Cost effectiveness of caplacizumab in acquired thrombotic thrombocytopenic purpura.

Acquired thrombotic thrombocytopenic purpura (TTP) is a life-threatening disease characterized by thrombotic microangiopathy leading to end-organ damage. The standard of care (SOC) treatment is therapeutic plasma exchange (TPE) alongside immunomodulation with steroids, with increasing use of rituximab ± other immunomodulatory agents. The addition of caplacizumab, a nanobody targeting von Willebrand factor, was shown to accelerate platelet count recovery and reduce TPE treatments and hospital length of stay in TTP patients treated in 2 major randomized clinical trials. The addition of caplacizumab to SOC also led to increased bleeding from transient reductions in von Willebrand factor and increased relapse rates. Using data from the 2 clinical trials of caplacizumab, we performed the first-ever cost-effectiveness analysis in TTP. Over a 5-year period, the projected incremental cost-effectiveness ratio (ICER) in our Markov model was $1 482 260, significantly above the accepted 2019 US willingness-to-pay threshold of $195 300. One-way sensitivity analyses showed the utility of the well state and the cost of caplacizumab to have the largest effects on ICER, with a reduction in caplacizumab cost demonstrating the single greatest impact on lowering the ICER. In a probabilistic sensitivity analysis, SOC was favored over caplacizumab in 100% of 10 000 iterations. Our data indicate that the addition of caplacizumab to SOC in treatment of acquired TTP is not cost effective because of the high cost of the medication and its failure to improve relapse rates. The potential impact of caplacizumab on health system cost using longer term follow-up data merits further study.

Clinical research in hospital pharmacy during the fight against COVID-19.

The health crisis resulting from the rapid spread of SARS-CoV-2 worlwide, added to the low evidence of currently used treatments has led to the development of a large number of clinical trials (CT) and observational studies. Likewise,  important measures have been adopted in healthcare and research centers  aimed at halting the pandemic as soon as possible. The objective of this study is  to gather the main aspects of the clinical research studies undertaken by the  Departments of Hospital Pharmacy (DHP) of Spain during the COVID-19 crisis. The decision of the Spanish Society of Hospital Pharmacy (SEFH) to sponsor CTs made it possible that 13% of DHP had been led at least one CT.  The Spanish Agency for Medicines and Medical Devices (AEMPS), in coordination  with Institutional Review Boards, has adopted a fast-track review procedure to  accelerate authorizations for CTs related to the treatment or prevention of  COVID-19. There have also been numerous public and private calls for financing  research projects aimed at contributing to the fight against this virus. Despite  the pandemic, actions have been taken to continue ongoing CTs and studies  while the safety and well-being of patients are guaranteed. More specifically, the AEMPS and the European Medicines Agency (EMA) have issued guidelines that  incorporate changes to CT protocols that will have to be applied until the  pandemic is over. In this health emergency, the scientific community has found  itself in a race against time to generate evidence. It is at this moment that  hospital pharmacists emerge as key players in clinical research and are  contributing to a rational, effective and safe healthcare decision-making.

La presente crisis sanitaria derivada de la rápida expansión del virus SARS-CoV- 2 a nivel mundial, así como la falta de evidencia de los tratamientos empleados  actualmente, ha provocado la aparición de un gran número de ensayos clínicos y estudios observacionales. Del mismo modo, ha ocasionado la puesta en marcha  de importantes medidas en el entorno sanitario e investigador con el fin de  conseguir detener la evolución de la pandemia lo antes posible. El objetivo del  actual trabajo es recopilar aspectos fundamentales relacionados con la  investigación clínica desarrollada por los servicios de farmacia hospitalaria  durante la crisis provocada por la COVID-19. La iniciativa de la Sociedad  Española de Farmacia Hospitalaria de actuar como promotor de ensayos clínicos  ha posibilitado que el 13% de estos servicios de farmacia hospitalaria haya  podido liderar uno. En este sentido, la Agencia Española de Medicamentos y  Productos Sanitarios, junto con los Comités de Ética de Investigación, ha  acelerado los procedimientos de autorización de nuevos ensayos clínicos  destinados a tratar o prevenir la COVID-19. Asimismo, han sido numerosas las  convocatorias públicas y privadas destinadas a la financiación de proyectos de  diversa índole con el fin de contribuir a la lucha contra este virus. A pesar de la  irrupción de la pandemia, también han surgido acciones destinadas a mantener  las actividades de los ensayos clínicos y estudios puestos previamente en  marcha, garantizando la seguridad y bienestar del paciente. Concretamente, la  Agencia Española de Medicamentos y Productos Sanitarios y la Agencia Europea  de Medicamentos han publicado guías que incluyen cambios en los protocolos de los ensayos clínicos que deben mantenerse mientras dure la pandemia. La  emergencia sanitaria actual ha obligado a la comunidad científica a la generación de evidencia a contrarreloj. Por ello, en este momento en el que se requiere del  mayor rigor posible, el farmacéutico de hospital debe alzarse como una figura  clave en la investigación en salud, contribuyendo a que las decisiones sanitarias  sean racionales, eficientes y seguras.

Managing clustering effects and learning effects in the design and analysis of multicentre randomised trials: a survey to establish current practice.

BACKGROUND: Patient outcomes can depend on the treating centre, or health professional, delivering the intervention. A health professional's skill in delivery improves with experience, meaning that outcomes may be associated with learning. Considering differences in intervention delivery at trial design will ensure that any appropriate adjustments can be made during analysis. This work aimed to establish practice for the allowance of clustering and learning effects in the design and analysis of randomised multicentre trials. METHODS: A survey that drew upon quotes from existing guidelines, references to relevant publications and example trial scenarios was delivered. Registered UK Clinical Research Collaboration Registered Clinical Trials Units were invited to participate. RESULTS: Forty-four Units participated (N = 50). Clustering was managed through design by stratification, more commonly by centre than by treatment provider. Managing learning by design through defining a minimum expertise level for treatment provider was common (89%). One-third reported experience in expertise-based designs. The majority of Units had adjusted for clustering during analysis, although approaches varied. Analysis of learning was rarely performed for the main analysis (n = 1), although it was explored by other means. The insight behind the approaches used within and reasons for, or against, alternative approaches were provided. CONCLUSIONS: Widespread awareness of challenges in designing and analysing multicentre trials is identified. Approaches used, and opinions on these, vary both across and within Units, indicating that approaches are dependent on the type of trial. Agreeing principles to guide trial design and analysis across a range of realistic clinical scenarios should be considered.

Cómo poner en marcha y desarrollar un estudio multicéntrico prospectivo, controlado y aleatorizado / How to start and develop a multicenter, prospective, randomized, controlled trial

El objetivo de este artículo es ilustrar cómo poner en marcha y desarrollar un estudio multicéntrico prospectivo, controlado y aleatorizado. Por ello, lo primero que se necesita es crear una idea que genere una hipótesis y un objetivo principal. La búsqueda bibliográfica nos permite ver su relevancia clínica y las evidencias publicadas. Además, hay que plantearse si el estudio es viable económicamente y si puede ser completado en un período menor a 4 años. Una vez ideado el estudio multicéntrico, para ejecutarlo se debe redactar un protocolo (según la guía Standard Protocol items: Recommendations for Interventional Trials [SPIRIT 2013]). En él se recogerán el tipo de diseño, el tamaño muestral y los centros que participarán. La aleatorización es clave en el diseño. Si puede ser aleatorizado, se recomienda utilizar la guía Consolidated Standards of Reporting Trials (CONSORT), si no, la Transparent Reporting of Evaluations with Non-Randomized Designs (TREND). Cuando el protocolo es aprobado por el Comité Ético de Investigación Clínica del hospital, hay que darle visibilidad. Es por eso que se recomienda su registro en ClincalTrials.gov y su publicación en revistas indexadas. Para el inicio del estudio, se requiere buscar fuentes de financiación. Estas permiten tener una base de datos on line, que permiten aleatorizar al momento y mantener el registro al día desde cualquier centro. Por último, hay que destacar que es imprescindible la motivación. La multicentricidad solo se entiende si todos los centros participan. Así que informar de resultados y dar ánimos cada 1-3 meses (en forma de newsletter) es una manera de conseguir un buen funcionamiento del estudio

Our main goal is to describe how to start and develop a multicenter, prospective, randomized, controlled trial. The first step is to have an idea that will become the hypothesis and a main objective. A bibliographic search should be done to check for clinical interest and originality. Moreover, the study must be feasible and should be finished within 4 years. In order to start the multicenter study, a protocol should be written (in accordance with the SPIRIT guidelines Standard Protocol items: Recommendations for Interventional Trials), including the design type, sample size and participating hospitals. Randomization is key to the design and, therefore, the CONSORT (Consolidated Standards of Reporting Trials) guidelines must be followed. However, if the study cannot be randomized, the TREND (Transparent Reporting of Evaluations with Non-Randomized Designs) guidelines are recommended. When the protocol is approved by the Ethics Committee for Clinical Investigation of the hospital, we ought to create visibility. It is suggested to register the trial on ClincalTrials.gov and submit its publication to indexed magazines. Financial resources are necessary to execute the study and maintain an online database. This allows the registry to be updated and accessible to all the participants in the study. What is more, randomization can be done immediately. And last, but not least, is motivation. Multicentricity equals to participation of all the chosen medical centers. Updating and motivating them by sending a newsletter every 1-3 months keeps participants engaged in the study

Cost-effectiveness analysis of gemcitabine plus cisplatin versus docetaxel, cisplatin and fluorouracil for induction chemotherapy of locoregionally advanced nasopharyngeal carcinoma.

BACKGROUND: Recently, patients who received induction chemotherapy plus concurrent chemoradiotherapy for locoregionally advanced nasopharyngeal carcinoma were found to have survival advantages compared with those receiving concurrent chemoradiotherapy alone in two large randomized trials. Based on these two trials, we present a cost-effectiveness analysis to compare gemcitabine and cisplatin (GP) versus cisplatin, fluorouracil, and docetaxel (TPF) for induction chemotherapy to treat locoregionally advanced nasopharyngeal carcinoma. METHODS: We constructed a Markov model to compare the cost and effectiveness of GP versus TPF. Clinical data including the frequency of adverse events, recurrence and death obtained from two randomized phase III trials were used to calculate transition probabilities and costs. Health utilities were estimated from the literature. Incremental cost-effectiveness ratios, expressed as dollars per quality-adjusted life-year (QALY), were calculated, and incremental cost-effectiveness ratios less than $27,534.25/QALY (3 × the per capita GDP of China, 2018) were considered cost-effective. One-way sensitivity and probabilistic sensitivity analyses explored the robustness of the model. RESULTS: Our base case model found that the total cost was $53,082.68 in the GP group and $45,482.66 in the TPF group. The QALYs were 6.82 and 4.11, respectively. The incremental cost-effectiveness ratio favoured the GP regimen, at an incremental cost of $2,804.44 per QALY. The probabilistic sensitivity analysis found that treatment with the GP regimen was cost-effective 100% of the time at a willingness-to-pay threshold of $27,534.25‬/QALY. CONCLUSION: In this model, GP was estimated to be cost-effective compared with cisplatin, fluorouracil, and docetaxel for patients with locoregionally advanced nasopharyngeal carcinoma from the payer's perspectives in the China.

How to start and develop a multicenter, prospective, randomized, controlled trial. / Cómo poner en marcha y desarrollar un estudio multicéntrico prospectivo, controlado y aleatorizado.

Our main goal is to describe how to start and develop a multicenter, prospective, randomized, controlled trial. The first step is to have an idea that will become the hypothesis and a main objective. A bibliographic search should be done to check for clinical interest and originality. Moreover, the study must be feasible and should be finished within 4 years. In order to start the multicenter study, a protocol should be written (in accordance with the SPIRIT guidelines Standard Protocol items: Recommendations for Interventional Trials), including the design type, sample size and participating hospitals. Randomization is key to the design and, therefore, the CONSORT (Consolidated Standards of Reporting Trials) guidelines must be followed. However, if the study cannot be randomized, the TREND (Transparent Reporting of Evaluations with Non-Randomized Designs) guidelines are recommended. When the protocol is approved by the Ethics Committee for Clinical Investigation of the hospital, we ought to create visibility. It is suggested to register the trial on ClincalTrials.gov and submit its publication to indexed magazines. Financial resources are necessary to execute the study and maintain an online database. This allows the registry to be updated and accessible to all the participants in the study. What is more, randomization can be done immediately. And last, but not least, is motivation. Multicentricity equals to participation of all the chosen medical centers. Updating and motivating them by sending a newsletter every 1-3 months keeps participants engaged in the study.

Budgeting of non-commercial clinical trials: development of a budget tool by a public funding agency.

BACKGROUND: Investigator-led multicentre randomised trials are essential to generate evidence on the optimal use of medical interventions. These non-commercial trials are often hampered by underfunding, which may lead to difficulties in gathering a team with the necessary expertise, a delayed trial start, slow recruitment and even early trial discontinuation. As a new public funder of pragmatic clinical trials, the KCE Trials programme was committed to correctly pay all trial activities in order to assure timely delivery of high-quality trial results. As no appropriate trial budget tool was readily publicly available that took into account the costs for the sponsor as well as the costs for participating sites, we developed a tool to make the budgeting of a clinical trial efficient, transparent and fair across applicants. METHODS: All trial-related activities of the sponsor and sites were categorised, and cost drivers were identified. All elements were included in a spreadsheet tool allowing the sponsor team to calculate in detail the various activities of a clinical trial and to appreciate the budget impact of specific cost drivers, e.g. a delay in recruitment. Hourly fees by role were adapted from published data. Fixed amounts per activity were developed when appropriate. RESULTS: This publicly available tool has already been used for 17 trials funded since the start of the KCE Trials programme in 2016, and it continues to be used and improved. This budget tool is used together with additional risk-reducing measures such as a multistep selection process with advance payments, a recruitment feasibility check by sponsor and funder, a close monitoring of study progress and a milestone-based payment schedule with the last payment made when the manuscript is submitted. CONCLUSIONS: The budget tool helps the KCE Trials programme to answer relevant research questions in a timely way, within budget and with high quality, a necessary condition to achieve impact of this programme for patients, clinical practice and healthcare payers.

Factors associated with the successful completion of randomized controlled trials in gynecological oncology.

PURPOSE: The aim of our review was to ascertain factors associated with the successful completion of a randomized controlled trial in gynecological oncology. MATERIALS AND METHODS: This retrospective cohort study utilized data collected from the National Institutes of Health's US National Library of Medicine database on ClinicalTrials.gov. Data was collected over a five year period (2009-2013). Utilizing the search terms under the National Institutes of Health recommended "Studies by Topics" gynecological oncology studies were identified. Randomized controlled trials were selected for based on intervention and randomization criteria. Elements were then compared with statistical analysis performed using SASS. RESULTS: As of September 1st 2018, 149 of the 318 identified randomized controlled trials were successfully completed over a median length of 44 months (IQR 30.0-55.0). Completed randomized controlled trials were more likely to be performed at single centers (p < 0.005). Interventional, drug and device trials were not significantly more likely to be completed. There was no difference in funding sources for completed or not completed randomized controlled trials. CONCLUSIONS: Prospective randomized trials are essential for establishing the standard of care in clinical medicine. They are, however, time and resource intensive. Herein we have attempted to identify factors associated with successful and timely completion of gynecologic oncology randomized controlled trials including site of origin, number of participating sites, funding source, intervention type, enrollment size, and study length; however, none of these factors were observed to have an association with increased rates of trial publication.

Challenges of international oncology trial collaboration-a call to action.

International collaboration in oncology trials has the potential to enhance clinical trial activity by expediting the recruitment of large patient populations, testing treatments in diverse populations and facilitating the study of rare tumours or specific molecular subtypes. However, a number of challenges continue to hinder the efficient and productive conduct of both commercial and non-commercial international clinical trials. These challenges include complex and burdensome regulatory requirements, the high cost of conducting trials, and logistical challenges associated with ethics review, drug supply and biospecimen collection and management. We propose solutions to promote oncology trial collaboration, such as regulatory reform, harmonisation of trial initiation and management processes and greater recognition and funding of academic (non-commercial) clinical trials. It is only through coordinated effort and leadership from researchers, regulators and those responsible for health systems that the full potential of international trial collaboration can be realised.

Globalization of clinical trials: Variation in estimated regional costs of pivotal trials, 2015-2016.

BACKGROUND/AIMS: Despite the increasing globalization of clinical trials, little is known regarding how the trial site costs vary around the world. We quantified the geographical distribution and regional cost differences for the clinical trials that established the benefits for new therapeutic drugs approved by the US Food and Drug Administration in 2015 and 2016. METHODS: We included all pivotal clinical trials for 59 new molecular entities approved by the US Food and Drug Administration in 2015 and 2016 that included at least one site in North America. We derived cost estimates from IQVIA's CostPro, a global clinical trial cost-estimating tool used by pharmaceutical sponsors. We assessed the patient and site allocation of these trials across eight geographic regions. To quantify the region-specific cost differences, we conducted a within-trial comparison by expressing the estimated regional costs associated with the sites in each global region as a percent of the same costs in North America. We also estimated the percentage breakdown of regional cost components (pass-through, site management, regulatory, and study conduct costs) for each trial and for all endpoints reported the median and interquartile range. RESULTS: Overall, 127 pivotal clinical trials enrolled 91,415 patients from 13,264 sites. Most patients (60.3%) and sites (57.3%) were outside North America. A median of 66% of the total estimated trial costs (interquartile range: 60%-72%) were spent on regional tasks, with the largest share (53.3%) going directly to trial sites and the remainder going to other regional trial management tasks. Differences were greatest in four lower cost regions: Africa, with an estimated regional cost per site of 49% of North America (interquartile range: 44%-56%), Central Europe 50% (interquartile range: 41%-63%), Middle East 53% (interquartile range: 42%-64%) and Latin America 59% (interquartile range: 50%-70%). Overall, 90 (71%) of the 127 pivotal trials had a total of 3160 sites in these lower cost regions. In contrast, savings were more limited in Western Europe, Oceania, and Asia, where estimated regional costs were 78% of North America (interquartile range: 67%-89%). One-quarter of the trials with sites in Asia and Oceana did not achieve cost savings in those regions relative to North America. CONCLUSION: Among this sample of pivotal trials for recently approved US Food and Drug Administration products, most patients and sites enrolled were outside of North America, with selection of regional sites having a significant impact on total trial costs.

Cost-Effectiveness of Web-Based Patient-Reported Outcome Surveillance in Patients With Lung Cancer.

INTRODUCTION: A multicenter randomized clinical trial in France found an overall survival benefit of web-based patient-reported outcome (PRO)-based surveillance after initial treatment for lung cancer compared with conventional surveillance. The aim of this study was to assess the cost-effectiveness of this PRO-based surveillance in lung cancer patients. METHODS: This medico-economic analysis used data from the clinical trial, augmented by abstracted chart data and costs of consultations, imaging, transportations, information technology, and treatments. Costs were calculated based on actual reimbursement rates in France, and health utilities were estimated based on scientific literature review. Willingness-to-pay thresholds of €30,000 per quality-adjusted life year (QALY) and €90,000 per QALY were used to define a very cost-effective and cost-effective strategy, respectively. Average annual costs of experimental and control surveillance approaches were calculated. The incremental cost-effectiveness ratio was expressed as cost per life-year gained and QALY gained, from the health insurance payer perspective. One-way and multivariate probabilistic sensitivity analyses were performed. RESULTS: Average annual cost of surveillance follow-up was €362 lower per patient in the PRO arm (€941/year/patient) compared to control (€1,304/year/patient). The PRO approach presented an incremental cost-effectiveness ratio of €12,127 per life-year gained and €20,912 per QALY gained. The probabilities that the experimental strategy is very cost-effective and cost-effective were 97% and 100%, respectively. CONCLUSIONS: Surveillance of lung cancer patients using web-based PRO reduced the follow-up costs. Compared to conventional monitoring, this surveillance modality represents a cost-effective strategy and should be considered in cancer care delivery.

Costs of clinical trials with anticancer biological agents in an Oncologic Italian Cancer Center using the activity-based costing methodology.

AIM: The aim of the present study was to assess the estimated "per patient" total cost for a single Oncologic Italian Cancer Center participating in a multicenter clinical trial with new anticancer biological agents using the activity-based costing (ABC) methodology. METHODOLOGY: Nine randomized phase 3 clinical trials employing biological agents at the National Cancer Institute of Napoli, Italy, were analyzed to indentify "per patient" costs of each trial, according to the ABC methodology. The average consumption of resources for a patient completing the entire planned treatment was estimated for each trial. Through interviews of the personnel (doctors, nurses and technicians) and by analyses of the clinical trials protocols, the main activities of the 9 clinical trials were identified and, for each trial, the complete health care pathway of the patients and the treatment programmes were minutely reconstructed. Drug costs were not included because provided by Sponsors. PRINCIPAL FINDINGS: The average costs of the pre-study, treatment, monitoring, follow-up, audit, and administrative activities accounted for 2.357, 4.783, 700, 372, 1.263, and 9 Euro, respectively. The average total cost estimated for all "per patient" activities, including overhead costs, was 11.379 Euro. Staff costs accounted for € 5.988, while costs of diagnostic test accounted for 3.494 Euro. Clinical trials with immunotherapeutic drugs accounted for higher costs (+601 Euro as oncological staff costs, +1.318 Euro as intermediate services cost and +384 Euro as overheads). CONCLUSIONS: The average total cost estimated for all "per patient" activities of a clinical trial with new anticancer biological agents was 11.379 Euro using the ABC methodology.

Learning from OCTET - exploring the acceptability of clinical trials management methods.

BACKGROUND: Conducting research can be time consuming, difficult and challenging. Guidance and pragmatic advice focussing on randomised controlled trial conduct are available but do not necessarily constitute comprehensive guidance. A successful trial is one that recruits to time and target and collects high-quality data within the originally agreed budget. Standardised trial management tools have outlined key project management elements for a successful trial as a method of ensuring good practice in research trials: initiation, planning, execution, monitoring and closure. Lessons are also frequently learnt during the development and conduct of trials but rarely shared for the benefit of others. For the wider research team, the key focus will always be on the execution and delivery of a study. The aim of this study was to evaluate the acceptability of clinical trials management methods, focussing on study execution and monitoring, as implemented in the National Institute for Health Research Health Technology Assessment Programme-funded Obsessive Compulsive Treatment Efficacy Trial (OCTET). METHODS: Workshops, questionnaires and semi-structured interviews were used to explore acceptability of trial management methods with members of the OCTET Trial research team. Nine members participated in the focus group, 10 completed a questionnaire and 20 were interviewed as part of qualitative work for the main OCTET study. Data was collected and analysed using thematic analysis. RESULTS: Six key themes were identified: support; communication; processes; resources; training and ethos. Clear and open communication, enthusiasm and accessibility of the trial managers and chief investigator were consistently noted as an important facet of the successful running of the trial. Clear resources and training materials were also found to be crucial in helping staff to work within the trial setting. Constructive suggestions were also made for improvement of these resources; for example, including both checklists and flowcharts within trial processes. CONCLUSION: Organisation, openness and positivity are crucial for executing a trial successfully, whilst clear and focussed processes and resources are essential in monitoring and controlling the trial progress. Although derived from a single study, these findings are likely to be applicable to the successful conduct of all trials. Trial managers should consider developing these elements when setting up a study. TRIAL REGISTRATION: Clinical Trial Registry, ID: ISRCTN73535163 . Registered prospectively on 5 April 2011.

Managing the link and strengthening transition from child to adult mental health Care in Europe (MILESTONE): background, rationale and methodology.

BACKGROUND: Transition from distinct Child and Adolescent Mental Health (CAMHS) to Adult Mental Health Services (AMHS) is beset with multitude of problems affecting continuity of care for young people with mental health needs. Transition-related discontinuity of care is a major health, socioeconomic and societal challenge globally. The overall aim of the Managing the Link and Strengthening Transition from Child to Adult Mental Health Care in Europe (MILESTONE) project (2014-19) is to improve transition from CAMHS to AMHS in diverse healthcare settings across Europe. MILESTONE focuses on current service provision in Europe, new transition-related measures, long term outcomes of young people leaving CAMHS, improving transitional care through 'managed transition', ethics of transitioning and the training of health care professionals. METHODS: Data will be collected via systematic literature reviews, pan-European surveys, and focus groups with service providers, users and carers, and members of youth advocacy and mental health advocacy groups. A prospective cohort study will be conducted with a nested cluster randomised controlled trial in eight European Union (EU) countries (Belgium, Croatia, France, Germany, Ireland, Italy, Netherlands, UK) involving over 1000 CAMHS users, their carers, and clinicians. DISCUSSION: Improving transitional care can facilitate not only recovery but also mental health promotion and mental illness prevention for young people. MILESTONE will provide evidence of the organisational structures and processes influencing transition at the service interface across differing healthcare models in Europe and longitudinal outcomes for young people leaving CAMHS, solutions for improving transitional care in a cost-effective manner, training modules for clinicians, and commissioning and policy guidelines for service providers and policy makers. TRIAL REGISTRATION: "MILESTONE study" registration: ISRCTN ISRCTN83240263 Registered 23 July 2015; ClinicalTrials.gov NCT03013595 Registered 6 January 2017.

A checklist for clinical trials in rare disease: obstacles and anticipatory actions-lessons learned from the FOR-DMD trial.

BACKGROUND: Trials in rare diseases have many challenges, among which are the need to set up multiple sites in different countries to achieve recruitment targets and the divergent landscape of clinical trial regulations in those countries. Over the past years, there have been initiatives to facilitate the process of international study set-up, but the fruits of these deliberations require time to be operationally in place. FOR-DMD (Finding the Optimum Steroid Regimen for Duchenne Muscular Dystrophy) is an academic-led clinical trial which aims to find the optimum steroid regimen for Duchenne muscular dystrophy, funded by the National Institutes of Health (NIH) for 5 years (July 2010 to June 2015), anticipating that all sites (40 across the USA, Canada, the UK, Germany and Italy) would be open to recruitment from July 2011. However, study start-up was significantly delayed and recruitment did not start until January 2013. METHOD: The FOR-DMD study is used as an example to identify systematic problems in the set-up of international, multi-centre clinical trials. The full timeline of the FOR-DMD study, from funding approval to site activation, was collated and reviewed. Systematic issues were identified and grouped into (1) study set-up, e.g. drug procurement; (2) country set-up, e.g. competent authority applications; and (3) site set-up, e.g. contracts, to identify the main causes of delay and suggest areas where anticipatory action could overcome these obstacles in future studies. RESULTS: Time from the first contact to site activation across countries ranged from 6 to 24 months. Reasons of delay were universal (sponsor agreement, drug procurement, budgetary constraints), country specific (complexity and diversity of regulatory processes, indemnity requirements) and site specific (contracting and approvals). The main identified obstacles included (1) issues related to drug supply, (2) NIH requirements regarding contracting with non-US sites, (3) differing regulatory requirements in the five participating countries, (4) lack of national harmonisation with contracting and the requirement to negotiate terms and contract individually with each site and (5) diversity of languages needed for study materials. Additionally, as with many academic-led studies, the FOR-DMD study did not have access to the infrastructure and expertise that a contracted research organisation could provide, organisations often employed in pharmaceutical-sponsored studies. This delay impacted recruitment, challenged the clinical relevance of the study outcomes and potentially delayed the delivery of the best treatment to patients. CONCLUSION: Based on the FOR-DMD experience, and as an interim solution, we have devised a checklist of steps to not only anticipate and minimise delays in academic international trial initiation but also identify obstacles that will require a concerted effort on the part of many stakeholders to mitigate.

Financial management of large, multi-center trials in a challenging funding milieu.

BACKGROUND: Randomized clinical trials that have public health implications but no or low potential for commercial gain are predominantly funded by governmental (e.g., National Institutes of Health (NIH)) and not-for-profit organizations. Our objective was to develop an alternative clinical trial site funding model for judicious allocation of declining public research funds. METHODS: In the Vitamin D and Type 2 Diabetes (D2d) study, an NIH-supported, large clinical trial testing the effect of vitamin D supplementation on incident diabetes in 2423 participants at high risk for diabetes, a hybrid financial management model for supporting collaborating clinical sites was developed and applied. The funding model employed two reimbursement components: Core (for study start-up and partial efforts throughout the study, ~40% of the total site budget), invoiced by sites, and Performance-Based Payments (for successful enrollment of participants and completion of follow-up visits, ~60% of the total site budget), automatically issued to the sites by the Coordinating Center based on actual recruitment and visits conducted. Underperforming sites transitioned to Performance-Based Payments only. RESULTS: Recruitment occurred from October 2013 through December 2016, requiring one additional year than the 2-year projection. Median enrollment at each site was 88 participants (range 29-318; 20 to 205% of the site target). At the end of year 1, study-wide recruitment was at 12% of the target (vs. 50% projected) and 12% of the total grant award was invested. The model constantly evaluated sites' needs and re-allocated resources to meet the study enrollment goal. If D2d had issued cost reimbursement subaward agreements and sites invoiced for their entire budget, 83% of the award would have been spent for all study activities over the first 4 years of the trial compared to 65% of the award spent (US$26M) under the hybrid model used by D2d. CONCLUSIONS: It is feasible to foster a hybrid financial management approach to steward limited available public funds for research in a dynamic and consistent way that does not compromise the trial's scientific integrity and ensures conservation of funds to complete recruitment and continue to follow up participants.

[Standard or specific unit costs: Which criteria for choosing an economic evaluation of health strategies in multicentric studies?] / Coûts unitaires standards ou coûts unitaires spécifiques : quels critères de choix pour l'évaluation économique de stratégies de santé dans les études multicentriques ?

The question of what monetary value should be assigned to consumed resources, that is to say the choice of the unit cost, is a major consideration in terms of impact on the cost analysis results. To date, no agreement has been reached regarding this methodological question. The choices made by methodologists and the subsequent impact on the results of the analysis are only rarely put forward. This work addresses the theoretical framework of health strategy evaluations that can be carried out either in the normative framework of the conventional economic approach of well-being, referred to as welfarist, or in that of an approach referred to as extra-welfarist. It also provides elements that help clarify the choice of the hospital unit costs used to calculate the cost of health strategies, so as to reconcile the use of such studies and improve their comparability. What is preferable, opting for specific per hospital unit costs or applying a standard unit cost to all facilities? How should a standard cost be calculated? Is it appropriate to calculate an average of the unit costs, as recommended by certain guidelines? The advantages and the limitations of the various modes of assessing hospital resources in the setting of multicentric trials are discussed.

The institutional development award states pediatric clinical trials network: building research capacity among the rural and medically underserved.

PURPOSE OF REVIEW: The institutional development award (IDeA) program was created to increase the competitiveness of investigators in states with historically low success rates for National Institutes of Health (NIH) research funding applications. IDeA states have high numbers of rural and medically underserved residents with disproportionately high rates of infant mortality, obesity, and poverty. This program supports the development and expansion of research infrastructure and research activities in these states. The IDeA States Pediatric Clinical Trials Network (ISPCTN) is part of the environmental influences on child health outcomes program. Its purpose is to build research capacity within IDeA states and provide opportunities for children in IDeA states to participate in clinical trials. This review describes the current and future activities of the network. RECENT FINDINGS: In its initial year, the ISPCTN created an online series on clinical trials, initiated participation in a study conducted by the pediatric trials network, and proposed two novel clinical trials for obese children. Capacity building and clinical trial implementation will continue in future years. SUMMARY: The ISPCTN is uniquely poised to establish and support new pediatric clinical research programs in underserved populations, producing both short and long-term gains in the understanding of child health.

Cost-efficacy analysis of 3% diclofenac sodium, ingenol mebutate, and 3.75% imiquimod in the treatment of actinic keratosis.

Actinic keratosis (AK) is a clinical condition characterized by keratinocytic dysplastic lesions of the epidermis, affecting individuals chronically exposed to sunlight. Topical therapies allow the treatment of a whole area of affected skin and currently include diclofenac sodium gel, 5-fluorouracil cream, 5-fluorouracil and acetylsalicylic acid solution, imiquimod cream, and ingenol mebutate gel. Due to the comparable efficacy of 3% diclofenac, ingenol mebutate, and 3.75% imiquimod in treating AK multiple lesions, a pharmacoeconomic evaluation of cost-effectiveness of the three treatments was needed. A cost-efficacy analysis comparing 3% diclofenac sodium with ingenol mebutate and 3.75% imiquimod was performed. In this analysis, efficacy data were combined with quality-of-life measurement derived from previous studies as well as the costs associated with the management of these lesions in Italy. Patients' demographics and clinical characteristics were assumed to reflect those from the clinical studies considered.

Non-commercial vs. commercial clinical trials: a retrospective study of the applications submitted to a research ethics committee.

There are many difficulties in undertaking independent clinical research without support from the pharmaceutical industry. In this retrospective observational study, some design characteristics, the clinical trial public register and the publication rate of noncommercial clinical trials were compared to those of commercial clinical trials. A total of 809 applications of drug-evaluation clinical trials were submitted from May 2004 to May 2009 to the research ethics committee of a tertiary hospital, and 16.3% of trials were noncommercial. They were mainly phase IV, multicentre national, and unmasked controlled trials, compared to the commercial trials that were mainly phase II or III, multicentre international, and double-blind masked trials. The commercial trials were registered and published more often than noncommercial trials. More funding for noncommercial research is still needed. The results of the research, commercial or noncommercial, should be disseminated in order not to compromise either its scientific or its social value.