1	Human Cells, Tissues, and Cellular and Tissue-Based Products (HCT/Ps) Melissa Greenwald, MD Division of Human Tissues; Office of Cellular, Tissue and Gene Therapies IVD Roundtable 11 May 2005
2	What is an HCT/P? Human cells, tissues, or cellular or tissue-based products are articles containing or consisting of human cells or tissues that are intended for implantation, transplantation, infusion or transfer into a human recipient An HCT/P is NOT an organ – vascularized organs (e.g., liver, kidney, heart) are regulated within the DHHS by HRSA 21 CFR 1271.3(d)
3	Examples of HCT/Ps Currently regulated tissues Bone Tendon Corneas Skin Ligament “Newly” regulated tissues after 5/25/05 Reproductive Tissues Hematopoietic stem/progenitor cells from peripheral blood and from umbilical cord blood Heart Valves Dura Mater
4	Overview of Tissue Rules
5	Overview, cont. Draft – Preventive Measures to Reduce the Possible Risk of Transmission of CJD/vCJD by HCT/Ps - June 2002 Draft – Eligibility Determination for Donors of HCT/Ps - May 2004 Final - donor eligibility guidance will combine the above drafts –FDA addressing comments to the docket now GTP guidance – currently leveraging with industry professional associations to develop draft guidance
6	Donor Eligibility and RCDADs Donor Eligibility rule defines relevant communicable disease agents or diseases (RCDADs); establishments must screen and/or test for RCDADs Defined in 1271.3(r) – (1) lists particular RCDADs and (2) describes when communicable disease agents or diseases may be added to the list of RCDADs – in order to allow additions based on emerging infectious diseases Additions to the “list” of RCDADs would be added through guidance (draft, public comment, then finalize, except in cases of public health emergency)
7	RCDADs For all HCT/Ps HIV, types 1 and 2 HBV HCV Human TSE, including CJD Treponema pallidum (agent of syphilis) For viable, leukocyte-rich HCT/Ps HTLV, types I and II For reproductive HCT/Ps Chlamydia trachomatis Neisseria gonorrhea
8	Additional RCDADs The donor eligibility draft guidance adds new RCDADs according to definition in § 1271.3(r)(2) (published May 2004) “FDA believes that the following meet the standards for identification of relevant communicable disease agent”— West Nile Virus Sepsis Vaccinia (Smallpox vaccination) Severe Acute Respiratory Syndrome (SARS)
9	Donor Testing Donor testing must be performed at lab Registered with FDA CLIA certified or CMS equivalent Donor tests FDA-licensed, approved, or cleared donor SCREENING tests Used in accordance with the PI Should be labeled for use for cadaveric donors if such a test is available Recommendations for may change with time and increasing technology
10	Donor Testing Interpretation of test results ONLY according to manufacturer’s instructions in the PI Triplicate testing is NOT recommended in any manufacturer's test kit instructions Specimen collection should be at same time as, or within 7 days before or after, collection of the cells or tissues with certain exceptions Donors who have had transfusions or infusions 48 hours prior to specimen collection should be evaluated for plasma dilution or excluded
11	Donor Testing Specifically recommended tests include FDA licensed (or cleared) screening tests for HIV types 1 and 2 – anti-HIV-1 and anti-HIV-2 or licensed combination test HBV – HBsAg and anti-HBcore (total=IgG+IgM) HCV – anti-HCV Treponema pallidum serological test for syphilis (Donor with reactive non-Treponemal screening test and nonreactive specific Treponemal confirmatory test is permitted to donate)
12	Donor Testing Additional screening tests for viable, leukocyte-rich cells or tissue HTLV types I and II – FDA-licensed anti-HTLV I/II CMV – not RCDAD, but must test, using FDA- cleared (CBER) screening test for anti-CMV. Additional tests for genitourinary diseases for donors of reproductive cells and tissues Chlamydia trachomatis Neisseria gonorrhea Currently no FDA-licensed, approved, or cleared donor screening tests for either.
13	Donor Testing NAT – test living donors for RCDADs using available FDA-licensed NAT screening tests; currently licensed tests for HIV and HCV – anticipate NAT for cadaveric donors as well DE Draft Guidance published before any NAT was approved for use in cadaveric specimens; states “As more information becomes available, FDA may recommend these tests for use in cadaveric tissue donors.”
14	Cadaveric claims for infectious disease screening test kits Claims may be obtained as an additional claim (or supplement on already approved test kits) for test kits with an indication for use in screening blood donors Guidance published November 2004 “Recommendations for Obtaining a Labeling Claim for Communicable Disease Donor Screening Tests Using Cadaveric Blood Specimens from Donors of Human Cells, Tissues, and Cellular and Tissue-Based Products (HCT/Ps)” Least burdensome approach
15	Minimal requirements for cadaveric claims Studies – sensitivity, specificity, reproducibility May do studies of matched pairs of pre- and post-mortem specimens OR spiking studies (approach we have seen) of cadaveric specimens + unmatched pre-mortem specimens Minimun of 50 specimens for each study Indication for use with specimen type (clot tube vs anticoagulated tube vs both) should be taken into consideration when choosing specimens to use in studies – include all specimen types for which you wish to get an indication
16	Minimal requirements for cadaveric claims Minimum of 3 test kit lots for each study Plasma dilution must be taken into consideration Additional information about donors of the cadaveric specimens: Time between death and specimen collection; how/where specimen was collected Use hemolyzed specimens, note degree of hemolysis Note information about storage and handling conditions of the specimens
17	Cadaveric testing claims Notable issues with HCT/P specimens No validation of testing after long term specimen storage (this would be very helpful to the HCT/P industry) Claims for HCT/P donors may only use ID testing and not be pooled testing unless separate validation is performed (none to date) Turnaround time is often an issue with cadaveric HCT/Ps – corneas are released in <7 days It is helpful to have claims for both serum and plasma for cadaveric donors because of limited specimen volume
18	Further Information Cadaveric guidance located at http://www.fda.gov/cber/gdlns/cadbldhctp.pdf Recommend you speak to CBER prior to initiating study to review study plan Cadaveric claims are jointly reviewed by OCTGT and OBRR You may contact me at: Melissa.Greenwald@fda.hhs.gov 301-827-2002 All tissue related publications can be found at http://www.fda.gov/cber/tissue/docs.htm