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data safety monitoring board [keywords]
- Building a More Connected DSMB: Better Integrating Ethics Review and Safety Monitoring. [Journal Article]
- Account Res 2015; 22(2):81-105.
Data and Safety Monitoring Boards (DSMBs) have become an increasingly common feature of clinical trial oversight, yet a paucity of legal or ethical frameworks govern these Boards' composition or operation, or their relationship with other actors with monitoring responsibilities. This paper argues that prevailing structural gaps are impeding harmonized systems for monitoring the ongoing ethical acceptability of clinical trials. Particular tensions stem from DSMBs' sweeping discretion in deciding whether and when to recommend that a trial should be terminated or amended based on safety and efficacy information. This discretion becomes especially challenging in light of DSMBs' monopoly over emerging trial data, which prevents Institutional Review Boards, sponsors, and investigators from participating in certain pivotal and ethically charged decisions. To address these disconnects, I advocate for strengthened pre-trial and post-trial communication in addition to innovative strategies to support DSMB decision making through the life of a trial.
- Underinsurance Before the Implementation of the Affordable Care Act: From the Research Involving Outpatient Settings Network (RIOS Net). [Journal Article]
- J Am Board Fam Med 2014 Nov-Dec; 27(6):855-7.
As the Affordable Care Act (ACA) is implemented and many uninsured become insured, rates of underinsurance may persist or increase. This study was designed to estimate the rate of underinsurance in primary care safety net clinics serving low income, multiethnic populations in New Mexico.Data were collected from 2 primary care clinics in an urban setting during a 2-week period in 2011 and 2012. Voluntary, anonymous, self-administered surveys were distributed to adult patients waiting to be seen by their doctor. Surveys were available in English and Spanish.Of those insured, 44% were underinsured. The underinsured comprised higher proportions of patients who were Hispanic, young, and poor; 39% reported fair or poor health, 23% reported that their health suffered from an inability to seek care because of cost, and 53% had either Medicaid or state coverage insurance. Patients with an income of ≤$25,000 were 8 times more likely to be underinsured.A high level of underinsurance was found in these safety net clinics. Because millions of Americans gain health care insurance benefits, monitoring whether the current reform provides adequate health care coverage or whether those with new and existing health care insurance are underinsured is critical.
- Laboratory Medicine Handoff Gaps Experienced by Primary Care Practices: A Report from the Shared Networks of Collaborative Ambulatory Practices and Partners (SNOCAP). [Journal Article]
- J Am Board Fam Med 2014 Nov-Dec; 27(6):796-803.
The majority of errors in laboratory medicine testing are thought to occur in the pre- and postanalytic testing phases, and a large proportion of these errors are secondary to failed handoffs. Because most laboratory tests originate in ambulatory primary care, understanding the gaps in handoff processes within and between laboratories and practices is imperative for patient safety. Therefore, the purpose of this study was to understand, based on information from primary care practice personnel, the perceived gaps in laboratory processes as a precursor to initiating process improvement activities.A survey was used to assess perceptions of clinicians, staff, and management personnel of gaps in handoffs between primary care practices and laboratories working in 21 Colorado primary care practices. Data were analyzed to determine statistically significant associations between categorical variables. In addition, qualitative analysis of responses to open-ended survey questions was conducted.Primary care practices consistently reported challenges and a desire/need to improve their efforts to systematically track laboratory test status, confirm receipt of laboratory results, and report results to patients. Automated tracking systems existed in roughly 61% of practices, and all but one of those had electronic health record-based tracking systems in place. One fourth of these electronic health record-enabled practices expressed sufficient mistrust in these systems to warrant the concurrent operation of an article-based tracking system as backup. Practices also reported 12 different procedures used to notify patients of test results, varying by test result type.The results highlight the lack of standardization and definition of roles in handoffs in primary care laboratory practices for test ordering, monitoring, and receiving and reporting test results. Results also identify high-priority gaps in processes and the perceptions by practice personnel that practice improvement in these areas is needed. Commonalities in these areas warrant the development and support of tools for use in primary care settings.
- Endocrine Therapy With or Without Inhibition of Epidermal Growth Factor Receptor and Human Epidermal Growth Factor Receptor 2: A Randomized, Double-Blind, Placebo-Controlled Phase III Trial of Fulvestrant With or Without Lapatinib for Postmenopausal Women With Hormone Receptor-Positive Advanced Breast Cancer-CALGB 40302 (Alliance). [JOURNAL ARTICLE]
- J Clin Oncol 2014 Oct 27.
CALGB 40302 sought to determine whether lapatinib would improve progression-free survival (PFS) among women with hormone receptor-positive metastatic breast cancer treated with fulvestrant.Eligible women had estrogen receptor-positive and/or progesterone receptor-positive tumors, regardless of human epidermal growth factor receptor 2 (HER2) status, and prior aromatase inhibitor treatment. Patients received fulvestrant 500 mg intramuscularly on day 1, followed by 250 mg on days 15 and 28 and every 4 weeks thereafter, and either lapatinib 1,500 mg or placebo daily. The study planned to accrue 324 patients and was powered for a 50% improvement in PFS with lapatinib from 5 to 7.5 months.At the third planned interim analysis, the futility boundary was crossed, and the data and safety monitoring board recommend study closure, having accrued 295 patients. At the final analysis, there was no difference in PFS (hazard ratio [HR] of placebo to lapatinib, 1.04; 95% CI, 0.82 to 1.33; P = .37); median PFS was 4.7 months for fulvestrant plus lapatinib versus 3.8 months for fulvestrant plus placebo. There was no difference in overall survival (OS) (HR, 0.91; 95% CI, 0.68 to 1.21; P = .25). For HER2-normal tumors, median PFS did not differ by treatment arm (4.1 v 3.8 months). For HER2-positive tumors, lapatinib was associated with longer median PFS (5.9 v 3.3 months), but the differential treatment effect by HER2 status was not significant (P = .53). The most frequent toxicities were diarrhea, fatigue, and rash associated with lapatinib.Adding lapatinib to fulvestrant does not improve PFS or OS in advanced ER-positive breast cancer and is more toxic.
- Transcranial Laser Therapy in Acute Stroke Treatment: Results of Neurothera Effectiveness and Safety Trial 3, a Phase III Clinical End Point Device Trial. [JOURNAL ARTICLE]
- Stroke 2014 Oct 7.
On the basis of phase II trials, we considered that transcranial laser therapy could have neuroprotective effects in patients with acute ischemic stroke.We studied transcranial laser therapy in a double-blind, sham-controlled randomized clinical trial intended to enroll 1000 patients with acute ischemic stroke treated ≤24 hours after stroke onset and who did not undergo thrombolytic therapy. The primary efficacy measure was the 90-day functional outcome as assessed by the modified Rankin Scale, with hierarchical Bayesian analysis incorporating relevant previous data. Interim analyses were planned after 300 and 600 patients included.The study was terminated on recommendation by the Data Monitoring Committee after a futility analysis of 566 completed patients found no difference in the primary end point (transcranial laser therapy 140/282 [49.6%] versus sham 140/284 [49.3%] for good functional outcome; modified Rankin Scale, 0-2). The results remained stable after inclusion of all 630 randomized patients (adjusted odds ratio, 1.024; 95% confidence interval, 0.705-1.488).Once the results of the interim futility analysis became available, all study support was immediately withdrawn by the capital firms behind PhotoThera, and the company was dissolved. Proper termination of the trial was difficult but was finally achieved through special efforts by former employees of PhotoThera, the CRO Parexel and members of the steering and the safety committees. We conclude that transcranial laser therapy does not have a measurable neuroprotective effect in patients with acute ischemic stroke when applied within 24 hours after stroke onset.http://www.clinicaltrials.gov. Unique identifier: NCT01120301.
- The Esophageal Pressure-Guided Ventilation 2 (EPVent2) trial protocol: a multicentre, randomised clinical trial of mechanical ventilation guided by transpulmonary pressure. [Journal Article, Research Support, N.I.H., Extramural]
- BMJ Open 2014; 4(9):e006356.
Optimal ventilator management for patients with acute respiratory distress syndrome (ARDS) remains uncertain. Lower tidal volume ventilation appears to be beneficial, but optimal management of positive end-expiratory pressure (PEEP) remains unclear. The Esophageal Pressure-Guided Ventilation 2 Trial (EPVent2) aims to examine the impact of mechanical ventilation directed at maintaining a positive transpulmonary pressure (PTP) in patients with moderate-to-severe ARDS.EPVent2 is a multicentre, prospective, randomised, phase II clinical trial testing the hypothesis that the use of a PTP-guided ventilation strategy will lead to improvement in composite outcomes of mortality and time off the ventilator at 28 days as compared with a high-PEEP control. This study will enrol 200 study participants from 11 hospitals across North America. The trial will utilise a primary composite end point that incorporates death and days off the ventilator at 28 days to test the primary hypothesis that adjusting ventilator pressure to achieve positive PTP values will result in improved mortality and ventilator-free days.Safety oversight will be under the direction of an independent Data and Safety Monitoring Board (DSMB). Approval of the protocol was obtained from the DSMB prior to enrolling the first study participant. Approvals of the protocol as well as informed consent documents were also obtained from the Institutional Review Board of each participating institution prior to enrolling study participants at each respective site. The findings of this investigation, as well as associated ancillary studies, will be disseminated in the form of oral and abstract presentations at major national and international medical specialty meetings. The primary objective and other significant findings will also be presented in manuscript form. All final, published manuscripts resulting from this protocol will be submitted to PubMed Central in accordance with the National Institute of Health Public Access Policy.ClinicalTrials.gov under number NCT01681225.
- HyperOxic Therapy OR NormOxic Therapy after out-of-hospital cardiac arrest (HOT OR NOT): A randomised controlled feasibility trial. [JOURNAL ARTICLE]
- Resuscitation 2014 Sep 24.
To investigate the feasibility of delivering titrated oxygen therapy to adults with return of spontaneous circulation (ROSC) following out-of-hospital cardiac arrest (OHCA) caused by ventricular fibrillation (VF) or ventricular tachycardia (VT).We used a multicentre, randomised, single blind, parallel groups design to compare titrated and standard oxygen therapy in adults resuscitated from VF/VT OHCA. The intervention commenced in the community following ROSC and was maintained in the emergency department and the Intensive Care Unit. The primary end point was the median oxygen saturation by pulse oximetry (SpO2) in the pre-hospital period.159 OHCA patients were screened and 18 were randomised. 17 participants were analysed: nine in the standard care group and eight in the titrated oxygen group. In the pre-hospital period, SpO2 measurements were lower in the titrated oxygen therapy group than the standard care group (difference in medians 11.3%; 95% CI 1.0-20.5%). Low measured oxygen saturation (SpO2<88%) occurred in 7/8 of patients in the titrated oxygen group and 3/9 of patients in the standard care group (P=0.05). Following hospital admission, good separation of oxygen exposure between the groups was achieved without a significant increase in hypoxia events. The trial was terminated because accumulated data led the Data Safety Monitoring Board and Management Committee to conclude that safe delivery of titrated oxygen therapy in the pre-hospital period was not feasible.Titration of oxygen in the pre-hospital period following OHCA was not feasible; it may be feasible to titrate oxygen safely after arrival in hospital.
- Persistence and risk assessment of spiromesifen on tomato in India: a multilocational study. [Journal Article]
- Environ Monit Assess 2014 Dec; 186(12):8453-61.
Supervised field trials were conducted at four different agro-climatic locations of India to evaluate the dissipation pattern and risk assessment of spiromesifen on tomato. Spiromesifen 240 SC was sprayed on tomato at 150 and 300 g a.i. ha(-1). Samples of tomato fruits were drawn at 0, 1, 3, 5, 7, 10 and 15 days after treatment and soil at 15 days after treatment. Quantification of residues was done on gas chromatograph-mass spectrophotometer in selective ion monitoring mode in the mass range of 271-274 (m/z). The limit of quantification of the method was found to be 0.05 mg kg(-1), while the limit of determination was 0.015 mg kg(-1). Residues were found below the LOQ of 0.05 mg kg(-1) in 10 days at both the doses of application at all the locations. Spiromesifen dissipated with a half-life of 0.93-1.38 days at the recommended rate of application and 1.04-1.34 days at the double the rate of application. Residues of spiromesifen in soil were detectable level (<0.05 mg kg(-1)) after 15 days of treatment. A preharvest interval (PHI) of 1 day has been recommended on tomato on the basis of data generated under All India Network Project on Pesticide Residues. Spiromesifen 240 SC has been registered for its use on tomato by Central Insecticide Board and Registration Committee, Ministry of Agriculture, Government of India. The maximum residue limit (MRL) of spiromesifen on tomato has been fixed by Food Safety Standard Authority of India, Ministry of Health and Family Welfare, Government of India as 0.3 μg/g after its risk assessment.
- Rationale and Design of the Vitamin D and Type 2 Diabetes (D2d) Study: A Diabetes Prevention Trial. [JOURNAL ARTICLE]
- Diabetes Care 2014 Sep 9.
Observational studies suggest that vitamin D may lower the risk of type 2 diabetes. However, data from long-term trials are lacking. The Vitamin D and Type 2 Diabetes (D2d) study is a randomized clinical trial designed to examine whether a causal relationship exists between vitamin D supplementation and the development of diabetes in people at high risk for type 2 diabetes.D2d was designed with support from a U34 planning grant from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). The final protocol was approved by the D2d Research Group, the data and safety monitoring board, and NIDDK. Key eligibility criteria are age ≥30 years, BMI of 24 (22.5 for Asian Americans) to 42 kg/m(2), increased risk for diabetes (defined as meeting two of three glycemic criteria for prediabetes established by the American Diabetes Association [fasting glucose 100-125 mg/dL (5.5-6.9 mmol/L), 2-h postload glucose after 75-g glucose load 140-199 mg/dL (7.7-11.0 mmol/L), hemoglobin A1c 5.7-6.4% (39-46 mmol/mol)]), and no hyperparathyroidism, nephrolithiasis, or hypercalcemia. D2d participants are randomized to once-daily vitamin D3 (cholecalciferol 4,000 IU) or placebo and followed for an average of 3 years. The primary end point is time to incident diabetes as assessed by laboratory criteria during the study or by adjudication if diagnosed outside of D2d. Recruitment was initiated at the end of 2013.D2d will test whether vitamin D supplementation is safe and effective at lowering the risk of progression to diabetes in people at high risk for type 2 diabetes.
- Phase I/II Study of Azacitidine, Docetaxel, and Prednisone in Patients With Metastatic Castration-Resistant Prostate Cancer Previously Treated With Docetaxel-Based Therapy. [JOURNAL ARTICLE]
- Clin Genitourin Cancer 2014 Aug 1.
Methylation-mediated silencing of genes contributes to docetaxel resistance in prostate cancer. We propose that azacitidine, a demethylating agent, can reverse docetaxel resistance.Metastatic castration-resistant prostate cancer (mCRPC) patients, who progressed during or within 6 months of docetaxel chemotherapy, were eligible. Fifteen and 7 patients were treated in phase I and II, respectively. In phase I, azacitidine and docetaxel were alternately escalated in a standard 3 + 3 design. All patients received prednisone 5 mg twice daily continuously. Patients were evaluated for toxicity and efficacy. Growth arrest and DNA damage-inducible alpha (GADD45A) methylation was measured before and after azacitidine treatment in the first cycle in phase I patients.In phase I, no dose-limiting toxicity was observed. At the highest dose (azacitidine 150 mg/m(2) daily for 5 days followed by docetaxel 75 mg/m(2) on day 6), Grade 4 neutropenia was frequent, but infrequent with growth factor. Six patients in the phase II study received the highest dose including growth factor support. The sixth phase II patient died because of neutropenic sepsis. After data and safety monitoring board review, the phase II dose was reduced to azacitidine 75 mg/m(2) daily for 5 days followed by docetaxel 75 mg/m(2) on day 6 with growth factor support. Prostate-specific antigen response was seen in 10 of 19 evaluable patients and objective response was observed in 3 of 10 evaluable patients. Significant demethylation of GADD45A was observed with azacitidine treatment.The combination of azacitidine, docetaxel, and prednisone with growth factor support is active in mCRPC patients.