Rare Diseases and Orphan Products Accelerating Research and Development (2010) / Chapter Skim
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4 Discovery Research for Rare Diseases and Orphan Product Development
4 Discovery Research for Rare Diseases and Orphan Product Development
Pages 111-146
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From page 111... ...
Interview with Brian Druker (Dreifus, 2009) The research undertaken by Brian Druker and his colleagues and predecessors offers a classic example of the foundation that basic research builds for the subsequent development of therapies for rare diseases.
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From page 112... ...
As discussed in Chapter 1, research on rare diseases can illuminate disease mechanisms and therapeutic opportunities for more common diseases. Box 4-1 briefly summarizes several additional examples of rare diseases research that have yielded broader knowledge.
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From page 113... ...
All along this continuum from basic research through clinical trials, infrastructure and innovation are needed to accelerate the development of therapies for people with rare diseases. The discussion here
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From page 114... ...
Both this and the next chapter discuss the infrastructure for rare diseases research and orphan product development and "innovation platforms" to encourage and support collaborative work. Such collaboration is needed to bridge the gulf -- sometimes referred to as the "valley of death" -- between basic research findings and beneficial products, especially in the stages that precede clinical studies of efficacy.
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From page 115... ...
Animal models also offer the ability to use targeted genetic or pharmacologic perturbations to test focused hypotheses regarding modifier genes and pathways. The identification of modifier genes is of particular value in rare diseases, where diagnosis is already difficult due to the small number of cases.
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From page 116... ...
They can, however, be helpful in working out pathways that are dysfunctional in both genetic and acquired rare disorders (Wong and Wang, 2008)
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From page 117... ...
, the construction of molecular networks and pathways relevant to specific rare disorders is increasingly possible. Bioinformatic analyses of data from gene expression arrays, proteomics studies, and clinical observations on patients with rare diseases can define signatures of fundamental disease mechanisms (Dudley et al., 2009; Patel et al., 2010; Suthram et al., 2010)
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From page 118... ...
Thus, as discussed later in this chapter, the infrastructure for rare diseases research and product development should include structures and processes for sharing research resources, including data and biological specimens. THERAPEUTICS DISCOVERY Once basic research is performed and findings implicate a specific biological target, which could be an enzyme, a product of a biochemical pathway, an altered gene, an epigenetic mechanism, or a combination of the above, then the search begins for an appropriate therapeutic agent.
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From page 119... ...
Products from natural sources such as plants, fungi, bacteria, and sea organisms can be integrated within compound libraries. Most compounds, though, are derived through the use of chemical synthesis techniques, in which researchers create chemical compounds by manipulating "parent" chemicals.
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From page 120... ...
, this provides researchers with an opportunity to gather a preclinical proof of therapeutic concept, which can be very important before the compound enters development. This process of drug discovery for rare diseases is no different than that for common diseases -- the costs and infrastructure required for both are significant.
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From page 121... ...
Rather, the opportunities and obstacles must be elucidated for each disease, and the approach must be tailored accordingly -- a truly daunting task for thousands of rare disorders. Nevertheless, biologics have strong appeal because they have the potential to address the etiologic foundation of a disease process (e.g., through replacement of a deficient protein)
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From page 122... ...
. Other Forms of Therapy Applicable to Rare Diseases Cell Therapy Cell therapies for rare disorders are largely confined to blood and marrow transplants to repopulate key cell subpopulations through differentiation of hematopoietic stem cells.
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From page 123... ...
Extensive research will be needed to create gene therapies that provide efficient, stable, and safe correction across a range of rare disorders. Future research should overcome many of the current barriers to corrective gene therapy including avoidance of insertional mutagenesis and deleterious immunologic responses, maintenance of gene expression, and promotion of the targeting, engraftment, and viability of genetically altered cells.
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From page 124... ...
Once the primary genes are identified, the development of laboratory tests for rare disorders becomes feasible. (As described in Chapter 7, many diagnostic tests are regulated as medical devices.
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From page 125... ...
Along with them, models for providing the infrastructure necessary for discovery research have also undergone a transformation in recent years. This section describes some elements of the necessary infrastructure, including animal models, patient registries and biospecimen repositories, research funding, and training and also describes innovations in the area of sharing data and other resources, which can lower the considerable costs of basic and translational research.
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From page 126... ...
. Although the patenting process is the same for products for common and rare diseases, questions about the status of patents on genes and proteins may present special challenges for rare genetic diseases research that relate to development of new drugs (discussed in Chapter 5)
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From page 127... ...
Animal Models Development of disease models in animals yields major opportunities for discovery of the genetic and biochemical basis for rare diseases, the identification of therapeutic targets, and the testing of new drugs and biologics for efficacy and safety. A number of genetic diseases occur naturally in animals (e.g., hemophilia B in dogs [Kay et al., 1994]
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From page 128... ...
. Patient Registries and Sample Repositories Patient registries can address many obstacles faced in the study of rare disorders including provision of a centralized source of information regarding disease incidence, prevalence, regional or temporal clustering of cases, and natural history or response to treatment.
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From page 129... ...
Later in this chapter, Recommendation 4-1 proposes that NIH collaborate on a comprehensive system of shared resources for discovery research on rare diseases. In Chapter 5, Recommendation 5-3 calls for NIH to support a collaborative public-private partnership to develop and manage a freely available platform for creating or restructuring patient registries and biorepositories for rare diseases and
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From page 130... ...
It understands that the Office of Rare Diseases Research at NIH has requested that the process for categorizing and collecting data on spending by category be revised to allow the easier generation of disease-specific totals and totals for all spending on rare diseases research. This would allow a more systematic assessment of current resources and resource allocation.
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From page 131... ...
H -- Huntington disease Y -- Cryptosporidiosis I -- Tuberous sclerosis Z -- Non-Hodgkin lymphoma J -- Leber congenital amaurosis 1 -- Albright hereditary K -- Sickle cell anemia osteodystrophy L -- Cystic fibrosis 2 -- Scleroderma M -- Acute myeloid leukemia 3 -- Tetralogy of Fallot N -- Congenital diaphragmatic hernia 4 -- Narcolepsy (cataplexy) O -- Sarcoidosis 5 -- Melanocortin-4 receptor P -- Familial dilated cardiomyopathy deficiency Q -- Hereditary spherocytosis 6 -- Noonan syndrome R -- Turner syndrome
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From page 132... ...
This may reflect the time lag between scientific discovery and clinical therapeutics research, the difficulties of conducting clinical research on very rare conditions, NIH's traditional emphasis on basic research, and the dominance of industry in funding clinical trials of drugs or other thera TABLE 4-1 Active NIH Awards for Four Rare Diseases by Number, Funding Total, and Type as of April 2010 Number of Disease Annual Grants Prev- Total Directly alence Total Funding Targeting Pre- Other (per Grants (millions the clinical Clinical Clinical Condition 100,000) Listed of dollars)
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From page 133... ...
Beyond those cited above, other factors contributing to the variation in federal funding of rare diseases research may include the number of scientific issues raised by a particular rare disease, the potential broader relevance of those issues, the availability of pilot grants from disease-specific foundations, the extent to which clinical care and clinical research are focused in disorder-specific clinics or centers, and workforce issues such as numbers of trained basic and clinical investigators. Federal agencies beyond NIH also fund some biomedical research on rare diseases, particularly clinical studies.
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From page 134... ...
Individual foundations often seek to leverage relatively limited funds through the use of seed grants that help investigators develop the data needed to support competitive NIH grant proposals. Investigator Training and Recruitment A decision to pursue basic or translational rare diseases research is inherently risky, especially for young investigators.
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From page 135... ...
Existing study sections may be predisposed toward more common diseases, may not appreciate the critical importance of natural history studies for rare diseases, or may lack expertise to evaluate proposals that involve innovative trial designs and analytic methods for small populations. Possible responses include creating special NIH review mechanisms for rare diseases research proposals or developing guidance for existing study sections on the review of rare diseases proposals.
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From page 136... ...
Beyond scientific training, successful investigators must know how to build and sustain productive collaborations and must be comfortable communicating their work to interdisciplinary audiences. Training of young investigators or retraining of experienced investigators to conduct research on specific rare diseases will depend on the existence of productive and funded programs in rare disorders-specific research that can serve as training sites for both basic and clinical research.
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From page 137... ...
The emphasis here is therefore more generally on the need for training in basic and translational or clinical research areas that will be relevant to many rare diseases. INNOVATION PLATFORMS FOR TARGET AND DRUG DISCOVERY The high costs and low success rates associated with drug discovery and development, combined with the absence, in the case of rare diseases, of a large market for approved therapies, have stimulated the development of innovation platforms on a number of levels.
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From page 138... ...
Other groups may have more expansive interpretations of the concept. The formation of public-private partnerships involving government, industry, and nonprofit organizations has been a successful model for the infrastructure gaps in the area of neglected tropical diseases, which share with rare diseases the lack of commercial incentives for product development.
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From page 139... ...
The project focuses on optimizing lead compounds and making them available to researchers for preclinical testing. NIH has initiated several broader programs to support drug discovery for rare diseases.
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From page 140... ...
Given the increasing information richness of biology, similar integration of knowledge about biochemical pathways and networks from a wide range of researchers may spur productivity in the identification of molecular targets for diseases and otherwise advancing discovery research and product development. Existing examples of such efforts to share biological information or technology development resources include the following: • Enlight Biosciences, a private company created in partnership with major pharmaceutical companies to develop enabling technologies that
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From page 141... ...
. The data shared with Sage will eventually be publicly available and could be particularly valuable for rare diseases research.
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From page 142... ...
RECOMMENDATIONS Two critical issues for rare diseases research are the small number of patients available to participate in research on rare diseases and the limited sources of funding for discovery and development of potential therapies for these diseases. It is therefore particularly important to make the best use possible of the information and other products that research generates -- whether the research is directed specifically at a rare condition or at a more common condition that potentially has relevance for a rare condition.
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From page 143... ...
Creating such a system of shared resources for rare diseases research will require a significant developmental effort and commitment of public, commercial, and nonprofit funding and other resources, for example, assistance in creating mechanisms for coordination and oversight and model provisions for public access to the information developed with government and nonprofit grant support. Key elements of this system would include, among other possible features, • a repository of publicly available animal models for rare disorders that reflect the disease mechanisms and phenotypic diversity seen in humans; • a publicly accessible database that includes mechanistic biological data on rare diseases generated by investigators funded by NIH, private foundations, and industry;
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From page 144... ...
for making relevant portions of compound libraries available to researchers in rare diseases areas; and • further exploration of precompetitive models and opportunities for developing technologies and tools for discovery research involving rare diseases. Given the challenges outlined in this chapter and other parts of this report and given the important role that NIH plays in supporting research on rare diseases, the committee believes that a comprehensive NIH action plan on rare diseases would be useful to better integrate and expand existing work.
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From page 145... ...
With respect to the review of proposals for research on rare diseases, the NIH action plan would include the development of guidance for study sections and institute councils. This guidance would, for example, clarify the potential public health relevance of rare diseases research, the range of appropriate methods for studying rare diseases, and the use of alternative mechanisms to ensure expert review of grant applications on rare diseases.
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From page 146... ...
RARE DISEASES AND ORPHAN PRODUCTS will interfere with the ability of these groups to target their resources and collaborate effectively. The following chapter shifts the focus from basic research to the preclinical and clinical development investigations that are required to establish safety and efficacy and otherwise meet regulatory standards for approval of pharmaceuticals and biologics.
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