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PubMed2006

Cancer and leukemia group B clinical research associates committee.

The Cancer and Leukemia Group B is dedicated to developing and implementing training programs that will enhance the skills and abilities of Clinical Research Associates (CRA) involved in all aspects of data collection and research. Training programs not only improve overall knowledge and professionalism but also improve the integrity of study data. The CRA roles and responsibilities include the following: collect, analyze, and monitor data; collaborate with other members of the health care team; insure regulatory mandates are followed; manage the care of research participants; assist in the recruitment and enrollment of human subjects; protect subjects rights by adhering to Institutional Review Board guidelines, the Code of Federal Regulations; prepare and submit timely adverse event experience reports; maintain case report forms and drug accountability records; educate other health care professionals, patients, and families regarding clinical trials; participate in research audits; and function as a team member with the research team. In addition, CRAs may also be responsible for writing reports, grant, and budget development and the development of protocols, forms, and informed consent documents.

Allied Health Personnel↗

PubMed1991

North American Symptomatic Carotid Endarterectomy Trial. Methods, patient characteristics, and progress.

Fifty North American centers have combined to evaluate the benefit of carotid endarterectomy in randomized patients who have experienced symptoms related to arteriosclerotic stenosis of the carotid artery and who have received either best medical therapy alone or best medical therapy plus carotid endarterectomy. The outcome events are nonfatal and fatal stroke or death. A three-tier system identifies and adjudicates the type, severity, and location of each stroke and the cause of any death. Data about patients submitted to carotid endarterectomy outside the trial are compiled at the Nonrandomized Data Center at the Mayo Clinic. Between December 27, 1987, and October 1, 1990, 1,212 patients were randomized, 596 to medical therapy, 616 to carotid endarterectomy. Cross-over from the medical to the surgical arm has been low (4.2%). Patients eligible for the trial, but not randomized totaled 1,044; their characteristics were similar to those randomized so that, for the type of symptomatic patient in this study, our conclusions about the benefit of carotid endarterectomy can be generalized. Patients excluded by medical criteria totaled 679. Another 1,591 had carotid endarterectomy, but either lacked the disease under study, were asymptomatic, or received inadequate investigation to meet entry criteria. We set sample size at 1,900 patients, with continuing enrollment. The Monitoring Committee reviews at intervals the confidential analyses performed on the groups with moderate (30-69%) and severe (70-99%) stenosis. Stopping rules will be invoked for one or both groups if unequivocal benefit or harm is identified.

Aged↗

PubMed1991

Risk monitoring of randomized trials in emergency medicine: experience of the Brain Resuscitation Clinical Trial II.

Risk monitoring for the Brain Resuscitation Clinical Trial II, a multicenter, placebo-controlled trial to evaluate the efficacy of the calcium-entry blocker lidoflazine in the amelioration of brain damage in comatose cardiac-arrest survivors, posed unexpected challenges. Concern arose when monitoring of adverse reactions showed an excess of dangerous cardiac arrhythmias, including rearrest, in the lidoflazine group. To ascertain the cause of this problem and determine whether it was ethical for the trial to continue, an in-depth review of data was conducted, outside experts were consulted, and additional data were collected. These efforts suggested possible causes for the problem. Existing drug administration protocols for blood pressure control were reinforced, resulting in lower subsequent arrhythmia rates. Thus, through an efficient monitoring system, an important problem was uncovered and resolved, allowing the trial to be completed without major changes.

Arrhythmias, Cardiac↗

PubMed2005

Targeted glycemic reduction in critical care using closed-loop control.

BACKGROUND: Critically ill patients are often hyperglycemic and extremely diverse in their dynamics. Consequently, fixed protocols and sliding scales can result in error and poor control. Tight glucose control has been shown to significantly reduce mortality in critical care. An improved physiological system model of the glucose-insulin dynamics of a critical care patient is used to develop an adaptive tight glucose control protocol that accounts for variable patient dynamics, and is verified in limited clinical trials. METHODS: A physiologically based two-compartment system model that accounts for time-varying insulin sensitivity, time-varying endogenous glucose removal, and two saturation kinetics mechanisms is developed. A bolus-based adaptive control protocol is developed that monitors the physiological status of a critically ill patient, enabling tight glycemic regulation to preset glycemic targets. The model and protocol are verified in three, 5-h preliminary proof-of-concept clinical trials. Ethics approval was granted by the Canterbury Ethics Committee (Christchurch, New Zealand). RESULTS: Preset glycemic targets are achieved with an average absolute error of 9%, with 75% of all targets achieved within the 7% measurement error. Absolute errors greater than 7% ranged from 17% to 21%. CONCLUSIONS: Tight stepwise control was exhibited in all cases, and the adaptive system was able to match the model and observed patient dynamics. Most errors are associated with external perturbations such as drug therapies, or mismodeled parameters that can be easily adjusted with longer trials and/or more data per hour. The overall result is targeted stepwise tight glycemic regulation using insulin boluses.

Aged↗

PubMed1993

Behind closed doors: the data monitoring board in randomized clinical trials.

Many randomized clinical trials include a data and safety monitoring board (DSMB) that is responsible for reviewing accruing data, monitoring performance of the trial, assuring safety of the participants in the trial, and assessing the efficacy of treatment. The DSMB often makes recommendations about continuation of the trial or alteration of the protocol. Although such boards are very influential in both the conduct and interpretation of randomized clinical trials, there is no standard mode in which DSMBs operate nor do they routinely report publicly about their deliberations. This paper describes the composition of DSMBs as well as their functions. It concludes with a series of questions that needs to be addressed to ensure that the DSMBs operate effectively.

Aged↗

PubMed2006

A clinical trial of trimethobenzamide/diphenhydramine versus sumatriptan for acute migraines.

BACKGROUND: Although various classes of medication are used to treat acute migraine in the emergency department (ED), no treatment offers complete pain relief without side effects or recurrence of headache. Consequently, even though several antiemetic medications as well as SQ sumatriptan have demonstrated efficacy and tolerability for the ED treatment of migraine, there remains a need for more effective parenteral therapies. Open-label studies suggest that the combination of trimethobenzamide and diphenhydramine (TMB/DPH) may provide effective relief in a high proportion of migraineurs. OBJECTIVE: To test the hypothesis that ED patients with acute migraine, given intramuscular TMB/DPH, would have a larger reduction in their pain scores than patients given SQ sumatriptan. METHODS: This was an ED-based, randomized, double-blind, "double-dummy" clinical trial comparing 2 parenteral treatments for acute migraine headaches. Subjects received a combination of TMB 200 mg and DPH 25 mg as a single intramuscular injection or 6 mg of SQ sumatriptan. Pain scores, disability scores, associated symptoms, and adverse effects were assessed for 2 hours in the ED and by telephone 24 hours after medication administration. The primary outcome was the between-group difference in reduction of pain intensity as measured by a validated numerical rating scale 2 hours after medication administration. This study was designed to detect superiority of TMB/DPH; therefore, a 1-tailed t-test was used. An interim analysis was planned to terminate the trial if predetermined endpoints in the primary outcome variable were reached. RESULTS: The trial was stopped by the data monitoring committee after 40 subjects were enrolled because a substantial benefit in the primary outcome was found favoring sumatriptan. Baseline pain scores were comparable between the 2 groups. By 2 hours, sumatriptan subjects had improved by a mean of 6.1 and the TMB/DPH subjects had improved by a mean of 4.4 (95% CI for difference of 1.7: -0.1 to 3.4). By 24 hours after medication administration, sumatriptan subjects had a mean improvement from baseline of 4.9 as compared to 5.3 for TMB (95% CI for difference of -0.4: -2.4 to 1.6). The need for rescue medication was comparable between the groups. No serious or frequent adverse effects were noted in either group. CONCLUSIONS: SQ sumatriptan is probably superior to TMB/DPH for treating the pain of acute migraine at 2 hours. However, TMB/DPH was well-tolerated, efficacious, and relieved pain comparably to sumatriptan at 24 hours. TMB/DPH might have a role in select populations in which sumatriptan is contraindicated or likely to be ineffective.

Acute Disease↗

PubMed2001

[Reflections on some methodological errors in the evaluation of drugs. Ten years experience at the National Marketing Authorization Commission].

A ten year experience at the national french marketing authorization committee has permitted to notice the most commonly methodological errors in the field of clinical research and, particularly, in the dossiers for drug approval: a frequent insufficient sample size resulting in lack of statistical power, an unsatisfactory optimal dosing research, a misuse of the so-called surrogate markers, an erroneous opinion about the meaning of the p value, an abusive claim for equivalence in non significant superiority trials, a misuse of unadjusted multiple comparisons and too much confidence in subgroup analysis results.

Bias↗

PubMedDate not supplied

Triangular test and randomized trials: practical problems in a small cell lung cancer trial.

The triangular test has been used to monitor survival data from a randomized trial in patients with small cell lung cancer. The results of consecutive interim analyses and the problems met by the data monitoring committee and the co-ordinators are described. The methods as well as the consequences of the early stopping on the analysis and the results of this trial are discussed. From this experience, we believe that statistical stopping rules--only one of the factors to be taken into account when deciding to stop a trial--should be used with caution. Independent data monitoring committees may be useful in helping to review the ongoing results and advise the participants in the trial.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed2002

It's time to step up the management of community-acquired pneumonia.

Optimal therapy for serious Streptococcal pneumoniae infections with intermediate or high-grade resistance to penicillin is controversial. It should be noted that data regarding the efficacy of penicillins or cephalosporins for penicillin-resistant strains are limited. Despite the paucity of clinical trials, most clinicians still agree that penicillins remain the mainstay of therapy for community-acquired pneumonia caused by Streptococcal pneumoniae-susceptible strains. Macrolide antibiotics are effective for treatment of community-acquired pneumonia caused by susceptible strains of Streptococcus pneumoniae. But resistance to all macrolides, based on current National Committee for Clinical Laboratory Standards breakpoints, should be assumed among isolates with erythromycin resistance. The late-generation fluoroquinolones have a role for treatment of community-acquired pneumonia, however, there is also the potential for evolution of antimicrobial resistance. Performance indicators for community-acquired pneumonia are being established with implementation of protocols for inpatients with pneumonia. These indicators are being monitored by the Center for Medicare and Medicaid Services (CMS) for medicare patients as part of a national project. The indicators also address documentation of influenza and pneumococcal vaccine status in patients. Several other indicators, such as obtaining blood cultures before antibiotic administration, using antibiotics according to current guidelines, and timely administration of antibiotics, will play critical roles in the management of community-acquired pneumonia. Because of increased incremental costs associated with community-acquired pneumonia, early diagnosis and timely intravenous to oral switch therapy will continue to be emphasized and monitored in those admitted into hospitals, together with the appropriate decision tree-based pneumonia specific severity of illness scoring system.

Anti-Bacterial Agents↗

PubMedDate not supplied

Stopping a clinical trial early: frequentist and Bayesian approaches applied to a CALGB trial in non-small-cell lung cancer.

In May 1984, the Cancer and Leukemia Group B (CALGB) opened a phase III clinical trial for patients with stage III non-small-cell lung cancer (NSCLC). The experimental design entailed randomization of 240 patients equally to one of two treatments: radiotherapy alone or chemotherapy followed by radiotherapy. The original design was a fixed sample size design with the intent to analyse the results after 190 deaths. Shortly after the trial began, it was decided to apply group sequential concepts by using a truncated O'Brien-Fleming stopping rule, implemented via a Lan-DeMets alpha-spending function. A study monitoring committee was established to review the analyses as they were produced. The study was stopped at the fifth interim analysis in May 1987 after 155 eligible patients had been entered. This paper reviews the statistical and other considerations leading to this decision and presents later follow-up information on these patients. Some Bayesian alternatives to the standard frequentist approaches are also explored and it is demonstrated how these alternatives provide a natural way to address many of the issues raised in monitoring clinical trials.

Bayes Theorem↗

PubMed1975

An assessment of institutional review committees in human experimentation.

A study of the functioning of an institutional review committee, when combined with the Barber et al. survey data on 300 institutions, allows for a useful provisional assessment of the strengths and weaknesses of existing procedures for protecting human research subjects. The evidence shows that there is an important role for such committees; however, most committees are relatively permissive. While on committees' performance showed that such committees can have an impact on proposed research, the absence of effective monitoring procedures and lack of feedback from research subjects limits the impact of the review procedure on the actual conduct of research. The question is also raised whether the review procedure, because of its legitimizing functions, may have some regressive consequences for the protection of human subjects.

Clinical Trials as Topic↗

PubMed1980

Perceptions of the coordinating center: as viewed by an advisory board.

As an advisory group appointed by and directly accountable to the sponsoring agency, the advisory board has a unique relationship with the coordinating center. The coordinating center provides the data and analyses by which the board assesses progress and monitors safety of a trial. Although assessment of quality of performance of the units of the study is the direct concern of the coordinating center, corrective measures frequently become advisory board matters. Ideally, the relationship between the coordinating center and the advisory board is one of mutual trust and support in pursuit of the goal of a trial that is planned carefully, conducted with tight control of performance and safety, and reported accurately to the appropriate professional groups.

Clinical Trials as Topic↗

PubMed1993

Experiences with GCP in the pharmaceutical industry [corrected].

The Declaration of Helsinki and the "new" Germany Drug Law of 1976 may be regarded as the first and all important step in the evolution of Good Clinical Practices (GCP) in Germany. "Regulations on the orderly conduct of clinical studies" (published in 1987), reflecting most elements of the GCPs, caused the German industry to make provisions for more successful drug approvals in the future. Pharmaceutical companies have improved their documentation systems with regard to study protocols and reports, increased their monitoring capacity, and began setting up SOPs. In preparation for the issuing of the E.C. GCP guidelines companies established Clinical Quality Assurance (CQA) units responsible for various CQA tasks such as training of monitors and investigators, auditing of protocols, reports, systems, and data. Typical problems connected with the implementation of GCP in Germany appear to be contradictory opinions of the various ethics committees, reluctancy on the part of investigators to assume additional bureaucratic workload, difficulties on the part of the sponsor resulting from the high financial and manpower requirements, as well as the relatively unfavorable political and public opinion of clinical research. The benefits achieved by the introduction of GCP are already visible, i.e., increased quality of study protocol, conduct and report of studies, reduced number of studies, transparency at all stages of clinical research and increased ethical awareness.

Clinical Trials as Topic↗

PubMed1998

Randomized study of carotid angioplasty and stenting versus carotid endarterectomy: a stopped trial.

BACKGROUND: Carotid angioplasty (CA) has been suggested to be a safer and more cost-effective alternative to carotid endarterectomy (CEA) in the management of symptomatic severe internal carotid artery (ICA) disease. METHODS: The study was conducted as a prospective consecutive randomized trial of CEA versus CA for symptomatic severe ICA disease in a university teaching hospital. All patients were assessed before and after surgery by a neurologist. The study consisted of 23 patients with focal carotid territory symptoms and severe ICA stenosis (> 70%) who were randomized to either CEA or CA. However, only 17 had received their allocated treatment before trial suspension. CEA with patching or CA with stenting were used as interventions. The main outcome measures were death or disabling or nondisabling stroke within 30 days. RESULTS: All 10 CEA operations proceeded without complication, but 5 of the 7 patients who underwent CA had a stroke (P=.0034), 3 of which were disabling at 30 days. CONCLUSIONS: After referral, the Data Monitoring Committee invoked the stopping rule and the trial was suspended. The investigators and the Ethics Committee subsequently concluded that the trial could not be restarted--even in an amended format-primarily because of problems with informed consent. We review many of the ethical dilemmas encountered in the performance of this study. If future trials do suggest a selected role for CA, it is essential that both the inclusion and the exclusion criteria are fully documented.

Aged↗

PubMed2005

Phase II multi-institutional randomized trial of docetaxel plus cisplatin with or without fluorouracil in patients with untreated, advanced gastric, or gastroesophageal adenocarcinoma.

PURPOSE: The purpose of this study was to define the contribution of docetaxel to combination chemotherapy in the outcome of patients with advanced gastric or gastroesophageal adenocarcinoma. We compared the overall response rate (ORR) and safety of docetaxel plus cisplatin (DC) with DC plus fluorouracil (DCF) to select either DC or DCF as the experimental treatment in the ensuing phase III part of trial V-325. PATIENTS AND METHODS: In this phase II randomized study, untreated patients with confirmed advanced gastric or gastroesophageal adenocarcinoma received either DCF (docetaxel 75 mg/m2, cisplatin 75 mg/m2 on day 1, and fluorouracil 750 mg/m2/d as continuous infusion on days 1 to 5) or DC (docetaxel 85 mg/m2 and cisplatin 75 mg/m2 on day 1) every 3 weeks. An independent data monitoring committee (IDMC) was to select one of the two regimens based primarily on ORR and safety profile. RESULTS: Of 158 randomly assigned patients, 155 (DCF, n = 79; DC, n = 76) received treatment. The confirmed ORR was 43% for DCF (n = 79) and 26% for DC (n = 76). Median time to progression was 5.9 months for DCF and 5.0 months for DC. Median overall survival time was 9.6 months for DCF and 10.5 months for DC. The most frequent grade 3 and 4 events per patient included neutropenia (DCF = 86%; DC = 87%) and GI (DCF = 56%; DC = 30%). CONCLUSION: Both regimens were active, but DCF produced a higher confirmed ORR than DC. Toxicity profiles of DCF were considered manageable. The IDMC chose DCF for the phase III part of V-325, which compares DCF with cisplatin plus fluorouracil.

Adenocarcinoma↗

PubMed2003

Ethical considerations in psychopharmacological research involving decisionally impaired subjects.

RATIONALE: Research subjects who are unable to provide informed consent must be protected from exploitation. The federal regulations governing human subjects research mandate additional protections for "mentally disabled" subjects but include neither a definition of this "vulnerable" population nor any guidance on what safeguards should be employed or how they should be implemented. OBJECTIVES: This article begins with a definition of vulnerability due to a mental disorder in the context of the clinical research setting. It is organized along the following sequential phases of psychopharmacological research: study design and methodology; protocol review; subject recruitment and enrollment; conduct and monitoring of the study; and manuscript preparation and publication. Practical recommendations are then offered to clinical researchers and Institutional Review Boards (IRBs) for implementing additional protections for decisionally impaired subjects at each phase of the psychopharmacological research process. METHODS: A computer-assisted literature review was performed to identify descriptions of safeguards for decisionally impaired subjects. Recommendations for additional protections were also drawn from the authors' experiences with the IRB review process and the conduct and monitoring of clinical research with decisionally impaired subjects. RESULTS: The use of informed consent monitoring and the independent assessment of decision-making capacity are two feasible safeguards that IRBs can mandate for research with decisionally impaired subjects. There has been little systematic implementation of other safeguards such as research advance directives or prospective authorization for research participation. CONCLUSIONS: Clinical investigators and IRBs are under considerable scrutiny with respect to the protection of decisionally impaired research subjects. There is a pressing need for data-driven strategies for the optimal protection of decisionally impaired research subjects.

Biomedical Research↗

PubMed2001

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. METHODS: We used computer simulation to evaluate the effect of the sweeps. RESULTS: The sweeps led to an estimated 5 to 8% increase in the number of reported deaths at the fourth and fifth interim analyses. The data crossed the statistical boundary at the fifth interim analysis. If investigators had reported all deaths within the protocol-required 24-h window, the DSMB might have recommended stopping after the fourth interim analysis. DISCUSSION: Although endpoint sweeps can cause practical problems at the clinical centers, sweeps are very useful if the intervals between patient visits or contact are long or if endpoints require adjudication by committee, reading center, or central laboratory. CONCLUSION: We recommend that trials with interim analyses institute active reporting of the primary endpoints and endpoint sweeps.

Journal Article↗

PubMed2003

A randomized trial of letrozole in postmenopausal women after five years of tamoxifen therapy for early-stage breast cancer.

BACKGROUND: In hormone-dependent breast cancer, five years of postoperative tamoxifen therapy--but not tamoxifen therapy of longer duration--prolongs disease-free and overall survival. The aromatase inhibitor letrozole, by suppressing estrogen production, might improve the outcome after the discontinuation of tamoxifen therapy. METHODS: We conducted a double-blind, placebo-controlled trial to test the effectiveness of five years of letrozole therapy in postmenopausal women with breast cancer who have completed five years of tamoxifen therapy. The primary end point was disease-free survival. RESULTS: A total of 5187 women were enrolled (median follow-up, 2.4 years). At the first interim analysis, there were 207 local or metastatic recurrences of breast cancer or new primary cancers in the contralateral breast--75 in the letrozole group and 132 in the placebo group--with estimated four-year disease-free survival rates of 93 percent and 87 percent, respectively, in the two groups (P< or =0.001 for the comparison of disease-free survival). A total of 42 women in the placebo group and 31 women in the letrozole group died (P=0.25 for the comparison of overall survival). Low-grade hot flashes, arthritis, arthralgia, and myalgia were more frequent in the letrozole group, but vaginal bleeding was less frequent. There were new diagnoses of osteoporosis in 5.8 percent of the women in the letrozole group and 4.5 percent of the women in the placebo group (P=0.07); the rates of fracture were similar. After the first interim analysis, the independent data and safety monitoring committee recommended termination of the trial and prompt communication of the results to the participants. CONCLUSIONS: As compared with placebo, letrozole therapy after the completion of standard tamoxifen treatment significantly improves disease-free survival.

Adult↗