Guidance for Industry

Variances for 

Blood Collection from Individuals with 

Hereditary Hemochromatosis

Additional copies of this guidance document are available from:

Office of Communication, Training and Manufacturers Assistance (HFM-40)

1401 Rockville Pike, Rockville, MD 20852-1448

(Tel) 1-800-835-4709 or 301-827-1800

(Internet) http://www.fda.gov/cber/guidelines.htm

U.S. Department of Health and Human Services

Food and Drug Administration

Center for Biologics Evaluation and Research (CBER)

August 2001
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Table of Contents

I. PURPOSE............................................................................................................................. 1

II. INTRODUCTION................................................................................................................ 1

III. BACKGROUND .................................................................................................................. 2

IV. CONTENT OF VARIANCE REQUESTS ........................................................................ 3

V. SUBMISSION OF VARIANCE REQUESTS ................................................................... 3

VI. REFERENCES..................................................................................................................... 5
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GUIDANCE FOR INDUSTRY

Variances for Blood Collection from 

Individuals with Hereditary Hemochromatosis

This guidance document represents FDA’s current thinking on the distribution of blood and 

blood components from individuals with hereditary hemochromatosis without disease labeling, 

and collecting blood more frequently than every eight weeks without a physical examination on 

the day of donation. It does not create or confer any rights for or on any person and does not 

operate to bind FDA or the public. An alternative approach may be used if such approach 

satisfies the requirements of the applicable statutes and regulations.

I. PURPOSE

This guidance document provides recommendations to you, blood establishments, that wish to 

distribute blood and blood components collected from individuals with diagnosed hereditary 

hemochromatosis without indicating the donor’s disorder on the container label. This guidance 

also provides recommendations if you wish to collect blood from such individuals more 

frequently than every eight weeks without a physical examination and certification of the donor’s 

health by a physician on the day of donation. This document identifies conditions under which 

we, FDA, will consider approving the above as alternative procedures, or variances, to the 

current regulations, under the provisions of Title 21, Code of Federal Regulations, Section 

640.120 (21 CFR 640.120). It also provides guidance on what you should submit to us when 

requesting these variances. These recommendations apply to all blood establishments, whether 

or not you hold a U.S. License for the manufacture of blood and blood components.

II. INTRODUCTION

Hereditary hemochromatosis (HH) is an inherited disorder of iron metabolism, with an estimated 

prevalence of 0.25-0.50% among Caucasians. An epidemiologic study is currently underway to 

determine the prevalence, as well as the genetic and environmental determinants, of iron 

overload related to hereditary hemochromatosis in a multiethnic population. This iron 

metabolism disorder often results in the deposition of excess iron in body tissues that can reach 

toxic levels leading to organ damage. The toxicity can affect most tissues and organs, but 

particularly the liver, endocrine organs, and the heart. Early initiation of therapeutic phlebotomy 

before organ damage occurs may restore a normal life expectancy and improve symptoms. (Ref. 

1, 2)

Treatment of HH typically has two phases. First, the patient undergoes iron depletion therapy, in 

which excess iron is removed. In one study of current practices, two to three units of blood were 

withdrawn per month, for approximately one year. In the second phase, maintenance therapy, an 

average of one unit was withdrawn every two months. In the same study, 76% of respondents 
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reported full or partial insurance coverage of therapeutic phlebotomy charges. Charges ranged 

from a mean of $48 for home phlebotomy, $52 for blood centers, $69 for physician’s offices, to 

$90 for hospitals. (Ref. 3)

On the basis of the currently understood molecular mechanisms of disease, there is no evidence 

that blood from HH patients would carry any added risk for transfusion recipients from HH. In 

addition, there is no evidence to support a transfer of a genetic disorder by transfusion. Blood 

from HH patients has been used for transfusion in other countries without reports of adverse 

reactions in recipients. (Ref. 2)

Currently, FDA does not prohibit the use of blood from therapeutic bleedings, but requires that 

blood intended for transfusion be labeled with the donor’s disease (21 CFR 640.3(d)). In 

addition, the regulations state that a person may donate a unit of blood more than once in eight 

weeks only after a physical examination and certification of health by a physician (21 CFR 

640.3(f)). 

Many blood establishments that collect blood during a therapeutic phlebotomy have not routinely 

distributed this blood for transfusion, because consignees have refused to accept blood that is 

labeled with a disease. Thus, the labeling requirement is considered to be a barrier to the use of 

blood from HH donors for transfusion, despite evidence that this blood is safe.

There have been several studies that have shown an increase in the prevalence of bloodborne 

viral pathogens in blood obtained from paid donors as compared to volunteer donors. Therefore, 

there is concern about creating an incentive for HH patients to donate blood for free, rather than 

pay for a therapeutic phlebotomy. If a blood establishment charged a fee for therapeutic 

phlebotomy, but not for a blood donation for transfusion, the HH donor would have an incentive 

to deny risk conditions that might preclude cost-free donation. In this circumstance, blood 

donation provides indirect compensation for medical phlebotomy. (Ref. 4) 

III. BACKGROUND

On April 29, 1999, the Public Health Service Advisory Committee on Blood Safety and 

Availability (ACBSA) recommended that the Department of Health and Human Services 

(DHHS) “create policies that eliminate incentives to seek [blood] donation for purposes of 

phlebotomy” from patients with diagnosed hemochromatosis who require phlebotomy as therapy 

for their disorder. Further, ACBSA recommended that DHHS “create policies that eliminate 

barriers to using this resource” to augment the country’s blood supply. (Ref. 5)

On August 10, 1999, the Commissioner of Food and Drugs made a commitment to consider 

case-by-case exemptions to existing blood labeling and donor suitability regulations for blood 

establishments that can verify that therapeutic phlebotomy for hemochromatosis is performed at 

no expense to the patient (Ref. 6). The Commissioner wrote that as part of any exemption, we 

would request that safety data be collected and submitted to the Agency and that this data would 

be compared with data gathered on the general donor pool.
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Additionally, we made a commitment to work with the Health Care Financing Administration 

(HCFA) in ensuring that the financial incentives for persons with HH to donate blood for 

transfusion are removed. This issue was further discussed at the FDA Blood Products Advisory 

Committee meeting on September 16, 1999. For the foreseeable future, if you wish to distribute 

blood collected from donors with HH without disease labeling, you will have the responsibility 

of removing financial incentives for these donors. You will have to evaluate the advantages of 

entering these donors into your donor pool. (Ref. 7, 8)

IV. CONTENT OF VARIANCE REQUESTS

We will consider requests for variances to the labeling and physician examination regulations. 

We believe that variances incorporating the following provisions would be acceptable.

A. Blood donors with HH would meet the same suitability requirements as other 

donors (21 CFR 640.3(d)).

B. To collect blood products from a donor with HH more frequently than every eight 

weeks you would:

1. collect blood products from a donor who has presented a physician’s 

prescription (bearing instructions regarding frequency of phlebotomy and 

heamtocrit/hemoglobin limits) for therapeutic phlebotomy for HH; or, 

2. have your physician examine and certify the good health of the donor on 

the day of donation in accordance with 21 CFR 640.3(f) if you do not have 

a prescription on file for the donor’s therapeutic phlebotomy for HH. 

C. You would not charge a fee for phlebotomies performed on any individuals with 

HH, including those who do not meet allogeneic donor suitability requirements at 

the initial or subsequent donations. At the initial donation, you would obtain the 

donor’s written acknowledgement that the donor understands that you are 

providing therapeutic phlebotomy free of charge even if the donor is ineligible as 

an allogeneic blood donor. We note that you are required to maintain health 

history records of donors (21 CFR 606.160(b)(1)), and we would expect this 

health history to include diagnoses of HH.

V. SUBMISSION OF VARIANCE REQUESTS

A. In accordance with 21 CFR 640.120, you must not implement changes at variance 

to the regulations prior to receiving approval from us. 

B. To obtain approval for a variance to 21 CFR 640.3(d) (labeling with the donor’s 

disease) under the provisions of 21 CFR 640.120, you must submit a written 

request to us to omit HH labeling. You should include a statement that HH 

individuals whose blood will be used for transfusion will meet your allogeneic 

donor suitability criteria. You should also include a copy of the donor 

acknowledgement form (informed consent or other written statement), to be 

signed by the donor, that she/he will not be charged a fee for the phlebotomy even 

if found to be ineligible as an allogeneic blood donor.
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C. To obtain approval for a variance to 21 CFR 640.3(f) (physician examination) 

under the provisions of 21 CFR 640.120, you must submit a written request to 

collect blood products from donors with HH more frequently than every 8 weeks 

without examination by a physician at the time of donation. The submission 

should include statements that you are requiring a physician’s prescription for 

therapeutic phlebotomy for HH, and that your physician would examine 

previously diagnosed HH donors without a prescription on the day of donation if 

less than 8 weeks have elapsed since the last donation.

D. You may request these variances concurrently.

E. If you hold a U.S License, you must submit variance requests as major changes 

(prior approval supplements) pursuant to 21 CFR 601.12(b). If you do not hold a 

U.S. License, you are not subject to 21 CFR 601.12, but are still required to obtain 

approval of variance requests before implementing changes at variance with the 

regulations.

F. If you discontinue operating under the terms of the approved variance (e.g., start 

charging a fee for therapeutic phlebotomies for HH donors who do or do not meet 

allogeneic donor suitability criteria), the variance is no longer in effect and you 

must comply with the current regulations. You should notify us of this change in 

writing. If you hold a U.S. License, include this notification in your Annual 

Report.
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VI. REFERENCES

1. Iron Overload and Hereditary Hemochromatosis Study. RFP No. NIH-NHLBI-HC99-19, 

July 12, 1999. http://www.nhlbi.nih.gov/funding/inits/archive/rfp99-19.htm

2. Jeffrey G, Adams PC. Blood from patients with hereditary hemochromatosis-a wasted 

resource? Transfusion 1999;39:549-550.

3. McDonnell SM, Grindon AJ, Preston BL, Barton JC, Edwards CQ, Adams PC. A survey of 

phlebotomy among persons with hemochromatosis. Transfusion 1999;39:651-656. Title 21, 

Code of Federal Regulations, Parts 600-799.

4. Tan L, Khan MK, Hawk III JC. Use of blood therapeutically drawn from hemochromatosis 

patients. Transfusion 1999;39:1018-1026.

5. Nightingale SD, Summary of Advisory Committee Meeting of April 29 and 30, 1999, May 

13, 1999. http://www.hhs.gov/partner/bloodsafety/04-99sum.html

6. Henney JE, Memorandum: Blood Donations by Individuals with Hemochromatosis, August 

10, 1999. http://www.hhs.gov/partner/bloodsafety/JEH8-10.jpg

7. Nightingale S, Advisory Committee on Blood Safety and Availability, Ninth Meeting, 

August 26, 1999. http://www.hhs.gov/partner/bloodsafety/Aug26_99.html

8. Blood Products Advisory Committee, 64th Meeting, September 16, 1999. 

http://www.fda.gov/ohrms/dockets/ac/cber99.htm - Blood Products Advisory Committee