CYTX Phacilitate Cell & Gene Therapy Forum


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Presented by Ken Kleinhenz, VP of Regulatory Affairs on Monday, January 24 2011 at the Phaciliate Cell & Gene Therapy Forum

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CYTX Phacilitate Cell & Gene Therapy Forum

  1. 1. Unique Challenges with Autologous Cell Therapies<br />Kenneth K. Kleinhenz<br />Vice President Regulatory Affairs <br />and Quality Assurance<br />Phacilitate Cell & Gene Therapy Forum <br />The Grand Hyatt, Washington, D.C.<br />January 24-26, 2011<br />1<br />
  2. 2. Applicable Regulations <br />(Europe)<br />
  3. 3. Europe vs Member States<br />European Union as a Whole<br /><ul><li>Directives and Regulations Apply to All Member States
  4. 4. Individual Member States may have regulations and rules that exceed the EU Directives and Regulations
  5. 5. Examples:
  6. 6. German Law treats all cells as drugs
  7. 7. UK has an HTA authority to regulate cell banks
  8. 8. Italy treats autologous banks as illegal due to lack of availability to ALL citizens (exclusivity) </li></li></ul><li>Applicable Regulations to EU <br />Medical Device Directive 93/42/EEC<br /><ul><li>Rule 3
  9. 9. “All non-invasive devices intended for modifying the biological or chemical composition of blood, other body liquids or other liquids intended for infusion into the body are in class IIb, unless the treatment consists of filtration, centrifugation or exchanges of gas, heat, in which case they are Class IIa.”</li></li></ul><li>Other EU Cell Therapy Regulations<br />Medicinal Product Directive - 65/65/EEC<br /><ul><li>Replaced by 2001/83/EEC</li></ul>Medicinal Products for Human Use - 2001/83/EEC<br /><ul><li>Gene Therapies
  10. 10. Somatic cell Therapies – manipulated cells</li></li></ul><li>Other EU Cell Therapy Regulations<br />Advanced Therapies Directive - 2003/63/EEC<br /><ul><li>Created to cover advanced cell therapies
  11. 11. Only covers manipulated cells – “Autologous Cells expressed in vitro under culture conditions”</li></ul>Human Blood and Blood Components Directive – 2002/98/EEC<br /><ul><li>Created to add blood components to 2001/83/EEC
  12. 12. Exempts stem cell from blood (Article 2, section 4)</li></li></ul><li>Other EU Cell Therapy Regulations<br />Regulation 1394/2007 – Amendment to 2001/83/EEC<br />Article 2 – Definitions<br />1 (a) Advanced Therapy Product means ANY of the following:<br /><ul><li>A Gene Therapy 2001/83/EEC
  13. 13. A somatic Cell Therapy 2001/83/EEC
  14. 14. A Tissue Engineered Product as define in point (b)</li></ul>1 (b) Tissue Engineered Product means:<br /><ul><li>Contains or consists of engineered cells or tissue AND
  15. 15. Is presented as having properties for, or is used in or administered to human beings with a view to, regenerating, repairing, or replacing a human tissue. </li></li></ul><li>Other EU Cell Therapy Regulations<br />1 (C)- Cells or tissues shall be considered “engineered” if they fulfill at least one of the following points:<br /><ul><li>1).Cells or tissues have been subjected to substantial manipulation, so that the biological characteristics, physiological functions, or structural properties relevant for the intended regeneration, repair, or replacement, are achieved. The manipulations listed in Annex I in particular, shall not be considered as substantial manipulations. </li></ul>OR<br /><ul><li>2). The cells or tissues are not intended to be used for the same essential function in the recipient as in the donor. </li></li></ul><li>Nuances in the Regulations<br />2001/83/EEC (Medical Device Directive)<br /><ul><li>Scope- Article 2: The provisions of this directive shall apply to industrially produced medicinal products for human use intended to be placed on the market in member states.
  16. 16. Article 3 (1): This Directive shall not apply to any medicinal product prepared in a pharmacy in accordance with a medical prescription for an individual patient. </li></ul>93/42/EEC (Medical Device Directive) 2007/47/EEC<br /><ul><li>Definitions- Article 1 (2)h: ‘Placing on the market’ means the first making available in the return for payment…with a view to distribution and or use in the community market.</li></li></ul><li>Nuances in the Regulations<br />1394/2007 (ATMP Regulation)<br /><ul><li>Article 28 (2): This Directive shall not apply to any Advanced Therapy Medicinal Product… which is prepared on a non-routine basis according to specific quality standards, and used within the same Member State in a hospital under the exclusive professional responsibility of a medical practitioner.</li></li></ul><li>Other EU Cell Therapy Regulations<br />Storage and Preservation of Human Tissue Cells Directive 2004/23/EEC<br /><ul><li>Designed for cell banking activities.
  17. 17. “Tissues and cells used as an autologous graft within the same surgical procedure” are exempt per Article 2 section 2(a). </li></li></ul><li>Other EU Cell Therapy Regulations<br />1394/2007<br /><ul><li>Article 2 (1): “In addition to the definitions laid down in Directive 2001/83/EEC and in Article 3(a) to (l) and (o) to (q) of Directive 2004/23/EEC, the following definitions shall apply for the purpose of this regulation. </li></li></ul><li>
  18. 18. Practice of Medicine?<br />1394/2007 Engineered Tissue<br /><ul><li>Minimally Manipulated
  19. 19. The cells or tissues are not intended to be used for the same essential function in the recipient as in the donor.
  20. 20. Minimally manipulated allogeneic tissues used homogonously? Regulated?
  21. 21. No. Why? Bone Marrow Transplantation
  22. 22. Recipient and Donor is allogeneic language and not intended to cover autologous? </li></li></ul><li>
  23. 23.
  24. 24.
  25. 25.
  26. 26. Annex I Exemptions<br />
  27. 27. US Food and Drug Administration <br />Considerations<br />
  28. 28. Key US FDA Regulations<br />21 CFR 1271.15(b) – you are not required to comply with the requirements of this part if you are an establishment that removes HCT/Ps from an individual and implants such HCT/Ps into the same individual during the same surgical procedure. <br />
  29. 29. Minimally Manipulated Autologous Peripheral Blood Stem Cell Draft Guidance Document -2007<br />For autologous PBSCs processed at the clinical site, the presence of all the following 5 factors supports the conclusion that the cells are removed and subsequently implanted in the “same surgical procedure” and, therefore, compliance is not required.<br />The cells are autologous and are intended for use for a specific clinical indication<br />The cells are minimally manipulated<br />The device is solely responsible for the production of the autologous cells (i.e., no other manufacturing steps take place outside of the device other than the recovery of the source cells)<br />The cells are used within a short period of time (i.e., they are not stored or shipped)<br />The device and selected cells are only used at the point of care (i.e., cell processing is performed at and by the clinical site where cells are directly administered). <br />
  30. 30. 21 CFR 1271.10: Practice of Medicine with HCT/Ps<br />A product regulated as a “361 HCT/P” solely under Part 1271 does not require premarket clearance or approval, if it meets the following criteria:<br /><ul><li>The HCT/P is minimally manipulated
  31. 31. The HCT/P in intended for homologous use only, as reflected by the labeling, advertising, or other indications of the manufacturer’s objective intent
  32. 32. The manufacture of the HCT/P does not involve the combination of the cell or tissue component with a drug or a device, except for a sterilizing, preserving, or storage agent, if the addition of the agent does not raise new clinical safety concerns with respect to the HCT/P, and
  33. 33. Either:</li></ul>The HCT/P does not have a systemic effect and is not dependent upon the metabolic activity of living cells for its primary function, or<br />The HCT/P has a systemic effect or is dependent upon the metabolic activity of living cells for its primary function, and:<br /><ul><li>Is for autologous use,
  34. 34. Is for allogeneic use in a 1st degree or 2nd degree blood relative, or
  35. 35. Is for reproductive use.</li></li></ul><li>Risk! <br />How much is too much?<br />
  36. 36. Interpretation of Definitions <br /><ul><li>Same Essential Function in the Donor and Recipient (Homologous Use)
  37. 37. Minimum Manipulation
  38. 38. Effecting the relevant biological characteristics</li></li></ul><li>Regulatory Burden in EU<br />ENGINEERED CELLS ARE DEFINED:<br /><ul><li>Substantial Manipulation – device actions (Device’s Actions)</li></ul>OR<br /><ul><li>Same Essential Functions – physicians actions </li></ul> (Physician’s Actions / Labeling)<br />
  39. 39. Principles of Proportionality in EU<br /><ul><li> Risk Based Approach
  40. 40. Regulations are Proportional to the Risks
  41. 41. Procedure Risks
  42. 42. Autologous cells – low risk
  43. 43. Non-manipulated cells – low risk
  44. 44. Allogeneic cells – higher risk
  45. 45. Manipulated cells – higher risk</li></li></ul><li>Case Study:<br />Autologous Cells in <br />Same Surgical Procedure<br />
  46. 46. Rinsing<br />Rinsing<br />Matrix Digestion<br />ADRCs<br />Fat mixing with ADRCs<br />Centrifugation<br />Automating and Standardizing An Existing Laboratory / Manual Process<br />29<br />
  47. 47. Not Available in the United States of America<br />
  48. 48. Celution Disposables – Closed System<br />31<br />
  49. 49. Disposables mounted onto Device<br />32<br />
  50. 50. Harvest adipose <br />tissue (liposuction)<br />Isolate adipose regenerative cells<br />Return cells to same patient in about an hour<br /><ul><li> Adult ADRC’s cells
  51. 51. Endothelial progenitor cells
  52. 52. Other key cell types</li></ul>Autologous in Same Surgical Procedure<br />33<br />
  53. 53. Defined Population of <br />Regenerative Cells<br />Adipose Tissue Aspiration<br />Liquid fat<br />Fat cells/collagen<br />Washing media<br /> Cellpellet<br />Pre / Endothelial<br />7%<br />Hematopoietic<br />stem cells<br />2%<br />Adipose<br />Stem Cells<br />2-5%<br />Fibroblasts<br />47%<br />Pericyte/<br />Smooth muscle<br />2%<br />Other<br />33%<br />Adipose Derived Regenerative Cells (ADRC)<br />
  54. 54. Release Criteria Considerations<br /><ul><li>Point of Care
  55. 55. Cell Viability
  56. 56. Cell Count
  57. 57. Validation
  58. 58. CFU-F
  59. 59. CD Markers- Flow Cytometry
  60. 60. Residual Reagents
  61. 61. Cells/g of tissue </li>