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David L DeMets

Publications and source records attributed to David L DeMets.

14 recordsLinked to original sources
PubMed2003

Her-2/neu overexpression and response to oophorectomy plus tamoxifen adjuvant therapy in estrogen receptor-positive premenopausal women with operable breast cancer.

PURPOSE: Studies evaluating the relationship of HER-2/neu breast tumor status and response to adjuvant endocrine therapy have reached conflicting conclusions about resistance of HER-2/neu-positive tumors to this treatment. We studied 282 patients participating in a randomized controlled trial of adjuvant oophorectomy and tamoxifen or observation who had estrogen receptor-positive tumors and whose tumors were evaluated for HER-2/neu overexpression by immunohistochemistry. PATIENTS AND METHODS: Univariate and multivariate Cox proportional hazards regression models and Kaplan-Meier disease-free and overall survival estimate methods were used. RESULTS: HER-2/neu overexpression was a negative prognostic factor for overall survival. In univariate analyses, in HER-2/neu-positive patients, the hazard ratio (HR) for disease-free survival (DFS) with adjuvant endocrine therapy was 0.37 (95% confidence interval [CI], 0.26 to 0.89); for HER-2/neu-negative patients, the corresponding HR for DFS was 0.48 (95% CI, 0.31 to 0.71). The overall survival (OS) data were HR=0.26 (95% CI, 0.07 to 0.92) and HR=0.68 (95% CI, 0.32 to 1.42) for HER-2/neu-positive and HER-2/neu-negative patients, respectively. In multivariate models, the P values for tests of interaction of HER-2/neu status and response to adjuvant endocrine therapy were 0.18 and 0.07 for DFS and OS, respectively. Kaplan-Meier DFS and OS curves and 3-year DFS estimates were consistent in showing greater benefit to the HER-2/neu-positive subgroup given adjuvant treatment. CONCLUSION: HER-2/neu overexpression does not adversely and may favorably influence response to adjuvant oophorectomy and tamoxifen treatment in patients with estrogen receptor-positive tumors.

Adult↗
PubMed2003

Monitoring mortality at interim analyses while testing a composite endpoint at the final analysis.

Mortality is often used as the clinical endpoint in clinical trials for acute diseases and takes precedence over any other outcome. A composite outcome such as death plus disease occurrence (or recurrence) or death plus hospitalization may also be considered, sometimes even as the primary outcome due to practical sample size issues. That is, a composite endpoint should have a higher event rate and thus a smaller sample size than for mortality alone to reach the same power. Two different scenarios are considered: in Scenario 1, the composite outcome is the primary endpoint and the mortality outcome is secondary; in Scenario 2, the mortality outcome is the primary endpoint and the composite outcome is secondary. In either scenario, the trial will be stopped if the simple mortality outcome shows an adverse effect or a significant benefit at an interim analysis, while the composite outcome will be tested at the final analysis if the mortality outcomes fails to show significance. These scenarios are typical in many trials sponsored by industry for regulatory approval. We refer to them as a switching the primary endpoint process. Two switching-endpoint procedures are proposed to calculate the efficacy boundary for the composite test statistic at the final analysis. The Bonferroni method is used in Method 1. In Method 2, the calculation is based upon the joint distribution of the test statistics for the simple mortality and the composite outcomes. A completed clinical trial, prospective randomized amlodipine survival evaluation (PRAISE-1), is used to illustrate the two switching-endpoint procedures. A simulation study shows that the two switching-endpoint procedures allow a trial to be stopped early due to a clinically relevant benefit in the mortality while preserving the overall alpha level.

Clinical Trials as Topic↗
PubMed2003

Toward protecting the safety of participants in clinical trials.

It is a widely held belief that the current system of oversight of clinical research, particularly the means of assessing risks and minimizing harms to participants in clinical trials, could be improved. In particular, the system is inefficient with overemphasis on the monitoring ability of some groups such as research ethics review boards and investigators, underemphasis on others such as data monitoring committees (DMCs) and sponsors, confusion about responsibilities for safety and imperfect communication between these different groups. Research ethics review boards are not able to perform safety monitoring by review of individual adverse events and are often burdened by duplicative reviews of large multicenter studies. There are no standards for DMCs to ensure they can reliably identify safety issues. Sponsors may be overreliant on data audits and slow to disseminate safety data in a coherent summary. Investigators, their staffs and clinical sites may not fully appreciate all the nuances of good clinical practice or may be inattentive to the daily conduct of studies. Regulators, particularly those in the United States, have failed to completely harmonize their policies with each other or with international regulatory agencies. We recommend well-designed monitoring plans for all studies that are appropriate to their scope and risk, more centralized review of large multisite studies and closer local scrutiny of single-institution studies. In addition, sponsors should pay greater attention to monitoring adverse events and keeping up-to-date databases or investigator's brochures emphasizing safety issues. A minimal standard of education or expertise in good clinical practice should be established for investigators, their staffs and research ethics review board members. DMC composition and functions should be standardized and regulations should be harmonized nationally and internationally. Finally, there should be a concerted effort to study the efficacy of various components of the system.

Clinical Trials Data Monitoring Committees↗
PubMed2002

Effect of carvedilol on the morbidity of patients with severe chronic heart failure: results of the carvedilol prospective randomized cumulative survival (COPERNICUS) study.

BACKGROUND: Beta-blocking agents improve functional status and reduce morbidity in mild-to-moderate heart failure, but it is not known whether they produce such benefits in severe heart failure. METHODS AND RESULTS: We randomly assigned 2289 patients with symptoms of heart failure at rest or on minimal exertion and with an ejection fraction <25% (but not volume-overloaded) to double-blind treatment with either placebo (n=1133) or carvedilol (n=1156) for an average of 10.4 months. Carvedilol reduced the combined risk of death or hospitalization for a cardiovascular reason by 27% (P=0.00002) and the combined risk of death or hospitalization for heart failure by 31% (P=0.000004). Patients in the carvedilol group also spent 27% fewer days in the hospital for any reason (P=0.0005) and 40% fewer days in the hospital for heart failure (P<0.0001). These differences were as a result of both a decrease in the number of hospitalizations and a shorter duration of each admission. More patients felt improved and fewer patients felt worse in the carvedilol group than in the placebo group after 6 months of maintenance therapy (P=0.0009). Carvedilol-treated patients were also less likely than placebo-treated patients to experience a serious adverse event (P=0.002), especially worsening heart failure, sudden death, cardiogenic shock, or ventricular tachycardia. CONCLUSION: In euvolemic patients with symptoms at rest or on minimal exertion, the addition of carvedilol to conventional therapy ameliorates the severity of heart failure and reduces the risk of clinical deterioration, hospitalization, and other serious adverse clinical events.

Adrenergic beta-Antagonists↗
PubMed2002

Clinical trials in the new millennium.

Since the introduction of the randomized clinical trial (RCT) over 50 years ago, this method has become the corner stone for evaluating new pharmacologic or biologic agents with many disease areas benefiting. There are numerous examples demonstrating beneficial interventions as well as others either not beneficial or harmful. Statistical methodology for clinical trials has grown rapidly. Advances in information technology for data collection have allowed trials to be conducted around the world. Academia, industry and government have worked in partnership to conduct RCTs. Despite these many RCT achievements, the most interesting and challenging era of clinical trials lies ahead of us. With the human genome now sequenced, we face a new set of challenges to transform vast amounts of data into useful information. The post-genomics era will better identify the disease mechanism and thus help design better treatments, and be more selective in screening patients, yielding more efficient clinical trials. For some areas of medicine, such as medical devices, standards of acceptance and regulatory approval are changing. Other areas, such as medical procedures and alternative medicines, are generally not well evaluated and could benefit greatly from a wider use of RCT methodology. As the ICH guidelines facilitate and encourage international clinical trials, the scientific and ethical dimension of conducting trials in Third World countries are raised. For example, Western society's best standard of care may not be available or affordable to these countries as the control Western investigators should not exploit patients in the Third World. Those and many other challenges face us in the decade ahead. It is truly an exciting time with new opportunities for the RCT to contribute to medicine and health care or prevention.

Data Interpretation, Statistical↗
PubMed2002

Monitoring clinical trials: issues and controversies regarding confidentiality.

During phase III clinical trials in life-threatening disease settings, it is important to ensure that the Data Monitoring Committee (DMC) has exclusive access to the interim efficacy and safety data generated by the data analysis centre, in order to minimize the risk of widespread prejudgement of unreliable trial results based on limited data. This prejudgement could adversely impact rates of patient accrual, continued adherence to trial regimens and ability to obtain unbiased and complete assessment of trial outcome measures. This also could result in publications of early results that might be very inconsistent with final study data on the benefit-to-risk profile of the study interventions. Circumstances arise only rarely in which unblinding of interim data beyond the DMC would enhance the ability of the trial to provide reliable results. However, to address the ethical imperative to protect the interests of study participants, the DMC itself should have access to unblinded efficacy and safety results.

Acquired Immunodeficiency Syndrome↗
PubMed2002

Oophorectomy and tamoxifen adjuvant therapy in premenopausal Vietnamese and Chinese women with operable breast cancer.

PURPOSE: In 1992, the Early Breast Cancer Trialists' Collaborative Group reported that a meta-analysis of six randomized trials in European and North American women begun from 1948 to 1972 demonstrated disease-free and overall survival benefit from adjuvant ovarian ablation. Approximately 350,000 new cases of breast cancer are diagnosed annually in premenopausal Asian women who have lower levels of estrogen than western women. PATIENTS AND METHODS: From 1993 to 1999, we recruited 709 premenopausal women with operable breast cancer (652 from Vietnam, 47 from China) to a randomized clinical trial of adjuvant oophorectomy and tamoxifen (20 mg orally every day) for 5 years or observation and this combined hormonal treatment on recurrence. At later dates estrogen- and progesterone-receptor protein assays by immunohistochemistry were performed for 470 of the cases (66%). RESULTS: Treatment arms were well balanced. With a median follow-up of 3.6 years, there have been 84 events and 69 deaths in the adjuvant treatment group and 127 events and 91 deaths in the observation group, with 5-year disease-free survival rates of 75% and 58% (P =.0003 unadjusted; P =.0075 adjusted), and overall survival rates of 78% and 70% (P =.041 unadjusted) for the adjuvant and observation groups, respectively. Only patients with hormone receptor-positive tumors benefited from the adjuvant treatment. In Vietnam, for women unselected for hormone receptor status, a cost-effectiveness analysis suggests that this intervention costs $350 per year of life saved. CONCLUSION: Vietnamese and Chinese women with hormone receptor-positive operable breast cancer benefit from adjuvant treatment with surgical oophorectomy and tamoxifen.

Adult↗
PubMed2002

Mastectomy and oophorectomy by menstrual cycle phase in women with operable breast cancer.

BACKGROUND: It is unclear whether the phase of the menstrual cycle in which primary surgical treatment occurs influences disease-free survival (DFS) and overall survival (OS) in premenopausal women with breast cancer. We investigated this question in the context of a clinical trial comparing mastectomy alone with mastectomy plus adjuvant oophorectomy and tamoxifen in premenopausal women with operable breast cancer. METHODS: The date of the first day of the last menstrual period (LMP) was used to estimate the phase of the menstrual cycle when the surgeries were done. Follicular phase was defined as day 1-14 from LMP. Luteal phase was defined as day 15-42 from LMP. DFS and OS statistics were determined and analyzed by Cox proportional hazards ratios and Kaplan-Meier methods. All statistical tests were two-sided. RESULTS: We analyzed results for 565 women who reported an LMP within 42 days before surgery. For women in the mastectomy only arm (n = 289), there were no differences in DFS or OS by menstrual cycle phase. For women in the adjuvant treatment arm (n = 276), those whose surgery occurred during the luteal phase (n = 158) had better DFS (relative risk [RR] = 0.54; 95% confidence interval [CI] = 0.32 to 0.96; P =.02) and OS (RR = 0.53; 95% CI = 0.30 to 0.95; P =.03) than those whose surgery occurred during the follicular phase (n = 118). Moreover, women whose surgery occurred during the luteal phase and who received adjuvant therapy had better 5-year DFS than did women whose surgery occurred during the follicular phase (84%; 95% CI = 78% to 90% versus 67%; 95% CI = 58% to 78%; P =.02); they also had better OS (85%; 95% CI = 78% to 92% versus 75%; 95% CI = 66% to 84%; P =.03). CONCLUSIONS: The phase of the menstrual cycle at which surgery was done had no impact on survival for women who received mastectomy only. However, women who received a mastectomy and surgical oophorectomy and tamoxifen during the luteal phase had better outcomes than women who received surgery during the follicular phase.

Adult↗