Melissa A. Greenwald, M.D. Office of Cellular, Tissue and Gene Therapies (OCTGT); CBER Cell Tissue and Gene Therapies Ad

1. Chlamydia trachomatis and Neisseria gonorrhoeae transmission by HCT/Ps recovered from the reproductive system, gestational tissues or other sources: Introduction Melissa A. Greenwald, M.D. Office of Cellular, Tissue and Gene Therapies (OCTGT); CBER Cell Tissue and Gene Therapies Advisory Committee 14 May 2009

2. What is an HCT/P? • Human cells, tissues and cellular and tissue-based products • 21 CFR 1217.3(d) defines HCT/Ps as articles containing or consisting of human cells or tissues that are intended for implantation, transplantation, infusion, or transfer into a human recipient • HCT/Ps encompass a wide variety of products • HCT/Ps are regulated by OCTGT

3. From deceased (cadaveric) donors: Musculoskeletal tissues Skin Dura Mater Cardiovascular tissues Ocular tissues Tissue/device and other combination products From living donors: Hematopoietic stem/progenitor cells derived from peripheral and cord blood Other cellular therapies(e.g. pancreatic islets, mesenchymal stem cells, fibroblasts) Reproductive cells and tissues Examples of HCT/Ps

4. Not HCT/Ps • Vascularized human organs for transplantation (HRSA oversight); • Whole blood or blood components or blood derivative products; • Secreted or extracted human products, such as milk, collagen, and cell factors

5. Not HCT/Ps (continued…) • Minimally manipulated bone marrow for homologous use and not combined with a drug or a device; • Ancillary products used in the manufacture of HCT/P; • Cells, tissues, and organs derived from animals other than humans; and • In vitro diagnostic products

6. Goal of 21 CFR 1271 Regulations • HCT/Ps carry a risk of communicable disease transmission from the donor to the recipient • 1271 regulations are designed to minimize the risk of communicable disease transmission • Donor screening • Donor testing • Ensure cells or tissues are not contaminated during recovery, processing, storage or distribution • Can only require donor screening and testing for relevant communicable disease agents or diseases (RCDADs)

7. HCT/P Donor Screening • Donor screening • medical history interview (relevant risk factors or conditions), • physical assessment/examination (physical evidence), and • medical record review (clinical evidence)

8. HCT/P Donor Testing • HCT/P donors must be tested • using an appropriate FDA-licensed, approved, or cleared donor screening test • in accordance with the manufacturer’s instructions • to adequately and appropriately reduce the risk of transmission of the relevant communicable diseases

9. RCDADs—General Information CDC

10. What are RCDADs? • RCDADS—Relevant Communicable Disease Agents or Diseases • Defined by the regulations in two ways • First part of the definition lists some RCDADs by name • Second part of the definition describes criteria by which emerging or newly identified agents may be added to the “list” of RCDADs

11. Adding a “new” RCDAD A communicable disease agent or disease meeting the following criteria (Sec. 1271.3(r)(2)), but not specifically listed, is relevant if it is one: • For which there may be a risk of transmission by an HCT/P, either • to the recipient of the HCT/P; or • to those people who may handle or otherwise come in contact with the HCT/P, such as medical personnel, because the disease agent or disease is potentially transmissible by an HCT/P;

12. Adding a “new” RCDAD • and either • (1) has sufficient incidence and/or prevalence to affect the potential donor population (Sec. 1271.3(r)(2)(i)(B)(1)), or • (2) may have been released accidentally or intentionally in a manner that could place potential donors at risk of infection (Sec. 1271.3(r)(2)(i)(B)(2));

13. Adding a “new” RCDAD • That could be • fatal or life-threatening, • could result in permanent impairment of a body function or permanent damage to body structure, or • could necessitate medical or surgical intervention to preclude permanent impairment of body function or permanent damage to a body structure (Sec. 1271.3(r)(2)(ii));

14. Adding a “new” RCDAD • and for which • appropriate screening measures have been developed, and/or • an appropriate screening test for donor specimens has been licensed, approved, or cleared for such use by FDA and is available (Sec. 1271.3(r)(2)(iii)).

15. Adding a “new” RCDAD—How does it happen? • According to the definition, consider 1) severity of effect, 2) risk of transmission, and 3) availability of screening and/or testing measures • No expectation for individual establishments to make this determination; FDA notifies the public via guidance if we determine that an infectious disease meets the definition of a RCDAD (or if something no longer meets the criteria for being “relevant”)

16. RCDADs added to the “list” since HCT/P regulations went into effect • Added and implemented: • WNV • Sepsis • Vaccinia • Proposed, not determined relevant: • SARS • Proposed: • Chagas (Trypanosoma cruzi)

17. RCDADs—Specific Information

18. Requirements for RCDAD Screening and Testing

19. Requirements for RCDAD Screening and Testing

20. Reproductive HCT/Ps • Interpreted to include semen, oocytes, and embryos to which the donor contributed the spermatozoa or oocyte http://research.unc.edu/endeavors/spr2005/sperm.php http://www.absoluteastronomy.com/topics/In_vitro_fertilisation www.wikimedia.org Courtesy: RWJMS IVF Program

21. Specific HCT/Ps Under Discussion • Amniotic membrane and cells recovered from amniotic membrane • Placenta and cells recovered from placenta • Placental blood-derived stem cells • Umbilical cord blood (HPC-C) • Cells recovered from menstrual blood • Foreskin and cells recovered from foreskin

22. Specific HCT/Ps Under Discussion • HCT/Ps under discussion today are not considered reproductive HCT/Ps • Reproductive HCT/Ps are the only HCT/Ps where CT/NG are currently identified as RCDADs • Therefore, Neisseria gonorrhoeae and Chlamydia trachomatis testing is not currently required

23. The Take-Home Message http://fwmusicstore.co.uk/images/tp.jpg

24. Final Comments • Chlamydia trachomatis and Neisseria gonorrhoeae are not currently RCDADs for the HCT/Ps in question • Screening and/or testing is required only for RCDADs • According to the definition of a RCDAD, consider 1) severity of effect, 2) risk of transmission, and 3) availability of screening and/or testing measures

25. Final Comments • Today you will hear several presentations to give what information is known about the risk of transmission of Chlamydia trachomatis and Neisseria gonorrhoeae via these HCT/Ps, as well as information about some of the specific HCT/Ps in question

26. Today’s Talks • Literature Review – Ana Kolin Ph.D. (FDA) • Overview of Infectivity and Epidemiology – John Papp Ph.D. (CDC) • Utilization and Processing of Human Amnion – Scheffer C.G. Tseng, M.D., Ph.D. (Bio-Tissue, Inc.) • Cord Blood Collection and Donor Testing – John Miller M.D., Ph.D. (NMDP)

27. Questions for the Committee http://www.kennardconsulting.com/kc/questionsAndAnswers.jsf http://www.co.santa-clara.ca.us/fire/pub_ed/safesitters.html

28. Questions for Committee 1. Please comment on the potential for transmission of C. trachomatis and N. gonorrhoeae by HCT/Ps that are recovered from the reproductive system or gestational tissues, for example: • Amniotic membrane and placenta, or cells recovered from these tissues • Cells recovered from menstrual blood • Foreskin • Placental/umbilical cord blood derived cell products

29. Questions for Committee 2. Please comment on whether additional HCT/Ps should be considered for potential risk for transmission of C. trachomatis and N. gonorrhoeae (e.g., cells recovered from bladder and kidneys).

30. Questions for me?

31. Contact Information: • melissa.greenwald@fda.hhs.gov CBER Information: • Web site • http://www.fda.gov/cber • http://www.fda.gov/cber/tiss.htm • E-mail • Manufacturers: matt@cber.fda.gov • Consumers, health care: octma@cber.fda.gov • Phone • 301-827-1800