GFI Malaria

Guidance for Industry
Recommendations for Donor
Questioning, Deferral, Reentry and
Product Management to Reduce the
Risk of Transfusion-Transmitted
Malaria
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 anytime. Submit electronic comments to http://www.regulations.gov. Submit
written comments 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 docket number [Docket No. FDA-2000-D-0187 (formerly Docket No. 2000-D1267)].
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 240-402-7800, 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
August 2013
Updated August 2014

Guidance for Industry
Recommendations for Donor
Questioning, Deferral, Reentry and
Product Management to Reduce the
Risk of Transfusion-Transmitted
Malaria
Note: Changes have been made to update the “Guidance for Industry: Recommendations for
Donor Questioning, Deferral, Reentry and Product Management to Reduce the Risk of
Transfusion-Transmitted Malaria” dated August 2013, including:
Updates to recognize revisions to certain flow charts contained in the accompanying
materials for the Full-Length Donor History Questionnaire (v.1.3 dated May 2008) and
Abbreviated Donor History Questionnaire (v.1.3 dated December 2012) prepared by the
AABB Donor History Task Force, as acceptable for use in screening donors of blood and
blood components for risk of malaria (see new section VI).
Revised recommendations in section VII on how licensed establishments must report the
implementation of the recommendations contained herein to FDA.

U.S. Department of Health and Human Services
Food and Drug Administration
Center for Biologics Evaluation and Research
August 2013
Updated August 2014

Contains Nonbinding Recommendations

Table of Contents
I.

INTRODUCTION............................................................................................................. 1

II.

BACKGROUND ............................................................................................................... 2

III.

DEFINITIONS .................................................................................................................. 4

IV.

RECOMMENDATIONS.................................................................................................. 5
A.
B.
C.
D.
E.

Donor History Questionnaire............................................................................... 5
Donor Deferral and Reentry ................................................................................ 5
Product Retrieval and Quarantine, and Notification of Consignees of Blood
and Blood Components......................................................................................... 6
Product Disposition and Labeling ....................................................................... 7
Reporting a Biological Product Deviation (BPD) .............................................. 8

V.

ADDITIONAL CONSIDERATIONS ............................................................................. 8

VI.

RECOGNITION OF THE REVISED DONOR HISTORY QUESTIONNAIRE
(DHQ) DOCUMENTS ...................................................................................................... 8
A.
B.

VII.

Recognition of the Revised DHQ Documents ..................................................... 8
Implementation of the Acceptable DHQ Documents ........................................ 9

IMPLEMENTATION OF RECOMMENDATIONS .................................................. 10

VIII. REFERENCES ................................................................................................................ 12

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Contains Nonbinding Recommendations

Guidance for Industry
Recommendations for Donor Questioning, Deferral, Reentry and
Product Management to Reduce the Risk of TransfusionTransmitted Malaria
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 document provides you, blood establishments that collect blood and blood
components, with our, FDA’s, recommendations for questioning and deferring donors of blood
and blood components, allowing their reentry, and product management to reduce the risk of
transfusion-transmitted malaria. The recommendations contained in this guidance apply to the
collection of Whole Blood and all blood components with the exception of Source Plasma.
Donors of Source Plasma are excluded from deferral due to malaria risk under Title 21 of the
Code of Federal Regulations 640.63(c)(9) (21 CFR 640.63(c)(9)).
This guidance supersedes the guidance of the same title dated August 2013 (78 FR 50421,
August 19, 2013), which in turn finalized the draft guidance entitled “Recommendations for
Donor Questioning, Deferral, Reentry and Product Management to Reduce the Risk of
Transfusion-Transmitted Malaria” dated June 2012, and superseded the FDA memorandum to all
registered blood establishments entitled “Recommendations for Deferral of Donors for Malaria
Risk” dated July 26, 1994 (July 26, 1994 memorandum) (Ref. 1).
In this guidance, we recognize revisions to certain flow charts contained in the accompanying
materials for the Full-Length Donor History Questionnaire (v.1.3 dated May 2008) and
Abbreviated Donor History Questionnaire (v.1.3 dated December 2012) prepared by the AABB
Donor History Task Force, as acceptable for use in screening donors of blood and blood
components for risk of malaria. The revised flow charts are dated April 2014.
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 guidance means that something is suggested or
recommended, but not required.

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Contains Nonbinding Recommendations
II.

BACKGROUND

Transfusion-transmitted malaria occurs rarely, but is a serious concern in transfusion medicine
(Refs. 2, 3). It has been shown to be caused by any of the following four Plasmodium species:
P. falciparum; P. malariae; P. ovale; or P. vivax. In the absence of a licensed test for donor
screening, the measure used to reduce transfusion-transmitted malaria in the United States (U.S.)
has been the deferral of donors who have had a malaria infection or had a possible exposure risk
to malaria. Accurate identification of donors with the potential to transmit malaria depends on
the donor exposure history obtained during the donor interview, which may be facilitated
through use of a donor questionnaire (Refs. 4-6).
The July 26, 1994 memorandum had the following recommendations:
Permanent residents of non-endemic countries who travel to an area considered endemic
for malaria should not be accepted as donors of Whole Blood and blood components
prior to one year after departure from the endemic area. After one year after departure,
such otherwise suitable prospective donors may be accepted provided that they have been
free of unexplained symptoms suggestive of malaria.
Prospective donors who have had malaria should be deferred for three years after
becoming asymptomatic.
Citizens, residents, immigrants or refugees of endemic countries should not be accepted
as donors of Whole Blood and blood components prior to three years after departure from
the area. After the 3-year period, otherwise suitable prospective donors may be accepted
if they have remained free of unexplained symptoms suggestive of malaria.
Public comments on the July 26, 1994 memorandum and the June 2000 draft guidance on
screening of donors for malaria risk raised several concerns about the need to standardize
definitions used in the recommendations, and the scientific basis for the recommended deferral
periods. These concerns prompted public discussions, including a meeting of the FDA Blood
Products Advisory Committee (BPAC or Committee) on September 16, 1999. At that meeting,
BPAC reviewed the current status of transfusion-transmitted malaria and its impact on blood
safety in the United States BPAC also reviewed the usefulness of the available laboratory test
methods to detect current malaria infection or to provide evidence of past exposure to malaria
parasites.
On July 12, 2006, FDA convened a scientific workshop entitled “Testing for Malarial Infections
in Blood Donors” to seek public discussion of scientific developments that might support donor
testing for malaria infections as part of pre-donation testing, or as follow-up testing to permit a
reduced deferral period for donors deferred for malaria risk (Ref. 7). There are no FDA-licensed
tests to screen blood donors for malaria. Nucleic acid-based tests were deemed unsuitable for
donor screening due to the limitation of the small sample size used in nucleic acid extraction;
however, several speakers and panel members emphasized the value of antibody testing to
reenter deferred malaria-risk donors who tested negative for malarial antibodies (Refs. 7, 8). The
outcome of the workshop was summarized at the BPAC meeting held on July 13, 2006 (Ref. 9).

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At the BPAC meeting on September 11, 2008, the Committee discussed donor testing for
malarial antibodies as an indicator of possible exposure to malaria parasites (Ref. 10). At the
meeting, FDA presented risk assessment data for three possible scenarios in which antibody
testing could be of value: (1) testing all donors (universal testing); (2) reentry testing of all atrisk donors with a history of potential exposure to malaria anywhere in the world; and (3) reentry
testing of only those donors who had traveled to malaria-endemic areas in Mexico. The risk
assessment model assumed that donors would be deferred for four months after returning from
endemic areas of Mexico or other parts of the world before antibody testing would be performed
on the donor. At the meeting, two blood organizations (the American Red Cross and America’s
Blood Centers) also presented data from surveys showing that approximately 41% of all blood
donors deferred for risk of malaria exposure had been deferred because they had traveled to
malaria-endemic areas in Mexico (Refs. 10, 11). The Committee considered all three risk
assessment scenarios and the possible role that antibody testing could play in identifying or
reentering malaria-risk donors, especially those donors who had traveled to endemic areas in
Mexico. In the end, the Committee felt that additional risk analysis would be needed, and that
the analysis should account for malaria risk globally and in Mexico, with and without antibody
testing.
On November 16, 2009, FDA again sought advice from BPAC on an alternative strategy to
minimize donor loss associated with deferrals for malaria risk. Specifically, FDA asked the
Committee to consider a new risk assessment model which was focused on travel to malariaendemic states in Mexico, and asked whether it was acceptable to allow blood collections
without any deferral from individuals who have traveled to certain Mexican states that have a
low malaria transmission rate. At that meeting, FDA presented data which showed that while
travel to Mexico was a major contributor to donor deferrals due to malaria risk (about 41%),
from 2006-2009, malaria transmission in Mexico was shown to be very low (average 2400
malaria cases annually) and limited only to certain Mexican states (Ref. 12). The malaria
transmission rate was shown to be particularly low in Quintana Roo, a Mexican state that
includes Cancun and Cozumel and is known to receive a high volume of U.S. travelers.
Estimates also suggested that there was a great disparity in the contribution of different Mexican
states to the number of donor deferrals among U.S. travelers. Data collected by the American
Red Cross and Blood Systems Research Institute suggested that in 2006, among the 10 malariaendemic states, Quintana Roo alone contributed approximately 70% of all malaria-riskassociated donor deferrals for travel to Mexico (Refs. 12, 13). While donors deferred because of
travel to Quintana Roo were a significant percentage of deferrals, FDA’s risk assessment found
that the calculated overall risk to the blood supply would be expected to increase by 1.1% (an
absolute increase of 0.0166 infected blood unit per year, or one in 60 years) if prospective blood
donors who visited Quintana Roo and another state, Jalisco, which includes the cities of Puerto
Vallarta and Guadalajara, were allowed to donate blood without any deferral for malaria risk.
However, the donor pool would increase by approximately 45,000 donors (79,000 blood units)
each year (Ref. 13). FDA also found that the actual donor gain might be significantly higher if
the Agency took into account the total donor loss due to self-deferrals and the non-return of
donors deferred under the current policy (Ref. 7). After these presentations and discussion, the
Committee voted 17-1 in favor of allowing blood collection, without any deferral for malaria

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risk, from U.S. residents who have visited Quintana Roo. The Committee also discussed
extending the proposed policy to other malaria-endemic states of Mexico that have a low malaria
transmission rate.
III.

DEFINITIONS

Malaria - An infectious disease caused by a parasitic protozoan of the genus Plasmodium.
Malaria diagnosis in a prospective donor is based on a positive laboratory test indicating
Plasmodium infection, or a determination of a history of malaria made by the blood
establishment’s Medical Director. For additional information regarding malaria and its
associated symptoms, visit the Centers for Disease Control and Prevention (CDC) website at
http://www.cdc.gov/malaria/.
Malaria-endemic area - Any areas with malaria where CDC recommends anti-malarial
chemoprophylaxis in travelers in the most current version of the CDC Health Information for
International Travel (commonly known as The Yellow Book) at the time the donor is screened.
We recommend you access the “Malaria Information, by Country” table in the Malaria chapter
of The Yellow Book for the most current recommendations on anti-malarial chemoprophylaxis.
The Yellow Book is available on the CDC website at
http://wwwnc.cdc.gov/travel/page/yellowbook-2012-home.htm.
Malaria-endemic country - Any country having an area or areas with malaria where CDC
recommends anti-malarial chemoprophylaxis in travelers in The Yellow Book at the time the
donor is screened. A country that has any malaria-endemic areas should be considered to be
malaria-endemic in its entirety.
Residence in a malaria-endemic country - For purposes of this guidance, residence is defined
as a continuous stay of longer than 5 years in a country or countries having any malaria-endemic
area (see definition above). In determining residence, consideration is by malaria-endemic
country and not by malaria-endemic area since the geographic distribution of malaria-endemic
areas may change during the period of residence, or the resident may have traveled from a nonendemic area to an endemic area in the country during his or her stay.
Travel to a malaria-endemic area - Any travel to or through a malaria-endemic area or areas,
as identified by CDC (see definition above). The duration of travel to a malaria-endemic area is
defined as more than 24 hours to less than 5 years. Note that a passage greater than 24 hours
through a malaria-endemic area while on route to a malaria-free area is considered a sufficient
possible exposure to trigger donor deferral. Common examples of such possible exposure
include passage through a malaria-endemic area to visit a tourist resort in a malaria-free area, or
passage through a malaria-endemic area to board a cruise ship, or on-shore excursions into a
malaria-endemic area when traveling on a ship. Travel to or through a malaria-free area within a
malaria-endemic country does not constitute travel to a malaria-endemic area.

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IV.

RECOMMENDATIONS

FDA’s scientific rationale and further explanation for our recommendations are provided in the
Appendix.
A.

Donor History Questionnaire
1. We recommend that you update your donor history questionnaire, including full
length and abbreviated donor history questionnaires, to incorporate the
recommendations provided in this guidance.
2. We recommend that the updated donor history questionnaire include the
following elements to assess prospective donors for malaria risk (note definitions
in section III of this guidance):
a. A history of malaria in the past three years;
b. A history of prior residence in a malaria-endemic country;
c. A history of travel to a malaria-endemic area in the past one year; and
d. A history of travel to a malaria-endemic area in the past three years, if
previously a resident of a malaria-endemic country.

B.

Donor Deferral and Reentry 1
1. History of Malaria
a. We recommend that you defer for 3 years a donor who has a history of
malaria.
b. If that donor has remained free of malaria symptoms for a 3-year period while
residing in a non-endemic country, the Medical Director may decide to accept
the donor, provided the donor meets all other donor eligibility criteria.
2. Residence in a Malaria-endemic Country
We recommend that you defer a donor for 3 years who had been a prior resident (as
defined in section III of this guidance) in a malaria-endemic country. After the 3-year
deferral period, the donor may be eligible to donate provided the donor has been free
from malaria during this period and meets all other donor eligibility criteria.

1

See Appendix for detailed scientific rationale for the recommendations contained in this guidance.

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Contains Nonbinding Recommendations
3. Travel to a Malaria-endemic Area
a. We recommend that you defer for 1 year after the last departure from a
malaria-endemic area (as defined in section III of this guidance) a donor who
is a resident of a non-endemic country and who has traveled to or through any
malaria-endemic area, whether or not the donor has received malaria
chemoprophylaxis. After the 1-year deferral period, the donor may be eligible
to donate, provided the donor has been free from malaria during this period
and meets all other donor eligibility criteria.
b. We recommend that you defer for 3 years after a visit to a malaria-endemic
area a donor who is a prior resident of a malaria-endemic country (as defined
in section III of this guidance) and who has been a resident of non-endemic
countries for less than 3 consecutive years. After the 3-year deferral period,
the donor may be eligible to donate, provided the donor has been free from
malaria during this period and meets all other donor eligibility criteria.
c. We recommend that if a prior resident of a malaria-endemic country returns to
a malaria-endemic area after residence for 3 years consecutively in nonendemic countries, that you defer that donor for 1 year from the time that they
return to the non-endemic country. After the 1-year deferral period, the donor
may be eligible to donate, provided the donor has been free from malaria
during this period and meets all other donor eligibility criteria.
C.

Product Retrieval and Quarantine, and Notification of Consignees of Blood
and Blood Components

We recommend that you take the following actions if you determine that blood or blood
components have been collected from a donor who should have been deferred according
to the recommendations in section IV.B of this guidance.
1. If you collected cellular blood components intended for transfusion or for further
manufacturing from a donor who should have been deferred according to the
recommendations in section IV.B. of this guidance, we recommend that you
quarantine any undistributed in-date cellular blood components collected from
that donor.
2. If you distributed cellular blood components intended for transfusion or for
further manufacturing collected from a donor with a clinical history of malaria
who should have been deferred according to the recommendation in section
IV.B.1. of this guidance, we recommend that you notify consignees to retrieve
and quarantine the in-date cellular blood components collected from that donor.

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Contains Nonbinding Recommendations
Additionally, in this situation, if cellular blood components have been transfused,
you should encourage consignees to notify the transfusion recipient’s physician of
record regarding the need for monitoring of the recipient for a possible malaria
infection for a period of 3 months post-transfusion.
3. If you distributed cellular blood components intended for transfusion collected
from a donor who should have been deferred for malaria-risk associated with
travel or prior residence according to recommendations in sections IV.B.2 or 3 of
this guidance, we recommend that you notify consignees to retrieve and
quarantine the in-date cellular blood components collected from that donor.
4. If you collected acellular blood components (i.e., frozen plasma products)
intended for transfusion or for further manufacturing from a donor who should
have been deferred according to the recommendations in section IV.B. of this
guidance, we recommend that you quarantine any undistributed in-date acellular
blood components collected from that donor. (Note that based on the very low
risk for transmission of malaria, we are not recommending notification of
consignees if you distributed such acellular products.)
D.

Product Disposition and Labeling
1. We recommend that you destroy or relabel cellular blood components that were
collected from a donor who should have been deferred according to the
recommendations in section IV.B of this guidance. If you relabel the cellular
blood components, they may be released for research, or for manufacture into
noninjectable products or in vitro diagnostic reagents as described in section
IV.D.3. of this guidance.
2. Although not suitable for transfusion, acellular blood components inadvertently
collected from a donor who should have been deferred according to the
recommendations in section IV.B. of this guidance may be released for research,
or for further manufacture into injectable (i.e., plasma derivative) or noninjectable products, or in vitro diagnostic reagents, if labeled appropriately as
described below.
3. You should use the following statements to prominently relabel the blood
components:
a. “NOT FOR TRANSFUSION: Collected From A Donor Determined To Be
At Risk For Infection With Malaria Parasites”
and
b. “Caution: For Laboratory Research Only”
or

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“Caution: For Further Manufacturing into In Vitro Diagnostic Reagents For
Which There Are No Alternative Sources”
or
“Caution: For Use in Manufacturing Noninjectable Products Only”
or
“Caution: “For Manufacturing Use Only” (used for acellular products
intended for further manufacture into injectable products).
You should not label these products with a U.S. license number unless FDA
specifically approves you to do so. If appropriate, unlicensed products may be
shipped solely to a manufacturer of a product subject to licensure, under a short
supply agreement (21 CFR 601.22).
E.

Reporting a Biological Product Deviation (BPD)

If you have distributed any cellular blood components for transfusion or for further
manufacturing, collected from a donor at risk for malaria according to section IV.B. of
this guidance, you should report a BPD as soon as possible, but you must report within 45
calendar days from the date you acquire the information reasonably suggesting that a
reportable event has occurred (21 CFR 606.171).
You are not required to report a BPD if you have distributed an acellular blood
component intended for transfusion or further manufacturing from a donor at risk for
malaria.
V.

ADDITIONAL CONSIDERATIONS

Whole Blood and blood components intended for transfusion should not be collected from a
possible malaria risk donor with the intent of converting or relabeling those products for further
manufacturing use (e.g., relabeling of Fresh Frozen Plasma as recovered plasma).
VI.

RECOGNITION OF THE REVISED DONOR HISTORY QUESTIONNAIRE
(DHQ) DOCUMENTS
A.

Recognition of the Revised DHQ Documents

The AABB Donor History Task Force has revised the flow charts for the following
questions:

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The Full-Length Donor History Questionnaire, v.1.3 dated May 2008
o In the past 3 years have been outside the United States or Canada?
o Have you ever had malaria?
The Abbreviated Donor History Questionnaire, v.1.3 dated December 2012
o Since your last donation have you been outside the United States or Canada?
FDA finds the revised AABB DHQ flow charts for the questions above (v.1.3 dated April
2014) to be acceptable for use in screening blood donors consistent with the
recommendations contained in this guidance. 2
While we recognize the DHQ documents prepared by the AABB Task Force as
acceptable, you are not required to implement them. You may continue to use any donor
history questionnaire and accompanying materials developed by your establishment that
have been revised to reflect the recommendations contained in this guidance and, for
licensed blood establishments, have been approved by FDA. Your materials may include
procedures and wording that are different from those in the AABB DHQ documents.
B.

Implementation of the Acceptable DHQ Documents

To ensure the correct implementation of the revised DHQ flow charts described in
section VI. A of this guidance), we recommend you use the process described below:
Implementing the new flow charts for the full-length DHQ, v.1.3 dated April 2014:
o Replace the flow charts v.1.3 dated May 2008 with the revised flow charts v.1.3
dated April 2014
Implementing the new flow chart for the abbreviated DHQ, v.1.3 dated April 2014:
o Add the following question from the full-length DHQ to the abbreviated DHQ in
the space reserved for extra questions:
In the past 3 years have you been outside the United States or Canada?
o Include the v.1.3 dated April 2014 flow chart for this question from the full-length
DHQ in your procedures.

2

You may view v.1.3 of the DHQ documents prepared by AABB, including the revised flow charts, on the FDA
website at http://www.fda.gov/BiologicsBloodVaccines/BloodBloodProducts/ApprovedProducts/LicensedP
roductsBLAs/BloodDonorScreening/ucm164185.htm. On this website, you may also view the FDA guidance
documents that recognized v.1.3 of the full-length and abbreviated DHQs and accompanying materials.

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Contains Nonbinding Recommendations
o Retain this question and corresponding flow chart on the abbreviated DHQ for 1
year from the time that you implement these procedures. After 1 year, you may
remove this question and the corresponding flow chart from the abbreviated
DHQ.
o Concurrently, retain this current question on the abbreviated DHQ:
Since your last donation have you been outside the United States or
Canada?
o Replace the flow chart dated v.1.3 December 2012 for this question with the v.1.3
dated April 2014 flow chart from the abbreviated DHQ for same question.
o For the one year that you are including the question and flow chart from the fulllength DHQ, you may use one of the following methods to implement the revised
flowchart for the abbreviated DHQ:
Use the v.1.3 dated April 2014 flow chart for the abbreviated DHQ in its
entirety, or
Skip the part of the flow chart for the abbreviated DHQ that evaluates the
donor for travel to malaria-endemic countries and areas and proceed to the
sections on the flow chart for evaluating travel to HIV-1 Group O and
vCJD endemic countries.
o At the end of the 1 year period, if you are not already doing so, use the revised
v.1.3 dated April 2014 flow chart for the abbreviated DHQ in its entirety.
VII.

IMPLEMENTATION OF RECOMMENDATIONS

You may implement the recommendations contained in this guidance once you have revised
your donor history questionnaire (DHQ), including full-length and abbreviated DHQs, and
accompanying materials as necessary to reflect the new donor deferral recommendations.
Licensed blood establishments must report the changes to FDA in the following manner:
1. Revision of your own DHQ and accompanying materials: report as a major change if
revising your own DHQ and accompanying materials to implement the new
recommendations. Report such a change to FDA as a prior approval supplement (PAS)
under 21 CFR 601.12(b).
2. Revision of a previously FDA accepted DHQ and accompanying materials: report as a
major change if you are revising the FDA accepted DHQ and accompanying materials to
implement these new recommendations. Report such a change to FDA as a prior
approval supplement (PAS) under 21 CFR 601.12(b).

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3. Use of full-length DHQ (v.1.3 dated May 2008) and abbreviated DHQ (v.1.3 dated
December 2012) with revised flow charts v.1.3 dated April 2014:
a. If the revised flow charts are implemented without modifications and in their entirety
using the process in section VI. B of this guidance, the change is considered to be
minor. You must report such changes to FDA in your annual report consistent with
21 CFR 601.12(d), noting the date the process was implemented.
b. If you make changes to the format of the revised flow charts but the content remains
consistent, or you adopt stricter donor deferral criteria, the changes are considered
minor. You must report such changes to FDA in your annual report under 21 CFR
601.12(d), noting the date the process was implemented and describing how you
modified the acceptable flow charts.
c. If the revised flow charts are implemented with modifications other than formatting,
the change is considered to be major. You must report such changes as a prior
approval supplement (PAS) consistent with 21 CFR 601.12(b).
d. If the revised flow charts are implemented using a process that differs from that in
section VI.B, the change is considered to be major. You must report such changes as
a prior approval supplement (PAS) consistent with 21 CFR 601.12(b).

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VIII. REFERENCES
1.

Food and Drug Administration, Memorandum. Recommendations for Deferral of Donors
for Malaria Risk. July 26, 1994.

2.

Westphal, R. Transfusion-transmitted malarial infections. In Smith, D. and Dodd, R.
(eds). Transfusion Transmitted Infections. ASCP Press, Chicago 1991;167-180.

3.

Mungai, M., Tegtmeier, G., Chamberland, M., Parise, M. Transfusion-transmitted
malaria in the United States from 1963 through 1999. New England Journal of Medicine
2001; 344:1973-1978.

4.

Guerrero, I.C., Weniger, B.C., Schultz, M.G. Transfusion malaria in the United States,
1972-1981. Annals of Internal Medicine 1983; 99:221-226.

5.

Nahlen, B.L., Lobel, H.O., Cannon, S.E., Campbell, C.C. Reassessment of blood donor
selection criteria for United States travelers to malarious areas. Transfusion 1991;
31:798-804.

6.

Sazama, K. Prevention of transfusion-transmitted malaria: Is it time to revisit the
standards? Transfusion 1991; 31:786-788.

7.

FDA Workshop “Testing for malarial infections in blood donors,” July 12, 2006.
http://www.fda.gov/BiologicsBloodVaccines/NewsEvents/WorkshopsMeetingsConferen
ces/ucm090641.htm.

8.

Seed, C.R., Cheng, A., Davis, T.M.E., Bolton, W.V., Keller, A.J., Kitchen, A., Cobain,
T.J. The efficacy of a malarial antibody enzyme immunoassay for establishing the
reinstatement status of blood donors potentially exposed to malaria. Vox Sang 2005;
88:98-106.

9.

FDA Blood Products Advisory Committee “Testing for malarial infections in blood
donors,” July 13, 2006.
http://www.fda.gov/ohrms/dockets/ac/cber06.html#BloodProducts.

10.

FDA Blood Products Advisory Committee “Options for blood donor screening and
reentry for malaria.” September 11, 2008.
http://www.fda.gov/ohrms/dockets/ac/cber08.html#BloodProducts.

11.

Spencer, B., Steele, W., Custer, B., Kleinman, S., Cable, R., Wilkinson, S., Wright, D.
Risk for malaria in United States donors deferred for travel to malaria-endemic areas.
Transfusion 2009; 49(11):2335-45.

12.

FDA Blood Products Advisory Committee “Blood Donor Deferral for Malaria Risk
Associated with Travel to Mexico.” November 16, 2009.
http://www.fda.gov/AdvisoryCommittees/CommitteesMeetingMaterials/BloodVaccinesa
ndOtherBiologics/BloodProductsAdvisoryCommittee/ucm189553.htm.

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13.

FDA Blood Products Advisory Committee “Benefit: Risk Analysis for Malaria Exposure
in Blood Donors from Mexico and Its Effect on Blood Safety and Availability,” Mark
Walderhaug, November 16, 2009.
http://www.fda.gov/AdvisoryCommittees/CommitteesMeetingMaterials/BloodVaccinesa
ndOtherBiologics/BloodProductsAdvisoryCommittee/ucm189553.htm.

14.

Mali, S., Steele, S., Slutsker, L., Arguin, P.M. Centers for Disease Control and
Prevention (CDC). Malaria surveillance - United States, 2008. MMWR Surveill Summ.
2010 Jun 25; 59(7):1-15.

15.

Mali, S., Tan, K.R., Arguin, P.M. Centers for Disease Control and Prevention (CDC).
Malaria surveillance - United States, 2009. MMWR Surveill Summ. 2011 Apr 22;
60(3):1-15.

16.

Mali, S., Kachur, S.P., Arguin, P.M. Centers for Disease Control and Prevention (CDC).
Malaria surveillance - United States, 2010. MMWR Surveill Summ. 2012 Mar 2; 61(2):117.

17.

Liljander, A., Chandramohan, D., Kweku, M., Olsson, D., Montgomery, S.M.,
Greenwood, B., Farnert, A. Influences of intermittent preventive treatment and persistent
multiclonal Plasmodium falciparum infections on clinical malaria risk. PLoS One 2010,
5(10):e13649.

18.

Doolan, D.L., Dobano, C. Baird, J.K. Acquired immunity to malaria. Clin. Microbiol.
Reviews, 2009, 22(1):13-36.

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Contains Nonbinding Recommendations
APPENDIX
SCIENTIFIC RATIONALE AND FURTHER EXPLANATION FOR THE
RECOMMENDATIONS
The scientific basis and further explanation for the recommendations in section IV of this
guidance are as follows:
The recommendation for a 3-year deferral of a donor following residence in a malariaendemic country (recommendations B.2. and B.3.b.) is based on the possible presence
of low-grade parasitemia in individuals with clinical immunity to malaria, or with a
chronic malaria infection who have not received definitive treatment after departure
from the malaria-endemic area. Although it is not known how long parasitemia can
last in such persons, it is believed that most (though not all) will either develop clinical
malaria or else resolve their infection over time. This is because anti-malarial
immunity is thought to wane in the absence of repeated infections. Data reported by
CDC showed that out of 4,229 reported cases of malaria in foreign-born residents,
only 7 cases (0.2%) had an episode of clinical malaria more than three years after the
patient had left a malaria-endemic country (Ref. 3). These data suggest that a deferral
period of 3 years would be adequate for resolution of parasitemia in most cases. This
recommendation will be reconsidered periodically based on new scientific data.
Recommendation B.3.a of a 1-year deferral period for a donor who is a resident of a
non-endemic country and who has traveled to or through a malaria-endemic area
(whether or not the donor received malaria prophylaxis), is based on the malaria
surveillance reports by CDC showing that out of 2,167 imported malaria cases
reported between 2008-2010 for which the date of arrival and the onset of illness was
known, only 2 (0.09%) experienced clinical malaria more than 1 year after their return
to the U.S. (Refs. 14-16). The 1-year deferral for residents of non-endemic countries
applies to the last departure from the endemic area.
Blood centers should use the new definition of malaria-endemic area (see section III of
this guidance) in deciding whether a donor had traveled to a malaria-endemic area.
Based on the current epidemiological data and the definition of malaria-endemic area in this
guidance, FDA does not currently recommend deferral of donors who have traveled to the
Mexican states of Quintana Roo and Jalisco; thus, these donors, if otherwise eligible, may
donate. Please note that the designation of malaria-endemic areas in Mexico or in any malariaendemic country and accordingly, a recommendation for donor deferral, are subject to change
based on the most updated malaria transmission information with respect to that area, as listed in
The Yellow Book. For example, if malaria transmission in these states changes and anti-malarial
chemoprophylaxis is recommended by CDC, then the donor deferral recommendations would
encompass donors who travel to these areas.
The recommendation for a one year deferral from the time of return to a non-endemic
country of a donor who was a prior resident of a malaria-endemic country and who

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Contains Nonbinding Recommendations
had not traveled to a malaria-endemic area for 3 consecutive years preceding the most
recent travel to a malaria-endemic area (recommendation B.3.c.) is based on
information indicating that continued exposure to malaria parasites is necessary to
maintain clinical immunity (Refs. 17, 18). Consequently, we believe it is a reasonable
safeguard to assume that after 3 or more continuous years of residence in a nonendemic country, the majority of prior residents of malaria-endemic areas will not
maintain their clinical immunity. Thus, after 3 years of continued residence in a nonendemic country, a prior resident of a malaria-endemic country may be treated as a
resident of a non-endemic country. Such individuals should be deferred for only 1
year after each return from travel to a malaria-endemic area consistent with the
deferral for travelers from non-endemic countries.
In many parts of the world, transmission of malaria and dengue can occur in the same
area. FDA is aware that under the new definition of a malaria-endemic area,
potentially eligible donors may have traveled to areas where dengue virus is
transmitted. FDA is currently evaluating the risk of dengue virus infections in blood
donors that are acquired either locally or elsewhere in the world, and may address this
issue in future guidance.
The recommendation that consignee notification include instructions for notification of
the transfusion recipient or the transfusion recipient’s physician of record regarding
the need for monitoring of the recipient for a possible malaria infection for a period of
3 months post-transfusion (recommendation C.2.) is based on the analysis of
incubation periods in 57 cases of transfusion-transmitted malaria in the U.S., in which
the maximum period observed between transfusion and onset of clinical symptoms
was 90 days (range 8 to 90 days) (Ref. 3). This recommendation is limited to the
highest risk circumstance of unintentional release of a unit from a donor at risk of
malaria, namely a unit from a donor who had a clinical history of malaria who may not
have been treated or who failed to be deferred for at least 3 years.
The recommendation to allow the use of acellular blood components inadvertently
collected from a donor who was later determined to be at risk for malaria to make
injectable products is based on the knowledge that licensed plasma derivatives do not
transmit malaria. In addition, notification of consignees is not recommended and
reporting of biological product deviation is not required for acellular components
inadvertently collected and distributed from a donor at risk for malaria because of the
lack of a documented case of transfusion-transmitted malaria from acellular blood
components. According to a CDC surveillance study (Ref. 3), 93 cases of transfusion
transmitted malaria were reported in the U.S. from 1963-1999. Among the 70 cases
for which information was available, the following blood components were
implicated: whole blood (63%); red cells (31%); and platelets (6%). Plasma
components were not shown as a source of transfusion-transmitted malaria.

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