DEPARTMENT OF HEALTH AND HUMAN SERVICES

FOOD AND DRUG ADMINISTRATION

BLOOD PRODUCTS ADVISORY COMMITTEE

70th MEETING

December 13-14, 2001

8:12 a.m.

Friday, December 14, 2001

Maryland Room

Hilton Silver Spring

8727 Colesville Road

Silver Spring, Maryland

Kenrad E. Nelson, M.D.

Chairman

G. Michael Fitzpatrick, Ph.D.

Raymond S. Koff, M.D.

Jeanne V. Linden, M.D.

B. Gail Macik, M.D.

Daniel McGee, Ph.D.

Mark A. Mitchell, M.D.

Terry V. Rice

Paul J. Schmidt, Jr., M.D.

David F. Stroncek, M.D.

Sherri O. Stuver, Sc.D.

Jonathan S. Allan, D.V.M.

(by telephone)

Lianna Harvath

F. Blaine Hollinger, M.D.

Katherine E. Knowles

Toby L. Simon, M.D.

Linda A. Smallwood, Ph.D.

AGENDA

Page

Committee Updates

Consent Decree Update - Cecily Kodis-Kaufman 5

OPEN COMMITTEE DISCUSSION - HUMAN CELLS,

TISSUES AND CELLULAR AND TISSUE-BASED

PRODUCTS: RISK FACTORS FOR SEMEN DONATION

Introduction and Background -

Antonio Pereira, M.D. 28

Current Practices in Semen Banking -

Charles Sims, M.D. 36

Incidence and Prevalence of HIV, HBV,

HCV and other STDs Among High Risk Groups -

Linda A. Valleroy, PhD 66

Risk of and Actual Transmission of HIV,

Hepatitis, and Other STDs by Semen -

Deborah Anderson, PhD 105

HHV-8 as an Emerging Pathogen -

Michael Cannon, PhD 119

Open Committee Discussion

George Schreiber, Ph.D., Westat 129

Charles Simms, M.D. 141

Emmet J. Lamb, M.D. 156

Open Public Hearing 172

OPEN COMMITTEE DISCUSSION

Questions for the Committee -

Antonio Pereira, M.D. 231

Committee Discussion and Recommendations --

P R O C E E D I N G S

DR. SMALLWOOD: Good morning. Welcome to the second-day session of the Blood Products Advisory Committee. I am Linda Smallwood, the Executive Secretary.

Yesterday I read a conflict of interest statement that pertains to the proceedings of this meeting. That statement is available for anyone to review. Again, I would ask if there are any declarations to be made by the Committee members of anyone participating on this agenda, concerning the agenda items, please do so at this time.

[No response.]

DR. SMALLWOOD: For today's session we will have joining us, Dr. Michael Diamond, who has been appointed by the Senior Associate Commissioner as a temporary voting member with the Blood Products Advisory Committee. I don't see Dr. Diamond in here at this time, but I understand there is a terrific traffic jam, but nevertheless, we will proceed.

We have a very full agenda today, and we will try our best to keep on time. so at this time I will turn the meeting over to the Chairman, Dr. Kenrad Nelson. Dr. Nelson.

DR. NELSON: Thank you, Dr. Smallwood.

Because of the fact that many people have travel, airline and other travel arrangements, toward the end of the meeting, I'd urge all the speakers to keep on time, and if there are any major violations of this, I may cut you off in order to keep on time. So yesterday we got ahead of time to the break, and then after that we fell into a rut, as you remember.

The first speaker today is Cecily Kodis-Kaufman, to talk about FDA consent decree updates.

MS. KODIS-KAUFMAN: Good morning, everybody. I hope everybody survived the Beltway this morning.

I'm going to need a little bit of light behind me to see my notes if I could. Thank you.

I'm with FDA-CBER, Office of Compliance and Biologics Quality, in the Division of Case Management, and I'm going to give you an update on the consent decrees that we are working on right now. Steven Macialo, our office director, I believe, gave the Committee an update back in 1999, and this is sort of a follow-up to that.

Before I start I just want you to know that when these consent decrees are signed, there's a lot of work that goes into it up to that point, but that's really just the beginning of our work, and there's a lot of time and resources put into monitoring these consent decrees and performing the follow-up inspections, and reviewing the inspectional findings once a consent decree is put in place.

In the blood and blood products area we have the following consent decrees that I'll speak briefly about today: American Red Cross, Blood Systems, Inc., New York Blood Center and Cape Fear Valley Medical Center.

In the plasma derivatives area we have Alpha Therapeutic and Aventis Behring, which was formerly known as Centeon. In the in vitro diagnostic area we have Abbott Laboratories and Cal-Test Diagnostics.

These are some of the areas, just so you have an idea, of what is in the consent decrees. Most of these sections are taken from the regulations. For blood and blood products we have management controls, quality assurance quality control, computer systems and databases, records management and systems for HIV look-back in transfusion-associated infection. Also donor suitability, internal audits, training, testing of blood products, and air and accident reporting. So these are some of the areas that we've typically seen problems in that then get addressed in the consent decree, and we're looking for corrective action.

In the plasma derivative consent decrees, the sections relate more to the 211 sections of the CFR, training, reworked, reprocessed and returned or rejected products. There's normally a section asking for an expert consultant to come in and evaluate the firm's operations. Production and process controls, which is basically the manufacturing. Laboratory controls, buildings and facilities, equipment and recall procedures.

The first consent decree I want to talk to you about today is American Red Cross, and my slides, as of yesterday afternoon, I'm sure many of you have heard, are a little bit outdated now. FDA yesterday filed a contempt action against Red Cross, asking the judge to impose fines for continued violations of that consent decree. There's a press release on FDA's website. When you all get back to your desks, I'm sure you can get it. And I heard that there's an article in the Post today which I have not yet seen. This consent decree with Red Cross was entered on May 12th, 1993. There was a couple of recent letters issued under Section 6(a) which requires corrective action, one in fiscal year 2000 and a recent one just this past October. There was also an inspection of national headquarters, all of these things which led to the action yesterday.

That first bullet was my way of saying that at the time that I wrote the slide we were still in mediation, but now the action has actually been filed. And it's important to note that the existing decree remains in full force and effect. We will continue to monitor that decree and we will continue to conduct inspections while this case proceeds.

Okay. Blood Systems, Inc. That's a consent decree I worked on myself for many years after it was file,d and that was back in 1996, and the firm has submitted all the required documentation for all the sections that were required in the decree. Everything has been reviewed, and inspections are still ongoing, and we review periodic internal audit summaries from the firm and correspond with them about those as well, so we're continuing to monitor.

New York Blood Center was also entered in December of 1996. They too have submitted all the required documents and we continue to monitor them by inspection.

Cape Fear Valley Medical Center was back in 1993. All those requirements have been met, and the consent decree was vacated in January 2000.

Aventis Behring, formerly Centeon, was entered January 1997. There was an inspection in April/May 2001, which was a violative inspection, and the firm is making corrective actions and we are currently reviewing that with them. They continue to distribute albumin and they also distribute other medically-necessary products with third-party review and control.

Alpha Therapeutics was entered February 3rd, 1998. They were required to cease all manufacturing while they made corrective actions two times since the decree was entered. They have submitted the required documentation and taken corrective actions. They were reinspected April/May 2001, and as of June 2001 they have resumed manufacturing and distribution of all products, and that's been for almost six months now, they've been back in full operation.

Abbott Laboratories' consent decree was entered November 1999, requires the firm to bring all their IVD manufacturing processes and CAPA corrective action plan systems into compliance. They've been allowed to continue distribution of medically-necessary products, including viral marker test kits for blood screening. We continue to evaluate their corrective actions during inspections and to monitor their progress, and there is currently an inspection ongoing at Abbott right now.

Cal-Test Diagnostics was entered in June of 2000. They were selling unapproved diagnostic kits and failing to conform to GMPs. All those products were destroyed, all components and labeling as well.

Despite all the consent decrees that we have ongoing, there is a lot of firms in compliance out there. You can see we went from a low compliance rate of about 90 percent, and we're currently at about 94 percent compliance, and also in the blood area, 97, almost 98 percent compliance, up from a low of about 93 percent back in '94.

That's all I have. Questions?

DR. NELSON: We'll take some questions.

DR. SCHMIDT: Has there been any consent decrees which have resulted in a blood manufacturer going out of business or being put out of business, or in other words, any negative effect on the establishment?

MS. KODIS-KAUFMAN: Not that I'm aware of. Usually they can continue. They can make their corrective actions and get back and you know--

DR. SCHMIDT: And only the one has been vacated you're saying?

MS. KODIS-KAUFMAN: Yes. And that requires three years. We look for three years of compliance before we will allow the firm to vacate.

DR. SIMON: On your compliance rate, is that nonviolative, inspections where there is no warning letter or anything; is that how it's defined?

MS. KODIS-KAUFMAN: Yes.

DR. SIMON: And I guess the fact that the court action was taken yesterday, does that mean your mediation failed with the Red Cross; is that the conclusion?

MS. KODIS-KAUFMAN: Yes.

DR. FITZPATRICK: With a 98 percent compliance rate, we've seen a lot of information in the press that x percentage of the blood supply is collected under consent decree. So what would you respond? I mean how much of the blood supply is actually being compliant?

MS. KODIS-KAUFMAN: I can't really answer that, but what I can say is that even though with Blood Systems and American Red Cross under decree, there are so many locations that get inspected, and those numbers are generated inspection by inspection. So there are many locations that were in compliance, and that helps the numbers to stay up.

DR. FITZPATRICK: So it's within a large organization's license. Is it within the consent decree--is it within your section's purview to, if it were serious enough at one collection site, that there were enough deviations and findings, would you require that that site cease collection until they come in compliance, if you felt the there was one site within a license that was seriously out of compliance?

MS. KODIS-KAUFMAN: Yes, we could do that.

DR. MITCHELL: Can you sort of go over the steps that FDA takes from a minor violation to a serious violation? What are the enforcement tools that you have in your tool box?

MS. KODIS-KAUFMAN: When a firm has an inspection which is out of compliance and gets classified as "official action indicated", the first step is usually to send the firm a warning letter. We review that response and then we follow up quickly with a reinspection. Then once--if that inspection is again violative, then we would consider what other options we have available to us. We also have--keep in mind, for a licensed firm, we can also suspend, which can be done very quickly. If there's a danger to health, we can immediately suspend that firm's license, which would stop them from shipping anything. We can also take the longer term action of revoking a license, and usually they get a chance to come into compliance first.

On the legal side, if we have a continuing pattern of noncompliance, significant noncompliance, we can enjoin the firm, which is what we've been talking about today, where they've been asked to take corrective actions, or the injunction could cease manufacturing, but normally with blood, we can't do that because the danger of that is worse than the problems that we have. So there's injunction. And there's also seizure of products that are violative on the market. We also have that enforcement tool.

DR. NELSON: How frequently are inspections done?

MS. KODIS-KAUFMAN: Inspections are done, I believe, every other year unless--you know, if there's a history of noncompliance we would do them more frequently, but the law requires every other year.

DR. FITZPATRICK: In your presentation Aventis was the only organization that you mentioned third-party review and controls. Is that--was that a voluntary result of the firm wanting to come into compliance? Was that something you imposed? Could you impose that on others?

MS. KODIS-KAUFMAN: Yes. It's--I mean they agree to it in the consent decree that they signed. I don't know how voluntary it was, but they eventually came to agreement to have the third-party control. I think I mention it in that one because it's actually used more product by product with that firm. I know we've used it with other firms to inspect sort of their overall operations to have an outside consultant come in and do an audit for them and see what other types of problems they could find that maybe we hadn't picked up or the firm hadn't picked up itself, so that we make sure that the firm is correcting as much as it can, pretty much everything it can when they're going through this process, that we are not missing something.

DR. STRONCEK: I suppose it's hard to talk about details, but there have been--you listed several firms that have been, had these consent decrees, and many of them look like--you know, one was vacated and many look like they're making progress. But, you know, one large blood organization that has had a consent decree as long as anybody seems not to be. And what are the--and you said, and I understand, you really can't shut down blood collections, but what are the options after fines? You know, increasing fines or?

MS. KODIS-KAUFMAN: I don't know. I think we're hoping that this is going to work. You know, I think if there was a danger to health we could use our suspension powers, but I don't think we're at that stage right now.

MR. RICE: Just for my own understanding, it would seem to me that going to the extent of obtaining consent decree must be a fairly rare occurrence.

MS. KODIS-KAUFMAN: Yes, in the overall scheme of things, if you look at all the firms out there.

MR. RICE: So for the FDA to have to go to that extreme, there would have to be a pattern of noncompliance serious enough over an extended period of time for you to actually I guess decay into having to go that far to get somebody's attention?

MS. KODIS-KAUFMAN: Yes, that's correct.

MR. RICE: And the other thing that you had mentioned about many of the firms being in compliance, maybe as high as 98 percent, I think it's important to note that while that number may be somewhat reassuring, there are certain disease states that take certain products that only certain companies make. So when you consider the impact to the consumer, it can be far more interesting for certain consumers of blood products, depending on how manufacturers manufacture a particular product that may be as low as 50 percent of the companies that manufacture certain products are actually in compliance. So while the 98 seems somewhat reassuring, it all depends on what you're taking I guess for therapy.

MS. KODIS-KAUFMAN: Yes?

DR. MITCHELL: Can you tell me a little bit more about the consent decrees? Does the FDA have the power to enter into a consent decree with an organization, or do you always have to go through the courts? How is that negotiated?

MS. KODIS-KAUFMAN: What normally happens is we decide that we want to enjoin the firm and we draft the documents, the complaint that would be filed with the court, as well as the consent decree, which is very detailed and outlines all the steps we want the firm to take that we think would bring the firm into compliance. And then normally we will call a meeting with the firm and give them the opportunity to review the documents and voluntarily sign the decree, but it's not--after that, the documents get filed in the court. So the decree itself becomes nonvoluntary. They're binded by the court to abide by the decree once it's filed, but in many instances we've been able to voluntarily work out the language of the decree with the firm without having to go to court to do that.

DR. MITCHELL: I'm sorry, I'm not understanding. So are you saying that if you work out the language with the firm, that you don't have to file it with the court?

MS. KODIS-KAUFMAN: No, we do still file it with the court so that it's legally binding on them.

DR. MITCHELL: So in all of these cases, including with the Red Cross, you have worked out language that's been agreeable?

MS. KODIS-KAUFMAN: Well, in this case now with the Red Cross we could not work it out and that's why the contempt action was filed yesterday. So that will be done in front of the judge I believe.

DR. MITCHELL: Is it possible for you to close down one location of an organization even though they have a license, a broad license?

MS. KODIS-KAUFMAN: I'm really not 100 percent sure, but I think we could if we really needed to. I think since we issue the license, we could probably suspend it the way we want to. I'm not sure if we've done that.

Have we done that, suspended one location?

DR. EPSTEIN: We can suspend by location.

MS. KODIS-KAUFMAN: By location.

MS. KNOWLES: I want to thank the FDA for bringing this update to our Committee, to BPAC. I would like the record to show that I have been, as the consumer representative, asking for this update since March of 1998, so I appreciate that it has finally come, and I appreciate your work in terms of presenting it.

I don't mean to single out one group or anything here, but having followed HIV since the beginning of its emergence in this country, and also watching the blood supply, watching when the first consent decrees were filed in 1993. As I recall, there were 100 violations at that posting. The article a year ago that appeared, noted that there were 83 violations at the Red Cross with only two sites. When is this going to stop? When is corrective action going to happen? This is dismaying. It's terrible. And I really ask you to please do the right thing.

MR. RICE: I just wanted to support Kathy in that it is disturbing that it's gone on so long. But I think it also makes clear to us that really, I don't know what can be done about it, but the enforcement actions available to the FDA seem to be either, you know, you try to nudge them along in a cooperative fashion, or you have to go to the extreme of pulling a license that--I mean it seems like all there is is this big hammer at the very end that they can really pull the trigger on, but there's nothing--I guess a consent decree at least gets the attention, but it seems a little distressing that it's either a big hammer or a very small hammer, and there's nothing that I can understand from the enforcement actions you've brought to the attention of the Committee, that it's either all or nothing. Is that pretty much the case?

MS. KODIS-KAUFMAN: No. I would disagree with that. I mean when we inspect the firm, they get a warning letter. We go back. We reinspect. I mean it's sort of a buildup. It's an ongoing process. We look for a significant pattern of noncompliance. The firm knows, in the early stages, that things aren't right, and it just sort of builds from the small hammer of the warning letter to a bigger hammer of a suspension or an injunction or whatever we need. It's not all or nothing. It's a progression.

MR. RICE: It sounds like the progression in one case has taken 10 years though.

MS. KODIS-KAUFMAN: Well, no, because we took the enforcement action of the injunction back in '93. They've been under that decree and we've been trying to work toward compliance since then.

MS. KNOWLES: But I understand actually the agency's been out of compliance for almost 20 years.

DR. EPSTEIN: Well, I think part of the answer to your question, Terry, is that it's wrong to think that there has not been progress. It's just that the FDA is expressing its determination that there hasn't been enough progress or soon enough. What we expect is full compliance period, full stop. There's no reason that any blood establishment should not comply fully with FDA requirements and standards. But the perception that because we are still taking compliance action means that nothing has been corrected or nothing has been done is a misperception. There has been a great deal accomplished and a great deal of progress. It's just that we haven't reached the end point. And I'm not saying this to in any way minimize or excuse any company's violative behavior, but the course of action that we pursue, you know, as Ms. Kaufman outlined, is progressive and is iterative.

Now, we also have further tools. We can go beyond injunction to also seeking monetary penalties under injunction. And as you know, we did that with Abbott Laboratories, and this is the point of contention now with the Red Cross, is that FDA seeks in a revised injunction the authority to impose prospective monetary penalties. In other words, for each instance of noncompliance, there would then be a monetary penalty. And let me say that there are actions that go beyond that. I mean the Agency can seek civil action against individuals, and even where appropriate, criminal action. So we do have an array of tools. However, the Agency's approach is to go gradually in proportion to what we think the problems are. Now, when we think that the products on the market constitute immediate hazards, we can seize them, we can enjoin to stop manufacturing or to cease distribution, and we do those things based on our assessment of the health risk and of the likelihood of it continuing.

So I just want to balance this. I mean the actions that we're talking about are very serious. They do reflect the assessment by the FDA that these are matters of public health concern. You know, we are resolute in our mission, but the impression that this means that there's no progress and that it's all or none is incorrect. We are at the same time, in making gradual steps, achieving significant progress. And I would say that that's the pattern really across the spectrum of the decrees that have been outlined.

MR. RICE: Do you feel that you have enough tools? My misunderstanding may have been that, in an oversimplified review of what actions you have available to you, you sound as though you have an appropriate number of tools with an appropriate amount of enforcement availability behind each of those tools to get your job done.

DR. EPSTEIN: Well, I think the way I would put it is this: under the existing acts we have administrative remedies and then we have remedies that we can seek through the courts. The administrative remedies go to the extremes of suspension and revocation. Also with respect to product, we can seize product. Those are very powerful tools. In the case where we need to seek court-mediated remedies, we acquire the power of the court. Of course the court has to agree with the Agency. You know, you go to court, you plead your case, you ask for certain things. If the judge agrees, then you acquire the tools available under the judicial system, and those are also very powerful.

So I don't know that it falls to me to make any kind of global statement whether our tools are sufficient. I can only tell you that they are powerful tools and that we exercise them as we think we need to exercise them. I'm sure that the authorities within our enforcement groups would be happy to listen to suggestion if you think that there are other tools, but, you know, in reality we have quite an array of powerful tools.

DR. MITCHELL: Can you tell me about the amount of time that it takes--I know it will be very variable--but I mean is it not unusual for something to take 8 years to correct an action? What is typical for the time that it takes to come into compliance with a consent decree?

MS. KODIS-KAUFMAN: I can't really answer that, given that, you know, we just sort of--there's just too many variables. There's really no typical--it's really on a firm-by-firm, case-by-case basis, depending on what the violations are.

DR. MITCHELL: So can you tell me, do you have any idea why it's taking so long for the Red Cross to come into compliance?

MS. KODIS-KAUFMAN: I just think it's a long process. I can't really answer that. You have to ask Red Cross I think.

DR. EPSTEIN: FDA believes that the Red Cross has both the resources and the technical know-how to correct all its deficiencies. It's FDA's belief that for whatever reasons intrinsic to the culture at Red Cross, this matter has not been given a high enough priority, and that's why we are seeking now to move toward penalties to increase the incentive that this matter be fully and completely addressed.

DR. NELSON: I think I'd like to move on if--oh, go ahead.

DR. FITZPATRICK: When Canadian Blood Services reached a certain point, they were essentially dissolved and reorganized because they were a national blood collection agency. I think reading the article and the articles in the last couple days, there's going to be a renewed angst among the public about the blood supply, and a number of comparisons made. Could you put into perspective, or could somebody put into perspective where you feel the seriousness of the situation is in compliance? Are we at a state where, to draw a parallel--even though it's not a good one maybe--is it so bad if it were a national agency, you would suggest complete reorganization, or is it a matter of--not a matter of safety, but more a matter of meeting CGMP regulatory requirements?

DR. EPSTEIN: Well, we do see CGMP violations as having safety implications. So what I would say is that the failures of the Red Cross to fully comply with the requirements of current good manufacturing practice do create the potential for serious harm.

That said, it needs to be understood that safety is relative, and it's a question of balancing risks and benefits. There is no question that anyone who needs a blood transfusion is at far greater risk not receiving the transfusion than receiving it, and therefore, should not hesitate to receive a transfusion if medically indicated.

But because these quality assurance deficiencies exist, it would be our opinion that the blood supply could be safer and indeed should be safer. The fine line here is that we're talking about a degree of assurance. We're talking about the need for qualify assurance procedures and quality controls to be in place so that the products will have their expected safety and quality. So what's at issue here is improving the assurance of safety. In the face of these problems, it is nonetheless true that we have among the safest blood supplies in the world, and that it is certainly in every patient's interest who needs transfusion to receive that transfusion. Again, the benefits vastly outweigh the risks, even in the current circumstance.

DR. SCHMIDT: Mr. Chairman, I would like to say, as a person with a background in political Washington, and coming from a very political state, that I'd like to go on record to admire the courage of the individuals involved in today's activities or the very current activities, the courage of the government employees involved.

DR. NELSON: Okay. Thank you.

MS. KODIS-KAUFMAN: thank you.

DR. NELSON: The next topic is human cells, tissues and cellular and tissue-based products, risk factors for semen donation.

Dr. Pereira?

DR. PEREIRA: Good morning, members of the Committee, FDA and general public. My name is Antonio Pereira, and I'm a medical officer--

AUDIENCE: Can't hear you.

DR. PEREIRA: Okay. Now, better?

Okay. My name is Antonio Pereira. I'm a medical officer with the Human Tissue Staff of CBER.

Today I would like to give you an introduction and background to the theme that we're discussing, that is, risk factors for infectious disease transmission by semen insemination.

The purpose of bringing this topic to the BPAC is basically to review the scientific information as for today to enable the Food and Drug Administration to complete rule making aimed at preventing introduction, transmission and spread of communicable disease by human cells, tissues and cellular and tissue-based products, including reproductive cells and tissue. And today we are going to talk about semen.

In January of 1997 the Agency published a document titled "A Proposed Approach to the Regulation of Cellular and Tissue-Based Products" that would apply a tired approach to regulation of human tissue based on public health risk of these products. The plan was to propose three rules for comment, publish draft guidance for comment, review all the comments submitted to a docket and finalize the rules, and then the final rules and the guidance will be effective at the same time.

So today the status of this proposal is that in May of '98 an establishment registration and listing proposed rule was published and was finalized in January of this year, is implemented in April of this year for tissues that were already regulated by the FDA. In September of 1999 the suitability determination for donors was proposed, and in January of this year current good tissue practice inspection and enforcement proposed rule was published. The suitability determination for donors for human cellular tissue products was published and had a docket that received approximately 500 comments. The comments basically addressing the semen cryopreservation and donor retest requirements, and behavioral risk deferrals that will be specified into that guidance that is actually under development.

This is an opportunity for public discussion of the scientific data that will enable the FDA to finalize these policies. And we are aware that there are many considerations of semen banking and semen donation, legal, ethical and cost, but they're not the focus of today's discussion though.

The donor suitability rule introduced the concept of relevant communicable disease agents or disease, stating that it should be sufficiently prevalent among potential donors to warrant screening and testing of all donors; that it poses a risk of transmission to recipients of medical personnel; that it has significant health risk and that appropriate screening measures and/or appropriate FDA approved screening tests are available.

In the rule we define three types of semen donors. First on anonymous donors, where there's no relationship between the donor and the recipient, and this is geared for sperm banks that service infertile couples or individuals interested in reproduction. There is defined a directed donor where there is a designated donor who is chosen by the recipient and a sexually intimate partner, where couples are sexually intimate and need assistance for a successful pregnancy.

The rule proposed requiring for the anonymous semen donor a screening process that will show that is free from risk factors or/and clinical evidence of infection due to relevant communicable disease agents including at a minimum the HIV, hepatitis B virus, hepatitis C virus, HTLV and CMV; should also be free from risk factors for human transmissible spongiform encephalopathies, including Creutzfeldt-Jakob disease, and sexually transmitted and genital diseases including Chlamydia and Neisseria.

It also required testing for this anonymous semen donor to be negative for evidence of infection due to relevant communicable disease, and the agents in this case will be HIV-1 and -2, Hepatitis B virus, Hepatitis C virus, HTLV-1 and -2, and cytomegalo virus; also Trepanema pallidum, Chlamydia trachomatous and Neisseria gonorrhea.

It further proposed that for the anonymous semen donor to increase safety, the semen specimen should be cryopreserved and quarantined for at least six months until the donor is retested using a new blood specimen for evidence of infection to the relevant communicable disease agents that I stated, and found negative.

It stated the definition of a directed semen donor as a living person who is the source of cells or tissue designated for a specific potential recipient. It further adds that the reproductive cells--a living person who donates reproductive cells or tissue to a specific recipient, who knows and is known by the recipient.

The requirements for this directed semen donation on screening and testing will be the same as for the anonymous donor. It's also required the cryopreservation for at least six months and retesting of the donor, the same as for the anonymous. However, the use of this semen from a directed donor who screens or tests positive is not prohibited, okay, provided that the semen is labeled as a biohazard and the recipient's physician is notified of the screening and testing results, authorizes the use, explains the risks and obtains consent. Some commented that we shouldn't require the physician to authorize the use.

For the sexually intimate partner that already engaged in risk by having sexual relationships, the rule proposed screening and testing that is not required for them. The cryopreservation and six-month quarantine are not required, but again, the semen specimen should be labeled, infectious substances and biohazard if positive for a risk factor or a test.

As I said it before, there were more than 500 comments received, and this morning we will try to address comments that suggested two things, that a directed semen donor we should permit to use a fresh semen, not a six-month quarantine donor retest, because fresh semen is better than frozen semen for achieving pregnancy; and comments addressing the anonymous semen donor, that we should defer men who had sex with other men in the past five years because safe subsets can be identified through a questionnaire for these donors.

I want to make the Committee aware that when we looked into the legislation of the other states, there are some laws already on the regulation of semen. For example, New York State, in its regulation, states that if the semen to be released originates from a directed donor, the recipient may be given the opportunity to waive the quarantine period in writing after being advised by the director, his/her designee, or the person performing the examination of the risks. It further adds that the donor must have been tested within one month prior to donation and every three months thereafter.

California also has in its code, its health code, an exception where it goes like all donors of sperm should be screened and found unreactive for HIV, Hepatitis B and C viruses, HTLV-1 and syphilis, except in the following instances: a recipient of sperm from a sperm donor known to the recipient may waive a second and other repeat testing of that donor if the recipient is informed of the requirements for testing donors under this section and signs a routine waiver. I want to make clear that the California code does not define the term "directed donor."

At the end of the presentations of this morning, we would like the Committee to consider a series of questions and help us answer them. The first one will be: is safety increased when cryopreserved semen is quarantined and the donor is retested after at least six months?

The second question we would like to know: as compared with the use of fresh semen, does use of cryopreserved semen for artificial insemination reduce pregnancy rates? If it's true, what is the estimated reduction in pregnancy rates? And if there are procedures for cryopreservation and/or insemination that can improve the pregnancy rates using cryopreserved semen? If there exists, what are the benefits versus risks of these procedures?

We will further like to know and answer: is there existing data that identifies subsets of men who had sex with men in which the incidence and prevalence rates of HIV, Hepatitis B and C viruses of these subsets are similar to the population at large? If so, are there questions that could be asked to potential donors that would alternatively identify members of this subset to the exclusion of all others?

I hope that the presentations scheduled for this morning will have answered these questions, and I am sure that expert data that you will hear this morning will help us get a clear picture of the available science at this moment.

So that was my introduction. I would like then to ask Dr. Sims, as the first presenter, to come. Thank you very much.

DR. SIMS: I think while he's getting it started, I'm going to just go ahead and start at least some introductory parts of my presentation. And perhaps it's fitting that in some ways I'm going to use a low-tech presentation of overhead transparencies because sperm banking in many ways is a technology that originated many years ago, and the fundamental technology really has not changed for approximately 50 or 60 years, there have been improvements. Just one moment, please.

[Pause]

DR. SIMS: I'm going to just step around here so I can really see what's up there. Can you hear me all right?

First of all I'd like to tell you just a bit about who I am, where I come from, to give you some kind of perspective. I am a clinical pathologist by training and background. I am the Founder and Co-director of the California Cryobank, which is a human sperm bank. We organized in 1977. I've been a very active member of the American Association of Tissue Banks, and a supporter of well-thought-out and well-designed regulation, because I think that that protects the safety of the public. And I think it's the duty and responsibility of all of us who are in this field to have as paramount our primary concern, the safety of recipients.

There are many dimensions of that problem or those issues. I'd like to set the stage by describing sperm banks, how they work, how they're organized, to give you some kind of context in which to understand the issues that will be discussed. I'm not sure that any of you have ever--how many in this room have ever even been in a sperm bank? Okay, I see a small number of hands. That's good.

This is the scope of the presentation: organization, how donors are recruited, the evaluation of the prospective donor for suitability, the steps that are taken in the qualifying process, the management of the repeat semen donor, and post-donation management. That's the scope of the presentation.

Nearly all human sperm banks in the United States are organized as for-profit entities. I think there's one or two in the country that are nonprofits. Most sperm banks originally came out of fertility clinics. They were adjuncts to the practice of infertility, usually gynecologists treating women who are infertile. They recruited the available men as donors, a medical student walking down the hall or whoever was handy. That's kind of the background of that. Unfortunately, I think we're well aware of a few instances where a few people who ran infertility clinics became their own donors. Those are well publicized. So sperm banks run the gamut of highly-organized, well-structured organizations to free cowboy types.

The primary source of donors that nearly all sperm banks currently use are the campuses of colleges and universities. Why do we go there? Why do we do that? That's because that's where--it's like Willie Sutton, "Why did you rob banks?" "That's because that's where the money is." We go there because that's where there's a large number of young men who are healthy, who have high fertility potential and that are available. So that's the reason that--fundamental reason that we adopted as a strategy the student as the donor for sperm. We advertise in student newspapers, word of mouth, et cetera. We have to get creative at times because there's a shortage of donors.

There are many issues with being a donor. It's not a trivial process as we'll discover later.

Donors are compensated. This is nearly universal among anonymous donor programs. The amount of compensation is probably about $75 on the average. There is a range. The specimens are donated. We do not consider that the specimens that we obtain as being purchased, but we compensate the donor for their time and their expenses, and the time requirements that a donor makes to be a sperm donor is considerable. So it's not a trivial thing. It's much more complex than that of a blood donor. To donate blood, you can go to your local blood bank, roll up your sleeve, you answer the questionnaire; in an hour you can probably be out of there and eat some cookies and drink some orange juice. In sperm donors the time requirements span many, many months, in some cases several years, so it's not trivial, and there are enormous responsibilities that go with being a sperm donor.

The general principles for donor suitabilities are listed here because we can get bogged down into all the point-by-point issues, but from a conceptual standpoint, the donor has to be healthy, he has to be fertile, he has to have no evidence of infectious disease that's transmissible by semen. And there probably is some difference between a sexually-transmitted disease and a semen-borne disease, because with sex there's mucous membrane and mucous membrane contact. With semen, we're dealing with semen or seminal plasma. There is some distinctions there. The donor must have no apparent risk for a serious genetic disease, must have an acceptable social history that excludes behavior that's associated with known risks for acquiring sexually-transmitted diseases, must understand and accept the responsibility of being a semen donor, and must be compliant with the policies and procedures of the bank. Every bank had developed policies and procedures that donors must comply with. They have to give us information. It's not a trivial process, and the minimum time requirement, as mentioned earlier, is probably--I have put up here 9 to 12 months. In reality it probably is more like 12 to 18 months or 24 months. Next.

The specific health assessment of the donor is performed in the following manner. We obtain a complete medical history of each donor. Each donor is given a complete physical examination by a physician. And we also assess health by laboratory testing. This is really in two parts. The part that's put up here is general health testing. A CBC, a complete urinalysis and a general chemistry profile. The purpose for this is to get an understanding of the donor in terms of his general health. The CBC is a very useful tool, because for instance, in Beta thalassemia, the carrier trait is associated with a diminished MCV and MCH. So those are useful tools, both for genetic screening as well as general health. Next.

Infectious disease marker testings are those that have been--Dr. Pereira has mentioned earlier. We test for HIV-1 and -2, HTLV-1 and -2, B-surface antigen, B-core antibody, hepatitis C, CMV IgG and IgM, syphilis serology, Chlamydia testing and gonorrhea testing. The use of the core antibody is not to determine infectivity at the moment but is used in serial testing to detect a window period in which a person may have acquired Hepatitis B, have a transient elevation of B-surface antigen, and then on retesting, that antigen may have diminished below the levels of detection, but we can detect the footprint of that disease by the core antibody. That's the rationale for that test.

The fertility evaluation of a donor is done both by history and by predictive measurement such as semen analysis. If the donor has had children or has been responsible for pregnancies, this in essence is proof that the donor is fertile. We use the semen analysis as a surrogate for fertility. We measure volume, count or concentration, motility of the sperm and the morphology of the sperm. While each of these have some correlations with fertility, they are really surrogates for fertility. They are not exact measurements, and there are many exceptions to that.

The social history is an important adjunct in that it complements the laboratory testing. Laboratory testing, as all of you know, is not perfect. Laboratory testing has a potential for clerical error, analytical error, and there are some issues of matrix or the substance in which it's testing in can sometimes give you misleading results. The test may not come up in the--the marker may not come up in the expected time, so for a number of reasons, the use of the history of the donor for risky activities is an important dimension of measuring potential risk of transmitting infectious disease, sexual practices, sexual promiscuity, the use of nonmedically supervised drugs or recreational drug use. We want a donor who is stable, who has a productive lifestyle. We feel that a donor--it's more important to us that a donor, and certain other characteristics that are almost intangibles beyond just infectious disease testing. We want a donor who basically has a good lifestyle, a donor that has a well-integrated life. We're not--the bad rep that paid blood donors had was the old story of the alcoholic on the street recruited as a paid donor. Those elements do apply to sperm banking in that people who have a well-integrated life, they're productive, they can start a job or continue in it or they can go to school, is a marker or a surrogate for at least some elements of risk behavior, so those are elements that we also use.

The genetic evaluation of the donor, which is not covered by the proposed FDA regs, but are important from an operational standpoint, we are trying to evaluate the donor for risk of significant increase in genetic risk factors. To accomplish this goal we do a three-generation genetic and medical history. We do testing. The tests that we perform are listed up there, and some of the tests such as hemoglobin, like the pheresis, Tay-Sachs, Canavan's disease, are--those occur in higher frequencies in some ethnic subsets, and so our testing is limited in those subsets where there is known high-frequency of genes. Next please.

Each donor gets an interview by a genetics counselor in our operation. We have three full-time medical genetics counselors who do the donor interviews, review the donor charts, and assess those risks. They're also supervised by a board-certified medical geneticist for questions that may come up in terms of what is the risks of something? Is this a donor we should take or not? These risk reduction measures from a genetic standpoint have serious limitations that both the public and people in regulatory and other agencies need to be aware of, in that we get--the information that we get from the donor in terms of their medical and family history is always limited. It's limited by the knowledge of the donor. In some cases that information may even be incorrect. Those of you who have done some genealogy are pretty well grounded in the pitfalls of your immediate impressions and what you really find out later when you get documentation. So the genetic review is a matrix of both testing medical history and the genetic interview, but it always will have certain limitations.

The tests themselves have certain weaknesses. They're performed by human beings. It's possible to have analytical error. It's possible to have clerical error in tests. Many of the tests, such as cystic fibrosis mutation testing is limited by the number of mutations that you test for. For example, we currently use a method--or an outside laboratory which tests for approximately 85 or 90 mutations of cystic fibrosis, while there's more than 800 known. It's a very large gene, and a mutation at any one point can produce a carrier state and it may be not detectible by the test methods that you're using. So all of these are screening tests. They are not definitive tests that determine the presence or absence of a specific mutation in many cases. There are some tests where there is a single substitution such as hemoglobin C or hemoglobin S that lends itself to yes or no answers. In other cases the genetic tests themselves have inherent limitations because of large complex genes.

As stated, the goal of genetic screening or testing is to reduce risk. There are no genetically perfect donors, and there's no consensus as to what is perfect. Every one of us in this room carries bad genes. Fortunately they're infrequent and they don't cause problems most of the time, but there is no such thing as genetically perfect human being to my knowledge.

So to summarize the qualifying process of a donor, the donor must meet the bank's requirements in a number of parameters. We use--we currently use 19 to 35 as an age. We use--we have an education requirement that we use as a surrogate for intelligence. Obviously, there are extremely intelligent people who do not have college degrees. My own father is an example, he went through the fourth grade. So he would not have been an acceptable sperm donor by most sperm banks, but is a very bright man. So those are very arbitrary, and they're somewhat driven by social expectations of recipients as oppose to having a foundation in science in some cases. We measure the fertility potential of a donor. The specimens are giving test freeze and thaw. In other words, we freeze a specimen, thaw it out and retest it for preservation of motility, survivability.

After the completion of all the tests and everything that we do, the charts are then reviewed by the donor department. The donor department will recommend approval of a donor. There is a review and recommendation of approval by the geneticist. The physician who does the physical examination also reviews the health testing as well as the physical examination and recommends approval. Then this chart and all of the relevant documents are reviewed by the medical director of the semen bank, and then the donor is either approved or not approved as a donor for the bank.

The donor at this point is classified as provisionally qualified. Semen samples may be collected, processed, frozen and held in quarantine until release by the medical director or his or her designee. The approval for a donor is limited to one year. After one year the donor must be requalified, including a complete physical examination, complete review of social history, et cetera at the end of one year. The one-year period is an arbitrary number, but it's a workable one and I think it's appropriate, but that's our practice.

The donors are repeat donors. They donate, hopefully, one to three times a week. At each donation we ask the donor to provide us information. Has there been a change in either sexual partner, change in their health, has anything happened to them? This is done verbally with the donors at each donation. So if they're coming in twice a week, you know, they're asked to provide that information to us at each point. Each specimen is examined by laboratory personnel for count, motility and the presence of WBCs or white blood cells, and the white blood cells are a marker for potential infection that may not have shown up by history or by other measures.

If a specimen is satisfactory on examination, it's frozen. The exact number of vials that are produced depends upon the volume, the count and the number of motile sperms. We have a target goal of having 20 million total motile sperm in each vial on post thaw, and if you assume a 50 percent loss in survivability, then we need to start out with 40 to 40 million sperm in a cryovial to produce 20 million when it's thawed. Prior to freezing cryoprotectants are added. This is cocktail which we can describe later, that lessens the injury of the freezing and thawing process. Freezing by itself is akin to you or I jumping out of an airplane at 30,000 feet without a parachute. So the cryoprotectants give the cells a soft landing in the freezing and thawing process. We test the donors formally at two- to three-month intervals. We use a three-month interval. Perhaps we could go to the next one.

The testing schedule that we have employed is not a six-month repeat testing. We use a three-month repeat testing sequence. We do a baseline testing or zero, and let's assume that the results or the infectious disease markers are negative. Then we will test the donor then at three-monthly interval. And at each three-monthly interval we give a formal interval health questionnaire that the donor fills out with regard to health, sexual practices, the presence or absence of any illnesses in the interim, the use of drugs or medications, medically supervised or otherwise, and this is repeated at three-monthly intervals. And using the six-month quarantine period, as you can see--let's assume this is a new donor--so at baseline the donor tests negative, three months negative, six months negative, but at six months we only have one specimen. That's not enough inventory really to release, so it's impractical.

So we test at nine months, and at nine months, if a donor tests negative--and at this point we have four successive infectious disease marker test results, then at that point we release vials obtained in months zero to the third month, which gives us three months. And then in terms of shipping our release, we try to use the oldest vials first that we release, but they are released and moved from quarantine inventory to releasable.

We have physically separate LN2 refrigerator tanks that we have the quarantine inventory and releasal inventory. It's asking to a blood bank where you have different shelves or different refrigerators for specimens that are ready for release and those that are being held in quarantine. So these are physically separate, and this is for two purposes. One is potential for cross-contamination and the other is that there is a potential of accidental release of a vial. So physically separating releasable from the quarantined is a safety measure.

One of the least understood aspects of sperm banking is the post donation management of the donor and the records and information that occurs. The elements of post donation are we need to keep track of where the donor is in case something happens. We may need to contact the donor in terms of where they're living. We may need to contact them. So we ask the donor to keep us apprised of changes in address. We monitor pregnancies and live births. We ask each recipient and each inseminating physician to report any adverse reactions, and we investigate those reactions. We treat an adverse reaction report as anything that the recipient or the inseminating physician reports as some untoward event that they perceive. That's recorded as an adverse reaction report, and then we investigate it and try to come to a conclusion as to whether this is donor related or not or significant or not. But each report is sequentially numbered and recorded and investigated.

Occasionally we will need additional information from the donor in terms of historical information. We may need to retest. Occasionally, you may have a situation where a child is born with a recessive genetic disorder that is of significance and we may need to contact the donor and let the donor know that they are the carrier of a genetic mutation that has some risk and they should be aware of that. So those are reasons to contact a donor.

One of the more common reasons that we recall a donor is for additional specimens to achieve sibling pregnancies where a family has one child by the donor, and they want a second child with the same genetic origins. Other methods are vial recalls, recipient notifications, et cetera. There are many and numerous. We have an individual assigned full time to tracking and managing this aspect.

To accomplish what we need to do, it's essential that you have good records, you have a method of preserving those records, that they become accessible to you so you can find what you need. If you have records someplace, but if you can't find them, then they're no use to you. So a system of record retention, record management is essential to accomplish the post-donation even management of a donor program. How long should that be? There's a general consensus that it should be for not less than about 25 years, and most people feel that it should be indefinite. It certainly can go much beyond that, but there has to be a practical point where someone is not compelled to require record retention for hundreds of years.

An issue that is not as well addressed is what is the obligation of the sperm bank to children that have been born from anonymous donors? Do they have any needs? Do we have an obligation to them? I think we do. Most people think that there is an issue there. Those have not been formulated by standards or by accrediting or regulatory agencies, but I think that each bank needs to address that issue and have a formal policy as to how they will deal with it.

And I think that's the--no, there is something else. The fundamental goals of what we're trying to accomplish is that we're trying to allow for couples or individuals to have families. That's what we're about, family creation. And our obligation, our goal from an operational standpoint is the safety of the recipient and the effectiveness of the cryopreserved sperm. In order to accomplish these goals, there have to be appropriate policies, procedures and practices. A quality program, such as was discussed earlier. The American Association of Tissue Banks has provided national leadership in developing standards for practices in all of these areas, and they are to be commended for doing that. This led by many years the development of regulatory efforts by certain states and by the FDA's proposals. I think that the presence of regulations and accrediting bodies are in the best interest of our society. I think if the regulations are well designed or well thought out and are workable, that those are good things for sperm banks. They're good for our society and they're good for the public in general.

The fear, always, of course, is that we're like a little insect in the forest and the FDA is the big elephant that comes on and steps on us without even seeing us. So we have--while we have this somewhat paranoid fear of the government--maybe it's not paranoid--but the individuals that I've met and talked with and what I have seen so far, leads me to be very favorable disposed towards what the FDA is proposing to do. I think they're well thought out. I think they have been careful in the design. They have sought feedback and input from both individuals and by organizations that serve the interests of both semen banks and infertility clinics.

Thank you very much for your time.

DR. NELSON: Thank you, Dr. Sims, for a very lucid presentation. Comments?

DR. KOFF: Of the genetic disorders that you are testing for, the most common genetic disorder in the United States is hemochromatosis. There are only two mutations. Have you considered it, or was it rejected, or why isn't that being done?

DR. SIMS: Well, where do you stop? Hemochromatosis is a very common gene, the gene for that is probably just about as frequent as cystic fibrosis, if not perhaps a little more so. The difference is that cystic fibrosis is a disease that really doesn't have an effective treatment. Hemochromatosis can be treated by limitation of iron, by phlebotomy. In women the onset of clinical manifestations of hemochromatosis are really quite delayed because of the menstrual cycle, where they therapeutically in a sense get rid of excess iron every month.

Our chemical profile does measure iron. Iron is not a measurement for that, but it's one of the things that we have no adopted that's been discussed. We have a genetics advisory group that helps advise us as to what we select. The problem is, as mentioned earlier, is that if you excluded a donor because a donor carried a deleterious recessive genetic mutation, you would exclude everybody in this room. Now, hemochromatosis is a high-frequency gene. So do we try to minimize risk to the offspring by excluding donors only, or should there be an assessment of the genetic risk that the recipient and the donor both have what the risk is to the child? I propose and submit that what's needed to accomplish that goal of reducing genetic risk is complementary assessment of the specific genetic issues that are involved both with the recipient or the mother and the donor, and looking at potential risks in that combination.

DR. NELSON: Does your institution do directed donation? We heard that the FDA described the difference in different regulations.

DR. SIMS: Yes, we do. In our directed donor program the directed donors are required to undergo the same screening and testing that the anonymous donors are, including the six-month quarantine period. The difference is that we allow greater latitude in waiving either both certain test results or genetic issues when there is a known donor. There are several instances where this occurs. In heterosexual couples, there's frequently desire to have a genetic link between the donor and the family of the husband, so a brother or relative sometimes is sought. In this case we presume that the knowledge of the family that the husband and the wife have is sufficient to make that risk determination. If we find something, then we discuss this with them. For instance, we do cystic fibrosis testing even in that case because the genetics of a brother are not the same as another individual. Yes?

DR. SIMON: So you maintain data on how successful you are in terms of fertility, how often the sperm you provide results in an offspring?

DR. SIMS: Yeah. In other words, what's the pregnancy rates per cycle?

DR. SIMON: Yes.

DR. SIMS: We do our best to measure that. We do not have a complete database. We have people who use a specimen, who get pregnant and disappear. So we have limited information in some--from an overall standpoint. There are certain clinics that keep excellent data, where we have better follow up, and we can use that as a surrogate for the whole. We think that the pregnancy rate per cycle is approximately 15 percent in well-run fertility clinics where the inseminations are done by reproductive endocrinologists. To achieve good pregnancy rates you need to have both viable sperm, you need to have a knowledge of when the ovulation occurs so that the timing of the insemination is appropriate, and the technique of insemination isn't a factor.

There have been many studies that have shown that intrauterine insemination is superior to intracervical insemination, and that timing of insemination is critical. Knowledgeable people who are well trained have good results. People who are not well trained will have very bad results. We treat this as a medical procedure rather than a nonmedical procedure. To release a donor specimen, we require medical authorization and responsibility to supervise the insemination. We do not require the insemination to be performed by the physician, but merely that the physician be responsible for supervising the insemination.

DR. HOLLINGER: I'd like to sort of support what Dr. Koff just said about the hemochromatosis also. I think these are things that genetic groups need to look at because it is the most common genetic abnormality among caucasians in the world. And while treatment is effective, it's not effective by the time we often see them at the age of 40 when they come in with cirrhosis. So having that knowledge for the child becomes very important in that regard.

But on a question I have for you, on your records, are there regulations that require how the records are to be kept? I know you must have paper record from a long time ago that's not been--you may have records before that may not have been all computerized, your database and so on. It may all be computerized. But are there regulations about how that's secured and so on, so that there fireplugs and so on if these records are still mingled?

DR. SIMS: There are general regulations with respect to how records are maintained. They have to be maintained in a fashion that's readable, that's not going to be subject to being altered. We--the actual regulatory agencies have some variations in how they handle that. I do not think that that's an area that has been well thought out or has really come to a satisfactory conclusion.

What we do is that we maintain all of our original paper records. We scan the records into a computer as a scanned image, so it's like a graphics file so that you can't really alter it, and we can pull those up. We have some information that we have readily available on computers, but we try to have as the underlying basis, the hard copy or at the minimum a image that has been scanned and that we keep on a disk.

DR. HOLLINGER: As I said, I can just tell you from having gone through a major flood in Houston that there are many records in the hospital system and so on that were lost entirely because these things were not well thought out.

DR. HARVATH: I was curious about your comment that you had a fair number of requests for siblings for repeat donation for sibling donors, and I wondered if you could give us an idea what percentage that may be.

DR. SIMS: Could you repeat the last--

DR. HARVATH: The percentage of effort that may be in your--

DR. SIMS: Actually, it's quite common that, if it's a first or only child and the woman is still fertile, there is a high number of women who want a second child. And when they do, they nearly all want to have the child by the same donor.

DR. HARVATH: And do these same banks also then collect placental cord blood for any potential future need in that family?

DR. SIMS: There are--cord blood banking is really entirely separate from sperm banking. But by coincidence, we do have an umbilical cord blood bank, but it's a separate division, it's in a separate location, and the operations are very separate.

There are a number of places that provide family cord blood banking, but they are not necessarily a part of sperm banking.

MR. RICE: I don't want to speak for anyone else, but I failed this criteria on many fronts. I don't think I could be a donor, but I was wondering how many donors actually come in to apply as a donor and how many actually succeed, just a percentage.

DR. SIMS: Approximately, out of 100 potential donor applicants, we wind up with 4 or 5 donors, and that's for a variety of issues. It's a very small number. They range from infectious disease markers, social history, poor fertility parameters, failure to return. You can flunk at any one of these steps you can flunk, but it's an arduous process to go through, but it's a very small group.

And these are the donors who actually come in the door for an application. Because if you took the actual number of people that we contact, initially, the number would be lower because we use a telephone screening method to screen the donors on the telephone to determine overall qualifications, what the program is. Those we don't count in that number. We just count the ones who actually receive appointments, come to the door, fill out an application, and that's where we start counting the percentage numbers.

Yes?

DR. MACIK: I was interested that you target the colleges and universities, which tend to be a fairly mobile group of individuals. How often are you actually able to follow-up this group of people for this 24-month period that you're talking about, and what happens if they, I understand that the semen is kept for 6 months before it's released or that's a proposal, but how often--at what point is it critical in that 24 months that you might go back, remove their semen and throw it out, that they're not being followed up appropriately?

DR. SIMS: Well, if a donor, if the donor fails to come back, then we lose--all of our effort goes down the drain. We just have to throw it away because we can't use it.

That's part of the issue of donor compliance. We have a very good handle on what's going to happen if the donors, in the process, they're coming in 2 or 3 times a week. We get to know the donors. They understand what we're doing. Those donors will then usually continue to be compliant. So, in other words, compliance within the first few months is predictive of compliance 6 months or a year from now. So that's somewhat predictive.

This is why, you notice in the bullets that were presented, that compliance with our policies and procedures was an issue because if a donor is not going to be compliant, we don't want to waste our time and effort because we have to spread all of our costs of all donors over the ones we actually distribute. Otherwise it's just inventory in the tank.

So compliance is an extremely important issue and, yes, we do have to throw away inventory that we've invested a lot of money in.

DR. MACIK: So, with this, the minimum time, because you said it could be 18 months, could be 24 months, but at what point do you feel that it's important; is it the 6-month point, the 12-month point?

DR. SIMS: Well, in order to get the--we charge $195 per vial, cryo vial for semen. It costs us $3,000 to $4,000 in a donor to bring them from point zero to where we can have something that we can release, and we have to recover those costs. So we have to have a certain volume of specimens in order to make the system work.

I think I lost part of your question.

DR. MACIK: I know that you say that you want to follow them up for 18 months to 24 months, but what is the minimum acceptable time, do you feel? Is it the 6-month or the 1-year?

DR. SIMS: The minimum time would be, for actually being a donor, would be 9 months, and that's to allow us to acquire a sufficient number of vials to have a meaningful number to distribute. But at the end of that ninth month, at the end of six months after the ninth month, we would still have to have another blood sample to clear the last specimens from quarantine.

So no matter how you cut it, somewhere between a year to 2 years is the obligations that donors have with us. There's a difference between obligations to donate on a repeat basis and the post-donation specimens that are required. Blood specimens are required to clear from quarantine.

DR. NELSON: What if a donor had a treatable infectious disease like GC or chlamydia, would that person then be permanently excluded or at blood banks we talk about reentry. I don't know if you talk about that in here.

DR. SIMS: Well, I think there's a couple of questions that would have to be answered to us. In general, our principle, if it's a treatable infection, you could be treated and when the treatment is cleared, then the donor could reenter the program in theory.

When it comes to issues such as gonorrhea, we would have a serious question about how did the donor get that, what was the issue involved in his lifestyle that put that donor at risk.

Chlamydia is much more prevalent and doesn't carry the same social connotations of risk behavior as gonorrhea-syphilis. So, while all three of those are treatable, we view chlamydia much more benignly than we do syphilis or gonorrhea. That has to be answered in the context of the donor, though.

DR. NELSON: Thank you. Very good.

The next presentation is by Dr. Valleroy from CDC, Incidence and Prevalence of HIV, Hepatitis B and C, and Other STDs among High-Risk Groups.

DR. VALLEROY: Good morning. I'm Linda Valleroy. I'm an epidemiologist at the Centers for Disease Control and Prevention. I work in the Division of HIV-AIDS prevention. HIV-AIDS used to be the sexiest disease to work on at CDC, but now it's not. The new diseases are anthrax and smallpox. But I came here today to talk to you about the incidence and prevalence of HIV, HBV, and HCV among high-risk groups.

I'm going to do this in two sections. In the first section, I'm going to present a literature review about HIV, HBV, and HCV prevalence and incidence among high-risk groups using the general population as a backdrop.

Within that literature review, I'm going to take a little journey outside the literature review to talk about what we know about disclosure of disease, particularly in the HIV realm. And then in the second part, I'm going to talk about findings from the Young Men's Survey. The Young Men's Survey is a survey that's been conducted, it's from CDC, in seven cities across the United States since 1993, and I'm the project officer/senior scientist for the Young Men's Survey. So I'm going to talk about some findings from the Young Men's Survey.

So, first, we're starting with a literature review. The literature review was done last year in June of 2000. That's the only number mistake that I see in any of my slides. It was done in June of 2000, and it was prepared for a donor suitability consultation that was held at CDC.

It had been 6 years since CDC had reviewed their guidelines for preventing transmission of HIV through transplantation of human tissues and organs, and so now it was time to look at those guidelines again. And one of the things that was done was a literature review was done to find out about prevalence and incidence in different risk groups.

What you have here, what I'm going to do today is go through and present some summary numbers, but you have all of the numbers that you've been given out in your packet. You have this table of prevalence estimates, and you have this table of incidence estimates, but what I'm going to do is try to quickly summarize all of these data in a number of slides.

Let me tell you a little bit about the literature review. It was conducted by Analytical Systems, Incorporated, and what they did was search for data in articles from 1995 to 2000. And it also included unpublished data from consultants on this project. For example, Young Men's Survey data had not quite been published then when they were gathering the literature, and so some Young Men's Survey data show up in these tables under the MSM categories. And so data was gathered from the literature and also from consultants.

The literature review screened certain search areas, modes of transmission, infectious diseases, donor selection and screening processes, characteristics, risk behaviors, and experiences of potential donors and just the incidence and prevalence numbers on HIV and hepatitis B in a number of articles which were published from 1995 to 2000.

In all, 10,000 articles popped up in the title searches. Approximately 2,000 abstracts were reviewed. What you see in these two tables that are in your packet are the summary findings from 450 articles which appear in the final bibliography. So what did we learn by all of this?

First, I'll talk about baseline, and baseline would be what we know about hepatitis B and C and also HIV in the general population. Now the general population here for hepatitis B and C are the NHANES 3 data in which we know, through their efforts, that in the general population we find a 5-percent prevalence of hepatitis B, a 2-percent prevalence of hepatitis C, .07-percent incidence of hepatitis B, and a .01-percent incidence of hepatitis C.

The prevalence for HIV really comes from the now extinct and defunct Survey of Child-Bearing Women which was called to a halt a few years ago for political concerns, but this was this screening project in which all newborns were screened for HIV, not really to screen the newborns, but to try to get some idea of what HIV infection prevalence was among their mothers and from there to generalize on HIV infection in the United States. It was a population-based approach, and--well, we could talk about that forever--but, sadly, we no longer have those data.

What the Survey of Child-Bearing Women found was that there was a .2- to a .3-percent prevalence of HIV in the general population of the United States. Of course, there's variation in different race ethnic groups, and in age groups, and in different states and cities across the country. But what we know about the general population in the United States is that approximately 2 per 1,000 or 3 per 1,000 individuals are now infected with HIV, and this has been backed up by some mathematical modeling efforts that have been done on other databases by Dr. John Curran [ph] at CDC.

What do we know about HIV incidence in the general population? Well, this really comes from the military data in which people in the military are screened time and again for HIV and what we know about incidence in the general population is then a .02-percent to a .03-percent HIV incidence, which boils down to that if you took 10,000 individuals from the general population in the United States and they were uninfected and you watched them for a year, that at the end of that year, two to three individuals would be newly infected with HIV, and so this is our backdrop. This is our statistics from the general population.

The first group I'm going to talk about are the blood donors. Now blood donors, we all know this, are screened for risks and asked to defer if they have certain risks that they are questioned for when they donate blood. And so of course we all know that we would expect them to have absolutely no infection because of the screening procedures or at least incredibly low rates of hepatitis B, hepatitis C and HIV infection. And, indeed, they do compared to the general population.

The blood donor data shows us that prevalence of hepatitis B is 288 times lower than that of the general population, the prevalence of hepatitis C is at least 11 times lower than in the general population, and the prevalence of HIV is at least 8, and perhaps 20, times lower than HIV in the general population. But that leads us to the question why is anybody infected with anything? I have some really interesting unpublished data to show you about that.

These were data that were presented at the AIDS Conference in Durbin in 2000, and they have not yet been published. Oh, no, these aren't. This is the incidence data for blood donors. Seventeen times lower for hepatitis B, 3.5 times lower for hepatitis C, and 2 to 5 times lower for HIV. And so, again, incidence is lower among the blood donors than among the general population, and you can look at this in your tables.

But, anyway, these are the data that I wanted to tell you about, unpublished at this point, put together by, well, she was Teresa Jacobs then and now she's Teresa Finlayson now. But what she did was summarized what was known of follow-up data from first-time blood donors.

In this particular span of time in which the study was done, there were almost 4 million first-time blood donors and of those approximately 4 million first-time blood donors, 883 had confirmed HIV-positive infections. Well, people went back to hunt down these blood donors and find out what were their risks. And so of those initial 883, in which you see that the prevalence of HIV infection was .02 percent, they managed to--can people see that? Is that focused enough? Because I don't have a focus. Could it be better? Those are little numbers. Is that the same? Okay. Thank you. It seems a little worse, but anyway.

They managed to find 521 of those 883 HIV-positive blood donors, and they interviewed them about their risks, and so they found 59 percent of the original sample. What they found was that when reinterviewed about their risks, that 34 percent or 178 had deferrable risks and hadn't reported it the first time around for a number of reasons, like privacy or not wanting to report the risks or whatever. So 178 of those people did have deferrable risks or 34 percent.

Another 22 percent had nondeferrable risks and these are things not being an MSM, but being the sex partner of an IDU or being the sex partner of an MSM or being the sex partner of a commercial sex worker, these are the nondeferrable risks.

And then another 44 percent had no reportable risk, and this breaks down to that a certain percentage of them had had unprotected heterosexual sex which, at this point, is not a deferrable or a nondeferrable. It's just not considered a risk.

And so these are data on disclosure really about infection levels. And so we see that most people defer, some people don't, and of those people who don't defer, that some people do, indeed, have deferrable risks when they're rescreened for their deferrable risks.

And so I tried to think of what other areas of literature are there on deferrable risks and another one that came up to me was the HIV-AIDS database at CDC, the HIV-AIDS case reporting database, the people who show up with HIV infections and with AIDS and are reported into a database, and this is tracked through time.

Anyway, there is a problem at this point--well, there has been--that some people who have HIV, who have AIDS, don't have any identified risk. And I could talk for an hour or more about the history of no identified risk, but I wanted to tell you, based on a meeting that I just attended last week, of the surveillance branch at CDC, that this proportion is increasing right now, the people with no identified risk.

And they are debating what this means; whether it means that there are more heterosexuals infecting each other or the recordkeeping is not as good or it's the fact that electronic databases are being used and data are pouring into CDC that way, and so we're not finding out what the identified risks are for HIV and AIDS. But this particular situation, people with HIV-AIDS who don't seem to have a particular risk, is on the increase in the HIV-AIDS database.

The third area I want to talk about disclosure has to do with negotiated safety agreements. And so here we're in the realm of HIV-AIDS prevention. This is a strategy that's been used by some of the HIV-AIDS prevention campaigns for MSM to have them work out negotiated safety agreements with their partners if they're in steady relationships. Now steady does not necessarily mean ultimately monogamous. It just means that this is your main partner.

And so one prevention technique that's been used in prevention campaigns is to get MSM to work out negotiated safety agreements with their steady partners, and this would have to do with the fact that there would be an unambiguous agreement about sex, both within and outside the relationship.

And the agreement would have to do with unprotected sex within the relationship, that being both people are HIV tested, and safe sex if there's anything going on outside the relationship. That would either mean no anal sex with the outside, nonsteady partner or only protected anal sex with the outside, nonsteady partner or one-night stand or whatever it would be.

And so there have been four studies that I have found at this point that have delved into how good are people at keeping their negotiated safety agreements. And the situation is that negotiated safety agreements are set up, partners go into the negotiated safety agreement, and then one of the partners is reinterviewed afterwards to find out whether they keep to the negotiated safety agreement. What do you think they found? Well, I'll tell you.

There are four studies that I've found that have any sample size: Guzman, Wang, Davidovich, and Kippzax, and these are all published in the last few years. And they found when they asked men to set up negotiated safety agreements and then interviewed about compliance with the negotiated safety agreements, that the depending on the study and depending on the way it was done and where it was done, that compliance ranged from 60 to 94 percent, that men complied with their negotiated safety agreement. The low one was a 60-percent compliance in a study published in 2001, and the high one was 94-percent compliance in a study published in 1997.

And so I just did this little ramble and this excursion in this outside journey on disclosure about risks, about infection levels, and now I'm going back to the literature review.

Here, in the literature review, I'm going to talk about four categories of groups with high risk behaviors. The first one would be the prevalence and incidence of hepatitis and HIV among heterosexuals attending STD clinics. This is obviously a risk group because these people are showing up at STD clinics because they think they have sexually transmitted diseases.

Compared to the general population, the prevalence rates among heterosexuals attending STD clinics are three times higher for hepatitis B, three times higher for hepatitis C, and eight times higher for HIV.

Here are the incidence findings. We didn't find any incidence findings on hepatitis B or C, but the incidence findings on heterosexuals attending STD clinics is an HIV incidence rate at least 29 times as high as in the general population, and so this is the first risk group.

The next three risk groups are the people who are asked to defer from donating blood and other products, the first being the prevalence and incidence among men who have sex with men. Compared to the general population, the prevalence rates among men who have sex with men are five times higher for hepatitis B and 21 to 61 times higher for HIV, depending on the study, and you'll find these all in your table.

Incidence rates in comparison with the general population compared to the general population. Compared to the general population, the incidence rates among men who have sex with men are 87 to 193 times higher for HIV.

The next two groups are injection drug users and also commercial sex workers. We know that injection drug users we expect them to have much higher prevalence of incidence of hepatitis B and C through needle use and sharing needle use, and indeed we do find that. Compared to the general population, prevalence rates among injection drug users are at least 35 times as high for hepatitis B, 43 times as high for hepatitis C and at least 17 times higher for HIV.

Incidence among injection drug users is again higher, at least 145 times higher for hepatitis B, at least 457 times higher for hepatitis C, and at least 47 times as high for HIV.

Finally, we come to the commercial sex workers. Compared to the general population, prevalence rates among commercial sex workers are 21 times higher for hepatitis B, 6 times higher for hepatitis C and 77 times higher for HIV.

And finally, in the literature search, here are the HIV incidence rates among commercial sex workers compared to the general population. And the studies that we found in this literature search showed that incidence of HIV was 12 to 313 times as high. So that is the first part of my presentation.

The second part of my presentation has to do with the work that I have been doing with my group in seven cities across the country beginning in 1993. In 1993, we began writing protocols and thinking through how to do a survey of the youngest men who have sex with men.

In 1993, interestingly, very little had been done on young men who have sex with men, looking at teenagers and men in their early 20s. All of the studies had been done in 20-year-olds, 30-year-olds, and 40-year-olds, but there was almost nothing on the youngest guys. And you can think, when you think how do you do this anyway, you know, do a telephone survey, call on the phone and say, "Do you have a teenage man who has sex with men, a gay son in your house," and you're not going to get very far, nor if you're going to do that door to door.

And so we began thinking about how we could conduct this study, and I'll tell you something about it and something about our findings. We conducted Phase 1 of the survey between 1994 and 1998 in seven cities across the country, and we were sampling 15- to 22-year-old men who have sex with men.

This turned out to be so--the findings were so upsetting and the methods were so workable that we continued doing this study in 1998 through 2000, using the same methods to sample 23- to 29-year-olds in these same seven cities because we had teams that had been trained in this procedure, and the findings have been quite upsetting to CDC. I'll take it a step back--why did we do this thing in the first place? We did this thing in the first place because CDC had worked with the city of San Francisco to conduct Young Men's Survey in San Francisco in 1992 to 1993.

And in that early initial phase of the study in San Francisco, we had sampled 425 17- to 22-year-old MSM--these are young guys--and we found a 9.4-percent HIV prevalence and a 33-percent prevalence of unprotected anal sex in the last 6 months, and this shocked everybody. You know, how could this be--in 1992 and 1993, after 10 years of an AIDS epidemic in which presumably, at least in San Francisco, people had been reached with HIV-AIDS education messages--how could this be that there was a 9.4-percent HIV prevalence?

And so we decided to change the methods, expand the study and do this in seven cities across the United States. In your packet, you have two reprints: One from our findings from the initial phase among 15- to 22-year-olds. It's a JAMA article that was published in 2000, and the second is an MMWR article that was published in the 20th anniversary issue in June 2001. This is also in your packets. That has the incidence findings from the 15- to 22-year-olds and the preliminary findings from the 23- to 29-year-olds.

Anyway, what did we do? We did a cross-sectional, multi-site, venue-based sample survey. We tried to approach population-based methods by going to venues where young men who had sex with men went. We spent a lot of time in each of these cities doing formative research to find all of the places, find if it was feasible to go to those places, if you would find 15- to 22-year-old MSM, and then we had a 3-stage sampling frame of venues, time periods, and then went out and sampled young men at these venues.

We focused on 15- to 22-year-olds who were local residents, who attended public venues, and venues were everything from parks, beaches, street locations, restaurants, coffee shops, dance clubs, bars, gyms, any place that young men who had sex with men would go. We did this survey in Baltimore, Dallas, Los Angeles, Miami, New York City, San Francisco and Seattle. What did we find?

Oh, what we did was we went out to these places, we recruited young men, and they came to a van that was parked near the venue, in which they had a blood sample drawn, which was tested for HIV, hepatitis B and also syphilis, and they were asked a questionnaire by an interviewer, and the questionnaire lasted 30 minutes, 45 minutes, depending on the risks of the individual person.

We conducted it as an anonymous survey, but the young men were prevailed upon, please, you know, please, the most important thing you can do is come back for your test results, and we gave them numbers and dates to come back for their test results so that they could find out if they were HIV infected.

In these years, we enrolled 3,492 young men, approximately, 500 in each of the seven cities. Our enrollment rate was 62 percent, which is quite good considering that we were, you know, enrolling on the streets, but we tried to get our damndest to get every last person to enroll.

We found an HIV prevalence of 7.2 percent, and these are 15- to 22-year-olds in 1994 to 1998. When we started this study, we really hoped that San Francisco was some sort of fluke of San Francisco, that the 9.4-percent HIV prevalence that we'd seen in San Francisco was some sort of outrageous result, but we didn't find that. We found HIV prevalence to be high in this group, ranging from a 2.2-percent prevalence in Seattle to a 12.1-percent prevalence in New York City.

Hepatitis B prevalence was also high--10.7 percent, ranging from a 5-point--I can't remember where these were--but a 5.8-percent to a 13.2-percent prevalence for hepatitis B.

And sexual risk behavior was also high, ranging from--the overall was 41 percent, 41 percent reported having unprotected anal sex in the last 6 months.

The high--there's a lot of data in that JAMA article in 2000, so please look at that, and I tried to summarize it. And so I did it by showing two tables; one is where was the highest HIV prevalence, and that is here.

Of the different groups and subcategories, we found the highest HIV prevalence among the African Americans, 14.1 percent; men of mixed race, approximately 13 percent; the transgenders, 14 percent; men who'd had 20 or more lifetime male partners, 13 percent; those who'd injected drugs in their lifetime, 15 percent; those who'd had an STD in their lifetime, 18 percent.

I presented these data at the 2000 meeting of organ and tissue transplantation, and everybody said, well, that's really nice, but where' the lowest risk? I'd always been speaking before prevention crowds, and nobody had ever asked me, you know, where is there no risk, and so I learned that there are other audiences out here.

So the lowest risk that we found in these subcategories, the lowest risk prevalence we found really was the 15-year-olds. The 15-year-olds had no infection, you know, which was a wonderful thing. Zero infection among the 15-year-old MSM.

The next lowest was of the young men who reported never having anal sex. I'm not saying unprotected, I'm saying anal sex, they'd never had anal sex. That's what they reported, and that was about a 1-percent prevalence.

Among the white guys, 3 percent; the Asian Americans, 3 percent; the heterosexuals, and you're thinking, heterosexuals? She's talking about men who have sex with men. Well, these are the guys who identified as heterosexuals. Although they were having sex with men or had had sex with men in their lifetimes, they thought of themselves as heterosexuals, and the prevalence among those guys was 4 percent.

Those who'd had 1 to 4 lifetime male partners in their lives was 3 percent. And among the 15- to 19-year-olds, it was 6 percent.

This is another interesting thing we found, and dismaying, that's for sure. Guys didn't know they were infected, even though a high percentage had been tested. This is the data on the 249 HIV-positive men we found in the seven cities.

And in this group, 76 percent had had an HIV test at least once in their lives, but only 18 percent knew that they were currently infected, which means that we tested them again as part of our survey, and when they were asked if they thought they were HIV-negative or HIV-positive, only 18 percent knew, of the guys who turned out to be HIV-positive, knew at the time of our survey that they were currently HIV infected, and this goes down to something like a 7-percent knowledge among the African Americans. It varies by race. And so, you know, very few did know they were infected.

What was the incidence like? Well, if you think about it, it must be high. These are guys who are starting their sexual careers, they're making their sexual debuts. You have an HIV prevalence like this, incidence has got to be high, and it was.

When we started this survey, the STARS testing technology did not exist. It was just a glimmer in somebody's eye. But we had cross-sectional blood samples, and so ultimately we were able to test all of the bloods for HIV incidence. We found an overall HIV incidence among the 15- to 22-year-olds of 3 percent. It was 2 percent among the 15- to 19-year-olds, 4 percent among the 20- to 22-year-olds, 2 percent among the whites and Hispanics, 4 percent among the African Americans, and 5 percent among the men of mixed race.

And so incidence, new infections in this group is quite high, which probably also goes back to explain why so few young men knew that they were HIV infected because a lot of them were newly infected since their last HIV test. You know, this is the age when they're becoming infected.

So a little bit of data on Phase 2. And there's a paragraph on Phase 2 data in the MMWR article that you all got. In Phase 2, we worked in seven cities, but we only sampled Asian Americans in San Francisco, and so I am not including them. We worked and sampled all of the race ethnicities in Baltimore, Dallas, Los Angeles, Miami, New York City and Seattle. We used the same methods as in Phase 1.

Preliminary data from the six cities of 23- to 29-year-olds, we have approximately 3,000 people that I'm reporting on. Unfortunately, prevalence doubled. In the earlier phase, we found a 7-percent prevalence among 15- to 22-year-olds. In this phase of the survey, among 23- to 29-year-olds, we found a 13-percent HIV prevalence. We found a 32-percent HIV prevalence among African Americans, which really has been upsetting people, and a lot of program money is now going towards trying to reach African American men who have sex with men.

Prevalence didn't change among the Asians. It was 3 percent in the earlier phase, and it's 3 percent among 23- to 29-year-olds. It doubled among the Hispanics. It was 7 percent among the 15- to 22-year-olds. It's 14 percent among the 23-to 29-year-olds, and it doubled among the whites.

I didn't bring a slide on this, but the question is did the 23- to 29-year-olds know? Well, I believe there are 239 HIV-positive men in Phase 2. It's either 239 or 293. But, anyway, there's approximately in that realm in the 200s. And 91 percent of those HIV-positives, had been HIV tested and knowledge of sero status was better, but still it was 29 percent.

So 29 percent of the HIV-positive 23- to 29-year-olds knew that they were currently infected. Again, we can probably chalk this up to very high incidence rates, the fact that their test had been a while before, they continued with risk behaviors, and they had high incidence rates.

Here's our preliminary findings on HIV incidence, and they are very high. Overall, a 4-percent HIV incidence, which is really the highest incidence figure that we've seen for MSM published in the 1990s. Incidence among MSM in the 1990s is in the 2- to 3-percent range if you survey all of the surveys. Here, in the Young Men's Survey, Phase 2, it's 4 percent; among African Americans, it's quite outrageous. It's 15 percent; Hispanics, 4 percent; and whites, 3 percent.

This is what I have to say. Some data, maybe way too much data, about the Young Men's Survey. There's a lot of program response going towards young men now at CDC, trying to reach them with effective messages. And particularly in the past year, with our Phase 2 finding and publications, there's a lot of program effort going towards trying to reach African American MSM.

And so I've said a whole lot. I'd be very happy to answer any questions.

DR. NELSON: Thank you very much. I don't understand how you got incidence of hepatitis B and C from the NHANES data.

DR. VALLEROY: I don't know that. That's from the literature review. Isn't it in the table that way?

DR. NELSON: Yes, you mentioned that you were looking at incidence in the general population, and you mentioned the NHANES, and I don't know how you could get incidence from--because that was a cross-sectional study, I believe.

DR. VALLEROY: Well, what I wrote in my talk, after looking at the data, was what we know about hepatitis B and C prevalence and incidence in the general population comes from NHANES 3, and so--I mean, I wrote this pre--

DR. NELSON: Oh, so this was a comparison of NHANES 3 with NHANES 2; is that what you're doing?

DR. VALLEROY: Okay. I just--I wrote this--

DR. STUVER: [Off microphone.] I don't think they have HCV in--

DR. VALLEROY: They don't in NHANES 3?

DR. STUVER: In 2.

DR. NELSON: In 2, no. I think what they're comparing is two prevalence estimates.

DR. STUVER: Unless they did it within NHANES 3 and they had--what was that over several years, maybe they did some estimate that way, prevalence, to see a prevalence that year, and made it. I don't know where they--unless it comes from a different source.

DR. NELSON: Right.

DR. VALLEROY: Okay. I'm not an NHANES 2 or 3 person.

DR. NELSON: Because getting a hepatitis C incidence is pretty difficult.

DR. VALLEROY: Could somebody help me out, please.

DR. EPSTEIN: Those data on hepatitis C are foot-noted to Hiams' unpublished data, the Naval Medical Research Center. They're not footnoted NHANES.

DR. VALLEROY: Okay. Thank you.

DR. SIMON: I was at the June meeting of CDC and recall the discussion, and I think the--and I guess very relevant to what our questions are going to be later in the day, the issue was could we find a low-risk population of individuals who were MSM and could be accepted as donors, and we spent probably several hours dealing with this issue. But I gather, as you have represented the data, you simply aren't able to come with such a group based on your research.

DR. VALLEROY: Well, I mean, 15-year-old, zero, and the guys who reported never having anal sex in their lives, .09 percent.

DR. SIMON: But even that is much higher than the general population.

DR. VALLEROY: And these are young guys.

DR. NELSON: Other comments or questions?

DR. LACHENBRACH: I had a question.

DR. NELSON: Yes?

DR. LACHENBRACH: My name is Peter Lachenbrach. I'm head of the Division of Biostatistics at CBER.

The design of the survey suggests that you may have gotten or at least it suggests to me that you may have gotten the most active participants in MSM, and that might lead to an upward bias in the rates that you've gotten. I was wondering if you had considered anything like that and if there are any other data perhaps from random samples in San Francisco or any other place?

DR. VALLEROY: Okay. Hold on. All right. We thought that this was a very important thing to do, to try to get the best estimate of HIV prevalence among this age group, and so we worked a long time trying to come up with the best design. And the best design that we could come up with was to sample young men who went out of their houses, out of their schools, and went to places where young men congregated with each other.

And so this is not a survey of young men who don't go out; you know, who are staying home, who aren't sure of their sexual identity or who find partners at their high school and don't go out to places. This is a survey of men who go out.

And when we designed this, we realized, doing a venue-based design, that we needed to find each and every venue of any different kind that we could possibly find in these cities. This was not convenience sampling like, oh, there's this--no, no, I'm just trying to explain--

DR. LACHENBRACH: I'm agreeing with you--

DR. VALLEROY: But I just want to explain. This wasn't at all convenience sampling like there's this nifty gay bar in West Hollywood, let's go there. This was sitting down in level of level of interviews with people who were well-informed, of reading journals, of having focus groups of young men, of putting together a preliminary sampling frame of any place we could possibly think of where young men who went out would go.

And then within that, we figured out the places where we'd find at least seven men in this age group in a 4-hour time period, which isn't a lot because we just had to do that for the expense of the survey; you know, seven men in a 4-hour time period, and we sampled from there.

The only thing that I have to go on, from the literature, is, and I wrote about this, you know, it brings up the question how often do men go out in this age group? Is this 1 percent of all of the young gay guys? Is this 85 percent of all of the young gay guys? I hunted around to try to come up with an answer to that, and I have two sources on that.

According to the San Francisco Young Men's Health Study, a population-based, randomized, household survey of young men, 91 percent of the 18- to 23-year-old young MSM had gone to a gay bar in San Francisco in the past 6 months, and I hunted down somebody from that survey to analyze those data especially to try to get some scope.

The other thing was the Urban Men's Health Study, which I was working on a piece of that at the time, that's the population-based telephone sample survey of MSM in San Francisco, Los Angeles, New York and Chicago. And that survey, and I got Joe Catanya [ph] to do a special run on this, that survey found that 74 percent of the 18- to 23-year-olds sampled on the telephone population-based approach had gone to a bar, a nightclub or a dance club at least once a month in the past 12 months.

And so, as far as I can tell, young men go out a lot. This is from two population-based surveys. One is a household and one is a telephone. I mean, we're doing more analysis on that, the point with the GUM [ph] Survey.

DR. KOFF: I assume, I mean, you have data on prevalence of hepatitis B in this group.

DR. VALLEROY: Uh-huh.

DR. KOFF: How about C, have you done that, gotten sera?

DR. VALLEROY: No. We do have sera, and so, actually, we have a paper in draft form for both Phase 1 and Phase 2 from Seattle in which they have analyzed the data for hepatitis B and C, and I brought the draft to review, and it's up in my room. I can't tell you off the top of the head. I could go hunt it down, but that's from Seattle.

And now we're debating what to do with the remnant samples, and so hepatitis C seems like something important to do.

DR. KOFF: Can you give us any sense of what the prevalence was?

DR. VALLEROY: For Seattle. I could go upstairs later on and grab that paper. It's in a draft right now. It's for Seattle.

DR. NELSON: Yes?

DR. SIANI-ROSE: I am Mike Siani-Rose. I'm a private citizen.

I have a comment because these numbers are really disturbing. In the early '80s, I worked in medical schools, and I was involved with the San Diego AIDS Project. Back then pretty much all people with AIDS were gay men. Over the years, the people who are working in this field have targeted their concerns about the spread of AIDS to gay men, and it's been somewhat effective, but the population that's been addressed is aging. You know, I'm 42 years old now.

Now, as a parent, I think back, since it's 2001, as opposed to 1984, in 1984, people didn't really talk about gay issues as openly as they do today. In 2001, it's okay to approach a 15-year-old and say, "Are you gay? Have you had sex with another boy or a man?"

I think that maybe instead of the CDC focusing on youth, it may be too late. Maybe we need to start focusing on parents. It's okay to talk to parents about sexuality of their children now.

DR. VALLEROY: Oh, so instead of going out and finding the young people, try to work with parents to get them to find out about the sexuality of their children and to accept that if they have a gay son, is that what you're saying?

DR. SIANI-ROSE: Well, no, not to accept it, but to discuss sexuality and sexually transmitted diseases. I mean, this is something that we do normally, right, in the schools. We expect parents to talk about sexually transmitted diseases, but maybe since the prevalence is so high among young gay men, we should feel free to go and talk to the parents today about talking to their kids about sex more openly, and specifically with respect to sexually transmitted diseases.

I mean these are really disturbing numbers. I mean, 7 percent of the 15- to 22-year-old MSM are HIV-positive. I mean, that's really high.

DR. VALLEROY: That's really high. I do a lot of youth surveys, and if you want to compare to other youth surveys, for example, the HIV prevalence of youth who enter the job corps is approximately .2 percent or two out of every thousand; whereas, here it is 7 out of every 100. I mean, when you compare data on young gay and bisexual men to other groups of youth, this is where the infections are occurring, and it's probably a lot--you know, it's analogous to young teenage girls. Well, I shouldn't start.

But, anyway, yeah, this is definitely a real problem in the epidemic.

DR. SIANI-ROSE: I mean, it's pretty clear that teenage boys are having sex.

DR. VALLEROY: We have a continuing epidemic among MSM in this country. People talk about a resurgence. I just did a huge data review this summer about resurgence. I'm not sure if we should use that word, but if you survey the studies of HIV incidence among gay men, all the studies that have been published in the '90s, you find a 2- to 3-percent incidence of HIV across the board, and that's a strong epidemic.

And here, you know, you find 3- and a 4-percent incidence among the youngest guys, which, when you think about it, makes sense because they're more sexually active, and they're starting to have sex, and they're becoming infected. But, anyway, thanks for your remarks.

DR. NELSON: Dr. Mitchell?

DR. MITCHELL: Yes, I think that you're starting to get at my question. Do you believe that men who have sex with men that begin earlier are more at risk than the average man who has sex with men?

Do you understand the question?

DR. VALLEROY: Yes, I'm thinking. I like to think.

I don't know.

DR. NELSON: Question at the microphone.

MR. TREEIMAN: My name is Leland Treeiman, and I'll be addressing this body later. But as the godfather of a 23-year-old gay man, I can say that when he was at university, he and all of his gay male friends would have answered, yes, do you go to a bar at least once a month. But they, themselves, and when I visited with him and spoke with his friends, had a very different view of themselves going out, as college students, maybe once a month to a gay bar, to these venues, as you described them, as opposed to the other young gay men who are there, who are sort of like barflies, who would be there every night, be drunk every night, be going out and having a lot of sex.

And these gay men would be less likely to be caught up in your study because they're only there once a month, as opposed to the barflies who are there several times a week or, in some cases, every night. So I just wanted to make that comment about your methodology.

Having made that comment, I am very grateful that you are studying this area because it, I mean, however flawed this methodology may be, it's important to find out at least some data about this group.

DR. VALLEROY: Anyway, thank you. That's one of the things that we thought about, that we didn't want to oversample guys who went out night after night. And so there was a segment of the questionnaire in which we asked a series of questions--it took a little while--about all of the venues that we were going to and how frequently they went to these particular venues.

And we did it in groups of venues, and we made them look at lists of all of the venues that we were going to. And we kept refreshing the list, and we had sort of like an 8-point scale of how frequently they were going to these groups of venues. And so we collected data, really detailed data--it took a while--on frequency of venue attendance and what we meant to do at the end was to weight the HIV prevalence and the HIV risk behavior prevalence data according to frequency of venue attendance.

And there was a statistician who worked on that weighting for a few months of the summer, and it didn't make any difference, and so we did not weight the data. We intended to because we thought we didn't want to oversample people who were going out all of the time and going to these places all of the time, and so there was this statistical effort to weight the data, but the findings didn't make any difference whether you weighted it or not, just statistically.

MR. TREEIMAN: Right. It's interesting that you mentioned that because that was part of my discussion with Cory and his friends. And one of the things they noted was people who were barflies, as it were, were in denial about their actual participation, as a lot of alcoholics or drug abusers are.

You ask a drug abuser or, you know, as a clinician, I can say I'm a nurse practitioner, you know, how many drinks do you have in a day, and they'll say one or two, and the rule of thumb is to at least double it. So, you know, once again, I want to question how honest these people were because we're, again, talking about addictive behavior and the denial they're in.

And I appreciate that you did weight it, but once again I think that there's an honesty factor that needs to be considered.

DR. VALLEROY: Yes, some people went out a lot and reported going out a lot.

DR. CANNON: Briefly--and my name is Mike Cannon from CDC--the last comment was exactly what I was going to say. So, in other words, you're saying that, even among the people who went to these venues infrequently, their prevalence of these different infections would still be considerably higher than other individuals who might be donating semen, for instance.

DR. VALLEROY: Yes. This was designed to weight the prevalence data according to venue attendance, but we didn't have to do it because it prevalence didn't vary much at all by venue attendance. A lot of people went out quite a bit.

DR. NELSON: I think we'll take a break now until 11 o'clock. In order to get through the agenda, it's important that we try to get back at 11:00.

[Recess.]

DR. SMALLWOOD: We are running behind on our agenda schedule, and we will need to make adjustments in the timing.

Dr. Nelson will speak to the committee members with respect to how lunch will be arranged, and I would just like to announce that during our open public hearing, we will have to make adjustments relative to the timed presentations there. I have been notified that there are five individuals that desire to speak in the open public hearing. We would ask that you would limit your presentation to 7 minutes. Thank you.

Dr. Nelson?

DR. NELSON: How many--I'm trying to figure out, we have to vote on some issues, and before that we have to have a lot of speeches, and discussion and that kind of thing.

How many people have to leave let's say before 3:00?

[Show of hands.]

DR. NELSON: All right. How many people can stay until 3:30 or 4:00?

[Show of hands.]

DR. NELSON: Because I don't want to get to the end, and then we don't have a quorum, and then the whole thing is--so the issue is that it will depend on how long, where we are and how long it will take for lunch or we'll even have lunch.

Dr. Smallwood will check to see what--we can have lunch tomorrow, how's that?

[Laughter.]

DR. NELSON: The first presentation in this continuing session is Dr. Deborah Anderson from Harvard who will talk about the transmission of infectious agents by semen.

DR. ANDERSON: Thank you, Dr. Nelson.

My talk is going to be relatively brief because there's not that many documented cases of transmission of HIV by artificial insemination. I'll start with a literature review, and then I'm going to briefly introduce a new way of processing semen from directed donors and sexual partners that's been pioneered in Europe that could have implications for this committee down the road.

I am from Boston, the Brigham & Women's Hospital. I'm in the Department of OB-GYN, and my laboratory has been interested in HIV in semen for many years.

This is a list of all of the sexually transmissible pathogens that are known from the King Holmes Textbook on STDs. I just wanted to show you this list to make the point that we don't test for very many of these. I think we test for pathogens that have both a high prevalence and a known morbidity and for which there are no tests, reliable tests, and many of the pathogens on this list aren't tested for. So it's like looking under the light for something that you've lost, I guess.

This is the first report in the literature of HIV transmission through artificial insemination. It was a report out of Australia in 1985. Eight women in Australia were inseminated with cryo-preserved semen from one HIV donor and four sero-converted. This man was a very high--had a high potency for infection. This was whole semen inseminated at the cervix in these women.

Second report was a retrospective analysis of women in New York that had been inseminated with fresh semen from six HIV-positive donors, and one sero-converted out of 131 in this retrospective study.

A similar study was published in 1995, a retrospective study of 199 women in the USA and Canada inseminated with fresh and frozen semen from five HIV-positive donors and seven sero-converted.

The only other report in the literature on known transmission of a pathogen from artificial insemination is a case report published in 1987 of a woman infected with hepatitis B virus by artificial insemination. I'm not sure why there aren't more reports. Is it that we're just not detecting infections that occur or is it that they're not occurring? I don't think we know the answer to that.

Dr. Sims mentioned that there are leukocytes in semen, and it's the leukocytes and contaminated epithelial cells in semen samples that carry a lot of the infectious burden for many of the diseases that we're concerned about here.

I have put together this table which is our best estimate of where HIV--excuse me--of where sexually transmitted pathogens might segregate in the cellular fraction of semen. From the literature, there is very little evidence from good studies that any of these pathogens associate with modal sperm after they are washed thoroughly. What we know about the infection patterns from these pathogens would suggest that much of the burden at the level of the washed-cell palette is in the contaminating epithelial cells and white blood cells that will cosegregate with sperm if you simply do a sperm-wash procedure.

In Europe and also--well, I should say in this country we now are moving towards intrauterine inseminations of infertile couples, and this requires a sperm-wash procedure. You can't use whole semen when you go into the uterus. It causes contractions. The prostaglandins and seminal plasma cause contractions.

So the ART labs in this country and elsewhere are routinely washing semen to get rid of the seminal plasma, and they commonly use one of two techniques. They either use a Percoll-gradient method, which is on the left, or a swim-up procedure, which is on the right. Both of these procedures give you a highly enriched motile sperm fraction. They are fairly effective at getting rid of the leukocytes and epithelial cells. It depends on how carefully the procedures are done, but it's a way of getting fairly clean motile sperm fraction.

A number of European centers have taken this information and have used these two techniques in tandem. They, first, will process semen through Percoll gradient and then swim-up when they're dealing with a donor with a known infection. The most common case that they've been treating in Europe now for over 10 years is a case of a discordant couple, where the man is HIV-positive.

This could be a directed donor, where the couple is not intimate, but the man wants to achieve a child, which has occurred in a few cases or it can be an intimate couple, where the man is known HIV-positive, and I'm not even sure you can call these couples intimate if they're using condoms all of the time. But now in Europe there are a number of centers that are treating such known infected couples using a combination of these wash techniques.

The literature from this kind of work is pretty convincing that we're going a long way in removing HIV and other pathogens from the motile sperm fraction by using sperm-wash techniques. This is a compilation of the literature showing HIV DNA as the endpoint in semen samples that are washed using a combination of gradient and swim-up techniques.

As you can see, the percent-positive samples here are very low--in most cases, zero after the samples are washed. This is using HIV RNA as an endpoint. DNA would tell you if there are infected cells left in the sample. RNA would tell you if there is infectious virions left in the sample. Again, the good, quality studies are showing that this works very well in eliminating HIV from the motile sperm fraction.

The best data are yet to be published. As definitive reports, they are still in abstract form, but I went to a meeting in Genoa, Italy, in November, where all of the centers that are doing this presented their data, and these are the newest data. Quite large numbers now. The Semprini study from Milan has looked at 516 inseminating fractions from HIV-discordant couples and has found less than 1 percent positive after using routine sperm-wash techniques.

These are their insemination data. There are presently nine centers in Europe that are using sperm-wash techniques. They have done over 3,000 inseminations of over 1,000 women. They have achieved 571 pregnancies, 393 births, and there have been no seroconversions reported to date, with the caveat that the follow-up has been about 90 percent. I know that the CDC is working with some of these groups to get that final follow-up data so that this can be definitive data.

So I think this addresses one of the questions on the table here. Can we use fresh semen from targeted donors? Maybe we can if we couple it with a wash technique, such as are being pioneered here.

I'd be happy to answer any questions.

DR. NELSON: Maybe the question is for Dr. Sims, but how do the large or licensed sperm banks in the U.S. deal with the sample before it's cryo-preserved? Is it simply DMSO or is something added to preserve the freezing or is there a wash technique and how commonly is this used in the U.S.?

DR. SIMS: In our facility, we prewash prior to freezing approximately 80 percent of our specimens. The specimens that are actually used for insemination, even the ones that are not prewashed prior to insemination, we estimate that probably 90 percent or more of the donor specimens that are used are subject to either Percoll gradient washing or some other density gradient method separation or swim-up techniques.

So the vast number of reproductive endocrinologists were using intrauterine insemination which, as was noted, requires removal of the seminal plasma which contains prostaglandins, which causes uterine contractions. So this is being practiced, and it may account for the low prevalence rates. One is screening, quarantining, and the second one is the use of lowering the risk statistically by reducing the cell-associated viral infections.

DR. NELSON: Are these techniques anywhere required, recommended or commented upon by the FDA? In other words, to get license or so, would this be standard practice or is it just do you have a good sperm bank or a big one or whatever?

DR. SIMS: Well, I think it's not a standard practice. It's a prevalent practice. As the FDA regs are written, as I understand them, or proposed regs, they would not mandate this being done.

DR. NELSON: Do they talk about it at all?

DR. SIMS: No, it's not addressed, the specific issue of washing to remove the cellular component.

DR. NELSON: If they did, do you think that the currently active sperm banks could easily comply?

DR. SIMS: Well, I think, first of all, the sperm banks do not do inseminations, for the most part. It's done in physicians' offices.

DR. NELSON: No, but they'd collect the sperm, and they would do the washing and the swim-up. That's what I'm talking about.

DR. SIMS: Yes, but this can be done post-freezing also. So the prewashing gets into an area that borders on the practice of medicine. Whereas, infertility clinics--for instance, there are people who prefer to wash previously frozen sperm that has not undergone Percoll washing. They prefer doing swim-ups within their clinics. So they are achieving the same goal, but they are doing it post-thaw, as opposed to pre-thaw.

DR. NELSON: I would think all sperm banks would be practicing medicine. Blood banks are, I guess.

DR. ANDERSON: My impression is that the yield is much better if you do it pre-freeze because the motility is affected.

DR. SIMS: Nearly all of the major sperm banks in the country are offering IUI-ready semen samples which are prewashed.

DR. SIMON: Remembering what we went through in blood banking with washing and freezing red cells and the thought that they had diminished risk of transmission, but ultimately didn't turn out to be the answer, I caught in your final statement you may have a technique. So I gather that we're not at the point where we can say that this is protective.

DR. ANDERSON: Well, the CDC is looking very closely at this. Ann Duerr at the CDC is spearheading interpreting the European data in the U.S. setting, and the one missing piece are the 10-percent of follow-up patients who are international patients. They weren't lost to follow-up because they're a high-risk, irresponsible group. They're international patients that were lost to follow-up at the clinics that treated them, and they are tracking down those data. What I hear so far is the zero seroconversion rate is holding.

But I think that's a missing piece. I think that the CDC is going to recommend to the ASRM that sperm wash be allowed for known infected partners in the future. Right now there is a lot of hesitancy in offering assistance to known HIV-infected men because we just don't know if these techniques are 100-percent effective.

DR. NELSON: It looks like the pregnancy loss in these data are a little bit high, almost 20-some percent. Could any of that be due to HIV infection of the fetus?

DR. ANDERSON: There is a higher miscarriage rate, but I don't think it's dramatically higher. I think the pregnancy, the discrepant data here are due to the newness of the data. I think a lot of these women are still carrying their pregnancy.

DR. LINDEN: It's my understanding that the technique used in Europe on the HIV-positive men is not 100 percent and that they actually test the specimens by PCR and that a significant number, I believe it's in the range of 1 percent--I'm not certain about that--come up positive and then aren't used--

DR. ANDERSON: Not of women, of semen samples.

DR. LINDEN: Yes.

DR. ANDERSON: I think that's because this approach is so new they want to be very sure of the result, and also they're working on better wash techniques. I think that this probably isn't the final version, this combination of Percoll with swim-up.

DR. LINDEN: Right. But my point is that I think the techniques used in a known discordant couple are not the same that Dr. Sims was talking about that are used for IUI samples, and I don't think the impression should be left that 80 percent or whatever the number, you know, the significant number of the samples being released for IUI insemination are protected from HIV or other pathogens because it's not the same thing. It's apples and oranges. It's not the same technique we're talking about here, I don't believe.

DR. ANDERSON: It's a half-apple versus a whole apple.

DR. LINDEN: Yeah, I mean, there are similarities, but it's not--

DR. ANDERSON: Well, and maybe it should be discussed as to whether more rigorous sperm washing should be done routinely. I just wanted to present these data for discussion. I'm not endorsing them.

DR. FITZPATRICK: It looks like it's still technique dependent because there was variability within the data you presented about positives and negatives.

DR. ANDERSON: Well, I could go through the strength of the individual studies. Some of the studies that showed that there was residual HIV were not done well or they were done on an N of 2.

DR. FITZPATRICK: Sure. The other question I had, on the seroconversions that have been published, is there anything published on the status of the infant as a result of a seroconversion?

DR. ANDERSON: Well, I don't know about that.

DR. SIMS: If I could just comment about the issues that were raised regarding the techniques that were used to reduce the viral load or potential viral load, the wash techniques can vary a lot. The rigor with which you would approach washing would depend upon what you perceive the risk to be. If it's simply leukocyte reduction, you could have a more generous or looser procedure, but if you're trying to reduce total potential viral load, you probably would want to have a more rigorous wash than is done routinely.

There are a number of sperm banks who produce IUI-ready specimens that are really only, they've only reduced the seminal plasma. They don't really eliminate it. So there's a lot of very specific information that's needed to make those numbers meaningful.

The other one is that percentages with numbers that small are rather meaningless because of your coefficient variation of transmission. You know, the risks, it's just not a high enough number to be meaningful because it's like the risk of a needle stick is only about 1 in 200 to 1 in 500, depending on the site of the source. So it's similar to here.

I think it's promising to look at what can be done, but it's probably not zero reduction of risk, but it's probably a substantial reduction of risk, and the degree of reduction would be the degree with which you could remove cells and remove vestiges of the seminal plasma and any passively-bound viruses to the cells. So it's a risk-reduction method rather than an absolute reduction of risk.

DR. NELSON: Given the risk that's been calculated for unprotected sexual contact of around 2 to 3 per 1,000, you would expect 5 or 6 transmissions here, so--

DR. ANDERSON: Yeah, the numbers are getting up there.

DR. NELSON: Yes.

DR. ANDERSON: Ten years ago they didn't have as high of numbers, but now they're getting there.

DR. NELSON: But the fact is unprotected sex, particularly when the donor has been screened for STDs and leukocytes removed certainly would reduce the risk, but it may not be zero.

Thanks very much. Interesting data.

The next presentation is Dr. Michael Cannon from CDC talking about Human Herpesvirus Type 8 sexual transmission.

DR. CANNON: I'm going to use Human Herpesvirus-8 to illustrate some of the considerations surrounding emerging pathogens and semen donation.

Some of those issues include are there subsets of donors or potential donors such as HIV-negative men who have sex with men who have a higher sero prevalence of the emerging pathogen than you'd find in the U.S. population or the general donor population.

The second issue is are there assays available for identifying and screening out individuals who are infected with the pathogen. If you do identify seropositive donors, what is the actual risk of transmission through semen donation? And if you become infected with this pathogen, what is your probability of becoming ill?

First of all Human Herpesvirus-8 was discovered in 1994, and it's also known as Kaposi's sarcoma-associated herpesvirus because it's been shown to have a causal link to KS. It's an envelope DNA virus whose closest Human Herpesvirus relative is Epstein-Barr virus. In addition to causing Kaposi's sarcoma, it's also been shown to have a strong and probably causal association with some less-common diseases.

Now, if you look at HIV-negative men who have sex with men, I have listed here the studies who tested this population and in the same study also tested blood donors or the general population. And you can see that although these sero-prevalence estimates differ among the studies, in every study there was a significant difference, a significantly elevated prevalence of HHV-8 in HIV-negative men who have sex with men.

Now there aren't any studies of men who have sex with men who are HIV-negative, as well as hepatitis B- and C-negative, but in one study that we did at CDC in women, we found that in women who weren't infected with any of these viruses, but who did have sexual high-risk behaviors or injection drug use behaviors, that there was a significant difference in the sero prevalence of HHV-8 compared to blood donors.

To summarize, HHV-8 is more common in the HIV-negative men who have sex with men. Again, no data on those men who are seronegative for HBV or HCV. However, a lot of these HIV-negative men who have sex with men are also seronegative for hepatitis B and C, which would suggest that any testing which includes these viruses may not necessarily exclude individuals who are HHV-8 seropositive.

Moving on to whether there are assays that would allow for detection of HHV-8, there are a number of assays that are used. They detect antibody to either latent or lytic antigens. A number of assay formats are in use, but currently there are no FDA-approved assays.

This slide addresses, to some extent, how well the assays perform. As you can see here, ranging from individuals with KS and then in lower risk for KS, all the way down to blood donors, nearly all the assays can detect antibody in individuals with KS. You can see for the different studies most of the sero-prevalence estimates in HIV-negative men who have sex with men are between 10 and 20 percent and for blood donors between 1 and 5 percent.

The assays in a recent study in which CDC is collaborating to address assay performance issues, you can see that six different laboratories did testing on 40 KS specimens, as well as 1,000 blood donors. The first thing to note is that all of the laboratories were able to detect all of the KS specimens as positive.

The next thing to note is that there was still some degree of variation on sero-prevalence estimates in blood donors ranging from half a percent to about 5 percent, suggesting that the specificity for the sero assays is imperfect as yet.

To summarize one thing I didn't note on a previous slide that I intended to was that, even among individuals who have Kaposi's sarcoma, only about half are PCR-positive for HHV-8 DNA in their blood. So that PCR testing isn't as sensitive a method for identifying HHV-8 infection.

Regarding the serologic assays, there's good evidence that the assays have improved and are quite good for epidemiologic studies. However, if you want to diagnose individual infections in a population where the true prevalence of infection is likely to be very low, the assays need some improvement, and again there are no FDA-approved assays.

Moving on to how the virus is transmitted. In the U.S., the primary risk factor is having multiple male homosexual partners. However, it's also been shown that transmission may occur through heterosexual sex and needle sharing, and I'm going to present some more data on this following this slide.

In Africa, in contrast, most of the transmission appears to be through close nonsexual contact. In the United States, because of the low HHV-8 sero prevalence in the general population, it's thought that this type of transmission is quite rare.

What this slide shows is the evidence of the association between having multiple male sex partners and HHV-8 sero prevalence. In this column you can see--I don't know if it's cut off for everybody--well, I'll tell you about it. This is increasing numbers of homosexual partners. This number is greater than 250, and up here we have zero. This column here is HHV-8 seropositivity, and you can see it goes from half a percent up to 65 percent. After you control for a number of factors, you can see odds ratios here that are very large, suggesting a very strong association.

What this slide describes is data from a study that we did at CDC looking at women who are either HIV-positive or had HIV risk factors, and you can see that this column is supposed to show injection drug use with increasing frequency, and you can see that as injection drug use increases from never to this one says every visit of the study or every day the women were involved in the study, which was up to 6 years, that the sero prevalence of HHV-8 increases from about 13 percent to over 35 percent.

And these are the odds ratios after adjusting for a number of factors, including sexual behaviors using HIV and syphilis as markers for that. You can notice from this slide that the odds ratios for the associations are quite a bit lower than they are for homosexual sex.

From that same study, if you look just at women who don't inject drugs, this is lifetime male sex partners, commercial sex, and syphilis seropositivity. And what you find is that there are odds ratios ranging from 2 to 2.5, some of which are statistically significant, but suggesting that heterosexual sex is a risk factor for HHV-8.

Now moving on to--that was how HHV-8 can be transmitted--where do you find HHV-8 in different fluids in the body? And each circle here represents a study from the literature. The open circles are among HIV-negative individuals. The filled-in circles are HIV-positive individuals. And the risk groups here are divided up into the general population, injection drug users or STD clinic attendees, men who have sex with men and individuals with KS.

And you can see that in blood, HHV-8 DNA is fairly commonly found in men with KS, somewhat less common in men who have sex with men, and relatively infrequently in these other two groups. If you look at saliva, you see the same sort of thing here.

And then moving on to semen, it seems that half of this is cut off--well, an important thing to note is there is very little data on HHV-8 DNA in semen of HIV-negative individuals. One study here found 6 percent in HIV-negative men who have sex with men. This other study that's highlighted, that doesn't appear to be in focus, found some positive results, 3 percent in artificial insemination donors.

Now two things to remember is there is very little data on this, and these studies themselves didn't have large numbers in them, but it's also important to note that a lot of studies found no HHV-8 DNA in semen, so it's relatively infrequent.

To summarize transmission, the highest risk is through homosexual sex partners. However, since HHV-8 DNA is not found in semen very frequently, it is thought that perhaps other fluids are responsible for transmission. Currently, saliva is thought of as one of the more probable possibilities. However, there are no studies that actually measure the risk of transmission of HHV-8 via semen donation, but we can say, based on the prevalence in donors, that if such transmission occurs, it's probably quite rare.

Finally, the issue of to what extent is disease caused by this emerging pathogen. Your estimated annual risk of developing KS is one in a million, if you're healthy, each year. However, if you have an organ transplant, it's 1 in 80 per year; if you're HIV seropositive, it's 1 in 50; and if you're seropositive for both HIV and HHV-8, it's 1 in 20. So it's not much of a problem, as long as you're healthy. But if you're not, the risk is actually quite high.

To summarize the disease burden that might be due to semen transmission of HHV-8, first of all, HHV-8 is uncommon in semen. Even if you become infected, you need another factor to become ill. So the burden of disease is likely to be low if such semen transmission is occurring. However, the precise burden is not known because the studies haven't been done.

So, again, HHV-8 is a good example of a virus that's more common in groups such as HIV-negative men who have sex with men. However, the flip side of that is if you wanted to use a screening test to detect HHV-8, currently there are no approved tests.

The second dichotomy is, although HHV-8 is transmitted through intimate contact between male homosexual partners, it is not clear that that transmission is occurring through semen. Again, the risk of disease caused by this type of transmission is likely to be very low. But that brings up the issue of how low. Since we don't know, there are other examples, for instance, of HIV and hepatitis C, where the risk of becoming infected through, for instance, blood transfusions was already very low after serologic testing was implemented. Nevertheless, nucleic acid testing was implemented to further lower that risk.

Some of these things I already mentioned. Let me just conclude by saying that in addition to being a prototype virus for emerging infections that might be of relevance to semen donation, and in addition that the risk of harm caused by such transmission is very low, I don't think we're at the point yet, without doing the larger studies and the more directed studies, to be able to say that there is no disease risk involved.

DR. NELSON: Thank you, Dr. Cannon. Comments?

Yes?

DR. FITZPATRICK: Are there any studies on maternal-fetal transmission?

DR. CANNON: There are some studies. It is not clear whether infection occurs when the baby is actually being born or whether it's post-birth infection through exposure to the mother's saliva, but there is evidence of transmission from mother to child.

DR. MITCHELL: The nonsexual transmission that you talked about in Africa, is that thought to be because of saliva?

DR. CANNON: That's what people suspect, and the reason is is because you are more likely to find HHV-8 DNA in saliva than you are in fecal material, which is the other sort of hypothesis that might explain that type of transmission.

DR. NELSON: Thanks very much.

On the agenda there is open committee discussion, but I think we should move on.

The next presentation is by Dr. George Schreiber from Westat, talking about the benefits of semen quarantine and donor retesting.

DR. SCHREIBER: The topic that I am going to address is testing, and this will probably look very familiar to a lot of you, since this is a presentation that Steve Kleinman was supposed to be giving, and I am really substituting in for Steve. I have made some alterations to what you have in your packet, so it won't be as detailed.

Considering what you have in your packet, we spent a lot of time in that presentation looking at things like pre-ramp-up viremia, and I don't think it was really relevant to this particular topic. So, in the testing phase, I think I'll just go along fast. As I say, I think a lot of this will be familiar because many faces I see were at the FDA NAT testing workshop last week.

Infectious window period donations are really what we're looking as the prime sources of residual risk, and this is the time between the infectivity and the detection with screening test, and this may be different from time of exposure for a given agent.

The other residual risk factors are viral variance, and these are not detected by current tests--when I say current tests, I'm not talking about the NAT test, and you will see later these can be picked up--infectious chronic antibody-negative carriers, and then errors, and these are testing and product release errors.

You are familiar with this diagram, where we have two phases of the window period. One is the time between infectivity and serological detection, and that's what we call the W-2, where there's viremia, and the other is the Window Period 1, which is the time between exposure and infectivity. For most of the viruses for the HCB and HBV, most of the window period estimates are really based on the combination of Window Period 1 and 2, and for HIV, it's for the time between infectivity and the serological detection.

There are immuno-silent carriers, and these are people who are chronic N antibody carriers. They have persistent viremia in the absence of detectable seroconversion, and there have been case reports for the three viruses of interest. There is also recipient infection via transfusion has been documented for HCV. It appears to be rare, and we'll show some slides from the Red Cross that has data on HCV. And these immuno-silent carriers will not be picked up by quarantine unless we use NAT as a testing mechanism. As you can see, we're heaving into NAT.

Estimates of false negative test result errors, and this is in routine donor screening. You can see that there was 1 in 2,000 confirmed seropositive donors tested negative due to technical testing errors on subsequent donations. And these were for all of the positives. So this includes HIV, HCV, and HBV. When we looked at the three viruses, testing error was exceedingly small.

In a similar vein, the Red Cross, Sue Stramer, showed that there were 3 of 2,307, for a rate of .13 percent of HCV seropositive donations to ARC that were originally missed and then identified by NAT and then went back and looked at the sample again. In fact, it was serologically positive.

This is just an estimate of the window period to put everybody in the ballpark. As you can see, the estimates, and for some reason it doesn't fit on here either, but you can see that the range for HIV needle stick, and this is Glen Satten's work, it ranges from 10 to 190 days, and for HCV transfusion, it's 33 to 129 days, HBV it's 3 to 87, and this is from the Jamaican studies down here by Ed Murphy, and it ranges from about 36 to 72, but the ranges are all in about the 60-day range for the point estimates of these serological conversions.

This is a survival curve for time of infection from Glen Satten at CDC. The important thing, just to look at this, is if you track over to here and you come to about 180 days, which is the 6-month quarantine, you can see that you would still have about 5 percent of the people that would seroconvert more than 180 days out.

This is a summary of that slide, which probably makes it a little bit easier, but it's 95 percent of the cases seroconverted within 6 months of exposure. Importantly, too, the delayed sero-converters, once they're retested by NAT, were viremic for only a short period prior to their seroconversion, so that infectivity may be confined to the short time interval. So they are seroconverting and viremic in a heavy phase right before they are serologically converting.

These are several cartoons that we have seen, and the purpose of this is just to show that the NAT is picking up the RNA at a much earlier stage, at about 11 days. The pink one is the P24 antigen, which from the NAT testing sounds like it might go by the wayside, and here you can see the antibody testing, and we have a rise and a blip, with a subsequent rise again. As you can see, the antibody testing really kicks in at about 20 to 25 days.

This is a similar type of just pictorial showing that RNA testing is much more effective in picking up the hepatitis C. You can see that the RNA picks it up at a mean of about 13 days; ALT, surprisingly, is fairly good, it kicks in at about 52 days; and the EIA 3.0 has a time period of about 71 days. This is just another pictorial just showing the plateau phase of the RNA, and further out, at about 70 days, is where the antibody kicks in.

For HBV, the pictures are fairly similar. There is no plateau phase, but you can see that at around 30 days it's picked up by the DNA testing, surface antigen is picked up about 20-some-odd days later, but then the surface antigen disappears, so that a lot of people are people who can be viremic, and you would not detect since the transient period for surface antigen is about 63 days. So that if surface antigen is used as the marker, you'll have a lot of people that would go undetected themselves.

This is the duration of the viremic window periods prior to seroconversion, and this is detectable by NAT compared to the seroconversion. You can see it's 60 to 63 days for HCV, HIV is 9 to 13, HBV is about 6 to 17 days. So you can see that the NAT tests are fairly good at picking up early infection, but for HCV we still will have quite a bit of tailing. So, if we're talking about a potential quarantine period, for those that are more delayed, you have the added benefit of the quarantine.

Immuno-silent carriers. In over 2 years of NAT testing, ARC has identified two donors who are HCV RNA-positive and did not develop HCV antibody in the subsequent 6 months. The denominator for this is over 12 million donations, and in this time period there were about 12,000 HCV antibody-positive donors.

This cartoon from Sue Stramer just illustrates that here are the two that go a long time since NAT detection and then continue out to be seronegative, and this is based on about 35 people that were studied that were detected by NAT only. As you see, though, the incidence of these is fairly rare, but it is there.

The risk and the risk-reduction calculations are based on, the risk is based on the number of donors in the infectious window period, which is the annual incidence times the window period, which is expressed as a fraction of the year, plus the rate that we just showed of the silent carriers, plus the prevalence, times the error rate, and the error rate and the silent carriers are fairly small.

So you can see that most of the risk would be attributable to the window period infections. The risk reduction is the annual incidence times the reduction in the window period. Again, the other terms are fairly nonsignificant.

This is our summary slide, and I think what we want to illustrate is that with a quarantine, and a window, and a retest, the window period is greatly, the risk from window period is greatly reduced because here we are proposing or it has been proposed to have a 6-month quarantine period. With NAT, it's reduced even farther. Silent carriers, there's no effect of the quarantine in a retest, but again we suspect that there aren't very many silent carriers, and with NAT, that's reduced because the NAT picks up the silent carriers and detects the viremia.

Testing error is very small, and with the quarantine, expecting these people to come back or requiring them to come back, it's reduced almost to zero. The same thing with NAT. The NAT will reduce the error rate with repeat donations on the same individual to almost zero. The variant agents, there's no effect of the quarantine, but the NAT will pick up the variants.

So, in summary, I think what we're showing is that we believe that there is a benefit to have a quarantine period for reducing the chances of having a window-period infection, and I think this is true both to the blood sector, where we've looked at this extensively, and also probably to the sperm donations.

DR. NELSON: Thank you.

Questions? Jeanne?

DR. LINDEN: Can you clarify what you just said about the NAT testing and the testing errors going down to zero. You just said repeated donations?

DR. SCHREIBER: Yes. The assumption that we're working on is that the FDA or the proposal is, is that the people, there's a quarantine, and they have to come back and have a second donation. So I think the chances of having a false positive or a false negative on two donations from the same individual is very, very small.

DR. LINDEN: I guess I'm not clear then the difference between your first column and your second column on your last slide. I thought the first one was the quarantine retest issue.

DR. SCHREIBER: I'm sorry. I'm sorry. You're right, it wasn't clear. The first column is quarantine retest. The second column is quarantine retest, and the use of NAT and the benefits of having NAT. We didn't address, because I wasn't asked to, could you shrink the quarantine period. I think that could be another issue, but it was not on the table. I think what this data shows is that you could probably shrink the quarantine period, and use NAT, and be as effective as you would be with a much longer quarantine, depending on serological testing.

DR. NELSON: It's my understanding that NAT is not used for semen donations; is this correct, Dr. Sims, it's not used?

DR. SIMS: It's not mandated, that's correct.

DR. NELSON: But it has been used by certain people in the literature, right?

DR. SIMS: It has been used.

DR. HOLLINGER: So I guess in looking at this, George, why can't you use just NAT alone, I mean, without the quarantine and the retest?

DR. SCHREIBER: Well, I think--

DR. HOLLINGER: On a fresh sample.

DR. SCHREIBER: Yes. I think you could use NAT alone. Again, we haven't looked at it, but I think that a quarantine of some portion is still effective because the time to viremia still has a distribution around it. Particularly for HCV, I think the distributions are not small. So I think if you want to cover yourself and make sure that you're covering 95 or whatever percentage, then the best thing is to require the person to come back. And if you have 60 days or 90 days later, for argument sake, another negative sample, the chances are much, much smaller that the sample that you're holding would be viremic or positive.

DR. HOLLINGER: Just another question, and perhaps Dr. Sims can tell me. How quickly do the sperm have to be used when they're fresh?

DR. SIMS: If it's fresh semen, it can be used one day or something like that. Sperm will live outside the body, fresh sperm, in a media for days, up to a week, but normally it would be used within a 24-hour period.

Typically, it's used the same day it's collected or, if not, the next day.

DR. NELSON: Blaine, were you talking about not doing antibody testing or antibody plus NAT when you said NAT alone? Because we have shown, and you probably have, too, where the PCR positivity, particularly in the early phases of hepatitis C may be intermittent even in the presence of antibody. So you could get a false negative NAT in somebody who is infected. I think you need to do the antibody test.

DR. SCHREIBER: I think just one other comment is we showed, in other data that we've presented to BPAC before on plasma donors, which have a frequency of about every 5 days, that the plasma industry for source plasma has a 60-day hold, and the 60-day hold itself is effective in removing about almost 100 percent of HIV. There's about 85 to 90 percent of HCV, and it's about 80 percent of HBV, and that's a hold period versus a quarantine.

DR. MITCHELL: Now were you assuming in your quarantine that it was a 6-month quarantine; is that correct?

DR. SCHREIBER: We were just going by what the FDA, because that is what was on the table, we didn't address--

DR. MITCHELL: Which is 6 months.

DR. SCHREIBER: Which was 6 months, yes. Sorry.

DR. NELSON: Next is Dr. Sims again, talking about cryopreservation of semen.

DR. SIMS: Thank you. I think we should all remember that there is no such thing as an emergency insemination. There's always next month.

Well, I'm the designated pinch-hitter for John Kreitzer, who was not able to be here today. I guess in sperm banking I'm your utility man, to use a baseball term.

I am going to discuss cryopreservations, and my talk will be somewhat different than what John's would have been. John is a Ph.D. scientist cryobiologist. I'm a pathologist. We're quite different, so my approach will be from my own perspective.

I'd like to just give you a little bit of history about when we started and where we are now. Cryopreservation basically started, for all practical purposes, in about 1949, when Polge discovered, quite by accident, that the addition of glycerol to sperm would enhance cryo survivability. That was a very poorly defined experiment.

As I understand it, the way that happened, which is kind of interesting, is that they didn't know what they were doing. There were some labels that came off of some reagent vials, one contained glycerol. They thought they were adding something else. It turned out to be glycerol, and they got good results. And so quite by pure accident and sloppy technique, they stumbled into a discovery, and that discovery of glycerol as a cryo protectant makes possible everything we are discussing today.

It was used with blood successfully in about 1951, where they showed that you could freeze blood without significant hemolysis by the addition of glycerol. The first calf born using cryo-preserved sperm was in about 1952. And Jerry Sherman, who is still alive, in 1953, wrote the first paper demonstrating that human sperm could also be cryo-preserved, frozen, and used successfully to produce live birth.

At this time, they used plain glycerol. Usually about 10 percent was added to the specimens, and it was successful. It was not as successful as it is today.

First of all, freezing is not good for cells. Freezing is very hard on cells. It's not good for any human cells, just like walking without protective gear on the surface of the moon is harmful to human beings. So freezing is a very unnatural thing. These are some of the harmful effects of freezing. There's the formation of intracellular ice crystals. When that happens, these crystals, as they form, start in one place, and they shear through cell membranes, and they effectively destroy the cells by the formation of ice crystals.

Freezing is also associated with huge osmotic shifts. As you cool the specimen down, water is pulled out of the cells, where it does form ice, and the osmolality within the cell rises. That is hard on the cell. There is an entity called cold denaturization, which where cooling itself can cause naturization of intracellular proteins. Cold shock is not a problem in humans, but occurs in some species with sperm, and that's the irreversible loss of motility upon cooling, not a freezing, but just a cooling, and it's more associated with rapid cooling.

Another event that occurs in the freezing and thawing process is the formation of free radicals. These oxidative species can cause damage to the cells and cell membranes. Rewarming of cells also is another transient that cells have to make successfully. Not only are cells injured upon cooling and freezing, they are also injured on the rewarming of the cells. These same events occur somewhat in reverse. There's also changes in PHs.

So one of the goals of cryopreservation is what can we do to lessen the harmful effects of freezing, and the things that we add to minimize those effects are called cryoprotectants. We want to protect the formation of ice crystals, minimize osmotic shrinking and swelling during freezing and thawing. We want to lessen or stabilize cell membrane injury, and we want to prevent oxidated damage to the free radicals, and we want to maintain the functional capacity of the sperm. Basically, if sperm were a business and you wrote a mission statement for it, it said find the egg and fertilize it. That's the mission of the sperm.

But the functional requirements to accomplish that mission are it has to find the egg. That's motility. It has to adhere or bind to the surface of the egg, and then it has to penetrate the zona pellucida. The zona pellucida, if you remember, is equivalent to the shell of a chicken egg only it's a tough protein membrane, but it has to penetrate that. It has to fuse with the cell membrane of the egg. In other words, the nucleus of the sperm, which is enveloped by a cell membrane, it has to fuse with the cell membrane of the oolemma, the cell membrane of the egg, and then the sperm has to decondense its nucleus in order to form the zygote for the chromosomes to align each other and pair up and undergo cell division.

At some point, probably around the fusion of the cell membrane or the point of decondensing, the egg takes control. It's like getting married guys. Sometimes you lose some of your autonomy. Someone else may take control.

[Laughter.]

DR. SIMS: So restated, the requirements for functional capacity of sperm are to maintain motility. There is a physiological reaction that has to occur in the cells called capacitation. Capacitation is a chemical or physiologic change in cell membranes that sperm have to undergo before they can fertilize.

Fresh sperm, this occurs in the reproductive tract. It takes about 18 to 20 hours for the sperm to undergo capacitation before it's ready to fertilize. So, if you're doing an IDF procedure, you're collecting the sperm, you have to delay, you have to capacitate the sperm. There are things you can do to speed that up.

It has to bind to the cell surface of the oocyte, penetrate the zona pellucida, fuse with the oolemmal membrane and decondense, and this is restated from the previous slide.

Now why is it necessary to freeze sperm at all? The human race got along quite well for thousands of years, if not millions of years, without freezing sperm. These are the needs or the perceived needs of cryopreservation of sperm. One is to preserve fertility in men who face sterilization or serious genetic damage from surgery, chemotherapy, radiation therapy, et cetera. It was on the basis of Item No. 1 that sperm banking occurred in the United States.

Nearly everyone--in the beginning, the pioneers who opened sperm banks, the goal or the reason they open them was to provide long-term fertility insurance for men undergoing sterilization procedures, and that's actually the reason that we started in 1977. Our bank was going to store sperm for men. We had no idea about doing donor sperm at that time, but that was why we started it.

The second reason is to allow pregnancies in couples who face prolonged separation. For instance, women might be facing the end of their reproductive life, their husbands may be out of the country or away from them due to jobs, being in the military or they could be on a space mission, where they could be gone for long periods of time. So the ability to freeze sperm, store it and use it later is important for these couples and individuals. It also is used in donors to protect recipients from infectious disease through quarantining and retesting of donors.

Currently, it's Item No. 3 that provides the primary impetus for the discussions that we're having here today. It's widely used in animal husbandry. It's the predominant method in insemination in dairy cattle. It's used fairly widely in some breeds of beef cattle. It's used quite successfully in horses, although the American Thoroughbred Association doesn't allow it, but it works on horses. It's unsuccessful in swine. It's used widely in turkeys.

DR. NELSON: Dr. Sims, I wonder if you could, in the next 10 minutes, do you think you could finish?

DR. SIMS: I'll be through in just a moment.

DR. NELSON: Okay. I don't want to rush you, but there's a long line behind you, and we want to be able to--

DR. SIMS: I'll try to knock through the grass and move along.

The techniques for acquiring the specimen for freezing are, as you can see, there's masturbation. You can obtain it from nontoxic condoms. People who are quadriplegic, we can get sperm by electro-ejaculation. People who have blockage of the vas deferens, you can obtain it, in many cases, from percutaneous or open epididymal aspiration or epididymal biopsy. You can even obtain sperm from the testes. You can take a little biopsy of the testes, and if you tease it out, if you find a sperm that twitches, you can use it for an IVF procedure with intracytoplasmic sperm injection with a single sperm. There have been a few cases of postmortem harvest of the epididymis. The specimens are evaluated by microscopic examination to determine their suitability.

The cryo protectants are usually a cocktail of cryo-protective agents. Those vary from lab to lab. They are fully defined mixtures, and there are others that contain some nondefined mixtures such as egg yolk.

There are two methods of freezing, one is with the vapor phase of liquid nitrogen, which is the way nearly all sperm is frozen now. Control-rate freezing is used for embryos, but with sperm there's no clear-cut advantage of control rate freezers. It's slower, a little more costly.

The viability of cryo-preserved sperm is actually unknown, but it's at least decades, if not centuries. Below minus-120 to 130, there's no measurable thermal chemical reactions that occur. At minus-196, certainly, the only thing that happens there is probably photochemical damage from ionizing radiation.

There are no known upper limits as to how long sperm can be stored. Human children had been born after 18/19 years of storage. We have thawed out specimens that have been stored for well more than 20 years, and they look the same as they did the day after they were frozen. We see no deterioration over time. They are in virtually a state of suspended animation.

All of this material that I have here will be posted on the FDA website, so you can not worry about taking copious notes. The two methods of storage of sperm is in the vapor phase of liquid nitrogen, which is the way much blood products are stored. Sperm is more commonly stored in the liquid phase.

The advantages of vapor phase storage in sperm is that it's less costly because there's reduced LN2 consumption. There is also less risk of potential cross-contamination with or by liquid nitrogen in the cryo containers.

The disadvantages of the storage temperatures tended to be higher. They have to be very carefully monitored to maintain constant temperatures, and there's a risk of thermal shifts with micro-thawing where metabolic activity can occur because the temperatures have been raised to levels above minus 120. So these thermal shifts are reasons that most people do not use vapor phase.

The advantages of liquid storage are the converse of that. It's the coldest temperature. There's no variation in storage conditions. You don't have to measure temperature because temperature is determined as a calig-(?) property of liquid nitrogen, which is about minus 196. The disadvantage is that it's somewhat more costly. You have to control the level. And there is a theoretical risk of cross-contamination of vials within liquid nitrogen.

How well does cryopreservation work? When you freeze sperm, in healthy men, there is a 30 to 50 percent loss of motility. So you lose about half of the normal sperm when you freeze it. And this is in men who have good semen quality. People who have very low counts, poor morphology, the cryo-survivability is actually much lower than that. It can approach 10 percent or so, or even less if it's--in other words, the worse the sperm is before you freeze it, the poorer it survives the freezing-thawing process.

Pregnancy rates in healthy female with no known reproductive disorders, when performed by reproductive endocrinologists using intrauterine insemination, the pregnancy rates are approximately 15 percent per cycle. There are some people who have reported higher rates than that, but for all practical purposes, you could use a pregnancy rate per cycle of 15 percent.

Now, the pregnancy rates per cycle with frozen sperm are 20 to 30 percent, depending upon which bit of literature you read. The pregnancy rates for intracervical insemination as opposed to intrauterine is 2 to 4 percent per cycle less than that of intrauterine. But if you would take cumulative pregnancy rates at a period of, say, five or six months, the cumulative pregnancy rates of whether it's fresh sperm, frozen sperm, or intrauterine versus intracervical, they tend to converge at that point. Beyond that point, you're probably dealing with a population of women who have fertility problems. These are women that should go to IVF or some procedure like that who are still trying to get pregnant. It's a different population at that point.

Next?

Just for--we can skip that one. So that's it. So I can take some questions from the committee members. I hope I was short.

DR. NELSON: Yes, very good.

One comment you made that seemed to be a little bit of disagreement on was the difference between fresh and cryopreserved sperm, and it seemed--since that's one of the questions central to what the committee is supposed to discuss, I wonder if you could elaborate on that point.

DR. SIMS: Certainly. That's a very valid question. No one is advocating the use of frozen sperm for routine pregnancies. So there has to be a purpose or reason you're doing it, and there has to be a benefit from the use of frozen sperm.

The benefit from frozen sperm is that in anonymous donor situations it allows you to develop a strategy that will protect the safety of the recipient from infectious disease. That's the primary and compelling reason to use frozen donor sperm. We have had one HIV infection in our laboratory, some 15 years ago, so it's a real issue. And there's a real need to do that.

There is no such thing as an emergency insemination. While the pregnancy rate per cycle is somewhat less than that of fresh sperm, the cumulative pregnancy rates tend to be similar. So if you don't have to get pregnant this month but you can get pregnant over a period of two to three, four or five months, then you achieve the same pregnancy using frozen versus fresh. So the ultimate cumulative issue is that there is not a substantial difference.

DR. NELSON: But the use of fresh sperm in a single cycle would yield a 15 percent pregnancy rate? Is that--

DR. SIMS: No, that's frozen sperm.

DR. NELSON: That's frozen. What about with fresh sperm and a single exposure?

DR. SIMS: Five to 8 percent higher, probably.

DR. NELSON: Five to 8?

DR. SIMS: Eight percent higher than using intrauterine insemination with frozen sperm. So the pregnancy rate per cycle is higher.

DR. HOLLINGER: Yes, I think maybe you hit on one of the issues here, as you said, one of the issues between direct donors and anonymous donors. I think one of the issues was that the pregnancy rates were much less with frozen sperm. And what I'm hearing you say is that perhaps at one cycle there's a bigger issue, but at two or three cycles they start to probably not make much difference, or there may not be much difference between fresh and frozen, anyway, which removes the question of whether the quarantine period is really an issue, as I see it.

DR. SIMS: If you have one month in your lifetime to get pregnant, then fresh is better. If you have three or four months, the differences are probably hypothetical.

DR. HOLLINGER: Thank you.

MS. KNOWLES: And I would think that with your patients, your recipients, you would be explaining this in a consent form, anyway--right?--the differences between fresh and frozen and the ability to get pregnant?

DR. SIMS: We're a sperm bank. We don't do inseminations. That's done by physicians. But that is an issue that needs to be explained.

I think when you're talking about anonymous donors, it's really foolish to even consider the use of fresh sperm. It's irresponsible. In the case of directed donors, I see no compelling reason to waive the quarantine period in directed donors as opposed to anonymous donors. We treat them the same.

In the case of husband and wife, it's a different issue where they're sexually intimate partners.

DR. NELSON: Okay. That's a segue into the next presentation, which is achieving pregnancy using fresh versus cryopreserved semen for semen insemination. Dr. Emmet Lamb? And, again, because of the long list, Dr. Lamb, if you could do it in 15 minutes?

DR. LAMB: There seems to be another flap that hasn't come up. Oh, I see it. Okay. It's going to be difficult for me to do it in 15 minutes, but I'll give it a whirl.

In the last decade, the indications for use of donor insemination in cases of azoospermia and severe oligospermia has changed because of the availability of ICSI, intra-cytoplasmic sperm injection. A male who has no sperm in his ejaculate can now have a surgical procedure, his partner have a surgical procedure, and they have offspring with their genes. The remaining indications, genetic problems in the male, are relatively infrequent, and the remainder, no male partners, some of these are lesbians, some are straight. Dr. Sims mentioned several instances of separation.

The variables that improve fecundity that we cannot influence clinically are these. They're all surrogates for female fertility. The rate of pregnancy is higher when there's an azoospermic male, and the rate of pregnancy in the first cycle is also higher because in the presence of female factor infertility the rate per cycle drops down with succeeding cycles. So the first cycle is an unbiased estimate of the optimal fecundity. Fecundity is the chance of pregnancy per unit of measure. Here we're talking about an insemination cycle. In pregnancy--in other situations, we're talking about a month.

These are the variables that can be changed to improve fecundity. Selecting a donor who has good characteristics of the sperm is one. Using fresh sperm is another that we'll dwell on quite a bit. The cryopreservation methods and sperm preparation methods have already been covered. The insemination methods, intrauterine versus intracervical. Ovulation monitoring so that the sperm are delivered at the time when the egg is going to be present and fertilizable, and that's probably less than 24 hours. These are in progressing effectiveness, but also progressing complexity and cost.

Using ovulation enhancement with drugs, clomiphene citrate or gonadotropin injections will improve the timing and will also improve--increase--not improve but increase the multiple pregnancy rate, which in itself is a serious public health problem.

In your handout, there should be a reprint about methods of estimating fecundity or comparing fecundity between two treatments. The easiest of these is to estimate cycle fecundity, which is total pregnancies divided by the total cycles of exposure. That is an easy calculation. It's easy to tell people about. In the case of donor insemination, if the husband is azoospermic, it's about 90 percent accurate. It assumes a constant chance of pregnancy. The more female factors there are in the individual couple situation, the less accurate that estimate is.

The Kaplan Meier survival curves that are familiar to you from cancer adjust for the cycle-to-cycle variation in fecundity and improvement, and the Cox proportional hazards method is a further improvement which allows a quantitative analysis of the effect of variables such as the ones we saw on the previous slide.

In your handout, there is--I don't know how this happened. It comes up on my computer, but apparently not on this computer. There is a very complex table, and let's see what--well, it lists 14 studies. Of these, there were three randomized clinical trials and half a dozen cohort studies and some studies that used historical controls. We performed a meta-analysis using the techniques, the statistical techniques of meta-analysis. It's not a meta-analysis that meets the criteria for a good meta-analysis in that we did not go back to original data. We didn't contact the original authors. We didn't look through abstracts of journals and so on. But we used the techniques, and I will have a slide here in a minute.

Let's look at the summary statistics that can be derived from this sort of analysis. The summary--there were 23,000 not subjects but cycles of insemination. The summary odds ratio was 0.62 with a 95 percent confidence limit that excludes one. This means that frozen sperm were 62 percent as effective in getting people pregnant as were fresh sperm, and that's statistically significant. The test for heterogeneity means that not all of these studies showed the same thing, and that dictated--we can at least show one version of this. I guess the authors of these studies are not here, but the number of patients is, and we can see--this is two ways of showing the results of the individual studies.

In the left-hand side, we have the studies which are arranged according to the quality of the study. The randomized clinical trials are the first three. The next ones are--the next two are randomized in the first cycle and then alternating. It's a less good method.

These studies here are the cohort studies, and these down here are the historical controls. And the last one, the last individual study, this one, was a cohort study that had an experimental design that introduced severe bias in favor of the frozen method. Anything on the left-hand side of the line indicates that the fresh semen had a higher pregnancy rate. The summary statistic 0.62 is here. And since it's not possible for us to assign a meaningful number to the quality of the study, we took a different approach. We did a cumulative analysis on the right-hand side in which the second line is an expression of the first and the second study, and the third line is an expression of the first three studies. So it's the cumulative odds ratio for the studies progressively, and it converges down then onto the final estimate, which is still 0.62.

If we stopped after the fifth study here, which is the last randomized study--I'm sorry. The last randomized study--I'm trying to go backward. Yes, here we are. I'll try and keep my finger off that button.

If we stop at the fifth study, which is the last randomized study, we have achieved statistical significance here in that the 95 percent confidence limit does not cross the odds ratio of one. The other studies add less information, and they're not--they're actually going a little closer to the one. So we have--using only the best studies, we have the same information.

Cycle fecundity, we were asked to address the question of what can be done with donor frozen semen to improve the fecundity, and the only study that I could find a systematic review directly on that question dealt with intrauterine insemination as opposed to intracervical insemination or timed coitus, and this shows that the rate was 2.6 times as high, the odds ratio 2.6 times as good fecundity with intrauterine insemination.

With frozen semen, we have lower fecundity, and that means that more cycles are necessary to achieve the same--any given level of pregnancy. The more cycles you have, the more women are going to drop out. Insemination is not something that's free of stress, and women find--couples find that it is stressful and they stop treatment. The end result is that there are fewer children and greater uses of limited resources if we went to the same number of cycles--to the same pregnancy rates.

Doctors, in response to the lower fecundity, have used gonadotropin stimulation and clomiphene stimulation to compensate, and because of this we get more multiple pregnancies, and that's a big problem.

With these co-authors, we have written an analysis of the use of frozen semen to avoid HIV transmission, and we used the methods that have been recommended. I'm going to skip over a bit.

We used a Markov model. The events in a Markov model unfold over time so that it's a good one to use when the rates and probabilities change over time, as they do with insemination. The chance of getting pregnant changes.

We took as a starting point a cohort of 80,000 women, which approximates the number of people who are inseminated each year in the United States. We used the model which included a maximum of 12 cycles and a yearly follow-up for the lifetime of the patients.

We looked at two treatment options. The first of these using frozen semen is the one that you're discussing today. The use of fresh semen assumes that the donor is screened once with enzyme immunoassay and in other ways is screened the same as with the frozen. But the fresh semen is used.

It does not include the use of PCR. It does not include the use of repeated screening, chemical testing, immunologic testing of the donor before use of the fresh semen.

The Markov model is shown here. The patient enters the simulation in the treatment cycle. I can't see--

DR. NELSON: Can we get this focused?

DR. LAMB: This has insemination. She can have repeated inseminations until she becomes pregnant. If she becomes pregnant, she may have a miscarriage or an ectopic. She can either drop out and go on without pregnancy or restart insemination until she either gets pregnant or she--that's all right. I'll read them. Until she has had 12 inseminations or she becomes pregnant. She can become infected and go through the same pregnancy sequence.

After the initial 12 months, she is followed either in the non-pregnant state or in the pregnant state and non-infected, and these patients are followed until they die, a full lifetime, as determined by mortality tables. If they are infected, they go through five stages of HIV infection until they die.

The most--let me see if I can...each time the patient goes through one of these states, she collects two chips. One is the quality-adjusted life years. Quality-adjusted life years are [inaudible - off microphone] this type of analysis. The other one I'm not going to mention at the moment, but you'll hear from me later in the day.

And we have established probabilities for each of these transitions as indicated by these arrows, and we've given reward values to each of the states.

The most difficult probability for a transition is the risk of becoming infected with HIV by insemination. It's the product of two elements. One is the probability of infection from one insemination with an infected donor, and the second is the probability of having an infected person as a donor. The second of those is the sum of two possibilities. One is a prospective donor who is missed by the enzyme immunoassay and it's determined by that formula, and the other is the donor who is in the window period and does not fall out because he has a so-called false positive test. And it's given by that formula.

We needed to establish for each of the elements in that last slide the probabilities. There's an extra button that is down at the bottom that I didn't realize. Okay. Each of those elements in that slide required us to put a number on it, and for the risk of transmission by insemination, we took the risk of heterosexual transmission, and this has been estimated by these authors as between one in 500 to one in 1,000. We chose in our model to use one in 200, and in many instances of numbers that I'll mention, we took an approach that I'll call conservative in that it favors the outcome of advising the use of frozen semen only. That's what I mean by conservative.

Another blank slide. What appears here, I hope in your handout, is a table which compares the estimate of the prevalence of HIV first in blood donors, which was 0.03 percent, and in cornea donors about the same. And we used 0.05 percent as the baseline value for our model.

We needed to make an estimate then of the prevalence of donors in the window, and we took this approach. Again, using conservative estimates, 50,000 new HIV cases in males of which 35,000 were in high-risk individuals, 25 percent of whom we assumed would escape the screening mechanisms. And that would leave us with 8,700 high-risk individuals who came into the pool, plus 15,000 leftover who were not high-risk individuals, giving us 23,000 and change infected potential donors.

If we assume that they come in steadily throughout the year, that would be 1,980 per month. And if we assume that the window period was three months long, we would have 5,940 infected potential donors in the window, about one in 10,000 out of the 65 million males of reproductive age for that figure there.

Oh, this is impossible. Do you have the--

DR. NELSON: We have the tables.

DR. LAMB: Okay. It's in your handout. All right. The use of frozen insemination requires more insemination cycles, 3.8, and a half a cycle more. The life years after age 30 amount to a few days, but discounted for quality of life, it's about a month.

I'm going to--I guess I will skip--I just can't understand how this computer differs from mine.

Ron Howard has said that for unusual events that are risks to life, we can express them as micromorts or one chance in a million of dying. The micromorts assumed by a woman who makes a contract for 12 inseminations--and, remember, the average was only 3.8. If she assumes a risk of 12, that's 5.6 micromorts risk of dying that she assumes. This is somewhere between the risk she assumes by living in a town where planes fly overhead [inaudible - off microphone] crashing into your house, or additional cancer risk assumed by living in Denver--

VOICES: Microphone.

DR. NELSON: We can't hear you.

DR. LAMB: The risk for 12 inseminations over the course of a year is equivalent to the risk that a person assumes by living where planes are because that's the risk of a plane crashing into your house--and it's between these two--and the risk of living in Denver as opposed to a sea-level town in terms of cancer risks. It's considerably less than these risks, which you can see.

This is--I think of it as a gynecologic procedure, insemination. The insemination risk for a full year of insemination with fresh semen are about one-quarter of those of having a tubal ligation. They're a little bit less--a little bit more than that of having an abortion.

Pregnancy itself, which is the goal, is considerably more risky, and having any sort of gynecologic major operation is considerably more risky.

In conclusion, the risk of using fresh semen in donor insemination is quite small. It's in the range of risks that we accept with equanimity every day. The reward, higher fecundity, higher chance of having a family, is substantial, and informed patients might reasonably accept that risk in order to get that reward.

DR. NELSON: Thank you very much.

Are there any questions for Dr. Lamb?

[No response.]

DR. NELSON: Okay. I'd like to move to the open public hearing. Dr. Lamb, you're first.

DR. LAMB: I'm the first speaker, but I can't find my second set of slides.

DR. NELSON: Again, we have five people that want to speak, and, again, I'd like to--

DR. LAMB: Let me refer to...

DR. NELSON: Maybe we could give you a break. Is Mr. Leonard Treeiman here? I'm sorry. Leland. Do you have slides, also?

MR. TREEIMAN: No, I don't have slides.

DR. NELSON: While he's getting organized, why don't you...

[Pause.]

DR. HOLLINGER: While he's looking at it, Dr. Lamb--Dr. Lamb?

DR. NELSON: Dr. Lamb, there's a question for you.

DR. HOLLINGER: I have a question. From what I can gather from what you presented earlier, I mean just now, what I think you said was that the difference between fresh and frozen was only about half a cycle more in terms of fecundity if they were fresh, 3.83 for insemination versus 4.33, I think.

DR. LAMB: In the computer simulation, we took into account a dropout rate and pregnancy rate and a limitation of 12 cycles. Given all of these limitations, the average number of cycles for fresh semen was 3.8 and 4.33 for frozen. So that was half a cycle more. But if you want to compare how good they are, then the meta-analysis statistics giving the odds ratio is a much better way to do that. It's 60 percent, 62 percent.

DR. HOLLINGER: But then the other thing also is that there was about an 8,000 times greater risk of HIV between fresh and frozen--fresh and thawed.

DR. LAMB: Yes--8,000 times?

DR. HOLLINGER: Well, it's 0.0007 at a maximum of 12 versus 5.6.

DR. LAMB: Okay. The risk of HIV infection in women, if all 80,000 women in the United States, every one of them was treated with fresh semen, the risk would be one woman infected in seven years. During that--this is from the slide that didn't show.

DR. HOLLINGER: Okay.

DR. LAMB: During that time, there would be 60,000 more babies born if you had used fresh semen. I'm not proposing that every women be treated with fresh semen. I'm proposing that the woman who requests it be allowed that option.

During that time, there would be a quarter million babies born using--if everyone had fresh. The computer simulation can allow us to have everybody treated in the same way. There would be also a very small risk of infection in the newborn. If you look at the newborn figures, you can see that there would be something like six million uninfected infants born for each infant that was infected. But there is a risk. It's not zero in either instance.

DR. HOLLINGER: Thank you.

DR. FITZPATRICK: Dr. Lamb, in your model, you used HIV positive--you used the general population. You did not use--calculate based on subsets of, like, MSM rates of HIV infection. You just used the general population from corneal transplant.

DR. LAMB: In the baseline case, we used a figure of HIV prevalence that was lower than the general population, taking into account the screening for sexually transmitted disease, the screening by history and physical, and self-selection. We used a figure that was higher than the figure for blood donors and cornea donors. It was 0.005 percent.

DR. NELSON: I'd like to move on to--are your slides ready now?

DR. LAMB: We don't have them.

DR. NELSON: Do you want to speak up here, Mr. Treeiman?

DR. LAMB: I can tell you what was on the slides.

DR. NELSON: Okay. And if you could--since there are several behind you, if you could do it as concisely as possible.

DR. LAMB: Okay. I'll go as fast as I can. I thought I had a lot of material.

In our Markov model, the other reward set that we applied to each circuit through was dollars, and if we look at the outcomes now taking into consideration dollars, which I can use as a member of the public, the total insemination cost in the United States, assuming all 80,000 inseminations were done with fresh semen, would be $80 million less, and the insemination cost per live birth would be $6,000 less.

We looked at a variety of sensitivity analyses. The sensitivity analysis in this setting means that we vary the value assigned to variables across the full span of reasonable values and see what effect that has on the decision.

In terms of cost-effectiveness analysis, the decision between fresh and frozen was dominated by fresh, which means that it was not only more effective but also less costly, and that did not change with any of the changes in cost of health care or in the probabilities of transmission from infected donor, the HIV prevalence in potential donors, number of donors in the window, vertical transmission to the fetus, and so on. Nor did it change with quality-of-life factors, which are the softest of the variables that we have, things that we assigned primarily because there was no literature.

There were two variables where it did make a difference. One was relative cost. If the cost of frozen insemination were less than 83 percent of the cost of fresh insemination, then the preference between the two would fall to frozen. That doesn't seem to be likely to occur since, as Dr. Sims mentioned, each cycle has an additional $400 cost, and the total cost of insemination that we used in our estimate was about $2,000.

The second variable that could influence is the relative fecundity. If somehow frozen semen were made to be equally effective rather than 62 percent effective, then the preference could fall to using frozen semen. In all other instances, either the costs were higher or the effectiveness, the number of pregnancies, was lower. And in all those instances, one who makes decisions on the basis of cost-effectiveness analysis would be for the use of fresh.

DR. NELSON: Mr. Treeiman?

MR. TREEIMAN: My name is Leland Treeiman. I run the Rainbow Flag Health Services and Sperm Bank in Oakland, California. I was going to present a paper, but I feel like we have to look at the last two speakers in a different way.

Dr. Lamb said that there was a substantial increase in fresh insemination, and indeed that's the case. The literature supports that perspective. With all due respect to my esteemed colleague Dr. Sims, what he was comparing was sort of apples and oranges. If we were to take a man who--what he was comparing was fresh insemination of just heterosexual sex and the rate of pregnancy versus frozen semen coming from his bank.

Now, frozen semen coming from any sperm bank is based on men who have very high quality sperm that survives the freezing process because only about one out of six men have sperm that survives the freezing process. Indeed, Dr. Sims said that at his bank only about 4 or 5 percent of men get through the screening process for various reasons, one of which is poor fertility or semen quality. So if we were to take any particular man in this room whose brother was sterile and he wanted to be a directed donor for his sister-in-law, a personal family decision, he would only have about a one in six chance that his sperm would be freezed and thaw and have a high enough count post-thaw that it could be used for vaginal inseminations.

So, with all due respect to my colleague Dr. Sims, he was really comparing apples and oranges that are not comparable. We're talking about individuals with directed donors and not just anybody who could--you know, comparing them to any donor from a sperm bank.

Dr. Pereira talked about three types of donors, directed, anonymous, and sexually intimate partners, but in the anonymous category there are actually two types of donors. There's anonymous who remain anonymous forever, and there's identity release donors whose identity is revealed to the child or to the mother sometime after birth. And these are very different types of donors.

So what I am asking you here today is to be guided by the regulations of the State of New York that Dr. Pereira showed and the State of California that allow for fresh insemination with directed donors. Now, in both of these states--and Dr. Linden could probably speak better to this than I--they require testing and screening and counseling, appropriate things that a health professional can do. And why? Because we know that if you only have a one in six chance of sperm that survives the freezing process and you needed to do that, many of these people will simply lie to get around that process and say that they are sexually intimate partners.

Now, if people are going to lie to their physicians, it is then--we are not able--and I'm a nurse practitioner. I do this every day. It is not able then for me to take an appropriate sexual history that could protect the recipient. I can say, quite frankly, that I have stopped more fresh inseminations than I have done because I was able to take an appropriate sexual history because people were honest with me, because they didn't feel that the system was stacked against them. So I want you to put that in appropriate context.

These regulations that the FDA is proposing would do two basic things. One, it would make it illegal to do fresh insemination with directed donors, which, once again, the State of California and the State of New York have already extensively reviewed and said by statute and law that they approve of this. Two, it would make it illegal for gay men, men who have sex with men, to be anonymous sperm donors. And those are really the two questions--I know there are questions that this committee has to answer, but those are really the two questions that should be answered. And I have spoken with the Chair, and although it is generally not usual for this committee to come up with substitute questions, it is appropriate at this point, if you are going to truly guide the FDA, to answer those two questions directly. And, indeed, those two questions were asked by Dr. Pereira sort of indirectly in his own statement, his opening statement. He said that they received many letters about those points, and we should take Dr. Pereira's words exactly and answer those two questions.

I wanted to talk about--

DR. NELSON: So that the two questions--so that I'm clear, the two questions you want to ask are: Should men who have sex with men who would not meet a blood donor or other criteria within the last, let's say, year or recently, should or should they not be acceptable as donors? And then, secondly--

MR. TREEIMAN: Anonymous donors.

DR. NELSON: Anonymous donors. And then, secondly, what is the question with regard to directed--

MR. TREEIMAN: Should the FDA require a six-month cryopreservation and quarantine of semen from directed donors?

DR. NELSON: Okay.

MR. TREEIMAN: So those are the two questions. And, indeed, I've written those out, and I can pass those out to the committee.

DR. NELSON: I think we can remember them, or Dr. Pereira can, hopefully. He's got a better memory than I.

MR. TREEIMAN: And those two questions are taken directly from Dr. Pereira's presentation, which I thought was excellent.

I want to talk about, first, directed donors. Once again, if you make it illegal to do fresh insemination with directed donors, lesbians and gay men who are having children together will in all probability lie, hindering my ability or any health professional's ability to take an appropriate sexual history. Oddly enough, these regulations will probably impact heterosexuals more than lesbians and gay men because very few women who are married and have sterile husbands would be willing to lie and say that they are sexually intimate partners with their brother-in-law, which is, in fact, something I have found in my practice with increasing frequency. I see sterile husbands, and they make personal family decisions. And in one case, the wife was 42, with decreasing fertility herself. She did not have six months to wait because six months is a long time for a woman after 40. Her fertility declines dramatically. And as it turned out, her brother-in-law didn't have such great sperm quality to begin with. So a fresh IUI, intrauterine insemination, really was their only choice. And it is not appropriate in my opinion for the government to be sticking its nose in and saying, no, you can't do this. It is appropriate to say, yes, you can do this under these guidelines: safety, testing, counseling, that type of thing. But these things are not entered into serendipitously.

Now, I wanted to talk about identity release donors, which is a form of anonymous donors, and safety. More and more women are requesting gay men to be donors who eventually they can know their identity. Identity release donation uses only frozen sperm with the same quarantine and screening as anonymous donors. Denying the opportunity to have identity release donors will increase the possibility of unsupervised home fresh inseminations done with minimal or if any screening. I have had many clients who have come to me because I run a sperm bank where the identity is known after three months, after the child is three months old, and the donors are gay men. These women want gay men. They will do home fresh inseminations with friends, with minimal safety otherwise, and I am here to protect my community. I am here to offer that service to them, but I want to be able to do it in a safe way, supervised by our medical profession, done appropriately with a freeze and quarantine period, and not willy-nilly and just see women in my community get infected because their friends were in the window period or they didn't know what questions to ask. There are very few women who will sit down and ask the very personal questions of: Do you engage in unprotected oral sex? Do you engage in unprotected rectal sex? Do you only have one partner? Are you mutually monogamous?

They basically--and I hear it again and again--say: I asked my donor if he practices safe sex, and the answer is yes. Well, safe sex, as we all know, is a rubber term. And it is my job to pin these guys down. And as I said, I have stopped more inseminations than I have facilitated.

Now, in 1981, 20 years ago, I started a group for lesbians and gay men to have children together, and in 1982, I was one of the foremost loud-mouths in my community to stop lesbians and gay men having children together because of the dangers of HIV. I was doing the FDA's job 20 years ago.

If the FDA had come up with this proposal in 1985, I would be supporting it. I would have supported it back then. But with what we know now about the window period and HIV testing and its efficacy and the quarantine period, these are not appropriate for the year 2002.

It is particularly important to realize that blood and sperm are different in this way in that sperm, unlike blood, can be frozen for six months. And when I asked people at the CDC this five years ago, one of them being Tom Speira (ph), the Assistant Director of Medicine at the CDC, he said, "The false negative rate is quite low. I would not categorically want to exclude them"--referring to gay men--"since we have appropriate testing. If you do so, I believe you gain a false sense of security."

So if this committee sustains the present proposal that has been put forward by the FDA, you will be encouraging the Federal Government to engender in the population of the United States a false sense of security. And I wanted to tell you that that is wrong.

When I asked Charles Sable, who was then the director of the AIDS Diagnostic Laboratory, we had quite a spirited conversation, and his last quote to me was: "If one is freezing the sperm and retesting the donor after six months, the only reason to apply that criteria"--exclusion of gay men--"to semen donation is homophobia." His word, not mine.

Four years and three days ago, this committee had a discussion about gay men as blood donors, and Dr. Andrew Dayton proposed a two-phase testing scenario. And let me read to you exactly what was said four years and three days ago in front of this committee: One compromise which is suggested now, we are not proposing this as policy but we want to throw this on the table as a kind of issue that may want to be discussed, is basically to have a two-phase testing scenario whereby we reduce the exclusion to five years or one year, or whatever, and people who are newly admitted would first go through an HIV antibody test before they could donate, but they wouldn't give a unit. And then at a certain period thereafter, they would come back if the first test was negative and donate, as would anyone else, and then be tested again, of course. This would basically have the effect of dropping the prevalence problems to zero.

Earlier this year, this committee revisited this possibility of MSMs being blood donors, and Dr. Linden on this committee suggested a pre-test that, before an MSM come in to be a blood donor, he could have--he should be able to report a negative HIV test. Well, indeed, that's what I do. And that's what I think this committee should suggest: a pre-test, a test, quarantine, and retest. And that is the way to deal with MSMs as donors.

Of course, identifying low-risk gay donors is crucial for directed donation, but it is not necessary--it is not necessary for anonymous donation and identity release donation.

Now, some in the FDA has taken the Young Gay Men Health Study and extrapolated that inappropriately to all gay men. And I fail to see how the sexual habits and the HIV prevalence rate of men in their early 20s who are, for the most part, recruited from sexual venues relates to men in their 30s and 40s who are in long-term mutually monogamous relationships. In fact, to take that number defies any sort of scientific mind-set or dignity. One has to suspect that in order to snatch at that number, there are other reasons for it.

The first time I heard of that was at the CDC conference last year, and someone from the FDA did appropriately expropriate the Young Gay Men's Health Study number to all gay men in general, and I said that's an inappropriate thing to do. And he said to me, "Do you have a better number I can use?" His unscientific method seizing upon this number, regardless of how inappropriately, left me in stunned silence. But, sir, I say to you today I do have a better number, and it matches Dr. Dayton's number of zero. I simply studied the men who presented at my sperm bank. If we're going to talk about men, gay men, MSMs who might potentially be donors, let's look at them at the only sperm bank. And you have in your possession my study, 72 men screened as I have said, but in addition to that--in addition to that, we asked them very detailed questions about their sexual behaviors. And we came up with criteria that identity release donors--because I only work with identity release donors, which are the same, once again, in terms of safety as anonymous donors, is that they had a previous negative HIV test and had not had a sexually transmitted disease during the last five years and had never had syphilis or were celibate or in a long-term mutually monogamous relationship with a cohabitating HIV-negative partner or were single and did not engage in rectal sex or engaged in rectal sex but only used condoms without breakage--you have to ask very specific questions--and did not engage in oral sex or engaged in oral sex without ejaculation in the mouth.

Now, oral sex is a big bugaboo. A lot of people say that it's a safe practice. It is not a safe practice. It is a very low-risk practice, but it is not a safe practice, and it is around the issue of oral sex--and I'm really amazed that we haven't been talking about more about oral sex and directed donors here this morning. It is around the issue of oral sex that we need to ask people, Are you engaging in unprotected oral sex with partners you don't know their sero status or partners who you know to be positive?

The result of my study is that all 72 men came up negative, and as of July of this year, 24 of the identity release donors had completed the program and they were continuously negative. The other 12--

DR. NELSON: I wonder if you could conclude.

MR. TREEIMAN: Okay.

DR. NELSON: The panel may have some questions for you, but I think your remarks have been very important, and we have heard them, and, you know, I think that this is a critical issue. But I want to allow the committee to discuss the issues that you've raised.

MR. TREEIMAN: I do want to say there are legal and ethical differences between sperm and blood donation, and this is what I'm going to conclude with. When a blood donor gives a unit, he goes on his way, the recipient goes on his way. A sperm donor gives sperm, and he and the recipient become inextricably tied to each other by the creation of a new human being. And, in my opinion, we have a responsibility to that child to let that child know where he or she came from. And whereas there may be no constitutional right to be an anonymous sperm donor, I think you might be playing with fire here in terms of identity release donors because, in June 2000, Supreme Court Sandra Day O'Connor said the demographic changes of the past century make it difficult to speak of the average American family, and certainly the relationship that identity release donors have, men whose identity is known to the child after conception, after they're born--

DR. NELSON: Could I ask you to conclude with that statement? I think we understand what you're saying.

MR. TREEIMAN: --certainly defines that. So I ask you to address these issues directly, answer--not answer the questions proposed necessarily, but answer Dr. Pereira's preview.

DR. NELSON: Okay. Are there questions of the speaker from the committee?

MR. TREEIMAN: And I also want to say I apologize for sort of the random way I spoke, but I was invited, I originally was told I was going to get 30 minutes, and then I was told, oh, no, you're only going to get 15.

DR. NELSON: Right. That's happened to pretty much all of us. In fact, one time I got up to speak at a meeting, and somebody dropped my slides, and they all went upside down, and I couldn't--and it was--I still did okay. You got to be flexible, I guess.

The next speaker, if there are no questions for Mr. Treeiman--

DR. WARNER: Excuse me. I just have a comment to make from FDA.

DR. NELSON: Oh, yes.

DR. WARNER: Jill Warner, senior policy adviser and counselor for biologics with CBER. I just wanted to remind the committee that we do formulate our policies based on the science. The legal framework, which includes the statutes that we're responsible for following, as well as the constitutional framework which may in some cases, in this case involve certain reproductive freedoms for couples in a relationship. But what we would like your advice on is the science underlying some of these difficult policy decisions that we need to make. That's why we have formulated our questions to ask for the science, and that would be most helpful to us in formulating the answers to the difficult policy questions.

MR. TREEIMAN: I would like to respond--

DR. NELSON: Yes, I think the science is paramount, and it's also the economic issues. Some of them raised by Dr. Lamb are not the purview of this committee, I think, either.

MR. TREEIMAN: I would like to respond to that in one way, that the FDA has consistently said that 90 percent of all men have sperm that survives the freezing process well enough to do vaginal insemination after it is thawed. Despite all the medical literature to the contrary, we have been asking for years--for years--for one study from the FDA to support this contention, and they have not supplied us with one single study.

Indeed, I spoke with Dr. Ruth Solomon a week ago--

DR. NELSON: I think we're going to have to move on, Mr. Treeiman.

MR. TREEIMAN: --who said that she never saw any.

DR. NELSON: Mr. Treeiman, I'd like to allow the committee to do its job that the FDA has asked it to do.

I'd like to call on Mr. Michael Siani- Rose, the next speaker.

MR. SIANI-ROSE: I'm Mike Siani-Rose. I'm a scientist by training. I am not here to speak specifically about science, though, but I hope to address some of the issues that have come up today. Just so you know, I'm going to be talking about my family and some personal things that are totally relevant to what has been discussed here today. And although I'm used to discussing scientific issues among colleagues, this is a little bit difficult.

But, specifically, I'm one of those people that's a directed donor. I'm a gay man. I'm co-parenting with a lesbian woman, and we have a child together who's two and a half. We're both over 40, and because Carol--I'll use her first name--had some fertility problems, we had to go to a fertility clinic and use the services there.

What you're proposing here with freezing sperm, quarantining for six months, and the associated testing would really impact us. And I do want to--I believe it was Dr. Lamb who brought up the fact that this process is very emotional and very stressful and difficult. And I certainly have seen heterosexual friends go through the same process of trying to have children for years and then ending up in a fertility clinic and being sort of subjected to what's going on in the fertility clinic based on these rules. So I really want to push for fresh insemination of sperm for directed donors.

There is a cost issue, which I hadn't really thought about before, but, you know, currently what you do, the man goes into the sperm bank or clinic and gives a sample of sperm and it's washed and prepared, and then the woman goes in and is inseminated or she takes the sperm home and inseminates there.

The whole concept of doing that, that can be done in a day, assuming that all of the testing has been done beforehand for any relevant diseases and discussing any behavioral issues that might introduce diseases. But the whole concept of putting it into quarantine increases the cost and the stress level, you know, somewhat exponentially. I believe that, you know, it might be feasible, but hearing that 62 percent pregnancy rate for frozen versus fresh is really disturbing, because although it sounds like on average you can get, you know, one more cycle and you'll get pregnant, when you're actually the person where it's your sperm that isn't handling the freezing very well, that average doesn't help you. And this is a very stressful process.

So I just wanted to mention that my family--and it is one of these new constellation families that isn't traditional--consists of myself and my partner. We've been together for eight and a half years. And Carol and her partner, they've been together for seven years. We currently live one block apart, walking distance, with, which a two-and-a-half year-old, is quite feasible. He currently lives in both households. The four of us have taken on the same last name, which our child has, and my name is Siani-Rose. I hyphenated my child's last name, Rose. Actually, we all chose this name together. So this is a new type of family.

It is unusual. It's even unusual in San Francisco. But it's not unheard of. And I can't tell you the number of heterosexual colleagues and friends and neighbors that come to me and say, you know, this is fantastic, if I had two more parents, I would really be okay.

I'm telling you that not because I think every family should have four parents, but because it's acceptable. And I am concerned about these kind of guidelines that you're proposing or limitations that you're proposing that are going to affect me. And if I didn't have fertility issues, we could have done this at home, which we did do for years and it didn't work, and everything would be fine. But we ended up having fertility issues.

I have actually been a social activist most of my adult life, mainly on homeless issues, but on this issue, on the issue of parenting by gay and lesbian people, I'm actually pretty motivated now, now that I have a child. And I do feel like the social environment for discussing gay and lesbian issues certainly within the scientific community is open and certainly within the political community is open, and now within the family community. So I want all of you to feel free to talk about this openly.

I think that's about all I have to say. Currently the process that we went through in the State of California required an extensive history of my sexual activity. I had a battery of tests which covered all of the diseases that were discussed here, plus certainly many others. And I really felt like they addressed all the issues, although I was really disturbed by that study earlier about young MSM men and their infection rate with HIV about 7.2 percent for the 15- to 22-year-olds. I'm really concerned about that. But I'm not in that category, and I actually know a lo of gay men who are in monogamous long-term relationships, and they are very much aware of HIV infection issues and are concerned about it. And I agree with the previous speaker that if these can't be discussed in the setting of the fertility clinic openly, that's going to impact the number of HIV transmissions in the clinic.

It's okay to talk about these things openly, and I think we need to. Currently our child is thriving. He has four sets of grandparents. They all love him. He's a joy in our lives. We're currently trying to have another child. And we feel like this is our basic right. Everybody else in the United States is able to have a child, and I don't really feel like we should be restricted in some way simply because we're not having sex with each other.

So thank you for listening to me. Thank you for giving me the opportunity, and as you know, I feel really passionately about this. If you want to speak to me afterwards, please come up to me.

DR. NELSON: Thank you. I think your testimony is very important, and to me, of the last two--the whole day really underlines the fact that this is a very, very different issue than this committee is used to dealing with.

The FDA and the concept has mandated that we can take no known risks with any safety issue when we're dealing with a blood donor. Here we're dealing with two people trying to conceive, and this is extremely different. And I think your history to me was very important, and it underlined the difference in the type of issue that we're trying to deal with. At the same time, I think we do have to make every effort to make sure that we don't take any risks that could be prevented, that could be dealt with in terms of preventing transmission of a fatal disease like HIV or hepatitis C that could lead to long-term health events. But I think it's very different than the kinds of issues with a blood donor, some of which are pooled products and, you know, it's quite a different issue.

DR. SIMON: We do get into some similar issues, though, for example, with bone marrow transplantation where we often have it within a family and it's often a very personal, longstanding relationship. So I think we have dealt with this and--

DR. NELSON: There are directed blood donors, too, and the experience has been that they've sometimes been at higher risk.

DR. SIMON: But I guess those aren't--if I'm interpreting the comment made by the FDA on these questions, really the FDA is directing us to the scientific issues, and then they will legally determine what exceptions can be made for people who have a consensual relationship--

DR. NELSON: Right. And I would think in this arena, exceptions need to be made based on individual considerations and personal considerations, much more frequently than they would need to be made on, you know, blood transfusion, for instance.

Blaine?

DR. HOLLINGER: I didn't hear any information--one of the issues was as someone gets older, it may be more difficult to have a pregnancy. But I didn't hear any issues about does it really make that much difference between 40, somebody--in six months, is the fertility issue really that much more difficult waiting six months?

MR. TREEIMAN: Yes. Fertility in women decreases dramatically.

DR. HOLLINGER: Can you give me some actual data, some statistical data that's reported of some studies? Give me a--

MR. TREEIMAN: Well, I don't have those studies off the top of my head.

DR. HOLLINGER: Does anybody have any studies that's not off their head, but just actual data? Do any of the others? Dr. Lamb or Dr. Sims? Is Dr. Sims still here?

DR. SIMON: That data exists. I mean, it's in the--I don't have it. It's in the OB/GYN text. I think it is known that--

DR. HOLLINGER: But do we have any--

DR. LAMB: That has been studied, and I don't have it on the top of my head, but I can certainly send it to you, probably 24 hours too late, I guess, for your decisionmaking today.

DR. HOLLINGER: But within a six-month period, is that a--

DR. LAMB: Six months does make a difference, I think, and it's not--

DR. NELSON: It has much more to do with the female partner, I think, than the male.

DR. LAMB: Yes.

DR. HOLLINGER: That's what I'm talking about.

DR. LAMB: Yes, it is. And it has to do with ovulation and the response to gonadotropins, which declines progressively. And there is a marked_difference, but it's not a step function. It's a study function. And there's a decline that can be detected easily at age 35 compared to earlier ages. So it's not just at age 40.

DR. NELSON: Well, I'd like to move on. We still have two more. Mr. Grissinger? If there's any way you could abbreviate your--because there are committee members that are going to have to leave to catch a plane, and it may impact on whether or not we can discuss this issue or vote on it.

MR. GRISSINGER: First of all, I definitely want to say thanks for allowing me the opportunity to speak in front of you. My name is Tom Grissinger. I came here today on my own time. I'm from San Jose, California, and I'm missing work today because you're talking about a topic that is very near and dear to my heart.

I have four children. I am one of the identity release known donors that Leland was mentioning in his study, and I wanted to come out here to first kind of give you a chance to hear a little tiny bit about my background--I'll go quick--then secondly about what was involved in making my decision to use this program, and then last talk about the impact of what we're potentially proposing here.

First of all, my background. There's a lot of different things you can use to describe me. First, one is I'm an inside sales manager. Second, I'm an AIDS educator. I work in the field with the American Red Cross as a representative and also as our local AIDS agency representative, teaching anywhere from battered women shelters or schools. Anywhere that they need to learn about HIV and safe sex, I'm out there.

I'm also a gay man in a nine-year monogamous relationship. I'm also a widower. My partner--my second partner died of AIDS over 14 years ago. And I'm also HIV negative, so I know that safe sex works. I'm a biological father of four kids with four different couples, and I'm active in each of their lives. I bring these descriptions up only to give you a perspective of where I'm speaking from.

Secondly, the thought process I went through to become a father. I knew at 12 when I went into the post office and I bought stamps, I would say I want one stamp for me and one stamp for my future kid. I knew I had to have kids in my life. At age 15, when I realized I was gay, I was frustrated. How am I going to have kids? I thought, you know, I'll go out, get married, get a woman pregnant, and then get divorced. That will work. Fortunately, wisdom caught up to me and I didn't do that.

At age 18 I thought maybe I could become a stepfather. When I came out to my father and told him I was gay, his reaction was very positive. He said, you know, I have no issue with that, but the saddest thing is that you'll never know what it's like to be a father. I never imagined this many years later I'd have four kids.

The thought process when I decided to go through this program was I knew my partner, who's 12 years older, would be having a child at age 8 when he retired, so I thought having a child of our own would not work in our relationship. So I decided to go to Leland's bank because I knew he wouldn't discriminate, and plus I couldn't find a lesbian couple that was willing to go through this process and talk about all the legal issues: You know, whose kids is it really? Will I ever take custody? That sort of thing.

When I heard about Leland's program, I was ecstatic. We talked about it for weeks and both agreed that we were both committed to it.

I live in San Jose. Oakland is over 100 miles round trip. I made 20 trips up to Oakland, missed work, took vacation time. Everyone thought I was dying of cancer going up for some kind of treatment. But I bring that up and all this thought process to show you the commitment that's involved in making a decision and getting involved in these programs. That's not something that we just said overnight, hey, let's do this.

Let me introduce you to my family. I've already passed out some slides there. The reason why I brought the photos is on the first page you're going to see what you probably are thinking of as a known donor program. You see the two couples here, along with myself involved with the kid, and then down below we're extending the definition of family. And to be honest, you may not be quite comfortable with my definition of family, but this is what works for us.

Take a look at the bottom photo here. Here are two kids from two different sets of parents, same biological father, and both families are treating them as half-sisters. So they're treating them that they're related.

On the next page, the point I bring up showing you photos of my father, who is a grandfather, and my mother is that they are actively involved in the kids' lives. You can see them at Christmas and also at Easter time. So when you are talking of potentially banning a gay donor, you're not only looking at me, you're looking at my parents becoming grandparents, the lesbian couple, the potential children, and even on the last page, you'll see there's a picture of my partner, Skip, who's also involved with these kids. So there's a lot more on these photos, but I'm going to go past them real quick.

My role. What I play is an uncle. I am active in their life. I have no legal obligations, no financial obligations to these children. But just like an uncle that you may have grown up with, I'm a part of the kid's life. I'm there at different holidays. I'm there at different special events. I do a lot of babysitting. I'm a free babysitter.

Also, in talking with these kids, they each know me differently as "Papa Tom," "Father," or "Tom." One of the persons I was concerned that would not be represented here today is the woman who decides to use a gay donor, and I wrote to one of the mothers and asked her to write a brief note about why she went through this program.

Rebecca says, "We chose to inseminate with a gay donor because we felt that it's extremely important to try and create families within our community. The issue of HIV never was one after we understood the process of freezing, testing, and retesting and quarantine, not to mention the very nature of the virus and its inability to withstand freezing, thawing, and washing. I think that fear and lack of education are big parts of this problem when simple facts are considered that there really is no risk, that quarantine works. And to be frank," she wrote, "I would have never used a straight man. Who needs that kind of mentality in my life or my child's life." She's kidding there, by the way.

The second couple that I talked to said they felt that using a gay man would make it easier for them as a lesbian couple, there would be less issues there. They also said they liked the idea of knowing the medical history and also the answer when the child says, "Who's my father?" They've got someone there that's active in the kid's life.

The next question I asked, which is very important, is: What would you do if this was illegal? What would you have done? Both families that I talked to said they would find a way to make it happen. They would either do an at-home insemination, which Leland brought up could be very risky because the lesbian may not know the right questions to screen somebody. Or even the person--as an AIDS educator, one of the things I hear out there, I have to argue with people that safe sex is risky. So you can imagine if someone out there is under the impression that, hey, it's not risky, so if someone asked me if I had safe sex, I only do safe sex because I believe oral sex is not risky. A lesbian may not know to ask those specific questions that a medical expert could guide them through. So at-home insemination could actually potentially increase the transmission of this virus.

The other thing they brought up is they said, "Tom, I'd take you to the doctor. We'd go in, yeah, this is my husband here. We're having trouble having kids. You know, we've been having sex for a while. We want to do an insemination." The danger of that is the doctor may be caught off guard. They may decide, you know, they've been having sex, I don't need to do an HIV test, I don't need to ask those medical question tests, you know, about have you been having unprotected oral sex. They're supposedly straight. So, again, by banning a gay donor, you're potentially increasing the risk for transmission.

Going on with this, the last thing that Rebecca had said is, "If it does become illegal to use a gay man's sperm, I guess I'll have to become an outlaw because I have found my perfect man. He's gay. He's the father of my daughter and any other children that are coming my way. I wouldn't have it any other way than through this program."

What I do question the panel is: How are you going to police this? Think about all the doctors that are out there, throughout the U.S., all the medical facilities. Most doctors are able to do inseminations. Are you going to require that doctors identify and determine whether or not the man is gay? Okay. So if I go in in that scenario, if I present a wedding certificate and say we're married, if the guy thinks I'm effeminate and I'm gay, he may be under the obligation to say, look, you know, I don't want to lose my medical license here, I think you're gay, I'm not going to do this transaction.

I mean, I'm a gay man, and I know we're supposed to have gaydar and be able to identify other gay men, but it doesn't work for me. And I can't expect a doctor to have that ability, either.

The other thing that I am concerned about is that one woman in my office, who wasn't even involved in all this, said, "You're flying 3,000 miles to talk about this process?" She says, "I understand what you went through. You used this quarantine process," where we all know the window period is that 6 to 12 weeks where it, you know, may show up on a test, and after your last deposit, so to speak, they wait six months and then test you for HIV again and if you're negative, she says, "I'm not a scientist or a doctor, but I know that semen is safe then at that point. And you're going to talk to people about this? They're even having a meeting on it? I don't get this." And I kind of questioned what was the motivation behind that as well.

This potential ban that you're talking about includes me. You're deciding this not on the basis of my sexual practices and whether or not I'm being safe; but, rather, you want to ban me because I belong to a particular group or, as the wording in the question says, "subset," versus evaluating me as an individual.

For me, banning a person from being a donor just because they fit some demographic group like sexuality is a form of discrimination. After you ban gays, using the same thought process we need to look next at what other groups we should--or subsets--ban. Using the same logic that we're talking about here, we should go after next the high rising group. What ethnic group has the highest rise for HIV? And on the slide we saw it was African Americans. Are we going to go to African Americans next and say because you are part of a subset, we don't believe that you can be monogamous, and we don't believe that you can practice effective safe sex, therefore, we should exclude you from this program?

One thing I really want you to realize about the quarantine process is that quarantine is 100 percent safe. Don't discriminate. Apply it to every individual and not to a group of people.

The other thought process I had, okay, so if you make the decision to ban me from a donor by discriminating against men who have sex with men, based on this potential thought process that HIV is higher in that subset, then you're implying that all gay men cannot be monogamous and cannot effectively practice safe sex. Then I thought, now, what other subset should I go after then if we're going to ban this using the same logic? And it dawned on me: government.

Now, I got to be honest with you. I don't know a lot of people who work for government, but all I know is what I see in the media. And what I've been seeing--I've seen former President Clinton and Monica Lewinsky, and we all know he wasn't safe. We know about the blue dress. We know he wasn't monogamous with his wife.

Then I thought about it further, and I said, Who else? Gary Condit with Chandra Levy; Newt Gingrich, Gary Hart, Robert Livingston, Bob Packwood, Wilbur Mills.

If you're using the same philosophy that they're part of this subset and we should discriminate based on that subset, then you need to apply it to government officials, which means everyone at this table--you work for the government. I'm sorry, we can't make you a known donor. That's ridiculous.

I've watched some of the expressions, and some people are smiling about it, and I agree, that's a ridiculous philosophy. But that is exactly what you're asking me to accept. You're applying that same philosophy to me, saying that, Tom, we don't believe you can be monogamous. We don't believe that you can practice safe sex, when you know I can, when I had a partner who died of AIDS and I'm still HIV negative. That kind of philosophy for me is stereotyping.

In evaluating a prospective donor, you need to look at the individual. That's what's key. I would not ban you on the basis of being part of this subset. That's not fair to you. And I don't think it's fair to me in this situation. By banning me because of a subset, you're saying that you don't believe that I can be safe. And I know that's not the case.

What it comes down to is that you need to not discriminate. HIV doesn't discriminate. We all know that HIV can be transmitted to anyone, regardless of age, race, nationality, or religion. The screening guidelines need to apply equally to everyone.

Don't let politics or homophobia override science and facts. Quarantine, it's 100 percent safe. So don't discriminate.

Any questions? Yes?

DR. SIMON: I would like to clarify just for the record. I am under the assumption--and I hope it's not incorrect; I need to be advised if it is--that if a man and a woman come to a fertility specialist to seek to have a child together, whether they're married or not, or whatever their relationship, and go through the process, through a fertility specialist, that that is not regulated by FDA, that that's practice of medicine. What we're talking about is when someone goes to a sperm bank and has the sperm given that may go to someone. I'd like FDA to just clarify that, if I could. I think that will help with our further discussion.

DR. SOLOMON: Hello, Ruth Solomon, FDA. Our regulations would apply to semen banks, that is, places where semen is recovered, processed, stores, and distributed.

DR. SIMON: What if it's not stored but is used fresh and then--

DR. SOLOMON: Then the other, recovery and processing.

DR. SIMON: So that would still be covered?

DR. SOLOMON: Yes.

MR. GRISSINGER: Which would still apply to every doctor who has the potential to do the insemination, correct?

DR. NELSON: Would it apply to a physician? Dr. Solomon?

DR. SOLOMON: If the physician collected, processed, and stored semen, it would apply to him. But we've made an exception for the situation where the man and woman come to the physician and have an insemination there. That would be an exception.

DR. SIMON: So then that would be excluded from the regulations we're talking about.

DR. NELSON: But a directed donation that went through a sperm bank would be covered by--

DR. SIMON: Would be covered by these regulations.

DR. NELSON: Right.

DR. SIMON: Okay.

DR. NELSON: Yes, Jeanne?

DR. LINDEN: Dr. Solomon, can you please clarify that you're saying a directed donor, as has been described, you know, say a gay man and a lesbian who are not sexually intimate, would be excluded? I mean, it sounds like that's what you just said, but I'm not sure that's what you mean.

DR. SOLOMON: The issue is that we're regulating the product, and we're regulating a bank that collects, stores, or processes that product.

DR. NELSON: But would a doctor who collects, stores, inseminates be in the same category as a bank?

DR. EPSTEIN: Could I just clarify that in the proposed rule, which was published on September 30, 1999, what we state in a section on "Exemptions from the Requirement of Donor Suitability Determination; and Labeling Requirements, is that the exception would extend to bank cells and tissues for autologous use and reproductive cells or tissue donated by a sexually intimate partner of the recipient for reproductive use. So that exception does not automatically convey to a directed donor or an identity release donor, and certainly not to an anonymous donor, as proposed. I mean, that's a proposed rule.

DR. FITZPATRICK: But the question, though, is if a couple come to a fertility specialist without going through a bank and go through the process, and the donor comes in that day, provides the specimen, and the woman is fertilized, are they then regulated--is that doctor's office and practice regulated by the final rule?

DR. EPSTEIN: Well, I think what we keep trying to say is that our focus is the product, and we aren't trying to regulate product use. We're trying to regulate colleague, processing, storage, labeling, recordkeeping.

DR. FITZPATRICK: So if that's done within his own practice and the product is not transported, sold, or distributed, he's merely providing a service for that couple within his practice, he's not regulated?

DR. EPSTEIN: Well, I think it would depend what service is provided in regard to the product.

DR. FITZPATRICK: He performed the insemination with the specimen that was provided.

DR. SIMS: Under AABB standards, processing is covered as a banking activity.

DR. FITZPATRICK: He didn't get it from a bank.

DR. SIMS: The individual--

DR. FITZPATRICK: I will give you my own personal experience because I need to recuse myself from voting because I'm torn by the discussion. Okay? I have relatives who have been through this process, and I have been through it myself. I think the committee is beginning to discuss outside the realm of what FDA is asking. FDA has asked us to address the scientific data. My own experience with FDA and their regulatory requirements is that the physician that I went to and my wife went to to have our fertility problems resolved did not go to a bank. He didn't run a bank. He ran a fertility practice. We provided a specimen, he performed the insemination, and we have a daughter. To me that does not, in reading the proposed rule and final rule, come under the purview of the rule.

I may be totally wrong and the legal people will have to answer that question, but that's not what we're being asked to discuss here today.

DR. NELSON: I think we were just trying to define what we were asked to discuss or, you know, what were the boundaries, and if--yes?

DR. HOLLINGER: And maybe just a correction, too. I looked at the directed donor as a generic thing. This was not just the directed donor is gay or an MSM. But it's any directed donor. I mean, I think as was mentioned initially, if somebody was a brother of someone with a sister-in-law and so on, I mean, these are directed donors. So this is not just an issue related to males have sex with males, as I understand this issue on directed donor.

DR. NELSON: But, you know, initially we were told about the three types of donors and that directed donors was one that came under the issues for discussion. And I guess only directed donors where a sperm bank is in the loop are covered. Is that correct?

DR. SIMON: Well, I was hoping we could dispense with it, but obviously we can't. I think it relates apparently to the way the regulations were written because it talks about sexually intimate and does not allow for the non-traditional family. And I guess that's not something that FDA is asking about. It sounds like in regulating the product they are into that office situation which I guess we have our own personal opinions that perhaps they shouldn't be. But I was just hoping that we could make all these issues irrelevant to our discussion of the science and argue that it wouldn't--that what we're discussing wouldn't keep a couple like have been described by the last couple speakers from proceeding in a physician's office.

DR. NELSON: Right. So that there should be--the directed donor and a sexually intimate donor would be very similar.

DR. SIMON: Yes, two people come, whether they're having sex or not, is--

DR. NELSON: Right.

DR. SIMON: It's that they have come consenting to want to do this together.

DR. NELSON: Right.

DR. SIMON: But that's not the way the regulation's written, and I guess that's not what we've been asked to discuss.

DR. NELSON: Right.

DR. SIMON: So I can understand that the speakers are concerned that the things that we would do would impinge upon those relationships, but it looks like we have no choice but to--

DR. NELSON: There was one more person who wanted to testify. I'd like to get through that, if we could. Maybe he could be very brief. If there aren't any other burning issues, Mr. Christopher Anders from the American Civil Liberties Union. I hope you can be brief because we want to vote before everybody leaves.

MR. ANDERS: Thank you. I'm Christopher Anders, legislative counsel to the American Civil Liberties Union, and my comments today focus solely on the directed donor issue, which is the only issue that we've taken a position on.

I'd like to start out I guess by responding to the comment made by FDA staff a few minutes ago about that you're not to address the legal issues and the constitutional issues. We have addressed those issues with the FDA, but that's not what I'm here to talk about today.

Instead, I think our view is that the issues that you are hearing the last few speakers speak about really do relate to Question No. 1, and that there is no way that you can answer No. 1 in a vacuum, because unlike--I think there is--we view some important differences between blood and a lot of other body products and sperm. And I think there really--I see and for the ACLU we see really two important differences.

The first is that, unlike most other tissues, the woman has a very strong privacy interest in choosing who the biological father of her child is going to be. And that's a legal right, but it's also something that is just going to be there as a social matter.

And unlike probably every other tissue issue, with sperm and with insemination people can either opt out or try to opt out of a sperm bank system. People can't give themselves a blood transfusion, or most people can't give themselves a blood transfusion, or transfer bone marrow. But people can either inseminate themselves at home or try to inseminate themselves at home. And so if their interest, their strong privacy interest of choosing who the biological father is is frustrated, then they can either opt out or try to opt out of the system.

So I don't think that you can answer Question No. 1 in a vacuum. You can't just say, well, you know, this is what we know the transmission rates are, and, you know, the transmission rates are--you know, I think we could probably all agree that there's some improvement. It might be a very, very small improvement in transmission rates after quarantine. But if people pull themselves out of the whole system and this rule forces people to pull themselves out of the whole system, then doing this quarantine protocol is useless and you may actually increase the chances of people becoming HIV positive or becoming exposed to other communicable diseases.

We believe that the final regulation should adhere to two central principles regarding directed donors:

First, the regulation should prioritize patient autonomy when making choices about reproduction and reproductive health. Autonomous decisionmaking is a prerequisite for the meaningful exercise of informed consent and should guide the FDA as it moves into this emerging area.

Second, the regulation should ensure a health care environment that allows wide access based on sound medical judgments to the full potential of available reproductive technologies. Donor insemination regulation should recognize the diversity of the population seeking care and allow women maximum flexibility in choosing the biological father of their child. You can't address the safety issues without addressing the real context in which these decisions are made.

The ACLU urges that the proposed rule should be revised to allow all recipients of directed donations to use fresh sperm regardless of whether they've been sexually intimate with the directed donor by permitting recipients of directed donations to sign a written waiver exempting themselves from the six-month quarantine period. All directed donation recipients should be fully informed of the risks associated with fresh sperm.

Our suggested approach is not new. The California Health and Safety Code already applies similar provisions to sperm banks in California. It provides specifically, "If the recipient is informed of the requirements for testing donors under this section and signs a written waiver, they may receive the directed donation."

Even in the absence of a quarantine protocol, proper testing and screening of fresh sperm should reduce the risks to an extraordinarily low level. As Dr. Emmet Lamb just stated, he finds the risk to be "in the range of risk that we accept on a daily basis."

If the risks are that low, then I think the question for this committee really is not what is the perfect system if everybody were to use a system, but given the realities of the decisions that people make--and you just heard two live examples of people who have made decisions on how they're going to make their reproductive choices or how women made their reproductive choices, how these men decided to build their families, you have to weigh in that what is the risk that people are going to opt out of the system. When they opt out of the system, they opt out of everything, potentially. They opt out of all the testing that goes along with it. They opt out of all the screening that goes along with it. They opt out of, you know, maybe advice on prenatal care.

From a legal perspective, there also are advantages to going to a sperm bank in terms of cutting off parental rights and responsibilities, which is another thing that people would lose if they opt out of the system. We would prefer people to go--for lots and lots of reasons to go to sperm banks. And so if in an effort to come up with a perfect system you drive people out of the system, I think part of your response to Question No. 1 really does have to be when you are driving people out of the system, to make up some minuscule increase in safety, are you actually causing a much more dangerous situation?

Thank you.

DR. NELSON: Thank you.

Any questions?

MR. TREEIMAN: A clarification. I just wanted to point out that the speaker before you, Mr. Grissinger, was not a directed donor. He was an identity release anonymous donor. And, again, that's the question that should be before this committee. Is there sufficient scientific evidence to say that MSMs, given, you know, the two-phase testing scenario that all sperm banks already practice, should they be included as anonymous donors or should they be discriminated against?

DR. NELSON: Okay. Thank you.

Could we have the questions again--or, Toby, did you have--

DR. SIMON: Well, I was going to launch into the discussion if that's okay, while the questions are going up. I think this is a difficult issue, and I have become aware of what the position of industry that's involved in this, which is basically supportive of the concept of cryopreservation, the six-month wait and retesting, the continuation of the requirements for safety in terms of questioning on MSM and the lack of any subset that can help with that. I mean, I understand--I think the FDA, as I understand it, is really asking for our scientific advice and that some of these other issues, while they may be very important, it's not clear that they're asking us to weigh in on those. I do--I mean, it's sort of clear why the FDA in the regulations would give the exception for sexually intimate donors because they're already--or a sexually intimate couple because they're already exposed to each other's secretions and so forth and there would be no added risk from engaging in this without any additional testing.

So I think scientifically, you know, in terms of the data, I mean, certainly it appears that fresh sperm would increase the rate of pregnancy, but it appears that you can achieve an acceptable rate through sperm banks with these safety precautions. So that's at least the industry position as I understand it.

DR. STRONCEK: I think it makes sense for blood donors or unrelated bone marrow donors to have all the strict regulations we have, and probably for anonymous sperm bank, too. But I think what we're talking about here is kind of analogous to allogeneic bone marrow donation.

We all know that the criteria for a sibling bone marrow donor is much different than it would be for an unrelated donor, and we all know anecdotes where people with at-risk behavior or even with positive markers who, with proper informed consent, have donated, and there's no--we don't--I'm not aware that the FDA is interceding in that situation. And this is a little bit different, but not much. And I think by trying to regulate these directed sperm donations, they're getting into the practice of medicine.

DR. HARVATH: A number of times this afternoon Dr. Linden's program was mentioned, and I wondered, before we launched into the questions, Jeanne, if you would share with us what New York State is doing and what has been your experience. And the proposed approach that FDA has taken regarding this issue, would that affect the practices that are regulated by the State of New York?

DR. LINDEN: Our approach is that a directed donor is a donor, but that it is a special circumstance and that not necessarily all of the same requirements apply and that there is a need for flexibility. That may be the only donor. The husband's brother, there may be only one that may be it. So we have endeavored to strike a balance to achieve safety with informed consent while achieving, you know, flexibility. Basically the directed donors need to be tested, and the history needs to be taken. But if there's something there, including risk for HIV, that those can be waived, you know, as long as the recipient is aware of the situation. So, you know, it sort of does become a medical practice issue, but it is still regulated. That all needs to be documented. And the recipient can also waive the six-month quarantine so that there isn't that need for a wait, keeping in mind that there could be an increased risk for HIV or other infectious agents. They may want to still do a double test, test as close as possible to the time of the use of the specimen.

But there is that flexibility, but it is something that we feel does need to be regulated. Yes, it could occur in a physician's office, which does then, by our definition, become a bank. We actually regulate insemination sites separately, the way we do transfusion services as a separate issue, which would be different from FDA. But there is a public health and safety issue there, but there is a need for flexibility. So that's our approach.

DR. NELSON: So a directed donor that occurred in a physician's office would still--the donor would still be tested and--

DR. LINDEN: Yes, would still have to be tested and undergo a medical screening, have that all be documented, but there's flexibility as to the outcome of that.

DR. NELSON: What if the donor was known to be a man who had sex with men? Would that be legal or--

DR. LINDEN: Yes, that could be acceptable if the recipient agrees.

DR. SIMON: And you would not be able to continue doing this if these regulations are--

DR. LINDEN: If the FDA had stricter rules, they would supersede.

DR. HOLLINGER: And, Jeanne, if the donor was HIV positive or HBV positive, HCV positive, or so on, then they can still--the person could still decide that they would want to have that sperm anyway. That's still a--

DR. LINDEN: My recollection is that that is not specifically provided for. That would have to be an exception. I know that's something that FDA has talked about a lot, but, actually HIV positive would be a necessity for exclusion.

DR. HOLLINGER: You're saying that if it's positive, it could still be acceptable to the recipient, if the recipient chose to--

DR. LINDEN: No, that is not provided for. That would have to be a special exception.

DR. HOLLINGER: Okay.

DR. NELSON: Okay. The first--

DR. MITCHELL: I'm sorry. Is it the same thing for HBV and HCV? I don't mean to put you on the spot. I know that you didn't come here with your regulations in hand.

DR. LINDEN: Yes, I didn't bring them with me because I thought HIV was going to be the main issue so I looked at those. I believe for all donors the seropositives would still be excluded without a special exception.

MR. SIANI-ROSE: Can I address the safety issue? Because Dr. Simon said something. You just made the assumption that if there's a couple that's sexually intimate that comes into the clinic, that they've been sharing bodily fluids and, therefore, they would have been exposed to the same fluids. But in the case of--in my case, we're not sexually intimate, but we had certainly been trying for years to get pregnant. We certainly had been exposed to--Carol had been exposed to bodily fluids.

DR. NELSON: Okay.

MR. TREEIMAN: I also wanted to say that the State of California's regulation 1644.5, that it's similar to New York. It says that fresh insemination can be done, someone must be tested for hepatitis B, hepatitis C, syphilis, HTLV-1, and HIV 1 and 2. Even with a directed donor, however, if someone is positive for HTLV or HIV, then a clinician cannot do the insemination in the State of California, even for a directed donor. And that's something actually that I support and helped--worked with the state legislature on.

DR. NELSON: Okay.

DR. HOLLINGER: And what about for HBV or HCV?

MR. TREEIMAN: What was the second one?

DR. HOLLINGER: What about HBV or HCV?

MR. TREEIMAN: For hepatitis--

DR. HOLLINGER: Or HHVA?

MR. TREEIMAN: Hepatitis B, it says that the insemination can go forward only if the recipient is vaccinated against hepatitis B--

DR. NELSON: No, but what Blaine is talking about is when the donor is hepatitis B surface antigen positive.

MR. TREEIMAN: Right, yes, and if he is infected with hepatitis B, the insemination in California can go forward only if the recipient has been vaccinated against hepatitis B. And for hepatitis C--

DR. NELSON: Which would take six months.

MR. TREEIMAN: Yes. That would take six months. But, you know, again, that's the law there. And for hepatitis C, it can go forward only if the recipient is counseled as to her risks, because although we have seen some cases of hepatitis C transmitted sexually, it's uncommon. It also has a special--for syphilis, if a man tests positive on an RPR screening test, then he must be treated before the insemination goes forward.

DR. NELSON: Okay. Let's go to the first question.

DR. PEREIRA: Yes. The first question is: Is safety increased when cryopreserved semen is quarantined and the donor is retested after six months?

DR. NELSON: Is there discussion on this?

DR. SIMON: I would view that as a yes.

DR. NELSON: I think so. Linda, are you going to do the--or can we just do show of hands?

DR. STUVER: Are you waiting--

DR. NELSON: Oh, go ahead, sorry.

DR. STUVER: Can we get clarification. Increase compared to--are we supposed to assume increase compared to fresh semen? Are we supposed to assume increase compared to no quarantine period? What is the comparison?

DR. NELSON: To fresh.

DR. STUVER: Fresh?

DR. NELSON: Fresh.

DR. FITZPATRICK: I just had a question. Is there a provision for a fresh sample or directed donation to have a delay period between the selection of the donor, wait for six months, and then retest the donor and then provide a fresh specimen? Is there any provision for that?

DR. PEREIRA: No.

DR. FITZPATRICK: Okay.

DR. PEREIRA: There were no provisions for that.

DR. SMALLWOOD: I am polling the committee on Question No. 1. Before I do that, I would like to be clear on the position of Dr. Fitzpatrick on this question. Are you--

DR. FITZPATRICK: Linda, although I don't have any financial conflict of interest, I feel because of close personal associations for myself and my family that I should abstain from voting.

DR. SMALLWOOD: Okay. Thank you.

Dr. Schmidt?

DR. SCHMIDT: Yes.

DR. SMALLWOOD: Dr. Macik?

DR. MACIK: Yes.

DR. SMALLWOOD: Okay. Dr. Fitzpatrick has abstained. Dr. Stroncek?

DR. STRONCEK: Yes.

DR. SMALLWOOD: Dr. Mitchell?

DR. MITCHELL: Yes.

DR. SMALLWOOD: Dr. Stuver?

DR. STUVER: Yes.

DR. SMALLWOOD: Dr. Linden?

DR. LINDEN: Yes.

DR. SMALLWOOD: Dr. McGee?

DR. McGEE: Yes.

DR. SMALLWOOD: Mr. Rice?

MR. RICE: Yes.

DR. SMALLWOOD: Dr. Hollinger?

DR. HOLLINGER: Yes.

DR. SMALLWOOD: Dr. Harvath?

DR. HARVATH: Yes.

DR. SMALLWOOD: Dr. Nelson?

DR. NELSON: Yes.

DR. SMALLWOOD: Dr. Simon, the industry representative, agrees with the yes vote, and Ms. Knowles, the non-voting consumer rep, left a written note, and she would agree with the yes vote.

The results of voting, unanimous yes vote for those that are present here.

DR. PEREIRA: The second question has to do with when we compare fresh semen to cryopreserved semen, if there's a reduction in pregnancy rates.

DR. HOLLINGER: Does this take into account the number of cycles that are used? I mean, are we talking about in one cycle? Are we talking about six cycles, eight cycles?

DR. PEREIRA: We're talking basically about the end result as to pregnancy.

DR. FITZPATRICK: We're talking about...

DR. NELSON: Well, in reality, since some women won't go through a procedure six times, I think it's useful to--if you were to just say, you know, what happens in practice, I would guess that there probably is some reduction in the outcome of a viable pregnancy, yes.

DR. SIMON: Yes, I would say, you know, there are a couple questions here, and I guess we would take our data from the presentations, but it would--if I'm interpreting the combined presentations correctly, there is a reduction in the pregnancy rate, but with repeated attempts, the gap is closed and becomes close to the same. And I would just have to rely on the data that's being presented. But that would seem to be what we have heard today.

DR. NELSON: The other issue, where no exact data was presented, but it certainly makes logical sense that if the sperm donor is not an ideal--you know, with a 4 percent, but has a more marginal motility or volume or something like that, that cryopreservation might reduce the outcome even further. And I think that point was made, and it's probably correct, although we saw no data on it, but it certainly makes sense to me.

DR. SCHMIDT: But we also heard that the data for the cryopreserved was built on these super, super donors. So--

DR. NELSON: Yes, exactly, and what I'm saying is if you don't have a super, super donor, that a cryopreservation may be more deleterious.

DR. SCHMIDT: So who are we comparing in this question? Are we comparing good old fresh donor and super, super Joe, or are we just--

DR. NELSON: Well--

DR. SIMON: I think there's probably a difference in the caliber of sperm banks, I'm assuming, in terms of their ability. And if you were in this field, you would probably choose your bank the way people--am I correct?--you know, the way you would choose a tissue bank or--not the way we tend to accept the local blood bank, but I assume there's some choice here.

DR. NELSON: Or even a monetary bank. You can get hooked on that one, too.

Jeanne, you had a question.

DR. LINDEN: Yes, it's sort of along the same line. I'm not clear whether this question is intended to be donor for donor, is there a difference if you freeze versus fresh, you know, in which case the answer is clearly yes, or is it generic directed donors just taken fresh versus going to a bank where they've already selected, you know, the ones with the super swimmers that do survive well, you know, as you're saying? That may be fine. If you're only going for the creme de la creme--I'm not sure what we're comparing.

DR. NELSON: But the average directed--the average fresh donor may be weighted with the ones that aren't super, super swimmers, too. So, you know--

DR. SCHMIDT: But that has to be clarified in the question. What are we going to answer? Which one of those--

DR. LINDEN: I think the question needs to be clear. Are we talking donor for donor? And what is the question?

DR. NELSON: Let's ask the FDA how they want it clarified. Dr. Pereira, do you want to--

DR. PEREIRA: Let's clarify it. I'll be back in a second.

[Laughter.]

DR. NELSON: Okay.

DR. HOLLINGER: While they're doing that, I think it's clear from all the studies, though, that there is a 50 percent--or at least a reduction in sperm count after freezing like there is in cells or anything else. I think that's safe to say. I think we all probably agree with that, that there is a reduction. So then the question comes out: If the number of sperm that you have has to do with the pregnancy rate--and I'm sure there must be a relationship between if you have a lot of sperm, there may not be much differences between fresh and frozen than if you have just a little bit. So that's really where it comes down, I think, to an issue, and so that's--it is really critical for them to--

DR. NELSON: I think Dr. Lamb presented some data in his meta-analysis that was a randomized trial where the odds ratio was 0.62 for--and many of the studies--and five of them were randomized trials, and others were not randomized, and some were historical. So it's--but the sense I got from looking at that analysis was that there were none that showed cryopreserved to be superior, and nearly every study showed inferior, with the arrow bars being significant.

DR. SIMON: And the way I interpreted the question--they're still talking about it--was that if you had a donor who was fertile and you were inseminated by fresh sperm versus if you had that donor stored for six months and you were inseminated by frozen sperm, I believe your likelihood of pregnancy would be greater with the fresh semen, but it appears if you did multiple trials, you could narrow that gap. That was my interpretation.

DR. SCHMIDT: That's the way you interpret the question. I want to know what the FDA's question is.

DR. EPSTEIN: I think what would be most useful to the FDA would be what's been called donor for donor; in other words, were you to compare fertility outcome with a donor whose semen was used fresh versus cryopreserved, would there be a difference? And in that context, we're talking about over a course of insemination treatment or care. Okay? The reason is because that's the question that would help us the most understand the scientific implications of whether we do or do not in regulation require quarantine and retest for the directed donor, because no one is advocating that we waive quarantine for the anonymous donor, so, therefore, it's moot in that context. So let me just repeat it.

The question we would like you to interpret in the following way: Would there be a difference for the use of fresh semen versus cryopreserved semen in the instance that a donor provided a course of therapies either as fresh or as cryopreserved, an average donor? In other words, not a super-selected donor, an average donor.

DR. SCHMIDT: And is a course one attempt of each or one of these six-month repeated cycles?

DR. EPSTEIN: No. I think the scenario would be that in the one case you have repeated cycles of fresh insemination from Donor A and the comparator should be repeated cycles of cryopreserved semen from Donor A. And, again, with the understanding that Donor A is not highly selected for freeze/thaw viability because that's a factor in this which speaks to the issue of not just fertility outcome but the ability to select a donor in a directed donor context. Again--

DR. NELSON: But the course might also depend on the woman; that is, if the woman's--

DR. EPSTEIN: Absolutely.

DR. NELSON: --at an age where ovulation is not regular, waning, or whatever, so that needs to be factored into this somehow.

DR. EPSTEIN: Well, that's right.

DR. NELSON: It's a multivariate analysis, and that's Factor C.

DR. EPSTEIN: That's right. But I guess what I'm trying to highlight here is earlier speakers have correctly stated that the policy issue confronting the FDA is whether to require or not require quarantine and retest in the setting of directed donation. But what we are asking the committee to help us assess is the scientific implication for safety comparing the two scenarios. So, in the one scenario, you would use fresh semen from a donor who might not be prequalified for freeze/thaw, and in the other scenario, you would be using cryopreserved semen from a donor, again, who might not have been prequalified for freeze/thaw. So I hope that's clear enough.

I mean, clearly there are other strata we could consider but--

DR. SCHMIDT: Yes, because you're interested in the product and not the recipient, so we don't really care if the woman is 42 years old.

DR. EPSTEIN: Well, we are asking the safety question. Yes, we are asking--we're trying to weigh--ultimately the FDA must come up with some risk/benefit analysis, and the risk has to do with reducing risk of transmissible diseases, which we were asking in Question 1, and here we're getting at the issue of benefits. In other words, is there a downside or, conversely, an advantage comparing cryopreserved to fresh?

DR. SIMON: I think that is clear from my understanding, and I guess you're looking for some numbers. The way I would answer it, based on what I heard--I hope I interpreted everything correctly--is the use of cryopreserved semen for artificial insemination will reduce the pregnancy rates but modestly. And I think the numbers you can attempt to draw from the various studies that were presented.

MR. RICE: Well, the only thing I'm trying to--I think we could answer the question except that for the donor, do we know that that donor is strong enough to survive the cryopreservation? I mean that could be an issue. I mean if we know that the donor is going to be able to survive the cryopreservation and we don't even have to consider for this moment the age of the mother and the likelihood of the pregnancy with a time factor, then I think that's one of these questions.

But if you've got a donor whose sperm just won't survive the cryopreservation, irrespective of how old the recipient mother will be, then--but fresh will work, you see? So now we have to know, is this donor actually prequalified as going to have survivable cryopreserved semen or not? And then that makes the question easy.

If we're assuming that that's the donor we're talking about, we can answer the question. But if we're assuming that the donor's sperm won't survive, then that makes the question almost, if you want to have a pregnancy, go the other direction.

DR. NELSON: Since this is being applied to directed donation, I think that you have to maybe not assume a worst-case scenario, but certainly an average and perhaps even below-average-case scenario. You know, if it were the anonymous situation, then you could screen 100 and take the 4 best, but that's not what we're talking about here.

DR. FITZPATRICK: There is an alternative to cryopreservation for ensuring safety, and that's repetitive testing on the directed donor, and then he provides a fresh specimen upon the return of the results from the retesting, and you can do that without cryopreservation.

DR. NELSON: Yeah. That's not this question though.

DR. FITZPATRICK: I know.

DR. SIMON: I know, but, Mike, that doesn't really solve the issue of that particular sperm specimen, does it?

DR. FITZPATRICK: There is a time delay of 24 to 48 hours.

DR. SIMON: And it puts the person in a lower risk, I agree, but the whole idea of the quarantine and retesting is that specimen, and now the person is six months older.

DR. FITZPATRICK: Well, to take Jay's comment though, if you're comparing Donor A to Donor A, fresh versus cryopreserved--and from my own personal experience I did fairly extensive research on this along with the specialist who was helping us--if you look at the population as a whole, you could say, Toby, there's a moderate difference. And if you look at Donor A versus Donor A, the difference might be pregnancy versus nonpregnancy because there is a significant number of individuals whose semen could not be cryopreserved.

DR. HOLLINGER: I guess the problem is we don't have the proper experiment, and we're never going to get it. I mean to do the proper experiment you'd have to have two uteruses in the same person, and you'd have to have fresh and frozen samples to do it. You're looking at studies which looked at fresh semen in one woman or a woman, versus frozen semen, maybe that same one, but in somebody else. And they're all--all the tremendous variables are there.

DR. NELSON: Yeah, but there were a large number of studies, and there were several random. I mean I--

DR. HOLLINGER: Only three random control studies in that group, only three. And the meta-analysis was--I mean you can't do a meta-analysis with three random control studies and pool everything else together. It's just not appropriate.

MR. RICE: Well, we didn't see any studies that would--I think the studies that we saw would allow us to answer the question in this way. The question, the way it's worded, assuming that this donor survives--has survivable cryopreserved sperm, that over time you'll finally get the pregnancy. If we assume that this donor does have survivable sperm, then we can use the data that was presented to us, and we could go with that as being--that's who we are assuming this donor is, does have survivable--

DR. NELSON: I don't think we can make any assumptions under donor.

MR. RICE: Well, if we don't, then we didn't have any data that could really tell us which one would--which way would be the right way to go to survivable pregnancies.

DR. NELSON: But again, given that these are directed donations, I think that we can't assume that they're the best-case scenario.

MR. RICE: Well, only 5 percent survive. Well, I mean that's other questions too, but.

MR. SIANI-ROSE: Can I add something? Two things. One is people go to fertility clinics because they're having problems. I mean they may go to a sperm bank because they want to get the sperm donation, but people go to fertility clinics because they're having problems. The other thing is that in addition to age, like age 42 or any time over like 35, which is considered advanced maternal age, the number of miscarriages increases also, and that is something that a lot of my friends deal with, both straight and gay.

DR. HOLLINGER: But let me go back to the question. You started to say if you go to fertility clinics it's usually two people are having a problem, and I agree with that, but that's not the issue we're talking about. We were talking about a designated donor, and those two are not two people going because they've had fertility problems.

MR. SIANI-ROSE: Well, but I heard the numbers quoted that something like frozen sperm will give you 15 percent likelihood of pregnancy on each visit, and fresh sperm will give you something more on the order of 20 to 30 percent. You know, at the point where they begin to converge, it's certainly beyond four visits, and when there are fertility problems.

DR. HOLLINGER: He said about three cycles I think he said. I think-- is Mr. Sims here, because I recall--

DR. SIMON: He left unfortunately.

DR. HOLLINGER: He said about two to three cycles I think. That's where you start to see--

MR. SIANI-ROSE: I mean, it's true, two to three cycles works for some people, but I have friends who have been trying for years. I mean you must know people in their late 30s who have dealt with fertility issues.

DR. NELSON: Well, let's--let's deal with this. Linda, are you ready?

DR. SMALLWOOD: Read the question so it will be in the record.

DR. PEREIRA: As compared with the use of fresh semen, does the use of cryopreserved semen for artificial insemination reduce pregnancy rates?

DR. SMALLWOOD: Polling the Committee on Question No. 2. Dr. Schmidt?

DR. SCHMIDT: I'm answering no to the question as Dr. Epstein rephrased it or modified it or explained it.

DR. SMALLWOOD: Dr. Macik?

DR. MACIK: Yes.

DR. SMALLWOOD: Dr. Fitzpatrick?

DR. FITZPATRICK: Abstain.

DR. SMALLWOOD: Dr. Stroncek?

DR. STRONCEK: Yes.

DR. SMALLWOOD: Dr. Mitchell?

DR. MITCHELL: Yes.

DR. SMALLWOOD: Dr. Stuver?

DR. STUVER: Yes.

DR. SMALLWOOD: Dr. Linden?

DR. LINDEN: Yes.

DR. SMALLWOOD: Dr. McGee?

DR. McGEE: Yes.

DR. SMALLWOOD: Mr. Rice?

MR. RICE: Yes.

DR. SMALLWOOD: Dr. Hollinger?

DR. HOLLINGER: Yes.

DR. SMALLWOOD: Dr. Harvath?

DR. HARVATH: Yes.

DR. SMALLWOOD: Dr. Nelson?

DR. NELSON: Yes.

DR. SMALLWOOD: The nonvoting industry representative, what would be your position?

DR. SIMON: Agree with the yes.

DR. SMALLWOOD: And Ms. Knowles, the nonvoting consumer representative, left a message that she would have agreed with the yes vote.

I would like to make it clear for the record that only the voting by those voting members are counted. We ask the opinion of the nonvoting consumer and industry representative just for the record, but only the voting members votes are counted with respect to answering the questions. Thank you.

DR. NELSON: Okay.

DR. PEREIRA: So this question has two parts--three parts I guess. What is the estimated reduction in pregnancy rates?

DR. HOLLINGER: I just have to say I don't know under--I mean with all of the ramifications, and all the things--so I would have to--for myself, I'm going to have to abstain on this, because I just don't think there's data out there that could answer this question.

DR. NELSON: I think targeted to the directed donor population, I don't think we do have data on this. I mean, it would be lower, but I don't know how much lower.

DR. SIMON: I was going to try to be helpful. I don't know if I can, but it seems to me it's modest, as I said before, and I wouldn't know how to really answer 2b. I mean, we'd have to direct the FDA back to the experts I guess. I mean I assume the better the bank and the better the procedure is that they apply and the better the fertility clinic, the more likely that one would achieve good pregnancy rates.

So my answer would be modest. I don't know if you want to vote on something like that or just want to say we can't vote.

DR. NELSON: You want to rephrase the question?

DR. SIMON: No, I mean, as he said, what is the estimated reduction in pregnancy rates? I guess I'd agree with Dr. Hollinger. I don't--

DR. NELSON: That's not a yes or no. It's a modest.

DR. SIMON: You can't answer it yes or no anyway. So, yeah, I mean if that's agreeable, we could say a modest or slight reduction.

DR. MITCHELL: And I guess I would disagree with that. I would say that it could be severe, you know, particularly if the sperm can't withstand cryo--

DR. SIMON: I was taking this on the average now. If you ask about the specifics, you know, some it's going to be severe, some there's going to be no reduction, they'll get pregnant the first time.

DR. MITCHELL: Right, right. And so that's--and I agree with that, and that's why I think that we can't say on an individual basis, that some people are going to be much more effective than others.

MR. TREEIMAN: Dr. Lamb said that there was a substantial increase in pregnancy rates. That was the word that he used, if I'm correct.

DR. NELSON: But then he showed data, the menage ratio of a 38 percent reduction, and it was unclear whether this was one attempt, multiple attempts, a course. I mean, you know, it's substantial if you're the guy who's--if you're the couple that's on the wrong end of the--

MR. TREEIMAN: That got pregnant or didn't, yeah.

DR. NELSON: But Dr. Smallwood wanted to announce the results of the last vote.

DR. SMALLWOOD: For the record, the results of voting for Question No. 2, there were 10 yes votes, 1 no vote, and 1 abstention.

The nonvoting industry representative and the nonvoting consumer representative would have agreed with the yes vote.

DR. HOLLINGER: On just that 2b. part, I was under the impression, when Dr. Sims was talking, that--and again, you'd have to talk to the people who are doing this all the time, but that the intrauterine insemination was more favorable than the intracervical insemination process in terms of fertility rates.

DR. NELSON: Right. And they also talked about--

DR. HOLLINGER: I mean--

DR. NELSON: --that the way that the cryopreservation was done, which I guess there are a lot of tricks like there are when you're isolating a hepatitis virus.

DR. MACIK: I would say that with these questions here, we're getting out of the realm of our role of saying if something's safe or not safe of an infectious risk. To have a hematologist or blood banker or virologist comment on what's the estimated reduction in pregnancy rate is not appropriate, I don't believe. So I would say that these questions really should not be addressed to the Committee.

DR. NELSON: I agree. I think it's hard for us to be specific. I would say--I'd use the word maybe "modest" but also "significant." In the statistical and then the perhaps individual situation, I suspect that there would be a significant reduction.

DR. SIMON: I do agree with Dr. Macik. I think that obviously some of our discomfort--I guess Dr. Fitzpatrick has some specific information--most of us are getting out of our realm. And we listened, I hope intelligently, to the presentation and formulated some ideas, but I know what Dr. Epstein and the staff of the FDA are looking for, because they're going to have to do a weighing of risk benefit here in making a decision about the directed donor. So we've helped them some I guess on risk, and if they're asking if we can help them some on benefit, I would try to be helpful, but if we can't, we can't I guess.

DR. NELSON: Can we see the next question? Could we look at what the next question was that you have?

DR. PEREIRA: The next question was: What are the benefits of these procedures that can be used to increase the effectiveness of the cryopreserved semen?

DR. NELSON: I don't think we can answer this one either.

DR. STUVER: Yeah. I would agree with Dr. Macik also. I mean, these seem to be the kind of questions that you get the experts to come, and then they tell us the answers we would ask to get information on. I don't really see how we can provide this kind of information.

DR. NELSON: Right. And there was not that kind of detail presented by any of the experts.

DR. STUVER: No.

DR. PEREIRA: So that counts as a dismissed question or--

DR. NELSON: Well, yeah, it counts as a--maybe they need to present this to another committee or something. I think this was a useful discussion and exercise, and I think the data presented were very interesting, and I think we all agree that this--particularly the directed donor situation is very--is different at least than the average blood donor, and that the safety issues are part of the issue, but not all of the issue, and personally, I would think that my one--just my own personal opinion is that it might be using--screening donors if were worried about particularly a person who was a directed donor, who was a man who had had sex with men or was in what we would call a risk category, that one way to increase the safety, which is apparently not done now by all semen banks, would be to do PCR testing of the blood to reduce the likelihood that the person would be in the window period. It's quite feasible. The technology's there. You could test it for at least HIV, hepatitis B and C.

DR. SIMON: You could also do the follow-up testing that Dr. Fitzpatrick mentioned, yeah.

DR. NELSON: Right. Or you could do follow-up testing, and then also do--following that, do a directed donation without cryopreservation. I would think either one of those techniques would reduce the risk of a transmission of an infectious agent.

Any other comments?

DR. WILLA: I'd like to make a comment. If Antonio would go back to 2b. for a minute on the previous one. I think what we were getting at with 2b: "Are there any procedures that can improve the pregnancy rate using cryopreserved?"

What we had in mind here was the intrauterine insemination versus intracervical insemination. I believe Dr. Sims told us that you get better results with the intrauterine.

DR. NELSON: Do you want us--I mean I think we agree, but do you need us to vote on that? It sounds like intrauterine insemination is now the preferred procedure and the one that would be done by a professional gynecologist endocrinologist, but that it may not be routinely done in practice, and maybe that--you know, a lot of it may be just cervical or vaginal. And maybe we could vote on that if everybody agrees.

DR. MACIK: I still believe that we're getting into the realm of asking technical questions about how to increase pregnancy rates, that as a committee it goes outside of asking whether or not the safety issue of transmission of infectious agents are there, and I don't--you know, I think we would really have to put this to a field of experts of GYN endocrinologists who do this, to say what are the--how can you improve insemination; what's the risks/benefits of these procedures? That's really a technical issue that's outside the realm of what we can address.

DR. NELSON: Well, it is, but data were presented and nobody got the data.

DR. MITCHELL: Yeah, Dr. Nelson. I mean I agree. I think that we heard information, and that it didn't sound out of the realm of anything that anybody else knew, and that the Committee seems to accept the information.

However, I don't think that we need to vote on it. It seems to me that the discussion that we've had about that is enough, and that we should just move on.

DR. NELSON: The data that were presented are part of the record, and I guess just this discussion, if we--it seems reasonable.

DR. EPSTEIN: I think that we agree that 2b. and 2c. are essay questions, but we'd like a vote on Question 3, which is upcoming.

DR. PEREIRA: Okay. Question 3. We're asking: Are there existing data that identify subsets of men who have had sex with other men, in which the incidence and prevalence rates of HIV, HBV, and HCV of the subsets are similar to the population at large?

DR. HOLLINGER: I'm sure there are subsets. I'm sure there are individuals. I don't think there's any question in my mind that there are individuals. But if you're asking are there existing data that identifies those subsets, and what we had presented was information that does not identify any particular subsets. So based upon the question, I would have to answer no on this question based on that.

DR. NELSON: I agree. The one strategy that none of these large surveys have used, and as I was trying to do and survey and identify a low risk, I would choose monogamous partners in which both were interviewed about their sexual behavior. And if there was no high-risk behavior, I would bet that their rates would be lower, and I know many such people, but in terms of is that--are there data in the literature on this, I haven't seen it.

DR. SIMON: I just wanted to add quickly, I was at the June 2000 CDC Conference. I think a couple of others of us were there. And this issue was pushed hard, and I have to believe the CDC has looked at this very hard and have been pushed on this very hard, and they really have not been able to come up with anything usable. I know the REDS group has looked. So there may well be some, but I would have to concur that at this time we'd have to answer no to this question.

DR. STRONCEK: Based on the spirit of the discussion and what was presented, I think this is the wrong question. And I think the question should have been based on a combination of history and testing and quarantine, "can you get safe sperm from gay men?" Then I would vote yes. So because the question was wrong, I'm going to vote yes on this one. I'm not going the punish the process because the FDA didn't do their job and get the question right.

DR. NELSON: We could rewrite the question.

DR. MITCHELL: Yeah, and I would propose that we do that actually. You know, I think that I would propose that we revise the question to say that with the proposed screening--let me see, I don't know how to do it--and the rescreening and the quarantine, is it safe for men who have sex with men--

DR. NELSON: The other thing we could do is vote on this question, and then create another question. And I think I'd rather do that, because I think the FDA probably needs an answer to this and has a--you know, existing data and subsets of men, that those are specific modifiers. So why don't we vote on this question first, and then let's--let's, as advice to the FDA, let's devise another additional question.

DR. SIMON: I think this question is specifically--am I interpreting correctly--really pegged toward screening questions?

DR. NELSON: Yes.

DR. SIMON: So not the other things.

DR. NELSON: Right. Okay.

DR. PEREIRA: Read it again?

DR. NELSON: Yes.

DR. PEREIRA: Are there existing data that identify subsets of men who have had sex with other men, in which the incidence and prevalence rates for HIV, HBV, and HCV of the subsets are similar to the population at large?

DR. SMALLWOOD: I'm polling the Committee on Question No. 3. Dr. Schmidt?

DR. SCHMIDT: No.

DR. SMALLWOOD: Dr. Macik?

DR. MACIK: Abstain.

DR. SMALLWOOD: Dr. Fitzpatrick?

DR. FITZPATRICK: This doesn't refer specifically to fertility, so I'll leave it up to you whether you want me to abstain or vote.

DR. NELSON: What? You can vote on this one.

DR. FITZPATRICK: Okay.

DR. NELSON: It's up to you.

DR. FITZPATRICK: I'd say no.

DR. SMALLWOOD: Dr. Stroncek?

DR. STRONCEK: No.

DR. SMALLWOOD: Dr. Mitchell?

DR. MITCHELL: Abstain.

DR. SMALLWOOD: Dr. Stuver?

DR. STUVER: No.

DR. SMALLWOOD: Dr. Linden?

DR. LINDEN: No.

DR. SMALLWOOD: Dr. McGee?

DR. McGEE: No.

DR. SMALLWOOD: Mr. Rice?

MR. RICE: No.

DR. SMALLWOOD: Dr. Hollinger?

DR. HOLLINGER: No.

DR. SMALLWOOD: Dr. Harvath?

DR. HARVATH: No.

DR. SMALLWOOD: Dr. Nelson?

DR. NELSON: No.

DR. SMALLWOOD: Nonvoting industry representative, Dr. Simon?

DR. SIMON: No.

DR. SMALLWOOD: Ms. Knowles, the nonvoting consumer representative, would have agreed with the no vote.

The results of voting on Question No. 3: 10 no votes, 2 abstentions. Both the nonvoting consumer and industry representative would have agreed with the no vote.

DR. NELSON: Do you want to propose another question, David?

DR. STRONCEK: Yes. Let's try this for an alternative question: "Existing screening questions, laboratory tests and quarantine procedures can be used to identify a subset of men who have had sex with other men in which the prevalence rates of HIV, HBV and HCV of the subjects is similar to that of the public at large.

DR. NELSON: Could we get a comment from Dr. Valleroy on that? She's over here.

DR. VALLEROY: On this question?

DR. NELSON: Yes.

DR. VALLEROY: I couldn't hear it.

DR. SIMON: You don't mean, David, you don't mean "prevalence"; you mean "risk", don't you? The prevalence remains the same.

DR. STRONCEK: Well, if you have prevalence, there is a risk.

DR. SIMON: Prevalence at the end of the quarantine period?

DR. NELSON: You can use these procedures to identify a subset of men who have had sex with men whose prevalence or whose infection rates are similar to the general population.

DR. STRONCEK: So it was, existing screening questions, laboratory tests and quarantine procedures can be used to identify a subset of men who have had sex with other men in which the prevalence rates of HIV, HBV and HCV is similar to the public at large. We've got to make this into a question.

DR. HOLLINGER: This is similar to what is done with the anonymous donor basically.

DR. LINDEN: You're talking about comparing the general population that's also been subject to quarantine, or compared with the general population that hasn't been?

DR. NELSON: Yes, that has--

DR. LINDEN: I don't think we can say that. I mean if you're starting out with a higher prevalence and you're testing everybody, and then there's going to be incident infections in both, but more in one group than the other. I don't--

DR. NELSON: But he's talking about cryopreservation too which would deal with the incidence issue.

DR. LINDEN: Right. I mean you're talking about incident infections, and I think we heard incident infections are higher.

DR. NELSON: No, but if there's cryopreservation, then those sperm would not be used until the incidence window has passed, is what--

DR. LINDEN: Right. If they came in positive, it wouldn't be used.

DR. NELSON: If they had a--right. If they became positive at the end of the cryopreservation period, it would not be used.

DR. LINDEN: Right. So the sets that you're picking are those that are negative.

DR. NELSON: Yeah. Right, David? Isn't that correct?

DR. STRONCEK: Yeah. I wonder though, the way I have it written if it's not clear that we mean these for directed donors. Maybe we need something at the end that the prevalence of rates of HIV, HBV and HCV are low enough to permit the use of these donors as directed donors with the appropriate informed consent.

DR. MITCHELL: Yeah. I think that the issue is not whether there's one group that's higher or lower the other. I think that the issue is whether there's a group where it's safe to donate, and I think that that wording sort of helps to get toward there.

DR. SCHMIDT: I repeat my request. We have an expert in the field who talked to us before, and why don't we hear from her?

DR. VALLEROY: As I understand it, there would be four levels of screening. One level would be that these would be directed donors. The second level would be that they would be put through some sort of questionnaire screening. And the third and fourth level would be that they would be put through state-of-the-art screening of the biological specimens. And it seems at that point that you would be in a safe situation.

DR. FITZPATRICK: But the question is: are there data, and there's no data to support that yet.

DR. VALLEROY: Oh, are there data?

DR. FITZPATRICK: Right. That was the original question.

DR. PEREIRA: Well, the proposed regulations, the directed donation, allow for that, to have risk factors or have testing that has been positive.

DR. LINDEN: I can't hear you.

DR. PEREIRA: The proposed regulations of donor suitability, in the case of the directed donation, when somebody identifies somebody as the source of the reproductive cells, includes the possibility of that person having a risk factor, or a test that is positive, or a relevant disease agent, and still can be used with the physician's consent, and the waiver from the patient.

DR. NELSON: Okay. So then this is irrelevant I guess.

DR. EPSTEIN: Again, I think that we may have confused you because in Questions 2, we were trying to address the directed donor situation and the issue whether we should or should not require a quarantine retest, which essentially means use of cryopreserved semen. In this question, 3 and 3a., what we're trying to get at really is the issue of anonymous donation. And what we're asking, in effect, is whether there's a way to identify safe subsets of men who acknowledge history of sex with other men.

Now, I think the question that Dr. Stroncek was trying to put in front of us was whether you could go even further; in other words, could you decide that with existing tests and the use of quarantine retest you could discontinue an exclusion for MSM, males who have sex with males, which is in effect the proposal that Mr. Treeiman advocates.

So I think that the question that's moot is finding safe subsets among directed donors because the FDA is not proposing that we prohibit use of semen for AI from directed donors who admit risk factors. The question that's pertinent here is for anonymous donors. Do we think we have the tools, in effect, to identify safe subsets?

Many of us believe that there are individuals who have protected themselves over the years through their cautious practices, but unfortunately, that's not the issue. The issue is: can you properly select them in the AI donor room. That's the question. Can you select them?

And again, we can either entertain or not entertain the further question of, what if you don't try; are things still good enough? And again, that is the proposal of Mr. Treeiman and I assume other advocates.

MR. TREEIMAN: I also want to remind the Committee about Dr. Dayton's analysis four years ago that was presented here, and he basically agreed with what my study found, which was, yes, you know, assuming if you had a two-phase testing scenario, which is again what Dr. Linden suggested, and he basically said that that two-phase testing scenario would bring the prevalence problems down to zero, and he was not even talking about a quarantine period. He was talking about blood donors. So I think with a two-phase testing scenario, adding the quarantine period, that's already been looked at by the FDA, Dr. Dayton already reported on that four years ago. My experience with the study that you have in your packet, I think we have the tools already.

DR. EPSTEIN: Well, if I could make just two more comments that I hope will be clarifying. It has been explained that there is a scenario of subsequent identification of a donor who is anonymous at the time of use of donated semen. That is a scenario that somehow lies between the concept of a directed donor who is chosen up front and the concept of an anonymous donor whose identity is never known. FDA has not asked the Committee to try to parse that out. I mean in the end we will have to consider which scenario that really harkens to, or whether it needs its own special provisions by way of consent, labeling restrictions, et cetera.

So at the moment we are really only asking the Committee to entertain a scenario where there's a directed donor. That's someone known to the recipient at the time of use, and the anonymous donor. That's a setting in which the identity remains unknown to the recipient.

Now again, I'm not trying to, in any way, ignore the fact or conceal the fact that a category of donor identity--what's your correct term?

MR. TREEIMAN: Identity release.

DR. EPSTEIN: Identity release donation exists as a practice. But what we're trying to focus on here in Question 3 is what we think is the most difficult situation, which is an anonymous donor. And the question at hand is: on the one hand, can we identify safe subsets among men who admit to sex with other men?

And independent of that, I believe that Dr. Stroncek is proposing whether semen for AI can be obtained safely from persons with history of male sex with males.

And Mr. Treeiman would add, if there is a pretest as well as quarantine retest.

So if the Committee wishes to pursue that further question, that is how I would suggest it be formulated.

MR. TREEIMAN: And along that lines, I agree that it could be formulated that way, but also if the Committee wished to go one step further and specifically just say not anonymous, anonymous donors, but this would only apply to identity release anonymous donors. That would be acceptable.

DR. NELSON: Yes, but would you know that? Would you know who they would be?

MR. TREEIMAN: Excuse me?

DR. NELSON: Would you know who--if somebody came in to donate semen--

MR. TREEIMAN: Oh, you know ahead of time whether they're an identity release anonymous donors because that's--they either sign up for an anonymous program or an identity-release program. I mean that's in the telephone interview. That's not even--before they even walk in the door.

DR. LINDEN: Well, it seems if the quarantine retest addresses the analytes that we test for, when you have a double test, you don't have to have concerns about errors, and new sero conversions and so forth, but it doesn't address some of the other issues, the other agents, HVA, possibly others, or the immuno-silent ones who may not sero convert. So I mean it seems like there would be a small number of other concerns that might still be on the table. And I guess the question is what the risk is in that population.

MR. TREEIMAN: Well, that's why California has its regulations that include not only HIV, but hepatitis B and C and syphilis--

DR. NELSON: No, but they're not testing for HHV-8.

DR. LINDEN: Yeah, but that's the only things they're testing for, no--

DR. NELSON: And there may be others too.

DR. STRONCEK: I guess my intent was to make the question directed towards the directed donors or these identity release donors. Dr. Epstein has directed us not to consider the direct--the identify release donors, so I guess this question's not needed, and maybe we're--I wouldn't favor doing anything different with the anonymous donors, so maybe we're done for the day.

DR. NELSON: I think with the anonymous donors--that's fine.

MR. TREEIMAN: Well, let me ask Dr. Epstein directly.

Dr. Epstein, is it reasonable for this Committee the have a statement just on identity release donors?

DR. NELSON: Do all sperm banks have that?

MR. TREEIMAN: Not all sperm banks, only a minority--

DR. NELSON: It's kind of the problem.

MR. TREEIMAN: But a growing number.

DR. NELSON: It's kind of the problem, and the FDA's a federal agency and it's hard to tailor it to a few.

MR. TREEIMAN: Well, it's a few, but it's a growing number, because more and more we see women who are distressed because their children are saying, "Who's my daddy?" And they have no answer to that.

DR. EPSTEIN: Well, again, I think that we brought questions to the Advisory Committee that are underlying scientific questions. We recognize that there is a debate about reproductive rights. We're not here to discuss that. I think that the issue of identity release has to do with whether the recipient can give a proper informed consent, you know, whether risk can be properly assessed by the recipient in that scenario. But it doesn't help us ask the question of how much risk is there at the time of product use? In other words, who gets to decide risk is a question independent of how much risk is there?

So right now the reason we have not put that issue in front of you is because we're not asking you the question of who should decide the risk. We're only asking for your help on what is the risk? So I would submit that we don't need to ask you to separately answer the question in the scenario of identity release, because at the time of product use, it's the same risk as from an anonymous donor.

Now, understood, there may be a different ability of the recipient to make an informed choice, but that's not what we're asking the Committee. We're just asking the Committee how to address risk and what are the risks.

Now, I would also like to comment that if the Committee were to put forward the question whether semen for AI can safely be obtained from persons with MSM history in the scenario of a pretest plus quarantine retest, that that question in fact is not limited to MSM. Once you are changing that scenario, there really would be no logical reason to distinguish the donor with an MSM history from the donor with any other risk history.

And I think it's reasonable if you wish to comment on the general ability of various screening and retest algorithms to mitigate what I think Dr. Valleroy well presented to the rather alarming risks.

But I would encourage the Committee not to vote that question specific to MSM because we would want to come back and consider it in a broader context.

DR. HOLLINGER: You know, on the outside--I mean outside of--to me, outside of testing, of quarantine for six months and retesting, I don't think that there's any particular question that I can think of, or series of questions that would identify somebody, anybody, with risk of disease. I mean I think you can separate out a large pool, but we all see as clinicians patients coming in who seemingly have no risk but they have infectious, and they're always surprised about it. So I think that's one issue.

The second issue, however, is that it does appear that the risk of transmission through sperm, unwashed sperm, seems to be--I mean washed sperm, seems to be quite low. I don't think there's enough data yet to really do it, but I was very encouraged by the fact that most of the PCR work did not find much in the sperm. They mostly found it in the white cells or epithelial cells. And that was very encouraging to me to see that. And maybe one then can get to a point to do that.

The third thing, however, is that there probably are circumstances in which a clinician, by knowing a person having some tests done, including these tests, perhaps even PCR testing and so on, could come to determine that this is a safe alternative here. And I don't know how you go about doing that with regulations. We talk about variances and so on that blood banks get and so on, but I don't know how you do that. So I can certainly see that as a possibility.

But that's sort of my take on this issue.

DR. NELSON: Yeah, I agree. And I think probably given what Dr. Epstein said, we don't need to vote on it. So I think we're done. So we'll--there's a meeting in January I guess with the TSE Committee, January--what is it 15th and 16th?

DR. SMALLWOOD: The next meeting of the BPAC is tentatively scheduled for the second week in March. We would advise you to look at the FDA website to confirm the date. Thank you.

[Whereupon, at 3:10 p.m., the meeting was adjourned.]