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NINDS CREATE Bio Discovery Track: Optimization in Preparation for Development of Biotechnology Products and Biologics (U44)

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Agency: Department of Health and Human Services
Program/Year: SBIR / 2014
Solicitation Number: PAR-14-287
Release Date: July 18, 2014
Open Date: September 21, 2014
Close Date: May 7, 2017 (closing in 869 days)
001: Funding Opportunity Description
Description:
A. Overview

This Funding Opportunity Announcement (FOA) is part of a suite of complementary programs to encourage the translation of research discoveries into new treatments for disorders that fall under the NINDS mission.

The NINDS Cooperative Research to Enable and Advance Translational Enterprises for Biotechnology Products and Biologics (CREATE Bio) program is dedicated to biotechnology product- and biologics- based therapies, which broadly include modalities such as peptides, proteins, oligonucleotides, gene therapies, and cell therapies.  The program includes two tracks: the Discovery Track supports lead optimization in order to obtain a candidate appropriate for entering the Development Track, and the Development Track supports IND-enabling studies for the candidate, as well as early-phase clinical trials (See NINDS FOA PAR-14-289).

For entry into the Discovery Track, projects must have convincing proof-of-concept data and one or more lead(s) that are sufficiently profiled so that the parameters to be optimized can be quantitatively specified (see entry criteria for details) in the application.  At the end of the funding period, a candidate should be in hand that has sufficient bioactivity, stability, manufacturability, bioavailability, in vivo efficacy and/or target engagement (measurement of target binding or proximal downstream effects) with defined minimal and optimal doses, and other favorable properties consistent with the desired clinical application (see Scope below for details).

Projects are funded through the U44 cooperative agreement award mechanism, which involves NINDS Scientific/Research staff's participation in developing the project plan, monitoring research progress, and appropriate go/no-go decision-making.  NINDS staff will also provide assistance to academic investigators in familiarizing them with the therapeutic development process and the criteria needed to advance therapeutic leads to the clinic.  The expectations of the program are in line with those of industry with regards to advancing therapeutic agents through the developmental pipeline. 

For more information about other NINDS Translational Programs visit the website http://www.ninds.nih.gov/funding/areas/translational_research/index.htm and for more information  specifically about the CREATE Bio Program visit the website (http://www.ninds.nih.gov/funding/areas/translational_research/CREATE-Bio.htm) .  Applicants are strongly advised to read through the CREATE Program Announcement Frequently Asked Questions (FAQs) and examples at the website (http://www.ninds.nih.gov/funding/areas/translational_research/CREATE-FAQ.htm).

B. Scope

Projects should focus on a single disorder that falls within the NINDS mission.

The CREATE Bio FOAs focus on biotechnology products and biologics, which broadly include modalities such as peptides, proteins, oligonucleotides, gene therapies, and cell therapies.  Applicants should contact NINDS Scientific/Research staff regarding small peptide derivatives, natural products, molecules with complex structures, or combination products, to determine the fit for the FOA.  

Entry Criteria:

To be eligible for this Discovery Track FOA, projects must meet the following criteria:

(1) There must be a clear and convincing demonstration of proof-of-concept (e.g., clear dose-response relationship). The therapeutic leads should show either in vivo efficacy using clinically relevant outcome measures (e.g., anatomical, and functional when possible), and/or in vivo target engagement (measurement of target binding or proximal downstream effects) at the clinically intended site of action, using sufficient experimental and statistical rigor.  If an established animal model exists for the disease, demonstration of in vivo efficacy is the minimal requirement. 

(2) Applicants must have one or more therapeutic leads from which a candidate can potentially be derived.  For a therapeutic lead, a few final design characteristics may still need to be optimized. See Scope section for examples. The leads must have been sufficiently profiled so that all the essential key parameters to be optimized to fulfill criteria for a candidate can be quantitatively specified and prioritized. Critically, the preliminary findings need to be at a stage where IND-enabling studies are feasible at the end of the 4 years of funding.  Bioactive agents where little is known about their profile or where too many parameters (e.g., three or more) need to be optimized may not be advanced enough yet to enter the program.  

Note: NINDS recognizes that, depending on the type of agent and how it was identified and characterized, projects will enter at different stages, where certain required properties may have been optimized (repurposing a marketed therapy for a new indication is an extreme example). In the case of repurposing, the applications must show feasibility to proceed to an Investigation New Drug (IND) application and/or clinical evaluation, assuming the results from the Discovery Track funding period are positive.  For example, the applicants should have collaborations that enable access to existing toxicology or human trial data required by the Food and Drug Administrations (FDA), and have the decision rights or partnership(s) to further the development of the agent for the proposed new indication.

(3) For key in vitro and in vivo assays proposed to optimize the leads, applicants must have pre-existing data demonstrating that the assays are suitable for the proposed purpose and available in either the applicant's or collaborator's laboratories.  Appropriate controls should be employed and efforts should be taken to demonstrate dynamic detection range and acceptable variability so the feasibility of conducting the proposed studies can be adequately assessed.

At the end of the Discovery U44, successful projects should minimally achieve the following:

(1) Optimization is finished and final characterization of the candidate, such as structure/identity, selectivity, stability, manufacturability, and other modality- specific characteristics are complete.

(2) For a candidate with sufficient purity, its minimal effective dose, optimal effective dose, time and duration of treatment, have been determined in relevant in vivo assays using clinically relevant functional and/or anatomical outcome measures, and/or in vivo target engagement assays.  [This normally should have been done using the clinically intended route of administration and special formulations if proposed (such as slow release, liposomes, nanoparticles, etc.), unless justified to use other routes of administration in which case the dose-response must have been reliably bridged by pharmacokinetics measurements]. The in vivo study results should also include assessment of pharmacokinetics, bioavailability at the relevant site of action, and pharmacokinetics-pharmacodynamics relationship. In particular for CNS disorders, there needs to be rigorous evidence that the agent is blood-brain-barrier penetrant (unless the agent is proposed to be delivered directly to the CNS) and available at an effective dose or evidence that the agent can act in the periphery.  Key studies should be sufficiently powered and controlled with experimental and statistical rigor to lend a high degree of confidence in the results, with sufficient information available about study design, execution, analysis, and interpretation. 

(3) Feasibility for production and reproducible production of the candidate.

Only the most promising agents that have undergone rigorous preclinical testing and are considered state-of-the-art for the disease of interest will be considered for advancement to IND-enabling studies in the Development Track.   The Discovery Track thus affords applicants the opportunity to build collaborations, conduct comparative studies among related agents and standard of care agents, and, ultimately, advance their most promising candidate therapeutics. 

Activities appropriate for this FOA include, but are not limited to:

  • Optimization of the leads, like improvement of potency, specificity, bioavailability, and suitability for human testing, etc.  Specific examples include but are not limited to: optimize selectivity/specificity, selection of the best promoter or viral serotype for a gene therapy product, ideal length and/or sequence of an miRNA derivative to hone its specificity, optimization of a protein for an acceptable stability in vitro or half-life in vivo, humanization of a mouse monoclonal antibody, minimizing a predicted or previously encountered toxicity, acceptable level of production, optimization to have better suitability for the route of administration.
  • Characterization of identity and properties (e.g., cell phenotype, aggregation, epitope mapping, glycosylation or other post-translational modification, number of unpaired cysteines, oxidation, deamination, isomerization, proteolytic sites, sequences, viscosity, stability)
  • Assessment of in vitro activities (e.g., affinity, specificity, activity in cells, cellular uptake)
  • Assessment of in vivo pharmacology such as determination of dose range, dosing regimen and ideal time and duration of treatment. This includes but is not limited to assessment of efficacy  and/or target engagement; pharmacokinetics; pharmacodynamic measurement; relationships among pharmacokinetics, target engagement and/or pharmacodynamic measurement; correlations between in vitro and in vivo activities; bioavailbility at the site of action such as blood-brain-barrier penetration.
  • Assessment of efficacy in additional animal models if necessary to gain higher level of confidence for translation of the discovery to the clinic, along with the model in which the leads were shown to have efficacy. However, these activities are restricted to the purpose of supporting the proposed development of a therapy and should be a limited portion of the application.
  • Evaluation of metabolism, if applicable
  • Optimization of production (e.g., expression levels, purification yield, purity, yield of vector or cells)
  • Process development for scale-up manufacturing
  • Stage-appropriate bioanalytical assay development to develop and optimize bioanalytical assays in compliance with regulatory requirement
  • Optimization of delivery systems and special formulations (such as slow release, liposomes, nanoparticles, etc.), if applicable
  • Development of regulatory strategy and stage-appropriate interactions with regulatory agency
  • If projects at entry have in vivo efficacy data but do not have an optimized or validated target engagement assay (measurement of target binding or proximal downstream effects), the activities to optimize and validate the target engagement assays, including experiments using human specimens, are within the scope of this FOA. However, these activities are restricted to the purpose of supporting the proposed development of a therapy.

To minimize the funding gaps between the NINDS CREATE Bio Discovery and Development tracks, applicants of this Discovery Track FOA may propose limited initial work for the Development Track, such as starting to identify species for toxicology study or preliminary safety evaluations, preliminary biodistribution study, and piloting formulations.  These transitioning activities are generally restricted to the last year of the Discovery Track proposal. Awardees are encouraged to apply to the Development Track FOA as soon as they are eligible, while finishing up these studies in the Discovery Track.

Examples of Activities Inappropriate for this FOA include:

  • Developing animal models
  • Basic research of disease mechanisms
  • Early activities such as target identification and validation
  • Development of risk, detection, diagnostic, prognostic, efficacy prediction biomarkers.  (NINDS recognizes that target engagement markers developed may evolve into predictive markers for making clinical decisions for treatment trials, but it is not the intent of this FOA to support development of predictive biomarkers.)
  • Manufacture of therapeutics for clinical trials
  • Clinical research and clinical trials involving human subjects except those described in scope to develop and validate target engagement assays
  • Stand-alone studies to identify, validate, or qualify a target engagement marker and other bioanalytical assays
  • Activities already performed utilizing other private or public funds to advance the agent
  • Activities that are supported through the NINDS CREATE Bio Development Track FOA (PAR-14-289), with the exception of the transitioning activities designed to enable easy transition from the Discovery to the Development Track as described above
C. Milestones

Because therapy development is an inherently high-risk process, it is anticipated that there may be significant attrition as projects move through the therapy development process. Milestones are goals that are quantifiable for measuring success that can be used for go/no-go decision making for the project, and should have quantitative criteria associated with them (see section IV for details).

Prior to funding an application, NINDS Program staff will contact the applicant to discuss the proposed milestones and any changes suggested by the NINDS review panel or NINDS Program staff. A final set of approved milestones will be specified in the Notice of Award.

Progress towards achievement of the final set of milestones will be evaluated by NINDS Program staff.  NINDS Program staff may consult as necessary with independent consultants with relevant expertise. If justified, future year milestones may be revised based on data and information obtained during the previous year. If, based on the progress report, a funded project does not meet the milestones, funding for the project may be discontinued.  In addition to milestones, the decision regarding continued funding will also be based on the overall robustness of the entire data package that adequately allows an interpretation of the results (regardless if they have been captured in the milestones), overall progress, NINDS portfolio balance and program priorities, competitive landscape, and availability of funds.

NINDS emphasizes the importance of the robustness and reproducibility of experimental results.  In some cases, conducting additional critical experiments will be important for NINDS to have confidence in making a funding decision.  Therefore, NINDS Program staff, in consultation with the PD/PI, may add experiments that need to be conducted prior to or during the award as an additional milestone(s). In most cases, these studies will be supported by additional funds from NINDS.

D. Intellectual Property (IP)

Since the ultimate goal of the CREATE Bio program is to bring new therapies to the market/patients, the program strongly encourages the awardees and/or their collaborators to obtain and retain any IP developed around the therapy during the project period (see instructions on attachment or letters to address IP issues in Section IV). Recipients of awards are encouraged to identify and foster relationships with potential licensing and commercialization partners early in the therapy development process. PDs/PIs are expected to work closely with their institutional technology transfer officials to ensure that royalty agreements, patent filings, and all other necessary IP arrangements are completed in a timely manner and that commercialization plans are developed and updated over the course of the project. For rare or ultra-rare diseases where commercialization may be challenging, applicants are encouraged to discuss alternative strategies with NINDS Scientific/Research staff to get further guidance.

E. Pre-application Consultation

As an U44 cooperative agreement, implementation will involve the participation of NINDS Program staff in the planning and execution of the therapy-directed projects. Applicants are strongly encouraged to consult with NINDS Scientific/Research staff when planning an application. Early contact provides an opportunity for NINDS Scientific/Research staff to provide further guidance on program scope, goals, developing appropriate milestones, and budget. Applicants should contact NINDS Scientific/Research staff at least 12 weeks before a due date.