Identification and description of controlled clinical trials published in Spanish Gynaecology and Obstetrics journals and risk of bias assessment of trials on assisted reproductive techniques.

OBJECTIVES: To identify and describe controlled clinical trials (CCTs) published in Spanish Gynaecology and Obstetrics journals. In addition, to assess the quality of the CCTs on Assisted Reproduction Techniques (ART) identified in this project. STUDY DESIGN: In order to identify eligible CCTs, all Spanish Gynaecology and Obstetrics journals were handsearched. Handsearching was conducted following the guidelines provided by the Cochrane Collaboration, which state that each journal article must be carefully reviewed, including original articles and other types of studies, letters to the editor, abstracts, and conference presentations. The results of the handsearching process were compared with an electronic search conducted in MEDLINE (PubMed). A descriptive analysis of the main characteristics of the identified CCTs was performed, as well as a methodological assessment of CCTs on ART. RESULTS: Sixteen Gynaecology and Obstetrics journals were identified, four of which have been indexed in MEDLINE at some point, although not currently. The journal with the most CCTs was "Progresos de Obstetricia y Ginecología". A total of 235 CCTs were published in these journals, of which 29 were on ART. Most CCTs (216, 91.9%) were carried out in a hospital setting; 201 (89.4%) were unicentric. Obstetrics was the most studied subspecialty (46.4%). Among CCTs on ART, the risk of bias was predominantly high. CONCLUSIONS: The number of CCTs published in Spanish Gynaecology and Obstetrics journals is limited. CCTs on ART present deficiencies in the report of results and low methodological quality. It is advised that authors and journals adhere to the CONSORT statement and to the Cochrane Collaboration recommendations to reduce risk of bias when designing and disseminating research projects.

Comparison of global versus Asian clinical trial strategies supportive of registration of drugs in Japan.

The number of worldwide and Asian multiregional clinical trials (MRCTs) submitted for Japanese New Drug Applications increased markedly between 2009 and 2013, with an increasing number performed for simultaneously submission in the USA, EU, and Japan. Asian studies accounted for 32% of MRCTs (14/44 studies) and had comparatively small sample sizes (<500 subjects). Moreover, the number of Japanese subjects in Asian studies was 2.1- to 13.4-fold larger than the sample size estimated using the method described in Japanese MRCT guidelines, whereas the ratio for worldwide studies was 0.05- to 4.9-fold. Before the introduction of this guidelines, bridging or domestic clinical development strategies were used as the regional development strategy in accordance with ICH E5 guidelines. The results presented herein suggest that Asian studies were conducted when the drug had already been approved in the US/EU, when phase 3 clinical trials were not be planned in the USA/EU, when there was insufficient knowledge of ethnic differences in drug efficacy and safety, or when Caucasian data could not be extrapolated to the Japanese population. New strategies with Asian studies including the Japanese population could be conducted instead of Japanese domestic development strategy.

Ethical considerations in conducting pediatric research.

The critical need for pediatric research on drugs and biological products underscores the responsibility to ensure that children are enrolled in clinical research that is both scientifically necessary and ethically sound. In this chapter, we review key ethical considerations concerning the participation of children in clinical research. We propose a basic ethical framework to guide pediatric research, and suggest how this framework might be operationalized in linking science and ethics. Topics examined include: the status of children as a vulnerable population; the appropriate balance of risk and potential benefit in research; ethical considerations underlying study design, including clinical equipoise, placebo controls, and non-inferiority designs; the use of data monitoring committees; compensation; and parental permission and child assent to participate in research. We incorporate selected national (USA) and international guidelines, as well as regulatory approaches to pediatric studies that have been adopted in the USA, Canada, and Europe.

Interventions during pregnancy to reduce excessive gestational weight gain: a systematic review assessing current clinical evidence using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) system.

BACKGROUND: Excessive weight gain during pregnancy is common in developed countries and increases the risk of complications during pregnancy, delivery and the postpartum period, which can affect both maternal and fetal outcome. Interventions to reduce excessive gestational weight gain have previously not been systematically evaluated using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) system. OBJECTIVES: To determine whether published trials of interventions to reduce excessive gestational weight gain are of sufficient quality and provide sufficient data to enable evidence-based recommendations to be developed for clinical practice in antenatal care. SEARCH STRATEGY: A literature search was conducted in the scientific databases PubMed, Cochrane Library, Cinhal and Pedro, and the reference lists of relevant articles were reviewed. The literature search was concluded on 15 August 2009. SELECTION CRITERIA: All randomised controlled trials (RCTs) were considered for inclusion. As the number of published RCTs was limited, we also considered for inclusion all nonrandomised intervention studies that included a control group. Systematic reviews were examined to identify additional original studies. DATA COLLECTION AND ANALYSIS: Two reviewers independently assessed the quality of the methods and results of all included articles. Extracted data were classified using the GRADE system. MAIN RESULTS: Four intervention studies with a randomised controlled design and four intervention trials with a nonrandomised controlled design met the inclusion criteria. As a consequence of important limitations in study design, inconsistency and lack of directness, the overall quality of evidence was judged to be very low using the GRADE system. AUTHORS' CONCLUSIONS: The results of published intervention trials are of insufficient quality to enable evidence-based recommendations to be developed for clinical practice in antenatal care.

[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.

A placebo arm is not always necessary in clinical trials of amyotrophic lateral sclerosis.

Riluzole is currently the only approved medication for amyotrophic lateral sclerosis (ALS). While other potential neuroprotective agents have been tested in clinical trials, none has been effective, and few symptomatic treatments have been studied. Randomized placebo-controlled trials are necessary to establish the effectiveness of a drug, but an increasing number of potential therapies combined with limited resources means that only a few drugs at a time can be tested for efficacy in ALS. Therefore, priority must be given to agents that show an advantage in early phase trials before proceeding to Phase III efficacy trials. New strategies are being used to screen different agents, along with their correct dose, in a variety of neurological illnesses, including ALS. Early phase trial designs conducted without a placebo arm improve efficiency, reduce cost, and appeal to patients. Dose-ranging, futility, and selection trials are examples of Phase I and II trial designs that can be conducted without placebo groups.

European regulatory perspectives for innovative therapies.

The current regulatory requirements offer accelerated assessment of innovative therapies in Europe. Future perspectives include the need for increased interaction between stakeholders in pharmaceutical development. Development of new, high quality, effective and safe medicines in Europe is the common goal of academia, pharmaceutical industry and regulatory authorities. To achieve this, it is important that regulatory requirements do not hinder innovation and vice versa, innovation cannot be allowed to proceed without concerns for public health. Interaction between stakeholders in pharmaceutical development is of the utmost importance. A dialogue has begun and in the future it will be the responsibility of all stakeholders to ensure continuous exchanges in an environment that is characterised by new scientific advances and global development programmes.

Disciplined analyses in clinical trials: the dark heart of the matter.

Clinical research analyses must balance the desire to ;learn all that is learnable' from the database with the observation that sample-based data commonly lead to conclusions that are perfectly correct for the sample, but wholly incorrect for the population from which the data were based. Investigators who defend exploratory analyses as reliable, misuse important tools that have taken over three hundred years to develop. Statistical estimators in clinical trials function appropriately when they incorporate random data that is gathered in response to a fixed research question. Their prediction ability degrades rapidly when the selection of the research question is itself random, that is, left to the data. Operating like blind guides, these estimators mislead the medical community about what it would see in the population, based on sample observations. The result is a wavering research focus, leaping from one provocative but misleading finding to the next on the powerful waves of sampling error. Therefore, a primary purpose of the prospective design is to fix the research questions prospectively, thereby anchoring the analysis plan. Prospective statements of the research questions and rejection of tempting databased changes to the protocol preserve the best estimates of effect sizes, standard errors, confidence intervals and p-values. Embracing these principles promotes the prosecution of a successful research program, that is, the construction and protection of a research environment that permits an objective assessment of the therapy or exposure being studied. If there is any fixed star in the research constellation, it is that sample-based research must be hypothesis-driven and concordantly executed to have real meaning for both the scientific community and the patient populations that we serve.

[Controlled clinical trials before Archie Cochrane]. / Kontrollierte klinische Studien vor Archie Cochrane.

The James Lind Library is an excellent source for documents on the history of the controlled clinical trial. It was named after the 18th century naval surgeon James Lind who performed a multi-arm controlled clinical trial on the treatment of scurvy. Iain Chalmers is a co-founder of the James Lind Library. In his presentation at the 10th anniversary of the GCC, he told us about a number of exemplary studies with special consideration of the evolution of methods to avoid allocation bias. He particularly stressed that over the centuries many individuals from many different countries have contributed to the standard of the randomised controlled trials of our days.

[Assessment of clinical trial quality and its impact on meta-analyses]. / Avaliação da qualidade de estudos clínicos e seu impacto nas metanálises.

OBJECTIVE: To evaluate whether different quality assessment tools applied to a group of clinical trials could be correlated, and what would be their impact on meta-analysis results. METHODS: Thirty-eight randomized controlled clinical trials were analyzed. These had been selected for a systematic review of the therapeutic efficacy of alpha interferon for treating chronic hepatitis B. The following tools were utilized: Maastricht (M), Delphi (D), Jadad (J) and the Cochrane Collaboration (CC) method (gold standard). The Spearman correlation coefficient was used to compare the results from the three methods. The Kappa test was used to assess the concordance between the reviewers in applying the tools, and the weighted Kappa test was applied to compare the quality ranking determined by the tools. The outcomes assessed in the meta-analyses were clearance of HBV-DNA and HBeAg. RESULTS: The studies presented regular to low quality. The concordance between reviewers varied according to the instrument utilized: D=0.12; J=0.29; M=0.33; and CC=0.53. The correlation was moderate and homogeneous (D/J=0.51; D/M=0.53; and J/M=0.52). The meta-analysis result relating to HBV-DNA ranged from RR=0.71 (95% CI: 0.66-0.77) to RR=0.67 (95% CI: 0.58-0.79). For HBeAg, the results ranged from RR=0.85 (95% CI: 0.80-0.90) to RR=0.85 ( 95% CI: 0.77-0.93). These results depended on the quality of the studies included. CONCLUSIONS: The quality assessment tools presented good correlation. In systematic reviews with the same direction of effect, the quality assessment may not significantly change the results. The Cochrane Collaboration method was the most reproducible method and easiest to apply.

Issues in treatment-resistant depression.

Major depressive disorder is a debilitating disease that imposes significant social and economic burdens not only on patients but also on society. Although various treatment options are available, treatment-resistant depression is common. Determining the exact prevalence of treatment-resistant depression is difficult because definitions vary, as do definitions of antidepressant response. Operational definitions of antidepressant response, nonresponse, partial response, and remission will be discussed in this article. Pharmacotherapy options for patients with treatment-resistant depression include augmentation, combination, and switching therapies; however, data from controlled clinical trials supporting these therapies are limited. Electroconvulsive therapy and psychotherapy offer additional treatment strategies. New nonpharmacologic therapies are under investigation. Remission is the goal of treatment.

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.

Defining standard of care in the developing world: the intersection of international research ethics and health systems analysis.

In recent years there has been intense debate regarding the level of medical care provided to 'standard care' control groups in clinical trials in developing countries, particularly when the research sponsors come from wealthier countries. The debate revolves around the issue of how to define a standard of medical care in a country in which many people are not receiving the best methods of medical care available in other settings. In this paper, we argue that additional dimensions of the standard of care have been hitherto neglected, namely, the structure and efficiency of the national health system. The health system affects locally available medical care in two important ways: first, the system may be structured to provide different levels of care at different sites with referral mechanisms to direct patients to the appropriate level of care. Second, inefficiencies in this system may influence what care is available in a particular locale. As a result of these two factors locally available care cannot be equated with a national 'standard'. A reasonable approach is to define the national standard of care as the level of care that ought to be delivered under conditions of appropriate and efficient referral in a national system. This standard is the minimum level of care that ought to be provided to a control group. There may be additional moral arguments for higher levels of care in some circumstances. This health system analysis may be helpful to researchers and ethics committees in designing and reviewing research involving standard care control groups in developing country research.