scholarly journals The LORIS MyeliNeuroGene rare disease database for natural history studies and clinical trial readiness

2021 ◽  
Vol 16 (1) ◽  
Author(s):  
Aaron Spahr ◽  
Zaliqa Rosli ◽  
Mélanie Legault ◽  
Luan T. Tran ◽  
Simon Fournier ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Natural History ◽  
Rare Disease ◽  
Rare Diseases ◽  
Parental Stress ◽  
The United States ◽  
Historical Control ◽  
Surrogate Markers ◽  
Disease Research ◽  
Natural History Studies

Abstract Background Rare diseases are estimated to affect 150–350 million people worldwide. With advances in next generation sequencing, the number of known disease-causing genes has increased significantly, opening the door for therapy development. Rare disease research has therefore pivoted from gene discovery to the exploration of potential therapies. With impending clinical trials on the horizon, researchers are in urgent need of natural history studies to help them identify surrogate markers, validate outcome measures, define historical control patients, and design therapeutic trials. Results We customized a browser-accessible multi-modal (e.g. genetics, imaging, behavioral, patient-determined outcomes) database to increase cohort sizes, identify surrogate markers, and foster international collaborations. Ninety data entry forms were developed including family, perinatal, developmental history, clinical examinations, diagnostic investigations, neurological evaluations (i.e. spasticity, dystonia, ataxia, etc.), disability measures, parental stress, and quality of life. A customizable clinical letter generator was created to assist in continuity of patient care. Conclusions Small cohorts and underpowered studies are a major challenge for rare disease research. This online, rare disease database will be accessible from all over the world, making it easier to share and disseminate data. We have outlined the methodology to become Title 21 Code of Federal Regulations Part 11 Compliant, which is a requirement to use electronic records as historical controls in clinical trials in the United States. Food and Drug Administration compliant databases will be life-changing for patients and families when historical control data is used for emerging clinical trials. Future work will leverage these tools to delineate the natural history of several rare diseases and we are confident that this database will be used on a larger scale to improve care for patients affected with rare diseases.

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 Spontaneous improvement of carbohydrate-deficient transferrin in PMM2-CDG without mannose observed in CDG natural history study

2021 ◽  
Vol 16 (1) ◽  
Author(s):  
Peter Witters ◽  
Andrew C. Edmondson ◽  
Christina Lam ◽  
Christin Johnsen ◽  
Marc C. Patterson ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Natural History ◽  
Randomized Study ◽  
Short Term ◽  
Double Blind ◽  
Natural History Study ◽  
Natural History Studies ◽  
Carbohydrate Deficient Transferrin ◽  
Spontaneous Improvement

AbstractA recent report on long-term dietary mannose supplementation in phosphomannomutase 2 deficiency (PMM2-CDG) claimed improved glycosylation and called for double-blind randomized study of the dietary supplement in PMM2-CDG patients. A lack of efficacy of short-term mannose supplementation in multiple prior reports challenge this study’s conclusions. Additionally, some CDG types have previously been reported to demonstrate spontaneous improvement in glycosylated biomarkers, including transferrin. We have likewise observed improvements in transferrin glycosylation without mannose supplementation. This observation questions the reliability of transferrin as a therapeutic outcome measure in clinical trials for PMM2-CDG. We are concerned that renewed focus on mannose therapy in PMM2-CDG will detract from clinical trials of more promising therapies. Approaches to increase efficiency of clinical trials and ultimately improve patients’ lives requires prospective natural history studies and identification of reliable biomarkers linked to clinical outcomes in CDG. Collaborations with patients and families are essential to identifying meaningful study outcomes.

scholarly journals The Use of External Controls in FDA Regulatory Decision Making

2021 ◽  
Author(s):  
Mahta Jahanshahi ◽  
Keith Gregg ◽  
Gillian Davis ◽  
Adora Ndu ◽  
Veronica Miller ◽  
...  
Keyword(s):  
Decision Making ◽  
Natural History ◽  
Product Development ◽  
Rare Diseases ◽  
The United States ◽  
External Control ◽  
Common Source ◽  
Published Data ◽  
History Data ◽  
Benefit Risk Assessment

AbstractThe regulatory standards of the United States Food and Drug Administration (FDA) require substantial evidence of effectiveness from adequate and well-controlled trials that typically use a valid comparison to an internal concurrent control. However, when it is not feasible or ethical to use an internal control, particularly in rare disease populations, relying on external controls may be acceptable. To better understand the use of external controls to support product development and approval, we reviewed FDA regulatory approval decisions between 2000 and 2019 for drug and biologic products to identify pivotal studies that leveraged external controls, with a focus on select therapeutic areas. Forty-five approvals were identified where FDA accepted external control data in their benefit/risk assessment; they did so for many reasons including the rare nature of the disease, ethical concerns regarding use of a placebo or no-treatment arm, the seriousness of the condition, and the high unmet medical need. Retrospective natural history data, including retrospective reviews of patient records, was the most common source of external control (44%). Other types of external control were baseline control (33%); published data (11%); and data from a previous clinical study (11%). To gain further insights, a comprehensive evaluation of selected approvals utilizing different types of external control is provided to highlight the variety of approaches used by sponsors and the challenges encountered in supporting product development and FDA decision making; particularly, the value and use of retrospective natural history in the development of products for rare diseases. Education on the use of external controls based on FDA regulatory precedent will allow for continued use and broader application of innovative approaches to clinical trial design, while avoiding delays in product development for rare diseases. Learnings from this review also highlight the need to update regulatory guidance to acknowledge the utility of external controls, particularly retrospective natural history data.

An Imaging Approach to Deep Vein Thrombosis and the Lower Extremity Thrombosis Classification

2012 ◽  
Vol 27 (1_suppl) ◽  
pp. 143-148 ◽  
Author(s):  
C W K P Arnoldussen ◽  
C H A Wittens
Keyword(s):  
Clinical Trials ◽  
Deep Vein Thrombosis ◽  
Natural History ◽  
Lower Extremity ◽  
Systematic Approach ◽  
Vein Thrombosis ◽  
Natural History Studies ◽  
Imaging Approach ◽  
Deep Vein

In this article we want to discuss the potential of lower extremity deep vein thrombosis (DVT) imaging and propose a systematic approach to DVT management based on a DVT classification of the lower extremity; the LET classification. Identifying and reporting DVT more systematically allows for accurate stratification for initial patient care, future clinical trials and appropriate descriptions for natural history studies.

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.

A consensus conference for cognitive endpoints for clinical trials and natural history studies in MPS diseases

2018 ◽  
Vol 123 (2) ◽  
pp. S130
Author(s):  
Elsa G. Shapiro ◽  
Jennifer L. Greenberg ◽  
Mark Dant ◽  
Christine Lavery ◽  
Johanna van der Lee ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Natural History ◽  
Consensus Conference ◽  
Natural History Studies

scholarly journals Collaboration for rare disease drug discovery research

F1000Research ◽  
2014 ◽  
Vol 3 ◽  
pp. 261 ◽  
Author(s):  
Nadia K. Litterman ◽  
Michele Rhee ◽  
David C. Swinney ◽  
Sean Ekins
Keyword(s):  
Drug Discovery ◽  
Rare Disease ◽  
Rare Diseases ◽  
Research Collaboration ◽  
Drug Repurposing ◽  
Active Involvement ◽  
Disease Research ◽  
Discovery Research ◽  
Drug Companies ◽  
Drug Discovery Research

Rare disease research has reached a tipping point, with the confluence of scientific and technologic developments that if appropriately harnessed, could lead to key breakthroughs and treatments for this set of devastating disorders. Industry-wide trends have revealed that the traditional drug discovery research and development (R&D) model is no longer viable, and drug companies are evolving their approach. Rather than only pursue blockbuster therapeutics for heterogeneous, common diseases, drug companies have increasingly begun to shift their focus to rare diseases. In academia, advances in genetics analyses and disease mechanisms have allowed scientific understanding to mature, but the lack of funding and translational capability severely limits the rare disease research that leads to clinical trials. Simultaneously, there is a movement towards increased research collaboration, more data sharing, and heightened engagement and active involvement by patients, advocates, and foundations. The growth in networks and social networking tools presents an opportunity to help reach other patients but also find researchers and build collaborations. The growth of collaborative software that can enable researchers to share their data could also enable rare disease patients and foundations to manage their portfolio of funded projects for developing new therapeutics and suggest drug repurposing opportunities. Still there are many thousands of diseases without treatments and with only fragmented research efforts. We will describe some recent progress in several rare diseases used as examples and propose how collaborations could be facilitated. We propose that the development of a center of excellence that integrates and shares informatics resources for rare diseases sponsored by all of the stakeholders would help foster these initiatives.

Nationwide Comprehensive Epidemiological Study of Rare Diseases in Japan Using a Health Insurance Claims Database

2021 ◽  
Author(s):  
Kota Ninomiya ◽  
Masahiro Okura
Keyword(s):  
Health Insurance ◽  
Natural History ◽  
Rare Disease ◽  
Rare Diseases ◽  
Research Work ◽  
Insurance Claims ◽  
The West ◽  
Claims Database ◽  
History Of ◽  
Health Insurance Claims

Abstract BackgroundMore than 7,000 diseases constitute what are called rare diseases, and they mostly have no specific treatment. Disease profiles, such as prevalence and natural history, among the population of a specific country are essential in determining for which disease to research and develop drugs. In Japan, disease profiles of fewer than 2,000 rare diseases, called Nanbyo, have been investigated. However, non-Nanbyo rare diseases remain largely uninvestigated. Accordingly, we reveal the prevalence and natural history of rare diseases among the Japanese population, using the National Database of Health Insurance Claims and Specific Health Checkups of Japan, which covered 99.9% of public health insurance claims from hospitals and 97.9% from clinics as of May 2015. Then, we compared them with the data reported in Orphanet. This cross-disease study is the first to analyze rare-disease epidemiology in Japan with high accuracy, disease coverage, and granularity.ResultsWe were provided with the number of patients of approximately 4,500 rare diseases by sex and age for 10 years with the permission of the Ministry of Health, Labour and Welfare. About 3,000 diseases have equivalent terms in Orphanet and other medical databases. The data show that even if the Nanbyo systems do not cover a rare disease, its patients survive in many cases. Moreover, regarding natural history, genetic diseases tend to be diagnosed later in Japan than they are in the West. The data collected for this research work are available in the supplement and the website of NanbyoData.ConclusionsOur research work revealed the basic epidemiology and the natural history of Japanese patients with rare diseases using a health insurance claims database. The results imply that the coverage of the present Nanbyo systems is inadequate for rare diseases. Therefore, fundamental reform might be needed to reduce unfairness between rare diseases. Moreover, most diseases in Japan follow a tendency similar to those reported in Orphanet. However, some diseases are detected later, partly because fewer clinical genetic tests are available in Japan than there are in the West. Finally, we hope that our data and analysis accelerate drug discovery for rare diseases in Japan.

scholarly journals A Descriptive Review of Global Real World Evidence Efforts to Advance Drug Discovery and Clinical Development in Amyotrophic Lateral Sclerosis

2021 ◽  
Vol 12 ◽  
Author(s):  
Suzanne F. Cook ◽  
Thomas Rhodes ◽  
Courtney Schlusser ◽  
Steve Han ◽  
Chao Chen ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Amyotrophic Lateral Sclerosis ◽  
Natural History ◽  
Rare Disease ◽  
Real World ◽  
Market Access ◽  
Real World Data ◽  
World Data ◽  
Patient Reported ◽  
Lateral Sclerosis

Understanding patient clinical progression is a key gateway to planning effective clinical trials and ultimately enabling bringing treatments to patients in need. In a rare disease like amyotrophic lateral sclerosis (ALS), studies of disease natural history critically depend on collaboration between clinical centers, regions, and countries to enable creation of platforms to allow patients, caregivers, clinicians, and researchers to come together and more fully understand the condition. Rare disease registries and collaborative platforms such as those developed in ALS collect real-world data (RWD) in standardized formats, including clinical and biological specimen data used to evaluate risk factors and natural history of disease, treatment patterns and clinical (ClinROs) and patient- reported outcomes (PROs) and validate novel endpoints. Importantly, these data support the development of new therapeutics by supporting the evaluation of feasibility and design of clinical trials and offer valuable information on real-world disease trajectory and outcomes outside of the clinical trial setting for comparative purposes. RWD may help to accelerate therapy development by identifying and validating outcome measures and disease subpopulations. RWD can also make potential contributions to the evaluation of the safety and effectiveness of new indications for approved products and to satisfy post-approval regulatory and market access requirements. There is a lack of amalgamated information on available registries, databases, and other sources of real-world data on ALS; thus, a global review of all available resources was warranted. This targeted review identifies and describes ALS registries, biobanks and collaborative research networks that are collecting and synthesizing RWD for the purposes of increasing patient awareness and advancing scientific knowledge with the hope of expediting future development of new therapies.

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