Blood Safety Transcripts

U.S. PUBLIC HEALTH SERVICE
ADVISORY COMMITTEE ON BLOOD
SAFETY AND AVAILABILITY

EIGHTH MEETING

THE RESERVE CAPACITY OF THE NATION'S

BLOOD SUPPLY

Day Two

Friday, April 30, 1999

8:08 a.m.

Holiday Inn Bethesda

8120 Wisconsin Avenue

Bethesda, Maryland 20814

An Overview of Hemochromatosis:

Southern California Permanente

Medical Group 5

Statutory Requirements for Blood Donations

by Individuals with Hemochromatosis:

Ms. Mary Gustafson,

Food and Drug Administration 19

Perspectives on Blood Donation by Individuals

with Hemochromatosis:

American Red Cross 28

Mount Sinai School of Medicine 45

Public Comment 67

Committee Discussion and Recommendations 87

The Potential Therapeutic Benefits of

Blood Substitutes:

Dartmouth College and Biopure, Inc. 160

Food and Drug Administration Oversight of

Blood Substitute Development:

Food and Drug Administration 186

Food and Drug Administration 201

C O N T E N T S (continued)

of the Blood Supply (continued)

Presentations by:

Alliance Pharmaceuticals 220

Baxter Hemoglobin Therapeutics Division 252

Biopure, Inc. 281

University of Toronto and Hemosol, Inc. 310

University of Illinois and Northfield

Laboratories, Inc. 323

Sangart, Inc. 348

Committee Discussion: Old and New Business 359

- - -

DR. CAPLAN: Good morning. As you will recall yesterday, we took an overview of some of the problems facing supply of blood for Americans and the need to preserve access and safety, as we start to think about meeting the challenge of shortage and what to do in that area.

This morning, we are going to look at one particular possible avenue for increase, blood, which is the use of blood from individuals with hemochromatosis, and this subject has been around in the literature a bit. People have been discussing it and talking about it. Despite the Chair's best efforts, there were even outbreaks of discussion about it yesterday, but now is the time to really have the panel reflect upon this and come to understand what some of the pros and cons are here.

Our first presenter is Dr. Vincent Felitti from Southern California Permanente Medical Group, who we asked to give us an overview on hemochromatosis.

DR. FELITTI: Ladies and gentlemen, I thank you for inviting me to describe the clinical picture of hemochromatosis, particularly as it relates to blood donation. The knowledge base from which I will be speaking is as an internist with Kaiser Permanente in San Diego, where we have been screening 50,000 adults for hemochromatosis each year since 1997 and where I personally treat and follow over 300 patients with this disorder.

Hemochromatosis is a disease that most people have never heard of and with which many physicians are still unfamiliar, but it is also recognized now to be the most common, potentially fatal, genetic disorder in the United States.

The essence of the disease is the extra absorption of about 1 milligram a day of iron more than would be absorbed by a person who did not have hemochromatosis.

Once absorbed, iron cannot be excreted by humans. Therefore, given sufficient time over the course of years and decades, excess iron builds up in various tissues causing the serious damage that is the well-known end result of hemochromatosis.

As a result of autopsy studies, biochemical tests, and now genetic analysis, hemochromatosis is now known to be present in 4 per 1,000 Americans. That is to say, there are approximately 1 million Americans who have the full-blown genetic machinery to develop iron overload disease during their lifetimes.

I would like to show a few slides to help fix this in your mind visually and to help understand the relevance of this most common of genetic disorders to the national blood supply.

It will be important for you to remember throughout that hemochromatosis can only be inherited. It cannot be transmitted.

The importance of hemochromatosis to the national blood supply lies in the fact that the goal of hemochromatosis, the goal of treatment of this condition, is to normalize the total body iron load, and the only practical way of accomplish this is by removing blood because of the iron contained in blood and because of the ability of the body to rapidly regenerate blood so long as iron is present.

This is another way of looking at the prevalence data. On average, any physician in the country, no matter what the specialty, knowingly or commonly unknowingly, sees a case of homozygous hemochromatosis, the full-blown genetic disorder, every 2 to 3 weeks.

Many of those cases, fortunately, as pre-symptomatic. Unfortunately, the large number who are symptomatic usually have their illness attributed to some other common disorder, and I would like to show you the way in which hemochromatosis presents, usually masquerading as other more common conditions.

The important thing about hemochromatosis is that it is a totally preventable condition if diagnosed early and if treated early by phlebotomy.

This is essentially the machinery underlying iron absorption, whether it occurs at a normal level or at an abnormal level, as in hemochromatosis. Iron is absorbed from the intestine. It is bound to a carrier protein transferrin, which moves it to blood, to muscle, to enzymes, which moves it into appropriate storage depots, or in the case of hemochromatosis, into excess storage and abnormal organ deposits, and also is responsible for minor loss in menstruation and child birth.

A key point to remember is that in hemochromatosis, there is no biological method of excreting or secreting iron once it gets into the body.

The way this condition presents itself most commonly is as skeletal manifestations, as joint pains, as true arthritis, which can mimic osteoarthritis, seronegative rheumatoid arthritis, or gout or pseudo-gout, even leading to the necessary for joint replacement. A surprising number of people with hemochromatosis have joint replacement at an early age.

Gastrointestinal manifestations of this condition are enlarged liver, abdominal pains, which appear to be not associated with stretching the liver capsule, diarrhea, cirrhosis, and primary liver cancer. All of these obviously have other causes and, in general, people with hemochromatosis are considered to have other causes, much to their misfortune.

There are cardiac presentations of hemochromatosis involving heart enlargement, slow heart rate, rhythm disturbances and congestive heart failure. The hematologic manifestation of hemochromatosis is anemia. We are certainly used to the concept of iron deficiency in anemia. That occurs because there is an inadequacy of a key building block for hemoglobin. At the other extreme, anemia occurs from an excess of iron because of the toxic suppressive effect that iron excess has on bone marrow function.

There are neuropsychiatric manifestations of iron overload of hemochromatosis. They include depression, dementia, profound fatigue, peripheral neuropathy, including deafness and tinnitus.

This is a photograph of two sections of a brain that have been stained with iron. The amount of iron in this brain is really quite extraordinary.

There are skin changes in hemochromatosis, bronzing of the skin, loss of bodily hair, and a rare condition called porphyria cutanea tarda.

The endocrine manifestations are numerous. Diabetes is a well-recognized complication and a common one of hemochromatosis. Sterility, infertility, testicular atrophy, and impotence are all the end result either of pituitary damage or of ovarian or testicular damage. Premature menopause is fairly common, and hypothyroidism is common.

So this is really an extraordinary array of presentations of this one condition. Diagnosis of the clinical case is precisely what one does not want to accomplish because it excludes the possibility of pre-symptomatic treatment.

Certainly, any internist is proud typically to make a diagnosis of clinical hemochromatosis. It is far better as a result of population screening to find pre-symptomatic cases.

I think an appropriate analogy would be to the pride one might have in diagnosing a case of tetanus versus the real social accomplishment that one might have by immunizing a population with tetanus toxoid.

So the goal in hemochromatosis, as in hypertension, is to find and treat the pre-symptomatic condition. Treatment of this pre-symptomatic condition involves the removal of blood repetitively over a lifetime, and that is what makes hemochromatosis a totally preventable condition, if it is diagnosed early and appropriately treated.

Treatment of hemochromatosis typically consists of removing 1 pint of blood per week for whatever number of months, sometimes beyond a year, that it takes to normalize the total body iron load. After that is accomplished, people subsequently must have blood withdrawn several times a year for the remainder of their lives in order to keep iron levels normal.

At present, this blood is drawn and discarded, even though no knowledgeable person believes that it is intrinsically dangerous to transfuse. Indeed, it has been transfused in Sweden for approximately 30 years without a problem, and in Canada for almost a decade.

I think in addition, anyone familiar with hemochromatosis patients will quickly realize that a large number of them have been super donors, having donated 40, 50, 80 pints of blood over the course of a lifetime to the Red Cross, but instantly becoming ineligible for further donation once the diagnosis is made, the diagnosis that explains their extraordinary ability to be super donors.

Lastly, because of the ability of people with hemochromatosis to regenerate blood so rapidly, these people are less likely than most ever to have needed a transfusion, and therefore, they are less likely to have previously contracted any transfusion-related disease that they might pass on.

Their need to recurrently donate blood, coupled with the observation that repeat donors are generally believed to be safer than one-time donors, makes a forceful argument that the United States should update its procedures for screening blood donors. A well-intentioned rule of thumb that excluded donors who might benefit from donation might well have served a good purpose in another area, but it is embarrassingly anachronistic in a time of advanced laboratory technology.

Because of all these factors, a situation exists that is truly a win-win situation, both for the Nation and for individuals, the 1 million Americans who carry two sets of abnormal genes for this condition, the Nation needs more pure blood. Approximately 1 million repeat donors need to give blood to prevent iron overload. That blood is acknowledged by all parties, and by the experience of several nations to be intrinsically safe. So a wonderful solution is at hand if you allow us to discard a much outdated rule of thumb that is inhibiting progress.

Is there anything that I can make more clear?

DR. PENNER: What is the incidence of the phenotype, the figure that you would have?

DR. FELITTI: The question was: What is the incidence of the phenotype?

DR. PENNER: Not the genotype.

DR. FELITTI: Correct.

The phenotype has a population prevalence for the most common mutation of approximately 1 in 8. You raise a very implementation question, namely how many of these people who are genetically homozygous will go on to develop the full-blown disease. That totally is a function of time.

I can tell you, we have looked at our own population of homozygotes, people with the full-blown disorder, and in those who were over 65 years of age, that is to say had adequate time to absorb iron if they were going to in their life, 90 percent of them had either signs or symptoms that logically were attributable to hemochromatosis.

Whatever the exact number is, most people feel that a clear majority of people who are homozygous for hemochromatosis will develop the phenotype, given sufficient time.

DR. PENNER: So that is the 1 out of 200, plus or minus?

DR. FELITTI: That is correct.

DR. CAPLAN: Other questions?

DR. HOOTS: I presume you are talking about, in terms of monitoring them phenotypically, you are following their ferritins. Is that correct, primarily, or are you using actually spec scans and other sophisticated means to follow?

DR. FELITTI: No. We follow their iron levels typically by ferritin.

DR. HOOTS: I know in secondary hemosiderosis in hematologic diseases like thalassemia that there is pretty good data that it correlates not 1 to 1, by any means.

So I guess what you are saying is it really should never get to the point where you would even have to do more sophisticated monitoring because, once you recognize the ferritin over 1,000 and you do the genotypes, then you would obviously preempt any of that morbidity, anyway.

DR. FELITTI: I think the basic point that you are raising, if I follow you correctly, is that ferritin is handy, but a less than 100-percent perfect measure of iron levels.

DR. HOOTS: Correct.

DR. FELITTI: That is absolutely correct.

So what we do initially to track iron levels is quantitative phlebotomy; in other words, keep track of the amount of weekly removal of blood to bring a person from their starting hemoglobin typically to the borderlines of anemia. Usually, that correlates well with ferritin, but as you are pointing out, it does not correlate perfectly with ferritin.

DR. CAPLAN: Did you have one more, John?

DR. PENNER: Yes.

Do you routinely do the genetic typing on your patients?

DR. FELITTI: We do. We do largely because it is available through the courtesy of Dr. Ernest Boitler at Squibbs Clinic at no charge.

Before the genetic test was available, it was certainly possible to diagnose and treat and follow people quite satisfactorily.

I think the main advantage of genetic typing is that it settles the argument with dubious physicians as to whether their patients have hemochromatosis or not.

DR. PENNER: Do you think any of the heterozygotes represent a problem?

DR. FELITTI: Oh, yes. There is no question about that. We have people who are currently genetically normal who are significantly iron overloaded. Presumably, there is another as-yet-to-be-discovered gene or more, and we certainly have heterozygotes who are significantly overloaded.

DR. CAPLAN: Let's do Jay, and then we have got to move on.

DR. EPSTEIN: Dr. Felitti, thank you for the very nice overview.

Since you are involved in surveillance, can you tell us what percent of persons at the time of their first diagnosis are discovered to be regular blood donors, and can you also comment whether in your opinion physicians are directing people to go to blood banks to have their phlebotomies, other than prescriptions for therapeutic phlebotomy?

DR. FELITTI: Yes. Let me answer the last half first. Yes, I believe that is true. I believe that there are physicians who direct patients to go to blood banks to donate blood, telling them not to mention that they have hemochromatosis. Yes, there is no question that that happens.

How often it happens, I do not know, but certainly often enough that I have seen it without any great search.

In terms of the first part of your question, could you restate that for me, please?

DR. EPSTEIN: Yes. At the time of their diagnosis, what percent of hemochromatosis patients are discovered to be already regular blood donors?

DR. FELITTI: I cannot give you a precise fix on that. I am impressed, however, from speaking with hemochromatosis patients that a surprisingly large number have been so-called super donors.

DR. CAPLAN: All right. We have got a lot of presentations. I want to thank you for that excellent overview.

I am going to ask Mary Gustafson from FDA to come and tell us a bit about the statutory requirements that influence the availability of blood from persons with hemochromatosis.

MS. GUSTAFSON: Thank you.

I will start with a couple of items about the agenda. I was given an honorary title of "Doctor," in which I appreciate, but I do not actually have one.

Also, the topic is entitled "Statutory Requirements for Blood Donations by Individuals with Hemochromatosis." The statutes governing blood and blood components, primarily the Food, Drug and Cosmetic Act and the Public Health Service Act, do not specifically address these issues. The laws provide broad governing principles about product quality and include prohibitions against adulteration of products and misbranding.

The Federal agencies that implement the laws passed by Congress are given the authority to interpret the laws, and they do so by promulgating regulations that are published in the Code of Federal Regulations.

FDA's regulations are codified in Title 21 of the Code of Federal Regulations, and what is published as a Final Rule, the regulation has the effect of the law under which it was written.

The next overhead.

It is in the Code of Federal Regulations that we find a rule that affects the collection and use of blood from donors with hemochromatosis. The regulation is found at 21 CFR 640.3(d). This section of the regulation addresses the suitability of donors for whole blood donation.

The specific citation pertains to therapeutic bleedings and reads: "Blood withdrawn in order to promote the health of a donor, otherwise qualified under the provisions of this section, shall not be used as a source of whole blood unless the container label conspicuously indicates the donor's disease that necessitated withdrawal of blood."

The intent of some of the older regulations is not very clear in our history, but I think the regulation was meant to be informative and not prohibitory. However, use of such labeled blood has fallen into disfavor over the past years.

From anecdotal reports, this appears to be related to concerns over blood safety in general. The consumer's greater attention to the blood they receive, that is, persons being transfused actually reading the blood container label as the blood is infused and the transfusing blood establishments implementing notification to physicians of patients receiving blood, is that the unit of blood has an additional therapeutic bleeding label.

Given the choice of transfusing a special-labeled unit or a unit without such labeling, the physicians would often choose the unit without the therapeutic bleeding designation.

Although this regulation is the only one directly related to today's topic, I would like to clarify another blood labeling requirement and its relationship to donations from persons with hemochromatosis.

The blood labeling regulations in 21 CFR 606.121 include provisions for labeling blood for transfusion according to the donor status; that is, whether the blood was donated from a volunteer donor or a paid donor.

The regulation was promulgated in the 1970's to reduce the risk of hepatitis B transmission by transfusable blood components. The regulations are very specific in the interpretation of who is a paid donor and who is a volunteer donor.

A paid donor is a person who receives monetary payment for a blood donation. A volunteer donor is a person who does not receive monetary payment for a blood donation.

The regulation continues by noting that benefits, such as time off from work, membership in blood assurance programs, and cancellation of non-replacement fees that are not readily convertible to cash do not constitute monetary payment within the meaning of this paragraph.

The preamble to the 1978 Final Rule contains more examples of benefits that do not constitute monetary payment for the purpose of labeling a donation that is from a paid donor. These include a large amount of time off from work, additional vacation time, rewards generally used as a motivation for donations such as lotteries, giveaways, a chance interest in a prize with significant dollar value, or non-monetary rewards associated with product promotion, reduction or cancellation of hospital charges that are unrelated to the transfusion and the cancellation of refund of non-replacement fees in blood assurance insurance benefits.

In essence, the only instances in which blood must be labeled as having come from a paid donor is when the donor receives direct monetary compensation or a gift that is readily converted to cash.

Under this rule, the donation from a person with hemochromatosis, even if there are benefits to the person associated with the use of the blood for transfusion versus bleeding the donor for strictly therapeutic purposes, would not require a "paid donor" label.

Now having provided a pretty black-and-white description of "paid" versus "volunteer," does that mean that FDA is not interested in the gray areas of incentives and what constitutes a good motivator to encourage donations from safe donors and what constitutes an undue enticement for the donation from an unsafe donor? The answer is no. We are very interested in this issue.

In the instance of hemochromatosis donors, the issue is not whether the donor will provide false information about having hemochromatosis, but whether being able to donate a unit of blood for transfusion as opposed to having to pay for a therapeutic phlebotomy might provide an undue incentive to not be candid in the donor interview about risk factors unrelated to hemochromatosis.

This discussion is not limited to hemochromatosis. Several years ago, we had the same discussion about autologous donors, do they truly meet the definition of a volunteer donor.

As noted yesterday in Miriam Sullivan's talk, this has resulted in, I think she said, less than 1 percent of all autologous bleeds being crossed over for general donation.

I think this all ties back into the discussions yesterday, particularly Dr. Williams' report on incentives for donation. We were most pleased with the inclusion of the incentive issue in the REDS survey and in terms of being able to collect data on a multi-center basis, and we will be most interested in seeing the final report of the 1998 data.

Are there questions?

DR. NIGHTINGALE: Captain Rutherford?

CAPTAIN RUTHERFORD: Mary, I have two questions. From your discussion, would it be safe to say that the FDA would not disapprove of the use of hemochromatosis donors as a raw product source for hemoglobin and hemoglobin-based oxygen carriers, provided they are biomarker-negative and meet the many physicals?

MS. GUSTAFSON: Where we have been on source material for any human blood-derived product is that the source material must meet the requirements in the regulations for transfusion or source material, and since we have not prohibited the use of blood from hemochromatosis donors, then meeting other donor suitability requirements, it would be suitable source material.

CAPTAIN RUTHERFORD: The second question is: Could they be collected more often or more frequently than the 56 days as a raw source provider, provided the physician sets the minimum hemoglobin levels?

MS. GUSTAFSON: We do have a section in the regulations that allows for collection more frequently if a physician examines the donor and finds that the donor is suitable for more frequent collection.

DR. NIGHTINGALE: Any other questions from the panel?

[No response.]

DR. NIGHTINGALE: If not, Dr. Gustafson--"doctor"--Captain Gustafson, I thank you very much, and I apologize for mislabeling an excellent talk.

MS. GUSTAFSON: Misbranding?

[Laughter.]

DR. NIGHTINGALE: Misbranding an excellent talk.

We will next have two perspectives. The first will be by Dr. Al Grindon and the second by Dr. Victor Herbert. They are scheduled for 30 minutes on the program because we anticipate substantial public comment.

I wish to give the two perspective speakers as much time as possible without impinging on the public comment. So could I have a show of hands, please, of the people in the audience who wish to give public comment?

I see four. If there are only four in the room, then I would hope that Dr. Grindon and Dr. Herbert could take the time that they need to express their perspectives, leaving time for both the comment and questions from the Advisory Committee. So we will play the time by ear, and we thank you all for your interest.

Dr. Grindon?

DR. GRINDON: Thank you very much. I appreciate the opportunity to visit with this group today.

I am employed by the Red Cross and on the faculty at Emory University, but I am here speaking as an individual and do not represent either of those groups.

I would like to spend a few minutes today addressing three questions: If patients with hemochromatosis were to be blood donors, how many units would be available? The second question, why is blood from patients with hemochromatosis not used today? And the third, can such patients be blood donors tomorrow?

I would like to begin with the data that you have already seen from Dr. Felitti that these are not Hispanic Caucasians. If you add Hispanics, that is another 30,000, and you end up at 5 percent of this group, a million. If it is .4 percent of a larger number, it still is a million, and that is about the same number that you have heard earlier today.

Note that these are homozygotes and not necessarily patients needing treatment throughout their course. So the question from the treatment of these folks is how much blood might be available.

I would like to share with you data from two publications that are in the press and will be published in June of 1999 in the Journal of Transfusion, and I will be going through a little bit of the data from each of these presentations.

The first one is McDonnell and coworkers, and these folks did an international convenience sample survey. What they did was to contact every patient they could find by whatever means they could find, including contacting patients directly, contacting organizations who might be able to have patient identity, contacting blood centers, and contacting practitioners. In each case, each of these groups would then contact the patient. They also used the Internet toll-free numbers, newsletters and other media sources. So they sent this survey to anyone expressing interest in having one.

This was an international survey. 2,300 of the 80 percent of respondents were from this country, and of those, 62 percent were men and 99 percent were white.

The data that I wanted to focus on, though, was these two numbers. The number of units withdrawn a month had a mean of about 2.6, and the maintenance, which is perhaps more germane to our discussion today, was .5 units per month for maintenance of the respondents in this survey. That is, of course, 6 units per year.

The other paper that I would like to discuss briefly was data from Barton and coworkers. This represents a group of patients who were treated by Dr. Barton's group in Alabama. They used probands as the subjects of this study rather than all their patients with hemochromatosis because they felt that probands were usually more severe than the relatives who might be subsequently diagnosed and, secondly, because probands may represent the general population more than relatives would because they are unselected. So these are probands.

They were diagnosed during routine medical care, and all probands treated by this group were included.

They were compared, then, to volunteer donors from the same part of the country. The testing throughout the course of these years was not identical, but reasonably comparable, and the eligibility also was comparable using the standards of the AABB. These standards were applied retrospectively.

Dr. Barton used what I hope many who are experts in treating this disease. He used what I think are standard approaches to the treatment of these patients and after induction sought to provide phlebotomy to keep the levels of less than 50 nanograms per Ml.

What is of interest here is that this produced a little more than 1 unit a year during the first year, and this is what is published or what will be published in June, but also with smaller numbers for subsequent years in Dr. Barton's experience.

The results, however, go on, and I would like to focus on two numbers here, the 59 percent and the 88 percent.

For the volunteer donors, the Red Cross donors, of all those who walked in to present, 88 percent were units that ended up being available for sending out to hospitals.

For the patient group, 59 percent during maintenance turned out to have units that would have gone through our system and been available for distribution. The number was a little lower during inducement, 44 percent, primarily because of the lower hemoglobin levels in these patients during the induction process.

So now we can get to a conclusion and say how many units would be available annually if you used phlebotomy during maintenance and used those units. If you have 50 percent who need treatment--and let me spend just a minute talking about that number--I am thinking about this not from Dr. Felitti's statement that 99 percent of people at age 65, or 90 percent, whatever it was, are going eventually to develop signs and symptoms and should be phlebotomized, but rather from the perspective of people being eligible as blood donors.

You begin by saying that three-quarters of the population are going to be greater than 17 years old. So it is not 100 percent that are eligible as blood donors, but only three-quarters of those.

Secondly, at any given time, women are less likely to be symptomatic. The obvious reason would be because of premenopausal blood loss or child-bearing. It is not quite that simple, but that is a reasonable kind of a statement.

There are some penetrants issues. The penetrants may not be 100 percent, and I think also the larger numbers that we hear assume perfect screening systems. Really, we may not be able to identify this 1 million people, at least right away.

So, when you go through this 50 percent, you start with 500,000. If you draw 6 units a year, you end up with 3 million units.

Dr. McDonnell's study did not address donor eligibility or unit suitability. So we have the assumption, which, of course, we recognize is not correct, that 100 percent would be eligible as donors and 100 percent of these units would be suitable. That is just unstated in the survey paper.

If you are drawing a little more than one a year and you start with 500,000 units, but only 60 percent of those end up being acceptable by our current techniques, then you end up with 300,000.

So the point of this is that it is not really clear how many units would be available were we to use blood from patients with hemochromatosis as blood donors. There is a log difference in these two numbers.

Could these numbers be off? Yes. Could it be more than 3 million? Certainly. I think that Dr. Felitti has told you that some heterozygotes become symptomatic, and if you include heterozygotes, you have a larger number.

There are also those who might be interested in having blood drawn from them because of concern about the so-called iron lesion and prevention of heart disease.

Understand also that these numbers deal only with maintenance, and if one were to address the use of units of blood obtained during the induction or de-ironing phase, you would have more units available.

Could the number be less than 300,000? Yes, I think so. I think that the biggest issue here is the issue of recognition of these patients with screening.

I might say also that there is a regulatory constraint. Some of these donors are going to need phlebotomy more often, even in maintenance, than several times a year, and might be constrained because of the ruling of the current CFR rule that Ms. Gustafson discussed that donors need to wait 56 days, unless, of course, they are seen personally by a physician on the day of donation.

So that is the number of units of blood that are available, and I think we do not know how many units there.

The next question is: Why is blood from these patients not used today? I have these three issues that I would like to address. The first of them, I think Ms. Gustafson had addressed really quite handsomely.

The first bullet is the CFR regulation. The second bullet, she discussed, and the third bullet is from the standards of the American Association of Blood Banks. Because of this confusion, the AABB has said this blood really should not be used.

The second is a financial motivation. These are data taken from the survey conducted by McDonnell and coworkers and show that the charge--not the cost now, but the charge--was ranging from $90 to $52, depending upon the place the patient went to get phlebotomy.

Most of those in the survey had some sort of insurance, and 39 percent had no out-of-pocket cost, but the mean out-of-pocket cost for the whole group was $45. So there really was for many of these folks a significant out-of-pocket cost.

As you have heard from Ms. Gustafson this morning, the FDA has been concerned about this. The FDA and the NHLBI convened a workshop in September of 1996 at which time Dr. Zoon, speaking for the agency, said what Ms. Gustafson has just said, that this is an area of great concern to the agency.

The AABB in a bulletin regarding what donor incentives would be unacceptable, dated 1994, and reaffirmed subsequently has said that an incentive is unacceptable if it is sufficient to entice someone who, acting solely on the basis of altruism, would not give blood.

I think the feeling of the people that I have talked to is that a $45 out-of-pocket cost is felt generally to be such an enticement. So there is this financial concern.

The third area I would like to discuss briefly is why this blood is not used. It is non-financial motivation. Patients with hemochromatosis are patients, and they are giving as a patient and not primarily as an altruistic donor.

Again, as Ms. Gustafson has said, almost as if she knew what I was going to say, she discussed the issue of autologous donations, and I think this is a helpful analogy to consider.

The issue is if an autologous donor meets all of our historical screening criteria and passes successfully all the blood tests that we do, should that blood be used for other patients, if not used by the autologous donor patient himself. That is to say, should that blood, if unused by the patient, be crossed over into the general population.

So do we do that? The answer is no, we do not. Why not? Well, there is an increased market frequency in donors who pass our regular screening criteria. There is an increased marker frequency in the autologous population.

In order to determine this, you have to do this very carefully. You have to match first-time donors with first-time donors. You have to match zip codes. You have to match age and sex. When you do all of that work very carefully, then you find that there still is about a three-times-higher marker frequency of anti-HBC, anti-core. This was before hepatitis C testing was available, much of this work.

As a result of this marker frequency, the assumption, which may be erroneous, is that there is a higher risk in marker-negative donors from the same population, and, therefore, the AABB standards in 1997 reflecting what has become common practice said that this blood should be used only for autologous transfusion.

I would like to move on to the third question, which is can these factors change. Well, yes, clearly, the CFR can be changed, and the labeling requirement removed. I would like to note here, as Ms. Gustafson noted, that the labeling requirement is not by itself prohibitive. Despite the label, that blood can be used. It is just that it adds such concern on the part from the blood center to the transfusion service, transfusion service to the clinician, and clinician to the patient, that it became unwieldy.

If you change the labeling requirement, though, I think there are concerns that need to be addressed, and that is the potential for the loss of patient autonomy, the right to know, the issues off informed consent. It is not that we feel that this blood intrinsically is any less safe, but that patients really have a right to know that this is blood from the patient rather than from a volunteer donor, at least there is that risk of losing that.

The second is the financial motivation. Clearly, we can change--"we," not me, but this group can consider reimbursement patterns and work to see those changed.

Some of the discussion yesterday that this group had was focussed in that area. So those things, i think, can be changed.

The non-financial motivation is a little more difficult. How do we demonstrate that patients with hemochromatosis are different than patients giving for themselves, the so-called autologous donors? I think because of the autologous issues that the blood banking community has gone through, it may be important to do such a demonstration.

Does it make any difference that we now have vastly improved testing, the NAP technology, for instance, for known agents that makes the risk of known transfusion transmitted disease very, very, very small?

What if we had viral inactivation technology for cellular components? That is not available today, but if it were available 2, 3, 5 years from now, would that make a difference? I think it would. If such technology were available, then paid donors even outside Rochester, Minnesota, and Iowa might be acceptable for blood donation generally.

Let me conclude, then, by stating that the number of units available, at least from maintenance of patients with hemochromatosis, is unclear. My feeling is that it may be far fewer than the numbers that have been discussed.

My personal feeling is that the 300,000 number may be closer than the 3 million number per year, and I say that to this group because I think the numbers of units is worth considering as you look at potential shortages of blood down the road.

The common constraints are fixable, with some difficulty, but they can be fixed. The non-altruistic motivation, if this is felt by this group or regulatory agencies to be a concern, that is going to be more difficult to address. It may not be a concern, but if it is, that is more difficult to address.

Finally, these concerns may be much less important and perhaps irrelevant with viral inactivation of cellular components.

Thank you. I would be happy to answer questions.

DR. NIGHTINGALE: Thank you very much, Dr. Grindon.

In the interest of time and making sure that everybody understands the ground rules in advance, Dr. Grindon, I would like to thank for keeping within his allotted time, which was 20 minutes.

I propose 5 minutes of questioning from the panel for Dr. Grindon, and propose that Dr. Herbert also have 20 minutes and 5 minutes for questioning. That would give each of the four public speakers 5 minutes to speak, plus some time for the panel to ask them questions, so we could have our break at 10:00 and the committee could have adequate discussion after that time.

So are there any questions from the panel?

Dr. Epstein?

DR. EPSTEIN: Are you aware of any actual studies on marker rates or window-period risks, that is to say, seroconversion rates, in this population?

DR. GRINDON: No, particularly if you consider this from the perspective that Dr. Busch spoke yesterday. Clearly, we have marker rates in the work of Dr. Barton, but that is not answering your question, which is what is the incidence and not the current prevalence, and the answer is no, we do not have such data.

Yes. Dr. Chamberland?

DR. CHAMBERLAND: I was just wondering if you could comment perhaps from the McDonnell paper on a question that Jay Epstein had asked earlier.

In that survey, I believe respondents were asked about previous history of blood donation?

DR. GRINDON: Yes. I am sorry. I did not write that down. I have the paper, and I can get it for you.

I do know in Dr. Barton's study, it was 29 percent. So a substantial number had been blood donors previously.

DR. CHAMBERLAND: I think my recall from the McDonnell paper was that it was around a third or a little bit over, about 35, 36 percent.

DR. GRINDON: Which is the same kind of range, yes.

DR. CHAMBERLAND: So in the same range?

DR. GRINDON: Right.

DR. NIGHTINGALE: Are there any other questions?

[No response.]

DR. NIGHTINGALE: If not, thank you very, very much, Dr. Grindon.

Dr. Herbert?

DR. HERBERT: Good morning.

I apologize for being physically handicapped, but no good deed goes understand punished, and when the Gulf War broke out, I rejoined my paracommando Green Beret unit, and my first Gulf War jump, which was my 153rd jump in 4 wars, resulted in damaging my spinal cord. So no good deed goes unpunished, and I am temporarily crippled.

I would like you all to pick up the handout I left for you, which is our two-paged paper in last November's issue of the American Journal of Hematology, because what I am going to do in my allotted time is elaborate on it, including material presented this morning.

I will start first with Al Grindon's excellent presentation in which he stated indirectly that his organization was the culprit in creating the blood shortages twice a year and in creating not using good hemochromatosis blood.

You will recall he told us that his organization mandated in 1996, and I quote him, "This blood should not be used." I had spoken with Mort Spevak, and you will notice on my handout the first full paragraph on the full page of the written document that Mort Spevak, after pointing out that this hemochromatosis blood would solve all the problems in blood banking, both problems of contamination and problems of availability. What he did not say in that article when I asked him, "Mort, so why don't you use hemochromatosis blood at our blood bank?," he said, "Look, Victor, if I have one disaffected technician, all he has to do is call the AABB and tell them that I used hemochromatosis blood, and they will withdraw my blood bank approval by the AABB and I will be out of business. That is why I cannot do it." So the AABB is clearly the culprit in this matter.

As to the allegation that the Red Cross and the AABB will not use hemochromatosis blood, that is a lie. They use hemochromatosis blood all the time, and why do they use it? Because they do not know it is hemochromatosis blood, nor does the donor, because there are years of iron overload from hemochromatosis before there is any disease from it. So the donor does not know it, and the percentage of Americans who are heterozygous is 12 percent, which means about 12 percent of blood donors have at least 10 years of giving blood before they have any symptoms of iron overload, such as diabetes or liver disease or cardiac arrhythmias, all of which would preclude their giving blood anyway in the first place. The percentages vary according to ethnic groups in the United States.

For example, right here in Washington, D.C., Victor Guardia published in the New England Journal of Medicine, almost a decade ago, that 32 percent of all African Americans are heterozygous for hemochromatosis, and at least 1 in 100 African Americans are homozygous. That figure is now 1 in 80 who are homozygous for hemochromatosis.

There was a blood bank study by the Utah Group published in the New England Journal of Medicine in 1988 in which they took Salt Lake City blood donors, over 20,000 of them, and found that those blood donors who are given blood, 1 in 300 of that highly inbred Mormon population was homozygous. They had already given blood, and the blood banks did not know it and they used it, and 1 in 12 was heterozygous for hemochromatosis. That was published in 1988 in the New England Journal of Medicine.

We know that the frequency is much higher among Irishmen in Dublin, as Roberta Crawford's handout tells you and as you can read yourself in the 1999 issue of the Journal of Blood Cells, Molecules and Disease. A group in Dublin found that the frequency of homozygous hemochromatosis in Dublin is 1 in 100, and the frequency of heterozygous hemochromatosis is 1 in 5. So 1 in 5 Irishmen are heterozygous for hemochromatosis. They are all given blood until they get overt disease.

Their blood banks do not know it. Why? Because the blood banks do not bother to test iron status. They test hemoglobin because they lack the knowledge from the literature to know that you can have anemia from iron overload, just as you can have anemia from iron deficiency. So they turn these patients away who have low hemoglobins, and they tell them you are iron-deficient because they do not know, if you are iron-overloaded, you can be anemic from the iron deposited in your bone marrow. When you are repeatedly phlebotomized, your anemia goes away because the iron in your bone marrow, which is crushing your baby bone marrow cells, is gone. So now you make blood normally. So the blood banks are just kidding themselves.

After yesterday's session, Dr. Ronald Gilcher, who was the last speaker yesterday morning, came up to me, and he said, "Just between us."

[Laughter.]

DR. HERBERT: I said, "Is it all right if I repeat this tomorrow morning?," and he said, "Yes." He said, "Just between us," and I repeat he authorized me to tell you this morning.

We at my Oklahoma Blood Institute send our blood-banking vans all over our area, and we tell people, "Come, give a unit of blood. We will examine your blood for any disease that we might pick up in there, any viremia, hepatitis A, B, or C, iron deficiency, iron overload. Just give us a unit of your blood, and we will give you all of this knowledge in exchange and tell you if you have got some disease that we picked up and how to get it treated, how to get it promptly treated."

He tells me that by doing this, he never has a blood shortage. He uses the hemochromatosis blood, and those people then become regular donors because he tells them they have got iron overload and they have got to give blood regularly because that is the treatment.

You have got to get fixed in your mind the difference between a genotype and a phenotype. A phenotype is a person with iron overload disease. A genotype is a person who has a gene that predisposes to a disease. To have a genotype is not a disease. It is not an abnormality in the body. It is a warped gene which may or may not ever be expressed.

Fifteen percent of patients with genotypic hemochromatosis never express it as disease. They never get iron overload because we also have anti-hemochromatosis genes, which block iron absorption. If you are such a person, your gene for iron overload cannot be expressed.

Also, you can express a genotype where a person is just hemochromatosis into the disease. Why? Giving him iron, which blood banks, AABB blood banks, recommend to all patients who are turned away for a low hemoglobin, with the simplistic thinking that a low hemoglobin means low iron, means you should take iron, which is pure nonsense.

So I would like to go on with a few more notes, and then I will quit. If you read the title of our article, you will see it is a triple hematologic nightmare, "Under-diagnosing and Not Treating the Most Common U.S. Genetic Disorder: Iron Overload," and discarding each year tons of their good donor blood, creating artificial donor blood shortages in each of the past 30 years.

As Dr. Gilcher told me and allowed me to pass on to you today, that is not a problem for Oklahoma City because he does not let it become a problem for them.

I further wanted to draw to your attention the importance of using this blood and the importance of all blood banks starting to add to their blood testing, simply transferrin saturation. By taking a low hemoglobin and saying that is high in deficiency, that is nonsense and it is dangerous. You also must determine transferrin saturation. If it is over 45 percent, as it will be in 12 percent of your donors, you have got a patient with probable heterozygous hemochromatosis.

So you then go back and you get the serum ferritin, and if that is over 200, you have got a patient with hemochromatosis who needs phlebotomy regularly. You should phlebotomize him regularly for his and your benefit.

Thank you.

DR. NIGHTINGALE: Dr. Herbert, thank you very much, and I would specifically like to thank you in addition for your presentation, for keeping well within your time limit. This is of a great relief to the Acting Chair.

Are there questions for Dr. Herbert?

Dr. Gilcher, of course, gets to speak first.

DR. GILCHER: With all due respect to Dr. Herbert for whom I have a lot of admiration for over 30 years, I did say it a little bit differently, and I think I need to tell you what I did say to Dr. Herbert.

[Laughter.]

DR. GILCHER: What I told him was that in our community, we made the decision to remove the phlebotomy charge. So this is now done as a community service benefit. Therefore, there is no potential for secondary gain.

We did that over a year ago with the idea that we could move forward with the concept of utilizing these donors, but currently, we do not. I personally believe that these donors could be used, but that there do need to be changes made. So we have made a first step forward.

Dr. Grindon, if I can discuss what you and I talked about, when you think you have a good idea, what you usually find out is that somebody else thought about it first. So I think Dr. Grindon deserves that credit because he told me that he has actually done this about 7 or 8 years ago in his community, and that is remove the phlebotomy charge and made it a community service benefit.

So I think that what we have heard this morning has a lot of validity, and I think this is an issue that should be re-looked at, at this point in time, but certainly one of the steps I believe that would be necessary would be to remove the potential secondary gain that the patient or the person with hemochromatosis could get by getting "no charge," or that is elimination of the charge.

DR. NIGHTINGALE: Dr. Hoots?

DR. HOOTS: Just a question, Dr. Herbert, in terms of clarification or perhaps any of the other blood bankers who are here.

I presume in the screening, a routine hemoglobin is being done, not a CBC. Is that correct?

DR. HERBERT: Excuse me. Are you asking me?

DR. HOOTS: Yes, if you want to answer it, or if you would like to defer to somebody.

DR. HERBERT: All I can speak of in blood bank experience is our own blood bank experience.

DR. NIGHTINGALE: Could we ask Dr. AuBuchon or Dr. Davey to comment?

DR. DAVEY: Yes. It is either a routine hematocrit or a routine hemoglobin.

DR. HOOTS: The reason I am asking the question is just from a pure hematologic point of view, and the last thing I want to do is propose other things for blood banks to do, I think, under this aegis.

I was asking mainly in the case that if it were a CBC, rather than putting the blood bank in the unenviable position of kind of making diagnostic demands, that one could at least use an MCV as perhaps a screen, but since you do not have one, you can do that.

I think maybe one of the things that we could suggest, and maybe it is already routine, is if it is the practice to make therapeutic recommendations based on a low hemoglobin, which I would hope would not be true, that that not be done and that patients who are diagnosed with anemia based on one hemoglobin be recommended to be seen by their primary physician for further workup.

DR. AuBUCHON: In all of the blood centers that I have worked in, all the blood collection facilities, it has been always the recommendation that the patients see their physician for continued anemia and that a direct recommendation for therapy is not made by the nurse or other individual who is performing the hemoglobin, although I would note that in the population in general, the prevalence of iron deficiency anemia far, far outweighs the prevalence of anemia due to iron overload.

DR. HERBERT: But the number of patients with iron overload is twice the number of patients with iron deficiency, and those with iron deficiency are primarily infants, adolescents, and fertile females.

DR. NIGHTINGALE: Dr. Epstein?

DR. EPSTEIN: Yes. Dr. Herbert, I have a question for you. You have very clearly educated us that many of our donors do have hemochromatosis. They just do not know it and their doctors do not know, and we use the blood all the time and that is certainly true.

I am struck by the fact that when that happens, without anyone knowing it, it is an entirely different circumstance than whether it would happen knowingly. It troubles me that you seem not to focus on the issue of whether there is an undue incentive when the donor knows that he or she has hemochromatosis that the future health of the individual depends on phlebotomy and then is faced with a more complex choice when asked about behavioral risk.

I put this in the consent that, certainly, you could argue that the risk on the whole would be no greater than in the general population and, therefore, relatively low, but the problem is that in the arena of blood safety, we deal with extraordinarily low risks and an effort to eliminate them. I think it is the possible occurrence of a person that knows they have a need for phlebotomy and also knows that they have a risk factor and the is asked to be a truthful historian. I find it simply unhelpful to comment that it occurs unknowingly when the situation of whether it would occur knowingly is quite different.

So could you comment on the issue of knowing donation?

DR. HERBERT: Sure.

DR. EPSTEIN: How does life change after the donor knows?

DR. HERBERT: First of all, only 1 in 100 donors knows, and that 1 in 100 donors, who know, have all been told they have hemochromatosis by their primary care physician because they have started to develop symptoms of diabetes or cirrhosis or cardiac arrhythmias or sterility. That is how they may know, but that is only 1 out of 100 donors, because the vast majority of the donors or the people who would be donors who know, know because they have already been diagnosed as having diabetes, and the doctor was one of the rare physicians who did a transferrin saturation, as we require at Mount Sinai in every patient accessed to our diabetes clinic, but outside of Mount Sinai, I would guess that no patient knows he or she has hemochromatosis until they have severe diabetes, cardiac arrhythmias, et cetera, which would preclude them from being donors anyway.

So your question is a hypothetical, but unreal one.

DR. NIGHTINGALE: Dr. Epstein, for a follow-up?

DR. EPSTEIN: The world is going to change if there is mass screening for the genetic disorder.

DR. HERBERT: Is that bad?

DR. EPSTEIN: No, no. I think that is very good for public health, but we also have to consider the implications for the blood supply, and I do not think you have answered my question. It simply does not help to tell me that unknowingly hemochromatosis donors donate.

What I am asking you is, do you consider the issue of an undue incentive to be irrelevant, and if so, how do you explain that? The whole issue is how does it change once someone knows.

Once you know you have an obligate need for phlebotomy, do we expect that you will be an equally truthful altruistic donor?

DR. HERBERT: I would say that if you have an obligate need because you have iron overload, then it does not matter because if you sneak in somewhere else and give blood as a donor, you will be rejected anyway as a donor because of your diabetes, because of your abnormal liver function tests, which those who are no longer genotypes, but are already phenotypes have. They are rejected because of their abnormal liver function tests. All of them have abnormal liver function tests.

DR. NIGHTINGALE: Dr. Gomperts?

DR. GOMPERTS: Dr. Herbert, what is the utilization of deferoxamine in this patient population?

DR. HERBERT: Of what?

DR. GOMPERTS: Desferal.

DR. HERBERT: Deferoxamine?

DR. GOMPERTS: Yes.

DR. HERBERT: First of all, it is not good for genetic hemochromatosis. So it is not used because it has been shown not to be good.

However, it is the therapy of choice for iron overload due to repeated blood transfusions to counter a genetic hemolytic anemia, as in thalassemia, and there, as you know, thalassemics have to get blood frequently. They develop iron overload which would kill them and has killed many until they started using deferoxamine in all of them. So they are all getting regular deferoxamine therapy.

DR. GOMPERTS: I understand that, but in this particular disease process, especially in the symptomatic patient with diabetes, et cetera, Desferal is used or is not used?

DR. HERBERT: It is not used because it is too slow. Phlebotomy is much faster and, therefore, much more effective.

DR. GOMPERTS: It is not a financial issue?

DR. HERBERT: No. It has got nothing to do with money. It is just that when you do a phlebotomy, you take out 250 milligrams of iron with each phlebotomy.

DR. NIGHTINGALE: Dr. Gilcher?

DR. GILCHER: My comment actually is a question to you, Dr. Epstein.

After we made the decision that I told you about, removing the charge in our community, we looked at the idea of actually doing a similar study as to the one that was done and reported in the New England Journal of Medicine. However, we had not proceeded because in fact we are concerned about taking people who are actually blood donors and now identifying them. This is the situation that is in between really the question that you have asked Dr. Herbert.

How do you feel about taking a group of blood donors and then actually testing them to determine if they do have hemochromatosis and identifying them? Then, would you still consider them to be blood donors after that? This is a concern that we have had.

So we actually have not done the study for fear of actually losing donors, not actually increasing donors.

DR. EPSTEIN: Well, as Mary Gustafson stated, the FDA regulations do not preclude the donation. They only require the label. So we would require to label the blood as therapeutic phlebotomy.

DR. GILCHER: Of course, we know it would not be used by our physicians.

DR. EPSTEIN: I understand that, but if what you are asking is, are studies possible, I would say yes, studies are possible.

Are studies worth doing to try to resolve these issues? I would say yes. They are not going to be easy, though. Ultimately, what you are trying to do is look at seroconversion rates in individuals who are denying risk factors and continuing to donate in the face of a known diagnosis. That is really what you want to know here. Even that is a surrogate for ultimate transmission to recipients, but I think that is close enough.

DR. GILCHER: I agree with you.

DR. EPSTEIN: But those are not going to be easy studies.

DR. PENNER: As Mary Gustafson, the former Dr. Mary Gustafson, had mentioned, there are really two sticking points that we are running into on this situation. One is the identification of a disease state that would be benefitted by the phlebotomy or whatever procedure is done.

That issue was really, I think, developed to protect us from the blood donations from the polycythemic patients, a condition in which there is a malignancy rate that develops, and therefore, removing blood is beneficial to the patient, but one does not know when the patient is going to develop a form of an acute leukemia. Therefore, the question of whether you might have a transmissible something or another there has to be avoided.

I do not think those who put that issue together really reflected on the possibilities of hemochromatosis, and it would seem to me that it would be possible to address that very simply by asking for a change in the Act to allow hemochromatosis to be acceptable.

The second issue is the volunteer aspect and reward which has developed. In about an hour before I left to come to this meeting, my hemochromatosis patient was complaining, as usual, about the fact that he had to come in to our clinic to have his blood drawn, and that in the old days, he used to be able to go to the Red Cross and just have the blood drawn and there was no problem.

Then I explained to him again, "Well, you are not a volunteer when you go in, and therefore, your blood is going to be looked at differently." He said, "You already talked to me about that. That is foolish. Why can't I just go in, if the blood will be drawn as it used to for this condition by any of the Red Cross or any of the blood banks? Why can't I say after they draw it, I want to volunteer that blood or I do not want to volunteer that blood? And that will get me around the fact that I am just volunteering, and I am not doing this on a reward basis," but that would mean all of the blood would have to be drawn, as Dr. Gilcher has put forth, as they used to many, many years ago, just on the benefit of the fact that the patient was asked by his physician to go in and have his blood drawn for his hemochromatosis condition and that there would be no charge whether the patient donated the blood or did not donate the blood to the Red Cross.

So I said, "Well, that sounds like a very good idea. I do not know how that will fly, but I will bring it up at the meeting," and that is what I did.

DR. CAPLAN: I think we are to our public comment period. Did you have a list of names?

DR. NIGHTINGALE: Yes, I do.

I recognize two of those who wish to comment publicly. I see there are three. If we could move from left to right with Dr. Krikker and then Mr. Alexander, and then we will move along the front row.

DR. CAPLAN: I know we have got statements. So, if you could keep your comments relatively brief, that will let the panel ask questions, too.

DR. NIGHTINGALE: Dr. Krikker?

DR. KRIKKER: I think that before I make any comments about my statement, there are so many issues that were raised and so much should be commented upon that I think I would prefer to make some of the comments about some of the questions that were raised.

First of all, with reference to your question about what percentage of hemochromatotic patients have been donors, since 1982, I began to survey our patient members, and 39 percent had been blood donors anywhere between 5 and 46 years. Most of them, after diagnosis, in most cases, their bloods were no longer acceptable.

Since the hemochromatosis gene was discovered in 1996, it has raised so many more questions that the issue of hemochromatosis is not quite as simple as some may feel it is.

We now know that there are many transferrin saturations in ferritins which are not hemochromatosis, and there are many patients who never expressed the disorder. So that, the whole picture now is getting a lot more confusing than it had been.

First of all, there is the very important issue of the volunteer donor. I think that is unfair to compare the pre-1970 paid blood donors to hemochromatotics for this reason. The paid donors had a habit that they had to pay for, usually drugs, and we know the relationship of hepatitis to a drug habit. So that issue of volunteers as an altruism, I do not think it is quite applicable to the hemochromatotics who are very health-conscious. They take care of themselves, especially those who want to maintain their phlebotomies, and I think it is unfortunate that so very many families, where they have very many members who require phlebotomies, have no insurance or no jobs. I think it is really criminal that something is not done about this situation.

Recently, Senator Daschle's office contacted me, and I did send them some material, especially a position statement that our advisory board drew up. In 1997, I revised the 1983-1985 position statement that we had drawn up.

In my experience with the various blood bank executives, I was amazed at the variability of knowledge that each had. In 1994, I received a number of faxes and phone calls from some of the blood directors, especially out in the California area, out West, that President Clinton's recent Executive Order was a request to all the agencies to please review all their regulations and see which regulations could be revised, perhaps with the thought of rescinding, because they are now not in keeping with the times and should be changed.

With that, I began to get our new advisory board members, and we include, among our advisory board, people who have been involved with hemochromatosis, way back since the '30s and '40s, Drs. Bothwell and Charlton from South Africa, Dr. Olsen from Sweden, and in this the country, the Finch brothers.

It is significant that in Sweden and in South Africa and more recently in Canada, the bloods are being used, and in my conversations with the representatives of the transfusion organizations, they all admit that they have had no problems using hemochromatosis bloods.

First of all, the bloods are screened. If they have any overt disorder, certainly many of them are not going to be donating blood.

I have made the suggestion to several blood bank directors, why not do the usual screening techniques of people who want to give blood, even those who have hemochromatosis. We have to redefine what is "disease." Is a genotype individual diseased?

Dr. Herbert is correct that a phenotype does represent disorder, and first of all, they are not going to be donating. They do not want to.

I think that instead of the board making any snap decision at this time, as your Dr. Nightingale has provided you with some very excellent data, especially the recent journal, the Annals of Internal Medicine, you all were given copies of our position statement, the various blood communities, the FDA advisory board. Please re-read that. These are people who contributed to the position statement. They are knowledgeable. This is their work. They know every detail of it, and they recognize now that this is getting much more complex than it had been.

In all reason, do not disqualify someone because suddenly you find that he has hemochromatosis. He may never have expressed the disorder.

I did have a 5-minute talk prepared, but I will just forget about it.

DR. CAPLAN: Thank you.

DR. HERBERT: It should be noted that Dr. Krikker, who just spoke, is a physician on the staff of the State University of Albany Medical School, and she is exceptionally knowledgeable in this subject, more knowledgeable than anybody sitting around the table here and has been for many years.

She became interested when she, as an internist, did not recognize, until he died of iron overload at age 46, that her husband had iron overload. She then formed this organization. Well, maybe she did know it beforehand, but she then formed this very effective organization, and she is really the lead speaker in the world for this subject.

DR. KRIKKER: I would like to make one correction. I became a physician because as a young bride, my husband, who was a research chemist, was given a diagnosis of Mediterranean anemia by the professor of a teaching university. I always wanted to be a physician, and I was going to save my husband, go to med school, and diagnose him. By golly, my second year as a pathology student, there, setting the liver slides, was the diagnosis. I am biting my nails. How do I tell my medical professor, who is his physician, he may be all wet?

As a matter of fact, we said to him, "You know, Doctor, we want to get a second opinion on this." "Well, what do you think he has?," and I said, "Well, he thinks he has hemochromatosis." He says, "Nonsense. He does not have diabetes." So this is how I became a physician, and the story is a little more involved and you knew about it.

DR. CAPLAN: We have got to get these other people going.

DR. HERBERT: I just had to elaborate on the CFR.

DR. CAPLAN: No, no. Let me let the next person speak. Then we will get back to the discussion.

MR. ALEXANDER: Hello. My name is Randy Alexander, and I have hemochromatosis. I do appreciate everyone who is here, the committee members, all the present presenters. I appreciate very much their knowledge, expertise, and enthusiasm.

I have experienced firsthand the frustrations, the emotions, having to have blood drawn off and was very expensive, and I had few alternatives because I was unable to work for long periods of time. It was costing me over $800 a month to have blood drawn off, and it was going to save my life.

There are people out there who are going to blood clinics. They have no choice. The hemochromatosis patients do not understand why this blood cannot be used. I do not understand why this blood cannot be used. It is an emotional issue.

However, I do see all of the complications here. As Dr. Krikker pointed out, this is very complicated. What we have experienced in working on this issue for a number of years and working with Dr. Krikker, the Hemochromatosis Foundation, Roberta Crawford, the Iron Overload Disease Association, and my association, the Iron Disorders Institute, is that patients are screaming and clamoring for something to be done or to be heard. They feel that they are being ignored and they are not being listened to. This is a very good first step for people to be able to tell people that something is being looked at, that this issue is being addressed.

I think what is needed here and what has been demonstrated here, Dr. Grindon, they have opened the door, so to speak, in showing us the way of how to resolve some of these issues and in showing that people working together, sitting down, working together on a common ground, that no matter how difficult these studies or the information or what is before us is, anything worthwhile is worth working hard for. I have found that out.

I think we need to bring the CDC to be involved in this and looking at specifically what is the science that is needed, what is in question here, what data do we need, identify that. Let's work with the FDA. Let's work with the CDC, the NIH, the AABB, the Red Cross, the insurance industry. I do see the problem here with costs.

Running a non-profit organization and helping people is expensive, and blood is a good value, but we have to have consistency in the fact that if some people are going out and paying $300 for a pint of blood and it puts them in financial ruin, what options do they have?

We have an opportunity. We have a resource of blood here, people who have hemochromatosis, and when they find out, they feel they can contribute to help somebody else. Then, when they sit there and they have the blood drawn up and a biohazard sticker is put on that bag, that really does not set well with them and they do not understand. So those are some of the issues we face, and that is where the emotional aspect comes in.

I think working together, everyone coming together, stop the finger-pointing and everybody working in harmony in a goodwill environment, to resolve these tough issues, we need to do that.

I think today is the beginning of that, and I offer myself personally and my organization and the organizations represented here to work together. Safety is paramount because you see, even though I would like to have this blood being used and my blood being used, I know that any time that I may need blood and I want to be safe.

I appreciate your interest in this. Thank you very much.

DR. HERBERT: May I now comment?

DR. CAPLAN: No, no. Let me do these public comments. Then we will come back to the discussion.

DR. HERBERT: Okay.

DR. CRAWFORD: Hello. I am Roberta Crawford, Iron Overload Diseases. I would like to make three brief points.

Dr. Herbert has already made these points, but I want to make them again. The blood banking is a non-profit life-saving organization. I believe it has a moral obligation to test for the most common genetic disease in our society, and they do not know that they are not testing iron.

Maybe the medical directors and nurses do not do this, but we know, as we have heard from thousands of patients over 20 years and blood banks give out lists of high-iron foods to people with low hemoglobin. They say your iron is low and you need to eat these high-iron foods.

The problem is that some of these people with low hemoglobin, as Dr. Herbert pointed out, are already dying of iron overload, and they have not been diagnosed. They do not even know it. So that is reckless to tell people they have low iron just because they have low hemoglobin.

My last point is they do not know they are measuring iron, but if you are not blood testing, if you do not want to use this blood, you are using it if you do not test the iron because most of the people with iron overload are not diagnosed. They die undiagnosed, and they become blood donors.

Thank you.

DR. COLBURN: Good morning, everyone. Donald Colburn from the National Hemophilia Foundation.

We had a discussion with respect to this issue on our Blood Safety Working Group, and I want you to be aware that the group is against transfusion of this product.

However, I have been educated a great deal this morning to problems that this community has. How shall I say this? They are kind of not unsimilar to our community, and the problems revolve around costs, obviously, and then. where we are concerned, recipient safety, but they are two very separate issues.

We know that this is the most common genetic condition. That is what we have been told this morning.

One of the questions that would have to be asked is, is there any germ-line contamination and is this how we have made this the most common genetic disorder. Those are possibilities, but I think there is a solution here, though, that goes a little bit beyond, and depending upon whose numbers you want to believe that we saw today, it is something that I think a joint task force of the AABB, the RFC, and the ABC could really do something of a community service which would get back to something that Dr. Penner has been talking about and literally open up their collection sites at no charge for therapeutic phlebotomies. I think that might be one solution for this type of thing that the person comes in with a prescription for the draw, hands it to the nurse, and they get the draw done and there is no charge.

Instead of "biohazard" being marked on it, it could be whatever is done with "not to be used for transfusion" on the check-off. That would be a suggestion.

Thank you.

DR. CAPLAN: Let me ask you a question while I have got you up there. You said you were opposed, and safety, I assume was the--

DR. COLBURN: Yes. It sounds like it should not be a problem, but those are challenges that I am not sure all the information is in on. From where I sit and stand, there is a very common-sense thing that says: Why would a person want to receive a blood product from a known person with another problem? That is the simple context of it.

DR. CAPLAN: Any other comments?

Yes.

DR. SCHREIBER: George Schreiber from REDS.

Can I just throw out a couple of numbers from our REDS survey which might be of interest to people? We surveyed roughly 52,650 donors, and we have a survey ongoing now, a little over 90,000. So all of the returns are not in yet, but I am just reporting on what we have so far.

Out of that, we have 206 people, or a rate of 3.9 per 1,000, that identify themselves as being hemochromatosis.

This is an anonymous survey. So the donors are sampled. The survey goes out, and it comes back anonymously.

Just as a point of reference, we also have 1.5 per 1,000 that are polycythemic, and of those people who are hemochromatosis, 48 percent claim that a physician told them to donate blood for treatment versus 79 percent for the polycythemic patients. So you have another group that is creeping in that have probably much more of a health threat than hemochromatosis patients.

Forty-five percent of those with hemochromatosis donated primarily every donation or some donations because of the condition, again, versus 61 percent for those who have polycythemia.

Two other numbers, just as points of reference. 4.85 percent of those with hemochromatosis were repeat reactive on screening, on some screening tests. The way we do it, we do not have the confirmatory test back by the time we sample because it takes too long to get the confirmatory test, but we do mark the questionnaires so we know who is repeat reactive.

That is versus 4.32 percent of the general population. So it does not look like there is very much difference, particularly with the small number. You would not see very much.

Just in contrast, again, polycythemia has 16.25 percent that are repeat reactive. So, just as a point of reference for what we find in this survey, probably by the end of the summer we should have all the results in, in a more detailed analysis, breaking it down by every which way you can imagine.

DR. CAPLAN: Thank you.

Dr. Herbert?

DR. HERBERT: Yes.

Dr. Krikker mentioned this, and the discussion of it is in our Reference 6 in my handout. If you go to Reference 6, you will see it is the petition to the Food and Drug Administration, a docket number, filed September 5, 1996. This is the solution, action requested, that the FDA insert in 21 Code of Federal Regulations, et cetera, after the title "Therapeutic Bleedings" the following words, "Except for blood withdrawn from persons with iron overload disease whose blood should not be stigmatized, but should be labeled solely 'volunteer donor' in accordance with another CFR."

That is what I hope you folks on the committee will recommend approval of by the FDA. It solves the whole problem. It solves the problem that was brought up from the audience. Get rid of that "biohazard" sticker. You should get rid of the "biohazard" sticker, and the way you get rid of it is the FDA adopting our simple petition.

DR. CAPLAN: Good.

I think what we will do is let Jane say something.

[Laughter.]

DR. PILIAVIN: I am going to try one more time to get through to these people who are arguing that there is no problem.

I want to give you a little example of something that is a possibility. Say that there is a person who has been diagnosed with this disease, a fortunate person who is diagnosed early enough so that he has no symptoms, no other diseases, and is told that he has to pay $100 per draw for however long to get this iron out of his system. This person happens to be relatively poor and a closet homosexual. I would like you to think about the possibility that this person is going to decide instead to go to the local Red Cross and have his blood drawn and not bother to tell them that he has this risk.

That is in the most glaring terms what those of us who think about people's motivation are concerned with here. It seems to me that the only solution to this problem, if we want to be able to take advantage of this blood, most of which would be from people who apparently would otherwise be perfectly safe donors, is to do what Dr. Gilcher is more or less suggesting, and that is to have therapeutic draws for people with this illness be free at blood centers. That, therefore, removes the incentive for lying about dangerous health habits that we may have that would make our blood unsuitable for other people, but, otherwise, it is perfectly clear to me that this serves as a dangerous incentive, just like payment for blood did in the past.

DR. CAPLAN: I might have been out of the room when I missed this little pertinent fact, but in the phlebotomies and the blood draws, where is the money going? Who is making the money?

DR. PENNER: The staff. Essentially, you bring somebody in. You have to buy the bags. You have to have a nurse attend. You have to use a room, and that goes into it. So there is a fee tucked on--

DR. CAPLAN: For that.

DR. PENNER: --like everything else.

DR. HERBERT: According to this survey made by U.S. News and World Report in their story, "Throwing Away Good Blood," 2 years ago, the blood banks make $200 million a year from this.

DR. CAPLAN: All right. Let's take a 10-minute break and reassemble, and we will go at this issue with some discussion.

[Recess taken, 9:58 a.m. to 10:28 a.m.]

DR. CAPLAN: I am going to ask as we start this next session that we let the committee talk about this. I am not going to go into the audience unless there is a question of fact or something that one of the committee members wants to address, but then we will open it up a little bit for discussion towards the end of the session.

We have up until about 11:45 to talk about this. Let me set the stage with a couple of facts or opinions or statements that I think are interesting as we try to address the question of do we want to say anything about the use of blood derived from hemochromatosis individuals in the general blood supply, and this is me talking personally now, but hogging the podium again as Chair.

One, it is important to know that other countries have done this. Canada and Sweden, I guess Australia, and South Africa are all using this blood. So there must be some information available either in a general epidemiological way, or maybe there are some studies there. It would be useful for us to ask Steve or the FDA or anybody who might have information in CDC to see what could be found. I think it would be helpful, although I am actually not convinced that we have to await that information because, if there was a massive problem, we would probably know about. It would seem to me that we heard these countries had done this without any overt and obvious difficulty for their recipients.

The second thing we heard was that there is some presence of persons with hemochromatosis in the blood supply now. So what we are talking about is not necessarily allowing a new entry, but an increased entry into the blood supply. That is to say, there are people for various reasons who act as blood donors now.

Third, there is currently a fiscal issue. Jane's case is very striking about what sort of motivation somebody might have to disguise risk factors and take advantage of access.

A fourth question, to put it bluntly, is: If we trust our microbial and screening tests, are they adequate to pick up whatever risk factors would be introduced by these motivational things? Are we really going to put our trust in this safety screening system that we built?

Then, the last issue that might bear on this that I heard was there are different ways to allow people to indicate. This is John's patient's idea that you could do it or just put people in as donors. You could put them in under the system now, where they are paying for their phlebotomies, but designate the blood over, and we could certainly talk some about ideas about paying for phlebotomy, the real cost, so that blood centers could get the blood. People could designate it after it has been drawn, but that you minimize the financial incentive or barrier, depending on how you want to describe it, for people who have to get these bleedings done.

So there is a lot of interesting claims up on the table. Oh, let me add one last one.

There seems to be, which I heard, a fear still that the people providing the blood in this category of person are either diseased or abnormal or perhaps even, I guess I said to Steve, contagious. That, obviously, from a science point of view is just not true. So it is important to understand that this is not communicable, not infectious, not something you are going to give someone else, and the disorder, to the extent that it is seen as a disorder, is only a disorder if it builds up iron in you for a long period of time, and that brief exposure to this is not in any way risky or harmful. So that, even though there is concern, I think it is one that we can acknowledge that people have a concern, but I think it is one we can also address by saying this is not communicable and it is not a grounded concern.

It is obvious that people are right to wonder, but I do not think that should be a reason to provide a hurdle or an obstacle here in terms of whether or not we want to say something about trying to put this blood into the supply.

So, with that, what I would like to do is just open it up for preliminary thoughts or comments by committee members.

DR. GUERRA: Art, if I could just add a point to the last one that you made. Would children constitute a special case in terms of recipients of this blood? I am just not sure in terms of the load.

DR. HOOTS: Are you talking about from a risk standpoint?

DR. GUERRA: Right, in terms of the load.

DR. HOOTS: I do not really think so. If you are talking about either unbound iron or ferritin--

DR. GUERRA: Right.

DR. HOOTS: --and, again, I am speaking entirely off the top of my head and not with any calculated data.

DR. CAPLAN: That is my role. Do not take my role.

[Laughter.]

DR. HOOTS: If you look at ferritin in the modest range and also if you look at an elevation of serum iron, the amount of free iron that you are giving, the amount of bound iron you are giving is so negligible, relative to even what a child would do in the context of an upper respiratory infection where their ferritin as an acute-phase reactant goes up from 60 to 180, just because of the stimulation of the cytokines during an acute inflammatory event.

So I do not foresee that there would be even an infinitesimal risk of the extra amount of iron in there, and as far as I can ascertain from everything we have heard and also from what in dealing with iron states more on the iatrogenic side, like thalassemia, that this part of the threat issue would be virtually negligible.

DR. HAAS: I have just a quick follow-up.

Is that the same type of argument if there are patients receiving multiple units of these red cells?

DR. HOOTS: Yes, exactly.

DR. HAAS: I am thinking of the hemophilia model on the plasma side.

DR. HOOTS: I cannot conceive that even if you fractionated and it would all fractionate to one fraction, that there still would be enough extra unbound or bound iron or protein to cause any untoward events. You are talking about orders and orders of magnitude below the threshold of toxicity here.

DR. CAPLAN: Come up towards the mike. It looks like there is a technical answer or an additional answer.

DR. GRINDON: I am Al Grindon from Atlanta.

It is important to clarify that the blood that we are talking about being donated by these patients and used for recipients is not iron overloaded. Typically, this is during maintenance. So there is no risk of iron transmission.

DR. HOOTS: Even if it were during an overload state, I do not think it would be enough extra iron to add any morbidity whatsoever.

MR. WALSH: As a point of clarification, there seems to be three different groups of people affected here. One is the genotype group that is not symptomatic, has not been diagnosed, predisposed and may never present with disease. Two are those people who are phenotype and symptomatic, being treated for diabetes, cirrhosis, arrhythmia, that would be disqualified, anyway, from a center, I understand. Three would be those who would be perhaps phenotyped and not presenting with symptoms yet that would obviously benefit and that need phlebotomies.

Is that correct?

DR. CAPLAN: Right.

MR. WALSH: So, if we started out by just talking about whether all these groups would be included in a recommendation or one of the groups would be taken out, would that be helpful?

DR. CAPLAN: Sort of, although the first group, the undiagnosed is in. They are in there, anyway.

MR. WALSH: Right.

DR. CAPLAN: People who have overt symptomatology are out because they will go out on the screens. So we are probably talking in the third category for the most part.

DR. AuBUCHON: The blood-collecting agencies have invested an incredible amount of effort and resources to making the blood supply as safe as possible, and the FDA has helped to direct us to make sure that we are asking all the right questions of donors over the last decade, to the point where the blood supply is incredibly safe, as we heard yesterday.

I would find it antithetical that now this committee or anyone else in the Federal Government would then recommend that we take a step that would potentially decrease the safety of the blood supply, particularly when it appears that there is roughly little to be gained in terms of increased availability through that step.

On the other hand, I was very disturbed to hear the data from REDS this morning that was offered during the public comment session that not only are a fair number of hemochromatotics donating blood, but also polycythemics. That group is truly a concern, although no one really thinks that polycythemia or even acute leukemia is transmissible by transfusion. It clearly is a group that we would not want to have in our blood donor line.

I do not really know how we would approach that to "clean up" the blood supply, not that it truly is at any increased risk at the moment, but other than asking one more question, do you have polycythemia or hemochromatosis, which is kind of going in the direct opposite way that several of our speakers would have us go this morning, I am wondering if this is one thing we might consider.

I am offering this just off the top of my head and we probably need some additional thought and some additional calculations, but one approach would be a la the OBI approach, to allow the collection and transfusion of blood from patients with hemochromatosis on recommendation of their physician, as it were.

If the blood center offered free phlebotomy for anyone who needs it for therapeutic purposes, that would then allow us to possibly get the polycythemics to come out of the closet, identify themselves. We would not use their blood, but they would not be at any financial decrement, and it would take away the financial incentive of the situation that Jane was mentioning. At the moment, it bothers me very greatly.

DR. CAPLAN: Ed?

DR. GOMPERTS: The issue of labeling a unit of blood as hemochromatosis came up, clearly this is simply one way through this. Everything that I have heard and what I know about would indicate that there is no hazard from the point of view of transfusing a unit of blood from a patient with hemochromatosis.

Under those circumstances, what is the hesitation of actually putting that label on?

DR. AuBUCHON: Maybe someone transfuses directly could answer that, but I would think that anything that distinguishes a unit in any way would decrease a patient's willingness to receive that unit, and it would require the transfusing physician or nurse to spend a lot of time explaining to the patient exactly what hemochromatosis was and why this unit was not really at any increased risk.

I think we would have to be willing to accept those units into the blood supply without label or they will not get used. Logistically, it is too difficult.

DR. GOMPERTS: Is it just an education issue?

DR. AuBUCHON: Yes, but you would have to educate each and every recipient, and that is just too much time and effort in today's modern fast-paced health care, frankly.

DR. GOMPERTS: Maybe, maybe not.

DR. CAPLAN: One other issue about labeling is, do you label it because you are not sure that it is at risk or because you know it is at risk, and what I have not heard yet, and I wanted Jim to say something else or Jane, too, if she wanted to add to her story, if we are screening effectively and we heard the REDS data about what the incidence of infectious agents and risk factors were, if they were not different from the average population and we have got some number of people entering in, what is the risk?

I understand that there might be a risk or there could be a risk or we might attract in people who are not there yet, but before I throw a label on something, I want to know is it more risky or isn't it. I do not want to label it just because it might be. That would open us up to a lot more labels.

DR. AuBUCHON: The only risk that I see is the infectious disease risk associated with the monetary incentive to donate and not disclose the presence of hemochromatosis.

I agree with Keith. I do not think the blood itself is of any different quality.

DR. McCURDY: Independent Counsel think that there is an analogy here that might be useful. I do not think there is any question. Maybe there is, but there is very little question that so-called "paid donor blood" carries a higher marker rate and a higher seroconversion rate than so-called "volunteer donor blood," even with all of the incentives that have been put in it yesterday.

It has been assumed that this is because paid donors do not tell the truth in their history. It is my understanding that the amount of money that is provided to paid donors, mostly plasma phoresis donors these days, is relatively small compared to the overall economy at the present time.

We have no data that indicates that they do or do not tell the truth more often. There has never been, to my knowledge, a questionnaire sent out for anonymous return, like the REDS study, for paid donors.

I do not think we have really any good idea at all as to why paid donors are more risky, but they seem to be.

I am not aware of any study other than what George Schreiber presented earlier that gives marker rates in patients with hemochromatosis.

I have asked the question on one or two occasions about whether anybody screened either a random sample or consecutive sample for, say, hep C or one of the other or all of the other markers, and I do not know that such data exists.

It might not be too difficult to get that kind of data if it was desirable.

DR. CAPLAN: Other comments?

DR. HERBERT: Dr. Ray Gambino of Quest Laboratories reviewed 1.5 million sequential blood samples sent to his lab from physicians all over the metropolitan area for routine standard first testing for glucose, et cetera. He on his own on all of them did transferrin studies. He found in 1.5 million samples that 12 percent were heterozygous for hemochromatosis, and these are just normal healthy people going for routine exams in the New York metropolitan area. He published that in 1992.

DR. McCURDY: That is not the type of screening I was talking about, Victor. I was talking about screening for the infectious disease markers that are generally done in blood banks. They are done on a selected group of healthy normal individuals, who have passed a history screen for being blood donors. There is a small percentage of those. I do not have it. Rick Davey or somebody might have it, but there is a small proportion of those who have infectious disease markers without having any knowledge of it themselves. That is what I was talking about.

DR. CAPLAN: Let me put this point another way, and I am just tossing it up there for people to think about and answer. Then I will go back to John.

If you sampled, and there is no shortage of material to sample, people who have been through phlebotomy with a condition and saw what the different markers were in the pool, the fear is, though, that if you make this free or minimize the cost of phlebotomy, you will bring forward more at-risk people who will come in and use this, attracted by both the incentive than might have before. So you might get a skew in what the donation pool looks like from what the baseline pool is.

I guess my nuts-and-bolt question, to come back to it again, if you put an incentive forward and we cannot get the fiscal barrier removed, which I am not sure we cannot--that might be possible, but if we could not, would the testing, even with the behavioral distortions, still minimize the risk? That is what I have not heard anybody answer for me yet.

If you trust the testing, microbial level, that we have got now, then even if you had somebody stepping forward out of Jane's scenario, would you really raise the risk background incidence that much?

DR. PILIAVIN: Is everybody forgetting about the window period? Isn't that why we are so careful about the screening that we do? There is no reason to think that people with hemochromatosis are likely to have any cleaner lifestyles than all of the rest of us, especially since there seem to be so many of them.

[Laughter.]

DR. PILIAVIN: They are probably just like the rest of us. So it is the window period that the questioning is designed to solve.

We know it does not solve it completely, and partly, that is because other people lie, too, or simply have no clue that they are at risk because they did not know the person they were having sex with had used I.V. drugs, for example.

I just cannot imagine that an incentive, a major monetary incentive, is not going to have the same influence on these folks as it in the past has had on paid donors.

In regard to whether there is any evidence that paid donors are more dangerous, sure, nobody has done a study that asked them these same questions like the REDS study, but I would take the three-fold increase in markers as pretty good evidence.

DR. PENNER: To get back just to the labeling briefly, I agree with Dr. AuBuchon's comments that the minute we put a label on, then we have to go through the institutional review board. We have to then touch bases with the patient to see if he will accept it. They will not know about what hemochromatosis is, and the harangue to just get use of that blood would just not pay for it. That was, I think, our concerns all along.

Since we have already established, I think fairly well, that there is nothing wrong with the blood, it represents not a risk to the individual, why not address the first part of the problem and try to exclude hemochromatosis from that initial act of having to label? This would seem to me to be an approach where you exclude only that.

We do not add other labels because of other diseases. So why should we do for hemochromatosis? The only reason we are adding the label is because we want to exclude the polycythemics who are going to benefit from having their blood removed at this point.

DR. CAPLAN: Yes.

MS. O'CONNOR: Speaking as a consumer or somebody who has been transfused and so on, I think the patients have a right to know if this blood was collected from a therapeutic draw. So I would be opposed to putting a label on there that says this was obtained from a therapeutic draw.

When you guys test a unit of blood to see if it is C&B-negative or C&B-positive and you have actually tested it and found out that it is positive, the sticker goes on a unit of blood and goes on the floor. It does not go through an institutional review board or anything of that nature in the facility.

For the most part, patients do not even notice it, but for that astute patient who wants to know what they are receiving, I think it is important that that information be there.

DR. PENNER: If we addressed the other part of that by allowing it be volunteered by the patient who has given that blood, wouldn't that represent the same sort of response we get for any volunteer who walks in who says you can either use my blood or not? He is coming in because he is saying you can use my blood. The hemochromatosis patient can say the same thing and say, "I don't want you to use my blood. I want to take it home and put it on the tulips to keep the rabbits from eating them."

Enough said.

DR. CAPLAN: Let me go to Rich.

DR. DAVEY: If we are going to talk about labeling, it has to be linked with the incentive issue. We cannot talk about removing a label without removing the incentive, in my opinion. So, if we do not, we cannot unlink them. If the label goes, the incentive has to go, and that means we may have to think about somehow offering this as a service, or perhaps letting the donor, as you suggest, John, decide whether or not he or she has risk factors, but not involving the incentive issue to cloud their thinking. So labeling has to go with incentive.

DR. CAPLAN: Steve and I were just noodling along. Do you want to read this? This is something to think about.

DR. NIGHTINGALE: This would be a paraphrase of Dr. AuBuchon's previous statement: "A blood center should be able to use blood from patients with hemochromatosis without any restriction if that blood center offered free phlebotomy for all patients with hemochromatosis." That is not precisely what Dr. AuBuchon said. I believe that Dr. AuBuchon said "any therapeutic purpose," but that would be the notion that seems to be floating around the table at this time.

DR. HOOTS: I think one caveat that I thought Jim astute put in that that does not address is instead of just saying "with hemochromatosis," would you want to add "erythrocytosis" to that? That is what you want to screen out. So, if you use hemochromatosis or erythrocytosis, then it would give the opportunity and you would be able to screen that out.

DR. PENNER: For instance, for polycythemics?

DR. HOOTS: I was using "erythrocytosis" as a generic term to cover P-vera and everything else.

DR. PENNER: Oh, you wanted to include "erythrocytosis."

DR. HOOTS: Yes, because I thought I understood Jim to say that he would like those people to get free--

DR. PENNER: No. Just the hemochromatosis.

DR. AuBUCHON: I would think it would be essential that free phlebotomy be offered to any person who has it prescribed. The polycythemics would not have their blood transfused.

DR. HOOTS: Right, exactly.

DR. McCURDY: Could I ask for a point of clarification from something that Rick Davey said earlier?

Do all of the donors in the Red Cross system get either hemoglobins or hematocrits? They do not use the copper sulfate technique anymore.

DR. DAVEY: No, that is not correct. It varies from region to region in the Red Cross. Copper sulfate is used as a rough screen for hemoglobin.

DR. McCURDY: My thought was that if you really did a hemoglobin--and that measures density, not hemoglobin, but if you really did a hemoglobin or a hematocrit, then you would screen out those with erythrocytosis because they would be too high.

As far as I know, there are few, if any, blood banks who do that routinely. Maybe, Ron, you do.

DR. AuBUCHON: I am not sure that would solve the problem, Paul, because after these polycythemics have been in therapy for a while, their hemoglobin comes down to a range that is indistinguishable from mine.

DR. McCURDY: Yes, that is true.

DR. AuBUCHON: If I could return to the proposal that I guess I made, though I was not sure I was making one, I would like to hear more from the users on this committee. We heard Carolyn's comments. We have talked a lot in past meetings about patients' rights to know, and obviously, patients are very interested in having enough blood and they are very interested in having safe blood, but this is another patient-right-to-know issue.

In the system, as we are talking about it now, as a proposal, there would be no labeling of hemochromatosis units. They would just go into the inventory like any other unit.

Clearly, some of the units that we are transfusing right now already are from hemochromatosis patients, and we just do not know it. There would be a few more with this approach. What do the recipients think about this?

MR. WALSH: First of all, I think it is appropriate if you do a phlebotomy, it has to be on a script basis, and you would have to know why the physician was prescribing a phlebotomy, first and foremost.

If somebody was symptomatic, it would be red-flagged by the center, wouldn't it, for the indications we have already talked about? If somebody was not symptomatic, there would be no reason.

DR. DAVEY: They would have to go through a donor screen, like everyone else.

DR. CAPLAN: I take that as without reason to see that there is risk, you are saying what?

MR. WALSH: I would say in regards to free phlebotomy, absolutely, but with the physician's prescription and a reason for it to the center, which would theoretically red-flag a lot of the issues that we would be concerned with.

DR. CAPLAN: Yes, Larry.

MR. ALLEN: I am just wondering, if we are talking about labeling these units, would it also be necessary, then, at that point to label all blood to say that it might contain this?

DR. CAPLAN: I can only remind the committee that we went down this road a little bit with the CJD issue, talking about endemic and being in the supply and do we want to have special labels for something that might be there anyway. We talked about that a little bit.

I am personally moved quite a bit by the fact that I think there is some material in the blood supply now. So I take that question pretty seriously about trying to label. How would you label? This could be there, anyway. You could get big labels. It would be good for the label industry.

DR. PENNER: Use a broad label as opposed to a special label.

DR. HOOTS: I agree with you. I think it opens a can of worms. Here, I think the whole idea is to try to dis-incentivize the donation so that you can say that this donor population is no different from the regular population, and if you then label it and then later on we decide to label for other things, then essentially you have undone what you intended to do, which is you have put them in a labeled category in the same way that we might have done with CJD and chose not to do. I think that would be a mistake.

DR. HOOTS: I guess the question that I would like to ask is: What is labeled on blood right now?

DR. HERBERT: Hemochromatosis blood is labeled "biohazard."

MS. GUSTAFSON: By regulation, only the statement that I had on the overhead, which is that it was a therapeutic bleeding and the disease that caused the disease state for which the therapeutic bleeding was done.

Did you want general labeling?

DR. CAPLAN: Sure. We have time. Go ahead.

MS. GUSTAFSON: Do you want to go home this afternoon?

[Laughter.]

MS. GUSTAFSON: In the U.S. now, there is a uniform label that is used by the vast majority of blood centers, and it is accompanied by a circulate of information that gives more information about the blood component in terms of the transfusion state.

Actually, the infectious disease testing is in the circular of information. It is assumed that if a unit is labeled and released into an inventory that it would be negative for all of the infectious disease tests.

It has a donor number, and there is an identification of where the unit was collected. There is, obviously, the expiration date. There is the ABA and RH. There is the blood component's name and the statement that if it is for transfusion from a volunteer paid donor, and that is in the same prominence as the proper name of the product.

There are warning statements that are on now, which every unit of blood does tell anyone who reads the container that it may transmit an infectious agent. So that is on there now as a broad general statement.

Bruce, have I missed anything? Special typing. If there were special typings, like if it was chel-negative or any of those types, CMV negative, it is listed on the unit.

DR. EPSTEIN: Anticoagulant.

MS. GUSTAFSON: Oh, yes, the anticoagulant.

DR. EPSTEIN: The expiration date.

MS. GUSTAFSON: I mentioned the expiration date. Any additives that are added are listed on the container label.

DR. CAPLAN: Any unused blood, just to be clear about this, if you are going to toss it, there is a biohazard stick that is slapped on it, anyway, right?

MS. GUSTAFSON: No. A biohazard is only added if in fact there is an infectious agent.

DR. CAPLAN: No. I mean when you are about to throw it out.

MS. GUSTAFSON: No, no. If it is expired, you can tell it from the expiration date.

For some reason, if it was decided that it should be destroyed during processing, for whatever reason, generally an interim label "not for transfusion" would be added to it.

DR. EPSTEIN: I think it is important to clarify because there is misunderstanding.

The regulations do not require a biohazard label in the face of a therapeutic bleeding, and that would apply to hemochromatosis.

What is required is a statement that it was a therapeutic bleeding and the diagnosis that was the basis for the therapeutic bleeding. That is different than a biohazard label.

The problem, and I hear this very clearly, is that there is the implication in people's minds that that has the same meaning as a biohazard because it has been distinguished. I understand that, but, technically, it is not a biohazard label. That is not what is required or intended.

DR. HERBERT: Does your blood bank label "biohazard"? I have walked into 14 blood banks all over the U.S., and every one of them labels hemochromatosis blood "biohazard."

DR. GILCHER: No, we do not because we test every unit.

If the unit is untested, then it does have to have a "biohazard" label. We do test every unit. So we do not have to put the "biohazard" label on. I think that is the difference, where the blood center does not test it.

DR. HERBERT: You are one of the few.

MS. JONES: I think you need to be very clear when you are talking about a "biohazard" label on a unit of blood. Anything that is not going to be used for transfusion has "biohazard."

DR. HERBERT: No. It is labeled "biohazard."

MS. JONES: It is labeled "biohazard" because it is not going to go for anything further. It is not specifically directed at the hemochromatosis.

If somebody else comes in and does not want their blood used for transfusion, we put a "biohazard" label on, if they check that. It is not labeled. It is not tested.

DR. HERBERT: We d not require you to do that.

MS. JONES: I know, but it is just to keep it separate from everything else so that the techs do not make a mistake and put it into the transfusion.

DR. CAPLAN: That was my point that the labeling extended beyond hemochromatosis.

MS. JONES: Yes.

DR. CAPLAN: That is what I was trying to say. The trigger seems to be is it untested, not is it for disposal, although I think we slap "biohazard" stickers on everything at the University of Pennsylvania that we are about to throw out so that people do not take them home.

DR. HERBERT: The AABB solved this problem. It has not been mentioned because the AABB just added PCR, and when you add PCR, you pick up right away if it is infected with hepatitis C or infected with AIDS months before the test for AIDS comes back positive or the test for hepatitis C comes back positive. So there is no problem.

DR. CAPLAN: Jay?

DR. EPSTEIN: Two comments. First, I think that Jim AuBuchon hit the nail on the head, which is that we should not be talking about removing the label without removing the incentive.

At that point, if we think that hemochromatosis therapeutic phlebotomies are different than other therapeutic phlebotomies because the product has no known intrinsic risk, I think we are home-free. We have all been saying that the only issue here is the possibility of an undue incentive to a person who has obligate need for phlebotomy and knows it, above and beyond the fact that there can be a dramatic cost, especially in some cases an uninsured cost.

So, to the extent that it is a premise that there may be an undue incentive, one has to address the undue incentive in order to talk about changing the labeling. So we cannot put the cart before the horse. We understand labeling is part of the issue. There is actually no resistance by the agency to consider that as a remedy if we have a resolution to the incentive problem.

The second point that I would make is that we all realize that there are technologies that are making blood products safer and safer. These include improvements in donor screening and testing. They also will, we think at some point, include viral inactivation or pathogen inactivation strategies for cellular blood components, but we are not quite there yet, and we are still in an environment where we have residual risks and where we are very concerned about those residual risks, even though they are low.

We know from studies that have been presented and at these advisory committee meetings that the residual risks from infectious diseases are driven by window-period infections for which we do not have fully effective testing.

Yes, NAT further closes the window. There is a scientific debate whether it will completely close the window for HIV and HCV. Certainly, at this stage, it will not for HBV, and it is not clear that it will completely close the windows for HIV and HCV while we are doing mini-pool testing because when you pool samples prior to screening, there is a dilution factor.

Although we know that the viral titers ramp up very quickly, you have still got that dilution that you are dealing with when you do the test.

So there will still be a window period. There will still be a residual risk. It will be smaller, but all the more reason not to let through knowingly any additional window-period cases because you have got to realize that with these very low residual risks, the ones you let through may become the largest proportion of the ones that exist. The goal here is to lower that risk as much as possible.

I think at the present time, we still see donor screening, donor testing, and processing controls that reduce pathogens as a set of interacting safeguards, each of which is independently important. We do not want to compromise any of those safeguards, and that is the current outlook.

Perhaps in 10 years, if we think that we can truly sterilize pathogens in blood, it will be a different world, but we are not there yet.

DR. CAPLAN: Let's try another little thought. We are hedging about trying to separate the incentive from the actual blood product.

DR. NIGHTINGALE: The addendum was that the Health Care Financing Administration should consider therapeutic phlebotomy for individuals with hemochromatosis as a cost of ensuring and adequate and safe blood supply and reimburse providers accordingly.

DR. CAPLAN: In other words, what we are trying to do is get them to pay for phlebotomy. That should minimize the incentive.

DR. DAVEY: You may just want to make sure you include Jim's point that we want to include polycythemia in general or erythrocytosis in general, and make sure that P-vera is included in this.

DR. CAPLAN: Right.

I understand what the issue is about there is another group of people that are in there that maybe should not be.

I was actually just holding that on the side for a second to try and go at the issue of breaking financial incentive away from the hemochromatosis donor.

I do understand the other concern that is up on the table. That probably gets written as an amendment.

To go to Jane's point, if you want to shut down the window infections and you are afraid of incentivizing too strongly, if we are going to go in this direction, we need a recommendation that says we want the incentive minimized and then you can open the door.

MS. O'CONNOR: I missed who was going to pay for it.

DR. CAPLAN: We will, all of us.

MS. O'CONNOR: This committee?

DR. CAPLAN: Not individually.

MS. O'CONNOR: Did you specify?

DR. CAPLAN: This is a HCFA "ought to."

MS. O'CONNOR: HCFA, okay.

DR. SNYDER: Are you talking about for everybody? Are you talking Medicare, or are you talking Medicaid? Everybody that cannot do, you have got to look at what their congressional mandates are. You may be into legislation again. You really need to talk to somebody from HCFA about that.

DR. McCURDY: Art?

DR. CAPLAN: Yes, Paul.

DR. McCURDY: I do not feel that I have a good handle on what various insurance companies, including HCFA, will or will not pay for therapeutic phlebotomy. It is a legitimate treatment for a legitimate disease, and I have no understanding as to why they will not do that.

The uninsured or under-insured are a different problem than this. It could be taken care of by community service by the blood banks, but it is really a different problem.

I have heard from multiple sources through the last couple of years all sorts of different things about what the price of phlebotomy is and what insurance companies will and will not do, and I must confess, I am totally confused.

DR. CAPLAN: Again, I am not tossing out resolutions yet, but what I am trying to say is if we say that we recommend to the Surgeon General and the Department that the pool of donors is a valuable resource to deal with the supply issue and they must take steps to minimize the fiscal incentives, whether it is dealing with the managed care people or getting the blood banks to eat one more cost or talking to 11,000 HCFA bureaucrats about what they want to do, it seems to me our mission is to say we have to make sure that there is no incentive to disclose or hide any behavioral risk factor.

If the agency wants to go get this blood, which is pretty good quality blood, it must then find out why they do not pay for therapeutic phlebotomies or what to do about poor people. It has to minimize the fiscal hurdle or take away the incentive.

That is not bad because it does not make us solve it. It just tells them what they got to do if we think that that is blood that they ought to go get. There must be a coherent resolution in there somewhere.

Let me remind the committee. All we are trying to do, we do not have to micromanage the health care system. That is the good news. All we have to do is tell the Government to go minimize the financial incentive, take it to zero on why people come in for phlebotomy. You will then open up what we now believe to be a good additional source of blood to enter into the system.

That seems to be what I keep hearing. If you take the incentive out, then no one has objection to putting the blood in, even not labeled, so to speak, but the incentive must go out. Otherwise, there is risk from the window infection.

DR. AuBUCHON: You noted that several countries, Canada, Australia, Sweden I think you mentioned, used blood from hemochromatosis patients. I would note that all of those countries have socialized health care, and patients do not pay for things like phlebotomy.

DR. CAPLAN: I know. I know.

Then, another idea is they should finance tickets to Sweden for all people with hemochromatosis. They will bleed them there.

[Laughter.]

MR. ALEXANDER: Well, this is very interesting. I will go to Sweden. I would love to. I have never been there.

Randy Alexander, Iron Disorders Institute. I have hemochromatosis.

Something that is coming up here, and I thank you for the opportunity to speak, is that talking about costs in the insurance industry, talking about who is going to pay for this, the insurance industry does not understand this. The public does not understand hemochromatosis.

I respect your wanting to know if I am going to be transfused, what is hemochromatosis. Invariably, when we talk to patients or talk to people and they say what is hemochromatosis and then we educate them about it, it does not take forever to do it. We give them the very basics, and when they understand it, we tell them the treatment is blood. Then, they understand that they are not using the blood. The question is why. This is such a phenomenal resource that is being wasted.

We have had a tremendous record of success with the life insurance side of insurance industry. State Farm. We got to the head underwriter of State Farm. When that underwriter, that decision-maker, worked with us and understood what this was, they changed the whole underwriting procedure for State Farm. So has Indianapolis Life Insurance. So has TransAmerica.

So, when the public is aware of what this is, when the insurance industry is aware of what this is, and we are talking about costs, we all need to work together and educate the public and the insurance industry because, working together on this, it is