From scientific discovery to treatments for rare diseases – the view from the National Center for Advancing Translational Sciences – Office of Rare Diseases Research
We now live in a time of unprecedented opportunities to turn scientific discoveries into better treatments for the estimated 30 million people in the US living with rare diseases. Despite these scientific advances, more than 90% of rare diseases still lack an effective treatment. New data and genetics technologies have resulted in the first transformational new treatments for a handful of rare diseases. This challenges us as a society to accelerate progress so that no disease and no patient is, ultimately, left behind in getting access to safe and effective therapeutics. This article reviews initiatives of the National Center for Advancing Translational Sciences (NCATS) Office of Rare Diseases Research (ORDR) that are aimed at catalyzing rare diseases research. These initiatives fall into two groups: Promoting information sharing; and building multi-disciplinary multi-stakeholder collaborations. Among ORDR’s information sharing initiatives are GARD (The Genetics and Rare Diseases Information Center), RaDaR (The Rare Diseases Registries Program) and the NCATS Toolkit for Patient-Focused Therapy Development (Toolkit). Among the collaboration initiatives are the RDCRN (Rare Diseases Clinical Research Network), and the NCATS ORDR support for conferences and workshops. Despite the success of these programs, there remains substantial work to be done to build enhanced collaborations, clinical harmonization and interoperability, and stakeholder engagement so that the recent scientific advances can benefit all patients on the long list of rare diseases waiting for help.
The scientific landscape for rare diseases has been changing rapidly, and this change is expected to accelerate. People living with rare diseases are increasingly benefiting from new therapeutics, some resulting from the break-through technologies now emerging in medicine. However, less than 5% of the more than 7, 000 rare diseases believed to affect humans currently have an effective treatment. While individually rare, in the aggregate there are an estimated 30 million people in the United States (US) living with rare diseases, or 1 in 10 Americans. Most rare diseases affect children, and many are lethal or severely disabling. This great unmet need makes it imperative that we find ways to accelerate the therapy development process so that we can help the many patients and families who are in search of better treatments.
How We Make An Impact
To examine the question of how to best accelerate rare diseases research, we will review some of the challenges in rare diseases research and opportunities for therapy development that recent scientific advances are presenting. Fig. 1 represents a schematic summary of these challenges and opportunities. We will also discuss relevant programs and initiatives in the Office of Rare Diseases Research (ORDR) at the National Center for Advancing Translational Sciences (NCATS), part of the National Institutes of Health (NIH) that are intended to facilitate and accelerate moving more treatments to more rare disease patients faster.
Bringing a new drug or biological product (“drug”) to market can take over a decade and cost more than $2.5B, and these numbers are increasing [1]. High development costs are particularly difficult for rare diseases to overcome because the market for the product, once approved, is inherently small, thus limiting the potential for return-on-investment. Adding to this are often high manufacturing costs for innovative technologies, such as gene therapy approaches, until better production and characterization methods can be developed and automated. For mutation-specific nucleic acid therapies such as oligos, morpholinos, and aptamers there are additional challenges in reaching all rare diseases patients given the mutational heterogeneity in most conditions. Patient-specific cell therapies have the further challenge that a separate batch needs to be produced for each patient.
Long development times are also of particular concern for rare diseases where often a knowledge base for the disease, such as natural history data, needs to be built, outcome measures need to be identified and developed, and where trial recruitment of the relatively small number of available trial participants can be prolonged. Such delays add costs, and, more importantly, cost lives. In life-threatening rare diseases, most of which are chronic progressive disorders, patient access to an effective new treatment can change the trajectory of the disease and reduce morbidity and mortality.
Genomics Of Rare Diseases: Understanding Disease Genetics Using Genomic Approaches (translational And Applied Genomics): 9780128201404: Medicine & Health Science Books @ Amazon.com
Weighing the cost, time and risk associated with therapy development, academic and industry researchers and developers have been largely focused on a subset of less than 100 rare diseases, often competing for trial participants and researchers’ time while “racing” to be first to achieve marketing authorizations. How can we promote both national and international interest in the many other rare diseases that are currently perceived as too uncommon to merit public sector investment, or too ‘risky’ to attract much private sector attention? How can we find vital scalable and sustainable pathways to help the many families afflicted with rare diseases who are searching for effective treatments?
The recent success stories in getting regulatory approvals for transformative therapies have also raised new dilemmas in ensuring access to all patients in need. New payment frameworks are being explored, and often aim to take into account the disease and financial burden now borne by individuals and societies over a patient’s lifetime relative to the cost of the successful treatment. To be sustainable, rare disease treatments ideally would not place undue stress on health systems, payers, and patients, and would eventually become accessible to patients in resource-poor environments. Ideally, such reimbursement frameworks would also foster the continued growth of rare diseases therapy development.
Our understanding of what causes human disease is unprecedented. We can diagnose more and more diseases using genomic analysis. There is growing experience in developing small molecule therapies. Also, we can increasingly design tailored treatment approaches that address the underlying genetic cause of many diseases. Gene transfer therapies are now successful in patients, replacing missing genes by using viral vectors [2, 3, 4, 5]. Gene disruption technologies such as antisense oligonucleotides, RNA interference (RNAi), or microRNA modulation are used to modify or block a disease-causing protein [6, 7]. Gene-modified cell therapy has been successful at using cells such as chimeric antigen receptor (CAR) T cells that have been changed to treat cancer [8, 9]. Gene editing approaches can be deployed to directly modify genes in vivo and ex vivo using clustered regularly interspaced short palindromic repeats (CRISPR) and zinc finger (ZFN) technologies [10, 11]. A growing number of patients are now participating in clinical trials that test gene therapy modalities. In the past year, the first patient has been enrolled in a clinical trial using in vivo gene editing. Also, this decade has seen a steady increase in drug approvals for rare diseases, including rare cancers.
Precision Medicine In Rare Diseases: What Is Next?
The task is now to find ways to reduce the time, costs, and risks associated with rare disease therapy development; only then will effective treatments be more likely reach all patients in need.
The authors believe that decreasing the cost, time and risk of developing new rare diseases therapies will require a focus on commonalities, scale, and technological as well as sociolocultural innovation, including:
Figure 2 is a schematic overview of ORDR initatives aimed at these four strategies listed above, along with examples of US and international partnerships.
A Guide For The Diagnosis Of Rare And Undiagnosed Disease: Beyond The Exome
By definition, rare diseases are uncommon so that there are fewer patients, clinicians, and researchers. It is important to keep in mind that research in rare disease etiology, mechanisms and treatment approaches can advance progress in common diseases. The infrastructure needed for clinical studies is too often established de novo for each disease and clinical development program, making it a costly enterprise, especially when the expense is considered per research participant. One approach is therefore the use of national and international networks for research that can take on therapy development.
The NIH’s NCATS, together with several other NIH Institutes and Centers (IC) is supporting the Rare Diseases Clinical Research Network (RDCRN) to facilitate rare disease study coordination, enrollment of research participants, and data sharing. The RDCRN consists of several distinct clinical research consortia with a shared Data Management and Coordinating Center, through which research into more than 200 diseases is being conducted at sites across the nation and, when needed, internationally. To maximize the impact of the RDCRN, each consortium is focused on more than one related rare disease and fosters a broad range of clinical research including registries and natural history studies. The RDCRN encourages the collaboration of physician scientists, their multidisciplinary teams and patient groups, and also provides training in rare diseases research to new investigators [12].
Rare diseases research also may benefit from advances in the NCATS Clinical and Translational Science Awards (CTSA) Program that supports academic medical centers across the nation. After a review of the Program by an Institute of Medicine panel, [13] NCATS has placed greater emphasis on collaboration and launched a Trial Innovation Network so that needed contracting, ethics reviews, training, and other building blocks can be shared more readily. To streamline in particular the ethics reviews conducted by multiple Institutional Review Boards (IRBs) at each institution participating in a multi-site study, NCATS supports the SMART IRB Platform with now over 350 institutions having agreed to one IRB authorization agreement
Hope For Rare Foundation
The task is now to find ways to reduce the time, costs, and risks associated with rare disease therapy development; only then will effective treatments be more likely reach all patients in need.
The authors believe that decreasing the cost, time and risk of developing new rare diseases therapies will require a focus on commonalities, scale, and technological as well as sociolocultural innovation, including:
Figure 2 is a schematic overview of ORDR initatives aimed at these four strategies listed above, along with examples of US and international partnerships.
A Guide For The Diagnosis Of Rare And Undiagnosed Disease: Beyond The Exome
By definition, rare diseases are uncommon so that there are fewer patients, clinicians, and researchers. It is important to keep in mind that research in rare disease etiology, mechanisms and treatment approaches can advance progress in common diseases. The infrastructure needed for clinical studies is too often established de novo for each disease and clinical development program, making it a costly enterprise, especially when the expense is considered per research participant. One approach is therefore the use of national and international networks for research that can take on therapy development.
The NIH’s NCATS, together with several other NIH Institutes and Centers (IC) is supporting the Rare Diseases Clinical Research Network (RDCRN) to facilitate rare disease study coordination, enrollment of research participants, and data sharing. The RDCRN consists of several distinct clinical research consortia with a shared Data Management and Coordinating Center, through which research into more than 200 diseases is being conducted at sites across the nation and, when needed, internationally. To maximize the impact of the RDCRN, each consortium is focused on more than one related rare disease and fosters a broad range of clinical research including registries and natural history studies. The RDCRN encourages the collaboration of physician scientists, their multidisciplinary teams and patient groups, and also provides training in rare diseases research to new investigators [12].
Rare diseases research also may benefit from advances in the NCATS Clinical and Translational Science Awards (CTSA) Program that supports academic medical centers across the nation. After a review of the Program by an Institute of Medicine panel, [13] NCATS has placed greater emphasis on collaboration and launched a Trial Innovation Network so that needed contracting, ethics reviews, training, and other building blocks can be shared more readily. To streamline in particular the ethics reviews conducted by multiple Institutional Review Boards (IRBs) at each institution participating in a multi-site study, NCATS supports the SMART IRB Platform with now over 350 institutions having agreed to one IRB authorization agreement
0 comments:
Post a Comment