Type 1 Diabetes Preclinical Testing Program (T1D-PTP)
I. About the Type 1 Diabetes Preclinical Testing Program (T1D-PTP)
A. Background
1. Type 1 Diabetes- Rapid Access to Investigational Drugs (T1D-RAID)
T1D-RAID is a cooperative program designed to facilitate translation to the clinic of novel, scientifically meritorious therapeutic interventions. It does this by making available, on a competitive basis, NCI resources for the pre-clinical development of drugs, natural products, and biologics. A partial listing of those services includes: high-throughput screening, studies in animal models, formulation, pharmacology and toxicology studies, and bulk substances acquisition.
2. Type 1 Diabetes- Preclinical Testing Program (T1D-PTP)
In some cases, additional preclinical testing is needed to validate potential therapies under disease-specific conditions and in multiple animal models before therapeutics can enter the T1D-RAID development pipeline. In recognition of this need, NIDDK recently established the Type 1 Diabetes Preclinical Testing Program (T1D-PTP) to provide investigators with access to the established facilities and expertise needed to extend, enhance and validate preclinical studies of promising new therapeutics. The T1D-PTP program currently supports two contracts, which are separate from each other and from the T1D-RAID NCI contract resources mentioned above, to assist in preclinical development of therapeutics for T1D:
- Agents to be tested for Preclinical Efficacy in Prevention or Reversal of Type 1 Diabetes in Rodent Models. Type 1 Diabetes Preclinical Testing Program (T1D-PTP) (NOT-DK-08-012)
- Testing for Preclinical Efficacy in Prevention or Reversal of Diabetic Complications in Rodent Models (NOT-DK-07-013)
The T1D-RAID and T1D-PTP are programs intended to remove the most common barriers to progress in identification and development of new therapies for Type 1 Diabetes. The common goal of these programs is to support and provide for the preclinical work necessary to obtain "proof of principle" establishing that a new molecule or novel approach will be a viable candidate for expanded clinical evaluation.
What the Type 1 Diabetes Preclinical Testing Program is not:
The T1D-RAID and T1D-PTP programs are not intended to be a pipeline for materials for NIH-held INDs. It is assumed that most of the products will be studied clinically under investigator-held INDs within the originating (or a collaborating) institution.
Acceptance into the NIDDK T1D-PTP program does not imply any future commitment for services under T1D-RAID. Future T1D-RAID service requests should be submitted separately and will be reviewed according to T1D-RAID program guidelines.
Like T1D-RAID, NIDDK T1D-PTP does not award grants to a particular laboratory. Support will be provided in the form of access to NIDDK-supported contract facilities that will assist investigators by providing expertise and facilities needed for preclinical testing in multiple disease-relevant animal models. It may happen that some assays are best carried out in the originating laboratory, in which case NIDDK will advise on other mechanisms available for support of this work. The focus will be on using NIDDK staff and contractor expertise to define the most effective and cost-efficient means of accomplishing the necessary tasks to establish preclinical efficacy of new therapeutics.
B. Services
NIDDK’s Type 1 Diabetes Preclinical Testing Program is designed to assist in accomplishing tasks that are rate-limiting in bringing discoveries from the laboratory to the clinic. Once a project has been approved, NIDDK staff interact directly with the Principal Investigator (PI) and T1D-PTP contractors to design, perform and oversee execution of approved tasks. The necessary tasks will vary from project to project, and will vary depending on the specific T1D-PTP Contract required to perform services (see NOT-DK-07-009 or NOT-DK-07-013).
The output of T1D-PTP activities will be data and information that will be made fully available to the originating investigator, as well as to the public, for support of further preclinical development from an IND application to clinical trials.
C. Eligibility
The following are acceptable types of organizations that can request program resources:
- Academic institutions
- Non-profit research institutions
- Biotechnology and pharmaceutical companies
- U.S. and non-U.S. entities
II. T1D-PTP Request Process
A. Overview
The NIDDK Type 1 Diabetes Preclinical Testing Program will receive requests twice each year as indicated in the NIH notices describing each activity (NOT-DK-07-009 and NOT-DK-07-013). A letter of intent is encouraged one month prior to submission of a Request. Proposals will consist of a written description of the request including rationale and preliminary data supporting the concept; recommendations about dosing, route and timing of the intervention; methods for documenting biochemical and physiologic effects; and assays to monitor compound concentration and stability. The Request itself should be no more than 15 single-spaced pages (Public Health Service grant application materials ARE NOT required). An individual product has three chances to be approved by T1D-PTP. Revisions should directly address the concerns raised by the reviewers and NIDDK staff. After three unsuccessful attempts, subsequent requests focusing on the same product will be returned without review. All requests should be submitted by an individual scientist "sponsor" whose responsibilities include:
- Providing a rationale for the choice of intervention including strong preliminary data showing evidence of efficacy on animal models of T1D, other organ specific autoimmune diseases and/or data derived from human studies.
- Making recommendations about proper dosage and timing of the intervention.
- Proposing methods for documenting the intervention has the expected biochemical and/or physiological effects.
- Proposing methods to assay pharmacokinetics of the compound to ensure that is stable and reaches expected blood serum levels.
- Information, if available for mechanistic testing which could lead to biomarkers useful for monitoring efficacy in clinical trials.
B. Components of the Request (15 pages, not including appendices)
Investigators requesting consideration of a specific intervention (single agent or combination of agents) for inclusion in the T1D-PTP program should send a request prepared in accordance with the format described below. Individuals or groups who wish to recommend more than one intervention for consideration are encouraged, but should use separate requests for each proposed intervention. The request should be submitted in Microsoft Word format and include the following, in order:
Title Page
- The title of the request should include the name of the substance(s) or formulation being tested and its purpose.
- Indicate which T1D-PTP opportunity solicited this proposal (NOT-DK-07-009, or NOT-DK-07-013).
- Provide contact information, including the name, institutional address, telephone, fax, and e-mail of the individual submitting the proposal.
Abstract
300 words or less
Background
Describe concisely the reason why the compound(s) deserves to be evaluated for its potential beneficial effects on the prevention, delay or reversal of T1D or its complications. The rationale should include:
- Theoretical framework
- Pilot data in animal models or humans if available
- Pharmacokinetic, pharmacodynamic and toxicity data if available.
- Clinical Potential
If including unpublished data, provide enough information (i.e., figures, tables, protocols) to permit rigorous evaluation. If including published data, provide similar information and a reference citation to the publication(s) from which the data are derived. The background section should be no longer than five pages (including figures and tables).
Suggested Intervention Protocol
Provide a detailed description of the compound(s) to be tested and the rationale for the protocol proposed. This information will assist in development of a final testing protocol.
The following should be addressed:
- Nature and proposed biological activity of the agent.
- Route of administration of the agent and justification. Dosage and frequency of administration.
- Source and suggested suppliers. Cost estimate.
- What is the best way to monitor or test whether the agent produces the expected physiological or pharmacological effects in the animal model? Will this require blood tests or other fluid samples, or will it require that some of the animals be sacrificed to obtain internal tissues? If a blood test is required, how much blood is needed? At what age, or at what time after treatment initiation, should the test be performed? How expensive is the test to conduct? If the test requires specialized expertise or equipment not provided by the contractor, is this available in the sponsor's laboratory, other locations?
- At what age should the intervention be initiated? Is there a range of ages that would be acceptable? Duration of the treatment and rationale for study design must be provided.
- Expected outcome.
- Data analysis and interpretation.
Animal Safety
Describe what is known about potential harmful side effects the treatment might have on rodents. If the sponsor knows of any pilot data based on either short-term or long-term exposure of rodents or other mammals to the treatment, the application should state this and describe any harmful side effects noted in the previous study. If the sponsor knows of toxicity data related to other doses of the compound or to related compounds, this should be summarized for evaluation by an institutional animal use committee.
Costs of Testing
The T1D-PTP program provides support to its contractors for animal acquisition, animal housing, testing, statistical analysis, and purchase, or cost-shared purchase, of test agents. The sponsor should provide information on the source and cost of the agent(s) to be studied: (1) If the agent is available from commercial sources, will it be donated or what is the estimated cost to obtain a sufficient supply of the agent for the number of animals to be tested? (2) Can the sponsor provide the agent to the program at no cost? or (3) If the agent is not available commercially and cannot be provided by the sponsor, the sponsor should: (a) provide a justified cost estimate of a sufficient supply of the compound to treat the number of animals proposed for the duration of the treatment and (b) state the proportion of the cost that the program is requested to provide.
*Special Cost Considerations: If cost is associated with the acquisition of the agent(s) and you have a negotiated General Services Administration (GSA) rate, please apply this rate to any and all costs.
Statement of Understanding
The application should include the following statement of understanding:
"In submitting this request, I agree to the following: I understand all information presented in the request can be shared freely with members of the NIDDK T1D-PTP advisory panel during its evaluation of applications, but will otherwise be considered confidential. I understand that NIDDK intends to make publicly available the results of all supported studies—regardless of whether they produce data showing positive or negative effects on the prevention, delay or reversal of T1D or its complications. Such data may then be used in applications for further research support by anyone. I also will be free to use NIDDK generated data in the context of applications for research support or for any other purpose."
*Include only if applicable: "The agent/compound recommended makes use of materials that are not yet freely available and whose production depends on proprietary or unpublished methods. If my application is approved for incorporation in this program, a mutually acceptable Materials Transfer Agreement that would permit me to provide the contractor with the compound(s) needed for the experimentation will be developed with the institutions involved in this program."
Appendix
Provide a biographical sketch of the sponsoring investigator (1-2 pages). Include any background preprints or reprints (maximum of five; not included in the page limitation) and relevant patents. Attach relevant letters of collaboration. Provide any analytical characterization (e.g. proof of identity, purity) or any product for which biological data is provided.
*Additional Important information:
- Requests are NOT expected to ask for specific funds or even estimate costs except as indicated above under "Costs of Testing".
- Requests should not include colored graphics, glossy photographs, or other materials that cannot be accurately reproduced as black and white photocopies. If absolutely essential, please be aware that not all reviewers will have access to the color copies.
- Resubmitted requests must include a response to reviewer critiques of the original Request.
- If a re-request is made to T1D-PTP for continuation of a previously completed task, summaries of the relevant completed NIDDK studies should be included in the "Background" section as a specifically indicated basis for the current Request.
Study Results
Study results will be made available to the public. The protocol should provide sufficient statistical power to detect significant differences in terms of prevention, delay, reversal or amelioration of T1D or its complications. In addition, compounds may be tested to determine their possible mechanism of action and whether biomarkers/surrogate markers that quantitatively assess their beneficial effects or the organism response to them may be identified (immune response and function, beta cells/islet function markers, markers of insulitis progression/beta cell autoimmune destruction, metabolic parameters, markers of tissue injury, etc).
C. Submission Information
Requests prepared in MS Word format can be submitted electronically to contact personnel listed in NOT-DK-07-009 or NOT-DK-07-013. Alternatively, three complete copies of each request may be submitted by FAX or regular mail to these same individuals.
III. T1D-PTP Review Process
Requests will be reviewed for support by a specially convened T1D-PTP Review Panel consisting of outside experts from academia and industry. An internal NIDDK Review Panel will also discuss the submitted requests. Review Panel members are bound by confidentiality agreements customary for review of NIH grants. The review criteria will reflect an emphasis on fostering development of T1D therapeutics and relevant preclinical testing. Acceptance into the program will be based on scientific merit, programmatic relevance, perceived translational potential and availability of resources.
A. Review Criteria
External Review
A specially convened ad hoc Review Panel of experts from academia and industry will initially evaluate the Requests in a confidential manner for scientific and technical merit. The Panel will review and prioritize each Request on the basis of the following evaluation criteria:
- Strength of the hypothesis: the extent to which the Request is associated with a compelling hypothesis that strongly merits exploration.
- Novelty: the extent to which the Request will enable preclinical development of new therapeutic and prevention strategies that have not been adequately explored.
- Research & Development plan: the clarity and appropriateness of the R & D plan and the likelihood that the planned tasks can be accomplished in a straight forward fashion. The Review Panel reserves the right to scale back an investigator's request based on development or feasibility concerns and may recommend approval of only a portion of the requested tasks.
Internal Review
Requests will receive a secondary level of review by the NIDDK internal oversight committee. NIDDK projects will be compared with tasks currently assigned to NIH contractors and a final prioritization of projects will be made taking into consideration the following additional factors:
- Importance of projects in addressing NIDDK research agendas
- Portfolio diversity (e.g., multiple projects directed against the same molecular target may be less favored than projects addressing diverse modes of action).
- Contract capacity (e.g., an individual contract may be better able to initiate a particular project based on the availability of resources).
B. Timelines
Submission timelines are as indicated in the Notices published in the NIH guide for each activity (see details provided in NOT-DK-07-009 for projects directed at prevention or reversal of Type 1 Diabetes, or in NOT-DK-07-013 for projects directed at diabetic complications).
C. Implementation of Supported Requests
T1D-PTP Review Committees have the authority to scale back an investigator's request based on development or feasibility concerns and to recommend approval of only a portion of the requested tasks. The number of projects to be supported in any review cycle will be a function of the level of merit and availability of funds and resources.
IV. Program Oversight
The NIDDK expects to convene an oversight committee consisting of outside advisers and a subgroup of its own members. This group will periodically review the progress and direction of the T1D-RAID and T1D-PTP programs and explore opportunities for program development and enhancement.
