> 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
>
> [Members of the Committee]{.underline}
>
> 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.
>
> [Temporary Voting Members]{.underline}
>
> Jonathan S. Allan, D.V.M.
>
> (by telephone)
>
> Lianna Harvath
>
> F. Blaine Hollinger, M.D.
>
> [Non‑Voting Consumer Representative]{.underline}
>
> Katherine E. Knowles
>
> [Non‑Voting Industry Representative]{.underline}
>
> Toby L. Simon, M.D.
>
> [Executive Secretary]{.underline}
>
> 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]{.underline} [R]{.underline} [O]{.underline} [C]{.underline}
> [E]{.underline} [E]{.underline} [D]{.underline} [I]{.underline}
> [N]{.underline} [G]{.underline} [S]{.underline}
>
> 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.
>
> \[Whereupon, at 3:10 p.m., the meeting was adjourned.\]