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BMJ (Clinical Research Ed.) Jan 2013High quality protocols facilitate proper conduct, reporting, and external review of clinical trials. However, the completeness of trial protocols is often inadequate. To...
High quality protocols facilitate proper conduct, reporting, and external review of clinical trials. However, the completeness of trial protocols is often inadequate. To help improve the content and quality of protocols, an international group of stakeholders developed the SPIRIT 2013 Statement (Standard Protocol Items: Recommendations for Interventional Trials). The SPIRIT Statement provides guidance in the form of a checklist of recommended items to include in a clinical trial protocol. This SPIRIT 2013 Explanation and Elaboration paper provides important information to promote full understanding of the checklist recommendations. For each checklist item, we provide a rationale and detailed description; a model example from an actual protocol; and relevant references supporting its importance. We strongly recommend that this explanatory paper be used in conjunction with the SPIRIT Statement. A website of resources is also available (www.spirit-statement.org). The SPIRIT 2013 Explanation and Elaboration paper, together with the Statement, should help with the drafting of trial protocols. Complete documentation of key trial elements can facilitate transparency and protocol review for the benefit of all stakeholders.
Topics: Checklist; Clinical Protocols; Clinical Trials Data Monitoring Committees; Clinical Trials as Topic; Computer Security; Data Collection; Ethics, Medical; Humans; Medical Audit; Patient Selection; Practice Guidelines as Topic; Professional Role; Quality Control; Random Allocation; Research Design; Research Personnel; Research Support as Topic; Sample Size; Social Responsibility; Statistics as Topic; Time Factors; Treatment Outcome
PubMed: 23303884
DOI: 10.1136/bmj.e7586 -
Frontiers in Public Health 2022Decentralized clinical trials (DCTs) are studies in which the need for patients to physically access hospital-based trial sites is reduced or eliminated. The CoViD-19... (Review)
Review
Decentralized clinical trials (DCTs) are studies in which the need for patients to physically access hospital-based trial sites is reduced or eliminated. The CoViD-19 pandemic has caused a significant increase in DCT: a survey shows that 76% of pharmaceutical companies, device manufacturers, and Contract Research Organizations adopted decentralized techniques during the early phase of the pandemic. The implementation of DCTs relies on the use of digital tools such as e-consent, apps, wearable devices, Electronic Patient-Reported Outcomes (ePRO), telemedicine, as well as on moving trial activities to the patient's home (e.g., drug delivery) or to local healthcare settings (i.e., community-based diagnosis and care facilities). DCTs adapt to patients' routines, allow patients to participate regardless of where they live by removing logistical barriers, offer better access to the study and the investigational product, and permit the inclusion of more diverse and more representative populations. The feasibility and quality of DCTs depends on several requirements including dedicated infrastructures and staff, an adequate regulatory framework, and partnerships between research sites, patients and sponsors. The evaluation of Ethics Committees (ECs) is crucial to the process of innovating and digitalizing clinical trials: adequate assessment tools and a suitable regulatory framework are needed for evaluation by ECs. DCTs also raise issues, many of which are of considerable ethical significance. These include the implications for the relationship between patients and healthcare staff, for the social dimension of the patient, for data integrity (at the source, during transmission, in the analysis phase), for personal data protection, and for the possible risks to health and safety. Despite their considerable growth, DCTs have only received little attention from bioethicists. This paper offers a review on some ethical implications and requirements of DCTs in order to encourage further ethical reflection on this rapidly emerging field.
Topics: Humans; COVID-19; Delivery of Health Care; Pandemics; Telemedicine; Clinical Trials as Topic
PubMed: 36590004
DOI: 10.3389/fpubh.2022.1081150 -
Diabetes Care Mar 2019This study evaluated the association of time in range (TIR) of 70-180 mg/dL (3.9-10 mmol/L) with the development or progression of retinopathy and development of...
OBJECTIVE
This study evaluated the association of time in range (TIR) of 70-180 mg/dL (3.9-10 mmol/L) with the development or progression of retinopathy and development of microalbuminuria using the Diabetes Control and Complications Trial (DCCT) data set in order to validate the use of TIR as an outcome measure for clinical trials.
RESEARCH DESIGN AND METHODS
In the DCCT, blood glucose concentrations were measured at a central laboratory from seven fingerstick samples (seven-point testing: pre- and 90-min postmeals and at bedtime) collected during 1 day every 3 months. Retinopathy progression was assessed every 6 months and urinary microalbuminuria development every 12 months. Proportional hazards models were used to assess the association of TIR and other glycemic metrics, computed from the seven-point fingerstick data, with the rate of development of microvascular complications.
RESULTS
Mean TIR of seven-point profiles for the 1,440 participants was 41 ± 16%. The hazard rate of development of retinopathy progression was increased by 64% (95% CI 51-78), and development of the microalbuminuria outcome was increased by 40% (95% CI 25-56), for each 10 percentage points lower TIR ( < 0.001 for each). Results were similar for mean glucose and hyperglycemia metrics.
CONCLUSIONS
Based on these results, a compelling case can be made that TIR is strongly associated with the risk of microvascular complications and should be an acceptable end point for clinical trials. Although hemoglobin A remains a valuable outcome metric in clinical trials, TIR and other glycemic metrics-especially when measured with continuous glucose monitoring-add value as outcome measures in many studies.
Topics: Adult; Blood Glucose; Blood Glucose Self-Monitoring; Clinical Trials as Topic; Diabetes Complications; Diabetes Mellitus; Disease Progression; Female; Glycated Hemoglobin; Humans; Longitudinal Studies; Male; Middle Aged; Outcome Assessment, Health Care; Patient Care Planning; Prognosis; Research Design; Time Factors; Treatment Outcome
PubMed: 30352896
DOI: 10.2337/dc18-1444 -
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 -
Seizure Jan 2017Status epilepticus (SE) requires not only urgent symptomatic treatment with antiepileptic drugs but also rapid identification and treatment of its cause. This narrative... (Review)
Review
PURPOSE
Status epilepticus (SE) requires not only urgent symptomatic treatment with antiepileptic drugs but also rapid identification and treatment of its cause. This narrative review summarizes the most important advances in classification and treatment of SE.
METHOD
Data sources included MEDLINE, EMBASE, ClinicalTrials.gov, and back tracking of references in pertinent studies, reviews, and books.
RESULTS
SE is now defined as "a condition resulting either from the failure of the mechanisms responsible for seizure termination or from the initiation of mechanisms, which lead to abnormally, prolonged seizures (after time point t1). It is a condition, which can have long-term consequences (after time point t2), including neuronal death, neuronal injury, and alteration of neuronal networks, depending on the type and duration of seizures." A new diagnostic classification system of SE introduces four axes: semiology, aetiology, EEG correlates, and age. For the acute treatment intravenous benzodiazepines (lorazepam, diazepam, clonazepam) and intramuscular midazolam appear as most effective treatments for early SE. In children, buccal or intranasal midazolam are useful alternatives. In established SE intravenous antiepileptic drugs (phenytoin, valproate, levetiracetam, phenobarbital, and lacosamide) are in use. Treatment options in refractory SE are intravenous anaesthetics; ketamine, magnesium, steroids and other drugs have been used in super-refractory SE with variable outcomes.
CONCLUSION
Over the past 25 years major advances in definition, classification and understanding of its mechanisms have been achieved. Despite this up to 40% of patients in early status cannot be controlled with first line drugs. The treatment of super-refractory status is still an almost evidence free zone.
Topics: Clinical Trials as Topic; Databases, Factual; Electroencephalography; History, 20th Century; History, 21st Century; Humans; Status Epilepticus
PubMed: 27890484
DOI: 10.1016/j.seizure.2016.11.001 -
The Journal of Pain Feb 2008A consensus meeting was convened by the Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT) to provide recommendations for interpreting...
UNLABELLED
A consensus meeting was convened by the Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT) to provide recommendations for interpreting clinical importance of treatment outcomes in clinical trials of the efficacy and effectiveness of chronic pain treatments. A group of 40 participants from universities, governmental agencies, a patient self-help organization, and the pharmaceutical industry considered methodologic issues and research results relevant to determining the clinical importance of changes in the specific outcome measures previously recommended by IMMPACT for 4 core chronic pain outcome domains: (1) Pain intensity, assessed by a 0 to 10 numerical rating scale; (2) physical functioning, assessed by the Multidimensional Pain Inventory and Brief Pain Inventory interference scales; (3) emotional functioning, assessed by the Beck Depression Inventory and Profile of Mood States; and (4) participant ratings of overall improvement, assessed by the Patient Global Impression of Change scale. It is recommended that 2 or more different methods be used to evaluate the clinical importance of improvement or worsening for chronic pain clinical trial outcome measures. Provisional benchmarks for identifying clinically important changes in specific outcome measures that can be used for outcome studies of treatments for chronic pain are proposed.
PERSPECTIVE
Systematically collecting and reporting the recommended information needed to evaluate the clinical importance of treatment outcomes of chronic pain clinical trials will allow additional validation of proposed benchmarks and provide more meaningful comparisons of chronic pain treatments.
Topics: Clinical Trials as Topic; Humans; Pain Management; Pain Measurement; Research Design; Treatment Outcome
PubMed: 18055266
DOI: 10.1016/j.jpain.2007.09.005 -
Blood May 2011It is essential that there be consistency in the conduct, analysis, and reporting of clinical trial results in myeloma. The goal of the International Myeloma Workshop...
It is essential that there be consistency in the conduct, analysis, and reporting of clinical trial results in myeloma. The goal of the International Myeloma Workshop Consensus Panel 1 was to develop a set of guidelines for the uniform reporting of clinical trial results in myeloma. This paper provides a summary of the current response criteria in myeloma, detailed definitions for patient populations, lines of therapy, and specific endpoints. We propose that future clinical trials in myeloma follow the guidelines for reporting results proposed in this manuscript.
Topics: Clinical Trials as Topic; Clinical Trials, Phase III as Topic; Humans; Multiple Myeloma; Recurrence; Treatment Outcome
PubMed: 21292775
DOI: 10.1182/blood-2010-10-299487 -
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 -
Journal of Nuclear Medicine : Official... Jun 2021This article explores basic statistical concepts of clinical trial design and diagnostic testing, or how one starts with a question, formulates it into a hypothesis on... (Review)
Review
This article explores basic statistical concepts of clinical trial design and diagnostic testing, or how one starts with a question, formulates it into a hypothesis on which a clinical trial is then built, and integrates it with statistics and probability, such as determining the probability of rejecting the null hypothesis when it is actually true (type I error) and the probability of failing to reject the null hypothesis when it is false (type II error). There are a variety of tests for different types of data, and the appropriate test must be chosen for which the sample data meet the assumptions. Correcting type I error in the presence of multiple testing is needed to control the error's inflation. Within diagnostic testing, identifying false-positive and false-negative results is critical to understanding the performance of a test. These are used to determine the sensitivity and specificity of a test along with the test's negative predictive value and positive predictive value. These quantities, specifically sensitivity and specificity, are used to determine the accuracy of a diagnostic test using receiver-operating-characteristic curves. These concepts are briefly introduced to provide a basic understanding of clinical trial design and analysis, with references to allow the reader to explore various concepts at a more detailed level if desired.
Topics: Clinical Trials as Topic; Diagnostic Techniques and Procedures; Humans; Predictive Value of Tests; ROC Curve; Sensitivity and Specificity; Statistics as Topic
PubMed: 33608427
DOI: 10.2967/jnumed.120.245654