Table of Contents
Overview
In October 2010, the NDSI-IEM program was launched in the Office of Dietary Supplements (ODS) to explore the research evidence supporting the use of nutrition and dietary supplement interventions for inborn errors of metabolism (IEM) and the infrastructure needed to carry out new research. In collaboration with the National Center for Advancing Translational Sciences (NCATS) and with input from a broad range of interested and involved parties, challenges and barriers to conducting research on nutritional treatments for IEM are being identified. Strategies will be developed to support evidence-based research on the safety and effectiveness of nutritional management modalities in IEM.
Background
Nutrition and dietary supplement interventions are the main management strategies for a number of IEM. Many IEM are identified through newborn screening, a successful public health program that screens virtually all newborns in the United States within the first 48 hours of birth (Newborn Screening
and Advisory Committee on Heritable Disorders in Newborns and Children). Early identification and treatment of an IEM reduces the medical and developmental problems associated with these conditions. The inherited genetic mutation(s) in each IEM prevent the body from breaking down substances contained in the diet. Infants with these conditions are generally healthy at birth. Symptoms begin to appear when they are exposed to breast milk or infant formula containing dietary components that their bodies cannot use properly. As a result, compounds build up in the blood and brain, leading to undesired health outcomes. These conditions are managed by restricting the offending dietary components and providing nutrients that become deficient due to the limited diet.
Over the past 50 years, technological advances and public demand have led to an increase in the number of conditions screened in the newborn period from one (phenylketonuria, PKU) to over 50 different conditions in some states. Although individuals identified with IEM in infancy are now living into adulthood, the nutritional management that promotes proper growth and development and maintains long-term health for these individuals is not known for many of the conditions.
Additionally, IEM are rare diseases and the nutrition and dietary supplement interventions are regulated as foods, not as drugs. These factors have contributed to the difficulties in conducting research on these management strategies.
Mission
To identify gaps in understanding the safety and effectiveness of nutrition and dietary supplement interventions used to treat individuals with IEM. Through collaboration and partnerships with a wide range of interested parties, this program will develop and implement a plan to conduct evidence-based research to eliminate these gaps.
Meetings, Workshops, and Other Activities
Nutritional Interventions in Primary Mitochondrial Disorders: Developing an Evidence Base, December 2–3, 2014, Rockville, Maryland. Sponsored by ODS. Co-sponsors included NIH’s National Center for Advancing Translational Sciences (NCATS) and the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), the Wellcome Trust (London, United Kingdom), and the United Mitochondrial Diseases Foundation (UMDF). The focus of this workshop was on the use of nutritional interventions, including dietary supplements (e.g., vitamins, minerals, and other dietary ingredients) in primary mitochondrial disorders. Eighty researchers, clinicians, patient advocates, industry representatives, and federal regulators and funders from the United States, Canada, and the United Kingdom participated. Following presentations and panel discussions designed to identify gaps in knowledge regarding the safety and effectiveness of nutritional interventions and the challenges and barriers to conducting research, a research agenda was identified. Short and long-term activities have been identified and will be triaged to appropriate organizations.
NIH Phenylketonuria Scientific Review Conference sponsored by NICHD, ODS, and ORDR/NCATS in February 2012 to address new clinical findings, particularly the use of the medication sapropterin to treat some individuals with PKU, and to develop a research agenda.
Support of PKU guideline development: ODS hosted a meeting in August of 2012 of PKU guideline developers representing various metabolic professional organizations. ORDR, the Eunice Kennedy Shriver National Institute for Child Health and Human Development (NICHD), and the Agency for Healthcare Research and Quality (AHRQ) held a training session on guideline development. The developers worked together to prepare nutrition and medical guidelines.
Nutrition and Dietary Supplement Interventions for Inborn Errors of Metabolism (NDSI-IEM), Building a Framework for Evidence-Based Research Workshop: This workshop was held in December 2011 to engage the wider metabolic community and develop a plan to promote evidence-based research of nutrition and dietary supplement interventions used in IEM. Participants represented advocacy and patient organizations; professional associations; companies that make medical foods and other nutritional products and, prescription drugs used in the management of IEM; the Health Resources and Services Administration’s Regional Genetic and Newborn Screening Services Collaboratives; agencies, institutes, and centers within the Department of Health and Human Services; and the metabolic clinical, research, and academic communities.
Selected References
- Therrell BL, Lloyd-Puryear MA, Camp KM, and Mann MY. Inborn errors of metabolism identified via newborn screening: Ten-year incidence data and costs of nutritional interventions for research agenda planning. Mol Genet Metab 2014;113:14-26.
- Phenylketonuria Scientific Review Conference: State of the Science and Future Research Needs 2014
- Camp KM, Lloyd-Puryear MA, Yao L, Groft SC, Parisi MA, Mulberg A, Gopal-Srivastava R, Cederbaum S, Enns GM, Ershow AG, Frazier DM, Gohagan J, Harding C, Howell RR, Regan K, Stacpoole PW, Venditti C, Vockley J, Watson M, Coates PM.Expanding Research to Provide an Evidence Base for Nutritional Interventions for the Management of Inborn Errors of Metabolism. Mol Genet Metab 2013;97:1235-42.
- Camp KM, Lloyd-Puryear MA, Huntington KL. Nutritional treatments for inborn errors of metabolism: Indications, regulations, and availability of medical foods and dietary supplements using phenylketonuria as an example. Mol Genet Metab 2012 107:3-9.
- Lloyd-Puryear MA, Camp K, Berry SA. Pediatricians may play role in nutritional management of patients with inherited metabolic disorders. AAP News. 2012;33:11.
- Fact sheet on Primary Mitochondrial Disorders
Resources for Researchers and Health Professionals
- Office of Dietary Supplements (ODS)
- ODS fact sheet on Primary Mitochondrial Disorders
- National Institutes of Health (NIH)
- Extramural research grants are awarded to investigators throughout the United States and abroad. Approximately 10 percent of the NIH budget supports intramural investigators, NIH staff who conduct research.
- NIH Institutes and Centers (ICs)
- NIH is made up of 27 ICs, each with a specific research agenda, often focusing on particular diseases or body systems.
- Office of Extramural Research (OER)
- OER provides leadership, oversight, tools, and guidance to administer and manage NIH grants policies and operations. OER serves as a link between the NIH and the biomedical research community by guiding investigators through the process of obtaining grant funding.
- Funding Opportunities and Notices
- OER (above) maintains a listing of active Requests for Applications (RFAs) and Program Announcements (PAs). The website includes links to related resources.
- Center for Scientific Review (CSR)
- CSR serves as the central receipt point for most federal grant applications submitted to NIH. CSR assigns the grant application to an NIH Institute and to a Scientific Review Group, also known as a Study Section.
- Solicited Grant Applications
- This resource lists all active RFAs with the ability to browse or search by topic area.
- Research Portfolio Online Reporting Tools Expenditures and Results (RePORTER)
- This tool allows users to search a repository of NIH-funded research projects. The information found in RePORTER is drawn from several current databases: eRA [Electronic research administration] databases; Medline; PubMed Central; the NIH Intramural Database (NIDB); and iEdison.
- NIH Grant Writing Tips Sheets
- This resource includes information on choosing an appropriate NIH funding mechanism, peer review guidelines and information, and advice on preparing grant applications.
- National Center for Complementary and Integrative Health NNCCIH) Tips for New NIH Research Grants Applicants
- This website provides tips on grant writing for NIH research applicants.
- Glossary of Funding and Policy Terms and Acronyms
- This website provides a glossary to help research applicants with the NIH application process.
- The NIH Clinical Center’s website
- The Clinical Center’s website provides details on ongoing NIH clinical trials. At this time, use of the Clinical Center is restricted to NIH staff who conduct research and their collaborators. However, NIH may open the Clinical Center to external researchers in the future.
- Common Fund Regulatory Science Program
- This program fosters development, availability, and evaluation of new or improved ways to understand and improve product safety, quality, effectiveness, and manufacturing throughout the life- cycle of a product.
National Institutes of Health—Rare Diseases
- National Center for Advancing Translational Sciences (NCATS)
- NCATS develops new technology that can be transferred through collaborations and licenses to others for further research, development, and commercialization. NCATS strives to develop innovations to reduce, remove or bypass costly and time-consuming barriers in the research process in an effort to speed the delivery of new drugs, diagnostics, and medical devices to patients..
- The Rare Diseases Clinical Research Network (RDCRN)
- RDCRN, an initiative of the National Center for Advancing Translational Sciences (NCATS), is made up of 22 distinctive consortia and a Data Management and Coordinating Center that are working in concert to improve availability of rare disease information, treatment, clinical studies, and general awareness for both patients and the medical community. RDCRN also aims to provide up-to-date information for patients and to assist in connecting patients with advocacy groups, doctors who have expertise in rare disease diagnosis and treatment, and clinical research opportunities.
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- ODS provides funding to the North American Mitochondrial Disorders Consortium (NAMDC) , one the of the RDCRN consortia, along with the Eunice Kennedy Shriver National Institute for Child Health and Human Development (NICHD), the National Institute of Neurological Disorders and Stroke (NINDS), and NCATS. NAMDC was established to create a network of all clinicians and clinical investigators in North America (U.S. and Canada) who follow sizeable numbers of patients with mitochondrial diseases and are involved or interested in mitochondrial research.
- Global Rare Diseases Patient Registry and Data Repository (GRDR)
- GRDR provides the rare disease community a resource of collective standardized patient information (unidentifiable), to accelerate research and advance therapeutic development.
- Rare Disease-HUB (RD-HUB) of NCATS
- This website contains a searchable database of biological specimens collected, stored, and distributed by biorepositories in the United States and around the globe.
- Genetic and Rare Diseases Information Center (GARD)
- This Center was established to provide access to information specialists who supply current and accurate information about genetic and rare diseases in both English and Spanish.
- Undiagnosed Diseases Program (UDP)
- UDP promotes the use of genomic data in disease diagnosis and engages basic researchers to define clearly the mechanisms underlying the diseases so that treatments may be identified.
- Therapeutics for Rare and Neglected Diseases
- TRND builds collaborations with NIH, FDA, academic scientists, nonprofit organizations, and pharmaceutical and biotechnology companies to speed development of new therapies.
- Cures Acceleration Network (CAN)
- CAN was established to stimulate the development of high need cures for debilitating and life threatening diseases by reducing the number of barriers that investigators face between the time of basic research discoveries and initiation of clinical trials.
- Bridging Interventional Development Gaps (BrIDG)
- BrIDG provides successful applicants developing therapeutic agents with access to critical resources in support of preclinical studies.
- Discovering New Therapeutic Uses for Existing Molecules
- This initiative is a collaborative pilot program of NCATS designed to develop partnerships between pharmaceutical companies and the biomedical research community to advance therapeutic development.
- Tissue Chip for Drug Screening
- This initiative represents an interagency collaboration with Defense Advanced Research Projects Agency (DARPA) and NCATS.
Food and Drug Administration
- FDA Office of Orphan Products Development (OOPD)
- OOPD’s mission is to advance the evaluation and development of products (drugs, biologics, devices, or medical foods) that demonstrate promise for the diagnosis and/or treatment of rare diseases or conditions.
- The Orphan Drug Act (ODA)
- Through the ODA, FDA grants special status to a product to treat a rare disease or condition upon request of a sponsor. A marketing application for such a product is not subject to a prescription drug user fee unless the application includes an indication for other than a rare disease or condition.
- Humanitarian Use Device (HUD) program
- HUD was established in 1990 with passage of the Safe Medical Devices Act and creates an alternative pathway for getting market approval for medical devices that may help people with rare diseases or conditions.
- The Orphan Products Clinical Trials Grants Program
- The goal of this program is to encourage clinical development of products for use in rare diseases or conditions. The products studied can be drugs, biologics, medical devices, or medical foods.
- FDA Pediatric Device Consortia Grant Program
- The goal of this program is to support the development of nonprofit partnership designed to stimulate projects that will promote pediatric device development.