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CBER Tissue Safety Team

CBER Tissue Safety Team. Ruth Solomon, M.D. Director Division of Human Tissues OCTGT/CBER/FDA Blood Products Advisory Committee May 1, 2008. Outline. Background What are HCT/Ps? How are they regulated? What is an Adverse Reaction? Which Adverse Reactions must be reported?

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CBER Tissue Safety Team

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  1. CBER Tissue Safety Team Ruth Solomon, M.D. Director Division of Human Tissues OCTGT/CBER/FDA Blood Products Advisory Committee May 1, 2008

  2. Outline • Background • What are HCT/Ps? • How are they regulated? • What is an Adverse Reaction? • Which Adverse Reactions must be reported? • Tissue Safety Team • Challenges • Summary Data on Reports

  3. WHAT ARE HCT/Ps?

  4. What are HCT/Ps? • Human cells, tissues or cellular or tissue based products (HCT/Ps) • means articles containing or consisting of human cells or tissues that are intended for implantation, transplantation, infusion, or transfer into a human recipient 21 CFR 1271.3(d)

  5. Musculoskeletal tissues Skin Dura mater Cardiovascular tissues Ocular tissues Reproductive tissues Hematopoietic stem/progenitor cells derived from peripheral and cord blood Other cellular therapies Examples of HCT/Ps

  6. Not HCT/Ps • Vascularized human organs • Whole blood or blood components or blood derivative products • Secreted or extracted human products s.a. milk, collagen, cell factors • Minimally manipulated bone marrow for homologous use and not combined with another article

  7. Not HCT/Ps, cont. • Ancillary products used in manufacture of HCT/Ps • Cells, tissues, and organs derived from animals other than humans • In vitro diagnostic products • Blood vessels recovered with an organ, intended for use in organ transplantation and labeled “For use in organ transplantation only”

  8. HOW ARE HCT/Ps REGULATED BY FDA?

  9. HCT/P Regulations(all effective 5/25/05) • 21 CFR Part 1271 • Establishment Registration and Product Listing • Donor Eligibility • Current Good Tissue Practice—contains requirements for adverse reaction reporting • Legal Authority: Section 361 of Public Health Service (PHS) Act—prevent the introduction, transmission, or spread of communicable disease

  10. Regulatory Pathways • “361” HCT/Ps • No pre-market review; follow Part 1271 only • Compliance with regulations determined on inspection • Biological Products • Follow Part 1271 and other applicable regulations • Pre-market review and approval (BLA)—must show safety, purity, potency • Medical Devices • Follow Part 1271 and other applicable regulations • Pre-market review and clearance/approval (510(k), PMA)—must show safety and efficacy

  11. ADVERSE REACTIONS

  12. What is an Adverse Reaction? • Adverse reaction [1271.3(y)] (for “361” HCT/Ps) means a noxious and unintended response to any HCT/P for which there is a reasonable possibility that the HCT/P caused the response • Adverse experience [600.80(a)] (for biological products) means any adverse event associated with the use of a biological product in humans, whether or not product related…

  13. What Adverse Reactions Must Manufacturers Investigate? • Manufacturers must investigate • Any adverse reaction involving a communicable disease related to an HCT/P they made available for distribution 21 CFR 1271.350(a)(1) • Manufacturers are not required to investigate (but are encouraged to do so) • Adverse reactions that do not involve a communicable disease (e.g., product defects)

  14. What Adverse Reactions Must Manufacturers Report? • Manufacturers must report to FDA any adverse reaction involving a communicable disease, if it: • Is fatal • Is life-threatening • Results in permanent impairment or damage • Necessitates medical or surgical intervention 21 CFR 1271.350(a)(1)

  15. Reporting Required Bacterial infection in HCT/P recipient Graft failure surgeon believes is secondary to infection Viral seroconversion of recipient suspected to be allograft related Reporting not Required* Package labeled incorrectly Mechanical failure of graft Allergic reaction Product damage Donor-transmitted malignancy Examples * Reports may be submitted, even if not required

  16. How are Adverse Reactions Reported to FDA? • For Manufacturers: • Use Form FDA 3500A (MedWatch) • Report w/in 15 days of receipt of information • Via fax/mail 21 CFR 1271.350(a)(2)

  17. How are Adverse Reactions Reported to FDA? • For Voluntary Reporters: • Use Form FDA 3500 (MedWatch) • Via online, fax, mail, telephone • Recommend prompt reporting to HCT/P establishments (CBER does not forward consumer reports to manufacturer)

  18. Sources of Reports • Reports received from various sources Tissue Establishment Consumer/ Healthcare Professional CBER MedSun MedWatch Office CDC, Other CDRH

  19. MedWatch Website • http://www.fda.gov/medwatch • Provides information on the MedWatch reporting program, reporting forms

  20. CBER TISSUE SAFETY TEAM

  21. Tissue Safety Team (TST) • First CBER Safety Team • First meeting in May 2004 • Purpose: • Provide a coordinated, efficient approach to the receipt, routing, investigation, evaluation, documentation and trending of reported adverse reactions involving HCT/Ps across 5 Offices in CBER and beyond the Center

  22. FDA’s Tissue Safety Team • Includes multiple offices at CBER • Reviews all MedWatch reports received • Conducts follow-up on infectious adverse reactions related to HCT/Ps • Seeks additional information from clinician and manufacturer as needed • Evaluates cases at Tissue Safety Team meetings • SOPP 8508 describes procedures for handling AR reports www.fda.gov/cber/regsopp/8508.htm

  23. OBE Office of Biostatistics and Epidemiology OCTMA Office of Communication, Training, and Manufacturer Assistance OD Office of the Director OCTGT Office of Cellular, Tissue and Gene Therapies OCBQ Office of Compliance and Biologics Quality FDA’s Tissue Safety Team

  24. TST Points of Contact Outside of CBER • Outside of CBER, within FDA • Center for Devices and Radiological Health • Office of Regulatory Affairs • Office of Crisis Management • Outside of FDA • CDC • CDC Epidemic Intelligence Service (EIS) Officer at FDA • HRSA • CMS • Special government employee consulted on unusual cases

  25. Tracking and Routing Reports • Reports received by OBE—determine if “361” HCT/P • Enter into database • If an infectious adverse reaction, determine if High Priority (criteria) and immediately notify TST Working Group and begin follow-up • For other reports, determine if follow-up is needed (criteria)

  26. High Priority Cases • Fatality; infection with Clostridium sp., or group A Streptococcus • Serious viral disease or seroconversion (e.g., HIV, HBV, HCV); or CJD • Two or more recipients of tissues or organs from a single donor develop infections with the same organism • Same unusual organism cultured from recipient as was found in one or more recovery, pre-processing or post-processing cultures (on tissues) or environmental cultures

  27. Clinical Follow-up: OBE • Specific name/type of product/lot number/ manufacturer • Time interval from implantation to onset of symptoms • Culture results (e.g., transport fluid, pre-implant, wound, explanted graft) • Patient—immunosuppressed? Infection prior to graft implant? • Anything unusual about the surgery?

  28. Clinical Information (cont.) • Medical or surgical interventions • e.g., debridement, explant, antibiotics started or changed • Special handling or preparation of allograft prior to implantation • Devices implanted along with tissue? • General impression/indicators that adverse reaction was related to the allograft • Results of hospital infection control investigation, if any

  29. Manufacturing Information: OCBQ • Processor’s investigation—conclusion? • Donor medical records reviewed • Processing methods reviewed—any deviations? • Environmental monitoring reviewed • Pre- and post- processing culture results—do any match recipient’s culture results? • Whether there are other complaints related to same donor—if so, same organism?

  30. Challenges in HCT/P Adverse Reaction Surveillance • Limitations of passive surveillance (under-reporting, biases, etc.) • Distinguishing graft-attributable infections vs. common post-operative wound infections • Labor intensive follow-up activities • Case closed when investigation complete and based on the available information, further TST action is not indicated. Usually no conclusion that adverse reaction was due to graft

  31. SUMMARY DATA ON HCT/P REPORTS

  32. Reported Adverse Reactionsby Tissue Type

  33. Reported Adverse Reactionsby Outcome

  34. Reported Adverse Reactionsby Reporter

  35. Further Information • Tissue Home Pagehttp://www.fda.gov/cber/tiss.htm • Tissue-Related Documents/Publicationshttp://www.fda.gov/cber/tissue/docs.htm • For general questions contact Office of Communication, Training and Manufacturers Assistance (OCTMA) at: • matt@cber.fda.gov • 301-827-1800

  36. Questions?

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