment effect falls above or below some critical value (not necessarily zero); (ii) stochastic curtailment based on prediction of final results. The latter is examined somewhat critically. Most trials will involve group sequential analyses at discrete time points. The effect of repeated data inspection on (i) is well known, although its relevance is debatable. Bayesian and likelihood methods do not entirely remove the difficulty.

Bayes Theorem↗

PubMed2006

The Managed Ventricular pacing versus VVI 40 Pacing (MVP) Trial: clinical background, rationale, design, and implementation.

BACKGROUND: Implantable cardioverter defibrillators (ICDs) reduce mortality among appropriately selected patients who have had or are at risk for life-threatening ventricular arrhythmia. Right ventricular apical (RVA) pacing has been implicated in worsening heart failure and death. The optimal pacemaker mode for bradycardia support while minimizing unnecessary and potentially harmful RVA pacing has not been determined. METHODS: The Managed Ventricular pacing vs. VVI 40 Pacing Trial (MVP) is a prospective, multicenter, randomized, single-blind, parallel, controlled clinical trial designed to establish whether atrial-based dual-chamber managed ventricular pacing mode (MVP) is equivalent or superior to back-up only ventricular pacing (VVI 40) among patients with standard indications for ICD therapy and no indication for bradycardia pacing. The MVP Trial is designed with 80% power to detect a 10% reduction in the primary endpoint of new or worsening heart failure or all-cause mortality in the MVP-treated group. Approximately 1,000 patients at 80 centers in the United States, Canada, Western Europe, and Israel will be randomized to MVP or VVI 40 pacing after successful implantation of a dual-chamber ICD. Heart failure therapies will be optimized in accordance with evidence-based guidelines. Prespecified secondary endpoints will include ventricular arrhythmias, atrial fibrillation, new indication for bradycardia pacing, health-related quality of life, and cost effectiveness. Enrollment began in October 2004 and concluded in April 2006. The study will be terminated upon recommendation of the Data Monitoring Committee or when the last patient enrolled and surviving has reached a minimum 2 years of follow-up. CONCLUSION: The MVP Trial will meet the clinical need for carefully designed prospective studies to define the benefits of atrial-based dual-chamber minimal ventricular pacing versus single-chamber ventricular pacing in conventional ICD patients.

Canada↗

PubMed1996

Defining the regulatory role of ambulatory blood pressure monitoring. ABPM Steering Committee.

Our division is in a privileged position to study the usefulness of ABPM in the clinical development of antihypertensive agents. Most trials involving ABPM are commercially sponsored, and in due course, much of that data is presented to the Division. As such studies become more prominent in drug development, the Agency must make decisions on how such data are analyzed and interpreted. These should be seen as this project's short-term goals. In the longer term, the accumulation of ABPM data from clinical trials will be a valuable resource that researchers can use to address questions about what aspects of hypertension are most associated with prognosis and which treatments affect those aspects.

Antihypertensive Agents↗

PubMed1995

Optic nerve decompression surgery for nonarteritic anterior ischemic optic neuropathy (NAION) is not effective and may be harmful. The Ischemic Optic Neuropathy Decompression Trial Research Group.

OBJECTIVE: To assess the safety and efficacy of optic nerve decompression surgery compared with careful follow-up alone in patients with nonarteritic anterior ischemic optic neuropathy (NAION). DESIGN: The Ischemic Optic Neuropathy Decompression Trial (IONDT) is a randomized, single-masked, multicenter trial. SETTING: Twenty-five US clinical centers. PARTICIPANTS: The IONDT ceased recruitment on October 20, 1994, on the recommendation of its Data and Safety Monitoring Committee. The preliminary results presented herein are based on data as of September 8, 1994, from 244 patients with NAION and visual acuity of 20/64 or worse. One hundred twenty-five patients had been randomized to careful follow-up, and 119 had been randomized to surgery, with 91 and 95, respectively, having completed 6 months of follow-up. INTERVENTION: Patients in the surgery group received optic nerve decompression surgery and follow-up ophthalmologic examinations; those in the careful follow-up group received ophthalmologic examinations at the same times as the surgery group. MAIN OUTCOME MEASURES: Gain or loss of three or more lines of visual acuity on the New York Lighthouse chart at 6 months after randomization, as measured by a technician masked to treatment assignment. RESULTS: Patients assigned to surgery did no better when compared with patients assigned to careful follow-up regarding improved visual acuity of three or more lines at 6 months: 32.6% of the surgery group improved compared with 42.7% of the careful follow-up group. The odds ratio (OR) for three or more lines better, adjusted for baseline visual acuity and diabetes, was 0.74 (95% confidence interval [CI], 0.39 to 1.38). Patients receiving surgery had a significantly greater risk of losing three or more lines of vision at 6 months: 23.9% in the surgery group worsened compared with 12.4% in the careful follow-up group. The 6-month adjusted OR for three or more lines worse was 1.96 (95% CI, 0.87 to 4.41). No difference in treatment effect was observed between patients with progressive NAION and all others. CONCLUSION: Results from the IONDT indicate that optic nerve decompression surgery for NAION is not effective, may be harmful, and should be abandoned. The spontaneous improvement rate is better than previously reported.

Aged↗

PubMedDate not supplied

An economic evaluation of the JNC hypertension guidelines using data from a randomized controlled trial. Joint National Committee.

BACKGROUND: We wanted to determine the clinical cost of managing hypertension when following the Joint National Committee on Hypertension (JNC) guidelines, including drug therapy, the cost of monitoring for and treating side effects, compliance, and the cost of switching after therapeutic failures. METHODS: The base-case analysis considers antihypertensive agents from four therapeutic classes that were recently evaluated in a large randomized trial: enalapril, amlodipine, acebutolol, and chlorthalidone. Clinical evaluation, therapy, and monitoring for hypertension are modeled with an incidence-based Markov model. Clinical inputs include agent efficacy, side effects, and compliance with dosing schedules. JNC-recommended clinical and laboratory monitoring schedules are followed for each agent. Switches between classes occur for therapeutic failures. Drug and medical care costs are valued in 1995 US dollars. RESULTS: Although patients whose hypertension was initially treated with amlodipine achieved control more readily than patients who were given the other agents, the initial costs to achieve and maintain hypertension control were lowest for chlorthalidone ($641), followed by acebutolol ($920), amlodipine ($946), and enalapril ($948). Maintenance costs were lowest for chlorthalidone. For all agents except chlorthalidone, drug costs were the largest component of overall costs, followed by the costs of office visits, laboratory monitoring, and switching between classes for therapeutic failures. CONCLUSIONS: By following JNC guidelines, a slightly higher percentage of patients will achieve hypertension control with a newer class calcium channel blocker (amlodipine) but at a substantially higher cost than with a generic diuretic (chlorthalidone).

Acebutolol↗

PubMed2004

Where are clinical trials going? Society and clinical trials.

Clinical trials now increasingly impinge on society at large. First there is growing emphasis from health organizations on the need for unbiased evidence about the effectiveness of promoted remedies. Second, as most novel treatments accrue increased costs to society, these need to be evaluated in terms of value for money. Third, there has been confusion and concern about the resolution of conflicting evidence, especially the role of advertising and commercial pressures from a powerful pharmaceutical industry motivated by profit. Fourth, there is concern about research fraud and the ethics of clinical trials. Fifth, there is increasing suspicion of political advice, which sometimes has sought to reassure an anxious public on the basis of complex and possibly inadequate scientific information. Some of these issues are addressed by truly independent and properly constituted data and safety monitoring committees, which are of particular importance when academic investigators or universities have a large financial conflict of interest. This is now more problematic with the current encouragement of investigator-led spin-off companies. These issues are best resolved by independent financial support (from government or other institutions) rather than relying on the commercial sponsor.

Clinical Trials as Topic↗

PubMed1991

[Audit of clinical trials in Argentina. Assessment of standardized operational procedures in 12 centers].

The purpose of these audits was to ensure the quality, integrity and validity of investigational data. Audits were performed by control of compliance to standard operational procedures (SOPs) for Good Clinical Practice (GCP). Guidelines were proposed and established by the Food and Drug Administration (FDA) in 1977-1979 and adopted by several countries of the European Community in 1987-1989 and 1990. In Argentina, 12 on site audits of clinical trials performed between 1987 and 1990, were carried out. Basic data of GCP, audited in 58 out of 153 patients included in 12 different centers, were: protection of individual rights, compliance to standard operational procedures, adverse event reports, access to original investigational data and source document archives. The analysis of all audited data showed that patient case reports form recorded findings are credible and reliable and that researchers and monitors had conducted the study with an acceptable level in accordance to SOPs of good clinical practice. Otherwise, several in need of change to obtain better clinical data were identified: ethical committees, written informed consent, protocol adherence, data record, drug accountability, document source archives and the necessity of a thorough theorical and practical training on SOPs for GCP for researchers and monitors of clinical trials.

Argentina↗