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.

Observational human studies in allergic diseases: design concepts and highlights of recent National Institute of Allergy and Infectious Diseases-funded research.

PURPOSE OF REVIEW: To present and discuss key design concepts for optimizing the impact of observational studies in the field of allergy and to highlight recent findings from NIAID-funded research networks. RECENT FINDINGS: We discuss three concepts. First, the benefit of prospective, longitudinal observational studies exemplified by recent findings on the seasonal nature of all rhinitis phenotypes in children with asthma and the protective effects of high house dust allergen content during the first year of life on the development of asthma at age 7 years. Second, the benefit of detailed (deep) phenotyping exemplified by the identification of a MALT1 gene variant as a strong genetic link to peanut allergy and the determination that atopic dermatitis with food allergy constitutes a distinct cutaneous endotype, compared with atopic dermatitis alone. Third, the benefit of hypothesis-generating research combined with prospective design and deep phenotyping as exemplified by the unveiling of potential pathophysiologic pathways leading to asthma exacerbations in children, after a 'cold'. SUMMARY: Observational studies can be highly impactful if designed well. Longitudinal study design, deep phenotyping, and hypothesis-generating research are three major design concepts that should be considered in the development of these studies.

Importance of operating room case scheduling on analyses of observed reductions in surgical site infections from the purchase and installation of capital equipment in operating rooms.

BACKGROUND: We review the impact of the consequences of operating room (OR) management decision making on power analyses for observational studies of surgical site infections (SSIs) among patients receiving care in ORs with interventions versus without interventions involving physical changes to ORs. Examples include ventilation systems, bactericidal lighting, and physical alterations to ORs. METHODS: We performed a narrative review of operating room management and surgical site infection articles. We used 10-years of operating room data to estimate parameters for use in statistical power analyses. RESULTS: Creating pivot tables or monthly control charts of SSI per case by OR and comparing among ORs with or without intervention is not recommended. This approach has low power to detect a difference in SSI rates among the ORs with or without the intervention. The reason is that appropriate OR case scheduling decision making causes risk factors for SSI to differ among ORs, even when stratifying by surgical specialty. Such risk factors include case duration, urgency, and American Society of Anesthesiologists' Physical Status. Instead, analyze SSI controlling for the OR, where the patient had surgery, and matching patients using these variables is preferable. With α = 0.05, 600 cases per OR, 5 intervention ORs, and 5 or 1 control patients for each intervention patient, reasonable power (≅94% or 78%, respectively) can be achieved to detect reductions (3.6% to 2.4%) in the incidence of SSI between ORs with or without the intervention. CONCLUSIONS: By using this matched cohort design, the effect of the purchase and installation of capital equipment in ORs on SSI can be evaluated meaningfully.

The use of real-world data in cancer drug development.

Excitement about the dramatic increase in potential successful anticancer medicines in recent years is hampered by the high costs involved as well as the length of time traditional pathways take for regulatory approval. The translation of experimental clinical data into real-world evidence is also problematic. While the randomised controlled trial remains the gold standard for assessing efficacy and safety, there is increasing interest in the use of observational data to enable more rapid, informed and widespread availability and access to important anticancer medicines. Taking real-world evidence into account in regulatory and health technology assessment in a thoughtful and balanced fashion will enrich and justify sound decision-making.

Community detoxification for alcohol dependence: A systematic review.

ISSUES: Despite the potential advantages of community detoxification for alcohol dependence, in many countries the available resources are mostly focused on specialist services that are resource-intensive, and often difficult to access because of financial or geographical factors. The aim of this systematic review is to synthesise the existing literature about the management of alcohol detoxification in the community to examine its effectiveness, safety, acceptability and feasibility. APPROACH: The systematic review was guided by an a priori defined protocol consistent with the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) statement. Cochrane library, Medline, EMBASE, PsycINFO, Global Health and CINAHL databases were searched using appropriate search terms. A qualitative synthesis of the data was conducted as the heterogeneity of study designs, samples and outcomes measured precluded a meta-analyses. KEY FINDINGS: Twenty studies with a range of designs were eligible for the review. Community detoxification had high completion rates and was reported to be safe. Compared to patients undergoing facility based detoxification, those who underwent community detoxification had better drinking outcomes. Community detoxification was cheaper than facility based detoxification and generally had good acceptability by various stakeholders. IMPLICATIONS: For certain patients, community detoxification should be considered as a viable option to increase access to care. CONCLUSIONS: Although the current evidence base to some extent supports the case for community detoxification there is a need for more randomised controlled trials testing the cost effectiveness of community detoxification in comparison with inpatient detoxification. [Nadkarni A, Endsley P, Bhatia U, Fuhr DC, Noorani A, Naik A, Murthy P, Velleman R. Community detoxification for alcohol dependence: A systematic review Drug Alcohol Rev 2017;36:389-399].

Measuring the effects of CVD interventions and studies across socioeconomic groups: A brief review.

There is a known socioeconomic skew in prevalence and outcomes of cardiovascular disease (CVD). To document the proportion of clinical trials and observational studies related to CVD recently published in peer-reviewed journals that report the socio-economic distributional differences in their outcomes. We undertook a review of peer-reviewed clinical trials and observational studies relating to CVD published between 01/06/2015-31/12/2015 in PubMed; and identified the proportion that included measures of socioeconomic status and the proportion that stratified results by, or controlled for, socioeconomic status when reporting outcomes. 414 peer reviewed publications reporting the outcomes of clinical trials or observational studies that related to CVD were identified. 32 of these reported on the socioeconomic status of participants. Of these, 20 stratified the results by socioeconomic status or adjusted the results for socioeconomic status. 18 studies measured education attainment, 5 measured income, 1 measured rurality and 1 measured occupation. Of the 414 articles reporting the outcomes of clinical trials or observational studies related to cardiovascular disease in 2015, the effectiveness of the intervention, or the differences in outcomes, between socioeconomic groups was assessed in 5% of studies. This lack of consideration of the effectiveness of trial outcomes or the differences in outcomes across socioeconomic groups impairs the ability of readers, healthcare professionals and policy makers to assess the impact of new treatments or interventions in closing the inequality gap associated with CVD.

Cost-effectiveness modelling of novel oral anticoagulants incorporating real-world elderly patients with atrial fibrillation.

BACKGROUND: Novel oral anticoagulants (NOACs) expand the treatment options for patients with atrial fibrillation (AF). Their benefits need to be weighed against the risk-benefit ratio in real-world elderly patients, prompting this cost-effectiveness study of NOACs (apixaban, dabigatran, edoxaban and rivaroxaban), warfarin and aspirin for stroke prevention in AF. METHODS: Applying effectiveness estimates from a network meta-analysis involving over 800,000 patients from randomised controlled trials and observation studies, our Markov model projected cost and health outcomes for a cohort of 65-year-old AF patients over a life-time. We performed subgroup analysis stratified by age (65-74 and ≥75years), with further analysis limited to observational studies involving dabigatran and rivaroxaban. RESULTS: Compared to warfarin, NOACs (except dabigatran 110) were associated with incremental cost-effectiveness ratios ranging from USD 24,476 to USD 41,448 that were within cost-effectiveness threshold of USD 49,700 (one gross domestic product per capita in Singapore in 2015). Aspirin regimens were dominated. In elderly aged ≥75years, cost effectiveness of NOACs (except apixaban) decreased, owing to worsened performance in safety profile. Analysis limited to observational studies revealed that dabigatran 150 and rivaroxaban were not cost-effective, reflecting increased bleeding risks in non-controlled settings. Threshold analyses revealed that apixaban was no longer cost-effective at two to three times higher bleeding risk. CONCLUSIONS: Whilst NOACs are cost-effective in the younger elderly compared to warfarin, their benefits appear to be offset by worsened risk profile in older elderly, especially in non-controlled settings. Decisions on appropriate AF treatment should balance treatment-related benefits, risks, and patient preference.

Using Certification to Promote Uptake of Real-World Evidence by Payers.

Most randomized controlled trials are unable to generate information about a product's real-world effectiveness. Therefore, payers use real-world evidence (RWE) generated in observational studies to make decisions regarding formulary inclusion and coverage. While some payers generate their own RWE, most cautiously rely on RWE produced by manufacturers who have a strong financial interest in obtaining coverage for their products. We propose a process by which an independent body would certify observational studies as generating valid and unbiased estimates of the effectiveness of the intervention under consideration. This proposed process includes (a) establishing transparent criteria for assessment, (b) implementing a process for receipt and review of observational study protocols from interested parties, (c) reviewing the submitted protocol and requesting any necessary revisions, (d) reviewing the study results, (e) assigning a certification status to the submitted evidence, and (f) communicating the certification status to all who seek to use this evidence for decision making. Accrediting organizations such as the National Center for Quality Assurance and the Joint Commission have comparable goals of providing assurance about quality to those who look to their accreditation results. Although we recognize potential barriers, including a slowing of evidence generation and costs, we anticipate that processes can be streamlined, such as when familiar methods or familiar datasets are used. The financial backing for such activities remains uncertain, as does identification of organizations that might serve this certification function. We suggest that the rigor and transparency that will be required with such a process, and the unassailable evidence that it will produce, will be valuable to decision makers.

Implementation Processes and Pay for Performance in Healthcare: A Systematic Review.

BACKGROUND: Over the last decade, various pay-for-performance (P4P) programs have been implemented to improve quality in health systems, including the VHA. P4P programs are complex, and their effects may vary by design, context, and other implementation processes. We conducted a systematic review and key informant (KI) interviews to better understand the implementation factors that modify the effectiveness of P4P. METHODS: We searched PubMed, PsycINFO, and CINAHL through April 2014, and reviewed reference lists. We included trials and observational studies of P4P implementation. Two investigators abstracted data and assessed study quality. We interviewed P4P researchers to gain further insight. RESULTS: Among 1363 titles and abstracts, we selected 509 for full-text review, and included 41 primary studies. Of these 41 studies, 33 examined P4P programs in ambulatory settings, 7 targeted hospitals, and 1 study applied to nursing homes. Related to implementation, 13 studies examined program design, 8 examined implementation processes, 6 the outer setting, 18 the inner setting, and 5 provider characteristics. Results suggest the importance of considering underlying payment models and using statistically stringent methods of composite measure development, and ensuring that high-quality care will be maintained after incentive removal. We found no conclusive evidence that provider or practice characteristics relate to P4P effectiveness. Interviews with 14 KIs supported limited evidence that effective P4P program measures should be aligned with organizational goals, that incentive structures should be carefully considered, and that factors such as a strong infrastructure and public reporting may have a large influence. DISCUSSION: There is limited evidence from which to draw firm conclusions related to P4P implementation. Findings from studies and KI interviews suggest that P4P programs should undergo regular evaluation and should target areas of poor performance. Additionally, measures and incentives should align with organizational priorities, and programs should allow for changes over time in response to data and provider input.

Embedding clinical interventions into observational studies.

Novel approaches to observational studies and clinical trials could improve the cost-effectiveness and speed of translation of research. Hybrid designs that combine elements of clinical trials with observational registries or cohort studies should be considered as part of a long-term strategy to transform clinical trials and epidemiology, adapting to the opportunities of big data and the challenges of constrained budgets. Important considerations include study aims, timing, breadth and depth of the existing infrastructure that can be leveraged, participant burden, likely participation rate and available sample size in the cohort, required sample size for the trial, and investigator expertise. Community engagement and stakeholder (including study participants) support are essential for these efforts to succeed.

Costs of unstructured investigation of unexplained syncope: insights from a micro-costing analysis of the observational PICTURE registry.

AIMS: The observational PICTURE (Place of Reveal In the Care pathway and Treatment of patients with Unexplained Recurrent Syncope) registry enrolled 570 patients with unexplained syncope, documented their care pathway and the various tests they underwent before the insertion of an implantable loop recorder (ILR). The aims were to describe the extent and cost of diagnostic tests performed before the implant. METHODS AND RESULTS: Actual costs of 17 predefined diagnostic tests were characterized based on a combination of data from PICTURE and a micro-costing study performed at a medium-sized UK university hospital in the UK. The median cost of diagnostic tests per patient was £1114 (95% CI £995-£1233). As many patients received more than the median number of tests, the mean expenditure per patient was higher with £1613 (95% CI £1494-£1732), and for 10% of the patients the cost exceeded £3539. Tests were frequently repeated, and early use of specific and expensive tests was common. In the 12% of patients with types of tests entirely within the recommendations for an initial evaluation before ILR implant, the mean cost was £710. CONCLUSION: Important opportunities to reduce test-related costs before an ILR implant were identified, e.g. by more appropriate use of tests recommended in the initial evaluation, by decreasing repetition of tests, and by avoiding early use of specialized and expensive tests. A structured multidisciplinary approach would be the best model to achieve an optimal outcome.

[Impact of the economic crisis on the activity of a clinical research ethics committee]. / Impacto de la crisis económica en la actividad de un comité ético de investigación clínica.

PURPOSE: Analyze the impact of economic and social crisis in volume and funding of clinical trials (CT) and observational studies (ES) from the activity of an Research Ethics Committee (REC). METHOD: REC memories 2003-2012 were reviewed. Financing of evaluated projects, CT and OS were analyzed classifying them into four groups: 1) promoted by pharmaceutical industry, 2) by scientific societies with industry support, 3) by scientific societies with government support and 4) unfunding.Two periods were compared: pre-crisis (2003-2007) and crisis (2008-2012). RESULTS: During 10 studied years, 744 protocols were evaluated: a 71% of group 1, a 9% of group 2, a 3% of group 3 and a 17% was no funding. Regarding OS, 40%, 5,4%, 8,6% and 46% were the groups 1, 2, 3 and 4 respectively. Analyzing crisis versus pre-crisis period, statistically significant differences were observed in the decreasing of number of CT phase 2 and 3 and in the rising EO. Comparing crisis related to the pre-crisis period, the Group 4 increased statistically significantly. CONCLUSIONS: Evolution of total number of studies evaluated by REC tends to be maintained and even increased over time. REC maintains its activity and even increased at the expense of financing and unfunded OS.

Objetivos: Analizar el impacto de la crisis económico-social en volumen y financiación de los ensayos clínicos (EC) y estudios observacionales (EO) a partir de la actividad de un Comité Ético de Investigación Clínica (CEIC). Método: Se revisaron las memorias del CEIC desde 2003 hasta 2012. Se analizó la financiación de los EC y los EO clasificándolos en cuatro grupos: 1) promovidos por la industria farmacéutica, 2) por sociedades científicas con soporte de la industria, 3) por sociedades apoyadas por las administraciones públicas y 4) sin financiación. Se compararon dos períodos: precrisis (2003- 2007) y crisis (2008-2012). Resultados: Se evaluaron 744 protocolos: un 71% del grupo 1, un 9% del grupo 2, un 3% del grupo 3 y un 17% carecía de financiación. En cuanto a los EO, un 40%, un 5,4%, un 8,6% y un 46% correspondían a los grupos 1, 2, 3 y 4 respectivamente. Analizando periodo crisis versus precrisis, se observaron diferencias estadísticamente significativas en el número de los EC de fase 2 y fase 3 que disminuyeron y en los EO que aumentaron. En el periodo crisis respecto al precrisis, el Grupo 4 aumentó de manera estadísticamente significativa. Conclusiones: La evolución del número total de estudios evaluados por el CEIC tiende a mantenerse e incluso incrementarse en el tiempo. El CEIC mantiene su actividad e incluso la incrementa, a expensas de EO con y sin financiación.

Optimal combination of number of participants and number of repeated measurements in longitudinal studies with time-varying exposure.

In the context of observational longitudinal studies, we explored the values of the number of participants and the number of repeated measurements that maximize the power to detect the hypothesized effect, given the total cost of the study. We considered two different models, one that assumes a transient effect of exposure and one that assumes a cumulative effect. Results were derived for a continuous response variable, whose covariance structure was assumed to be damped exponential, and a binary time-varying exposure. Under certain assumptions, we derived simple formulas for the approximate solution to the problem in the particular case in which the response covariance structure is assumed to be compound symmetry. Results showed the importance of the exposure intraclass correlation in determining the optimal combination of the number of participants and the number of repeated measurements, and therefore the optimized power. Thus, incorrectly assuming a time-invariant exposure leads to inefficient designs. We also analyzed the sensitivity of results to dropout, mis-specification of the response correlation structure, allowing a time-varying exposure prevalence and potential confounding impact. We illustrated some of these results in a real study. In addition, we provide software to perform all the calculations required to explore the combination of the number of participants and the number of repeated measurements.