Test result-based sampling: an efficient design for estimating the accuracy of patient safety indicators.

OBJECTIVE: Accuracy studies of Patient Safety Indicators (PSIs) are critical but limited by the large samples required due to low occurrence of most events. We tested a sampling design based on test results (verification-biased sampling [VBS]) that minimizes the number of subjects to be verified. METHODS: We considered 3 real PSIs, whose rates were calculated using 3 years of discharge data from a university hospital and a hypothetical screen of very rare events. Sample size estimates, based on the expected sensitivity and precision, were compared across 4 study designs: random and VBS, with and without constraints on the size of the population to be screened. RESULTS: Over sensitivities ranging from 0.3 to 0.7 and PSI prevalence levels ranging from 0.02 to 0.2, the optimal VBS strategy makes it possible to reduce sample size by up to 60% in comparison with simple random sampling. For PSI prevalence levels below 1%, the minimal sample size required was still over 5000. CONCLUSIONS: Verification-biased sampling permits substantial savings in the required sample size for PSI validation studies. However, sample sizes still need to be very large for many of the rarer PSIs.

Design, conduct, and analyses of Breast International Group (BIG) 1-98: a randomized, double-blind, phase-III study comparing letrozole and tamoxifen as adjuvant endocrine therapy for postmenopausal women with receptor-positive, early breast cancer.

BACKGROUND: Aromatase inhibitors provide superior disease control when compared with tamoxifen as adjuvant therapy for postmenopausal women with endocrine-responsive early breast cancer. PURPOSE: To present the design, history, and analytic challenges of the Breast International Group (BIG) 1-98 trial: an international, multicenter, randomized, double-blind, phase-III study comparing the aromatase inhibitor letrozole with tamoxifen in this clinical setting. METHODS: From 1998-2003, BIG 1-98 enrolled 8028 women to receive monotherapy with either tamoxifen or letrozole for 5 years, or sequential therapy of 2 years of one agent followed by 3 years of the other. Randomization to one of four treatment groups permitted two complementary analyses to be conducted several years apart. The first, reported in 2005, provided a head-to-head comparison of letrozole versus tamoxifen. Statistical power was increased by an enriched design, which included patients who were assigned sequential treatments until the time of the treatment switch. The second, reported in late 2008, used a conditional landmark approach to test the hypothesis that switching endocrine agents at approximately 2 years from randomization for patients who are disease-free is superior to continuing with the original agent. RESULTS: The 2005 analysis showed the superiority of letrozole compared with tamoxifen. The patients who were assigned tamoxifen alone were unblinded and offered the opportunity to switch to letrozole. Results from other trials increased the clinical relevance about whether or not to start treatment with letrozole or tamoxifen, and analysis plans were expanded to evaluate sequential versus single-agent strategies from randomization. LIMITATIONS: Due to the unblinding of patients assigned tamoxifen alone, analysis of updated data will require ascertainment of the influence of selective crossover from tamoxifen to letrozole. CONCLUSIONS: BIG 1-98 is an example of an enriched design, involving complementary analyses addressing different questions several years apart, and subject to evolving analytic plans influenced by new data that emerge over time.

Label-free cytotoxicity screening assay by digital holographic microscopy.

Abstract We introduce a label-free technology based on digital holographic microscopy (DHM) with applicability for screening by imaging, and we demonstrate its capability for cytotoxicity assessment using mammalian living cells. For this first high content screening compatible application, we automatized a digital holographic microscope for image acquisition of cells using commercially available 96-well plates. Data generated through both label-free DHM imaging and fluorescence-based methods were in good agreement for cell viability identification and a Z'-factor close to 0.9 was determined, validating the robustness of DHM assay for phenotypic screening. Further, an excellent correlation was obtained between experimental cytotoxicity dose-response curves and known IC values for different toxic compounds. For comparable results, DHM has the major advantages of being label free and close to an order of magnitude faster than automated standard fluorescence microscopy.

The TREAT-NMD Duchenne Muscular Dystrophy Registries: Conception, Design, and Utilization by Industry and Academia.

Duchenne muscular dystrophy (DMD) is an X-linked genetic disease, caused by the absence of the dystrophin protein. Although many novel therapies are under development for DMD, there is currently no cure and affected individuals are often confined to a wheelchair by their teens and die in their twenties/thirties. DMD is a rare disease (prevalence <5/10,000). Even the largest countries do not have enough affected patients to rigorously assess novel therapies, unravel genetic complexities, and determine patient outcomes. TREAT-NMD is a worldwide network for neuromuscular diseases that provides an infrastructure to support the delivery of promising new therapies for patients. The harmonized implementation of national and ultimately global patient registries has been central to the success of TREAT-NMD. For the DMD registries within TREAT-NMD, individual countries have chosen to collect patient information in the form of standardized patient registries to increase the overall patient population on which clinical outcomes and new technologies can be assessed. The registries comprise more than 13,500 patients from 31 different countries. Here, we describe how the TREAT-NMD national patient registries for DMD were established. We look at their continued growth and assess how successful they have been at fostering collaboration between academia, patient organizations, and industry.

Incorporation and washout of n-3 PUFA after high dose intravenous and oral supplementation in healthy volunteers.

BACKGROUND & AIMS: Although the physiological effects of n-3 polyunsaturated fatty acids (n-3PUFA) are generally thought to require several weeks of exposure to allow their incorporation into plasma membranes, intravenous (IV) n-3PUFA attenuate the cardiovascular and neuroendocrine response to stress within 3 h. Whether oral n-3 PUFA exert similar early effects remains unknown. OBJECTIVE: To assess whether acute IV or short term oral n-3PUFA administration reproduces the metabolic effects of long term oral supplements during exercise, and how it relates to their incorporation into platelets and red blood cells (RBC) membranes. DESIGN: Prospective single center open label study in 8 healthy subjects receiving a 3-h infusion of 0.6 g/kg body weight n-3PUFA emulsion, followed one week later by an oral administration of 0.6 g/kg over 3 consecutive days. Maximal power output (cycling exercise), maximal heart rate (HR), blood lactate at exhaustion, and platelet function were measured at baseline and after IV or 3-day oral supplementation; platelet and RBC membrane composition were assessed until 15 days after n-3PUFA administration. RESULTS: Both IV and oral n-3PUFA significantly decreased maximal HR (-6% and -5%), maximal power output (-10%) and peak blood lactate (-47% and -52%) Platelet function tests were unchanged. The EPA and DHA membrane contents of RBC and platelets increased significantly, but only to 1.7-1.9% of fatty acid content. CONCLUSION: The cardiovascular and metabolic effects of n-3 PUFA during exercise occur already within 1-3 days of exposure, and may be unrelated to changes in membranes composition. Effects occur within hours of administration and are unrelated to lipid membrane composition. Trial registered at clinicaltrials.gov as NCT00516178.

Design and establishment of a biobank in a multicenter prospective cohort study of elderly patients with venous thromboembolism (SWITCO65+).

In the field of thrombosis and haemostasis, many preanalytical variables influence the results of coagulation assays and measures to limit potential results variations should be taken. To our knowledge, no paper describing the development and maintenance of a haemostasis biobank has been previously published. Our description of the biobank of the Swiss cohort of elderly patients with venous thromboembolism (SWITCO65+) is intended to facilitate the set-up of other biobanks in the field of thrombosis and haemostasis. SWITCO65+ is a multicentre cohort that prospectively enrolled consecutive patients aged ≥65 years with venous thromboembolism at nine Swiss hospitals from 09/2009 to 03/2012. Patients will be followed up until December 2013. The cohort includes a biobank with biological material from each participant taken at baseline and after 12 months of follow-up. Whole blood from all participants is assayed with a standard haematology panel, for which fresh samples are required. Two buffy coat vials, one PAXgene Blood RNA System tube and one EDTA-whole blood sample are also collected at baseline for RNA/DNA extraction. Blood samples are processed and vialed within 1 h of collection and transported in batches to a central laboratory where they are stored in ultra-low temperature archives. All analyses of the same type are performed in the same laboratory in batches. Using multiple core laboratories increased the speed of sample analyses and reduced storage time. After recruiting, processing and analyzing the blood of more than 1,000 patients, we determined that the adopted methods and technologies were fit-for-purpose and robust.

Efficacy of an adjunctive brief psychodynamic psychotherapy to usual inpatient treatment of depression: rationale and design of a randomized controlled trial.

BACKGROUND: A few recent studies have found indications of the effectiveness of inpatient psychotherapy for depression, usually of an extended duration. However, there is a lack of controlled studies in this area and to date no study of adequate quality on brief psychodynamic psychotherapy for depression during short inpatient stay exists. The present article describes the protocol of a study that will examine the relative efficacy, the cost-effectiveness and the cost-utility of adding an Inpatient Brief Psychodynamic Psychotherapy to pharmacotherapy and treatment-as-usual for inpatients with unipolar depression. METHODS/DESIGN: The study is a one-month randomized controlled trial with a two parallel group design and a 12-month naturalistic follow-up. A sample of 130 consecutive adult inpatients with unipolar depression and Montgomery-Asberg Depression Rating Scale score over 18 will be recruited. The study is carried out in the university hospital section for mood disorders in Lausanne, Switzerland. Patients are assessed upon admission, and at 1-, 3- and 12- month follow-ups. Inpatient therapy is a manualized brief intervention, combining the virtues of inpatient setting and of time-limited dynamic therapies (focal orientation, fixed duration, resource-oriented interventions). Treatment-as-usual represents the best level of practice for a minimal treatment condition usually proposed to inpatients. Final analyses will follow an intention-to-treat strategy. Depressive symptomatology is the primary outcome and secondary outcome includes measures of psychiatric symptomatology, psychosocial role functioning, and psychodynamic-emotional functioning. The mediating role of the therapeutic alliance is also examined. Allocation to treatment groups uses a stratified block randomization method with permuted block. To guarantee allocation concealment, randomization is done by an independent researcher. DISCUSSION: Despite the large number of studies on treatment of depression, there is a clear lack of controlled research in inpatient psychotherapy during the acute phase of a major depressive episode. Research on brief therapy is important to take into account current short lengths of stay in psychiatry. The current study has the potential to scientifically inform appropriate inpatient treatment. This study is the first to address the issue of the economic evaluation of inpatient psychotherapy. TRIAL REGISTRATION: Australian New Zealand Clinical Trial Registry (ACTRN12612000909820).

The effect of three or six years of denosumab exposure in women with postmenopausal osteoporosis: results from the FREEDOM extension.

CONTEXT: The Fracture Reduction Evaluation of Denosumab in Osteoporosis Every 6 Months (FREEDOM) extension is evaluating the long-term efficacy and safety of denosumab for up to 10 years. OBJECTIVE: The objective of the study was to report results from the first 3 years of the extension, representing up to 6 years of denosumab exposure. DESIGN, SETTING, AND PARTICIPANTS: This was a multicenter, international, open-label study of 4550 women. INTERVENTION: Women from the FREEDOM denosumab group received 3 more years of denosumab for a total of 6 years (long-term) and women from the FREEDOM placebo group received 3 years of denosumab (crossover). MAIN OUTCOME MEASURES: Bone turnover markers (BTMs), bone mineral density (BMD), fracture, and safety data are reported. RESULTS: Reductions in BTMs were maintained (long-term) or achieved rapidly (crossover) after denosumab administration. In the long-term group, BMD further increased for cumulative 6-year gains of 15.2% (lumbar spine) and 7.5% (total hip). During the first 3 years of denosumab treatment, the crossover group had significant gains in lumbar spine (9.4%) and total hip (4.8%) BMD, similar to the long-term group during the 3-year FREEDOM trial. In the long-term group, fracture incidences remained low and below the rates projected for a virtual placebo cohort. In the crossover group, 3-year incidences of new vertebral and nonvertebral fractures were similar to those of the FREEDOM denosumab group. Incidence rates of adverse events did not increase over time. Six participants had events of osteonecrosis of the jaw confirmed by adjudication. One participant had a fracture adjudicated as consistent with atypical femoral fracture. CONCLUSION: Denosumab treatment for 6 years remained well tolerated, maintained reduced bone turnover, and continued to increase BMD. Fracture incidence remained low.

Local Public-Services Provision under Public-Private Partnerships : Contractual Design and Contracting Parties Incentives

When deciding to resort to a PPP contract for the provision of a local public service, local governments have to consider the demand risk allocation between the contracting parties. In this article, I investigate the effects of demand risk allocation on the accountability of procuring authorities regarding consumers changing demand, as well as on the cost-reducing effort incentives of the private public-service provider. I show that contracts in which the private provider bears demand risk motivate more the public authority from responding to customer needs. This is due to the fact that consumers are empowered when the private provider bears demand risk, that is, they have the possibility to oust the private provider in case of non-satisfaction with the service provision, which provides procuring authorities with more credibility in side-trading and then more incentives to be responsive. As a consequence, I show that there is a lower matching with consumers' preferences over time when demand risk is on the public authority rather than on the private provider, and this is corroborated in the light of two famous case studies. However, contracts in which the private provider does not bear demand risk motivate more the private provider from investing in cost-reducing efforts. I highlight then a tradeoff in the allocation of demand risk between productive and allocative efficiency. The striking policy implication of this article for local governments would be that the current trend towards a greater resort to contracts where private providers bear little or no demand risk may not be optimal. Local governments should impose demand risk on private providers within PPP contracts when they expect that consumers' preferences over the service provision will change over time.

Unlicensed and off-label drug use in a Swiss paediatric university hospital.

BACKGROUND: Many medicines used in newborns, infants, children and adolescents are not licensed ("unlicensed") or are prescribed outside the terms of the marketing authorization ("off-label"). Several studies have shown that this is a common practice in various healthcare settings in the USA, Europe and Australia, but data are scarce in Switzerland. OBJECTIVES: The aim of our prospective study was to determine the proportion of unlicensed or off-label prescriptions in paediatric patients. METHODS: This pilot study was conducted prospectively over a six month period in the department of paediatrics of a university hospital. RESULTS: Sixty patients aged from three days to 14 years were included in the study. A total of 483 prescriptions were written for the patients. More than half of all prescriptions (247; 51%) followed the terms of the marketing authorization. 114 (24%) were unlicensed and 122 (25%) off-label. All patients received at least one unlicensed or offlabel medicine. CONCLUSION: The use of unlicensed or off-label medicines to treat children was found to be common. Co-operation between the pharmaceutical industry, national regulatory authorities, clinical researchers, healthcare professionals and parents is required in order to ensure that children do not remain "therapeutic orphans".

Learning from failure - rationale and design for a study about discontinuation of randomized trials (DISCO study).

BACKGROUND: Randomized controlled trials (RCTs) may be discontinued because of apparent harm, benefit, or futility. Other RCTs are discontinued early because of insufficient recruitment. Trial discontinuation has ethical implications, because participants consent on the premise of contributing to new medical knowledge, Research Ethics Committees (RECs) spend considerable effort reviewing study protocols, and limited resources for conducting research are wasted. Currently, little is known regarding the frequency and characteristics of discontinued RCTs. METHODS/DESIGN: Our aims are, first, to determine the prevalence of RCT discontinuation for specific reasons; second, to determine whether the risk of RCT discontinuation for specific reasons differs between investigator- and industry-initiated RCTs; third, to identify risk factors for RCT discontinuation due to insufficient recruitment; fourth, to determine at what stage RCTs are discontinued; and fifth, to examine the publication history of discontinued RCTs.We are currently assembling a multicenter cohort of RCTs based on protocols approved between 2000 and 2002/3 by 6 RECs in Switzerland, Germany, and Canada. We are extracting data on RCT characteristics and planned recruitment for all included protocols. Completion and publication status is determined using information from correspondence between investigators and RECs, publications identified through literature searches, or by contacting the investigators. We will use multivariable regression models to identify risk factors for trial discontinuation due to insufficient recruitment. We aim to include over 1000 RCTs of which an anticipated 150 will have been discontinued due to insufficient recruitment. DISCUSSION: Our study will provide insights into the prevalence and characteristics of RCTs that were discontinued. Effective recruitment strategies and the anticipation of problems are key issues in the planning and evaluation of trials by investigators, Clinical Trial Units, RECs and funding agencies. Identification and modification of barriers to successful study completion at an early stage could help to reduce the risk of trial discontinuation, save limited resources, and enable RCTs to better meet their ethical requirements.

Subsidy design: wealth versus benefits

A government would like to subsidize an indivisible good. Consumers' valuations of the good vary according to their wealth and benefits from the good. A subsidy scheme may be based on consumers' wealth or benefit information. We translate a wealth-based policy to a benefit-based policy, and vice versa, and give a necessary and sufficient condition for the pair of policies to implement the same assignment: consumers choose to purchase the good under the wealth-based policy if and only if they choose to do so under the translated benefit-based policy. General taxation allows equivalent policies to require the same budget.