![III. CLINICAL RESEARCH
I N D I A , C H I N A , M E X I C O , U S A , E U
S U B S T A N T I A T E D C L A I M S O F T E N A B S E N T
R I S K : B E N E F I T U N C L E A R
Stem cell treatments offered around the world:
• Allogeneic (from other humans), xenogeneic (animals and plants)
• Autologous stem cells: extracted from an individual, manipulated, and
reinfused or re-implanted back into the same person
• The use of tissue-specific stem cells
• Procedures offered by clinics vs. online (skincare)
The FDA “is concerned that the hope that patients have for cures not yet available may leave them vulnerable
to unscrupulous providers of stem cell treatments that are illegal and potentially harmful [and that] FDA will
pursue perpetrators who expose the American public to the dangers of unapproved stem cells” (FDA, 2012).](https://image.slidesharecdn.com/2016ddpstem-cells-200129201652/75/Stem-cell-therapies-a-special-case-of-therapy-and-research-16-2048.jpg)
Uploaded byArete-Zoe, LLC
Stem cell therapies - a special case of therapy and research
The document discusses the potential of stem cell therapies in advancing medical treatments, outlines their classification, and highlights ongoing clinical research and regulatory frameworks across different regions. It addresses patient demand and the regulatory challenges, emphasizing the need for clear communication of risks associated with unproven treatments. Overall, the document presents both the promising aspects and the complexities surrounding stem cell therapies and their regulation.
More Related Content
Similar to Stem cell therapies - a special case of therapy and research
Stem cell therapies - a special case of therapy and research
- 1. A S PE C I AL C AS E O F T H E R AP Y & R E S E AR C H STEM CELL THERAPIES
- 2. CONTENT • I. POTENTIAL •II. CLASSIFICATION • III. CLINICAL RESEARCH • IV. PATIENT DEMAND • V. REGULATORY AND LEGAL FRAMEWORK • USA • Europe • VI. PROFESSIONAL SOCIETIES
- 3. I. STEM CELLSPOTENTIAL BASIC RESEARCH – DRUG TESTING - THERAPIES
- 4. • Basic research •Cell division and differentiation • Genetic and molecular controls • Testing new drugs • Safety testing on pluripotent lines • Cancer cell used for efficacy testing of new treatments • Cell-based therapies • Renewable source of replacement cells and tissues Stem cells offer tremendous promise for advancing health and medicine: They hold the potential to replace damaged cells and organs or else by supporting the body’s intrinsic repair mechanisms. One day they may be used to treat such debilitating conditions as Parkinson’s disease, diabetes, and spinal cord injury POTENTIAL
- 5.
- 6. Source: NIH • Proliferateextensively and generate sufficient quantities of cells for making tissue. • Differentiate into the desired cell type(s). • Survive in the recipient after transplant. • Integrate into the surrounding tissue after transplant. • Function appropriately for the duration of the recipient's life. • Avoid harming the recipient in any way. • Avoid immune rejection. Stem cells must be manipulated so that they possess the necessary characteristics for successful differentiation, transplantation, and engraftment.
- 7.
- 8. • TOTIPOTENT • Embryonic,first 4 days • Most versatile, can form the whole body • PLURIPOTENT • Embryonic, after 4 days • Inner layer (excl. placenta) • MULTIPOTENT • Less plastic • More differentiated • ADULT (multipotent) • Undifferentiated cell present in differentiated tissue STEM cells are classified by their origin and ability to differentiate in specialized tissues and organs. Embryonic stem cells can form wide range of cells. Adult stem cells are multipotent stem cells present in differentiated tissue that can specialize in any cell within the tissue in which it originated. CLASSIFICATION
- 9. Morula Blastocyst Inner Cell Mass(ESCs) Epiblasts (ESCs) ENDODERM MESODERM ECTODERM TotipotentPluripotentMultipotentUnipotent EMBRYONICADULT Tissue-Specific Stem Cells (TSSCs)
- 10. ENDODERM MESODERM ECTODERM MultipotentUnipotent ENDODERM LUNGPANCREAS LIVER GIT UGT Pulmonary Epithelial SCs Pancreatic SCs β - cells α - cells γ - cells Hepatic Oval Cells Hepatocytes Gastro- Intestinal Tract SCs Uro- Genital Tract SCs
- 11. ENDODERM MultipotentUnipotent ENDODERM KIDNEY BONE &BONE MARROW BLOOD VESSELS HEART Kidney Hematopoietic SCs Leukocytes Erythrocytes Thrombocytes Mesenchymal Stromal SCs Osteoblasts Chondrocytes Adipocytes Myoblasts Endothelial SCs Cardiac SCs ECTODERMMESODERMMESODERM
- 12. Bonfield, TL: AdultMesenchymal Stem Cells: An Innovative Therapeutic for Lung Diseases (Discovery Medicine, 2010)
- 13. ENDODERM MultipotentUnipotent ENDODERM NERVOUS SYSTEM SKIN OcularSCs Neural SCs Neurons Astrocytes Oligodendrocytes Skin SCs ECTODERMMESODERM ECTODERM EYE
- 14. EMBRYONIC STEM CELLS MO U S E E M B R Y O N I C S T E M C E L L S F O R M I N G S T E M C E L L C O L O N I E S O N A F I B R O B L A S T F E E D E R L A Y E R ( P E R K I N E L M E R ) .
- 15. ADULT STEM CELLS AD U L T S T E M C E L L S C A N B E E X T R A C T E D F R O M M A N Y A R E A S O F T H E B O D Y , I N C L U D I N G T H E B O N E M A R R O W , F A T , A N D P E R I P H E R A L B L O O D .
- 16. III. CLINICAL RESEARCH IN D I A , C H I N A , M E X I C O , U S A , E U S U B S T A N T I A T E D C L A I M S O F T E N A B S E N T R I S K : B E N E F I T U N C L E A R Stem cell treatments offered around the world: • Allogeneic (from other humans), xenogeneic (animals and plants) • Autologous stem cells: extracted from an individual, manipulated, and reinfused or re-implanted back into the same person • The use of tissue-specific stem cells • Procedures offered by clinics vs. online (skincare) The FDA “is concerned that the hope that patients have for cures not yet available may leave them vulnerable to unscrupulous providers of stem cell treatments that are illegal and potentially harmful [and that] FDA will pursue perpetrators who expose the American public to the dangers of unapproved stem cells” (FDA, 2012).
- 17. CLINICALTRIALS.GOV ALL STEM CELLTRIALS Total: 5,101 studies Europe: 1,157 studies Poland: 328 Germany: 287 Italy: 239 UK: 203 Spain: 198
- 18. CLINICALTRIALS.GOV ALL STEM CELLTRIALS Approved for marketing: 1 Available: 12 Recruiting: 1,702 Enrolling by invitation: 77 Completed: 1,769 Active, not recruiting: 782 Not yet recruiting: 234 No longer available: 7 Temporarily not available: 2 Suspended: 40 Terminated: 352 Withdrawn: 123 Interventional: 4,514 Observational: 565 Expanded access: 22 RESULTS: Available: 366 None posted: 4,735 44 835 799 1418 113 401 125 1000 0 200 400 600 800 1000 1200 1400 1600 0 I I - II II II - III III IV not stated STEM CELL TRIALS BY RESEARCH PHASESTOTAL: 5,101 STUDIES
- 19. CLINICALTRIALS.GOV ALL STEM CELLTRIALS 2627 750 494 456 320 88 Other Other + NIH Industry Other + Industry NIH Combinations TRIALS BY SOURCE OF FUNDING Sponsor Trials Fred Hutchinson Cancer Research Center 192 National Cancer Institute (NCI) 177 M.D. Anderson Cancer Center 148 Memorial Sloan Kettering Cancer Center 100 National Heart, Lung, and Blood Institute (NHLBI) 91 Masonic Cancer Center, University of Minnesota 80 City of Hope Medical Center 72 Children's Oncology Group|National Cancer Institute (NCI) 59 St. Jude Children's Research Hospital 57 Baylor College of Medicine 53 Mayo Clinic 51 National Institute of Allergy and Infectious Diseases (NIAID) 44 Dana-Farber Cancer Institute 42 Northwestern University 42 Stanford University 40 Royan Institute 39 Washington University School of Medicine 39 Assistance Publique - HĂ´pitaux de Paris 38 Emory University 38 Sidney Kimmel Comprehensive Cancer Center 38 Hadassah Medical Organization 33 Case Comprehensive Cancer Center 31 Seoul National University Hospital 30 University of Michigan 29 University of California, San Francisco 28 Duke University 27 National Institutes of Health Clinical Center (CC) 27 Genzyme, a Sanofi Company|Sanofi 25 Massachusetts General Hospital 23 Medical College of Wisconsin 22 Asan Medical Center 21 Barbara Ann Karmanos Cancer Institute 21
- 20. CLINICALTRIALS.GOV ALL STEM CELLTRIALS Bacterial and Fungal Diseases Behaviors and Mental Disorders Blood and Lymph Conditions Cancers and Other Neoplasms Digestive System Diseases Diseases and Abnormalities at or Before Birth Ear, Nose, and Throat Diseases Eye Diseases Gland and Hormone Related Diseases Heart and Blood Diseases Immune System Diseases Mouth and Tooth Diseases Muscle, Bone, and Cartilage Diseases Nervous System Diseases Nutritional and Metabolic Diseases Occupational Diseases Parasitic Diseases Respiratory Tract (Lung and Bronchial) Diseases Skin and Connective Tissue Diseases Substance Related Disorders Symptoms and General Pathology Urinary Tract, Sexual Organs, and Pregnancy Conditions Viral Diseases Wounds and Injuries 0 500 1000 1500 2000 2500 NeoplasmsbyHistologicType ImmuneSystemDiseases LymphoproliferativeDisorders HematologicDiseases ImmunoproliferativeDisorders Leukemia Lymphoma Lymphosarcoma VascularDiseases LymphaticDiseases Leukemia,Myeloid Neoplasms,PlasmaCell BoneMarrowDiseases MultipleMyeloma Leukemia,Myeloid,Acute BloodCoagulationDisorders HemostaticDisorders HemorrhagicDisorders AcuteMyelocyticLeukemia Conditions tested
- 21. CLINICALTRIALS.GOV 37 EMBRYONIC STEMCELL TRIALS
- 22. CLINICALTRIALS.GOV 285 UMBILICAL STEMCELL TRIALS
- 23. CLINICALTRIALS.GOV 529 MESENCHYMAL STEMCELL TRIALS Middle East: 47 Iran (30) Europe: 123 Spain (49)
- 24. CLINICALTRIALS.GOV 4,968 ADULT STEMCELL TRIALS Poland: 322 France: 276 Italy: 235 Spain: 195 UK: 190 Israel: 110 Iran: 51 Turkey: 28
- 25. WHO REGISTRY ICTRP 5,401RECORDS FOR 4,804 TRIALS
- 26. STEM CELLS INPUBMED 233,458 RESULTS, OF WHICH 4,412 ARE CLINICAL TRIALS
- 27. IV. PATIENT DEMAND COMMUNICATIONOF BENEFITS AND RISKS
- 28. CHALLENGES IN RESEARCH ANDTHERAPY INVOLVING STEM CELLS The best ways to regulate stem cell therapies remain unclear. Stem cells have characteristics that distinguish them from drugs, biologics, or medical devices. Considerable body of science has not yet been accumulated to develop and deliver safe and effective treatments. Regulatory uncertainty: Countries have taken different approaches to the regulation of stem cell research and therapies, and enforcement of existing regulations also differs. As a result, patients who are willing and able to travel from one country to another can access treatments that are not available in their home countries. Advertising strategies: In an effort to attract patients, clinics offering stem cell therapies have engaged in advertising on the Internet and elsewhere which is often misleading. This advertising can lead patients to spend large amounts of money on treatments that may not be effective and may even be harmful. Generating needed information: Governments, professional associations, patient groups, and other organizations all can help generate the information needed to develop effective regulations and allow patients to make informed choices. Self- regulation by the providers also could help protect patients and the legitimacy of stem cell research and therapies. Needs and autonomy of patients: Patients are frustrated at not being able to access potentially effective stem cell treatments, some of which are being studied in clinical trials, some not. Governments have an obligation to protect patients from ineffective therapies and fraudulent advertising; public policies could also reflect the needs of patients autonomy in making medical decisions. NAP: Stem cell therapies (Nov 2014)
- 29. KNOWNS AND UNKNOWNS NAP:Stem cell therapies (Nov 2014) • •Objective outcome measures would be useful for assessing the effectiveness of stem cell therapies • Marketing claims by clinics offering stem cell therapies are not necessarily supported by clinical evidence in the scientific literature • Unproven stem cell treatments can harm patients by leading to complications such as tumors, meningitis, or even death • Patients who have no other treatment options may be willing to take these risks if there is a slight chance of success. • Improved communication of clear information about treatment benefits and risks as well as about the value of safety regulations would be useful for patients.
- 31. • Patients • Difficultto estimate true numbers of patients seeking stem cell treatments in the U.S. and overseas • Main destinations • China, Mexico, Germany, the Dominican Republic, India, Russia • Conditions treated • Blindness, paralysis, multiple sclerosis, cerebral palsy, brain injuries and brain damage • Within or outside a clinical trial • Complications • Tumor growth, meningitis, death • Effectiveness highly uncertain • Financial: $20,000 to 50,000 When patients are desperate, they may turn to experimental or unproven treatments: “I may die anyway, but at least I died fighting. This is an experiment. What did I have to lose?” PATIENT PERSPECTIVE
- 32. I N NO V A T I V E S U R G E R Y I S G O V E R N E D B Y T H E C O M M O N R U L E W H I C H I M P O S E S R E S T R I C T I O N S S I M I L A R T O T H A T O F C L I N I C A L T R I A L S . PATIENT EXPERIENCES
- 33. IV. STEM CELLSAS REGUATED THERAPEUTICS
- 34. APPROVED STEM CELLTREATMENTS ARE FEW AND FAR BETWEEN
- 35. APPROVED STEM CELLTREATMENTS ARE FEW AND FAR BETWEEN
- 36. REGULATORY AND LEGALFRAMEWORKS Stem cell therapies are regulated as biologics and are subject to premarket approval under the risk-based approach to approving cellular and tissue-based products. Treatments that are “minimally manipulated” are exceptions to this regulation. European Union law states that cells or tissues that are “substantially manipulated” are subject to regulation; however, an exemption is given to member states in the non-routine case of custom-made treatments for individual patients. Innovation, including innovation in stem cell research, was made a national priority, and new laws regarding regenerative medicine products are expected to provide a more efficient path to the translation of these therapies to the clinic. Mexico has benefited economically from offering stem cell therapies that are not available in other countries. Regulations for cells and tissues treatments based on evidence would address challenges relating to therapy, safety, and efficacy. While stem cell therapies offered in China must be registered, there are not yet approved quality control guidelines available.
- 37. 1995 2000 20052010 2015 U.S. POLICY REGARDING STEM CELL RESEARCH 1996 The Dickey- Wicker Amendment 2000 NIH guidelines for research using human pluripotent stem cells go into effect 2001 President Bush prohibits federal funding of most human embryonic stem cell research 2005 Congress passes the Stem Cell Research Enhancement Act (H.R. 810), vetoed by Pres. Bush 2007 Congress passes the Stem Cell Research Enhancement Act (S. 5), vetoed by President Bush 2011 U.S. District Court rules in favor of hESC research in Sherley v. Sebelius 2009 Sherley v. Sebelius filed 2009 President Obama reverses 2001 executive order 2013 SCOTUS declines to hear Sherley v. Sebelius Source: Research America
- 38. U.S. POLICY REGARDING STEMCELL RESEARCH Executive Order 13505 Removing Barriers to Responsible Scientific Research Involving Human Stem Cells The March 9, 2009 EO changes the way NIH can support and conduct human stem cell research. NIH Guidelines on Human Stem Cell Research (July 2009) The guidelines pertain primarily to the donation of embryos for the derivation of hESCs, human induced pluripotent stem cells, and research involving human adult stem cells. Presidential statement Aug 2001 EO 13435 June 2007 EO 13505 March 2009 NIH Guideline July 2009 The EO revokes: • the Presidential Statement of Aug 2001 (federal funding for research on hESCs) • Executive Order 13435 of June 2007
- 39. UNITED STATES REGULATORY ANDLEGAL FRAMEWORKS 1995 2000 2005 2010 2015 1997 Proposed Approach to Regulation of Cellular and Tissue-Based Products 2001 Human Cells, Tissues, and Cellular and Tissue-Based Products: Establishment Registration and Listing 2004 Current Good Tissue Practice for Human Cell, Tissue, and Cellular and Tissue-Based Product Establishments, Inspection and Enforcement 21 CFR 1271 (Title 21 of the Code of Federal Regulations, Part 1271 Current Good Tissue Practices (CGTPs) 21 CFR (FDA) 2009 EO 13505 Removing Barriers to Responsible Scientific Research Involving Human Stem Cells 2007 EO 13435 Expanding Approved Stem Cell Lines in Ethically Responsible Ways 1995 NIH Human Embryonic Research Panel requested embryos left over from IVFs for research
- 40. 21 CFR 1271:CGTP GENERAL PROVISIONS PURPOSE and SCOPE: • Unified registration and listing system • Manufacturing establishments, domestic or foreign must register with the FDA • Donor-eligibility • Current good tissue practice (CGTP) • Procedures to prevent communicable diseases • HCT/P’s must be registered regardless their distribution in interstate commerce. A MINIMAL MANIPULATION MEANS: (1) For structural tissue, processing that does not alter the original relevant characteristics of the tissue relating to the tissue's utility for reconstruction, repair, or replacement (2) For cells or nonstructural tissues, processing that does not alter the relevant biological characteristics of cells or tissues.
- 41. 21 CFR 1271:CGTP GENERAL PROVISIONS HCT/P’s Articles containing or consisting of human cells or tissues that are intended for implantation, transplantation, infusion, or transfer into a human recipient: • Bone, ligament, skin, dura mater, heart valve, cornea • Hematopoietic stem/progenitor cells derived from peripheral and cord blood • Manipulated autologous chondrocytes • Epithelial cells on a synthetic matrix • Semen or other reproductive tissue. NOT HCT/P’s • Vascularized human organs for transplantation • Whole blood or blood components or blood derivative • Human secrets and extracts: milk, collagen, and cell factors • Minimally manipulated bone marrow for homologous use • Ancillary products used in the manufacture of HCT/P • Animal cells, tissues, and organs • In vitro diagnostic products A
- 42. HCT/P is regulatedsolely under the Section 361 of the PHS Act if: (1) The HCT/P is minimally manipulated; (2) The HCT/P is intended for homologous use (3) The manufacture of the HCT/P does not involve the combination with another article, except for crystalloids, preservative or a sterilizing / storage agent (4) And either: (i) The HCT/P does not have a systemic effect and is not dependent upon the metabolic activity of living cells for its primary function; (ii) The HCT/P has a systemic effect and: (a ) Is for autologous use; (b ) Is for allogeneic use for a relative (c ) Is for reproductive use. A 21 CFR 1271: CGTP GENERAL PROVISIONS HCT/P that does not meet this criteria and does not qualify for exceptions will be regulated as a drug, device, and/or biological product under section 351 of the PHSA, and applicable regulations in title 21, chapter I.
- 43. A 21 CFR 1271:CGTP GENERAL PROVISIONS EXCEPTIONS for REGISTRATION: HCT/P’s solely for nonclinical scientific or educational purposes. Individual under contract with a registered establishment Same individual and surgical procedure A carrier who accepts, receives, carries, or delivers HCT/P's Only receives or stores HCT/P's solely for implantation, transplantatio n, infusion, or transfer within a facility. Recovers reproductive cells or tissue and transfers them into a sexually intimate partner of the donor.
- 44. REGISTRATION: • Register establishment •Submit a list of every HCT/P that the establishment manufactures • Submit any changes • Registration does not mean the facility is compliant • Form FDA 3356 (pdf)
- 45. B PUBLIC RECORDS Filled 3356Forms will be available for public inspection • A list of all HCT/P's • A list of all HCT/P's manufactured by each establishment • A list of all HCT/P's discontinued • All data or information that has already become a matter of public record. • Office of Communication, Training, and Manufacturers Assistance, CBER, FDA • Find a tissue establishment (query) • Also available for inspection at FDA district offices 21 CFR 1271: CGTP REGISTRATION & LISTING
- 46. C Donor-eligibility determination required: •Manufacturer must screen and test donors for eligibility • Concern: relevant communicable disease agents and diseases • Embryos: eligibility determination required for both oocyte and semen donor. Prohibition on use: HCT/P from ineligible donors, exceptions apply 21 CFR 1271: CGTP DONOR ELIGIBILITY ELIGIBILITY OF DONORS • Determination based on Screening and Testing • A responsible person must determine and document of donor’s eligibility • A donor is eligible if: • Is free from risk factors and evidence of communicable disease • Is free from risks associated with xenotransplantation • The results of donor testing are negative or nonreactive Guideline
- 47. DONOR SCREENING All donors •Risk factors and clinical evidence of HIV, hepatitis B and C, CJD, syphilis • Xenotransplantation risks • Donors of viable leukocyte-rich cells or tissue: Human T-lymphotropic virus • Reproductive HCT/P’s: medical records, Chlamydia trachomatis, Neisseria gonorrhea. Ineligible donors. • A risk factor for or clinical evidence of any of the relevant communicable diseases including social behavior • Xenotransplantation risks • Abbreviated procedure for repeat donors DONOR TESTING C Testing for relevant communicable diseases is required. • Infants: test mothers • Collection up to 7 days before or after specimen recovery, exceptions apply. • FDA-licensed/approved tests Ineligible donors. • Tested reactive on a screening test • Plasma dilution that affects results • 12 years or younger after transfusion 21 CFR 1271: CGTP DONOR ELIGIBILITY
- 48. C 21 CFR 1271:CGTP DONOR ELIGIBILITY INELIGIBLE DONORS’ HCT/PS CAN BE USED: • For a close blood relative • Reproductive cells for a sexual partner • Documented urgent medical need • Limited use clear from labelling • Nonclinical use (labelled as such) EXCEPTIONS Donor-eligibility determination not required: • HCT/P’s for autologous use • Reproductive cells or tissue donated by a sexually intimate partner • Cryopreserved cells or tissue for reproductive use, other than embryos, • If additional donations are unavailable • Appropriate measures are taken to screen and test the donor(s) • A cryopreserved embryo intended for directed or anonymous donation • Appropriate measures are taken to screen and test the donor(s) REQUIRED LABELING: "FOR AUTOLOGOUS USE ONLY, "NOT EVALUATED FOR INFECTIOUS SUBSTANCES" "WARNING: Advise recipient of communicable disease risks" Biohazard legend if the results of any screening or testing were positive. QUARANTINE & STORAGE Eligible and ineligible must be separate
- 49. C ESTABLISH AND MAINTAINPROCEDURES Design, Define, Document, Implement, Follow, Review and Revise • All steps in testing, screening, determining donor eligibility • Review and approval by Responsible Person before implementation • Readily available to personnel • Record and justify any departure from procedures 21 CFR 1271: CGTP DONOR ELIGIBILITY RECORDS • Accompanying records with identification and results • Determination of eligibility without PHI of the donor, who made the assessment • Tests performed, certification of the laboratory, retention requirements • Records must be retained at least 10 years after the expiration date.
- 50. Regulations more specificallyapplicable will supersede the more general. 21 CFR 1271: CGTP CURRENT GOOD TISSUE PRACTICE Section 505 of the FD&C Act DRUGS Section 351 of the PHS Act BIOLOGICS Device provisions of the FD&C Act DEVICE Section 361 of the PHS Act only Minimally manipulated Sec. 505 New drugs Section 351 of the Public Health Service (PHS) Act defines a biological product as a “virus, therapeutic serum, toxin, antitoxin, vaccine, blood, blood component or derivative, allergenic product, or analogous product, … applicable to the prevention, treatment, or cure of a disease or condition of human beings.” Biological products subject to the PHS Act also meet the definition of drugs under the FD&C Act.
- 51. CGTP governs themethods used in, and the facilities and controls used for, the manufacture of HCT/Ps including all steps in recovery, donor screening, donor testing, processing, storage, labeling, packaging, and distribution. ENVIRONMENTFACILITIES EQUIPMENT SUPPLIES REAGENTS PROCESSRECOVERY LABELLING STORAGE DONORSDISTRIBUTION CURRENT GOOD TISSUE PRACTICE 21 CFR 1271: CGTP
- 52. 21 CFR 1271:CGTP CURRENT GOOD TISSUE PRACTICE PERSONNEL: Manufacturer must have sufficient, competent and appropriately trained personnel to ensure compliance. PROCEDURES: Procedures appropriate to meet core CGTP requirements for all manufacturing steps and design these procedures to prevent circumstances that increase the risk of the introduction, transmission, or spread of communicable diseases ENVIRONMENTFACILITIES EQUIPMENT SUPPLIES REAGENTS PROCESSRECOVERY LABELLING STORAGE DONORSDISTRIBUTION
- 53. ENVIRONMENTFACILITIES EQUIPMENT SUPPLIES REAGENTS PROCESSRECOVERY LABELLING STORAGE DONORSDISTRIBUTION 21 CFR1271: CGTP CURRENT GOOD TISSUE PRACTICE QUALITY PROGRAMS • Manufacturer must establish and maintain a quality program • Procedures must be reviewed, approved and revised as appropriate. • Procedures for receiving, investigating, evaluating, and documenting core CGTP requirements, including complains and possible contaminations • Provisions on risk assessment and appropriate follow-up (recall, FDA reporting) • CAPA, audits, re-audits, deviations from procedure, monitoring systems • Training and education • Validated performance of computer software
- 54. ENVIRONMENTFACILITIES EQUIPMENT SUPPLIES REAGENTS PROCESSRECOVERY LABELLING STORAGE DONORSDISTRIBUTION 21 CFR1271: CGTP CURRENT GOOD TISSUE PRACTICE FACILITIES: • Suitable size, construction, and location • Clean, sanitary, and orderly • Operations: control systems to prevent improper labeling, mix-ups, contamination, cross-contamination, and accidental exposure to communicable disease agents. ENVIRONMENTAL CONTROL: • Temperature and humidity controlled via ventilation and air filtration • Cleaning and disinfecting of rooms and equipment to ensure aseptic operations • Maintenance of equipment used to control aseptic conditions
- 55. ENVIRONMENTFACILITIES EQUIPMENT SUPPLIES REAGENTS PROCESSRECOVERY LABELLING STORAGE DONORSDISTRIBUTION 21 CFR1271: CGTP CURRENT GOOD TISSUE PRACTICE EQUIPMENT • Appropriate design, suitable location and installation • Must produce valid results. • Must be properly maintained, sanitized, calibrated and routinely inspected RECOVERY Establishment that recover HCT/Ps, must do so in a way that does not cause contamination or cross-contamination during recovery. SUPPLIES AND REAGENTS • Verified supplies and reagents that meet specifications • Production of in-house reagents must be validated • Records and receipts of al operations, equipment, supplies and reagents
- 56. ENVIRONMENTFACILITIES EQUIPMENT SUPPLIES REAGENTS PROCESSRECOVERY LABELLING STORAGE DONORSDISTRIBUTION 21 CFR1271: CGTP CURRENT GOOD TISSUE PRACTICE PROCESSING AND PROCESS CONTROLS • Prevent contamination or cross-contamination Do not pool cells or tissue from different donors • Representative in-process control and testing Dura mater: validated process to prevent CJD • Any change to a process must be verified or validated and approved before implementation by a responsible person. • Changes have to be communicated to staff. PROCESS VALIDATION • Validation activities and results must be documented and signed off • Any written representation must be based on a fully verified or validated process. • Changes in process must be validated, and process revalidated.
- 57. ENVIRONMENTFACILITIES EQUIPMENT SUPPLIES REAGENTS PROCESSRECOVERY LABELLING STORAGE DONORSDISTRIBUTION 21 CFR1271: CGTP CURRENT GOOD TISSUE PRACTICE LABELLING • Establish and maintain procedures • Ensure identification, prevent mix-ups • Verify accuracy, legibility and integrity • Donor eligibility • Type of HCT/P • Expiration date, storage temperature • Warnings if applicable • Instructions for use • Name and address of the establishment STORAGE • Control storage areas and stock rooms to prevent mix-ups, contamination, and unapproved release • Appropriate temperature • Expiration dates • Any corrective actions documented
- 58. ENVIRONMENTFACILITIES EQUIPMENT SUPPLIES REAGENTS PROCESSRECOVERY LABELLING STORAGE DONORSDISTRIBUTION 21 CFR1271: CGTP CURRENT GOOD TISSUE PRACTICE RECEIPT, DISTRIBUTION • Evaluate each incoming HCT/P • Pre-established criteria Determine: • Accept • Reject • Quarantine • Pre-distribution: HCT/P not available for distribution must be shipped in quarantine. • Availability for distribution: release criteria have been met, shipment signed off • Packaging and shipping: establish appropriate shipping conditions • Procedures: release criteria, identification, audit trail for all activities, quantity of HCT/P subject, disposition of the HCT/P, and return to inventory. • Traceability: HCT/P must be traceable.
- 59. ENVIRONMENTFACILITIES EQUIPMENT SUPPLIES REAGENTS PROCESSRECOVERY LABELLING STORAGE DONORSDISTRIBUTION 21 CFR1271: CGTP CURRENT GOOD TISSUE PRACTICE RECORDS • Maintain records of each step as required • Accurate, indelible, and legible, identifiable and retrievable • Identify Responsible Person • Records management system • Records must be retained for 10 years • Contracts and agreements must be kept. COMPLAINT FILE Maintain, record, and review complaints EXEMPTIONS AND ALTERNATIVES • Exemptions may be requested • Provide justification and alternative Operation under exemption or alternative can only begin once granted.
- 60. ADVERSE REACTIONS • Non-reproductiveonly • Manufacturers must investigate and follow-up any adverse reaction involving a communicable disease related to an HCT/P that it made available for distribution. • Adverse reactions are reportable to FDA if: • fatal; • life-threatening; • result in permanent impairment or permanent damage • necessitate medical or surgical intervention, including hospitalization. Form FDA-3500A within 15 calendar days (Guidance for industry) 21 CFR 1271: CGTP REPORTING, IMPORT, INSPECTIONS
- 61. BIOLOGICAL PRODUCT DEVIATIONREPORT Manufacturers must report HCT/P deviations relating to the core CGTP requirements within 45 days of discovery 21 CFR 1271: CGTP REPORTING, IMPORT, INSPECTIONS INSPECTIONS Establishment that manufactures HCT/Ps must permit the FDA to inspect its facilities, equipment, finished and unfinished materials, containers, processes, HCT/Ps, procedures, labeling, records, files, and papers. IMPORT The importer must notify the FDA which the HCT/P is offering for import Exceptions include reproductive HCT/Ps of the PHSA and to peripheral blood stem/progenitor cells regulated solely under section 361. RETENTION, RECALL, DESTRUCTION, CESSATION OF MANUFACTURING • written order that the HCT/P be recalled and/or destroyed • take possession of and/or destroy the violative HCT/P Form FDA-3486 Guidance for industry
- 62. INTERNATIONAL LAW “Practices whichare contrary to human dignity, such as reproductive cloning of human beings, shall not be permitted. States and competent international organizations are invited to co-operate in identifying such practices and in taking, at national or international level, the measures necessary to ensure that the principles set out in this Declaration are respected." Universal Declaration on the human genome and human rights, UNESCO, Article 11, 1997 UNESCO Source: Drze Report of the International Bioethics Committee (IBC), UNESCO "The Use of Embryonic Stem Cells in Therapeutic Research" (2001) “Research involving human embryonic stem cells is an ethical question and it is not only the right but also the obligation of each individual society to discuss this question in its own right.” • Promote free and informed public debates in all countries • Suggests state regulation • The use of "surplus" embryos should be tied to donors’ informed consent • Research projects should be reviewed by Ethics Committees • Careful assessment of advantages and risks of alternative of stem cell derivation.
- 63. EUROPE RESEARCH ON EMBRYOS 20002005 2010 2015 2000: Opinion on the Ethical Aspects of Human Stem Cell Research and Use 2002: Decision of the European Parliament and of the Council Council Decision September 2002 2003: European Commission proposal 2006: Federal Patent Court in Germany 2002: Sixth Framework Programme of the EC for Research, Technological Development and Demonstration Activities, Contributing to the Creation of the European Research Area and to Innovation (2002 to 2006) 2011: European stem cell patent has been answered with the judgment of the Court of Justice of the EU 2013: European Citizens' Initiative (ECI) “One of Us”: the landmark decision of ECJ suggests that funding of the embryo-consuming research at European level should be terminated. 2014 EC response to One of Us
- 64. EUROPE RESEARCH ON EMBRYOS TheBiopatent Directive (98/44/EC) Human Tissues and Cells Directive (2004/23/EC) 2013 The European Patent Convention 2011: The Brüstle case (ECJ) 2012 Resolution on voluntary and unpaid donation of tissues and cells Heterogeneous implementation of this legislation across the EU, with stances ranging from very permissive to very restrictive
- 65. EUROPE RESEARCH ON EMBRYOS •63% fall into the first two categories • Legal sources of human embryonic stem cells (hESCs) vary across Europe • Some authorize the creation of embryos exclusively for research • Most only allow for the derivation of hESCs from surplus (IVF) embryos. • Few countries ban the derivation of these cells altogether, • Some permit cell line imports under strict conditions. • At the national level, positions vary widely from one country to another. THE ESF AND THE EUROPEAN MEDICAL RESEARCH COUNCILS (EMRC) • Support human stem cell research and regenerative medicine • Science Policy Briefings 20013, 20023 and 20104 THE EUROPEAN SCIENCE FOUNDATION (ESF) REPORT VERY PERMISSIVE PERMISSIVE WITH RESTRICTIONS RESTRICTIVE BY DEFAULT VERY RESTRICTIVE UNLEGISLATED
- 66. EUROPE RESEARCH ON EMBRYOS •Human embryos excluded from patentability for industrial or commercial purposes • “Embryo” not defined, many interpretations across Europe • Patentability of pre-existing cell lines remains • EPO only affects signatories of the European Patent Convention2. • Consumables, procedures, protocols, devices patentable • Research on adult stem cells, mesenchymal stem cells (MSCs) or induced pluripotent stem cells (iPSCs) is less restricted BIOPATENT DIRECTIVE (EPO) Support of research and innovation in regenerative medicine VERY PERMISSIVE PERMISSIVE WITH RESTRICTIONS RESTRICTIVE BY DEFAULT VERY RESTRICTIVE UNLEGISLATED
- 67. EUROPE RESEARCH ON EMBRYOS VERY PERMISSIVE PERMISSIVEWITH RESTRICTIONS RESTRICTIVE BY DEFAULT VERY RESTRICTIVE UNLEGISLATED Very permissive: hESC often can derive from different sources, including surplus IVF embryos and embryos created for research Permissive with restrictions: hESC only on surplus IVF embryos Restrictive by default: Legislation explicitly prohibits hESC research Very restrictive: Legislation clearly prohibits hESC research Unlegislated: There is no specific legislation concerning hESC research
- 68. EUROPE RESEARCH ON EMBRYOS UK Sweden Belgium Romania Turkey Lithuania Germany Italy Slovakia Croatia Austria Ireland Poland Luxemburg Cyprus CzechRepublic Denmark Estonia Finland France Greece Hungary Iceland The Netherlands Norway Portugal Slovenia Spain Switzerland (Bulgaria) VERY PERMISSIVE PERMISSIVE WITH RESTRICTIONS RESTRICTIVE BY DEFAULT VERY RESTRICTIVE UNLEGISLATED
- 69. STEM CELL RESEARCHIN EUROPE ADVANCED-THERAPY MEDICINAL PRODUCTS Advanced-therapy medicinal products (ATMPs) are medicines for human use that are based on gene therapy, somatic-cell therapy or tissue engineering. Gene-therapy medicines Somatic-cell therapy medicines Tissue-engineered medicines Combined advanced-therapy medicines The Agency's Committee for Advanced Therapies (CAT) plays a central role in the scientific assessment of advanced-therapy medicines. It provides the expertise that is needed to evaluate advanced-therapy medicines.
- 70. HOLOCLAR APPROVED AS ATMPIN EUROPE FIRST STEM-CELL THERAPY RECOMMENDED FOR APPROVAL IN EU The applicant is Chiesi Farmaceutici S.p.A. The active substance is ex-vivo expanded autologous human corneal epithelial cells containing stem cells. Holoclar was designated as an orphan medicine and an advanced therapy medicinal product (ATMP) and EMA provided protocol assistance to the applicant during the development of the medicine on multiple occasions. ATMPs are innovative medicines that are intended for gene therapy, cell therapy or tissue engineering. The CHMP recommendation follows the draft opinion of the Committee for Advanced Therapies (CAT), the Agency’s expert committee for ATMPs. Conditional approval allows the marketing authorization of medicines that target areas of unmet medical need before comprehensive data sets are available, to speed up patient access to much needed new medicines. • EPAR Summary for the public (pdf) • Summary of Risk Management Plan (pdf) • EMA Approval (pdf)
- 71. STEM CELL RESEARCHIN EUROPE ADVANCED-THERAPY MEDICINAL PRODUCTS
- 72. REGULATORY AND LEGAL FRAMEWORKSIN CHINA NEW REGULATIONS: • Ethical guidelines and regulations for human embryonic stem cell research • Guidelines on quality control and preclinical research on SC preparations Isolation, purification, culture, amplification, modification, differentiation, cryopreservation and resuscitation, and in vivo implantation of stem cells, including hESCs, iPSCs, mesenchymal stem cells, hematopoietic stem cells, and other progenitor cells. OVERSIGHT OF STEM CELL TREATMENTS • Since June 2012, all organizations conducting SC therapy have to register • Security evaluations include the detection microbes • The Chinese government has been halting illegal stem cell therapies The Ministry of Science and Technology Chinese Academy of Sciences (CAS) National Science Foundation of China National Stem Cell Research Supervision and Coordination Committee • Funding of SC research in China totaled almost $500 million over 5 years • About 200 hospitals and many institutions are working on stem cell research • China now publishes the second largest number of stem cell publications
- 73. IV. PROFESSIONAL SOCIETIES THEINTERNATIONAL SOCIETY FOR STEM CELL RESEARCH (ISSCR) • the largest professional organization of stem cell scientists, encourages responsible clinical translation through the education of scientists and medical practitioners on professional standards GUIDANCE FOR STEM CELL RESEARCHERS • In 2007, ISSCR impaneled a broad international taskforce with 30 members from 14 countries to develop a set of professional guidelines for responsible translational stem cell research. • Bedrock principles were conceived, including high standards of pre-clinical evidence, peer review, scrupulous review of clinical protocol by IRBs, rigorous informed consent, and publication of results whether positive or negative. • The panel also developed principles for preserving medical innovation.
- 74. IV. PROFESSIONAL SOCIETIES THEINTERNATIONAL SOCIETY FOR CELLULAR THERAPY (ISCT) • The general scientific consensus is that most stem cell therapies are not ready for marketing or commercialization. • Industries that are providing these treatments are increasingly sophisticated and organized and are challenging established regulatory frameworks. • ISCT has an interest in the promotion of stem cell research and development, immune cell interventions, reproductive medicine, and gene therapy. • 2013: Presidential taskforce on the use of unproven cellular therapies • Working groups on definitions, scientific evidence and biological rationale, laboratory cell processing, clinical practice, regulation, commercial implications, communications, and policy. • The taskforce will be looking at the ethics of unregulated direct-to-consumer marketing of therapies as well as the implications for industry.
- 75.