Trials Of New Drugs Research Articles

OvarianTag biomarker panel in order guide treatment decisions cisplatin-based for women with epithelial ovarian cancer.

e18075 Background: Ovarian cancer (OC) represents the most lethal gynecologic cancer. Late-stage diagnosis associated with a lack of effective markers to detect chemotherapy resistance contributes to high mortality and poor prognosis of epithelial ovarian cancer (EOC). OvarianTag Biomarkers Panel was developed as biopsy-based gene expression assay to discriminate prognosis in EOC patients, to understand the aggressiveness and relapse causes of these patients. Methods: Patients were admitted into this study in two phases. First, 45 women were included prospectively, and RNA was obtained from fresh normal ovarian (NO) tissues (n = 18), ovarian serous cystadenoma tumors (n = 11) and EOC (n = 16). The total RNA content was quantified and quantitative PCR (qRT-PCR) was performed to determine relative gene expression, starting set genes related to apoptosis and necroptosis regulated cell death pathway. Machine Learning algorithms were used to classify patient’s data associated and to characterize molecular targets as prognostic markers, named OvarianTag panel. Later, others 55 EOC patients, attended between 2008 and 2016, were included. Within this cohort, tissues were obtained from 106 FFPE samples and shared into primary and metastatic EOC, and from the same NO tissues (as control). RNA was extracted and qRT-PCR determined the OvarianTag panel expression level from each sample. Then, hierarchical clustering allowed us to classify the samples using the cut off obtained by classifier algorithm. Results: Significant differences in gene expression profile were observed between patients’ groups. Molecular classifier algorithm proved the prognostic value of genes evaluated. Decisions trees and biomarker clusters were constructed. In the full training, were obtained 90% of correct classifications and in cross-validation, 89%. In the second phase, the classifier reported specificity of 100% and sensibility of 79% to predict tumor recurrence and platinum resistance. Conclusions: OvarianTag panel is a putative prognosis biomarker of EOC subgroups and could be considered to drive the clinical practice of EOC treatment options, improving outcomes because providing an opportunity for guide clinical intervention for increasing survival rates. Besides of that, it will be allowed include patients in clinical trials of new target drugs or for repositioning of target drugs that have already been tested in humans.

Transforming Performance of Clinical Trials in Pediatric Type 2 Diabetes: A Consortium Model.

Background: Completing phase 3 trials of new drugs for youth with type 2 diabetes is challenging. The Pediatric Diabetes Consortium (PDC) of U.S. pediatric treatment centers developed a Consortium model to improve the efficiency of successfully completing these trials. Aims and Innovations: An aim of the PDC model is to utilize the resources of the PDC Coordinating Center and Executive Committee to improve study protocols, centralize interactions with sponsors, and oversee the performance of PDC Clinical Centers. Key features include a Consulting Group to improve protocol design; Master Service Agreements between the Coordinating Center and Clinical Centers covering confidentiality agreements and contract language; negotiation of a standard Site Budget with Contract Research Organizations (CROs)/Sponsors that reflect actual Clinical Center costs; Weekly Conference Calls with CROs/sponsors to track progress of Clinical Center launches, Monthly Oversight Calls with investigators and study Coordinators to track Clinical Center performance, discuss enrollment strategies, and identify emerging problems. Successes and Challenges: The Consortium model played a key role in the completion of the pivotal trial of liraglutide for treatment of youth with type 2 diabetes. PDC centers also played a pivotal role in exceeding the projected number of randomized subjects needed by two ongoing studies that are nearing completion. Conclusions: While the Consortium model is still a work in progress, PDC has assisted in the successful launch of new type 2 diabetes studies, and negotiations are in underway for PDC participation in pediatric type 1 diabetes and other diabetes-related studies.

Clinical trial analysis of 2019-nCoV therapy registered in China.

So far, there is a lack of effective drugs for the new coronavirus pneumonia. With more and more patients diagnosed, China has carried out more than 100 clinical studies of new coronavirus infection, including antiviral drugs, antimalarial drugs, glucocorticoids, plasma therapy, virus vaccine, and other Western drugs, while Chinese medicine research accounted for half of the studies. Most of the trials were initiated by investigators and the study period would last for 1 to 11 months. The primary endpoints included symptom improvement and virus nucleic acid turning negative, but the optimal endpoint has not been determined. Although the final results of studies will take a long time to complete, the interim research data may provide some help for the current urgent demand for drug treatment. Compared with that of during SARS period in 2003, China has the stronger capability to carry out clinical trials of new drugs in emergency period.

SAT-153 CORRELATION BETWEEN HBA1c LEVEL AND RENAL FUNCTION IN DIABETIC NEPHROPATHY

Tight glycemic control may have limited effect on the protection of renal function. No large clinical trials conducted since 2000 have clearly shown that the management goal of HbA1C is 6% better than 7%. In addition, recent clinical trials of many new drugs have compared the HbA1c levels of 8% and 7% groups. Therefore, in this study, HbA1C was divided into each stratum by 1%, and the effect of HbA1c level on renal function was examined. This single-center retrospective observational study examined the HbA1C and Cr data of patients for five consecutive years between 2007 and 2017, beginning from the date of the first measurement of HbA1C. Annual mean values were used as representative values for blood tests. Considering the possibility of a high HbA1C level in the first year, the mean HbA1C level after year 2 was calculated, and the four groups (6%, 7%, 8% and 9%) were compared. Primary endpoints were mean estimated glomerular filtration rate (eGFR) slope and the proportion of patients with rapid renal insufficiency (≥ 5 mL/min/1.73 m2/year). Dialysis patients and those aged 18 years or younger were excluded from the study. The HbA1C 6%, 7%, 8% and 9% groups consisted of 630, 399, 95, and 23 subjects, respectively. The mean ages of these groups were 64.6, 65.0, 60.6, and 61.0 years, respectively, and the mean HbA1C during the course was 6.5 ± 0.3, 7.4 ± 0.3, 8.4 ± 0.3, and 9.4 ± 0.3, respectively. The mean eGFR at 1 year was 69.6, 70.7, 75.7, and 78.4 ml/min/1.73 m2, respectively. The higher the HbA1C level, the greater was the eGFR slope. The eGFR slopes were -1.2 ± 2.8, 1.2 ± 2.7, 1.5 ± 3.3, and 2.6 ± 3.6 mL/min/1.73 m2/year for the four groups, respectively. The incidence of rapid decreased renal function was 7.3%, 6.5%, 10.5% and 21.7% for HbA1C 6%, 7%, 8% and 9% groups, respectively, showing similar tendency with the eGFR slope. Furthermore, only the 6% and 7% groups were analyzed by matching background factors, but no significant difference was found (P = 0.74). In the present study, there was no significant difference in either the eGFR slope or the percentage of patients with rapid decreased renal function between HbA1C in the 6% and 7% ranges.

Acceptance and Related Causes of Clinical Trials among Cancer Patients in China

背景与目的我国的抗肿瘤新药临床试验开展如火如荼，患者的临床试验接受度是影响临床试验开展速度和质量的重要因素。既往研究仅针对未参与过临床试验的肿瘤患者接受度展开调查，未分析参加过临床试验患者的相关情况。本研究调查并比较参加过和未参与过试验的肿瘤患者对于临床试验的接受度，并分析相关原因。方法2018年6月-2019年4月，采用标准化问卷在中国医学科学院肿瘤医院针对肿瘤患者（参加过vs未参加过试验）开展调查，分析比较两组患者临床试验的接受度和差异，并分析主要原因及医生对其接受度的影响。结果共纳入538例患者，男性51.1%，平均年龄53.5岁，43.3%的患者参加过试验。总体而言，502例（93.3%）患者愿意参加或推荐亲友参加试验，参加过试验的患者接受度较高（96.6% vs 90.8%, P=0.008）。参加过和未参加过试验患者愿意的最主要原因均为“期待最佳治疗效果”（100.0% vs 99.3%），次要原因分别为“可减轻经济负担”（56.0%）和“主治医生建议”（43.7%）。参加过试验的患者不愿意参加的主要原因为“放弃其他治疗选择”、“分到对照治疗组”或“额外访视影响生活”；未参加过试验的患者为“治疗效果不佳”或“出现严重不良反应”。对参加过试验的患者，医生推荐对88%患者参与试验的决策起到关键作用；对未参加过试验的患者，医生推荐可使60.9%无参与意愿者改变其选择。研究也报告了患者对临床试验获取信息和途径等的倾向选择。结论肿瘤患者临床试验接受度普遍较高，尤其是参加过试验的患者。充分发挥主治医生的作用对提高我国肿瘤患者临床试验接受度有重要意义。

Heart failure outcomes in patients with type 2 diabetes mellitus: findings from the cardiovascular outcome trials of antidiabetes agents

Type 2 diabetes mellitus (T2DM) is a recognised risk factor for several cardiovascular (CV) conditions including heart failure (HF). Findings that reflect CV risk associated with T2DM medications have led to regulatory requirement of conducting CV outcome trials (CVOTs) for new antidiabetes drugs. Over the years, several CVOTs using different glucagon-like peptide-1 receptor agonists, dipeptidyl peptidase-4 inhibitors and sodium-glucose co-transporter-2 inhibitors have reported neutral or improved CV risks or hospitalisation for HF. However, these studies included only a small proportion of the patients with baseline HF thus limiting the available evidence. Ongoing trials such as EMPEROR programme and DAPA-HF in large patient populations with chronic HF could potentially broaden the use of these drugs beyond their conventional therapeutic indication.

Hereditary hemolytic anemia in newborns: clinical significance of genetic diagnosis

Hereditary hemolytic anemia (HHA) is a group of monogenic diseases arising from the increased destruction of circulating erythrocytes. HHA is caused by germline mutations in genes encoding components of the red blood cell membrane, hemoglobin, and enzymes. Comprehensive gene analyses have identified various HHA-associated germline defects. However, early HHA diagnosis can be difficult in newborns because they present with hydrops and severe jaundice, which require urgent blood transfusions. Considering neonatal physiological hemolysis and pediatric infection, we select efficient diagnostic procedures following the exclusion of "syndromic hemolytic diseases". Clinical sequencing is performed for atypical cases, although phenotypic and laboratory tests remain essential for the verification of pathogenicity when certain variants are identified. The diagnostic gene panel can also be useful for predicting prognosis and determining treatment options. Although transfusion-dependent adult patients with HHA are rare in Japan, their management remains challenging. Clinical trials of new drugs and genetic controls are ongoing in other countries. However, the long-term management of a small group of patients with severe HHA must still be addressed in Japan. Here, we review the strategy and clinical significance of using genetic diagnostic methods for HHA in newborns.

Assessing the Quality of Life of Filipino Cancer Patients: A Survey of Filipino Oncologists

Abstract Introduction Recent trials of new drugs have placed much emphasis on survival. However, several guidelines have emphasized the need for assessing health-related quality of life (HRQoL) as part of the holistic approach in the management of cancer patients. There are currently no national governing guidelines and no existing data on the status of HRQoL assessments by Filipino oncologists, thus this study. Study Design This was a cross-sectional study that utilized a validated questionnaire. Descriptive and multivariate analyses were used to analyze the data. Results A total of 312 oncologists participated in this study. Majority were medical oncologists (41%), followed by radiation oncologists (25%), hematologists (14%), gynecologic oncologists (12%), and surgical oncologists (8%). About 96% reported that HRQoL assessment was important for clinical work; however, 58% perceived HRQoL to be a vague term and 55% felt they were insufficiently trained to assess HRQoL. About 89% reported that they will be more confident if local HRQoL assessment guidelines will be present, and 93% agreed to the use of a unified HRQoL assessment tool for Filipino cancer patients. About 85% thought that the optimal number of questions for a HRQoL assessment tool should be between 5 and 15 questions. The significant predictors of HRQoL assessment among oncologists were field of oncology and years in practice/training (p < 0.05). Conclusion Filipino oncologists perceived HRQoL patient assessments to be important in clinical practice. However, majority did not know which tool to use and did not feel sufficiently trained to assess HRQoL. The creation of a practice guideline that would facilitate the use of a unified HRQoL assessment tool for Filipino cancer patients is highly recommended.

Amyloid cardiomyopathy: the different facets of a not so rare disease (RCD code III 3A.1, III 3A.2)

Amyloidosis is a rare disorder which can affect multiple organs, with cardiac amyloidosis (CA) being one of its main clinical manifestations. CA has 2 distinct subtypes, AL amyloidosis and transthyretin amyloidosis (ATTR), with different histopathological appearances and subsequently different treatment strategies. The diagnostic methods available include multiple modalities to properly detect CA, ranging from the surface electrocardiogram and simple 2D‐echocardiography to more sophisticated methods such as specific biomarkers, speckle tracking echocardiography, or even bone scintigraphy with radioisotopes. However, the definitive diagnosis is reached with an endomyocardial biopsy or a biopsy from peripheral tissue. CA is a particularly challenging disorder in terms of patient management, which ranges from symptomatic treatment for heart failure symptoms to special medication and multiple drug regimens. For AL amyloidosis, a 3‐drug regimen is used as a first‐line therapy including cyclophosphamide, a proteasome inhibitor, and dexamethasone. For ATTR amyloidosis, specific medications are used such as Tafamidis, depending on the specific stage of the disease. Clinical trials of new drugs are pending with the ultimate goal of improving treatment rates and quality of life in patients with any type of CA. JRCD 2019; 4 (2): 34–41

Study on the Rights and Interests of Subject in Clinical Trials

Clinical trials are essential measures to determine the efficacy and safety of drugs. Clinical trials of new drugs and new medical devices have also received strong support at the national level. In the case of more and more clinical trial cases, how to better protect the rights of the subject becomes a problem that needs to be discussed in more depth. Based on the background of the development of clinical trials, this paper describes the lack of rights protection under the traditional support methods of clinical trial subject and then analyzes the problems of the subject’s right to life, body autonomy, informed consent, privacy and compensation. Problems with current subject rights protection and possible safeguards. The paper believes that the development and application of new life technologies make the clinical trial process more complicated and the results more uncertain. Therefore, the protection of traditional subject rights is not perfect, we need to expand legislative coverage, improve the rights dimension of subject rights protection and the structural dimension analysis of the ethics review committee which are effective measures to protect the rights of subject. Keywords: clinical trial, subject rights, rights protection DOI : 10.7176/PPAR/9-12-01 Publication date: December 31 st 2019

Editorial introductions

Editorial introductions

Novel therapeutic approach targeting mucosal APRIL in IgA nephropathy

Immunoglobulin A nephropathy (IgAN) is a form of glomerulonephritis. Also known as Berger's disease, it is the most common type of primary glomerulonephritis worldwide and is characterised by IgA deposits in the glomerulus. IgA nephropathy expert Prof. Yusuke Suzuki, who is based at Jutendo University Faculty of Medicine in Japan, explains that studies suggest that a number of factors, including aberrently-glycosylated IgA1, or its immune complex with glycan-specific IgG and IgA may play key roles in the pathogenesis of the condition. 'A proliferation-inducing ligand (APRIL) is one of protein froms the tumour necrosis factor (TNF) ligand superfamily. Research suggests a key role for this ligand in the long-term survival of plasma cells in the bone marrow and lymphoid tissues including mucosae and it is being explored as a potential target for the development of therapeutic options for autoimmune diseases and B cell malignancies. 'Recent studies into the pathological role of APRIL in IgAN, including our own recent findings, have led us to consider a new therapeutic approach,' he outlines. 'Our data using human samples from patients with IgAN and targeting APRIL in animal models has provided proof of concept (POC) of the beneficial effects of neutralising APRIL in IgAN.' Based on this work, clinical trials of new drugs that target APRIL have so far demonstrated exciting possibilities as one of the most promising new treatments for IgAN. A number of pharmaceutical companies are currently working on this and other, related drugs to treat the condition.

Use of Zebrafish in Drug Discovery Toxicology.

Unpredicted human safety events in clinical trials for new drugs are costly in terms of human health and money. The drug discovery industry attempts to minimize those events with diligent preclinical safety testing. Current standard practices are good at preventing toxic compounds from being tested in the clinic; however, false negative preclinical toxicity results are still a reality. Continual improvement must be pursued in the preclinical realm. Higher-quality therapies can be brought forward with more information about potential toxicities and associated mechanisms. The zebrafish model is a bridge between in vitro assays and mammalian in vivo studies. This model is powerful in its breadth of application and tractability for research. In the past two decades, our understanding of disease biology and drug toxicity has grown significantly owing to thousands of studies on this tiny vertebrate. This Review summarizes challenges and strengths of the model, discusses the 3Rs value that it can deliver, highlights translatable and untranslatable biology, and brings together reports from recent studies with zebrafish focusing on new drug discovery toxicology.

Design characteristics, risk of bias, and reporting of randomised controlled trials supporting approvals of cancer drugs by European Medicines Agency, 2014-16: cross sectional analysis

ObjectiveTo examine the design characteristics, risk of bias, and reporting adequacy of pivotal randomised controlled trials of cancer drugs approved by the European Medicines Agency (EMA).DesignCross sectional analysis.SettingEuropean regulatory documents,...

Pursuit of anti-hepatitis B virus therapy

The World Health Organization (WHO) has put forward the strategic goal of eliminating viral hepatitis as a major public health threat by 2030, and the research and development of new treatment for chronic hepatitis B (CHB) patients is an important part of this. In recent years, functional or clinical cure marked by HBsAg clearance and continuous undetectable HBV DNA has gradually become an ideal treatment endpoint recommended by clinical guidelines at home and abroad. Studies have shown that CHB patients who achieved long-term viral suppression after nucleoside analogues (NAs), adding or switching to interferons may have the potential to improve the clearance rate of HBsAg. However, the HBsAg conversion rate of patients in each treatment group in these studies was still low, and a reasonable combined therapy strategy and suitable patient population need to be further explored. In addition, some new drugs are being developed in pursuit of a CHB cure, though many clinical trials of new drugs are still based from a long-term treatment of NAs. Therefore, NAs antiviral therapy remains the cornerstone at this stage for CHB.

Postnatal Cardiac Development and Regenerative Potential in Large Mammals.

The neonatal capacity for cardiac regeneration in mice is well studied and has been used to develop many potential strategies for adult cardiac regenerative repair following injury. However, translating these findings from rodents to designing regenerative therapeutics for adult human heart disease remains elusive. Large mammals including pigs, dogs, and sheep are widely used as animal models of humans in preclinical trials of new cardiac drugs and devices. However, very little is known about the fundamental cardiac cell biology and the timing of postnatal cardiac events that influence cardiomyocyte proliferation in these animals. There is emerging evidence that external physiological and environmental cues could be the key to understanding cardiomyocyte proliferative behavior. In this review, we survey available literature on postnatal development in various large mammal models to offer a perspective on the physiological and cellular characteristics that could be regulating cardiomyocyte proliferation. Similarities and differences between developmental milestones, cardiomyocyte maturational events, as well as environmental cues regulating cardiac development, are discussed for various large mammals, with a focus on postnatal cardiac regenerative potential and translatability to the human heart.

Design of Idiopathic Pulmonary Fibrosis Clinical Trials in the Era of Approved Therapies.

The approval of nintedanib and pirfenidone for treatment of idiopathic pulmonary fibrosis has introduced complexity into the design of clinical trials for new drugs on many levels. Placebo-controlled trials excluding background therapy may have issues with feasibility. Those that allow background therapy must consider the possibility of drug-drug interactions with existing therapies, as well as the narrower therapeutic window available to demonstrate incremental slowing of lung function decline with a new agent. While many trial participants will already be on background therapy, a significant number will not, complicating the study design and analysis. Various approaches to improve the efficiency of IPF clinical trials include attempts to validate new endpoints and biomarkers that reflect functional status or quality of life as well as the use of pragmatic and adaptive trial designs.

Percutaneous coronary intervention for patients with type 2 diabetes mellitus: risks and novel way to manage

The article is a literature review devoted to issues of planned percutaneous coronary intervention for patients with type 2 diabetes mellitus. Pathogenetic base of poor prognosis and new ways to pharmacological risk correction are described.
 The article highlights the trends in the incidence of carbohydrate metabolism disorders, their role in the development of complications of myocardial revascularization. The results of studies comparing different tactics of revascularization and their results in patients with different status of carbohydrate metabolism are presented.
 The article discusses the methods of risk management within percutaneous coronary revascularization, the role of glycemic metabolism in the risk of an poor prognosis of myocardial revascularization, describes the results of clinical trials of new drugs that can have a positive effect on the prognosis of revascularization in patients with carbohydrate metabolism disorders.

The paradigm of the professional education program “Clinical Research Management”

Aim. To substantiate the need to develop professional management knowledge essential to conduct clinical research in Ukraine, as well as develop the paradigm of the professional education program “Clinical Research Management”. Materials and methods. Scientific and statistical publications, as well as the results of a questionnaire survey designed to interview specialists working for medical and scientific institutions were used as research materials; the methods of systematization of theoretical and practical materials, content analysis, generalization of the survey results were applied. Results. The relevance of the professional education program “Clinical Research Management” has been substantiated based on scientific literature and recommendations of professional organizations for conducting clinical studies in healthcare. The questionnaire survey of specialists working for medical and scientific institutions has shown their participation in planning, organizing, and controlling the clinical studies. The results of the survey have demonstrated that a significant part of the specialists is involved directly in the clinical studies at different phases; it actualizes the need for professional knowledge on modern management. The study has revealed that all categories of specialists interviewed create the demand for an advanced training or additional education in the field of management. However, medical specialists and researchers are the most interested in gaining new knowledge. Based on the peculiarities of phases of clinical research the paper develops the main learning outcomes that convey the knowledge, skills, and competencies required to conduct clinical research and assure enhanced quality. Conclusions. Taking into account the urgent need for training the specialists who should be able to carry out clinical research in Ukraine the program for training professional clinical research managers has been offered. After completion, the specialist should be able to organize the clinical trials of new drugs, ensure effective allocation of limited resources, develop and implement the quality management system according to the requirements of current standards, carry out audits and manage risks to assure the appropriate quality of clinical research.

Systematic Review of Gender Bias in the Clinical Trials of New Long-Acting Antipsychotic Drugs.

This article evaluates gender bias in the published clinical trials of new long-acting antipsychotics. We conducted a review of controlled clinical trials of the new prolonged-release antipsychotics (aripiprazole, risperidone, or paliperidone) for the treatment of schizophrenia published in MEDLINE over the last 10 years and available in full text in English. The study followed the corresponding international recommendations. We identified 132 trials, and of these, 40 met the inclusion and exclusion criteria. We found that only 36.41% of the total patients were women. The separate analysis of the main variable between the subpopulations of men and women was carried out in only 6 of the 40 works included. In contrast, in 15 trials, this analysis was performed on secondary variables, generally related to safety. Only 3 of the 40 trials discussed the results separately according to sex. The clinical trials of long-acting atypical antipsychotic drugs show a far-from-negligible gender bias. Women are underrepresented, and the main and secondary variables are not analyzed separately according to gender. This is despite international recommendations establishing these criteria as part of a package of minimum requirements for meeting scientific validity and making results apt to extrapolate to the general population of patients.