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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
OCTGT Update
• Three new research programs
• Retroviral vectors
• Tissue safety
• Shyh-Ching Lo
• Joydeep Ghosh
• Tolerance and immune regulation
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
Tissue lab capabilities to be developed:
• 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.
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)
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
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
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
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
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
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
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
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
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
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
Regulations/Guidance
• http://www.fda.gov/cber/guidelines.htm
• http://www.fda.gov/cber/rules.htm
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
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.h
tm
Meetings/Workshops
• http://www.fda.gov/cber/minutes/worksh
op-min.htm
• http://www.fda.gov/cber/scireg.htm
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/ti
ssue/prod.
htm#approved
• Specific testing
requirements listed at:
http://www.fda.gov/cber/ti
ssue/hctptestreq.htm
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
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.
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
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
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
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).
FY08 HCT/P
Inspections Accomplished
Type of HCT/P # Inspections Hours/
establishment Accomplished Inspection
Reproductive tissues 158 42.4
Cord blood stem cells 19 31.7
Peripheral blood stem cells
All other HCT/Ps 213 34.4
(e.g. musculoskeletal, ocular,
recovery, distributors)
Total 383* 37.5
*Sum of individual inspections do not equal total due to some inspections that
were conducted for products in multiple categories
FY08 HCT/P
Inspection Classifications
Type of HCT/P NAI VAI OAI
establishment
Reproductive tissues 106 40 10
Cord blood stem cells 15 4 0
Peripheral blood stem
cells
All other HCT/Ps 164 46 1
(e.g. musculoskeletal,
ocular, recovery,
distributors)
Total 285 90 11
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….”
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
FY08 HCT/P
Inspection Results
• Approx. 30% of HCT/P inspections
resulted in issuance of Form FDA-483s;
• Consistent with FY07 and FY06.
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
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
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)
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.”
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
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
instructions 21 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).
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.
HCT/P Deviation Reporting
FY06 FY07 FY08
Reportable 144 153 223
Electronic 100 118 164
Reports (69%) (77%) (74%)
Non-Reportable 76 48 63
Total Reports 220 201 286
HCT/P Deviation Reports
Products Involved
Product FY06 FY07 FY08
Peripheral Blood Stem
Cells 71 98 109
Cornea/Sclera 51 35 44
Skin 6 6 27
Musculoskeletal 21 14 26
Somatic Cells 0 1 19
Donor Leukocytes 6 10 12
Cord Blood Stem Cells 2 4 4
HCT/P Deviations Reported
Reportable HCT/P FY 05 FY 06 FY 07 FY 08
Deviations
Donor Eligibility 8 32 24 37
Donor Screening 0 12 8 17
Donor Testing 0 33 54 54
Environmental Control 0 1 2 0
Supplies and Reagents 0 3 6 1
Recovery 0 2 8 8
Processing 0 14 17 68
Labeling Control 1 2 1 2
Storage 0 1 0 0
Receipt, Pre-Dist., Dist. 4 43 32 36
Total 13 143 152 223
Non-Reportable 15 77 48 63
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
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
HCT/P Deviation Reporting FY08
Cellular Tissue
HCT/P Deviation Code HCT/P HCT/P Total
Donor Eligibility 4 33 37 16.6%
Donor Screening 2 15 17 7.6%
Donor Testing 42 12 54 24.2%
Environmental Control 0 0 0 0.0%
Supplies and Reagents 1 0 1 0.4%
Recovery 8 0 8 3.6%
Processing and
Processing Controls 50 18 68 30.5%
Labeling Controls 0 2 2 0.9%
Storage 0 0 0 0.0%
Receipt, Pre-Distribution,
Shipment & Distribution 33 3 36 16.1%
Total 140 83 223 100%
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
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
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
Classified Recalls
FY 2007
HCT/P CBER Total
Recalls Recalls
(all products)
FY 07 Class I 7 7
FY 07 Class II 15 1041
FY 07 Class III 0 381
Classified Recalls
FY 2008*
HCT/P CBER Total
Recalls Recalls
(all products)
FY 08 Class I 3 4
FY 08 Class II 11 950
FY 08 Class III 7 345
* This table does not include 3 “mixed class” recalls
FY 2008 Class I
HCT/P Recalls
• Donors met all DE requirements using
diagnostic HBsAg and HBcAb tests. Re-
testing of donors using FDA licensed donor
screening tests revealed three donors
reactive (confirmed positive) for HBsAg
• 2 recalls
• Clostridium perfringens infection in recipient.
HCT/P Recalls
45
40
35
30
25 Class I
20 Class II
15 Class III
10
5
0
FY00 FY01 FY02 FY03 FY04 FY05 FY06 FY07 FY08
Adverse Reaction Data
Adverse Reactions Reported*
by Tissue Type
Tissue type CY 2005 CY 2006 CY 2007 CY 2008**
Total Infections 35 98 91 77
Bone 9 26 21 9
Musculoskeletal
Tissue 4 21 38 29
Skin 12 22 18 18
Eye 8 27 12 16
Cardiac 1 1 1 2
Blood Vessel 1 1 0 1
Tissue, NOS 0 0 1 2
*Numbers reflect reports, not confirmed cases. Most reports are of routine post-op
infections and it is difficult to conclusively distinguish if allograft-related.
** 2008 includes reports received 1/1 through 12/11/ 2008
Reported Adverse
Reactions by Outcome
Type of event 2005* 2006 2007 2008** Total
Infectious AE 35 98 91 77 301
Non-Infectious
AE 20 32 27 25 104
No AE 20 17 6 18 61
Total 75 147 124 120 466
* Data for 2005 includes only reports after May 25
** Includes reports received 1/1/08-12/16/2008
Reported Adverse Reactions
by Reported Organism
2006 2007 2008** Organism
57 63 45 Bacteria
6 5 12 Fungi
23 8 3 Virus
3 CJD
12 15 14 Unknown
98 91 77 Total
** Includes reports received 1/1/08-12/16/2008
Biomedical Tissue Services (BTS)
Order to Cease and Retain HCT/Ps
• Immediately cease manufacturing operations and
retain HCT/Ps.
• To BTS and its CEO and Executive Director, Michael
Mastromarino, D.D.S.
• After initially focusing efforts on assessing the safety
of distributed tissue and facilitating recalls, FDA
determined that the violations uncovered at BTS,
because of their serious nature, constitute a danger
to health and took this unprecedented action
• Order to Cease Manufacturing and to Retain HCT/Ps
issued January 31, 2006
• www.fda.gov/cber/compl/bts013106.htm
BTS Order
• Despite records maintaining otherwise:
• The firm inadequately screened donors for
risk factors for, or clinical evidence of,
relevant communicable disease agents and
diseases;
• FDA found numerous instances where death
certificates maintained in BTS’ files were at
variance with the death certificates FDA
obtained from the state where the death
occurred:
• Cause, place, and time of death, and the
identity of next of kin.
• FDA continued to work with other federal, state
and local authorities
CDC: MMWR
Brief Report May 26, 2006
• “Investigation into Recalled Human Tissue for
Transplantation---United States, 2005--2006.”
• Approximately 25,000 BTS-recovered tissue
products distributed to all 50 states and
internationally
• FDA and CDC continue to investigate reports
of BTS recipients who have undergone
screening and tested positive for one of the
four tested diseases
• Some positive results would be expected in
any U.S. population tested (prevalence data
provided)
MMWR cont..
• Relationship between implanted BTS
tissue and positive test results reported
to FDA and CDC is difficult to ascertain
because of inaccurate BTS donor
records and, in some cases, the
absence of properly linked donor
samples.
BTS Update
• In March 2008, Michael Mastromarino pleaded guilty
in Brooklyn Supreme Court to body stealing, forgery,
grand larceny and enterprise corruption and was
sentenced to 18 to 54 years. He is serving a
concurrent sentence of 25 to 58 years after pleading
guilty to similar changes in Philadelphia.
• Co-defendant Lee Cruceta pleaded guilty to
conspiracy, taking part in a corrupt organization,
abuse of a corpse and 244 counts each of theft and
forgery in Philadelphia and also has pleaded guilty
to related charges in Brooklyn and negotiated pleas
to serve concurrent sentences of 6½ to 20 years.
• Co-defendant Chris Aldorasi was found guilty of
enterprise corruption and other criminal counts in
Brooklyn and sentenced to 9 to 27 years.
BTS Update - 2
• Co-defendant Joseph Nicelli has yet to stand trial in
Brooklyn
• On December 12, 2008, Jason Gano, a former
funeral director in Rochester, NY, was found guilty of
17 counts each of opening graves, body stealing, and
unlawful dissection, as well as one count of scheming
to defraud. He faces up to 20 years in prison when
he is sentenced.
• Six others are expected to stand trial in Rochester
• FDA will continue to work cooperatively with other
Federal, State and local authorities
Donor Referral Services (DRS) Order to
Cease Manufacturing and Retain HCT/Ps
• Immediately cease manufacturing operations
and retain HCT/Ps.
• To DRS and its Owner, Philip Guyett
• FDA determined that the violations uncovered
at DRS, because of their serious nature,
constitute a danger to health and took action
• Order to Cease Manufacturing and to Retain
HCT/Ps issued 18 August, 2006
• http://www.fda.gov/cber/compl/drs081806.htm
DRS Order
• FDA found numerous instances where
information provided by DRS to a tissue
processor was at variance with the
death certificates FDA obtained from
the state where the death occurred:
• Cause, place, and time of
death
DRS Public Health Notification
• August 30, 2006
• FDA and CDC strongly recommended health
care providers inform all patients that
received tissue initially recovered by DRS
and offer access to communicable disease
testing
• Distributing firms had already voluntarily
recalled tissue in inventory
• Where FDA had previously identified specific
cases of concern, the firms cooperated fully in
efforts to inform patients and offer testing in
those cases
DRS Update
• On March 9, 2009, Philip Guyett pleaded
guilty in U.S District Court in Raleigh, North
Carolina to three counts of mail fraud
• He is scheduled to be sentenced June 1,
2009, and faces up to 60 years in prison and
$750,000 in fines
• FDA continues to investigate DRS working
with other federal, state and local authorities
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
