Requalification of Donors Previously Deferred for a History of Viral Hepatitis after the 11th Birthday: Guidance for Industry

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

Requalification of Donors Previously
Deferred for a History of Viral Hepatitis
after the 11 th Birthday
Guidance for Industry
This guidance is for immediate implementation.
FDA is issuing this guidance for immediate implementation in accordance with
21 CFR 10.115(g)(4)(i). Submit one set of either electronic or written comments on this
guidance at any time. Submit electronic comments to http://www.regulations.gov. Submit
written comments to the Dockets Management Staff (HFA-305), Food and Drug Administration,
5630 Fishers Lane, Rm. 1061, Rockville, MD 20852. You should identify all comments with
docket number FDA-2017-D-5152.
Additional copies of this guidance are available from the Office of Communication, Outreach
and Development (OCOD), 10903 New Hampshire Ave., Bldg. 71, Rm. 3128, Silver Spring,
MD 20993-0002, or by calling 1-800-835-4709 or 240-402-8010, or email ocod@fda.hhs.gov, or
from the Internet at
http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guida
nces/default.htm.
For questions on the content of this guidance, contact OCOD at the phone numbers or email
address listed above.
U.S. Department of Health and Human Services
Food and Drug Administration
Center for Biologics Evaluation and Research
September 2017

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Table of Contents
I. 	INTRODUCTION............................................................................................................. 1
II. 	BACKGROUND ............................................................................................................... 2
III. 	DISCUSSION .................................................................................................................... 3
IV. 	RECOMMENDATIONS.................................................................................................. 4
A. 	Standard Operating Procedures for Requalification of Donors Previously
Deferred for a History of Viral Hepatitis ........................................................... 4
B. 	Requalification of Donors Previously Deferred for a History of Viral
Hepatitis ................................................................................................................. 4
V. 	IMPLEMENTATION ...................................................................................................... 5
A. 	Implementation without Modification or with More Restrictive Criteria ...... 5
B. 	Implementation with Modification...................................................................... 6
VI. 	REFERENCES .................................................................................................................. 7

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Requalification of Donors Previously Deferred for a History of Viral
Hepatitis after the 11 th Birthday
Guidance for Industry
This guidance represents the current thinking of the Food and Drug Administration (FDA or
Agency) on this topic. It does not establish any rights for any person and is not binding on FDA
or the public. You can use an alternative approach if it satisfies the requirements of the
applicable statutes and regulations. To discuss an alternative approach, contact the FDA staff
responsible for this guidance as listed on the title page.
I. 	INTRODUCTION
We, FDA, are issuing this guidance to provide you, establishments that collect Whole Blood or
blood components intended for transfusion or for further manufacture, including Source Plasma
and Source Leukocytes, with recommendations for a requalification method under Title 21 of the
Code of Federal Regulations (CFR) 630.35(b) (21 CFR 630.35(b)) for donors who had been
indefinitely deferred for a history of viral hepatitis after the 11 th birthday, prior to the elimination
of the donor suitability requirement under 21 CFR 640.3(c)(1) and 21 CFR 640.63(c)(11).1
This guidance also advises licensed manufacturers who choose to implement the
recommendations on how to report the manufacturing change to FDA under 21 CFR 601.12.
This guidance does not apply to individuals with reactive donor screening test results for
hepatitis B virus (HBV) and hepatitis C virus (HCV) who are deferred under 21 CFR 610.41(a)
or to the requalification methods after reactive donor screening test results for HBV and HCV
under 21 CFR 610.41(b) recommended in separate guidance documents.
This guidance supersedes the following memoranda to blood establishments: “Donor Suitability
Related to Laboratory Testing for Viral Hepatitis and a History of Viral Hepatitis” dated
December 22, 1993 (1993 Memorandum) and “Exemptions to Permit Persons with a History of
Viral Hepatitis Before the Age of Eleven Years to Serve as Donors of Whole Blood and Plasma:
Alternative Procedures, 21 CFR 640.120” dated April 23, 1992.
1 See Requirements for Blood and Blood Components Intended for Transfusion or for Further Manufacturing Use;
Final Rule (80 FR 29842, May 22, 2015), effective May 23, 2016. Sections 640.3 and 21 CFR 640.63 were
removed in this final rule.

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FDA’s guidance documents, including this guidance, do not establish legally enforceable
responsibilities. Instead, guidances describe 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.
II. 	BACKGROUND
The longstanding requirement to evaluate donors for a history of hepatitis was introduced in the
1950’s before HBV and HCV were recognized and before specific laboratory tests became
available to screen all donations. The regulations, in place until May 23, 2016, precluded
donation by individuals with “a history of viral hepatitis after the 11th birthday” from Whole
Blood and Source Plasma donation (21 CFR 640.3(c)(1) and 21 CFR 640.63(c)(11),
respectively). The age-related exception was allowed because most cases of viral hepatitis that
occurred in donors when they were younger than 11 years were attributed to hepatitis A virus
(HAV). HAV would not have caused a chronic and therefore potentially transfusion-
transmissible infection in the donor. The regulations persisted for many years because it was
unknown if there were viruses other than HBV and HCV that could cause chronic
posttransfusion hepatitis.
FDA provided further recommendations for evaluating donors for a history of hepatitis in a 1993
Memorandum (Ref. 1). FDA advised manufacturers to assess donor suitability by asking the
donor about physical signs or symptoms of clinical hepatitis (e.g., jaundice), history of liver
disease, viral hepatitis or a positive test for hepatitis. As a result, the deferral captured not only
individuals with HBV or HCV, but also those who reported HAV or certain other, common viral
infections associated with jaundice, such as cytomegalovirus (CMV) and infectious
mononucleosis caused by Epstein-Barr virus (EBV), which do not cause chronic posttransfusion
hepatitis. The deferral rate exceeded 1 in 5,000 individuals who presented to donate blood each
year (Ref. 2). The policy ultimately resulted in the disqualification of thousands of individuals
who did not have HBV or HCV and required blood establishments to maintain their names in
donor deferral records (Ref. 3).
In March 2000, FDA held a Blood Products Advisory Committee (BPAC) meeting to consider
whether there was sufficient information to eliminate the exclusion of donors with a history of
viral hepatitis (Ref. 3). The points that emerged were that the regulations were likely useful in
the past to prevent posttransfusion hepatitis, but their contribution to transfusion safety was
questionable after the introduction of sensitive donor screening tests for HBV and HCV. In
addition, data presented at the BPAC meeting demonstrated the limited utility of asking
questions about hepatitis, because most infected individuals did not report a history of hepatitis
(Ref. 3). The committee voted unanimously (13-0) that the exclusion of donors with a history of
viral hepatitis should be eliminated or modified to exclude donors only for a limited time (e.g.,
for one year after disappearance of symptoms).

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Since the discovery of HCV as the cause of non-A/non-B transfusion-transmitted hepatitis, no
additional viral hepatitis agents have been identified to cause chronic, asymptomatic infections in
donors that might pose significant health risks to transfusion recipients based on a prior history
of hepatitis (Refs. 4-7). Moreover, public health initiatives to increase awareness have
prioritized prevention strategies for HBV and HCV (Ref. 8). Current donor screening tests have
reduced the window periods of viral detection to 18.5 – 26.5 days for HBV and 7.4 days for
HCV (Refs. 9 and 10). The corresponding calculated transfusion risk of viral transmission per
unit is 1:1,149,000 for HCV and 1:843,000 – 1:1,208,000 for HBV based on mathematical
models (Refs. 9 and 10).
On May 22, 2015 (80 FR 29842), FDA published revised regulations for the determination of
blood donor eligibility and eliminated the requirement to defer donors with a history of viral
hepatitis after the 11th birthday. The revised regulations also include donor requalification
requirements under 21 CFR 630.35. This guidance describes an acceptable process for blood
establishments to requalify donors previously deferred for a history of viral hepatitis, as required
by 21 CFR 630.35(b).
III. 	DISCUSSION
Individuals with a history of viral hepatitis after the 11th birthday who had been indefinitely
deferred prior to the effective date of the revised donor eligibility regulations (80 FR 29842, May
22, 2015, effective May 23, 2016) may be requalified as donors if the reason for the hepatitis-
related deferral was not infection with HBV or HCV and all other eligibility requirements are
met.
Current regulations require that donors must be in good health and free from transfusion-
transmitted infections (21 CFR 630.10(a)). Blood establishments must assess the donor’s
medical history to identify clinical evidence of a relevant transfusion-transmitted disease
(21 CFR 630.10(e)). In the context of this guidance, clinical evidence of HBV or HCV includes
a medical diagnosis of HBV or HCV at any age regardless of symptoms, including a history of
spontaneous resolution, treatment, or diagnostic test results that indicate current or past HBV or
HCV infection.
Individuals are not eligible to donate if the purpose of donating is to obtain test results for a
relevant transfusion-transmitted infection (RTTI) (21 CFR 630.10(e)(2)(vi)). Individuals with
reactive test results for RTTI including HBV and HCV are deferred under 21 CFR 610.41(a).

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IV. 	RECOMMENDATIONS
A. 	Standard Operating Procedures for Requalification of Donors Previously
Deferred for a History of Viral Hepatitis
Blood establishments that choose to requalify donors must: a) establish a standard
operating procedure (SOP) to include the criteria used to determine donor eligibility for
those individuals who were previously deferred for a history of viral hepatitis after the
11th birthday (21 CFR 606.100(b)(1)). The SOP should describe processes to evaluate
the previous reason for deferral and assess the donor’s eligibility for reentry. The process
could include but is not limited to reviewing donor records, re-interviewing the donor or
obtaining further medical consultation, as appropriate. The blood establishment should
have a process to manage information provided by the donor or reliable third party at any
stage in the screening process.
With respect to the recommendations for the responsible physician to assess an individual
donor’s eligibility, as described below in section IV.B.3, the determination cannot be
delegated to a trained person or physician substitute. However, the responsible physician
may make this eligibility determination by telephonic or other offsite consultation.
Blood establishments must follow their SOPs for documenting the criteria used to
determine donor eligibility for those individuals who were previously deferred for a
history of viral hepatitis after the 11th birthday (21 CFR 606.100(b)). We recommend
that requalified individuals be removed from the donor deferral registry.
B. 	Requalification of Donors Previously Deferred for a History of Viral
Hepatitis
Individuals who have had HBV or HCV infection at any age, regardless of symptoms,
spontaneous resolution or treatment, must be indefinitely deferred (21 CFR 630.10(a))
and are not eligible for reentry.
Currently, FDA has not identified an acceptable method or process for requalification of
previously deferred individuals with the following history:
a. 	Clinical diagnosis or confirmed laboratory tests for HBV at any age.
OR
b. 	Clinical diagnosis or confirmed laboratory tests for HCV at any age.

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1. 	History of viral hepatitis or specific diagnosis of hepatitis other than HBV or
HCV
The following donors may be eligible for reentry without performing predonation
testing if the donor otherwise meets all eligibility criteria:
a. 	Previous reason for deferral was for HAV.
b. 	Previous reason for deferral was for infectious mononucleosis or viral
hepatitis due to EBV or CMV.
2. 	History of viral hepatitis with an unknown or uncertain clinical diagnosis
If the deferred donor is uncertain about his or her medical diagnosis, test results or
whether they had HBV or HCV, the responsible physician should determine if the
donor qualifies for reentry. The responsible physician’s assessment may include but
is not limited to interviewing the donor, interpreting the results of laboratory testing
for HCV and HBV, if available, and/or referring the donor for further evaluation as
necessary.
If the blood establishment performs testing for HBV and HCV to obtain additional
information about the donor’s infection status, a sample should be drawn separate
from a donation. The test results should be available and be negative/non-reactive
before donations can begin.
If the responsible physician determines that the previously deferred donor does not
have evidence of current or past HBV or HCV infection, the donor may be eligible
for reentry provided all eligibility criteria are met.
V. 	IMPLEMENTATION
A. 	Implementation without Modification or with More Restrictive Criteria
We consider the recommendations in this guidance to be an acceptable method or process
within the meaning of 21 CFR 630.35(b), for requalifying donors who were previously
deferred for a history of viral hepatitis.
If the recommendations in this guidance are implemented without modification in their
entirety or if a more restrictive process is adopted, we consider this to be a minor change.
Blood establishments should report the change as follows:
1. 	Licensed blood establishments must report this change to FDA in the annual
report under 21 CFR 601.12(d), noting the date the method or process was
implemented. See 21 CFR 601.12(a)(3).
2. 	Unlicensed blood establishments are not required to report this change to FDA.

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B. 	Implementation with Modification
Procedures for determining donor eligibility potentially may have an adverse effect on
the identity, strength, quality, purity, or potency of blood and blood components, as they
may relate to the safety or effectiveness of the product. Therefore, implementing a
method or process that is less restrictive than the recommendations in this guidance is a
major change.
Therefore, blood establishments must report modified, less restrictive donor
requalification processes to FDA as follows:
Licensed blood establishments must report the change as a Prior Approval
Supplement (PAS) under 21 CFR 601.12(b). We recommend that the supplement
include the following:
a. 	Form FDA 356h “Application to Market a New or Abbreviated New Drug or
Biologic for Human Use” which may be obtained at
http://www.fda.gov/AboutFDA/ReportsManualsForms/Forms/default.htm.
b. 	A cover letter describing the request and the contents of the submission.
c. 	A written SOP describing the requalification method or process.
Similarly, before an unlicensed establishment implements a modified, less restrictive
requalification method or process from that described in this guidance, FDA must first
find the method or process to be acceptable for such purpose (21 CFR 630.35(b)).

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VI. 	REFERENCES
1. 	Memorandum: Donor Suitability Related to Laboratory Testing for Viral Hepatitis and a
History of Viral Hepatitis, December 22, 1993.
2. 	Eder, AF and Bianco, C, Screening Blood Donors, AABB Press, Bethesda MD, 2007; p.xvi.
3. 	FDA Blood Products Advisory Committee, Sixty-fifth meeting “Blood Donor Deferral for a
History of Hepatitis”, March 16, 2000; 179-252. Available at
https://www.fda.gov/ohrms/dockets/ac/cber00.htm#Blood%20Prducts.
4. 	Akiba J, et al. SEN virus: epidemiology and characteristics of a transfusion-transmitted
virus. Transfusion 45:1084-1088 (2005).
5. 	Alter MJ, et al. Acute non-A-E hepatitis in the United States and the role of hepatitis G virus
infection. New Engl J Med 336:741-746 (1997).
6. 	Moorman AC, et al. Baseline characteristics and mortality among people in care for chronic
viral hepatitis: The chronic hepatitis cohort study. Clin Infect Dis 56:40-50 (2013).
7. 	CDC, Viral hepatitis: Statistics and Surveillance. Available at
https://www.cdc.gov/hepatitis/statistics/index.htm.
8. 	Department of Health and Human Services, National Virus Hepatitis Action Plan 2017-2020.
Available at https://www.cdc.gov/hepatitis/policy/strategicplansrpts.htm.
9. 	Zou S, et al. Prevalence, incidence, and residual risk of human immunodeficiency virus and
hepatitis C virus infections among United States blood donors since introduction of nucleic
acid testing. Transfusion 50:1495-1504 (2010).
10. Stramer, SL, Notari, EP, Krysztof, DE, Dodd, RY. Hepatitis B virus testing by minipool
nucleic acid testing: does it improve blood safety? Transfusion 53:2449-58 (2013).