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Contemporary Clinical Trials Sep 2020Theranostics in drug development is an evolving framework, known as combining 'thera' (a therapeutic drug) with 'nostics' (a diagnostic imaging drug) and with the latter...
Theranostics in drug development is an evolving framework, known as combining 'thera' (a therapeutic drug) with 'nostics' (a diagnostic imaging drug) and with the latter being mostly used to select patient for evaluation of safety and efficacy of an investigational therapeutics. However, when a diagnostic imaging drug is still investigational, patient selection performance of a nostics imaging has not been demonstrated. Clinical trials conducted to assess the effect of an investigational therapeutics in a theranostics setting may focus only on the therapeutics development and not necessarily require definitive truth standard or reference standard to also assess patient selection performance of an investigational diagnostic imaging drug. We propose an In-Parallel with Leveraging development pathway in view of current practice of theranostics for a nostics imaging development. We rationalize minimum statistical metrics necessary for patient selection to allow for rigors of a nostics or diagnostics imaging drug development. We highlight tangible benefits with newer design considerations. We articulate potential indications of a nostics development including prognostic, predictive and treatment response monitoring in addition to patient selection. We further articulate potential additional clinical utilities of risk stratification and clinical management. To take full advantage and the likely payoff in the benefit of leveraging, a group sequential design or an adaptive design for the therapeutic trial is highly encouraged.
Topics: Clinical Trials as Topic; Drugs, Investigational; Humans; Patient Selection; Prognosis; Research Design
PubMed: 32768681
DOI: 10.1016/j.cct.2020.106100 -
AJR. American Journal of Roentgenology Dec 1978
Clinical Trial
Topics: Clinical Trials as Topic; Contrast Media; Digestive System; Endoscopy; Humans; Radiography
PubMed: 104591
DOI: 10.2214/ajr.131.6.1116-a -
Minerva Cardioangiologica Aug 2009Ultrasound contrast agents, used with contrast-specific imaging techniques, have an established role for diagnostic cardiovascular imaging in the echocardiography... (Comparative Study)
Comparative Study Review
Ultrasound contrast agents, used with contrast-specific imaging techniques, have an established role for diagnostic cardiovascular imaging in the echocardiography laboratory. The advent of tissue harmonic imaging, albeit a significant advancement in ultrasound technology, still fail to produce diagnostically useful images in a significant proportion of patients. This therefore, often leads to inaccurate assessment of left ventricular function, neccesitating the use of other more laborious and expensive imaging techniques purely for diagnostic purposes. Historically, contrast agents have not been an integral component of the echocardiography imaging laboratory. However the need for a more robust method for the assessment of left ventricular function facilitated the developement of a unique class of contrast agents composed of microbubbles, which together with ultrasound, produce opacification of the left ventricular cavity, thus enabling accurate quantification of its function. The use of these contrast agents have now gone beyond the assessment of wall motion and function to the assessment of myocardial perfusion. Myocardial contrast echocardiography has enabled the assessment of cardiac anatomy, function and perfusion, all in one sitting, by the bedside. Contrast ultrasound imaging has now been applied to even newer techniques such as real-time three-dimensional echocardiography and is also showing promise in the assessment of carotid ultrasound for intima-media thickness. Contrast agents therefore have a significant role in cardiovascular diagnostics and its use can only improve patient care.
Topics: Clinical Trials as Topic; Contraindications; Contrast Media; Coronary Disease; Echocardiography, Stress; Electrocardiography; Humans; Microbubbles; Multicenter Studies as Topic; Phospholipids; Practice Guidelines as Topic; Randomized Controlled Trials as Topic; Sulfur Hexafluoride; Tomography, Emission-Computed, Single-Photon; Ultrasonography; United States; United States Food and Drug Administration; Ventricular Function, Left
PubMed: 19763070
DOI: No ID Found -
BMJ (Clinical Research Ed.) Mar 2002
Topics: Clinical Trials as Topic; Diagnosis, Differential; Evidence-Based Medicine; Humans; Research Design
PubMed: 11872558
DOI: 10.1136/bmj.324.7336.539 -
Hematology/oncology Clinics of North... Aug 2000In designing and analyzing any clinical trial, two issues related to patient heterogeneity must be considered: (1) the effect of chance and (2) the effect of bias. These... (Comparative Study)
Comparative Study Review
In designing and analyzing any clinical trial, two issues related to patient heterogeneity must be considered: (1) the effect of chance and (2) the effect of bias. These issues are addressed by enrolling adequate numbers of patients in the study and using randomization for treatment assignment. An "intention-to-treat" analysis of outcome data includes all individuals randomized and counted in the group to which they are randomized. There is an increased risk of spurious results with a greater number of subgroup analyses, particularly when these analyses are data derived. Factorial designs are sometimes appropriate and can lead to efficiencies by addressing more than one comparison of interventions in a single trial.
Topics: Clinical Trials as Topic; Factor Analysis, Statistical; Humans; Motivation; Patients; Random Allocation; Randomized Controlled Trials as Topic; Research Design; Sampling Studies; Treatment Outcome
PubMed: 10949773
DOI: 10.1016/s0889-8588(05)70311-7 -
Clinical Pharmacology and Therapeutics Nov 2021The rapid evolution of science and technology allows innovative approaches to generate new types of evidence about the effectiveness of medical product development so as... (Review)
Review
The rapid evolution of science and technology allows innovative approaches to generate new types of evidence about the effectiveness of medical product development so as to speed up patients' access to better diagnostics and treatment. Our study explored how two emerging approaches, the use of real-world evidence (RWE) and complex clinical trial (CCT) design, are currently being used by the pharmaceutical industry to support premarketing authorization of medical product development and reviewed the international landscape for regulatory acceptance of such novel approaches. Combining evidence from a literature review, company survey, and interviews with international regulators and experts, we found that 80% of Europe-based pharmaceutical companies have used RWE and 50% have used CCTs, in some capacity. Further, we present case examples of how companies are using these approaches and how international regulators are preparing for such developments. To conclude, we provide a set of recommendations for European industry and regulators to consider so that these novel approaches achieve their full potential within the EU regulatory system.
Topics: Clinical Trials as Topic; Data Analysis; Drug Industry; Europe; Humans
PubMed: 33216976
DOI: 10.1002/cpt.2103 -
JACC. Heart Failure Mar 2019
Topics: Clinical Trials as Topic; Communication; Hope; Humans; Motivation; Patient Advocacy; Patient Participation; Patient Selection; Research Personnel; Treatment Outcome
PubMed: 30819384
DOI: 10.1016/j.jchf.2018.12.003 -
Journal of Dental Research Aug 2010Randomized controlled clinical trials offer the best evidence for changing clinical practice and informing public health policy. Using examples from the literature, this... (Review)
Review
Randomized controlled clinical trials offer the best evidence for changing clinical practice and informing public health policy. Using examples from the literature, this paper reviews clinical trials for those who may be unfamiliar with their design, operation, and interpretation. In the design of a clinical trial, the question to be answered and a clinically meaningful outcome must be clearly defined. Ethics must be considered, sample size carefully estimated, and use of biomarkers and surrogate outcomes understood. Prominent issues in trial implementation include developing a manual of operations, trial registration, subject recruitment and retention, use of a data coordinating center, and data and safety monitoring. Interpretation of clinical trials requires understanding differences between efficacy and effectiveness; superiority, equivalence, and non-inferiority; intent-to-treat; primary and secondary analyses; and limitations of unregistered small clinical trials compared with large multi-center Phase III trials that are more likely to be representative of a population and change clinical practice or public health policy.
Topics: Biomarkers; Clinical Trials as Topic; Data Interpretation, Statistical; Dental Research; Humans; Multicenter Studies as Topic; Research Design; Sample Size; Treatment Outcome
PubMed: 20581353
DOI: 10.1177/0022034510374737 -
Hematology/oncology Clinics of North... Aug 2000This article discusses the problems in basic design, conduct, and interpretation associated with phases I, II, and III of the cancer clinical trials and explains the... (Review)
Review
This article discusses the problems in basic design, conduct, and interpretation associated with phases I, II, and III of the cancer clinical trials and explains the various statistical solutions to these problems. The fundamental problem common to all three trials is achieving a correct and precise answer to the question posed to inform future testing and treatment while protecting trial patients from receiving treatment that has demonstrated excessive toxicity or lack of clinical efficacy. This shared problem gives rise to statistical designs with basic similarities across the three trial types.
Topics: Antineoplastic Agents; Area Under Curve; Bayes Theorem; Biomarkers; Clinical Trials as Topic; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Controlled Clinical Trials as Topic; Dose-Response Relationship, Drug; Endpoint Determination; Forecasting; Guidelines as Topic; Humans; Information Services; Logistic Models; Multicenter Studies as Topic; Neoplasms; Prospective Studies; Random Allocation; Randomized Controlled Trials as Topic; Research Design; Stochastic Processes; Treatment Outcome; United States
PubMed: 10949777
DOI: 10.1016/s0889-8588(05)70315-4 -
Pharmaceutical Statistics 2014It is frequently noted that an initial clinical trial finding was not reproduced in a later trial. This is often met with some surprise. Yet, there is a relatively... (Review)
Review
It is frequently noted that an initial clinical trial finding was not reproduced in a later trial. This is often met with some surprise. Yet, there is a relatively straightforward reason partially responsible for this observation. In this article, we examine this reason by first reviewing some findings in a recent publication in the Journal of the American Medical Association. To help explain the non-negligible chance of failing to reproduce a previous positive finding, we compare a series of trials to successive diagnostic tests used for identifying a condition. To help explain the suspicion that the treatment effect, when observed in a subsequent trial, seems to have decreased in magnitude, we draw a conceptual analogy between phases II-III development stages and interim analyses of a trial with a group sequential design. Both analogies remind us that what we observed in an early trial could be a false positive or a random high. We discuss statistical sources for these occurrences and discuss why it is important for statisticians to take these into consideration when designing and interpreting trial results.
Topics: Clinical Trials as Topic; Empirical Research; Humans; Treatment Outcome
PubMed: 25182453
DOI: 10.1002/pst.1633