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Leukemia Research May 2018Treatment regimens for acute myeloid leukemia (AML) have remained largely unchanged until recently. Molecular advances have opened the door to targeted therapies, many... (Review)
Review
Treatment regimens for acute myeloid leukemia (AML) have remained largely unchanged until recently. Molecular advances have opened the door to targeted therapies, many of which are in late-phase clinical trials. As new therapeutic opportunities arise, it is appropriate to review key aspects of clinical trial design, statistical interpretation of outcomes, and methods of data reporting. Complete remission and overall survival (OS) are common primary endpoints in early-phase AML clinical trials. OS and event-free survival are frequent primary endpoints in phase 3 trials. Clinical trials are designed to address the primary endpoint using prespecified α and power levels. Interpretation of additional endpoints (eg, secondary endpoints and subgroup analyses) must be viewed in light of a trial's statistical design. Furthermore, variations in reporting of endpoints must be considered in order to understand trial outcomes. Time-to-event endpoints are typically reported using Kaplan-Meier curves, which are visually informative. Statistical data derived from these curves can be complex, and a variety of factors may impact interpretation. The purpose of this review is to discuss the nuances of common AML trial endpoints and their data presentation to better inform evaluation and understanding of clinical trial data.
Topics: Clinical Trials as Topic; Data Interpretation, Statistical; Endpoint Determination; Humans; Kaplan-Meier Estimate; Leukemia, Myeloid, Acute; Remission Induction; Treatment Outcome
PubMed: 29524739
DOI: 10.1016/j.leukres.2018.02.002 -
Clinical Cancer Research : An Official... Oct 2008Many cancer treatments benefit only a minority of patients who receive them. This results in an enormous burden on patients and on the health care system. The problem... (Review)
Review
Many cancer treatments benefit only a minority of patients who receive them. This results in an enormous burden on patients and on the health care system. The problem will become even greater with the increasing use of molecularly targeted agents whose benefits are likely to be more selective unless the drug development process is modified to include co-development of companion diagnostics. Whole genome biotechnology and decreasing costs of genome sequencing make it increasingly possible to achieve an era of predictive medicine in oncology therapeutics. The challenges are numerous and substantial but are not primarily technological. They involve organizing publicly funded diagnostics of deregulated pathways, adopting new paradigms for drug development, and developing incentives for industry to incur the complexity and expense of co-development of drugs and companion diagnostics. This article reviews some designs for phase III clinical trials that may facilitate movement to a more predictive oncology.
Topics: Biometry; Biotechnology; Clinical Trials as Topic; Computational Biology; Drug Design; Drug Industry; Genome, Human; Genomics; Humans; Medical Oncology; Neoplasms; Prognosis; Research Design; Technology, Pharmaceutical; Treatment Outcome
PubMed: 18829477
DOI: 10.1158/1078-0432.CCR-07-4531 -
Alimentary Pharmacology & Therapeutics Sep 2003Appropriate guidelines for clinical trials in irritable bowel syndrome are needed because of the inadequacy of previously performed trials, the use of new and more... (Review)
Review
Appropriate guidelines for clinical trials in irritable bowel syndrome are needed because of the inadequacy of previously performed trials, the use of new and more adequate patient definition, new emerging pathophysiological models and the unique requirements related to the assessment of treatment outcome that, in the absence of a biological marker, can rely only on the evaluation of clinical manifestations. This consensus report highlights the following points. (a) A 4-week period is considered to be adequate to assess drug efficacy for the control of symptoms. (b) For the cyclic and non-life-threatening nature of the disease, a long-term study of 4-6 months or more of active treatment to establish efficacy is considered to be inappropriate in the large majority of patients. (c) In the initial assessment phase of drug efficacy, the withdrawal effect of treatment can be ascertained during a follow-up period prolonged for a sufficient time (4-8 weeks) after stopping treatment. Subsequent trials with proper withdrawal phase design and duration can then ascertain the drug post-treatment benefit. (d) Considering the intermittent clinical manifestations of irritable bowel syndrome, designing trials with on-demand or repeated cycles of treatment could be envisaged. However, the lack of a definition of what constitutes an exacerbation is a major obstacle to the design of such trials. In the absence of an established gold standard, appropriately justified novel trial designs are welcome. (e) Patients eligible for inclusion should comply with the Rome II diagnostic criteria for irritable bowel syndrome. (f) The main efficacy outcome of the treatment should be based on one primary end-point. (g) The primary efficacy end-point could combine, in a global assessment, the key symptoms (abdominal pain, abdominal discomfort, bowel alterations) of irritable bowel syndrome or rate any single symptom for drugs considered to target specific symptoms. (h) A 50% improvement in the primary efficacy end-point seems to be a reasonable definition of a responder.
Topics: Clinical Trials as Topic; Colonic Diseases, Functional; Humans; Mental Disorders; Patient Selection; Patients; Practice Guidelines as Topic; Time Factors; Treatment Outcome
PubMed: 12969083
DOI: 10.1046/j.1365-2036.2003.01709.x -
Neurology Jul 2015This review addresses decision-making underlying the frequent failure to confirm early-phase positive trial results and how to prioritize which early agents to... (Review)
Review
This review addresses decision-making underlying the frequent failure to confirm early-phase positive trial results and how to prioritize which early agents to transition to late phase. While unexpected toxicity is sometimes responsible for late-phase failures, lack of efficacy is also frequently found. In stroke as in other conditions, early trials often demonstrate imbalances in factors influencing outcome. Other issues complicate early trial analysis, including unequally distributed noise inherent in outcome measures and variations in natural history among studies. We contend that statistical approaches to correct for imbalances and noise, while likely valid for homogeneous conditions, appear unable to accommodate disease complexity and have failed to correctly identify effective agents. While blinding and randomization are important to reduce selection bias, these methods appear insufficient to insure valid conclusions. We found potential sources of analytical errors in nearly 90% of a sample of early stroke trials. To address these issues, we recommend changes in early-phase analysis and reporting: (1) restrict use of statistical correction to studies where the underlying assumptions are validated, (2) select dichotomous over continuous outcomes for small samples, (3) consider pooled samples to model natural history to detect early therapeutic signals and increase the likelihood of replication in larger samples, (4) report subgroup baseline conditions, (5) consider post hoc methods to restrict analysis to subjects with an appropriate match, and (6) increase the strength of effect threshold given these cumulative sources of noise and potential errors. More attention to these issues should lead to better decision-making regarding selection of agents to proceed to pivotal trials.
Topics: Clinical Trials as Topic; Humans; Stroke; Time Factors
PubMed: 26109712
DOI: 10.1212/WNL.0000000000001757 -
Statistics in Medicine Nov 2012Although the frequentist paradigm has been the predominant approach to clinical trial design since the 1940s, it has several notable limitations. Advancements in... (Review)
Review
Although the frequentist paradigm has been the predominant approach to clinical trial design since the 1940s, it has several notable limitations. Advancements in computational algorithms and computer hardware have greatly enhanced the alternative Bayesian paradigm. Compared with its frequentist counterpart, the Bayesian framework has several unique advantages, and its incorporation into clinical trial design is occurring more frequently. Using an extensive literature review to assess how Bayesian methods are used in clinical trials, we find them most commonly used for dose finding, efficacy monitoring, toxicity monitoring, diagnosis/decision making, and studying pharmacokinetics/pharmacodynamics. The additional infrastructure required for implementing Bayesian methods in clinical trials may include specialized software programs to run the study design, simulation and analysis, and web-based applications, all of which are particularly useful for timely data entry and analysis. Trial success requires not only the development of proper tools but also timely and accurate execution of data entry, quality control, adaptive randomization, and Bayesian computation. The relative merit of the Bayesian and frequentist approaches continues to be the subject of debate in statistics. However, more evidence can be found showing the convergence of the two camps, at least at the practical level. Ultimately, better clinical trial methods lead to more efficient designs, lower sample sizes, more accurate conclusions, and better outcomes for patients enrolled in the trials. Bayesian methods offer attractive alternatives for better trials. More Bayesian trials should be designed and conducted to refine the approach and demonstrate their real benefit in action.
Topics: Bayes Theorem; Clinical Trials as Topic; Likelihood Functions; Research Design; Software
PubMed: 22711340
DOI: 10.1002/sim.5404 -
Journal of Crohn's & Colitis Sep 2016Endoscopic assessment of the presence and severity of endoscopic lesions has become an essential part of clinical trials in ulcerative colitis and Crohn's disease, for... (Review)
Review
Endoscopic assessment of the presence and severity of endoscopic lesions has become an essential part of clinical trials in ulcerative colitis and Crohn's disease, for both patient eligibility and outcome measures. Variability in lesion interpretation between and within observers and the potential bias of local investigators in patient assessment have long been recognized. This variability can be reduced, although not completely removed, by independent evaluation of the examinations by experienced off-site (central) readers, properly trained in regard to lesion definition and identification, that should be removed from direct patient contact and blinded to any other clinical or study data. Adding endoscopic demonstration of active disease to eligibility criteria has the potential to reduce placebo response rates, whereas in outcome assessment it has the potential to provide a more precise estimation of the treatment effect, increasing the efficiency of the study. Central endoscopy reading is still at the beginning of its development, and the paradigms of central reading need refinement in terms of the number of readers, the process by which a final score is assigned, the selection and sequence of central readers, and the endoscopic indices of choice.
Topics: Clinical Trials as Topic; Colitis, Ulcerative; Crohn Disease; Eligibility Determination; Endoscopy, Digestive System; Humans; Observer Variation; Outcome Assessment, Health Care; Patient Acuity; Treatment Outcome
PubMed: 27604978
DOI: 10.1093/ecco-jcc/jjv171 -
American Journal of Clinical Pathology Jan 2020The National Cancer Institute (NCI) National Clinical Trials Network performs phase II and III clinical trials, which increasingly rely on the submission of diagnostic...
OBJECTIVES
The National Cancer Institute (NCI) National Clinical Trials Network performs phase II and III clinical trials, which increasingly rely on the submission of diagnostic formalin-fixed, paraffin-embedded tissue blocks for biomarker assessment. Simultaneously, advances in precision oncology require that clinical centers maintain diagnostic specimens for ancillary, standard-of-care diagnostics. This has caused tissue blocks to become a limited resource for advancing the NCI clinical trial enterprise and the practice of modern molecular pathology.
METHODS
The NCI convened a 1-day workshop of multidisciplined experts to discuss barriers and strategic solutions to facilitate diagnostic block submission for clinical trial science, from the perspective of patient advocates, legal experts, pathologists, and clinical oncologists.
RESULTS
The expert views and opinions were carefully noted and reported.
CONCLUSIONS
Recommendations were proposed to reduce institutional barriers and to assist organizations in developing clear policies regarding diagnostic block submission for clinical trials.
Topics: Clinical Trials as Topic; Histological Techniques; Humans; National Cancer Institute (U.S.); Paraffin Embedding; Specimen Handling; Tissue Fixation; United States
PubMed: 31613330
DOI: 10.1093/ajcp/aqz141 -
American Journal of Orthodontics and... Oct 2011Proper sample size estimation is an important part of clinical trial methodology and closely related to the precision and power of the trial's results. Trials with... (Review)
Review
Proper sample size estimation is an important part of clinical trial methodology and closely related to the precision and power of the trial's results. Trials with sufficient sample sizes are scientifically and ethically justified and more credible compared with trials with insufficient sizes. Planning clinical trials with inadequate sample sizes might be considered as a waste of time and resources, as well as unethical, since patients might be enrolled in a study in which the expected results will not be trusted and are unlikely to have an impact on clinical practice. Because of the low emphasis of sample size calculation in clinical trials in orthodontics, it is the objective of this article to introduce the orthodontic clinician to the importance and the general principles of sample size calculations for randomized controlled trials to serve as guidance for study designs and as a tool for quality assessment when reviewing published clinical trials in our specialty. Examples of calculations are shown for 2-arm parallel trials applicable to orthodontics. The working examples are analyzed, and the implications of design or inherent complexities in each category are discussed.
Topics: Clinical Trials as Topic; Humans; Nomograms; Orthodontics; Randomized Controlled Trials as Topic; Reproducibility of Results; Research Design; Sample Size; Treatment Outcome
PubMed: 21967951
DOI: 10.1016/j.ajodo.2011.04.021 -
Advances in Experimental Medicine and... 2010Whenever possible, standard methodological approaches should be applied in the design and analysis of a clinical trial that warrant adequate informative value. However,... (Review)
Review
Whenever possible, standard methodological approaches should be applied in the design and analysis of a clinical trial that warrant adequate informative value. However, there are circumstances when the number of experimental subjects is unavoidably small. In such circumstances it is justified to consider abandoning standard statistical methodology in place of alternative approaches. Performing a small clinical trial however it should be pointed out, that a such trial can never be as meaningful and provide as much evidence as a larger trial. In the present text, basic concepts are presented, that apply to small clinical trials in general. Moreover, several specific methodological approaches are presented, that either enhance the efficiency of standard statistical procedures or evolve from the idea of abandoning classical paradigms in the design and analysis of clinical trials. Within the scope of the former approach, (Bayesian) adaptive randomisation, group sequential (adaptive) designs, repeated measurement designs for longitudinal data, and meta-analyses are illustrated and discussed. The latter approach comprises alternative strategies such as (non-randomised) risk-based allocation designs, statistical prediction designs, ranking and selection designs, as well as the application of Bayesian statistics.
Topics: Bayes Theorem; Biostatistics; Clinical Trials as Topic; Controlled Clinical Trials as Topic; False Positive Reactions; Humans; Meta-Analysis as Topic; Models, Statistical; Random Allocation; Randomized Controlled Trials as Topic; Rare Diseases; Reproducibility of Results
PubMed: 20824446
DOI: 10.1007/978-90-481-9485-8_11 -
Current Opinion in Oncology Sep 2018We aimed to summarize the recent reflections and collaborative initiatives pertaining to the definition of more appropriate eligibility criteria in cancer clinical... (Review)
Review
PURPOSE OF REVIEW
We aimed to summarize the recent reflections and collaborative initiatives pertaining to the definition of more appropriate eligibility criteria in cancer clinical trials.
RECENT FINDINGS
There is an intrinsic tension between two opposite purposes when it comes to defining eligibility criteria: on the one hand, participants must be protected, and on the other, the study population must be defined as accurately as possible. However, stringent eligibility criteria jeopardize the feasibility of trials, and, consequently, the generalizability of trial results. Therefore, interdisciplinary working groups under the auspices of the American Society of Clinical Oncology and Friends of Cancer Research propose to adapt/relax some of the classical eligibility criteria.
SUMMARY
In-depth reflection of the existing eligibility criteria, and implementation of recent recommendations are needed.
Topics: Clinical Trials as Topic; Humans; Neoplasms; Patient Selection
PubMed: 30020120
DOI: 10.1097/CCO.0000000000000470