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Osteoarthritis and Cartilage May 2011Osteoarthritis (OA) is a chronic and slowly progressive disease for which biomarkers may be able to provide a more rapid indication of therapeutic responses to therapy...
OBJECTIVE
Osteoarthritis (OA) is a chronic and slowly progressive disease for which biomarkers may be able to provide a more rapid indication of therapeutic responses to therapy than is currently available; this could accelerate and facilitate OA drug discovery and development programs. The goal of this document is to provide a summary and guide to the application of in vitro (biochemical and other soluble) biomarkers in the development of drugs for OA and to outline and stimulate a research agenda that will further this goal.
METHODS
The Biomarkers Working Group representing experts in the field of OA biomarker research from both academia and industry developed this consensus document between 2007 and 2009 at the behest of the Osteoarthritis Research Society International Federal Drug Administration initiative (OARSI FDA initiative).
RESULTS
This document summarizes definitions and classification systems for biomarkers, the current outcome measures used in OA clinical trials, applications and potential utility of biomarkers for development of OA therapeutics, the current state of qualification of OA-related biomarkers, pathways for biomarker qualification, critical needs to advance the use of biomarkers for drug development, recommendations regarding practices and clinical trials, and a research agenda to advance the science of OA-related biomarkers.
CONCLUSIONS
Although many OA-related biomarkers are currently available they exist in various states of qualification and validation. The biomarkers that are likely to have the earliest beneficial impact on clinical trials fall into two general categories, those that will allow targeting of subjects most likely to either respond and/or progress (prognostic value) within a reasonable and manageable time frame for a clinical study (for instance within 1-2 years for an OA trial), and those that provide early feedback for preclinical decision-making and for trial organizers that a drug is having the desired biochemical effect. As in vitro biomarkers are increasingly investigated in the context of specific drug treatments, advances in the field can be expected that will lead to rapid expansion of the list of available biomarkers with increasing understanding of the molecular processes that they represent.
Topics: Biomarkers; Clinical Trials as Topic; Drug Discovery; Drug Monitoring; Humans; Osteoarthritis; Specimen Handling; Treatment Outcome
PubMed: 21396468
DOI: 10.1016/j.joca.2010.08.019 -
British Journal of Clinical Pharmacology Apr 2016Over the past 10 years, thousands of first-into-human (FIH) clinical trials have been performed in Europe, with few severe adverse events (SAEs). Each has received...
Over the past 10 years, thousands of first-into-human (FIH) clinical trials have been performed in Europe, with few severe adverse events (SAEs). Each has received detailed prior safety review at both the local clinical research facility and at national drug regulatory authority level. The recent fatal SAE in the BIA-102474-101 clinical trial shows the limitations of this process. Although criticized for not sequentially dosing subjects both within and between cohorts - as recommended by the European Medicines Agency for high-risk compounds after the TeGenero clinical trial disaster in 2006 - BIA-102474-101 was not considered to be high risk. Indeed, compounds with similar mechanisms of action had previously been taken through phase I and II trials without incident, and higher doses had been safely given for longer durations to nonhuman primates. If the available data are comprehensive and accurate, and further investigation does not reveal unreported warning signs, this study has serious implications for ongoing and future review of FIH clinical trials. All preclinical study documents and clinical data collected during the BIA-102474-101 trial should be made available urgently so that lessons can be learnt. In the meantime, reviewers and clinical researchers should always ask for information on drug and target interactions and full reports of preclinical toxicity studies, and plan sequential dosing with longer delays between patients and cohorts, particularly if late SAEs might be anticipated. The use of individual patient pharmacokinetic and dynamic data should guide sequential dosing. A process for systematic risk assessment, like that currently used in the Netherlands, should be applied routinely to all trials with novel compounds.
Topics: Clinical Trials as Topic; Cyclic N-Oxides; Drug Discovery; Early Termination of Clinical Trials; Humans; Pyridines
PubMed: 26996741
DOI: 10.1111/bcp.12920 -
Journal of the American College of... Dec 2013A greater understanding of the epidemiology, pathogenesis, and pathophysiology of pulmonary artery hypertension (PAH) has led to significant advances, but the disease... (Review)
Review
A greater understanding of the epidemiology, pathogenesis, and pathophysiology of pulmonary artery hypertension (PAH) has led to significant advances, but the disease remains fatal. Treatment options are neither universally available nor always effective, underscoring the need for development of novel therapies and therapeutic strategies. Clinical trials to date have provided evidence of efficacy, but were limited in evaluating the scope and duration of treatment effects. Numerous potential targets in varied stages of drug development exist, in addition to novel uses of familiar therapies. The pursuit of gene and cell-based therapy continues, and device use to help acute deterioration and chronic management is emerging. This rapid surge of drug development has led to multicenter pivotal clinical trials and has resulted in novel ethical and global clinical trial concerns. This paper will provide an overview of the opportunities and challenges that await the development of novel treatments for PAH.
Topics: Animals; Clinical Trials as Topic; Drug Discovery; Familial Primary Pulmonary Hypertension; Humans; Hypertension, Pulmonary; Research Design
PubMed: 24355645
DOI: 10.1016/j.jacc.2013.10.026 -
Trials Sep 2017Academic clinical trials play a fundamental role in the development of new treatments, the repurposing of existing treatments and in addressing areas of unmet clinical...
BACKGROUND
Academic clinical trials play a fundamental role in the development of new treatments, the repurposing of existing treatments and in addressing areas of unmet clinical need. With cancer treatments increasingly targeted at molecular subtypes, and with priority placed on developing new treatments for rare tumour types, the need for international trial participation to access sufficient patient numbers for successful trial conduct is growing. However, lack of harmonisation of international legal, ethical and financial systems can make this challenging and the cost and effort of conducting trials internationally can be considered prohibitive, particularly where the sample size is comparatively small.
METHODS
The Institute of Cancer Research - Clinical Trials and Statistics Unit (ICR-CTSU) is a UK-based academic clinical trials unit that specialises in the design, conduct and analysis of clinical trials of cancer treatments with an expanding portfolio of trials in molecular subtypes of breast and urological cancers and in other rare cancer types. Implementing appropriate mechanisms to enable international participation has therefore been imperative. In this article, we explain how we have approached the challenges involved and describe examples of successful international trial conduct, achieved through robust collaborations with academic and industry partners.
CONCLUSION
Conducting academic trials internationally is challenging but can and should be achieved through appropriate governance mechanisms and strong collaborations.
Topics: Antineoplastic Agents; Clinical Trials as Topic; Drug Costs; Humans; International Cooperation; Multicenter Studies as Topic; Neoplasms; Policy Making; Public-Private Sector Partnerships; Research Design; Research Support as Topic; Treatment Outcome
PubMed: 28950887
DOI: 10.1186/s13063-017-2176-0 -
Current Opinion in Neurology Aug 2009The intent of this study is to review trends in multicenter neuroimaging trials and their value for research and implications for clinical treatment. (Review)
Review
PURPOSE OF REVIEW
The intent of this study is to review trends in multicenter neuroimaging trials and their value for research and implications for clinical treatment.
RECENT FINDINGS
The rise in availability of MRI for detecting disorders in the living brain has made it an attractive technology for assessing neural structure and function in a number of prominent diseases. Geographic factors underlying diseased populations coupled with complementary neuroimaging research programs have led to an increase in multicenter neuroimaging trials and consortia. Neuroimaging has become a major focus for multiinstitutional research in progressive changes in brain architecture, proxy biomarkers of treatment response, and the effects of disease on patterns of cognitive activation and connectivity. Notable consortia and research trial studies have focused on Alzheimer's disease, pediatric brain cancer, and fetal alcohol syndrome, in addition to multiinstitutional collaborative programs for mapping the normal brain. Such large-scale efforts necessitate close coordination of image data collection protocols, ontology development, computational requirements, concerted data archiving, and sharing.
SUMMARY
Multicenter neuroimaging trials, consortia, and collaboratives enable the acquisition of large-scale, purpose-driven datasets that can then be used by the broader community to model and predict clinical outcomes as well as guide clinicians in selecting treatment options for neurological disease.
Topics: Brain Diseases; Clinical Trials as Topic; Cooperative Behavior; Databases, Factual; Humans; Magnetic Resonance Imaging; Multicenter Studies as Topic
PubMed: 19506479
DOI: 10.1097/WCO.0b013e32832d92de -
Fertility and Sterility Oct 2014Clinical trials testing infertility treatments often do not report on the major outcomes of interest to patients and clinicians and the public (such as live birth) nor...
Clinical trials testing infertility treatments often do not report on the major outcomes of interest to patients and clinicians and the public (such as live birth) nor on the harms, including maternal risks during pregnancy and fetal anomalies. This is complicated by the multiple participants in infertility trials which may include a woman (mother), a man (father), and a third individual if successful, their offspring (child), who is also the desired outcome of treatment. The primary outcome of interest and many adverse events occur after cessation of infertility treatment and during pregnancy and the puerperium, which creates a unique burden of follow-up for clinical trial investigators and participants. In 2013, because of the inconsistencies in trial reporting and the unique aspects of infertility trials not adequately addressed by existing Consolidated Standards of Reporting Trials (CONSORT) statements, we convened a consensus conference in Harbin, China, with the aim of planning modifications to the CONSORT checklist to improve the quality of reporting of clinical trials testing infertility treatment. The consensus group recommended that the preferred primary outcome of all infertility trials is live birth (defined as any delivery of a live infant after ≥20 weeks' gestation) or cumulative live birth, defined as the live birth per women over a defined time period (or number of treatment cycles). In addition, harms to all participants should be systematically collected and reported, including during the intervention, any resulting pregnancy, and the neonatal period. Routine information should be collected and reported on both male and female participants in the trial. We propose to track the change in quality that these guidelines may produce in published trials testing infertility treatments. Our ultimate goal is to increase the transparency of benefits and risks of infertility treatments to provide better medical care to affected individuals and couples.
Topics: Checklist; Clinical Trials as Topic; Consensus; Endpoint Determination; Female; Humans; Infertility; Male; Patient Selection; Pregnancy; Pregnancy Outcome; Research Design; Risk Assessment; Risk Factors; Sample Size; Treatment Outcome
PubMed: 25225072
DOI: 10.1016/j.fertnstert.2014.08.002 -
Chinese Clinical Oncology Sep 2015High-throughput technologies enable the measurement of a large number of molecular characteristics from a small tissue specimen. High-dimensional molecular information... (Review)
Review
High-throughput technologies enable the measurement of a large number of molecular characteristics from a small tissue specimen. High-dimensional molecular information (referred to as omics data) offers the possibility of predicting the future outcome of a patient (prognosis) and predicting the likely response to a specific treatment (prediction). Embedded in the vast amount of data is the hope that there exists some signal that will enable practitioners to deliver therapy personalized to the molecular profile of a tumor, thereby improving health outcomes. The challenges are to determine that the omics assays are valid and reproducible in a clinical setting, to develop a valid and optimal omics-based test that algorithmically determines the optimal treatment regime, to evaluate that test in a powerful and unbiased manner, and finally to demonstrate clinical utility: that the test under study improves clinical outcome as compared to not using the test. We review the statistical considerations involved in each of these stages, specifically dealing with the challenges of high-dimensional, omics data.
Topics: Clinical Laboratory Techniques; Clinical Trials as Topic; Data Interpretation, Statistical; Genomics; High-Throughput Screening Assays; Humans; Models, Statistical; Neoplasms; Prognosis
PubMed: 26408296
DOI: 10.3978/j.issn.2304-3865.2015.01.02 -
Advances in Experimental Medicine and... 2019Biomarkers have a key role in Alzheimer's disease (AD) drug development. Biomarkers can assist in diagnosis, demonstrate target engagement, support disease modification,... (Review)
Review
Biomarkers have a key role in Alzheimer's disease (AD) drug development. Biomarkers can assist in diagnosis, demonstrate target engagement, support disease modification, and monitor for safety. The amyloid (A), tau (T), neurodegeneration (N) Research Framework emphasizes brain imaging and CSF measures relevant to disease diagnosis and staging and can be applied to drug development and clinical trials. Demonstration of target engagement in Phase 2 is critical before advancing a treatment candidate to Phase 3. Trials with biomarker outcomes are shorter and smaller than those required to show clinical benefit and are important to understanding the biological impact of an agent and inform go/no-go decisions. Companion diagnostics are required for safe and effective use of treatments and may emerge in AD drug development programs. Complementary biomarkers inform the use of therapies but are not mandatory for use. Biomarkers promise to de-risk AD drug development, attract sponsors to AD research, and accelerate getting new drugs to those with or at risk for AD.
Topics: Alzheimer Disease; Biomarkers; Clinical Trials as Topic; Drug Development; Humans; Neuroimaging
PubMed: 30747416
DOI: 10.1007/978-3-030-05542-4_2 -
Current Opinion in Rheumatology Jan 2009
Topics: Biomarkers; Clinical Trials as Topic; Diagnosis, Differential; Granulomatosis with Polyangiitis; Humans; Immunosuppressive Agents; Interdisciplinary Communication; Patient Care Team; Patient Selection; Rheumatology; Vasculitis
PubMed: 19077712
DOI: 10.1097/BOR.0b013e32831e4250 -
Urologic Oncology Mar 2021Clinical trials are pillars of modern clinical evidence generation. However, the clinical trial enterprise can be inefficient, and trials often fail before their planned...
OBJECTIVES
Clinical trials are pillars of modern clinical evidence generation. However, the clinical trial enterprise can be inefficient, and trials often fail before their planned endpoint is reached. We sought to estimate how often urologic oncology trials fail, why trials fail, and associations with trial failure.
METHODS
We queried phase 2/3 urologic clinical trial data from ClinicalTrials.gov registered between 2007 and 2019, with status marked as active, completed, or terminated. We extracted relevant trial data, including anticipated and actual accrual, from trial records and ClinicalTrials.gov archives. We manually coded reasons given in the "why stopped" free text field for trial failure into categories (poor accrual, interim results, toxicity/adverse events, study agent unavailable, canceled by the sponsor, inadequate budget, logistics, trial no longer needed, principal investigator left, no reason given, or other). We considered trials terminated for safety or efficacy to be completed trials. Trials marked as terminated for other reasons were considered failed trials. We then estimated the rate of trial failure using competing risks methods. Finally, we assessed associations with trial failure using a Cox proportional hazards model.
RESULTS
A total of 1,869 urologic oncology trials were included. Of these, 225 (12.0%) failed, and 51 (2.7%) were terminated for "good" reasons (e.g., toxicity, efficacy). Of the 225 failed trials, 122 (54%) failed due to poor accrual. Failed trials had a lower anticipated accrual than successfully completed trials (55 vs. 63 patients, P<0.001). A total of 6,832 patients were actually accrued to failed trials. The 10-year estimated risk of trial failure was 17% (95% CI 15%-22%). Single center trials, phase 3 trials, drug trials, and trials with exclusively USA sites were more likely to fail.
CONCLUSION
We estimate that 17%, or roughly 1 in 6, of urologic oncology trials fail, most frequently for poor accrual. Further investigations are needed into systemic, trial, and site-specific factors that may impact accrual and successful trial completion.
Topics: Clinical Trials as Topic; Early Termination of Clinical Trials; Humans; Urologic Neoplasms
PubMed: 33257221
DOI: 10.1016/j.urolonc.2020.10.070