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Trends in Pharmacological Sciences Aug 2019Clinical trials consume the latter half of the 10 to 15 year, 1.5-2.0 billion USD, development cycle for bringing a single new drug to market. Hence, a failed trial... (Review)
Review
Clinical trials consume the latter half of the 10 to 15 year, 1.5-2.0 billion USD, development cycle for bringing a single new drug to market. Hence, a failed trial sinks not only the investment into the trial itself but also the preclinical development costs, rendering the loss per failed clinical trial at 800 million to 1.4 billion USD. Suboptimal patient cohort selection and recruiting techniques, paired with the inability to monitor patients effectively during trials, are two of the main causes for high trial failure rates: only one of 10 compounds entering a clinical trial reaches the market. We explain how recent advances in artificial intelligence (AI) can be used to reshape key steps of clinical trial design towards increasing trial success rates.
Topics: Artificial Intelligence; Clinical Protocols; Clinical Trials as Topic; Clinical Trials, Phase III as Topic; Drug Development; Humans; Patient Compliance; Patient Selection
PubMed: 31326235
DOI: 10.1016/j.tips.2019.05.005 -
Postgraduate Medicine Sep 2011The recent focus of federal funding on comparative effectiveness research underscores the importance of clinical trials in the practice of evidence-based medicine and... (Review)
Review
The recent focus of federal funding on comparative effectiveness research underscores the importance of clinical trials in the practice of evidence-based medicine and health care reform. The impact of clinical trials not only extends to the individual patient by establishing a broader selection of effective therapies, but also to society as a whole by enhancing the value of health care provided. However, clinical trials also have the potential to pose unknown risks to their participants, and biased knowledge extracted from flawed clinical trials may lead to the inadvertent harm of patients. Although conducting a well-designed clinical trial may appear straightforward, it is founded on rigorous methodology and oversight governed by key ethical principles. In this review, we provide an overview of the ethical foundations of trial design, trial oversight, and the process of obtaining approval of a therapeutic, from its pre-clinical phase to post-marketing surveillance. This narrative review is based on a course in clinical trials developed by one of the authors (DJM), and is supplemented by a PubMed search predating January 2011 using the keywords "randomized controlled trial," "patient/clinical research," "ethics," "phase IV," "data and safety monitoring board," and "surrogate endpoint." With an understanding of the key principles in designing and implementing clinical trials, health care providers can partner with the pharmaceutical industry and regulatory bodies to effectively compare medical therapies and thereby meet one of the essential goals of health care reform.
Topics: Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Clinical Trials, Phase IV as Topic; Drug Evaluation; Humans; Randomized Controlled Trials as Topic; United States
PubMed: 21904102
DOI: 10.3810/pgm.2011.09.2475 -
Annals of Internal Medicine Feb 2013The protocol of a clinical trial serves as the foundation for study planning, conduct, reporting, and appraisal. However, trial protocols and existing protocol...
The protocol of a clinical trial serves as the foundation for study planning, conduct, reporting, and appraisal. However, trial protocols and existing protocol guidelines vary greatly in content and quality. This article describes the systematic development and scope of SPIRIT (Standard Protocol Items: Recommendations for Interventional Trials) 2013, a guideline for the minimum content of a clinical trial protocol.The 33-item SPIRIT checklist applies to protocols for all clinical trials and focuses on content rather than format. The checklist recommends a full description of what is planned; it does not prescribe how to design or conduct a trial. By providing guidance for key content, the SPIRIT recommendations aim to facilitate the drafting of high-quality protocols. Adherence to SPIRIT would also enhance the transparency and completeness of trial protocols for the benefit of investigators, trial participants, patients, sponsors, funders, research ethics committees or institutional review boards, peer reviewers, journals, trial registries, policymakers, regulators, and other key stakeholders.
Topics: Checklist; Clinical Protocols; Clinical Trials as Topic; Humans
PubMed: 23295957
DOI: 10.7326/0003-4819-158-3-201302050-00583 -
Urologic Oncology May 2019Clinical trials organization can be daunting especially when orienting to a new system. The steps to a successful clinical trial are not concrete and vary based on the... (Review)
Review
BACKGROUND AND PURPOSE
Clinical trials organization can be daunting especially when orienting to a new system. The steps to a successful clinical trial are not concrete and vary based on the system.
METHODS
In this section the discussion centers on how to shape the question for the clinical trial which is rational and feasible to answer within the planned study design.
FINDINGS
Senior mentorship, collaboration and early involvement of stakeholders can help shape a successful clinical trial. Keeping in mind ethics and the processes within a system will make planning easier. Questions about key elements of the trial should be answered early to prevent delays of study initiation.
CONCLUSION
Clinical trial development and implementation can be very rewarding, but successful outcomes require careful planning and considerations.
Topics: Clinical Trials as Topic; Humans; Research Design
PubMed: 29395953
DOI: 10.1016/j.urolonc.2017.12.017 -
Journal of the National Cancer Institute May 2009Phase I clinical trials are an essential step in the development of anticancer drugs. The main goal of these studies is to establish the recommended dose and/or schedule... (Review)
Review
Phase I clinical trials are an essential step in the development of anticancer drugs. The main goal of these studies is to establish the recommended dose and/or schedule of new drugs or drug combinations for phase II trials. The guiding principle for dose escalation in phase I trials is to avoid exposing too many patients to subtherapeutic doses while preserving safety and maintaining rapid accrual. Here we review dose escalation methods for phase I trials, including the rule-based and model-based dose escalation methods that have been developed to evaluate new anticancer agents. Toxicity has traditionally been the primary endpoint for phase I trials involving cytotoxic agents. However, with the emergence of molecularly targeted anticancer agents, potential alternative endpoints to delineate optimal biological activity, such as plasma drug concentration and target inhibition in tumor or surrogate tissues, have been proposed along with new trial designs. We also describe specific methods for drug combinations as well as methods that use a time-to-event endpoint or both toxicity and efficacy as endpoints. Finally, we present the advantages and drawbacks of the various dose escalation methods and discuss specific applications of the methods in developmental oncotherapeutics.
Topics: Antineoplastic Agents; Biomarkers, Tumor; Clinical Trials as Topic; Clinical Trials, Phase I as Topic; Combined Modality Therapy; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Approval; Drug Screening Assays, Antitumor; Humans; Medical Oncology; Neoplasms; Research Design; United States
PubMed: 19436029
DOI: 10.1093/jnci/djp079 -
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 -
BMJ (Clinical Research Ed.) Jun 2007Looking back and moving ahead
Looking back and moving ahead
Topics: Clinical Trials as Topic; Organizational Policy; Publishing; Registries
PubMed: 17548363
DOI: 10.1136/bmj.39233.510810.80 -
Trials Apr 2022Clinical trial managers play a vital role in the design and conduct of clinical trials in the UK. There is a current recruitment and retention crisis for this specialist...
Clinical trial managers play a vital role in the design and conduct of clinical trials in the UK. There is a current recruitment and retention crisis for this specialist role due to a complex set of factors, most likely to have come to a head due to the COVID-19 pandemic. Academic clinical trial units and departments are struggling to recruit trial managers to vacant positions, and multiple influences are affecting the retention of this highly skilled workforce. Without tackling this issue, we face major challenges in the delivery on the Department of Health and Social Care's Future of UK Clinical Research Delivery implementation plan. This article, led by a leading network of and for UK Trial Managers, presents some of the issues and ways in which national stakeholders may be able to address this.
Topics: COVID-19; Clinical Trials as Topic; Humans; Pandemics; Research Design; Workforce
PubMed: 35477835
DOI: 10.1186/s13063-022-06315-8 -
CPT: Pharmacometrics & Systems... Dec 2021This NONMEM tutorial shows how to evaluate and optimize clinical trial designs, using algorithms developed in design software, such as PopED and PFIM 4.0. Parameter...
This NONMEM tutorial shows how to evaluate and optimize clinical trial designs, using algorithms developed in design software, such as PopED and PFIM 4.0. Parameter precision and model parameter estimability is obtained by assessing the Fisher Information Matrix (FIM), providing expected model parameter uncertainty. Model parameter identifiability may be uncovered by very large standard errors or inability to invert an FIM. Because evaluation of FIM is more efficient than clinical trial simulation, more designs can be investigated, and the design of a clinical trial can be optimized. This tutorial provides simple and complex pharmacokinetic/pharmacodynamic examples on obtaining optimal sample times, doses, or best division of subjects among design groups. Robust design techniques accounting for likely variability among subjects are also shown. A design evaluator and optimizer within NONMEM allows any control stream first developed for trial design exploration to be subsequently used for estimation of parameters of simulated or clinical data, without transferring the model to another software. Conversely, a model developed in NONMEM could be used for design optimization. In addition, the $DESIGN feature can be used on any model file and dataset combination to retrospectively evaluate the model parameter uncertainty one would expect given that the model generated the data, particularly if outliers of the actual data prevent a reasonable assessment of the variance-covariance. The NONMEM trial design feature is suitable for standard continuous data, whereas more elaborate trial designs or with noncontinuous data-types can still be accomplished in optimal design dedicated software like PopED and PFIM.
Topics: Algorithms; Clinical Trials as Topic; Computer Simulation; Humans; Models, Biological; Models, Statistical; Research Design
PubMed: 34559958
DOI: 10.1002/psp4.12713 -
Trials Jul 2020Clinicians, patients, and policy-makers rely on published evidence from clinical trials to help inform decision-making. A lack of complete and transparent reporting of... (Review)
Review
BACKGROUND
Clinicians, patients, and policy-makers rely on published evidence from clinical trials to help inform decision-making. A lack of complete and transparent reporting of the investigated trial outcomes limits reproducibility of results and knowledge synthesis efforts, and contributes to outcome switching and other reporting biases. Outcome-specific extensions for the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT-Outcomes) and Consolidated Standards of Reporting Trials (CONSORT-Outcomes) reporting guidelines are under development to facilitate harmonized reporting of outcomes in trial protocols and reports. The aim of this review was to identify and synthesize existing guidance for trial outcome reporting to inform extension development.
METHODS
We searched for documents published in the last 10 years that provided guidance on trial outcome reporting using: an electronic bibliographic database search (MEDLINE and the Cochrane Methodology Register); a grey literature search; and solicitation of colleagues using a snowballing approach. Two reviewers completed title and abstract screening, full-text screening, and data charting after training. Extracted trial outcome reporting guidance was compared with candidate reporting items to support, refute, or refine the items and to assess the need for the development of additional items.
RESULTS
In total, 1758 trial outcome reporting recommendations were identified within 244 eligible documents. The majority of documents were published by academic journals (72%). Comparison of each recommendation with the initial list of 70 candidate items led to the development of an additional 62 items, producing 132 candidate items. The items encompassed outcome selection, definition, measurement, analysis, interpretation, and reporting of modifications between trial documents. The total number of documents supporting each candidate item ranged widely (median 5, range 0-84 documents per item), illustrating heterogeneity in the recommendations currently available for outcome reporting across a large and diverse sample of sources.
CONCLUSIONS
Outcome reporting guidance for clinical trial protocols and reports lacks consistency and is spread across a large number of sources that may be challenging to access and implement in practice. Evidence and consensus-based guidance, currently in development (SPIRIT-Outcomes and CONSORT-Outcomes), may help authors adequately describe trial outcomes in protocols and reports transparently and completely to help reduce avoidable research waste.
Topics: Clinical Trials as Topic; Consensus; Endpoint Determination; Humans; Information Dissemination; Research Design; Treatment Outcome
PubMed: 32641085
DOI: 10.1186/s13063-020-04440-w