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): Guidance for Industry

Administrative guidance, not enacted legislation. This captured publisher edition preserves the listed document and attachments; later developments are not independently consolidated.

Guidance for Industry
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)
FDA is issuing this guidance for immediate implementation in accordance with 21 CFR
10.115(g)(4)(i). Submit comments on this guidance at any time to the Division of Dockets
Management (HFA-305), Food and Drug Administration, 5630 Fishers Lane, rm. 1061,
Rockville, MD 20852. You should identify all comments with the docket number listed in the
notice of availability that publishes in the Federal Register.
Additional copies of this guidance are available from the Office of Communication, Training and
Manufacturers Assistance (HFM-40), 1401 Rockville Pike, Rockville, MD 20852-1448, or by
calling 1-800-835-4709 or 301-827-1800, or from the Internet at
http://www.fda.gov/cber/guidelines.htm.
For questions on the content of this guidance, contact Melissa Greenwald, M.D., at 301-827-
2002.
U.S. Department of Health and Human Services
Food and Drug Administration
Center for Biologics Evaluation and Research
November 2004

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Table of Contents
I. 	INTRODUCTION............................................................................................................. 1
II. 	BACKGROUND ............................................................................................................... 2
III. 	DISCUSSION .................................................................................................................... 3
A. 	What data about specificity and sensitivity are recommended when matched pairs
of pre- and post-mortem serum/plasma specimens are available? .............................. 3
1. Specificity ........................................................................................................................... 3
a. 	Clinical Specificity...................................................................................................... 3
b. 	Analytical Specificity.................................................................................................. 3
2. Sensitivity ........................................................................................................................... 3
a. 	Clinical Sensitivity...................................................................................................... 3
b. 	Analytical Sensitivity.................................................................................................. 4
B. 	What data about specificity and sensitivity are recommended when matched pairs
of pre- and post-mortem serum/plasma specimens are not available?........................ 4
1. Specificity ........................................................................................................................... 4
a. 	Clinical Specificity...................................................................................................... 4
b. 	Analytical Specificity.................................................................................................. 4
2. Analytical Sensitivity.......................................................................................................... 4
C. 	What is an example of a recommended reproducibility study? ................................... 5
D. 	How many test kit lots are recommended to be included in the studies? .................... 5
E. 	What plasma dilution issues are recommended for consideration?............................. 5
F. 	What information about specimen collection times does FDA recommend I note?... 6
G. 	Where do I submit my data? ........................................................................................... 6
IV. 	REFERENCES.................................................................................................................. 7

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Guidance for Industry
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)
This guidance represents the Food and Drug Administration’s (FDA’s) current thinking
on this topic. It does not create or confer any rights for or on any person and does not
operate to bind FDA or the public. You can use an alternative approach if the approach
satisfies the requirements of the applicable statutes and regulations. If you want to
discuss an alternative approach, contact the appropriate FDA staff. If you cannot
identify the appropriate FDA staff, call the appropriate number listed on the title page of
this guidance.
I. 	INTRODUCTION
This guidance provides to you, medical device manufacturers of communicable disease
tests, information about performing studies to support modifying the indication for use to
include testing of cadaveric blood specimens to screen donors of human cells, tissues,
and cellular and tissue-based products (HCT/Ps). This guidance makes recommendations
about:
• 	Sensitivity and specificity studies
• 	Reproducibility studies
• 	Number of test kit lots to include in studies
• 	Plasma dilution issues
• 	Information about specimen collection times to be included
This document contains information which has been provided in Center for Biologic
Evaluation and Research’s (CBER’s) letters to manufacturers of communicable disease
tests. We, FDA, continue to encourage manufacturers of communicable disease tests to
evaluate these tests for cadaveric HCT/P donor use and seek such labeling.
FDA’s guidance documents, including this guidance, do not establish legally enforceable
responsibilities. Instead, guidances describe the FDA’s current thinking on a topic and
should be viewed only as recommendations, unless specific regulatory or statutory
requirements are cited. The use of the word should in FDA’s guidances means that
something is suggested or recommended, but not required.

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II. 	BACKGROUND
Recognizing the need for appropriately evaluated and labeled test kits, we issued letters
in 1995 to manufacturers of donor screening tests introducing the subject of expanding
the indication for use of blood donor screening tests to include testing of cadaveric blood
specimens and suggesting a minimum protocol. In the Federal Register of July 29, 1997
(62 FR 40429), we issued a final rule, “Human Tissue Intended for Transplantation,” (the
tissue final rule) which requires “certain infectious disease testing, donor screening, and
recordkeeping to help prevent the transmission of the human immunodeficiency virus
(HIV), and hepatitis viruses through human tissue used in transplantation” (62 FR 40429
at 40429) (Ref. 1). Additionally, the tissue final rule requires that “FDA licensed
screening tests labeled for cadaveric specimens must be used when available” (21 Code
of Federal Regulations 1270.21(d)). Also, in the Federal Register of July 29, 1997 (62
FR 40536), we announced the availability of a “Guidance for Screening and Testing of
Donors of Human Tissue Intended for Transplantation,” dated July 1997, which further
discussed the use of donor screening tests (Ref. 2).
We approved two biologic license supplements with the modified indication for use to
include testing of cadaveric blood specimens. On December 28, 1999, FDA approved the
Genetic Systems Corporation's Supplement to its Product License Application for
Antibody to Hepatitis B Surface Antigen (Mouse Monoclonal) Enzyme-Linked
Immunosorbent Assay to modify the intended use of the Genetic Systems HBsAg EIA
2.0 and the Genetic Systems HBsAg Confirmatory Assay 2.0 to include the testing of
cadaveric serum samples. On February 9, 2000, FDA approved the Genetic Systems
Corporation's Supplement to their Product License Application for Human
Immunodeficiency Virus Types 1 and 2 (Synthetic Peptide) to modify the intended use of
the Genetic Systems HIV-1/HIV-2 Peptide EIA to include the testing of cadaveric serum
samples. These approved tests detect antibodies to Hepatitis B Surface Antigen and
antibodies to Human Immunodeficiency Virus (HIV)-1 and HIV-2, respectively, in a
cadaveric donor’s serum.
In June 2000, we issued a “Guidance for Industry: Availability of Licensed Donor
Screening Tests Labeled for Use with Cadaveric Blood Specimens” (the June 2000
guidance), which informed establishments of the availability of these two licensed donor
screening tests labeled for use with cadaveric blood specimens (Ref. 3). In the Federal
Register of May 25, 2004 (69 FR 29786), we issued a final rule “Eligibility
Determination for Donors of Human Cells, Tissues, and Cellular and Tissue-Based
Products” (Ref. 4) which requires that donors of cells and tissue be tested for evidence of
infection due to relevant communicable disease agents or diseases. Those relevant
communicable disease agents include HIV, types 1 and 2; hepatitis B virus; and hepatitis
C virus, and, for certain donors, Human T-Lymphotrophic Virus, types I and II.
Manufacturers of tests used to screen blood donors for communicable diseases have
requested information on studies to support modifying the indication for use to include
testing of cadaveric blood specimens from donors of HCT/Ps.

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III. 	DISCUSSION
We recommend you address the following areas when preparing a protocol to modify the
indication for use to include testing of cadaveric blood specimens.
A. 	What data about specificity and sensitivity are recommended when
matched pairs of pre- and post-mortem serum/plasma specimens are
available?
1. 	Specificity
We recommend that you test at least 50 paired specimens (1 pre-
and 1 post-mortem specimen from the same donor).
a. 	Clinical Specificity
Clinical specificity is a measure of how often the test is
negative in non-diseased donors.
We recommend that you determine if a statistically
significant difference exists between pre- and post-mortem
specimens based on frequency of false positive results.
b. 	Analytical Specificity
Analytical specificity measures a test’s ability to
exclusively identify a target substance rather than different
substances.
We recommend that you determine if a statistically
significant difference exists between pre- and post-mortem
specimens based on signal strength.
2. 	Sensitivity
We recommend that you test at least 50 paired reactive specimens
(1 pre- and 1 post-mortem specimen from the same donor).
a. 	Clinical Sensitivity
Clinical sensitivity is a measure of how often the test is
positive in diseased donors.
We recommend that you determine if a statistically
significant difference exists between pre- and post-mortem
specimens based on frequency of false negative results.

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b. 	Analytical Sensitivity
Analytical sensitivity measures a test’s ability to detect a
low concentration of a given substance.
We recommend that you determine if a statistically
significant difference exists between pre- and post-mortem
specimens based on signal strength and endpoint dilutions
of positive specimens.
B. 	What data about specificity and sensitivity are recommended when
matched pairs of pre- and post-mortem serum/plasma specimens are
not available?
1. 	Specificity
We recommend that you concurrently test at least 50 cadaveric
(post-mortem) specimens from 50 different cadaveric donors and
an equal number of random living donor specimens (unmatched
pre-mortem specimen) with the same test kit lots.
a. 	Clinical Specificity
We recommend that you determine if a statistically
significant difference exists between the cadaveric
specimens and the random living donor specimens based on
the frequency of false positive results, i.e., the number of
pre-mortem nonreactives/post mortem reactives.
b. 	Analytical Specificity
We recommend that you determine if a statistically
significant difference exists between the cadaveric
specimens and the random living donor specimens based on
signal strength.
2. 	Analytical Sensitivity
We recommend that you concurrently test at least 50 nonreactive
cadaveric specimens from 50 different cadaveric donors with an
equal number of random living donor specimens with the same kit
lots, with both types of specimens spiked with the infectious
disease marker at a potency near the assay’s cutoff. You should
use a minimum of 5 individual positive sources for the spiking
experiment.

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We recommend that you determine if a statistically significant
difference exists between the spiked living donor specimens and
the spiked cadaveric specimens based on signal strength.
C. 	What is an example of a recommended reproducibility study?
We recommend that you conduct a reproducibility study to determine if a
statistically significant difference exists between the coefficients of
variations of cadaveric specimens compared to those of living donors.
One possible experimental design might include comparing at least 20
random cadaveric specimens with at least 20 random living donor
specimens (confirmed true positives may be excluded) spiked to be
reactive near the cutoff. Test each specimen individually, in 6 separate
runs on 6 separate days using each of 3 different kit lots (18 data points
per specimen). We also recommend that the specimens to be tested on 6
separate days be stored at 4° Centigrade to avoid repeated freezing and
thawing.
D. 	How many test kit lots are recommended to be included in the
studies?
We recommend that you include at least three test kit lots in all studies.
E. 	What plasma dilution issues are recommended for consideration?
Prior to including a cadaveric blood specimen in these studies, we
recommend that you determine whether the specimen has been
appropriately evaluated for plasma dilution. You can obtain information
about plasma dilution from FDA’s “Guidance for Industry: Screening and
Testing of Donors of Human Tissue Intended for Transplantation,” dated
July 1997 (the July 1997 guidance). This document can be found on the
Internet at www.fda.gov/cber/tissue/docs.htm. As stated in the July 1997
guidance, plasma dilution is due to the transfusion or infusion of fluids
into the donor prior to specimen collection, and can result in false negative
test results. In an adult donor, if blood loss is known or suspected to have
occurred and there was transfusion/infusion of more than 2000 mL of
blood or colloids within 48 hours, or more than 2000 mL of crystalloids
within 1 hour, or any combination thereof, prior to the collection of the
blood specimen, plasma dilution may have occurred. In this case, we
recommend that you use a specimen taken from the donor prior to
transfusion or infusion, or an algorithm designed to evaluate volumes
administered in the 48 hours prior to specimen collection, to ensure that
plasma dilution sufficient to affect test results has not occurred. An
example of an algorithm can be found in the July 1997 guidance.

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F. 	What information about specimen collection times does FDA
recommend I note?
1. 	We recommend that you note the time between death and
specimen collection. In order to accurately document test kit
performance, we recommend that the time at which cadaveric
specimens are taken incorporate the full range of time points
typically encountered during tissue recovery, e.g., 0-24 hours.
2. 	We recommend that you include hemolyzed specimens in the
study, since a large percentage of cadaveric specimens are
hemolyzed due to biological processes that occur immediately
post-mortem. You should quantify the degree of hemolysis, if
possible, of the cadaveric specimens.
3. 	We recommend that you note information about storage and
handling conditions of both living donor specimens and cadaveric
specimens.
G. 	Where do I submit my data?
We intend to review any applications for cadaveric blood specimens
jointly in the Offices of Cellular, Tissue and Gene Therapies and Blood
Research and Review.
1. 	If you seek an indication for use of cadaveric blood specimens and
blood donor specimens, you may submit an Investigational New
Drug Application (IND), or a Biologics License Application
(BLA), as appropriate, with data for both intended uses, to:
Center for Biologics Evaluation and Research
Attn: Office of Blood Research and Review
HFM-99, Suite 200N
1401 Rockville Pike
Rockville, MD 20852-1448
2. 	If an IND or BLA has already been submitted for blood donor
screening, and you seek to modify the indication for use to include
testing of cadaveric blood specimens, you may submit an
amendment to the IND, or a supplement to the BLA with cadaveric
blood specimen data, as appropriate, to the same address as above.
3. 	If you seek to modify the indication for use to include testing of
cadaveric blood specimens only, you may submit an IND or BLA
with cadaveric blood specimen data, to:

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Center for Biologics Evaluation and Research
Attn: Office of Cellular, Tissue and Gene Therapies
HFM-99, Suite 200N
1401 Rockville Pike
Rockville, MD 20852-1448
If you have questions about this guidance, please contact Melissa
Greenwald in the Office of Cellular, Tissue and Gene Therapies at 301-
827-2002.
IV. 	REFERENCES
1. 	Human Tissue Intended for Transplantation; Final Rule, July 29, 1997 (62
FR 40429), (http://www.fda.gov/cber/genadmin/frtissue.txt or
http://www.fda.gov/cber/tissue/docs.htm).
2. 	Guidance for Industry: Screening and Testing of Donors of Human Tissue
Intended for Transplantation; Notice of Availability, July 29, 1997 (62 FR
40536), (http://www.fda.gov/cber/gdlns/tissue2.txt or
http://www.fda.gov/cber/tissue/docs.htm).
3. 	Guidance for Industry: Availability of Licensed Donor Screening Tests
Labeled for Use with Cadaveric Blood Specimens, June 2000,
(http://www.fda.gov/cber/gdlns/cadbld.htm or
http://www.fda.gov/cber/tissue/docs.htm).
4. 	Eligibility Determination for Donors of Human Cells, Tissues, and
Cellular and Tissue-Based Products; Final Rule, May 25, 2004 (69 FR
29786), (http://www.fda.gov/cber/tissue/docs.htm).