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18 Finally, there was a commitment made that the

19 Public Health Service would monitor the effects of this

20 revised broad policy on the blood supply, and as part of

21 that commitment the TSE Advisory Committee meeting was held

22 on June 1 and 2.

23 [Slide]

24 There is reason to think that exposures to the BSE

25 agent in the United Kingdom have been markedly reduced after


40 1 1996 and, in general, recent news from the United Kingdom is

2 guardedly good. Perhaps it is fair to say that at least it

3 is not bad news in that cases of BSE, after peaking at the

4 end of 1992, have continued to decline although there were

5 over 2200 cases diagnosed in cattle last year, and this year

6 in the first third of the year there have been more than 300

7 cases of BSE recognized, but the various precautionary

8 measures to reduce exposure are well in place and the rate

9 of recognition in cattle continues to drop markedly. Cases

10 of new variant CJD continue to increase but not at an

11 accelerating rate and interim results of a survey of

12 lymphoid tissue from normal, healthy, younger patients, 3000

13 of them, have not revealed any protease-resistant prion

14 protein.

15 [Slide]

16 But concerns about BSE in some other European

17 countries are increasing, and I just want to remind you that

18 since January of 1998 the United States Department of

19 Agriculture has considered all European countries to be

20 suspect as BSE countries.

21 [Slide]

22 During the past year diagnosed BSE cases have

23 increased in several European countries and a new country,

24 Denmark, has been recognized as having the disease in its

25 native-born cattle. It has also been recognized that


41 1 substantial exports of U.K. cattle beef and beef products

2 continued from the U.K. to several European countries during

3 the high BSE years. France may have imported at least 5

4 percent of its meat and meat products from the U.K. during

5 that period. The Netherlands also imported a significant

6 amount of beef, and other countries did as well. Finally,

7 cases of new variant CJD have increased. There are now

8 three cases confirmed and others are under suspicion.

9 [Slide]

10 So, on June 1, the TSE Advisory Committee was

11 asked to evaluate new information concerning new variant CJD

12 and BSE in the United Kingdom, France, as well as BSE in

13 other European countries besides France and the U.K.

14 [Slide]

15 And, to look at any effects that recent changes in

16 blood deferral policy might have had on the blood supply and

17 blood products in the United States, as well as effects to

18 be anticipated if additional deferral of donors was to be

19 recommended. Dr. McCurdy presented earlier information from

20 the same survey that you heard this morning.

21 [Slide]

22 The committee reviewed recent events concerning

23 new variant CJD and BSE in the United Kingdom. They looked

24 at projections of potential exposures to BSE and cases of

25 new variant CJD recognized and expected to occur in France


42 1 and the Republic of Ireland, and CJD and BSE surveillance in

2 Switzerland where there have been no cases of new variant

3 CJD recognized. They also heard USDA estimates of BSE

4 occurrence in various European countries.

5 [Slide]

6 They looked at estimates of possible human

7 exposure to the agent elsewhere in the European Union and

8 heard results of a very interesting assessment by Canadian

9 authorities of the risk of new variant CJD in Canadians who

10 had traveled to the United Kingdom and to France, and

11 finally reviewed the effects of recent policies on the

12 supply of blood and blood products in the United States.

13 [Slide]

14 When asked if the committee thought that the

15 available scientific data on the risk of transmitting CJD

16 and new variant CJD warranted a change in the current FDA

17 policy regarding deferrals of blood and plasma donors and

18 product retrievals based on their travel or residence in the

19 United Kingdom, the committee members voted three in favor

20 and 15 opposed. The members felt that insufficient time had

21 passed since the implementation of the new policy to assess

22 its effects on supply and they were, therefore, reluctant to

23 advise any further changes at the moment. There were a

24 couple of contingent questions concerning it. They felt

25 comfortable staying with the current policy concerning


43 1 deferral of donors resident in the U.K.

2 [Slide]

3 When asked if FDA should recommend deferral from

4 blood or plasma donations for persons with a history of

5 travel or residence in France, the vote was 17 against such

6 deferral and only one in favor. The committee seemed

7 impressed that both the assessments of exposure to U.K. beef

8 and beef products in France and the rates of new variant CJD

9 both suggested that the risk to residents of France was only

10 about 5 percent of that in the U.K. The apparently

11 concluded that such a risk was not sufficiently significant

12 to recommend any deferral even for much longer periods of

13 residence in France.

14 [Slide]

15 Essentially the same advice was offered for donors

16 resident in other BSE countries, although there was concern

17 about the lack of information concerning potential exposures

18 to BSE in some of those countries.

19 [Slide]

20 The secondary issue of possible effects of

21 leukoreduction on CJD risk was addressed. Since a large

22 part of the infectivity in blood of rodents experimentally

23 infected with TSE's is in the buffy coat, it has been

24 proposed that leukofiltration might reduce the risk of

25 blood-borne transmission of CJD, and several European


44 1 countries have decided to do that as a precautionary measure

2 to reduce the risk of transmitting CJD. So, the committee

3 was asked to consider evidence that leukoreduction might be

4 expected to reduce the theoretical risk of transmitting CJD

5 and new variant CJD by human blood, blood components and

6 plasma derivatives and whether the reduction in risk is

7 likely to be substantial enough to have practical value and,

8 consequently, whether universal leukoreduction of blood and

9 blood components should be recommended by the FDA for that

10 purpose.

11 [Slide]

12 The committee reviewed information on the work of

13 this committee, that is, recent recommendations and

14 prospects for the implementation of universal leukoreduction

15 techniques and theoretical applications of leukoreduction to

16 remove TSE agents from blood, and the possible role of

17 leukocytes in experimental pathogenesis of TSEs in rodents

18 and the implications for human blood, the main one being

19 that since circulating cells of lymphoid origin seemed to be

20 obligatory for pathogenesis of TSEs in rodents, it was to be

21 expected that there would be infected cells in the blood of

22 humans as well, although that has never been convincingly

23 demonstrated. They also looked at TSE infectivity in the

24 blood of experimentally infected rodents and that

25 implementation for human disease as a model. The available


45 1 information was very limited and one small but troubling

2 study even suggested that animals infected by the

3 intravenous route cleared infected cells better than they

4 did the same amount of infectivity presented in a cell free

5 form.

6 [Slide]

7 So, when asked if leukoreduction can be expected

8 to reduce significantly the infectivity theoretically

9 present in blood of persons during the course of CJD and new

10 variant CJD, the committee concluded that available data

11 were simply insufficient to decide and, with two dissenting

12 votes, they advised that leukoreduction not be recommended

13 as a precaution to reduce the risk of transmitting CJD until

14 its potential effects are better understood. Thank you very

15 much.

16 DR. HOLLINGER: Thank you, Dr. Asher. Any

17 questions for Dr. Asher on the issues raised on TSE? If

18 not, thank you. Are there any general comments from the

19 committee before we move into the next major portion of our

20 meeting today? If not, we are going to move into the next

21 portion of our meeting. This is going to be a discussion on

22 plasma pool screening by nucleic acid tests for HAV. Robin

23 Biswas will give us an introduction and background to this

24 issue. Robin?

25 Plasma Pool Screening by Nucleic Acid Tests


46 1 for Hepatitis A Virus

2 Introduction and Background

3 DR. BISWAS: Good morning. This will be music to

4 your ears --

5 [Laughter]

6 [Slide]

7 The FDA has received a submission from a

8 manufacturer for plasma derivatives for the plasma screening

9 of minipools by using nucleic acid tests for hepatitis A

10 virus and human parvovirus B19. Currently, the agency has

11 articulated policies for NAT plasma pool testing for

12 parvovirus B19, human immunodeficiency virus, hepatitis B

13 virus and hepatitis C virus, but has not yet developed a

14 policy in regard to HAV plasma pool testing, and that is

15 what we will be discussing for the rest of this morning,

16 namely, plasma pool screening by nucleic acid tests (NAT)

17 for hepatitis A virus (HAV).

18 [Slide]

19 The issues that will be discussed here stem from a

20 manufacturer's intention to perform testing of minipools of

21 samples from donated plasma units by HAV NAT and then

22 discarding the HAV positive units, thereby withholding them

23 from the manufacturing pool from which plasma derivatives

24 are made. The intention is to lower the viral load in the

25 manufacturing pool from which the plasma derivatives are


47 1 made. This should enhance the margin of safety for these

2 plasma derivatives.

3 [Slide]

4 While transmission of HAV by plasma derivatives is

5 not a major clinical problem, plasma derived volume

6 expanders and immunoglobulins have been historically safe,

7 rare transmissions by coagulation Factors VIII and IX have

8 been reported, and Dr. Farshid will go into this in a little

9 more detail later on.

10 I should say at this point that there is a

11 recommendation for persons receiving coagulation factors to

12 receive vaccine hepatitis A. Stephen Feinstone will go into

13 this in a little bit more detail later.

14 [Slide]

15 Solvent/detergents are widely used in the

16 manufacture of coagulation factors, and immune globulins to

17 inactivate lipid-enveloped HIV, HBV and HCV, and are very

18 effective in doing this, but HAV is a non-lipid-enveloped

19 virus and is not inactivated by these solvent/detergents.

20 [Slide]

21 There is an underlying general plasma pool NAT

22 testing assumption here: If a certain pool of samples from

23 donated units is NAT positive, then a particular positive

24 unit and donor can be identified.

25 [Slide]


48 1 In the past, FDA has viewed plasma NAT pool

2 testing of samples of units as either in-process control in

3 which the donor is not identified or as donor screening

4 where the donor is identified.

5 [Slide]

6 In 1997 when NAT pool testing was under

7 development for HIV, HBV and HCV, the Blood Products

8 Advisory Committee endorsed FDA's position that NAT pool

9 testing for these three viruses should be considered donor

10 screening and that the donor should be identified. Clinical

11 studies to validated the clinical efficacy of NAT for these

12 viruses under IND is required.

13 In the case of parvovirus B19 NAT pool testing, in

14 September last year the committee agreed with FDA that

15 studies to validate clinical efficacy of B19 NAT under IND

16 for plasma for further manufacture need not be required.

17 This was considered then to be in-process control testing

18 and the donor need not be identified. In this case, the NAT

19 test requires validation as an analytical test only in

20 regard to sensitivity, specificity and reproducibility, and

21 Sheryl Kochman will be going into this a bit later. In

22 regard to parvo B19 NAT testing, no clinical correlates need

23 be established if no decisions regarding donor or recipient

24 management are taken.

25 [Slide]


49 1 I would now like to describe briefly, in a bit

2 more detail, some of the decisions that need to be made when

3 NAT pool testing of samples of donated units for a

4 particular virus are introduced, and also the types of data

5 and information that need to be considered to make those

6 decisions.

7 [Slide]

8 The first decision -- do you go ahead an identify

9 the individual donor?

10 [Slide]

11 Are you going to retrieve products from that
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