Donald Fink

FDA Regulation of Stem Cell–Based Products

Cell self-renewal and the capacity to differentiate into multiple cell types (pluripotency) are biological attributes casting stem cells as attractive candidates for development of therapies targeting indications that involve functional restoration of damaged tissues. In the United States, clinical trials designed to demonstrate the safety and effectiveness of stem cell–based products are regulated by the U.S. Food and Drug Administration (FDA). To ensure that subjects enrolled in a clinical study involving stem cell–based products are not exposed to significant and unreasonable risk, the FDA reviews medical and scientific information that encompasses delineation of product-specific characteristics and preclinical testing to determine whether there is sufficient safety assurance to permit initiation of human clinical studies.

Expression of human p140trk receptors in p140trk‐deficient, PC12/endothelial cells results in nerve growth factor‐induced signal transduction and DNA synthesis

Nerve growth factor (NGF) regulates proliferation, differentiation, and survival of sympathetic and sensory neurons through the tyrosine kinase activity of its receptor, p140trk. These biological effects of NGF depend upon the signal‐mediating function of p140trk substrates which are likely to differ from cell to cell. To define p140trk receptor substrates and the details of signalling by NGF in the hybrid cell PC12EN, we stably transfected cultures with a vector encoding a full‐length human p140trk cDNA sequence. Two stably transfected clones, one expressing p140trk with higher affinity (PC12EN‐trk3; Kd 57.4 pM, Bmax 9.7 pmole/mg) and one expressing p140trk with a lower affinity (PC12EN‐trk1; Kd 392.4 pM, Bmax 5.7 pmole/mg) were generated. Radioreceptor assays indicate that transfected p140trk receptors show slow NGF‐dissociation kinetics, are resistant to trypsin or Triton X‐100 treatment, are specific for NGF compared to other neurotrophins, and are internalized or downregulated as are native PC12 p140trk receptors. NGF stimulates p140trk tyrosine phosphorylation in a dose‐ (0.01‐10 ng/ml) and time‐ (5‐120 min) dependent manner, and tyrosine phosphorylation was inhibited by 200‐1,000 nM K‐252a. NGF‐induced Erk stimulation for 60 min was assessed using myelin basic protein as a substrate. NGF treatment also led to an increased phosphorylation of p70S6k, SNT, and phospholipase Cγ, demonstrating that the major NGF‐stimulated signalling pathways found in other cells are activated in PC12EN‐trk cells. Staurosporine (5‐50 nM) rapidly and dBcAMP (1 mM) more slowly, but not NGF induced morphological differentiation in PC12EN‐trk cells. Rather, NGF treatment in low‐serum medium stimulated a 1.3‐ and 2.3‐fold increase in DNA synthesis measured by [3H]thymidine incorporation in PC12EN‐trk1 and PC12EN‐trk3, respectively. These data highlight the functionality of the transfected p140trk receptors and indicate that these transfected cells may serve as a novel cellular model facilitating the study of the mitogenic properties of NGF signalling and the transducing role of the p140trk receptor substrates. J. Cell. Biochem. 66:229‐244.

Overview of the FDA Regulatory Process

Publisher Summary This chapter provides a brief historical review of the Food and Drug Administration (FDA) and its organizational structure and discusses topics pertaining to the regulation of regenerative medicine products including possible regulatory pathways for combination products and relevant jurisdictional issues. FDA regulations are contained in the Code of Federal Regulations (CFR). Regulations for drugs, biologics, devices, and tissues, along with related regulations, may be found in various parts of Title 21 of the CFR. Guidance documents are nonbinding publications that describe the FDAs interpretation of policy pertaining to a regulatory issue or set of issues related to the design, production, labeling, promotion, manufacturing, and testing of regulated products, the processing, content, and evaluation, or approval of submissions inspection, and enforcement policies. Guidance documents, which are developed in accordance with Good Guidance Practices found at 21 CFR §10.115, are intended to clarify the FDAs current thinking related to regulatory issues and procedures. The FDA has issued “Guidance for Industry: Eligibility Determination for Donors of Human Cells, Tissues, and Cellular and Tissue-Based Products to assist establishments making donor eligibility determinations with complying with the Donor Eligibility rule (21 CFR 1271 Subpart C).” This guidance also incorporates and finalizes the content of “Guidance for Industry, Preventive Measures to Reduce the Possible Risk of Transmission of Creutzfeldt–Jakob Disease (CJD) and Variant Creutzfeldt–Jakob Disease (vCJD) by Human Cells, Tissues, and Cellular and Tissue-Based Products (HCT/Ps).” The US Public Health Service (PHS) agencies including the FDA, National Institutes of Health (NIH), Centers for Disease Control and Prevention (CDC), and Health Resources and Services Administration (HRSA) have worked together to address the risk of infectious disease transmission, publishing the “PHS Guideline on Infectious Disease Issues in Xenotransplantation.”

Dexamethasone-Induced Down-Regulation of Nerve Growth Factor Receptor p75NTR is Mediated by Glucocorticoid Type II Receptor in PC12 Cell Model

PC12 clones are established neuronal models to investigate mechanisms involved in the cross-talk between the neurotrophins and drugs. Chronic treatment of PC12 cells with the glucocorticoid agonist drug, dexamethasone (Dex), elicited a 50% decrease in the selective binding of 125 I-NGF along with a reduction in the NGF receptor p75 NTR mRNA and protein levels, suggesting a transcriptional mechanism. This down regulation of p75 NTR was antagonized by the glu- cocorticoid type II receptor (GR-2), RU-38486 but not by the minerallocorticoid receptor, RU-28318, antagonists. This process was associated with increased autophosphorylation of the NGF receptor, TrkA. Chronic treatment of PC12 with Dex abolished the NGF-induced proliferation of the cells after 20 hours and inhibited by 45% the neurite elongation after 96 hours. RU-38486 blocked Dex-induced shift of PC12 cells from dopaminergic to noradrenergic phenotype. Dex- induced down regulation of p75 NTR receptor is mediated by GR-2 and is correlated with disruption of NGF induced prolif-

Translation of Regenerative Medicine Products Into the Clinic in the United States: FDA Perspective

Abstract The field of regenerative medicine encompasses a breathtaking array of interdisciplinary scientific approaches with the promise of delivering future therapies to meet current unmet medical needs for patients. Increasingly more of these innovative products are being translated into human clinical trials in the United States, and general familiarity of the FDA is important to efficiently navigate the process. The basics of FDA history, organization, and processes are described herein for those new to clinical translation, with more detailed content added regarding approval pathways, regulations, guidances, and select special topics of relevance to regenerative medicine. In addition to the cumulative experience of previous products, the FDA regulatory approach to medical products evaluation includes an ongoing assessment of how the science of those products informs regulatory policy. FDA engages in ongoing dialogue with the scientific community and product sponsors to continue to develop science-based regulatory review policies that are robust and predictable in order to meet the needs of the challenging array of products that are on the horizon.

Chapter 41 – Overview of the FDA Regulatory Process

Regenerative medicine encompasses a breathtaking array of interdisciplinary scientific approaches which address a broad spectrum of clinical needs. Recent advances in scientific knowledge related to cell biology, gene transfer therapy, biomaterials, immunology, and engineering principles applicable to biological systems place this community in a position to address a number of challenging and critical health needs. These include treatment of disease conditions resulting from pancreas, liver, and kidney failure; structural cardiac valve repair; skin and wound repair; and orthopedic applications. Scientific challenges include expanding the knowledge base in each discipline as well as developing an interdisciplinary approach for identifying and resolving key questions. The Food and Drug Administration’s (FDA’s) regulatory review process mirrors the scientific challenges with regard to the development of review paradigms that cross scientific disciplines. This chapter provides a brief historical review of the FDA and its organizational structure, and discusses topics pertaining to the regulation of regenerative medicine products.

Regulatory considerations of stem and progenitor cell-based products: US Food and Drug Administration

Abstract: This chapter focuses on US Food and Drug Administration (FDA) regulatory considerations for stem/progenitor cell-based products (S/PCPs) intended to treat, mitigate or cure disease. Information critical to the regulatory decision-making process for determining the safety and efficacy of investigational S/PCPs is described. Included are sections that cover cellular product manufacturing and characterization, preclinical testing and clinical trial design. Increased regulatory complexity associated with stem/progenitor cell-based combination products is also discussed.

Chapter 83 – Overview of the FDA Regulatory Process

This chapter provides a brief historical review of the Food and Drug Administration (FDA) and its organizational structure and discusses topics pertaining to the regulation of regenerative medicine products including possible regulatory pathways for combination products and relevant jurisdictional issues. FDA regulations are contained in the Code of Federal Regulations (CFR). Regulations for drugs, biologics, devices, and tissues, along with related regulations, may be found in various parts of Title 21 of the CFR. Guidance documents are nonbinding publications that describe the FDAs interpretation of policy pertaining to a regulatory issue or set of issues related to the design, production, labeling, promotion, manufacturing, and testing of regulated products, the processing, content, and evaluation, or approval of submissions inspection, and enforcement policies. Guidance documents, which are developed in accordance with Good Guidance Practices found at 21 CFR §10.115, are intended to clarify the FDAs current thinking related to regulatory issues and procedures. The FDA has issued “Guidance for Industry: Eligibility Determination for Donors of Human Cells, Tissues, and Cellular and Tissue-Based Products to assist establishments making donor eligibility determinations with complying with the Donor Eligibility rule (21 CFR 1271 Subpart C).” This guidance also incorporates and finalizes the content of “Guidance for Industry, Preventive Measures to Reduce the Possible Risk of Transmission of Creutzfeldt–Jakob Disease (CJD) and Variant Creutzfeldt–Jakob Disease (vCJD) by Human Cells, Tissues, and Cellular and Tissue-Based Products (HCT/Ps).” The US Public Health Service (PHS) agencies including the FDA, National Institutes of Health (NIH), Centers for Disease Control and Prevention (CDC), and Health Resources and Services Administration (HRSA) have worked together to address the risk of infectious disease transmission, publishing the “PHS Guideline on Infectious Disease Issues in Xenotransplantation.”