Form 3 Solicitation Instructions (TRND).

Form
 Approved

OMB
 NO.
 0925-­‐XXXX

Exp.
 Date
 XX/XX/2015

Solicitation for Collaborative Projects
Therapeutics for Rare and Neglected Diseases (TRND) Program
NIH Center for Translational Therapeutics (NCTT)
National Institutes of Health
Introduction to TRND
TRND Program Application Instructions
Overview
General Instructions
Required Documents for Therapeutics for Rare and Neglected Diseases
Applications
A. TRND Concept Application
1. Background
2. Therapeutic Hypothesis
3. Current State of Project
4. Proposed Development Strategy
5. Justification
6. Timeline and Milestones
B. Appendices
• References
• Public Abstract
• Intellectual Property (IP) Information
• Key Investigators Biosketch
Evaluation Process
Projects Selected by TRND
• Project Team
• Project Plan
• Project Termination
Collaborative Agreements
TRND Proposal Resubmission Instructions
Introduction to TRND
Public
 reporting
 burden
 for
 this
 collection
 of
 information
 is
 estimated
 to
 average
 1
 hour
 per
 response,

including
 the
 time
 for
 reviewing
 instructions,
 searching
 existing
 data
 sources,
 gathering
 and
 maintaining

the
 data
 needed,
 and
 completing
 and
 reviewing
 the
 collection
 of
 information.

 An
 agency
 may
 not

conduct
 or
 sponsor,
 and
 a
 person
 is
 not
 required
 to
 respond
 to,
 a
 collection
 of
 information
 unless
 it

displays
 a
 currently
 valid
 OMB
 control
 number.

 Send
 comments
 regarding
 this
 burden
 estimate
 or
 any

other
 aspect
 of
 this
 collection
 of
 information,
 including
 suggestions
 for
 reducing
 this
 burden,
 to:
 NIH,

Project
 Clearance
 Branch,
 6705
 Rockledge
 Drive,
 MSC
 7974,
 Bethesda,
 MD
 20892-­‐7974,
 ATTN:
 PRA

(0925-­‐XXXX).

 Do
 not
 return
 the
 completed
 form
 to
 this
 address.

The National Institutes of Health (NIH) Therapeutics for Rare and Neglected
Diseases (TRND) program is a new Congressionally mandated program that
performs preclinical and early clinical development of new drugs for rare and
neglected diseases, and develops new technologies and paradigms to improve the
efficiency of therapeutic development for these diseases. The operational model of
TRND is collaboration between intramural NIH drug development scientists and
partners having promising leads and disease/target knowledge but lacking the
expertise and resources to develop these projects into clinical stage programs
attractive to biopharmaceutical or other suitable organizations.
The last several decades of research have produced unprecedented understanding
of the genetics and pathobiology of many rare
(http://rarediseases.info.nih.gov/files/Rare_Diseases_FAQs.pdf) and neglected
(http://rarediseases.info.nih.gov/files/Neglected_Diseases_FAQs.pdf) diseases, but
the vast majority of these disorders have no drug treatment available. Of the
approximately 7,000 human diseases, fewer than 500 are of interest to the
biopharmaceutical industry, due to limited commercial potential and high perceived
development risk. High-throughput screening centers in the private and public
sectors, including those supported by the NIH Molecular Libraries Program, have
produced a large number of chemical probes useful for the understanding and
validation of novel targets for many rare and neglected diseases (RND). However,
the difficulty, expense, time, and expertise and resource requirements of the
development process required to transform a promising probe or lead into a clinical
candidate molecule have prevented all but a few RND programs from reaching
clinical testing or approval. This process, encompassing what is sometimes referred
to as the “Valley of Death” because of its difficulty and risk of failure, is preventing
the realization of the promise of basic biomedical research from reaching patients
with rare and neglected diseases, and is what the TRND was specifically created to
address.
The minimal starting point for TRND, and the subject of this solicitation, is a highquality chemical or biological lead with validated biology and efficacy models that
can support preclinical and early clinical development. Another starting point is a
repurposed, marketed therapeutic with sufficient data to support its use in an RND
indication. The exit point for TRND projects adopted from this solicitation will be
licensing to an organization outside TRND that will carry the program forward to
regulatory approval. It is expected that is most cases, TRND will perform the
medicinal chemistry, drug metabolism and pharmacokinetics (DMPK), toxicology,
formulation, and other studies required to create compounds that meet Food and
Drug Administration (FDA) requirements for Investigational New Drug (IND)
approval. TRND will perform proof-of-concept human studies (Phase I-IIa) only as
needed to enable successful licensing.
The TRND program is an NIH Intramural activity, part of the newly-established NIH
Center for Translational Therapeutics (NCTT). NIH TRND scientists will be
responsible for the development process. However, well-validated targets, efficacy
models, starting point lead compounds, and deep target and disease expertise are
critical for success, and are sought in this solicitation. TRND will establish

2

collaborations with researchers in the public and private sectors to together “derisk” RND drug development projects by accomplishing lead optimization through
IND and proof-of-concept human studies.

TRND Program Application Instructions
Overview
This is not a grant application. Rather, it is an application to collaborate with the
scientific capabilities, expertise, and resources of TRND, with the goal of moving
promising small molecules and biologics into clinical testing. If successful, you will
partner with the TRND to develop and execute a milestone-driven drug
development program. TRND will provide drug development expertise and
operations. The applicant collaborator(s) will provide starting points for the project,
ongoing biological/disease expertise, and when appropriate and with the support of
TRND funding, efficacy or other testing of compounds developed in the course of
the project.
As discussed above, the primary focus of TRND is the preclinical phase of small
molecule and biologic drug development for rare and neglected disease. It is
expected that projects will enter TRND at a variety of stages, but no earlier than
the stage of optimization of well-characterized leads, and no later than an NME,
NBE, or repurposed drug in need of IND-enabling studies. The endpoint of TRND
projects will be their adoption by organizations outside TRND, which will complete
clinical development and registration. While these endpoints will be projectspecific, it is expected that most projects will exit TRND at the stage of IND
application/approval, or when required, when initial safety and efficacy studies in
humans have been completed.
The purpose of this solicitation, the first of the newly-initiated TRND program, is to
select initial drug development programs for collaborative development. All
rare/orphan and neglected diseases are of interest. It is anticipated that TRND will
issue two solicitations for this type of project per year.

General Instructions
At this time, TRND is considering only small molecule or biologic therapeutic
development projects for collaboration. Devices, diagnostics, and medical
procedures are not responsive at this time.
Proposed projects must target an untreated or poorly treated rare or neglected
disease, as defined here:
http://rarediseases.info.nih.gov/files/Rare_Diseases_FAQs.pdf
http://rarediseases.info.nih.gov/files/Neglected_Diseases_FAQs.pdf.

 Special
consideration will be given to projects with the potential to address more than one
rare or neglected disease by virtue of shared pathophysiology, and projects with a

3

well-developed strategy to exit TRND and complete clinical development,
registration, and marketing.
Projects must be at least at the stage of a validated lead series in order to be
considered for TRND. Projects requiring earlier-stage resources, including assay
development, high-throughput screening, and initial medicinal chemistry
optimization of screening hits, are not appropriate for TRND; researchers interested
in these resources are directed to other NIH resources including the Molecular
Libraries Program (http://mli.nih.gov/mli/) and the NCI Chemical Biology
Consortium/NExT program (http://next.cancer.gov/about/default.htm).
This "TRND Concept Application" includes eight (8) sections as described in detail
below; additional material can be uploaded as an appendix. Please use the TRND
Concept Application Template, available only when the solicitation is open,
at proposalCENTRAL. Please convert all documents to searchable PDF files before
submission. All materials submitted to proposalCENTRAL are considered
confidential. All reviewers will sign conflict of interest and confidentiality
agreements before being given access to applications.
TRND encourages potential applicants to contact TRND staff via our webpage at
http://trnd.nih.gov/?page_id=121 prior to submitting a proposal in response to this
solicitation.
Required Documents for Therapeutics for Rare and Neglected Diseases
Program Applications
A. TRND Concept Application
The concept application document should not exceed 5 pages (Arial 11pt, single
space, 1” margins, not including the pages that contain tables provided to collect
data on lead compounds). Graphs, pictures and tables should be included in the
text. The application should succinctly define the scientific nature and rationale of
the proposed project and the current stage of its development, and should include
the following:
1. Background: Provide a brief summary of the disease to be treated and the
rationale for the type of small molecule compound or biologic therapeutic in
order to provide the reviewers an understanding of the opportunity. Include
data on rare or neglected disease status, the current standard of care for the
disease, and why new therapies are needed. Very briefly describe the
competitive landscape and efficacy data on comparator compounds, if any.
2. Therapeutic Hypothesis: Include a clear statement on the therapeutic
hypothesis and the clinical indication to be targeted for FDA approval. This
can include the projected reduction of symptoms, slowing of disease
progression, or the feasibility of treating the disease. Review the level of
consensus in the field supporting the proposed mechanism of disease and
hypothesis that modulation of the proposed target will substantially improve

4

morbidity and/or mortality in the disease. Summarize the evidence that
validates the drug target from cellular or animal models and clinical studies.
Assess feasibility to reach first in human studies. Manuscripts and supporting
publications can be uploaded in the appendix.
3. Current State of Project: Projects of interest will be at one of the following
stages: (1) lead optimization including clear structure-activity relationships
(SAR) in at least two structurally distinct chemical series or well defined
biological lead, reproducible activity in primary and orthogonal assays,
efficacy in an accepted animal model (or when not available, cellular model)
of the disease, and initial indications of favorable Absorption, Distribution,
Metabolism, and Excretion (ADME) properties, (2) high-quality New Molecular
Entity (NME) lead(s) with clear efficacy, good DMPK properties and initial
non-GLP safety studies demonstrating absence of gross toxicities, (3) NME
clinical candidates with incomplete IND-enabling
PK/PD/toxicology/formulation studies; or (4) a drug previously approved for
another indication by FDA with efficacy in an animal (or when not available,
cellular) model of a rare or neglected disease, making it a candidate for
repurposing but in need of formulation, dose-finding, disease-specific
toxicology, or other studies to allow clinical testing to commence. As
appropriate for the stage of the program, please describe:
a. Compound or biologic optimization status and strategy, including the
assays and efficacy studies used to guide medicinal chemistry
optimization and define structure-activity relationships (SAR),
including evidence of their robustness, reproducibility, and relevance
to the human disease or symptom. Include results of molecular
pharmacology assays, including in vitro functional activity, potency,
and pharmacology, including evaluation of efficacy in biochemical,
cellular, and model organism assays, and justification of the relevance
of those assays to the human symptom/disease to be treated
b. Medicinal chemistry optimization performed to date, including
questions remaining and potential for further optimization.
c. Evaluation of Absorption, Distribution, Metabolism, and Excretion
(ADME) properties in vitro and in vivo, including routes and products
of metabolism, microsomal stability, and related studies
d. Evaluation of pharmacokinetics (PK), pharmacodynamics (PD), and
efficacy, including oral bioavailability and half-life in serum and other
relevant fluids/tissues
e. Toxicology studies in rodents and non-rodents, including IND-directed
toxicology, with correlative pharmacology and histopathology
f. Definition or optimization of dose and schedule for in vivo activity in
animal models
g. Pharmacodynamic measures in animals, and their applicability as
biomarkers in human studies
h. Acquisition of bulk substance (Good Manufacturing Practices - GMP and
non-GMP), and availability of protocols for scale-up production from
lab-scale to clinical-trials lot scale, and analytical methods

5

i. Development of suitable formulations
j. Production and stability assurance of dosage forms
k. Projected dose, dose regimen, length of treatment and duration of
therapeutic response in humans, if known
l. Biomarkers developed, and evidence of their utility and predictive
value in the clinical setting
m. Determination of clinical endpoints, and whether these are accepted by
regulatory agencies
n. Describe natural history studies of the disease and their relevance to
the indication of the candidate therapy
o. Status of biobanks and registries of patients with the disease and
which organizations maintain them
p. Potential clinical trial designs and evidence of feasibility
q. Results of consultations with FDA or other regulatory agencies, if any,
on the project
r. Results of assessments you have received from impartial clinical
experts in the field on why modulation of the
target/pathway/phenotype is expected to decrease the morbidity or
mortality of the disease.
s. Results of discussions and assessments with potential drug
development partners that would support this drug candidate to FDA
registration and market launch.
t. For projects with clinical data: provide a summary of clinical efficacy,
safety, and PK/PD data. Describe the clinical trial strategy (e.g.,
primary and secondary study objectives, endpoints, patient population,
eligibility criteria, estimated sample size, treatment arms/regimens,
statistical endpoints, correlative studies, and patient samples required
to perform correlative studies). Describe availability of clinical trial
support, infrastructure resources, and experts available. If available,
the Investigator's Brochure should be uploaded in the appendix.
4. Proposed Development Strategy: Describe what is needed to advance the
program to IND status for the rare or neglected disease indication, what the
current roadblocks to development are, and the stage that the project will
need to be taken to in order to attract outside development resources. If the
development plans are not established or clear, please indicate this. Include
specific details as necessary to demonstrate that the project has been well
thought out (for example, the availability of appropriate cellular and animal
models, patent searches on the compounds and components of the assays
used to evaluate efficacy, etc.). Address the scientific feasibility of the
proposed development strategy, and whether and why proof-of-concept
human studies are likely to be needed for the project to be licensed.
5. Justification: Address how the resulting drug from this collaboration will
change standard of care and impact the practice of medicine for this rare or
neglected disease. Provide a statement that the applicant team will engage
and collaborate for the length of this drug development project and what
expertise and/or resources the applicant will bring to the project team.

6

Describe the likelihood of the drug candidate being adopted at the completion
of preclinical development (i.e., once an IND is approved), and why another
organization (biotechnology companies, venture capital firms, pharmaceutical
companies) is presently unwilling to fund or develop this drug project as it
currently stands.
6. Timeline and Milestones: Outline a potential timeline for conducting the
collaborative research with TRND. Include potential milestones. Describe
potential challenges and go/no go decision points (a timeline chart is
acceptable). (Note: Following acceptance the project, a project team of
TRND investigators and applicant investigators will establish a new timeline,
milestones, and go/no go decisions points based on the evaluation
recommendations.)
7. Appendix 1: Tables are provided in the appendix 1 to facilitate data
collection on proposed lead compound or compound series. In each table,
clearly indicate the ID/name of the molecular entity of which the data were
generated. In the first group of tables, provide the structure (s) of the
chemical lead compound for NME or composition for NBE; populate the tables
with any current physical property data, in vitro and in vivo efficacy data,
and PK data on the proposed lead compound(s). If there is no data
generated for a particular property, leave the data cell empty or enter N/A if
not applicable to your proposal. Do not delete any cells in the tables. If there
are relevant data specific to your proposal, but not included in the tables,
add rows and indicate clearly in the ID column, what type of data are
included. Populated tables in appendix 1 are REQUIRED to be included in the
uploaded proposal, but are not counted towards the 5 page limit of the
proposal.
8. Appendix 2: References are provided to applicants for in vitro ADME assays
and in vivo pharmacokinetics assays. This portion of the template need not
be included in uploaded proposal.
B. Appendices
• References: Please provide no more than 15 references that relate directly
to the project. Upload at least 5 key reference papers as PDF files to
accompany the proposal.

•

Public Abstract: The selected drug development projects that put
collaborative agreements into place with TRND will have a public abstract and
timeline posted on the TRND website. Please provide a non-confidential
abstract that describes the disease, the projects, the medical treatment
goals, and the timeline.

•

Intellectual Property (IP) Information: The applicant should include a
list of any patents issued or pending with respect to either the agent or to
any non-commercially available technology/material required for the
7

development of the agent. In the event that an application requires the use
of non-commercially available technology/equipment that is patented by a
third party, the applicant must provide documentation that the patent holder
does not object to the applicant's use with the proposed project.
Each TRND application must include the information described below
signed by an authorized staff member overseeing IP and/or
technology transfer at the applicant's institution or company. This
verifies that he/she has reviewed the TRND request and that the technology
is eligible for consideration by the TRND program. If the technology is found
not to be eligible for use as outlined in the TRND application, and it is central
to the investigator's proposal, submission to the TRND program is not
encouraged.
If available, the following information is requested:
• Details of all the following rights that are owned by your institution and
will be used in the project (the "institution's IP"):
§ Patents and patent applications
§ Significant know-how
§ Registered trademarks, applications for registered trademarks,
and other marks
§ Registered designs, applications for registered designs, and
significant other designs
§ Significant copyright works and other IP rights
• Details of all employees, consultants, and other parties involved in the
development of the institution's IP related to the TRND project
submission. (Are there contributors outside the institution, and if so,
what was their role in development?)
• A complete list and brief description of all agreements with third
parties related to the TRND project submission:
§ Granting rights to those third parties under the institution's IP
§ Granting rights under third-party IP to the institution
• A complete list and brief description of all confidentiality agreements
with third parties related to the TRND project proposal
• Details of any:
§ Claims made by third parties against the institution related to
the project proposal that the institution has infringed a third
party's IP rights
§ Circumstances where a third party has or may have infringed
the institution's IP or other IP used in the institutions' business
related to the project proposal
Institution IP constitutes background IP. Inventorship of new IP created
from this partnership/collaboration will be determined according to patent
law.
•

Key Investigators Biosketch: All Key Investigator (all investigators
intellectually involved in the project) bio-sketches should follow the NIH
8

standard format (http://grants.nih.gov/grants/funding/phs398/phs398.html).
In the list of publications, please highlight any that are directly related to
proposed project by preceding them with a double asterisk (**). All Key
Investigators should list all current external sources of research funds. The
lead PI (point of contact) should provide additional contact information.
Evaluation Process
Applications to the TRND Program are evaluated by a Technical Evaluation
Panel (TEP) consisting of non-NIH experts in drug development. The
applications will be evaluated according to the following criteria.
Criteria (weight of criteria):
1. Target and therapeutic validation (30%),
2. Strength of current data package (30%)
3. Feasibility to reach First in Human clinical trials (20%),
4. Medical impact relative to current Standard of Care (10%),
5. Likelihood of external adaption (10%).
In addition, the TEP will rate the strength of the development project in
(where applicable):
1. Medicinal Chemistry
2. ADME
3. PK/PD
4. Toxicology
5. In vivo models
6. Secondary and tertiary assays
7. Formulation
8. Chemical Manufacturing and Controls (CMC) for small molecule projects
9. Expression/Purification for biologics projects
10. IP Status
Following the TEP evaluation, the top applications will be discussed by NIH
staff in relevant Institutes and Centers for synergy and overlap. A second
level of evaluation for program balance, workload distribution, and resources
will be conducted by the Advisory Committee to the Director, NIH (ACD)
TRND Working Group. The ACD TRND WG will share their recommendations
with the full ACD. The Director of the NIH and the Director of the NCTT will
make final decisions on projects to be adopted by TRND.
Collaborative Agreements
Once selected applicants are notified, NCTT/TNRD and the applicant will
initiate an NIH collaborative agreement. When the collaborative agreement
is agreed to and signed by all parties, the collaborative project will start.
Please see the TRND website (http://trnd.nih.gov) for more information on
this topic.

9

Projects Selected by NCTT/TRND
• Project Team: Once the project is selected for collaboration (and as the
collaborative agreement is being discussed), a project team will be formed of
both TRND and applicant investigators. The project team will develop a
Project Plan and define the:
• Development Plan
• Timeline
• Milestones and Deliverables
• Go/No Go decision points
•

Project Plan: The Project Plan will be approved by NCTT leadership. Any
changes to the Project Plan will need to be approved by the NCTT leadership.
Go/No Go decisions will be evaluated by an NCTT advisory panel for
recommendations to NCTT leadership in stopping a project.

•

Project Termination: Upon not meeting timeline, milestones, and/or
deliverables, or with the recommendation of an NCTT advisory panel, NCTT
will terminate a project. Whenever possible, the applicant investigators will
be provided guidance on how to move the project forward. Applicants will be
encouraged to submit a new application if barriers are outcome.

TRND Proposal Resubmission Instructions
A resubmission is submission of an application that has previously been reviewed
and not selected. TRND will accept only two resubmissions to the TRND program.
The resubmission consists of a Resubmission Summary not to exceed 2 pages.
Applicants are encouraged to include an amended concept application in which
changes are marked. Reviewers will have access to the original application.
The resubmission should include the following:
1. A Resubmission Summary not to exceed 2 pages.
o Explain how the application has been modified and strengthened.
o Respond to the comments and recommendations from the scientific
reviews. Address any disagreements with reviewers' comments.
2. Applicants are encouraged to submit an amended version of the original
concept application to highlight substantial scientific changes.
o The amended application should follow the current "TRND Proposal
Instructions" as described under “Required Documents for
Therapeutics for Rare and Neglected Diseases Applications" and should
not exceed 5 pages.
o Substantial scientific changes must be clearly marked
with underlining, italics, bold, or other formatting. However, if the
changes are so extensive that essentially all of the text would be
marked, explain this in the Resubmission Summary.

10

3. Any work completed since the original application was submitted can be
included as an appendix.
Applications should be resubmitted according to the published TRND submission
cycle (see TRND Website, http://trnd.nih.gov).
Submit or Resubmit an Application

11