Draft Guidance for Industry Recommendations for Donor Questioning, Deferral, Reentry and Product Management to Reduce the Risk of Transfusion-Transmitted Malaria

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Draft Guidance
This guidance document is being distributed for comment purposes only.

Submit one set of either electronic or written comments on this draft guidance by the date provided in the Federal Register notice announcing the availability of the draft guidance. 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 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, Outreach and Development (OCOD) (HFM-40), 1401 Rockville Pike, Suite 200N, Rockville, MD 20852-1448, or by calling 1-800-835-4709 or 301-827-1800, or e-mail ocod@fda.hhs.gov, or from the Internet at http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/default.htm

For questions on the content of this guidance, contact OCOD at the phone numbers or e-mail address listed above.

U.S. Department of Health and Human Services
Food and Drug Administration
Center for Biologics Evaluation and Research (CBER)

June 2012

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TABLE OF CONTENTS

I. INTRODUCTION
II. BACKGROUND
III. DEFINITIONS
IV. RECOMMENDATIONS
A. Donor History Questionnaire
B. Donor Deferral and Reentry
C. Product Retrieval and Quarantine, and Notification of Consignees of Blood and Blood Components
D. Product Disposition and Labeling
E. Reporting a Biological Product Deviation (BPD)
V. ADDITIONAL CONSIDERATIONS
VI. REFERENCES
APPENDIX
 

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Guidance for Industry Recommendations for Donor Questioning, Deferral, Reentry and Product Management
to Reduce the Risk of Transfusion- Transmitted Malaria 

This draft guidance, when finalized, will represent the Food and Drug Administration's (FDA's) current thinking on this topic.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.

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I. INTRODUCTION

This draft 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 Code of Federal Regulations, 640.63(c)(9) (21 CFR 640.63(c)(9)).

This guidance replaces the draft guidance entitled "Guidance for Industry: Recommendations for Donor Questioning Regarding Possible Exposure to Malaria" dated June 2000, 65 FR 36452 (June 8, 2000), (June 2000 draft guidance) (Ref. 1). When finalized, this guidance will supersede 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. 2).

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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II. BACKGROUND

Transfusion-transmitted malaria occurs rarely, but is a serious concern in transfusion medicine (Refs. 3-4). 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. 4-7).

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 to 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 U.S. 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. 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. 8-9). The outcome of the workshop was summarized at the BPAC meeting held on July 13, 2006 (Ref. 10).

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. 11). 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 at-risk 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 (Ref. 12). 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 malaria-endemic 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. 13). 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 malaria-endemic states, Quintana Roo alone contributed approximately 70% of all malaria-risk-associated donor deferrals for travel to Mexico (Refs. 13-14). 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 that 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. 14). 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. 8). After these presentations and discussion, the Committee voted 17-1 in favor of allowing blood collection, without any deferral, 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.

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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 malariamade 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 (Ref. 15).

Malaria-endemic area - Any area designated in "Areas with Malaria" in the CDC's Travelers' Health Yellow Book (Ref. 15). This information is also available on the CDC's Malaria Map Application (Ref. 16). A determination of a malaria-endemic area is based on the information on the CDC website (Refs. 15-16) at the time the donor is screened. An area with any level of malaria transmission (described as high, moderate, low, residual or any other terminology used by the CDC) should be considered a malaria-endemic area.

Malaria-endemic country - Any country having an area or areas designated in "Areas with Malaria" in the CDC's Travelers' Health Yellow Book (Ref. 15). This information is also available on the CDC's Malaria Map Application (Ref. 16). A determination of a malaria-endemic country is based on the information on the CDC website (Refs. 15-16) at the time the donor is screened. A country that has an area with any level of malaria transmission (described as high, moderate, low, residual or any other terminology used by the CDC) should be considered a malaria-endemic country.

Residence in a malaria-endemic country - For purposes of this guidance, residence is defined as a continuous stay of longer than one year in a country or countries having any malaria-endemic area or areas, as identified by CDC. In determining residence, a country that has any malaria-endemic area should be considered to be malaria-endemic in its entirety since the geographic distribution of malaria-endemic areas may change during the period of residence, or the resident may have traveled from a non-endemic area to an endemic area in the country during his or her stay.

Residence in a non-endemic country - For purposes of this guidance, residence in a non-endemic country is defined as a continuous stay for at least three years within countries having no malaria-endemic area, as identified by CDC.

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 may be as short as a few hours, or as long as one year. Note that brief passage 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 malaria exposure.

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IV. RECOMMENDATIONS

A. Donor History Questionnaire

1. We recommend that you update your donor history questionnaire 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:
   1. A history of malaria;
   2. A history of prior residence in a malaria-endemic country; and
   3. A history of travel to a malaria-endemic country.

B. Donor Deferral and Reentry¹

1. History of Malaria
   1. We recommend that you defer indefinitely a donor who has a history of malaria and does not have documentation of successful treatment with anti-malarial drugs administered in a non-endemic country.
   2. We recommend that the Medical Director of your establishment review the documentation of successful treatment with anti-malarial drugs administered according to established treatment protocols in a non-endemic country. If your Medical Director finds the documentation satisfactory, the donor may be eligible to donate, provided the donor meets all other donor eligibility criteria.
2. Residence in a Malaria-endemic Country
   
   We recommend that you defer a donor for three years following residence (as defined in section III) 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. 
    
3. Travel to a Malaria-endemic Area
   1. Except as described in section IV.B.3.b. below, we recommend that you defer for one year after the last departure from a malaria-endemic area 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 prophylaxis. 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.
   2. You may accept a donor who is a resident of a non-endemic country and who has traveled to the Mexican states of Quintana Roo or Jalisco without any deferral for malaria risk. However, we recommend that you defer for one year after the last departure from a malaria-endemic area a donor who is a resident of a non-endemic country and who has traveled to or through any of the malaria-endemic areas in Mexico other than the states of Quintana Roo and Jalisco. 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.
   3. We recommend that you defer for one year after a visit to a malaria-endemic area a donor who is a prior resident of a malaria-endemic country and who has been a resident of a non-endemic country for the past three consecutive years. 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.
   4. We recommend that if a prior resident of a malaria-endemic country returns to a malaria-endemic country after residence for less than three years consecutively in non-endemic countries, that you defer that donor for three years from the time that they return to the non-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.

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.
 

1. If you collected blood or blood components (both cellular and/or non-cellular) intended for transfusion or blood or cellular blood components for further manufacturing from a donor who should have been deferred according to the recommendations above, we recommend that you quarantine any undistributed blood or blood components collected from that donor.
    
2. If you distributed blood or blood components (both cellular and/or non-cellular) intended for transfusion or blood or cellular blood components 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., we recommend that you notify consignees to retrieve and quarantine the blood and blood components collected from that donor.
   
   Additionally, in this situation, if blood or blood components (both cellular and non-cellular) 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 three months post-transfusion.
     
3. If you distributed blood or blood components (both cellular and non-cellular) intended for transfusion collected from a donor who should have been deferred according to recommendations in sections IV.B.2 or 3, we recommend that you notify consignees to retrieve and quarantine the blood and blood components collected from that donor.
    

D. Product Disposition and Labeling

1. We recommend that you destroy or re-label blood and cellular blood components that were collected from a donor who should have been deferred according to the recommendations in section IV.B. If you re-label the blood and 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. below.
    
2. Although not suitable for transfusion, blood and non-cellular blood components inadvertently collected from a donor who should have been deferred according to the recommendations in section IV.B. may be released for research, or for further manufacture into injectable (i.e., plasma derivative) or non-injectable products, or in vitro diagnostic reagents, if labeled appropriately as described below.
    
3. You should use the following statements to prominently re-label the blood and blood components:
   1. "NOT FOR TRANSFUSION: Collected From A Donor Determined To Be At Risk For Infection With Malaria Parasites"
      and
   2. "Caution: For Laboratory Research Only"
      or
      "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 non-cellular 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 blood or blood components (both cellular and non-cellular) intended for transfusion, or blood or cellular blood components intended for further manufacturing, collected from a donor at risk for malaria according to section IV.B. 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 a non-cellular blood component intended for further manufacturing from a donor at risk for malaria.

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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).

FDA will continue to monitor the situation of malaria transmission in Mexico and elsewhere and consider additional revisions when warranted.

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VI. REFERENCES

1. Food and Drug Administration, "Guidance for Industry: Recommendations for Donor Questioning Regarding Possible Exposure to Malaria" (June, 2000)
http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/Blood/ucm077061.htm
2. Food and Drug Administration, Memorandum. Recommendations for Deferral of Donors for Malaria Risk. July 26, 1994. http://www.fda.gov/downloads/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/
OtherRecommendationsforManufacturers/MemorandumtoBloodEstablishments/UCM062799.pdf
3. Westphal, R. Transfusion-transmitted malarial infections. In Smith, D. and Dodd, R. (eds). Transfusion Transmitted Infections. ASCP Press, Chicago 1991;167-180.

4. 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.

5. 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.

6. 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.

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

8. FDA Workshop "Testing for malarial infections in blood donors," July 12, 2006. http://www.fda.gov/BiologicsBloodVaccines/NewsEvents/WorkshopsMeetingsConferences/ucm090641.htm.

9. 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.

10. FDA Blood Products Advisory Committee "Workshop summary FDA Workshop on testing for malarial infections in blood donors," July 13, 2006. http://www.fda.gov/ohrms/dockets/ac/cber06.html#BloodProducts.

11. 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.

12. 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.

13. 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/BloodVaccinesandOtherBiologics/
BloodProductsAdvisoryCommittee/ucm189553.htm.
14. FDA Blood Product 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/BloodVaccinesandOtherBiologics/
BloodProductsAdvisoryCommittee/ucm189553.htm.
15. Travelers' Health: Yellow Book, CDC. http://wwwnc.cdc.gov/travel/page/yellowbook-2012-home.htm

16. Malaria Map Application, CDC. http://www.cdc.gov/malaria/map/

17. Vinetz, J.M., Li, J., McCutchan, T.F., Kaslow, D.C. Plasmodium malariae infection in an asymptomatic 74-year-old Greek woman with splenomegaly. The New England Journal of Medicine 1998; 338:367-371.

18. Kitchen, A., Mijovic, A., Hewitt, P. Transfusion-transmitted malaria: current donor selection guidelines are not sufficient. Vox Sang 2005; 88:200-201

19. Griffith, K. S., Lewis, L.S., Mali, S., Parise, M.E. Treatment of malaria in the United States: a systematic review. JAMA 2007; 297:2264-2277.

20. 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.

21. 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.

22. 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):1-17.

23. 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.

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

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APPENDIX
SCIENTIFIC RATIONALE FOR THE RECOMMENDATIONS

The scientific basis for the recommendations in section IV is as follows:

• The recommendation for an indefinite deferral of a donor who had a history of clinical malaria but had not undergone a successful anti-malarial treatment is based on the reports that in the absence of complete treatment, infections with some Plasmodium species may establish a chronic and prolonged asymptomatic infection (Refs. 17-18). For example, P. malariae has been reported to persist for up to 40 years in the absence of a new exposure (Ref. 17). Recommendation B.1.a. of documentation of anti-malaria drug treatment before a donor with a history of clinical malaria is allowed to donate is based on findings that anti-malaria treatment, when administered using the appropriate guidelines (see Ref. 19), is highly effective in the eradication of malaria parasites in infected individuals. The recommendation that the anti-malarial treatment be administered in a non-malaria endemic country is to avoid the possibility of a new exposure after the completion of drug treatment but prior to departure from the endemic area.
  
   
• The recommendation for a 3-year deferral of a donor following residence in a malaria-endemic country (recommendations B.2. and B.3.d.) 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 region. 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. 4). These data suggest that a deferral period of three 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 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 2167 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 one year after their return to the U.S. (Refs. 20-22). The 1-year deferral for residents of non-endemic countries applies to the last departure from the endemic area.
  
   
• The scientific rationale for recommendation B.3.b. that a resident of a non-endemic country (such as the U.S.) who had traveled to the Mexican states of Quintana Roo or Jalisco, where malaria is transmitted at a very low level, be allowed to donate blood without any deferral for malaria risk is as follows:
  1. During 2006-2009, malaria transmission in Mexico remained very low and is relatively stable (average 2400 malaria cases annually) (Ref. 13).
  2. During the same period, malaria transmission was particularly low in Quintana Roo and Jalisco (combined average 20 cases annually, or 0.75% of all malaria cases in Mexico) (Ref. 13-14).
  3. Quintana Roo (which includes the resorts of Cancun and Cozumel) and Jalisco (which includes the cities of Puerto Vallarta and Guadalajara) are highly popular states among U.S. tourists.
  4. Approximately 70% of donor deferrals among U.S. travelers to Mexico were because they had visited Quintana Roo and/or Jalisco (Refs. 13-14).
  5. An FDA risk assessment model has suggested a very small increase in malaria risk to blood safety by allowing for donation from donors who had traveled to malaria-endemic areas in Quintana Roo (0.0163 infected blood unit per year in Quintana Roo vs. 0.088 infected blood unit per year for all of Mexico) (Refs. 13-14). The suggested increase in risk by exempting Jalisco, another low-malaria transmission state, is even smaller (0.000245 infected blood unit per year for travel to Jalisco) [Mark Walderhaug et al., CBER, FDA, unpublished data]. The calculated cumulative risk to the blood supply according to the risk assessment model would be expected to increase by 1.1% (an absolute increase of 0.0166 infected blood unit per year, or one per 60 years) if prospective blood donors who visited Quintana Roo and Jalisco are allowed to donate blood without any deferral for malaria risk.
  6. The recommendation for a 1-year deferral of a donor who is a resident of a non-endemic country and who traveled to or through a malaria-endemic area in Mexico that is outside the states of Quintana Roo and Jalisco (recommendation B.3.b.) is consistent with a 1-year deferral for travel to a malaria-endemic area in any other part of the world (see recommendation B.3.a.).
     • The recommendation for deferral of a donor who is a prior resident of a malaria-endemic country and has not traveled to a malaria-endemic area for the past three continuous years for one year after a subsequent visit 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. 23-24). Consequently, we believe it is a reasonable safeguard to assume that after three or more continuous years of residence in a non-endemic country the majority of prior residents of malaria-endemic areas will not maintain their clinical immunity. Thus, after three years of continued residence in a non-endemic 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 one year after each return from travel to a malaria-endemic area consistent with the deferral for travelers from non-endemic countries.
     • 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 three 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. 4). 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 clinical history of malaria who may not have been treated or who failed to be deferred for at least three years.
     • The recommendation to allow for use of non-cellular 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. For this same reason, reporting of a BPD is not required if you have distributed a non-cellular blood component intended for further manufacturing from a donor at risk for malaria. BPD reporting is only required when the deviation may affect the safety, purity or potency of the product

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Footnote

¹ See Appendix for detailed scientific rationale for the recommendations.