1 department of health and human services




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3 of our first detection until approximately two weeks

4 thereafter that would be useful in terms of interdicting

5 spread. Am I correct?

6 DR. FEINSTONE: I am not clear why you would not

7 be detecting window cases.

8 DR. SIMON: I think we used the definition of

9 window before a positive test result --

10 DR. FEINSTONE: Okay, antibody appears at about

11 the time of clinical symptoms. The major period of viremia

12 and the major period of stool shedding is prior to the

13 appearance of antibody and clinical symptoms.

14 DR. SIMON: So, we are calling that the window

15 period?

16 DR. FEINSTONE: That would be the classic window

17 period.

18 DR. SIMON: So, it is from the first appearance of

19 an NAT positive test until symptoms begin --

20 DR. FEINSTONE: Yes, and that is the period when

21 people are infectious. That is when they are dangerous to

22 their contacts.

23 DR. SIMON: And that period is approximately two

24 weeks.

25 DR. FEINSTONE: it is quite variable I believe,


125 1 but it is on the order or two weeks.

2 DR. EPSTEIN: Steve, could I press the point a

3 little bit? I thought I heard you say that these

4 recurrences occur in about 10 percent of patients, and it

5 was not clear whether the recurrences were the same thing

6 also being observed with chronic, persistent detection of

7 RNA. The question is in the earlier studies that looked at

8 infectivity of plasma and stool, what were the numbers?

9 And, were the numbers sufficient to capture the relatively

10 infrequent cases that might have the relapses or chronic

11 viremia? In other words, isn't there a statistical problem

12 here? If you had a small number of volunteer studies and if

13 only 10 percent or less might have actually had this chronic

14 course, one simply could have missed them in the studies.

15 So, I am not sure that the early studies are dispositive,

16 although I don't think that in any way imputes the quality

17 of those studies. It is a statistical problem.

18 DR. FEINSTONE: I understand what you are saying

19 but, again, there is no epidemiologic evidence that these

20 patients who have recurrent symptoms are infectious for

21 their contacts. I don't believe there have been any

22 secondary cases reported from those groups. Is that right?

23 DR. ALTER: One, in a premature infant.

24 DR. FEINSTONE: One.

25 DR. ALTER: There has been one instance of


126 1 transmission due to fecal-oral exposure from an index case

2 with prolonged viremias, and it involved a premature infant

3 who had an extended hospitalization in an intensive care

4 nursery, whose source of infection was actually a

5 transfusion. Four months or so after the original infection

6 that infant transmitted to nurse. It is the only instance

7 and we believe that it is unique to that particular

8 situation and the immune competence of the premature infant.

9 DR. HOLLINGER: Dr. Koff?

10 DR. KOFF: Yes, just to follow up on that, Dr.

11 Epstein, I think the evidence is if you look at fecal-oral

12 transmission virtually all of the secondary cases occur

13 within one incubation period. So, even though there may be

14 some kind of RNA that still is present in stool and maybe

15 some kind of denatured RNA -- I don't know -- that in some

16 instances is still present in blood, really evidence of

17 infectivity, other than this one instance, just isn't there,

18 and that has been true now for about 30 years of looking at

19 secondary cases. Most of the secondary cases that occur

20 that were shown, in fact, occurred in the neonatal intensive

21 care unit. Household cases have just been exceedingly

22 unusual.

23 DR. HOLLINGER: Thanks, Ray. Is there anyone else

24 who has not spoken and wants to speak from the public right

25 now? If not, what I would like to do at this point is to


127 1 have Robin Biswas present the questions that are going to be

2 focused on here for the committee so we can sort of focus on

3 what we are really here for, and then discuss around those

4 parameters. So, Robin, let's start with the first two

5 questions, 1a and 1b.

6 Open Committee Discussion

7 FDA Perspective and Questions

8 [Slide]

9 DR. BISWAS: Questions for the committee, 1a.

10 Should the Food and Drug Administration recommend that, if a

11 plasma pool or minipool is found to be HAV NAT positive, the

12 individual HAV NAT positive donor should be identified and

13 notified of the test result?

14 1b. If so, should the FDA recommend that the

15 implicated donor be deferred from donating for three months?

16 [Slide]

17 2. Should the FDA recommend that unpooled units

18 from donors, that were donated within the three months prior

19 to the HAV NAT positive collection, be quarantined?

20 3. Should the FDA recommend that recipients of

21 transfused components from donors that were donated within

22 three months prior to the donor's HAV NAT positive

23 collection be traced and notified?

24 Committee Discussion and Recommendations

25 DR. HOLLINGER: Let's go back to the first


128 1 question, 1a, which is concerned with notification of the

2 positive donor, identified and notified, and deal with this

3 issue right here. So, I would like to sort of focus the

4 questions on this particular question. Any comments? Yes,

5 Dr. Linden?

6 DR. LINDEN: Well, I have a question for Dr.

7 Epstein. Following up on what you said before in terms of

8 understanding the implications of this, if somebody is

9 identified and notified, that means that they would then

10 have a history of hepatitis? Maybe I misunderstood what you

11 said earlier.

12 DR. EPSTEIN: As Dr. Biswas stated, we currently

13 interpret the regulation on history of viral hepatitis only

14 to encompass clinical hepatitis, which means identified

15 signs and symptoms and/or clinical diagnosis. The sticky

16 wicket here is that if you create a report of a positive NAT

17 test and then the donor is 80 percent likely also to then

18 become recognized symptomatic, it would be captured as

19 having had a history of clinical hepatitis. So, then they

20 would be captured by the current by the lifetime deferral

21 policy, and there would be a 20 percent subset that might

22 not because they never had colleague symptoms but the

23 majority would. Since we don't currently have a policy

24 whereby a well-established diagnosis of hepatitis for a

25 hepatitis with no chronic implication can be exempt from the


129 1 lifetime deferral, there would have to be sought a case by

2 case exemption. So, that is what I was trying to explain.

3 But, I also stated that that entire policy is being

4 reexamined.

5 DR. HOLLINGER: Jay, while you are still there, I

6 want to clarify for the committee that NAT testing for HAV

7 is currently being done by the plasma industry. Is that

8 correct? We are not dealing with that issue here, are we?

9 DR. EPSTEIN: No.

10 DR. HOLLINGER: The issue here is not whether it

11 should be done but what should be done about the results,

12 and so on? Is that correct?

13 DR. EPSTEIN: No, it is not correct. There are

14 some fractionators that have voluntarily introduced NAT and

15 at different levels of their process. We have one request

16 for modifying the license specifically to include that

17 procedure. Other companies have suggested that they may

18 become interested. So, we don't currently have an industry

19 practice.

20 DR. HOLLINGER: But there are no questions here --

21 unless I am just missing them -- that specifically say

22 should the plasma industry test -- whatever, many pools or

23 pools or a certain size for HAV by nucleic acid testing. Am

24 I correct in saying that? I don't see the questions here.

25 They are dealing with the assumption that it is being tested


130 1 and then what should be done with the results.

2 DR. EPSTEIN: Well, I think we are responding to

3 the fact that we have an application which requests approval

4 as an in-process procedure as part of a license. So, that

5 is what we are trying to deal with.

6 Perhaps we should have also simply asked the

7 committee should all donations be screened for HAV, but the

8 agency wasn't expecting that that would be our interest and

9 concern. I mean, if you want to raise that question

10 initially and have the committee vote, I think that is fine

11 but we were reacting to a specific request to do this as an

12 in-house, in-process procedure and, therefore, how should

13 the FDA view this? Should we require that the scope be

14 extended? But we were really not envisioning moving that to

15 a requirement to screen all donations. But that is

16 certainly a logical and pertinent question if you want the

17 committee to look at it.

18 DR. HOLLINGER: Well, I would just like to ask the

19 committee. I mean, I would think that the first question

20 should be should plasma pool screening be performed by

21 nucleic acid tests for hepatitis A virus, or should we not

22 deal with that? I would like to hear what the committee

23 would like to do about this. Yes, Dr. Simon?

24 DR. SIMON: Well, just from the industry point of

25 view, I am sure industry would prefer to be able to deal


131 1 with this on a voluntary basis. My take on the

2 presentations we have heard is that there is not an

3 overwhelming or highly compelling case in terms of recipient

4 safety for the FDA to mandate this, but one or more

5 companies may wish to do this as a further enhancement of

6 safety. So, my preference would be that we not extend the

7 discussion and that we stick to the questions FDA has given

8 us, which is how should they handle the situation when a

9 company wishes to introduce hepatitis A virus nucleic acid

10 testing.

11 DR. HOLLINGER: Col. Fitzpatrick?

12 COL. FITZPATRICK: Based on what we heard from the

13 Paul Ehrlich Institute and the comments after, I question

14 the utility of saying you have a safe process when the odds

15 are you are doing a test that is going to detect nothing.

16 So, I think we should address that question.

17 DR. HOLLINGER: Which question?

18 COL. FITZPATRICK: Whether or not testing for HAV

19 by NAT should be done.

20 DR. HOLLINGER: I think John's comments were that

21 with pools of 3200 L and even a concentration of virus that

22 is 105 -- most are 104 or less, you know, you would have to

23 have something that is going to detect 10 genomic

24 equivalents/ml at best to even pick up one, and that would

25 be without looking at the Poisson distribution. I mean,


132 1 unless you do it multiple times that would be very

2 difficult. I think it is a good comment. Yes, Dr. Schmidt?

3 DR. SCHMIDT: I don't think the FDA can stop the

4 companies from doing it if they want to do it. It just

5 brings up the question and becomes part of their SOP and how

6 you handle it from there. Right?

7 DR. HOLLINGER: Yes. Dr. Mitchell?

8 DR. MITCHELL: I think it is a valid question

9 because I think it needs to be clear that presumably we are

10 not recommending that this be done, and that there is sort

11 of a discussion about the usefulness of HAV testing.

12 DR. HOLLINGER: Yes, Dr. Ohene-Frempong?

13 DR. OHENE-FREMPONG: If the recommendation is made

14 that those who receive plasma products that are likely to

15 transmit HAV, they must be vaccinated against something that

16 we presume exists. If we are vaccinating or recommending

17 vaccination but we will not survey the products that they

18 receive, it would seem to me that we are trying not to find

19 out whether the problem exists at all. Maybe at some point

20 vaccination will no longer necessary.

21 DR. MACIK: I think part of the answer to that

22 though is that the vaccination is for HAV that they might

23 contact in the community, not necessarily what they are

24 getting from their concentrate. So, if they already have

25 hepatitis C from their blood product and you want to protect


133 1 them with the hepatitis A vaccine so if they get hepatitis A

2 from a restaurant they are okay, and I don't know if the

3 idea to vaccinate them wasn't totally driven on the fact

4 that we are trying to protect them from their concentrates

5 on that one.

6 DR. HOLLINGER: Yes, Dr. Boyle?

7 DR. BOYLE: I don't think we have heard enough

8 about what people are doing. It sounds like there is a

9 variety of things out there. Some are not doing

10 minipooling; some may be proposing minipooling; and I don't

11 think we really have enough information to speak to the

12 broader issue of whether or not people should be doing the
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