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Current Treatment Options in Oncology Jul 2021Clinical trials play a critical role in discovering new treatments, but the path to regulatory approval can be cumbersome and time consuming. Efforts to increase the... (Review)
Review
Clinical trials play a critical role in discovering new treatments, but the path to regulatory approval can be cumbersome and time consuming. Efforts to increase the efficiency and interpretability of clinical trials within the neuro-oncology community have focused on standardization of response assessment, development of consensus guidelines for clinical trial conduct, decentralization of clinical trials, removal of barriers to clinical trial accrual, and re-examination of patient eligibility criteria.
Topics: Clinical Trials as Topic; Humans; Medical Oncology; Nervous System Neoplasms; Outcome Assessment, Health Care; Practice Guidelines as Topic; Research Design
PubMed: 34213625
DOI: 10.1007/s11864-021-00875-8 -
Clinical Microbiology and Infection :... Jan 2019The development of an in vitro diagnostic test from a good idea to a clinically relevant tool takes several steps, with more stringent requirements at every step. (Review)
Review
BACKGROUND
The development of an in vitro diagnostic test from a good idea to a clinically relevant tool takes several steps, with more stringent requirements at every step.
OBJECTIVES
This article aims to summarize the necessary questions to be asked about a test and to illustrate study designs answering these questions. We also aim to relate Regulation (EU) 2017/746 to the needs of evidence-based diagnostic testing, where applicable.
SOURCES
We used literature on evidence-based diagnostics, a text book on clinical trials in the development and marketing of medical devices and the English version of Regulation 2017/746 of the European Parliament and of the Council on in vitro diagnostic medical devices.
CONTENT
The combination of different test uses and different stages of development determine the required test characteristics and suitability of study designs. In an earlier stage of test development it may be crucial to know whether a test can differentiate diseased persons from healthy controls, although this tells us little about how a test will perform in practice. Later stages focus on the diagnostic accuracy of a test in a clinically relevant situation. However, a test that perfectly distinguishes between patients with and without a certain condition may still have little effect on patient outcomes. Therefore, randomized controlled trials of testing may be needed, as well as post-marketing monitoring.
IMPLICATIONS
Both researchers and users of tests need to be aware of the limitations of diagnostic test accuracy and realize that accuracy is only indirectly linked to people's health status.
Topics: Clinical Trials as Topic; Diagnostic Techniques and Procedures; Evaluation Studies as Topic; Reagent Kits, Diagnostic; Reproducibility of Results; Research Design
PubMed: 29906592
DOI: 10.1016/j.cmi.2018.06.011 -
Circulation Journal : Official Journal... 2015Despite the growing number of patients affected, the understanding of diastolic dysfunction and heart failure with preserved ejection fraction (HFpEF) is still poor.... (Review)
Review
Despite the growing number of patients affected, the understanding of diastolic dysfunction and heart failure with preserved ejection fraction (HFpEF) is still poor. Clinical trials, largely based on successful treatments for systolic heart failure, have been disappointing, suggesting that HFpEF has a different pathology to that of systolic dysfunction. In this review, general concepts, epidemiology, diagnosis, and treatment of diastolic dysfunction are summarized, with an emphasis on new experiments suggesting that oxidative stress plays a crucial role in the pathogenesis of at least some forms of the disease. This observation has lead to potential new diagnostics and therapeutics for diastolic dysfunction and heart failure caused by diastolic dysfunction.
Topics: Animals; Clinical Trials as Topic; Diastole; Heart Failure; Humans; Oxidative Stress; Stroke Volume
PubMed: 25746522
DOI: 10.1253/circj.CJ-15-0064 -
Neurotherapeutics : the Journal of the... Jul 2021
Topics: Anticonvulsants; Clinical Trials as Topic; Epilepsy; Genetic Testing; Humans; Precision Medicine
PubMed: 34704188
DOI: 10.1007/s13311-021-01147-x -
Journal of Clinical Oncology : Official... Mar 2017Personalization of therapy to target specific molecular pathways has been placed in the forefront of cancer research. Initial reports from clinical trials designed to... (Review)
Review
Personalization of therapy to target specific molecular pathways has been placed in the forefront of cancer research. Initial reports from clinical trials designed to select patients for appropriate treatment on the basis of tumor characteristics not only have generated considerable excitement but also have identified several challenges. These challenges include the overcoming of regulatory and logistic difficulties, identification of the best selection biomarkers and diagnostic platforms that can be applied in the clinical setting, definition of relevant outcomes in small preselected patient populations, and the design of methods that facilitate rapid enrollment and interpretation of clinical trials by aggregating data across histologically diverse malignancies with common genetic alterations. Furthermore, because our knowledge of the functional consequences of many genetic alterations lags, investigators and sponsors struggle with choosing between ideal clinical trial designs and more practical ones. These challenges are amplified when more than one biomarker is used to select patients for a combination of targeted agents. This review summarizes the current status and challenges of clinical trials in the genomic era and proposes ways to address these challenges.
Topics: Clinical Trials as Topic; Genomics; Humans; Molecular Targeted Therapy; Neoplasms
PubMed: 28297622
DOI: 10.1200/JCO.2016.70.8891 -
The Journal of Toxicological Sciences 2019Biomarkers are invaluable drug development tools to assess and monitor safety in early clinical trials especially when exposure margins are limiting for promising... (Review)
Review
Biomarkers are invaluable drug development tools to assess and monitor safety in early clinical trials especially when exposure margins are limiting for promising therapeutics. Although progress has been made towards identifying and implementing translational safety biomarkers for a number of organ toxicities such as kidney and liver, significant biomarker gaps still exist to monitor toxicities for testis, pancreas, etc. Several precompetitive consortia [e.g., Predictive Safety Testing Consortia (PSTC), Innovative Medicines Initiative (IMI)] are working with industry, academia, government, patient advocacy groups and foundations with a goal to qualify biomarkers such that they can be used in preclinical studies and clinical trials to accelerate drug development. This manuscript discusses the complexities of novel biomarker discovery, validation and international regulatory qualifications intended for clinical trial applications and shares specific examples from Pfizer Research and Development. As safety biomarkers become widely accepted and qualified by the regulatory agencies, they will increasingly be implemented in early clinical trials, play a key role in decision making and facilitate the progression of promising therapeutics from preclinical through clinical development.
Topics: Animals; Biomarkers, Pharmacological; Clinical Decision-Making; Clinical Trials as Topic; Drug Development; Drug Discovery; Drug Evaluation, Preclinical; Drug-Related Side Effects and Adverse Reactions; Humans
PubMed: 30944276
DOI: 10.2131/jts.44.225 -
Neurology May 2021Drug development for Alzheimer disease and other neurodegenerative dementias, including frontotemporal dementia, has experienced a long history of phase 2 and phase 3... (Review)
Review
Drug development for Alzheimer disease and other neurodegenerative dementias, including frontotemporal dementia, has experienced a long history of phase 2 and phase 3 clinical trials that failed to show efficacy of investigational drugs. Despite differences in clinical and behavioral characteristics, these disorders have shared pathologies and face common challenges in designing early-phase trials that are predictive of late-stage success. Here, we discuss exploratory clinical trials in neurodegenerative dementias. These are generally phase 1b or phase 2a trials that are designed to assess pharmacologic effects and rely on biomarker outcomes, with shorter treatment durations and fewer patients than traditional phase 2 studies. Exploratory trials can establish go/no-go decision points, support proof of concept and dose selection, and terminate drugs that fail to show target engagement with suitable exposure and acceptable safety profiles. Early failure saves valuable resources including opportunity costs. This is especially important for programs in academia and small biotechnology companies but may be applied to high-risk projects in large pharmaceutical companies to achieve proof of concept more rapidly at lower costs than traditional approaches. Exploratory studies in a staged clinical development program may provide promising data to warrant the substantial resources needed to advance compounds through late-stage development. To optimize the design and application of exploratory trials, the Alzheimer's Drug Discovery Foundation and the Association for Frontotemporal Degeneration convened an advisory panel to provide recommendations on outcome measures and statistical considerations for these types of studies and study designs that can improve efficiency in clinical development.
Topics: Alzheimer Disease; Clinical Trials as Topic; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Dementia; Drug Development; Frontotemporal Dementia; Humans; Neurodegenerative Diseases; Outcome Assessment, Health Care; Proof of Concept Study; Research Design; Treatment Failure; Treatment Outcome
PubMed: 33674360
DOI: 10.1212/WNL.0000000000011774 -
British Journal of Cancer Oct 2019International collaboration in oncology trials has the potential to enhance clinical trial activity by expediting the recruitment of large patient populations, testing... (Review)
Review
International collaboration in oncology trials has the potential to enhance clinical trial activity by expediting the recruitment of large patient populations, testing treatments in diverse populations and facilitating the study of rare tumours or specific molecular subtypes. However, a number of challenges continue to hinder the efficient and productive conduct of both commercial and non-commercial international clinical trials. These challenges include complex and burdensome regulatory requirements, the high cost of conducting trials, and logistical challenges associated with ethics review, drug supply and biospecimen collection and management. We propose solutions to promote oncology trial collaboration, such as regulatory reform, harmonisation of trial initiation and management processes and greater recognition and funding of academic (non-commercial) clinical trials. It is only through coordinated effort and leadership from researchers, regulators and those responsible for health systems that the full potential of international trial collaboration can be realised.
Topics: Antineoplastic Agents; Clinical Trials as Topic; Government Regulation; Humans; Information Dissemination; International Cooperation; Medical Oncology; Multicenter Studies as Topic; Neoplasms; Research Support as Topic; Specimen Handling
PubMed: 31378784
DOI: 10.1038/s41416-019-0532-4 -
Trials Jan 2018Once the excitement of trial design, grant-writing and award are behind us, the great open expanse of the next few years is filled almost exclusively by trial...
Once the excitement of trial design, grant-writing and award are behind us, the great open expanse of the next few years is filled almost exclusively by trial management, the nitty-gritty of getting stuff done - delivering the goal. The most important members of the trial team now are not the professors and investigators but the trial managers. These trial managers have limited published information to help them make informed decisions about how to handle the day-to-day challenges that trials present. This special series aims to highlight the fact that writing on trial management is important, publishable and that Trials would welcome more of it.
Topics: Access to Information; Attitude of Health Personnel; Clinical Decision-Making; Clinical Trials as Topic; Evidence-Based Medicine; Health Knowledge, Attitudes, Practice; Humans; Information Dissemination; Periodicals as Topic; Research Design; Research Personnel; Writing
PubMed: 29310691
DOI: 10.1186/s13063-017-2322-8 -
Clinical and Translational Science Mar 2021The rapidly advancing field of digital health technologies provides a great opportunity to radically transform the way clinical trials are conducted and to shift the... (Review)
Review
The rapidly advancing field of digital health technologies provides a great opportunity to radically transform the way clinical trials are conducted and to shift the clinical trial paradigm from a site-centric to a patient-centric model. Merck's (Kenilworth, NJ) digitally enabled clinical trial initiative is focused on introduction of digital technologies into the clinical trial paradigm to reduce patient burden, improve drug adherence, provide a means of more closely engaging with the patient, and enable higher quality, faster, and more frequent data collection. This paper will describe the following four key areas of focus from Merck's digitally enabled clinical trials initiative, along with corresponding enabling technologies: (i) use of technologies that can monitor and improve drug adherence (smart dosing), (ii) collection of pharmacokinetic (PK), pharmacodynamic (PD), and biomarker samples in an outpatient setting (patient-centric sampling), (iii) use of digital devices to collect and measure physiological and behavioral data (digital biomarkers), and (iv) use of data platforms that integrate digital data streams, visualize data in real-time, and provide a means of greater patient engagement during the trial (digital platform). Furthermore, this paper will discuss the synergistic power in implementation of these approaches jointly within a trial to enable better understanding of adherence, safety, efficacy, PK, PD, and corresponding exposure-response relationships of investigational therapies as well as reduced patient burden for clinical trial participation. Obstacle and challenges to adoption and full realization of the vision of patient-centric, digitally enabled trials will also be discussed.
Topics: Ambulatory Care; Clinical Trials as Topic; Drug Development; Humans; Monitoring, Ambulatory; Patient Participation; Patient-Centered Care; Telemedicine; Wearable Electronic Devices
PubMed: 33048475
DOI: 10.1111/cts.12910