Request for Information (RFI): To Solicit Input on Expanding the NIH Undiagnosed Diseases Program

Notice Number: NOT-RM-12-031

Release Date: August 28, 2012

National Institutes of Health (NIH)
Office of Strategic Coordination (Common Fund)

Building on the success of the NIH Undiagnosed Diseases Program (NIH-UDP) in diagnosing both known and novel disorders, the NIH is considering expanding the number of clinical sites capable of providing diagnoses to patients presenting with difficult to diagnose diseases.

The NIH Common Fund seeks input from the scientific community and other members of the public on a proposed national network of new Clinical Sites added to and building upon the NIH-UDP.

Background

Undiagnosed diseases primarily include rare diseases that have been described but are often not recognized because they are rare, or disorders not previously described and thus of unknown prevalence, phenotype and etiology.

Rare and yet to be described disorders are a difficult problem for patients, their families and their physicians. To aid these individuals, and to make progress in uncovering, understanding, and treating these disorders, the NIH established an intramural research program on undiagnosed diseases in 2008. This program is described in more depth at NIH Undiagnosed Diseases Program and NIH Common Fund Undiagnosed Diseases Program and in multiple publications (Gahl WA, Tifft CJ, JAMA. 305:1904-5 2011; Gahl et al, Genet Med. 14(1):51-9 2012).

Since its inception in 2008, the NIH UDP has received approximately 6,300 inquiries, reviewed 2,300 medical records, and admitted 450 patients to the NIH Clinical Center for thorough, one-week evaluations. Even without a systematic approach to advertising the program, there is a substantial unmet demand for these services-- a major reason to create a national network of diagnostic sites. Another reason is that a network may ease the travel burden for some patients seeking help from the UDP. In addition to the benefit to patients with rare diseases, the UDP creates important opportunities for research: Uncovering the biochemistry, physiology, and underlying genetic etiology leads to a better understanding of disease processes and those of related disorders.

Objectives of this Research Program

Improve the level of diagnosis and care for patients with undiagnosed diseases through the development of common protocols designed by an enlarged community of investigators.

Facilitate research into the etiology of undiagnosed diseases, by collecting and sharing standardized, high-quality clinical and laboratory data including genotyping, phenotyping, and documentation of environmental exposures.

Create an integrated and collaborative research community across multiple clinical sites and among laboratory and clinical investigators prepared to investigate the pathophysiology of these new and rare diseases.

The NIH is considering creating an Undiagnosed Diseases Network to include a Coordinating Center and 5-7 new Undiagnosed Diseases Clinical Sites in FY 2014. To the degree possible, common protocols for data collection and common approaches to patient selection, evaluation, and diagnosis will facilitate pooled analyses and cross-site collaborations, ultimately advancing the clinical approach to undiagnosed diseases.

This RFI invites input from the scientific community, medical schools and other members of the public on all aspects of the program. NIH is particularly interested in feedback on the following issues:

Need for a national undiagnosed diseases network

• Perceived magnitude of the problem of undiagnosed diseases, such as number of patients encountered per large-scale practice per year
• Particular demographic groups or conditions represented disproportionately, such as infants or children, or developmental or neurological disorders
• Frequency of referral to specialized center(s) and, if referred, to what centers and at what distances
• Specialized services sought and/or lacking at available referral centers, such as expert clinical diagnosticians or specialized imaging/laboratory technologies
• Need for training in diagnosis/management of patients with undiagnosed diseases

Network design

Please suggest how best to structure a national network of undiagnosed diseases clinical sites and Clinical Coordinating Center, including collaborative, cross-site approaches to:

• Patient selection and triage among centers
• Standardization of data collection and joint analyses
• Assignment of final consensus diagnoses
• Opportunities to exchange knowledge and experience with colleagues from other institutions
• Access to core diagnostic technologies, such as whole exome or whole genomic sequencing, metabolomic analysis, proteomics, and glycomics
• Use of a centralized Institutional Review Board (IRB)
• Role of a Network Coordinating Center in promoting standard methods, ensuring data quality, facilitating pooled analyses, and other collaborative functions
• Data sharing across sites consistent with informed consent and privacy or HIPAA regulations
• Data submission to a Network Coordinating Center and deposition in controlled access databases such as dbGaP

Existing or planned similar programs at U.S. institutions

Please describe any programs currently in operation, or proposed to begin by early 2014, that apply genomic and other technologies to establish diagnoses in patients who have eluded diagnosis after extensive clinical investigation, including such aspects as:

• Numbers of patients evaluated, and over what timeframe
• Proportion in whom definitive diagnosis made
• Whether studied as inpatients or outpatients and typical duration of investigation before and after presenting to your facility
• Estimated cost of diagnostic work-up at your facility and proportion reimbursed by third party payers
• Approach to covering costs not reimbursed by third party payers
• Estimated time (in weeks or months), were funding to be made available, for your facility to be able to investigate undiagnosed disease patients thoroughly at a rate of roughly 2 patients per month, and then roughly 1 patient per week
• Approach to selection of undiagnosed patients for investigation at your facility
• Major differences in approach to investigating undiagnosed patients at your facility compared to that of the NIH intramural UDP
• Areas of specialized diagnostic expertise at your facility, such as neurological disorders or blood dyscrasias
• Availability of trainees at your institution who may participate in a program aimed at undiagnosed diseases
• Availability of specialized investigative technology at your facility, such as whole exome or whole genomic sequencing, metabolomic analysis, proteomics, glycomics and other technology useful in the diagnosis of rare diseases

Training programs

Please describe the types of short courses and fellowships that should be offered to newly-established Undiagnosed Diseases Network clinical sites, and any related training programs currently available.

Lastly, please describe important potential pitfalls and barriers to the establishment of an Undiagnosed Diseases Network and suggest ways to mitigate them.

Response to this RFI is voluntary. Interested parties are invited to respond. Responders are free to address any or all of the above items. Please note that the Government will not pay for response preparation or for the use of any information contained in the response.

All comments must be submitted electronically to: [email protected]

Responses to this RFI will be accepted through September 18, 2012. You will receive an electronic confirmation acknowledging receipt of your response, but will not receive individualized feedback on any suggestions. No basis for claims against the U.S. Government shall arise as a result of a response to this request for information or from the Government’s use of such information.

A summary of responsive input will be made publicly available. Personally identifiable information will be removed to the extent possible prior to making the comments public. We recommend that respondents remove personal identifiers prior to submission and that no proprietary information be included in the response.

Please direct all inquiries to:

Carson Loomis, Ph.D., Program Director, Molecular Libraries Program
National Human Genome Research Institute (NHGRI)
National Institutes of Health
5635 Fishers Lane, Suite 4076, MSC 9305
Bethesda, MD 20892-9307
Rockville, MD 20852 (courier/FedEx/UPS)
Telephone: 301-594-5936
Email: [email protected]