DSMB. 1. What role, what responsibilities?

In addition to the IRB (Institutional review board), the DSMB (data safety and monitoring board) takes an increasing role in the monitoring of clinical trials, especially in large multicenter trials. The DSMB is a an expert committee, independent from the investigators and the sponsor of the trial, which periodically examines the safety data accumulated during progress of the trial and ensures that the benefit/risk ratio remains acceptable for participating patients. The DSMB is also a safeguard for the scientific integrity of the trial. It is the only committee which can have access to unblinded data from the trial. The DSMB may recommend termination of the trial in three situations : (1) occurrence of unanticipated adverse events which may pose a serious risk for participating patients; (2) demonstration of efficacy before the planned accrual \; (3) and because of "futility" (the most difficult situation), i.e. in absence of a reasonable probability that the trial may reach a conclusion within its planned frame.     

Clinical trials in developing countries: Discussions at the '9th International Symposium on Long Term Clinical Trials', London, UK, 19-20 June 2000

This symposium provided a useful forum for the discussion of issues relating to the design and conduct of clinical trials. There is a need for greater awareness of the complexity of modern day trials, in which a host of statistical, logistical, regulatory and ethical issues are involved. Issues discussed ranged from the effect of sample size on the outcome, and subgroup analysis, to defining and maintaining discrete endpoints. Some useful debate centred on the use of meta-analysis and the current limitations of combining information from different data sets. This brought up the subjects of trial registries and raw data repositories for all clinical trials. Progress and relevance of the Cochrane collaboration were reviewed. The economics of clinical trials was another important topic. Regulatory issues such as the role of data and safety monitoring boards (DSMB) and the guidelines in place for effective data monitoring and progress analysis were discussed. Representatives of government organisations and industry gave both European and American perspectives. This report however focuses specifically on the section devoted to the subject of clinical trials in developing countries.     

Experience collecting interim data on mortality: an example from the RALES study

Introduction  

The Randomized Aldactone Evaluation Study (RALES) randomized 822 patients to receive 25 mg spironolactone daily and 841 to receive placebo. The primary endpoint was death from all causes. Randomization began on March 24, 1995; recruitment was completed on December 31, 1996; follow-up was scheduled to continue through December 31, 1999. Evidence of a sizeable benefit on mortality emerged early in the RALES. The RALES data safety monitoring board (DSMB), which met semiannually throughout the trial, used a prespecified statistical guideline to recommend stopping for efficacy. At the DSMB's request, its meetings were preceded by an 'endpoint sweep', that is, a census of all participants to confirm their vital status.     

Data quality assurance and quality control measures in large multicenter stroke trials: the African-American Antiplatelet Stroke Prevention Study experience

Data quality assurance and quality control are critical to the effective conduct of a clinical trial. In the present commentary, we discuss our experience in a large, multicenter stroke trial. In addition to standard data quality control techniques, we have developed novel methods to enhance the entire process. Central to our methods is the use of clinical monitors who are trained in the techniques of data monitoring.     

Management strategies of dyslipidemia in the elderly: 2005

During the past 3 years, the treatment of dyslipidemia has evolved significantly. The impact of recent trial data on management strategies in older patients is especially important, because the elderly segment of the US population continues to grow. Several clinical trials have been completed since the publication of the National Cholesterol Education Program (NCEP) Adult Treatment Panel III guidelines were published in 2001. Recent trial data strongly support the use of lipid-lowering therapy in the elderly population. Although therapeutic lifestyle changes remain highly important, supplementation with lipid-lowering therapy has been shown to reduce the risk of cardiovascular events in both primary and secondary prevention models. Compelling data noted from recent clinical trials have prompted the NCEP to publish an updated report that addresses the significant interim developments.     

Stopping Rules for Clinical Trials Implicitly Incorporating Safety Information

Clinical trials research is mainly conducted for the purpose of evaluating the relative efficacy of two or more treatments. However, a positive response due to treatment is not sufficient to put forward a new product because one must also demonstrate safety. In such cases, clinical trials which show a positive effect would need to accrue enough patients to also demonstrate that the new treatment is safe. It is our purpose to show how the efficacy and safety problems can be combined to yield a more practical clinical trial design. In this paper we propose an asymmetric stopping rule which allows the experimenter to terminate a clinical trial early for a sufficiently negative result and to continue to a specified number of patients otherwise. As it turns out, a few interim tests will have negligible effects on the overall significance level.     

Les essais cliniques en médecine nucléaire

The EU clinical trials directive (2001/20/EC) was published on the 4th April 2001 and was transposed into French law in 2004. This new clinical trial regulation has modified considerably the research area including clinical trials conducted with radiopharmaceutical medicinal products. This new regulation aims at ensuring the protection of the health and safety of clinical trial participants, the ethical soundness and the reliability and robustness of data generated in clinical trials. In practice, the sponsor has to submit a clinical trial application to the Afssaps for authorization and to the concerned Ethics Committee for a positive opinion. The content of the clinical trial application regarding the investigational medicinal product is very detailed and a heavy technical dossier could be required in order to justify the quality of the medicinal product used in the clinical trial. Furthermore, pharmacy and radiopharmacy required specific authorizations for preparing these medicinal products. This new regulation could refrain nuclear medicine from conducting clinical trials.     

Monitoring the rates of composite events with censored data in phase II clinical trials

In many phase II clinical trials, interim monitoring is based on the probability of a binary event, response, defined in terms of one or more time-to-event variables within a time period of fixed length. Such outcome-adaptive methods may require repeated interim suspension of accrual in order to follow each patient for the time period required to evaluate response. This may increase trial duration, and eligible patients arriving during such delays either must wait for accrual to reopen or be treated outside the trial. Alternatively, monitoring may be done continuously by ignoring censored data each time the stopping rule is applied, which wastes information. We propose an adaptive Bayesian method that eliminates these problems. At each patient's accrual time, an approximate posterior for the response probability based on all of the event-time data is used to compute an early stopping criterion. Application to a leukemia trial with a composite event shows that the method can reduce trial duration substantially while maintaining the reliability of interim decisions.     

Applying results of randomised trials to clinical practice: impact of losses before randomisation.

The problem of generalisability in randomised clinical trials was highlighted by studies that entered only 10-14% of screened patients. To determine the magnitude and source of prerandomisation losses in clinical trials a survey was conducted of 41 trials listed in the 1979 inventory of the National Institute of Health. Two thirds of the trials maintained screening logs, but only half maintained any records of the number of patients who met the eligibility criteria but were not entered into the trial. Among 21 trials (51%) that kept data on the number of patients who were eligible but not entered, losses of eligible subjects were attributable to refusals by patients in 25% and refusals by physicians in 29%. Other protocol requirements accounted for the remaining losses of eligible patients. Only a few trials documented the characteristics of patients who were eligible but not entered; in those trials the patients who were not entered were similar demographically but differed clinically from those enrolled. Thus minimising prerandomisation losses of eligible patients requires the use of less restrictive criteria for entering patients. Twenty four of the trials achieved 75% or more of their recruitment goals, eight between 25% and 74%, and six less than 25%. Among trials that screened less than twice their projected sample size, only three out of 13 (23%) achieved 75% or more of their recruitment goal. By contrast, 12 out of 16 trials (75%) that screened more than twice their projected sample size achieved 75% or more of their recruitment goal. Screening large numbers of patients appears to be a pragmatic requirement for success in achieving recruitment goals; therefore, trials should not be criticised as lacking generalisability on that basis alone. The number and characteristics of eligible patients who were not entered, however, were documented by only a few trials; these data are critical in the assessment of generalisability. Additionally, the number of patients with the index disease who did not meet the eligibility criteria should also be documented. Together, these two types of data characterise the population to whom the trial results may be applied.     

Conjectures on some curious connections among social status, calorie restriction, hunger, fatness, and longevity

Since the original publication of the article "Development of the IL-12/23 antagonist ustekinumab in psoriasis: Past, present and future perspectives" in March 2011 (see Appendix),(1) there have been several new publications and developments of note. A number of new reports from the ustekinumab psoriasis clinical development program have been published. The analysis of efficacy and safety in the PHOENIX 1 long-term extension demonstrated that continuous stable maintenance dosing of ustekinumab was generally well tolerated and sustained durable efficacy through up to three years of treatment.(2) Pooled safety data from the phase 2 and phase 3 global trials showed that the safety profile of long-term continuous ustekinumab treatment through up to three years(3,4) and four years(5) of follow-up was favorable and comparable to what has been reported previously in the shorter-term ustekinumab psoriasis studies.(6-8) This represents the greatest exposure and longest follow-up of psoriasis patients treated with a biologic published to date. Additional phase 3 trials in Asian populations demonstrated similar high levels of efficacy and favorable safety profiles in Japanese,(9,10) Korean,(11,12) and Taiwanese(11,12) patients as those observed in trials conducted in mostly White populations in North America and Europe.(6-8) These data support the positive benefit:risk profile and consistency of response to ustekinumab over years of usage, and in multiple ethnic groups. Results from up to five years of treatment with ustekinumab in the long-term extensions of the phase 3 trials, and the efficacy, safety, and effect on quality of life in Chinese patients will be available in 2012. In addition to clinical trials of ustekinumab for the treatment of psoriasis, 24-week data from one phase 3 study of ustekinumab for the treatment of psoriatic arthritis has recently been presented(13) and another study is ongoing. A Phase 2b trial in Crohn's disease has also been presented,(14) and three phase 3 studies in Crohn's disease are currently in progress.     

Evidence-based management of acute myocardial infarction in the elderly--current perspectives

Cardiovascular disease accounts for significant morbidity and mortality in the elderly. Despite several, large cardiovascular clinical trials, data to guide therapy in this growing population subset are relatively limited. This review focuses on treatment approaches and recommendations for the management of elderly patients with acute myocardial infarction (MI) obtained from subgroup analyses from major clinical trials.Treatment options for acute MI in the elderly have changed dramatically since the 1990s. Reperfusion therapy by primary percutaneous coronary intervention has superseded the use of thrombolytic therapy for the treatment of acute ST-elevation myocardial infarction (STEMI). Clinical trial data have demonstrated that even transferring patients to facilities that have primary angioplasty capabilities is better than thrombolytic therapy, if the anticipated transfer time is of acceptable duration. Additionally, adjunctive use of the intravenous glycoprotein (GP) receptor antagonist, abciximab, during primary angioplasty affords a reduction in the composite primary end point of death, reinfarction, and target vessel revascularization, with much of the benefit derived from the latter. Thrombolytic therapy, barring any contraindication, must be used when mechanical revascularization is not available; however, the risk for complications in the elderly is higher, especially for those 75 years and older. Studies investigating the use of thrombolytics plus GP receptor antagonists with and without percutaneous coronary intervention show questionable benefit in the elderly.     

Medical Product Development, Innovation, and Life-Cycle Regulation: The Challenges for Biostatistics

The article provides a perspective on the challenges for biostatistics as well as on contributions that biostatisticians are making and can make to medical product development and regulation and what the future might be in these areas. The current environment in the United States for pharmaceutical development and regulation is discussed along with the expectations that the public has for how medical products should contribute to public heath. The globalization of research and the use of study designs that incorporate multi-regional populations present new challenges for design and inference. The emerging interest in and development of the science of safety assessment and quantitative approaches to risk evaluation is considered. Guidance development, especially in the area of clinical trials design, continues to be one of the needs that FDA is asked to meet. Guidance development is proceeding for non-inferiority study designs, adaptive designs, multiple endpoints in clinical trials, and missing outcome data in clinical trials. Biostatisticians will be asked and challenged to take on leadership roles in new areas such as personalized medicine, biomarker and genomics, development of new tools for visual display of clinical data, quality assurance and monitoring in clinical trials.     

Monitoring late-onset toxicities in phase I trials using predicted risks

Late-onset (LO) toxicities are a serious concern in many phase I trials. Since most dose-limiting toxicities occur soon after therapy begins, most dose-finding methods use a binary indicator of toxicity occurring within a short initial time period. If an agent causes LO toxicities, however, an undesirably large number of patients may be treated at toxic doses before any toxicities are observed. A method addressing this problem is the time-to-event continual reassessment method (TITE-CRM, Cheung and Chappell, 2000). We propose a Bayesian dose-finding method similar to the TITE-CRM in which doses are chosen using time-to-toxicity data. The new aspect of our method is a set of rules, based on predictive probabilities, that temporarily suspend accrual if the risk of toxicity at prospective doses for future patients is unacceptably high. If additional follow-up data reduce the predicted risk of toxicity to an acceptable level, then accrual is restarted, and this process may be repeated several times during the trial. A simulation study shows that the proposed method provides a greater degree of safety than the TITE-CRM, while still reliably choosing the preferred dose. This advantage increases with accrual rate, but the price of this additional safety is that the trial takes longer to complete on average.     

Review of Covid-19 vaccine clinical trials - A puzzle with missing pieces

A year after the initial outbreak of Covid-19 pandemic, several Phase III clinical trials investigating vaccine safety and efficacy have been published. These vaccine candidates were developed by different research groups and pharmaceutical companies with various vaccine technologies including mRNA, recombinant protein, adenoviral vector and inactivated virus-based platforms. Despite numerous successful clinical trials, participants enrolled in these trials are limited by trial inclusion and exclusion criteria, geographic location and viral outbreak situation. Many questions still remain, especially for specific subgroups, including the elderly, females with pregnancy and breastfeeding status, and adolescents. At the same time, vaccine efficacy towards asymptomatic infection and specific viral variants are still largely unknown. This review will cover vaccine candidates with Phase III clinical trial data released and discuss the scientific data available so far for these vaccine candidates for different subgroups of people and different viral variants.     

Specific and nonspecific immunotherapy as an adjunct to curative surgery for cancer of the lung.

Attempts to improve survival following curative surgery for non-small-cell lung cancer are reviewed. Most of these approaches have been designed to stimulate the resistance of lung cancer patients in a non-specific fashion. Living bacteria or products of dead bacteria have been given as adjunctive treatment. Various routes have been used; oral, intradermal, subdermal, or intrapleural, with either BCG or Corynebacterium parvum. No reproducible benefit has been observed. Levamisole has not been proven to be useful. Trials have yet to be completed to confirm the use of thymosin fraction V for small cell carcinoma in improving the effectiveness of chemotherapy. A pilot trial using specific active immunotherapy is described. Prolongation of survival four years after closure of the trial in those patients immunized, compared with non-immunized patients, has prompted two further clinical trials. A small trial has confirmed the effectiveness of specific immunotherapy as adjunctive therapy for squamous cell carcinoma. A large multicenter trial in Canada and the United States should be completed and open to analysis in 1984 and may shed light on the role of tumor-associated antigens in stimulating specific resistance to lung cancer.     

Design and current status of CONTINT: continuous versus interrupted abdominal wall closure after emergency midline laparotomy - a randomized controlled multicenter trial [NCT00544583

ABSTRACT: BACKGROUND: The optimal strategy for abdominal wall closure has been an issue of ongoing debate. Available studies do not specifically enroll patients who undergo emergency laparotomy and thus do not consider the distinct biological characteristics of these patients. The present randomized controlled trial evaluates the efficacy and safety of two commonly applied abdominal wall closure strategies in patients undergoing primary emergency midline laparotomy. Methods/design The CONTINT trial is a multicenter, open label, randomized controlled trial with a twogroup parallel design. Patients undergoing a primary emergency midline laparotomy are enrolled in the trial. The two most commonly applied strategies of abdominal wall closure after midline laparotomy are compared: the continuous, all-layer suture technique using slowly absorbable monofilament material (two Monoplus(R) loops) and the interrupted suture technique using rapidly absorbable braided material (Vicryl(R) sutures). The primary endpoint within the CONTINT trial is an incisional hernia within 12 months or a burst abdomen within 30 days after surgery. As reliable data on this primary endpoint is not available for patients undergoing emergency surgery, an adaptive interim analysis will be conducted after the inclusion of 80 patients, allowing early termination of the trial if necessary or modification of design characteristics such as recalculation of sample size. DISCUSSION: This is a randomized controlled multicenter trial with a two-group parallel design to assess the efficacy and safety of two commonly applied abdominal wall closure strategies in patients undergoing primary emergency midline laparotomy. Trial registration NCT00544583.     

Number of Published Randomized Controlled Multi Center Trials Testing Pharmacological Interventions or Devices Is Increasing in Both Medical and Surgical Specialties

Background

In general, there is a need for testing new interventions in large randomized controlled trials. Depending on the research question it may be advantageous to establish multicenter studies as a way of organizing clinical trials in order to increase study power.

Main Objectives

The object of this study was to investigate the development in the organization of multicenter studies, the distribution of studies within different clinical specialties, across continents, and investigate the differences related to testing various interventions.

Methods and Materials

A literature search was done in MEDLINE for multicenter studies published in 1995, 2000, 2005, and 2010, respectively. Data extraction identified data related to clinical specialties, interventions, participating patients, departments, countries, and continents.

Results

The number of multicenter studies increased from 112 in 1995 to 1,273 in 2010, with a larger share of multicenter studies being performed in Europe and North America. The pharmacological interventions were primarily being tested in medical studies followed by the device tests predominantly in surgical studies. The number of included patients as well as the number of participating departments increased during the time span, though the increase in studies was most evident in Europe and North America compared with the rest of the world.     

Adjusted regression trend test for a multicenter clinical trial

Studies using a series of increasing doses of a compound, including a zero dose control, are often conducted to study the effect of the compound on the response of interest. For a one-way design, Tukey et al. (1985, Biometrics 41, 295-301) suggested assessing trend by examining the slopes of regression lines under arithmetic, ordinal, and arithmetic-logarithmic dose scalings. They reported the smallest p-value for the three significance tests on the three slopes for safety assessments. Capizzi et al. (1992, Biometrical Journal 34, 275-289) suggested an adjusted trend test, which adjusts the p-value using a trivariate t-distribution, the joint distribution of the three slope estimators. In this paper, we propose an adjusted regression trend test suitable for two-way designs, particularly for multicenter clinical trials. In a step-down fashion, the proposed trend test can be applied to a multicenter clinical trial to compare each dose with the control. This sequential procedure is a closed testing procedure for a trend alternative. Therefore, it adjusts p-values and maintains experimentwise error rate. Simulation results show that the step-down trend test is overall more powerful than a step-down least significant difference test.