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PubMed2005

Randomized trials stopped early for benefit: a systematic review.

CONTEXT: Randomized clinical trials (RCTs) that stop earlier than planned because of apparent benefit often receive great attention and affect clinical practice. Their prevalence, the magnitude and plausibility of their treatment effects, and the extent to which they report information about how investigators decided to stop early are, however, unknown. OBJECTIVE: To evaluate the epidemiology and reporting quality of RCTs involving interventions stopped early for benefit. DATA SOURCES: Systematic review up to November 2004 of MEDLINE, EMBASE, Current Contents, and full-text journal content databases to identify RCTs stopped early for benefit. STUDY SELECTION: Randomized clinical trials of any intervention reported as having stopped early because of results favoring the intervention. There were no exclusion criteria. DATA EXTRACTION: Twelve reviewers working independently and in duplicate abstracted data on content area and type of intervention tested, reporting of funding, type of end point driving study termination, treatment effect, length of follow-up, estimated sample size and total sample studied, role of a data and safety monitoring board in stopping the study, number of interim analyses planned and conducted, and existence and type of monitoring methods, statistical boundaries, and adjustment procedures for interim analyses and early stopping. DATA SYNTHESIS: Of 143 RCTs stopped early for benefit, the majority (92) were published in 5 high-impact medical journals. Typically, these were industry-funded drug trials in cardiology, cancer, and human immunodeficiency virus/AIDS. The proportion of all RCTs published in high-impact journals that were stopped early for benefit increased from 0.5% in 1990-1994 to 1.2% in 2000-2004 (P<.001 for trend). On average, RCTs recruited 63% (SD, 25%) of the planned sample and stopped after a median of 13 (interquartile range [IQR], 3-25) months of follow-up, 1 interim analysis, and when a median of 66 (IQR, 23-195) patients had experienced the end point driving study termination (event). The median risk ratio among truncated RCTs was 0.53 (IQR, 0.28-0.66). One hundred thirty-five (94%) of the 143 RCTs did not report at least 1 of the following: the planned sample size (n = 28), the interim analysis after which the trial was stopped (n = 45), whether a stopping rule informed the decision (n = 48), or an adjusted analysis accounting for interim monitoring and truncation (n = 129). Trials with fewer events yielded greater treatment effects (odds ratio, 28; 95% confidence interval, 11-73). CONCLUSIONS: RCTs stopped early for benefit are becoming more common, often fail to adequately report relevant information about the decision to stop early, and show implausibly large treatment effects, particularly when the number of events is small. These findings suggest clinicians should view the results of such trials with skepticism.

Clinical Trials Data Monitoring Committees↗
PubMed2002

Regulatory perspectives on data monitoring.

Data monitoring is a critical component of the conduct of clinical trials that provide the evidence of efficacy and safety of investigational drugs. These trials may be conducted either by a pharmaceutical sponsor or by the government, especially those large trials that assess the impact of therapies on serious morbidity and/or mortality. While not extensive, I will review a regulatory history of FDA's evolving concerns and positions on data monitoring. I will review the key aspects of data monitoring and interim analysis of clinical trials contained in the recently published International Conference on Harmonization's statistical guidance as well as some other issues being considered for a draft guidance on data monitoring. Finally, some suggestions for improving and enhancing tools and statistical methods for monitoring clinical trials for safety assessment will be offered. This latter area deserves more consideration by statisticians than it has received to date.

Clinical Trials Data Monitoring Committees↗
PubMed2003

Introducing new technologies: protecting subjects of surgical innovation and research.

The system for protecting human research subjects is under increasing pressure. Under the currently dominant Regulatory Ethics Paradigm, clinical research protocols must be reviewed and approved by an institutional review board (IRB) or equivalent. Although the IRB was introduced into health care in part to protect patients and investigators from the inherent conflict between the best clinical interest of the individual patient and the interest of science and society in answering a clinical question, its rigorous standards and rigid framework discourage surgeons from seeking potentially valuable early IRB consultation. Most of the important advances in the history of medicine, such as anesthesia, appendectomy, antibiotics, intensive care, and immunization, were introduced through an informal, unregulated innovation process that has been enormously productive but can lead to ratification of ineffective or harmful treatment by credulous physicians and patients. We propose a surgical innovation ethics paradigm that is a more nimble, flexible source of institutional and public oversight and approval of innovations that are in the gray zone prior to their conversion to formal protocols that then require IRB approval. We also discuss the management of personal and institutional conflicts of interest.

Biomedical Research↗
PubMed2006

Understanding genetic risk for aggression: clues from the brain's response to social exclusion.

BACKGROUND: Although research indicates a relationship between the monoamine oxidase-A (MAOA) gene and aggression, the intervening neural and psychological mechanisms are unknown. Individuals with the low expression allele (MAOA-L) of a functional polymorphism in the MAOA gene might be prone to aggression because they are socially or emotionally hyposensitive and thus care less about harming others or because they are socially or emotionally hypersensitive and thus respond to negative social experiences with defensively aggressive behavior. METHODS: We investigated the relationships between the MAOA polymorphism, trait aggression, trait interpersonal hypersensitivity, and neural responses to social exclusion in 32 healthy men and women. RESULTS: The MAOA-L individuals (men and women) reported higher trait aggression than individuals with the high expression allele (MAOA-H). The MAOA-L individuals reported higher trait interpersonal hypersensitivity and showed greater dorsal anterior cingulate cortex (dACC) activity (associated with rejection-related distress) to social exclusion compared with MAOA-H individuals, consistent with a social hypersensitivity hypothesis. Moreover, the MAOA-aggression relationship was mediated by greater dACC reactivity to social exclusion, suggesting that MAOA might relate to aggression through socioemotional hypersensitivity. CONCLUSIONS: These data suggest that the relationship between MAOA and aggression might be due to a heightened rather than a reduced sensitivity to negative socioemotional experiences like social rejection.

Adult↗
PubMed2006

Respiratory adverse event profiles in cystic fibrosis placebo subjects in short- and long-term inhaled therapy trials.

The frequency and nature of adverse events (AEs) are important safety endpoints in clinical trials of therapies for cystic fibrosis (CF) subjects, yet published tables of background AE rates in the CF population are not readily available. Our objective in this study was to produce tables of respiratory AE rates for placebo subjects (pediatric and adult) for inhaled therapy trials in CF subjects. Respiratory AE rates in inhaled therapy trials were computed by combining data on placebo subjects from early-phase dosing studies and middle/late-phase studies, where placebo consisted of 4 or 5 mL of inhaled saline solution. AE rates were computed as number of events divided by number of placebo-subject days of observation, and 95% confidence intervals were computed based on a Poisson model. AEs were categorized as both broad (e.g., respiratory, reactive airway disease) and specific (e.g., cough, chest tightness, hemoptysis). In short-term studies, respiratory AE rates (95% confidence interval) were 1.1(0.7, 1.6)/person-week and 1.0(0.7, 1.4)/person-week in pediatric and adult subjects, respectively. In long-term studies, respiratory AE rates were 1.7(1.6, 1.8)/person-month and 2.2(2.1, 2.3)/person-month in pediatric and adult subjects, respectively. Stepwise Poisson models were fit to determine if baseline covariates were important in predicting AE rates. Forced expiratory volume in one second (FEV(1)) percent of predicted and age in short-term studies, and FEV(1) percent predicted and gender in long-term studies were statistically important in predicting respiratory AE rates. Although these variables were statistically significant, the models' predictive abilities were low, with adjusted R(2)'s of 0.06 and 0.12 in the short- and long-term studies, respectively. Combining placebo-subject AE data recorded from multiple CF clinical trials yields better estimates of true rates of occurrence in the CF population. The tables published from this study can be used to assist those charged with safety monitoring in CF clinical trials.

Administration, Inhalation↗
PubMed2003

Unique roles of a data and safety monitoring board in vaccine safety trials with compressed timelines and urgent implications.

Studies with urgent implications for public policy and programs represent a special case for monitoring boards, whose responsibilities must include ensuring applicability to policy making and timely communication of results as well as data and safety monitoring. We recently conducted two preseason evaluations of an influenza vaccine, results of which would influence the supply of vaccine for the Canadian annual program. Only 12 weeks were available for planning the studies and 6 weeks for fieldwork and data analysis. The enlisted board played key roles in determining appropriate study design, setting and enforcing rules for study initiation and early termination, monitoring safety, and encouraging timely dissemination of results. An extended role in data monitoring would have been desirable. Providing a safety valve for inevitable tensions between investigators and sponsor was an understated but significant role. Lessons from our experience will be particularly pertinent to future studies of pandemic influenza vaccines.

Canada↗
PubMed2003

DSMB case study: decision making when a similar clinical trial is stopped early.

Two similarly designed, placebo-controlled clinical trials are fully accrued and following patients for safety and outcome data. One trial is stopped at a planned interim analysis by its data safety and monitoring board (DSMB) due to a statistically significant treatment benefit. The statisticians and DSMB of the other trial are informed of these results. What are the responsibilities of the statistical center? How should the DSMB deal with the situation if the data do not support the stopped trial? What should the patients be told concerning the results of the two trials when one trial continues and the other is stopped? This DSMB case study reports on such a situation for two randomized clinical trials of oral ganciclovir for the prevention of cytomegalovirus disease in HIV/AIDS patients.

AIDS-Related Opportunistic Infections↗
PubMed2003

A model for the interim analysis process: a case study.

To evaluate data from a clinical trial before its completion, researchers routinely perform interim analyses. However, if not performed carefully, interim analyses can compromise the integrity of a clinical trial. In the last 10-15 years, regulatory authorities and the pharmaceutical industry have developed procedures and guidelines to allow trial sponsors access to unblinded data in an ongoing clinical trial without affecting the outcome. In December 1996, Abbott Laboratories was codeveloping a drug for treatment of an autoimmune disease. The pivotal phase II/III trial for the new drug application was very expensive, large, long term, and slow-accruing. The trial was initiated with a great deal of uncertainty concerning the safety and efficacy of the proposed treatment. An interim analysis was a logical part of the trial design. Two interim analyses were performed; the second analysis resulted in early termination of the trial. This article describes the interim analysis, including the process used for planning and execution and the lessons learned from the experience. In addition, the methodology for performing an interim analysis and the roles and responsibilities of involved members are discussed.

Clinical Trials Data Monitoring Committees↗
PubMed2004

Natural sunlight and its association to civil aviation accidents.

BACKGROUND: Glare is a temporary visual sensation produced by luminance within the visual field that is significantly greater than that to which the eyes are adapted. Glare from natural and artificial light sources can result in temporary visual impairment, increasing the risk of an accident. This study investigates the relationship between visual impairment from natural sunlight and aviation accidents. METHODS: The National Transportation Safety Board Aviation Accident/Incident Database was queried for the period January 1, 1988 to December 31, 1998 for terms, which included "sun," "glare," "vision," "blind ed," and "reflections." Reports annotated with one or more of these terms were reviewed to determine whether glare was considered a direct or contributing factor in the event. RESULTS: There were 130 accidents in which glare was found to be a contributing factor. The majority of these events occurred during clear weather and atmospheric conditions (85%), and were associated with approach/landing and takeoff/departure phases of flight (55%). CONCLUSIONS: Exposure to glare from natural sunlight has contributed to aviation accidents, primarily under otherwise optimal visual conditions at low altitude in congested airspace. Preventative techniques are presented that may protect a pilot's visual performance against the debilitating effects of glare from the sun.

Accidents, Aviation↗
PubMed2006

Labeling solutions and medications in sterile procedural settings.

BACKGROUND: Confusion resulting from unlabeled solutions and medications during sterile procedures can result in serious medication errors. CASE STUDY: During elective surgery; a seven-year-old boy was mistakenly injected with 100 times the intended dose of epinephrine. Cardiac arrest ensued, and the child died the next day. HOW ONE HOSPITAL MET THE CHALLENGE: At Marion General Hospital (Marion, Ohio), sterile procedures are performed in the surgery department, the cardiac catheterization lab, the labor and delivery area, intensive care unit rooms, and the emergency department. MGH's surgical services management team developed a policy and protocol for medication safety that refers to labeling of medications in sterile procedural settings. DISCUSSION: Sterile procedures often require medications or solutions to be placed in syringes or sterile basins. Facilities can eliminate the need for some solutions by using commercially available applicators or swabs, and can purchase some medications in sterile, labeled syringes. Sterile marking pens and blank sterile labels are available, as are preprinted sterile labels. The Association of periOperative Registered Nurses has helpful guidance statements and a medication safety toolkit. CONCLUSION: This requirement can be challenging to meet, but good resources are available.

Child↗