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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 -
JACC. Cardiovascular Imaging Nov 2019The myocardial interstitium has emerged as a potential therapeutic target and as a biological entity to improve risk stratification and better guide existing... (Review)
Review
The myocardial interstitium has emerged as a potential therapeutic target and as a biological entity to improve risk stratification and better guide existing interventions. Clinical trials focusing on the myocardial interstitium are required to establish causality and improve patient outcomes. This review will discuss issues around clinical trials targeting the myocardial interstitium, including antifibrotic therapies, efficacy outcome measurements, mechanistic outcome measurements and mediation analysis, sample size, trial duration, considerations for multicenter trials, stratifying trial recruitment according to the interstitium, and approaches to enrich recruitment, using examples of ongoing clinical trials.
Topics: Cardiomyopathies; Clinical Trials as Topic; Endpoint Determination; Extracellular Space; Fibrosis; Humans; Myocardium; Patient Selection; Research Design; Sample Size; Time Factors; Treatment Outcome; Ventricular Remodeling
PubMed: 31422145
DOI: 10.1016/j.jcmg.2019.03.034 -
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 -
JACC. Cardiovascular Imaging Aug 2016Numerous observational studies have shown that coronary artery calcium (CAC) imaging can improve cardiovascular risk assessment in asymptomatic adults. Whether CAC... (Review)
Review
Numerous observational studies have shown that coronary artery calcium (CAC) imaging can improve cardiovascular risk assessment in asymptomatic adults. Whether CAC imaging can improve cardiovascular outcomes as part of an overall risk reduction strategy compared to alternative care approaches has not been demonstrated in clinical trials. Therefore, the role of CAC imaging in primary prevention of cardiovascular disease is somewhat contentious. Advocates for expanded CAC testing offer the large amount of observational data as support for their position, while opponents to wider CAC testing propose that only a clinical trial can resolve the matter. This paper reviews the arguments for and against such a trial based on clinical, safety and economic considerations. We also propose potential trial approaches based on recent changes in clinical practice that could make a new CAC trial design feasible.
Topics: Clinical Trials as Topic; Computed Tomography Angiography; Coronary Angiography; Coronary Artery Disease; Evidence-Based Medicine; Humans; Predictive Value of Tests; Prognosis; Research Design; Risk Assessment; Risk Factors; Vascular Calcification
PubMed: 27491486
DOI: 10.1016/j.jcmg.2016.03.012 -
Journal of Hepatology Mar 2018Alcoholic hepatitis (AH) is the most severe form of alcoholic liver disease, contributing to significant morbidity and mortality. Yet, the only available therapies that... (Review)
Review
Alcoholic hepatitis (AH) is the most severe form of alcoholic liver disease, contributing to significant morbidity and mortality. Yet, the only available therapies that improve survival are corticosteroids and liver transplantation, with no new drugs successfully developed for decades. This article briefly describes the current state of affairs in AH therapy and examines the practical and ethical challenges of conducting controlled trials in patients with severe AH. While prednisolone is considered standard of care in severe AH, this recommendation remains controversial given the marginal benefits and questionable long-term safety of steroids. Placebo-controlled trials without steroids may be necessary and ethically justified in certain populations with AH who have not been adequately investigated. Ultimately, we suggest that the field will advance with the development of a plausible animal model of true AH, a consensus on a composite clinical endpoint that does not rely solely on mortality, as well as the adoption of the NIAAA Alcoholic Hepatitis Consortia recommendations regarding standard definitions and when to request a liver biopsy prior to study entry.
Topics: Animals; Biopsy; Clinical Trials as Topic; Disease Models, Animal; Hepatitis, Alcoholic; Humans; Liver; Patient Care Management
PubMed: 28966126
DOI: 10.1016/j.jhep.2017.09.013 -
Clinical Cancer Research : An Official... May 2021Performance status (PS) is one of the most common eligibility criteria. Many trials are limited to patients with high-functioning PS, resulting in important differences... (Meta-Analysis)
Meta-Analysis Review
PURPOSE
Performance status (PS) is one of the most common eligibility criteria. Many trials are limited to patients with high-functioning PS, resulting in important differences between trial participants and patient populations with the disease. In addition, existing PS measures are subjective and susceptible to investigator bias.
EXPERIMENTAL DESIGN
A multidisciplinary working group of the American Society of Clinical Oncology and Friends of Cancer Research evaluated how PS eligibility criteria could be more inclusive. The working group recommendations are based on a literature search, review of trials, simulation study, and multistakeholder consensus. The working group prioritized inclusiveness and access to investigational therapies, while balancing patient safety and study integrity.
RESULTS
Broadening PS eligibility criteria may increase the number of potentially eligible patients for a given clinical trial, thus shortening accrual time. It may also result in greater participant diversity, potentially reduce trial participant and patient disparities, and enable clinicians to more readily translate trial results to patients with low-functioning PS. Potential impact on outcomes was explored through a simulation trial demonstrating that when the number of Eastern Cooperative Oncology Group PS2 participants was relatively small, the effect on the estimated HR and power was modest, even when PS2 patients did not derive a treatment benefit.
CONCLUSIONS
Expanding PS eligibility criteria to be more inclusive may be justified in many cases and could result in faster accrual rates and more representative trial populations..
Topics: Biomedical Research; Clinical Decision-Making; Clinical Trials as Topic; Disease Management; Humans; Medical Oncology; Neoplasms; Research Design
PubMed: 33563633
DOI: 10.1158/1078-0432.CCR-20-3868 -
The European Respiratory Journal Jan 2019Until 20 years ago the treatment of pulmonary arterial hypertension (PAH) was based on case reports and small series, and was largely ineffectual. As a deeper... (Review)
Review
Until 20 years ago the treatment of pulmonary arterial hypertension (PAH) was based on case reports and small series, and was largely ineffectual. As a deeper understanding of the pathogenesis and pathophysiology of PAH evolved over the subsequent two decades, coupled with epidemiological studies defining the clinical and demographic characteristics of the condition, a renewed interest in treatment development emerged through collaborations between international experts, industry and regulatory agencies. These efforts led to the performance of robust, high-quality clinical trials of novel therapies that targeted putative pathogenic pathways, leading to the approval of more than 10 novel therapies that have beneficially impacted both the quality and duration of life. However, our understanding of PAH remains incomplete and there is no cure. Accordingly, efforts are now focused on identifying novel pathogenic pathways that may be targeted, and applying more rigorous clinical trial designs to better define the efficacy of these new potential treatments and their role in the management scheme. This article, prepared by a Task Force comprised of expert clinicians, trialists and regulators, summarises the current state of the art, and provides insight into the opportunities and challenges for identifying and assessing the efficacy and safety of new treatments for this challenging condition.
Topics: Animals; Clinical Trials as Topic; Cost of Illness; Drug Therapy, Combination; Exercise Test; Humans; Practice Guidelines as Topic; Pulmonary Arterial Hypertension; Research Design
PubMed: 30545975
DOI: 10.1183/13993003.01908-2018 -
Clinical Microbiology and Infection :... Jul 2019
Topics: Biostatistics; Clinical Trials as Topic; Diagnostic Tests, Routine; Humans; Sample Size
PubMed: 30986555
DOI: 10.1016/j.cmi.2019.04.011 -
The Lancet. Oncology May 2024The requirement of large-scale expensive cancer screening trials spanning decades creates considerable barriers to the development, commercialisation, and implementation... (Review)
Review
The requirement of large-scale expensive cancer screening trials spanning decades creates considerable barriers to the development, commercialisation, and implementation of novel screening tests. One way to address these problems is to use surrogate endpoints for the ultimate endpoint of interest, cancer mortality, at an earlier timepoint. This Review aims to highlight the issues underlying the choice and use of surrogate endpoints for cancer screening trials, to propose criteria for when and how we might use such endpoints, and to suggest possible candidates. We present the current landscape and challenges, and discuss lessons and shortcomings from the therapeutic trial setting. It is hugely challenging to validate a surrogate endpoint, even with carefully designed clinical studies. Nevertheless, we consider whether there are candidates that might satisfy the requirements defined by research and regulatory bodies.
Topics: Humans; Early Detection of Cancer; Neoplasms; Biomarkers, Tumor; Clinical Trials as Topic; Research Design; Biomarkers; Endpoint Determination
PubMed: 38697164
DOI: 10.1016/S1470-2045(24)00015-9 -
Radiologia 2014Lung cancer is a very important disease, curable in early stages. There have been trials trying to show the utility of chest x-ray or computed tomography in Lung Cancer... (Review)
Review
Lung cancer is a very important disease, curable in early stages. There have been trials trying to show the utility of chest x-ray or computed tomography in Lung Cancer Screening for decades. In 2011, National Lung Screening Trial results were published, showing a 20% reduction in lung cancer mortality in patients with low dose computed tomography screened for three years. These results are very promising and several scientific societies have included lung cancer screening in their guidelines. Nevertheless we have to be aware of lung cancer screening risks, such as: overdiagnosis, radiation and false positive results. Moreover, there are many issues to be solved, including choosing the appropriate group to be screened, the duration of the screening program, intervals between screening and its cost-effectiveness. Ongoing trials will probably answer some of these questions. This article reviews the current evidence on lung cancer screening.
Topics: Clinical Trials as Topic; Early Detection of Cancer; Humans; Lung Neoplasms
PubMed: 23830728
DOI: 10.1016/j.rx.2013.04.002