Clinical Trials Of New Drugs Research Articles

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

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.

Multiple Myeloma :Trends in Consulting Fees and Drug Utilization

Introduction Per the National Cancer Institute epidemiological data, the incidence of multiple myeloma has not changed significantly over the past decade. Mortality from myeloma has not changed significantly between 2007-2016 with an estimated 5-year survival of 55.2 % between 2009-2015. The treatment of multiple myeloma has improved significantly over the past decade with the approval of several new drugs. In the recent IFM trial, the 4-year overall survival in a select group of myeloma patients was 82% when treated with bortezomib, lenalidomide and dexamethasone followed by autologous stem cell transplant and maintenance therapy. These numbers may further improve with approval of monoclonal antibodies and several new drugs in clinical trials. The cost of healthcare has been growing consistently for the past several years. Per CMS data, healthcare spending grew 3.7% in 2017 reaching $3.5 trillion, or $10,739 per person. National health spending is projected to grow at a rate of 5.5% per year from 2018-2027 reaching nearly $6.0 trillion. Health share of the GDP is expected to rise from 17.9% to 19.4%. Pharmaceutical costs have been rising consistently over the past several years with cancer therapies being some of the costliest. Most new cancer therapy costs more than $100,000 per year with the triplet combinations for myeloma costing upwards of $200,000 per year. Methods Our goal was to evaluate the utilization of the newer drugs approved for myeloma by the Medicare population and assess the economic burden of growing drug prices on the health care system. We queried the national CMS database from 2013-2017 to obtain information on Medicare payments made, number of providers making claims and consulting fees for bortezomib, carfilzomib, daratumumab, elotuzumab, ixazomib, lenalidomide, panobinostat and pomalidomide. Results Between 2013-2017 there has been a significant increase in the annual Medicare payments made for myeloma drugs. The amount of payments has tripled between 2013-2017. The number of claims made and providers making those claims have increased. There has also been an exponential increase in consulting fees paid by various pharmaceutical companies to promote prescription of the aforementioned drugs. The amount of money paid in consultation has nearly quadrupled since 2013. Results are consolidated in Table 1 and Figure 1. Discussion This past decade has been an exciting period in cancer research and drug approvals, with myeloma being one of the many malignancies benefitting from this progress. This was made possible by the collaboration between pharmaceutical companies and academic institutions. With the need for continuous combination therapy in multiple myeloma along with increasing prices of existing drugs and high upfront market prices for newly approved drugs, there is significant financial burden placed on the healthcare system. Based on the published literature substitution of carfilzomib for bortezomib or addition of monoclonal antibodies in induction would double cost. Some of these drug approvals are based solely on surrogate endpoints of overall response rates and progression free survival benefit of few months. This is without proven overall survival data while harboring significant toxicity. Conclusion: With pharmaceutical companies spending millions of dollars for drug development there has been a trend towards higher drug pricing. These companies also pay large amounts of consulting fees to physicians dedicated to aggressively market these newly approved drugs which are priced higher than existing therapy. Some of the current cancer guidelines include authors who have financial conflicts of interest and receive consulting fees from pharmaceutical companies. It would be interesting to investigate the correlation between the consulting fees and its effect on prescription patterns. Even the cancer care guidelines do not consider the cost effectiveness of equally effective regimens. There has been a push from various pioneers in the field to incorporate value-based recommends into their guidelines. Given the trajectory of rising costs within our healthcare system, it is imperative for all physicians to be mindful of value-based care while seeking therapy options that provide true benefit to their vulnerable patient populations. Disclosures No relevant conflicts of interest to declare.

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.

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.

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.

The critical importance of basic animal research for neuropsychiatric disorders.

The challenges and critical importance of keeping our thinking about neuropsychiatric disorders mechanisms and classifications up-to-date have prompted a dynamic discourse as to the value, appropriateness, and reliability of the animal models we use and the outcomes we measure. At a time when most major pharmaceutical companies are disbanding their research and development in neuroscience and mental health programs, academia is the remaining bastion for the identification and validation of novel drug targets and the development of novel therapeutic approaches. The 2018 ACNP meeting provided the ideal audience for a discussion centered on this topic, offering a professional setting in which diverse viewpoints could be presented, and allowing voices from all arenas of basic and translational neuroscience to be heard. At its core, there is a growing and healthy discussion about the degree of confidence we have that our preclinical animal models and their behavioral endpoints can predict the success of new drugs in clinical trials. While it is clear that we cannot completely model complex neuropsychiatric and neurodevelopmental disorders in animals, there is certainly agreement across domain criteria and endophenotypes of disease that have proven informative, particularly when multiple levels of outcome measures, including genomics, epigenomics, cellular properties, circuits, network dynamics, and behaviors are included. This issue is now of critical importance with the arrival of big ‘omics data sets that provide novel and informative insights about genetic risk and molecular pathophysiology. How can we best examine these insights into disease risk and resilience using preclinical measures? Similarly, while genome-wide association studies and genome sequencing studies provide valuable clues into the genes and pathways that are associated with disease risk, how can we determine how these loci interact with each other as well as with the environment to assess their importance across developmental and life stages? Most importantly, we seek to identify ways to develop novel therapeutic approaches to improve the lives of those with neuropsychiatric disorders including those of neurodevelopmental origins, a challenge that remains even after decades of intensive research.

Amyotrophic lateral sclerosis: pathogenetic mechanisms and new approaches to pharmacotherapy (literature review)

Amyotrophic lateral sclerosis is a neurodegenerative disease, resulting in the loss of self-service and death of the middle-aged and elderly people. In the last 2 decades, significant progress has been made in the study of the pathogenesis of this disease. Two known drugs (riluzole and edaravone) have been approved by the Food and Drug Administration for treatment of amyotrophic lateral sclerosis. The efficacy of these drugs is extremely low, so clinical trials of new drugs are ongoing all over the world. This review discusses the current achievements and future directions of therapy of this disease.

GCP Inspection of Clinical Trials of New Drugs Approved in Japan from FY2013 to FY2017 and FDA GCP Inspection in Japan

GCP Inspection of Clinical Trials of New Drugs Approved in Japan from FY2013 to FY2017 and FDA GCP Inspection in Japan

Systems Biology: A Powerful Tool for Drug Development.

The conventional way of characterizing a disease consists of correlating clinical symptoms with pathological findings. Although this approach for many years has assisted clinicians in establishing syndromic patterns for pathophenotypes, it has major limitations as it does not consider preclinical disease states and is unable to individualize medicine. Moreover, the complexity of disease biology is the major challenge in the development of effective and safe medicines. Therefore, the process of drug development must consider biological responses in both pathological and physiological conditions. Consequently, a quantitative and holistic systems biology approach could aid in understanding complex biological systems by providing an exceptional platform to integrate diverse data types with molecular as well as pathway information, leading to development of predictive models for complex diseases. Furthermore, an increase in knowledgebase of proteins, genes, metabolites from high-throughput experimental data accelerates hypothesis generation and testing in disease models. The systems biology approach also assists in predicting drug effects, repurposing of existing drugs, identifying new targets, facilitating development of personalized medicine and improving decision making and success rate of new drugs in clinical trials.

Update of diagnosis and treatment of plasma cell leukemia

Plasma cell leukemia (PCL) is a rare and aggressive malignant plasma cell tumor that is clinically susceptible to extramedullary lesions. It is classified into two types: primary PCL (pPCL) and secondary PCL (sPCL), of which 60 % are pPCL. The treatment of new drugs such as bortezomib and lenalidomide is important for improving the overall survival and disease-free survival of PCL, especially after induction of bortezomib-based chemotherapy, combined with autologous hematopoietic stem cell transplantation (auto-HSCT) can improve the survival of patients. Whether to adopt the next step of allogeneic hematopoietic stem cell transplantation (allo-HSCT) still needs further investigation. For young and suitable patients, early new drug-based regimen chemotherapy combined with auto-HSCT can be used, and if a suitable donor is available, the further allo-HSCT consolidation therapy is feasible. For elderly patients (≥65 years old), a new drug-based regimen can be used to induce chemotherapy, and further followed consolidation therapy plus maintenance therapy. Whether to take auto-HSCT after early induction chemotherapy depends on the individualized factors of the patient. The next generation anti-plasma cells drugs, monoclonal antibodies and other immunotherapies or new drugs in clinical trials are also worth exploring. Key words: Leukemia, plasma cell; Hematopoietic stem cell transplantation; Bortezomib; Lenalidomide

Clinical and molecular characterization of Korean children with infantile and late-onset Pompe disease: 10 years of experience with enzyme replacement therapy at a single center.

PurposePompe disease (PD) is an autosomal recessive disorder caused by a deficiency of acid alphaglucosidase resulting from pathogenic GAA variants. This study describes the clinical features, genotypes, changes before and after enzyme replacement therapy (ERT), and long-term outcomes in patients with infantile-onset PD (IOPD) and late-onset PD (LOPD) at a tertiary medical center.MethodsThe medical records of 5 Korean patients (2 male, 3 female patients) diagnosed with PD between 2002 and 2013 at Samsung Medical Center in Seoul, Republic of Korea were retrospectively reviewed for data, including clinical and genetic characteristics at diagnosis and clinical course after ERT.ResultsCommon initial symptoms included hypotonia, cyanosis, and tachycardia in patients with IOPD and limb girdle weakness in patients with LOPD. Electrocardiography at diagnosis revealed hypertrophic cardiomyopathy in all patients with IOPD who showed a stable disease course during a median follow-up period of 10 years. Patients with LOPD showed improved hepatomegaly and liver transaminase level after ERT.ConclusionAs ERT is effective for treatment of PD, early identification of this disease is very important. Thus, patients with IOPD should be considered candidates for clinical trials of new drugs in the future.

Clinical Overview of Innovative New Drug Approvals in 2017

The FDA has approved 46 new drugs in 2017, another record approval in two decades on a similar pace to the gangbuster year of 2015. Many of these new medicines address significant and meaningful needs, or offer additional therapeutic choices for patients worldwide. These new drugs also cover a broad range of indications including immuno-oncology (Imfinzi and Bavencio), Parkinson’s disease (Xadago), eczema (Dupixent), psoriasis (Siliq and Tremfya), multiple sclerosis (Ocrevus), and different types of cancer (Idhifa, Aliqopa, Calquence, and Besponsa). A few important orphan drugs were approved, including in mucopoly-saccharidosis type VII (Mepsevil) and Batten’s Disease (Brineuria). Many of these new drugs are for rare diseases and sub-types of cancer, which often target very small populations, although they can cost hundreds of thousands of dollars. Yet the pharma companies saw average returns on their research and development spending fall, reflecting more competitive pressures and the growing share of new products now coming from biotech companies. Recently, the US has introduced the Right-to-Try Act, wherein patients can access experimental treatments if they are unable to participate in any clinical trial of new drugs and if they have no other options. Such policies are expected to increase the database for new experimental drugs and help accelerate drug approvals.

Changing role of histopathology in the diagnosis and management of hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is one of the most common and fatal cancer in the world. HCC frequently presents with advanced disease, has a high recurrence rate and limited treatment options, which leads to very poor prognosis. This warrants urgent improvement in the diagnosis and treatment. Liver biopsy plays very important role in the diagnosis and prognosis of HCC, but with technical advancements and progression in the field of imaging, clinical guidelines have restricted the role of biopsy to very limited situations. Biopsy also has its own problems of needle tract seeding of tumor, small risk of complications, technical and sampling errors along with interpretative errors. Despite this, tissue analysis is often required because imaging is not always specific, limited expertise and lack of advanced imaging in many centers and limitations of imaging in the diagnosis of small, mixed and other variant forms of HCC. In addition, biopsy confirmation is often required for clinical trials of new drugs and targeted therapies. Tissue biomarkers along with certain morphological features, phenotypes and immune-phenotypes that serve as important prognostic and outcome predictors and as decisive factors for therapy decisions, add to the continuing role of histopathology. Advancements in cancer biology and development of molecular classification of HCC with clinic pathological correlation, lead to discovery of HCC phenotypic surrogates of prognostic and therapeutically significant molecular signatures. Thus tissue characteristics and morphology based correlates of molecular subtypes provide invaluable information for management and prognosis. This review thus focuses on the importance of histopathology and resurgence of role of biopsy in the diagnosis, management and prognostication of HCC.

Investigating the Food and Drug Administration (FDA) Biotherapeutics Review and Approval Process: A Scoping Review

BackgroundBiopharmaceutical products have become an important sector of the pharmaceutical industry in the United States (U.S.). This fast-growing sector is in a critical position in which therapeu...

Optimal Patient Enrollment in Sequential Adaptive Clinical Trials with Binary Response

Adaptive clinical trials for new drugs or treatment options promise significant benefits to both trial sponsors and patients, but complicate resource allocation. We study the patient enrollment and trial termination decision in a Phase 3 group sequential adaptive trial, which allows for early trial termination due to established efficacy or anticipated futility. Our objective is to quantify the impact of interim analyses on key performance metrics, including the new drug’s misclassification risk and time-to-market, and the firm’s profit. To this end, we build a stochastic dynamic programming model that incorporates Bayesian updates on the drug’s efficacy. The patient enrollment decision in this setting is characterized by endogenous uncertainty, and a trade-off between the incentive to establish the drug’s efficacy early on (exploitation), due to a time-decreasing market revenue, and the benefit from collecting information on the drug’s performance (exploration) prior to committing a large amount of resources. We characterize important structural properties of an optimal patient enrollment policy and perform a numerical study utilizing realistic data. Our results suggest that sequential adaptive clinical trials, even with a single interim analysis, outperform their traditional counterparts (i.e., fixed sample size trials) across all metrics, because patient enrollment is re-optimized adaptively, based on updated information on the drug’s efficacy.

Pathophysiology and therapeutic progress of diabetic macular edema

Diabetic macular edema (DME) is the leading cause of vision loss in diabetics. The destruction of blood retinal barrier is the primary pathological feature. At present, a large number of animal experiments and clinical studies show that DME not only has abnormal vascular structure, but also is an inflammatory disease. A variety of inflammatory media and chemokine are involved in the process of DME. With the extensive clinical application of anti-vascular endothelial growth factor (VEGF), the treatment of DME got a revolutionary breakthrough. However, unlike proliferative diabetic retinopathy (PDR), DME patients response intensively to anti-VEGF agents and couldn't resolve completely despite of multiple injections. Therefore, in addition to VEGF, other possible therapeutic targets and clinical trials of new drugs are also widely carried out. This article reviews the therapeutic process of DME. (Chin J Ophthalmol, 2018, 54: 625-630).

Dr. Joseph Siu-Kie Au: beyond immunotherapy—discovering new possibilities

Dr. Au ( Figure 1 ) is a consultant clinical oncologist in Hong Kong Adventist Hospital. He has special interest in bioinformatics, translational research, clinical trials of new drugs and radiotherapy.