Guidance for Industry

Revised Recommendations for Donor 

and Product Management Based on 

Screening Tests for Syphilis

DRAFT GUIDANCE

This document is being distributed for comment purposes only.

Submit comments and suggestions regarding this draft document by the date provided in the 

Federal Register notice announcing the availability of the draft guidance. Submit comments to 

Dockets Management Branch (HFA-305), Food and Drug Administration, 5630 Fishers La., rm. 

1061, Rockville, MD 20857. All comments should be identified with the docket number listed in 

the notice of availability that publishes in the Federal Register.

Additional copies of this draft guidance are available from the Office of Communication, Training 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 regarding this draft document contact Robin Biswas, M.D., 301-827-3011.

U.S. Department of Health and Human Services

Food and Drug Administration

Center for Biologics Evaluation and Research

June 2003
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Table of Contents

I. INTRODUCTION..............................................................................................................1

II. BACKGROUND ................................................................................................................1

III. RECOMMENDATIONS FOR DONOR TESTING AND MANAGEMENT, AND 

PRODUCT DISPOSITION, WHEN USING SCREENING TESTS FOR 

SYPHILIS...........................................................................................................................4

A. Donor Testing and Management, When Using Nontreponemal-Based 

Screening Assays as the Test of Record for the Detection of Syphilis 

(see Figure A)......................................................................................................... 4

B. Donor Testing and Management, When Using Treponemal-Based Screening 

Assays as the Test of Record for the Detection of Syphilis (see Figure B)....... 4

C. Release for Transfusion of Units Negative for Syphilis in a Confirmatory 

Test......................................................................................................................... 5

D. Syphilis Testing and Donor and Unit Management Issues Specific to Whole 

Blood and Components for Transfusion............................................................. 6

E. Syphilis Testing and Donor and Unit Management Issues Specific to Source 

Plasma .................................................................................................................... 6

IV. REFERENCES...................................................................................................................8

Figure A: Donor testing algorithm when a nontreponemal-based screening assay is the test 

of record and establishment conducts confirmatory testing.................................. 9

Figure B: Donor testing algorithm when a treponemal-based screening assay is the test of 

record and establishment conducts confirmatory testing.................................... 10
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GUIDANCE FOR INDUSTRY

Revised Recommendations for Donor and Product Management 

Based on Screening Tests for Syphilis

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 FDA staff responsible for implementing this guidance. If you cannot 

identify the appropriate FDA staff, call the appropriate number listed on the title page of this 

guidance.

I. INTRODUCTION

We, the Food and Drug Administration (FDA), are providing recommendations to you, blood 

establishments, about testing donors of blood and blood components for syphilis, and the actions 

we recommend that you take regarding donors and their donations in relation to those test results. 

The attached recommendations replace previous FDA recommendations contained in the 

memorandum of December 12, 1991 (Ref. 1).

FDA’s guidance documents, including this guidance, do not establish legally enforceable 

responsibilities. Instead, guidances describe the Agency’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 Agency guidances means that something is suggested or 

recommended, but not required.

II. BACKGROUND

Syphilis, caused by the spirochete Treponema pallidum, can be acquired after sexual contact 

with an infected individual and can be transmitted through transfusion of blood and blood 

components. Blood establishments instituted testing of blood donations for syphilis in 1938. 

Such testing has been required by regulation since 1958. Our current regulatory requirements for 

syphilis testing of blood and blood components are in 21 CFR 610.40, 610.41, 640.5(a), 640.14, 

640.23, 640.33, 640.53, 640.65, and 640.70.

Serologic assays for syphilis can be divided into two groups: (1) nontreponemal assays, and (2) 

treponemal assays:

(1) Nontreponemal assays, such as the Venereal Disease Research Laboratory (VDRL) test, the 

Rapid Plasma Reagin (RPR) test, and the Automated Reagin Test (ART), detect nonspecific 
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antibodies (reagin) to an antigen called cardiolipin present in host tissues as well as in 

treponemes. These assays are useful in monitoring the progression of disease and response to 

therapy. Samples that give reactive results using nontreponemal assays may be retested using a 

treponemal-based assay as a confirmatory assay, such as the fluorescent treponemal antibody 

with absorption test (FTA-ABS), to distinguish true positives from false positives. 

Nontreponemal test results usually become nonreactive within a year or two after successful 

treatment of syphilis.

(2) Treponemal assays incorporate specific treponemal antigens into the testing system and 

detect specific antibodies to these antigens. With a few exceptions, unlike nontreponemal 

assays, results of tests for treponemal antigens remain reactive for specific antibodies throughout 

an individual’s life, even after successful treatment for syphilis. Treponemal assays include the 

FTA-ABS, the Treponema pallidum immobilization test (TPI) and the T. pallidum 

hemagglutination assay (TPHA). In general, treponemal assays have a higher sensitivity in 

detecting primary and late syphilis than do nontreponemal assays. However, as both types of 

assays detect antibodies, neither may identify some very early syphilis infections, before 

antibodies either to cardiolipin or to specific treponemal antigens have appeared.

In the memorandum to all blood establishments dated December 12, 1991, we recommended that 

blood establishments defer potential blood and plasma donors who provide positive responses to 

a question about having had or having been treated for syphilis or gonorrhea during the 

preceding 12 months. The recommendation also specified that donors who are found to have a 

reactive screening test for syphilis by ART, RPR, VDRL, or other screening test should be 

temporarily deferred pending the outcome of a confirmatory test such as FTA. According to 

these recommendations, donors found to have a positive FTA or other confirmatory test should 

be deferred for 12 months, and prior to re-entry, blood establishments should obtain evidence of 

adequate treatment for syphilis by a letter from a physician or public health clinic. FDA 

regulations 21 CFR 610.41(a) and 630.6 require that donors who test reactive for a serological 

test for syphilis be deferred and be notified of their deferral.

In the past, establishments typically used nontreponemal serologic tests to screen individuals, 

and usually used a treponemal serologic test to confirm reactive nontreponemal test results. In 

1990, the Center for Biologics Evaluation and Research cleared, by the 510(k) premarket 

notification process, the Olympus PK-TP assay system, a modified microhemagglutination test. 

Unlike previously cleared nontreponemal-based screening tests, the PK-TP assay is an 

automated, treponemal-based test, capable of detecting specific antibodies to T. pallidum. After 

this new assay was adopted for screening blood and blood components, significant increases in 

donor reactive rates were encountered with a corresponding increase in donor deferrals.

The reason for this increase in reactive screening test results with treponemal-based assays was 

that, with few exceptions, detectable antibodies to T. pallidum persist for a lifetime, as explained 

above. Thus, once reactive, treponemal-based antibody tests will remain reactive regardless of 

whether (1) the individual is currently infected or (2) the individual has been infected in the past 

but has undergone successful treatment and is no longer infected. Sustained reactivity is not a 

characteristic of nontreponemal-based tests because their results generally reflect an individual's 
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current status, i.e., persons with current or recently treated infections have reactive 

nontreponemal test results, while those without detectable infections or whose infections were 

successfully treated have nonreactive results.

On October 20, 1994, FDA's Blood Products Advisory Committee (BPAC) recommended a new 

algorithm to reduce the number of deferrals resulting from treponemal-based donor screening 

assays using an initial treponemal screening followed by a nontreponemal test (Ref. 2). 

However, since treponemal tests are more sensitive than nontreponemal tests in detecting early 

primary and late latent syphilis, there remained a remote possibility that some donors deemed 

suitable by such a testing scheme might still carry treponemes, and therefore we did not 

recommend the scheme.

In 1995, a National Institutes of Health Consensus Development Conference discussed infectious 

disease testing for blood transfusions. One issue was the value of testing for syphilis in 

protecting the safety of the blood supply. The expert panel concluded that testing donors for 

syphilis should continue until further information about the contribution of testing donors for 

syphilis in preventing transfusion-transmitted syphilis is obtained (Ref. 3).

Recognizing an overall decline in incidence of syphilis in the United States during recent 

decades, and the virtual disappearance of transfusion-transmitted syphilis (no case of transfusiontransmitted syphilis has been reported since 1968), we, in a proposed rule published on August 

19, 1999, "Requirements for Testing Human Blood Donors for Evidence of Infection Due to 

Communicable Disease Agents," raised questions about the utility of testing donors for syphilis 

(Ref. 4). We solicited public comments with supporting data regarding the value of testing 

donors for syphilis, both (1) as a marker of high-risk behavior (that is, as a surrogate test for 

other infectious diseases that might be acquired by such behavior and transmitted by blood), and 

(2) in preventing the transmission of syphilis through blood transfusion. While the majority of 

the comments received supported eliminating syphilis testing of blood donations, some 

comments opposed eliminating testing and argued that there was not enough information to 

eliminate blood donation-testing requirements. On September 14, 2000, BPAC advised that, 

while data are still insufficient to support the discontinuation of syphilis testing as part of donor 

screening to prevent transmission of syphilis, syphilis testing should not be retained as a 

surrogate marker of deferrable high-risk behavior (Ref. 5). On June 11, 2001, we issued a final 

rule based on the proposed rule published on August 19, 1999. The new rule became effective 

on December 10, 2001 (Ref. 6). This rule contains a requirement to test blood donations for 

syphilis. (See 21 CFR 610.40(i))

After considering available information and the opinions of BPAC members, we are issuing this 

guidance with recommendations for testing, donor management, and product disposition based 

on screening tests for syphilis. The document provides recommendations for blood 

establishments that use either nontreponemal-based screening assays or treponemal-based 

screening assays to test donors for serological evidence of syphilis infection.
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III. RECOMMENDATIONS FOR DONOR TESTING AND MANAGEMENT, AND 

PRODUCT DISPOSITION, WHEN USING SCREENING TESTS FOR SYPHILIS

Blood establishments must perform a serologic test for syphilis using either a nontreponemal or a 

treponemal-based test that has been cleared by FDA for donor screening following the 

instructions in the test kit package insert. (See 21 CFR 610.40(i), 640.5(a), 640.14, 640.23, 

640.33, 640.53, 640.65(b)(2) and 640.70.) After obtaining a reactive result on that screening 

test, you may also perform confirmatory testing. The following recommendations are applicable 

when you perform confirmatory testing in accordance with the package insert. 

A. Donor Testing and Management, When Using Nontreponemal-Based Screening 

Assays as the Test of Record for the Detection of Syphilis (see Figure A)

1. If the nontreponemal-based screening test is nonreactive, the donor is considered 

to be negative for syphilis infection. The unit may be used and the donor retained.

2. If the nontreponemal-based screening assay is reactive or indeterminate, you must 

determine the donation to be unsuitable and defer the donor, unless you conduct 

confirmatory testing. When the initial test result is reactive based on a nontreponemal assay, we recommend that the donor be tested using a confirmatory 

treponemal-based assay, such as an FTA test.

a. If the FTA or other confirmatory test is nonreactive, you may reenter the donor 

under 21 CFR 610.41(b). Note: See section C.

b. If the FTA or other confirmatory test is reactive, the donor should be deferred 

for at least 12 months. You may then re-enter under 21 CFR 610.41(b) a donor 

who presents evidence of successful treatment of syphilis, if all other donor 

criteria are fulfilled. For the later donation to be found suitable, the donor must 

have a negative test result in a nontreponemal assay at the time of donation. (See 

21 CFR 610.40(i))

B. Donor Testing and Management, When Using Treponemal-Based Screening 

Assays as the Test of Record for the Detection of Syphilis (see Figure B)

1. If the treponemal-based screening test is nonreactive, the donor is considered to be 

negative for syphilis infection. The unit may be used and the donor retained.

2. If the treponemal-based screening test result is reactive, you must determine the 

donation to be unsuitable and defer the donor, unless you conduct confirmatory 

testing. When the initial test result is reactive based on a treponemal assay, we 

recommend that the donor be tested using a confirmatory treponemal-based assay, 

such as an FTA test.
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a. If the FTA or other confirmatory test is nonreactive, you may re-enter 

the donor under 21 CFR 610.41(b). Note: See section C.

b. If the FTA or other confirmatory test is reactive, you may either,

i) test the donor using a nontreponemal-based test, such as the RPR 

test, the VDRL test or the ART test.

If the nontreponemal test is nonreactive, you may reenter, under 21 

CFR 610.41(b), a donor (who has tested reactive in both a 

treponemal-based screening assay and an FTA or other 

confirmatory assay) who presents documentation of successful 

treatment for syphilis. The successful treatment for syphilis should 

have been completed more than one year prior to re-entry.

If the nontreponemal test is reactive, we recommend that the donor 

be deferred for a minimum time period of 12 months. You may 

then re-enter, under 21 CFR 610.41(b), a donor who presents 

evidence of successful treatment for syphilis, if all other donor 

criteria are fulfilled. For the later donation to be found suitable, 

the donor must have a negative test result in a nontreponemal assay 

at the time of donation (See 21 CFR 610.40(i)) or,

ii) defer the donor for a minimum time period of 12 months. You 

may then re-enter, under 21 CFR 610.41(b), a donor who presents 

evidence of successful treatment for syphilis, if all other donor 

criteria are fulfilled. For the later donation to be found suitable, 

the donor must have a negative test result in a nontreponemal assay 

at the time of donation. (See 21 CFR 610.40(i))

C. Release for Transfusion of Units Negative for Syphilis in a Confirmatory Test

We recommend that units of Whole Blood and blood components intended for 

transfusion be released for transfusion if they tested reactive for syphilis by screening 

tests but have negative results by FTA or other confirmatory assay on the reactive 

collection. Such testing must be performed in a FDA-registered and CLIA-qualified 

laboratory. (See 21 CFR 610.40(f)) You must label such units as reactive by a screening 

test for syphilis and negative by FTA or other specified confirmatory test. (21 CFR 

610.40 (h)(2)(vi))
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D. Syphilis Testing and Donor and Unit Management Issues Specific to Whole 

Blood and Components for Transfusion

We are not recommending lookback and quarantine of previously collected units of blood 

and blood components for transfusion from donors who subsequently provide a history of 

syphilis within the last 12 months, or who subsequently test reactive in a syphilis 

screening test or positive in a syphilis confirmatory test. In regard to such units, we are 

also not recommending that notification of consignees be performed for the purpose of 

recipient notification.

E. Syphilis Testing and Donor and Unit Management Issues Specific to Source 

Plasma

1. For Source Plasma, current collection and labeling requirements related to the results 

of serologic tests are found in 21 CFR 640.65 and 640.70. 

2. FDA regulations require that Source Plasma donors be tested for syphilis on the 

day of the first medical examination for plasmapheresis and at least every four 

months thereafter. (21 CFR 640.65(b)(1)(i))

3. The regulations require that a donor with a reactive test for syphilis shall not be 

plasmapheresed until the donor tests non-reactive, except as stated in points 4 and 

5, below. (21 CFR 640.65(b)(1)(ii)) 

4. The regulations permit a donor with a reactive biologic false-positive syphilis test 

result to be plasmapheresed, provided 1) that the reactive serologic test results and 

the results used to confirm the biologic false-positive results are documented, and 

2) that the physician has documented that the false-positive result does not 

indicate an underlying condition that would disqua lify the donor. (21 CFR 

640.65(b)(1)(iii))

5. The regulations permit a donor with a reactive syphilis test result to be 

plasmapheresed to obtain plasma for reagents for syphilis tests, provided 1) that 

the physician documents approval of the donation, 2) tha t there is signed 

documentation by the physician or establishment that treatment for syphilis has 

commenced, and 3) that continued donation will not interfere or jeopardize 

treatment. (21 CFR 640.65(b)(1)(iv))

6. Plasma collected from a donor with a reactive test for syphilis must be 

appropriately labeled, as stated in 24 CFR 640.70(a)(2) and (9). 

7. Product retrieval need not be performed when repeat donors test reactive for 

syphilis. FDA has not recommended product retrieval when repeat donors test 

reactive for syphilis because transmission of syphilis has not been considered a 
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health risk for plasma derivatives. This is due to the processing and inactivation 

procedures the Source Plasma undergoes during the manufacturing process.
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IV. REFERENCES

1. FDA Memorandum to Registered Blood Establishments, December 12, 1991.

2. BPAC meeting transcripts, October 20, 1994.

3. Infectious Disease Testing for Blood Transfusion. NIH Consensus Statement 1995, 

January 9-11; 13 (1): 1-27.

4. FDA's Proposed Rule: “Requirements for Testing Human Blood Donors for Evidence of 

Infection due to Communicable Disease Agents and Requirements for Blood, Blood 

Components, and Blood Derivatives.” August 19, 1999 (64 FR 45340).

5. BPAC meeting transcripts on “Current Utility of Screening Blood Donors for Antibodies 

to Syphilis” September 14, 2000.

6. FDA’s Final Rule: “Requirements for Testing Human Blood Donors for Evidence of 

Infection Due to Communicable Disease Agents.” June 11, 2001 (66 FR 31146).
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Figure A: Donor testing algorithm when a nontreponemal-based screening assay is the test 

of record1and establishment conducts confirmatory testing.

 

Initial screening Nontreponemal-based assay

 

 

 Nonreactive Reactive or 

 or indeterminate

 

Use unit, retain donor 

2

Perform FTA or other

 confirmatory test

Confirmatory FTA or other confirmatory test

 Nonreactive Reactive

 Reenter donor 3Defer donor for at least12 months

 

1

 The flow chart in Figure A is a graphic illustration, which summarizes the verbal text of the document and is meant 

to facilitate understanding of the recommendations made in this guidance document.

2

 A fresh sample from the same donor may be used.

3

 After a minimum time period of 12 months, the donor may be reentered with evidence of successful treatment for 

syphilis, a ngatvive nontreponemal test and provided all other donor criteria are fulfilled.
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Figure B: Donor testing algorithm when a treponemal-based screening assay is the test of 

record1and establishment conducts confirmatory testing.

Initial Screening Treponemal-Based Test

 Nonreactive Reactive

 

 Use unit, retain donor Perform FTA or other confirmatory test

Confirmatory Test FTA or other confirmatory test

 Reactive either 3Defer donor for at least 

 12 months

 Nonreactive or 

 Nontreponemal-based assay

 

 Reenter donor 

 Nonreactive Reactive 

 

 

2Reenter donor with documentation 3Defer donor for at least

 of treatment for syphilis 12 months

 

1

The flow chart in Figure B is a graphic illustration which summarizes the verbal text of the document and is meant 

to facilitate understanding of the recommendations made in this guidance document.

2 A donor who has tested reactive in both a treponemal-based screening assay and a FTA or other confirmatory test, 

but tests negative in a nontreponemal test, may be retained only with written documentation of successful treatment 

for syphilis. The successful treatment for syphilis should have been completed more than one year prior to reentry.

3 After a minimum time period of 12 months, the donor may be re-entered with evidence of successful treatment for 

syphilis and a negative nontreponemal test, provided all other donor criteria are fulfilled.