CBER Presentation

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FDA Update

Melissa Greenwald, M.D.
Division of Human Tissues
OCTGT, CBER, FDAOCTGT, CBER, FDA


AATB 11th Annual Spring Meeting
27 March 2007
Hollywood, CA

FDA Update

  • Registration and Listing
  • Current Good Tissue Practices (CGTPs CGTPs)
  • Exemptions and Alternatives
  • Adverse Reactions (AR)
  • Human Cells, Tissue, and Cellular and Tissue Based Products (HCT/P) Deviations
  • Regulatory Updates
  • New Publications

Registration

  • Annual registration update required in December
  • Electronically registered establishments were notified via email if not updated email
  • Electronic registration is encouraged

Registration

  • Changes to listing are required within 6 months
  • Change of ownership or location required within 5 days
  • Inactivation Inactivation—check box #2(d)

Failure to Register

Registration/Listing

  • Total (as of 3/8/07) = 2550 (488 inactive)
    • Musculoskeletal/ocular Musculoskeletal/ocular = 846
    • HematopoieticHematopoieticstem cell stem cell = 623
    • Reproductive = 604
    • International = 174 (mostly stem cell)

Registration

  • Many registered establishments perform more than one manufacturing activity
  • Relatively even distribution of manufacturing manufacturing activities
  • Storage and distribution largest categories (18 % and 16% respectively)

Proposed Rule for Registration and Listing for Foreign and Domestic Establishments

  • Published August 29, 2006
  • Comment period extended/ended 1/26/07
  • Public meeting 12/11/06 discussed proposed changes to National Drug Code system
    • Would affect HCT/Ps licensed as biological products (e.g., hematopoietic stem cells and other cell therapy products)
    • Assigned by FDA
    • Must be on the product label

Proposed Registration & Listing Rule Changes to Part 1271

  • New definitions: importer, US agent
  • Would require electronic registration unless a waiver is granted
  • Foreign establishments importing HCT/Ps would submit information on all known consignees US consignees
  • Changes to ownership or location would be reported within 30 days rather than 5 days

CGTPs

  • Draft guidance in progress
  • Contains Q and As from various industry groups
  • Guidance for Industry: Compliance with 21 Guidance for Industry: Compliance with 21 CFR 1271.150(c)(1) Manufacturing CFR 1271.150(c)(1) Manufacturing Arrangement, September 2006 Arrangement, September 2006
    • Discusses your responsibility for ensuring the establishments with which you have manufacturing arrangements are in compliance with CGTP requirements compliance
  • Provides examples for doing so http://www.fda.gov/cber/gdlns/cgtpmanuf.htm

Exemptions and Alternatives

  • May request exemption or alternative from donor eligibility and CGTP requirements (1271.155) (1271.155)—currently does not include registration & listing
  • Must be accompanied by supporting documentation justifying the request
  • OCTGT SOPP 9151 - 6/13/06
    • Division of Human Tissues coordinates
    • Consults experts outside of division
    • Draft letter presented to Tissue Policy Team for discussion/concurrence
    • Center Director sign-off

Adverse Reactions

  • Adverse reaction means a noxious and unintended response to any HCT/P for which there is a reasonable possibility that the HCT/P caused the response
  • If adverse reaction is reportable, manufacturers must submit a MedWatch 3500A to FDA within 15 days of receipt of information
  • Must also submit follow-up MedWatchreport within 15 days of receipt of new information from the investigation of reportable adverse reactions

(1271.3(y))

Adverse Reaction Reporting

  • Manufacturers must investigate:
    • Any adverse reaction involving a communicable disease related to an HCT/P that they made available for distribution.
  • Manufacturers must report to FDA
  • • An adverse reaction involving a communicable disease if it:
    • Is fatal
    • Is life-threatening
    • Results in permanent impairment of function or permanent damage to body structure; or
    • Necessitates medical or surgical intervention, including hospitalization
(1271.350)

How are Adverse Reactions Reported to FDA?

  • For Manufacturers:
    • • Use Form FDA 3500A (MedWatch)
    • Report w/in 15 days of receipt of information
  • For Voluntary reporters:
    • Use Form FDA 3500 (MedWatch)
    • Recommend prompt reporting to HCT/P establishments
  • • FDA MedWatch reporting system: http://www.fda.gov/medwatch

Adverse Reactions

  • Provides additional information and instructions for filling out the MedwatchForms

Adverse Reaction Reports Internal Procedures

  • SOPP 8508 describes procedures for handling AR reports—coordinating 5 offices within CBER: www.fda.gov/cber/regsopp/8508.htm
  • MedWatchreports involving “361”and biological product HCT/Ps come to CBER
  • Follow-up on infectious adverse reactions
  • Interoffice review; discussed at Tissue Safety Team meetings
  • Seek more information from reporter and manufacturer as needed

Adverse Reactions Reported to CBER (January 06 through February 2007)

  • Total reports: 207
  • Product Type
    • Tissue: 170 (82%)
    • Cells: 37 (18%)
  • Tissue Type
    • Blood Vessel3 (2%)
    • Bone: 41 (24%)
    • Eye: 40 (24%)
    • Skin: 36 (21%)
    • Soft Tissue: 38 (22%)
    • Cardiac: 6 (3.5%)
    • Tissue NOS6 (3.5%)

Adverse Reactions Reported to CBER (January 06 through February 2007)

  • Reporter
    • Manufacturer: 98
    • Direct: 53
    • Med Sun: 18
  • Adverse Event Type
    • Infectious: 47
    • Non-Infectious

HCT/P Deviation 21 CFR 1271.3(dd)

  • An event that represents a deviation from applicable regulations, standards or established specifications that relate to prevention of communicable disease transmission or contamination; or
  • An unexpected or unforeseeable event that may be related to transmission or potential transmission of a communicable disease or may lead to HCT/P contamination

HCT/P Deviation Reporting 21 CFR 1271.350(b)

  • Required for “361”nonreproductiveHCT/Ps recovered on or after 5/25/05
  • Deviations related to a distributed HCT/Ps
  • All deviations must be investigated
  • Only report deviations related to “core” CGTPs(1271.150(b))
  • Must report those that occurred in your facility or in a facility that performed a manufacturing step for you under contract, agreement or other arrangement

When, How, Where

  • As soon as possible, not to exceed 45 days after discovery: www.fda.gov/cber/biodev/biodev.htm
  • Form FDA-3486 and instructions
  • Electronically or by mail
  • Indicate HCT/P Deviation Codes

HCT/P Deviation Codes

DE

Donor Eligibility

DS

Donor Screening

DT

Donor Testing

EC

Environmental Control

SR

Supplies and Reagents

RE Recovery
PC Processing
LC Labeling Control
ST Storage
SD

SD Receipt, Pre-distribution Shipment, Distribution



Reportable HCT/P Deviations

FY'05
FY'06
FY'07
Donor Eligibility
8 32 11
Donor Screening
  12 2
Donor Testing
  33 22
Environmental Control
   1  
Supplies and Reagents
   3 1
Recovery
   2 2
Processing
   14 8
Labeling Control
1 2  
Storage
   1  
Receipt, Pre-Dist., Dist.
4 43 12
Not reportable
15 77 16
Total
 28 20 74

HCT/P Deviation Reports (Reportable and Non-reportable)

FY ‘2006/’2007 (10/1/06-2/28/07)

  • Musculo-skeletal: 42/5
  • Skin: 10/4
  • Ocular: 68/17
  • Hematopoieticstem cell: 103/46
  • Somatic cells/leukocytes: 8/5
  • Reproductive: 4/1

FY 06 HCT/P Inspections Performed

Type of HCT/P establishment
# Inspections
Accomplished

Hours/
Inspections
Reproductive tissues
87 45.7

Cord blood stem cells
Peripheral blood stem cells

36 42.8

All other HCT/Ps
(e.g. musculoskeletal, ocular, recovery, distributors)

234 44.1
Total
 354*  

* Sum of individual inspections do not equal total (354) due to two inspections that were conducted for products in multiple categories

FY06 HCT/P Inspection Classifications

Type of HCT/P establishment

NAI
VAI
OAI
Reproductive tissues
55 26 5

Cord blood stem cells Peripheral blood stem cells

24 11 0

All other HCT/Ps
(e.g. musculoskeletal, ocular, recovery, distributors)

170 59 5
Total
 249 96 10

FY06 HCT/P Inspection Results

  • Less than 30% of HCT/P inspections resulted in issuance of Form FDA-483s
  • Regulatory Actions Issued in FY06
    • 2 Orders to Cease Manufacture and Retain HCT/Ps –Recovery establishments
    • 1 Warning Letter–Reproductive
    • 2 Untitled Letters -Reproductive

Classified Recalls FY 2006

 
HCT/Ps
CBER Total (all products)
Class I
13
13
Class II
22
1377
Class III
1
451

FY 2006 Class I HCT/P Recalls

  • Biomedical Tissue Services (BTS), Ft. Lee, New Jersey
    • HCT/Ps, recovered from donors without adequate donor eligibility determinations, were distributed.
  • Recalled HCT/Ps collected from 761 donors
  • Subrecallsperformed at several processors
  • 9 of 13 Class I recalls related to HCT/Ps recovered by BTS

FY 2006 Class I HCT/P Recalls
Other Reasons for Recall

  • Companion tissue + for microorganisms
  • Recipient of companion tissue reported infection with Clostridium septicum
  • Donor HCV NAT + (firm informed after distribution)
  • Donor HCV + by EIA and NAT (results attributed to wrong donor)

HCT/P Recalls Classified

 
Class I
Class II
Class III
FY 00
1
17
6
FY 01
4
31
0
FY 02
10
23
6
FY 03
7
41
6
FY 04
5
20
4
FY 05
0
29
1
FY 06
17
22
1

Draft Cord Blood Guidance

  • Published 1/17/07, comments due by 4/17/07
  • Recommends a path to licensure for establishments that manufacture cord blood for specified indications (hematopoieticreconstitution in patients with hematologic malignancies)

Draft Cord Blood Guidance

  • Describes FDA's approach to the regulation of cord blood regulation hematopoietic stem/progenitor cells that are:
    • Minimally manipulated
    • Used to replenish the bone marrow in patients with blood-related malignancies and
    • Used in recipients unrelated to the donor of the stem cells

Draft Cord Blood Guidance

  • Rather than submitting their own clinical data, manufacturers may cite existing data in the docket
  • Guidance also provides recommendations for
    • Content and format of information to submit with an application
    • Manufacturing cord blood products
    • Compliance with applicable regulatory requirements

Draft Cord Blood Guidance

  • Will be discussed at upcoming Cellular, Tissue and Gene Therapies Advisory Committee
  • March 30, 2007 from 8 a.m. to approximately 3 p.m.
  • Hilton Hotel , Washington DC North/Gaithersburg, 620 Perry Parkway, Gaithersburg, MD
  • http://www.fda.gov/cber/advisory/ctgt/ctgt0307.htm

Guidance: HCT/Ps Tested Using Pooled Specimens or Diagnostic Tests

Guidance: HCT/Ps Tested Using Pooled Specimens or Diagnostic Tests

  • Addresses:
    • Distributed HCT/Ps and those in inventory
    • Need for HCT/P deviation reports if distributed
    • Retesting/labeling for future distribution of HCT/Ps in-inventory

Testing Guidance –cont.

  • FDA is exercising enforcement discretion to allow distribution of these HCT/Ps
  • Limited to the two testing deficiencies
  • Pertains only to recently regulated living donors (hematopoieticstem/progenitor cells and reproductive cells and tissues)
  • For distributed HCT/Ps, deviation reports only required for hematopoieticstem cells from first or second degree blood relatives
    • One report for all affected HCT/Ps

Testing Guidance: In Inventory HCT/Ps-Retesting Before Distribution

  • Recommended using original donor sample
    • As long as it can be tested in accordance with the manufacturer’s instructions
    • New specimen OK
    • Distribute “as is”if negative/nonreactive

Testing Guidance: In Inventory HCT/Ps-Retesting Before Distribution

  • If retesting not feasible
    • Document reason that retesting is not feasible in accompanying records and in files
    • Physician notification
    • Labeled “WARNING: Advise patient of communicable disease risks”

Testing Guidance: Retesting Donors

  • You can distribute in-inventory HCT/Ps from the following donors, even if you are unable to retest them
    • Hematopoieticstem cells (non-autologous)
    • Cryopreservedembryos formed using 3rdparty gametes
  • If you cannot retest anonymous or directed donors of cryopreservedsemen or oocytes, you cannot distribute

Blood Vessel Final Rule

  • Final Rule published in March 2007 and is effective 30 days after publication
  • Revises 21 CFR Part 1271.3(d) for articles not considered HCT/Ps
  • New 1271.3(d)(8): Blood vessels recovered with an organ, as defined in 42 CFR 121.2, that are intended for use in organ transplantation and labeled “For use in organ transplantation only”
  • Revises 42 CFR to make these blood vessels “part of”organs

Blood Vessel Final Rule

  • This was a joint rule by FDA and HRSA
  • Addresses blood vessels recovered with organs and intended for use in organ transplantation
  • Health Resources and Services Administration (HRSA) oversight

Human Tissue Task Force

  • Formed in August to evaluate effectiveness of new regulations and to identify whether additional steps necessary to strengthen regulatory framework
  • Collaborative effort between CBER, Collaborative effort between CBER, ORA and OCORA and OC

Human Tissue Task Force

  • Extremely productive three months
  • Memo containing recommendations provided to CBER and ORA senior management

Contact Information

Melissa A. Greenwald, M.D.
1401 Rockville Pike HFM-775
Rockville , MD 20852

melissa.greenwald@fda.hhs.gov
301-827-2002
FAX 301-827-2844

CBER Information

HTTP://WWW.FDA.GOV/CBER

 

 
Updated: May 14, 2007