scholarly journals Reasons for Failed trials of Disease-modifying Treatments for Alzheimer Disease and their Contribution in Recent Research

2019 ◽  
Author(s):  
Konstantina G. Yiannopoulou ◽  
Aikaterini I. Anastasiou ◽  
Venetia Zachariou ◽  
SH Pelidou
Keyword(s):  
Clinical Trial ◽  
Clinical Trials ◽  
Alzheimer Disease ◽  
Drug Development ◽  
Inappropriate Drug ◽  
Trial Methodology ◽  
Prodromal Ad ◽  
Csf Biomarker ◽  
Disease Modifying ◽  
Drug Development Research

Despite all scientific efforts and many protracted and expensive clinical trials, no new drug has been approved by FDA for treatment of Alzheimer disease (AD) since 2003. Indeed, more than 200 investigational programs have failed or have been abandoned in the last decade. The most probable explanations for failures of disease-modifying treatments (DMTs) for AD may include late initiation of treatments during the course of AD development, inappropriate drug dosages, erroneous selection of treatment targets, and mainly an inadequate understanding of the complex pathophysiology of AD, which may necessitate combination treatments rather than monotherapy. Clinical trials’ methodological issues have also been criticized. Current drug-development research for AD is aimed to overcome these drawbacks. Preclinical and prodromal AD populations, as well as traditionally investigated populations representing all the clinical stages of AD, are included in recent trials. Systematic use of biomarkers in staging preclinical and prodromal AD and of a single primary outcome in trials of prodromal AD are regularly integrated. The application of amyloid, tau, and neurodegeneration biomarkers, including new biomarkers—such as Tau positron emission tomography, neurofilament light chain (blood and CSF biomarker of axonal degeneration) and neurogranin (CSF biomarker of synaptic functioning)—to clinical trials allows more precise staging of AD. Additionally, use of the Bayesian statistics, modifiable clinical trial designs, and clinical trial simulators enrich the trial methodology. Besides, combination therapy regimens are currently assessed in clinical trials. The abovementioned diagnostic and statistical advances, which have been recently integrated in clinical trials, are consequential to the recent failures of studies of disease-modifying treatments. Their experiential rather than theoretical origins may better equip potentially successful drug-development strategies.

scholarly journals Reasons for Failed Trials of Disease-Modifying Treatments for Alzheimer Disease and Their Contribution in Recent Research

Biomedicines ◽  
2019 ◽  
Vol 7 (4) ◽  
pp. 97 ◽  
Author(s):  
Konstantina G. Yiannopoulou ◽  
Aikaterini I. Anastasiou ◽  
Venetia Zachariou ◽  
Sygkliti-Henrietta Pelidou
Keyword(s):  
Clinical Trial ◽  
Clinical Trials ◽  
Alzheimer Disease ◽  
Drug Development ◽  
Inappropriate Drug ◽  
Trial Methodology ◽  
Prodromal Ad ◽  
Csf Biomarker ◽  
Disease Modifying ◽  
Drug Development Research

Despite all scientific efforts and many protracted and expensive clinical trials, no new drug has been approved by FDA for treatment of Alzheimer disease (AD) since 2003. Indeed, more than 200 investigational programs have failed or have been abandoned in the last decade. The most probable explanations for failures of disease-modifying treatments (DMTs) for AD may include late initiation of treatments during the course of AD development, inappropriate drug dosages, erroneous selection of treatment targets, and mainly an inadequate understanding of the complex pathophysiology of AD, which may necessitate combination treatments rather than monotherapy. Clinical trials’ methodological issues have also been criticized. Drug-development research for AD is aimed to overcome these drawbacks. Preclinical and prodromal AD populations, as well as traditionally investigated populations representing all the clinical stages of AD, are included in recent trials. Systematic use of biomarkers in staging preclinical and prodromal AD and of a single primary outcome in trials of prodromal AD are regularly integrated. The application of amyloid, tau, and neurodegeneration biomarkers, including new biomarkers—such as Tau positron emission tomography, neurofilament light chain (blood and Cerebrospinal fluid (CSF) biomarker of axonal degeneration) and neurogranin (CSF biomarker of synaptic functioning)—to clinical trials allows more precise staging of AD. Additionally, use of Bayesian statistics, modifiable clinical trial designs, and clinical trial simulators enrich the trial methodology. Besides, combination therapy regimens are assessed in clinical trials. The above-mentioned diagnostic and statistical advances, which have been recently integrated in clinical trials, are relevant to the recent failures of studies of disease-modifying treatments. Their experiential rather than theoretical origins may better equip potentially successful drug-development strategies.

Current Advances in Clinical Trials for Rare Disease Populations: Spotlight on the Patient

2021 ◽  
Vol 16 ◽  
Author(s):  
Erica Winter ◽  
Scott Schliebner
Keyword(s):  
Clinical Trial ◽  
Clinical Trials ◽  
Drug Development ◽  
Rare Disease ◽  
Rare Diseases ◽  
Statistical Analyses ◽  
Clinical Trial Designs ◽  
Novel Approaches

: Characterized by small, highly heterogeneous patient populations, rare disease trials magnify the challenges often encountered in traditional clinical trials. In recent years, there have been increased efforts by stakeholders to improve drug development in rare diseases through novel approaches to clinical trial designs and statistical analyses. We highlight and discuss some of the current and emerging approaches aimed at overcoming challenges in rare disease clinical trials, with a focus on the ultimate stakeholder, the patient.

scholarly journals Preclinical Alzheimer Disease Drug Development: Early Considerations Based on Phase 3 Clinical Trials

2020 ◽  
Vol 26 (7) ◽  
pp. 888-900
Author(s):  
Anna Hung ◽  
Monika Schneider ◽  
Marianne Hamilton Lopez ◽  
Mark McClellan
Keyword(s):  
Clinical Trials ◽  
Alzheimer Disease ◽  
Drug Development ◽  
Phase 3

scholarly journals DIAN-TU ARGENTINA

2021 ◽  
Vol 2 (1) ◽  
pp. e00173805
Author(s):  
Patricio Chrem-Mendez ◽  
Pablo Bagnati
Keyword(s):  
Clinical Trials ◽  
Risk Factor ◽  
Alzheimer Disease ◽  
Neurodegenerative Disease ◽  
New Disease ◽  
Main Risk Factor ◽  
Classical Form ◽  
Novel Therapeutics ◽  
Disease Modifying ◽  
Global Aging

Alzheimer’s disease is, by far the first, cause of dementia and the more frequent neurodegenerative disease. Considered as a result of multifactorial causes, aging is the main risk factor for the classical form of the disease and because of global aging, a very significant increase in the prevalence is expected in the upcoming decades, especially in countries in development. Several drugs with different targets have been tried so far and, still with no success. Frenzied efforts seeking a new disease-modifying drug are constantly being pursued and innovative models of the clinical trials have emerged. The DIAN initiative studies individuals with known mutations in the deterministic genes of the disease. Autosomal Dominantly Alzheimer Disease (ADAD) showed to be a more predictable model in terms of whom and when will get the disease. This allows testing novel therapeutics agents by choosing the drug according to the biological moment of the disease. But ADAD is also a uniquely human story full of courage and hope. The DIAN trial has started in Argentina and a new anti-tau age has begun as well.

Accelerating clinical trial enrollment with comprehensive genomic profiling (CGP) and just-in-time clinical trial sites: An index case of a paradigm shift.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 6539-6539
Author(s):  
Gaurav Singal ◽  
Deepu Madduri ◽  
Lara Yuan ◽  
David Luo ◽  
Aparna Upadhyay ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Clinical Trials ◽  
Drug Development ◽  
Therapeutic Option ◽  
Just In Time ◽  
Trial Participation ◽  
Community Settings ◽  
Patient Identification ◽  
Access Methods ◽  
Comprehensive Genomic Profiling

6539 Background: In many instances, trials may offer the best or only therapeutic option for patients with rare findings. However, conducting clinical trials of novel therapeutics targeting rare molecular variants is challenging. Patient populations are small, distributed, and predominantly in community settings where trial access remains limited by awareness and site availability. These challenges increase costs of drug development and approval, delaying widespread patient access. Methods: Foundation Medicine deployed a trial education and access program, “Precision Enrollment,” with Ignyta (a trial sponsor) and Pharmatech (a site management organization, or SMO, enabling “Just-In-Time” clinical trials) (Wiener, JCO 2007). Infrastructure and algorithms developed at Foundation Medicine (“SmartTrials Engine”) matched sequenced patients (avg n = 800/wk) with activating NTRK, ROS1, or ALK fusions to the phase II study of Entrectinib (NCT02568267). Oncologists at Foundation Medicine, through peer-to-peer outreach, facilitated trial access by providing trial and nearest site information to treating providers of matched patients. Results: 107 treatment-eligible patients with NTRK, ROS1, or ALK fusions were matched by the SmartTrials Engine; 36 (33%) expressed interest in trial participation. One such patient with NSCLC and a CD74-ROS1 fusion was unable to participate at an open trial site due to inability to travel. The patient’s site was part of the “Just-In-Time” network, with IRB and contract pre-approval, and was activated in only 3 days. Total time from patient identification to initiation of therapy was 7 days. Conclusions: We demonstrate a novel methodology for patient matching to trials targeting rare genomic findings, including in community settings. If extended, such innovative partnerships combined with computational matching infrastructure, could improve drug development and therapeutic access.

Global drug development in cancer: A cross-sectional study of clinical trial registries

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 2520-2520
Author(s):  
P. Hertz ◽  
B. Seruga ◽  
L. W. Le ◽  
I. F. Tannock
Keyword(s):  
Clinical Trial ◽  
Clinical Trials ◽  
Drug Development ◽  
Phase Ii ◽  
New Drugs ◽  
Phase Iii ◽  
Cancer Site ◽  
Cancer Type ◽  
Clinical Trial Registries ◽  
Global Drug Development

2520 Background: Clinical trials are increasingly funded by industry. High costs of drug development may lead to attempts to develop new drugs in more ‘profitable’ (i.e., more prevalent) as compared to ‘less profitable’ (i.e., more deadly) cancers. Here we determine the focus of current global drug development. Methods: We determined characteristics of phase II and III clinical trials evaluating new drugs in oncology, which were registered with WHO International Clinical Trial Registries between 01/2008 and 06/2008. Estimates of incidence, mortality, and prevalence in the more- and less-developed world (MDW, LDW) were obtained from GLOBOCAN 2002. Simple correlation analysis was performed between the number of clinical trials and incidence, mortality and prevalence per cancer site after log transformation of variables. Results: We identified 399 newly registered trials. Of 374 trials with information about recruitment, 322 (86.1%) and 39 (10.4%) recruited patients only from the MDW and LDW, respectively, while 13 (3.5%) had worldwide recruitment. 229 (58%) of trials were sponsored by industry and 324 trials were phase II (81%). Most trials (and most phase III trials) evaluated treatments for globally prevalent cancers: breast, lung, prostate, and colorectal cancer (Table). Prevalence of a particular cancer type in both the MDW and LDW correlated significantly with the number of clinical trials (Pearson r = 0.63 and 0.55; p = 0.01 and 0.03, respectively). In contrast, mortality in the MDW (Pearson r = 0.73; p= 0.002), but not in the LDW (Pearson r = 0.38; p= 0.17), correlated significantly with the number of clinical trials. Conclusions: Global drug development in cancer predominates in globally prevalent cancers, which are a more important cause of mortality in the MDW than in the LDW. Cancer sites that are major killers globally, and especially in the LDW (e.g., stomach, liver, and esophageal cancer) should receive priority for clinical research. [Table: see text] No significant financial relationships to disclose.

scholarly journals Clinical trials in the Coronavirus era: management of risks

2020 ◽  
pp. 18-24
Author(s):  
Aleksey Vodovozov ◽  
Keyword(s):  
Risk Assessment ◽  
Clinical Trial ◽  
Decision Making ◽  
Clinical Trials ◽  
Trial Methodology ◽  
Ministry Of Health ◽  
Trial Team ◽  
Clinical Trial Methodology ◽  
Regulatory Authorities ◽  
The World

The COVID-19 pandemic has caused unique problems facing the clinical trials (CT) community both in terms of the rapid implementation of CTs of COVID-19 drugs and vaccines, and many ongoing non-COVID-19 CTs that are either suspended or adapted to new realities. The CT organizers have played a key role in decision making, risk assessment and adaptation of trial processes, working side by side with other members of the trial team. Regulatory authorities (FDA, EMA, Ministry of Health of Russia, etc.), which issued initial recommendations for adapting the clinical trial methodology to new conditions as far back as March 2020, and then later on, generalized the experience in the management for clinical trials. The recommendations made based on the reviewed experience can help all CT parties to cope with the risks associated with both COVID-19 itself and anti-epidemic measures in different countries of the world with minimal losses.

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