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 
Contains Nonbinding Recommendations 

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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
Contains Nonbinding Recommendations 

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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. 
Contains Nonbinding Recommendations 

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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 preand 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. 
Contains Nonbinding Recommendations 

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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: 
Contains Nonbinding Recommendations 

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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).