Systematic review of controlled clinical studies using umbilical cord blood for regenerative therapy: Identifying barriers to assessing efficacy.

Clinical use of umbilical cord blood (UCB) for novel indications in regenerative therapy continues to rise, however, whether new indications are proven is less clear. An updated systematic search of the literature, focusing only on controlled clinical studies, is needed to properly assess potential efficacy. After updating our systematic search to April 1, 2018 (PROSPERO protocol CRD42016040157), a total of 16 studies were identified that addressed the treatment of cerebral palsy (four studies), type 1 diabetes (three studies), and nine other novel potential indications where only a single controlled study was identified. In the four controlled studies of patients with cerebral palsy, three used allogeneic cells and reported greater improvement in motor-related scores at 1, 3 and 6 months compared with controls. The results were mixed for other scores at other time points, including additional measures of mental and motor function. One study of autologous UCB treatment reported an improvement in motor function scores at 12 months compared with controls. In the three controlled studies of type 1 diabetes, two studies used autologous cells whereas one used allogeneic cord blood cells to "educate" autologous lymphocytes. Taken together, there was no clear difference in HbA1c levels or daily insulin requirements between treated patients and controls. For the nine published reports with a single controlled study, eight used allogeneic UCB cells and seven infused mesenchymal stromal cells derived from UCB. All but one study reported benefit. Many other published reports that lack a control group were not included in our analysis. More controlled studies are needed that use similar approaches regarding cell source and outcome measures at similar time points. Pooled estimates of results from multiple studies will be essential as published studies remain modest in size. Patients should continue to be enrolled in clinical trials because there are no novel potential indications remain unproven.

Análisis crítico de un ensayo clínico de no-inferioridad / Critical analysis of a noninferiority trial

In the era of diseases with highly efficacious treatments, the publication of randomized noninferiority clinical trials is increasingly frequent. However, users of medical literature are less familiar with this type of studies. The aim of this article is to give an introduction to the critical assessment of noninferiority clinical trials, through the solving of a therapeutic dilemma, which will be addressed through the analysis of a recently published trial of this type.

Ensayos clínicos publicados en el Boletín Médico del Hospital Infantil de México: un análisis crítico / Clinical trials published in the Boletín Médico del Hospital Infantil de México: a critical analysis

Resumen Introducción: El ensayo clínico es la manera más rigurosa de conducir los experimentos en seres humanos. Desde su introducción en investigación biomédica se han implementado cambios en el modo de establecer las bases para el diagnóstico, pronóstico y la terapéutica en la práctica clínica. Se han realizado estudios para identificar los ensayos clínicos publicados en diferentes áreas médicas, pero hasta el momento ninguno había identificado los ensayos clínicos publicados en el Boletín Médico del Hospital Infantil de México (BMHIM). El objetivo de este trabajo fue identificar y describir los ensayos clínicos controlados (ECC) publicados en el BMHIM. Métodos: Se realizó búsqueda manual y sistemática en cada uno de los números y volúmenes del BMHIM de 1968 a 2016. Se registraron los ECC para obtener sus principales características. Adicionalmente, se evaluó su calidad metodológica mediante la herramienta de riesgo de sesgo. Los resultados se presentan de forma descriptiva, gráfica y temporal. Resultados: Se revisaron 73 números con 363 volúmenes, analizando 4925 artículos. La proporción de ECC identificados en el BMHIM fue del 1% (67/4925). En general, los ensayos clínicos se realizaron en el contexto nacional, en el tercer nivel de atención, con un tamaño de muestra reducido, y las intervenciones farmacológicas fueron las más utilizadas. La calidad metodológica de los estudios fue baja, con alto riesgo de sesgo. Conclusiones: Los ensayos clínicos representan el 1% de todos los artículos de investigación originales publicados en el BMHIM. Aún existen áreas de investigación pediátrica, las cuales requieren del desarrollo de ECC para mejorar la práctica clínica, así como para elevar la calidad de la investigación.

Abstract Background: Controlled clinical trials (CCT) are the study design with the highest accuracy and evidence level. From its introduction in biomedical research, changes have been implemented in the way of establishing the basis for diagnosis, prognosis and treatment in clinical practice. Studies to identify published CCTs regarding different medical fields have been carried out. To date, none of them has identified the clinical trials that have been published in the Boletín Médico del Hospital Infantil de México (BMHIM). The aim of this study was to identify and describe the controlled clinical trials published in the BMHIM. Methods: A manual and systematic search was performed in each of the volumes of the BMHIM from 1968 to 2016. CCTs were recorded to obtain their main characteristics. Additionally, their methodological quality was assessed through the "risk of bias" tool. Results are presented in a descriptive, graphic and time-based manner. Results: In total, 73 issues with 363 volumes were reviewed, and 4925 articles were analyzed. The proportion of CCTs identified in the BMHIM was 1% (67/4925). In general, clinical trials were performed in the national context and in the third-level of medical care. CCTs also presented reduced sample sizes; pharmacological interventions were the most frequent. The methodological quality of the studies was low with a high risk of bias. Conclusions: Clinical trials represented 1% of all the original research articles published in the BMHIM. There are still pediatric research fields that require CCTs to be developed in order to improve clinical practice, as well as to increase the quality of the research.

Pautas de chequeo, parte IV: STARD y CARE / Checklists, part IV: STARD and CARE

Los ensayos clínicos controlados representan el diseño más destacado en la investigación biomédica. Sin embargo, existen otros diseños metodológicos que aportan información relevante para la medicina basada en la evidencia: los estudios sobre precisión de pruebas diagnósticas y reportes de caso. Al igual que con otros diseños, estos necesitan cumplir con estándares de calidad en su reporte, para lo que se han diseñados las pautas STARD y CARE, respectivamente. La pauta STARD comenzó a desarrollarse en 1999, siendo publicada en 2003, e incluye 25 ítems agrupados en 5 dominios (título/resumen/palabras clave, introducción, métodos, resultados, discusión). La pauta CARE se elaboró de acuerdo a la Guía para Desarrolladores de Guías de Reporte de Investigación en Salud, siendo publicada en 2013, e incluye 13 ítems, sin dominios declarados y que es de uso general para todos los ámbitos de la medicina. Así como con otras pautas de chequeo, el uso de STARD se ha asociado a una mejora en la calidad del reporte de estudios sobre precisión diagnóstica. En el caso de CARE, es necesario evaluar con el paso de los años su impacto en la calidad de los reportes de caso. Este último artículo de la serie describe ambas pautas de chequeo para su uso por parte de los autores de la REVISTA CHILENA DE CIRUGÍA, con el fin de lograr una mejora de sus artículos de una forma simple y eficiente.

Controlled clinical trials represent the design highlight in biomedical research. However, there are other methodological designs that provide relevant information for evidence-based medicine: studies of diagnostic test accuracy and case reports. As with other designs, they need to meet quality standards in their reporting, that is the reason for the design of STARD and CARE checklists, respectively. The STARD checklist began to develop in 1999, being published in 2003, it includes 25 items grouped into five domains (title / abstract / keywords, introduction, methods, results, discussion). The CARE checklist was made according to the Guidance for Developers of Health Research Reporting Guidelines, was published in 2013, it includes 13 items, without declared domains and is commonly used for all areas of medicine. As with other checklist, the use of STARD has been associated with an improvement in quality report of studies on diagnostic accuracy. In the case of CARE, it is necessary to assess over the years its impact on quality of case reports. This last article in the series describes both checklists for use by the authors of the REVISTA CHILENA DE CIRUGÍA, in order to achieve an improvement in their articles in a simple and efficient way.

Conducting an antidepressant clinical trial in oncology: challenges and strategies to address them.

OBJECTIVE: The aim of this report is to discuss the design of an antidepressant clinical trial and discuss the challenges and potential solutions to these challenges to successful recruitment of oncology patients for psychopharmacology trials. METHOD: We utilize meeting minutes and investigator discussions to identify the modifiable and nonmodifiable variables that affected successful subject recruitment for this study. RESULTS: No subjects were enrolled in our placebo-controlled antidepressant trial. After study modification to remove the placebo arm, we enrolled 21 subjects with depression and cancer. We identified the following recruitment difficulties during the study: diagnostic ambiguity in patients with depression and cancer, lowered subject retention in a medically ill population, patient reluctance to enroll in placebo-controlled studies and lack of a standardized referral processes for antidepressant studies in oncology at our institution. CONCLUSION: Our experience provides guidance on specific factors that future clinicians and researchers can consider when implementing psychopharmacologic trials in the medically ill.

A critical evaluation of migraine trigger site deactivation surgery.

Migraine headache trigger site deactivation surgery is a term that encompasses 4 different surgical procedures that are performed based on headache onset location for the preventative treatment of migraine headaches. Multiple studies have demonstrated some efficacy of these procedures, but closer evaluation of the methodology of these studies reveals major flaws in study design. In this article, the author provides an overview of the procedures and presurgical screening tools, as well as a critical evaluation of 2 of the major studies that have been published. In addition, the author provides his opinion on future study designs that may help to better determine the potential efficacy of these experimental procedures and potential headache subtypes (contact point headache, supraorbital neuralgia, and occipital neuralgia) that may respond to peripheral decompression surgery.

[Barriers to clinical studies involving medical devices]. / Hürden bei Studien mit Medizinprodukten.

Clinical trials with medical devices need to be considered in terms of the complexity of surgical procedures. Creating the proper environment for the conduct of trials includes improved academic career opportunities in the field of clinical research, methodological competence, and established structures. The challenges and pitfalls in the design of clinical trials involving medical devices are based on aspects such as blinding, placebo, learning curves and surgeons' expertise. Surgical procedures should be standardised, and a study hypothesis needs to be established which is answerable by a relevant and feasible sample size. Besides the above-mentioned challenges, efficient interactions between authorities, universities, hospitals, and medical device manufacturers are mandatory to allow for quality and relevance of clinical studies in this field.

[Utility of medical devices: approaches to planning and conducting clinical trials]. / Nutzen von Medizinprodukten: Lösungsansätze bei der Planung und Durchführung von Studien.

Medicines and medical devices do not only differ in the approval process, but also in the aim and conduct of clinical trials. We first discuss important differences between medicinal products and medical devices. Emphasis is put on the differences in the framework for clinical trials. We point out that a different analysis set should be used in clinical trials of medical devices when compared with medicinal products and medical devices in the USA. Specifically, regulators generally ask for the full analysis set based on the intention-to-treat principle as proof of efficacy of medicines. A central aspect of clinical trials of medical devices is that they have to be tested under normal conditions of use according to the performance data. As a result, all data acquired while the medical device was not during normal conditions of use should be excluded from statistical analyses. We discuss statistical methodological particularities of medical devices, such as blinding and the control of placebo effects. Using the conservative treatment of anal incontinence as an example, we show that comprehensive technical and physical knowledge is required for assessing the utility of medical devices. Finally, we consider reporting of severe adverse events and of severe adverse device effects of medical devices.

[Problem-based evidence: non-conventional methods of clinical investigations in surgery]. / Problem-based evidence: nem konvencionális klinikai vizsgálati metodikák a sebészetben.

In the era of evidence-based medicine the application of randomised controlled trials (RCT) are crucial for innovations. In contrast with pharmacological studies surgical innovations have several difficulties: setting up a control group is not always simple, placebo is not easy to define and ethico-legal regulation of sham-operations is not well established yet. Risks of the learning curve, which are variable in time and space are quite characteristic for surgical innovations. There is a need therefore to develop new methodologies to overcome these difficulties and resulting in a widely acceptable outcome. The method of problem-based evidence (PBE) obtains the evidences from particular problems of health care using knowledge and experience; and hereby providing advantage for surgical innovations compared to RCT's. PBE provides more opportunity for organizing surgical research and their international acceptance.

[Clinical applicability of evidence-based orthopedics--a cross-sectional study of the quality of orthopedic evidence]. / Die klinische Anwendbarkeit evidenzbasierter Orthopädie--Eine Querschnittsstudie der Qualität der Evidenz orthopädischer Studien.

INTRODUCTION: The demand to routinely apply evidence-based methods in orthopedic surgery increases steadily. In order to do so, however, the validity and reliability of the "evidence" has to be scrutinized. AIM: The object of this study was to assess the quality of the most recent orthopedic evidence and to determine variables that have an influence on quality. METHOD: All 2006 controlled trials from orthopedic journals with high impact factors were analysed in a cross-sectional study. A score based on the CONSORT statement was used to assess study quality. Selected variables were tested for their influence on the quality of the study. RESULTS: Two independent blinded observers reviewed 126 studies. The overall quality was moderate to high. The most neglected parameters were power analysis, intention-to-treat, and concealment. The participation of a methodologically trained investigator increases study quality significantly. There was no difference in study quality irrespective of whether or not there was statistically significant result. CONCLUSION: Using our quality score we were able show fairly good results for recent orthopedic studies. The most frequently neglected issues in orthopedic research are blinding, power analysis, and intention-to-treat. This may distort the results of clinical investigations considerably and, especially, lack of concealment causes false-positive findings. Our data show furthermore that participation of a methodologist significantly increases quality of the study and consequently strengthens the reliability of results.

Management of confounding in controlled orthopaedic trials: a cross-sectional study.

Confounding occurs when the effect of an exposure on an outcome is distorted by a confounding factor and will lead to spurious effect estimates in clinical studies. Although confounding can be minimized at the design stage, residual confounding may remain. An argument therefore can be made for controlling for confounding during data analysis in all studies. We asked whether confounding is considered in controlled trials in orthopaedic research and hypothesized the likelihood of doing so is affected by participation of a scientifically trained individual and associated with the magnitude of the impact factor. We performed a cross-sectional study of all controlled trials published in 2006 in eight orthopaedic journals with a high impact factor. In 126 controlled studies, 20 (15.9%; 95% confidence interval, 9.5%-22.3%) studies discussed confounding without adjusting in the analysis. Thirty-eight (30.2%; 95% confidence interval, 22.2%-38.2%) controlled for confounding, although we suspect the true proportion might be somewhat higher. Participation of a methodologically trained researcher was associated with (odds ratio, 3.85) controlling for confounding, although there was no association between impact factor and controlling for confounding. The question remains to what extent the validity of published findings is affected by failure to control for confounding.

Chemonucleolysis in lumbar disc herniation: a meta-analysis.

PURPOSE: To carry out a systematic review and meta-analysis of the efficacy of chemonucleolysis in the treatment of lumbar disc herniation. METHODS: Clinical trials were selected from 3 electronic databases (The Cochrane Controlled Trials Register, MEDLINE, and EMBASE). Data were analyzed with the software STATA, using the meta command. RESULTS: Twenty-two clinical trials were eligible. For chemonucleolysis versus placebo, the summary risk ratio estimate for pain relief as outcome was 1.51 (95% CI: 1.27-1.80). The summary estimate was 1.07 (95% CI: 0.95-1.20) for the comparison between chymopapain and collagenase. Regarding chemonucleolysis with chymopapain versus surgery, the fixed-effect summary estimate of effect for pain relief was 0.93 (95% CI: 0.88-0.98) with surgery as the reference group. In this case, heterogeneity was statistically significant. CONCLUSIONS: Chemonucleolysis with chymopapain was superior to placebo and was as effective as collagenase in the treatment of lumbar disc prolapse. Results for studies comparing chemonucleolysis with surgery were heterogeneous, making it difficult to interpret the summary measure of effect.

Chemonucleolysis in lumbar disc herniation: a meta-analysis

PURPOSE: To carry out a systematic review and meta-analysis of the efficacy of chemonucleolysis in the treatment of lumbar disc herniation. METHODS: Clinical trials were selected from 3 electronic databases (The Cochrane Controlled Trials Register, MEDLINE, and EMBASE). Data were analyzed with the software STATA, using the meta command. RESULTS: Twenty-two clinical trials were eligible. For chemonucleolysis versus placebo, the summary risk ratio estimate for pain relief as outcome was 1.51 (95 percent CI: 1.27-1.80). The summary estimate was 1.07 (95 percent CI: 0.95-1.20) for the comparison between chymopapain and collagenase. Regarding chemonucleolysis with chymopapain versus surgery, the fixed-effect summary estimate of effect for pain relief was 0.93 (95 percent CI: 0.88-0.98) with surgery as the reference group. In this case, heterogeneity was statistically significant. CONCLUSIONS: Chemonucleolysis with chymopapain was superior to placebo and was as effective as collagenase in the treatment of lumbar disc prolapse. Results for studies comparing chemonucleolysis with surgery were heterogeneous, making it difficult to interpret the summary measure of effect.

OBJETIVO: Avaliar a eficácia da quimonucleólise no tratamento da hérnia de disco lombar por meio de uma metanálise de ensaios clínicos. MÉTODOS: Os ensaios clínicos foram selecionados de três bases de dados eletrônicas( Cochrane, MEDLINE, e EMBASE). Os dados foram analisados por intermédio do aplicativo STATA, com o comando meta. RESULTADOS: trabalhamos com 22 ensaios clínicos. Para a comparação entre quimonucleólise e placebo, a estimativa da razão de riscos, tendo melhora da dor como desfecho, foi de 1,51 (I 95 por cento C: 1,27-1,80). Aquela medida foi de 1,07 (I 95 por cento C: 0,95-1,20) para a comparação entre quimopapaína e colagenase. Em um modelo de efeitos fixos, a razão de risco, para melhora da dor, foi 0,93 (I 95 por cento C: 0,88-0,98), tendo a discectomia como grupo de referência. Nesse caso, um teste de heterogeneidade foi considerado estatisticamente significante. CONCLUSÕES: a eficácia da quimonucleólise foi superior à do placebo e semelhante à da colagenase. Os resultados dos estudos referentes à comparação entre quimonucleólise e cirurgia foram heterogêneos, o que implica interpretação não-trivial da medida de efeito.

Implementation and evaluation of a central coordination office for clinical trials in a tertiary care hospital.

BACKGROUND: Controlled clinical trials are essential tools for establishing new standards in patient care. Nevertheless, the majority of cancer patients are not treated within clinical trials. We report about a project now running for 7 years that was started in order to enhance the recruitment of patients into clinical trials, to improve trial-related quality, and to comply with the regulatory issues related to these studies. MATERIAL AND METHODS: We established a Central Coordination Office (CCO) for clinical trials, an associated internal clinical trials review board, a register of active clinical trials, and a computer-based medical information system at our department. RESULTS: Inpatient recruitment into clinical trials at our department improved over the last 7 years from 40% in 1997 to 70% in 2003. The internal review board approved 276 trial projects since its establishment. A clinical trials register is now in its 9th edition. Currently, 50 to 60 clinical trials in oncology/hematology are active while 10 to 20 new trials are being implemented per year. All clinical trials comply with the regulatory requirements, and trial documentation is provided in a timely manner. CONCLUSIONS: The establishment of a CCO for clinical trials substantially improves and maintains patient recruitment into clinical trials and improves the quality of clinical research.