1
DEPARTMENT OF HEALTH AND HUMAN SERVICES
FOOD AND DRUG ADMINISTRATION
BLOOD PRODUCTS ADVISORY COMMITTEE
70th MEETING
December 13-14, 2001
8:10 a.m.
Thursday, December 13, 2001
Hilton Silver Spring
Maryland Room
8727 Colesville Road
Silver Spring, Maryland
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MEMBERS OF THE COMMITTEE
Kenrad E. Nelson, M.D.
Chairman
G. Michael Fitzpatrick, Ph.D.
Raymond S. Koff, M.D.
Jeanne V. Linden, M.D.
B. Gail Macik, M.D.
Daniel McGee, Ph.D.
Mark A. Mitchell, M.D.
Terry V. Rice
Paul J. Schmidt, Jr., M.D.
David F. Stroncek, M.D.
Sherri O. Stuver, Sc.D.
TEMPORARY VOTING MEMBERS
Jonathan S. Allan, D.V.M.
(by telephone)
Lianna Harvath
F. Blaine Hollinger, M.D.
NON-VOTING CONSUMER REPRESENTATIVE
Katherine E. Knowles
NON-VOTING INDUSTRY REPRESENTATIVE
Toby L. Simon, M.D.
Executive Secretary
Linda A. Smallwood, Ph.D.
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AGENDA
ITEM PAGE
Statement of Conflict of Interest
Linda A. Smallwood, Executive Secretary 5
Presentation of Committee Member Certificates -
Dr. Jay Epstein 8
Committee Updates
Current TBE Guidance
Dorothy Scott, M.D. 11
Summary of CDC Workshop on Factor VIII
Mark Weinstein, Ph.D. 23
Disaster Response
Alan Williams, Ph.D. 28
Summary of Nat Workshop, December 4-5, 2001
Edward Tabor, M.D. 38
OPEN COMMITTEE DISCUSSION - POTENTIAL CONCERNS
FOR SIMIAN FOAMY VIRUS TRANSMISSION BY BLOOD
AND BLOOD PRODUCTS
Introduction - Hira Nakhasi, Ph.D. 61
Review of SFV Biology and Pathogenesis
Arifa Kahn, Ph.D. 66
Review of CDC Investigation on Human Infections
with SFV - Louisa Chapman, M.D. 81
Review of Health Canada Study: Risk Assessment
Paul Sandstrom, Ph.D. 112
FDA Proposed Animal Study on SFV Transmission
by Blood - Arifa Kahn, Ph.D. 139
Open Public Hearing
American Association of Blood Banks
Kay Gregory 166
America's Blood Centers
Dr. Celso Bianco 169
Immune Deficiency Foundation
Jonathan Goldsmith 170
Questions for the Committee
Hira Nakhasi, Ph.D. 176
Committee Discussion and Recommendations 176
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AGENDA (cont.)
ITEM PAGE
OPEN COMMITTEE DISCUSSION - LEUKOCYTE REDUCTION
GUIDANCE
Introduction and Background
Alan Williams, Ph.D. 209
Review of Filter Performance Data
Betsy Poindexter 221
Establishing the Appropriate QC Cut-Off for
Contaminating Leukocytes
Edward Snyder, M.D. 235
QC Methodology for Leukoreduced Blood Products
Linda Kline, American Red Cross, Holland Lab 266
QC Strategy
Alan Williams, Ph.D. 274
Open Public Hearing
NIH Department of Transfusion Medicine
Dr. David Stroncek 302
Becton, Dickinson and Company
Leonard Buchner 313
Haemanetics
John Sokolowski 316
America's Blood Centers
Dr. Celso Bianco 321
American Association of Blood Banks
Kay Gregory 330
American Red Cross
Dr. Linda Chambers 334
Maco Pharma
Yasir Sivan 349
Questions for the Committee
Alan Williams, Ph.D. 351
Committee Discussion and Recommendations 352
Adjournment 365
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1 P R O C E E D I N G S
2 DR. SMALLWOOD: Good morning. Welcome to
3 the 70th meeting of the Blood Products Advisory
4 Committee. I am Linda Smallwood, the Executive
5 Secretary. We're going to start the meeting as
6 close as possible to on time, although we don't
7 have all of the committee members here, but we do
8 have enough to constitute a quorum.
9 At this time I will read the conflict of
10 interest statement that will apply to both days'
11 session of this meeting. The following
12 announcement is made part of the public record to
13 preclude the appearance of conflict of interest at
14 this meeting.
15 Pursuant to the authority granted under
16 the committee charter, the Director of FDA's Center
17 for Biologics Evaluation and Research has appointed
18 Drs. Jonathan Allan, Lianna Harvath, and Blaine
19 Hollinger as temporary voting members. In
20 addition, the Senior Associate Commissioner of FDA
21 has appointed Dr. Michael Diamond as a temporary
22 voting member.
23 To determine if any conflicts of interest
24 existed, the agency reviewed the submitted agenda
25 and all relevant financial interests reported by
6
1 the meeting participants. As a result of this
2 review, the following disclosures are being made.
3 Drs. Kenrad Nelson and Paul Schmidt had
4 waivers previously approved by the agency that are
5 applicable for this meeting. The following
6 participants have associations with firms that can
7 be affected by the committee discussions: Dr.
8 Boyle, Diamond, Fitzpatrick, Harvath, Hollinger,
9 Koff, Knowles, Linden, Macik, Nelson, Schmidt, and
10 Simon. However, in accordance with our statutes,
11 it has been determined that a waiver or an
12 exclusion is not warranted for these deliberations.
13 With regards to FDA's invited guests, the
14 agency has determined that the services of these
15 guests are essential. There are reported interests
16 which are being made public to allow meeting
17 participants to objectively evaluate any
18 presentations and/or comments made by the
19 participants.
20 Related to the discussions on potential
21 concerns for Simian Foamy Virus transmission by
22 blood and blood products, Dr. Louisa Chapman is
23 employed by the Centers for Disease Control and
24 Prevention. Dr. Paul Sandstrom is employed by the
25 National HIV lab in Canada.
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1 For discussions on the current leukocyte
2 reduction guidance, Dr. Linda Kline is employed by
3 the American Red Cross, Holland Labs. Her lab has
4 performed leukoreduction evaluations for and has
5 collaborated with Baxter, Hemasure, Pall, and
6 Terumo. Dr. Edward Snyder is the principal
7 investigator on research projects supported by
8 Baxter, Pall, and Terumo. He also consults with
9 Baxter. He is an ad hoc advisor for Terumo, and is
10 a member of Pall's board of directors.
11 For the discussions on human cells,
12 tissues, and cellular and tissue-based products,
13 risk factors for semen donation, Dr. Charles Sims
14 is employed as the Director of California Cryobank,
15 Inc., a sperm bank. He has financial interests in
16 Cryobank. He is a founder and a member of its
17 board of directors. He is also a member of the
18 board of governors, American Association of Tissue
19 Banks, and a member of its accreditation committee.
20 Dr. Linda Valleroy is employed at the National
21 Center for HIV, STD, and TB Prevention at the
22 Centers for Disease Control and Prevention.
23 In the event that the discussions involve
24 other products or firms that are already on the
25 agenda, for which FDA's participants have a
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1 financial interest, the participants are aware of
2 the need to exclude themselves from such
3 involvement, and their exclusion will be noted for
4 the public record. With respect to all other
5 meeting participants, we ask in the interest of
6 fairness that you state your name, affiliation, and
7 address any current or previous financial
8 involvement with any firm whose products you wish
9 to comment upon.
10 Copies of waivers addressed in this
11 announcement are available by written request under
12 the Freedom of Information Act. At this time I
13 will ask if there are any additional declarations
14 by any committee members or anyone involved in this
15 meeting.
16 [No response.]
17 DR. SMALLWOOD: At this time I would like
18 to call upon Dr. Jay Epstein, the Director of the
19 Office of Blood Research and Review.
20 According to our agenda, we will have a
21 presentation of committee certificates, because we
22 have some members of the Advisory Committee whose
23 terms have expired and they will be leaving us, so
24 that we want to acknowledge them.
25 DR. EPSTEIN: Well, first I just would
9
1 like to extend my personal thanks, and thanks on
2 behalf of the Center for Biologics Evaluation and
3 Research, to those outgoing members of the
4 committee who have served us so well in recent
5 years. We depend a great deal on this committee
6 process to provide external scientific advice to
7 the FDA, and we feel that it is a very important
8 part of our decisional process, that we can have
9 open public meetings and fully vet the scientific
10 concerns that affect our regulatory policies.
11 So Linda is going to assist me by
12 prompting me to mention the names of those who are
13 outgoing, since I just assume you will all be on
14 the committee forever. And don't worry, we can
15 still call you ad hoc.
16 So among these are Jeanne Linden. Again,
17 my thanks. Gail Macik. Mark Mitchell. And I
18 guess Kathy Knowles, our Consumer Representative,
19 as well. So once again, our very special thanks.
20 We hope that it has been an enjoyable and perhaps
21 edifying experience, and in any case that you have
22 learned something about our organization and its
23 ways that you can carry in your other endeavors.
24 Thank you.
25 [Applause.]
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1 DR. SMALLWOOD: Thank you, Dr. Epstein. I
2 just wanted to mention that there were some that
3 were absent, and I wanted Dr. Epstein to
4 acknowledge those of you who were here. John Boyle
5 and Dr. Richard Kagan, they are not here with us
6 today, but they will also be leaving.
7 And we will present certificates to you
8 before the end of this meeting, but in the interest
9 of time, we would like to proceed with the agenda.
10 Thank you.
11 At this time now I will introduce the
12 members of the Advisory Committee. Would you
13 please raise your hand as I call your name? The
14 Chairman of the committee, Dr. Kenrad Nelson.
15 Sitting to Dr. Nelson's left is Dr. Paul Schmidt.
16 Dr. Gail Macik. Dr. Michael Fitzpatrick. Dr.
17 David Stroncek. Dr. Sherri Stuver. Dr. Jeanne
18 Linden.
19 Sitting to Dr. Nelson's right we have Dr.
20 Daniel McGee. Mr. Terry Rice. Dr. Raymond Koff.
21 Dr. Blaine Hollinger. Dr. Lianna Harvath. Ms.
22 Kathy Knowles. And Dr. Toby Simon.
23 I assume that some of our members will be
24 coming in later. Dr. Mary Chamberland, Dr. Kagan,
25 and Dr. Koerper will not be in attendance at this
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1 meeting.
2 With no further announcements, at this
3 time I will turn the meeting proceedings over to
4 our Chairman, Dr. Kenrad Nelson.
5 CHAIRMAN NELSON: Thank you, Dr.
6 Smallwood.
7 The first items on the agenda are a series
8 of committee updates. The first one is TSE
9 Guidance, Dr. Dorothy Scott from FDA.
10 DR. SCOTT: Good morning. I'm going to
11 review for you the new FDA draft guidance which was
12 published in August 2001, "Revised Preventive
13 Measures to Reduce the Possible Risk of
14 Transmission of CJD and vCJD by Blood and Blood
15 Products." I believe you already have this
16 document, but I'm going to walk you through some of
17 the salient features.
18 Just to quickly review, the previous
19 guidance, which is currently in effect, was
20 published in November of 1999. And that
21 recommended deferrals for variant CJD, CJD, risk
22 factors for classical CJD, and for BSE exposure
23 risk, and that particular deferral was for travel
24 or residence in the United Kingdom for six months
25 or more between 1980 and 1996, as well as for
12
1 injection of bovine insulin with a U.K. source.
2 Since the November 1999 guidance, there
3 has been an increasing rate of the vCJD epidemic in
4 the United Kingdom. That is, there is an increased
5 rate of onset of cases. In addition, there has
6 been an increased BSE epidemic detected in Europe.
7 There have been more countries described, and in
8 fact between the draft guidance in August and now
9 we've had four additional countries--five, actually
10 --with BSE, and more cattle in a lot of the
11 European countries have now been detected with BSE,
12 partly as a result of increased surveillance. But
13 it appears that the epidemic is increasing, and is
14 expected to peak in Europe in different countries
15 sometime between 2002 and 2005, There was also a
16 single sheep transfusion transmission of BSE that
17 was reported in the Lancet.
18 But all this tells us that there is
19 continued scientific uncertainty about where the
20 BSE epidemic is and whether it's going to be a
21 problem for blood. So we're left with the question
22 whether or not vCJD is transmitted by blood.
23 The TSE Advisory Committee last June
24 considered increased donor deferrals for variant
25 CJD risk, and this risk we base on BSE exposure.
13
1 They weighed the risk of the shortages of blood
2 against the need to take precautionary measures,
3 and I'm just pointing out some of the things that
4 make this kind of decision complicated.
5 First of all, the long incubation period
6 of transmissible spongiform encephalopathies, and
7 presumably variant CJD, limits the power of any
8 epidemiological studies to tell us whether or not
9 blood can transmit the disease. But if
10 transmission is possible, donor deferrals have
11 current importance.
12 Experimental studies on the infectivity of
13 blood from vCJD patients or people who are
14 incubating vCJD are limited to date. We do know,
15 though, that a blood shortage is possible if large
16 donor deferrals for travel to countries with BSE
17 are recommended.
18 The opinions and votes for new donor
19 deferrals by the TSE Advisory Committee back in
20 June were incorporated into the FDA draft guidance,
21 which you have a copy of. I'm going to go into the
22 questions about supply a little bit more later, but
23 the new donor deferrals decrease the risk based on
24 exposure days to BSE by about 90 percent, and it's
25 estimated from REDS survey data that about a 5
14
1 percent donor loss will occur.
2 There are some things written into the
3 guidance that are designed to help attenuate the
4 impact on supply. The first is phased
5 implementation, so not all the donor deferrals have
6 to go into effect at once. Phase 1 will begin in
7 May, and Phase 2 in October of 2002--at the end of
8 May and the end of October, by the way.
9 We've also recommended pilot studies for
10 establishments which wish to institute more
11 stringent deferrals than those that we have
12 recommended. And finally I'll talk about the
13 differential deferral for blood and blood
14 components and source plasma with regard to the
15 European donor deferral.
16 So first I'm going to just list for you
17 the deferrals that we're recommending. In Phase 1
18 we have implementation beginning on May 31, 2002,
19 and these are the Phase 1 deferrals. These Phase 1
20 deferrals capture most of the risk or most of the
21 BSE exposure, and they have to do mainly with the
22 consumption of British beef.
23 The first one is for residence in the U.K.
24 for three months now, rather than six months, still
25 between the periods 1980 and 1996--still between
15
1 the years 1980 and 1996. The second is for France,
2 residence for five years or more between 1980 and
3 the present, and this is because France was a large
4 importer of British beef, and as you all know,
5 France now has five variant CJD cases.
6 Third, for residence on U.S. military
7 bases for the time periods that I've shown here,
8 between '80 and '90 north of the Alps and '80 and
9 '96 south of the Alps. And this is because people
10 who lived on these military bases ate British beef
11 under the British Beef to Europe program, and it's
12 estimated that, worst case, they may have consumed
13 35 percent British beef. That's a substantial
14 amount.
15 And, finally, we have recommended deferral
16 for recipients of transfusion in the United
17 Kingdom.
18 I just want to mention something about the
19 time period of 1980 through 1996 for donor deferral
20 for people who have lived in the U.K., and the
21 reason there's a cut-off at 1996 is because the
22 U.K. implemented measures to prevent entry of BSE
23 into the human food chain by 1996. And if you want
24 to know a lot more about these, they have a web
25 site where they go into great detail about their
16
1 inspections and enforcements of all of these food
2 chain controls.
3 I've just listed some, well, most of them
4 here, the important ones. They have a specified
5 risk material ban, so that brain, spinal cord,
6 intestines, and other tissues with potentially high
7 titers of the BSE agent can't enter the human food
8 chain. They are removed at slaughter. They have
9 also banned mechanically recovered meat from
10 vertebral columns because this can contain a lot of
11 contaminating neural tissue. And they have
12 instituted the over-30-months scheme, whereby
13 animals over 30 months can't be consumed, with rare
14 exceptions, under the beef assurance scheme.
15 And I just wanted to mention that we
16 anticipate or we think it's likely that the TSE
17 Advisory Committee/BPAC combined meeting in January
18 of 2002 will have a review of the food chain
19 controls in the U.K. and Europe.
20 Now I'm going on to Phase 2, and we have
21 recommended implementation of this donor deferral
22 on October 31, 2002, and this is deferral of blood
23 donors who have lived in Europe for five years or
24 more between 1980 and the present, again for the
25 consumption of beef. But in this case for the most
17
1 part in other European countries, most of the beef
2 consumed was their own, but they now have their own
3 epidemics of BSE, which are, I should point out,
4 considerably less than the U.K. epidemic, probably
5 on the order of several percent in terms of size
6 relative to the U.K. epidemic.
7 However, donors of source plasma for
8 plasma derivatives remain eligible to donate, and
9 that's what I want to talk about next, why source
10 plasma is an exception. First of all, we know now
11 from publications in peer-reviewed journals that
12 model TSE agents are partitioned and removed during
13 plasma fractionation, and there are several
14 different kinds of steps which are capable of
15 accomplishing this. Secondly, the European risk of
16 vCJD is likely to be low because they have a small
17 BSE epidemic.
18 The magnitude of risk reduction achieved
19 by fractionation at a minimum is likely to be
20 several logs greater than that possibly achievable
21 by donor deferral. It is believed that the effects
22 on nationwide and worldwide plasma supplies are
23 potentially severe if we have this pan-European
24 donor deferral, not because we have so many donors
25 that donate plasma who have lived in Europe for
18
1 five years or more, but because of the perception
2 of the safety of European plasma and the demand for
3 U.S. plasma that might ensue.
4 And, finally, I just want to point out
5 that the highest estimated risk deferrals remain in
6 place for donors of source plasma, that is, the
7 U.K. deferral, the deferral for residence in
8 France, the military donor deferral, and
9 transfusion in the United Kingdom.
10 I also want to say something about source
11 versus recovered plasma, because this has been a
12 worrisome issue for establishments. We have
13 recommended that source plasma from donors with
14 European residence may be used, but recovered
15 plasma may not be used. And this is not due to any
16 perception that recovered plasma is less safe than
17 source plasma, but rather these are differentiated
18 to prevent potential accidental use of blood
19 components from donors who are deferred for
20 residence in Europe.
21 And I also want to say that this
22 particular source plasma recommendation will be
23 reevaluated continually, really, in light of
24 additional epidemiologic evidence, transmission
25 studies, and advances in the validation of removal
19
1 of TSE agents by manufacturing.
2 I want to talk a little bit now about
3 supply and the anticipated supply effects. Our
4 recommended deferrals, and I am contrasting those
5 later with some other industry initiatives or
6 another industry initiative, are estimated to
7 result in the deferral of 5 percent of blood
8 donors, based on the REDS study. However, there
9 will be a greater proportion of deferrals likely in
10 coastal cities, perhaps double the amount, 10
11 percent.
12 In addition, 35 percent of the New York
13 Blood Center supply may be affected, and this is
14 because about 25 percent of their supply comes from
15 the Euroblood program, and they also are expected
16 to have a higher than 5 percent deferral of donors
17 for travel.
18 There has been also an industry-proposed
19 and now implemented deferral, which is three months
20 in the United Kingdom and six months in Europe, and
21 an industry survey suggests that 3 percent of their
22 donors would be deferred under this set of
23 deferrals. The REDS study estimated 9 percent. We
24 expect that the actual rate of deferral is likely
25 to be somewhere in between.
20
1 The TSE Advisory Committee proposed that
2 before new donor deferrals are implemented, that a
3 national recruitment campaign and a system to
4 monitor adequate blood supply be instituted. I
5 just want to mention again the efforts that we have
6 made to attenuate the effect of the new donor
7 deferrals: The phased-in plan. Recommending pilot
8 studies for establishments who wish to institute
9 more stringent deferrals, and this is in the
10 guidance; we have recommended that they institute
11 first a pilot program which includes donor
12 recruitment schemes, evaluation of donor loss, and
13 end points for the pilot donor deferral study. And
14 that they monitor their recruitment efforts and
15 fluctuations in hospital demands. Also, the
16 implementation dates are skipping the summer, so we
17 hope that that will also be useful in terms of the
18 potential for shortage.
19 Before I finish, I just want to mention
20 non-European BSE, because we don't have deferrals
21 for any countries other than Europe, but the first
22 case of BSE in a non-European country that appears
23 to be endemic was documented in September 2001 in
24 Japan, and this was confirmed by testing in the
25 United Kingdom. The USDA announced an import ban,
21
1 also in September 2001, for bovine materials from
2 Japan.
3 Now, meat and bone meal from the United
4 Kingdom was shipped to many non-European countries,
5 and these are now presumably at risk for BSE also.
6 So it appears that the BSE epidemic is likely to be
7 globalized, and the shipments, while not officially
8 published, shipments of meat and bone meal from the
9 U.K. during the BSE epidemic before they stopped
10 shipping, these shipments went to South American
11 countries, African countries, and other Asian
12 countries.
13 So it isn't likely that Japan itself is
14 going to be singled out as the only non-European
15 country with BSE. However, we feel the need to
16 assimilate the current donor deferrals, but we will
17 probably in the future consider additional
18 deferrals after weighing the risk and benefit of
19 any new donor deferrals for possible exposure to
20 BSE.
21 What is the future of the draft guidance?
22 Well, we have collected and evaluated the comments.
23 The comment period ended on October 28th. We
24 anticipate issuance of a final guidance with
25 revisions in the very near future, and the
22
1 revisions are the result mainly of many comments
2 that we received and which we found very helpful.
3 In addition, a plan to monitor the blood
4 supply which was initiated by HHS is in effect, and
5 that's being led by Dr. Nightingale, and this is
6 already up and running and will be in place, of
7 course, as these recommendations are effected.
8 Just to mention how is the final guidance
9 likely to be different from the draft guidance that
10 you have, we've accomplished some streamlining of
11 donor questions. We've clarified product
12 retrievals and reporting requirements. We are
13 going to have summary tables and a list of
14 definitions, and we've updated the science and the
15 epidemiology.
16 So I thank you very much.
17 CHAIRMAN NELSON: Thank you, Dr. Scott.
18 Are there any questions from the committee, or
19 comments?
20 The Red Cross donor deferral is already in
21 place?
22 DR. SCOTT: That's what we understand,
23 yes.
24 CHAIRMAN NELSON: Are there any data from
25 New York, since you singled out that important
23
1 Euroblood--I guess that won't occur until May of
2 next year, though, so we won't know anything.
3 DR. SCOTT: That's correct. I understand
4 they're working hard on absorbing these, and there
5 are commitments for them to obtain blood and some
6 assistance that's being provide from other
7 organizations.
8 CHAIRMAN NELSON: Okay. Thank you very
9 much.
10 The next presentation is by Dr. Robin
11 Biswas, talking about the--I got an old one. Okay.
12 It's Mark Weinstein, summary of a CDC workshop on
13 Factor VIII.
14 DR. WEINSTEIN: Thank you. The
15 availability of Factor VIII has been problematic
16 and highly erratic for most of 2001. In March,
17 April, May, and July of this year, recombinant
18 Factor VIII distribution was 15, 50, 25, and 60
19 percent respectively below the historical monthly
20 average. In June, August, and September,
21 distribution was 60, 32, and 39 percent above
22 average.
23 On October 3rd the Centers for Disease
24 Control and Prevention and the FDA held a national
25 workshop in Atlanta, Georgia to discuss issues
24
1 related to managing life- or limb-threatening
2 emergencies for persons with hemophilia, should
3 shortages of clotting factors significantly worsen.
4 Among those attending the workshop were 120
5 representatives from manufacturers, hemophilia
6 organizations, Federal agencies, home health care
7 companies, and hemophilia treatment centers.
8 While the worldwide demand for recombinant
9 Factor VIII has rapidly increased, manufacturing
10 problems have delayed the capacity to meet the
11 demand. Further unforeseen events or unplanned
12 manufacturing restrictions could create dangerous
13 shortages, especially for individuals who suffer
14 life-threatening bleeding episodes and must receive
15 clotting factor within one to two hours of such an
16 episode. CDC data indicate that approximately 100
17 such episodes occur each year among the 13,000
18 patients with hemophilia in the United States.
19 That's hemophilia A in the United States.
20 Inventories of plasma-derived Factor VIII
21 have decreased significantly since March, as more
22 plasma-derived products were distributed to
23 partially make up for the recombinant Factor VIII
24 shortage. This decrease of inventory further
25 reduces the flexibility of the distribution system
25
1 to react to unforeseen emergencies.
2 During the Atlanta workshop, speakers
3 discussed issues related to developing a
4 contingency plan for managing the supply of
5 clotting factor to meet any life-threatening
6 emergency throughout the country. Important issues
7 included when should such a plan be implemented;
8 where and how should the emergency factor inventory
9 be maintained, that is, should this inventory be
10 stockpiled or set up as a virtual system; what
11 criteria warrant individual use; how is inventory
12 tracked and distributed; what communication
13 channels are available; and how will expenses be
14 met.
15 As part of the workshop, Dr. Keith Hoots
16 presented the recommendations of the National
17 Hemophilia Foundation's Medical and Scientific
18 Advisory Council, or MASAC, concerning management
19 of the current short supply of recombinant Factor
20 VIII in the United States.
21 There was general agreement that at
22 present the short supply is being managed by
23 MASAC's recommendations to limit Factor VIII usage
24 and by cooperation among the hemophilia treatment
25 centers in informal product transferring. It was
26
1 recognized that further disruption of the supply
2 would require much more planning and action, and
3 attendees agreed to work toward developing a
4 contingency plan, with the hope that it would never
5 need to be used.
6 Initial thoughts concerning the plan were
7 that in case of severe shortages, the immediate
8 need would be for local emergency supplies to treat
9 life-threatening episodes for 24 hours, with
10 subsequent national redistribution of factor to
11 accommodate the emergency. Thus, it was thought
12 that a virtual inventory would be most effective,
13 that is, one that does not require a separate
14 distribution channel from the ones already in
15 place. Such an inventory would rely on an
16 independent information clearinghouse operated 24
17 hours a day to field requests and to pinpoint the
18 nearest location of factor needed in an emergency.
19 The workshop adjourned with a renewed
20 spirit and feeling of cooperation among the various
21 groups represented to try to accomplish this goal
22 for the continued safety and health of the
23 hemophilia community.
24 Subsequent to this workshop, the National
25 Hemophilia Foundation issued a resolution on
27
1 November 18th, resolving that a depot network be
2 set up to provide immediate, 24-hour access to
3 clotting factor for hemophilia patients seeking
4 emergency treatment around the country. It was
5 recommended that all efforts be made to use
6 existing locales such as hemophilia treatment
7 centers where clotting factor is already present.
8 It was also recommended that the emergency
9 depot system provide a single, toll-free number for
10 use around the country that would allow an
11 emergency physician to have access to factor within
12 two hours. The same toll-free number should
13 facilitate dialogue between the emergency physician
14 and the hemophilia treatment center physician, to
15 ensure that the emergency physician can obtain
16 accurate and timely medical advice about the
17 management of the patient. Further discussions
18 among interested parties will be needed to
19 facilitate implementation of this resolution.
20 Thanks for your attention.
21 CHAIRMAN NELSON: Comments or questions?
22 Dr. Koerper isn't here. So thank you very much.
23 The next presentation is the disaster
24 response. I assume that means September 11th,
25 synonymous terms, lately. Dr. Alan Williams from
28
1 the FDA.
2 DR. WILLIAMS: Thank you. Like the
3 Kennedy assassination and the Challenger shuttle
4 disaster, most of us know exactly where we were
5 when the events unfolded on September 11th. I was
6 in a room like this, learning how to be a Federal
7 supervisor, but soon found myself with colleagues
8 around a large conference table in the Office of
9 Blood, trying to gather as much information as
10 possible about the unfolding events by working the
11 telephones and e-mail and so forth.
12 Basically, on September 11th FDA and its
13 many entities monitored developments closely and
14 tried to anticipate the range of blood supply and
15 supply scenarios that could unfold, recognizing
16 that we had very little information in the early
17 stages. We didn't know if these events could be
18 occurring at multiple sites or just what the final
19 impact might be.
20 We readily established close contact with
21 blood organizations, manufacturers, the Department
22 of Defense, and other HHS agencies, and based on
23 information gathered in the early hours, issued a
24 policy statement in the evening of September 11th
25 allowing for modifications within the existing
29
1 regulatory framework that would allow training and
2 certification of emergency staff members coming
3 from a health care environment, who could be
4 trained to collect blood in a safe manner.
5 Also, we made provisions for release and
6 use of units that may have to be transfused prior
7 to completion of all testing. In fact, this was
8 not used to any great extent, but provisions were
9 made so that this could happen if supply shortages
10 occurred that really indicated that.
11 Because of the lines of donors that were
12 there, that presented to donate blood to help in
13 the disaster situation, we allowed that shipping of
14 unlicensed blood components could be done in
15 interstate commerce providing that adequate
16 labeling was provided. And to monitor all
17 collections and blood shipments that were occurring
18 under these modified policies, we required product
19 identification and record-keeping for each of the
20 collections and distributions occurring during that
21 time period.
22 Within really a day to a day and a half,
23 it became clear that the need for blood was not
24 what the potential could have been, and by
25 September 14th a revised policy statement was
30
1 issued, essentially returning policy regarding
2 collection and distribution to a relative state of
3 normalcy. Training and certification of emergency
4 staff was revised to allow some necessary use of
5 urgently trained staff where indicated, but for the
6 most part it returned to normal.
7 We asked for quality assurance
8 investigations within 72 hours for all units
9 collected during that time period, to make sure
10 that they met all current safety and regulatory
11 requirements. The release of units that were not
12 fully tested was revised, as was the shipment of
13 unlicensed blood components in interstate commerce,
14 which was discontinued. And now the emergent
15 scenario was the fact that the airlines were shut
16 down and supplies and test reagents were becoming
17 limited in some areas, so we made provision for use
18 of alternative FDA-registered laboratories to allow
19 continuity of testing.
20 The transportation disruptions in fact did
21 prove to be somewhat challenging, and in the course
22 of the several days following September 11th we
23 needed to take measures to assure continuing
24 availability of supplies, reagents, which involved
25 lot release measures and looking into means in
31
1 which samples could be shipped in a reliable manner
2 not using the airlines, which were not working.
3 At the end of this experience, and
4 actually throughout the experience, we instructed
5 staff to formalize records in terms of the
6 interactions with industry and the steps that we
7 were taking and the inquiries that were made in to
8 the Office of Blood. And this formal documentation
9 of these experiences really became the first
10 component of what has developed as our new
11 emergency response strategic plan within the
12 office, and I'll say more about that in a moment.
13 Then came anthrax. In October, while many
14 of us were at the AABB annual meeting, some
15 remaining FDA staff were meeting extensively with
16 scientific experts to determine appropriate
17 policies in the event that potential blood donors
18 might be exposed to the anthrax agent. And it was
19 agreed that no known risk of transmission would be
20 there from blood collected from asymptomatic donors
21 who may have been exposed to bacteria or spores, as
22 long as those donors were healthy.
23 This resulted in issuance of a guidance in
24 October entitled "Recommendations for the
25 Assessment of Donor Suitability and Blood and Blood
32
1 Product Safety in Cases of Possible Exposure to
2 Anthrax," with the provisions included in this
3 guidance that in cases of proven anthrax, donor
4 deferral should be mandated or recommended until
5 completion of appropriate treatment, and that
6 quarantine and retrieval of in-date products should
7 occur. This is in case of proven anthrax
8 infection.
9 In instances where there is demonstration
10 of colonization or suspected skin lesions, donor
11 deferral should be accomplished until an alternate
12 diagnosis is established or a course of treatment,
13 appropriate treatment, is completed. And in cases
14 where there is potential exposure but with an
15 unconfirmed diagnosis, medical discretion is
16 advised in terms of donation.
17 Subsequent to these events, like many
18 other organizations, both Federal and non-Federal,
19 FDA has been working hard on an emergency response
20 strategic plan. In general terms it boils down to
21 four different elements, the first being actions to
22 treat or protect affected individuals by looking at
23 potential blood products or components or
24 derivatives that might be appropriate for
25 treatment.
33
1 And the second entity, actions to protect
2 the blood supply, bioterrorism or other terrorist
3 activities that might limit blood donors or
4 facilities or reagents or staff that would be
5 available to collect blood, we're trying to
6 anticipate different scenarios and develop
7 emergency procedures that could be brought into
8 place. And the special emphasis here is of course
9 bioterrorism agents.
10 Third, we're taking actions to assure
11 continued supply availability, again anticipating
12 potential scenarios, looking at ways to monitor the
13 blood supply, working with HHS, and in general just
14 anticipating factors that could compromise supply
15 and trying to preempt those.
16 And then finally, extensive outreach
17 activities. The major blood organizations and
18 manufacturers are developing contingency plans of
19 their own, and we're working carefully with those
20 external and agency-related components to develop a
21 working plan that hopefully will form the basis of
22 a well-coordinated emergency plan. And there are
23 several meetings coming up in the ensuing months,
24 including the PHS Safety and Availability
25 Committee, which will be extensively discussing
34
1 some of these aspects of the emergency plan.
2 CHAIRMAN NELSON: Thank you.
3 David?
4 DR. STRONCEK: Well, good luck with your
5 planning. I think it's going to be very difficult.
6 You know, it's easy to decide on these things if
7 you know there's an emergency. But what happened
8 on September 11th, everyone thought there was going
9 to be an emergency with the blood supply and there
10 really wasn't. So then the blood was collected, I
11 think in many centers under practices that would
12 not be--they didn't use their normal SOPs.
13 And so what happens when you don't have
14 the emergency, you have all this blood, are you
15 going to address that issue? So you collected
16 blood under emergency SOPs, but then there's no
17 emergency.
18 DR. WILLIAMS: Well, as I mentioned
19 earlier, the emergency SOPs were put into place
20 because it was an unknown situation, and they were
21 in place if we needed them. In response to the
22 safety of the blood collected, we did require a
23 complete audit of those units collected. In terms
24 of over-collection, this is not an area that FDA
25 has any direct control over.
35
1 DR. STRONCEK: But it's clear that units
2 that were collected on September 11th, 12th and
3 13th were collected with people screening blood
4 donors that were not trained to do that, and those
5 units then went into inventory. I know you asked
6 that people audited everything, but still, you
7 know, if you went back and looked and there was no
8 emergency, nobody would say those units were
9 collected in a way of their normal SOPs. So then
10 all of a sudden, you know, you're using those units
11 a month later when there's an excess of blood, and
12 what happens if one of those units really shouldn't
13 have been collected at all?
14 DR. WILLIAMS: Well, we are aware of some
15 reports where the audits turned up a proportion of
16 units that did not meet current standards, and
17 those units were removed from distribution. And
18 the whole idea of an audit is that the safety and
19 usability of units should be documented and
20 demonstrated, and then they are appropriate for the
21 normal supply.
22 DR. FITZPATRICK: Alan, my question was
23 about just that thing. Was there an increase in
24 variance reports to the FDA? Is there an analysis
25 being done on what happened to the audits of those
36
1 units collected after the incident? Did you see
2 increased product recalls or withdrawals? And
3 what's being done by the agency to examine the
4 impact of your policy?
5 I want to commend you on being proactive
6 and developing a policy and putting it out, and
7 dealing with the anthrax and responding to the
8 incident, but what's being done now to analyze the
9 impact of those things that you did? How many
10 products were shipped in an unlicensed state, and
11 that sort of thing?
12 DR. WILLIAMS: The data regarding use of
13 the alternate policies that were put into place at
14 that time, we have primarily results collected I
15 would say anecdotally in terms of results of
16 audits. We don't have that currently on a
17 universal basis. I think it would be appropriate
18 to obtain that, and I think it probably is
19 something which would be determined at the end of a
20 current collection year, but we have not in a
21 uniform way attempted to collect that information.
22 I think it's a good point.
23 CHAIRMAN NELSON: Was there any evidence
24 of increased infectious markers during--donors
25 during that period, or are the numbers too small to
37
1 look at that?
2 DR. WILLIAMS: The numbers aren't too
3 small. The numbers are actually quite large. I
4 think the difficulty is, the mix of first-time and
5 repeat donors changes, and potentially the mix of
6 demographics of the incoming donors changes. There
7 are studies underway, including REDS, and I know
8 some individual blood centers that are looking at
9 marker rates. Preliminary data that has been
10 shared with us indicates no higher rates above what
11 would be anticipated when corrected for the first-time donor
12 status.
13 MS. KNOWLES: I understand that there was
14 actually a fair number of hepatitis C cases
15 uncovered as a result, too.
16 DR. WILLIAMS: That's correct, and in fact
17 the rates of hepatitis C infection are higher in
18 first-time donors. Rather than being attributable
19 to the emergency outpouring of blood donors, it is
20 probably more due to the fact that it's an incoming
21 population that has not been previously screened.
22 DR. MITCHELL: Now with the bioterrorism
23 issue I know that the post office is moving toward
24 irradiation of the mail and that that might be a
25 problem. What is the FDA doing to address that
38
1 issue?
2 DR. WILLIAMS: Could you develop that a
3 little further?
4 DR. MITCHELL: Okay. My understanding is
5 that the shipment of some of the testing components
6 through the mail, that the irradiation might affect
7 the viability of some of the test kits, and that's
8 what I was wondering.
9 DR. NAKHASI: I think at this point we
10 don't--thank you for bringing it to our attention--we don't
11 know anything about it. We'll look into
12 it. So at this point we don't have any
13 information.
14 CHAIRMAN NELSON: Mark, do you have any
15 other information on this?
16 DR. NELSON: No. No, that's all.
17 CHAIRMAN NELSON: Other comments? Thanks.
18 Dr. Ed Tabor is going to discuss a summary
19 of the NAT workshop December 4th and 5th.
20 DR. TABOR: A workshop sponsored by FDA
21 was held on December 4th and 5th, 2001, at the
22 National Institutes of Health, with the title
23 "Application of Nucleic Acid Testing to Blood Borne
24 Pathogens and Emerging Technologies." A number of
25 challenging regulatory issues were discussed
39
1 concerning the implementation of NAT screening of
2 blood and plasma to detect viruses.
3 I will try to highlight some of the
4 difficult or controversial issues that we
5 discussed. However, interested persons should
6 check the FDA web site for the transcript, which
7 should be available on line by the end of the
8 month, to read the text of the talks on such topics
9 as the development of reference standards and other
10 aspects of assay validation for NAT, the detection
11 of emerging pathogens, and the use of DNA
12 microarray chips and other new technologies to
13 enhance NAT screening.
14 In addition to preventing window period
15 transmission of blood borne viruses, NAT screening
16 can prevent rare cases of transmission by atypical
17 carriers. In an opening summary at the workshop,
18 Dr. Busch mentioned several anti-HCV negative
19 donors who were NAT positive and transmitted HCV to
20 recipients over a long period of time. Dr.
21 Neubling described HIV transmission by three NAT-positive,
22 p24 antigen negative, and anti-HIV
23 negative individuals.
24 The workshop also included a session on
25 the possible substitution of NAT screening for
40
1 various tests that are currently licensed. One
2 such issue was whether NAT screening for HIV could
3 permit elimination of the screening test for p24
4 antigen, a test that was originally recommended as
5 an interim measure in 1996.
6 Dr. Stramer reported that since 1996, the
7 test for p24 antigen has only detected six units
8 donated to the American Red Cross and nine units
9 donated to America's Blood Centers that would not
10 have been detected by tests for anti-HIV. In all
11 of the data presented at the workshop, HIV NAT was
12 more sensitive than p24. No one reported any
13 instance in which a unit that was anti-HIV negative
14 and p24 positive would not have been detected by
15 NAT.
16 Dr. Conrad and Dr. Stramer both described
17 studies in which NAT on minipools of 512 units
18 detected every sample that was positive for p24.
19 Dr. Stramer reported studies in which NAT on
20 minipools of 128 units or 16 units detected p24
21 negative samples that would not have been detected
22 without NAT. These data suggest that licensed NAT
23 screening might make p24 screening unnecessary in
24 the future.
25 Dr. Kleinman presented an excellent
41
1 summary of data indicating that HBV NAT on
2 minipools would not permit the elimination of the
3 currently recommended anti-HBC screening of whole
4 blood donations or the replacement of the required
5 HB-sAg testing of all blood and plasma donations.
6 There is sufficient evidence that a very
7 small number of donor samples are HB-sAg negative,
8 anti-HBC positive, and have detectable HBV DNA, but
9 the HBV DNA copy number is very low, less than 100
10 copies per mL. These samples are presumably
11 infectious but would not be detected by HBV NAT on
12 minipools.
13 Thus, only the development of very
14 sensitive single unit NAT screening might permit
15 the elimination of anti-HBC screening of whole
16 blood donations. Further, reports of HB-sAg
17 positive donations that were NAT negative but were
18 found to be NAT positive when larger volumes of
19 plasma were tested, combined with the long history
20 of HB-sAg screening of blood donations, makes it
21 unsafe to consider eliminating HB-sAg screening
22 simply because of NAT minipool screening.
23 Further consideration of this issue will
24 require data from a large study using sensitive
25 assays to detect HBV DNA and quantitate HBV viral
42
1 load, in which follow-up samples from the donors
2 are also obtained and tested, and in which the
3 focus is on single unit NAT. Of course, it is
4 hoped that using NAT to test individual units
5 rather than to test minipools will eventually be
6 technologically possible and cost-effective. This
7 would make NAT screening far more sensitive.
8 Nevertheless, it was not clear from
9 presentations at the workshop exactly how long it
10 will be before single unit NAT is available.
11 Clearly, most of the companies working on
12 developing minipool NAT are also working on and
13 evaluating single unit NAT, but it appeared from
14 the workshop presentations that a cost-effective
15 single unit NAT is still not available.
16 NAT screening for parvovirus B19 and NAT
17 screening for hepatitis A virus were discussed in a
18 session of the workshop, and more extensively in
19 the panel discussion at the end of the second day
20 of the workshop. NAT systems for these two viruses
21 are usually discussed together because of similar
22 regulatory issues, even though there is no
23 scientific similarity.
24 FDA has permitted NAT screening to detect
25 parvovirus B19 and HAV in minipools as in-process
43
1 control testing rather than as donor screening.
2 NAT assays geared to detect only high
3 concentrations of parvovirus B19 are expected to
4 detect between one positive unit in 1,000 and one
5 positive unit in 13,000 blood donations or source
6 plasma donations, based on the results of testing
7 reported by the American Red Cross, Alpha, Aventis,
8 Baxter, and Bayer.
9 The number of HAV positive units is
10 expected to be from 1 in 1 million blood donations,
11 based on Red Cross testing, to between 1 in 100,000
12 and 1 in 400,000 source plasma donations, based on
13 the results of testing reported by Aventis and
14 Baxter. NAT for parvovirus B19 now has been
15 initiated voluntarily by all four major
16 fractionaters as an in-process control.
17 Some but not all of the fractionaters are
18 screening for HAV, or will be doing so by early
19 2002. They are doing screening for parvovirus B19
20 according to standards that they expect FDA to
21 recommend, namely, to keep the titer of parvovirus
22 B19 below 10,000 international units per mL in all
23 manufacturing pools for plasma derivatives.
24 Screening for parvovirus B19 was reported at the
25 workshop to remove about 10 logs of virus from the
44
1 production pool.
2 Dr. Stramer said that the American Red
3 Cross plans a two-phase introduction of screening
4 blood donations for parvovirus B19 and HAV by NAT.
5 Phase one will involve screening minipools that are
6 larger than those for NAT screening of HIV and HCV,
7 and will involve doing so after 42 days have
8 elapsed. This will be in-process control testing.
9 Effectively, this will amount to screening
10 recovered plasma. Since all cellular components
11 will be outdated at the time of testing, any
12 positive pool will be discarded entirely without
13 identifying the specific positive unit. In phase
14 two the testing protocol would be modified in a way
15 that would incidentally make donor notification
16 possible, and this could amount to donor screening.
17 The Red Cross expects to have further discussions
18 with FDA about this phase.
19 Dr. Bianco said that America's Blood
20 Centers probably will perform in-process NAT
21 minipool testing for parvovirus B19 and HAV. In
22 addition, America's Blood Centers plan to identify
23 units with low levels of parvovirus B19 and to use
24 only these, or preferably only negative components,
25 for transfusing high-risk recipients such as
45
1 pregnant women. However, comments made by other
2 meeting participants indicate that some internal
3 discussion about such selective screening will be
4 likely to occur.
5 It should be emphasized that screening by
6 NAT for parvovirus B19 and HAV are considered by
7 FDA to be in-process control testing because only
8 minimal public health benefit would be expected to
9 result from donor or recipient notification within
10 the time frame that testing is currently being
11 performed. It is current thinking at FDA that any
12 testing for parvovirus B19 or HAV that was done in
13 real time, and at the same time identified specific
14 donors who are infected with either virus, would
15 constitute donor screening because it would permit
16 donor or recipient notification or targeted
17 donations that would have a public health benefit.
18 Such donor screening would be subject to the same
19 types of requirements as other donor screens.
20 There was a substantial and fascinating
21 session in the program on the use of DNA microarray
22 technology to enhance NAT screening. However, the
23 panel discussion after the session revealed that
24 application of this technology for blood screening
25 is still 5 to 10 years away. At present,
46
1 microarray methods are not suitable for use by
2 routine or non-research labs because of a variety
3 of factors that can interfere with proper testing.
4 However, the technology is constantly improving.
5 One workshop attendee pointed out that
6 microarray technology is designed to test a small
7 number of samples for up to 50,000 genes. In
8 contrast, blood bank testing needs a technology to
9 test thousands of samples for a half dozen to a
10 dozen genes. It was suggested that HLA screening
11 might be most suitable for the first blood bank use
12 of microarray technology. Once a testing format
13 such as this is in place in the blood centers, it
14 becomes much easier to modify it for new screening
15 purposes thereafter.
16 Dr. Hewlett pointed out that at the 1994
17 NAT workshop, skepticism was expressed concerning
18 the utility of NAT for blood bank testing, and that
19 five or six years later NAT was being widely used
20 for just that purpose. She urged that we reserve
21 judgment on how fast microarrays could be
22 introduced into blood and plasma screening, since
23 the technology can rapidly evolve.
24 Thank you.
25 CHAIRMAN NELSON: Comments or questions
47
1 for Dr. Tabor? Yes?
2 DR. FITZPATRICK: Ed, is there a process
3 for the elimination of a test like p24?
4 DR. TABOR: Well, I think the tests have
5 to be discussed in two different categories: tests
6 that are recommended and tests that are required.
7 p24 was recommended, and as I said, it was
8 recommended as an interim measure. I think we were
9 anxious to give the blood supply as close to a zero
10 risk as possible at the time, and it was recognized
11 that better tests would be available in the future.
12 A recommended test has inherent in the
13 recommendation the understanding that any applicant
14 can come to FDA with an alternative way to approach
15 screening, and so if a group has sufficient
16 evidence that NAT screening would be of equal or
17 greater sensitivity as for instance p24 testing
18 without any loss in specificity, that FDA would
19 consider those data and could permit the
20 substitution of NAT screening for p24 by that
21 applicant.
22 DR. FITZPATRICK: So the applicant has to
23 come to you with the information, rather than you
24 withdrawing the recommendation once it's licensed?
25 DR. TABOR: I assume that if we had--first
48
1 of all, we have to have the data brought to us
2 because the data is almost always generated outside
3 of FDA. I would assume that if we had sufficient
4 data to withdraw the recommendation, we would be
5 able to do so.
6 DR. FITZPATRICK: Okay, and just one other
7 comment. I understand the cost-effective issue of
8 single unit testing, but we have been doing single
9 unit NAT for a year and a half now on all our
10 specimens, and Chiron has all that information and
11 all that data.
12 DR. TABOR: Just for the benefit of both
13 myself and the audience, could you elaborate on
14 that a bit? When you say "we", do you mean all
15 military--
16 DR. FITZPATRICK: The Army and Navy. Army
17 is doing all testing for the Navy, so the Army and
18 Navy units collected have been tested by single
19 unit NAT since--
20 DR. TABOR: For HIV and HCV?
21 DR. FITZPATRICK: Yes.
22 DR. TABOR: And for how long ago?
23 DR. FITZPATRICK: Since we started, which
24 is about a year and a half now.
25 DR. TABOR: And where is it actually being
49
1 conducted?
2 DR. FITZPATRICK: At Fort Hood, Texas and
3 at Fort Knox, Kentucky.
4 DR. TABOR: So all samples are sent there?
5 DR. FITZPATRICK: Right.
6 DR. TABOR: And you're doing it with
7 Chiron, it sounds like you said?
8 DR. FITZPATRICK: Yes, and then the Air
9 Force is contracting with local civilian, so that
10 their samples are being done by minipool. And
11 Chiron has that information and the results.
12 CHAIRMAN NELSON: Dr. Epstein has a
13 comment.
14 DR. EPSTEIN: Well, I wanted to comment
15 upon the p24 issue. Regarding the single unit--can
16 I be heard in the back? Can you raise your hand?
17 No? Maybe I'll move to a new mike.
18 Can I be heard now? Okay. With regard to
19 single unit testing, you know, it falls to the
20 manufacturer to submit data to the agency to
21 support a licensing claim, so unless and until such
22 data is reviewed and approved in product
23 application, we would regard continued use as
24 investigational. In other words, it should be
25 under and IND. But nothing prevents Chiron or any
50
1 other company that has gathered such data from
2 making a submission to the agency, so that's the
3 pathway.
4 With regard to p24, what Dr. Tabor said is
5 correct, but let me also mention that FDA has
6 issued a final regulation which became effective
7 December the 10th on donor testing, and it says
8 that the agency periodically in guidance will
9 recommend which tests are deemed adequate and
10 suitable to reduce the risk of transfusion
11 transmitted infections.
12 And that's a paradigm shift, because in
13 previous regulation we enumerated certain agents
14 for which one had to test, and indeed certain
15 tests. So, for example, the HB-sAg was mandated in
16 the regs as serologic test for syphilis, antibody
17 to HIV. Those were the only tests enumerated in
18 the regs. Everything else was under
19 recommendations.
20 However, under the paradigm of the new
21 regulation we specify etiologic agents, and then we
22 indicate that we will through guidance establish
23 which test technology is appropriate. So
24 basically, at a certain point in time it may be
25 possible for us to decide that the HIV-1 p24 is no
51
1 longer necessary to adequately and appropriately
2 reduce the risk for transfusion-transmitted HIV.
3 What has happened, as described, is that
4 in the first license, which was for NAT for source
5 plasma by National Genetics Institute, and then a
6 corresponding license supplement from Alpha
7 Therapeutic Corporation for implementation, we did
8 approve an NAT minipool method both for HCV and for
9 HIV, and in that same approval we approved
10 discontinuing the HIV-1 p24 upon implementation of
11 the HIV-1 NAT. So we do regard it as a case-by-case
12 decision based on the data submitted for the
13 HIV NAT. And so then, you know, it would convey to
14 the approved user. If they are using the test
15 approved with that condition, then they can drop
16 the HIV-1 p24 NAT.
17 CHAIRMAN NELSON: Has that happened?
18 DR. EPSTEIN: I don't know if it has been
19 implemented yet. In other words, we have approved
20 it, but I don't actually know whether they have
21 implemented. Perhaps there is a representative
22 here who could comment.
23 DR. FITZPATRICK: On the single-unit
24 testing, Jay, since resolution of a minipool that
25 comes up positive has to be done by single-unit
52
1 testing, isn't there sort of an inherent licensure
2 of a single-unit test within that?
3 DR. EPSTEIN: Well, no, because the
4 performance characteristic of a single-unit test
5 when used for mass screening could be different.
6 In other words, when you use it to secondarily test
7 a pre-screened set of presumptive positives, you
8 get a higher positive predictive value than if you
9 simply use it randomly screening. So I think what
10 you're suggesting is that the added work to
11 validate it might be a lot less than if you had,
12 you know, no previous experience, and I would agree
13 with that.
14 And we have had some dialogue with the
15 companies about the possibility to establish the
16 single-unit test with the labeling for the
17 minipool, provided that a small trial shows it to
18 be non-inferior. And then later, presumably phase
19 four, one could then establish the exact
20 performance characteristic, already knowing that it
21 is as good or better than what it was originally
22 labeled to be.
23 So there are ways that we can try to
24 expedite the progress here, but I would contend
25 that the use as a secondary test does not have the
53
1 same performance characteristic as the up-front
2 use.
3 CHAIRMAN NELSON: Yes? Could you identify
4 yourself?
5 MR. HEATON: Yes. Good morning. I'm
6 Andrew Heaton with Chiron Corporation. I wanted to
7 confirm to the committee that we have submitted
8 material to allow the replacement of p24 antigen
9 testing with nucleic acid testing, and that
10 information was submitted to the agency
11 approximately 12 weeks ago. In addition, to answer
12 Colonel Fitzpatrick, we have also compiled the U.S.
13 military individual donor testing data which has
14 been collected over the past 18 months, where I
15 might add individual donor testing has performed
16 extremely satisfactorily, and that data has also
17 been submitted to the agency within the last two
18 weeks. We believe this should allow individual
19 donor testing.
20 CHAIRMAN NELSON: You're not testing NAT
21 for HBV, right? Just HIV and hepatitis C?
22 MR. HEATON: No, just HIV and hepatitis C.
23 MS. WAGNER: Hi. I'm Tori Wagner with
24 Alpha Therapeutic, and we have discontinued the p24
25 antigen testing.
54
1 CHAIRMAN NELSON: Okay. Well, we've got a
2 rare event. We're way ahead of time. Next was
3 supposed to be a break, but I think it's a little
4 early for--yes?
5 DR. DAVEY: I'm Richard Davey. I'm the
6 chief medical officer of the New York Blood Center,
7 and I'd like to make just a few comments related to
8 the September 11th events and the disaster comments
9 that Dr. Williams made, and also some observations
10 that we are noting in the current blood supply
11 situation.
12 I guess as you know, we were the blood
13 center at the epicenter of the events on September
14 11th, and we've learned a lot from that experience,
15 and we're looking with great anticipation to the
16 Advisory Committee on Blood Safety and Availability
17 meeting on January 31st and February 1st which is
18 going to evaluate disaster response in the blood
19 community in much more detail.
20 Very briefly, we observed very quickly
21 that it was very important to assess the medical
22 need around the catastrophe. We sent 600 units
23 within one hour of the first attack to the downtown
24 New York hospitals, and unfortunately even that
25 amount of blood was not needed, but it was unclear
55
1 for a day or two. The communications were down.
2 And we did find very quickly, and we want
3 to talk about this more at the end of January, that
4 communication is so essential. We fortunately had
5 cell phones that operate on some wave phase, I
6 don't know the technology, but they worked when
7 everything else was down. All the other cell
8 phones and telephones were gone. And those phones
9 were critical for us to manage our response to the
10 catastrophe.
11 Transportation was clearly a problem, and
12 we quickly were able to get the police and fire to
13 help us move blood around, but that was an issue
14 with the planes and bridges and tunnels closed.
15 There were clearly issues in managing the
16 influx of donors. We within two days decided that
17 we were going to ask people to come back. Just a
18 bit of data on that, which isn't really tight at
19 the moment, but we asked approximately 24,000 to
20 25,000 people to please come back, that we had
21 enough blood. We have contacted or attempted to
22 contact all 25,000-plus people.
23 We've had over 8,000 folks have signed up
24 to donate blood. About 2,500 of those have
25 actually shown up to donate, and we've had about
56
1 2,000 usable units. So about 9 percent of the
2 24,000 or 25,000 people that we did ask to come
3 back have actually come back and donated. I'm not
4 sure that that's bad or good. We haven't teased
5 out how many of those are first-time donors, how
6 many are repeat donors, but that's our experience
7 thus far.
8 By the way, Dr. Mitchell, at this meeting
9 in January the post office will be invited. They
10 are already on the docket. Another concern, by the
11 way, which is interesting for that meeting--I'm
12 diverging a second--is smallpox immunizations, if
13 they are recommended nationally, could possibly
14 impact the blood supply because there is a deferral
15 for live vaccines, and if a lot of people are
16 vaccinated, it could have an issue. These are
17 spin-offs that are very interesting in terms of the
18 September 11th episode.
19 Another repercussion that we are noting is
20 a worrisome trend now in terms of our donor base.
21 We had this great surge in donations, very
22 heartwarming, but now we're seeing a very worrisome
23 downturn in our donations. We look at the
24 efficiency of our donor drives, the number of
25 people who actually show up vis-a-vis the bookings.
57
1 We usually run 100 or 110 percent because there are
2 a lot of walk-ins. We are down to about 80
3 percent.
4 The Police Academy of New York, for
5 instance, yesterday cancelled a 500-unit drive
6 because the police have been, the cadets have been
7 on the streets. They have to come back and get
8 some lessons. They can't accommodate a donor
9 drive. We have noticed other corporations, a
10 little bit of a burnout, whatever. Obviously there
11 has been negative media attention about the surplus
12 and how it was handled.
13 And we think this is a nationwide trend.
14 I believe there are several blood centers on appeal
15 right now. So I think the blood supply is very
16 volatile, very unstable at the moment, and the
17 repercussions of September 11th, not only the
18 immediate repercussions, the disaster response, but
19 the short- to medium-, maybe even long-term effects
20 on the blood supply are yet to be determined. Of
21 course the vCJD deferrals will not help, and we are
22 impacted, as you know, most significantly by those
23 deferrals.
24 So we have a lot to learn. I think the
25 meeting in January is going to be very useful, and
58
1 I think the caution flags are flying right now in
2 terms of the donor base, its volatility, and
3 perhaps the decline in donors that we're seeing.
4 Thank you.
5 CHAIRMAN NELSON: Maybe you could, maybe
6 you or some other blood bankers could tell, what
7 was the change in the proportion of first-time and
8 repeat donors in the period around September 11th?
9 DR. DAVEY: We're looking at that. We
10 haven't looked at that yet, Mr. Chairman, but we
11 are trying to tease it out. That's very important
12 information.
13 We have found, though, as I think Alan
14 mentioned, that our marker rates in the people that
15 did show up after the 11th were essentially
16 identical to the marker rates that we have
17 identified in a normal mix of donors that present
18 at our donor centers.
19 CHAIRMAN NELSON: So normally about 30
20 percent are first-time donors? Is that about
21 right?
22 DR. DAVEY: That's about right, 25, 30
23 percent.
24 DR. FITZPATRICK: I'm sorry. I had one
25 more question for Dr. Tabor. On the hepatitis A
59
1 and the parvo B notification and recall, when you
2 made the comment that all cellular products would
3 be expired by the time you knew the test results,
4 I'd just like to remind the agency that there is a
5 resurgence of interest in frozen red cells, and
6 those cells would not be expired by the time you
7 got those results, so you need to make a
8 consideration for that during your deliberations.
9 DR. TABOR: Yes. Thank you. We are aware
10 of that, and I left that out of the discussion just
11 for simplicity. But the point being that if tests
12 in situations that Dr. Stramer had discussed in
13 their phase one, where the testing is done at a
14 point after most of the components or all of the
15 components have expired, obviously notification is
16 not relevant unless there were a situation where
17 there were frozen components.
18 DR. SCHMIDT: Mr. Chairman, earlier agenda
19 notices that we received indicated that in this
20 committee report section we would have a report on
21 consent decree update, and that has disappeared
22 from the agenda. Is there any comment on that?
23 DR. SMALLWOOD: If you will notice, on
24 your agenda it's scheduled for Friday morning. The
25 presenter was unable to make this session, so
60
1 that's why it was moved.
2 DR. SCHMIDT: Thank you. Excuse me.
3 DR. SMALLWOOD: And that's why we have
4 more time.
5 CHAIRMAN NELSON: Well, I would think
6 that--is Dr. Kahn here? Yes? No? How about Dr.
7 Chapman? Okay. I wonder if we could--Dr. Nakhasi,
8 do you think we could move in to begin discussion
9 on the Simian Foamy Virus issue?
10 DR. NAKHASI: Right now?
11 CHAIRMAN NELSON: Yes.
12 DR. NAKHASI: I think we could, but I
13 think Arifa Kahn is going to be presenting the--
14 CHAIRMAN NELSON: Okay. Right. So it
15 doesn't make sense to start.
16 DR. NAKHASI: That's the problem.
17 CHAIRMAN NELSON: Okay. I guess then
18 we'll have a half-hour break, unless somebody has a
19 speech to make. So we'll come back at 10 o'clock.
20 [Recess.]
21 DR. SMALLWOOD: May I ask all of the
22 committee members to please return to your seats?
23 We are ready to reconvene. We're sorry about the
24 delay, but you know that the Blood Products
25 Advisory Committee meetings are always unique, and
61
1 we try to live up to our reputation.
2 Dr. Nelson, whenever you're ready.
3 CHAIRMAN NELSON: The next group of
4 presentations is on the Simian Foamy Virus and the
5 issue of transmission by blood and blood products,
6 which I think the virology may be more interesting
7 than the transfusion risk, but it is an interesting
8 virus. I think we all will agree with that. And
9 to introduce the topic, Dr. Hira Nakhasi from the
10 FDA.
11 DR. NAKHASI: Thank you, Dr. Nelson. I
12 want to apologize to all the committee members for
13 the delay here, because I thought we will get
14 started earlier, but traffic and other things don't
15 let you. Mother Nature doesn't want it to be that
16 way. So I again want to apologize, and let's get
17 started with the topic.
18 Today I am going to present in front of
19 you the topic, which is basically the potential
20 concerns for Simian Foamy Virus transmission by
21 blood and blood products. The issue here is to
22 seek advice from the Advisory Committee to assess
23 the possible transfusion risk from SFV. I will
24 sort of build up the issue, why we are concerned
25 and why we brought this issue to the Advisory
62
1 Committee meeting here.
2 As a way of background, and you will hear
3 a little bit more about the background and the
4 pathogenesis of this virus by Dr. Arifa Kahn in the
5 presentation following mine, however, just to give
6 you a little bit brief introduction to this virus,
7 Simian Foamy Virus belongs to the Retroviridae
8 family, and the prevalence of SFV infection in wild
9 animals is very high. Seroprevalence is higher in
10 captive animals versus the wild animals. Precise
11 mode of transmission is not clear. However, we
12 believe to start that it is transmitted by the
13 saliva when the animals bite other animals or
14 animals bite humans.
15 The infection, in several pathogenesis
16 models using the small animals like rabbits and
17 mice, they found out that they get infected by the
18 respective Simian Foamy Viruses, but without any
19 evidence of pathology in those animal studies.
20 With regard to infection in humans, SFV
21 infection is not believed to be prevalent in human
22 population. However, humans who are handling or
23 are occupationally exposed to non-human primates
24 can be infected by SFV. There have been several
25 studies done where they have shown, in the past
63
1 there were several studies done where they showed
2 that several diseases such as myasthenia gravis and
3 some other diseases I cannot even pronounce,
4 multiple sclerosis, there has been some association
5 with this foamy virus. However, that association
6 was tenuous. However, further analysis of those
7 studies, they are using several methodologies like
8 Western blot, PCR, IFA, it turned out to be there
9 was no association between foamy virus infection
10 and these diseases.
11 Then a current concern for us is basically
12 on the following studies, which you will hear more
13 from both CDC presentation as well as from Health
14 Canada presentation, that in an unlinked CDC
15 serosurvey of North American zoo workers, they
16 found out that 4 out of 322 individuals who were
17 tested were positive for this SFV infection. And I
18 would like to emphasize here, out of 322, 133 were
19 potentially people who had handled the non-human
20 primates, and all the four were positive from that
21 group, whereas they had 189 people who had not
22 handled, and none of the infections were in that
23 group. From these studies and other studies, the
24 seroprevalence of this infection is between 1.8 to
25 3 percent among the people who are occupationally
64
1 exposed to non-human primates.
2 Another study about which you will hear
3 from Health Canada, a recent study which was done,
4 again unlinked serosurveillance of non-human
5 primate handlers, they found 2 out of 46
6 seroreactive people, and one of them was very
7 strongly positive for the antibody on the Western
8 blot, and one was weakly reactive. That prompted,
9 basically that prompted Health Canada to sort of
10 ask CDC and FDA what can be done.
11 They were thinking at that time, can there
12 blood people who will be deferred donors? These
13 non-human primate handlers can be deferred for
14 donation. However, at this point you will hear
15 from Health Canada they are not considering that at
16 the moment. But then again, this is again a
17 seroprevalence study, very limited.
18 Not only that, they found that SFV can be
19 isolated from humans, these workers who are exposed
20 to non-human primates. And in another look-back
21 study which was done by CDC and Atlanta Red Cross,
22 where basically you will hear more of that in
23 Louisa Chapman's presentation, where they found out
24 one positive person who had donated over I guess
25 several years, and seven donations from that person
65
1 were transfused, and four were basically traced
2 back, and those four people who had got the
3 transfusion from this positive donor did not show--are
4 negative for the last 1.7 to 7 years post-transfusion, so
5 obviously they are not infected.
6 So, however, based on these observations,
7 which are the studies I presented to you, the CDC
8 study which you will hear more detail, the Health
9 Canada study you will hear more in detail from, and
10 other studies from the literature survey, it looks
11 that there is insufficient data to exclude the risk
12 from transfusion at this time.
13 So the topics we will be discussing this
14 morning will be the review of SFV biology and
15 pathogenesis by Arifa Kahn, and she will educate us
16 all about what this SFV--I mean how this
17 pathogenesis of SFV takes place. Then we will hear
18 a review of investigation on human infections from
19 SFV and proposed human studies from Louisa Chapman
20 from CDC. And then we will hear the review of risk
21 assessments from Paul Sandstrom from Health Canada.
22 And then the last, we will hear the
23 proposed animal study which FDA is proposing,
24 especially Arifa Kahn is proposing. And in
25 collaboration with Arifa Kahn, we would like to ask
66
1 the question: Can this SFV be transmitted through
2 the blood?
3 Therefore, while you are listening to
4 their presentation, I would like you to please pay
5 attention to these following questions. The three
6 questions we will be asking to the committee are:
7 One, does the committee agree that the currently
8 available data are insufficient to determine
9 whether SFV can cause adverse health effects in
10 humans? That's one.
11 Number two, does the committee agree that
12 the currently available data are insufficient to
13 determine whether SFV can be transmitted by blood
14 transfusion?
15 Number three, we would request your
16 comments on the adequacy of the proposed study to
17 evaluate SFV transmission by blood transfusion?
18 So at this point I would like to ask Dr.
19 Arifa Kahn to present the first part of the talk.
20 DR. KAHN: Good morning. Today I would
21 like to describe to you a group of retroviruses
22 that are distinct from other retroviruses in many
23 of their properties, as well as different from HIV
24 and HTLV, which you are quite familiar with.
25 Foamy viruses form a unique genus called
67
1 Spumavirus, due to their unique biological and
2 genetic properties, which include an extremely
3 broad host-, tissue-, and cell-tropism. To date
4 there is no known cell line that is resistant to
5 infection by Simian Foamy Virus. Also, in most
6 situations in culture these viruses are highly
7 cytopathic. However, there is no known
8 pathogenicity to date with this group of viruses.
9 Simian Foamy Viruses share many of the
10 genomic structural features of other viruses, such
11 as LTRs at both ends of the viral genome, as well
12 as structural genes gag, pol, env. However, they
13 are distinct from the simple retroviruses in that
14 they have open reading frames, such as tas and orf-2, of
15 which the tas is known to encode a
16 transactivating protein which is necessary for
17 transcriptional activation of the two promoters
18 that are shown in the figure.
19 All right. So therefore these viruses are
20 considered complex retroviruses because of the
21 additional open reading frames. However, foamy
22 viruses have properties that are distinct from
23 other retroviruses and are similar to the family of
24 Hepadnaviridae, in that the infectious particles
25 have been shown to have associated linear DNA
68
1 genomes. Also, persistently infected cells contain
2 very large amounts of linear DNA.
3 This is showing a diagrammatic figure of
4 the replication cycle of foamy viruses. The virus
5 cycle is complex because it does share certain
6 features of retroviruses and others of
7 Hepadnaviridae. However, what I would like to
8 focus is that like all retroviruses, foamy viruses
9 do have the critical step in their life cycle of
10 integration, which leads to persistence of stable
11 viral DNA in the host. So therefore these
12 sequences reside in the life of the host, or
13 throughout the life of the host, and it is this
14 critical feature of retroviruses that make this
15 class of retroviruses of special safety concern in
16 biologics.
17 Foamy viruses are highly prevalent in a
18 wide variety of species. They have been identified
19 in simian, bovine, equine, ovine, feline, murine,
20 and otariidine. In non-human primates, foamy virus
21 infection is widespread. In whatever species that
22 has been looked at, foamy virus can be isolated,
23 for example in New World primates, Old World
24 primates, including macaques, African green
25 monkeys, baboons, as well as in apes.
69
1 The natural infection in non-human
2 primates, some of the distinct features are
3 described here. There are 11 serologically
4 distinct subtypes of foamy virus, and these are
5 identified in the variety of species that I showed,
6 the non-human primate species. Seroprevalence is
7 high in captivity. And again you will see
8 throughout my presentation that the studies done on
9 foamy viruses are limited, so basically we have to
10 extract whatever information we can based upon
11 these studies, and this is very unlike what you see
12 in the literature for HIV and some of the other
13 retroviruses.
14 In the natural situation there is a report
15 that it may be as high as 70 percent, and there is
16 higher incidence in adults than in infants, and
17 this is again based on this one study that's
18 indicated here. The sequences, however, are
19 genetically stable, and this is I guess expected
20 because the virus is white cell-associated, and it
21 does not have a high replication efficiency as you
22 are aware of in the case of HIV, where there is a
23 lot of mutations due to high reverse transcriptase
24 activity.
25 There is very broad tissue distribution.
70
1 In one study in African green monkeys it was
2 reported that viral DNA was found in all of the
3 tissues in the animal that were looked at
4 extensively. However, the infection is latent and
5 persistent, and viral RNA in this same study was
6 only detected in the oral mucosa. This is one of
7 the reasons, or this study is one of a few studies
8 based upon which it is believed that the virus is
9 transmitted through the saliva.
10 However, it should be noted that humans
11 are not the natural host of foamy viruses. The
12 human foamy virus that is in the literature has
13 been confirmed to be of chimp origin. This is the
14 new designation of this virus. And this has been,
15 I guess based upon the sequence analysis, is
16 believed to be acquired by cross-species infection
17 from a chimpanzee. And as Dr. Nakhasi mentioned
18 earlier, based upon seroprevalence studies and I
19 guess limited analysis in various human
20 populations, there is no known foamy virus
21 infection in the natural situation.
22 However, accidental infection of humans
23 occupationally exposed to non-human primates has
24 been reported, and you will hear more about this in
25 the subsequent presentations. SFV infection in
71
1 non-human primate handlers and zookeepers has been
2 shown due to exposure to African green monkeys,
3 chimpanzees, baboons, and macaques, and Dr.
4 Sandstrom will talk more about this today.
5 The infection is persistent. In one case
6 that I'm aware of, infectious virus was isolated at
7 least 30 years post exposure to the animal, and
8 based upon limited sequence analysis, the sequences
9 were shown to be almost identical to the virus that
10 was present in the original animal. This is work
11 from the CDC.
12 Latent virus infection has been I guess
13 observed in all of the human infections, based upon
14 the fact that there is no evidence of plasma
15 viremia, and virus has been isolated in co-culture
16 from PBLCs. However, there has been no evidence of
17 virus transmission in close contacts, and no signs
18 of any foamy associated disease in the individuals.
19 And again, these will be, this aspect will be much
20 more elaborated in the next two presentations.
21 In terms of the host range of Simian Foamy
22 Virus, as I have mentioned earlier, the host range
23 is exceptionally broad. I have listed here various
24 species ranging from chicken, avian species, to
25 feline here, various tissues of origin. In all
72
1 cases Simian Foamy Virus was shown to replicate
2 with CPE.
3 In terms of primate species, there are a
4 variety of cell types, fibroblast, epithelial,
5 macrophage, lymphoid cells, in both monkeys and in
6 humans; various tissues of origin. I all cases the
7 in vitro studies on Simian Foamy Virus have
8 resulted in virus replication, and in almost all
9 cases also CPE, cytopathic effect.
10 Based upon the published reports on Simian
11 Foamy Virus in vitro studies, the infection is
12 productive. Either it's acute, in which case there
13 is variable amounts of extracellular virus
14 produced, and there is cytopathic effect seen
15 either due to lysis or apotosis; and in some cases
16 based in other cell lines you can have chronic
17 infection, in which case you have low level virus
18 production and no cytopathic effect.
19 Now, it should be noted that the studies,
20 all the in vitro studies that I have described are
21 based upon using prototype Simian Foamy Viruses,
22 mainly SFV-1, -2, or -3, and in many cases also the
23 Human Foamy Virus, which is the simian, chimpanzee
24 isolate actually. So all of the studies thus far
25 have been based upon these prototype viruses which
73
1 have had extensive passage in a variety of
2 different species for a different number of
3 passages.
4 And the reason for this primarily was to
5 create working virus stock. The virus replicates
6 very poorly, so in order to generate some, you
7 know, I guess, material with enough virus titer,
8 the propagation may have been done. This is again
9 historical. This is what I think the reason might
10 be.
11 However, these lab-adapted viruses may not
12 represent the properties of the naturally occurring
13 parent viruses. Therefore, it is important that
14 the properties of naturally occurring Simian Foamy
15 Viruses be studied to understand the mechanism of
16 Simian Foamy Virus infection in humans, such as
17 transmission, persistence, as well as pathogenic
18 potential.
19 In order to investigate this aspect, my
20 lab had initiated studies a few years ago in which
21 we isolated foamy viruses from rhesus and pigtail
22 macaques by very limited in vitro passage, and we
23 have extensively characterized the replication
24 kinetics of these limited passage, low passage
25 macaque isolates and compared them with the
74
1 prototype lab-adapted viruses in a variety of
2 different cell lines of different species,
3 different tissue origins, including a wide variety
4 of deployed transformed as well as tumor human cell
5 lines.
6 And I'm just going to summarize our
7 results in the next slide. What we have found is
8 that the naturally occurring viruses also have the
9 broad host-, tissue-, and cell-tropism as do the
10 lab-adapted viruses. However, in all cases the
11 macaque isolate showed slower replication kinetics
12 than the prototype lab-adapted virus, for example,
13 SFV-1. And the order of the kinetics of
14 replication was the same with the viruses
15 regardless of which cell line we tested.
16 Interestingly, there was a wide difference
17 in the replication efficiency of the different
18 macaque isolates. Some of them were extremely poor
19 in their replication regardless of the cell line,
20 and some of them were much better, however, not as
21 good as the prototype viruses.
22 Interestingly, all the macaque isolates
23 that we tested showed unique characteristics from
24 the prototype SFV, in that non-productive infection
25 was seen in the case of a human tumor cell line,
75
1 the A549 cell line. This is quite unique in the
2 sense that thus far all these studies have shown
3 that foamy viruses replicate productively.
4 In this case we showed that using the
5 naturally occurring viruses, we did get non-productive
6 infection in one particular cell line,
7 whereas in this cell line the prototype virus
8 replicated efficiently. There was no evidence of
9 virus replication of the naturally occurring
10 viruses by a variety of parameters, including
11 reverse transcriptase activity, by the traditional
12 assay as well as by a PCR-based RT assay which is
13 highly sensitive. There was no protein expression,
14 particle production, or unintegrated viral DNA by
15 Southern blot.
16 However, by DNA PCR we did demonstrate
17 that in all cases the viruses did enter and were
18 present in the host DNA even at 60 days post-infection. So
19 these viruses could enter, but after
20 entry they remained quiescent. And in the case of
21 one of the isolates, we did show that the infection
22 was latent, in that we were able to recover virus
23 after co-culture. So we are continuing to
24 investigate this system further to see in terms of
25 analyzing it as a model of latent foamy virus
76
1 infection in humans.
2 To switch gears now and talk a little bit
3 about SFV pathogenesis, or I guess I should say
4 lack of, SFV, as Robin Weiss indicated in 1999,
5 still remains "A Virus in Search of a Disease."
6 There have been limited studies to investigate the
7 pathogenesis, and I'll just mention them briefly
8 here, based upon whatever information we have.
9 These are experimental infections, and these
10 studies again have been done with prototype
11 viruses, lab-adapted viruses.
12 In immunocompetent rabbits and mice,
13 persistent infection can be achieved. Transient
14 immunosuppressive effect is seen in both species.
15 However, there is no sign of any disease and no
16 pathology associated.
17 There is another study, one study in which
18 transgenic mice which expressed, I guess, certain
19 of the orf proteins, the tas and the bet, for this
20 particular virus, were found to have some pathology
21 which was described to be probably due to the
22 presence of the structural genes. However, virus
23 replication was not demonstrated. And this
24 pathology was associated with the cerebellar
25 nervous system.
77
1 However, it should be noted that in terms
2 of the transgenic mouse system, here we are looking
3 at experimental results in which all these cells
4 are expressing proteins probably at much higher
5 levels than what you would see in the natural
6 infection. However, this does indicate a possible
7 pathological effect if the virus were to be able to
8 replicate to high levels, which we have not seen
9 yet in the natural situation.
10 In summary--and again, the difference in
11 the bullets does not signify any importance. It's
12 a glitch of the PowerPoint. There has been no
13 evidence of any disease in non-human primates due
14 to naturally occurring viruses, and it should be
15 mentioned that the transmission in this situation
16 is probably due to the saliva. In small animal
17 models using prototype lab-adapted viruses, no
18 disease was seen in immunocompetent rabbits or
19 mice. However, some pathology was seen in
20 transgenic mice due to protein expression.
21 And there has been no evidence of disease
22 in SFV-infected humans. However, it should be
23 noted that there has been no evidence of foamy
24 transmission by blood due to the lack of relevant
25 animal studies, and this will be further discussed
78
1 in the proposed study.
2 And I think I will just like to stop at
3 this point and thank everyone for their attention.
4 CHAIRMAN NELSON: Questions for Dr. Kahn?
5 DR. STRONCEK: You had a slide here, I
6 don't know if you showed it, you talked about SFV
7 viruses in dogs and cats.
8 DR. KAHN: Yes.
9 DR. STRONCEK: Do you know the prevalence
10 of those, and does anybody know if--it seems, you
11 know, to put this into context, do those transmit
12 from dogs and cats to humans?
13 DR. KAHN: In terms--well, I should
14 mention that from the literature there is a
15 statement which indicates that the prevalence in
16 the other species is similar to that in non-human
17 primates. I don't believe the host range in other
18 species has been as extensively looked at as in the
19 case of the Simian Foamy Viruses. One may expect
20 it may be the same. In terms of the feline
21 situation, and I see Dr. Folks standing up, I think
22 he may be able to comment about some of his data in
23 looking at that.
24 DR. FOLKS: Yes, I'll just make a comment.
25 We looked at about 300 individuals that are feline
79
1 practitioners and have been over a long period of
2 time scratched and chewed up pretty bad by cats,
3 and we saw no transmission of feline foamy.
4 DR. KAHN: But it should also be mentioned
5 that there has been no evidence for transmission of
6 feline leukemia viruses, either, and that has
7 always been a mystery to me.
8 CHAIRMAN NELSON: I think one of the early
9 cases in humans was a person with a nasopharyngeal--
10 DR. KAHN: That was the Human Foamy Virus.
11 CHAIRMAN NELSON: Right. How many people
12 with--how often has this been looked for in people
13 who have nasopharyngeal carcinoma? One would
14 expect that if there was any pathology, it would
15 relate to where the virus might replicate. If the
16 virus is latent, it's hard to imagine a pathology,
17 and you mentioned the saliva and etcetera. Have
18 focal studies been done on this subset of patients?
19 DR. KAHN: I'm not aware of that. I don't
20 believe so.
21 DR. FITZPATRICK: In the humans that have
22 evidence of the virus, I missed it if you said what
23 cell lines in those individuals are infected.
24 DR. KAHN: Well, lymphocytes have been
80
1 looked at, and virus, infectious virus, can be
2 recovered from the lymphocyte. And I think Dr.
3 Chapman may shed more information on the patients,
4 but it's clear that it's in the lymphocytes.
5 DR. NEUMANN-HAEFELIN: To comment on the
6 nasopharyngeal carcinoma question--
7 CHAIRMAN NELSON: Could you identify
8 yourself for the record?
9 DR. NEUMANN-HAEFELIN: Yes. I am Dieter
10 Neumann-Haefelin from Freiburg, Germany. To
11 comment on that question concerning nasopharyngeal
12 carcinoma, at the time of the detection of this so-called
13 Human Foamy Virus, intensive studies have
14 been carried out on NPC patients, and no
15 seropositivity has been found at that time. And
16 that was the only possibility to trace foamy virus
17 infections.
18 DR. KAHN: Thank you.
19 CHAIRMAN NELSON: Thanks for your comment.
20 DR. NAKHASI: Dr. Nelson, I would like to
21 at this point take the opportunity to introduce, we
22 have two, actually three experts on SFV in the
23 audience here. I think, I don't know whether you
24 know them. Dr. Neumann-Haefelin has introduced
25 himself. Dr. Tom Folks. And we have one person on
81
1 the telephone, Dr. Jonathan Allan, also. so if you
2 need any clarification or things like that, please
3 ask. We can ask these gentlemen.
4 CHAIRMAN NELSON: Thank you. Other
5 comments? Okay. Thanks very much, Dr. Kahn.
6 Dr. Louisa Chapman from CDC.
7 DR. CHAPMAN: Thank you. I'm going to be
8 talking about a body of work that has been done out
9 of the Division of AIDS, STD, and TB Laboratory
10 Research, HIV and Retrovirology Branch primarily.
11 Dr. Folks, who just spoke, is the chief of that
12 branch. I want to thank the BPAC for the
13 opportunity to present this body of largely
14 unpublished and actually, due to the cancellation
15 of the foamy virus international meeting that was
16 scheduled for September, at this point largely also
17 previously unpresented data on Simian Foamy Virus
18 infections in humans.
19 The work I present was led by the HIV and
20 Retrovirology Branch, NCI, CDC, but involves a
21 large number of collaborators both within and
22 outside of CDC, and I'm not going to attempt to
23 acknowledge all of those collaborators because of
24 the time limitations and the nature of the
25 presentation. But I just want you to know it's
82
1 composite data, largely out of the HAR Branch, and
2 largely both unpublished and unpresented at this
3 point.
4 I'm going to summarize the studies that
5 have been done and are being done there before I
6 talk about the one on this slide. Though let me go
7 back and talk about one that Dr. Folks alluded to,
8 that we had decided not to put into this
9 presentation, but since it has come up, the study
10 Dr. Folks mentioned, looking at over 300 feline
11 practitioners, is a study that has been done, has
12 been completed, and is published in the Journal of
13 the Veterinary American Medical Association.
14 Dr. Sandstrom, Sal Butera, and I, and I
15 think Dr. Folks are all co-authors on that. I
16 don't remember who the first author is. Are you,
17 Paul, or Sal? It was initiated by Paul Sandstrom
18 when he was at CDC, and finished up by Sal Butera,
19 and one or the other is the first author, but you
20 should be easily able to find it with a MedLine
21 search.
22 And again, it was over 300 highly exposed
23 feline practitioners, multiple injuries, multiple
24 years of exposure to sick cats, no evidence of any
25 of the feline retroviruses we looked for, but of
83
1 specific interest here was Feline Foamy Virus.
2 Now, the studies that we did plan to talk
3 about, this is a completed study that again is
4 published. It was an unlinked serosurvey of zoo
5 workers, an unlinked serosurvey of 322 North
6 American zoo workers which was published in the
7 Lancet in 2000, the year 2000, identified four
8 seropositive samples using a Western blot assay
9 containing combined antigens from three
10 antigenically distinct Simian Foamy Viruses.
11 The four reactive sera were subsequently
12 tested against antigens from SFV-6, chimpanzee,
13 SFV-3, African green monkey, and SFV-2, macaque,
14 separately. They were tested separately. The
15 single antigen testing indicated that all four were
16 infected with SFV originating from chimpanzees.
17 All four were from the 133 workers whose jobs
18 involved potential contact with non-human primates,
19 and none of the 189 workers whose jobs did not
20 involve potential contact with non-human primates
21 were seroreactive.
22 We have several ongoing studies that I'll
23 summarize for you. We have three specific ongoing
24 studies relative to potential for SFV transmission
25 by transfusion. The first is the "Voluntary
84
1 Seroprevalence Study of Non-Human Primate
2 Retrovirus Infections Among Occupationally Exposed
3 Workers."
4 It was developed in response to a need to
5 define the prevalence of SIV infection, Simian
6 Immmunodeficiency Virus infection, among
7 occupationally exposed persons. It was therefore
8 originally designed many years ago, at this point,
9 to enroll institutions that employed persons
10 exposed to either non-human primates, to their
11 biologic materials, or to Simian Immunodeficiency
12 Virus, SIV, and to survey the entire worker
13 population for evidence of SIV infection.
14 The current study has been modified
15 through the years to allow enrollment of self-selected
16 workers within these institutions or
17 potentially exposed individuals who are tested for
18 a variety of simian retroviruses. And let me stop
19 and say of course when we enrolled institutions,
20 individuals within that institution had the right,
21 as human research subjects always do, to refuse
22 participation. But it was, the design at that
23 point was specifically to capture populations
24 without exception for enrolling individuals.
25 These changes were made in response to the
85
1 reluctance of institutions to test their workers
2 for infections of uncertain significance, combined
3 with requests for testing from specific individuals
4 who had a history of specific high-risk exposures.
5 The current modified protocol identifies infections
6 in exposed individuals rather than defining the
7 prevalence of infection in exposed populations.
8 The strength of this study is its ability
9 to identify persons infected with simian
10 retroviruses. Weaknesses include enrollment biases
11 that may favor enrollment of persons with increased
12 likelihood of infection, thereby limiting the
13 confidence with which prevalence of infection among
14 tested workers can be extrapolated to the greater
15 worker population. Additionally, the retrospective
16 exposure information collection limits our ability
17 to identify specific risk factors that may be
18 associated with infection.
19 We reported the first human SFV infections
20 identified under this protocol in Nature Medicine
21 in 1998. At that time we began to work on two
22 additional protocols that were intended to address
23 other issues raised by evidence of these
24 infections.
25 The second protocol is called the "Long
86
1 Term Follow-up of Persons Infected with Unusual
2 Retroviruses." It enrolls persons documented to be
3 infected with unusual retroviruses and their close
4 contacts, or it is designed to enroll these persons
5 and their close contacts. You will hear later that
6 we haven't actually succeeded in enrolling any
7 contacts.
8 By "unusual retroviruses" we intend any
9 retrovirus infection that is not recognized to be
10 endemic in human populations. All participants are
11 followed for five years. Contacts, when we enroll
12 them, will be tested annually for evidence of
13 infection. Primary participant infection is
14 reconfirmed at the time of enrollment, and infected
15 participants are questioned about their health
16 status as well as risk factors for acquisition or
17 for secondary transmission of infection. This
18 questioning is done by telephone interview using a
19 standard questionnaire.
20 Standard clinical laboratory testing,
21 including complete blood counts, blood chemistries,
22 liver function tests, characterization of lymph
23 site subsets, including CD4, is performed annually.
24 Blood, saliva, throat swabs, urine, and semen or
25 vaginal fluid specimens are collected annually for
87
1 study.
2 The strength of this study is that it
3 allows prospective virologic, immunologic, and
4 clinical characterization of unusual retrovirus
5 infections, including determination of virus
6 presence in body fluids relevant to secondary
7 transmission. It allows prospective collection and
8 more complete characterization of the health status
9 of infected persons and the prospective study for
10 evidence of secondary transmission.
11 Weaknesses include incomplete availability
12 of health records and of specimen collection. In
13 particular, we have had difficulty getting people
14 to submit semen specimens. It has potential
15 enrollment biases--you will hear later that only a
16 subsegment of the people eligible for the study
17 have chosen to participate--and incomplete
18 enrollment of contacts.
19 And our last ongoing investigation is the
20 "Investigational Look Back Study for Recipients of
21 Blood Products from Simian Foamy Virus (SFV)
22 Infected Donors." It identifies recipients of
23 blood products from donors confirmed to have been
24 infected with Simian Foamy Virus and tests these
25 recipients for infection.
88
1 The strength of this study is the
2 provision of specific information on infection
3 status of recipients of blood products from donors
4 who are documented to be SFV infected. Weaknesses
5 include the absence of information on infectivity
6 of the blood products per se, and limited power to
7 define transmission risk due to very small numbers
8 of recipients and an even smaller number of
9 traceable recipients.
10 So I'm going to present sort of composite
11 data from all of these studies, and I'm dividing it
12 by questions it addresses rather than which study
13 it comes out of, but I have sketched for you the
14 protocols under which we are collecting this
15 information. So first let's talk about data in our
16 hands that may address SFV transmissibility,
17 beginning with primate-to-human transmission.
18 Of 279 participants enrolled from 12
19 institutions, 11, or 3.7 percent, are seroreactive
20 for SFV by Western blot. And all the data that I
21 am presenting to you is up to date as of the date
22 in September when we originally expected to present
23 this talk. There may be some small additional data
24 collected in various places. There is nothing that
25 changes the overall picture.
89
1 So 3.7 percent seroreactive for SFV by
2 Western blot. Due to enrollment bias, this likely
3 overestimates the prevalence of infection in the
4 exposed population, although we can't give you any
5 estimate of to what extent. SFV DNA was identified
6 by PCR and peripheral blood lymphocytes of all 10
7 of the 11 who provided additional samples for
8 genetic testing, for DNA testing.
9 Biogenetic analysis of the integrate
10 sequence indicated that the infecting SFV viruses
11 probably originated from chimpanzees (n = 5), from
12 baboons (n = 4), and from an African green monkey
13 in one instance. These 10 workers confirmed
14 frequent exposures to body fluids of the implicated
15 species, and in some but not all instances,
16 injuries associated with these species. The
17 duration of occupational exposure ranged from 4 to
18 41 years, with a median of 20 years.
19 And the testing of archived serum when it
20 was available--which there was very limited
21 availability--identified durations of documentable
22 seropositivity between 2 and 25 years, with a mean
23 of 19.5 years. And again, the two-year limit is,
24 we could get archived serum two years back. We
25 couldn't get archived serum further back, so that
90
1 it's an open question as to in fact how long that
2 person has been infected.
3 Five of the 11 SFV seroreactive persons,
4 but no contacts, have enrolled for long-term
5 follow-up. These five represent the extremes of
6 the larger group in terms of exposure, having
7 worked from 4 to 41 years, with a mean of 21.2
8 plus/minus 12.2 years, and having documented
9 durations of seropositivity of 10 to 24 years, with
10 a mean of 17.5 years. Combined, they represent a
11 total of 85 person-years of infection. All five
12 reported histories of both mucocutaneous exposures
13 to non-human primate body fluids and of
14 occupational injuries with skin penetration.
15 Now, this slide, I attempted to capsulize
16 our data that may speak to human-to-human
17 transmission, beginning with evidence of virus
18 presence in body fluids.
19 So SFV DNA was identified by PCR in
20 peripheral blood lymphocytes from all 10 infected
21 persons on at least two separate occasions. In
22 other words, each person had blood collected and on
23 at least two separate occasions tested positive by
24 PCR. Virus isolation from peripheral blood
25 lymphocytes was successful in four of the nine SFV-infected
91
1 persons, but was isolated again on at
2 least two separate occasions from each of these
3 four who were positive.
4 Additional biologic specimens have been
5 received from four enrollees in the long term
6 follow-up study. Throat swabs from two of the four
7 were SFV DNA positive by PCR, but virus was
8 isolated from only one, who we will call Case A.
9 However, virus was isolated from throat swabs from
10 Case A on two separate serial attempts, by which I
11 mean the throat swabs were collected on two
12 separate serial occasions.
13 Saliva samples were PCR positive for DNA
14 from only one of these four persons, again Case A,
15 the only person from whom virus was isolated from
16 throat swab, but virus was not isolated from this
17 saliva sample. A single specimen each of urine and
18 semen were available from only one participant,
19 again Case A, who importantly has a history of
20 hemospermia; which, for the non-medical people in
21 the audience, that is a relatively common but
22 abnormal but completely benign condition in which
23 blood is present in the sperm. It's not that
24 uncommon, actually.
25 SFV DNA was identified in both fluids by
92
1 PCR, both urine and sperm. But unfortunately, due
2 to this condition of hemospermia, you can reason
3 that if we know viral DNA is present in the blood
4 and we know the blood is present in the sperm, the
5 only reason to not find viral DNA in the semen and
6 the urine would be sampling error. So
7 unfortunately, the only case in which we have to
8 date been able to collect semen can't tell us
9 anything definitive about whether we identify viral
10 PCR there because it's normally present in the
11 semen and the urine, or because in this person
12 blood contaminates the semen and the urine.
13 SFV DNA was identified in both semen and
14 urine, but the volume was insufficient to attempt
15 culture. So we're hoping to get some more semen
16 specimens from Case A and also from other
17 participants, since that's obviously an important
18 exposure route to define.
19 This data suggests that virus can be
20 repeatedly isolated from peripheral blood
21 lymphocytes of only about half of infected persons,
22 despite consistent PCR identification of the
23 presence of viral DNA in PBLs of all infected
24 persons. SFV DNA was present in the throat swab of
25 only about half, two of the four tested people, and
93
1 the virus was isolated from throat swabs of only
2 one of these two. SFV DNA was identified in saliva
3 of only the throat culture positive person.
4 Now, again I remind you that for the five
5 people in the long term follow-up study, and we're
6 hoping to enroll additional people in that, we will
7 be recollecting and retesting these specimens at
8 periodic intervals for at least five years, so with
9 time we'll have more information on this.
10 In terms of our combined data that may
11 address the question of contact testing or
12 transmissibility between humans, all 10 of the SFV-infected
13 workers are male. The wives of six have
14 been tested and remain uninfected, despite a
15 documented mean of at least 14.5 years of exposure.
16 And by that I mean we're looking at how long the
17 infected husbands have been documented to be
18 seropositive, as opposed to how long they have
19 potentially been exposed and may potentially have
20 been infected.
21 These six wives include the wives of three
22 persons who, again, have enrolled for the long term
23 follow-up study, including Case A. These three
24 remain negative after a combined minimum of 51
25 person-years of intimate exposure. And we have
94
1 questioned these participants about the nature of
2 their relationships and also use of barrier
3 contraceptives or other things that might minimize
4 exposure, and they all report ongoing sexual
5 intimacy and no significant use of barrier
6 contraceptives, spermicides, anything that you
7 might hypothesize would artificially account for a
8 lack of transmission.
9 Six of the 10 SFV-infected workers report
10 a blood donor history. One of these six had
11 stopped donating prior to the retrospectively
12 identified date of infection. Four of the
13 remaining five, including Case A, were
14 retrospectively confirmed to have been infected
15 prior to the date of the most recent donation.
16 Recipients of blood components donated by one of
17 these four have been traced.
18 Case A, a blood donor, has been
19 characterized more extensively than the other
20 infected cases, and over a two-year period Simian
21 Foamy Virus was isolated from Case A's peripheral
22 blood lymphocytes on two of three serial attempts,
23 and from the throat swab on each of two serial
24 attempts. This is the data you've already heard
25 about. PCR positive cell pellets from throat
95
1 swabs, saliva, urine, semen, and peripheral blood
2 lymphocytes from Case A argue that SFV-infected
3 cells are present in all of these sites.
4 Case A made six donations between 1992 and
5 1997. Recovered plasma from two donations, 1993
6 and 1994, was sent for manufacturing into plasma
7 derivatives. Samples of on