CREATE Bio Development Track: Nonclinical and Early-Phase Clinical Development for Biologics (U44 Clinical Trial Optional)

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 Biologics (CREATE Bio) program is dedicated to biotechnology products and biologics-based therapies, which broadly include modalities such as peptides, proteins, oligonucleotides, gene therapies, cell therapies, and novel emerging therapies.  The CREATE Bio program includes two tracks: The Optimization Track (PAR-17-457) supports lead optimization to obtain a clinical candidate eligible for entry into the Development Track. This Development Track supports IND-enabling studies for the candidate with the possibility to include an optional small delayed-onset first in human Phase I clinical trial at the end of the funding period.

At entry, for this NINDS CREATE Bio Development Track FOA, a project should have an identified clinical candidate that has undergone rigorous nonclinical testing and has demonstrated bioactivity, stability, manufacturability, bioavailability, in vivo efficacy and/or target engagement, and is considered state-of-the-art for the disease (see entry criteria for details). At a minimum, projects are expected to achieve filing of an Investigational New Drug (IND) application to the U.S. Food and Drug Administration (FDA), at the end of the U44 Phase II funding period.  For more advanced projects, a small delayed-onset first in human Phase I clinical trial may also be proposed, but is not required (see 'Scope' for more details). The Development Track has two Phases, U44 Phase I and U44 Phase II. While the U44 Phase I supports preparatory activities needed before executing IND-enabling studies (e.g. preliminary pharmacology and/or dose-range finding toxicology, conducting a pre-IND meeting with FDA, manufacturing and release testing of enough material needed for IND-enabling studies), the U44 Phase II Phase supports the actual IND-enabling studies (e.g., GLP toxicology, biodistribution, immunogenicity evaluations), submission of an IND package, and conducting an optional small delayed-onset Phase I clinical trial at the end of the funding period.

Projects are funded via a U44 cooperative agreement mechanism, which involves NINDS Program staff's participation in developing the project plan, monitoring research progress, and appropriate go/no-go decision-making. NINDS staff will provide assistance to investigators in helping them to distinguish activities that fall under the U44 Phase I versus U44 Phase II of a Development project.  NINDS staff will also provide assistance to investigators in guiding 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 in regards to advancing therapeutic agents through the developmental pipeline. 

 For more information about earlier stage translational funding opportunities and programs, visit the NINDS Division of Translational Research website and, for more information specifically about the CREATE Bio Program, visit the website.  Applicants are strongly advised to read through the CREATE Program FAQs.

B. Scope

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

The CREATE Bio FOAs focus on development of biotechnology products and biologic therapeutics, which broadly include modalities such as peptides, proteins, antibodies, oligonucleotides, gene therapies, cell therapies and novel emerging therapies.  Applicants are encouraged to contact

NINDS Scientific/Research staff regarding small peptide derivatives, natural products, molecules with complex structures, or combination products, to determine the fit for this FOA.

Applicants are expected to develop a Target Product Profile (TPP) based on the FDA guidance (see CREATE Bio Example: Target Product Profile (TPP)) that shows the ultimate goals of the proposed therapy development effort, such as disease indication and stage, patient population, delivery mode and dosing regimen, treatment duration, and standards for clinical efficacy. 

Entry Criteria:

Applicants are not required to have received and completed a prior NINDS CREATE Bio Optimization Track award to be eligible to apply to the NINDS CREATE Bio Development Track. Applicants are encouraged to talk to Scientific/Research staff about the stage of their activity and receive advice as to which program is the best fit. 

Only the most promising agents that have undergone rigorous nonclinical testing and are considered state-of-the-art for the disease of interest will be considered for advancement to IND-enabling studies. To be eligible for this Development Track FOA, applicants must have a candidate with the final structure for human testing that minimally satisfies all 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 for example 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. Particularly, 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) Demonstrated feasibility for reproducible production of the clinical candidate.

(4) An established and engaged multi-disciplinary project team to execute the proposed project plan that will submit at least an IND application to the FDA at the end of the funding period.

U44 Phase I Scope

Examples of studies that can be proposed during the U44 Phase I include, but are not limited to:

• Preliminary pharmacokinetic and/or safety evaluations in species relevant for toxicology or human dose-prediction.
• Dose-range finding toxicology studies
• Pre-IND meeting with FDA (if not done before).
• Chemistry, Manufacturing, and Control (CMC) related activities (e.g., master and working banks development, purification development, CMC analytical development, final formulation development, scale-up manufacturing or cGMP manufacturing) for IND-enabling pharmacology/toxicology testing.
• If needed for certain therapeutic modalities, final and definitive verification of in vitro and in vivo activities such as nonclinical target engagement and/or efficacy studies, using the final manufactured material (using final cGMP process depending on regulatory requirement) intended for IND-enabling toxicology studies.
• Validation of existing assays for pharmacokinetics, target engagement markers or other assays to monitor safety and/or efficacy outcomes to enable human use.

The length of the U44 Phase I can be brief depending on the maturity of the project at entry.  Funding for the U44 Phase I cannot exceed two years.

U44 Phase II Scope

The U44 Phase II will support IND-enabling development activities. For more advanced projects, an optional small, delayed-onset first in human Phase I clinical trial can also be supported when feasible during the U44 Phase II.  It should be noted that in this FOA clinical trials are only supported for projects where the nonclinical activities are conducted under this funding mechanism and have transitioned from the U44 Phase I.

In-scope nonclinical development activities during U44 Phase II include, but are not limited to:

• IND-enabling safety pharmacology and toxicology, with toxicokinetics if applicable, in relevant animal model(s)
• Tumorigenicity evaluations particularly for gene therapies and cell therapies, if applicable
• Immunogenicity evaluations, if applicable 
• Biodistribution studies, if applicable 
• Large animal study to assess biocompatibility of means of clinical delivery of the candidate, if applicable
• Validation of appropriate assays such as for target engagement markers to enable human use
• Preparation and submission of an IND package to FDA

Optional: conduct a small, delayed-onset, first in human Phase I clinical trial during U44 Phase II include:

• Population: patients with indicated disease or healthy volunteers
• Total number of subjects not exceeding 50
• Design is single dose or single ascending dose treatment, and may be placebo-controlled or open-label studies; multiple ascending dose may be requested only if agent has a short half-life
• Clinical trial outcomes may include safety, tolerability, pharmacokinetics and pharmacodynamics/target engagement/target modulation endpoints.

Note: clinical efficacy outcome data may be collected to prepare for clinical trial Phase 2 studies, but efficacy cannot be the primary objective of this delayed-onset clinical study

• The duration of the delayed-onset clinical trial, from initiation at first informed consent signature to the completion of data analysis, should rarely exceed 2 years

In-scope activities for optional small delayed-onset first in human clinical trial preparatory activities (only if clinical trials are proposed), which may be performed concurrently with IND-enabling nonclinical studies during U44 Phase II include, but are not limited to:

• Manufacturing of cGMP (current Good Manufacturing Practices) material for the small, early-Phase clinical trial if not done earlier.
• Development and validation of biochemical assays required for clinical trials if not already completed (e.g., pharmacokinetic, pharmacodynamic, and/or immunogenicity assays)
• Preparation of documents such as a clinical trial protocol, investigator's brochure etc.
• Preparation of documents required to support a clinical trial (e.g., case report forms, pharmacy manual, study coordinator manual, monitoring plan)

Within scope clinical trial activities during U44 Phase II include, but are not limited to:

• Patient/subject recruitment and enrollment
• Site monitoring
• Data collection and quality assurance
• Statistical analysis
• Safety reviews

Examples of activities inappropriate for this FOA include:

• Animal model development
• Basic research and studies of disease mechanisms
• Early research such as identifying and validating targets and generation of preliminary agents that are not suitable for human testing
• Activities to optimize an agent or lead that are covered under CREATE Bio Optimization Track, except for activities to transition to IND-enabling studies
• Activities already performed utilizing other private or public funds to advance the agent
• Inclusion of a clinical trial with the objective of demonstrating clinical efficacy or clinical proof-of-concept
• Clinical trial activities that require more than 2 years to complete and/or are beyond the funding period of the FOA.
• Stand-alone clinical trials. Applicants proposing clinical trials or biomarker studies that fall outside of the scope of this FOA may wish to consider applying to the NINDS NeuroNEXT clinical trials program, the NINDS Exploratory Clinical Trials program (PAR-17-122), and NIH StrokeNet programs.

C. Milestones

Milestones are quantifiable goals that are used to monitor project progress and facilitate dialogue and go/no-go decision making between program staff and the project team to effectively manage the project (see Section IV.2 for details). NINDS recognizes time sensitivity in developing therapeutics for patients who urgently need new or better treatment. If the research contains parallel activities from an independently funded, ongoing study prior or during the funding period, its impact should be noted in the milestone section of the application.

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 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 seek advice from independent consultants with relevant expertise as necessary. If justified, future year milestones may be revised based on data and information obtained during the previous year. Funding for the project may be discontinued if milestones are not met.  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.

Since the primary focus of this Development Track is to determine the safety and toxicology of the product that will move into human testing, applicants should keep in mind that the efficacious dose levels should, ideally, be non-overlapping with a dose(s) resulting in significant toxicity and reflect the fact that one must carefully assess toxicity in relationship to efficacy.  NINDS intends to only support candidates that are both efficacious and safe.  Although the primary goals of this Development Track are to assess safety and toxicology, lack of evidence of robust efficacy in the dose range where the candidate is safe can also be a consideration for discontinuation.

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.

Applicants are encouraged to read examples of milestones (CREATE Bio Example Milestones), and see a summary chart of a milestone timeline (CREATE Bio Milestone Summary and Timeline).

U44 Phase I/II transition

An administrative review will be conducted by NINDS Program staff to decide whether a project will be considered for transition from the U44 Phase I to the U44 Phase II. U44 Phase II eligible projects must have a candidate that has been manufactured with satisfactory purity and stability, verified to have activity in vivo and/or in vitro as necessary, have bioavailability with a proper formulation, and have a good preliminary safety profile. Specifically, projects entering the U44 Phase II must satisfy the following:

• For certain therapeutic modalities, the final manufactured material for IND-enabling toxicology studies needs to have final characterization and definitive verification for in vitro and in vivo activities.  In these cases, these studies should have been satisfactorily completed prior to the U44 Phase II
• Have bioavailability with a proper formulation; addressed blood-brain-barrier penetrant issues if it is a CNS target
• Pharmacokinetics and pharmacokinetics-pharmacodynamics relationships are known and allow feasible dose for human testing
• Preliminary toxicology studies in animal models have been completed; any safety concerns raised based on these studies can be addressed
• Evidence that IND-enabling nonclinical testing plans and study protocols have been reviewed by the FDA and input received in the context of pre-submission interaction with the agency (e.g., Pre-IND meeting with FDA)

Transition to an optional small delayed-onset, first in human Phase I clinical trial: 

Some clinical trial preparatory activities may be performed concurrently with IND-enabling nonclinical U44 Phase II activities with approval by NINDS staff. General criteria for starting clinical preparatory activities, if applicable, will be based on:

• Meeting previous project milestone criteria during U44 Phase I and U44 Phase II
• Progress with IND-enabling studies
• Assessment that submission of an IND appears feasible on a timeline allowable within the grant

Prior to commencement of the small delayed-onset first in human clinical trial (defined as first subject signature on an informed consent form), the grantee must provide required documentation to NINDS for evaluation by a clinical trial working group. After the clinical protocol is fully developed, but before submitting the IND package to FDA, a NINDS convened working group must review the proposed small delayed-onset first in human clinical trial. This working group may require inclusion of additional specifications before the IND package is submitted and reviewed by FDA. Subsequently, if the submitted IND package is not on clinical hold, the working group will make a recommendation to the NINDS council. Therefore, NINDS council funding approval must be obtained for the proposed small delayed-onset first in human clinical trial prior to release of NINDS funds and commencement of clinical trial activities. 

General requirements before initiating a small delayed-onset, first in human Phase I clinical trial:

• Successful completion of the established project milestones for the preceding nonclinical studies of the U44 Phase II period;
• Successful completion of any clinical trial preparatory activities
• Submission of clinical protocol, clinical team members with their qualifications, and supporting documents to NINDS Clinical Trial Working Group for review prior to filing IND package to FDA
• NINDS Clinical Trial Working Group recommendation and NINDS Council approval of clinical protocol, safety monitoring plan and feasibility of proposed clinical trial
• If applicable, obtained Recombinant DNA Advisory Committee (RAC) approval
• Submission of an IND package to FDA and IND not on clinical hold for any reason
• Agreement with NINDS staff on updated timeline, milestones and budget for clinical trial

D. Quality and Compliance Requirements

Since the goal of this program is to develop therapeutics that may be eligible for FDA approval, the use of Good Laboratory Practices (GLP) and current Good Manufacturing Practices (cGMP) for investigational products and IND enabling nonclinical studies should be performed in compliance with FDA regulations.  

E. 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 of letters to address IP issues in Section IV).   In compliance with the Bayh-Dole Act, this program is structured so that the awardee institution can elect to retain title to inventions; not withstanding the rights reserved by the U.S. Government if title is elected by awardee institution, NINDS/NIH does not intend to hold any additional IP rights for therapies developed in this program.  NIH policy requires invention reporting in iEdison.  Patents should also include a reference to NIH funding support by including the grant/cooperative agreement number in the patent.  The small business concern will take responsibility for patent filings, prosecution, and maintenance as well as licensing efforts toward eventual commercialization.  Award recipients are encouraged to identify and foster relationships with potential licensing and commercialization partners early in the therapy development process. 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.

F. Pre-application Consultation

As a  cooperative agreement, implementation will involve the participation of NINDS Program staff in the planning and execution of the therapy-directed projects.  Applicants and their multidisciplinary team 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 receipt date.     

See Section VIII. Other Information for award authorities and regulations.