FDA and Regulation of Human Cells, Tissues, and Cellular and ...

FDA Regulation of Human
Cells and Tissues
Melissa A. Greenwald, MD
Chief, Human Tissue and Reproduction Branch
Office of Cellular, Tissue and Gene Therapies
CBER/FDA
AATB Workshop
WNV: Scientific Considerations for Tissue Donors
9 July 2010
McLean, VA

Today’s Discussion
Describe regulations related to relevant
communicable disease agents or diseases
(RCDADs)
– Describe criteria that, according to the regulations,
would be used to make decisions to include
something on the list of RCDADs,
Describe how infectious disease tests for HCT/P
indications (living donors, specimens collected
post-asystole) are licensed and approved and
related challenges;
Describe two FDA critical path research projects
related to specimens collected post-asystole
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Relevant Communicable
Disease Agent or Disease
(RCDAD) Considerations
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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)
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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
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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:
1. 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;
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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));
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Adding a “new” RCDAD
2. 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));
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Adding a “new” RCDAD
3. 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)).
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Adding a “new” RCDAD —
How does it happen
According to the definition, FDA considers
– risk of transmission
Incidence/prevalence in donor population
Transmissibility
– severity of effect
– availability of screening and/or testing measures
The Agency relies on existing data which are
often incomplete or imperfect
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Test Review
mirror.co.uk
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Specimens Collected Post-
Asystole
FDA considers post-asystole (“cadaveric”)
specimens to be different than blood donor
specimens—e.g., may contain interfering
substances; additional validation studies must
be performed by the test kit manufacturer to
get this claim
Claims for testing specimens collected postasystole
have been obtained as an additional
claim (or supplement to already licensed test)
for tests with an indication for use in screening
blood donors
FDA works with industry to encourage
development of tests for use with blood
specimens obtained post-asystole
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Specimens Collected Post-
Asystole
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
Predicated on blood donor screening claim;
largely focused on excluding significant
differences in assay performance introduced by
the specimen type
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Minimal study requirements for
post-asystole specimen claim
Studies – sensitivity, specificity, reproducibility
May do studies utilizing matched pairs of pre- and
post-asystole specimens OR using unmatched
specimens (specimens obtained from living
donors + non-living donors, but the specimen
sets are not from the same individuals)
– sensitivity performed using spiking study--spike
analyte into both the pre-asystole and postasystole
specimens (at a potency near the
assay’s cutoff)
Minimum of 50 specimens for sens/spec; 20
specimens for reproducibility
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Minimal study requirements for
post-asystole specimen claim
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
– Include some hemolyzed specimens, note degree of
hemolysis
– Note information about storage and handling
conditions of the specimens
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Performance validation
Laboratory testing--Non-clinical data to demonstrate that
the manufactured product meets prescribed requirements
for safety, purity, and potency
– Assay precision and laboratory proficiency
– Analytical sensitivity and specificity
– Chemistry, Manufacturing and Controls
Clinical evaluation--Clinical data that demonstrate safety
and effectiveness for the specific intended use
– Clinical sensitivity and specificity
– Reproducibility
– Stability
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Assay Specificity
Analytical Specificity – measures a test’s
ability to exclusively identify a target substance
rather than different substances
interfering substances
other viral infections
disease conditions
compare signal strength between pre-asystole and postasystole
specimens
Clinical Specificity – measure of how often the
test is negative in non-diseased donors
specimens from low risk populations
compare frequency of false-positive results between preasystole
and post-asystole specimens
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Assay Sensitivity
Analytical Sensitivity – measures a test’s
ability to detect a low concentration of a given
substance
dilutional panels
reference preparations to determine endpoint or LOD/LOQ
low titer and seroconversion panels
compare positive signal strength between pre-asystole and
post-asystole specimens
Clinical Sensitivity – measure of how often the
test is positive in diseased donors
specimens from seroconverting individuals
known positive and high risk individuals
compare frequency of false negative test results between
pre-asystole and post-asystole specimens
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Assay Precision and Reproducibility
Assay precision – the closeness of agreement
between a series of measurements obtained
from multiple sampling of the homogenous
sample under the prescribed conditions
– Multiple operators, lots and days
Reproducibility – a measure of precision
between different laboratories
– Multiple operators, lots, days, at different sites
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Analytical Sensitivity
Example: WNV
Reactivity of assay in samples containing analyte
of interest, e.g., WNV RNA:
– Test serial dilutions of samples containing WNV RNA
– Test serial samples from individuals with WNV; if
possible, samples collected frequently very early in
infection (seroconversion panel)
– Estimate the Limit of Detection
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Clinical Sensitivity
Example: WNV
Reactivity of assay in individuals with WNV
infection:
– test samples from persons with clinical WNV infection
– test samples in epidemic WNV regions
[Would also evaluate test performance in blood
donor population]
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Limitations of Knowledge in Post-
Asystole Specimen Testing
Specificity
– Data collected is relevant to “real-life” use of
the test
– Small numbers = large confidence intervals
Sensitivity
– Spiking studies are used to evaluate clinical
sensitivity
– Small numbers = large confidence intervals
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Other Limitations
Fewer options sometimes available for
post-asystole specimens
– Specimen tubes
– Shipping
– Storage
Balance
– Availability of information
– Volume of information
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Testing Research
http://www.fda.gov/ScienceResearch/SpecialTopics/CriticalPathInitiative/default.htm
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Post-Asystole Clinical Sensitivity
Post-asystole specimens obtained from
individuals with known HIV, HCV, HBV positive
status plus controls
Will test at least 25 specimens from individuals
known to have been positive for each of HIV,
HCV and HBV (some may have co-infections)
and 25 negative controls
Unlabeled specimens tested across multiple
assays
– Antibody
– NAT
– Licensed tests
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Post-Asystole Clinical Sensitivity
Improve understanding of clinical performance of
tests on post-asystole specimens collected from
infected individuals
Overview of test performance across various
tests
Limitations
– Prevalent disease
– Small numbers
– Hypothesis generating
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Post-Asystole Clinical Specificity
Concern about rate of false positive test
results (assay specificity performance)
Clinical performance: Follow-up testing to
verify “truth” of a positive test result in a
deceased individual is not possible, so
difficult to discern false positive from true
positive
Wide confidence intervals in licensed tests
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Post-Asystole Clinical Specificity
Obtaining specimens from the same
individual both pre- and post-asystole
Specimens will be tested across multiple
tests (Ab, NAT) for multiple viruses
– WNV
– HIV
– HCV
– HBV
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Post-Asystole Clinical Specificity
Advantageous to directly compare results
of specimens from the same individual
both pre- and post-asystole (more likely to
know “truth” of post-asystole specimen
result)
Sample size analysis performed to
determine optimal number of specimens to
improve precision of the specificity
estimates (narrow confidence intervals)
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Other Research Topics
EID Workshop (11-12 May 2010)
Tissue industry-led research initiatives
Tissue Safety Lab
Ideas
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Closing Thoughts
Many opportunities for increased data
collection and review to inform donor
screening and testing policy
Interested in opportunities to better inform
regulatory review
Review policy decisions in light of new/
better data, once collected
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Questions
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CBER Contact Information
Website:
http://www.fda.gov/BiologicsBloodVaccines/default.htm
Email CBER:
– Manufacturers: matt@fda.hhs.gov
– Consumers, health care professionals
ocod@fda.hhs.gov
Phone:
301-827-1800 800-835-4709
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