CREATE Bio Example: Cell Therapy Product Profile FAQ Reference

CREATE Bio Example-Cell Therapy Product Profile-FAQ-References

The following table represents example categories to consider in describing your current results/status and desired results at the end of the funding period.


Description of product, intended use, clinical application
Description of the delivery device, if applicable
Rationale for therapeutic strategy, proof of concept, evidence product has desired biologic effect
In vitro and in vivo preclinical studies – summary of results and interpretation. Rationale for animal model(s).
Dosing, route of administration
  • Dose/activity and dose/toxicity relationship.
  • Proposed initial safe dose, dose escalation scheme(s)
  • Relationship of ROA and dosing to efficacy and toxicity
Risk evaluation – significance/severity of observed toxicities vs. disease-related adverse events
Toxicity - type, frequency, and severity of toxicities in normal animals and disease model(s)
Potential clinical toxicities, projected risks, organ(s) affected, indicators
Immunologic effects
Tumorigenicity (in vitro, in vivo)
Unintended differentiation (especially for stem cell products)
Unintended distribution
Manufacturing scheme – outline and description, process control and monitoring. Sampling points. Critical Process Parameters.
Process development status and issues.
  • Feasibility of scale-up (allogeneic) or scale-out (autologous)
  • Potential for automation
Manufacturing risk assessment, including frequency and causes of process failure
Raw materials – source, grade, qualification
Final formulation (excipients, container) – status, development needs
Critical Quality Attributes
Analytical methods for release and in-process testing. Assay development status. Proposed specifications.
Potency testing development
Stability studies
Manufacturing process qualification/validation
Technology transfer (to manufacturer, or other)
Comparability studies
Target indication, objective, sample size, study site location(s)
Clinical study
  • Study design, blinding, study duration.
  • Dose(s) and route(s) of administration.
  • Patient eligibility criteria, key inclusion and inclusion criteria. Concomitant medications and treatments.
  • Outcome measures and end-points, termination criteria.
  • Data analysis plan
  • Safety monitoring plan
How will the planned study contribute to understanding mode of action, pharmacokinetics, biodistribution?
Risk assessment, including clinical risks and limitations
Previous clinical experience?
Administration procedure
Informed consent, IRB approval
Regulatory Interactions
Pre- Pre-IND Meeting. Comments from FDA.
Pre-IND Meeting. Comments from FDA.
Patent protection?

Reference to consider when preparing you application and managing your project:

Stem Cell Therapy FAQ

  1. 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 (, 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.

  1. 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 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


  • 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 (pdf, 236 kb)

PAS 83:2012 Developing human cells for clinical applications in the European Union and the United States of America

  1. 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.

  1. 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. 

  1. 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. 

  1. 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. 


Kleitman, Naomi, Rao, Mahendra, and Owens, David. Pluripotent Stem Cells in Translation: A Food and Drug Administration-National Institutes of Health Collaboration.  Stem Cells Translational Medicine. 2013; 2:483–487

NIH-FDA Workshop: Pluripotent Stem Cells in Translation: Preclinical Considerations  July 10-11, 2012
Videocast presentations:  Day 1 and   Day 2

NIH-FDA Workshop:  Pluripotent Stem Cells in Translation: Early Decisions  March 21-22, 2011
Videocast presentations:  Day 1 and Day 2