Adaptive dose‐response studies to establish proof‐of‐concept in learning‐phase clinical trials

The clinical failure rate for disease-modifying treatments (DMTs) that slow or stop disease progression has been nearly 100% for the major neurodegenerative disorders (NDDs), with many compounds failing in expensive and time-consuming phase 2 and 3 trials for lack of efficacy. Here, we critically review the use of pharmacological and mechanistic biomarkers in early phase clinical trials of DMTs in NDDs, and propose a roadmap for providing early proof-of-concept to increase R&D productivity in this field of high unmet medical need. A literature search was performed on published early phase clinical trials aimed at the evaluation of NDD DMT compounds using MESH terms in PubMed. Publications were selected that reported an early phase clinical trial with NDD DMT compounds between 2010 and November 2020. Attention was given to the reported use of pharmacodynamic (mechanistic and physiological response) biomarkers. A total of 121 early phase clinical trials were identified, of which 89 trials (74%) incorporated one or multiple pharmacodynamic biomarkers. However, only 65 trials (54%) used mechanistic (target occupancy or activation) biomarkers to demonstrate target engagement in humans. The most important categories of early phase mechanistic and response biomarkers are discussed and a roadmap for incorporation of a robust biomarker strategy for early phase NDD DMT clinical trials is proposed. As our understanding of NDDs is improving, there is a rise in potentially disease-modifying treatments being brought to the clinic. Further increasing the rational use of mechanistic biomarkers in early phase trials for these (targeted) therapies can increase R&D productivity with a quick win/fast fail approach in an area that has seen a nearly 100% failure rate to date.

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Optimizing Cancer Clinical Trials Research Investment Decisions In The United States: A Proof Of Concept Portfolio Management Evaluation

Value in Health ◽

10.1016/j.jval.2015.03.055 ◽

2015 ◽

Vol 18 (3) ◽

pp. A8

Author(s):

C.S. Bennette ◽

J.A. Roth ◽

A. Basu ◽

J.J. Carlson ◽

S. Ramsey ◽

...

Keyword(s):

United States ◽

Clinical Trials ◽

Portfolio Management ◽

Investment Decisions ◽

The United States ◽

Cancer Clinical Trials ◽

Proof Of Concept ◽

Management Evaluation ◽

Research Investment

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Hemophilia gene therapy: ushering in a new treatment paradigm?

Hematology ◽

10.1182/hematology.2021000254 ◽

2021 ◽

Vol 2021 (1) ◽

pp. 226-233

Author(s):

Lindsey A. George

Keyword(s):

Clinical Trial ◽

Gene Therapy ◽

Clinical Trials ◽

Hemophilia A ◽

Full Potential ◽

Proof Of Concept ◽

Aav Vector ◽

Treatment Paradigm ◽

Clinical Trial Enrollment ◽

New Treatment

Abstract After 3 decades of clinical trials, repeated proof-of-concept success has now been demonstrated in hemophilia A and B gene therapy. Current clinical hemophilia gene therapy efforts are largely focused on the use of systemically administered recombinant adeno-associated viral (rAAV) vectors for F8 or F9 gene addition. With multiple ongoing trials, including licensing studies in hemophilia A and B, many are cautiously optimistic that the first AAV vectors will obtain regulatory approval within approximately 1 year. While supported optimism suggests that the goal of gene therapy to alter the paradigm of hemophilia care may soon be realized, a number of outstanding questions have emerged from clinical trial that are in need of answers to harness the full potential of gene therapy for hemophilia patients. This article reviews the use of AAV vector gene addition approaches for hemophilia A and B, focusing specifically on information to review in the process of obtaining informed consent for hemophilia patients prior to clinical trial enrollment or administering a licensed AAV vector.

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Blood Pressure Effects of Sodium Reduction

Circulation ◽

10.1161/circulationaha.120.050371 ◽

2021 ◽

Vol 143 (16) ◽

pp. 1542-1567 ◽

Cited By ~ 2

Author(s):

Tommaso Filippini ◽

Marcella Malavolti ◽

Paul K. Whelton ◽

Androniki Naska ◽

Nicola Orsini ◽

...

Keyword(s):

Blood Pressure ◽

Clinical Trials ◽

Linear Relationship ◽

Dose Response ◽

Sodium Intake ◽

Experimental Studies ◽

Dietary Sodium ◽

Response Analysis ◽

Sodium Reduction

Background: The relationship between dietary sodium intake and blood pressure (BP) has been tested in clinical trials and nonexperimental human studies, indicating a direct association. The exact shape of the dose–response relationship has been difficult to assess in clinical trials because of the lack of random-effects dose–response statistical models that can include 2-arm comparisons. Methods: After performing a comprehensive literature search for experimental studies that investigated the BP effects of changes in dietary sodium intake, we conducted a dose–response meta-analysis using the new 1-stage cubic spline mixed-effects model. We included trials with at least 4 weeks of follow-up; 24-hour urinary sodium excretion measurements; sodium manipulation through dietary change or supplementation, or both; and measurements of systolic and diastolic BP at the beginning and end of treatment. Results: We identified 85 eligible trials with sodium intake ranging from 0.4 to 7.6 g/d and follow-up from 4 weeks to 36 months. The trials were conducted in participants with hypertension (n=65), without hypertension (n=11), or a combination (n=9). Overall, the pooled data were compatible with an approximately linear relationship between achieved sodium intake and mean systolic as well as diastolic BP, with no indication of a flattening of the curve at either the lowest or highest levels of sodium exposure. Results were similar for participants with or without hypertension, but the former group showed a steeper decrease in BP after sodium reduction. Intervention duration (≥12 weeks versus 4 to 11 weeks), type of study design (parallel or crossover), use of antihypertensive medication, and participants’ sex had little influence on the BP effects of sodium reduction. Additional analyses based on the BP effect of difference in sodium exposure between study arms at the end of the trial confirmed the results on the basis of achieved sodium intake. Conclusions: In this dose–response analysis of sodium reduction in clinical trials, we identified an approximately linear relationship between sodium intake and reduction in both systolic and diastolic BP across the entire range of dietary sodium exposure. Although this occurred independently of baseline BP, the effect of sodium reduction on level of BP was more pronounced in participants with a higher BP level.

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Web Based Data Capture for Clinical Research

10.28945/3201 ◽

2008 ◽

Author(s):

Stephen Smith ◽

Samuel Sambasivam

Keyword(s):

Clinical Trials ◽

Clinical Research ◽

Medical Device ◽

Rapid Development ◽

Research Data ◽

Data Capture ◽

Electronic Data Capture ◽

Proof Of Concept ◽

Web Based ◽

Tools And Techniques

Electronic Data Capture (EDC) is increasingly being used in the pharmaceutical, biotech and medical device industries to gather research data worldwide from doctors, hospitals and universities participating in clinical trials. In this highly regulated environment, all systems and software must be thoroughly tested and validated, a task that is burdensome in terms of time and cost. Starting with database structures that are designed to be copied easily, this paper proposes a simple framework that allows for rapid development and minimal testing. The framework includes tools for building modules, for copying modules from one trial to the next, and tools to validate that the modules are the same as modules that have been fully tested previously. A proof-of-concept prototype has been built to demonstrate certain tools and techniques that can be used when designing and building a simplified EDC interface.

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