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Pediatric Research Nov 2017The conduct of clinical trials in small pediatric subspecialties such as pediatric nephrology is hampered by both clinical demands on the pediatric nephrologist and the... (Review)
Review
The conduct of clinical trials in small pediatric subspecialties such as pediatric nephrology is hampered by both clinical demands on the pediatric nephrologist and the small number of appropriate patients available for such studies. The American Society of Pediatric Nephrology Therapeutics Development Committee (TDC) was established to (1) identify the various stakeholders with interests and/or expertise related to clinical trials in children with kidney disease and (2) develop more effective partnerships among all parties regarding strategies for successful clinical trial development and execution. This article discusses the rationale, structure, and function of the TDC, the status of progress toward its goals, and the insights gained to date that may be useful for other subspecialties that face similar challenges.
Topics: Age Factors; Child; Clinical Trials as Topic; Consensus; Humans; Kidney Diseases; Nephrology; Pediatrics; Practice Guidelines as Topic; Research Design; Stakeholder Participation; Treatment Outcome; Workflow
PubMed: 28853726
DOI: 10.1038/pr.2017.180 -
Transplantation Jan 2015Prospective clinical trials are constructed with high levels of internal validity. Sample size and power considerations usually address primary endpoints. Primary... (Review)
Review
Prospective clinical trials are constructed with high levels of internal validity. Sample size and power considerations usually address primary endpoints. Primary endpoints have traditionally included events that are becoming increasingly less common and thus have led to growing use of composite endpoints and noninferiority trial designs in transplantation. This approach may mask real clinical benefit in one or the other domain with regard to either clinically relevant secondary endpoints or other unexpected findings. In addition, endpoints solely chosen based on power considerations are prone to misjudgment of actual treatment effect size as well as consistency of that effect. In the instances where treatment effects may have been underestimated, valuable information may be lost if buried within a composite endpoint. In all these cases, analyses and post hoc analyses of data become relevant in informing practitioners about clinical benefits or safety signals that may not be captured by the primary endpoint. On the other hand, there are many pitfalls in using post hoc determined endpoints. This short review is meant to allow readers to appreciate post hoc analysis not as an entity with a single approach, but rather as an analysis with unique limitations and strengths that often raise new questions to be addressed in further inquiries.
Topics: Clinical Trials as Topic; Data Interpretation, Statistical; Endpoint Determination; Humans; Models, Statistical; Prospective Studies; Reproducibility of Results; Research Design; Sample Size; Treatment Outcome
PubMed: 25525920
DOI: 10.1097/TP.0000000000000581 -
Transplantation Jan 2020
Review
Topics: Clinical Trials as Topic; Data Interpretation, Statistical; Humans; Organ Transplantation; Research Design; Treatment Outcome
PubMed: 31365474
DOI: 10.1097/TP.0000000000002865 -
Tomography (Ann Arbor, Mich.) Jun 2020The Clinical Trial Design and Development Working Group within the Quantitative Imaging Network focuses on providing support for the development, validation, and... (Review)
Review
The Clinical Trial Design and Development Working Group within the Quantitative Imaging Network focuses on providing support for the development, validation, and harmonization of quantitative imaging (QI) methods and tools for use in cancer clinical trials. In the past 10 years, the Group has been working in several areas to identify challenges and opportunities in clinical trials involving QI and radiation oncology. The Group has been working with Quantitative Imaging Network members and the Quantitative Imaging Biomarkers Alliance leadership to develop guidelines for standardizing the reporting of quantitative imaging. As a validation platform, the Group led a multireader study to test a semi-automated positron emission tomography quantification software. Clinical translation of QI tools cannot be possible without a continuing dialogue with clinical users. This article also highlights the outreach activities extended to cooperative groups and other organizations that promote the use of QI tools to support clinical decisions.
Topics: Clinical Trials as Topic; Clinical Trials, Phase III as Topic; Diagnostic Imaging; Humans; Neoplasms; Positron-Emission Tomography; Radiation Oncology; Randomized Controlled Trials as Topic; Tomography, X-Ray Computed
PubMed: 32548281
DOI: 10.18383/j.tom.2019.00022 -
Epilepsy & Behavior : E&B Dec 2019Convulsive status epilepticus (SE) is a relatively common emergency condition affecting individuals of all ages. The primary goal of treatment is prompt termination of... (Review)
Review
Convulsive status epilepticus (SE) is a relatively common emergency condition affecting individuals of all ages. The primary goal of treatment is prompt termination of seizures. Where first-line treatment with benzodiazepine has failed to achieve this, a condition known as established SE (ESE), there is uncertainty about which agent to use next. The Established Status Epilepticus Treatment Trial (ESETT) is a 3-arm (valproate (VPA), fosphenytoin (FOS), levetiracetam (LEV)), phase III, double-blind randomized comparative effectiveness study in patients aged 2 years and above with established convulsive SE. Enrollment was completed in January 2019, and the results are expected later this year. We discuss lessons learnt during the conduct of the study in relation to the following: ethical considerations; trial design and practical implementation in emergency settings, including pediatric and adult populations; quality assurance; and outcome determination where treating emergency clinicians may lack specialist expertise. We consider that the ESETT is already informing both clinical practice and future trial design. This article is part of the Special Issue "Proceedings of the 7th London-Innsbruck Colloquium on Status Epilepticus and Acute Seizures".
Topics: Adult; Anticonvulsants; Benzodiazepines; Child, Preschool; Clinical Trials as Topic; Diagnostic Tests, Routine; Double-Blind Method; Emergency Service, Hospital; Female; Humans; Levetiracetam; Male; Status Epilepticus; Treatment Outcome; Valproic Acid
PubMed: 31653603
DOI: 10.1016/j.yebeh.2019.04.049 -
Expert Review of Molecular Diagnostics Jun 2020Advances within molecular diagnostics have enabled us to identify a number of oncogenic drivers across different cancers. Many cancers can now be divided into subgroups...
INTRODUCTION
Advances within molecular diagnostics have enabled us to identify a number of oncogenic drivers across different cancers. Many cancers can now be divided into subgroups based on molecular characteristics, and an increasing number of targeted anticancer drugs have been developed together with a predictive biomarker assay using the drug-diagnostic codevelopment model. With the recent approval of entrectinib, larotrectinib, and pembrolizumab for site-agnostic indications, biomarker-guided drug development has entered into a new phase.
AREAS COVERED
The review focuses on the general principles of drug-diagnostic codevelopment, especially basket trials and site-agnostic drug development. Special attention is paid to entrectinib, larotrectinib, and pembrolizumab.
EXPERT OPINION
The recent approval of entrectinib, larotrectinib, and pembrolizumab must be regarded as a paradigm shift in biomarker-guided oncology drug development. For a site-agnostic indication, it is important to have in mind the central role of the companion diagnostic (CDx), as the assay defines the 'disease' and the patient population to be treated. A number of site-agnostic drugs are currently in development and here, it is important that CDx assay development is given high priority, so an analytical and clinical validated assay is available at the time of drug approval.
Topics: Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Benzamides; Biomarkers, Tumor; Clinical Decision-Making; Clinical Trials as Topic; Drug Approval; Drug Development; Humans; Indazoles; Molecular Targeted Therapy; Neoplasms; Organ Specificity; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines; Randomized Controlled Trials as Topic
PubMed: 31813299
DOI: 10.1080/14737159.2020.1702521 -
Fertility and Sterility Jun 2018Personalized medicine has many definitions. This term is often used synonymously with precision medicine, which is defined as the classifying patients with a disease or... (Review)
Review
Personalized medicine has many definitions. This term is often used synonymously with precision medicine, which is defined as the classifying patients with a disease or condition based on their phenotypic findings, such as biomarkers or genomics, into subpopulations that differ in their response to a specific treatment. Personalized medicine, however, can also mean the treatment of individual patients based on many contextual factors, such as response to therapy and patient preferences, in addition to predefined phenotypic findings. Regulatory approval for the marketing of a new drug or a new indication for a marketed drug requires a positive benefit risk profile and substantial evidence of effectiveness. The indication is based on the eligibility criteria and outcomes of the clinical trial(s) underpinning the regulatory approval. For precision medicine, drugs are often developed with companion diagnostics that are necessary for selection of the subgroup of patients, in contrast to personalized medicine which may be directed at a single patient. Most drugs are approved with a fixed dosage regimen for the approved population, but some drugs and biologics are approved with instructions to tailor therapy for individual patients, whether it be dosing, combination with other therapies, or selection among a class of medications. Hence, more often than not, personalized medicine directed at individual patients is achieved through the practice of medicine rather than regulatory action.
Topics: Clinical Trials as Topic; Drug Approval; Drug Industry; Fertility Agents; Humans; Legislation, Medical; Precision Medicine; Reproductive Medicine; Reproductive Techniques, Assisted
PubMed: 29935654
DOI: 10.1016/j.fertnstert.2018.03.027 -
Current Problems in Cancer Oct 2021Evaluation of novel treatments through clinical trials remains the backbone of oncological clinical research, but only a minor portion have been tested in Phase III... (Review)
Review
Evaluation of novel treatments through clinical trials remains the backbone of oncological clinical research, but only a minor portion have been tested in Phase III trials. The continued publication of underpowered trials provides an ongoing need for meta-analyses to detect clinically significant outcomes. Although tumor relapse and survival are important issues and easily measured outcomes in trials, they are often not the most relevant indicators for treatment success. As diagnostic technologies and treatments continue to advance, methodologies defining high quality studies have been established, but still enthusiasm to adopt novel technologies that leads to studies holding well-described bias that do not aid the rational use of the studied test. Global awareness of such bias and standard research methodology is the clue toward iconic studies giving rational supporting novel cancer treatments and patients' support.
Topics: Clinical Trials as Topic; Humans; Neoplasms; Prognosis; Randomized Controlled Trials as Topic; Treatment Outcome
PubMed: 33715867
DOI: 10.1016/j.currproblcancer.2021.100725 -
Current Gastroenterology Reports Aug 2018Since the first clinical trial of cortisone in ulcerative colitis in 1955, remarkable progress has been made in the design and conduct of clinical trials in inflammatory... (Review)
Review
PURPOSE OF REVIEW
Since the first clinical trial of cortisone in ulcerative colitis in 1955, remarkable progress has been made in the design and conduct of clinical trials in inflammatory bowel diseases (IBD). In this review article, we will discuss evolution of clinical trials in IBD over the last 3-5 years.
RECENT FINDINGS
Recognizing limitations intrinsic to clinical disease activity indices in IBD, regulatory authorities have recommended evaluating co-primary endpoints of patient-reported outcomes and endoscopic disease activity in clinical trials. Biomarker-enriched trial enrolment and central endoscopy reading have emerged as critical events in trial recruitment and outcome assessment and have driven placebo response rates down. While trials of novel biologic therapies and advanced small molecules continue at an accelerated pace, pragmatic comparative efficacy trials of treatment strategy aimed at optimizing current therapies (such as early combined immunosuppression [REACT], tight disease control [CALM], therapeutic drug monitoring [TAXIT, TAILORIX]) have directly informed clinical practice. With emphasis on value-based care and population health management, multi-pronged remote monitoring, self-management, and telemedicine approaches in the era of smartphones have re-emerged with promise. Non-conventional therapies such as fecal microbiota transplantation, though still experimental, have provided insight into disease pathogenesis and offered hope for microbial manipulation strategies for treating these complex diseases. Clinical trials have rapidly evolved over the last 5 years not only focusing on novel therapies but also optimizing existing treatment approaches and population health management. Over the next decade, these trials will continue to advance the field, and be readily translatable into clinical practice.
Topics: Clinical Trials as Topic; Endoscopy, Gastrointestinal; Fecal Microbiota Transplantation; Humans; Inflammatory Bowel Diseases; Patient Reported Outcome Measures
PubMed: 30078058
DOI: 10.1007/s11894-018-0648-3 -
Drug Discovery Today Nov 2015The development of novel drugs for the treatment of atherosclerosis faces many challenges, particularly caused by the need for large and costly outcome trials. When... (Review)
Review
The development of novel drugs for the treatment of atherosclerosis faces many challenges, particularly caused by the need for large and costly outcome trials. When predictive biochemical biomarkers are not available, clinical imaging data can serve as intermediate Phase II endpoints to demonstrate mechanistic and anti-atherosclerotic activity of new compounds. These data can support risk mitigation before continuing development in large Phase III outcome trials. Imaging techniques such as magnetic resonance imaging (MRI), computed tomography (CT) and ultrasound [intima-media thickness (IMT) and intravascular ultrasound (IVUS)] can provide detailed information on vascular plaque volume and morphology, whereas functional changes can potentially be captured by positron emission tomography (PET) techniques in the vessel wall. We will review the application and operational aspects of clinical imaging methods and endpoints used in interventional atherosclerosis trials.
Topics: Atherosclerosis; Clinical Trials as Topic; Diagnostic Imaging; Drug Design; Endpoint Determination; Humans; Plaque, Atherosclerotic; Positron-Emission Tomography
PubMed: 26151479
DOI: 10.1016/j.drudis.2015.06.014