Search

A question that routinely arises in medical device clinical studies is the homogeneity across demographic subgroups, geographical regions, or investigational sites of the enrolled patients in terms of treatment effects or outcome variables. The main objective of this paper is to discuss statistical concepts and methods for the assessment of such homogeneity and to provide the practitioner a statistical framework and points to consider in conducting homogeneity assessment. Demographic subgroups, geographical regions, and investigational sites are discussed separately as each has its unique issues. Specific considerations are also given to randomized controlled trials, non-randomized comparative studies, and single-arm studies. We point out that judicious use of statistical methods, in conjunction with sound clinical judgment, is essential in handling the issue of homogeneity of treatment effect in medical device clinical studies.

Challenging statistical issues often arise in the design and analysis of clinical trials to assess safety and effectiveness of medical devices in the regulatory setting. The use of Bayesian methods in the design and analysis of medical device clinical trials has been increasing significantly in the past decade, not only due to the availability of prior information, but mainly due to the appealing nature of Bayesian clinical trial designs. The Center for Devices and Radiological Health at the Food and Drug Administration (FDA) has gained extensive experience with the use of Bayesian statistical methods and has identified some important issues that need further exploration. In this article, we discuss several topics relating to the use of Bayesian statistical methods in medical device trials, based on our experience and real applications. We illustrate the benefits and challenges of Bayesian approaches when incorporating prior information to evaluate the effectiveness and safety of a medical device. We further present an example of a Bayesian adaptive clinical trial and compare it to a traditional frequentist design. Finally, we discuss the use of Bayesian hierarchical models for multiregional trials and highlight the advantages of the Bayesian approach when specifying clinically relevant study hypotheses.

Specification of the study objective of superiority or non-inferiority at the design stage of a phase III clinical trial can sometimes be very difficult due to the uncertainty that surrounds the efficacy level of the experimental treatment. This uncertainty makes it tempting for investigators to design a trial that would allow testing of both superiority and non-inferiority hypotheses. However, when a conventional single-stage design is used to test both hypotheses, the sample size is based on the chosen primary objective of either superiority or non-inferiority. In this situation, the power of the test for the secondary objective can be low, which may lead to a large loss of resources. Potentially low reproducibility is another major concern for the single-stage design in phase III trials, because significant findings of confirmatory trials are required to be reproducible. In this paper, we propose a hybrid Bayesian-frequentist approach to evaluate reproducibility and power in single-stage designs for phase III trials to test both superiority and non-inferiority. The essence of the proposed approach is to express the uncertainty that surrounds the efficacy of the experimental treatment as a probability distribution. Then one can use Bayes formula with simple graphical techniques to evaluate reproducibility and power adequacy., (2007 John Wiley & Sons, Ltd)

Object: The authors set out to evaluate the quality of life (QOL), social-emotional functioning, and behavioral functioning of children treated surgically for craniopharyngiomas., Methods: Twelve girls and 17 boys with a mean age at diagnosis of 8 +/- 3.8 years were surgically treated between 1985 and 1998 at the New York University Medical Center. After a mean follow-up period of 6.8 +/- 3.5 years, these 29 patients were administered either the 36-item Short Form Health Survey version 2 or the Child Health Questionnaire-Parent Form to assess QOL, as well as the Achenbach Child Behavior Checklist or Young Adult Checklist to measure social-emotional and behavioral functioning. Patients older than 19 years of age and parents of patients younger than 19 years of age reported low average overall physical QOL, with overall psychosocial QOL in the average range. Behavioral difficulties were noted, including internalizing, attention, somatic, and social difficulties. Further analyses indicated that retrochiasmatic tumor location, recurrence, and additional surgery were associated with poorer outcomes. In contrast, hydrocephalus, tumor size, and sex were not prognostic variables, and patients significantly improved as post-operative time increased., Conclusions: Attention toward late effects arising after the treatment of pediatric craniopharyngioma, including decreased postoperative physical health and behavioral functioning, is warranted. Future approaches to treatment should consider the documented effects of either gross-total resection or limited surgery followed by cranial irradiation on QOL, with specific evaluation for those with retrochiasmatic tumors, a recurrent tumor, or the need for additional surgery. Psychosocial QOL and social-emotional functioning should be maintained through ongoing counseling and education.

Background: This study evaluates differences in the utilization of breast conservation surgery (BCS) between major metropolitan areas in the United States (US) and the United Kingdom (UK)., Methods: Surgical and staging information were obtained from the Cancer Surveillance Program for Los Angeles County (LAC), the New York State (NYS) Department of Health Cancer Registry, and the UK National Health Service (NHS) Breast Screening Program. Demographic data were obtained from the census databases from the US, UK, Northern Ireland, and Scotland. Descriptive statistics, correlation analysis, and chi-square tests were used to compare rates of BCS across the locations under study., Results: Breast conservation rates were highest in London (79.3%) compared to New York City (NYC) (69.7%) and LAC (66.5%) (P < .0001). Both in NYS and the UK, the cities differ from the surrounding regions in population density, education levels, agricultural activities, and unemployment. BCS rates tended to increase with population density and education levels, and decrease with increased unemployment and agricultural activity, but there was no impact on BCS rates when adjustments for these variables were included in regression models. BCS rates increase with increasing hospital case volume in LAC and NYC (P < .0001)., Conclusion: When comparing large metropolitan areas in the US and UK there are significantly different rates of BCS in different locations. These differences reflect differences in population density, socioeconomic status (SES), education levels, hospital volume, and the effects of a nationally funded screening program.

Purpose: To report the clinical and dose-volume histogram results of the first 47 patients accrued to a protocol of accelerated partial breast irradiation. Patients were treated in the prone position with three-dimensional conformal radiotherapy after breast-conserving surgery., Methods and Materials: Postmenopausal women with Stage T1N0 breast cancer were eligible only after they had first refused to undergo 6 weeks of standard radiotherapy. Planning CT in the prone position was performed on a dedicated table. The postoperative cavity was defined as the clinical target volume, with a 1.5-cm margin added to determine the planning target volume. A total dose of 30 Gy at 6 Gy/fraction was delivered in five fractions within 10 days., Results: The median age of the patients was 67.5 years (range, 51-88 years). The median tumor diameter was 9 mm (range, 1.3-19 mm). In all patients, the prescribed dose encompassed the planning target volume. The mean volume of the ipsilateral breast receiving 100% of the prescription dose was 26% (range, 10-45%), and the mean volume contained within the 50% isodose surface was 47% (range, 23-75%). The lung and heart were spared by treating in the prone position. Acute toxicity was modest, limited mainly to Grade 1-2 erythema. With a median follow-up of 18 months, only Grade 1 late toxicity occurred, and no patient developed local recurrence., Conclusion: These data suggest that this approach is well tolerated, with only mild acute side effects and sparing of the heart and lung.

We investigated how frequently the imaging procedure we use immediately prior to radiosurgery--triple-dose gadolinium-enhanced MR performed with the patient immobilized in a nonrelocatable head frame and 1-mm-thick MPRAGE (magnetization-prepared rapid gradient echo) images (SRS3xGado)-identifies previously unrecognized cerebral metastases in patients initially imaged by conventional MR with single-dose gadolinium (1xGado). Between July 1998 and July 2000, the diagnoses established for 47 patients who underwent radio-surgical procedures for treatment of cerebral metastases at The Gamma Knife Center of New York University were based initially on the 1xGado protocol. In July 1998, we began using SRS3xGado as our routine imaging protocol in preparation for targeting lesions for radio-surgery, using triple-dose gadolinium and acquisition of contiguous 1-mm Tl-weighted axial images. Because our SRS3xGado scans sometimes unexpectedly revealed additional metastases, we sought to learn how frequently the initial 1xGado scans would underestimate the number of metastases. We therefore reviewed the number of brain metastases identified on the SRS3xGado studies and compared the results to the number found by the 1xGado protocol, which had initially identified the brain metastases. Additional metastases, ranging from 1 to 23 lesions per patient, were identified on the SRS3xGado scan in 23 of 47 patients (49%). In 57% of the 23 patients, only one additional lesion was identified. The mean time interval between the 1xGado and the SRS3xGado scans was 20.6 days (range, 4-83 days), and the number of additional lesions detected and the time interval between two scans were negatively correlated (-0.11). The number of lesions detected on the SRS3xGado was associated only with the number of lesions on the 1xGado and not with any other patient or tumor pretreatment characteristics such as age, gender, largest tumor volume on the 1xGado, or number of days between the 1xGado and the SRS3xGado or prior surgery. The identification of additional lesions with SRS3xGado MR may have implications for patients who are treated with stereotactic radiosurgery alone (without whole-brain irradiation) with single-dose gadolinium imaging, in that unidentified lesions may go untreated. As a result of these findings we continue to use and advocate SRS3xGado scans for radiosurgery.