HHS SBIR PAR-15-074

This Funding Opportunity Announcement (FOA) encourages the translation of research discoveries into new treatments for disorders that fall under the mission of NIAAA.  The goal is to advance the commercialization of small molecules, natural products or biologics that have shown therapeutic potential for alcohol use disorder or alcohol-related diseases in preclinical testing, by supporting efforts to achieve IND approval. For application to the FOA, at entry, the project should have an identified candidate that has undergone rigorous preclinical testing and has sufficient 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). Projects are expected to achieve filing of an Investigational New Drug (IND) application to the U.S. Food and Drug Administration (FDA) by the end of the funding period.  The SBIR U44 award has two phases, Phase I and Phase II. While the U44 Phase I supports the preparatory activities needed before launching IND-enabling studies (such as manufacturing for IND-enabling toxicology and verification of such manufactured material for its activities), the U44 Phase II phase supports the IND-enabling studies (e.g., GLP toxicology, biodistribution, immunogenicity evaluations).

Projects are funded via a U44 cooperative agreement mechanism, which involves NIAAA Program staff's participation in developing the project plan, monitoring research progress, and appropriate go/no-go decision-making.  The expectations of the program are in line with those of industry in regards to advancing therapeutic agents through the developmental pipeline. 

For this funding opportunity announcement, U44 Phase I and II refer to the project phases of the SBIR program, and are not to be confused with phase I of clinical trials, which are not supported.

This FOA is open to small molecules, natural products, and biologics, which broadly include peptides, proteins, oligonucleotides, gene therapies, and cell therapies.  Applicants should contact NIAAA Scientific/Research staff regarding the agent under development, to determine the fit for the FOA.  

Entry Criteria

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. Applicants should have a candidate with the final structure for human testing that minimally satisfies all of 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-active agents, 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.

U44 Phase I Scope

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

• Chemistry, Manufacturing, and Control (CMC) activities (e.g., master and working banks development, purification development, CMC analytical development, formulation development, scale-up manufacturing or cGMP manufacturing) for IND-enabling pharmacology/toxicology tests
• Pharmacokinetic evaluations in species relevant for toxicology or human dose-prediction
• If needed for certain therapeutic modalities, final characterization and definitive verification of in vitro and in vivo activities such as preclinical 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
• Preliminary safety such as safety pharmacology and/or dose-range finding toxicology
• Optimizing and/or validation of appropriate assays for pharmacokinetics, bioactivity (potency), target engagement markers or other assays to monitor safety to be used in human trials

The length of Phase I can be brief depending on the maturity of the project at entry.  

U44 Phase II Scope

The Phase II will support IND-enabling development activities.

Preclinical development activities appropriate for Phase II include, but are not limited to:

• IND-enabling toxicology, with toxicokinetics, if applicable
• 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
• IND and other regulatory submissions

Small, early-phase clinical trials that are appropriate include:

Population: patients with indicated disease, or healthy volunteers
Total subjects ≤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
Outcomes are safety, pharmacokinetics and pharmacodynamics/target engagement/target modulation. Note that clinical efficacy outcome data may be collected to prepare for Phase 2 clinical studies, but efficacy cannot be the primary objective of the study
The duration of the clinical trial, from initiation at first informed consent signature to the completion of data analysis, should rarely exceed 2 years.

Activities that are appropriate for clinical trial preparatory activities (only if clinical trials are proposed), which may be performed concurrently with IND-enabling preclinical studies during 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 already in Phase I
Development and validation of biochemical assays required for clinical trials if not already complete (e.g., pharmacokinetic, pharmacodynamic, and/or immunogenicity assays)
Preparation of clinical trial protocol, Investigator's brochure
Preparation of documents required to support a clinical trial (e.g., case report Fforms, pharmacy manual, study coordinator manual, monitoring plan)

Clinical trial activities that are appropriate during 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
• Development of risk, detection, diagnostic, prognostic, efficacy prediction biomarkers.  (NIAAA recognizes that target engagement markers developed under the Phase I may evolve into predictive markers for treatment trials, but it is not the intent of this FOA to develop predictive biomarkers.)
• Activities already performed utilizing other private or public funds to advance the agent
• Performance of a clinical trial with the objective of demonstrating clinical efficacy or clinical proof-of-concept

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.2 for details).

Since the primary focus of IND-enabling research is to determine the safety and toxicology of the product that will move into humans, 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 has to carefully assess toxicity in relationship to efficacy.  NIAAA intends to only move forward agents that are both efficacious and safe.  Although the primary goals 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.

U44 Phase I/II transition

An administrative review will be conducted by NIAAA Program staff to decide whether a project will be considered for transition from the Phase I to the Phase II. 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 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 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 preclinical 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 Small, Early-Phase Clinical Trial 
• Clinical Trial preparatory activities may be performed concurrently with IND-enabling preclinical Phase II activities with approval of NIAAA staff. General criteria for starting clinical preparatory activities, if applicable, will be based on:
• Meeting previous milestone criteria during Phase I and Phase II
• Progress in IND-enabling studies
• Assessment that submission of an IND appears feasible on a timeline allowable within the grant
• Prior to commencement of the clinical trial (defined as first subject signature on an informed consent form), the applicant must provide sufficient documentation to NIAAA for review. On scientific or clinical grounds, NIAAA may require inclusion of additional procedures beyond those required by the FDA. Therefore, approval must be received from NIAAA prior to commencement of the clinical trial. 
• General criteria for starting a clinical trial:
• Successful achievement of the defined milestones for the preclinical portions of the Phase II period;
• Successful completion of any clinical preparatory milestones
• Submission of an IND with a "may proceed" letter or email from the FDA
• Submission of the clinical protocol and supporting documents to the NIAAA
• Agreement with NIAAA staff on updated timeline, milestones and budget for clinical trial
• NIAAA approval of protocol and safety monitoring plan

Since the goal of this program is to generate therapeutics which will be eligible for FDA approval, adherence to compliance and quality criteria is required. 

• It is expected that all IND-enabling nonclinical studies will be performed in a manner consistent with Good Laboratory Practices (GLP).
• Investigational products should be produced under current Good Manufacturing Practices (cGMP). Bioassays such as pharmacokinetics, pharmacodynamics or immunogenicity should, when possible, be performed under GLP guidelines.
• All clinical trials must be performed following Good Clinical Practices (GCP) and be in accord with NIAAA Policy.
• Investigational products should be produced under current Good Manufacturing Practices (cGMP). Bioassays such as pharmacokinetics, pharmacodynamics or immunogenicity should, when possible, be performed under GLP guidelines.

Since the ultimate goal of the SBIR/STTR 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.2). Awardees 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 NIAAA Scientific/Research staff to get further guidance.

As an U44 cooperative agreement, implementation will involve the participation of NIAAA Program staff in the planning and execution of the therapy-directed projects.  Applicants are strongly encouraged to consult with NIAAA Scientific/Research staff when planning an application. Early contact provides an opportunity for NIAAA Scientific/Research staff to provide further guidance on program scope, goals, developing appropriate milestones, and budget. Applicants should contact NIAAA Scientific/Research staff at least 8 weeks before the first receipt date.