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PubMedDate not supplied

Some practical aspects of the interim monitoring of clinical trials.

The decision to stop accrual early to a clinical trial is often difficult and multifaceted. Interim monitoring boundaries have been found useful in U.S. oncology trials for such decisions for reasons described here. This paper also discusses rationale that lead to more conservative approaches to early stopping decisions than are currently employed. A recent initiative of the National Cancer Institute to achieve the objectives of independent data monitoring committees in the phase III clinical trials which it sponsors is also described.

Bias↗
PubMed2005

Issues in clinical trial design: stopping a trial early and the large and simple trial.

During the conduct of a clinical trial, a primary function of the Data Safety and Monitoring Committee is to select the trial conduct and the accumulating data to determine whether the trial should continue or be discontinued earlier than planned. Reasons for early discontinuation of a trial include: evidence of benefit, evidence of harm, and evidence of futility. More than 1 of these elements will often be present. These principles will be illustrated with examples from National Institute of Child Health and Human Development-Maternal-Fetal Medicine Units clinical trials. The "large and simple clinical trial" is a study design rarely undertaken in the United States but commonly used elsewhere. The principles of this type of trial will be introduced and contrasted with those of the "conventional clinical trial."

Clinical Trials Data Monitoring Committees↗
PubMed2000

[The role of the Japan Clinical Oncology Group].

The Japan Clinical Oncology Group (JCOG), a cooperative oncology group funded by the government of Japan, was founded in 1989. Over the past decade, the quality of clinical trials in Japan has improved greatly. The purpose of the JCOG is to establish and to improve the standard treatment of cancer by carrying out large, prospective, randomized, multicenter, clinical trials. The organizations to conduct clinical trials, such as a data center, clinical trial review committee, and monitoring committee, have been developed. One of the most important roles of the JCOG is the establishment and development of the necessary infrastructure. The JCOG is the largest cooperative oncology group in Japan and is conducting clinical trials to establish new "state of the art" treatment. However, the expansion of the data center and positioning of research nurses in each institute are essential for further development of the JCOG and clinical trials in Japan.

Clinical Trials as Topic↗
PubMed2001

Monitoring of large randomised clinical trials: a new approach with Bayesian methods.

BACKGROUND: In judging whether or not to continue enrolling patients into a randomised clinical trial, most data-monitoring and ethics committees (DMECs) rely on the p value for the difference in effect between the study groups. In the 1990s, two randomised controlled trials-one in patients with lung cancer and one in those with head and neck cancer-were instead monitored by Bayesian methods. We assessed the value of this approach in the monitoring of these clinical trials. METHODS: Before the trials opened, participating clinicians were asked their opinions on the expected difference between the study treatment (continuous hyperfractionated accelerated radiotherapy [CHART]) and conventional radiotherapy. These opinions were used to form an "enthusiastic" and a "sceptical" prior distribution. These prior distributions were combined with the trial data at each of the annual DMEC meetings. If, during monitoring, a result in favour of CHART was seen, the DMEC was to decide whether the results were sufficiently convincing to persuade a sceptic that CHART was worthwhile. Conversely, if there was apparently no or little difference, the DMEC was asked whether they thought the results sufficiently convincing to persuade an enthusiast that CHART was not worthwhile. FINDINGS: At each of the annual meetings, the DMEC concluded that there was insufficient evidence to convert either sceptics or enthusiasts, and that the trials should therefore remain open to recruitment. Neither trial was closed to recruitment earlier than planned. However if a conventional (p-value-based) stopping rule had been used, the lung-cancer trial would probably have been stopped. INTERPRETATION: This Bayesian approach to monitoring is simple to implement and straightforward for members of the DMEC to understand. In our opinion, it is more intuitively appealing than conventional approaches.

Bayes Theorem↗
PubMed1993

Data monitoring committees and capturing relevant information of high quality.

The integrity and credibility of randomized clinical trials, designed to provide a definitive evaluation of therapeutic interventions, can be substantially enhanced if periodic review of results on the relative efficacy of treatments is conducted by a data monitoring committee (DMC). The role of the DMC can include some important activities which promote obtaining relevant information of high quality. In the final stage of study development, these include review of protocol-specified study objectives and design, and review of procedures planned for capturing high-quality data and for reporting to the DMC. At analyses during the trial, these include careful review of data completeness and accuracy to assist in early detection and resolution of evolving problems.

Clinical Trials as Topic↗
PubMed1996

Changes in clinical trials mandated by the advent of meta-analysis.

Service on the Data Monitoring Committee of the CPEP (Calcium for Pre-eclampsia Prevention) has led us to four conclusions about clinical trials which we should like to present to this gathering of biostatisticians for their reactions: (i) meta-analyses of the pertinent published trials of the same therapy should always be undertaken before the start of a new trial, and the results examined to help determine the design of a new trial or determine if a trial should be undertaken at all; (ii) assuming that a decision is made to go ahead, the results of the past trials should be used in sizing the new one; (iii) in the course of the new one, regardless of the size estimates, stopping early should be considered if the trends conform to the results of the meta-analysis; and (iv) heterogeneity of patients entering clinical trials is desirable and should be specifically studied, and it should never be concluded that an average outcome is applicable to all future patients.

Calcium↗
PubMed1998

The Collaborative Ocular Melanoma Study (COMS) randomized trial of pre-enucleation radiation of large choroidal melanoma II: initial mortality findings. COMS report no. 10.

PURPOSE: To report initial mortality findings from the Collaborative Ocular Melanoma Study (COMS) randomized clinical trial of pre-enucleation radiation of large choroidal melanoma. METHODS: Patients were evaluated for eligibility at one of 43 participating centers in the United States and Canada. Eligible consenting patients were assigned randomly at the time of enrollment to standard enucleation or to external radiation of the orbit and globe prior to enucleation. Eligibility was confirmed at the COMS Coordinating Center, Echography Center, and Photograph Reading Center. Adherence to the radiotherapy protocol was monitored at the Radiological Physics Center. The diagnosis of choroidal melanoma was confirmed following enucleation by a three-member Pathology Review Committee. Patient accrual began in November 1986 and was completed in December 1994; 1,003 patients enrolled. Patients have been followed at annual clinical examinations. Cause of death was coded by a Mortality Coding Committee whose members were not involved in the care of COMS patients; the clinical trial was monitored by an independent Data and Safety Monitoring Committee. RESULTS: A total of 1,003 patients were enrolled; 506 were assigned to enucleation alone and 497 to pre-enucleation radiation. Treatment groups were well balanced on baseline characteristics. Only nine patients were found to be ineligible after enrollment, seven in the interval between randomization and enucleation and two after enucleation based on histopathology. All but nine patients were treated as assigned; in only six of 491 eyes treated with pre-enucleation radiation was there a major deviation from the radiotherapy protocol. With 5-year outcome known for 801 patients enrolled (80%), the estimated 5-year survival rates and 95% confidence intervals (CIs) were 57% (95% CI, 52% to 62%) for enucleation alone and 62% (95% CI, 57% to 66%) for pre-enucleation radiation. Among the baseline covariates evaluated, only age and longest basal diameter of the melanoma affected the prognosis for survival to a statistically significant degree. The risk of death among patients treated with pre-enucleation radiation relative to those treated with enucleation alone after adjustment for baseline characteristics of patients, eyes, and tumors was 1.03 (95% CI, 0.85 to 1.25). Of 435 deaths classified by the Mortality Coding Committee, 269 patients had histologically confirmed melanoma metastases at the time of death. Estimated 5-year survival rates for this secondary outcome were 72% (95% CI, 68% to 76%) for enucleation alone and 74% (95% CI, 69% to 78%) for pre-enucleation radiation. CONCLUSIONS: No survival difference attributable to pre-enucleation radiation of large choroidal melanoma, using the COMS fractionation schedule, has been demonstrated to date in this randomized trial. The trial had statistical power of 90% to detect a relative difference in mortality rates between the two treatment arms of 20% or larger. A smaller difference is possible, but a clinically meaningful difference in mortality rates, whether from all causes or from metastatic melanoma, is unlikely.

Adult↗
PubMed1993

Some FDA perspectives on data monitoring in clinical trials in drug development.

The FDA's interest in data monitoring of clinical trials derives from its public health responsibility to assure the safety and efficacy of new drugs based on evidence from adequate and well-controlled studies. Therefore the FDA is concerned that clinical trials of new drugs are designed and carried out in a manner that will insure the integrity and validity of study inferences. The FDA regulation and guidelines recognize the role of data monitoring and the variety and diversity of situations utilizing a data monitoring process in clinical studies. This paper describes relevant aspects of the regulations and guidelines, some concerns the FDA has with regard to monitoring of both government- and industry-sponsored trials and the consequences of early termination of trials of new drugs in the investigational and marketed stages. Comments include advice on communication between the FDA and data monitoring committees.

Clinical Trials as Topic↗
PubMed1987

Policies for study monitoring and interim reporting of results.

Interim analyses of comparative trials are necessary in order to monitor for extreme therapeutic results. However, closing studies and reporting results whenever "trends" appear increases the probability of a false conclusion to well over the desired .05 level. Guidelines for early stopping of comparative trials must be carefully defined to avoid this problem. In addition, to avoid inappropriate early closure of studies due to declining accrual (as investigators draw their own conclusions from early unreliable data), it is recommended that access to interim data be limited to a multidisciplinary monitoring committee responsible for (1) performing and reviewing interim analyses, and (2) deciding when early termination should be considered. Accrual and reporting of studies from two clinical trials groups, one with a policy of limited access to interim data and one without, are compared. The group without monitoring committees had a higher incidence of accrual and reporting problems than the group with monitoring committees.

Clinical Trials as Topic↗
PubMed1993

The NHLBI model: a 25 year history.

Although newer techniques and procedures have been developed, many of the clinical trial design and monitoring concepts used today in the NHLBI were implemented 25 years ago. Among these are the organizational structure of multicentre trials and the use of an independent data monitoring committee. Examples of data monitoring committee discussions and decisions are provided.

Clinical Trials as Topic↗
PubMed2006

PROactive study.

Explore the source record for details and available documents.

Clinical Trials as Topic↗
PubMed1986

Monitoring boundaries for adverse effects in long-term clinical trials.

The typical long-term trial has a data monitoring committee. A primary responsibility of this committee is maintenance of patient safety. In this role, this committee is likely to recommend stopping a trial when a new treatment appears worse than the control even when the difference is not statistically significant or if it appears that the new treatment will not be clearly beneficial. Several approaches, including the use of conditional power, can be used to help the monitoring committee decide if a study should be stopped early because of a harmful or insufficiently effective treatment. These monitoring approaches have altered the way in which we view one-sided or two-sided tests of significance.

Clinical Trials as Topic↗
PubMed1993

Monitoring clinical trials: experience of, and proposals under consideration by, the Cancer Therapy Committee of the British Medical Research Council.

The accumulating data from all randomized trials conducted by the Cancer Therapy Committee (CTC) of the British Medical Research Council are monitored on a regular basis. However, for important practical reasons the form of this data monitoring may vary from trial to trial. Thus a trial addressing what is considered a major question in the treatment of cancer patients, (a 'pivotal' or 'high profile' trial), has a formal data monitoring committee (DMC). This is usually made up of two clinicians and one statistician who are completely independent of the trial organization and do not enter patients into the trial. Other trials, which constitute the majority, are monitored by a less formal trial progress group made up of the clinical co-ordinator and trial statistician, sometimes supplemented by a trial participant. Experience with this dual system has led to a new proposal: if the trial progress group wish to modify or stop a trial then they are required to set up and consult an ad hoc DMC for independent advice. This proposal has many advantages, including maximizing the use of resources available, while achieving the degree of objectivity in decision-making required for the many different types of cancer trials conducted by the CTC.

Clinical Trials as Topic↗
PubMed1995

Robust Bayesian methods for monitoring clinical trials.

Bayesian methods for the analysis of clinical trials data have received increasing attention recently as they offer an approach for dealing with difficult problems that arise in practice. A major criticism of the Bayesian approach, however, has focused on the need to specify a single, often subjective, prior distribution for the parameters of interest. In an attempt to address this criticism, we describe methods for assessing the robustness of the posterior distribution to the specification of the prior. The robust Bayesian approach to data analysis replaces the prior distribution with a class of prior distributions and investigates how the inferences might change as the prior varies over this class. The purpose of this paper is to illustrate the application of robust Bayesian methods to the analysis of clinical trials data. Using two examples of clinical trials taken from the literature, we illustrate how to use these methods to help a data monitoring committee decide whether or not to stop a trial early.

Bayes Theorem↗
PubMed1993

Data monitoring in the cardiac arrhythmia suppression trial.

OBJECTIVE: This report discusses practical aspects of data monitoring in a clinical trial which stopped ahead of schedule due to adverse findings. DESIGN: A review of the considerations and decisions made by the data-monitoring committee of the Cardiac Arrhythmia Suppression Trial (CAST), a randomized, double-blind clinical trial. PATIENTS: CAST consisted of men and women with a recent myocardial infarction, asymptomatic or minimally symptomatic ventricular arrhythmias, and reduced left ventricular ejection fraction. INTERVENTIONS: In CAST, 3 antiarrhythmic agents, encainide, flecainide, and moricizine, were compared against placebo. MAIN OUTCOME MEASURES: The main outcome measures in CAST were arrhythmic death and total mortality. RESULTS: CAST found the 3 agents to be harmful. Encainide and flecainide were stopped first. Subsequently, moricizine was discontinued ahead of schedule. CONCLUSIONS: The complexity of the study design and a midcourse protocol modification raise several data-monitoring issues not previously discussed. These include how to handle apparently dramatic yet unexpected results, the need for flexibility in modifying study design and goals, and the conflict between existing study data and both conventional wisdom and medical practice.

Anti-Arrhythmia Agents↗
PubMedDate not supplied

The management of interim analyses in drug development.

The ethical need for interim analyses in long-term trials of life-threatening conditions is well established, but recently there has been increased enthusiasm for the use of interim analyses in other areas of clinical research. Interim analysis is seen as a powerful tool in drug development to help reduce 'time to market' by allowing key decisions to be made earlier on the basis of one or more ongoing clinical trials. However, this goal can only be achieved without serious penalties if interim analyses are properly designed and executed, so that the integrity of the whole drug development programme is maintained. The purpose of this paper is to define procedures for the design and management of clinical trials which involve interim analyses. These procedures are intended to incorporate good clinical and statistical practice, hence maintaining high scientific standards not only of individual trials but also of the overall development programme. Aspects of design, conduct, analysis and dissemination of results are considered, with particular focus on the effective use of data monitoring committees in confirmatory efficacy trials.

Bias↗