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PubMed1997

Rationale and design features of a clinical trial examining the effects of cholesterol lowering and angiotensin-converting enzyme inhibition on coronary atherosclerosis: Simvastatin/Enalapril Coronary Atherosclerosis Trial (SCAT). SCAT Investigators.

BACKGROUND: In the treatment of coronary atherosclerotic artery disease (CAD), the mechanisms by which lipid lowering, a proven therapy, produces beneficial clinical effects remain unclear. Moreover, although potential mechanisms of benefit are well known and increasingly applied clinically, there are no conclusive data from clinical trials studying primarily the antiischemic effects of angiotensin-converting enzyme (ACE) inhibition in patients with normal heart function. The Simvastatin/Enalapril Coronary Atherosclerosis Trial (SCAT) is designed to clarify some of these issues in CAD patients with normal or mildly elevated cholesterol. DESIGN AND OBJECTIVES: SCAT is a three- to five-year, multicentre, randomized, double-blind, placebo controlled, 2 x 2 factorial trial evaluating the effects of cholesterol lowering therapy by simvastatin and/or ACE inhibition by enalapril on anatomic coronary atherosclerosis progression assessed by quantitative coronary angiography in CAD patients with preserved left ventricular function and total cholesterol levels between 4.1 and 6.2 mmol/L. PATIENTS: Of 460 patients (age 61 +/- 9 years; 409 males, 51 females) enrolled between June 1991 and July 1995, 230 were randomized to simvastatin and 230 to placebo, and 229 to enalapril and 231 to placebo. Average baseline total cholesterol level was 5.20 +/- 0.61 mmol/L, high density lipoprotein cholesterol was 0.99 +/- 0.25 mmol/L, low density lipoprotein cholesterol was 3.36 +/- 0.57 mmol/L and triglycerides were 1.82 +/- 0.75 mmol/L. The trial will be completed in June 1998. SIGNIFICANCE: Insights gained from this long term angiographic trial will lead to a better understanding of the mechanisms of benefits of these two treatments, both alone and in combination. Of particular interest is that this trial will be able to examine a suspected beneficial interaction, if present, between these two treatments.

Aged↗
PubMed1997

Comparison of serological results in the NIAID Multicenter Acellular Pertussis Trial with recent efficacy trials.

Comparison of the serological results from the NIAID-funded Multicenter Acellular Pertussis Trial (MAPT) and the efficacy trials are complicated by differences in assay methods, immunization schedules, vaccine lots and populations immunized. In spite of these differences, serological results closely approximating those obtained in the MAPT were found for most or all of the assayed antibodies in the Mainz and Erlangen studies. Serological results for some of the antigens included in the vaccines used in the Italian and Stockholm trials were similar to the MAPT results, while significant differences were noted with other antigens. Differences in immunization schedules and serological assay methods made comparisons between MAPT and the Gothenburg and Senegal trials more difficult. Our understanding of the efficacy trial results, and our ability to apply those results to the U.S. population, would be enhanced markedly by simultaneous re-analysis of stored sera from MAPT and selected efficacy trials. This goal should be given priority by the study organizers and sponsors.

Clinical Trials as Topic↗
PubMed2006

National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease: VI. Design of Clinical Trials Working Group report.

The complexity of chronic graft-versus-host disease (GVHD) and the lack of established research methods have made it difficult to design, conduct, and analyze clinical trials involving subjects with this disease, even when promising treatment options are available. This consensus document was developed to offer an approach for overcoming these obstacles. Clinical trials in chronic GVHD should adhere to principles of good trial design and practice. Inclusion and exclusion criteria should allow as many subjects to participate as possible without compromising the interpretation of results. Pre-enrollment assessment of chronic GVHD characteristics should be standardized. The protocol should provide clear guidance about administration of study medication and other interventions. Methods of assessing response should be defined and validated in advance. Efficacy endpoints should be selected to reflect clinical benefit. Expert biostatistical support is needed to ensure the validity and reliability of trial results. The use of consistent standards in clinical trial designs to evaluate agents that have activity in pathogenic pathways could facilitate advances in the treatment of chronic GVHD.

Adrenal Cortex Hormones↗
PubMed2003

The Dual Chamber and VVI Implantable Defibrillator (DAVID) Trial: rationale, design, results, clinical implications and lessons for future trials.

T he Dual Chamber and VVI Implantable Defibrillator (DAVID) trial randomized 506 patients and tested the hypothesis that the dual-chamber pacing mode would produce improved hemodynamics and would in turn reduce congestive heart failure, heart failure hospitalizations, heart failure deaths, atrial fibrillation, strokes, ventricular arrhythmias, and total mortality compared to backup ventricular pacing in patients indicated for implantable defibrillator therapy. Patients had either primary prevention indications (47%) or secondary prevention indications (53%) for implantable defibrillator therapy but had no indications for bradycardia pacemaker support. All the patients had moderate to severe left ventricular dysfunction with a left ventricular ejection fraction of 40% or less (mean = 27%) and were consistently treated with angiotensin converting enzyme inhibitors or angiotensin II receptor blockers (86%) and beta adrenergic blocking agents (85%). The primary combined endpoint of hospitalization for congestive heart failure or death was paradoxically increased and statistically significant ( p = 0.03) at one year in the patients paced in the dual chamber mode (22.6%) compared to patients randomized to ventricular backup pacing (13.3%). Both heart failure hospitalization and mortality contributed outcome. Another perspective would consider this a randomized controlled study of presence or absence of pacemaker therapy in patients with left ventricular dysfunction and indications for implantable defibrillator therapy. Ventricular backup pacing produced less than 3% ventricular and no atrial pacing, while dual chamber pacing produced approximately 60% atrial and ventricular paced heart beats. The poor outcome in the dual chamber paced group correlated with the percentage of right ventricular pacing and suggests that right ventricular pacing caused ventricular dyssynchrony. The poor outcome associated with right ventricular pacing compared to intrinsic activation in the control group of the DAVID trial is reminiscent of the poor outcome associated with prolonged intraventricular conduction activation in the control groups compared to biventricular pacing in the intervention groups of the cardiac resynchronization trials. The direct conclusion from these results are that patients with indications for implantable defibrillators and no indication for pacing should not be paced in the dual chamber pacing mode. It is not appropriate to conclude that only single chamber implantable defibrillators should be implanted. There are other potential advantages to having an implanted atrial lead including improved secondary outcomes. However the DAVID trial results suggest that the dual chamber paced mode was not associated with improved quality of life or decreased frequency of hospitalization, inappropriate shocks from the defibrillator or atrial fibrillation. The more important question is what is the optimal pacing mode in these patients? The AAIR mode is under investigation in the DAVID II study in an attempt to identify a pacing mode that preserves atrio-ventricular synchrony, normal atrio-ventricular timing, prevents bradycardia and also prevents right ventricular stimulation. Caution should be taken to not directly apply these results to patients with either an indication for pacemaker therapy or to patients with an indication for cardiac resynchronization therapy since patients from neither population were included. However, considering the large magnitude of the deleterious effects associated with dual chamber pacing in the DAVID trial future studies should explore the possibility that left ventricular stimulation may be the only pacing mode capable of preventing bradycardia without increasing death and congestive heart failure.

Anti-Arrhythmia Agents↗
PubMed1998

A placebo-controlled trial of the immune modulator, lentinan, in HIV-positive patients: a phase I/II trial.

Lentinan is a beta 1-->3 glucan isolated from Lentinus edodes (Shiitake mushroom) which has immune modulating properties. We have conducted two phase I/II placebo-controlled trials on a total of 98 patients. In one study at the San Francisco General Hospital (SFGH), ten patients each were administered 2, 5, or 10 mg of lentinan or placebo i.v. once a week for eight weeks. In the second study at the Community Research Initiative in New York (CRI), two groups of 20 patients each were administered 1 or 5 mg of lentinan i.v. twice a week for 12 weeks, and ten patients were administered placebo (vehicle containing mannitol plus dextran 40) i.v. twice a week. Entry criteria were an HIV positive test, CD4 levels of 200-500 cells, age 18-60 years, and without current opportunistic infections. This study confirms, in Caucasian subjects also, the good tolerability of lentinan observed in Japanese cancer patients. Side effects were mainly mild, especially when infusion was carried out over a 30-minute period. In the SFGH study, where administration was over a ten minute period, there were nine side effects severe enough to be reported to the FDA (one case each of anaphylactoid reaction, back pain, leg pain, depression, rigor, fever, chills, granulocytopenia and elevated liver enzymes) and there were four patients who discontinued therapy because of side effects. In the CRI study, where infusion was over a 30-minute period, there were no side effects reportable to the FDA and there were four dropouts due to side effects or personal preference. Most side effects resolved promptly after the discontinuation of medication, and all of them were relieved within 24 hours. Patients in the study have shown a trend toward increases in CD4 cells and in some patients neutrophil activity. Because of the small numbers, these values do not have statistical significance. Inasmuch as no side effects such as anemia, leukopenia, pancreatitis or neuropathy were seen, and in view of the positive effects of lentinan on certain surrogate markers (recognizing that these were small studies), we recommended a long-term clinical trial of lentinan in combination with didanosine (ddI) or zidovudine in HIV positive patients. Most patients in these trials did not have measurable p24 levels. In the CRI trials of ten patients with elevated p24 levels, eight on lentinan and two on placebo had decreased p24 levels. Of these decreases, those with lentinan and one with placebo were marked. These results were provocative and needed confirmation. Subsequent to this study, a trial of lentinan in combination with didanosine (ddI) showed a mean increase of 142 CD4 cells/mm3 over a twelve month period, in contrast to a decrease in CD4 cells in patients on ddI alone (Gordon et al. 1995).

Adjuvants, Immunologic↗
PubMed2005

[The community clinical trial system EudraCT at the EMEA for the monitoring of clinical trials in Europe].

The GCP-Directive 2001/20/EG has been implemented in Germany by the 12th Amendment to the Drug Law of 6 August 2004 and the GCP-Ordinance of 9 August 2004, introducing new regulations for performing clinical trials. The information and documentation requested by the GCP-Ordinance to apply for the approval of a clinical trial can be partially prepared by using the EudraCT database. Crucial administrative and scientific information on a clinical trial is presented by the applicant to the EU member states in a harmonized manner. After the implementation of the data into the Community Clinical Trial Database System for member states, the clinical trials performed in some member states become comprehensible for the whole of the community. This increased transparency of planned, ongoing or finalized clinical trials will be an advantage for the safety of the participants.

Academies and Institutes↗
PubMed2003

[Differences between clinical trials according to the German law on pharmaceuticals (Arzneimittelgesetz) and trials according to the German law on medical products (Medizinproduktegesetz)].

PURPOSE: Similar to the registration process for pharmaceutical agents, medical devices have to undergo standardized clinical evaluation before being marketed and used in routine therapy or diagnostics. However, conduction, submission, and reporting of such clinical evaluations to authorities has to follow the German law on medical products(Medizinproduktegesetz,MPG), which in some central aspects differs remarkably from the German law on pharmaceuticals (Arzneimittelgesetz,AMG). METHODS: Relevant deviations of MPG requirements from those of the AMG are reviewed with particular emphasis on submission, conduction, and reporting of trials to the authorities in charge. RESULTS: Whereas AMG-based trials focus on the proof of efficacy of pharmaceutical agents, the MPG demands instead proof of functionality of the medical devices; the MPG therefore concentrates more on technically satisfactory results in the context of function and patient safety. The aim of MPG trials is thus CE marking instead of AMG-based registration. However, this focus on functionality implies that medical devices need not necessarily be tested in a clinical trial--in some settings evidence-based evaluation alone will be sufficient. The decision on the necessity of a clinical trial is based mainly on the risk profile and invasive character of the device at hand. CONCLUSIONS: The early consideration of differences between AMG and MPG concerning the role and conduction of clinical trials will remarkably increase the (CE) certification process's outcome quality and juridical validity.

Certification↗
PubMed2004

Challenges in the conduct of large simple trials of important generic questions in resource-poor settings: the CREATE and ECLA trial program evaluating GIK (glucose, insulin and potassium) and low-molecular-weight heparin in acute myocardial infarction.

BACKGROUND: Approximately 15.5 million deaths from cardiovascular diseases occur every year. About half are due to acute myocardial infarction (AMI), and 80% occur in low- and middle-income countries. Therefore, low-cost therapies would be invaluable. Although glucose-insulin-potassium (GIK) infusion and low-molecular-weight heparin (LMWH) appear to be promising in AMI, the available trials are inconclusive and these treatments require rigorous evaluation. METHODS: The Clinical Trial of Reviparin and Metabolic Modulation in Acute Myocardial Infarction Treatment and Evaluation-Estudios Clinicos Latino America (CREATE-ECLA) study is a randomized controlled trial in ST-elevation AMI patients evaluating a 24-hour infusion of Glucose-Insulin-Potassium (GIK) intravenous vs usual care (control) on 30-day mortality in 20,000 patients from 21 countries. Patients from India and China (n = 15,000) are also randomized using a factorial design to receive low-molecular-weight heparin (Reviparin) or placebo injection twice daily for 7 days to assess the impact on the composite outcomes of death, reinfarction or stroke (first co-primary outcome) or the composite + refractory ischemia (second co-primary outcome). RESULTS: Twenty thousand two hundred and one (20,201) GIK/control patients and 15,570 Reviparin/placebo patients have been included, with results expected in November 2004. CONCLUSIONS: The CREATE-ECLA trial will provide definitive answers to the role of 2 practical, promising and low-cost therapies, LMWH and GIK, in AMI patients. If effective, these therapies could be used in small medical centers in low- and middle- income countries. The experiences in this trial indicate that large trials of important questions can be successfully conducted in resource-poor settings, by academic groups without industry involvement.

Clinical Protocols↗
PubMed2006

The effects of oral anticoagulants in patients with peripheral arterial disease: rationale, design, and baseline characteristics of the Warfarin and Antiplatelet Vascular Evaluation (WAVE) trial, including a meta-analysis of trials.

AIMS: Patients with peripheral arterial disease (PAD) are at a high risk for cardiovascular (CV) morbidity and mortality even when treated with antiplatelet therapy. We present the rationale (including a meta-analysis of relevant trials), design, and baseline characteristics of the WAVE trial evaluating oral anticoagulants (OAC) in PAD. METHODS AND RESULTS: Nine trials involving 4889 patients with PAD evaluating OAC have conflicting results. Combining the data, it appears that OAC may reduce mortality and graft occlusion but increase major bleeding compared with no treatment. Compared with aspirin, OAC do not appear to reduce mortality (odds ratio [OR] = 1.04, 95% CI 0.55-1.29), although the CI are wide, or graft occlusion (OR = 0.91, 95% CI 0.77-1.06), and major bleeding is increased (OR = 1.96, 95% CI 1.43-2.69). Compared with aspirin, OAC used together with aspirin appears to increase mortality (OR = 1.57, 95% CI 1.16-2.12); may reduce graft occlusion (OR = 0.84, 95% CI 0.62-1.12), and major bleeding is increased (OR = 2.13, 95% CI 1.27-3.57). To further clarify the efficacy and safety profile of OAC in patients with PAD, we initiated the WAVE trial in which patients with PAD are randomized to receive OAC (target international normalizing ratio 2-3) plus antiplatelet therapy or antiplatelet therapy alone. Patients are treated for a minimum of 2.5 years and a maximum of 3.5 years. The co-primary efficacy outcomes are (1) CV death, MI, and stroke; and (2) CV death, MI, stroke, and acute limb or coronary ischemia requiring urgent intervention. The baseline characteristics of the study population confirm that patients with PAD represent a high-risk group. CONCLUSIONS: The results of previous randomized trials evaluating OAC in patients with PAD (who represent a group at a high risk for thrombotic events) are inconclusive. WAVE is a large, international, randomized clinical trial designed to determine if moderate levels of oral anticoagulation (international normalizing ratio 2-3) improve upon antiplatelet therapy alone.

Administration, Oral↗
PubMed2005

Pre-trial evaluation of the potential for unblinding in drug trials: a prototype example.

Blinding is an important design feature of randomised trials that may reduce bias in the results, compared to the situation where blinding is not possible or is not maintained. The literature provides some guidance for the evaluation of blinding in ongoing or completed studies, but the question of pre-trial assessment of the potential for unblinding has not been addressed. This paper describes the design and analysis of a prototype experiment for the pre-trial assessment of blinding in a drug trial. This work was motivated by a trial using antibiotic therapy, in which the investigators were concerned about the possibility of subjects being able to differentiate active medication from placebo, and thus become unblinded to their treatment assignment. A small experiment was mounted in which participants had to divide a random mixture of tablets into two groups. Statistical methods were developed to calculate the probability of a given number of similar tablets being classified into the same group by chance, with a modification to allow for some participants having constrained their responses to have equal numbers of tablets in each group. Differentiation of tablets by taste (the initial concern of the investigators) was not statistically different from chance. A smaller set of data on differentiation by appearance (a possibility not originally considered) had borderline statistical significance. After reviewing all these results, the investigators decided to proceed with the study without modifying the tablets, in part because subjects in the study would be unlikely to compare the two types of medication side-by-side. Our results suggest that blinding might sometimes be compromised in unexpected ways. Whenever possible, we suggest that similar and larger such experiments be carried out before the trial to assess whether blinding might be compromised. The methods proposed here could easily be adapted to evaluate the results of such experiments.

Anti-Bacterial Agents↗
PubMed2006

Cancer prevention trials and primary care physicians: factors associated with recommending trial enrollment.

BACKGROUND: To explore the willingness of primary care providers (PCPs) to encourage enrollment of patients into cancer prevention trials. METHODS: A self-administered survey was mailed to a random sample of PCPs in three geographic regions. Physicians were asked questions about their knowledge and attitudes towards cancer prevention trials. We presented a clinical vignette of a woman at high risk for breast cancer and asked if they would encourage her enrollment into a breast cancer chemoprevention trial (yes/no). Each survey included one of 16 possible clinical vignettes where patient characteristics (age, race socioeconomic status, physical mobility and co-morbidity) varied dichotomously. Bivariate analyses and logistic models were used to examine the independent effects of patient and physician characteristics on physician decisions. RESULTS: Two hundred and sixty-six surveys (50% response) were analyzed. The mean age of respondents was 48; 54% were White, 35% Asian and 5% Black. By design physicians were evenly distributed by gender, specialty and geographic location. Overall, 53% would encourage enrollment into a breast cancer chemoprevention trial. Significant predictors of a recommendation to enroll were: geographic location in California or Georgia, younger vignette patient and anticipating an increase in patient trust after recommending enrollment. CONCLUSION: PCPs are less likely to encourage elderly patients to enroll into cancer chemoprevention trials. Decisions differ based on geographic location and perceived trust in the patient-provider relationship. To achieve successful enrollment, trial investigators must continue to educate PCPs and ensure a strong PCP-patient relationship is maintained.

Aged↗
PubMed2006

Multinational clinical trials in oncology and post-trial benefits for host countries: where do we stand?

International collaboration has undoubtedly played a key role in the extraordinary progress we have witnessed in some areas of oncology in recent years. It has allowed us, for instance, to design trials large enough to depict very small benefits, as well as high-quality trials in less incident types of cancer. For different reasons, developing countries have also shown growing interest in this international effort and have been participating in many international trials. However, the ever-growing costs of novel anti-cancer treatments and technologies have created unprecedented difficulties for health economies in developing countries. Although the issue of individual benefit for patients must also be taken into account, the actual benefit for their society may be minimal. This paper discusses the ethics of including patients from non-developed countries in clinical trials evaluating the role of treatments that are unlikely to be made available to them after the trial because of prohibitive costs. Upfront arrangements ensuring post-trial access to interventions that have been proven successful might be the best alternative to exclusion from the research.

Clinical Trials as Topic↗
PubMed2006

The Trial Protocol Tool: The PRACTIHC software tool that supported the writing of protocols for pragmatic randomized controlled trials.

OBJECTIVE: To develop a tool that would make it easier for researchers, especially those in low- and middle-income countries, to write research protocols for pragmatic randomized controlled trials. STUDY DESIGN AND SETTING: A series of focus groups was held at the inaugural meeting of the Pragmatic RAndomized Controlled Trials in Health Care (PRACTIHC) project in 2001 to develop a desired specification for the Trial Protocol Tool. A working group of five individuals from the PRACTIHC group was formed to develop content for the tool. RESULTS: The Trial Protocol Tool was developed in English and Spanish as a Microsoft Windows HTML help system. A Web-based version is also available. This main body of the tool provides information, advice, and resources about the major headings that should be part of every research protocol. Illustrative examples are used throughout and are taken directly from the tool's protocol library. Additional resources include checklists, programs (e.g., a sample size calculator), and example documents (e.g., patient information leaflets). CONCLUSION: The Trial Protocol Tool packages all the key requirements for the development of a research protocol into one resource. We believe that the use of the tool will help researchers to design effective trials and to write high-quality protocols.

Clinical Protocols↗
PubMed2004

The Consolidated Standards of Reporting Trials (CONSORT): better presentation of surgical trials in the Journal of Hand Surgery.

To assure readers that study results are scientifically valid, the methods of a clinical trial should be described adequately. Since randomization, blinding, and intention-to-treat-analysis are major bias-reducing techniques, these aspects should be reported most accurately. The Consolidated standards of reporting trials (CONSORT) are recommendations to improve the reporting of trials. CONSORT requires that trial authors describe basic methodological aspects that readers need to appraise the strengths of reported clinical trials. This article presents the CONSORT recommendations and explains some of their main aspects. From now on, the Journal of Hand Surgery will use CONSORT to assist authors of randomized controlled trials in improving the description of their studies. We believe that this decision increases the scientific validity of study reports and helps readers when critically appraising articles.

Data Interpretation, Statistical↗
PubMed1998

Methods for economic evaluation alongside a multicentre trial in developing countries: a case study from the WHO Antenatal Care Randomised Controlled Trial.

The WHO is testing a new rationalised programme of antenatal care in a multicentre randomised trial. The motivation for this trial arose from the current uncertainty about the effectiveness of different approaches to provision of routine antenatal care. Decision makers also lack information about the costs of providing routine antenatal care and the cost-effectiveness of one programme over another. Such information will be needed before the final choice of programme can be made. The WHO trial provides an ideal opportunity to estimate and compare the incremental costs and cost-effectiveness of the new programme in four countries (Argentina, Cuba, Saudi Arabia, Thailand). A separate economic component has been organised to measure the costs of antenatal care. Methods for cost identification and measurement, and methods for economic analysis in the context of an international study are based on current recommendations for the conduct of economic evaluations alongside trials. However, several aspects require further development. In particular, this includes defining standard methods for costing in different countries; measuring women's costs of access to care; and making comparisons across international settings. The economic evaluation will also inform similar multicentre international trials and investigate issues of generalisability beyond trial settings.

Argentina↗
PubMed2000

Response criteria for clinical trials on osteoarthritis of the knee and hip: a report of the Osteoarthritis Research Society International Standing Committee for Clinical Trials response criteria initiative.

BACKGROUND: The domains of pain, function and patient's global assessment are identified as core variables and frequently measured in clinical trials of patients with osteoarthritis (OA) of the hip and knee. OBJECTIVE: To develop response criteria for OA of hip and knee based on the domains of pain, function and patient's global assessment. METHODS: A methodology was developed by an interaction of the Osteoarthritis Research Society International Standing Committee on Clinical Trials, biostatisticians, pharmaceutical company representatives and health agency representatives. Data from previously conducted placebo-controlled clinical trials were normalized and collated. Data were subset by location of OA (knee, hip), active agent used in the clinical trial (non-steroidal anti-inflammatory drug, other agent) and route of administration (oral, intra-articular). Statistical analysis identified response criteria which best discriminate active agent from placebo. RESULTS: Based on the analysis of data from 14 studies (totaling 1886 patients) and consensus opinion, the optimal responder criteria set differed for location of OA, active agent to be used, and route of administration. Because of nearly identical statistical results, two sets of responder criteria are proposed: (1) 'high' pain response or, alternatively, a 'moderate' response for at least two of three domains: pain, function and patient's global assessment; (2) 'high' response for either pain or function or, alternatively, a 'moderate' response for at least two of three domains: pain, function and patient's global assessment. The sensitivity (i.e., the percentage of responders in the active group) ranged from 52 to 96% and the specificity (i.e., the percentage of nonresponders in the control group) from 47 to 73%. CONCLUSION: Based on data from clinical trials, two sets of responder criteria have been developed that can categorize an individual's responses to treatment in a clinical trial. These responder criteria require validation in additional datasets.

Aged↗
PubMed2001

Monitoring a clinical trial conducted under the Food and Drug Administration regulations allowing a waiver of prospective informed consent: the diaspirin cross-linked hemoglobin traumatic hemorrhagic shock efficacy trial.

In 1996, the US Food and Drug Administration (FDA) enacted Rule 21 CFR section 50.24, which allows a narrow exception to the requirement for prospective informed consent from human research subjects in clinical trials investigating potentially beneficial therapies for acute, life-threatening conditions. The first clinical trial to be conducted under this rule was sponsored by Baxter Healthcare Corporation and approved by the FDA on November 21, 1996. This large, multicenter, randomized clinical trial was designed to compare the addition of diaspirin cross-linked hemoglobin (DCLHb) with standard care in the initial resuscitation of adults experiencing severe, uncompensated, traumatic hemorrhagic shock. Before the first planned interim analysis of the data, review of fatal adverse events revealed an imbalance in mortality between the 2 treatment groups. The Data Monitoring Committee (DMC) recommended suspension of patient enrollment 24 days later. Additional data collection and analyses confirmed the excess number of deaths in patients treated with DCLHb but failed to reveal the cause of these deaths. The trial was formally terminated after only 112 of the planned 850 patients had been enrolled. We review the events leading up to and the rationale behind the DMC recommendations for suspension of patient enrollment and trial termination. Although the DCLHb trial was unsuccessful in achieving its goals, the monitoring process worked well. Emergency research was facilitated by DMC oversight, and the interests of research subjects were protected by the actions of the DMC.

Aspirin↗
PubMed2006

Dosimetric verification in participating institutions in a stereotactic body radiotherapy trial for stage I non-small cell lung cancer: Japan clinical oncology group trial (JCOG0403).

A multicentre phase II trial of stereotactic body radiotherapy for T1N0M0 non-small cell lung cancer was initiated in Japan as the Japan Clinical Oncology Group trial (JCOG0403). Before starting the trial, a decision was made to evaluate the treatment machine and treatment planning in participating institutions to minimize the variations of the prescription dose between the institutions. We visited the 16 participating institutions and examined the absolute dose at the centre of a simulated spherical tumour of 3.0 cm diameter in the lung using the radiation treatment planning systems in each institution. A lung phantom for stereotactic body radiotherapy (SBRT) was developed and used for the treatment planning and film dosimetry. In the JCOG radiotherapy study group, the no model-based calculation algorithm or the model-based calculation algorithm with a dose kernel unscaled for heterogeneities were selected for use in the initial SBRT trials started in 2004, and the model-based calculation algorithm with a dose kernel scaled for heterogeneities was selected for the coming trial. The findings of this study suggest that the clinical results of lung SBRT trials should be carefully evaluated in comparison with the actual dose given to patients.

Algorithms↗