How do I know which program to apply for developing therapy?
If you are an academic or small business concern and are not sure which program to apply to for your therapy development refer to the decision tree for assistance.
Does your human subjects research study meet the NIH Definition of a clinical trial?
Check out this helpful site: https://grants.nih.gov/ct-decision/index.htm
What is the budget for the CREATE Bio programs?
Budget Guidance (Non-SBIR)
- ≥ $500K in any year: must contact NINDS program at least 6 weeks before submission to get NINDS senior leadership permission to submit
- For both tracks: Budget not limited but must reflect the actual needs of the proposed project. Suggestions below:
| Optimization Track (U01) | Development Track (U01) | |
|---|---|---|
| Non-SBIR | < $500 K/year in direct cost for up to 5 yrs | Applications should rarely exceed $1,000,000 in direct costs per year unless during the optional clinical trial phase in which up to $1,500,000 in direct costs per year may be justified. The duration of the U01 is for up to 5 yrs. |
Budget Guidance (SBIR)
- Set-aside budget
- SBIR eligible applicants should apply through SBIR PARs
| Optimization Track (U44) | Development Track (U44) | |
|---|---|---|
| SBIR | < $700K in total cost in Phase 1 for up to 2 yrs <$4M total cost in Phase II for up to 3 yrs |
< $1M/year in total cost for Phase I for up to 2 yrs < $1.5M/year in total cost for Phase II for up to 3 yrs |
How can an investigator get guidance? Does an applicant have to contact NINDS before they submit?
It is strongly recommended that all potential applicants consult NINDS staff very early in the planning stage and a minimum of 12 weeks before submission of an application is anticipated.
Applicants requesting $500K or more direct costs in any year (excluding consortium F&A) must contact NINDS program staff at least 6 weeks (at least 12 weeks is strongly encouraged) before submitting the application. NINDS program staff are required to get approval from NINDS senior leadership to accept the application for review.
What are the entry criteria for the CREATE Bio Optimization and Development track?
See the entry criteria in the CREATE Bio Optimization Track and Development Track comparison table.
What are appropriate transition activities in the CREATE Bio Optimization U01 track?
To keep the momentum of projects moving forward projects in the CREATE Bio Optimization track 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 Optimization Track. Awardees are encouraged to apply to the Development Track NOFO as soon as they are eligible, while finishing up these studies in the Discovery Track.
Is a team required prior to submitting an application?
NINDS strongly encourages applicants to form multidisciplinary teams before they submit their application. It’s recommended that teams consist of preclinical and clinical scientists, CMC experts, regulatory experts, statisticians, and other academic/industry experts relevant to the therapeutic modality as appropriate. The multidisciplinary team will be able to better define the desired TPP, to design the details of the plans and experiments, inform decision making, and execute the research strategy.
Do I have to submit the structure/sequence for my therapeutic in my application? How can I be sure the information in my application will remain confidential?
Enough information on the structure/sequences is required to enable evaluation of the application.
Applications are submitted for evaluation purposes only and are reviewed in closed private (non-public) sessions by reviewers who are under strict confidentiality agreements with the federal government. Therefore, information contained in applications would normally not be considered as a public disclosure and should not affect the applicant’s ability to apply for patents. However, filing patent applications prior to submission of a funding application is something an applicant should consider in conjunction with their legal counsel. Also, it should be noted that the submitted abstract would be published upon award of the grant, so the abstract should be drafted carefully so as not to be considered as an enabling disclosure. You can also mark sections of your application confidential. Please review NIH’s Guide Notice (NOT-OD-14-073) about maintaining confidentiality during review.
If I don’t have in vivo efficacy measures that are clinically relevant will in vivo target engagement data satisfy the CREATE Bio Optimization track criteria?
Yes, in the absence of preclinical in vivo efficacy measures that are clinically relevant in the field, projects can apply by presenting evidence of in vivo target engagement at the clinically intended site of action. However, if animal models do exist in the field they should be used.
Does the CREATE Bio program enable validation of target engagement biomarkers?
Yes, the CREATE Bio program allows the validation of target engagement markers in conjunction with therapeutic development.
Is current Good Manufacturing Practices (cGMP) supported in the CREATE Bio program?
The principle is that we support manufacturing of the material that is stage appropriate. Therefore, cGMP that is stage appropriate is supported under the CREATE Bio Development track only depending on the modality. Stand-alone cGMP for clinical studies are not supported. Please contact us for details before you submit your application to make sure your activities are appropriate for the program.
What is a TPP and why do I need to include a TPP in the application?
A Target Product Profile (TPP) is a planning tool for therapeutic candidates based on the FDA Guidance for Industry and Review Staff Target Product Profile — A Strategic Development Process tool. TPP is a good tool to ensure the applicants, the reviewers, and the NINDS program staff are on the same page about the ultimate goal of the projects.
CREATE BIO Example: Target Product Profile (TPP).
How do I write milestones?
Guidance on how to write milestones can be found at CREATE Bio Example: Milestones
Are IND enabling toxicology studies supported in the CREATE Bio Optimization track?
No, they are only supported in the CREATE Bio Development track.
If my project does not yet meet the CREATE Bio entry criteria, is there a new feeder program?
The new IGNITE program supports the development of small molecules, as well as peptide, proteins, antibodies, gene therapies, and cell therapies to get you ready for the CREATE Bio program. If you feel the IGNITE Notice of Funding Opportunity does not closely correlates with the therapeutic modality you are developing or you have questions regarding your project fit for the program, please contact NINDS program staff for guidance.
At what point in development of a stem cell therapy product, or under what conditions, should we request a Pre-Pre-IND meeting with FDA? Are we required to have a Pre- Pre-IND meeting?
You are not required to have a Pre-Pre-IND meeting, but it’s very good way to facilitate early-stage product development and help you on the path to successful IND submission.
Pre-Pre-IND meetings are primarily to discuss and provide guidance on IND-enabling preclinical studies, and to some extent CMC (manufacturing and testing). Accordingly, a Pre-Pre-IND meeting can be most useful after you have done some initial preclinical (in vitro and in vivo) studies of the product, and are planning further preclinical studies (toxicity/safety and proof-of-concept) in preparation for an IND. You should have specific questions to discuss about the pharmacology/toxicology aspects of your product and study plan. CMC questions can be discussed as well.
If you are considering requesting a Pre-Pre-IND meeting, you should contact Mercedes Serabian (mercedes.serabian@fda.hhs.gov), Chief of the Pharmacology/Toxicology Branch of FDA CBER Office of Cell, Tissue, and Gene Therapies, to ask for the Pre-Pre-IND Process checklist, which has a wealth of information that will help you prepare for a productive discussion with FDA.
What is the CMC component of stem cell therapy product development? What should CMC address?
CMC stands for Chemistry, Manufacturing and Controls, and covers all aspects of product manufacturing and testing. CMC should address the following:
Manufacturing
- Manufacturing process development, control, consistency, and process qualification
- Donor screening and testing
- Cellular or tissue raw material, process reagents and reagent qualification
- Procedures for all process steps, optimize yield
- Final formulation, containers, and labeling
- Product tracking
Testing
- Product safety and quality testing
- Safety (sterility, mycoplasma, viral agents, karyotype, tumorigenicity), purity, identity, viability, cell count, and potency
- Analytical methods development, controls, standards, and validation
- Establishing critical quality attributes, and specifications for product release and in-process testing
- Stability testing
- Comparability
The following documents have further information on this topic:
- Guidance for FDA Reviewers and Sponsors: Content and Review of CMC Information for Human Somatic Cell Therapy INDs, 2008
- PAS 83:2012 Developing human cells for clinical applications in the European Union and the United States of America
How to elucidate the structure of a stem cell therapy product?
Determining structure of a stem cell therapy product is not feasible, due to its complexity. Instead, development seeks to establish a pattern of phenotypic characteristics, such as differential levels of expression of specific cell surface molecules, secreted factors, etc.
How to develop the formulation for a stem cell therapy product?
Product formulation is determined by multiple factors, some of which are listed below. It may be necessary to test multiple candidate formulations to optimize viable, functional cell content of the product.
- Need for excipient(s) to enhance safety, effectiveness, or stability
- Compatibility with the site and route of administration
- Suitability for patient population and clinical setting
- Feasibility of pre-administration cell washing/resuspension prior to administration
- Cell concentration necessary to achieve the desired cell dose
- Container/closure
PAS 83:2012 Developing human cells for clinical applications in the European Union and the United States of America is helpful on this point as well.
What does the pharmacokinetics of stem cell therapy products, refer to?
Pharmacokinetics of small-molecule pharmaceuticals refers to parameters such as onset and duration of a drug’s effect, volume of distribution, and bioavailability. The term is rarely used with regard to stem cell therapy products, but similar parameters, such as clearance kinetics and biodistribution, relate to administered cells.
What are the major toxicity concerns or tests or assays for stem cell therapy products?
Potential toxicities may include untoward differentiation or other biological effects, engraftment in undesired location, tumor formation, transmission of adventitious agents, disease transmission, and undesired immune responses. Toxicity profile can vary greatly depending on type of stem cells, patient population and immune status, route and site of administration, among other factors.
There are scores of assays for stem cell therapy products, measuring a broad range of characteristics and functions of the many different types of stem cells.
Who do we contact if we have questions?
Chris Boshoff, Ph.D.
CREATE Bio Project Manager
chris.boshoff@nih.gov