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FDA Update

FDA Update. Melissa Greenwald, M.D. Division of Human Tissues AATB Spring Meeting Plenary Session March 30, 2009 Orlando, FL. Today’s Talk. OCTGT Office Update Donor Testing Inspections Regulatory Actions Deviation Reports Adverse Reaction Data Follow-Up on Legal Issues.

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FDA Update

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  1. FDA Update Melissa Greenwald, M.D. Division of Human Tissues AATB Spring Meeting Plenary Session March 30, 2009 Orlando, FL

  2. Today’s Talk • OCTGT Office Update • Donor Testing • Inspections • Regulatory Actions • Deviation Reports • Adverse Reaction Data • Follow-Up on Legal Issues

  3. OCTGT Update • Three new research programs • Retroviral vectors • Tissue safety • Shyh-Ching Lo • Joydeep Ghosh • Tolerance and immune regulation

  4. A new Tissue Laboratory developed under the Division of Cellular & Gene Therapies (DCGT) in collaboration with the Division of Human Tissues (DHT) of OCTGT/CBER/FDA: • Promote safety of tissue grafts for transplantation • Understand and help validation of various procedures for human tissue processing • Support evaluation of licensed donor screening tests • Develop and apply new methodologies for detection of microbes in tissues to be used as grafts • Develop capability of identification and characterization of microbes associated with unusual infections or emerging infectious diseases • Collaborate with OBE and support biovigilance study relevant to communicable diseases and disease agents in human tissues

  5. Clinical microbiology methodology for detection and characterization of various microbes with tissue safety concerns Molecular technologies of rapid detection of specifically targeted microbes with high sensitivity using real-time quantitative PCR arrays and viral/pathogen chips Evaluation and application of high-throughput sequencing technology for identification of unusual microbes or emerging infectious disease agents Many of the capabilities of Tissue lab will be supported through outreach and collaborations with various laboratories at FDA and at the NIH. Tissue lab capabilities to be developed:

  6. Guidances in Development • Characterization and Qualification of Cell Banks Used in the Production of Cellular and Gene Therapy Products • Use of Serological Tests on Samples from Donors of Whole Blood and Blood Components for Transfusion and Donors of Human Cells, Tissues, and Cellular and Tissue-Based Products (HCT/Ps) to Reduce the Risk of Transmission of Trypanosoma cruzi infection (OBRR lead) Adapted from FDA Annual Guidance Agenda (http://first.fda.gov/fedreg/08/oc0860.pdf)

  7. Guidances in Development • Preparation of INDs for Certain Unlicensed Minimally Manipulated, Unrelated Allogeneic Placental/Umbilical Cord Blood Products (HPC-C) • Clinical Study Design for Early Phase Studies of Cellular and Gene Therapies • Clinical Study Design Considerations for Cancer Vaccine Development • Initiation and Conduct of Clinical Trials Using Cellular Therapies for Cardiac Disease

  8. Guidances in Development • Devices Involved in Manufacture, Storage and Administration of Cellular Products and Tissues • Preparation of Investigational Device Exemptions and Investigational New Drugs for Tissue Engineered and Regenerative Medicine Products • Submission of Information for the National Xenotransplantation Database

  9. Regulation • Current Good Manufacturing Practice and Investigational New Drugs Intended for Use in Clinical Trials; Final Rule 7/15/2008 – effective date 9/15/08

  10. Guidance • Draft Guidance for Industry: Validation of Growth-Based Rapid Microbiological Methods for Sterility Testing of Cellular and Gene Therapy Products 2/11/2008 • Guidance for Industry: Content and Review of Chemistry, Manufacturing, and Control (CMC) Information for Human Somatic Cell Therapy Investigational New Drug Applications (INDs) 4/9/2008

  11. Guidance • Draft Guidance for Industry: Use of Nucleic Acid Tests to Reduce the Risk of Transmission of West Nile Virus from Donors of Whole Blood and Blood Components Intended for Transfusion and Donors of Human Cells, Tissues, and Cellular and Tissue-Based Products (HCT/Ps) 4/25/08 • Two FDA-licensed tests for living and cadaveric donors • All HCT/P donors tested by Individual Donor NAT • Comments under review • Request for Data 7/7/2008 • Request for complete data for 2008 WNV season by 1/31/09

  12. Guidance • Guidance for Industry: CGMP for Phase 1 Investigational Drugs 7/15/2008 • Well-defined written procedures • Adequately controlled equipment and manufacturing environment • Accurately and consistently recorded data from manufacturing (including testing) • Draft Guidance for Industry: Considerations for Allogeneic Pancreatic Islet Cell Products 5/21/2008

  13. Guidance • Guidance for FDA Reviewers and Sponsors: Content and Review of Chemistry, Manufacturing, and Control (CMC) Information for Human Gene Therapy Investigational New Drug Applications (INDs) - 4/9/2008 • Draft Guidance for Industry: Potency Tests for Cellular and Gene Therapy Products - 10/9/2008

  14. Guidance • Draft Guidance for Industry: Current Good Tissue Practice (CGTP) and Additional Requirements for Manufacturers of Human Cells, Tissues, and Cellular and Tissue-Based Products (HCT/Ps) - 1/16/2009

  15. Guidance • Draft Guidance for Industry: Use of Serological Tests to Reduce the Risk of Transmission of Trypanosoma cruzi Infection in Whole Blood and Blood Components for Transfusion and Human Cells, Tissues, and Cellular and Tissue-Based Products (HCT/Ps) - 3/26/2009

  16. Guidance • Draft Chagas guidance, cont. • Not for implementation • Notification of intent to make Chagas Disease (T. cruzi infection) a RCDAD • Makes recommendations for donor screening and testing • Docket open for comments

  17. Regulations/Guidance • http://www.fda.gov/cber/guidelines.htm • http://www.fda.gov/cber/rules.htm

  18. Meetings/Workshops • Animal Models for the Treatment of Acute Radiation Syndrome September 17-18, 2008 • Public Workshop: America’s Blood Centers: Blood Establishment Computer Software (BECS) Conference July 10-11, 2008 • FDA Workshop to Consider Approaches to Reduce the Risk of Transfusion-Transmitted Babesiosis in the United States September 12, 2008

  19. Meetings/Workshops • Blood Products Advisory Committee (1 April 2009); one topic will discuss blood donor screening, and testing donors of human cells, tissues, and cellular and tissue-based products (HCT/Ps) for hepatitis B virus infection by nucleic acid testing • http://www.fda.gov/cber/advisory/bp/bp0409.htm

  20. Meetings/Workshops • http://www.fda.gov/cber/minutes/workshop-min.htm • http://www.fda.gov/cber/scireg.htm

  21. HCT/P Donor Tests for RCDADs • Updated listing of all available donor screening tests and appropriate specimens (originally posted Feb 2007) at: http://www.fda.gov/cber/tissue/prod. htm#approved • Specific testing requirements listed at: http://www.fda.gov/cber/tissue/hctptestreq.htm

  22. HRSA RFI on Vascularized Composite Allografts • HRSA seeking comment on whether vascularized composite allografts should be included in definition of organ • See Request for Information (RFI) at:http://www.gpoaccess.gov/fr/index.html • Public meeting April 4, 2008 at Parklawn Bldg, Rockville MD • Comment period closed May 2, 2008 • Contact HRSA for more info: 301-443-7577

  23. General Testing Requirements • 1271.80(c) Tests. You must test using appropriate FDA-licensed, approved, or cleared donor screening tests, in accordance with the manufacturer’s instructions, to adequately and appropriately reduce the risk of transmission of relevant communicable diseases.

  24. Maximum specimen storage claims in selected HCT/P donor screening tests • HCV NAT: • COBAS Ampliscreen HCV Test, version 2.0: Living donor (LD) specimens, maximum time frozen is one month; cadaveric specimens (CAD) up to 72 hours. • COBAS Taqscreen MPX: LD maximum time frozen 30 days, No current CAD claim • Procleix HIV-1/HCV Assay: LD 5 days at 2-8; “longer periods of time at </= -20 degrees C” [a specific time-frame has not been validated]; CAD “long term storage of plasma at </= -20 has not been established” • Procleix Ultrio Assay: LD up to 6 months frozen, CAD up to 2 weeks

  25. Maximum specimen storage claims in selected HCT/P donor screening tests • HIV NAT: same as for HCV NAT • COBAS Ampliscreen HIV-1 Test has same storage claim as the Ampliscreen HCV test – up to one month • all other tests are the same

  26. Antibody Test Storage Claims • Many have language similar to below*: For cadaveric specimens, follow general standards and/or regulations for collection, storage and handling. Cadaveric specimens may be stored frozen (-20°C or colder) or stored for up to 2 days at 2 - 8°C. If storage periods greater than 2 days at 2 - 8°C are anticipated, the serum should be removed from the clot to avoid hemolysis and stored frozen. * Abbott PRISM HBsAg Assay

  27. Antibody Test Storage Claims Ortho HCV and Chagas ELISA tests (Ab) • Cadaveric specimens may be stored for up to 10 days at 2-8°C and up to 4 weeks at –20°C undergoing 5 freeze/thaw cycles. Store specimens in appropriately qualified freezers. Specimens may be frozen and thawed up to 5 times. Mix specimen thoroughly after thawing and before testing. • Studies have demonstrated that specimens may be shipped at ambient temperature (up to 37°C) for up to seven days or refrigerated (2 to 8°C) for up to seven days. Upon arrival, specimens should be stored at 2 to 8°C. For shipments requiring extensive transit times (greater than seven days), specimens should be kept frozen (-20°C or below).

  28. FY08 HCT/P Inspections Accomplished *Sum of individual inspections do not equal total due to some inspections that were conducted for products in multiple categories

  29. FY08 HCT/P Inspection Classifications

  30. FDA Form 483 • “This document lists observations made by the FDA representative(s) during the inspection of your facility. They are inspectional observations, and do not represent a final agency determination regarding your compliance. If you have an objection regarding an observation, or have implemented, or plan to implement, corrective action in response to an observation, you may discuss the objection or action with the FDA representative(s) during the inspection or submit this information to FDA at the address above….”

  31. OAI/VAI/NAI? • OAI – Official Action Indicated – objectionable conditions found that warrant action • VAI – Voluntary Action Indicated – objectionable conditions found but do not meet the threshold for regulatory action • NAI – No Action Indicated – no objectionable conditions found (generally no FDA-483) • http://www.fda.gov/ora/inspect_ref/fmd/fmd86.htm

  32. FY08 HCT/P Inspection Results • Approx. 30% of HCT/P inspections resulted in issuance of Form FDA-483s; • Consistent with FY07 and FY06.

  33. Inspectional Observations:Storage and Distribution • Failure to store HCT/Ps at appropriate temperatures; establish acceptable temperature limits; and/or maintain and record storage temperatures 21 CFR 1271.260 (b) and (e) • Storage room temperatures are not recorded • Freezer did not have a functioning recording device and was not equipped with an alarm. The freezer temperature is not recorded or monitored after normal operating hours • Temperature monitoring logs not reviewed prior to removal/transfer of grafts as required in the SOP

  34. Inspectional Observations:Processors • Failure to maintain facility in good state of repair 21 CFR 1271.190(a) • Several processing rooms have damage to the walls – areas of damage show exposed dry wall below the level of the paper layer • Failure to maintain documentation of equipment maintenance, cleaning, sanitization and calibration 21 CFR 1271. 200(e) • Cleaning of equipment was not documented. There were no records of cleaning from 1/2006 – 3/2008

  35. Inspectional Observations:Processors - 2 • Failure to process HCT/Ps in a way that does not increase the risk of introduction, transmission or spread of communicable disease 21 CFR 1271.220(a) • There were five occurrences where containers holding tissue from two different donors were opened at the same time in the processing hood. (Note – a cross contamination event had been documented)

  36. Inspectional Observations:Donor Testing • Failure to perform testing for communicable disease agents according to the manufacturer’s instructions 21 CFR 1271.80(c) • Cadaveric samples tested by NAT assay were routinely tested using a 1:5 dilution. The package insert instructs that cadaveric donors be tested “neat.”

  37. Regulatory Actions • Regulatory Actions Issued • 1 Warning Letter (repro) • 1 Untitled Letter (repro) • 1 Untitled Letter –website/stem cell treatment – part of our internet surveillance

  38. FY08 HCT/P Regulatory Actions: Deviations Cited • Failure to test specimens from anonymous or directed reproductive donors using appropriate FDA-licensed, approved, or cleared donor screening tests, in accordance with the manufacturer's instructions21 CFR 1271.80(c). • Failure to screen an anonymous or directed reproductive donor of cells or tissue by reviewing the donor's relevant medical records for risk factors for, and clinical evidence of, relevant communicable disease agents and diseases 21 CFR 1271.75(a).

  39. Regulatory Actions - 2 • Failure to establish and maintain procedures for all steps that are performed in testing, screening, determining donor eligibility, and complying with all other requirements of Subpart C "Donor Eligibility" in 21 CFR Part 1271. "Establish and maintain" means define, document, and implement; then follow, review, and as needed, revise on an ongoing basis [21 CFR 1271.47(a)]. • The firm's standard operating procedures did not address all steps required for donor screening and determining donor eligibility, including, but not limited to: (1) donor screening for risk factors for, or clinical evidence of relevant communicable disease agents and diseases; and (2) the criteria used to determine donor eligibility and ineligibility.

  40. HCT/P Deviation Reporting

  41. HCT/P Deviation ReportsProducts Involved

  42. HCT/P Deviations Reported

  43. HCT/P Deviation Reports Non-Reportable Events • No products were distributed • Not associated with disease transmission or contamination • Not related to core GTP • Product released under urgent medical need • Product not subject to HCT/P deviation reporting • Reproductive tissue • Unrelated Allogeneic Stem Cells • Reporting establishment is not an HCT/P manufacturer

  44. HCT/P Deviation Reports Non-Reportable Events • Positive pre-implant culture is in general not reportable as a deviation • Unless a complaint results in an investigation that reveals a departure from GTPs or • If the recipient had an adverse reaction then might be reported as an adverse reaction not HCT/P deviation

  45. HCT/P Deviation Reporting FY08

  46. Tissue HCT/P Reports • Donor Eligibility – 33 reports • Donor accepted when risk factors, clinical evidence or physical evidence identified – 18 • Donor accepted when reactive for relevant communicable disease – 4 • Donor incorrectly evaluated for plasma dilution – 10 • Donor testing not performed or documented - 1

  47. Tissue HCT/P Reports - 2 • Processing and process controls – 18 • HCT/P contaminated, potentially contaminated or cross contaminated – 17 • In-process controls inadequate – 1 • Microorganisms involved: • Bacillus, Candida, Clostridium, Enterobacter, Group D Enterococcus, Staphylococcus, Proteus

  48. Tissue HCT/P Reports - 3 • Donor Screening – 15 • Donor screening not performed or documented – 1 • Donor screening (medical history interview) performed incorrectly (incomplete or inaccurate) – 13 • Donor screening (medical record review) performed incorrectly (incomplete or inaccurate) - 1

  49. Classified RecallsFY 2007

  50. Classified RecallsFY 2008* * This table does not include 3 “mixed class” recalls

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