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 Tackling rare diseases: Clinical trials on chips

2020 ◽  
Vol 245 (13) ◽  
pp. 1155-1162 ◽  
Author(s):  
Sandra H Blumenrath ◽  
Bo Y Lee ◽  
Lucie Low ◽  
Ranjini Prithviraj ◽  
Danilo Tagle
Keyword(s):  
Clinical Trial ◽  
Clinical Trials ◽  
Data Collection ◽  
Rare Disease ◽  
Study Design ◽  
Rare Diseases ◽  
Working Group ◽  
Design Data ◽  
Chip Technology ◽  
Microphysiological Systems

Technological advances with organs-on-chips and induced pluripotent stem cells promise to overcome hurdles associated with developing medical products, especially for rare diseases. Organs-on-chips—bioengineered “microphysiological systems” that mimic human tissue and organ functionality—may overcome clinical trial challenges with real-world patients by offering ways to conduct “clinical trials-on-chips” (CToCs) to inform the design and implementation of rare disease clinical studies in ways not possible with other culture systems. If applied properly, CToCs can substantially impact clinical trial design with regard to anticipated key outcomes, assessment of clinical benefit and risk, safety and tolerability profiles, population stratification, value and efficiency, and scalability. To discuss how tissue chips are best used to move the development of rare disease therapies forward, a working group of experts from industry, academia, and FDA as well as patient representatives addressed questions related to disease setting, test agents for microphysiological systems, study design and feasibility, data collection and use, the benefits and risks associated with this approach, and how to engage stakeholders. While rare diseases with no current therapies were considered the ultimate target, participants cautioned against stepping onto too many unknown territories when using rare disease as initial test beds. Among the disease categories considered ideal for initial CToC tests were well-defined diseases with known clinical outcomes; diseases where tissues on chips can serve as an alternative to risky first-in-human studies, such as in pediatric oncology; and diseases that lend itself to immuno-engineering or genome editing. Participants also considered important challenges, such as hosting the chip technology in-house, the high variability of cell batches and the resulting regulatory concerns, as well as the financial risk associated with the new technology. To make progress in this area and increase confidence with the use of tissue chips, the re-purposing of approved drugs ought to be the very first step. Impact statement Designing and conducting clinical trials are extremely difficult in rare diseases. Adapting tissue chips for rare disease therapy development is pivotal in assuring that treatments are available, especially for severe diseases that are difficult to treat. Thus far, the NCATS-led National Institutes of Health (NIH) Tissue Chip program has focused on deploying the technology towards in vitro tools for safety and efficacy assessments of therapeutics. However, exploring the feasibility and best possible approach to expanding this focus towards the development phase of therapeutics is critical to moving the field of CToCs forward and increasing confidence with the use of tissue chips. The working group of stakeholders and experts convened by NCATS and the Drug Information Association (DIA) addresses important questions related to disease setting, test agents, study design, data collection, benefit/risk, and stakeholder engagement—exploring both current and future best use cases and important prerequisites for progress in this area.

Challenges in Evaluating Safety and Efficacy in Drug Development for Rare Diseases: A Review for Pharmacists

2020 ◽  
pp. 089719002093097
Author(s):  
Kanya K. Shah ◽  
Stephen Kogut ◽  
Angela Slitt
Keyword(s):  
Clinical Trials ◽  
Drug Development ◽  
Rare Disease ◽  
Rare Diseases ◽  
The United States ◽  
Priority Review ◽  
Pharmaceutical Companies ◽  
Federal Programs ◽  
Financial Barriers ◽  
Safety And Efficacy

A rare disease, or orphan disease, in the United States is a condition with a national prevalence of fewer than 200,000 diagnoses. As therapies for rare diseases are developed and brought to market, pharmacists should understand the challenges of drug development for rare diseases and aid in educating patients about the approval process for rare disease therapies. Developing drugs for treating rare diseases presents unique challenges in proving the drug’s safety and efficacy with adequate study design, power, and validity. Results of the clinical trials for rare diseases may be weakened by small patient populations, limited disease information, and difficulty defining end points and biomarkers. In addition to investigational barriers, pharmaceutical companies face financial barriers in justifying the investment of bringing a rare disease therapy to market. Federal programs, such as the Orphan Drug Act of 1983, expedited review, the Rare Pediatric Disease Priority Review Vouchers (RPD PRV) program, and the 21st Century Cures Act, give pharmaceutical companies motivation to develop therapies for rare diseases. The objective of this article is to provide pharmacists with an understanding of the challenges in designing clinical trials for drugs for rare diseases and discuss federal programs that address efforts to develop safe and efficacious drugs for rare diseases.

scholarly journals Trends of Clinical Trials for Drug Development in Rare Diseases

2018 ◽  
Vol 13 (3) ◽  
pp. 199-208
Author(s):  
Ryuichi Sakate ◽  
Akiko Fukagawa ◽  
Yuri Takagaki ◽  
Hanayuki Okura ◽  
Akifumi Matsuyama
Keyword(s):  
Clinical Trials ◽  
Drug Development ◽  
Rare Diseases

A novel, hybrid, single- and multi-site clinical trial design for CLN3 disease, an ultra-rare lysosomal storage disorder

2019 ◽  
Vol 16 (5) ◽  
pp. 555-560 ◽  
Author(s):  
Heather R Adams ◽  
Sara Defendorf ◽  
Amy Vierhile ◽  
Jonathan W Mink ◽  
Frederick J Marshall ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Clinical Trials ◽  
Rare Diseases ◽  
Trial Design ◽  
Neurodegenerative Disorder ◽  
Clinical Trial Design ◽  
Trial Participation ◽  
Local Participation ◽  
Cln3 Disease ◽  
Study Participants

Background Travel burden often substantially limits the ability of individuals to participate in clinical trials. Wide geographic dispersion of individuals with rare diseases poses an additional key challenge in the conduct of clinical trials for rare diseases. Novel technologies and methods can improve access to research by connecting participants in their homes and local communities to a distant research site. For clinical trials, however, understanding of factors important for transition from traditional multi-center trial models to local participation models is limited. We sought to test a novel, hybrid, single- and multi-site clinical trial design in the context of a trial for Juvenile Neuronal Ceroid Lipofuscinosis (CLN3 disease), a very rare pediatric neurodegenerative disorder. Methods We created a “hub and spoke” model for implementing a 22-week crossover clinical trial of mycophenolate compared with placebo, with two 8-week study arms. A single central site, the “hub,” conducted screening, consent, drug dispensing, and tolerability and efficacy assessments. Each participant identified a clinician to serve as a collaborating “spoke” site to perform local safety monitoring. Study participants traveled to the hub at the beginning and end of each study arm, and to their individual spoke site in the intervening weeks. Results A total of 18 spoke sites were established for 19 enrolled study participants. One potential participant was unable to identify a collaborating local site and was thus unable to participate. Study start-up required a median 6.7 months (interquartile range = 4.6–9.2 months). Only 33.3% (n = 6 of 18) of spoke site investigators had prior clinical trial experience, thus close collaboration with respect to study startup, training, and oversight was an important requirement. All but one participant completed all study visits; no study visits were missed due to travel requirements. Conclusions This study represents a step toward local trial participation for patients with rare diseases. Even in the context of close oversight, local participation models may be best suited for studies of compounds with well-understood side-effect profiles, for those with straightforward modes of administration, or for studies requiring extended follow-up periods.

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.

Highly efficient clinical trial designs for reliable screening of under-performing treatments: Application to the COVID-19 Pandemic

2020 ◽  
Vol 17 (5) ◽  
pp. 483-490
Author(s):  
Steven Piantadosi
Keyword(s):  
Clinical Trial ◽  
Clinical Trials ◽  
Sample Size ◽  
Trial Design ◽  
Ranking And Selection ◽  
Design Elements ◽  
Highly Efficient ◽  
Clinical Trial Designs ◽  
Under Performing ◽  
The Many

Background: The COVID-19 pandemic presents challenges for clinical trials including urgency, disrupted infrastructure, numerous therapeutic candidates, and the need for highly efficient trial and development designs. This paper presents design components and rationale for constructing highly efficient trials to screen potential COVID-19 treatments. Methods: Key trial design elements useful in this circumstance include futility hypotheses, treatment pooling, reciprocal controls, ranking and selection, and platform administration. Assuming most of the many candidates for COVID-19 treatment are likely to be ineffective, these components can be combined to facilitate very efficient comparisons of treatments. Results: Simulations indicate such designs can reliably discard underperforming treatments using sample size to treatment ratios under 30. Conclusions: Methods to create very efficient clinical trial comparisons of treatments for COVID-19 are available. Such designs might be helpful in the pandemic and should be considered for similar needs in the future.

scholarly journals Novel Clinical Trial Designs to Improve the Efficiency of Research

2020 ◽  
Vol 132 (1) ◽  
pp. 69-81 ◽  
Author(s):  
Daniel I. Sessler ◽  
Paul S. Myles
Keyword(s):  
Clinical Trial ◽  
Clinical Trials ◽  
Real Time ◽  
Randomized Trials ◽  
Clinical Evidence ◽  
Adaptive Designs ◽  
Large Numbers ◽  
Clinical Trial Designs ◽  
Study Sites ◽  
Trial Efficiency

Abstract SUMMARY Large randomized trials provide the highest level of clinical evidence. However, enrolling large numbers of randomized patients across numerous study sites is expensive and often takes years. There will never be enough conventional clinical trials to address the important questions in medicine. Efficient alternatives to conventional randomized trials that preserve protections against bias and confounding are thus of considerable interest. A common feature of novel trial designs is that they are pragmatic and facilitate enrollment of large numbers of patients at modest cost. This article presents trial designs including cluster designs, real-time automated enrollment, and practitioner-preference approaches. Then various adaptive designs that improve trial efficiency are presented. And finally, the article discusses the advantages of embedding randomized trials within registries.

Patients Driving the Clinical Trial Designs – Democracy in Clinical Research

2019 ◽  
Vol 14 (4) ◽  
pp. 237-246
Author(s):  
Payal Bhardwaj ◽  
Jeba Kumar ◽  
Raj Kumar Yadav
Keyword(s):  
Clinical Trial ◽  
Clinical Trials ◽  
Clinical Research ◽  
Retention Rate ◽  
Patient Centered ◽  
Regulatory Review ◽  
Patient Organizations ◽  
Patient Reported ◽  
Clinical Trial Designs ◽  
The Right

Background: Many of the clinical trials remain inefficient owing to the low retention rate, and an impact on the power of the study. In addition, regulatory bodies recommend including the patients’ experience, especially, patient-reported outcomes, while making clinical decisions, and approvals. Introduction: Patient centricity has reached the stage where patients are both willing and required to participate in clinical trial designs, regulatory review and experts on other panels. Efforts are being made in the right direction and there are multiple aspects that have been or are being addressed. Objective: The current article focuses on how to include patients in clinical trial designs, the benefits, challenges, and solutions. This means patients who were merely the participants until now, they will be the drivers of trials now, and hence the clinical trials will be more efficient and productive. Key Findings: There is a drive to enhance patients’ participation in clinical trial designs, especially, visits, efficacy outcomes and their expectations with the treatment. Patients want to remain informed, right from before participation to the completion of the trial. Patients are now an important part of regulatory review, as apparent from recent initiatives by the FDA and EMA. This will enhance patients’ awareness, and bring ownership and transparency. Various patient organizations, advocacy groups have made some great suggestions and taken initiatives in this direction. Clinical Trials Transformation Initiative, European Patient’s Academy on Therapeutic Innovation, and Patient- Centered Outcomes Research Institute are a few key initiatives. However, there is a set of challenges emanating from the complexity of trials, associated with unique mechanism of action of drugs, their efficacy and safety profiles, which has to be dealt with properly. Conclusion: Overall, the pharma domain is at the verge of putting the patient in the spotlight, to achieve a near-real democracy, where the clinical research is the by the patient, for the patient, and, of the patient.

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