FOOD AND DRUG ADMINISTRATION

	
	XENOTRANSPLANTATION SUBCOMMITTEE
	OF THE BIOLOGICAL RESPONSE MODIFIERS
	ADVISORY COMMITTEE

	

	
	
	Gaithersburg, Maryland
	Thursday, January 13, 2000
	
	P R O C E E D I N G S
	DR. AUCHINCLOSS:  My name is Hugh Auchincloss, and I want to get this meeting started today by introducing Gail Dapolito, and you have the announcements about people and conflicts of interest.
	MS. DAPOLITO:  Good morning.  I'd also like to welcome Dr. Auchincloss, the subcommittee participants, the FDA, members of the audience, all here today to this meeting of the Xenotransplantation Subcommittee.  I am Gail Dapolito, as Dr. Auchincloss as has mentioned.  I am the executive security for the subcommittee and the designated federal official for today's proceedings.
	I would like to begin by stating, as announced as a notice in the {IOn}Federal {IOff} {IOn}Register{IOff}, this meeting will be conducted as a subcommittee of the Biological Response Modifiers Advisory Committee.  There are two differences between this subcommittee meeting and a meeting of the full advisory committee. One is that as the Xenotransplantation Subcommittee is not an independently chartered subcommittee, there are only two standing members.  They are from the Parent Biological Response Modifiers Advisory Committee, and I will introduce them to you in a moment.
	The other difference is that the report that will be generated today by the subcommittee following the discussions will be presented to the parent committee for approval at a future meeting of the Biological Response Modifiers Advisory Committee.  Other than that, this meeting will be conducted as a full advisory committee meeting.
	I will begin by introducing the participants.  I will begin on my left. Dr. Nicholas Lerche, California Regional Primate Research Center.  Dr. Richard Kagan, University of Cincinnati College of Medicine. Dr. Richard Kaslow, University of Alabama at Birmingham.  Dr. Robert McCauley, Shriners Burns Hospital.  Dr. McCauley is also participating today as a representative of the general and plastic surgery panel of the FDA Center for Devices and Radiological Health.
	Next is Dr. Harold Vanderpool, Institute for Medical Humanities, University of Texas Medical Branch.  Dr. Kenrad Nelson, Johns Hopkins School of Hygiene and Public Health. Dr. John Coffin, Tufts University School of Medicine.  Dr. Blaine Hollinger. Dr. Hollinger is also the chair of the blood products advisory committee, and we are pleased today to have the participation of several members of the BPAC, including Drs. Hollinger, Kagan, Linden, Nelson, and Ms. Knowles.
	Dr. David Onions, University of Glasgow.  Coming around the table, Dr. Gene Linden, New York State Department of Health. Dr. Jonathan Allan, Southwest Foundation for Biomedical Research.  Dr. Prem Paul, Iowa State University.  Dr. Hugh Auchincloss Jr. As noted, Dr. Auchincloss is the chair of the Xenotransplantation Subcommittee.  He is also a standing member of the Biological Response Modifiers Advisory Committee.
	Ms. Katherine Knowles, Health Information Network.  Ms. Knowles is participating today as a consumer representative of the subcommittee. Mr. William Lawrence, United Network for Organ Sharing.  Mr. Lawrence and Mr. Antonio Benedi, who could not make it today due to an illness, they participate as the patient representatives of the subcommittee.
	Dr. Claudia Mickelson, Massachusetts Institute of Technology.  You switched seats on me.  I knew I'd forget that.  Dr. Daniel Salomon, Scripps Research Institute.  Dr. Salomon is a member of the Biological Response Modifiers Advisory Committee.  He serves as the chair of that committee.  Then we have Dr. Mickelson.
	Following Dr. Mickelson, Dr. Stephen Rose, National Institutes of Allergies and Infectious Diseases. Dr. Louisa Chapman, representing the Centers for Disease Control and Prevention.  The FDA Center for Biologics Evaluation and Research is represented today by Dr. Jay Epstein.  And Dr. Andrew Dayton, he is here from the Office of Blood Research and Review.  The CBER Office of Therapeutics Research and Review is represented today by Dr. Carolyn Wilson, who will be joining the discussion later today; Dr. Eda Bloom; Dr. Phil Noguchi; and Dr. Jay Siegel.
	I would also like to introduce the committee management specialists here today, Ms. Rosanna Harvey and Ms. Sheila Langford. They are available at the registration table to handle any questions you might have.
	As a courtesy to the participants and to your neighbors in the audience, we ask that cellular phones be turned off in the conference room and we also ask that pagers be set to silent mode.
	Additionally, the materials that are provided today to the committee are displayed -- this is a first time for this committee -- on the FDA dockets Internet Web site.  I'd also like to point out to the participants today, the microphones work by pressing the on/off button.  If you want to speak, please press the button and a little red light will show up.
	Dr. Auchincloss, with your permission, I'll read the conflict-of-interest statement.
	This announcement is made part of the public record at this meeting of the Xenotransplantation Subcommittee on January 13th.  Pursuant to the authority granted under the committee charter, the direct of FDA's Center for Biologics Evaluation and Research has appointed the following participants as temporary voting members:  Dr. Hugh Auchincloss Jr.; Mr. Antonio Benedi; Drs. Jonathan Allan, John Coffin, Blaine Hollinger, Richard Kagan, Richard Kaslow, Ms. Katherine Knowles, Mr. William Lawrence, Drs. Nicholas Lerche, Gene Linden, Robert McCauley, Claudia Mickelson, Kenrad Nelson, Prem Paul, Daniel Salomon, and Harold Vanderpool.
	Based on the agenda made available and on the relevant data reported by the participants, it has been determined that all financial interests in firms regulated by the Center for Biologics Evaluation and Research that may be affected by the committee discussions have been considered.  In accordance with 18 U.S.C. 208, the following participants have been granted a waiver which permits them to participate in the committee discussions:  Drs. Hugh Auchincloss, David Onions, and Daniel Salomon.
	With regards to FDA's invited guests, the agency has determined that the services of these guests are essential.  The following interests are being made public to allow meeting participants to objectively evaluate any presentation and/or comments made by the participants.  Dr. Louisa Chapman is employed by CDC.  She and other CDC employees are involved in collaborative research with a firm that could be affected by the discussions.  No financial support is received.  Ms. Katherine Knowles is a part-time instructor providing HIV/AIDS training to a blood bank that could be affected by the discussions.
	In the event that the discussions involve other products or firms not already on the agenda for which FDA's participants have a financial interest, the participants are aware of the need to exclude themselves from such involvement, and their exclusion will be noted for the public record.  Copies of the waivers addressed in this announcement are available by written request under the Freedom of Information Act.
	With respect to all other meeting participants, we ask in the interest of fairness that they address any current or previous financial involvement with any firm whose products they wish to comment upon.
	Thank you, and I'll turn it over to you, Dr. Auchincloss.
	DR. AUCHINCLOSS:  Thank you very much, Gail.  I believe our first speaker will actually be Jay Siegel, who just arrived in time to come to the microphone.  Thank you, Jay.
	DR. SIEGEL:  I was looking at an earlier draft of the program, where I wasn't --
	DR. AUCHINCLOSS:  Jay, you'll need to do buttons for your microphone.
	DR. SIEGEL:  Thanks.  It's my pleasure to welcome you here.  In substantial part, this meeting will be a continuation of discussions we've been holding really over the last 5 years with this committee to provide guidance as to show to deal with safety of xenotransplantation products, and more specifically, discussions we held last year regarding applicability of various concepts that were expressed in the draft Public Health Service guidance of several years back, a guidance which has received significant public comment and is being updated and revised as we speak.
	I think that when we hold these public discussions, hearings, and receive comments, we always receive valuable data and information and advice.  But then as we do our day-to-day work we find new questions arising for which we haven't quite got the specific or precise advice, and each application we see raises different types of implications.
	So there is a difficult balance that we're facing and I know this committee faced with us last summer as we discussed these issues.  It would be nice to get very general advice that can be applied in the day-to-day work and general guidance, both by sponsors and by ourselves.  Yet at the same time, it's very important, we've seen, to consider the specific implications of a group of therapies that range as broadly as, say, transplantation of a heart of kidney from a mammal to in vitro exposure of a patient's lymphocytes to, say, insect cells that are presenting a tumor antigen.
	The general advice has been, however, somewhat difficult, as it's hard in the theoretical to consider all those circumstances.  So what we're going to try to do over the course of today is discuss issues regarding a particular product in the hopes of getting some general ideas as to what specific factors should impact on what are the right precautions.  Try to generalize those issues, as well as discuss in more detail particular questions and concerns regarding safety of the blood supply.
	So with those comments, I'll welcome you.  Thank you all for coming.  We look forward to hearing your advice.
	DR. AUCHINCLOSS:  Jay, thank you very much.  Topic I for this morning is blood donor deferral, and we will start that discussion with an FDA perspective, Dr. Andrew Dayton.
	DR. DAYTON:  I'm Andrew Dayton from the Division of Emerging and Transfusion Transmitted Diseases from the Office of Blood Research and Review.
	I'm going to be presenting to you today the highlights of a draft guidance document that we have just put out on the Web, and the title of that is "Precautionary Measures to Reduce the Possible Risk of Transmission of Zoonoses by Blood and Blood Products from Xenotransplantation Product Recipients and their Contacts."  This not only addresses issues of donor deferral, but it also addresses issues of product withdrawal, which in the context of blood are very serious considerations.
	So as I said, this is going to be highlights of the document, and of course to this committee, many of the things we're seeing are fairly well known.  In some cases, for instance with definitions, we need to play close attention, because they will have implications to policy.
	The document defines zoonoses as infectious diseases of animals that can be transmitted to humans through exposure to or consumption of animals.  Xenotransplantation is any procedure that involves the transplantation, implantation, or infusion into a human recipient of either live cells, tissues, or organs from a nonhuman animal source, or human body fluids. Xenotransplantation is any procedure that involves the transplantation, implantation, or infusion into a human recipient of either live cells, tissues, or organs from a nonhuman animal source, or human body fluids, cells, tissues, or organs that have had {IOn}ex {IOff} {IOn}vivo{IOff} contact with live nonhuman animal cells, tissues, or organs.
	It's a lot to bite off and chew.  I believe you all have copies of that, and I invite you to refer to them as needed.
	Xenotransplantation products include live cells, tissues, or organs used in xenotransplantation; biological products, drugs, or medical devices sourced from nonliving cells, tissues, or organs from nonhuman animals, including but not limited to porcine insulin and porcine heart valves are not considered xenotransplantation products.  The heart valves and so on are by way of example and not the sole exclusions.
	A xenotransplantation product recipient is a person who receives or undergoes {IOn}ex vivo{IOff} exposure to a xenotransplantation product.  Now, the definition of close contacts, again, this seems fairly simple and straightforward.  But I think it's the one definition that we most need to pay close attention to, because it has significant policy implications.
	Close contacts of xenotransplantation product recipients are defined as household members and others with whom the recipient participates in activities that could result in exchanges of bodily fluids.  Because transplantation necessitates disruption of the recipient's usual protective physical and immunological barriers, xenotransplantation may facilitate transmission of known or as yet unrecognized zoonotic agents to humans.  This, of course, is one of the primary considerations we took into account in developing our policies.
	Xenotransplantation is considered at risk for transmitting zoonoses even when the exposure is extracorporeal.  For instance, let us say even when no live cells are transplanted into the recipient.
	Some xenotransplantation procedures maintain a barrier between host and foreign tissue.  A typical example are encapsulated islet cells.  Even when such barriers are nonpermeable for virus, the risks of barrier failure require consideration.
	Now, the origins of our proposed policies come from the 1997 meeting of this committee.  And at the end of the meeting, the chairperson was asked about deferral for blood donors and their contacts, and he reasoned that although the risks were small, if there were a problem spread through the blood supply, it would be disastrous.  If anything were going to get out, this is where it would get out.
	He therefore recommended on behalf of the committee that xenotransplantation product recipients and their close contacts be deferred from donating blood and plasma.
	Now, again, to get back to our considerations in developing our policies, the risks of zoonotic transmission to xenotransplant recipients and their contacts remained undefined, which is not to say that they are not very real and very troublesome. The risks to the public health of blood or blood plasma becoming unavailable, however, are immediate and significant.  Withdrawal of plasma derivatives to address even small numbers of erroneous donations could cause serious product shortages.  The obvious problem you're getting into here is, when you make plasma derivatives or you basically have pooled thousands of units of plasma, and if one donor is found out to be suspect or someone who shouldn't have donated, you can lose a very significant part of the plasma supply.
	The FDA has developed a draft policy on donor deferral for xenotransplantation product recipients and their contacts.  The original definition of xenotransplantation was broadened to include {IOn}ex vivo{IOff} exposure.  We have had somewhat of a broadening of the original definition of close contacts.  The exclusions -- in other words, donor deferral and product withdrawal -- were related to the categories of highest perceived risk.
	I think you can understand the problems we face in developing this policy, and we quantitatively don't know and even qualitatively don't know the full extent of the risk of zoonosis.  Yet we have to come up with a workable and coherent policy.  So many of the risks that we take into account in our policy considerations are known, but effectively, we're having to deal with half of an equation and not a full equation.
	In the document, the FDA proposes that on a case-by-case basis, donor deferral and product withdrawal may not be warranted for certain {IOn}ex vivo{IOff} exposures such as exposure to a well-characterized cell line or exposure across a physical barrier.  In other words, we can't legislate everything.  We need to reserve some judgment for case-by-case considerations.
	Now, in the development of this policy, nonhuman primate material was given special consideration because nonhuman primate material poses a special risk.  But on the other hand, nonhuman primate transplantation, at least for the near future, will not be a large factor quantitatively, because the FDA policy is that there is not sufficient information to assess the risks posed by nonhuman primate xenotransplantation, and that clinical protocols proposing its use should not be submitted to the agency until sufficient scientific information exists addressing the risks.
	As I mentioned, one of the big problems we face is loss of pooled material from the donation from donors who should not have donated.  And this puts plasma derivatives in a special category.  Also, current manufacturing methods are likely to mitigate many of the potential infectious risks for enveloped agents such as retroviruses.  Therefore, withdrawal of plasma derivatives generally is not recommended for donor exposures to animal sources other than nonhuman primates.
	Persons who have received xenotransplantation products should be indefinitely deferred from donating whole blood and blood components, including Source Plasma and Source Leukocytes.  That's, of course, the key central piece of the document, the central recommendation. Persons who are close contacts of xenotransplantation product recipients should be indefinitely deferred from donating whole blood, blood components, including Source Plasma and Source Leukocytes.
	Health care workers, including laboratory personnel and other individuals who have had contact with blood and body fluids from a xenotransplantation product recipient through percutaneous inoculations, such as accidental needle stick or through contact with an open wound, nonintact skin or mucous membranes, should be indefinitely deferred from donating whole blood and blood components, including Source Plasma and Source Leukocytes.
	We are proposing three questions to be added to the questionnaire to determine whether or not a donor should be deferred from donating, and the slide is the first two.  Potential donors should be asked the following three questions:  Have you, you sexual partner, any member of your household or any other close contact ever received a transplant of living cells, tissues or organs from any animal source?
	Second, have you, your sexual partner, any member of your household or any other close contact ever received human body fluids, cells, tissues or organs that came into contact outside of the body with live cells, tissues or organs from an animal?
	Have you ever come into contact with blood or body fluids from a xenotransplantation product recipient through injury, accidental needle stick, an open wound, nonintact skin, and mucous membranes?
	Potential donors answering any of these questions affirmatively -- any of these three questions -- should be indefinitely deferred unless the nature of the exposure to the contact is unlikely to result in the exchange of bodily fluids and the medical director concurs that deferral is not warranted.  So we do reserve space for judgment.
	Deferral for certain {IOn}ex vivo{IOff} exposures such as exposure to a well-characterized cell line or exposure across a physical barrier may not be warranted and will be considered by the FDA on a case-by-case basis.  Again, we try to reserve the potential for informed and professional determination of possible exceptions.
	Whole blood and blood components, including unpooled plasma and Source Leukocytes, intended for transfusion or for further manufacturing into injectable products if made from donations obtained from persons eligible for a deferral under these rules should be withdrawn from distribution and held in quarantine or destroyed.  Again, exceptions for certain {IOn}ex vivo{IOff} exposures, such as exposure to a well-characterized cell line or exposure across a physical barrier, may be considered by the FDA on a case-by-case basis.
	On the other hand, in-date plasma derivatives, including pooled plasma that were made from plasma containing a donation obtained from persons eligible for deferral on the basis of xenotransplantation exposure, should be withdrawn from distribution and quarantined or destroyed only if the xenotransplantation product is from or has been exposed to nonhuman primate cells, tissues or organs.  Again, this is because of the pooling problem threatening to decimate the plasma supply.
	Withdrawal and quarantine may not be warranted for certain {IOn}ex vivo{IOff} exposures, again, such as exposure to well-characterized cell lines or across a physical barrier and, again, will be considered by FDA on a case-by-case basis.  Withdrawal is not recommended for donor exposures to animal sources other than nonhuman primates.
	In conclusion, the FDA considers donations by xenotransplantation recipients and their close contacts to represent a significant theoretical risk to both the safety of the blood supply and its availability.  FDA has tried to develop a deferral withdrawal policy that balances these risks and allows for flexibility in confronting unusual situations.
	Did the committee did a list of the questions that we're going to propose?
	DR. AUCHINCLOSS:  Yes.
	DR. DAYTON:  Then I don't think at this point I need to go through them in deep detail, but I will give you a brief introduction to them for their structure.
	You'll notice that we did not ask questions about definitions, but these are consistent with a Public Health Service document on xenotransplantation which is nearing finalization.
	We also have not put in questions about implementation -- in other words, how to achieved the desired deferral withdrawal criteria.  We feel at this point -- of course, the decision is yours -- that the deferral issues are really what you need to decide here, and withdrawal issues.  And the implementation issues, such as how to achieve this, might be better entertained in front of the Blood Products Advisory Committee.  But of course, that's your decision.  But I wanted you to know why those questions were not included in this group.
	Then the first question is, if you totally agree with everything we've suggested in the document, you can vote yes to number 1, which is, "Does the committee concur with all the donor deferral and withdrawal policies outlined in the draft guidance document?"  In other words, the ones I've recommended.  Life is seldom that simple, though, and if you don't agree with all of them, then you go on to number 2, and that will lead to a series of questions who are highlights from the document and what we think are the key policy issues that need voting on, and you'll be able to vote on each one separately.
	That pretty much concludes my presentation.  Do we have questions?
	DR. AUCHINCLOSS:  Thank you very much.  What we'll be doing now is, there will be some time for some questions from the committee, and then there will be a period of time for comments from the open public hearing, and there are a number of people who have asked for time to speak.  Then I believe we'll probably have a break and then we'll come back for further committee discussion that specifically comes to focus on the questions in front of us.
	Can I start the questioning?  As the definition of xenotransplantation was expanded and in particular to include the {IOn}ex {IOff} {IOn}vivo{IOff} contact, the implication of that expanded definition, did it create a situation in which we found that xenotransplantation, according to that definition, had been occurring in large numbers for years and years?  If so, to what extent is all of this regulation sort of {IOn}ex {IOff} {IOn}post facto{IOff}?
	DR. DAYTON:  I'm not familiar with the actual numbers of {IOn}ex vivo{IOff} treatments.  Is there anybody here who knows the number on that?
	DR. BLOOM:  I can speak to some of that.
	DR. AUCHINCLOSS:  I don't mean to talk about the specific {IOn}ex vivo{IOff} treatment of an individual.  I'm talking about individuals receiving products that were treated {IOn}ex vivo{IOff} and coming in contact with animal cells.
	DR. BLOOM:  Yes, there were some. There were not a large number, and I can't give you the exact number, but there were at least two or so ongoing INDs that we've had to go back to the sponsors and point out to them that, guess what, you are now a xenotransplantation product and we need some information from you.  So there were at least a couple.
	DR. AUCHINCLOSS:  Can you elaborate a little bit on this?  I mean, are we talking about 1,000 patients have already been --
	DR. BLOOM:  No, no.  We're talking patient-wise probably an order of magnitude less than that.  Maybe 100 or so.  They're not -- by and large they have had {IOn}ex vivo{IOff} contact with well-established cell lines, and we'll be discussing some of that later today.
	We haven't gone back and found anything, for example, where we've had {IOn}ex {IOff} {IOn}vivo{IOff} contact with fresh porcine cells or fresh primate cells that had been going on prior to this time.  It has been established cell lines.
	DR. SIEGEL:  It probably should be added that we can't be sure we know the full extent of this practice.  It turns out, as those of you who work in tissue culture probably know, there are certain animal cells lines that are not uncommonly used for coculture.  And periodically we come across information of people using certain animal cell lines maybe not for products under IND at the present time.  We've come across this for example in some of the assisted reproductive technologies where certain animal cells lines are used.
	So I think it would be fair to say that we don't fully know the extent.  But the answer, as you've heard, is more in the order of hundreds than thousands of what we know about.
	DR. SALOMON:  Vaccines?  You mean, vaccine product development?  That's been going on for years and years, animal cells used to make the vaccines.
	DR. SIEGEL:  That's correct.  That does not meet the expanded definition as defined.  Animal cells are used, actually, to make a fairly large number of drugs as well as biologics.  But products that are secreted from or purified from live animal cells, if they do not meet the definition of xenotransplantation, which requires either that the animal cells, tissues or organs be transplanted into the body or with the expansion that human cells, tissues or body fluids be exposed to animal cells and then reinfused.  So surely there is in fact a continuum of risks and of issues.  And one couldn't say there's a clear black-and-white line where one should draw it, but that is where the line currently is drawn.  And as noted by Dr. Dayton, that has followed after a great deal of discussion with this group and many others groups and many public health service agencies.
	I don't think that there's any intent that we say, "Well, we won't worry about risks of things that fall on one side of the line any more than there's an intent to say that everything that falls on the xeno side has the same level of risks."  In fact, that's part of the second topic of discussion.  But in fact, vaccines are not on that side of the line.
	DR. COFFIN:  I'm just a little curious about how the boundaries of this in some ways were determined.  For example, the health care workers dealing with tissues in xenotransplantation products, it seems to be a logical extension of that.  You have almost exactly the same risk in almost anybody that works in a retrovirus laboratory, or probably a large fraction of the people sitting at this table would also have encountered a very similar kind of risk which, although because it wasn't in the context of xenotransplantation but was dealing with cells and tissues that were infected with retroviruses or other agents that are in fact potentially infectious for humans, would be equally at risk.  So why does one draw the line just at whether there is a xenotransplantation word somewhere in the history?
	DR. DAYTON:  Well, it's a very difficult question to answer, and we did not have an easy time answering it, and that issue still could be hashed out.  Part of the worry was that it was getting to be an unwieldy definition, and we were worried we were going to draw in everyone in the universe, and we felt we had to stop somewhere.
	Your point is certainly well taken. In situations like that, we tried to limit it to obvious percutaneous or mucosal membrane exposures, so if there's a lab accident, they should know to defer themselves.  Presumably that's an educable group.
	Other than that, we certainly have to draw the line somewhere, and in many cases it's very debatable exactly where you draw the line.
	So the answer to your question is, I'm not sure I have an answer for your question except what we did, which was wrestle with it and make the decisions based on those criteria, that it just seemed to us that we had to limit the definition somewhere.
	DR. ONIONS:  Thank you.  There are just two comments which are perhaps not totally relevant to the committee, but clearly obviously {IOn}ex vivo{IOff} gene therapy procedures will fall into this definition, or many {IOn}ex vivo{IOff} gene therapy procedures.  That just poses, I think, a problem for regulation on how you divide who controls what, and that's an internal issue for the agency, clearly.
	My main comment, though, was really about, if I understood correctly, that you suggested that for plasma pool products that are purified products, that there was no need to withdraw pools that had material from a nonhuman primate, because the downstream processes would normally activate retroviruses.  I think that was the working assumption.  Is that correct?
	DR. DAYTON:  Well, that was an addendum and sort of a secondary point. Where this leads, of course, is we're dealing with risks that may not be enveloped agents.
	DR. ONIONS:  Exactly.
	DR. DAYTON:  We may not know what they are, and of course I believe that's the basis of your question.
	DR. ONIONS:  Yes.
	DR. DAYTON:  Our thinking along those lines was, first and foremost, it's because it's pooled and because we'll lose a large amount of the plasma supply if we're not careful, and then immediately endanger the public health.  That is the primary point.
	As a secondary, somewhat supporting point, we said, well, at least we know we're getting rid of most of the retroviruses by most of these techniques.
	DR. ONIONS:  I understand.
	DR. DAYTON:  So that it sort of helps out, but it doesn't win the day for the argument.
	DR. ONIONS:  I think that's where it lacks clarity.  I honestly believe that if we're dealing with limited numbers of xenotransplantation cases, and I mean that including your broad definition, there is still the case at the moment for none of those being allowed into the plasma pool.  I really think that at this stage of the game that you really need to exclude them all.
	I think Prem Paul and I have argued in the past that although we get involved in detailed discussions about retroviral risk, it's quite likely that one of the significant risks may be something completely different. It could be a parvovirus that could easily go through some of the fractionation procedures.
	So I really feel at this stage that you need to have a blanket policy.  It's easier to enforce, for a start.  It's clear. And at this stage, it shouldn't jeopardize the size of the pools.
	DR. DAYTON:  We certainly understand that line of thinking, and it's certainly very valid.  However, what was it, 14 cases of CJD almost shut down what percent of the plasma supply?  I mean, you have a very serious -- and there, you have immediate known and real risk.
	This is always a problem in the blood regulation, in that we're always stuck having to balance these two competing factors, and that's where the policy came from.
	DR. ONIONS:  I'm well that the issue that CJD has had here, obviously, in terms of the impact on plasma products, particularly gamma globulin.  But there, you've got a rather different situation, where this is {IOn}post hoc{IOff} where somebody is diagnosed as having CJD and you have to retrospectively go back to the plasma pool.
	I mean, what I really think you need here -- we're not discussing implementation, but one of the clear things is, you need a very tight policy on how you do implement this deferral of donation.  I mean, that seems to be where the effort has to be, and that, provided you have clear guidelines it should be relatively easy to keep those plasmas from every into the pool. So you're not going to have this situation of going back all the time and withdrawing pools later.
	DR. DAYTON:  Well, we would like it to be that way.  But we know that the system, no matter how tight we make it, just doesn't work that well, and people do get through, and they get through for HIV testing and exposure to HIV.  So we know that the system is not totally enforceable.
	If I could go back to John's comment, by the way, the extension of this policy to workers in a retroviral lab is not that different than extending it to slaughterhouse workers.  Again, where do you draw the line?  So I'll play the same trick on you.  I'll draw the line one past you in this.
	DR. VANDERPOOL:  I have a question about our making our judgment about this without thinking about implementation and another group implementing on the basis of our judgment.  It seems to me we're got to go back and forth with that.
	I couldn't approve of several of these without some awareness of what the implementation procedures are.  I would hate for the implementation group to think that the wording as approved would be a kind of written-in-stone set of rules that they would have to try to implement in a rather hard and fast way.  I doubt that that would occur. But still, I think we have to talk a little bit about implementation and maybe go back and forth with it, because I'm not sure we can decide all these issues this time. That's my first point.
	The next point is, I'm curious about why did you expand close contacts the way you did.  What do you have in mind there? Do you have in mind really sexual partners and maybe moms and dads who lick thermometers and put it in their children's mouths?  Or what kinds of specifics do you have in mind with close contact?  It seems to me the net is thrown awfully wide just as a phrase, "close contact," which means {IOn}ipso facto{IOff} household members -- you know, a grandmother who's living there, an aunt who happens to live in the house.  It's household members who share bodily fluids, but that itself is conceptually porous.
	DR. DAYTON:  If I can answer this question.  Absolutely.  We understand exactly what you're saying, and we agree with it.
	Again, our biggest problem is, we're dealing with the unknown.  For something like a retrovirus, you might be able to limit it to sexual contacts.  But then what if it's tuberculosis or something? You just don't know.  And we were always stuck in having to draw the line somewhere.
	So there was another consideration too, and this gets into an implementation issue.  If we try to really accurately define close contacts to the {IOn}n{IOff}th degree, you get into this humongous question, well, did you share a toothbrush?  Well, what about razor blades?  Did you use safe sex practices?  Was it in the last year?  You can get into this incredible problem of actually determining what really happened, and it's almost a Heisenberg uncertainty principle when you get that complicated.
	So I guess, then, I'm answering your question with affirming your first point, that we really can't consider this without also considering implementation issues.
	But that was our thinking in terms of close contact.  We don't know what it is. It may be nosocomial transmission, it may be just bodily fluids.  We don't know.  Also, the questionnaire design, the design of the questions was easier to handle if we kept it the way it was, as opposed to trying to nail it down at every possible type of exposure.
	We know perfectly well that we've still left some ambiguity.  We don't know what you can do to get rid of all ambiguity.
	Now, with respect to your first point about implementation, basically we have three methods for achieving donor deferral in this context.  One, in this context, is education of the xenotransplant recipient. That actually should be very effective, because the xenotransplant recipient goes through a whole workup and has a close contact with the physician.  He signs documents that it says, you know, he's been told all this works.  Included in that is you shouldn't donate blood and tissue, et cetera. So he is well educated.
	Also, xenotransplant recipients are generally medically deferred for all of the procedures they're undergoing, and so they're not too much of a problem, although they're obvious deferral cases.
	Getting to the close contacts is a different story, because they're not going to have gone through this education process.  So that leaves us two more methods to get to them.  One would be educational material distributed to them or made available to them that they can read before they decide to give blood.  In theory, that's a very nice way of doing it.  In practice, we are very worried about how well that would actually be implemented in a tough, or I should say, a very hectic blood-donor situation.  Even the people with the best of intentions of donating and even with the people with the best intentions of collecting the donations, it would be considered a high probability that that kind of educational material may let a lot of stuff leak through.
	Which leaves us with the third weapon in our armament, which is the actual donor deferral questionnaire.  There is where we put in the specific questions that we would like to put in, the specific questions that we recommended.  Now, that again would seem like a wonderful tool, but there are problems with putting things in the donor questionnaire as well.  The donor questionnaire is very complicated.  It's very long.  It's hard for me to understand.  And I'm quite sure that most lay donors don't fully understand all of the questions.  It's very difficult to deal with.  But still, it's quite effective in achieving deferral, but we know that it's not perfect.
	So those are basically the choices that we have.  Other than that short description, I'm not sure what else I can tell you about implementation that will help you make a decision.
	Jay?
	DR. SIEGEL:  Could I have just response to what you say, which is very helpful?  I think implementation issues are {IOn}ipso facto{IOff} involved in the three questions we're supposed to think about.  I can imagine the great majority of people saying instead of -- if they say "yes" then you've got the information you want.  But it seems to me, short of rather extensive education, the great majority of people are going to say "I have no idea."
	DR. DAYTON:  Well, you've focused on exactly the problems in all of those issues.
	DR. AUCHINCLOSS:  Dr. Kaslow, you had a comment you wanted to make?
	DR. KASLOW:  Well, you may have answered the question mostly.  I was concerned too about why you included household members as well as other individuals who would have had close contact. And you explained the potential alternative possibilities of risk.  But then it raises the question of what's a household member. Are you going to use the census definition, and is a maid who lived in a household at some point in the distant past really considered a household member?  Do you have to track her down?
	I think you started to address that issue, but that implementation then becomes the real major concern.
	DR. AUCHINCLOSS:  Dr. Epstein?
	DR. EPSTEIN:  First I just want to make a couple of general comments.  I think it's obvious to everyone that blood issues are a subject of major public concern that in the wake of the AIDS era, sensitivity over safety has been acute.  But the public is also concerned reasonably about availability, and so there's always this need to strike a balance.
	We operate since July '95 under a principle that's been called the precautionary principle that was outlined to us in a report from the Institutes of Medicine, which examined decision-making in the AIDS era and basically said, don't want for all the answers; if you think there's a risk and you think you can address it without causing major harm, you should do this.
	This led us to some very highly precautionary policies, such as to address the theoretical possibility of transmission of CJD, which have had, I would say, some unintended effects affecting derivative supply and also whole blood supply.  I think that the lesson here is that the blood system is in fact very highly complex, and that although we can sometimes articulate a simple scientific principle and implementation goal, the fact of the matter is that when we try to do something in the real world with the blood system, we have often unintended effects because of the complexity.
	With respect to that particular risk of transmission of zoonoses, of course, we all owe a debt to the subcommittee for raising the issue in December '97 and charting a course, if you will, a vision of how we might address this theoretical risk.
	We need to understand that the guidance document that has been crafted is, first of all, a straw man.  It's for comment. It's not yet for implementation.  And it was drawn stringently, and the reason is because it is easier to put forward for public discussion a stringent policy and then discuss how it might be moderated than to put in the public eye a moderate policy and then try to strengthen it without further discussion.  So we welcome the concept that we may have been too strict in some areas, and the whole idea is a judicious moderation to try to balance all these factors.
	Lastly, I'd like to comment that it needs to be recognized that human exposure to animals and animal tissues is far from new; that of course we have had wide exposure from abattoir, animal care workers, farmers and abattoirs throughout history.  Beyond that, we have many animal-derived products, including blood products, which have not presented themselves as significant individual or public health threats, and these include such things as porcine-derived factor 8 and insulin, bovine thrombin, bovine Heparin, bovine surfactant.  There is some investigational immune globulins made from goats and sheep, as well as particular tissues like heart valves, fascia, et cetera -- your pericardium that have been implanted in humans for decades.
	However, the novel feature introduced by xenotransplantation is the intimate exposure of the human host to a living animal cell, and often in the context of immunosuppression.  I think it is that fact or set of facts that has heightened concern, and rightly so.  The problem, though, is that as one tries to figure out where the boundary lies, it starts to diffuse over to areas that start to look similar to things that we've done many, many times in the past, such as making vaccines in cell lines, or such as having exposure to products derived subsequent to contact with an animal cell.
	To my way of thinking, that's really a very gray area, and it does need a critical focus.  But once again, what we've done is, we've put in front of you the more stringent view of the problem, trying to encompass all the possible {IOn}ex vivo{IOff} as well as {IOn}in vivo{IOff} exposures, and we do welcome thinking how one could judiciously moderate the policy in a practical way.
	As far as the comments by Dr. Vanderpool, I'm very sympathetic that it would be quite arbitrary to try to separate implementation issues from a policy recommendation {IOn}per se{IOff}.  I agree.  However, in putting forward that notion, what we really have in mind is this.  We have different ways in which we communicate with the donor.  It's possible that this committee could establish the boundary of concerns that we're trying to address and leave for either another committee or another day the question of how best to try to get those messages to the donor.  That's really what we were trying to say.
	So for instance, one could decide that we don't have to have uniform exclusion of household members outside of some further evidence of an intimate contact.  That would then be a policy decision.  Whether we communicate that to a donor with a direct question about that intimate exposure or we do it in educational material or we do it through attempts to educate the recipient partners can be separated logically from the intent of the policy.  But I agree that that's a difficult dance, and I don't have a preconceived view.  But we've tried to assist the committee by having Blood Product Advisory Committee members here today so that we could make the possible progress.
	Thank you.
	DR. AUCHINCLOSS:  Thank you. Dr. Kagan?
	DR. KAGAN:  Yes.  I have one brief question.
	What is FDA's position on frozen porcine skin, which has been long used in management of burn patients, some of whom are innately immunosuppressed from extensive injury, or more often it's used in patients probably with more minor injuries?  I wasn't sure on the living issue which side of the line porcine skin would fall under.
	DR. DAYTON:  I'm not sure I know the answer to that.  Do either of you know what frozen porcine --
	DR. BLOOM:  Well, we have some CDRH representatives sitting behind us, Dr. Peter Hudson and Dr. Chekter (?).  The frozen skin, my understanding is that it's not viable. It's not alive.  Therefore, it would not be considered for these purposes a xenotransplantation product.
	Jay Siegel will speak more to a point, but we need to correct a misstatement that I made earlier in response to Dr. Auchincloss's question about the number of patients that are out there that had had {IOn}ex vivo{IOff} contact.  I wasn't considering a very large class that you'll hear about.
	DR. SIEGEL:  As you know from your briefing materials, there's 550 patients who have received Epicel, and I wanted to put those numbers in context about the implementations because, yes, this is nascent, and we would expect -- aside from the fact that there may be numbers we don't know of, we would expect the numbers of people exposed to increase.
	But even at these numbers, if we're talking in the neighborhood of 700 patients total with assumptions that they might have, say, a couple of adult contacts, you're talking about 2,000 people.  I don't have good census figures for adult Americans, but that may represent about -- if there's 120 million adult Americans, 2,000 would represent 1 in 60,000 adult Americans.
	Deferring them from donating would not have a huge effect on the number of available donors.  But 60,000 also happens to be a typical number for the number of donors in a plasma pool.  So it is not unlikely that a plasma pool might have -- factors like somebody's who's received this product more or less likely to donate, and what about their close contacts.  But it's not unlikely that a plasma pool would have a donor who has received one of the products under study or a close contact, as defined, of that donor.  We couldn't get too precise, but it would certainly not be a rare occurrence.
	I think one of the concerns we have to face if we defer is that if those donors are deferred, and then one subsequently comes forward and says "When I filled out the questionnaire, I didn't realize it, but I have this close contact and I should have been deferred," that gets then into the questions of quarantine or destruction.  And those are not unlikely occurrences either, even at the current level of use of xenotransplantation.
	DR. AUCHINCLOSS:  I want to go further with this question of scope.  So now we're up to some 2,000 patients have already had xenotransplants?
	DR. EPSTEIN:  No.
	DR. AUCHINCLOSS:  750.
	DR. EPSTEIN:  No, I'm saying the 550 plus the 100 Eda talked about.  But we're talking about close contacts -- deferring close contacts as well.  So that's just a very wild guess of where we might be, order of magnitude.
	DR. AUCHINCLOSS:  My guess is, it may even be an order of magnitude short of where the actual exposure is with the broad definition.  I don't know that, but I suspect the numbers are higher than we have yet realized.
	My question then is, the next part is, over what period of time do you think this exposure has been occurring, a decade?
	DR. EPSTEIN:  I think the folks from CDRJ know better.  The Epicel exposures, I think, are occurring about 100 patients per year and it's been going over a 5- to 10-year range, roughly.  Is that -- I'm sorry?
	DR. GOODMAN:  1987.
	DR. EPSTEIN:  Since '87.
	DR. AUCHINCLOSS:  So then one of my questions becomes, at what point does the fact of having allowed donation to occur over a decade of people who fall into this category without having seen an ill effect, and this is much a question for my committee members:  At what point does that become reassuring enough to tell you that the policy is more stringent than it needs to be?
	DR. EPSTEIN:  Right.  And I guess I would add to that, that might tell you about risks of this particular product, obviously. I think we'd all concur that it may not be applicable to risks of, for example, live nonhuman primate organ.
	DR. AUCHINCLOSS:  I think that's a very important point.  I think we're mostly talking, with these whatever number of patients' well-characterized cell lines, is the exposure {IOn}ex vivo{IOff} that we're really talking about.  Is that a fair statement?
	I had another question there for Dr. Onions.  I just wanted a clarification. You made the blanket statement that all gene therapy would now fall under the category of xenotransplantation regulation.  Can you elaborate a little bit more on that?
	DR. ONIONS:  No, I'm sorry, Chairman.  I'll try to correct it.
	I said certain {IOn}ex vivo{IOff} procedures would fall into this definition where people, for instance, use retroviral packaging lines, and even if they have a semipermeable membrane between the packaging line and the cells that they're trying to transduce, that, as I understand it, would now fall under that definition.
	In fact, that's where I think some of the problems might arise, is if you coculture cells with a semipermeable membrane, under your definition, that now covers xenotransplantation.  But presumably if you take that material off and you then filter it and clarify it in some way, that doesn't.
	So you're into these sort of -- these are the sorts of gray areas that I think are going to be the problem ones.  But certainly certain {IOn}ex vivo{IOff} gene therapy procedures fall under this new definition.
	DR. NOGUCHI:  Well, I would say that at least to our current understanding, the gene therapies in the United States, we do not allow coculture of {IOn}ex vivo{IOff} between dissimilar species.  There has been a xenotransplant in an equivalent of a xenotransplantation type for the injection of live retrovirally transduced mouse cell lines, yes.
	DR. ONIONS:  That was an interesting one, because that actually was at the back of my mind.  Because in the United Kingdom, if I remember correctly -- I could be wrong, but I think that was actually referred to the U.K. Zero Committee, because it was viewed as a xenotransplantation as well as a gene therapy procedure.
	DR. NOGUCHI:  I believe that's correct.  I believe that's right.
	DR. AUCHINCLOSS:  Dr. Coffin?
	DR. SIEGEL:  The administrative concerns you alluded to are not too big a problem in the United States as you're looking at the same people, whether it's xeno or gene therapy.
	DR. ONIONS:  Sure.  That's fine.
	DR. COFFIN:  I'd like just a little bit of clarification regarding David's earlier point on plasma products.  Plasma products in fact have been shown to transmit HIV.  Is it part of the logic of that that all plasma products are now treated in such a way as to remove HIV and therefore are likely to remove all other retroviruses as well? Was that in the thinking for the way you framed that?
	DR. DAYTON:  Well, as I said, it was sort of a minor backdrop, an adjunctive point, and the real point was the risks of impairment of the plasma supply.  Many of the procedures do inactivate HIV.  I'm not sure which products still have procedures which allow HIV.
	DR. COFFIN:  It's not an automatic assumption, though, because clearly, it's not trivially assumable that retroviruses are inactivated in the course of preparation of any plasma product.
	DR. DAYTON:  No.
	DR. AUCHINCLOSS:  I'm sorry, did you have a --
	DR. COFFIN:  I was hoping Dr. Epstein could answer the end of the question, though.
	DR. EPSTEIN:  Yes.  All of the plasma derivatives have been validated for inactivation of HIV.  The procedures that are in place are in most cases either heating procedures or extraction with solvent-detergent mixtures, which are thought to be highly effective generally for enveloped agents.  We do know that they are effective for, in particular, the major transfusion-transmitted in infections: Hepatitis C, hepatitis B, and HIV.
	But we do know that there are agents that can escape those procedures, particularly agents like hepatitis A and parvoviruses.
	DR. AUCHINCLOSS:  Dr. Vanderpool?
	DR. VANDERPOOL:  I am very pleased that the FDA took the suggestion of the committee in December of '97 as seriously as we made it at the time.  My concern is in part historical, and that is at that time, we were most concerned about infectivity, particularly the new articles that were showing PERV {IOn}in vivo.{IOff}  Since that time, we've had a number of reassuring articles that PERV is not as worrisome as it first appeared, the latest of which were sent to us, if we didn't already see it, in {IOn}Science{IOff}.
	Does that assurance that we are receiving from PERV studies have an impact on this document?  I mean, I think at the same time we realize through some of Jonathan Allan's work and others that we know that nonhuman primates are fraught with all kinds of viral and bacteriological concerns.  But is the committee at this time with its knowledge now of less worrisome concerns over PERV wanting to take the same stand that would end up being expressed in the form of this guidance for industry?
	I may try to be more direct.  Are we as concerned as we were in December of '97 about these issues?  Are we as concerned now as we were then?  If not, does that have an impact on the reach and specificity of this document?
	DR. AUCHINCLOSS:  Go ahead.
	DR. PAUL:  I guess I'm still as concerned about other viruses.  I was never concerned a great deal about PERV, and I have been on record.  But I think there are some additions.  It seems like swine virologists keep on coming with new viruses; just in the last few years, arteriovirus, circovirus, hepatitis E virus, and more recently gamma herpesvirus.  We just don't know what else is out there, because this area has not been extensively studied.  If we don't look for some of these new agents, we don't really know the risk.
	Some of these viruses which we initially thought only viraemia was only 1 week or 2 weeks.  Now we are finding out, like, arteriovirus for at least 3 months if not 6 months, and also viruses shed in semen, and there is just an enormous amount of information that is coming out.  The same thing with circovirus; it's shed in urine and other body fluids.
	So I think that I am just as concerned as I was in '97, and I'm really concerned about the restriction exclusion is only to the nonhuman primate, not the other animal sources.
	I would also respectfully disagree with Dr. Epstein that these guidelines are very stringent.  I think they are not.
	DR. AUCHINCLOSS:  Can I ask you just to elaborate a little bit on the unknown and newly discovered viruses of the pig that might be of concern to us?  I guess everybody recognizes that in xenotransplantation, there may be a risk to the individual recipient that is very small but finite, and could even be very damaging.  But that risk, we can recognize and deal with relative to a benefit.
	The issue for us at this committee and the FDA is, what is the risk to the population at large?  What is the possibility for transmission in an uncontrolled way of a brand new virus that would not occur without xenotransplantation occurring?
	So just because new pig viruses are discovered each day doesn't necessarily tell me that we're embarking on a huge, risky thing.
	DR. PAUL:  I think many of these viruses, or at least some of them, there is a high mutation rate, and especially if they are present in tissue that are being transplanted.  In an immunosuppressed patient, there is a high degree of potential that they may get adapted in people and then become a public health risk.
	DR. AUCHINCLOSS:  Dr. Onions?
	DR. ONIONS:  I'm just going to comment on Colin Parish's data from Cornell, who has done really elegant work on the transmission of what was cat parvovirus to dogs, and that caused a world epidemic that around the world initially in the space between 6 months and a year and killed probably proportionately about 10 percent of the dog population, domestic dog population as puppies.  That virus spread very rapidly. It involved three immuno changes in its first series of changes from the cat virus to the dog virus.  And yet --
	DR. AUCHINCLOSS:  As a result of xenotransplantation?
	DR. ONIONS:  No, no.  This is just a natural transmission.
	DR. AUCHINCLOSS:  That's my point, that this event could occur -- zoonoses could occur -- but the question is will they occur -- well, I guess zoonoses we're defining as occurring as a result of xenotransplantation.
	DR. ONIONS:  I think the background is a kind of stranger probability.  It was really to reinforce Prem's point, that the viruses that you should consider in a blood transmission are the ones that are resistant, and parvoviruses fall into that.  The porcine parvovirus is very similar to the feline and the canine and can change hosts.  For instance, can infect mink cells, and you can actually get it to infect human cells if you try.
	So that virus is potentially a virus of concern, and that if you started to transmit that through a blood supply, I would be very, very concerned.  That's why I think this blanket assumption that the only thing of concern in blood transmission is the retrovirus, I agree with Prem, I think is a mistaken one, and that you should really be cautious about these other viruses that if got into the blood supply could potentially be very serious.
	DR. AUCHINCLOSS:  Then why isn't the farmer the most risky blood donor?  I don't understand.
	DR. ONIONS:  Well, I was actually going to make the point that the data that's come from the CDC -- I mean, I wouldn't take a blood donation from me, because I eat British beef.  But on the other hand, I wouldn't take a blood donation from Jonathan Allan, because he works with primates.
	I think the word from the CDC, for instance, of ÄÄÄÄ virus as being present in animal workers is of real concern.  Maybe if you're widening the discussion, which is perhaps not for this committee, but if you're widening the discussion about blood deferrals, I would actually be concerned about people who work with primates being regular blood donors.  I don't think that's something that should happen.
	DR. AUCHINCLOSS:  I promised John Coffin we'll come back.
	DR. COFFIN:  In the same line though, however, one has to consider that the agents that are of concern here have to have a very special set of properties.  They have to be transmissible both by some kind of close contact and by blood.  They have to establish a persistent viraemia, not just a transient one.  They have to be pathogenic, but they have to have a long latency, because if they're rapidly pathogenic, they'll be apparent right away.  There's a long list of properties that I think lowers the probability.
	Clearly, there are some agents that have had those properties, HIV being one of them.  But the probability that any agent happens to have that set of properties, I think, is fairly small, and I think we should keep that in mind.
	DR. AUCHINCLOSS:  Jonathan?
	DR. ALLAN:  Yes.  I just wanted to reiterate, since I've been sort of outspoken about these in nonhuman primate tissues and cells, and I see that this excluding nonhuman primates -- at the same time, as Prem mentioned and other people have mentioned, I don't know that you want to make that distinction when you're talking about plasma derivatives or others because of what Prem has said, and others, that you have other potential viruses and pathogens that you may have recognized or not even yet recognized. And to make that distinction in some sense becomes a bit arbitrary, because these are animal pathogens that could be potential zoonoses in humans.
	So I would weigh in on the fact that if you're gong to make a decision to limit plasma derivatives, that you need to do it for not just nonhuman primates, but for other species as well.
	DR. AUCHINCLOSS:  Dr. Onions, one more comment, then I want to bring our public in.
	DR. ONIONS:  Yes, very briefly. John Coffin, of course, is precisely correct. We're dealing with very improbable events.
	I think the only concern is that improbable events do occur, because we always look at snapshots of history, that we look at what's happened in the last 20, 30 years, and I would again caution.  I think the new CJD example is one where, again, a group of people sat around and we would have all argued that this agent is not transmissible from cattle to people.  And yet clearly it has been transmitted from cattle to people. So caution is always required.
	DR. AUCHINCLOSS:  Thank you very much.  Now I would like to open the public hearing, because I know there are some people in the audience who want to provide their comments.  And the first on the schedule is Ms. Kay Gregory from the American Association of Blood Banks.
	If you could state your affiliation and any conflicts or potential conflicts, that would be helpful.
	MS. GREGORY:  Good morning.  I'm here representing the American Association of Blood Banks, and in particular their transfusion/transmitted diseases committee.
	The American Association of Blood Banks is a professional society for over 9,000 individuals involved in blood banking and transfusion medicine and represents roughly 2,200 institutional members, including community and Red Cross collection centers, hospital-based blood banks and transfusion services, as they collect, process, distribute, and transfuse blood and blood components and hematopoietic stem cells.
	Our members are responsible for virtually all of the blood collected and more than 80 percent of the blood transfused in this country.  For over 50 years, the AABB's highest priority has been to maintain and enhance both the safety and the availability of the nation's blood supply.  The association operates a wide array of programs to meet the safety and availability priority and is proud to have played a key role in ensuring that the nation's blood is safer today than ever before.
	The AABB appreciates this opportunity to comment on the draft guidance document addressing the potential deferral of donors due to precautionary measures to reduce the possible risk of transmission of zoonoses by blood and blood products from xenotransplantation product recipients and their contacts.
	Xenotransplantation is an exciting emerging technology that holds future promise for ameliorating the shortage of donor tissues for the treatment of serious disabling diseases.  Recognizing the important potential risk of transmitting zoonotic pathogens to patients by this route, we agree that xenotransplant recipients are unacceptable donors of allogeneic blood and tissue.  Parenthetically, because of donor restrictions regarding medication use and general health, virtually no transplant recipient would be a qualified donor anyway.
	The theoretical risk was well articulated in the August 1996 draft Public Health Service guidelines on infectious disease issues in xenotransplants, which states, "Consent forms should state clearly that xenograft recipients should never subsequent to receiving a transplant donate whole blood, blood components, Source Plasma, Source Leukocytes, tissues, breast milk, ova, sperm, or any other body parts for use in humans."  The language appropriately recognizes the primary responsibility of the transplant community for the apprisal of their patients about zoonotic risk.
	We believe strongly that this aspect of the guidance should be implemented. Even pending formal implementation of the guidance, FDA could insist on inclusion of such information in consent procedures as a condition for acceptance of clinical protocols for xenotransplantation.
	The FDA can also require that all current surviving xenotransplant recipients be contacted to assure that they understand that they must not donate blood or tissue. Blood collection facilities can reinforce the prohibition on donation by including the xenotransplant exclusion in the written materials that blood donors are required to study prior to each donation.  This avoids addition of time-consuming, confusing, and unvalidated questions for the donor interview.
	That said, several aspects of the draft guidance are problematic.  Donor screening is already lengthy and complex.  We have provided the committee members with a copy of the most recent AABB uniform donor history questionnaire, which has been reviewed and sanctioned by the FDA, and it contains 32 separate elements, including inquiries into highly sensitive personal areas of sexual activity and drug use, and reference to such rare diseases as babesiosis and the TSEs.
	The FDA proposes to add three more complex questions to this process.  REDS investigators have reported that 1.8 percent of anonymously surveyed accepted blood donors admit to deferrable risk.  And we suspect that a substantial proportion of that is due to the length and complexity of the donor interview.
	The proposed donor questions in this draft guidance are far too arcane to add to the current screening process and will produce donor confusion.  In fact, the individuals that I asked to review these questions unanimously agreed that they had trouble understanding them, let alone expecting the normal donor to understand them.
	This will result in unneeded deferrals at a time of borderline blood supply adequacy and declining donations.  At a minimum, additional questions proposed by FDA for the reduction of deminimis risk must be validated for sensitivity, specificity, and positive predictive value before being added to what is already referred to as the donor interrogation process.  Further antagonism of the altruistic blood donor is unwarranted by current data.
	A related concern is that increasing the complexity of the donor-screening process for marginal theoretical risk may detract from an efficacy for documented risk, like traditional viral transfusion-associated infections and malaria.  The result is then a paradoxical decrease in transfusion safety.
	The requirement to defer as blood donors sexual partners, any member of your household or any other close contact is ambiguous, lacking a concise definition of "household" and "other close contact."  More important, this requirement for deferral is unsupported by any evidence of transmission of potential or unrecognized pathogens to such contacts after xenotransplantation. It's a slippery slope from such donor deferrals to disqualification of large populations with significant occupational animal exposures such as abattoir workers, farmers, veterinarians, and medical researchers working with large animal models.
	We suggest that a risk assessment be undertaken among those with close contact to the relevant species for evidence of transfusable disease associations that would support zoonotic transmission of disease-causing organisms.  Given the small numbers of xenotransplants currently being performed and the potentially large population with contact to nonhuman primates and swine, these epidemiological studies can be carried out long before xenotransplantation becomes prevalent.
	In summary, we accept the necessity to defer recipients of xenotransplants, but respectfully suggest that the transplant programs have primary responsibility to initiate this process as part of the consent process.  Blood-collection facilities can reinforce this with written information.
	We suggest that the addition of unvalidated donor interrogation questions for the theoretical risk of xenotransplantation may at worst paradoxically increase other risk of transfusion, and at best will contract further an already shrinking donor base.  Deferral for contact with xenotransplant recipients is unwarranted at present, and the risk of such contact is amenable to study in populations with occupational exposure to the relevant species.
	Thank you.
	DR. AUCHINCLOSS:  Thank you very much.  Can I ask Mr. Chris Healey, if Mr. Chris Healey is here?  I appreciate your staying within time constraints.
	DR. HEALEY:  Good morning.  My name is Chris Healey and I'm the senior director of government affairs for ABRA.
	ABRA is the standard-setting organization and trade association for the Source Plasma collection industry.  We provide roughly 60 percent of the world's supply of plasma that's manufactured into a variety of life-saving drugs and medicines. We're also committed to ensuring the continued safety and adequacy of that supply.
	Like AABB, we agree that xenotransplantation recipients should not be blood or plasma donors.  However, we don't support the questions as currently written in the FDA draft guidance, and we don't believe that look-back10 and product quarantine are warranted under these circumstances.
	Turning briefly to the questions, we believe that they are too long and somewhat convoluted.  Instead of having their intended effect, we think they're likely only to alarm and confuse donors.  Furthermore, we believe that these potential donors, xenotransplantation recipients, are likely already covered and deferred by the current screening requirements.
	Plasma centers, like blood centers, routinely ask donors whether they are under a doctor's care, whether they have had any recent surgery, or whether they have received any tissue or organ transplants.  We think that this is effective to meet the risk that this committee has identified to help defer these individuals who have xenotransplantations or may be at risk for zoonotic infections.
	Furthermore, FDA already has safeguards in place through the informed consent process.  As you all know I'm sure, xenotransplantation takes place under FDA-approved clinical protocols.  And based on the transcript of this committee last meeting, back in 1997, I understand that the informed consent process specifically requires that recipients be counseled never to become blood or plasma donors.  Again, we think that this is adequate to the risk.
	If the committee does feel compelled to take some additional steps or some additional action to meet this risk that's been identified, we think that information distributed through a card such as Kay Gregory identified or another information circular at the donation process would also be adequate.
	Turning to the look-back requirements, we also think that this is unwarranted at present.  We think that the clinical protocols that are required for xenotransplantation require health monitoring and close tracking of xenotransplantation recipients, and we'd offer that we think that that sort of monitoring would be adequate to identify people who develop infections, and that there's adequate traceability through the plasma pools and through blood donations, so that that health monitoring again is an adequate surrogate for the look-back process.
	Furthermore, as we've heard, there are relatively few recipients, and the risk is theoretical.  In addition, FDA has a national registry to monitor the number of xenotransplantation recipients.  As we've heard a number of times, we think that as the number of xenotransplantation recipients grows, this registry could be used to monitor and track that, and as I say, as the number grows, that the need for revising for the guidance could be assessed, so that as it becomes a more prevalent practice within the health care industry, the guidance could be revised or addressed as needed and appropriate.  Finally, all plasma derivatives, as was noted, undergo robust viral inactivation procedures.
	So in conclusion, we don't believe that a product look-back or quarantine is warranted at this time.  We don't believe the questions as written are appropriate or helpful for the donation process.  And we think that an information circular or some other surrogate would be adequate.
	Thank you.
	DR. AUCHINCLOSS:  Thank you very much.  I'd next like to call Dr. Becky Haley from the American Red Cross.
	DR. HALEY:  The American Red Cross is pleased to have this invitation to speak regarding the FDA's recommendation for the prevention of the transmission of zoonotic pathogens from xenotransplantation recipients through blood transfusions.
	The American Red Cross collects over 6 million units of blood from volunteers each year in the United States.  I'm Rebecca Haley, senior medical officer for the biomedical headquarters, responsible for the medical aspects of donor qualification.
	The ARC agrees that the deferral policy for xenotransplantation is appropriate.  We understand that there is a theoretical risk of disease transmission from recipients of xenotransplants if they should become blood donors in the post-transplant period.  Facilities performing xenotransplants are guided by draft Public Health Service guidance that was mentioned by Ms. Gregory earlier on the infectious disease issues in xenotransplantation in 1996 to include in their consent forms for patients that they should no longer be blood donors. The current proposed questions assume that this guidance has not been followed.
	In addition, we're very concerned that the guidance in its current form needs considerable clarification and revision before it would be workable for the blood collection facilities.  The guidance is quite expansive and includes a number of groups of the deferred-donor category.
	ARC believes that only donors who need to be deferred are the ones receiving the transplantation itself.  Dr. Dayton, we suggest that the line be drawn here.  We do not believe there's justification of other donors such as those in the same household, those with close contact with xenotransplantation recipients, and that's because we haven't seen any evidence that these people need to be deferred.  The recipient is iatrogenically compromised as an element of the treatment necessary for the patient to tolerate the graft.  This treatment puts the recipient at risk for such infections.  To date, there have not been spread reports of spread of zoonoses to close contacts or family members.
	Additional questions, we believe, also are unnecessary.  We'll get to Dr. Epstein's point that implementation has to happen, and it has to happen at the places where the blood is donated, and if this cannot be managed, then no policy can be effective.  We have to ask the donor the question if he or she has received a blood transfusion or an organ or tissue transplantation.  We can include the information in what-you-must-know section that donors must read before they give blood to point out that organ xenotransplants are inappropriate, and it could also include a xenotransplantation tissue precaution as well.  If the donor answers affirmatively, the health historian can ask additional questions separate from the questionnaire about their transplantation experience and whether it involves animal tissue.
	With long experience, we have found that with the donor questionnaire, as it gets longer, it takes more times for the donor to go through the questioning process for them to recognize questions closer to the bottom of the page, because as they begin to memorize the questions at the top of the page, it may be the eighth or the tenth time that they've been through the donor questionnaire before they actually hear the ones after some very complicated sort of turn-off questions are asked.
	The terms used to define which types of transplantations and/or exposures are vague, and better definitions are needed as well as more examples.  The deferral policies are based on criteria discussed in the guidance.  Yet the criteria are neither defined or are vaguely defined, and these include such concepts as xenotransplantation of living versus nonliving cells.  There's already been a discussion in this committee as well:  Is this in or is that out?  You can imagine how this discussion would go on at our blood-donation sites.
	Without clear definitions, collection staff will not be able to assist the donors that answer affirmatively.  Thus deferral policies are not quite clear for those receiving organ or tissue transplants not listed as one of the guidance examples. Actually, the organ is pretty clear.  Some of the tissues, as to whether living or nonliving or whether they've had contact would be less clear.
	We also need a better definition for {IOn}in vivo{IOff} versus {IOn}ex vivo{IOff} exposure, particularly as it may apply to potential blood donors as laboratory personnel. Similarly, this concern applies to animal workers, veterinarians, veterinary staff, zoo workers, and others who may come in contact with animals, alive or very freshly killed, such as farmers or meat slaughtering and packing staff.  This could disqualify a very significant percentage of the donor population.
	The majority of the public is not familiar with xenotransplantation or disease transmission by this route.  Thus there's likely to be a significant amount of confusion at the donor-collection sites and a lack of consistency in implementation.  The suggested questions talk about medical situations that are unfamiliar to most Americans, and if such a line of questioning is pursued, the potential donor, does not what you're talking about connote an "I don't know" answer suffice for "no"?  Because if you say "Have you had a xenotransplant" and they say "What's that?  Maybe I have and maybe I haven't," that seems rather unfair to the poor donor.
	In Section 3-A-5, you allow discretion on part of the medical director to permit donation if the nature of the exposure of he contact is unlikely to result in the exchange of bodily fluids and the medical director concurs that the deferral is not warranted.  Well, we tell our medical directors to accept donors on evidence of risk, and I think the evidence of risk for contacts of these kinds is not very much in evidence.
	The donors themselves also demand to know why was I deferred, why am I not allowed to give blood?  And we spend a great deal of time communicating with our donors about problems that they have with our deferral policies.  I can see a lot of those looming on the horizon if this is implemented.
	These questions engender an adversarial tone in the donor interview that discourages the donors from returning.  As we discuss these matters, most of the United States is on appeal for blood donors, and elective surgeries are being cancelled.  The potential harm for a lack of blood donors is very real, and has often been highlighted by the secretary of health and human services, Dr. David Satcher, as a serious concern for medicine in the United States and our concern today.
	In the case of plasma derivatives, there's a great deal of discussion that has already gone on, and we think that the manufacturing methods are likely to mitigate many of the potential infectious risks, not all.  Unfortunately, we can never rid of all the risks, particularly for enveloped agents such as retroviruses.
	Withdrawals of plasma derivatives have caused serious supply problems in the recent past.  This will be likely to happen again, with definite potential for harm where the theoretical exposure to zoonoses does not have a definable risk.  This is, of course, assuming that we do not include the transplant recipients in the donor base.
	So in conclusion, we certainly agree that the recipients of zoonotic transplants should be deferred.  We think that it should stop at that point, until or unless there's further evidence that tells us that we need to defer the other people.  We think that we should be very clear about what we mean with the things that we take out to the donor site and that we ask the general public to answer on with some intelligence and assurance.
	Thank you.
	DR. AUCHINCLOSS:  Thank you very much.
	Dr. Celso Bianco from the America's Blood Centers.
	DR. BIANCO:  Hi.  Good morning. I'm Celso Bianco, and I'm the president of America's Blood Centers.  I'm also the vice president for medical affairs of the New York Blood Center.
	You are going to realize here that there's where the word "consensus" comes from.  What I'm going to say overlaps very much with other organizations.  That's actually common sense.
	ABC thanks the FDA for the opportunity to make these public comments. ABC is a consortium of 73 not-for-profit community-based blood centers that collect about half of the U.S. blood supply from volunteer blood donors.  ABC members agree with CBER that blood donated by xenotransplant recipients may post a theoretical risk to transfusion recipients because of the potential for transmission of known or yet unknown infectious agents.
	We are concerned about experiments documenting transmission of PERVs to human cells {IOn}in vitro{IOff}, and actually those concerns were somewhat clarified today.  We agree that xenotransplant recipients should be deferred from donating blood.  However, we do not agree with deferral contacts.  There are millions of individuals who have been in contact with animal tissues without evidence of retroviral or other types of infections.
	ABC members believe that the approach taken in the draft guidance is inappropriate and actually may increase the risk of transmission of known infectious diseases to blood recipients.  Given the complexity of the medical history form, any additional questions risk diverting the attention of donors from those related to major risks of the blood supply.  For instance, donors in the window of seroconversion for hepatitis and HIV.
	Consider the following regarding the blood donor medical history.  Volunteer blood donors donate over 13 million units of whole blood apheresis platelets every year. The plasma industry collects double this number of units of plasma by plasmapheresis every year.  Volunteer donors of whole blood and donors of Source Plasma are subjected to FDA- and AABB-required questions every time they donate.
	The current medical history questionnaires are extensive.  The uniform donor questionnaire of the AABB has 32 separate questions.  Many of those questions are complex and refer donors to unusual entities and issues:  Babesiosis, Chagas, Creutzfeldt-Jakob disease, bovine-derived insulin, human-derived pituitary growth hormone, Acitretin, Proscar, dura matter, Isle of Man, Channel Islands, immunoglobulin, clotting factor concentrates.
	Other history questions address risk behavior or focus donors' attention on events that took place a long time ago, despite evidence that the major risk of transmission of infectious disease are associated with the window periods of weeks. Have you had sex with another man since 1977? Many donors tell us, I wasn't born.
	In an anonymous post-donation survey carried out in the context of the NHLBI-funded retrovirus epidemiology and donor study, 1.9 percent of donors revealed information that would have led to their deferral as blood donors at the time of donation.
	Consider the following regarding xenotransplants.  Xenotransplants are at this point rare events.  I used a number -- there have been less than 300 xenotransplants in the U.S.  I'm more confused about this number at this point.  FDA had declared that clinical protocols proposing the use of some of them should not be submitted until further safety data becomes available.  Thus many xenotransplants cannot be performed even under research protocols.
	Recipients of xenotransplants are known to the program that sponsored the transplants.  ABC members believe that the responsibility for the safety of xenotransplants should be assigned to the people and institutions performing these experiments.  We interpret the fact that FDA has not allowed many of these experiments as {IOn}de facto{IOff} recognition of these risks and responsibilities.
	ABC members also believe that institutions performing xenotransplants are equipped with specific means to notify individuals at risk and require that they abstain from donating blood and tissues. This certainly will be more effective than searching for xenotransplant recipients among millions of individuals who show up to donate blood.
	ABC has an alternative proposal. Blood collecting facilities would include in the written information provided to donors a definition of xenotransplants and an explanation why these recipients should not donate blood and tissues.  FDA would require that every past xenotransplant recipient be notified that they are indefinitely deferred from donating blood or tissues.  These individuals should be made aware of the theoretical adverse consequences associated with the transfusion of their blood or transplantation of their tissues to another recipient.
	On another more general issue, ABC has further concerns about the blood donor medical history.  ABC members are extremely concerned about the lack of information about the sensitivity, specificity, and predictive value of donor questions.  There are no data showing the impact of additional complex questions and the safety related to sensitivity or availability related to specificity in relation to the blood supply. There is no quantitative assessment of the benefit of such additional questions that would be of positive predictive value.
	ABC believes that before mandating any additions to the donor medical history, FDA must require scientific documentation that the admissions will not decrease the safety of the blood supply for known infectious agents such as HIV, HCV, and HPV.
	I thank you.  In the last minute, I brought some of the donor history forms and information in the back for those members of the committee that have not donated blood in recent times.  I encourage them to donate.
	DR. AUCHINCLOSS:  Thank you very much.  Dr. Michael Egan from Diacrin, and while Dr. Egan is coming up, is there somebody here from Circe Biomedical?  No. Then Dr. Egan will be our last presentation from the public, unless there's anybody else who wishes to make themselves know.
	MR. EGAN:  Good morning, and I thank you for the opportunity to speak.  My name is Michael Egan.  I'm from Diacrin. We're a biotechnology company.  We have a number of ongoing clinical trials using porcine cells.
	Although I appreciate the degree, I'm not a doctor.  Any hard technical questions, I'd have to punt.
	One of the things that we have wanted to talk about but has been discussed quite a bit -- I still think that's worth emphasis -- is the issue of the expanded definition of close contacts.  From the discussion this morning, it appears that there's a number of people that agree that it's over-inclusive.  But on its surface, when we first looked at it, it became clear that the numbers could become exponential when you consider the transmission possibilities through things like sweat, tears, mucus, semen, blood, et cetera, that could occur in any combination.  I think from the discussion, it's clearly not the intent, but initially when we looked at it, the thought came to us that sweating and coming in contact with someone else at the gym could certainly put people under this definition, as could someone sneezing on a train.
	But I think more specifically and more to the reality is the fact that under the proposed definition, for example, a needle stick would put a health care worker under restriction, but there are no such restrictions for veterinarians or farm workers who handle this type of material every day, and this has been mentioned.
	In our own particular clinical trial situation, we have in fact limited a xenotransplantation recipient from donating blood tissue, et cetera.  We have also extended this limitation to the recipient's sexual partners, even though a use of a condom is recommended is part of not only the clinical trial, but also the consent process that had been mentioned earlier.
	I wanted to make the point that to date, the regulation of this new field of xenotransplantation in the U.S. has been based on a scientific and data-driven approach.  When a new issue, question, concern has been raised, the scientists from all the involved sectors have labored to get the answers, and then decisions have been made based on those data.  Other countries are now actually looking to the FDA as the example in how to establish the regulatory approach to xenotransplantation.
	It is not clear to us what this proposed change in restriction is based on. Certainly not the data regarding the transmission of PERV that is available to support the safety of porcine xenotransplants.  In our studies, we have transplanted approximately 37 patients with porcine fetal cells with data out over 3 years with no evidence of PERV infection. The retrospective study that was mentioned a while ago that was recently published in {IOn}Science{IOff} includes data from 160 patients treated with porcine spleen, liver, kidney, islet, and skin cells over a 12-year period with no PERV transmission detected in the tested patients.
	The proposed guidance, as far as we can see, is not responding appropriately to this body of evidence demonstrating long- and short-term exposure at high and low volumes and in a number of uses in the human body that has caused no transmission of porcine viruses to humans.  In addition, there's been no recent incident to drive a restriction of this nature in the name of protecting public health that we're aware of.
	Through continued monitoring of xenotransplant recipients, which was discussed earlier, which is quite extensive, there continues to be no evidence of transmission of unknown pathogens specifically associated with porcine xenotransplantation through common bodily fluid exchange that would suggest expanded restriction is necessary.
	One other point I would like to make, and that is, other infection possibilities have been raised, but one of the things that has not been discussed is the fact that any tissue that's used in xenotransplantation goes through extensive screening processes before it's even allowed into such a use.  So a lot of the other than PERV-type infections that people alluded to are screened out through a lot of these processes.
	In conclusion, we would respectfully ask that the scientific approach to regulation not be forsaken at this juncture when in fact we collectively must admire what all involved in this new field have accomplished thus far.
	Thank you.
	DR. AUCHINCLOSS:  Thank you.
	I think we have one additional speaker.  When you get to the podium, if you could identify yourself and your association.
	While the speaker is coming to the podium, schedule-wise, I think what will happen is immediately at the conclusion of this presentation, the committee will go ahead and address the questions in front of us.  My hope is that we can conclude that by 11:00, take a 10, 15-minute break for coffee, and then we'll come back and start the topic II presentation.  Then lunch will probably be about 15 minutes late.  We'll take a break in the middle of topic II for lunch.
	MR. CAVENAUGH:  Thank you, Mister Chairman.  My name is Dave Cavenaugh.  I'm on the government relations staff for The Committee of Ten Thousand.  I do not have prepared remarks, but I wanted to bring to your attention during this debate some questions that I think have not been heard yet this morning.
	It seems like it's necessary to repeatedly come to discussions such as this and indicate that there need not always be a simple balance between safety and supply. Supply is somewhat elastic, and it need not depend only on compromises of safety.  There are such things as blood drives; there are such things as presidential calls to donate; there are such things as wartime levels of donation, which allow a lot of room beyond the current 13 million units a year that we could look to for safe blood.  We need not always work around the edges and say science doesn't hold that there is a risk here.  That sounds too much like what we were hearing in 1982 and 1983, there is no scientific evidence that there is HIV in the blood.  We heard that a year ago regarding CJD.  We can hear is now regarding some of these issues. We've heard from the committee members themselves.  There are many issues beyond just those already documented, such as PERV, to pay attention to:  Nonlipid envelope, other kinds of parvo, other kinds of viruses in general.
	We hear millions of people have worked with animals and there's been no transmission.  Were those millions immunocompromised?  No.  Transplant recipients are.
	We hear the screening questionnaires now fail to bring to people's attention some of the later questions on the form.  We hear two percent are proven to be giving blood when they later indicate that they have deferrable conditions.  Do we go back and evaluate the conditions of the supply that are impacted by those failures, those breakdowns in the current system? We've heard no discussion today about methods for evaluating the method of screening out these close contacts or recipients, if you will, or some of the more subtle questions.
	Certainly, xenotransplantation as a term would be a very difficult one to put in a donor questionnaire, and there have been a couple of approaches mentioned, both in terms of putting it in advanced materials and in terms of possibly doing studies, although that particular thing wasn't emphasized, that document whether the existing screening items do in fact screen all such persons at these risks.
	The IOM report in 1995 that led to the FDA's position on precautionary measures was over the HIV contamination of the blood supply, as I'm sure you know, and it leads to people looking to the food and drug agency as a protective agency, the way the Environmental Protection Agency is supposed to be a protective agency.  Supply issues can be handled in other ways.  Industry developments can be handled pursuant to controls from that agency.
	So I would indicate that we had a concern about this issue last year when there was proven transmission of PERV viruses in porcine Factor 9.  It turned out to be inactive virus, but it was a little bit out of the blue for us.  We also watch the CJD discussions, because there is some evidence, not much, but some, of transfusion-transmitted CJD.  So please do not think that this is a wide-open field.
	Thank you very much.
	DR. AUCHINCLOSS:  Thank you very much.  We're going to push right on now to address the questions.  I think I have a strategy for doing that, but let me start by a question from myself to the FDA and then expand on the question.
	By way of background, as we considered xenotransplantation in this committee over the past several years, we really thought of it as contact of an individual with an animal tissue or organ, and wisely the FDA brought to our attention that there would potentially be contact between a recipient's cells, tissues, and animal tissues {IOn}ex vivo{IOff} under some circumstances.
	So what you've done now is to come to this committee that has in the past taken a fairly stringent view of the regulation of xenotransplantation and the exposure that we would allow the rest of the world to have to patients who have had xenotransplants.  Now you said to us, well, the implication of this change of definition is that the scope is now much bigger than you ever realized than it was before.  How do we handle that?
	What I'd like to do first is to try and put that in some context.  Using the wide definition of xenotransplantation and the exposure to xenotransplants when that has involved well-characterized cell lines {IOn}ex {IOff} {IOn}vivo{IOff}, we came up with a number that sounded like it might be 750 people have been exposed to xenotransplants over the course of the past decade, plus or minus whatever.  If you took out xenotransplant recipients who had been exposed as a result of {IOn}ex vivo{IOff} contact with well-characterized cell lines, and we'll come later in the day to what that really means, but use that broad phrase, how many xenotransplant recipients are left if you take those out?
	Now, I'm going to suggest that the number is 50 or something like that.  Does that sound right?
	DR. NOGUCHI:  I think for what we've described today, that's probably on the order of magnitude we would be expecting.
	I'll just expand a little bit.  One of the reasons for expanding our definition is, we became aware that in this country and other countries, the use of, in some cases, well-characterized monkey cell lines for human embryo coculture as an adjunct to reproductive technologies has been used. It's been estimated in France perhaps several thousand individuals have been born in which this has taken place.  So our understanding, now that we've come out with our policy on nonhuman primates, we've made sure that the reproductive technologists in this country know about that, that that number is decreasing.
	But it's also an example of just how pervasive the use of animal cells, tissues, et cetera go on.  We know also, for example, that to develop human embryonic stem cells from human embryos requires the use of mouse feeder layers.  Those are probably less well-characterized than some of the other things.
	So I guess that while in fact the number that you quote is probably accurate for what we might consider currently the universe, there are other universes that may be developing that may or may not present future hazards to other individuals.
	DR. AUCHINCLOSS:  So to me, this issue comes down to one of scope and definition.  I think that it is more profitable to deal with this; I think the committee, and maybe I'm wrong, will find it easier to deal with this if they think of the group of people who have had xenotransplants or who are likely to receive xenotransplants as very small, and that you would deal with the other group of patients how have contact with "well-characterized {IOn}ex vivo{IOff} cell lines" as something different that you would regulate in a different fashion.  I'm going to suggest that as part of the solution to the regulatory problem.
	What I'm going to now do is open the questions by skipping Question 1 and going to Question 2.  If in fact everybody said Question 2 was true, true, true, true, all the way down, we'd come back to Question 1, and then Question 1 would be yes, but I assume that won't be the case.
	So we'll go directly to Question 2, and I would like to actually push the committee to go to Question 2.d.  What Question 2.d. is, is it a deferral for certain {IOn}ex vivo{IOff} exposures such as exposure to well-characterized cell line or exposure across a physical barrier may be exempted by the FDA on a case-by-case basis?
	I'm going to ask my committee, is it possible in fact to not only say yes to that, but that in fact, to suggest that there may be certain broad principles that can be stated about the characterization of cell lines that would exempt those contacts with those cell lines from any regulation of blood donation.
	Comments from my committee members?
	DR. NELSON:  You've given us an estimate of the numbers that might be included in the definition of {IOn}in vivo{IOff} or xenotransplant and {IOn}ex vivo{IOff} exposure.  Nobody has given us the number of when you use the word "contact."  How many people is that?  I suspect it's more than a couple thousand, but does anybody have any estimate?
	DR. AUCHINCLOSS:  It's clearly a matter of how you define "contact," right? Contact as I heard it would have to be at least 10 people per individual recipient as I heard it.  So another thing that I was going to suggest here is that the word "close contact" should be changed to "intimate contact," and I think that's what the FDA means, because when the FDA says -- and we heard the members earlier this morning -- they said 750 people have had xenotransplants by the broad definition, and therefore there are about 2,000 people who are contacts.
	DR. SIEGEL:  I was broadly speculating.  I wouldn't say that's what the FDA means.
	DR. AUCHINCLOSS:  I understand.  I understand.  But what that said to me is that a person is likely to have three close contacts.  That's not a household.  What you're thinking about are people where there is intimate contact.  I mean, that's what it sounded to me like, and I would change the word "close" to "intimate."
	DR. SIEGEL:  Please don't use those numbers.  But I would note also that I was speaking of numbers of adult close contacts, since I was looking at a donor pool.  But fair enough.  We'll leave it at that.  But that was just a wild guess.  That was not an FDA estimate.
	DR. NELSON:  It will always remain a wild guess.  I think it's pretty ill-defined.  It will be if it becomes part of the regulation also.
	DR. AUCHINCLOSS:  We'll have to come back to the issue in some of these questions as to what context we're talking about.  But let me stick with this question now of, do my committee members feel that it is possible to characterize certain cell lines in which there would be contact {IOn}ex {IOff} {IOn}vivo,{IOff} but you would not feel the kind of stringent regulation as xenotransplantation is possible?  You don't have to define for me right now what that is.  We'll spend this topic, too, trying to do that, I think.
	I'm going to ask you, Dr. Onions, to respond to that, because I saw your head sort of moving in response to my question.
	DR. ONIONS:  Yes, Chairman, I think that is the case.  I mean, the FDA with industry over many years has evolved a strategy which really has characterized a number of cell lines in great detail. There's no such thing as risk-free.  But I think those are in a different order of magnitude of potential risk, compared to some of the other procedures that we would normally consider as xenotransplantation.
	I would be very content with the proposal that you would exempt or treat differently procedures that involve close contact with characterized cell lines.  I think those are in a different category, and I'd be content with that.
	DR. AUCHINCLOSS:  Jonathan, would you comment on this also?
	DR. ALLAN:  I would just agree with that.  The only question I would ask in regard to that would be your definition of physical barrier.  I mean, is that membranes that exclude viruses?
	DR. SIEGEL:  We'll have more discussion of that later.  The intent is membranes with porcine that exclude virus. But the intent also, and we're not sure we've seen this yet, are membranes that are well validated to perform that function under the conditions of use, which is tricky to say the least.
	DR. AUCHINCLOSS:  Now, so I think I'm hearing, and let me look around the table, that there is a sort of consensus that 2.d. is okay.  But the question that I think will take it a little bit further, is it case by case?  Does that mean can we do better for you?  Can we say that there are some principles that, maybe later on this morning, we can establish for you that you can use in evaluating each product that would fall under these categories?
	I guess that's case by case.  Is that what you mean by case by case?  We'd give you principles and you'd look at all your INDs and product.
	DR. DAYTON:  It would include general things like that and also specific individual one-of-a-kind cases.
	DR. AUCHINCLOSS:  You had --
	DR. KASLOW:  As a principle, one thing that I'm sitting here thinking about is, what is the responsibility of an expert committee like this, and trying to see it as, what will people say 10 years from now?
	We've seen examples of that, and we've talked about it before, like what we would have done then if we'd known about HIV or bovine BSE?
	So one of the things that occurs to me is that there's no doubt and there's no way we can change the fact that the biotechnology revolution is basically pushing the edges everywhere you look.
	At the same time, none of us would argue, I think, with the concept that we have to be responsible about it.  You can't take a position here that you just end all biotechnology and make it so ridiculous that no company can make a biotech product, because our patients are waiting for these products to cure diseases before they die.
	So somewhere along the line, you've got to be able to agree, and I do agree, with the concept that there ought to be acceptable principles to exclude a cell line and move forward.  But at the same time, I think we have to remember and remind ourselves that the guidance to the FDA and to the other regulatory agencies is that there has to be adequate oversight, so that if anything does occur that changes the risk profile, that's immediately changed and adjusted to.
	DR. AUCHINCLOSS:  Well, Topic II is basically to look at the question of what is adequate characterization of a cell line, so we'll be coming there.  So we're going to leave it a little vague what that means right now.
	But at this point we're going to say -- in fact, I'm going to call it for a vote, because I think this is a voting question, is it not, Gail?  Topic I is a voting question?
	DR. HOLLINGER:  I certainly have no problem with deferral as it's stated here, except I wonder whether you would include in there also nonhuman primate cells as part of the cell lines, and that would be one that I would be a little bit more concerned with.
	DR. AUCHINCLOSS:  It's a very important point, and I think it needs to come up on Topic II, is is it a general principle that contact with nonhuman primate cell lines are never deferable?  I mean, that's a subject that I think we need to discuss under the topic of which kinds of cell lines are safe in principle and which ones we're just not going to accept as being safe under any principle.
	So I promise to come back to that, but please remind me, because I think it's very important.
	So I think what I'm now going to do is ask for a vote from my committee that does the committee agree yes to Question 2.d? Raise your hand if you do.  Anybody who is opposed or wants to vote against 2.d?
	MS. DAPOLITO:  Can you do that again so I can count?
	DR. AUCHINCLOSS:  You want the hands up again for a count?  I'm sorry.
	Now I'm going to suggest, and now I'm interjecting personal point of view again, that having done that, and as we go to today's conversation later on, we will take care of 90 percent of our problem.
	So now I believe we are looking at the 50 patients who we traditionally think of as patients who receive xenotransplants, and there may be some additional ones as well that will come out this afternoon.
	When I get down to that scale, I personally become much more comfortable in proceeding the way I think we thought we were proceeding over the last several years, which is that the responsibility for blood deferral, and indeed of blood deferral of the close contacts, is really the responsibility of the xenotransplantation program.
	The implication to me is that the questions added to the donor evaluation form for blood donors would all be unnecessary, because we're only talking about 50 people and their two intimate contacts, plus or minus, obviously, and that this is a responsibility of the program that's doing the xenotransplant regulated by the FDA to have a system in place for dealing with those 150 people, which will be much more effective than any question of the sort that we've looked at here.
	Now, that's my personal view, so I'll throw it open for others.
	DR. VANDERPOOL:  I want to state my entire agreement with your point of view, Dr. Auchincloss.  It strikes me that the guest speakers have made a very strong case for the problems that would be created by these questions being raised at the blood donor, plasma donor sites, and that one of the requirements we have insisted on all along is an adequate database, and those donor sites could even be required to have an online listing of the database of recipients and intimate contacts, which I also agree with.
	It seems to me that the first question that was asked, do we agree with donor deferral and withdrawal policies outlined, we can agree with the donor deferral, but not with the withdrawal policies associated with all the questions at the blood and plasma donor sites.
	DR. ONIONS:  On the first reading of the questions, I had to read the questions three times before I actually understood what each of those questions meant.  I think they were overly complex.  I was very struck by the presentations we've heard this morning. It seems to me this is an incredibly inefficient way of catching what are going to be very rare slips of presumably not only the primary transplant recipients, but presumably what we are going to define as contacts.
	That takes me to my second point, and here, Chairman, I absolutely agree.  I think that the emphasis should be on intimate contacts.  I think otherwise the definition becomes too complex.  I think if we keep it like that and we put the responsibility back on the xenotransplantation team, this solves the problem for the blood donation centers, and it actually puts the responsibility where it should be.
	DR. AUCHINCLOSS:  I agree.
	DR. ALLAN:  The only question I would ask is, in terms of the developing consent forms for the xenotransplant recipients in terms of the intimate contacts, can you be certain that the intimate contacts are going to be informed properly so that they'll know that they've been exposed so that when they do go to donate blood or if donation comes up, they know not to donate?
	DR. AUCHINCLOSS:  Jonathan's point is an important one.  I know we've discussed it before.
	Do you have any sense of this?  I mean, you've looked at consent forms.  You know how hard it is.  What do you think?
	DR. SIEGEL:  The answer to that is no, we can't be certain of that.  I've spoken to at least one xenotransplantation recipient who pointed out that for the remainder of your life, tell any sexual partner that I've received a tissue, and if you should choose to have sex with me, then you can't donate and all these other things, is something that may be an unreasonable expectation.
	But whether we try to do it through the questionnaire or through the study consent form or whatever, we're still going to have that problem, because if the contact doesn't know that he or she is a contact?
	DR. ALLAN:  So it's basically left up to the transplant recipient to inform contacts?
	DR. SIEGEL:  No.  I think a number of current protocols do education of family and current close contacts prior to treating a patient.  But we're talking about lifetimes.  So one assumes there may be new close contacts later.
	DR. HOLLINGER:  What is rare today may not be rare tomorrow, and so we might be taking about 50 today and 150 people, but later on and the decisions we make today may carry on in the future.  That's one issue.
	The other issue is that there are all kinds of donors.  We may be talking about a donor that's just going to donate once or twice.  We're talking about contacts now. I'm not dealing with the issue of the xenotransplant recipient which I'm comfortable with of excluding and deferring. But when you're talking about contacts and donors, this may be apheresis donors.  It may be somebody who donates multiple times.  That may be more than just one donation each year that you're looking at, and it's also for a lifetime.  So there are other issues that have to be dealt with here as well.
	DR. NELSON:  Fifty may sound like a small number, of 150 may sound small, but it's much larger than the pool of CJD patients which is probably 13 per year if it's one per million, and that's had a major impact on blood supply.  I think 50 sounds like a small number, but it could have a major impact I think.
	DR. AUCHINCLOSS:  I don't actually think it's really small, and I hope it is going to get lots bigger, but it is a group that you can approach from the point of view of education up front as opposed to regulation through a questionnaire that you know isn't going to be effective.  Jonathan?
	DR. ALLAN:  I just wanted to go back on what we were talking about earlier which is that in terms of contacts, it probably wouldn't make a difference whether you put it on a form or not because if the transplant recipient isn't going to inform his or her contacts, they're not going to know they've been exposed anyway.  So having it in the blood questionnaire is not going to be very helpful.
	DR. VANDERPOOL:  I have a problem with the language, since we wouldn't want the collection organizations to have to ask these questions of prospective donors, that the responsibility should be all on the xenotransplant community.  I think it should be on both, but in a different way.  It would be the responsibility of the xenotransplant community to communicate clearly what the guidelines are for all recipients and all intimate contacts.
	But why not also require these collection groups to access a database of these recipients and their intimate contacts? I realize this raises certain questions of confidentiality which could also be told to the recipients and the intimate contacts. But it seems to me that the collection groups ought to be responsible for accessing the database so that they would be able to identify those who should be deferred.
	DR. AUCHINCLOSS:  Dr. Hollinger, can you make a comment on that from the blood committee's point of view?  I mean, is that really a feasible thing to require of them?
	DR. HOLLINGER:  First of all, there's not a national database for the blood bank community.  I think it may be better dealt with by, say, Kay, perhaps you might want to comment on this.  Or Celso?
	MS. HALEY:  I can certainly address that for the Red Cross.  We have one database for about half of the blood supply, and if it were put on our computerized database so that the name would come up flagged when they presented at the donation site, we could immediately defer them.  So in our particular system, again, which is about half of the blood supply, we could do that very well.
	DR. AUCHINCLOSS:  Let's put it into the category of sort of technical implementation details.
	DR. COFFIN:  So a technical implementation detail is the question that if you're going to have sex with me you have to have your name put into this database it seems like.
	DR. AUCHINCLOSS:  That's why we're deferring it to the other committee.
	DR. COFFIN:  A very tricky issue.
	DR. SIEGEL:  I don't think current plans for the database have patient identifiers that you could -- or the database --
	DR. CHAPMAN:  Nor do they have contacts.
	DR. SIEGEL:  Right, nor do they have contacts.
	DR. AUCHINCLOSS:  Louisa, go ahead.
	DR. CHAPMAN:  This was more to the point of the earlier discussion, but when I'm hearing the committee talk about contacts, what I'm hearing you seeming to be thinking about are adult contacts and decisions between household contacts and sexual partners, and you're talking in terms of serial sexual partners which presumes a couple of things.  It presumes an adult recipient and it assumes somebody who has serial sexual contacts which is not descriptive of many people's lives even in this day and age.
	But I would to at least ensure that everybody here is aware that one of the xenotransplantation approaches that has been tried in the past, I'm not aware is under clinical trials anywhere here, but is a goal of moving from managing diabetes by injecting pig insulin to functionally curing diabetes by using living pig pancreatic cells.
	I'm not aware that it's under clinical trials now, but I know there's a lot of research going on in the area, that clinical trials have been done in the past, and if a trial of that promises efficacy, the people for whom that is going to be most valuable are young juvenile diabetics.  So when you're thinking about the issue of contact deferral and intimate contacts and close contacts, I think you need to at least have in your mind that many of these recipients, and may be in the foreseeable future, very young children and you're talking about lifetime exposure.
	So you're not just talking about their siblings and their parents, you're talking about if they go to summer camp and have bunk mates, you're talking about who they room with at college, whether they have roommates, whether have sexual partners, whether they have more than one sexual partner.  Just be aware.
	DR. AUCHINCLOSS:  True.  I agree. On the specific questions, I want to try and get about four of them wrapped up here in just a moment.  Suggestion B, that the committee has grown comfortable using the word intimate instead of close, and there is a sense that we know what that means, but maybe I'm wrong.
	C, let me be specific about C.  I'm a surgeon and I operate on people all the time who have HIV, but that doesn't mean that I am deferred as a blood donor just for that experience.  So that C doesn't imply here I assume that all health care personnel who come in contact with a person who has received xenotransplant need to be deferred. It applies to health care workers who have some breach of ordinary protection such that they know a contact, an unusual body fluid contact, has occurred.  If I understand C to mean that, the I have no problem with C.
	DR. DAYTON:  Yes, it's quite clearly stated there.
	DR. AUCHINCLOSS:  Excuse me.
	DR. COFFIN:  I actually do have a problem with C.  I have a lot of difficulty seeing the logical distinction between C and me and as I said many people around this room between veterinarians, between abattoir workers, farmers, anybody who can come in contact through some kind of injury with animal tissue seems to be at equal risk to that.
	I don't see the logic of making this a group here and not including all of these other people which obviously we don't include and never have included and for which there is obviously enormous experience with as donors.  I just don't see the point.
	DR. AUCHINCLOSS:  Good point.  So does C need to be there at all is your question.
	DR. COFFIN:  Exactly.
	DR. SALOMON:  I don't think it needs to be there either.  To back up the chair, I was equally confused the first time around, and I rarely admit that with respect to the chair.  I think this is going too far. I mean, there have to be some limits here, and I think this one could be deleted without a significant negative impact.
	DR. DAYTON:  There was a presumption here that laboratory workers would in many cases be dealing with very high concentrations of virus compared to what you'd normally come across in let's say an abattoir.  But that's not stated in question, however.
	DR. SALOMON:  I think we've got to deal with some facts in evidence here without perhaps going too far.  There's no evidence that this virus or any of these other viruses are going to be such high-tiders at this point.  If we find out differently, that's different, but there's no evidence that it's like lentivirus like HIV where one copy causes infection.  So I really think again this is going too far along the lines of doing everything analogous to HIV and should still be deleted.
	DR. DAYTON:  There's also an implementation issue here in that this is a highly educable group and we could have a policy to defer them and let it rely upon self-deferral as a possible solution.
	DR. AUCHINCLOSS:  I think that's correct, and my recollection of the way we talked about xenotransplantation programs in the past is that there somewhere needs to be some kind of education to the xenotransplantation team about what they're involved in, to the extent that we know anything about it.  We often don't know very much.
	DR. NELSON:  But studies of medical hospital personnel and the lifetime frequency of a percutaneous exposure is extremely high, and I suspect you would be deferred, anybody. I think it's too broad.
	DR. AUCHINCLOSS:  You mean by C you would?  Is there anybody in the committee who wants to keep C?  Do you want to speak on behalf of C?
	MR. LAWRENCE:  I don't want to keep it, but I'm the only lawyer here.  I can't speak to the likelihood of transmission of diseases, but I can tell you that a poorly drafted regulation or a vague regulation or one that everybody ignores as a matter of course leads to ignoring of other regulations, and so you're really better off writing nothing than writing something that's going to be perceived this way.  So I'll offer that just as a general rule of writing regulations.
	DR. AUCHINCLOSS:  I agree with that point.  Yes, Jonathan?
	DR. ALLAN:  I think I understand the reason this was put in here, and it I don't know if it's been articulated that well, and so I would disagree a little bit with John because if you put an animal virus into a human, it may be a different story than being exposed at a slaughterhouse or a veterinarian or whatever because if that virus adapts itself to that new host it could change its properties to the degree that it could be more dangerous or more infectious than it would be in the animals.  But, nevertheless, I would still agree with the committee in terms of eliminating this.
	DR. AUCHINCLOSS:  I follow your point, and I think it is important to keep in mind.
	DR. HOLLINGER:  We should realize that you are excluded for 12 months anyway if you have a needle stick or exposed to blood right at the present time anyway.
	DR. AUCHINCLOSS:  Yes?
	DR. KASLOW:  I'm not speaking in favor of it, but I think there would be a compromise if down the road there were some tissues that were discovered.  It's not as if you don't know what kind of transplant the person who is needle stuck is exposed to so that you could make some distinctions between which ones were at risk and which ones weren't at the time when you knew that.
	DR. AUCHINCLOSS:  I agree.  There's nothing here that we're going to say today that isn't subject to revision as we learn more over time.  I'm going to suggest to me committee members that we could change the close to intimate in B and vote on A, B, and dropping C, and how many of my committee members would be in favor of doing that?  All in favor?
	DR. HOLLINGER:  Wait a minute. This is just --
	DR. AUCHINCLOSS:  I'm saying you've changed close to intimate in B, and voted yes to A, B, and no to C.  With a change in wording.
	DR. NELSON:  Why don't you take them one at a time?
	DR. AUCHINCLOSS:  Sorry.  Trying to get to lunch.  A is the provision that says if you've had a xenotransplant you're deferred.  All in favor?
	Gail is counting, so that's why I'm asking you to keep your hands up there.
	MS. DAPOLITO:  I got it.
	DR. AUCHINCLOSS:  B is the provision that if --
	DR. HOLLINGER:  Are you going to vote on opposed and abstain?
	DR. AUCHINCLOSS:  Excuse me. Excuse me.  Thank you.  Thank you.  One chairman to another is keeping me line.
	Are there any opposed or any abstaining?  Thank you.
	Let's go to B.  I'm suggesting that we change the word to "intimate" and then approve it.  It's the provision that says intimate contacts of recipients of xenotransplants should be deferred from donating.  All in favor?
	MS. DAPOLITO:  Okay.
	DR. AUCHINCLOSS:  All opposed?
	I actually was caught by surprise, so let me ask you to just make clear what the issues are here.
	DR. HOLLINGER:  For me I have no problem with A, and it's my feeling that if this the most exposed group, they're also the immunosuppressed.  It seems to me that over time you're going to see something happen in that group if there is something in reality that is present, and it should happen earlier than it should happen anywhere else.  I think that the intimate group is one that's not described at all.  The other risk is theoretical anyway.  This is even more theoretical.  My feeling is that rather that put that group into the vote, I would rather have not deferred them at this point in time.
	DR. AUCHINCLOSS:  Dr. Linden, would you like to make a comment also?  I just want to make sure that this is clear what there is not complete agreement, and I apologize to all of you for trying to put it on one package that I didn't realize wasn't a package.
	DR. LINDEN:  Yes.  I basically agree with Dr. Hollinger.
	I'm not sure we have good evidence that this group which is not immunocompromised is really at risk, and the whole issue about other animal workers and so forth.  It seems kind of analogous, although I understand that the viruses can change.  I think that from a logistic and practical standpoint, it would be extraordinarily difficult to really accomplish the goals of truly deferring this group, and I'm not sure it can be done effectively.
	DR. AUCHINCLOSS:  I hear you. There was a third person.  Yes, Dr. Nelson?
	DR. NELSON:  I think with the current information it's almost impossible to define this group.  We don't know what the risk is.  It's theoretical at best.  But I think it's a can of worms, and I think it's like the lawyer said, it's an unenforceable rule or guideline, and intimate contact for some people could be thousands perhaps if you're talking lifetime.
	DR. AUCHINCLOSS:  My answer to that would be that it's not unenforceable.  It's probably incompletely enforceable, but the enforcement as I understand it is a plan of education of the recipient and that the recipient needs to be talking to the recipient's intimate contacts and that that's part of the xenotransplantation process.
	So this is not a regulation where we now are calling on the blood bank to figure out who these intimate contacts are and that kind of thing.  This is a conversation that takes place between two people.  It's not perfect.  It's not perfect.
	DR. NELSON:  I think it's just too vague, and I don't think there's any real evidence, and I agree with Gene that I don't think there is a real risk that we know of.
	DR. AUCHINCLOSS:  Actually, I think we'd all agree that we don't, there's no risk that we know of.  I guess.  Never mind. Risks are unknown inherently.  Right?
	DR. EPSTEIN:  Just a point of order.  I thought the vote was on whether to change the word, not whether to adopt or not adopt the provision, and doesn't that require a second vote?  I think there's some lack of clarity of what got voted here.
	DR. AUCHINCLOSS:  I tried to do too much railroading in getting to lunch.  Let's have a separate vote.  I propose changing the word close to intimate.  All in favor?
	All opposed?
	All abstaining?
	So there are one, two, three abstains, and one no.  Now assuming that the word is intimate, all in favor?
	DR. SALOMON:  What I'm hearing which I think is very interesting because I had sort of the same play, I thought it wasn't such a big issue and then I've been sort of looking for clues to my colleagues in blood banking and the people who commented.
	I think here there's always in transplantation these intersections.  Right? So I mean what we as transplanters feel is the risk and where we're comfortable and what level we're setting as the barrier upon which we feel like we're protecting the public as much as we can and yet trying to move the field forward.
	Now we're asking where are you guys comfortable.  The idea here is we all realize there is no evidence whatsoever that there's a risk to an intimate contact, and certainly no evidence of the intimate contact spreading it.  But for the last several years it has been an underlying assumption that the intimate contact is going to be the next place a retrovirus is going to go if it should get spread to the transplant recipient and adapt.
	DR. AUCHINCLOSS:  Jon?
	DR. ALLAN:  I just want to reiterate in the same sense which is you have to really think about there's like HIV and we've got so much experience, which is it's the introduction, it's the unique way that the virus is being introduced.  It's not a slaughterhouse and then exposure through sexual contact.  This is a unique introduction.  HIV was transmitted even though all these monkeys had these viruses is only a rare case in which the virus was transmitted.
	When you do transplants, that creates a unique source of transmission that you don't normally have, and so then you don't need immunosuppression to transmit that virus to sexual contacts.  You don't need anything to happen other than the introduction which then creates the spread. So I would say that the intimate contacts, it is important to address the intimate contacts for that reason.
	DR. COFFIN:  I would actually argue slightly against that for HIV where the key event almost certainly is not the introduction but the frequency of initial spread that allowed transmission of what is probably a fairly frequently introduced zoonotic infection.
	DR. ALLAN:  But it was through intimate contact.
	DR. COFFIN:  It doesn't actually change the point.  It just changes the logic slightly.
	DR. KASLOW:  I don't know if this is too technical, but under xeno-definitions you have close contacts defined.  So can we redefine xeno contacts?  The questions are dealing with donor deferral.  Are we allowed to redefine close contact because it's different from what we're been talking about altogether.
	DR. SIEGEL:  We can use a different term if we need to use a term.
	DR. AUCHINCLOSS:  We can do this and they can change the way they use -- if they feel like it.  They may not feel like it.  Now I think we've done B, so now I'm going to suggest that we vote on C which is the health care workers which I tried to package here.  I don't need to change any words.  All those in favor of approving -- I'm sorry?
	DR. KAGAN:  I don't think we came to a final thing on whether or not we approved B with the word "intimate" being substituted.
	DR. AUCHINCLOSS:  I didn't get that vote there?  I'm sorry.  All in favor of B with the wording change?  I'm sorry.
	MS. DAPOLITO:  Okay.
	DR. AUCHINCLOSS:  Opposed?
	Any abstentions?
	Now moving quickly to --
	DR. HOLLINGER:  Can you read that vote, please, for the public record?
	MS. DAPOLITO:  I had seven no, nine yes.
	DR. AUCHINCLOSS:  I'm sorry.  How many were in favor of it, Gail?
	MS. DAPOLITO:  I had nine yes.
	DR. AUCHINCLOSS:  Nine yes.
	MS. DAPOLITO:  And seven no.
	DR. AUCHINCLOSS:  Seven no.
	MS. DAPOLITO:  Maybe we ought to do that again.
	DR. AUCHINCLOSS:  All in favor of B with the wording changed to "intimate". Sorry.
	MS. DAPOLITO:  One, two, three, four, five, six, seven, right, nine.  Yes.
	DR. AUCHINCLOSS:  All opposed to B with the wording change?
	MS. DAPOLITO:  One, two, three, four, five, six.  Okay, seven.
	DR. AUCHINCLOSS:  Anybody abstaining?  You're going to be fired. Question C, health care workers.  All in favor of keeping C?
	DR. CHAPMAN:  Hugh, may I just ask, for the record, could we know how many of the people at the table are voting members? Could we have public recording of the counts on all the previous votes?  Because I thought there were 14 voting members.
	MS. DAPOLITO:  There are 16 voting members.
	DR. AUCHINCLOSS:  Trouble with voting questions.  It's better when we try and give you a consensus, but I would have missed the consensus perhaps, so I think it useful this time.  Question C, all those in favor of keeping question C?
	All those opposed to question C, or feel that it should be dropped?
	MS. DAPOLITO:  Sixteen.
	DR. AUCHINCLOSS:  I believe we've already voted on D.  Is that correct?
	DR. EPSTEIN:  Could we have the count read, please?  Correct, but the count was never read.
	MS. DAPOLITO:  Aye was 16 I thought.
	DR. AUCHINCLOSS:  Sixteen, zero?
	MS. DAPOLITO:  Sixteen, yes.
	DR. AUCHINCLOSS:  Now, I honestly don't -- when we get to the next group here of four, I don't have a good feel for -- so I think we should just go through them one at a time.
	E, whole blood and blood products including unpooled plasma and Source Leukocytes intended for transfusion or for further manufacturing into injectable products if made from donations made from persons eligible for deferral should be withdrawn from distribution and held in quarantine or destroyed.
	So this is anything that's out there now in the way of whole blood or blood components, if it's from a xenotransplantation recipient or I guess intimate contact, that product should be withdrawn and destroyed.  Would any of the experts tell me whether that's yes, no, right thing to do?
	DR. ALLAN:  I thought it was okay.
	DR. AUCHINCLOSS:  I think I guess it sounds reasonable.  It's certainly logical I guess.
	DR. NELSON:  Are there any current recommendations?  Is this a change of a current recommendation on xenotransplant recipients and pooled products?  Or is it are we changing?
	DR. EPSTEIN:  There is no current recommendation.  We have the draft guidance which would become our recommendation.  So what you're voting on is advising the FDA on the content of its guidance.
	DR. AUCHINCLOSS:  But is it not fair to say that --
	DR. EPSTEIN:  But this would not be the change --
	DR. AUCHINCLOSS:  For all xenotransplantation that has been done up until this time has been done, in the consent form, that recipients and their intimate contacts should not be donors?  I mean, we believe that there are no blood products out there from people who receive xenotransplants in the restricted sense of not the {IOn}ex vivo{IOff} contact with well-characterized cell lines. Is that true?
	DR. BLOOM:  Yes, because that follows the recommendation of the PHS 1996 guideline.
	DR. AUCHINCLOSS:  So I think we can vote yes to E and not feel that a whole lot of blood is about to get destroyed.
	DR. SALOMON:  The problem I'm having or maybe just needs to be clarified is I actually in balance changed my vote on the to not exclude the intimate contacts, and the reason I made that change was I decided that in this case we were doing a public policy that should more play to the guidelines typically used by the blood industry than the transplant group at this point until the facts changed.  So I actually changed that.
	DR. AUCHINCLOSS:  That's all right.
	DR. SALOMON:  Now when I'm looking at E.  So, the problem I'm having is I'm looking at E thinking nonetheless I was outvoted in the sense that the committee went for having excluded intimate contact.
	DR. AUCHINCLOSS:  Whoever is being deferred.  Whoever is being deferred.
	DR. SALOMON:  See, I'm concerned about this now because these guys make these humongous investments in big gigantic pooled plasma that no one argues is critically needed --
	DR. AUCHINCLOSS:  No, this isn't plasma.
	DR. SALOMON:  And you're going to pull all this.
	DR. AUCHINCLOSS:  This is not plasma.  This is blood.  Blood products or components.
	DR. SALOMON:  That's including unpooled plasma.
	DR. AUCHINCLOSS:  Unpooled plasma.
	DR. SALOMON:  Unpooled.  I'm sorry.
	DR. SIEGEL:  F is about pooled products.  E is about quarantine or withdrawal of individual users.
	DR. SALOMON:  Individual users. You clarified it for me.
	DR. AUCHINCLOSS:  From donors who should have been deferred.
	DR. SIEGEL:  Clarified.
	DR. AUCHINCLOSS:  I think we're spending too long.  This is not going to have a big impact.  All in favor of E?  F, rather. I'm sorry.
	All opposed to E?
	DR. SALOMON:  Can we have a count read in the record?
	MS. DAPOLITO:  Sixteen.
	DR. SALOMON:  Can we have a count in the record?
	MS. DAPOLITO:  I had a count of 16 in favor.
	DR. AUCHINCLOSS:  Now, F would have a big impact I believe.
	DR. SALOMON:  I'm sorry.
	DR. AUCHINCLOSS:  Because F is the pooled plasma.  Am I right?  Am I interpreting this correctly?  What the FDA is proposing that this stuff is okay unless it came in contact with nonhuman primates {IOn}ex {IOff} {IOn}vivo{IOff}.  Jonathan?
	DR. ALLAN:  Just what I said before which is I don't know what we want to make, in this particular case, I don't know that we want to make the distinction between nonhuman primates and nonprimate tissues because of what we know about porcine viruses and what we don't know about porcine viruses, and so I think that we shouldn't limit it to nonhuman primates.
	DR. AUCHINCLOSS:  Do you accept the argument from the FDA that the processing is such that the likelihood of the pooled plasma being dangerous is so small that we should not destroy what exists?
	DR. ALLAN:  You're only talking about in terms of enveloped viruses, and there are viruses that would withstand these treatments.
	DR. HOLLINGER:  There are several issues here that aren't real simple, and I'm certainly in favor of perhaps what this one says, but there is just more than just a person finding out a person at this point or finding that this blood has been used.  If somebody, a contact for example, or is this just from the patient?
	DR. COFFIN:  No it's contacts too.
	DR. AUCHINCLOSS:  At this point it would be intimate.
	DR. HOLLINGER:  Eligible.  That means that the patient after three months finds out or determines through talking says, you know, they got this question on there and I don't understand it.  They, yes, by the way, I did have sex with that person who had a transplant.
	Then all of a sudden they call the blood bank.  The blood bank then calls the plasma fraction agent they've made this into a huge numbers of plasma for albumin which been scarce in the past or something else.  I don't know if they would go to albumin, but if you're talking about immunoglobulins and albumin and so on, and this makes a big issue.  So it's not quite so simple.
	DR. AUCHINCLOSS:  I need some clarification.  What's the difference between F and H?
	DR. VANDERPOOL:  Isn't F just for nonhuman primate recipients and their intimate contacts?  Isn't that what we've got here then we get a chance to go on down here, don't we, on addition?
	DR. DAYTON:  H is probably not best considered as a question.  It was really meant to highlight, more of a comment than anything else.  So, I think if you just delete H and stick with F you're going to focus on the problem.
	DR. AUCHINCLOSS:  So, F really is the issue.  Yes?
	DR. COFFIN:  I think there are several issues tangled up here that I think we should try to separate.  First is the nonhuman primate versus other source, and the second probably is donor versus recipient. Maybe we should hit those individually and see if the question is -- because the question that's very --
	DR. AUCHINCLOSS:  Do you mean recipient versus contact?
	DR. COFFIN:  Donor versus -- recipient versus contact, yes.  If I misspoke.
	DR. ONIONS:  I'm not a voting member, but I just wanted to make a comment here that I agreed instinctively with Jonathan Allan's point that I don't really see there's a difference between nonhuman and human primates here if you're going to control it.
	But you're going to end up with a rather strange illogical position, and that is that there are products that are used like I believe mentioned earlier, various plasma products that are used from pig plasma that are put into people that actually do in fact contain the genomes of several viruses; they don't contain infectious virus, but they contain the genomes, and those to into patients.
	Then on the other hand you're saying that the contacts of people who have had pig tissue should be excluded.  I mean, that's an entirely illogical position.  On the one hand you're actually putting pig material into people, on the other hand you're saying that material taken from a person and processed in the same way as you process that pig material isn't acceptable. I'm just pointing out you're end up with a rather illogical situation.
	DR. AUCHINCLOSS:  Dr. Epstein?
	DR. EPSTEIN:  I just want to comment the issue has come up several times that there is evidence for porcine endogenous retrovirus and also porcine parvovirus in certain products that are currently in use. There is a product, porcine factor 8, which is used, although in a limited number of patients, and culturable, not inert, and not just gene sequence, but culturable.
	Porcine parvovirus was isolated from the product and the CDC conducted a study to determine whether there were any evident infections and/or seroconversions in the human recipient of dozens of lots of those products over a period of years, and there were not.
	Additionally, studies were done to determine whether there was evidence of porcine endogenous retrovirus infection in the human recipients of those products.  In that case someone would have to clarify whether the PDRV ever was cultured, but we did have gene sequence data.  Again, there was no evidence for the human infection.
	Now, I'm not saying this to suggest that I do not believe that there is zoonotic risk or that I do not believe that animal agents cannot become human adapted with potentially very serious consequences.  But at least I think there needs to be some clarity that we do have experience with those two agent exposures, intensive exposures repeated over time, in human populations with no evidence of transmission.
	Beyond that, I would just agree with Dr. Coffin.  I think that in approaching this question it would be very useful to separate the issue of product withdrawal based on a recipient collected inadvertently versus a contact collected inadvertently, and also to separately then consider the question of nonhuman primate versus other animal exposure.
	DR. AUCHINCLOSS:  So, let me put this in small bits and pieces.  Should plasma derivative that was obtained from a xenotransplantation recipient, in which the xenotransplant did not include a nonhuman primate, should that be withdrawn.  So, this is basically pig.  The recipient of a pig xenotransplant.  The plasma has been made with that individual.
	DR. COFFIN:  Could I make a suggestion that we consider the nonhuman primate first because I think perhaps we can find consensus on that and then move on.
	DR. AUCHINCLOSS:  Let's switch it around.  So, this is the recipient of a nonhuman primate xenotransplant and his body fluid is in a plasma derivative.  Should that be destroyed?
	DR. VANDERPOOL:  Right.
	DR. AUCHINCLOSS:  So you got that? The answer is?
	DR. NELSON:  Does that include the {IOn}ex vivo{IOff} or just the transplant?
	DR. AUCHINCLOSS:  It includes {IOn}ex {IOff} {IOn}vivo{IOff} unless we set up a set of rules later on today that says that got excluded from being a deferral candidate.
	DR. HOLLINGER:  So, this is the same question.  The only thing you'd change is instead of eligible for deferral, it would be the xenotransplant recipient.
	DR. AUCHINCLOSS:  This is just the recipient now.
	DR. ALLAN:  And the only taken out of it.
	DR. VANDERPOOL:  We need to take only out of that and just vote on that, the recipients if the xenotransplant is from a nonhuman primate.  Take out the word "only".
	DR. AUCHINCLOSS:  So, let's vote on that.  Jonathan?
	DR. ALLAN:  The FDA has already put out a guideline.
	DR. AUCHINCLOSS:  I understand.  I know that in a sense this is redundant but let it proceed.  So, all in favor of this form of this question?
	MS. DAPOLITO:  Sixteen.  Unanimous. Yes.
	DR. AUCHINCLOSS:  Now the question is the same, but the recipient didn't receive the xenotransplant from a nonhuman primate, he received it from a pig or some other; do people still vote yes?  All in favor, yes?
	DR. COFFIN:  Only recipient here?
	DR. AUCHINCLOSS:  They're only the recipient.  This is not contacts.
	DR. COFFIN:  Only recipient.
	DR. AUCHINCLOSS:  The recipient of a xenotransplant that is a nonhuman primate. Still 16-0?  No?  Dr. Onions?
	DR. ALLAN:  I'm confused.
	DR. AUCHINCLOSS:  This is the recipient of a pig xenotransplant.  His fluids have ended up in plasma derivatives. Should it be destroyed?
	DR. COFFIN:  Of any mammal?
	DR. AUCHINCLOSS:  Any animal.
	DR. COFFIN:  Any xenotransplant.
	MS. DAPOLITO:  I've get 16, yes.
	DR. AUCHINCLOSS:  Opposed?  So now we're going to go to the intimate contacts, and we'll do first intimate contacts with a recipient of a xenotransplant that was from a nonhuman primate.  All in favor?  All in favor?  Two, three, four?
	MS. DAPOLITO:  I have four yes.
	DR. AUCHINCLOSS:  All opposed?
	MS. DAPOLITO:  Nine opposed.
	DR. AUCHINCLOSS:  Were there some abstentions?
	MS. DAPOLITO:  There should be three.
	DR. AUCHINCLOSS:  Intimate contacts with a recipient of a xenotransplant that came from anything else except for nonhuman primates, should they be excluded.  All in favor?  Same question we just did.
	MS. DAPOLITO:  Four yes.
	DR. AUCHINCLOSS:  All opposed?
	MS. DAPOLITO:  Nine opposed.
	DR. AUCHINCLOSS:  Then abstained?
	MS. DAPOLITO:  Three abstained.
	DR. AUCHINCLOSS:  We're almost done I think.  Not quite done.
	Now, G is essentially the same as D for this same point, so I'm just going to ask you quickly all in favor of G.  "Withdrawal and quarantine may not be warranted for certain {IOn}ex vivo{IOff} exposures such as exposure to a well-characterized cell line or exposure across a physical barrier that may be considered by the FDA on a case-by-case basis."
	It really is the same point as D. So, I think if you said yes to D, you'll say yes to G, but if anybody is unhappy with that you can tell me.  So, all in favor of G?
	MS. DAPOLITO:  I can't count that fast.  I got 15.
	DR. AUCHINCLOSS:  All opposed?
	MS. DAPOLITO:  Is there an abstention?
	DR. AUCHINCLOSS:  Is there an abstain?
	MS. DAPOLITO:  No?  Then I missed a hand.
	DR. AUCHINCLOSS:  Then I'm going to suggest one additional issue that I thought we ought to be clear on for them.  I'm going to suggest that we vote on the question that all three of the additional questions that were proposed for the blood donor evaluation sheet, I'm going to propose the statement that the committee believes that those should not be added to the blood donor questionnaire or whatever its proper term is.
	DR. HOLLINGER:  But I presume could be included in the written statement.
	DR. AUCHINCLOSS:  I would leave it to your committee and you and the FDA to figure out how to handle the details, but I would not be in favor of including those specific questions on top of the long list that we know exists already.  Any further discussion of that?  Eda?
	DR. BLOOM:  Hugh, I'd like to point out I'd actually never seen this 32-question list before.
	DR. AUCHINCLOSS:  You haven't been a blood donor?
	DR. BLOOM:  Not in a few years. Never mind.
	DR. AUCHINCLOSS:  Never mind.
	DR. BLOOM:  The question about transplants, have you received a tissue or other transplant, and I'm not finding it at the moment, but it only says within the past 12 months.  So I think for xenotransplantation we may want to rethink that, whether that's included as a question or not.
	DR. AUCHINCLOSS:  I would toss that back to the blood committee.  Any other discussion, then, on this question, this issue?  So, I propose that the committee is expressing its feeling that you should not add those three questions to the long list of questions asked of potential blood donors. All in favor?
	MS. DAPOLITO:  I get 16 in favor.
	DR. AUCHINCLOSS:  All opposed or abstain?  FDA, further discussion topic I, Dr. Epstein in particular?
	DR. EPSTEIN:  I think that this deliberation by the committee has been very useful and we will follow-up on issues such as donor education, potential use of registry information, et cetera, with our blood products advisory committee.  But we're very grateful for the advice we received here today.
	DR. AUCHINCLOSS:  Let's take what will end up being a 15-minute break, but we'll call it a 10-minute break, and the we'll come back and get topic number II on the table before lunch.
	(Recess)
	DR. AUCHINCLOSS:  Can I ask people to come back to the table and back to their seats and we'll start again.
	I'm again going to ask everybody to come back to the table.  I think that I'm particularly in need of my own committee members.  Subcommittee members, grab your seat.  I'd like to just allow Mr. Lawrence to make one statement for the public record which I do think is important as a clarification on the morning's discussions.
	MR. LAWRENCE:  I would just like to state for the record that it is not the view of this committee that any action we've taken today affects self-donation by recipient prior to surgery and so forth.  So, we're not talking about self-donation here.
	DR. AUCHINCLOSS:  Any member of the subcommittee have any problem with that?
	In my judgment we've only just started the day's work, and now topic II is perhaps really the heart of the day's work. I think this process of defining what xenotransplantation really is, or where we can exclude some forms of xenotransplantation from the same kinds of regulations that we've so far been talking about is absolutely critical to really making the whole thing work.
	I think the FDA has been very wise in giving us a test case from which we can begin to look at this problem.  Then, what we'd like to do is expand from the specific case to try and identify more general statements we might make for them about forms of xenotransplantation that might not be subject to all of the aspects of the regulations as they currently exist.
	To begin this then we're going to have a presentation from Genzyme Tissue Repair Company about their corporation about their product Epicel, and I believe our first presentation will come from Ms. Doris Peterkin.
	MS. PETERKIN:  Thank you.  Good morning.  My name is Doris Peterkin.  I'm from Genzyme Tissue Repair, and I'd like to begin our presentation by providing you an overview of a treatment of patients who suffer severe burn injuries and the role Epicel plays in their care.
	Although 1.4 million people actually seek treatment for burn injuries each year, only about 50,000 of these people have injuries sufficient to warrant admission to the hospitals.  These patients are then further screened according to guidelines presented by the American Burn Association on whether they should be then referred to a specialty burn clinic or burn care unit.
	A little less than half of these patients, about 23,000, are then referred based on these criteria, and these criteria have to deal with the size and location of the burn injury and the presence of inhalation damage.
	These patients are referred to one of about 121 regional burn centers that are active each year.  These burn centers face some unique challenges in their treatment in that they generally cover a large geographic area, meaning that they sometimes treat patients out of state.  This complicates follow-up treatment because once these patients are discharged, very often they do not return back to the burn center.  They are then returned to a local provider.
	They also treat patients very often outside of the country, and of course then again they are again referred to a local provider.
	Another complication is that about 30 percent of the patient population from many of these units are indigent which, aside from just placing a large financial burden on the institution, also further complicates follow-up care and that these patients are most often lost to follow-up once they leave the burn care institution at discharge.
	The incidents of severe burn injury, and we've quantified that as being greater than 30 percent total body surface area, is an important point because as you can see, about 10 percent of patients that are admitted to the burn care facility suffer this type of injury.  The reason that is important is because these burn care facilities have a great deal of trouble in staffing and keeping up their technical expertise because very often although a burn care facility will see very serious wounds, they may see only just a handful of severe. There may be just one or two catastrophic injuries which is considered greater than 60 or 70 percent total body surface area.
	The incidents of these patients, you don't know when it's going to happen, and the incidents is quite varied amongst the burn institutions.  Some burn care facilities may see only one patient who is a catastrophic injury each year.  Other institutions may see 20 or 30 within the year.
	Epicel clearly falls into the catastrophic burn injuries.  The vast majority of our patients are burned greater than 60 or 70 percent of their total body surface area.  Although we receive about 200 biopsies a year, unfortunately about half of those patients, sometimes a little less than those, actually expire before they're able to be treated.
	So, clearly the key objectives for the burn care team, when choosing their treatment options, are to prevent mortality, and in a large extent that's how fast can we close the wound, preserving function so we're turning these patients back to their normal activities, and then optimizing cosmesis or the appearance of the injured tissue.
	Some of the key predictors of mortality are the extent of the full thickness injury, the extent of the burn, the age of the patient, and the presence of inhalation injury.  The predictive value of whether the patient is going to survive the injury, a patient who is 30 years old or 35 years old who suffers an 80 to 85 percent burn generally is considered to have the same survival chance as a 65-year-old who has suffered a 30 percent burn.
	Although burn care has come a great deal forward in the past 10 or 20 years in terms of treating infection and inhalation injury, the options to the burn care surgeon for replacing damaged skin has not really changed that much.  The standard of care remains split-thickness autograft whereby they are taking a piece of undamaged skin to cover the wound area.
	This often creates further complications in that it creates a donor site, a painful donor site, which can be very problematic in populations that are elderly, over 65, and the pediatric population which is under 10 years old.
	There have been some inroads in the appearance of new dermal substitutes for quite a few years.  Surgeons have had to rely on allograft or cadaver skin.  Of course, there are some complications there in terms of the quality of the allograft and just the availability.  Last year was a case in point where we had a great deal of trouble in locating suitable allograft for a number of our surgeons.
	As Dr. Kagan mentioned earlier, xenograft has been available.  It's a porcine product that's been available from a medical device company for the past 10 years, but is not widely in use.  Then most recently the synthetic substitutes such as Integra have been available.
	But these are dermal substitutes that cannot adequately and permanently close the wound.  You still need an epidermal layer which is where cultured skin comes in or in split-thickness autograft.  Again, in those patients that are burned 60 to 70 percent of their body, catastrophic, life-threatening condition, many of these patients do not have sufficient skin to cover from their own donor sites.
	They need to turn to something like cultured skin, or they have to wait a very long time which further complicates their ability to survive the wound.
	The technique for growing an epidermal graft has been around for quite a while in scientific literature.  It was first described by Rheinwald and Green in 1975, and used first in the clinic by Dr. O'Conner in 1981 with an adult patient.  It was followed-up in 1984 with treatment of two pediatric patients.  Actually, twin boys, by Dr. Gallico.
	It was introduced commercially under the trade name Epicel by Bio Surface Technology.  Bio Surface Technology was acquired by Genzyme in 1995, and Epicel continues to be provided to the public Genzyme Tissue Repair.  The product is a cultured epidermal autograft.  It's derived from a full thickness biopsy generally taking from the axilla or groin area.  These are areas that are generally not burned even in the most extensive full thickness injuries.
	Grafts are available, grafts in 15 to 21 days, generally when the patient is ready and suitable to undergo a grafting operation.  The grafts are very fragile. They're 5 to 8 cell layers thick, and they're delivered about the size of a playing card. Actually about the size of the palm of my hand.
	These skin grafts you can imagine are fragile and very thin.  You can actually read a paper through them, if you can imagine that, and they adhere to a petrolatum gauze which is very important to the product in that it provides support, so that they can be handled in the surgery and applied to the patient.  We also apply a moist background which is also beneficial to the cells as they are grafting onto the patient.
	They are hand delivered in a spill-resistant package.  We send out a clinical specialist with every delivery to the surgical procedure, and these clinical specialists actually are in contact throughout the treatment process with the surgeon and the burn care team.
	Also we know that this is a very time-intensive, important procedure for the patient.  The surgeon generally makes the decision to treat the patient within the first three days of admission.  We receive the biopsy at GTR and immediately start processing it.
	The reason that we are very confident that we can return a sufficient number of grafts adequate for the patient's needs in the time that the surgeon deems is appropriate for the patient is that this is a very robust manufacturing system.  For that reason, the reason that it is so robust, is that we follow the guidelines originally described by Dr. Rheinwald in using irradiated 3T3 feeder layer to make sure that we don't have to turn away any patient, that we are able to provide cells from every patient that we get in in a timely manner that makes sense for the patient's treatment algorithm.
	As I said, Epicel plays a major role in life-saving treatments for these patients.  They are very often in a situation where they do not have adequate donor sites and the surgeon has deemed that there is no other opportunity to close these patients in a timely manner, and it is well documented in medical literature.
	Just who are these patients?  You can see the range of patients that we treat in terms of age and height, weight, and total body surface area.  You can see that the vast majority of our patients are very young, and generally our average patient actually is male under about 30 years old.  You can see also that the extent of their injury is very extensive.  It's 68.6 percent total body surface area, and 80 to 99 percent of those generally are full-thickness injuries.
	The next speaker is Mark Doucey his is an Epicel recipient, and we've asked him to come speak to you about the role of Epicel, the impact that Epicel has had on his treatment process.  So, I'd like to turn this over to Mark.
	MR. DOUCEY:  Can everybody hear me? My name is Mark Doucey.  Genzyme asked me to come here today.  I do want everybody to know that I have no affiliation at all with the company.  They did cover my expenses to be here, but I've received no other compensation.
	Seven and a half years ago I was burned 80 percent in a midair airplane crash. Spent three and a half months in the hospital. I was the recipient of Epicel about three and a half weeks for the first time into my treatment process.  I had two different applications, one covering most of my lower thigh, lower leg areas, and the other one was done on the upper body.
	I guess from my standpoint, I'm here today probably because of the product. So, you're not going to find me saying bad things about it.  There were several negatives that they pointed out might possibly happen.  They talked about the fragility of it, the possible blistering and all of those other possible negative traits. But for me I had none of them.
	It's been durable.  It's been probably as durable as the full-thickness autograft that I had from myself.  I've not had blistering problems.  I really had no significant problems at all.  Like I say, we're talking seven and a half years later. When I got mine, the size of the sample was much smaller.  I think they were about a one-inch square and required many, many more staples.  So, I'm glad to see they have made that change.
	But I guess my statement is that once I got through my initial hospitalization and treatment, the 27 surgeries and three years of recovery, my health has returned to the same way that it was prior to getting the Epicel.  I'm not sick any more often or any less often, for that matter.
	I'm just like everybody else.  I get my occasional winter cold and the flu once in a while.  I am back flying.  I am a certified pilot.  I hold a second-class medical with the FAA.  Really other than the fact that the surface doesn't look quite the same, it is really no different for me and it really has allowed me to continue life the way I did prior.
	So, I don't know what else to say. If there's any questions, I'd entertain them.
	MS. PETERKIN:  I just wanted to say in closing, in talking about patients and their treatment program, one of the things that Mark didn't mention and I alluded to is that the treatment is in the first three days usually.  The surgeon makes his decision in the first three days upon the patient's admittance to the burn surgery.
	These are catastrophically ill patients.  They are not cognizant of the treatment options that the surgeon is going through and cannot necessarily respond to agree or not to agree.  Realistically, not given a lot of options at that point.
	That's generally for the first grafting.  Very often in the case in very large injuries there are subsequent graftings, and then the patient is cognizant of what is going on, but certainly not in that first receipt of grafts.  So, I'd like to turn this over now to Dr. Alan Moore from Primedica.
	DR. MOORE:  I'm with Primedica Corporation.  I've had the pleasure of addressing and working with this committee and the FDA in terms of the porcine endogenous retrovirus.  Today I've been asked to talk about what may constitute a well-characterized cell line and, specifically, there will be some information which follows on how the 3T3 cell line which is utilized with the Epicel product can be considered a well-characterized cell line.
	I run the risk with this presentation, however, of putting to sleep the folks at FDA who have endured probably thousands of conferences discussing all of the assays which constitute a well-characterized cell line, but for the committee members who may not understand that definition, I hope to provide some background and to contrast what a well-characterized cell line is in relation to fresh tissue.
	At the June xenotransplant subcommittee meeting in the chairman's summary comments, it was brought up that there were potentially some mitigating factors for the broadly defined xeno-products and that the committee should address some of the issues that surround the species or the source animal, the use of a well-characterized cell line or a cell line versus fresh tissue, the dose of the implant, duration of exposure, some of the patient factors, and barriers.
	I'm going to concentrate for the most part on the species and source of this xeno-component of the Epicel product and the cell line versus fresh tissue in the way that we, as folks involved in testing of these materials, look at them as potential exposure to adventitious or infectious agents.
	So, if we start, the mouse 3T3 cell line which is utilized in support of the Epicel product is certainly very well characterized.  This cell line has been in existence since 1962.  It was derived from a laboratory mouse, an albino Swiss mouse.  It was registered with the ATCC, the American Type Culture Collection, in 1963.
	It, by its nature, is a contact inhibited fibroblast, and rather uniquely so because it was later utilized for that characteristic as a screening method to potentially identify viral oncogenic agents.
	Another point that I want to make in looking at the lineage of this cell line is that if the cell line itself were contaminated with microbial or overt viral contaminants, that would be evident prior to its submission to the ATCC.  The line was carried for 112 passages prior to being registered with the ATCC, and then underwent ATCC testing prior to any distribution.
	The cell line as I mentioned was a key component of assays conducted in the 1960s and the 1970s to look for potential oncogenic virus, a virus which would cause cancer, and it relied on the cell line's characteristics to go from contact inhibited to noncontact inhibited, or to demonstrate unusual growth.
	The cell line has been widely used as a feeder layer to support the growth of human or other species' cell lines, and I think the Epicel product as well as potentially other innovative cells will still require some support from a cell line such as a mouse 3T3.
	The last point I want to make on this component is that since the advent of what we described as modern biotechnology, the murine retroviruses which were very well studied as part of the oncogenic virus efforts of the '60s and '70s were further studied very extensively in support of recombinant products, monoclonal antibody products, gene therapies relying on murine vectors, and there are members of this committee that are as well versed in the aspects of the endogenous murine retrovirus.
	Actually, there are some of the world's experts here.  A lot of the work which was done by Janet Hartley and Wally Rowe years ago has provided a very, very strong understanding of the murine retroviruses, and I see Carolyn Wilson nodding her head.
	I'd like to contrast to some extent some general properties of a characterized cell line versus fresh tissue.  If we think about a characterized cell line, we do have the ability to test significant quantities of cells.  In these cases of a cell line, we are relying on a cell banking system where we have basically in-process steps.
	We verify the freedom from contaminating agents prior to establishing the next master working cell bank or the next manufacturer's working cell bank.
	We also have what constitutes a uniform homogenous population of cells which is by its nature and results of the testing characterized a known quantity.  With fresh tissue there is limited testing of cells unless one tests to extinction, and there is a potential of variability in the quantity and quality of fresh tissue which is received.  In that instance, with fresh tissue one has to rely more extensively on the lineage and the information that one has on the source of the cells.
	The next point that I'd like to make is that when one has established a characterized bank, one at that stage has a profile which will be constant throughout any production activities which utilize that bank, and that includes the known infectious agent profile as well as the known endogenous virus profile of those cells.  When one is working with fresh tissue there is potential variability in both the quality of the cells, freedom from adventitious agents, and the infectious agent profile.
	Another component is that if there is potential concern regarding emergent viruses, those emergent viruses have a very tough time getting into the liquid nitrogen freezer where that preserved characterized cell bank is stored.
	So, to some extent, both characterized cell lines and fresh tissue have an opportunity for exposure for infectious agents utilized during the process, contributed by raw materials or the operators themselves.  One is starting with a known source material with a characterized cell line, and to some extent the processing of a characterized cell line reduces the opportunity for the entrance of new adventitious agents other than from the source itself.
	If I see Phil glossing over and going to sleep, this is where it will happen. Characterization of the cell line relies on a number of principles.  One is a confirmation of the identity of the cell line itself.  In all the test components which are going to be presented today and the results which I think are quite expected and quite boring to some extent for this committee, are the result of uniform regulatory guidance and review of the components which constitute that characterization battery.
	All the testing which is conducted in terms of characterization of a cell line is outlined in the International Conference Harmonization, guidance documents, numerous FDA points to consider documents, European notes for guidance for various products derived from these cells, and in many cases the CFR, which covers cells used for the production of live virus vaccines.
	The battery itself constitutes a confirmation that the cell population which is used for production, or in this case to supplement production, is what you think it is, and that's accomplished by assays for identity and to confirm the freedom from extraneous cell contaminants in the production bank.
	One of the most common contaminants of cultured cell lines are microbial agents, mycoplasmas and bacteria, which may find their way into a cell culture system if researchers are utilizing antibiotics or using poorly characterized sources of media or other raw materials.  There are a number very standardized assay systems which are utilized for the detection of mycoplasma. Methodology is not in question.
	For adventitious viral agents, there are very well established, broad-based viral screens.  These represent{IOn} in vitro{IOff} and {IOn}in vivo{IOff} systems designed specifically to detect as broad a range of viruses as possible.  So, in the case of viral contaminants that would present themselves in an{IOn} in vitro{IOff} assay, there are a number of human, rodent, and primate cell lines which are utilized to try and detect any virus capable of establishing a persistent infection in your cell culture.
	Viruses which are inapparent in {IOn}in {IOff} {IOn}vitro {IOff}cell culture systems can be detected in {IOn}in vivo{IOff} studies, and these are very extensive studies.  They utilize multiple species, adult mice, suckling mice, guinea pigs, embryonated eggs.  They provide multiple routes of exposure, injection of the animals via the IP route, PO, intracranial administration.  So, the idea is to provide as many opportunities to isolate or identify a virus present in that cell culture as possible.
	In addition, there are viral detection systems which look for specific viral agents inherent in the species of that cell.  In the case of a mouse 3T3 cell, the mouse antibody production test which involves inoculation of the cells into mice and them monitoring those animals for antibody raised to potential contaminating viruses is employed.  There on average I think about 16 different viral agents which are screened for specifically in that assay system, mouse PERV virus, hantavirus (?), and some of the agents which we know infect mice at least experimentally.
	We then turn to the component of the characterization battery which deals with endogenous retroviruses.  I don't belabor the point, but there is a tremendous historical database on the murine retroviruses.  There are various approaches which are taken to identify murine retroviruses capable of infecting species other than the mouse, as well as those viral agents which are capable of causing infection or transmission only in mouse cells.
	There are broad-based methods, transmission electron microscopy, which actually look to visualize viral particles, endogenous retroviruses which may or may not have budded from the cell's membrane.  An orthogonal approach to look for reverse transcriptase that is an indication of active retrovirus replication in the cells.
	A latter point, and this point is part of the characterization of the cell line is the ability of that cell in and of itself to produce tumors when injected into animals or when cultured in soft agar, and the tumorigenic potential of a cell line is part of a standard characterization battery which has now been limited to viral vaccine substrate, some zoonotic and gene therapy applications.  It actually was dropped from FDA guidelines for continuous cell lines used for the production of biologicals if they were known to be tumorigenic, and many of the standard lines used for production of biological products in fact are tumorigenic. I don't think it's the case with this mouse 3T3 cell line.
	If I could summarize, and I may have gone a little long, the ability to extensively characterize the cells which are used in support of the production of a biological product does provide a high level of confidence in the safety of that product. We believe that we are dealing with a very small range of potential unknown agents.
	Another point is that there is a long history of the safe use of cell lines, and I'm not aware of a biological product which has had contamination specifically from a characterized cell line.  I am aware of biological products where there have been breakdowns in inactivation procedures, but I think there is a long history of successful use of cell lines.
	The last point that I want to make is that there is extensive information, extensive experience, and I think some very adequate regulatory guidance for how one can describe their cell as being well characterized, both from a microbial and endogenous retroviral agent profile as well as adventitious agent profiles.  I'd like to end there, and I'm going to have to do this because it's going to take me a minute.
	DR. WENTWORTH:  I want to briefly describe to you the characterization that has gone on for our Swiss mouse embryo 3T3 cell bank as it's used in our autograft cultivation process for the product known as Epicel.  My name is Bruce Wentworth and I'm a principal research scientist with Genzyme Corporation.
	We have employed as described earlier the cell bank process to the testing of these cells.  They are described by Alan Green in the early '60s.  Later Genzyme Tissue Repair through Genzyme Corporation developed a master cell bank.  That was subsequently worked into a master working cell bank.  That, in turn, leads to the generation of production cell banks, the production cell bank testing of various sorts all along the way which I'll describe.
	The production cell bank leads to the use of radiated cells during the production process.  As well, we have taken cells from the production cell bank, pushed them to beyond the point of useful production and tested them there as well.
	As to the 3T3 master cell bank, cell culture authenticity tested by isoenzyme analysis confirming the species of origin as mouse.  Again, on the master cell bank, bacterial and fungal contaminates were tested through the direct inoculation method and no bacterial or fungal contaminates were detected.  The language that you see described here as to the outcome of the test is in most cases taken directly from the reports that the company has received on the testing.
	3T3 master cell bank again agar isolation and viral cell culture assay again proving to be negative for the testing of mycoplasma.  For general virology, looking for the presence of viral contaminates, inoculation, and observation of indicator cells, with no adventitious viral contaminates being identified.  Also looking for the presence of inapparent viruses using the inoculation into adult mice, guinea pigs, suckling mice, and embryonated hen's eggs with no evidence of contamination being found.
	Further, on the master cell bank as to general virology, looking for the presence of murine-specific adventitious agents through the mouse antibody production test, the cell bank was found to be free of all 16 murine viruses tested.  Further, looking for the presence of bovine viruses, using the bovine turbinate cells inoculated with cell lysate, all five specific bovine viruses were not detected.
	As to retrovirology on the master cell bank, we have examined for the presence of xenotropic murine retroviruses with the extended SøLø assay.  Those results were negative.  The presence of ecotropic murine retroviruses using the extended XC plaque assay, again, those results are negative.  We have looked for the presence of virus particles looking for transmission electron microscopy with no identifiable viral-like particles being found.  For the presence of retrovirus using an {IOn}in vitro{IOff} assay for retroviral-derived reverse transcriptase, again, with no evidence of Type C or DRT activity being found.
	The 3T3 master cell bank has also been examined tumorigenicity using growth of mammalian cells in soft agarose with no viable colonies being identified.
	Moving on to the master working cell bank, again, for microbiology, bacterial, and fungal contaminates through direct inoculation methods with no bacterial or fungal contaminates being detected.  Also for mycoplasma, those results are negative as well.
	For virology on the working cell bank, looking for the presence of viral contaminates using the indicator cell method with no adventitious viral contaminates being found.  Also for the presence of independent viruses, again, no evidence of contamination.
	The 3T3 working cell bank has been examined for tumorigenicity again using the growth of mammalian cells in soft agarose with no viable colonies formed.
	Moving on to the production cell bank for sterility testing looking for bacterial and fungal contaminates, no growth again as well for mycoplasma, negative.  We have examined irradiated production 3T3 cells.  That's the form used actually during the production process for retrovirology using the presence of xenotropic murine retroviruses, the SøLø assay.  That was negative for murine retroviruses.
	Through the extended XC plaque assay for ecotropic murine retroviruses, again, negative for murine retroviruses. Looking for the presence of a retrovirus by way of reverse transcriptase activity, with no evidence of the enzyme being found.
	The irradiated production cells have also been examined for the presence of viral-like particles using transmission electron microscopy, and no identifiable virus-like particles were found.
	Moving on to end-of-production cell characterization, there are the cells that we wouldn't be making and wouldn't be using in production we pushed them beyond the point that we think is useful for production. We've looked for tumorigenicity, again in the soft agarose method.  It's equivalent to that acceptable for negative control.
	We have examined a chromosome analysis through karyology, and it was again found to be mouse in origin with polyploidy which is expected for this particular cell line.
	We've also carried out characterization of Epicel final product, now different from the preceding cells for tumorigenicity, negative.  Also for chromosome analysis, karyology, and there was no evidence of numerical or structural chromosome abnormalities found in the product.
	In summary, what I'd like to point out is that we have a well-characterized bank in accordance with regulatory standards.  The master cell bank was established from a single clone.  The master cell bank in effect represents a cell reserve frozen in time and separate from all other forms of 3T3s that may exist.
	Now, the quality of this bank has been established from the master bank to production and to end-of-production cells which gives us great confidence that this is an appropriate substrate to use in the generation of the Epicel product.
	DR. AUCHINCLOSS:  Questions from the committee?
	DR. VANDERPOOL:  To what degree are some of these tests or perhaps several of these tests in response to the FDA's guidance on precautionary measures in 1999?  The FDA set forth this document in light of PERV infection and wanted the various people with MVAs to do testing to certify that their work was free of retroviral activity and so on. To what degree are the tests that you listed in response to that FDA initiative?
	MR. HERNDON:  My name is Russ Herndon.  I'm the president of Genzyme Tissue Repair.  The testing that was performed on the master production cell banks was standard testing that was performed by Genzyme Corporation, Genzyme Tissue Repair, as a matter of course because of our research in recombinant technology and were not because of any guidance that was presented by the FDA in 1999.
	We were asked to do some testing by the biologics organization for the final product after its exposure to irradiated cells to make sure there was no activation or changes within the material that was produced, and you saw that data today.  We were also asked to look at some extra post-production assays that were also done.
	I'd like to also point out that this product is regulated as a device by the Office of the Center of Devices and Radiological Health because of the major component, the cells being grown and delivered on a petrolatum impregnated gauze.
	DR. VANDERPOOL:  Thank you.
	DR. AUCHINCLOSS:  Did you have a follow-up?
	DR. VANDERPOOL:  No.  Go ahead.
	DR. COFFIN:  When you're talking about mouse cells, it's not only important that the species be verified, but also that the strain be verified and the reason for that is there's a very large virological difference from one mouse strain to another. In addition, 3T3 cells, I assume the cells you're talking about are a clone of what most scientists would call NIH 3T3 cells; Is that correct?
	DR. WENTWORTH:  Those may be a different isolate, but this was taken directly from Dr. Green's lab.
	DR. COFFIN:  Because the same workers also, or maybe Dr. Tadeo later on, also made cells from Bolb's C mice and there's an enormous difference in my level of comfort between Bolb's 3T3 cells and NIH 3T3 cells in the terms of being able to do this experiment and for this kind of use, and that is that Bolb's C cells carry a complete intact infectious pro virus, known as BXB1, that in fact is capable of releasing infectious xenotropic virus.  Even though you might not always detect that in cocultivation or other kinds of tests, it's certainly there.
	Have you ever done anything to verify that in fact that parvovirus specifically is missing or that these cells in fact are from NIH Swiss cells and not from some other strain?
	MR. HERNDON:  Alan, can you respond to it?
	DR. MOORE:  I think that's an excellent point.  This is not about 3T3 cells.  Specifically, I don't think nor is it common practice as part of the characterization to go and look specifically at the sequences in a murine substrate.
	DR. COFFIN:  We could argue whether it should or should not be, but I agree with you it's not.
	DR. MOORE:  Right.
	DR. COFFIN:  But I think it would certainly increase my level of comfort were that to be verified at some point down the road.
	DR. MOORE:  I think the assumption that one takes using any mouse cell line is that there is the potential for expression of a xenotropic retrovirus from that line.  The fact that these tests are negative is comforting at the post-production level, and the fact that they're radiated prior to their use as a feeder cell line is comforting to some extent in that they're not actively replicating.  But there is always a potential with any mouse line the assumption being that there is potentially endogenous retrovirus there.
	DR. COFFIN:  The problematic issue is that the virus will not spread through the cells that you're using, so that it will never get to amplify to a level where it's easy to detect in those cells.
	DR. MOORE:  Right.
	DR. COFFIN:  But when cocultivated, as you do, that potential for spread occurs at that point.
	DR. MOORE:  Right.
	DR. ONIONS:  I'd first like to reiterate my statement I made earlier that I'm very comfortable as a general approach to categorize xeno-products, if we're going to call these xeno-products for the moment, that had a characterized cell line, I think they are a different class, and as we have heard from Alan Moore and Bruce Wentworth and the very professional approach the way that they've tackled the problem.
	But I do share some of John's concerns, and that is that I think we have to adjust our thinking from a standard biotech product that goes through downstream processing when we look at xeno-products, because here we have intimate contact between the cell line and human cells, and I think that perhaps we need to go up another notch in terms of thinking of the testing strategies.
	For instance, like John has just reiterated, I would really have liked to have seen cocultivation procedures here because certain viruses are activated by irradiation. I know you looked at 3T3 cells.  I think I would have liked to have seen true cocultivation with human target cells as opposed to just taking off supernatants.  We know that that is a more sensitive procedure.
	I would liked to have seen the more sensitive assays for inverse transcriptase, for instance, perhaps used.  I think there are a number of procedures that could have been or perhaps one might in the future consider doing in these kinds of procedures.
	That's not to say that what's being done has not been a very professional and very thoughtful set.  But I just think we need to adjust our headset, make it a little bit more stringent in the future.
	DR. NOGUCHI:  Those are all good points, and I think some of the coculture experiments were actually required by FDA. I'm not sure of the details.  But we would also certainly later appreciate specific additional tests that might help assure the origin like the difference between Bolb C and the NIH 3T3.  So, any specific recommendations we certainly will take under very high advisement.
	DR. AUCHINCLOSS:  Dr. Hollinger?
	DR. HOLLINGER:  Just some other questions.  Of course, all this work which is very nice and very good is looking for viruses that you know about.  I mean, that makes it a little easier somewhat.  Are these grown in serum-free medium, or is there a fetal bovine serum used throughout any of this?
	DR. WENTWORTH:  There is FBS used in cultivation.
	DR. HOLLINGER:  In the cultivation. He said there is FBS used in the cultivation. How about at the time that the cells are used as feeder cultures for the human cells?
	DR. AUCHINCLOSS:  If I could just ask the company people to use the microphone partly just to keep it on the record.
	DR. WENTWORTH:  Yes.  I apologize. There is FBS used in the cultivation of the keratinocytes.
	DR. HOLLINGER:  Are antibiotics used through out, and antifungal agents also used throughout?
	DR. WENTWORTH:  Antibiotics are included in the culture medium, yes.
	DR. LERCHE:  Just a logistical question.  Is all your testing done in-house, or do you contract with other laboratories to screen?
	DR. WENTWORTH:  The vast majority of this testing was contracted out.  Some of the sterility testing is done in-house.
	DR. AUCHINCLOSS:  Dan?
	DR. SALOMON:  We do a lot of irradiating cells and then culturing them, and one of the things that's always striking to me is that sometimes you think you've irradiated them enough and then the fellow shows you the plate and the cells are growing away.  So, the two questions I had for you is what data do you have that you've actually successfully irradiated and destroyed the 3T3 monolayer.
	Secondly, do you have follow-up data that when you have the final product and you're ready to package it and send it to the clinical site that there is no 3T3 cells in that mixture that you're bringing?
	DR. WENTWORTH:  This very question we are currently attempting to grapple with, and so if you will, you're going to get insight into results that we're trying to evaluate and we're trying to figure ways to evaluate further.  But specifically, what has happened is we've hit lower limits of detection.  As it pertains to finding 3T3s potentially in the final product they're below the limits of detection of the assay system that we have used at the moment which is facts analysis, and we've made some --
	DR. SALOMON:  I agree, but you can't use facts.  I mean, there's lots of reasons why you can't use facts for that, because they are difficult to install, they may die when you detach them.  I mean, a lot of different things.
	DR. WENTWORTH:  We set a hurdle of looking for intact cells in the final product since that really seemed to be the question, and that's the reason we stuck with facts. Now, we've also had some preliminary investigations using other techniques to see where we have to set the register, if you will, of the assay.  Those too have not shown presence of 3T3 cells in the final product, so we're still stuck with below level limits of detection.
	There was a first part as well to your question as to the growth of 3T3s.
	DR. SALOMON:  Did you kill them?  I mean, what evidence do you have with the given amount of irradiation and a reasonable number of experiments that you've killed all the cells?
	DR. WENTWORTH:  We're also attempting to quantitate that as well at this point, and the results are not final, but we believe we have rendered the vast majority of cells effectively nonproliferative.  I can say that.  That might not give you -- your eyebrows are going up.
	DR. SALOMON:  This is not published data, but in collaboration with another investigator we've had some data that is more than preliminary demonstrating that when you irradiate 3T3 cells they become attachment deficient.  So, I mean, they actually grow without requiring attachment any longer and it's raising some interesting questions about these cells.
	DR. WENTWORTH:  That certainly doesn't happen in our case.  I mean, attachment is required for us to get through the product.  So, we know that they're attaching.  We also know that we're trying to come to the final number as to the efficacy of the irradiation process.  Again, we're dealing as it turns out with very small numbers to try to resolve.
	DR. SALOMON:  The final comment I had was that I was taking this not so much to criticize you, you've done a lot of work, but also I think the idea here was to use you as the example of sort of what we demand, and I think in that case I stand by what I said.
	DR. WENTWORTH:  I guess our conclusion at this point is that we're trying to grapple with a small number of cells and post-irradiation that might have some proliferative potential coupled with the fact that we can't find them in the final product as it stands right now.
	DR. AUCHINCLOSS:  John Coffin?
	DR. COFFIN:  Is it possible and feasible to do follow-up by biopsies to look for microchimerism, that kind of thing, that have been done?
	DR. WENTWORTH:  No, I don't think so.
	DR. AUCHINCLOSS:  Other questions of the company from the committee? Dr. Onions?
	DR. ONIONS:  Just one very brief comment, and one perhaps very slight disagreement with Alan that he made the statement that normally if you've got a cell line that you would pick up viral contaminates in there.  That's of course true for quite a lot of saluretic viruses, but there are viruses that we're only now just becoming aware of like for instance the porcine circovirus which now that when you go and get your ATCCPK 15 cell line, which lots of people around here have been doing, that carries a porcine circovirus and that was only recently observed and noticed.
	I know of other cell lines that contain similar sorts of contaminants.  So, it's perhaps just a caution that assuming that an ATCC line is clear of exlines, that is not always the case.
	DR. AUCHINCLOSS:  Dr. Vanderpool?
	DR. VANDERPOOL:  Maybe this is what John asked, but he asked it so succinctly I didn't get it.
	Some of the best articles we've seen are studies of patients who've received these treatments and do they have detectable viruses within their systems.  Have you or have you not done that kind of study?  What did you say the beginning, approximately 100 patients who have received this treatment?
	DR. HOLLINGER:  Five hundred.
	DR. VANDERPOOL:  Five hundred.
	MR. HERNDON:  One hundred a year at a maximum level.  No, we have not done those. I think it's important also to remind the committee that prior to the last meeting where the definition was posed to be modified, that this product did not fall within the xenotransplantation.
	So the work we've done on our own to support the safety and efficacy of the product to date.  We're very interested in doing additional testing as has been brought up here and that Bill has mentioned and it has been very, very helpful in sort of defining additional things to look at.
	But I think it's important to remember that this just started very, very recently, and we have not done those tests, specific to your question -- I can't say impossible because nothing is impossible, but incredibly improbable to believe, based on the information we provided today that we would be able to do a study like that.
	These patients as we said are severely ill patients who come into a situation where this is their only opportunity to survive.  They would agree to pretty much I would say anything.  If you would ask Mark I would reckon or believe he would say that he would do whatever you ask him to do at that moment to receive the product.
	Then to be able to say, okay, now we want you to come back and give a sample, sort of find these patients after they've gone from these specific treatment centers into the public domain would be incredibly difficult.
	DR. AUCHINCLOSS:  Any other questions?  Yes, Dr. McCauley?
	DR. McCAULEY:  I think that I disagree with that.  I think a lot of these patients when they obtain this product generally are taken care of by the same center that put the product out.  In particular, at the Shriners Burns Institute we take care of these patients until they're 21 years of age and we have used this product, and these patients have to come back for reconstructive efforts over an extended period of time.  So, I disagree.  I think it is possible to do some of these studies.
	MR. HERNDON:  I'd like to add to that though I think the Shriners is a very unique situation, and particularly that's one of the few Shriners centers that we provide cells to, that a lot of the Shriners centers culture their own material.  So, there is culturing being done outside of this type of an environment.
	It's also important to remember that the Shriners situation is very different than a lot of the other treatment centers that are used that use products like this throughout the U.S.
	DR. AUCHINCLOSS:  Dr. Hollinger?
	DR. HOLLINGER:  Just to follow-up with what you just said, there are a lot of other centers that are culturing their own virus?  Is that under any kind of control or anything like this?  What do you mean by that?  You mean culturing, doing feeder-type cultures and things like that?
	MR. HERNDON:  Yes, there are centers in the United States, burn centers and university laboratories, that are growing epidermal skin just as we're talking right here using a very similar, if not the exact same process because it is an available process, and they are providing that to patients on a daily basis, or routinely I should say.
	DR. HOLLINGER:  Are these required to be under any IND for doing anything like this?  Can somebody enlighten me about that?
	DR. SIEGEL:  Yes.
	DR. HOLLINGER:  You know about these?
	DR. SIEGEL:  I would say that in the general area of autologous cells that are grown up, expanded, or otherwise having their biological characteristics changed before being returned to the donor that the agency has made some clear statements that those should be under IND and has made some significant efforts through mailings to professional organizations and speaking at public meetings to alert the community about that, and when we learn of such activities we take efforts to notify.
	But if your question is are there activities out there not under IND that we believe should be under IND, I would be shocked if there weren't.
	DR. AUCHINCLOSS:  Now, the plan here is that we want to finish the questions for the company specifically.  Then we're going to come back after lunch and have a very brief open public hearing and the FDA presentation on this topic, and the full committee discussion.  So, are there any other questions specifically for the company? Obviously the bribe here is that you get lunch if you way no.  Let's adjourn until 1:20 for lunch.
	(Whereupon, at 12:40 p.m., a luncheon recess was taken.)
	
	A F T E R N O O N  S E S S I O N
	(1:26 p.m.)
	DR. AUCHINCLOSS:  If I could bring my subcommittee to the table, if we could get a quorum here and we can open our public hearing.  I'd like to open the afternoon session be resuming the open public hearing and asking Alix Fano to address us.  She is from the Campaign for Responsible Transplantation.
	MS. FANO:  I didn't really have a prepared statement, but I felt the necessity to make a comment based on what I've heard here so far today.
	Just for everybody's information, the Campaign for Responsible Transplantation is an international coalition of physicians, scientists, and about 80 public interest groups very concerned about the public health risks inherent in xenotransplantation and feel that ultimately if the FDA really wants to protect the public health that it should ban xenotransplantation.  So, that is where we are coming from.
	The first observation that we will make, and we will make these observations and comments that we will submit to this guidance, is that the guidance itself is imbued with what we see as biased value judgments about the purported desirability of xenotransplantation to being with; and this despite the fact that the public has yet to be consulted about technology's risks in a democratic forum; and the fact that the secretary's advisory committee on xenotransplantation which is advise Donna Shalala on policy has yet to be formed.
	Moreover, in 1996 the Organization for Economic Cooperation and Development raised several important issues about xenotransplantation.  Among them are the fact that the economic impacts of the technology had yet to be addressed.  That is still true today.  OECD also stated that the technology would have adverse impacts on the medical system by preventing efforts to keep medical costs down, by contributing to the development of multi-tier medicine, conflicting with efforts to develop better approaches to preventive medicine, and possibly discouraging donation of human organs, and may not be consistent with striving with humane and fair medicine. That's number one.
	CRT has also expressed its belief that pigs pose just as great a danger as nonhuman primates as donor species in xenotransplantation, and that the FDA's exclusion of this species in guidance is arbitrary, in our opinion.
	We are stunned that the FDA continues to make comments about the danger of this technology, and yet continues to allow clinical trials to go forward. Paradoxically, by their nature these guidelines are an admonition that the practice of xenotransplantation poses a threat to the nation's blood supply and to our public-health system.  It reveals, we believe, this guidance, the vulnerability of a system that is devoid of enforcement or legal safeguards that instead depends on the goodwill and honesty of individuals, patients and nonpatients alike, to protect public health.
	A method for protecting the blood system from zoonotic agents which relies on voluntary monitoring and a series of three questions which now have obviously been deleted as troubling.  There was no explanation about how hospitals and hospital staff would administer the precautionary measures outlined in the guidance.  Equally troubling is the absence of a national registry to keep track of all the patients dead or alive who have heretofore received xenotransplants, as well as a list of their close contacts which seems to be important now.
	Given the concern for close contacts expressed in this guideline, such a national registry and database, if it existed, would presumably list xenograft patients as close contacts and their current addresses.
	It's strange that casual contacts don't seem to be a issue for some reason. One can only assume that the possibility of aerosolized disease transmission … la swine{IOn}{IOff} flu for example has been arbitrarily dismissed.  This demonstrates quite a bit of hubris considering the fact that swine flu killed 20 to 40 million people worldwide in 1918 and that the Malaysian nepa viral encephalitis virus killed over 100 people just this past year alone and left dozens of survivors brain damaged.  Also Dr. Paul's raising the issue of numerous pig viruses that are constantly being discovered such as the circoviruses, parvoviruses, gamma herpesvirus, and the hepatitis E virus.
	The ramifications of contaminated blood supplies have been serious and deadly. Between 1994 and 1996 some 40,000 people received blood that had been improperly tested for HIV, hepatitis B, and hepatitis C, as well as human T lymphotropic virus.  The Manhattan Blood Center tried to reach patients through newspaper and radio announcements, though it's unknown how successful this outreach effort was.
	More recently, U.S. and Canadian health authorities announced an indefinite ban on blood donations from citizens who spent 6 months or more in Britain since 1980. This affected about 285,000 Americans, and 25,000 Canadians.  This was for fear of transmission of mad cow disease through the blood supply.
	Because it takes years or possibly decades before symptoms of CJD appear in humans, authorities are concerned that many people may be carrying the disease without knowing it.  If the disease can be spread by blood carriers who are blood donors, may be unknowingly infecting large blood pools. There is no test currently to detect traces of the disease as far as I know, unless someone knows otherwise.
	A recent report by the European Union said that one infected cow could contaminate 400,000 people with CJD.  It is possible that as yet unknown porcine viruses may already be lurking in the blood supply for all we know, and they're undetected by commercial testing methods.
	HIV nucleic acid detection tests were not commercially available when CDC revised its AIDS case definition in 1993. Today blood banks can use nucleic acid testing to screen for hepatitis of HIV, but those tests can't detect a brand-new virus, only one that's related to an existing virus.
	A novel zoonotic agent therefore could slip through the cracks.  However, it is discovered in the blood supply one year, five years, or ten years from now it would have a major impact on the blood supply and our health care system.  It would be virtually impossible, as it was during the AIDS crisis, to locate all infected individuals or those who may have had contact with infected individuals.  More importantly, it may be impossible to determine the original source of infection.
	Given that xenotransplant proponents would like to see tens if not hundreds of thousands of patients receive xenotransplant products, the blood-monitoring system proposed in the guidelines is insufficient and will quickly become unmanageable.  It will be impractical, for example, to allow medical directors to determine an individual's health status on a case-by-case basis if xenotransplantation is practiced on a larger scale.  Nonbinding guidelines are simply not going to protect the public health.
	A better plan would be to require the introduction of legislation to establish a computerized surveillance system which would include a national name-based registry listing the names and addresses of all xenograft patients in the U.S., and, ideally, also abroad because viruses don't respect national boundaries, and the hospital personnel that may attend him or her.  Such a system would always be vulnerable to hackers I think it's important to note.  There was a program on ABC News recently which talked about how hackers could shut down the Internet in 30 minutes.
	Similar though less elaborate registries already exist to track individuals infected with HIV, and Washington and Texas have implemented name-based HIV reporting to enable public-health follow- up.  The CDC has concluded, in a report issued last month, that name-based methods for collecting and reporting this information are really the best ways to monitor people with AIDS.
	These registries, however, are plagued by legal problems, raising substantive Fifth and Fourteenth Amendment due-process issues about individuals' right to privacy and liberty.  There have been numerous legal articles written about the complexity and problems that such name-based registries raise.
	In light of experiences with AIDS and CJD, however, the establishment of such a registry, with all its social intrusions, would perhaps provide the only hope of trying to prevent blood donations from xenograft recipients and their close contacts.
	If we are unwilling to enforce such a surveillance system through legislation, then we must acknowledge that xenotransplantation poses unacceptable risks to the blood supply and to the public health, and I'll just leave it for that right now.
	DR. AUCHINCLOSS:  Thank you very much.  An important part of today's conversation has to do with a somewhat expanded definition of xenotransplantation compared to what were working with say two or three years ago, and then the notion that with an expanded definition there might be a stratification of risks.  Do your comments apply to all of xenotransplantation as we were discussing it today?
	MS. FANO:  We'd have to go back and rethink that, but clearly based on what was said today, those are concerns that trouble this panel.  So, it seems like you guys have to figure out what your real definition of xenotransplantation is, and it seems like it's constantly changing.  So, that is a troubling issue from our perspective.
	DR. VANDERPOOL:  Could you identify yourself again?  Could you wait one second? I have a question to ask.
	MS. FANO:  I'm Alix Fano, the director of the Campaign for Responsible Transplantation.
	DR. VANDERPOOL:  I would just note for the record that your concerns and critique of xenotransplantation are a good bit like those of Margaret Clark who wrote an extensive article in the recent of issue of the {IOn}Journal of Law, Medicine, and Ethics,{IOff} and I wrote a critique analysis of her positions. So, for the sake of the group, you can see the issues joined in those two articles.  If you haven't seen that exchange, I would encourage you to see the exchange.
	MS. FANO:  I've seen it.  Thank you.
	DR. VANDERPOOL:  Because I think a number of the assumptions you set forth are generalized and problematic, and a number of your primary ethical concerns are all right in a world where people aren't suffering for loss of organs.
	DR. AUCHINCLOSS:  I'm going to push this on because we're going to start falling further and further behind.
	MS. FANO:  There are alternatives to xenotransplantation that are not being explored.
	DR. AUCHINCLOSS:  We're going to start this afternoon's portion now with the presentation from the FDA by Eda Bloom.
	DR. BLOOM:  A lot of what I have to say actually was covered in part by Dr. Dayton's talk earlier, so I'll gloss over what I think is redundant.
	First, I'd like to give a very, very, very brief background of where we've come from to be where we are at.  The first FDA announcement that xenotransplantation in any form was regulated by the agency came in 1993 with the publication of the application of current statutory authorities to human somatic self-therapy products and gene therapy products wherein we mentioned that xenogenetic cells would be regulated.
	For a xenograft product or a xenotransplantation product IND submitted to FDA came in 1984, and immediately raised some concerns within the agency and in fact within the whole Public Health Service as well as the public for the transmission of xenogeneic infectious diseases to patients and potential possible subsequent transmission to close contacts and to the public.
	That was followed by a whole series of meetings and consultations and resulted in the issuance by the Public Health Service of the draft guideline in 1996 on infectious disease issues in xenotransplantation.  For those of you who want to know when the revised version is coming out, it's coming out.
	There was another series of public meetings held by the Public Health Service including FDA and NIH, and just this past year, as has been alluded to, we issued the guidance for industry on the use of nonhuman primate xenografts, and then the more recent guidance document on blood donor deferral has been discussed.
	Andy showed these definitions.  I don't believe we need to spend a lot of time, but I do believe it's worth showing them again because, again, the expanded definition which was first published in April of last year, however, which had been spoken about in public meetings prior to that point, is the human body fluids, cells, tissues, or organs, this is part B, that have had {IOn}ex vivo{IOff} contact with live nonhuman animal cells, tissues, or organs, are considered xenotransplantation.
	The product is just the live cells, tissues, or organs used in xenotransplantation, and this is intentionally crafted to include both the human cells that may be administered after {IOn}ex {IOff} {IOn}vivo{IOff} contact with animal cells, or the animal cells, and so forth.
	The rationale for the expanded definition has already been discussed. Because of certain {IOn}ex vivo{IOff} exposures of which we were aware including extracorporeal perfusion which could have been taken care of in itself by just saying and extracorporeal perfusion, but also there is the instance of coculture for example with the early embryonic development on primate feeder cells.
	The definition also includes all nonhuman animals because cross-species infectivity of viruses are not always predictable, and this is another issue that we'll revisit in the second part of this afternoon's discussion.
	Implications from the definition are that xenotransplantation encompasses a diverse range of products.  Valuable information and guidance for sponsors of such products has been provided in the Public Health Service guidelines and the revised one when published, and the FDA guidance documents.  FDA must consider, however, the particulars of any given application and the proposals of its sponsor which may differ from this suggested in the guideline and may be equivalent or perhaps even better than what the guideline has suggested, and we must determine whether these suggestions adequately address the applicable laws and regulations, including those intended to address safety.
	I also wanted to make the point that continued public discussion of these risks will be an ongoing issue and of these definitions.
	We wanted to first discuss Epicel as a xenotransplantation product, and you heard before lunch a nice description of the product; that Epicel is a human autologous skin cell keratinocyte product that has been expanded on irradiated feeder layers of murine fibroblast 3T3 cells from NIH 3T3. It's a long-established and well-characterized cell line and maintained using a cell bank system.
	Now, we'd like for you to consider the recommendations made in the Public Health Service guideline and the FDA guidances, and we request input from the committee on what would constitute acceptable and appropriate approaches to addressing the risk of transmission of infectious agents by this particular product, and this will be our first set of questions.
	However, first I wanted to give a brief review of the recommendations, so that, although, we've recently discussed the blood-deferral document, just for the sake of being able to consider the questions, a brief review of the 1996 Public Health Service guideline because that's the one that's out there currently.  These will not cover the all of the recommendations in the guideline and will gloss over or abbreviate, although I think you'll find that, Dr. Vanderpool, I'm not very succinct, so maybe you'll like these.
	We recommend that regarding herd and colony surveillance that the source animals used to produce xenotransplantation products should be from closed herds or colonies with documented health-surveillance programs and appropriate staff to person these colonies.
	The colony should have standard operating procedures that govern such broad range of issues as animal admissions, movement through the facility, disease monitoring, isolation, cleaning, disinfecting, source and delivery of feed and water, measures to exclude arthropods and other animals that could transmit new diseases, animal transportation during which an animal conceivably could be infected, dead animal disposition, and criteria for screening and surveillance of the humans entering, and permanent individual animal identification.
	Again, regarding the herd colony and surveillance program, the veterinary care should include traditional physical exams and standard laboratory tests, but also should include monitoring for infectious agents that may not be clinically apparent.  Such monitoring should include collecting of blood samples and testing of such blood samples, and archiving of such blood samples.  We also have recommended the use of sentinel animals.
	Again, regarding the source animal, animals need to be individually qualified, individually screened.  They should come from documented lineage and from closed herds or colonies maintained using the appropriate barriers and means to minimize exposure. It's recommended that source animals be quarantined for at least three weeks prior to their use; that appropriate physical exams and tests take place during that quarantine. Again, the transportation of animals or products should maintain appropriate protection.
	We also recommend source animal archives and records that can be a linked records system documenting the use of the source animal and including all the animal health records.  The archive should contain also banking of source animal biologic specimens that should be accessible and linkable both to the source animal and to the recipient's health records, so that it would be easy enough to link a xenotransplantation product recipient with a source animal.
	Now, regarding screening of the product, we've made a few recommendations regarding pre-clinical studies and assay validation.  In pre-clinical studies, some of them, not all of them, they should be aimed at characterizing potential for pathogenicity of microbial agents identified in the product including endogenous retroviruses.
	As always with all products, assays need to have well-documented specificity, sensitivity, and reproducibility, and these would be whether they're performed on the herd, colony, or xenotransplantation product.
	Again regarding the product, there are recommendations that have been made regarding screening for infectious agents. The assays and programs appropriate for species and clinical application should be employed.  Samples of the product should be tested, that's of the final product as much as possible.  Aseptic conditions for procurement and processing need to be employed.  We recommend that tests include cocultivation assays to detect viruses that may not be detected by other assays.
	We recommend a necropsy at the time of euthanizing the source animal which may or may not be at the time that the product is obtained, and such necropsy should include gross histopathological and microbiological evaluation.
	The nonhuman cells should be archived, that is, an aliquot of the product used to product each lot of the product.  I say this because, again, we have products that may be xenotransplantation products comprised of human cells, but this is the animal component.  If it's not possible to archive an aliquot of the product itself, a proxy of the product may be used.
	In cases where human cells, tissues, or organs have had {IOn}ex vivo{IOff} contact, both the animal cells, tissues, and organs need to be archived as well as the final product which would be the human cells.
	Regarding recipient education and surveillance, we had some discussion this morning about recipient education vis-a-vis the guidance for blood donating and deferral. The informed consent should comply with applicable statute as always, but should also add the potential risk of infection from zoonotic agents, the potential risk of transmission of unknown xenogeneic infectious agents, and the uncertainty of the course of such infections, so that the potential recipient is informed of these.
	In addition, they should be informed of the potential for transmission to others, and information regarding use of barriers during sexual intercourse.
	Any need for isolation or specialized precautions need to be described in the informed consent along with a description of life-long surveillance and reporting of serious or unexplained illnesses to their physician, so that there is guidance upon which to educate the recipient on these issues, as well as that they should be indefinitely deferred from donating blood and tissues for use in humans.
	Again regarding the recipient education and surveillance, the 1996 guideline makes explicit and specific recommendations regarding clinical and laboratory surveillance, an active laboratory surveillance program, and with special attention to acute infectious episodes.  It also mentions behavioral modifications such that the recipient and close contacts need to be informed regarding the possibility of risk from xenogeneic infections.
	The 1996 guideline didn't place the responsibility I believe so much on any one person at that point, but there has been significant public discussion beyond that guideline.  Education should address behaviors known to transmit infectious agents and methods to minimize the risks.
	Archives and a database need to be established for the recipient as well as for the source of the xenotransplantation product, and a very specific schedule of pre- and post-transplant collection of biological specimens was recommended in the guideline.
	The guideline also mentioned a database which maintains records with the ability to link information.  I should add that there have been actually presentations publicly that there such a database in existence in pilot form at this point.  The development of this database is very central to the development of the xenotransplantation regulatory environment.
	Public Health Service and FDA made recommendations regarding, again, recipient education surveillance regarding hospital infection and control and health care workers.  Use of standard precautions and education of health care workers and surveillance of health care workers were all recommended.
	This is just an extraordinary brief summary of what you've spent most of this morning on regarding blood-donor deferral. The xenotransplantation product recipient should be indefinitely intimate.  I didn't have the chance to change the slide. Contacts should also be indefinitely deferred if activities could result in exchanges of body fluids.  We had, but I probably should cross that out, about the health care workers regarding indefinite deferral for percutaneous exposure.  That exceptions may be granted by FDA especially for well-characterized cell lines or exposure across a barrier.
	The firs set of questions that we wanted to address are now in regard to Epicel, and as you have heard, Epicel is one xenotransplantation product that is currently under review by FDA.  It is an autologous human cellular skin replacement product in which the human cells have been expanded on a mass feeder cell layer.  The agency will request input from the committee regarding what would constitute acceptable and appropriate approaches to addressing the risk of transmission of infectious agents by this product.
	Considering the general recommendations made in the draft guideline which I have just summarized, and also considering the specific case of Epicel, we'd like for you to discuss the following specific recommendations proposed by CBER at FDA and whether you agree with the proposed FDA approach.
	DR. AUCHINCLOSS:  Eda?
	DR. BLOOM:  Yes?
	DR. AUCHINCLOSS:  I think I would like to use this if it's all right with you unless you have a conclusion built into this, if we just go ahead and start addressing these questions one by one as they come up. Is that all right with you?
	DR. BLOOM:  That's absolutely fine, and this will be the first one.
	DR. AUCHINCLOSS:  Good.
	DR. BLOOM:  So, shall I sit, and you can change them as you wish.
	DR. AUCHINCLOSS:  So, I think that the most efficient way to do this will in fact be to go through the FDA questions in sequence, but I think there are some additional points that may come up as we do that.  Then part 2 or Question 2 seeks to generalize beyond the Epicel case to look for principles that we think are important.
	But let's start with Question 1.a, regarding the animal procurement sources and source facility control, FDA believes that this category of safeguards need not be applied to Epicel, and I would agree. Discussion on that point from the committee, that when dealing with this kind of cell line, and this is again a general principle, that the source is really trivially important; the issue is the degree of characterization.  Any other comments to be made there?
	Now, I don't believe we're in a voting situation here are we?  You don't need a show of hands at this point which would ballots things up.
	DR. SIEGEL:  You may vote whenever you wish, but we're not dealing with regulations or formulating a regulation. We're dealing with getting.  So, if there's consensus we have the advice we need.  So, we're not specifically requesting votes on any of these.  Even if there's not consensus, we'll be getting the advice we need.  The votes I think are not specifically going to add --
	DR. AUCHINCLOSS:  I understand. When it's close it may be useful to have some show of hands, but I get the idea.
	So, let's go then to 1.b regarding pre-procedure screening of the xenotransplantation product for infectious agents.  FDA has requested tests of the non-irradiated and irradiated murine cell line.  Well, that strikes me as fine, and I guess it should be irradiated and non-irradiated, but what tests was more important than anything else.  So, what tests?
	DR. BLOOM:  I was just going to say to perhaps shorten it we had requested cocultivation assays.
	DR. ONIONS:  Yes.  I think wanted to make a kind of extension.  I'll stick to that.
	DR. AUCHINCLOSS:  I'm sorry, Dr. Onions.  The point you were making was that cocultivation should be one of them?
	DR. ONIONS:  Yes.  Definitely, yes.
	DR. AUCHINCLOSS:  Okay. Dr. Coffin?
	DR. COFFIN:  I would just like to make a general point, and I don't think we need to consider it specifically here, but a general point that I think the retrovirology tests in here are a little bit old-time retrovirology.  I think, the FDA needs in general to consider updating the tests to more modern technology involving things like PERV assays and PCRS-based assays and so on, and to get the vendors that sell these tests to the companies to develop them because I think it's just not the way to do it.
	I think the PERV people have sort of led the way in a lot of this, and we could take some guidance from what's been going on there.
	DR. ONIONS:  I think in fairness in defense I absolutely agree with that.  I think a PERV assay should not be cocultivation.  I think in fairness to the strategy as I understand it, some of this testing was done historically quite a long time ago.  It's just that our standards have perhaps changed, and I think all we're saying is that for a product now coming towards testing it should incorporate these kinds of approaches.
	DR. BLOOM:  Do you think that needs to be done in the case of Epicel?
	DR. ONIONS:  I think it would be advisable to do that, yes, because in a sense what you've got here is something rather different than a product coming off the cell lines we've discussed this intimate contact with human cells, and therefore I think it would be prudent to take those more stringent assays that both John and I are suggesting.
	DR. SIEGEL:  I should note that there is a lot of activity in FDA labs in our labs at CBER as well as in industry in looking at PERV assays for retroviral as long as you're talking about supplementing them on more traditional tests we'd be quite comfortable.
	The issue as to whether they're adequately validated to replace certain other types are issues that we have under investigation.
	DR. COFFIN:  Clearly a research program is desirable to get this in the correct place.
	DR. KASLOW:  I guess you could go a little bit further, potentially, in saying that not just for retroviruses or viruses per se, but for other organisms and agents there are a whole new battery of tests coming on line, representational difference analysis and other sophisticated tests that may be used to identify nonculturable bacteria and other agents, and the question the FDA ought to address is at what point do we need to start incorporating those tests as a general rule.
	I don't have any comment about Epicel per se.  I think it depends on the literature on that cell line as to what the likelihood is.
	DR. AUCHINCLOSS:  Dr. Salomon wants to make a comment, and I'll come back to Dr. Onions.
	DR. SALOMON:  I just wanted to pick up and make a specific recommendation based on the discussion that we had.  So, what's missing here I believe is evidence that there isn't actually a xenotransplantation going on of the cells that are being used in the feeder layer.  So, to be specific, I think that there has to be, in addition to screening for infectious agents, it has to be clarified whether, A, the procedures that the company or producer has used to inactivate, kill, prevent replication, et cetera, of the feeder cell line are actually indeed doing so and to what extent that is.  Is it 99 percent which still means you have one percent competent cells, et cetera.
	Secondly, that the product itself is or is not free of the cell line from the feeder line.  Three, kind of related to both is, if it's not free, is it just that there's DNA contamination which isn't irrelevant actually because a lot of viruses and other things can be transmitted by naked DNA potentially, or RNA, I suppose.  Or is it just actually even there and alive, so, three things.
	DR. AUCHINCLOSS:  Dr. Onions?
	DR. ONIONS:  I just wanted to sort of extend the point, I think it was very important that the procedures used in preparing the product are actually tested. In other words, not just testing a cell line, but testing in this case the fact that the cells were irradiated because that can affect certainly endogenous retrovirus production.
	But it's also worth bearing in mind that certain other latent viruses can be affected by a number of procedures and one of those procedures could be the actual interaction between a human cell and the cell line through circovirus and so on.  I'll use the example again, for instance, the circovirus CCPK 15 is not normally expressed but can be induced by a variety of different insults to that cell.
	So, those kinds of interactions may also be important for us to see that, in fact, at least a final product had been tested.  Perhaps in part of these testing procedures you should at least consider validating a final product initially and perhaps when any key reagent is changed.  For instance, if you change a batch of SES that might be carried over in a procedure or it's used to stabilize the product at the end, perhaps you should then test as a kind of validation procedure just a small part of a lot -- that change.  So, those are the things that I would perhaps put some emphasis on.
	DR. AUCHINCLOSS:  I agree with everything that I have heard, but I want to put out a comment and see whether the committee would agree with it.  Perhaps there's a 3T3 cell there in the final product or some of them, but this form of xenotransplantation that we're talking about where the real product is in coculture {IOn}ex {IOff} {IOn}vivo{IOff} and the goes into a human being strikes me as vastly different from xenotransplantation that we ordinarily talk about where there is immunosuppression involved.
	Now, I understand that some of these recipients may be immunocompromised, burn patients, et cetera, but I still suspect that those 3T3 cells, the five of them that go with the product, are there for about 24 hours and gone.
	DR. SALOMON:  That's fine.  That's a reasonable statement.  I'm not sure of that, by the way, but it's possible.  But my point is the same.  We're looking for general precepts of what should be demanded or not, and I'd like to know.  Then if that were true, if I knew there were competent replication, competent 3T3 cells, in the final product then I would ask perhaps for skin biopsies at three months and six months to look for microchimerism for malspecific DNA sequences.  Something very simple like that.
	It turns out, John, that in the experience with transplantation chimerism that peripheral blood is pretty poor after about seven to ten days, but that skin biopsies and, well, of course, you can't do liver biopsies, have been much, much, much more sensitive, that's my only point, because dendritic cells are important in that.
	DR. COFFIN:  Kind of going back and cutting into this burned skin, I think it will raise a lot of resistance.
	DR. AUCHINCLOSS:  I want to bring this up another level again. Xenotransplantation creates risk for some very special reasons that are different from the ordinary environmental exposure to animal products and tissues.  The hundreds of times that a mouse has bitten me over the course of my career has exposed me to lots -- if a 3T3 cell got into me, it wouldn't bother me one iota.
	So, I think that we're getting a little carried away about the exposure to these cell lines even if it occurred that might come through the {IOn}ex vivo{IOff} cultivation process.
	DR. SALOMON:  I guess all I'm saying is you're implying that I would take a position that if I was told there was 3T3 cells that were living in this product that I would say that you can't use this product, and I'm not.  However, you're putting it in a place where there's been a full-thickness skin burn and you're transplanting it there, and I don't think the immune system is working all that well on that site in patients with a 70 percent total body burn and a mortality of 50 percent or greater.
	DR. AUCHINCLOSS:  I would still suggest to you that in the ordinary course of nature there has been more exposure of mouse tissue to humans in various immunocompromised ways than will ever come up with through xenotransplantation.
	DR. SALOMON:  Fine.  Then just do those things with your eyes open.  That's all.
	DR. AUCHINCLOSS:  The FDA's statement is correct, and we accept it, and we've amplified it by talking somewhat about additional tests that might be appropriate. The part 1.b goes further and says archived samples of xenotransplantation final product and nonhuman cells, tissues, or organs involved in manufacture, FDA requests the retention of samples of murine cells and the final patient product be archived. Dr. Onions, this is essentially what you said, is that correct, that you want final product?  Well, you want it tested.  They're saying archived.  You want it tested periodically?
	DR. ONIONS:  Yes.  My working suggestion is that when critical factors are changed in the manufacturing procedure. Clearly, when you first start doing it you want to validate the final product.  But when you change a critical factor in the manufacture, that might be a lot of a particular reagent, that you then validate the final product.  Perhaps presumptively with that it would be advisable to store material if you ever got a question that you need to go back and independently check it. So, that would be sensible.
	DR. AUCHINCLOSS:  I guess I did have question.  In a certain sense, archiving final product sounded like it could be extraordinarily cumbersome.  Does this mean that there are 552 samples that you wish were archived of Epicel?  I guess that is what you mean.
	DR. BLOOM:  That's what it means, yes.  Actually, the nature of the product is that it's a cell layer which would make it a little bit difficult to obtain a little portion of the cell layer without disrupting the cell layer.  So, it would have to be taken a little bit before the final product, and they could do that.  But yes, and I think that they actually have a number of stored vials of cells as they're proliferating along the way.  So, it's not one or three vials additional.  It's probably not an enormous amount.
	DR. NOGUCHI:  Also just as a biological product principle fairly standard because very often you may have a contamination problem and you want to go back and see is it the product, is it the hospital, and so forth.  So, it's not too uncommon.  The fact that it is a cell layer a little bit uncommon, but archiving in that sense is pretty usual.
	DR. AUCHINCLOSS:  It is usual and not cumbersome.  So, anybody want to say that this is unnecessary on our committee, or should we push forward and suggest that archiving of final product is appropriate? Yes, Dr. Vanderpool?
	DR. VANDERPOOL:  If indeed the pre-tests and post-tests are done and there's no evidence of xenotransplanted activity, why would you need to archive?  I mean, it seems to me that the answer to this question over archive activity could be answered, and the extent to which archival work would have to be done, would be in part on what the pre and post-testing might show.  I mean, this not be a xenotransplanted product by the time they get through with all they've done, and plus irradiation.  It may not be.  So, why archive that under xenotransplanted rules?
	DR. AUCHINCLOSS:  I think you're coming to the heart of the question:  Do we really think we really have a xenotransplant when the cell line has been characterized in the manner in which we're talking about getting it characterized?  I think that will emerge a little bit further in these several questions where it becomes operational.
	But archiving is such an ordinary thing that I guess I was sort of saying to myself that's not the place where you'd start quibbling.  Archiving sounds reasonable. It's going t come up again.  Your question?
	DR. ROSE:  Harold, the other thing is you don't know what you don't know is the point.
	DR. VANDERPOOL:  What I'm saying, in the light of the earlier discussion over hey we need some better pre-testing and we need some post-testing, and if the company would indicate that none of those gives any evidence of live xenotransplanted cell activity, then I think we're home free on this.  I don't want to say this should discourage archival work.  Seems to me that could be done anyway, but maybe not archival, maybe I'm not clear on this, but archive every patient, every procedure when it's done?  I don't know how extensive the archival work would need to be.
	DR. AUCHINCLOSS:  Go ahead.
	DR. SIEGEL:  Just to address that, even if the cells are completely gone we can show that it's still possible the issue was infected with something that we don't know about, and I think it would be very important to have a way to trace it back later on, if something came up.
	DR. AUCHINCLOSS:  Dr. Hollinger?
	DR. HOLLINGER:  It also depends a little bit about what they're talking about or what they're putting under a xenotransplantation final product or the other things, because I think that if they're going to use something like fetal bovine serum in the product, then, that, at least somewhere along the line, has to be tested or at least made certain that it doesn't have any viruses in it as well.
	So, it's not just necessarily the final product.  If it's a serum-free medium, then that's not an issue.  But if it's going to have serum in it, then that has to be looked at somewhere.
	DR. ONIONS:  I'd just like to get back to this issue of testing lots of final product because clearly you can't do this on very patient this is a time-limited procedure.  You've got to go back into the patient.  I want to make clear that I didn't mean that every new sample had to be tested. I did not mean that.  What I meant was that, actually using serum is quite a good example where, for instance, we now have concerns about new agents that I don't think were included in that testing strategy, things like the bovine parvovirus where that virus certainly can infect human cells and may be a true zoonotic virus.
	So, where you change lots of materials, you test the fetal serum, but you probably also ought to test the final product that's been produced with that using epithelium cells that you may have banked from a donor, or that you can use in this kind of validation procedure.  That's really what I was trying to get at.
	DR. AUCHINCLOSS:  Any other comments about arching samples?  Now, Questions C, D, and E are variations on a theme, and I'm going to suggest that we turn to 1.e as the next question.  The only reason that I'm going to turn to 1.e is that it's the blood-donor question, and since we spent the morning there we'll feel very comfortable that we know that we're talking about.
	So, 1.e is FDA recommends that information on blood-donor deferral be made available to the recipient and requests the committee's opinion on whether deferral should be recommended for, number one, xenotransplantation product recipient.
	Now, specifically this is Epicel. Tested in the way that we've seen so far, perhaps one could add further tested more with coculture and as modern techniques become available.  Do you believe, as the FDA recommends here, that the person who got Epicel should be told that they had a xenotransplant and they should never be a blood donor again?
	DR. ONIONS:  I think I would be content for deferral is not necessary provided these additional upgraded types of modern testing are put in place.  I think that would be acceptable.  That's my viewpoint.
	DR. AUCHINCLOSS:  I'd really like to get input on this from around the table from anybody who thinks they have expertise. I think it's a critically important question. Is this so well characterized that for all intents and purposes they didn't have a xenotransplant, which is what I think we're saying here?
	DR. ONIONS:  I should also say that I agree with Dr. Salomon.  I think he's made a very good point that really we don't quite know that the final product is and it would be better to have better characterization of the final product in terms of cells, I mean, I understand that facts work is being done, but I think I share Dr. Salomon's concerns about the limitations of that.
	DR. AUCHINCLOSS:  Jonathan?
	DR. ALLAN:  I'm a little stuck in the middle on that question because even if you do all these tests and whatever, there's always a possibility of something that will be discovered ten years from now that's a new class of agent that was transmitted in this or whatever.  So, I'm sort of straddling the fence on it myself in terms of whether to do it or not.
	I think a lot of people are sitting here with the same sort of attitude.  I'm not quite sure.  But in the end, I think you can err on safety and just say deferral for these recipients as you have listed would be the simplest way to handle it.  That way you eliminate any possibility.
	DR. AUCHINCLOSS:  It's not simple, obviously.  It's possible.  Again, it goes back to scope and scale of the morning, where at this point what we'd be saying if the answer to this is no, they haven't had a xenotransplant, then the people who are being blood deferred are the 50, who had a different kind of xenotransplant and their intimate contacts the way we talked about this morning.
	But if you say yes here, then their blood pool and the plasma derivatives that we were talking about this morning are subject to recall for all 552 people if ever were blood donors in the past.
	DR. COFFIN:  Hugh, but I think there's a distinction here that if I hear John right and David and Dan, since you're not sure what the final product is, then the question is the central one you got to, is this xenotransplant; is the cell line characterized enough to get to the central meat of what you're getting at.
	DR. AUCHINCLOSS:  As I was making clear or not making clear a little time ago, even if the 3T3 cells are there, I'm not worried about that as a way of transmitting new viruses or agents to the human population that would not occur in nature anyway, or could not occur in nature anyway.  We get exposed you and I to mouse or to pig or to a whole variety of animal viruses and tissues in a whole variety of ways.
	Xenotransplantation we've always agreed is a unique situation.  I think that the risk here in the {IOn}ex vivo{IOff} culture is only to the degree that the agent goes from the mouse cell to the human cell, and then with the human cell back into the body.  So, I'm not worried about the final product in that sense.  I'm worried about this conceivable risk of transfer {IOn}ex vivo{IOff}.
	DR. COFFIN:  I completely agree with what you just said.  What I'm torn the same way that John and I think David is sort of the risk-benefit.  I mean, the risk is extremely small, but on the other hand, the benefit of allowing these people to donate blood I think is also very small in societal terms.
	DR. AUCHINCLOSS:  Couldn't agree more.
	DR. COFFIN:  How is the balance, and I don't know actually.  I haven't decided.
	DR. AUCHINCLOSS:  Dr. Dayton?
	DR. DAYTON:  From a practical standpoint to throw this into the argument, this is probably a group that would be very effectively deferred by education and by the information they're going to receive during the treatment.  So, I think in this case deferral is certainly enforceable, if that makes the decision any easier.
	DR. ALLAN:  This is a little sticky too, but I mean, I guess the concern here is that you're going to have to go back and pull plasma, and if that's not a concern then like you said, I think the consent and just talking to the patients would ensure the safety.  So, I don't see a problem. Especially the way John mentioned it too, which is that it's not going to be that significant in terms of affecting the blood supply to defer these patients from donating blood.  So, why not do it.
	DR. HOLLINGER:  I have two comments.  One is that we're not talking about a large volume of patients necessarily unless the indications for use are expanded to include much small burns.  Secondly, regarding the point Dr. Dayton made is that we don't necessarily have a good educational pool particularly in the case of young children with extensive burn injuries, who as they become older perhaps their parents have died and they're not aware of what they went through.
	I even have a number of adult patients who we will graft, and because they tend to be relatively unconscious during the grafting procedures, even months later all they know is they got grafts, but they don't know much else about what happened during their hospital stay.  That's good, and it's bad.
	DR. ROSE:  But I'm going to throw it I think the way that Hugh was getting at it which is the Epicel is being used as a test case, i.e., you could say it's the best possible scenario.  You have a well-characterized cell line.
	So, whether you're dealing with 50 patients or 500 patients, a decision here has an effect of setting a bar for people doing blood donation, and if this doesn't meet the criteria, what are you going to set as the criteria to allow people to do blood donation.  Am I correct, Hugh?  That's where the discussion is coming from.
	DR. AUCHINCLOSS:  So, you that one look it in one of two ways.  You could ask the practical question, we know how Epicel was tested over the past five to ten years, and it's been out there and it's on people who were not cancelled, and so now there's a practical question, is if you say yes to this that they should have been deferred and they weren't, then you'd better start checking plasma derivatives that exist right now.  So, that's one level of practical question, and it could easily be that one would come to the decision that that was not necessary even though you wish it hadn't gotten to this position.
	Then you can ask the second question which is let's assume that the best testing that we can imagine is now in place in the future and that the situation changes. Now it becomes easy to give the patient education, but the question is, is it necessary or useful and it won't be just for these the next 552 patients, it will be for a large number of patients presumably who have similar kinds of {IOn}ex vivo{IOff} contact under the best possible circumstances.
	So, the committee members can try to address both of those.  Do we have to go back on what's happened before?  Supposing the best that you could ask for is being done in the future, do they have to be deferred, all of them?
	DR. ONIONS:  I just want to make clear that my comments were on the basis of your first question.  That is, I had assumed that there may be the possibility that you would have to go back and trace people and possibly pull plasma.  So, my statement was really colored by that position.  So, if you are asking the second question, and that is that should you defer patients now, if this is a new situation, then I think I would be more inclined to Jonathan's position and say, well, this is not, I assume, going to dramatically affect the availability of plasma in the United States, and it's just a simple act of prudence to suggest that they don't donate, and I think that it's not a major issue.
	So, if you're asking the second question, I would be in favor of deferral, but I thought we were primarily asking the retrospective question.
	DR. SIEGEL:  The question on the paper is about deferral.  I presume this committee believes that you can associate the answer to a question about deferral from a question about withdrawal given that I believe this morning you suggested that close contact should be deferred but that shouldn't be a basis for withdrawal of pooled plasma. So, I think there is some recognition here that it's not necessarily the same question. Right?
	DR. AUCHINCLOSS:  So, I think I heard that the committee, and this is broad because not everybody has spoken, but I think I heard that prudence, as in the future, no matter how good your characterized, contact with a xenotransplant in this form is grounds for the recipient being deferred.  You didn't like that?  Yes, Louise?
	DR. CHAPMAN:  I have a question for the FDA.  At the beginning of this you talked about, and some of the things said earlier about agreeing with the concept that for these sorts of exposures it might be appropriate for FDA to make deferral decisions on a case-by-case basis for the individual products.
	So, I'm a little unclear here about whether in this discussion you want the advisers to be having this discussion thinking about this product as one of those case-by-case deferral decisions, or this product, with recommendations they made now, being generalizable.
	DR. SIEGEL:  Both.  I think the committee said we should look at these on a case-by-case basis.  The second part of questions on this topic are going to ask the committee to talk about generalizable principles.  For example, is it that we don't need it deferred when it's a well-characterized cell line as some have suggested, or is it as Hugh has suggested we don't need to defer when it's not as highly immunosuppressed donor, what are the principles.
	But in trying to discuss the general principles in the past we have found that each product presents itself with a mixture of issues regarding not only how well-characterized it is, but what species it came from, how much the exposure is, are there cells transferred.  All the issues that have come out.
	So, what we would like would be what do you think we should do on this particular product, but I think all the discussion of that and the later discussion will help us make decisions on other products as well.
	DR. AUCHINCLOSS:  I think what I heard was that for this particular product don't go back and deal with things in the past, but in the future treat them as if, up your standards with some new assays, including coculture, and in the future those recipients of Epicel should be deferred as blood donors.
	Now, personally I don't happen to agree with that, but I think that's what I heard from the committee.  I think that it is possible to create a well enough characterized cell line that those patients would not have to be deferred, but I can't claim any great expertise on this.  So, that should be a very small opinion.
	DR. DAYTON:  I'm not a lawyer, but I think I'm becoming one, but I guess but disassociating withdrawn and deferral as we have done for the intimate contacts might be sticky in terms of liability or medical-legal implications.  But again, I'm not a lawyer, but I know that this is a worry for us.
	DR. AUCHINCLOSS:  It's illogical in a certain sense, but it's not fully illogical because it is a cost-benefit analysis.  To go back retrospectively and say oh, oh, we let them be donors and that's contaminated your plasma products out there, that's very costly.  But it's not costly to turn them in the future and say don't be donors.  That has no impact on the future blood supply.  I think we all agree on that.  So, while it's illogical, it's not unreasonable.
	MR. LAWRENCE:  Lawyers don't understand this any better than anybody else. How about political problems?
	DR. MICKELSON:  A lot of things change when you have to go into court and they read every way you dotted the I or crossed the T.  But I was wondering in this situation we're unable to arrive at any kind of agreement that some risk must be acceptable.  There has to be a level of characterization at which we can be satisfied.  Risk will never be zero.  NIH 3T3 cells, assuming that all those tests are carried out and turned out in a way that the results would support the fact that there's some minimal level of contamination that's below a level of detection with this cell line, we can't find it, it could be there, we're never going to find a way to answer risks that we can't identify.
	It's sort a part of being alive.  I mean, my gosh, we can eat peanut butter with little parts of insects in it and stuff like that, and it's good for you.  It's extra protein.
	I just feel that, in this particular instance, I think the suggestions of characterization of the product are certainly excellent suggestions, but to then talk about these patients, the people that would receive this, as requiring deferral, you will never get that patient population out of that category if we accept at this stage that the theoretical risk is so high that we can never answer the question that there is some unknown agent in that particular product.
	That's always going to be an issue so that none of these categories of people will ever be able to be moved out of deferral categories unless we begin to have some concept that there is an acceptable risk here.  I guess that's just a personal opinion, but there has to be some recognition that that happens, but that the use of this product and the positive aspects of it far outweigh this.
	I would be very uncomfortable with voting to defer because to me the characterization is not xenotransplantation.
	MR. LAWRENCE:  I would just remind everyone that there is a certain amount of risk inherent in transplanting human organs. As a recipient I can tell you, and I said this at a previous meeting of this committee, we're prepared to accept a certain amount of risk as long as it's a reasonable risk and everybody has done the best they can and the risk can be fairly well articulated and it's at a rationally low level.
	DR. AUCHINCLOSS:  Like remember the difference here.  I think we're willing to accept a lot of risk for the individual recipient.  The question is what risk are you willing to subject the population at large to.  That's the public health issue. Dr. Onions?
	DR. ONIONS:  I think the problem here is that we've really got two separate risks haven't we?  That there's the risk of an extremely improbable event of an agent getting into the blood supply and then being amplified through the blood supply.  That's a very improbable event, but with potentially disastrous consequences.  So, that's one element, and it's the element that drives Jonathan to take a precautionary view that go for deferral.
	The other risk is that if you apply this not just to this product but to many products, then you have the risk of jeopardizing the size of the blood supply and these interlinked but actually separate risks, and the problem seems to me that I am on the side of precaution when it's not going to affect the blood supply because why take that risk when it's not going to have any adverse impact.
	The problem arises when those number of treatments begin to affect the blood supply.  In effect you then alter your risk-benefit ratio, and that seems to me the problem.  But even doing it on a case-by-case basis is not entirely satisfactory because it turns on the total number of products out there.  But you may have to ameliorate and have to alter your views with time.
	DR. AUCHINCLOSS:  Dr. Vanderpool?
	DR. VANDERPOOL:  You asked for experts in the field.  That's why I haven't spoken up to this time.  From the standpoint of common sense, we told the FDA we would give them their ability to make judgments and it strikes me that in this case one should defer until they do the most recent pre- and post-tests.  But if those recent pre- and post-tests end up being nothing, quit having the people deferred.
	DR. AUCHINCLOSS:  So, it's a temporary deferral, but when the tests are done, they will show that they didn't have a xenotransplant.
	DR. VANDERPOOL:  Deferring deferral, right.  Then if those tests are all made when they presented all their testing, we saw nothing but negatives.  No evidence. No evidence of this.  No evidence of that. If they can say the same types of things, perhaps having people outside the company do the testing and they can still conclude that there is no evidence, then why continue deferral with the notion that one of these days ten years from now something might have ended up in the bloodstream?  That same thing could probably be applied for nearly every medical intervention you can think of, surgical-medical intervention.
	DR. AUCHINCLOSS:  Dr. Nelson?
	DR. NELSON:  Well, seems like we're almost presented a case like the Supreme Court, there's one person out there and we're testing some sort of abstract principles. But I'd be interested to know is this product unique, is it a loner in terms of the safety issues?  Or are there many others that are similar?  If there are many others that are similar, then I guess the cost-benefit is different because there might be a lot of donors deferred and they might have an impact and it's a risk we might want to take.  But if this is a unique product, then 500 donors, we can do without them.
	DR. SIEGEL:  The reason you are being presented this as a test case is because in fact there is a need for general principles because we are making decisions about a whole family of products.  As discussed earlier, not at the present time a large family, so you might argue with the 700, or whatever so far, and with however many more each year, 100 or 200, that you could just say defer everybody and wouldn't lose a large number of donors.
	On the other hand, there's a reasonable expectation that if one or another of these therapies proves effective and apparently safe for a substantially sized population that it may not be, and it hopefully wouldn't be the very distant future before we could be seeing much larger numbers.  So, I think that has to be borne in mind.
	Somebody made the conjecture, and somebody who probably knows about blood deferrals a lot more than I do, that once you defer a population it's hard to go back in the other direction.  So, if that's the case then I guess to make a very conservative approach based on a few hundred, once we're at a few tens of thousands it might not be, at least one has to look ahead to that situation.
	DR. AUCHINCLOSS:  Dr. Coffin?
	DR. COFFIN:  A few tens of thousands is still a very small fraction of the total population.  One percent of the population is several million people, and it's going to be a long, long time before one approaches that.  Sometimes this conversation sounds to me like we're treating blood donation as though it was a constitutionally guaranteed right and something the patient is --
	DR. AUCHINCLOSS:  In my view, using blood transfusion as a way of defining did the patient have a xenotransplant or not, and can you dispense with is the level of risk so low that you can dispense with the whole gamut of precautions that we're talking about for xenotransplants.
	DR. COFFIN:  I'm not comfortable saying that yet, I think.
	DR. AUCHINCLOSS:  That's what I'm pushing you on, and I think that blood donation is as clear an example of where you would consider the risk to present that that's why I'm pushing the blood donation.
	DR. COFFIN:  Again, I think the net benefit is so small, at least looking forward, that I would certainly think the case is quite strong for recommending deferral and revisiting the issue if it becomes important at a later date.
	DR. AUCHINCLOSS:  Can I ask you or the three of you and anybody else who claims any expertise, can you imagine a contact with a nonhuman cell line {IOn}ex vivo{IOff} which was so safe that you really would dispense with this conversation, the Drosophilia cell line.
	DR. COFFIN:  I think with insect cell lines I would certainly imagine that we could have a conversation that would turn out differently.
	DR. AUCHINCLOSS:  Nonmammalian cell lines in general?
	DR. COFFIN:  No, not nonmammalian, no.
	DR. AUCHINCLOSS:  Can you tell them some things?
	DR. COFFIN:  Vertebrates.  I would draw the line between vertebrates and invertebrates.
	DR. AUCHINCLOSS:  So, invertebrate cell lines, they're going to be characterized and tested?
	DR. COFFIN:  Probably not.  I mean, look, this is off the top of my head, but probably not the way I would think about it right now.  John?
	DR. ALLAN:  Can I just caution a little bit differently, and this may just be a particular case, and it's something I'm not suggesting that anyone do or change or whatever, but part of the interest here is using a mouse feeder layer essentially to grow these human cells, and that's a xeno.
	If you say, well, it's not that dangerous and we can allow blood transfusions or whatever, then you're basically saying that mouse cells are okay.  Because the other question is could you use human cells because of the mouse cells as a feeder layer.  In other words, do you have to have a xeno?
	I'm not saying they change at this point, but in terms of you might want to consider that because if you say that this okay then they don't have to use human cells, they can continue to use mouse or monkey or whatever cell type there is.
	DR. AUCHINCLOSS:  Well, I think for sure for the point of view of the conversation we ought to assume that the mouse cells are necessary.  It may well be that they're not.  I mean, there are people who go -- but that's not useful.  What we want to do is push this case, that you only get this product with those cells there. Okay?  That's the assumption you should work with.
	David, what would be the characteristics of exposure {IOn}ex vivo{IOff} that you would consider to be so safe you'll dispense with precaution?
	DR. ONIONS:  That's difficult to do in a kind of theoretical vacuum, really.  I suppose insects cells still need testing, but insects cells don't actually release retroviruses, as well.  Yes, I think probably if you could demonstrate, and I think Dan's point is a very important one, that is that there is no evidence that whatever stringent criteria we want to put in that there are viable xenotransplantation cells left in and that cell line has been characterized or whatever the monoclonal acceptable criteria are.  Yes then in general as a general principle I will go along with that as being a non-xenograft, if you like.  It's been exposed to materials, but it doesn't require all these precautionary steps that we've been discussing.
	DR. SALOMON:  I actually want to amplify that in the sense that what I'm hearing at this point is that the committee has gone too far in the direction of the precautionary principle in the sense that what you said, John, is absolutely correct of course, we'll never know for sure.  We've got to stay somewhat based on the facts here.
	Otherwise what we're setting here as Steve points out bars that are just impossible.  So my feeling is that with respect to the Epicel as the model here, I'm pretty sure you could get around most of the objections that we've brought up and come back here with some decent testing, and I probably would be ready to actually then say that this is not a xenotransplant product and that it could be safe and these people could be blood donors.
	DR. KASLOW:  It seems to me that the most important advice we can give to them because I think they've probably heard all of the discussions so far, is maybe to take a position that we very strongly believe that deferral should be reversible, that we should be able to make a decision now that can be changed later and let it be cast in capital letters that that's the strongest advice we can give them in whatever decision we make.
	DR. AUCHINCLOSS:  Now what I want to do is try to summarize where we are on that and then try to wrap up what I think will be -- well, we'll see.  Never mind. Don't prejudge it.  So, in response to 1- E, what I think I've heard is that the best experts think that the likelihood under the best testing conditions that you can develop for Epicel of there being a danger of viral transfer to the product is really tiny and remote, but nonetheless prudence on the part of our experts leads them to suggest that you should still recommend deferral for the recipients of that product is what I think I heard.  You're laughing.
	DR. SIEGEL:  The best experts recommend that, meaning the other experts who recommended something different weren't the best ones.
	DR. AUCHINCLOSS:  Okay.  Sorry.
	DR. SIEGEL:  Sorry.  I couldn't resist that.
	DR. AUCHINCLOSS:  It was not meant in that manner.
	DR. SIEGEL:  I don't anyone to go away offended.
	DR. AUCHINCLOSS:  What I think I was saying is that I don't claim any expertise.  Those guys can claim expertise. So, the experts say that the risk is very small but they still feel it's prudent to defer recipients of this product.
	DR. SIEGEL:  I guess the reason I asked that though is I guess, did not some of the experts say they wouldn't recommend blood deferral at this point in time?
	DR. VANDERPOOL:  Didn't we hear David change his point of view and say, look, when the testing is clear and negative then deferral is no longer --
	DR. AUCHINCLOSS:  Let's actually give me a show of hands on this one, and we don't characterize who's an expert and or not an expert.  I categorize myself as a nonexpert.  The statement is that the risk is considered extremely low with your best characterized 3T3 cell line.  Given that it's very low, would this committee recommend that these recipients of Epicel be deferred as blood donors?
	DR. HOLLINGER:  With the caveat that these other things be looked at that were mentioned today such as the bovine serum and the cells and --
	DR. AUCHINCLOSS:  Yes.  We're going to have testing to best available testing with modern technology.
	DR. ONIONS:  Can I also ask implications for withdrawal, because that's what influenced my change of opinion.
	DR. AUCHINCLOSS:  Yes.  We are not talking about patients who have already --
	MR. HOLLINGER:  You're saying we can't?
	DR. ONIONS:  We can't say that.
	DR. DAYTON:  It's very hard to isolate withdrawal.  I know there was a preference for that this morning, but it creates problems for us.
	DR. HOLLINGER:  You're talking just about withdrawal of the product that's available not in a pool.  You're talking about unpooled?
	DR. DAYTON:  I'll have to think about that, but yes, for certainly for pooled material there's a tremendous problem if you disassociate --
	DR. HOLLINGER:  Yes.  I understand that.
	DR. DAYTON:  I think it puts it in sticky position if you're saying, well, from a medical- legal standpoint we recommend that this category of donor be deferred, but then we don't do the withdrawal.  So, it's not an easy thing for us to do.
	DR. AUCHINCLOSS:  But nonetheless, I don't think we're here to make your life easy.  I think we're here to give you our sense of the degree of risk and what you can do about it.
	DR. SIEGEL:  It should be noted that in the proposed document, which I think went through Jay and others, we did draw a distinction for example between recipients of nonhuman primates where we deferred but didn't withdraw.  So, there must be thinking that that's doable.
	DR. DAYTON:  Actually, I think the way we originally proposed it we would have withdrawn for nonhuman primates.
	DR. SIEGEL:  Right.  But for other than nonhuman primates we said deferred, but we wouldn't withdraw.
	DR. DAYTON:  For product withdrawal for pooled material for other than nonhuman primates.
	DR. SIEGEL:  Right.  That's what I was trying to say.
	DR. DAYTON:  We were not withdrawing.
	DR. AUCHINCLOSS:  Show of hands. Who thinks that these recipients of this product in the future best testing should be deferred as blood donors?  Who on the committee?  Hands up high.  Best testing.
	DR. VANDERPOOL:  Best testing which is negative?
	DR. AUCHINCLOSS:  Absolutely.
	MS. DAPOLITO:  Four yes.
	DR. AUCHINCLOSS:  The show of hands is good here.  Now the other way.  They do not need to be deferred.
	MS. DAPOLITO:  Did I miss somebody?
	DR. AUCHINCLOSS:  Future.  Best testing, future.
	MS. DAPOLITO:  I get 10 not deferred.
	DR. SIEGEL:  Let me clarify.  When you say in the future, you say specifically we're not talking about withdrawals?  I'm not sure that there's been a vote that we not notify people who've already received this product, that if we were to defer people who receive it in the future, this vote wasn't saying we shouldn't notify people who've already received it that they're not deferred, it's only future people who are deferred.  Right?
	DR. AUCHINCLOSS:  I think it should be possible from here to go back to --
	DR. BLOOM:  Hugh, I have one more question.  I'm sorry.  I have one more question for clarification on that vote. When you talk about best testing for the future does that mean patients that are getting it right now prior to the best test, they should be deferred, and then as Dr. Kaslow says since it's possible then to not defer?
	DR. AUCHINCLOSS:  I think it's an FDA detail.
	DR. HOLLINGER:  Just one other question just for clarity, if I could.  As you know there are perhaps three kinds of deferral one of which we usually don't use, but a temporary deferral which really means soon you'll be able to donate.  Then there's indefinitely deferred which I've always interpreted meaning it's indefinite, but you could in the future be allowed to donate.
	But as the blood bankers will tell you, it is hard to get those people back into the pool again.  Then there's permanently deferred which is just what it means, permanent.  So, we were talking here indefinitely, but deferred.
	DR. AUCHINCLOSS:  In my view, this is a constantly evolving field where information is getting better and better and we're learning things and I could imagine that deferral now could stop being deferral in 5 years, but practicality-wise it may turn out that way.  So, do any of the people who said that the individual recipient should be deferred feel that that should not extend to their intimate contacts?  It should not?
	This would be just the recipient who would be deferred?  So, contact-wise, don't worry about them.  Because, again, it's all relative risk.  Right?  The relative risk is just so low that you've gotten to the point where the vanishing returns.
	DR. NELSON:  I had possibly an irrelevant question, but when you showed all the slides about the procedures for people receiving these transplants, you talked about that they should have protected sex.  Does that mean they're now not told they can't have children after they have this 3T3?  If so, what's the basis for that?  You're assuming it's sexually transmitted or there's something there?
	DR. BLOOM:  We're assuming that it could be possibly, it being whatever may be there could be sexually transmitted on the basis of previous --
	DR. NELSON:  I can't see any basis for that.  It's kind of crazy because here we have hepatitis C which we know there's some evidence of sexual transmission even though not common, and we're not recommending that these people who are carriers of hepatitis C have protected sex.  But here we've got somebody that we don't know that they're infected with anything.  It's not only the protected sex issue.  It's the not having children that I think could affect some -- and I don't see any basis for that.
	DR. AUCHINCLOSS:  I think we're back to question 1-C.
	DR. BLOOM:  Right.
	DR. AUCHINCLOSS:  So, how do you educate the recipients of Epicel in the future with best testing in place?  Do you tell them that they had a xenotransplant with the implications as outlined by Eda Bloom earlier for what that means which includes some of the things you were just talking about?
	DR. SALOMON:  Hugh, remember, one of the things that came out here is the possibility of exempting this as a xeno-product if the best testing is completely negative.  I believe that that's an option here.
	DR. SIEGEL:  Well, we can exempt any of the requirements we want to.  There's a written definition of a xeno-product.  You can't change that definition for each product based on its testing.
	DR. SALOMON:  What do you mean then that the FDA on a case-by-case basis can exempt a product?  That's what that meant.
	DR. SIEGEL:  It means exempt it from any of the guidelines that suggested somebody needs lifelong follow-up, that they need animal testing.
	DR. SALOMON:  Jay, that's all I'm saying, you could do that with this case.
	DR. SIEGEL:  I was just objecting to the notion that we'll say this isn't a xenotransplantation product.
	DR. SALOMON:  No.  I'm sorry.
	DR. SIEGEL:  Okay.  Right.  Right.
	DR. AUCHINCLOSS:  This is a xenotransplantation product that does not require blood donation deferral.
	DR. SALOMON:  But it's exempted from the thing.
	DR. AUCHINCLOSS:  Does it require patient education.  That's where we're at right now.
	DR. SALOMON:  I don't think it does.
	DR. CHAPMAN:  Could just clarify something with regard to your question?  I'm counting on the FDA and Steve to correct me if I'm misstating this.  But what the PHS guideline, both the draft guideline, and I don't believe this has changed in the revised one, say about the issue you brought up.
	It doesn't say xenograft recipients should be told that they should never have children.  What it says, the language that is used in talking about the informed-consent process is that they should be counseled about the uncertainty that exists; that they by getting this product are accepting some risk of infection that cannot be eliminated and they should be aware, and they are responsible to educate their sexual contacts that there may be some risk that extends to sexual contacts, and they should be aware if they're considering future child bearing that there may be some risk with a great deal of uncertainty about whether it exists no ability to quantify it to future offspring and that may be a transmissible activity.
	They're not told not to do it. They're advised to be aware that safety can't be entirely guaranteed and there be some risk to them and their partner and their offspring.
	DR. NELSON:  I didn't hear any data presented that there is a risk.
	DR. CHAPMAN:  There is no data.
	DR. SIEGEL:  This has been discussed at several other meetings.  I would just suffice to summarize that there are unknown risks and that we've been advised by many individuals that some of the unknown risks of greatest concern are those that can cause latent infection that may not be picked up in the immediate post-transplantation period such as say herpes viruses or retroviruses and that those are often sexually transmitted or blood transmitted, and that underlies some of these concerns. But I guess there we're talking theoretical risks.  We're not talking about documented risks at this point in time.
	DR. AUCHINCLOSS:  Let's take a show of hands on it.  Does the committee believe that the recipient of the product made with best-tested Epicel, should that recipient be told that they had a xenotransplant in just the way that Louisa characterized for us, the kinds of education that Louisa characterized for us?  Yes, or no.  Those who feel yes, show your hands.
	MS. DAPOLITO:  I have six.
	DR. AUCHINCLOSS:  Those who feel it's not necessary to go ahead with education as if they had had a xenotransplant.
	MS. DAPOLITO:  So, that's six.
	DR. MICKELSON:  I want to abstain too.
	MS. DAPOLITO:  So, that was --
	DR. AUCHINCLOSS:  So, it's something like --
	MR. LAWRENCE:  Hugh, we're trying to have it both ways here, and it's very difficult.  You can't on the one hand have a risk that's so low that it's negligible and on the other hand be warning patients that they have this risk that they need to be aware of.  So, these votes are muddied to me.
	DR. AUCHINCLOSS:  These are muddy hearings.  Let's talk about the database. They want to know about the database.
	DR. SIEGEL:  I think we have extensive frequency of follow-up.  I guess part of that also is extent and frequency of follow-up.  So, the guidelines for example talk about lifelong follow-up on recipients including reporting of infections to the sponsors of the trial or of the xeno-product and so forth.
	I think that's an interesting area that there ought to be some specific comment on.  You want to product more clarification as to what the guidance has said for example in that area?
	DR. BLOOM:  The original PHS guideline said something like I think it was a couple of samples prior to transplantation which clearly is not going to be possible I suspect here.  At the time of transplantation, 1 month after, 2 months after, 6 months after, and then annually.  So there are very specific recommendations.
	DR. SIEGEL:  You're talking about archiving samples.  I guess I'm also talking about giving instructions to the patient regarding medical follow-up.
	DR. BLOOM:  Right.  But those conceivably would be done with follow-up.
	DR. ONIONS:  Could I just make a comment?  Because I'm very much of the camp with the exception that I expressed an opinion before that I thought deferral would be a good idea on any new Epicel patients.
	I'm very marginal on this but just purely because as John Coffin said, there's no benefit to society of a few additional blood donations, or marginal benefit, where there is an unknown risk, so why take the unknown risk when there is marginal benefit to society.  That's the reason I was on the side of deferral purely.
	But I do appreciate Mr. Lawrence's point that this does lead to inconsistency because actually on all the other issues, as Dan said, I almost don't regard this as a xenotransplantation.  It really is in a different category of risk.
	So, I don't think all these other issues of archiving and counseling the recipients are necessary at all.  It just strikes me that this just one simple issue, why take any risk at all when there is absolutely marginal benefit to society of a blood donation.
	You probably can't do this, but I'd almost have done it as a counseling thing, well, we suggest you don't give a blood donation because this procedure has involved using mouse cells and we don't think it's a good idea, period.
	DR. KASLOW:  Again, I'm not sure I argue in favor of it because of this but following up people is one of the ways we find out where the risk exists and, in this case, given the low thresholds and the uncertainty, it may be the only way we'll ever find out.  So, again, I'm not arguing for it but we at least ought to make the decision knowing that.
	DR. SIEGEL:  Right.  I would knowing, to help and firm this discussion that we've had prior discussion I know in developing this guidance and I think with committee that this may not be as simple as it sounds cause when you ask an investigator or a sponsor or a manufacturer, if it's an improved product, to take responsibility for life long follow up of all recipients of the product given the way the patients move around, given the way doctors move around and investigators move around, this, this is not a simple thing to do.
	So, it's one thing to say yes it would be nice to follow up the patients.  It would be another thing to suggest that the treating physician or the company should implement some procedure that would ensure, to the extent possible, life long surveillance of these patients if that's what we're saying we want.
	DR. SOLOMON:  I was going to follow up and say that having been in many times the, just desperate to get one year follow up on kidney transplant patients or heart transplant patients on a clinical trial, thinking about not glibly recommending that we should be following these patients for years and years and years, archiving everything and keeping track of it.
	I think we have to be resource sensible here.  I don't think this is trivial.  Moreover, what concerns me is if you spend your resources and energy on something with this low a risk profile, you're not necessarily going to have the resources left over to do the stuff that's a lot more significant.
	Lastly there's a statistical problem here and if you have a real, real, real low chance, and you do a hundred different tests, what are you going to do with a couple positives?  I mean, that's Bay's Theorem of Uncertainty.  So, I think that it really would almost be argued even on statistical grounds that it's not worth doing.
	DR. ALLAN:  It's the same situation too where if we're not going to defer blood donations, then it just seems to me that that's the best way to prevent an epidemic and to then just do follow ups and allow blood transfusions to happen.
	It just goes against the best way to prevent an infection.  So, if you're not going to do blood deferrals then I'm not certain that all this follow up is going to be necessary.  Because if you believe, as many people have because they voted not to defer blood that the risk is so small that we don't have to worry about the blood supply, so then why put all the, all this effort into follow up.  I'm sort of like a devil's advocate kind of thing.
	DR. AUCHINCLOSS:  I understand but I agree with you.  I thought the green theory is an expression that blood donation was okay.  That everything else would fall by the wayside.  If you're not going to do that why, then you surely don't really have much indication to do anything else.  I guess I would say you'd want a data base of who got the pot in the first place so you could go back and try and capture information.
	DR. NELSON:  I'm not really arguing for an intensive follow up but there's nothing like data and I'm very glad that people in the U.K. decided to setup a new variance or a CJD Disease Registry in 1992 or whenever it was.  We got a lot of data from that.  I mean, I'm not saying intensive follow up but it is given that this area is really new, I think that there should be some data collection.  I don't want to specify what it is.
	DR. AUCHINCLOSS:  Let me ask the committee that question because, in fact, I agree.  I think as Dr. McCauley said, you could in fact find many of the patients, the 552 patients.  I really believe you could.
	If you wanted data, that would be the group of patients to go to in just the way that Novartis is coming to us later on today to say hey, we went out and tracked down a whole lot of people who were exposed to Pinktus (?).  You could, in fact, find people who had deceived Epicel in significant numbers and look at them.  I'm not sure that you'd know what you'd look for but you could do it.
	DR. CHAPMAN:  I'm noticing that the people arguing for data and follow up are the epidemiologists.  Being one myself, what has occurred to me is as a question is I'm wondering if we're all to give out the same thing in terms of follow up because I'm interpreting these questions in terms of the very specific follow up that's recommended in the Pages Guidelines for xenotransplantation which is quite extensive.  Are you all familiar with that?
	DR. KASLOW:  That's a good point. I think the distinction between simply having a registry and being able to track them, if necessary, is very different than saying we're going to have active follow up on the schedule that was described.  Yes, I am familiar with it and it is quite burdensome.
	DR. CHAPMAN:  So would it be worth having you expand on what you think would be appropriate in terms of follow up because as an epidemiologist I really respect your, the value placed on that.
	DR. KASLOW:  Well, I think the compromise position.  That there is some recording and some way to get back to it if necessary but not necessarily a fully prospective approach with all of the intense, intermediate specimen collection and so forth.
	DR. VANDERPOOL:  I'm in agreement with that, except for one proviso.  It strikes me that this is a judgment call.  If it looks like the, the risk are "very low or negligible," of course you wouldn't as a judgement put them in them in lockstep follow up frequency scheduled that's been outlined in the guidelines.
	At the same time it would make sense to say well we think that on a periodic basis or six month basis first, maybe a two year basis after that, we'd like to see one, a follow up study.  That's where you add to the data base.  But the lockstep, no.  But some follow up beyond registry I would say would be, would be in order on a judgement call.
	DR. MCCAULEY:  I think as a routine if you take care of these patients, particularly those that have at least 60 percent total body surface area burned and have received Epicel, you can follow these patients routinely at least one a month probably for the first six months.  Then you follow them about every three months probably up to about two years.
	So the opportunity for data collection is present.  These patients will always come back for problems related to open wounds, problems related to rehabilitation, problems related to reconstruction, and you can follow them, I think it's very easy to follow them at least five years out.
	DR. NOGUCHI:  Are you volunteering? No, that sounds a little specious but it's not.  I think that it's good to talk about data and it always is better to make policy decisions based on data but we have to have commitment to have the, the data being generated.
	DR. MCCAULEY:  I'm just saying this is what was routinely done at my own institution.  This is without any additional requirements. I mean, this is what we routinely do.
	DR. KAGAN:  Yes.  I would echo what Bob says.  Both of our Shriner's Hospital which is run very differently then theirs.
	We would have a certain set of rules for follow up and actually variables to capture the majority of these patients, particularly the ones with more extensive injuries because they need us during that time.  The same also holds true for the adult population which you would imagine to be more difficult to follow because those first three to six months, not only are they in pressure garments to reduce scar and they need to follow up but they need pain medication, they need antipyretics, they need us for insurance papers, they need us for return to work, they need us for disability, they're in touch with us because they need us.  So I don't think follow up is as difficult as it had been portrayed.
	DR. AUCHINCLOSS:  So you have 100 patients in front of you who have had Epicel. What tests do you want to do on them?
	DR. ONIONS:  I don't particularly want to.  I already said I don't think it's necessary.  So, and you were just looking at me.  That's why I answered.
	DR. AUCHINCLOSS:  Yes.  No, but I was looking at you.  John, is there a test that we can do to find out whether a horrible thing happened?
	DR. COFFIN:  I just want to find out if a normal thing has happened.  But I don't think, no.  I wouldn't recommend any tests.
	DR. AUCHINCLOSS:  So the fact that we know that they're being followed these patients.
	DR. COFFIN:  Yes.  I mean, I'm not, I'm not.  I haven't even decided on this issue at all whether I'd be in favor of it or not.
	DR. NELSON:  I think you would collect major morbidity.  I mean, they didn't decide to collect data on introsusception after the rotavirus vaccine.  But that's what turned out.  They found it, right?
	I mean you don't know what you're going to find.  You'll look for whatever's there and if nothing happens and it's just an antibody, well, find. I mean, you're not going to screen but if, I mean, surveillance is, we're looking for morbidity, mortality, problems.
	DR. ONIONS:  I don't wish to get into and drag something else into the debate but that probably highlights precisely the problem with this rather kind of ad hoc surveillance because there's great debate about the significance of those introsusception data particularly from the company concerned about what's the reference control here and clearly I don't want to get into that debate because that's something that doesn't need looking at.  But I think it's --
	DR. NELSON:  Nevertheless it's data.
	DR. ONIONS:  Yes, but bad data is sometimes worse than no data.
	DR. AUCHINCLOSS:  All right.  We need to take a break but we haven't really addressed Question Number Two where we tried to generalize.  But have we addressed Question Number One adequately, I mean, from your point of view.
	DR. BLOOM:  I think just for the sake of completeness if you could look at the next couple of slides because I think some of the recommendations that we made for the next slide for example is very close to what you guys have been saying.
	DR. AUCHINCLOSS:  What number?
	DR. BLOOM:  That one you just previous, previous.
	DR. AUCHINCLOSS:  1D?
	DR. BLOOM:  Previous.  That one.
	DR. AUCHINCLOSS:  1C.
	DR. BLOOM:  Yes.  The first.  Since no known agents have been identified we would request no passive monitoring and I think that's what we've kind of been hearing but I'm not sure.  We request, for example, that if there is an incident of unknown infectious, or of infectious disease of unknown origin that then there would be passive monitoring.
	But you didn't quite address that pre se.  I was hearing, well, we don't need to look at these people actively.  What do we do when we follow up?  Do we take samples?  I don't know.
	DR. SIEGEL:  Either way.  It might be useful and take not to much time to read both for 1C and 1D.  What we've put down as a {UOn} {UOff} {UOn}{UOff}strawman for what we would do and just get a sense as to whether that's on, as a, on the whole is on the right track for them.
	DR. BLOOM:  Right.  Since no known agents have been identified in the murine cell line, FDA requests no passive monitoring but rather achieve being baseline patient samples and samples as indicated, only for a suspicious event infectious episodes.  It is acknowledged that long term recipient cooperation would be integral in compliance with this request.
	DR. AUCHINCLOSS:  I think that sounds pretty reasonable.  Who thinks that sounds reasonable?
	DR. BLOOM:  That's what I thought they were saying.
	DR. HOLLINGER:  It depends on what you can do.
	DR. BLOOM:  Yes.
	DR. HOLLINGER:  It depends on what you call an infectious episode.  I mean, if you believe, as some people do that coronary artery disease may be, may be caused by a virus or diabetes.  I think this is part of the issue and I would agree with what Ken said that just looking primarily at either hospitalizations or major life threatening events, or something like this; death, things like this are what's really critical.
	Who cares if you get diarrhea or respiratory infections or things like this. That's not really so criterial.  But something that causes chronic disease, is more critical and that's all one would really have to look at.
	DR. AUCHINCLOSS:  Steve?
	DR. ROSE:  Hugh, I'm sorry. Dr. Nelson, I'm confused.  This says passive monitoring.  You were just talking about collecting data when patients come in.  Would you please tell me what you meant if that's not passive monitoring?
	DR. NELSON:  The borderline between passive and active surveillance or monitoring is sometimes, sometimes vague.  But I think we could passively, possibly collect major life events or major morbidity or mortality and if we saw some clustering that looked significant or looked suspicious then more active surveillance would be set up.
	DR. ROSE:  But this says no passive monitoring.  Not no active monitoring. It says no passive monitoring.
	DR. NELSON:  Just for clarification really.
	DR. ROSE:  No. I would argue for passive monitoring.
	DR. NELSON:  Yes.
	DR. SIEGEL:  I just voted yes on it.
	DR. NELSON:  I didn't vote on anything.
	DR. SIEGEL:  No.
	DR. NELSON:  We are discussing what level of excuses we disagree on.
	DR. SIEGEL:  Yes.  Let us make clear what was read there is relevant to archiving of patient samples not the discussion about medical histories.  More relevant to that, and quite to the point of looking at high risks is what's at the bottom of the next slide that we recommend that the data base that currently exists be expanded to "document clinical episodes potentially related to murine-derived infectious agents (e.g., fever of unknown etiology, neoplastic conditions, neurologic disorders)."
	Those things that we, those are e.g.s I'm saying that's the list but the idea would be not, not to capture every episode of the flu but to capture those things that might raise concerns about some of the types of pathogens we might be concerned about.
	DR. AUCHINCLOSS:  Louisa?
	DR. CHAPMAN:  Can I try restating the epidemiologic terms.  What I think you meant and they meant.  I think that, for people who are not epidemiologists, passive monitoring and active, passive surveillance and active surveillance, are technical terms and active surveillance means you put human effort into intentional and going out and acquiring data and passive surveillance means you accept the data when it comes in.
	So you capture more complete data when you do active surveillance.  You risk capturing less complete data or only really major episodes with passive surveillance.  I think what was intended here by the FDA and what, if I'm hearing people correctly, would be in line with what epidemiologists hear are talking about is the intent was to say no, the risk is low here.
	It's necessarily to do active surveillance monitoring.  Rather you can capture information on major like events onset of chronic diseases needing medical condition, hospitalizations and their causes and causes of death by doing passive monitoring and collecting the data when these things bring people to medical attention.  Is that what you all meant?
	DR. NELSON:  Perhaps an analogy that's relevant to what the FDA does is after a drug is licensed and somebody has some sort of thing, event that might be related, it may be reported as an adverse event in a licensed, tour licensed drug.  But it doesn't mean that each patient who's on that drug gets a phone call every week to say, what's happened to you last week.
	That's the difference. I'm saying that we should collect passive data for all of these xenotransplants or maybe this is a non-xenotransplant.  It's a transplant delay. It's not the whatever.
	But we still, there maybe risks there that are undefined.  I think we all agree with that even though we can't grow an agent or we can't find reverse transcriptase. That doesn't mean that there is no risk. Nobody's talked about prions and all these other things that you can't measure and that are resistant to radiation.
	Who knows?  But, the fact is that I, I don't think we want to close our eyes in that there should be some system of passive collection of data on cohorts or sets of people who have had a xenotransplant or exposed to animal tissues.
	DR. AUCHINCLOSS:  Unfortunately, I apologize to my subcommittee members.  I actually have to go at this point.  I think you're very nearly done Question One.  John Coffin has agreed to take over as chair and I guess I'll leave it in your hands whether you have a break before you go to Question Two or how you want to handle that and I apologize for leaving you early.  Thank you.
	DR. COFFIN:  So where are we with Question One finishing up?  Are we, as he suggested, about done here?
	DR. SIEGEL:  We're comfortable.  If there are members of the committee who would like to make further comments, that's fine.
	DR. MICKELSON:  I think all we're really talking about is taking the no out of there for the passive.  Isn't that what the committee is recommending?  Is it something akin?  1C.  On 1C aren't we just saying take out the no for passive monitoring?  Not no passive monitoring.
	DR. KASLOW:  No.  I think we're still making distinctions between getting samples from people versus getting reports of events, clinical events.
	DR. MICKELSON:  Passive monitoring. That not passive monitoring.
	DR. KASLOW:  Certainly taking samples isn't.  But, but what we're really saying, I think is that you have a list of people who received whatever we're going to call this.  A transplant.  You say tell us about what happens.
	DR. MICKELSON:  When they come in. That's not passive monitoring.
	DR. KASLOW:  That's passive monitoring as opposed to we're going to call you on a regular basis and find out whether you're seeing anything.
	DR. MICKELSON:  But, don't we want passive monitoring?
	DR. KASLOW:  Yes.
	DR. MICKELSON:  Isn't that what the committee --
	DR. KASLOW:  Yes, yes.
	DR. MICKELSON:  All I'm saying is that the wording in 1C says that the FDA requires no passive monitoring.
	DR. KASLOW:  But that refers to patient samples there.
	DR. SIEGEL:  But I think it was meant to say active and they didn't get it right.
	DR. MICKELSON:  So it was meant to say active?
	DR. BLOOM:  Yes, it was meant to say active.
	DR. COFFIN:  Given that change, are we happy with this statement since we already voted we were happy with the statement even without the change.  I assume we're even happier with a statement with a change.  Is there, is there anything else on Question One?
	DR. SIEGEL:  So that means the sense of the committee is, just so we understand, that if somebody comes in with a certain, with a suspicious type of infection, there should be both a data base recording but that also may well.  It's the standard for archiving specimens as well but otherwise there shouldn't be efforts to reach out and find them.
	DR. HOLLINGER:  No.  No.  From my standpoint, I'm sorry, I would feel that something a little bit more aggressive than that and I guess this would go under active.
	That would be that on a very minimal basis, whether you look at death certificates, I mean, those are easy to look at.  Whether you look at it at one year and five years.  But at some point, I do think that somebody ought to find out if there's a major problem that has occurred in an individual whether it's neurological, chronic or otherwise.  I don't think that's, that's a very difficult situation to do.  I mean, that's my own personal feeling with this.
	MR. COFFIN:  It may be useful to see how many people share that particular sub-feeling of this.  Just a quick straw, show of hands.  It looks like a sizeable majority of the committee although not quite unanimous.
	MS. DAPOLITO:  That was fifteen.
	MR. VANDERPOOL:  John?  So there seems to be saying substitute, the FDA requests no active monitoring rather archivial base lines and then we're making another sentence there, "periodic reviews of the, of the data from, of the passive monitoring of data, of patient data should be done."
	DR. COFFIN:  Would be advisable. We're not writing regulations here.
	DR. VANDERPOOL:  Would be advisable, would be advisable.
	DR. COFFIN:  Yes.  I think that's probably enough guidance on this particular point unless somebody has something new to raise.  One deal, what are we done here?  Are we okay for Question One?
	DR. SIEGEL:  I think we are.
	DR. COFFIN:  Why don't we take a short break, reconvene at 3:30.  Can we get settled again, please.
	(Recess)
	DR. COFFIN:  We have a number of questions.  It's actually one question but its got an awful lot of parts that the FDA still wants advice on and then we have a presentation following that so we're going to have to move right along.  Edie, do you want to introduce Question Two?
	MR. LAWRENCE:  Can I make a motion first?
	DR. COFFIN:  Yes.
	MR. LAWRENCE:  Right after lunch we had a presentation opposed to the xenotransplantation and Dr. Vanderpool mentioned that he had written a response to it and so forth.  None of our colleagues here have seen that.  I would like to move that those two documents be made a part of the record here and distributed to the committee.
	DR. COFFIN:  Without objection, so ordered.  Now if we could move on to Question Two.
	DR. BLOOM:  The FDA is now seeking advice regarding other xenotransplantation products.  Recognizing the inability to bring for expert discussion each application to study xenotransplantation, we seek additional guidance as to how various characteristics of the products may impact selection of appropriate approaches to address infectious risks.
	We ask the committee to consider and discuss the following characteristics of xenotransplantation products and the impact these characteristics or risks on the optimal procedures for controlling risk.  In several cases we provided again another straw person and requested the committee discuss whether or not it agrees with these proposals.  Next slide, please.
	So here we have at the beginning of Question A which is regarding the species of source animal.  Clearly a different source species pose different risks.  FDA believes that the types of controls which are appropriate for different species may vary based upon these risks.
	Several of the controls recommended in the draft, PHS Guidance, are targeted at specific risks such as transmissible spongiform encephalopathies, latent viruses and so forth; blood born diseases and so forth.  We ask that you discuss the following approaches.
	We've actually already issued our non-human primate document that this committee discussed six months ago and we said that we publically stated this but we have yet to see sufficient safety data to warrant the use of nonhuman primates as source animals.
	The use of nonhuman primates raises specific concerns because of their proximity to the feral state.  Currently possible levels of animal husbandry and isolation and the history of transmission of initially inapparent infectious disease to humans.  We have already based guidance based on.  We already based guidance on these concerns.
	However, in regard to nonhuman primate, excuse me.  Non-primate mammals, it is possible that certain species or strains do not express, for example, infectious endogenous retrovirus.  FDA suggests that the use of species retrains lacking infectious endogenous retrovirus may lower concerns about latent infection but not to the extent that changes in life long follow up or deferral of close contacts from blood donation would be prudent at this time.
	DR. COFFIN:  Why don't we stop here and discuss these two points.
	I think regarding the primates, we've been in general agreement on this for quite some time.  Does anybody want to change our opinion on that?   Okay.
	So the issue with non-primate manuals, it's on the slide in front of you. While there may be the point here is while it may be lower concerns, the, they are not really adequate especially given what we've heard from people who are concerned about exogenous agent introduction.  They're not adequate to really change our minds about how we treat one animal or one cell type or one strain versus another.  Is that a fair statement as far as the committee is concerned?
	Good.  We're moving right along.
	DR. SIEGEL:  While we're waiting for Edie to come back, just point out that we don't anybody to be unduly bias by the fact that on some of these questions we put down positions.  We put them there just to be used as you did to help facilitate either discussion or consensus and, but we feel quite open and encouraged any disagreement that people might want to express.
	DR. COFFIN:  Fair enough.  Yes?
	DR. KAGAN:  A point of clarification there.  Have we changed the word close to intimate in all of these documents or are we going back and forth?
	DR. BLOOM:  The slides still say close.  For the purposes of discussion, if you wish to change it back to close please feel free to.  However, I think what we're going to discuss is what you meant by intimidate.
	DR. SIEGEL:  Let's not discuss which word we mean because, in fact, and I understand that in some blood regulatory documents there, they are sometimes used interchangeably and we don't have precise definitions for either.  Let's simply say that to the extent that the deferral, we understand the sense of the committee to be that any deferrals that are made should be only for the more intimate contacts.  That's what we're talking about.  Whatever you want to call them.  Okay?
	DR. COFFIN:  Okay with me.  So the next regards non-manuals.  One of us can read it.
	DR. BLOOM:  Yes.  For non-mammalian cells including invertebrates, as noted previously by this advisory committee, that would be last June, data regarding ability of each species to harbor human pathogens should be carefully reviewed and controlled procedures designed accordingly.  Some of the controls designed with manuals in mind, may not be routinely necessary for protocols using invertebrate cells such as the Drosophila.
	FDA suggests that for use of non-mammalian sources including invertebrates in particular, source animal, colony surveillance and animal testing and procurement requirements may be quite limited and blood donor referral of fill in the blank contacts and health care workers, may be unnecessary.
	DR. COFFIN:  Is there any discussion on this, on the issue of invertebrates?  David?
	DR. ONIONS:  Just two very brief comments.  I think, there's always a little bit of a danger if you assume something's safer, by some arbitrary criteria, let's lower down the phylum genetic scale.  That would be my first comment.
	My second comment is, yes, in general agreement but certainly the testing or approaches might have to be different. But I would just flag two points.
	One is that, and I'm no expert in this area so, but there are certain transposable elements that have been taken from insect cells that have been used successfully in cells of mammalian origin, Not very efficiently but they have been used. So there are, there are other dangers that one might have to consider that are not normally ones we consider with mammalian cells.
	On this there are still surprises. For instance it is now clear that the tag retroposed on TB cells is actually a true retrovirus.  It's actually a infected retro verse and it's not an impact to other insect cells, it can affect viruses so you can get integration in tubercular virus.
	So often the amount of work that is being done has not been as extensive on mammalian cells so I think we need to just be a little bit cautious about assuming you don't have to do as much is really what I'm saying.
	DR. COFFIN:  Anything else?  That was a point well taken.  Then otherwise I think, I think that probably would.  Well, does that reflect everybody's position, that comment?  More or less?  So we'll move on.
	DR. BLOOM:  Extensive testing and characterization of cryopreserved cell lines may often provide an adequate or superior substitute for other recommended controls. We've already discussed the case of Epicel.
	For extensive characterization and testing.  For some cell lines, information about the source animal is quite limited.  In such cases and in general, FDA proposes that extensive testing and experience with long-term cell line may obviate most or all need for animal procurement sources and source facility controls.
	Additionally, definitive exclusion of various pathogens such a herpesviruses and retroviruses could lead to less intensive long-term monitoring and sample archiving and could obviate the need to inform contacts or defer them from blood donations.  So this is, basically, we think that this earlier discussion may be more generalizable.
	DR. COFFIN:  Go ahead.
	DR. VANDERPOOL:  It strikes me that this paragraph fairly effectively summarizes all two and a half hours of turgid and complex discussion.  That's what we came to agree to with and here we have it in print.
	DR. COFFIN:  I have the same sense. Is that also the sense of the committee?
	DR. SIEGEL:  This reminds me. Thank you.  I was thinking the same thing as well.  It does remind me though, we talked about informing contacts.  I don't know if we discussed that vis-a-vis Epicel.  We had some discussion and maybe some difference of option about donor deferral but it's another interesting question, would you tell all these burn patients that they should tell all their intimate contacts in for the remainder of their life that they're potentially exposing them to risk of an infection from a mouse.
	DR. NELSON:  If they had a baby it would look a little bit with long ears, is that what you're saying?
	DR. SIEGEL:  Well, just a, I'm sorry.  I guess everyone wants to go home now.  But these are pragmatic questions we will be facing in these and I wonder is there a general sentiment?
	I guess a lot of people felt that many of the, the precautions were not necessary. Is it safe to presume that that would be one that there's some consensus would not be necessary for a product given that the well-characterized cell line and given some agreement with this paragraph?
	DR. COFFIN:  Is there any disagreement on this point that extensive discussions of this sort in this particular kind of a case where all?  We're happy with all of the safety tests that have been done as the hypothetical we discussed with Epicel. Is there any feeling that there should be extensive requirement or at least urging for extensive discussions of these issues with contacts?
	DR. VANDERPOOL:  To urge extensive discussions with intimate others and on grounds of virtually no evidence, would be, to put it somewhat stickly, making a mountain out of a mouse hill.
	DR. COFFIN:  Particularly, even the scientist at this table would have a lot of trouble trying to make, have this kind of discussion.  I think it would be extremely difficult during practice to actually see how you even approach such a thing.  It's probably reasonable.  Well, I'll stop there. I guess we can move on.
	DR. BLOOM:  Thank you.  Regarding the products, cell line versus fresh tissue question.  Homogeneity of cell type in particular.
	While most fresh tissues are particularly, excuse me.  While most fresh tissues, in particular, vascularized organs, should be assumed to have an adversity of cell types, a cell line, or in some cases, a highly purified cell population, may lack or have the ability to transfer certain types of pathogens.  FDA proposes that the caution should be tailored to that type of pathogens of concern.
	DR. COFFIN:  I think, and it's my opinion in circumstances like this, yes, having cell lines can, can simply the testing procedure for known pathogens but I don't see how it helps us very much with unknown potential pathogens.  But the other people may feel differently about that.
	Apparently not.  See what a break does for people.  Getting a little sugar back in and allaying the hypoglycemia.
	DR. BLOOM:  Examples of approaches which may quantitatively now reduce risks, include the use of barriers or encapsulation, transient or short-term exposure, low dose exposures.  For example, a few cells versus vascularized organs.
	These practices have a potential to reduce but not eliminate risk.  Barriers impermeable to infectious organisms may provide protection but may also have a failure rate.  Shorter term and lower dose exposure may be less risky but are exposures nonetheless.
	In general, we feel that these factors should per se have at most a modest impact on safety precautions.  If you agree with that, however taken in combination with each other and/or other factors that may provide significant protection, obviating the need for certain precautions.
	For example, if a patient's blood is circulated over an animal's secretory cell line using a low molecular weight barrier which has been extensively validated to prevent transmission of infectious organisms under conditions of the study, not to break, risks may be substantially reduced.
	Does the committee agree that such consideration should be taken into account in determining additional protection such as frequency of long-term monitoring and archiving of specimens, notification and deferral of intimate contacts?
	DR. COFFIN:  What's the committee's pleasure?  Does anybody?  We had some discussion I think about this the last time. Does anybody?  Derrick?
	DR. ONIONS:  Yes.  It strikes me that just the way that this phrased it's slightly inconsistent with an earlier comment that suggested that, one of the ones we discussed way back but, it seems to me that I agree with the first statement.
	That is there's clearly going to be a failure rate.  It strikes me that the two main procedures that are being looked at are encapsulating cells and putting those back into the, say, the abdominal cavity.  Those definitely are going to have a failure rate. I mean, there's no doubt about that.  The slightly safer procedures it seems to me are the ones that are {IOn}ex vivo {IOff}and{IOn} {IOff}involve the semi-preamble membranes for instance the liver cells that we've seen discussed here before.
	But it seems to me that both of these procedures are still new and at the moment would not alter my view about long-term telemetry.  But, again, that's something that I think in the light of experience you might wish to change but at the moment my view would be that you would still want to adopt the same kinds of monitoring procedure until there's some established record with those procedures.
	I'd have to say that with the kinds of approaches within encapsulation, I would find it hard at the moment to see that you would ever change that view because there's going to be a definite pronounced failure rate.
	DR. COFFIN:  Other comments to this?  Let me.  Go ahead, Prem.
	DR. PAUL:  I don't feel quite comfortable with this especially some of the agents which, viruses which, are very, very small and I have not followed extensively what type of physical barriers that are available but it would be difficult for me to imagine that, like circovirus is probably very, very small that they could, that they would be stopped.
	Again, what happens in case there is the filter or the membrane is broken?  So what's the quality control?  So what happens to the monitoring and does that changes the picture?  It would for me.  So there are a lot of questions.
	Again, I think about getting some experience and the records and eventually you can have a little more faith.  But at this point I don't feel very comfortable.
	DR. SIEGEL:  As to the types of barriers here, there's a, there's a broad spectrum.  Some do get down to the hundred kilo-dolten or so range that have been used to allow passage of certain low molecular weight secretory proteins.  I think that the comments about failure are points very well taken.  I gather, Dr. Onions, that you are suggesting that there's a general presumption with any encapsulation of anything going {IOn}en {IOff} {IOn}vivo {IOff}we should work on the general presumption that there will be failure.  That you'd be more open and in certain {IOn}in vitro{IOff} cases possibly to validating ability to avoid failure.
	DR. ONIONS:  Yes.  I prepare to be stand corrected but at the moment without evidence in front of me I would assume that there would be a definable breakdown rate of encapsulation procedures that I've heard about that are being used at the moment.  I think the{IOn} ex vivo {IOff}systems that use semi-permeable membranes are inherently a lot safer.
	I think they are much safer systems.  But because those, nevertheless because these are still new systems, I would want, at least for the next few years certainly for that, for monitoring to proceed.  So we build up a data base that gives us comfort and I'll be then happy to change in the light of experience.
	DR. COFFIN:  Yes.  I think, the general problem I have with these things is that as you subdivide the risk it's still a very small hypothetical risk and it goes to a very small hypothetical risk.  So until one knows the starting point, one doesn't know where one's gotten to and I don't see how we can deal around that.
	DR. VANDERPOOL:  It strikes me that the paragraph, that the summary question to the committee doesn't particularly follow what the paragraph is saying.  It seems to me the question should be does the committee agree that such considerations should be taken into account in determining either fewer or additional detections should be required.
	Then I don't know what to do with the phrase such as a frequency but we're being asked, whether fewer requirements should, should be in place at times but then there's also the question of additional protections at other times and basically I as a committee member would agree, yes.
	You have, we would charge you with the ability to alter 19-6 regulations to be the stiffer or less, or slightly altered with fewer regulation requirements.
	We've been doing that and we will do that here.  I want to make one more point and that is, I generally agree with the wording of this paragraph but I think we ought to maintain what we've been maintaining through much of our discussions.  That the burden of proof for ever-moderating safety precautions should be on the IND Sponsors and in consultation with the FDA.
	This committee will help maybe alleviate some of those burdens of proof. But the burden of proof is to prove exactly what we are about.  It should not require safety precautions XYZ.  But I think those safety precautions, we should assume that they stay in place unless certain conditions would allow for some of them to be modified.
	DR. COFFIN:  Good point.  One thing that strikes me here is that with some of these device, I don't know enough about these devices to be sure but some of these devices there may be some good way of monitoring whether barrier failure has occurred or not. Then that might be, it may be possible to take that into consideration regarding some of these issues.
	DR. SIEGEL:  Can I make a point?  I recognize your concern Dr. Coffin but when you're going from an unquantitative risk to a lower unquantitative risk, you still have an unquantitative risk and you don't know where you are.
	On the other hand, everything we're dealing with is a spectrum of risks.  Some have noted even to lots of things like that we're not dealing with like eating for example or handling animals and there's a natural, these quantitative issues naturally come up.  There was earlier discussion this morning about what if you knew that a small number of 3T3 cells were carried over with the Epicel product.  Would that matter and for example Dr. Auchincloss said, that wouldn't bother him.
	I'm not sure what he would answer but I think some people might have, who think that wouldn't bother them if you had a protocol where you were injecting several million 3T3 cells into the abdomen or into the skin or into the blood.  What might be, you might have a different level of concern then some possibility that there is some small number of cells carried over.  So you know what I'm saying?
	DR. COFFIN:  But one has to be very careful on a case-by-case base because it's possible that some large numbers of some purified cell type like allod cells may, in fact, just because of what they are may be, might be expressing some endogenous viruses at a level that we don't know about.
	You can in some cases say clearly where there's a barrier, you can say clearly there is a reduced risk in general of things being transmitted.  But in other cases it's not, it's not so clear that you can always make the argument that the risk is reduced.
	You had your lights on.  Are you? Does anybody have anything else to add to this?  Then we'll move on.
	DR. BLOOM:  Immunosuppression of recipients is often cited as a reason for concern about risks of xenotransplantation. Please discuss whether the extent of immunosuppression of the recipient should be a factor in determining the types of protections involved.  At the current time, FDA proposes not modifying any recommendations for non-immunosuppressed recipients.
	DR. COFFIN:  I think the issue is similar in a sense we don't know.  We can imagine that immunosuppression could make a big difference but we don't really know that for sure and until we do, is that?  Committee in general on agreement on that?
	DR. ONIONS:  Just for clarification, really, John on what the actual stemming is.  What do you mean by protection here?  I'm not quite sure what's intended?
	DR. SIEGEL:  I'm sorry?
	DR. ONIONS:  Sorry.  I don't quite understand the question Phil, and it's late in the afternoon.
	DR. SIEGEL:  Let me say for example that Dr. Auchincloss, again, I hesitate but won't restrain from citing him in his absence but he said this morning that actually part of his reason for not being so concerned about Epicel was not simply that it was a well-characterized cell line but he said even if cells were carried over he wasn't so concerned because these individuals receiving it were immunocompetent than somebody who's being suppressed to tolerate a, a harder kidney graft.
	So what we're trying to, having talked about a specific, we're sort of trying to tease out so that we can do some generalization, recognizing that we're not going to have definitive answers to every product we might see but ought that just some general advice, what will role ought that play in the equation as we look at it.
	DR. NELSON:  Is this discussion, again, related to Epicel?  Is that what we're talking about?  Or are we talking about --
	DR. COFFIN:  No.  We're generalizing here.
	DR. NELSON:  We're generalizing.  I have problems with generalizing because people could not be generally immunosuppressed but could have a specific immunologic defect and if we don't know what the organism is, we could have a normal person, a seemingly normal person who is at high risk to a specific agent.  There are a lot of examples of that.
	DR. COFFIN:  You could also have a circumstance where somebody becomes a high risk later on and something latent gets in the graft reappears, too.
	DR. ALLAN:  The other thing about immunosuppression is that, I think it's overblown.  Generally it's the introduction of the virus and immunosuppression may or may not increase the levels of the virus that's present in the body but even without the immunosuppression it's the introduction through the xenotransplant that begins the process so I agree with what the FDA states here.
	DR. VANDERPOOL:  It is late in the day and some of our neurons are beginning to rest but I think there's a very important question.  I don't think we're giving it, right now, with the brevity in which we're reviewing these, the attention it deserves.
	Because I think we really need to open this question up about what data is there for far greater or greater or not so great vulnerabilities who a) infection, b) mutations occurring.  What data is there?
	Does your expert in this area or all the other experts who can bring to us those issues because I think you're right, Jay, in talking about the degree to which Dr. Auchincloss said really doesn't bother me if someone's not immunosuppressed.
	The compliment is very powerful. The human compliment is very powerful but what are the levels of vulnerability under immunosuppression?  There would have to be experts here and the experts here are dealing with immunosuppression tolerance who can give us a reading on that so we could give much more considered judgment to what you're asking.  It is, to me, it is a very serious question and I certainly don't have, I haven't heard, enough of people talking about it to feel I have any kind of a handle on it.
	DR. SIEGEL:  I'm not presuming to be an expert authority.  I am an immunologist in infectious disease physician and I think the problem with that question is, I think, was highlighted in one of the prior comments that it's hard to even speak about levels of immunosuppression.
	There's loss of skin barrier in a burn patient, there's losses or partial impairments of human immunity or cellular immunity, defenses against different types of pathogens.  There was a comment about not even knowing, whether you might have a patient with a deficiency for a specific with a disease that might have a deficiency in their ability to defend against a certain pathogen.  So I think your question is an important one but I think what you've heard from some of the committee is it's hard to address in the general.  You almost have to, because immunosuppression is so complicated.
	Maybe that's why this is not in.  I should note that we recognize, we're asking this committee to do the impossible.  We often do and you often come through in giving general rules and what we hope to do is and what we have been doing is to have an ongoing back and forth process and when we get more specific questions as we have in the past about certain porcine products or at-risk issues or this morning regarding Epicel, we'll come back for more specifics but in the, in the interim, we are dealing with the case, with proposals and need some general guidance because, unfortunately, although one can't often know what the right answer is, one does have to give an answer.  That's kind of, that's sort of where we are not in trying to get the general guiding principals.
	DR. COFFIN:  David?
	DR. ONIONS:  Just to try and answer the specific question, I agree with Jonathan and I think Jonathan is absolutely right that when the key thing, does the virus get into the animal?  Can it replicate, I mean, if it infects us can it replicate that?  Those are key, perhaps the key elements.
	Once the immunosuppression can modify the patten of infection that's seen afterwards.  You almost have to go do it on a virus-by-virus basis.  But we do have a very clear example and that is the example of anthrotrophic murine leukemia viruses that's been used in gene therapy systems in primate models where we have the one study from core matter and not so badly immunocompromised animals that didn't do anything.  Then we have an example from Donahue's Study where these animals had whole body radiation and were profoundly immunosuppressed and three out of eight of those became virulo-developement infirmed.
	So, the answer is, if you have to give a crude answer to this question which I think you have to, then clearly in the suppression in general, however defined, is probably worse than not having an expression.
	DR. NOGUCHI:  I'd like to follow up specifically on that one because we've also done experiments at FDA in which we tried to do a control injecting this retrovirus into juvenile monkeys.
	DR. ONIONS:  Yes.
	DR. NOGUCHI:  Actually they became both acutely and chronically infected and after follow up for a number of years seemed to be developing a very peculiar kind of disease.
	So what you may be seeing, what you're seeing is correct but, if in terms of latency it may well be that a normal physiology might under some conditions lead to a chronic condition which then could lead to some disease.
	DR. ONIONS:  Understood, yes.
	DR. NOGUCHI:  So I, every example has, as you see Harold, every example has these nuances which makes it very complex.
	DR. SIEGEL:  Let me ask another. Oh, go ahead, Louisa.
	DR. CHAPMAN:  If I could just speak to your question a moment.  I think Jon Allan's point is the most salient one because, if I understand what the FDA is asking, they're not saying should we begin with a base of precaution and then impose additional precautions based on specific kinds and degrees of immunosuppression.
	They're saying, we're beginning with the base of precautions that assumes immunosuppression.  Should we lighten that based on degrees of absence of immunosuppression and, from clinical infectious disease, the examples that immediately come to my mind where I'm aware of interactions between immunosuppression and infection.  There are opportunistic infections in immunosuppressed persons which are things that are latent in the body all the time and are given the opportunity to cause disease by immunosuppression.  But they're not new infections.
	So there are HIV and Hepatis B and HBV have clearly pursued more aggressive courses in immunosuppressed organ recipients. But remove the immunosuppression, those are still aggressive and destructive viruses.  So that does not give me a feeling of greater comfort.
	Influenza has been shown in immunocompromised hosts to become a persistent infection with multiple, with evolution of the viruses within that one host that you're isolating.  But that host actually by being hospitalized and under isolation precautions actually probably causes less risk to the general population than you or I when we get influenza and shed it prolifically for a few days and get on a plane and infect a plane-full.
	So I think if FDA had asked the opposite question which is should we impose greater precautions based on degrees of immunosuppression, it would need a very sense of discussion like your suggesting.  But I think Jon Allen hit the key point for the question they actually asked which is, is anyone comfortable at this point saying if you're not immunosuppressed we don't have to worry about these things.  Is that it?
	DR. SIEGEL:  Let me carry some of those concepts one step further.  Something I thought about but I haven't heard much discussion about which is that since most of these guidelines are designed to address the largest concern we have, or the most different or unique type of concern which is not so much that the risk to the patient, although there's a lot there and we have those concerns, but the risk to the general public.
	Then in fact the concerns we should be most concerned about, are those infections that are infectious to the non-immunosuppressed that among those infections that occur in an immunosuppressed individual, there's those subsets just discussed that also, that affect immunocompetent but there are also some subsets that you see the patient and you don't worry to much because this is not a disease I'm going to catch because I'm not immunocompromised.
	I guess in the logic in saying we should be more worried about immunocompromised individuals would apply only if we postulate that the immunocompromised individual may provide, if you will, the breeding ground for the development of an infection that may then also later be infectious to non-compromised contacts.  Which might happen or maybe that is the biggest concern but if the serious concern is about infections that are infectious to non-immunocompromised individuals, then surely the non-immunocompromised recipient is also at risk for those.
	DR. COFFIN:  Combined with the fact that, I think was a little to early that the immunocompromised person is always often in a situation where they are unlikely to be in, transmitting anywhere as readily.  They're not donating blood, may not be having sexual activity and so on and forth.
	But I think the issue that we are most concerned with is that of a pathogen undergoing some sort of evolution while it's in the recipient so that what comes out of that recipient is changed from what went in. That, it seems that in all the discussions we've had, that has sort of been the major focus of concern and there you have, do have to worry about it in cases of somebody who is immunosuppressed transiently so they come out of it at a later state and then are able to spread around.
	Now what's a now a modified organism, it's had a change to replicate and again we're talking hypotheticals but we can probably think of examples of things that might actually have happened or one can imagine thought experiments with viruses that we know about where such a thing could imagine to happen.
	DR. HOLLINGER:  I think that for most viruses, not all, and many of them which we may not know, immunosuppression at least leads to higher virus concentration which often are more likely to be associated with a non-percutaneous transmission through like sexual contact.
	So we see it with HIV, we see it with Hepatitis B, we see with Hepatitis C and so on.  It's very much, somewhat, not always, but related to viral concentration which seem to be higher in immunosuppressed patients.
	There are also very major differences in what happens with immunosupression.  You take a patient with Hepatitis B who gets a liver transplant and they often will get to a much more serious disease in a much shorter period of time then an immuno, then an immunocompetent patient. On the other hand, with Hepatis C, it's a little, it's the reverse of that.
	In five years they seem to be very similar with very little disease at the time. So I think it's very complex and we don't know.  I think for the immunocompromised, I'd be more concerned about the fact that they're more likely to so some transmission if there was a virus present then those who had a good immune system.  But you really don't just know what happens in the immunocompetent patients.  They may have more serious disease, they may have less serious.
	DR. COFFIN:  Jon?
	DR. ALLAN:  I just want to go back to what Louisa has said which is, regardless of the degrees of immunosuppression, if you're going to do this for the non-immunosuppressed, if you're going to do these types of things for the non-immunosuppressed individual, it's going to take care the immunosuppressed individuals, you're even more concerned about them and so you're going to do all the same things as well.
	So, it really doesn't matter in terms of the levels of immunosuppression because if you're going to do it for the non-immunosuppressed, you're going to cover the immunosuppressed.  Does that make sense?
	DR. SIEGEL:  I think Louisa has got the question right which was, given the guideline which suggests a whole bunch of things and is in part based on the fact that many people would be immunosuppressed, should, for those cases where there might be a recipient who is immunosuppressed, should we take different approaches?
	Our proposal here was no, that probably that we don't know enough that that's a factor that should change it and I think we've had some interesting discussion about the implications but I also see a lot of head nodding which I take to be a general agreement that, on the basis of current knowledge, this proposal is what people think is the right approach.
	DR. COFFIN:  It certainly sounds to me like that's the sense of the committee. Does anybody object?  In that case, we're right on schedule with the agenda.
	Unless somebody has something else to add at the moment to these issues.  We can move on to Topic III which is a couple of talks updating us on current state of knowledge of porcine endogenous retroviruses. The first talk will be given by Dr. Khazal Paradis from Novartis.
	MS. DAPOLITO:  When you get a chance will you mention that we'll open it up again at the end.
	DR. COFFIN:  Yes.  We will also at the end, following this we will have a brief reopening of open public discussion for another comment.
	DR. PARADIS:  I'd like to thank the committee for allowing me to present finally the results.  It's quite a relief to come to this committee and to actually be able to present this.
	This is a study on the retrospective multi-center state to detect circulating porcine endogenous retrovirus or antibodies to PERV in subjects who were intimately exposed to living pig tissue.  As you can see, there's a lot of names there that, a lot of people participated in this study and I was counting a little earlier and there are about 21 people in the audience who either directly or indirectly contribute to either testing and the design in the writing of the paper or, and as well as in reviewing our data.  I want to thank, I want to take the opportunity to thank everyone who participated in this.
	Now, when testing for PERV Infective States, if we're looking for active infection, since this is a retrovirus we're testing for RNA.  An RT-PCR was carried out and, either on serum for all patients or on saliva in a subset of patients.  These tests were carried out by Zephram Long and Ed Otto at Generic Therapy Institute, Inc. which is a Novartis company as well as under the direction of David Onions at Q-One.
	For latent infection we're looking for a DNA of the virus incorporated into human cells like PCR, and this was also carried out at GTI as well as at the Center for Diseases Control under the direction of Waleed Heneine.
	Now to look for the recovered or cleared state we're looking for antibodies and this was done by Western Blot on serum by Q-One as well as the CDC under the direction of Paul Sandstrom.  Now, since this study was carried out we've also had some serum retested by Professor Yokum Denner of the Paul Ehrlich Institute in Germany.
	Now, as mentioned before, when you do an allo-transplant, their leukocytes leave the transplanted organ and will migrate through the patients body in a condition that has been termed microchimerism.  Seeing as we had some patients who, especially the splenic perfusion patients, who had their blood perfused through the pig spleen.  We expected that there could be some pig cells that would be present in the patient's body.
	Now, as seeing every pig cell would contain PERV DNA, we had to find a way to distinguish between just simply microchimerism and a PERV infection.  So, I'm going to talk about the strategy which we used in the paper but I won't go into the actual details of the sensitivities of the tests.
	So, if one does a PCR test looking for PERV DNA, there are four potential outcomes.  If you imagine you have a sample here where there are only human cells and no infection, your test result would be negative.
	If you have a test sample where there are human cells and a pig cell such as you would find in microchimerism, because every pig cell contains PERV DNA, you would get a positive PCR.  If you have a test sample where there are infected human cells but no pig cells, then you would get, because this would be infected, of course, you'd get a positive DNA PCR for the PERV DNA.
	Finally, if you have a test sample where you have pig cells present as well as infected human cells, this will also give you a positive test.  So you have to have a way in which to distinguish between the positivity because, of course, if you only have microchimerism, that does not mean infection while the other two mean infection.
	So the area in which this was carried out was to know whether or not there were pig cells or infection was to look for a pig genomic sequence.  So, at GTI, this was done looking for the centromeric DNA sequence for the pig.  At the CDC this was done looking for pig mitochondrial DNA.
	Again, there are three potential outcomes.  If you have simply just microchimerism because every pig cell would contain a centromeric copy, you would get a positive test.  If you have in PERV infection, your PERV DNA was positive but here you have no pig centromeric sequence so this test will be negative.  However, if you have microchimerism in the presence of infection of human cells, the pig cell will also give you a positive result for the pig centromeric sequence.
	So, once again, we need to have a test to be able to distinguish between simply microchimerism and microchimerism and infection.  So the way in which this was done at GTI was to perform these tests as quantitative PCRs.  We know that on average a pig cell contains approximately 2,500 copies of pig centromeric sequences.  While, on average, a pig cell would contain approximately 50 copies of PERV DNA.
	So that if you have a sample that has pig cell in it, you would have a 2,500 to 50 or a ratio of 50.  If you continue to add pig cells to your sample, the ratio does not change.  On the other hand, if you have a microchimerism and you keep on adding infected human cells, the ratio, because of the number of copies of PERV DNA changes, the ratio will change as well.  So this was used to distinguish microchimerism alone from microchimerism and infection.
	Now this technique, with this technique, you could detect infection in the presence, if you had 20 pig cells in a sample with 107 human cells, and you could detect when greater than part .01 percent of the human cells were infected.  So quite a sensitive asset.
	Now we were able to recruit 160 patients into this study.  There was one patient from Canada who was in liver failure and had her blood perfused through a whole liver failure and survived to a successful human allo-transplant and has been immunosuppressed ever since.  Two patients participated in an experiment in Sweden where there blood was perfused through a pig kidney.
	There were 28 patients who were in liver failure and who had their blood profused through the HeptaAssist device. Twenty-six of these patients were subsequently transplanted and immunosuppressed.  There were 14 patients who had had pancreatic islet cell transplants. Eight of these were from Sweden and were in association with a human kidney transplant and were immunosuppressed.  While six of them came from New Zealand and did not have immunosuppression.
	There were fifteen patients from Bochum, Germany who had had pig skin grafts and the most interesting and largest group, of course, were 100 patients from St. Petersburg in Russia who had their blood perfused for approximately an hour through a pig's spleen for severe burns or cancer with chemotherapy.
	Now, although only 36 of these patients are pharmacologically immunosuppressed, as you heard before, a lot of these patients are actually immunosuppressed, the liver failure patients and, and the skin, the burn patients.
	So in total you had 83 males and 77 females and the exposure time was from the same day and these were the same patients with splenic perfusion.  You had perfused in the morning and blood tested in the afternoon up to twelve years prior to the testing.
	There were unusual symptoms that reported in six patients.  One patient had bone marrow aplasia and, and it says actually one of the Circe patients and this is a common thing seen with fulminant hepatitis. Then transplantation where bone marrow aplasia occurs.  There were four patients who reported skin rashes.  Three of these were liver failure patients and one was a skin graft patient.  Again, I think the clinicians in the room will tell you that in liver failure, the number of skin rashes of unknown etiology that occur is quite common.  This is a retrospective study so that it was difficult to make any conclusion.
	Again, there was one fever of unknown origin in a liver failure patient that lasted for three to four days.  So in turn we had 36 patients who had pharmacological immunosuppression continuously since the procedure and one patient who had received intermittent chemotherapy for a gastric leiomyoma.
	Now, I'm going to go straight to the results and in order to save time seeing I presented the sensitivities and specificities the last time.  So, when we're looking for active infection, that is the presence of RNA particles in the serum, we tested 160 patients and 160 patients were negative.
	Now, looking for results for looking for a latent infection with PERV, I first wanted to tell you that the results were not add up to 160 because with some patients we had to go back and retest them. So we actually have more than 160 results. So we had 153 patients whose total result was regular, 23 patients had evidence of pig cells circulating and in the 13 patients, only one patient who we were unable to actually isolate a peripheral blood mononuclear cells and were unable to go back to the patient.
	Twelve patients were considered uninterpretable.  Now out of those 12 uninterpretables, we were able to retest seven of them and four of them turned out to be negative and three of them remain uninterpretable because we had insufficient amount of DNA to complete the testing.
	Now the most interesting thing are of course the 23 patients with circulating pig cells.  All 23 were patients who had had splenic cell perfusion and what one sees here is that probably in the first two months, almost 50 percent of them you could actually detect pig cells that were circulating.  But more surprising is that at one year, two years, three years, four years, et cetera, up to eight and a half years after splenic perfusion, we were able to detect other incidents of pig cells circulating in these patients.  Remember, each of these pig cells contains PERV DNA.
	In terms of antibodies, 156 patients tested negative.  There were four patients who were seroreactive.  Two of these patients were seroreactive as tested at the CDC and fortunately these were patients who had received treatment with a HepatAssist, one with a HepatAssist device.  Another one was an islet cell transplant from Stockholm. Fortunately, both of these patients, we are able to have serum from before the procedures and both these patients tested positive at the time before the procedure so we know that this is cross reactivity or at least unrelated to the procedure.
	Two of the patients were positive at Q-One Biotech.  One became negative seven months later and, in these two patients, we tested them by RT-PCR on saliva.  It allows you to the feline leukemia where viruses shed in the saliva.
	We also were able to go back to the patients who were seroreactive and these were both Russian patients in St. Petersburg.  We were fortunate these were one of the few that we were able to get because actually the two patients were people who worked in the hospital themselves.  One was a surgeon and the other one was somebody who worked in the emergency room.  So we were to go back and test their five close contacts and they were negative for PERV DNA on their peripheral blood mononuclear cells.  They were negative when we tested them on saliva and on the antibodies, they were negative as well.
	Now, we were able to then do additional serological testing on the four seropositive patients.  We sent these samples to Professor Denner at the Paul Ehrlich Institute.  All four patients tested positive against the p27 (Gag) about Western Blot. All four were negative against the Recombinant p15E which is an envelop protein. Then they were all four, negative again, in the ELISAs using multiple peptides from the envelop proteins.
	Now, of interest is when he did a testing using his Western Blot with the Gag antigen, that two to four percent of five hundred random tests and this includes blood donor patients and butchers, et cetera, show Gag reactivity.  So that the conclusion is that the four patients were Gag positive, where we found Gag positivity are indeed due to cross-reactivity.
	So in conclusion, we have no evidence of active PERV infection in any patient, despite 36 who were pharmacologically immunosuppressed and presumed to be an increased risk of infection and despite prolonged exposure to pig cells for 43.7 patient years, there were no clinical or laboratory findings suggestive of a PERV infection.  Thank you very much.
	DR. COFFIN:  For the sake of efficiency, I'd like to take questions to this, are directed at this speaker in this presentation now.  I think it would be a little bit easier.  Actually I had one question.
	The antibody positive individuals were different from the individuals showing microchimerism?
	DR. PARADIS:  There was only one, oh, actually, there was only one patient that was a splenic perfusion patient and that patient did not show microchimerism.
	DR. COFFIN:  Are there any other questions?
	DR. HOLLINGER:  Yes.  What's your thoughts about why these cells are still around oh, eight years later and so on?
	DR. PARADIS:  That's a good question.  Unfortunately, as you can see the level of microchimerism is extremely low and so that we weren't really able to tell what kind of origin the cells were.  Our hypothesis is that seeing as these are all splenic perfusion cells that they probably find a nest somewhere in the body and what we catch are intermittent release into the circulation.  Our guess here is that these could be perhaps dendrite cells that are, perhaps they don't express as much gall as the other cells.  But just to say that this is not actually, since that we've also analyzed some xenotransplant in primates with porcine organs and we find extensive microchimerism even in the long-term survivors.
	DR. COFFIN:  Do these patients raise extensive antibodies against the transplanted cells?
	DR. PARADIS:  None of them have really any antibodies.
	DR. COFFIN:  Against the cells. Any other questions of this speaker?  Hal?
	DR. VANDERPOOL:  Very impressive study in terms of the variety of patients and their conditions and also we were privy to maybe very reassuring conclusions regarding worries we've had.  Does anyone on the committee want to comment about what you see as the import of the study for our deliberations and worries in the past and on deliberations at the present?
	MR. ALLAN:  I think the data demonstrates that you've got, even in the patients who had evidence of PERV, the levels were extremely low and the numbers of cells are very low and, in many cases, you show they disappeared.  In some cases you actually had microchimerism in for several years.
	Obviously the concern then is the fact that whatever virus is harbored by those pig cells is still there in the patient up to eight years later which, although the risk may be very small, the potential is that those viruses could express themselves at any given time during the post-transplant period. So, in some sense, the microchimerism is advantageous in some respects but it can also be a disadvantage in the fact that you'd be continually exposed to an infectious agent.
	DR. PARADIS:  If I may point out that once the patient will be transplanted, they will have a whole organ that will have cells that contain PERV and that they will be also hopefully keeping these organs for a long time.
	So I think that actually these patients with microchimerism are reassuring, telling us that even though you have cells circulating in your body for several years, that this has not caused any clinical symptoms nor any signs of infection.
	DR. ALLAN:  I don't know if this is the appropriate forum for this but I still have questions regarding the types of assays that are used to detect PERV and the validity of some of those assays.  I'm not sure that this is the form for that.  We may, whether we should discuss that now or not.
	There's several different assays that are being used and for the molecular assays at least in two different laboratories, the algorithms are such that if you get a positive, you rescreen it.  If you get a negative, it's a negative.
	I've always fundamentally had a problem with that.  Usually when you do a study what you generally do is you have some other asset to validate your results.  I know that there is statistical reasons to believe that you can actually get away with it by doing it once or twice or three times but it still can present problems in terms of interpretation.  The reason I bring that up is because when you're dealing in the situation where you're looking, where you may be looking for only one cell in a million, that changes your ability to detect something.
	So you may get a negative one time, you may get a positive another time.  It doesn't mean that the fact that you get a negative the second time means that the sample was negative.  Even statistically, if you got less than ten copies present in that sample, then the statistics about the false negative rate are not based on one to five copies or whatever it is.
	So, I think you really have to go back and really look at how you're validating these studies in terms of your algorithms. Having said that, still in most situations, what you're really looking for is whether the viruses is being expressed, whether the patient has actually gotten infected.  If that patient's infected, they should have much higher levels.  So I'm just talking about in terms of validation of the assay. I think the data's still good.
	DR. ONIONS:  The algorithms been referred to as one that has been developed by, by a doctor and colleagues at GTI and I don't want to get in a debate about defending that algorithm because I think it's probably not the right audience and it's certainly too late in the day.  But, I think, just as a general statement, since I wasn't involved in that bit of the study I can sort of, to some extent, look at it more objectively.
	I honestly believe that what's been happening here is really pushing these tests, using the kinds of technology that are the best technologies available.  Pushing these sensitivities to the limits.
	When you start doing this, this does get you into, in other words, if you use a less sensitive test and all these problems disappear, but the reason that this kind of analysis has to be done is that you're using the most sensitive assay systems available and however you look at the results of this, it is clear and regardless of what conclusion that you draw from it, it is clear there has been no, in my view, there's been no established infection of human cells at least on a scale, of the scale that is detectable by the best techniques that we have available at the moment.  That's, I think, a reasonable statement to make about these results.
	DR. COFFIN:  Might it not be reasonable in a case where you had a positive Env instead of doing one replicate reproduction to do ten replicate reproductions or something like that to try to address more specifically the exact statistical issue that Jon just raised.  I don't think it would solve all the problems but I think it would perhaps tell you whether you were seeing a real but very, give you a feeling toward a real but very low positive or a negative and false positive.
	DR. CHAPMAN:  My colleague Waleed Heneine asked me if he needed to come to this meeting.  I said no, I didn't think so.  Now, I'm regretting that he isn't here.  Not being the best person from the CDC Group involved to speak to this, still, let me try to address for the people for whom this is outside their expertise.
	I think the concepts, I think what you're saying is correct, Jon, in that you're inserting into the discussion the recognition that there's still a lot of uncertainty here. That no matter how much work we've done at CDC or they've done at GTI trying to validate the assays, there's still a limit to how validated they are and how much confidence you can have in the negative results.
	Having said that, let me say that one reason, there's several reasons as an agency, we felt that it was important to do the confirmatory testing that Novartis asked us to for this study.  One was because we wanted access to the assessments and we wanted to know what those results said in our hands.
	As an agency involved in developing policy.  The second is that we thought whatever the results of the study, it needed to be a study in which there was public confidence and, for that reason, there was value to having a laboratory that was taxpayer-funded and that had absolutely no vested interest in the outcome other than having the most valid possible interpretation of the outcome publicly involved.
	But the third reason is trying to do the best job we could have addressed in exactly what you're asking which is the usual way one would proceed is, you take an investigational assay and you test specimens and then you compare that to the results you get when you use the gold standard assay. There is no gold standard assay here.  If there was one, I suppose it was ours because we had already published one small series with.  But we've got two investigational assays and part of the reason of doing independent testing was given the circumstances and the limitations of reality and available specimens which is the absence of any known positive infected people against which to test as positive controls, we felt the best information could be gained by doing this kind of head-to-head comparison.
	I think a lot was gained that's reflected in the paper but I know there was also a lot and one reason it took so long to get this out is that every stage there was the additional R&D done in multiple labs on the basis of trying to make the comparisons.
	The point you raise which is if you've got uncertainty about a result, rather then doing a second test and taking the results of those, why not do ten additional tests, is, again, in ideal circumstances that would be terrific.
	But one of the problems here is that we ran into limitations with having enough DNA on the patient to actually complete ones that have testing at GTI and ones that have testing at CDC.  So, again, these are important points about the importance of people continuing to not only develop their assays, to test them against other assays to make those results public and to constantly exercise caution about the degree to which they get dogmatic about belief in their results versus reality.
	But I also agree with David Onions said at least for our folks and the folks we're collaborating with, this is the best we could do at the current state of knowledge.
	DR. COFFIN:  You can apparently get back to at least some of these patients.  I don't know if there's, so if there's only more, maybe at least in some cases more samples could be, could be obtained.  I don't know.
	DR. CHAPMAN:  Unfortunately, the ones we can get back to are not the ones which there was concern about what the results meant.
	DR. COFFIN:  They're not the ones you want.  They're not the ones you're interested in, yes.
	DR. MICKELSON:  I just had a quick question about the number, the 23 that appeared to be microchimeric.  Did that correlate with any difference in their particular clinical course or were they, did they have more fevers of unknown origin or is this just a fact?  You've pushed the limit of detection.  You've got a result here and it doesn't correlate with anything except your tests.
	DR. PARADIS:  Sorry.  Actually none of the patients from Russia reported any clinical symptoms whatsoever.  Of course there's a regional difference in how you report severe adverse events and Russians tend to be more stoic I guess.
	DR. MICKELSON:  Nicely put.
	DR. PARADIS:  But, none of them reported having any unusual symptoms.  The age of the patients did not seem to have any relevance.  Unfortunately, we didn't expect microchimerism and when we planned the study in our case report forms, we did not ask what the reason was for each individual patient, for them to undergo their splenic perfusion. So that all we did was go back to the investigator and ask overall what they were. So I really cannot give you any kind of correlation and anyways it would be retrospective and I don't think you could make any sort of conclusion.
	DR. MICKELSON:  No.  I was just wondering whether there might be precipitating factors.  If you're saying there's a sort of a --
	DR. PARADIS:  My suspicion is that if we followed all 100 patients, prospectively, with multiple samplings, that we would have had a lot more than 23 patients who are microchimeric.
	DR. MICKELSON:  Yes.
	DR. COFFIN:  Arifa?
	DR. KHAN:  I just wanted to ask you, the patients in which you have the persistence of the pig cells, have you attempted any stimulation or induction studies to see if you can induce the retrovirus on this may potentially address some potential risk concerns?
	DR. PARADIS:  I have to admit that we had a lot of difficulty going back to obtain samples again from Russia.  We were just able to get them again to retest them for microchimerism but we were unable to do any more than that.  I'm sorry.
	DR. LERCHE:  Did you indicate that one particular type of exposure was more associated with microchimerism than some of the others?
	DR. PARADIS:  Yes.  It was all in the splenic profusion patients.
	DR. LERCHE:  Only.  All 23 were?
	DR. PARADIS:  All 23 were splenic profusions.
	DR. VANDERPOOL:  I don't want to put you on the spot but I guess I am. Carolyn, do you have any comments about the importance of this study to you?  You're well-known as a researcher.
	DR. WILSON:  I think that this is a very important study and it's very valuable data and we're very encouraged by the results from this study but I think that, at least at the FDA, we still feel that it's an issue that requires continued data.
	The type of exposure that these patients, that they had, is not necessarily going to be the same as what's currently being tested and planning for being tested in clinical trials.  So, we feel that it is important to continue accruing this type of data in current and future clinical trials.
	DR. COFFIN:  I'd like to move on then to hear from David Onions.
	DR. ONIONS:  I wonder if somebody could be kind enough, is this on?
	DR. COFFIN:  He certainly needs no introduction at this point.
	DR. ONIONS:  That's fine.  I'd just like to give you a very brief outline of what I deemed here an experiment.  But that's perhaps an exaggeration.
	It's a very preliminary observation that derives out of a study to develop antibodies to one of the subgroups of PERV, that's PERV-B.  This virus had been prepared in human 293 cells and we have perhaps a sequence of this particular virus.  A standard viruses preparation was prepared so this does not contain cells.  We're looking at a virus preparation that was then inoculated subcutaneously into guinea pigs and because this was an antibody-raising experiment, the virus was given twice, 28 days apart.  The analysis I'm going to show was taken 14 days after the second inoculation.
	So this was really an antibody-raising study.  But we did actually analyze these animals to look to see whether there was actually evidence of infection in these guinea pigs and we looked for the presence of viraemia using a para-toxical ingredient we call F-PERT which I'll comment on in a moment.
	We looked for latent infection or the presence of proviruses, proviral DNA within cells and we looked for the expression of those proviruses by RT-PCR.  We looked for antibody by a number of criteria both Western Blots and the ELISAs using Hovius, recombinant p30 and recombinant envelop protein.
	First of all we just screened by a non-quantitative PCR just as a quick look see, was there anything there.  To perhaps a little bit surprising, perhaps all of these animals came up positive by a standard PCR with the signals being most intense in lymphoid tissue.  I'll come on and show you some quantitative data in a moment.
	Although this was not a cell preparation we did want to exclude that these animals had not just passively taken up contaminating DNA in the viral preparation. So we checked for the 293 DNA.  That's the DNA of the cell line from which the virus was prepared and in none of these animals did we detect such DNA.  Similarly, we obviously looked at non-infected controls. These were actually litimate (?) controls and there was no cross-reactive retrovirus in these guinea pigs.  There was a guinea pig retrovirus, the L2 virus.  But there was no cross-reactive virus in these animals.
	What was more, I think, interesting is when we did quantitative PCR, I won't go through the testing detail because, if you know it you know and if you don't you probably don't want to know it.  But simply, it uses a PCR technique and it uses a fluorescent labeled probe.  The point being that it allows you in real time to detect the quantity of the target that you're looking at.  In other words, it gives you a quantitative PCR result.  That's all you need to know really.
	For the afficionados, this just shows these particular results.  The black dots show proviruses that are spiked into DNA to quantitate the system and you can see that it's linear, it actually gives a coalition coefficient of .97.  You can then look in the test samples which are read and look for the number of proviruses that you find in your test sample and then those number proviruses have been normalized to a million cell equivalents of DNA.  So what I'm about to show are the number of proviruses detected in an equivalent of a million cells.  This is from the spleen only.
	So these are five of the eight guinea pigs that we analyzed in detail or are analyzing in detail, perhaps more accurate. As you can see, the counts very from around about 3000 proviruses per million cells right up to 70,000 parvovirusues per million cells.
	Now we only put in 106 billionths and those were actually assayed by electro-microscopy so the effect of the type was probably lower than that.  I think with this kind of count here it almost certainly means that there is evidence that those viruses must have undergone at least one round of replication to get those number of proviruses in those cells.  So it's not just a single one round hit.
	We then went on to look and see whether there was expression of these proviruses and this was done by RT-PCR.  You can do it two ways.  One is to look for the splice message which is the envelop message which is present at a lower level in these cells probably by the globular down, the full length message which we also detect and this was to use in this probe here, this PCR action, this pole region.
	The net results of that are that only one of the eight guinea pigs had detectable expression at the RNA level at this single time point.  Remember, we've only looked at one time point.  But, we're pretty convinced this is message because the signal was negative without reverse transcriptase indicating it wasn't due to contaminating DNA.  However, we did not detect the lower abundant spliced Env message.  So we've got one out of eight of guinea pigs that evidence of expression at the time, the single time point of sampler.
	We then asked the question, are these animals biorhythmic and to do that we use a PERT assay.  Again, this actually was been mentioned before and plus it is relevant just to quickly touch on this because it is one of these new generation retroviral assays that's useful.
	It utilizes an RNA from a plant, usually a plant virus. If you've got a virus that has reversed transcriptase and will cover that RNA into a DNA copy, and you can then amplify that residual DNA using a PCR approach, and in the old days we use to just block this out.  But now combining it with the type main technology we just say a moment ago, you can actually get a quantitative result because you can actually quantitate the amount of this PCR product.
	This just, the next slide just shows that this is a sensitive system.  This just shows the curves coming off the machine using a 106 billions or 102 billions and you can see even the at 102 billions, we're actually having a signal that we know through assay validations a valid signal.  So we have a system that has a detection level of 102 billions in the assay but we limit the quantification, quantitation is not an English word, quantification to 103 billions.
	In none of these eight guinea pigs was there evidence of viraemia.  So we have animals that have proviruses, one of the animals his level of RNA expression but we did not detect the level of sensitivity to the assay, free virus in the plasma.
	I want to go through all the antibody results just to explain that we use these multiple criteria.  We use recombinant p30.  We validated this assay quite extensively.  We've also validated the product that shows the mass spec analysis. This is recombinant p30 here.  These are secondary fragments, they're not contaminates.  They're just miss, different mass spots, mass charge fragments.  This is very low molecular weight contamination.  So it's a pretty clean product.
	But I'll just show you the results. One result from one animal with, in fact, whole virus antigen just to convince you. This just shows the curve of dilation.  You won't be able to read it.  I'm sorry.  But that says 1 in 12,800.  So the chances of antibodies going up very high in these animals, in the case of this particular animal out to a tie to 12,800.  So all eight guinea pigs had antibodies to both Env and Gag proteins by these multiple assay systems.
	Well, the important thing is what, how do you interpret these words, what's happening and the answers we don't know because we've only looked at a single time point.  But, this is a speculative interpretation based on other model systems like cat virus and feline leukemia virus in cats, given eight leukemia virus in Gibbons and you have to accept this as just hypothesis and could be altered.
	But we know that in most patients that frequently what you see after infection is a plasma viraemia.  In the majority of animals, you actually get recovery from infection.  So the majority of animals you eventually see a succession of viraemia and this usually is coincident with a development of antibody.  That's not to say that antibody is the only clearance mechanism.  It is not. T-cell immunity is absolutely critical but it's usually coincident.  These two events are coincident.
	You do get a latent infection.  So you do protect proviruses by PCR, either in peripheral blood or in spleen tissue and bone marrow.  This latent state can last for years but without any disease development. Eventually we see to appear clonal distinction.  That's what we see in cats.
	Now I don't know what's going on in guinea pigs what I might suggest is that probably what we're looking at is this sort of pattern of infection.  We're looking at the transition from where there's been active replication to this sort of stage where we've got latent infection in the presence of antibody.
	What is usually more serious in these infections and they are different to each other.  One is usually the serious consequence is when these animals don't go into recovery phase and they develop a persistent plasma viraemia, often with infection of many tissues, epithelioma surfaces.  Generally these animals don't develop antibody.
	So in conclusion, what I think we're seeing certainly cross-species infection where we're seeing this cross-species infection falling into this latent impossibly recovery pattern.  That's the thing that we're seeing.
	What might we use the model for? Well, we've already discussed, we don't have any evidence about what in this expression may or may not do.  I think this may provide a tool to actually look and see what kinds of expression and where it's modified the pattern of infection.  It may also provide other tools to look at other aspects of intervention in these kinds of retrovirus infections.  Thank you.
	DR. COFFIN:  Very interesting. This is open for discussion and I would like to ask a question.  What would you expect the outcome to be if you took these guinea pigs and infected them with a known pathogenic C-Type retrovirus like melomaniac leukemia virus or FELV?  Do you think you'd see anything much different from what you did see?
	DR. ONIONS:  The answer, I'm not sure.  I think, I'm not entirely surprised that you're able to get virus into guinea pigs{IOn} en vivo{IOff}.  I'm not entirely surprised by that.
	I think I'm a little bit surprised by the fact that all of them were positive and all of them were positive at relatively high levels which implies replication.  The answer is: I don't know.  People have put, for instance, feline leukemia virus into it, but that's a bad example, because it doesn't replicate in rodent cells very efficiently.
	DR. COFFIN:  Right.
	DR. ONIONS:  I don't know, anthrotrophic FELV might be interesting.  I don't know.  But given for instance the data from Phil and others, then, maybe, when you introduce these viruses by these other roots, intraperitoneal or subcutaneously, you bypass because of barriers.  If you don't have a compliment system that's going to clear, then maybe it's not unexpected that we will see infection.
	I believe that when we first discussed this issue at the first committee meeting, we did actually, on the sort of story scale, actually come to the conclusion that it was not unlikely that in a xenotransplant, that some human cells are likely to be infected.
	DR. COFFIN:  But, I mean, were these viruses, if you, these are immunocompetent animals that you infected.
	DR. ONIONS:  Yes.
	DR. COFFIN:  You did not obviously infect newborns for this experiment.  I assume you are planning to do that at some, at some time soon if you haven't already.
	DR. ONIONS:  We've obviously doing a time core study at the moment.  We are, obviously, a very interesting response study in suppression.  We have to do through this regulatory hurdle in the U.K. to get permission to do that experiment because it requires home office permission.  But, yes, that will be done eventually.
	DR. COFFIN:  Because many of these retroviruses are, of course, pathogenic.
	DR. ONIONS:  Sure.
	DR. COFFIN:  Most pathogenic are only pathogenic in newborn animals.
	DR. ONIONS:  Yes.  That's correct.
	DR. COFFIN:  Are there other questions or comments?  That's very interesting.  Is there any general discussion of these issues that anybody would like to raise even going back to the first talk?  Oh, we're getting quiet.
	DR. NOGUCHI:  I just wanted to say one comment here.  I think that it's very, this data is very encouraging because it's a possibility for actually having a model.
	Whether we might be able to model some of the potential outcomes that we need to look for.  Once you get something infected that's fine if the antibody stays up but if you later immunosuppress, could you get something coming out later?  So, I think from our point of view, it's always very encouraging when we can have actual models to work with.
	DR. COFFIN:  Actually, given that perspective, have you looked in circulating blood?  Circulating them for sites?
	DR. ONIONS:  No, sorry.  We haven't looked at circulating lymphocytes.  We looked at plasma but we didn't look at circulating lymphocytes.  But we will do that.
	DR. COFFIN:  Because that would carry us right back to the previous topic, of course.
	DR. ONIONS:  Yes, sure. Absolutely, yes.
	DR. COFFIN:  I believe we have one more request for a public discussion.  You can use that one.
	MS. FANO:  I wrote down a few comments and questions just for the record because I didn't get a chance to respond to Dr. Vanderpool's comment which I didn't really appreciate, where he said that my comments don't apply to the real world where people suffer.
	First of all, just for the record, my own parents died of chronic diseases and I know a little bit about suffering.  The comment I wanted to make before I was cut off was that should an infection spread by a xenotransplantation will be causing a lot more human suffering than is currently, currently going on.
	The other comment is that no guideline can account for latent or unknown infections.  While Dr. Onion's study on guinea pigs is interesting, guinea pigs are not human beings.  Just wanted to remind everybody that the gene therapy deaths that occurred and were reported in newspapers, the animal tests that were done did not predict the side effects that killed those patients.
	The question I had, questions I had were regarding the cost of monitoring patients and the blood supply.  I wonder if anybody has done any cost benefit analysis or cost analysis in general of how much the monitoring is going to cost.  There were -- read certain legal journals which said that the costs would be exorbitant.  Question about how to force compliance with monitoring when patients may not wish to be monitored anymore.  If they tire of monitoring and decide that they don't want to be monitored. What mechanism is there in place to force compliance, if that is even legal?
	I asked this particular question back in January of '98 and I never got an answer and it is, I think, important and I hope that you won't dismiss it because governments and corporations have been held liable in the case of infected blood with HIV virus and CJD and that is:  Who would, here or anywhere, would agree to be held legally responsible if a viruses did spread as a result of xenotransplantation?
	I think that's an interesting question and I don't think anybody's ever answered it and I, I do sincerely hope that you won't dismiss it and make light of it because I think it is an important question that everybody should begin to think about because I think the risk of the virus spreading is, is real and I think you've all acknowledged that.
	The other question is since follow up is the only hope of catching viruses, I think that's been expressed on the panel.  I was alarmed that Genzyme did not think of following up with it's patients who received the Epicel treatment and I was concerned that the FDA didn't seem to have a knowledge of these patients and where they were and any kind of monitoring procedure.
	Just generally, that I was alarmed by the sort of odd state of affairs here in terms of the regulatory status and the definitions that don't seem to be clear while xenotransplant trials are still ongoing and being approved.  I'm sort of puzzled as to how trials can be allowed to go forward before any kind of regulatory frame work is really fully defined and established.  So, that's a lot of questions and comments.
	DR. COFFIN:  Thank you. Is there any further discussion that anybody on the committee would like to have?  Jon.
	DR. ALLAN:  Can you tell us how many xeno trials are going on at the present?
	DR. NOGUCHI:  I don't think we can comment specifically but we could say that there are, there are on the order of a dozen or so that are active.  There's different amounts of enrollment in all of them.  I would like to take this opportunity to say it is not true that there is no regulatory framework for this and, in fact, the consequences of having a very active, not only FDA regulatory oversight but public health oversight is, I think, a commitment of the government to the seriousness of the situation.
	In fact, the changing definition is not one of being unclear about what we're talking about but saying exposure to animal tissue cells and potentially organs in the future, is something that we recognize as fraught with danger and, in fact, that's why we continually come to the public to ask, and to our advisors, to ask for advise and, of course, to solicit public comment and opinions.  We appreciate all viewpoints and it is appropriate to always make sure that all points of view are being heard and are continually addressed.  That doesn't answer the question of liability and I won't do that.
	DR. COFFIN:  Is there anything else?  Yes.
	DR. VANDERPOOL:  I want to second what Dr. Noguchi said.  You can be sure that, that I will not and surely most of the people on this committee will not dismiss what has just been said because it manifests fear and alarm and concern and that's why some of us travel from different parts of the U.S. to come here to hope that these types of concerns are taken into consideration.
	So rather than, I hope you don't think that I'm either defensive or hypercritical of your perspective.  I think this perspective is out there and it's shared by quite a number of people and unless we are able by our deliberations to address these concerns, as I believe we are doing over time, but if we're not able to address them, then we need to change our course.
	So, my point is, thank you for offering this perspective and we will keep these considerations in mind.  At the same time, you heard me say that I thought that that you had over generalized at some points in what you said earlier and I think that continues here because what else have we been about these many meetings other than trying to regulate xenotransplantation as seriously and carefully as we possibly can do and what else are we about then actually hearing of the particular regulations that have been outlined for us today yet again.
	So, the regulation is occurring, there have been indications that the FDA is quick and ready to put trials on hold if there is information that is alarming concerning infectivity and so we, we can be assured that the FDA acts when it becomes aware of alarming and worrisome developments. So, I think part of what we're about is witnessing not only a careful deliberation of these risks but a willingness to act quickly and decisively if we see they're serious.
	MS. FANO:  I just wanted to answer that that my impression is that much of the regulation is being done in hindsight.  I think it was Dr. Allan who said if you're putting your bets on containment it's a lost cause.
	I think that some of the experiments that are being done and the clinical trials that are ongoing started before there was really any regulatory system in place.  As you say, it's constantly evolving but given the public health risks involved with xenotransplantation it would seem as though, if you're talking about the precautionary principal in protecting public health, that you should have these measures in place before allowing clinical trials to go forward and that there should be a very precise monitoring program set up to make sure that you know every single xenotransplant patient that's had a xenotransplant and you know their names, where they live, if you're concerned about close contacts you know who they are and what I'm saying is that it doesn't seem like that system has been set up.  It seems like experiments, clinical trials, have been ongoing without these kinds of systems in place.
	DR. COFFIN:  Is there anything else?  Are there any further questions from the FDA that, while they have us here, they'd like to pounce on us with?  Any further comments or questions from the committee?  If not, I think we can declare it.  Oh.  One more, one more comment from the public.
	MR. BRESLIN:  Hi.  My name is Andy Breslin and I'm just here representing a concern citizen.  I have two points to make and they both concern math.
	One is, if you have an infectious agent with a very, very low rate of transmissibility across species which then has a much higher rate of transmissibility within that species, I think it should be mathematically intuitive that you're, and you add to that a long latency period before you see the development of any symptoms, it should be intuitive that you can have a very, very long period where you're going to see nothing, no symptoms and then a very rapid expansion of disease and a logarithmic growth of that disease and you could, you could map that out mathematically but I think it should be intuitive that you're going to see a very long period where there's nothing happening and then all of a sudden, very, very rapid expansion of disease.
	So I think that the fact that there has been no evidence of any disease transmission should not really give you very much assurance and, in fact, it would be very, very surprising considering the relatively low amount of xenotransplantation that has occurred thus far if you had seen anything yet.  So, I just think that should be factored in when considering the past evidence of no transmission.
	The other mathematical point I'd like to observe is that since this meeting began about eight hours ago, 2,000 human bodies full of organs and tissues have been burned and buried and only a very relatively small percentage of the organs and tissues that have been burned and buried have been made use of in any way, shape or form and, by the end of the day, about 6,000 human bodies full of organs and tissues will be burned and buried and by the end of this year over two million bodies full of human organs and tissues will be burned and buried.
	Meanwhile we're going to just continue to talk about oh, the organ shortage.  How do we meet the organ shortage by increasing xenotransplantation and to that end I'd like to invite any of the corporate interests who are so concerned about the organ shortage and who are developing xenotransplantation to discuss some of the philanthropic public service campaigns they've had to increase organ and tissue donation if they have any.  That's about all I have.
	DR. COFFIN:  Thank you.  Do we have another comment?  Okay.
	DR. LONG:  Yes. I just want to touch the topic that Dr. Allan raised about the validity.
	MS. DAPOLITO:  Have him identify himself.
	DR. COFFIN:  Oh, can you identify yourself please and your institution.
	DR. LONG:  Yes.  Zhifeng Long from GTI.  We participated in the 7-11 study for replicate.  Just to answer the question that Dr. Allan raised regarding the validity of the test.  Why we perform replicate testing.
	The reason that GTI has to perform replicate testing is because we push the assay to the most sensitivity so that we can detect a single copy of PERV DNA in the presence of half a million cells.  The answer was performed both and point detection as well as quantification so the assay can actually quantify from ten copy all the way to one million copies.  At the same time, we can detect single copy sensitivity.
	Now, during our assay validation, what we found is the assay, when we push to that extreme, we have a very high false positive rate. It's a 9.88 percent.  So, with this false positive rate, when you're only to do one replicate test, you have the consequences, either calling this sample positive with a chance of 10 percent false positive or, if you do three tests, you effectively reduce the false/positive rate to .1 percent because it's ten percent multiplied three times.  So that's the rationale and the reason why we perform replicate tests.
	Now, that to no way that this replicate test throwing away any legitimate data because what we claim is that by performing three tests, we essentially validate the assay with single copy sensitivity but we claim by doing three tests with a ten copy sensitivity, there's no way that you will miss any positive sample because the positive sample by the percentage of distribution with ten copy, you will have 99.99 percent of detecting it.
	So, it's additional work to us but it's not a loss of validity to the data itself because essentially we have to triple our work.
	DR. COFFIN:  Any comments?  Okay. Go ahead.
	DR. SAVILL:  My name is Corinne Savill.  I work for Novartis.  We are one of the companies working in the field of research into xenotransplantation.  I'd just like to make some comments in reference to the last speaker but one.
	Firstly, just because nobody else in the room has mentioned it, just to make the point that most people are aware that not everybody unfortunately who dies is in such a condition that their organs can be taken and used for transplantation.
	But secondly, to mention on behalf of our company, that through one particular drug which is very successful in transplantation which is cyclosporine or Neoral, but we've had a long association with allo-transplantation, and contrary to what is suggested, actually have but quite a lot of effort into supporting and promoting initiatives to raise the awareness of the success of transplantation and also to increase the number of human donors available for transplantation.
	So it's not that this is a case of either/or, and, in fact, the major rationale for xenotransplantation for solid organs is to provide an alternative for those people for whom human organs are not available.
	DR. COFFIN:  Thank you.  Is there anything else?  Any other comments from the public?  One last word, any last word from the FDA?  Last word from the committee?  Ah, Claudia.
	DR. MICKELSON:  No, no.  I'm not, never mind.  I just wanted to defend the use of animal models.  While they may not be 100 percent predictive, it is one of the few things you have that can allow you to progress from the theoretical bench through a living whole system that can respond.  But, it's in no way 100 percent predictive but it's an intermediate step that could never be gone around.
	MS. FANO:  Just to add to that, that from the June 3rd and 4th FDA subcommittee meetings that were held, the researchers involved in the field themselves acknowledged that even the baboon model that they had was really not a good model of the human scenario.  So, the trouble with animal models is recognized even by the researchers themselves.
	DR. COFFIN:  They're certainly not perfect.
	DR. SIEGEL:  I'm sorry but just a quick note to thank very much the members of the committee, the guests of the committee. Your deliberations were extremely helpful to us.  The chair, the previous chair for a well run meeting that ended on time, the commenters from the public and from, as well as the presenters.  We very much appreciate today's proceedings.
	DR. COFFIN:  With that we're adjourned.
	(Whereupon, the MEETING adjourned at 5:09 p.m.)
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