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Journal of Diabetes and Its... 2013Medical research continues to progress in its ability to identify treatments and characteristics associated with benefits and adverse outcomes. The principal engine for... (Review)
Review
Medical research continues to progress in its ability to identify treatments and characteristics associated with benefits and adverse outcomes. The principal engine for the evaluation of treatment efficacy is the randomized controlled trial (RCT). Due to the cost and other considerations, RCTs cannot address all clinically important decisions. Observational research often is used to address issues not addressed or not addressable by RCTs. This article provides an overview of the benefits and limitations of observational research to serve as a guide to the interpretation of this category of research designs in diabetes investigations. The potential for bias is higher in observational research but there are design and analysis features that can address these concerns although not completely eliminate them. Pharmacoepidemiologic research may provide important information regarding relative safety and effectiveness of diabetes pharmaceuticals. Such research must effectively address the important issue of confounding by indication in order to produce clinically meaningful results. Other methods such as instrumental variable analysis are being employed to enable stronger causal inference but these methods also require fulfillment of several key assumptions that may or may not be realistic. Nearly all clinical decisions involve probabilistic reasoning and confronting uncertainly, so a realistic goal for observational research may not be the high standard set by RCTs but instead the level of certainty needed to influence a diagnostic or treatment decision.
Topics: Bias; Case-Control Studies; Causality; Clinical Trials as Topic; Cohort Studies; Diabetes Mellitus; Humans; Observational Studies as Topic; Research Design; Treatment Outcome
PubMed: 24055326
DOI: 10.1016/j.jdiacomp.2013.07.007 -
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 -
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 -
Hepatology (Baltimore, Md.) Jul 2011Nonalcoholic fatty liver disease is a common cause of chronic liver disease in the general population. Nonalcoholic steatohepatitis (NASH), the aggressive form of...
UNLABELLED
Nonalcoholic fatty liver disease is a common cause of chronic liver disease in the general population. Nonalcoholic steatohepatitis (NASH), the aggressive form of nonalcoholic fatty liver disease, is associated with an increased risk of liver-related mortality and cardiovascular disease. At present, a liver biopsy is the only generally acceptable method for the diagnosis of NASH and assessment of its progression toward cirrhosis. Although several treatments have shown evidence of efficacy in clinical trials of varying design, there are no approved treatments for NASH, and published trials are often too divergent to allow meaningful comparisons. There is thus a lack of established noninvasive, point-of-care diagnostics and approved treatment on one hand and a substantial population burden of disease on the other. These provide the rationale for developing consensus on key endpoints and clinical trial design for NASH.
CONCLUSION
This article summarizes the consensus arrived at a meeting of the American Association for the Study of Liver Diseases on the key endpoints and specific trial design issues that are germane for development of diagnostic biomarkers and treatment trials for NASH.
Topics: Biomarkers; Biopsy; Clinical Trials as Topic; Disease Progression; Endpoint Determination; Fatty Liver; Humans; Liver; Non-alcoholic Fatty Liver Disease; Societies, Medical; United States
PubMed: 21520200
DOI: 10.1002/hep.24376 -
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 -
Journal of Visceral Surgery Feb 2014Endpoints are measurable clinical and biological findings that are used for the development and assessment of treatment options. In the treatment of cancer, endpoints... (Review)
Review
Endpoints are measurable clinical and biological findings that are used for the development and assessment of treatment options. In the treatment of cancer, endpoints can be classified into two categories: "patient-centered clinical endpoints" including overall survival (OS) and health-related quality of life (QoL), and "tumor-centered clinical endpoints" such as progression-free survival. Surrogate endpoints are tumor-centered clinical endpoints that can be used as substitutes for patient-centered clinical endpoints, particularly OS. The choice of endpoints in oncology trials is a major problem. The published Consolidated Standards of Reporting Trials (CONSORT) best-practice guidelines encourage the reporting of clearly defined primary and secondary outcome measures. OS is the gold standard of endpoints but as increasing numbers of effective salvage treatments become available for many types of cancer, much larger numbers of patients are included; this requires a longer follow-up period and increases the cost of clinical trials. Thus, tumor-centered clinical endpoints that can be assessed earlier and used as surrogates for overall survival are increasingly studied, but most of them currently lack standardized definitions to enable cross comparison of results among different clinical trials and they have not been validated as surrogate endpoints. In addition, the variability of their definition can strongly impact the trial's conclusions by affecting both statistical power and estimation. In this context, QoL constitutes an available and useful surrogate endpoint for trials to ensure treatment benefit from both the patient and public health points of view. Methodological research should be pursued to develop standard outcome definitions for use in cancer clinical trials and to define a standardized longitudinal analysis of QoL data.
Topics: Clinical Trials as Topic; Disease-Free Survival; Humans; Neoplasms; Outcome Assessment, Health Care; Quality of Life; Research Design; Survival Rate; Treatment Outcome
PubMed: 24440056
DOI: 10.1016/j.jviscsurg.2013.10.001 -
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 -
BMJ Open Jul 2022Malaria is one of the major public health problems in sub-Saharan Africa. It contributes significantly to maternal and fetal morbidity and mortality in affected...
INTRODUCTION
Malaria is one of the major public health problems in sub-Saharan Africa. It contributes significantly to maternal and fetal morbidity and mortality in affected countries. This study aims to evaluate the impact of enhanced case detection using molecular testing called loop-mediated isothermal amplification (LAMP) on birth outcomes in a prospective study design.
METHODS AND ANALYSIS
A pragmatic randomised diagnostic outcomes trial will be conducted in several health institutes in different Ethiopian regions. Women (n=2583) in their first and second trimesters of pregnancy will be included in the study and individually randomised to the standard of care or enhanced case detection arms, and followed until delivery. Enrolment will encompass the malaria peak transmission seasons. In the standard of care arm, a venous blood sample will be collected for malaria diagnosis only in symptomatic patients. In contrast, in the intervention arm, mothers will be tested by a commercially available Conformité Européene (CE)-approved LAMP malaria test, microscopy and rapid diagnostic test for malaria regardless of their symptoms at each antenatal care visit. The primary outcome of the study is to measure birth weight.
ETHICS AND DISSEMINATION
The study was approved by the following ethical research boards: Armauer Hansen Research Institute/ALERT Ethics Review Committee (FORM AF-10-015.1, Protocol number PO/05/20), the Ethiopia Ministry of Science and Higher Education National Research Ethics Review Committee (approval SRA/11.7/7115/20), the Ethiopia Food and Drug Administration (approval 02/25/33/I), UCalgary Conjoint Health Research Ethics Board (REB21-0234). The study results will be shared with the institutions and stakeholders such as the Ethiopia Ministry of Health, the Foundation for Innovative Diagnostics, WHO's Multilateral initiative on Malaria - Tropical Diseases Research (TDR-MIM), Roll Back Malaria and the Malaria in Pregnancy Consortium. The study results will also be published in peer-reviewed journals and presented at international conferences.
TRIAL REGISTRATION NUMBER
NCT03754322.
Topics: Female; Humans; Malaria; Mass Screening; Molecular Diagnostic Techniques; Nucleic Acid Amplification Techniques; Pragmatic Clinical Trials as Topic; Pregnancy; Pregnancy Complications, Parasitic; Prospective Studies; Randomized Controlled Trials as Topic; Technology
PubMed: 35851027
DOI: 10.1136/bmjopen-2021-058397 -
Trials May 2016Despite long-standing problems in decisions to stop clinical trials, stopping guidelines are often vague or unspecified in the trial protocol. Clear, well-conceived...
BACKGROUND
Despite long-standing problems in decisions to stop clinical trials, stopping guidelines are often vague or unspecified in the trial protocol. Clear, well-conceived guidelines are especially important to assist the data monitoring committees for effectiveness trials.
MAIN TEXT
To specify better stopping guidelines in the protocol for such trials, the clinical investigators and trial statistician should carefully consider the following kinds of questions: 1. How should the relative importance of the treatment benefits and hazards be assessed? 2. For decisions to stop a trial for benefit: (a) What would be the minimum clinically important difference for the study population? (b) How should the probability that the benefit exceeds that difference be assessed? (c) When should the interim analyses include data from other trials? (d) Would the evidence meet state-of-the-art standards for treatment recommendations and practice guidelines? 3. Should less evidence be required to stop the trial for harm than for benefit? 4. When should conventional stopping guidelines for futility be used for comparative effectiveness trials?
CONCLUSION
Both clinical and statistical expertise are required to address such challenging questions for effectiveness trials. Their joint consideration by clinical investigators and statisticians is needed to define better stopping guidelines before starting the trial.
Topics: Clinical Trials Data Monitoring Committees; Clinical Trials as Topic; Data Interpretation, Statistical; Early Termination of Clinical Trials; Humans; Medical Futility; Patient Safety; Practice Guidelines as Topic; Research Design; Risk Assessment; Treatment Failure
PubMed: 27165260
DOI: 10.1186/s13063-016-1367-4