3/20/2017. R 3 Repair Paradigm REGENERATIVE MEDICINE GLOSSARY OF STEM CELL PLATFORMS. Limitations of Embryonic Stem Cells

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1 R 3 Repair Paradigm CENTER FOR REGENERATIVE MEDICINE Regenerative Medicine Regulatory And Practice Management Focus Replacement ACL/UCL Reconstruction Regeneration Next generation therapy Repair Rejuvenation Self-healing Shane A. Shapiro, M.D. Assistant Professor Department of Orthopedic Surgery Fellow American Academy of Regenerative Medicine Human Regenerative Map 2012 MFMER GLOSSARY OF STEM CELL PLATFORMS Platform Defining Characteristics Embryonic stem cell: Derived from the inner cell mass of blastocyst Pluripotent with autonomous self-renewal Responsive to differentiation cues Perinatal stem cell: Derived from perinatal sources Pool of embryonic-like and adult-like stem cells Extensive availability at time of birth Adult stem cell: Derived from bone marrow, adipose tissue Include resident stem cells Multilineage hematopoietic and mesenchymal progenitors Bioengineered stem cell: Derived by reprogramming of adult sources Include therapeutic cloning and nuclear programming Generate customized embryonic-like stem cells From Nelson T, et al Regenerative Medicine and Stem Cell Therapeutics. In Waldman and Terzic, Pharmacology and Therapeutics, Elsevier, Limitations of Embryonic Stem Cells Ethical Considerations Rejection of the Cells Technically Difficult to Derive Regenerative Medicine Vocabulary MSC Mesenchymal Stem Cell ADSC Adipose Derived Stem Cell BMSC Bone Marrow Derived Stem Cell HSC Hematopoietic Stem Cell IPSCS Induced Pluripotent BMAC Bone Marrow Aspirate Concentrate SVF Stromal Vascular Fraction dhacm Dehydrated Amnion Chorion Membrane 2011 MFMER MFMER

2 The Food and Drug Administration Interstate Commerce Clause of the Federal Food, Drug, and Cosmetic Act of 1938 (FFDCA) FDA s Center for Biologics Evaluation and Research (CBER) Human cells, tissues, and cellular and tissuebased products (HCT/Ps) are defined in 21 CFR 1271 Two pathways 1 requiring Premarket Approval (PMA) and 1 that does not Stem Cell Regulation CFR Code of Federal Regulations (HCT/Ps) as defined in 21 CFR Pathway - Requires minimal manipulation and Homologous Use 351 Pathway Requires Pre-Market Approval PMA leads to an Approved Biologics License Application (BLA) Required in order to lawfully market a drug that is also a biological product 2011 MFMER MFMER HCT/P with Sole Regulation Under 361 Requires minimal manipulation Homologous use Not combined with other substances/drugs HCT/P Examples Amniotic membrane when used alone or without added cells Bone Cartilage Cornea Fascia Ligament Pericardium Peripheral or umbilical cord blood stem cells (for autologous use or use in a first or second degree blood relative) Sclera Skin Tendon Vascular graft Heart valves Dura mater Reproductive cells 2011 MFMER MFMER Same Day Concentrated (BMAC) Arteriocyte Arthrex Angel Biomet Marrowstim Harvest SmartPrep SC Signaling Growth Factors Minimal MSC Many HSC Bone Marrow Derived Culture Expanded Currently unavailable in US FDA v Regenerative Sciences Stem Cell Tourism Cayman, Asia, Carribean, Latin Am Amniofix, AmnioGen Bio-D, NeoxFlo AmnioClear AmnioPro, AmnioMatrix Adipose Derived Same Day - Enzyme or Mechanically Prepared Cytori Keia Kiso Lipogems Adivive Lipokit Osiris Umbilical Cord Blood Cartistem Tissue Gene C Purpose of Stem Cell Regulation Human Cellular Tissues and Tissue Products Must register product with CBER Donor Eligibility Current Good Tissue Practice Prevention of contamination Prevent spread of disease PRP? Stem Like Venous Derived? Amniotic Products Allogeneic 2011 MFMER MFMER

3 FDA Draft Guidances Recommendations for applying Title 21 of the Code of Federal Regulations (CFR) Part 1271 Minimal Manipulation Dec 2014 Homologous Use - Oct 2015 Same Day Surgical Exception Oct 2014 HCT/Ps from Adipose Tissue Dec 2014 Guidance, when finalized, will improve understanding of the definitions in 21 CFR and how to apply the regulatory criterion to HCT/Ps. Public Hearing Silver Spring, MD Minimal Manipulation Minimal manipulation means: Processing that does not alter the original structural characteristics of the tissue Processing that does not alter the relevant biological characteristics of cells or tissues 2011 MFMER MFMER FDA and Minimal Manipulation Example 12-1: A manufacturer performs cell selection on a mobilized peripheral blood apheresis product to obtain a higher concentration of hematopoietic stem/progenitor cells for transplantation. The HCT/P would generally be considered minimally manipulated because the cell-selected peripheral blood stem cells are not altered with regard to their relevant biological characteristics relating to repopulating the bone marrow. Homologous Use Recipient cells or tissues that are identical (e.g., skin for skin) to the donor cells or tissues Recipient tissues that perform one or more of the same basic functions in the recipient as the cells or tissues performed in the donor 2011 MFMER MFMER Adipose and The FDA Original relevant characteristics of adipose tissue to pad and cushion against shocks Includes bulk and lipid storage capacity. A manufacturer processes adipose tissue by removing the cells, which leaves the decellularized extracellular matrix portion The HCT/P generally is considered more than minimally manipulated because the processing alters the HCT/P s ability to provide padding and cushioning. Adipose and the FDA Example 10-1: A manufacturer recovers adipose tissue by tumescent liposuction and processes the adipose tissue to isolate cellular components, commonly referred to as stromal vascular fraction Considered more than minimally manipulated because the processing breaks down and eliminates the structural components that provide cushioning and support, thereby altering the original relevant characteristics of the HCT/P 2011 MFMER MFMER

4 FDA and Amniotic Cells Purpose is to provide environment, and to retain fluid in utero. Amniotic membrane is used for bone tissue replacement to support bone regeneration following surgery to repair or replace bone defects. This is not a homologous use because bone regeneration is not a basic function of amniotic membrane. Cord Blood A manufacturer of a placental/umbilical cord blood product performs cell selection and incubates the selected cells in a laboratory vessel containing culture media and growth factors to achieve large numbers of cells. This HCT/P derived from cord blood would generally be considered more than minimally manipulated because the processing affects the production of intracellular or cell-surface proteins and other markers... thereby altering the cells relevant biological characteristics of multipotency and capacity for self-renewal MFMER MFMER MSC Nomenclature Diversity ISCT proposed a set of criteria in 2006 Marker based/surface proteins Subsequent research has questioned the validity of those criteria FDA evaluating IND submissions looking for consistency in MSC classification FDA Definitions of a Stem Cell Studies and IND submission consistently using top 7 markers CD73+, CD90+, CD105+, CD11b-, CD34-, CD45-, HLA-DR- Many other markers submitted without consistency 2011 MFMER MFMER Current Good Manufacturing Practices Regulations enforced by the US FDA CGMPs provide for systems that assure: Proper design Control of manufacturing processes and facilities Monitoring Development of Standard Operating Procedures (SOPs) Operational Methods Quality Document control Environmental monitoring Advance the Science Regenerative Medicine Add Value New Assets 2011 MFMER

5 IND Approval Process IND Approval by FDA IND package preparation IND submission Pre-IND meeting IND Approval IRB Approval Bio-specimen review and approval IRB review and approval Translational Studies Identify the best source of stem cells Develop protocols for producing clinical grade cells Establish purity, potency and sterility FDA MSC Surveilance As of January 2014 no BLAs for MSC products have been awarded by the FDA x increase in applications for IND to the FDA 246 clinical trials worldwide listed on clinicaltrials.gov with MSC based product FDA Disciplinary Action Warning letter Untitled letter Notice of Initiation of Disqualification Proceedings and Opportunity to Explain Orders of Retention, Recall, Destruction, and Cessation of Manufacturing 2011 MFMER MFMER Current State of Cell use in Clinical Practice Do we own our own Stem cells? cells removed from patients Is autologous and reinjected MSC are drugs use a subject biologic to drug FDA or regulation a medical/surgical rather than the practice procedure? of medicine Regenerative Sciences vs. United States 2011 MFMER MFMER

6 FDA Response 2011 MFMER The Future of Human Cell Therapy 21 st Century Cures Act Passes House of Representatives in December 16 Easier Access to Stem Cell Therapy Questions re: Patient Safety 2011 MFMER Regenerative Advanced Therapy Designation (RAT) The drug is Reg Med defined as a cell therapy, tissue engineering product, or any combination product (not Section 361) Intended to treat lifethreatening disease Preliminary clinical evidence indicates that the drug addresses unmet medical needs What should we do? Define our cellular therapies Effort to conduct and recognize the value of well designed studies. Work with industry and regulatory agencies, not against Recognize best practices Understand what we can do and what we cannot Think of the needs of the patients 2011 MFMER MFMER slide-36 6

7 Bone Marrow Derived Adipose Derived Center for Regenerative Medicine Same Day Concentrated (BMAC) Culture Expanded Same Day - Enzyme or Mechanically Prepared Clinical Science Basic Science Arteriocyte Arthrex Angel Biomet Marrowstim Harvest SmartPrep SC Signaling Growth Factors Minimal MSC Many HSC Currently unavailable in US FDA v Regenerative Sciences Stem Cell Tourism Cayman, Asia, Carribean, Latin Am Amniofix, AmnioGen Bio-D, NeoxFlo AmnioClear AmnioPro, AmnioMatrix Cytori Keia Kiso Lipogems Adivive Lipokit Osiris Umbilical Cord Blood Cartistem Tissue Gene C Multi-specialty Human Cell Therapy Lab PRP? Stem Like Venous Derived? Amniotic Products Allogeneic Regulatory Support Legal Support 2011 MFMER FDA 510k Process MFMER