P R O C E E D I N G S (8:05 am)

Agenda Item: Welcome, Statement of Conflict of Interest, Acknowledge of New Members, Announcements

DR. FREAS: Members of the committee, invited guests, and public participants I would like to welcome you to this, our 82nd Blood Products Advisory Committee meeting. I am Bill Freas. I will be the acting Executive Secretary for today.

This meeting will be open to the public all today and half a day tomorrow. The meeting tomorrow, according to The Federal Register notice will go into closed session for discussion of personnel issues.

Before I go around and introduce the members seated at the head table, I would like to announce that we have five new members on the committee. They are: Dr. Matthew Kuehnert; Dr. George Schreiber; Dr. Keith Quirolo; Dr. Donna Whittaker; and Dr. Catherine Manno.

Now, I will go around the table, starting on the right-hand side of the table, and introduce all the members currently seated at the table. In the first chair we have Dr. Matthew Kuehnert, Assistant Director for Blood Safety, Division of Viral and Rickettsial Diseases, Centers for Disease Control and Prevention.

In the next chair we have Dr. Liana Harvath, Deputy Director, Division of Blood Diseases and Resources, NIH.

Next, we have Dr. Harvey Klein, Chief, Department of Transfusion Medicine, NIH.

In the next chair we have Dr. George Schreiber, Associate Director for Health Studies, Westat, Rockville, Maryland.

Next, we have Dr. Judy Lew, Assistant Professor of Pediatrics, University of Florida.

Next, we have Dr. Keith Quirolo, pediatrician, Department of Hematology, Children's Hospital and Research Center, Oakland, California.

Next is our chairman of this advisory committee, Dr. James Allen, President and CEO, American Social Health Association, Research Triangle Park, North Carolina.

Next we have Ms. Judith Baker. Ms. Baker is acting as our consumer representative for today. She is Regional Coordinator, Federal Hemophilia Treatment Centers, Region IX, Los Angeles, California.

Around the corner of the table we have Dr. Leonard Hudson, Professor of Medicine, University of Washington, Harborview Medical Center, Seattle, Washington.

Next we have Dr. Catherine Manno, Professor of Pediatrics, The Children's Hospital of Philadelphia, University of Pennsylvania, School of Medicine.

Next, we have Dr. Donna Whittaker, Director, Robertson Blood Center, Ft. Hood, Texas.

Next, we have Dr. Susan Leitman. Dr. Leitman is joining us today as a non-voting consultant. She is Chief, Blood Services Section, Department of Transfusion Medicine, NIH.

At the end of table we have our acting non-voting industry representative, Dr. Louis Katz. He is Executive Vice President of Medical Affairs, Mississippi Valley Regional Blood Center, Davenport, Iowa.

There are two committee members that could not be with us today. They are Dr. Kenneth Davis and Dr. Suman Laal. The others will be joining us shortly.

I would now like to read into the public record the conflict of interest statement for this meeting. The following announcement addresses conflict of interest issues associated with this meeting for the Blood Products Advisory Committee on March 17-18, 2005.

Pursuant to the authority granted under the committee charter, the director of FDA's Center for Biologics Evaluation and Research has appointed the following individuals as temporary voting members for the committee discussions: Ms. Judith Baker, and Dr. Liana Harvath. In addition, the Association Commissioner for External Relations, Food and Drug Administration has appointed Dr. Leonard Hudson as a temporary voting member.

Based on the agenda, FDA has determined there are no specific products being considered for approval at this meeting. Committee participants were screened for their financial interests to determine if any financial interests of conflict existed. The agency reviewed the agenda and all relative financial interests reported by the meeting participants. The Food and Drug Administration prepared general matters waivers for participants who required a waive under 18 US Code 208. Waivers were granted to: Dr. James Allen; Dr. Donna DiMichele; Dr. Catherine Manno.

Because of the general topics impact so many entities, it is not prudent to recite all potential conflicts of interest as they apply to each member. FDA acknowledges that there may be potential conflicts of interest, but because of the general nature of the discussion before the committee, these potential conflicts are mitigated.

Dr. Louis Katz will be participating as a non-voting industry representative on behalf of regulated industry for this meeting. Dr. Katz' appoint is not subject to 18 US Code 208. He is employed by the Mississippi Valley Blood Center, and thus has a financial interest in his employer. Dr. Katz reported that he is an associate investigator on the abbreviated donor study questionnaire. He also received speaker fees, and was a scientific advisor for firms that could be affected by today's committee discussions.

With regards to FDA's invited guest speakers, the agency has determined that these services are essential. For discussion of Topic 1 related to the safety of albumin, the following disclosures will assist the public to objectively evaluate presentations and/or comments made by the participants.

Dr. Paul Hebert is Chair, Transfusion and Critical Care Research, Ottowa Health Research Institute, University of Ottawa. Dr. Simon Finfer is Senior Staff Specialist in Intensive Care, Royal North Shore Hospital, Sydney; Clinical Associate Professor, Northern Clinical School, University of Sydney, and ANZICS Clinical Trials Group Executive.

For the discussions on Topic 2 related to the review of standards for plasma products for transfusion, Dr. Irma Szymanski is Professor of Pathology Emerita, University of Massachusetts Medical School, Worcester, Massachusetts.

FDA participants are aware of the need to exclude themselves from discussions involving specific products or firms for which they have not been screened for conflicts of interest. Their exclusion will be noted for the record.

With respect to all other meeting participants we ask in the interest of fairness that you state your name, affiliation, and the address any current or previous financial involvement with any firm whose products you wish to comment upon. Waivers are available under request through the Freedom of Information Act.

That ends the reading of the conflict of interest statement.

Before I turn the meeting over to the chair, I would like to ask if you have a cell phone or a pager or something, if you would put it in the silent mode. We would really appreciate it.

Dr. Allen, I turn the meeting over to you.

DR. ALLEN: Thank you, Dr. Freas.

And thank you for your very clear English statement on turning cell phones off or putting them silent. I get very annoyed with the airlines that tell you put it in the off position. I don't know exactly what that is.

Perhaps some of you attended congressional hearings yesterday, or listened to the news summary of Dr. Lester Crawford's interviews as the Commissioner for Food and Drug. I think that discussion certainly highlights the interaction between FDA as a regulatory body, the regulated community, manufacturers, blood collectors and others, the scientific community of practicing physicians and other who use products, and certainly the interests of the patients. This committee is charged to assist the FDA in its deliberations. And certainly listening to the discussion, I got a renewed sense of awe for the commitment that we have.

I do want to remind all of the speakers, including those who will be speaking during the open session, that we have a lot of requests. A very important part of the deliberations of the committee is an opportunity for discussion among ourselves, and consideration in full of the questions that are being raised before us. So, I would please remind everyone to keep within posted time limits. Make your points briefly, succinctly, and allow the committee then to discuss things.

I would also like to acknowledge the work of Dr. Bill Freas, Dr. Martin Riva, and others on the FDA staff who have picked up from Dr. Linda Smallwood after her retirement. I know she is significantly missed by the committee, and I greatly appreciate the work of everyone who has helped pick up after her retirement.

At this point I would like to turn the microphone over to Dr. Jay Epstein to make an announcement.

DR. EPSTEIN: Thank you very much, Jim.

Well, I have just one announcement, and it's a bit of a bittersweet task. That's to make know that Dr. Linda Smallwood retired from the federal service at the end of December, and in the same stroke concluded 17 years of service as the executive secretary of the Blood Products Advisory Committee.

In recognition of that singular contribution to the public health, it is my pleasure to award her a plaque from the Center for Biologics Evaluation and Research, which is an award of appreciation to Dr. Smallwood for exemplary service as the Executive Secretary to the Blood Products Advisory Committee from 1987 to 2004.

So, Linda, if you would like to come up, I would be pleased to present this.

[Applause.]

DR. FREAS: While they are taking that picture, I would just like to say for the new committee members who do not know Linda Smallwood, she really is to BPAC what Cal Ripken is to the Baltimore Orioles.

DR. EPSTEIN: And I just want to add my thanks to the new people who are joining the committee, as well as to those who are seated as temporary voting members. We know that it requires a special effort on your part to come and to participate, and to read through the voluminous materials that we provide to you. And just to say on behalf of the Center for Biologics Evaluation and Research how much we appreciate that effort, and how valuable the contribution is to our work in maintaining the safety, purity, and potency of blood and blood products.

Thank you.

DR. ALLEN: Thank you, Jay.

Dr. Smallwood, thank you for coming back. We miss you, and congratulations, and good luck in your retirement.

We'll move into the committee update session. First, will be Dr. Jerry Holmberg, Executive Secretary of the Advisory Committee on Blood Safety and Availability, providing meeting summary updates.

Dr. Holmberg.

Agenda Item: Committee Updates - Meeting Summary of DHHS Advisory Committee on Blood Safety and Availability - Jerry Holmberg, PhD, Executive Secretary

DR. HOLMBERG: Thank you.

First of all, I want to say thank you to Linda Smallwood for the years of service too. That's quite an accomplishment. I don't know if I will be able to do 17 years as an executive secretary for the Advisory Committee on Blood Safety and Availability, but in my previous life I was on the BPAC and Linda was the executive secretary during that period of time. So, I appreciate all the hard work there, and enjoy the retirement. She looks so relaxed, and in good health and good spirits.

Also, I'm not Irish, but would like to wish everyone that is Irish or has some Irish heritage in their bloodline, happy St. Patrick's Day. And my mentor -- I saw his wife just earlier today, so I'll to make sure I send an e-mail to him and wish him a happy St. Patrick's Day.

In the next few minutes I would like to update the committee on the activities of the Secretary's Advisory Committee on Blood Safety and Availability. Since I have not been here since last summer to highlight our activities, I thought that this would be a good time to bring you up-to-date with the recommendations that were made from the advisory committee to the secretary, and the action that the department and the agencies have taken.

I think that this will be very beneficial to you as members of the BPAC to hear some of the issues that have been presented to the advisory committee, because many of these issues you have also addressed.

If you have not been to our Web site, I would encourage you to do so. The Web site is posted there.

In August 2004, we took the opportunity to go through various issues that have been previously presented to the advisory committee, and to do an update on progress that has been made. The recommendation that came out of the August meeting was in regards to TRALI. That the committee review the Transfusion Related Acute Lung Injury data, and did not find scientific evidence to recommend an intervention at that this.

But the committee went on to recommend to the secretary to support the expeditious development of standardized definitions of the disease entity, and also the implementation of clinical education and effective surveillance. And also, the modeling the impact of deferral or screening interventions, and also to support to research into the etiology, diagnostic testing, epidemiology, treatment, and prevention.

The secretary's response to that is to continue to monitor the progress of the scientific community. And also, I'm pleased to say that NHLBI has taken on TRALI as a top priority of all non-infectious transfusion complications, and that two institutions are currently supporting investigation.

The next issue was the access to treatment for individuals with rare blood disorders. And the committee noted the importance of this, and encouraged the secretary to facilitate obtaining additional licensed indications for already licensed products, which is a real issue as far as the reimbursement; the approval of products and their indications in the United States for European-licensed products; and also to facilitate developing new products. Also, recommended to the secretary to support research, and also the reimbursement of the use of these plasma products.

The response from the secretary is that the recommendations are being considered. One of the most monumental initiatives that has come out in quite a while is the medical innovation document. This can be located on the Web site that I have given you there. And this is an initiative by the Department of Health and Human Services with all the agencies to try to forward and to move medical innovations ahead.

The FDA has their critical pathways, and also am pleased to say that we are working on various workshops to be able to bring these innovative or new treatments to light, and take action on what needs to be done, next steps that need to be done.

Of course, the bacterial contamination or detection in platelet concentrates and seven day platelets was another issue that the committee has reviewed in the past. The recommendations basically were that the department support through funding, development of bacterial screening suitable for release testing.

And then also that the department consider alternate strategies that could expedite licensure of seven day platelets in less than two years. And also that the department develop strategies to expedite licensure of pre-storage pool whole blood derived platelet components.

The response from the secretary is that these recommendations are being carefully considered, and that FDA innovative regulatory pathway allowing collection of post-approval information on QC data, and also their modified field study has moved the progress ahead very rapidly.

Also, the various agencies within the Department of Health and Human Services have worked very closely with the AABB Task Force, and providing guidance and information to try to move ahead in this area. Several things that the AABB Task Force has done is that over the last couple of months they produced two guidance documents to the blood community, and also conducted a secondary survey of the current status of platelet use in the United States.

And I'm pleased to say too that I hear of a lot of activity with manufacturers, and that I think that the recommendation of trying to move forward in the two year timeframe, we're well on our way, so I think we are making some great progress. And again, I think this is a good example of government working with the blood community to take care of a problem and to move forward with some solutions.

In August we were also asked to look at the hepatitis-B virus minipool nucleic acid test for blood donor testing, and to look at the public health impact of implementing that. The recommendation from the advisory committee was that the committee believes that the comparative expenditure of health care dollars to the general public health would be better served by expanding the HBV immunization program, and encourage the development of a multiplex direct pathogen testing on individual donors.

The response, the secretary felt that the discussion was extremely helpful, and that a status report would be forthcoming. The recommendations from the BPAC, from this committee, and also from the Advisory Committee on Blood Safety and Availability were presented to the internal committee of HHS, the Blood Safety Committee. And when the Blood Safety Committee was presented with the recommendations both advisory committees, they concurred with the FDA policy on hepatitis-B virus minipool NAT test.

The concurrence from the Blood Safety Committee's review of the previous discussion was that the Blood Safety Committee concurred with the FDA policy that: "Current data do not support a recommendation for routine use of the Roche Molecular System HBV minipool nucleic acid test to screen blood and plasma donors. Existing donor screening tests still appear to be adequate, and the new test appears to provide very limited public health benefits at this time. However, public health officials will reconsider possible recommendations for routine donor screening for HBV by nucleic acid tests based on experience with voluntary use of the test, further technology developments, and any other factors that might affect the public health benefit expected from such testing."

In our January meeting we reviewed three different topics. The first topic was the current status of bacterial detection of platelet concentrates, availability and progress towards seven day platelets. Identification of reimbursement issues associated with plasma, and recombinant analog therapy. And the third topic, which was the second day of our meeting was current and emergent infectious pathogens; sharpening our approach for the 21st century to reduce the risk of transfusion transmitted diseases.

Regarding the bacterial blood safety initiative, the recommendation was that the secretary request cooperation of appropriate agencies with blood organizations and transfusion facilities to establish an ongoing program to monitor residual bacterial contamination risk, to provide resources for surveillance of transfusion-associated sepsis, and make additional recommendations as needed to maintain recipient safety.

We, within the department, are still reviewing these recommendations, and I cannot give you at this time, the response from the secretary.

The second topic that we talked about was the reimbursement of plasma derived products and their recombinant analogues. The committee endorsed several principles for the department. And these principles were: plasma derived products and their recombinant analogues should be reimbursed at rates consistent with the true cost, including costs of distribution and administration.

Reimbursement should be sufficient to insure an adequate supply of these therapies; and individual products within product classes should be recognized as therapeutically unique; reimbursement should be provided in different care settings; and lifelong cost of treatment to the individual patient should be addressed in an any pricing structure, including the extraordinary impact of co-payment.

And then committee urged the secretary to support and propose policies or legislation to address the extraordinary financial burden for these patients.

Once again, comments that I made previously about the plasma issues from the August meeting we're continuing to work on, and again, the secretary has not responded to these recommendations at this time.

I also have to point out that we did have a change in secretaries. Sec. Thompson left the department at the beginning of February, and Sec. Levitt was at the beginning of February -- the nomination was approved by Congress.

The next topic that we talked about was on the second day, and this topic was a discussion on emergent infectious pathogens, sharpening our approach for the 21st century to reduce the risk of transfusion transmitted diseases. The overall structure was that we looked first at the IOM report on microbial threats to health. We also looked at an overview of the current blood-borne threats.

We looked at how the system approaches these threats, not only the government system, but also the public sector. And then included in the public sector, we addressed the consumer issues. And then we looked at various case studies. We used West Nile as a model response; Chagas as an unmet challenge; the HIV as evolving challenges, intervention, and donor management; and the HHV-8 as unresolved scientific evidence; and then with the vCJD, how do we handle risk communication.

In the interest of time I don't want to spend too much going through the IOM report, but I would encourage the advisory committee to take a look at the IOM report. It is on the Web site. You can go to the IOM Web page and take a look at that. But there was a very important outcome from that report with all the findings and recommendations there.

Based on our discussion at the Advisory Committee for Blood Safety and Availability, the committee did not make any recommendations to the secretary at that time. The Advisory Committee for Blood Safety and Availability will continue to address the emerging infectious pathogen issue, and we will be discussing this at the next meeting.

Some of the areas that have surfaced that need additional discussion are: surveillance, both known and unknown surveillance; appropriate research; product development; global information sharing; transparency in policy process; and also risk communication.

Thank you.

DR. ALLEN: Any questions? Thank you very much, Dr. Holmberg. Questions from the committee?

Thank you. We look forward to further updates in the future.

The next of our committee updates is by Dr. David Asher, a summary of the Transmissible Spongiform Encephalopathies Advisory Committee meeting.

Agenda Item: Committee Updates - Summary of the TSEAC Meeting - David Asher, MD, OBRR, FDA

DR. ASHER: Thank you. Good morning.

The 17th meeting of the FDA TSE Advisory Committee took place on February 8. Three informational issues and three decisional issues -- the bullets for those are bolded here -- were reviewed, two of those for discussion, and the last one for vote.

First, Lisa Ferguson of USDA reviewed the worldwide BSE situation.

Kate Soldan and Anna Molesworth of the UK Health Protection Agency, CJD Incidents Panel reviewed the UK September 2004 notification of certain recipients of plasma that they might be at increased risk for exposure to the variant CJD agent, and that they should not donate blood or tissues, and should tell their families, dentists, and surgeons to take special precautions to avoid secondary transmissions from their tissues.

Lynn Sehulster of the CDC reviewed what such precautions might be, although CDC currently recommends such precautions only for known CJD patients, and not for instruments exposed to tissues of persons at increased risk.

You may recall from a statement that I read at the last BPAC meeting that factor XI from the United Kingdom was used for a limited time in the US under IND. And that situation was reviewed by FDA's Mark Weinstein, Dorothy Scott.

The promised risk assessment model, which I will summarize briefly in a minute was presented by Steve Anderson, who also reviewed as a separate topic, a draft risk assessment model that we hope will be suitable for addressing the risk from US factors VIII, IX, and other plasma derivatives.

FDA's Pedro Piccardo and Steve Anderson then presented information on variant CJD in France from Jean-Philippe Brandel, who could not attend the meeting.

And finally, Alan Williams reviewed the issue of possible additional deferrals of blood and plasma donors for history of transfusion in Europe outside the United Kingdom on which the committee then voted.

The news on bovine spongiform encephalopathy is guardedly good. The diagnosis of the disease peaked in the United Kingdom at the end of 1992, beginning of 1993. Cases in the United Kingdom continued to drop. They diagnosed 612 cases there in 2002, and only 338 last year, although that number still exceeded the number reported for any other single country.

The 22 other countries' diagnosed cases in the European Union dropped about 40 percent, although 6 countries, which I show here in red, recognized increases in 2004 relative to 2003. It's not clear, at least to me, whether those increases represent better ascertainment or a trend in disease, but they certainly bear watching. We are all aware of the Canadian BSE cases. They were not discussed.

USDA has now completed more than 270,000 tests of brain from US cattle identified as being at increased risk for BSE. They have had 3 inconclusive tests by ELISA. None was confirmed by immunohistochemistry.

There is continued concern about countries of unknown BSE status. The UK customs and excise information showed that meat and bone meal was exported during high BSE years to a number of countries, several of which, like the US, have I understand no record of receiving the material, but it was exported with those countries designated as the country that was going to receive it.

A number of countries in Southeast Asia, not just Japan, and the former Soviet Union are on record as having imported substantial amounts, although that can't be independently confirmed. That also bears watching.

Now, let me turn to variant CJD, which has been, as you know, a major concern of the Food and Drug Administration for several years, because of the potential for regulated products of human origin to transmit the disease. The disease, as we discussed previously, differs significantly in its clinical presentation, histopathology, and epidemiology from other forms of Creutzfeldt-Jakob disease. And our concern of course was heightened by two credible reports of blood-borne variant CJD in December 2003 and December of last year from the United Kingdom. We have discussed those here before.

Concern about the risk of transfusion transmitted variant Creutzfeldt-Jakob disease, even before those two cases prompted FDA to issue revised guidance in 1999 and 2002 to reduce the geographic risk of exposure of donors to the BSE agent. I included in the set a slide summarizing the latest revised guidance 2002. Most of you are familiar with that. I won't discuss it today. Dorothy Scott, who is the keeper of the guidance, is here and any specific questions I suppose we could answer.

Worldwide cases of variant CJD continue to increase slowly to a current of 170, of which all but 16 are or were in UK residents, and only 8 of them had never been in the United Kingdom. Of special interest is a recent report from Japan of variant CJD in a man who had visited the United Kingdom for only 24 days in 1989, which is probably as close to a point exposure as we can expect to see, and implies an incubation period by the oral route of about 12 years.

New cases in the United Kingdom peaked in recognition of new cases in 1999, and deaths in 2000. Those were all in persons homozygous for the gene encoding methionine at codon 129 of prion protein encoding gene, which is a genotype known to increase susceptibility to other forms of sporadic CJD and iatrogenic CJD.

However, troubling new information suggests that as for the other forms of CJD, persons with the methionine valine heterozygous genotype are probably not absolutely resistant to the infection. They may have a lower -- we hope they have a lower attack rate, and they may have longer silent incubation periods.

Nine cases from France -- I think it's really too early to discern any trend in those cases. One of them is still living, two of them were active blood donors.

In case there are any specific questions, we have been over these before, I included in this set a summary slide describing the two cases presumptive transfusion transmitted variant Creutzfeldt-Jakob disease. Both recipients received non-leuko reduced red blood cell concentrates.

The second case was of special interest, because that person who died of unrelated causes during what is probably the asymptomatic incubation period of variant CJD died without CNS pathology, but had accumulation of disease-related prion proteins in spleen and a cervical lymph node, and it's that individual who is heterozygous for methionine valine at codon 129 of the prion protein encoding gene.

Now, let's turn to the Factor XI issue. A total of about 50 individuals in the US were treated with Factor XI concentrate under IND from 1989 through 1997. None of the Factor XI used here was from a so-called implicated lot. That is, no donor actually diagnosed with variant CJD contributed to the source material from which the Factor XI was prepared.

However, because variant CJD has at least a possible prevalence in the UK sufficiently high, it seems very likely that some asymptomatic infected donors may well have contributed. Steven Anderson, with Huong Yang(?) and others in the FDA developed a risk model and preliminary exposure estimates for recipients of the Factor VIII in those studies.

As promised in the last BPAC, Steve presented the model formally at the TSE Advisory Committee, and also as promised, FDA has engaged in discussions with the CDC about approaches to notification and the strategies and the messages that might be offered.

The risks for transmission of infectious agents by regulated products are often estimated and later managed by looking at the risk inherent in the source of the raw materials, the ability of the manufacturing processes to inactivate or remove contaminating agent, and the amount of agent to which the recipient of the product is likely to be exposed per dose per course of therapy per year per lifetime.

And Steve used that traditional model to develop a quantitative or so-called probabilistic risk model, looking at the source of the material, which was recovered plasma, the probability that a given donor to the pool was incubating variant CJD, the number of donations in the pool, and the possible infectivity levels in the plasma. Then he estimated the potential reductions in infectivity that might be assumed for the manufacturing process.

And then finally, at the total amounts of infectivity to which recipients of the product in three typical scenarios, because we didn't have the actual records of what -- we had reason to think that the recommended doses might not have been those doses that were actually used in the IND. So, Steve looked at three typical scenarios that seemed to be reasonable to have expected that the recipients might have received.

Modern probabilistic risk assessments account for biological variability, and especially for uncertainty of the assumptions by assigning to most of the assumptions, a distribution or range of values. Steve used so-called triangular distributions of most likely minimum and maximum values.

Of course the actual values assigned are always open to challenge, but the basic model allows for easy recalculations incorporating different values if people object to the magnitudes of the assumptions that are actually used. It's the computer model itself that is the most important thing.

So, for example based on a recent survey of abnormal prion protein detected in appendices, a survey conducted in the United Kingdom -- more about that in a minute -- Steve assigned a most likely value of two for donors incubating variant CJD who might have contributed to a pool of 20,000 donations, with a range anywhere from 0 to an assumed maximum of 14 donors, which was the greatest number that might reasonably have been expected of undiagnosed, unsuspected donors to have contributed.

Based on animal studies, a broad range of 0.1 to 1,000 animal intracerebral 50 percent infectious doses per milliliter of infected blood with 10 most likely was assumed. But point estimates were used for the percentage of infectivity expected to occur in plasma, 58 percent, and 5-10 fold reduction in infectivity was assumed to account for the relative inefficiency of the intravenous route compared to the intracerebral route, since the preponderance of evidence supports those assumptions. So, triangular ranges weren't used there.

For reduction of infectivity by manufacturing process for Factor XI the assumptions were based on published studies for other plasma derivatives. Steve assumed that anywhere from none to 10,000 fold reduction with 100 fold reduction considered the most likely. And from those, the model generated a series of varying each assumption over the range that has been selected, weighting towards the most likely. The computer model generates a number of outcomes, and those outcomes are analyzed.

The uncertainties of the results must not be dismissed. These are the results of Steve's analysis. You have them in your handout. For example, for scenario 3 in which a subject received 15,000 units of Factor XI, there might have been a mean estimated exposure to 0.28, 50 percent infectious doses, which suggests the chance that 14 percent or 50 percent of 0.28 individuals that received the dose, that dose of Factor XI from the United Kingdom might have been exposed, and some of them might have been infected with variant CJD.

However, the animal data may not accurately reflect the potential for variant CJD infection and illness in humans. Even animal vary in their susceptibility from one species, one strain to another. And these uncertainties are no less important than the computer generated most likely risk estimates.

CDC pointed out at the meeting that the BSE outbreak was at first identified in 1986, and peaked early in 1993, about seven years later, which should have been ample time for human plasma derivatives to have been implicated in transmissions of variant CJD. Yet, there has not been a single case in the United Kingdom attributed to exposure to a derivative, which gives some reason to hope that these estimates may be too high.

Quantitative probabilistic risk assessments have several advantages. First is transparency. If you distrust the assumptions, you are free to suggest other assumptions, and those can easily be incorporated. In response to suggestions at the meeting, Steve is now adjusting the prevalence assumptions to allow for differences in subject ages and years studied, and for the years in which the subjected donated.

Data gaps are easily identified, and by holding magnitudes of the assumptions constant, except for one, and then systematically increasing the magnitude of each assumption separately, and examining the estimated risk outcome called sensitive or importance analysis, the critical drivers, the most important elements of risk can be identified.

For data gaps, models of variant CJD in the United Kingdom in the past eight years have predicted a widely different number of cases, anywhere from a minimum of 29 -- there have 154 already, so that can't be right -- to 13.7 million, which also seems improbable, most recently from a few hundred.

But there is now actual empirical survey data available suggesting that somewhat more than 100 person per 1 million, 1 per 4,000 living in the UK may be in the preclinical incubation period of variant CJD, and several people there may eventually get the disease, although several authorities at the meeting suspect that those figures may be too high. It seems at least prudent to include them in any risk model.

Some data gaps are slowly filling. We have mentioned the incubation period 9-12 years seems reasonable for food-borne; 6 years is clearly an incubation period in one of the blood-borne cases, but of course there is more that we don't know. We don't know the infectivity levels in the blood during the incubation period. We know that blood is infectious for at three year before onset of symptoms, but we don't know how long before that. And all that would be important in estimating risk more precisely.

Two major drivers or risk, one the overall prevalence of infection, and second, the reduction by infectivity. I just want to mention briefly in this regard that other forms of CJD appear to be quite different. Many years of experience with sporadic and familial CJD in this country have failed to detect any transfusion transmitted cases. So, convention CJD seems to be quite different in its biology.

As you know, the FDA has recommended safety policies to reduce the risk that a donor might be incubating CJD of any kind, while not deferring so many donors as to compromise the blood supply. And we of course acknowledge that the policies cannot possibly eliminate all conceivable risk.

In October we offered to the TSE advisory committee, a question of considering whether the precautions were adequate to protect against variant CJD, whether they were still justified, and whether enhanced precautions are needed. And I list here the possible approaches to reducing the risk.

One, eliminating donors how had potential dietary or pharmaceutical exposures to BSE agent, and the other deferring donors who had exposure to human blood or blood products from donors who themselves might be incubating CJD. Those are the approaches that can be taken to enhance the risk reduction.

Alan Williams both in October and at the February meeting reviewed the estimated reductions in risk with the loss of donors that might result from three new policies which I summarize here. As usual, reducing the time that a suitable donor spent in the UK would reduce the risk the most, but would cost many, many donors.

I would add if we attempted to defer any donor who spent any time in the UK after 1980-1996 -- and Japan just implemented such a policy, we estimate that we would lose 23 percent of current donors. And if we tried it for the rest of Europe, it would be total loss of 36 percent. So, it's beyond the range of the possible.

Deferring donors transfused in France would reduce the risk slightly at a cost of 1.4 donors; the rest of Europe a cost of 3 donors per every 10,000. There is a problem in that European blood from US licensed establishments in the Netherlands, Germany, and Switzerland through the New York City Euro Blood Program or the major source of exposure to European blood in the US population, those recipients cannot be traced, and they could not be deferred without practically deferring all the other recipient transfused donors in the New York City area, which is a doubtful prospect. Alan Williams discussed it at the meeting. I won't discuss it further today.

So, in October we asked the committee, without offering specific options, to consider whether the deferral policies currently in place are still justified, and whether enhanced policies are indicated. They unanimously endorse the current policy, but did not recommend any enhancements in the October meeting.

However, in associated discussions, members seemed concerned about the growing number of cases of variant CJD in France, and the higher BSE exposure risk there because of major imports of UK beef products. Five to 10 percent of the French beef during the late 1980s to early 1990s, 60 percent of the total UK beef exports went to France. They had a high level of exposure. They have had the most variant CJD cases outside the UK.

So, the committee expressed some concern about the growing number of cases in France, and the higher BSE exposure risks there from the imports. And at the February meeting we offered them specific options to vote on. They voted overwhelmingly to recommend deferral of donors transfused in France, 12 to 3, with 1 abstention.

And they split narrowly on whether to defer plasma donors with that history, 5 to 4 with 7 against it, but with an unusually high number of 4 abstentions. No member felt that the deferral of blood or plasma donors transfused elsewhere in Europe outside the UK and France was currently advisable.

Let me close by saying that we realize that these deferral policies are inherently wasteful. We all look forward to the day when BSE and variant CJD are completely eradicated. Before that happens, it would be very useful to have effective screening tests to identify those donors, and only those donors who are infected, and devices that will remove infectivity from blood components.

Unfortunately, at the moment there is no FDA licensed technology to do either, but we look forward to hearing more about some of the exciting new technologies under study, and we will look forward to receiving applications for licensure of those methods as soon as possible.

I'm sorry that I ran over.

DR. ALLEN: It was indeed a lengthy and very involved discussion. I think the votes that Dr. Asher presented reflect the uncertainty of exactly what direction to go in each instance.

Comments or questions for Dr. Asher on this issue? Okay, thank you very much.

We'll move on to the next presentation, Dr. Alan Williams' update on West Nile virus guidance.

Agenda Item: Committee Updates - Update on West Nile Virus Guidance - Alan Williams, PhD, OBRR, FDA

DR. WILLIAMS: Thank you and good morning.

At this committee's last meeting in October you discussed extensively available data related to West Nile virus natural history and the testing programs, and made recommendations with respect to policy issues. What we wanted to do today was update the committee on FDA's current considerations, which should be interpreted as considerations which are serving to help frame policy development.

The thoughts here should not be really interpreted as FDA recommendations at this point. Those would only come with publication of final guidance. And we anticipate that with West Nile virus, that guidance, when issued, would issue as draft with the opportunity for a formal comment period.

Previous FDA recommendations were published in October 2002, and then revised May 1, 2003. Key recommendations included deferral for West Nile virus infection of 28 days from symptom onset, 14 days post-symptom resolution. And this was based on historic data with respect to the longest known incubation period in immunocompromised individuals.

In addition, with the revised guidance FDA recommended a deferral based on the donor self-report as a result of directed questions for report of a fever with headache in the past week, and this would also constitute a deferral for 28 days. And this was instituted based on limited case control data from some of the earlier known transmissions from donor to recipient of the infection.

Observational data, most of which was presented and reviewed at the last meeting, related to donor screening by West Nile virus NAT testing and follow-up studies conducted under IND. To date, the maximum observed West Nile virus viremic period in blood donors is 49 days. The observed or predicted range based on 1 model is 6.5 to 56.4 days, and this is projected to include 99 percent of the West Nile virus infected donor population.

It is known that low level viremia in the late stages of infection generally is co-existent with IgM antibody to West Nile virus, and the infectivity of this combination is currently not known definitively, although I think an important observation is that no post-transfusion West Nile virus cases observed to date have been from IgM positive donors.

The NAT testing for the major portion of the year is conducted by minipool testing from 6 to I believe 16 samples. But there is the option to conduct individual donation testing. This improves the sensitivity of the NAT donor screening, but currently is not feasible year round. And as discussed again at the last meeting, it is conducted on a targeted basis at the peak epidemic periods for different geographic areas.

Donor screening for West Nile virus-related symptoms introduced prior to widespread West Nile virus NAT screening is of questionable predictive value. The appropriate studies haven't been done to really assess formally the predictive value of the question. But data related to the relationship of the timing in the epidemic, and the deferrals related to this question do not seem to imply a close relationship.

The geographic focus, timing, and extent of what West Nile virus will do in 2005 is not known, but it is anticipated that there will be continued epizootic activity, including in those areas that were previously affected.

At the committee's last meeting, October 22, 2004, there were recommendations made by vote. One was based on the observation of the potential for a longer viremic period, to extend the deferral period from 28 to 56 days. And not a vote, but comment and discussion related to encouraging data collection to determine if 56 days is in fact sufficient to rule out viremia in rare instances.

There was discussion that at the 56 day period it may appropriate to conduct West Nile virus individual donation testing prior to re-entry, but that also a reasonable period of time beyond that, it might be appropriate to consider re-entry without specific testing at the time of re-entry, but simply the normal donor screening test that is done.

The committee also, by an ad hoc vote, recommended discontinuation of the previously recommended question regarding donor reports of fever with headache in the past week, and encouraged that better case control data may determine if there are any symptom clusters in the early prodrome or acute phase that may be more predictive of early West Nile infection. FDA currently considers that this recommendation of the committee is appropriate.

Additional considerations include 90 day deferral. And this is simply looking at it the other way. A 90 day deferral with the potential for re-entry at 56 days. Those donors with diagnosed or suspected acute West Nile virus illness or infection. This is based on 90 days after onset of illness or diagnosis, whichever is the latest date. Also, those donors with suspected post-donation West Nile virus illness, 90 days post-onset of illness. And donors who may have transmitted West Nile virus infection, 90 day deferral from the implicated donation.

And as mentioned, there is consideration that re-entry may be possible after 56 days based on negative individual donation testing NAT on a sample or a sample from a donation at the 56 day period or beyond. And that re-entry would be feasible without additional testing after a 90 day period.

In terms of product management, in cases of diagnosed West Nile infection or illness in a donor, consideration is for retrieval and quarantine of in-date products 14 days prior to onset of illness, reflecting the 2-14 day likely incubation period.

And 90 days after diagnosis or onset of illness, whichever is later, reflecting again the potential viremic period plus an additional margin of safety, with an exception for products collected more than 56 days after diagnosis or onset of illness in the donor, when that donor has been tested and found negative by individual donation testing NAT.

Product management for donors who are potentially associated with transfusion transmitted West Nile infection. This is defined as donors of suspect donations received by recipient up to 56 days prior to recipient West Nile infection. And the consideration is for retrieval and quarantine of other donations by a potentially associated donor 56 days before, and 56 days after the suspect donation, essentially bracketing the viremic period on either side of the potentially suspect donation.

Production management in cases of undiagnosed post-donation illness in individuals who may have been exposed, as in the previous recommendations this would appropriately be based on medical director judgment regarding the product quarantine and retrieval in light of the timing of the illness, its relationship to West Nile epizootic and epidemic activity in the geographic area, which would be typically May 1 to November 30, but could be one month in either direction depending on the status of the epizootic.

When conducted, quarantine and retrieval of in-date products would be 14 days prior to, and 90 days after onset of donor symptoms, with again, an exception for products collected more than 56 days after diagnosis or onset when a donor has been tested and found negative by IDT NAT. Product retrieval and quarantine are not recommended for source plasma, recovered plasma, or source leukocytes that have been pooled for fractionation.

And then finally, with respect to notification of prior transfusion recipients about the possibility of West Nile virus exposure, those units considered relevant are those that are collected 14 days prior, through 56 days after the onset of diagnosed West Nile virus illness in a donor. And this is definitive West Nile virus diagnosis, not non-specific symptoms or history of extensive mosquito bites for instance.

Or another situation, units collected from a donor 56 days prior to 56 days after a donation from that donor is identified uniquely as the likely source of a West Nile virus transfusion transmission. Consideration is that establishments should consider tracing records, and notifying transfusion services of relevant units.

Again, this represents current considerations of the agency, and recommendations that will be issued in draft with a formal comment period.

Thank you.

DR. ALLEN: Thank you, Alan.

DR. KATZ: Three things. First, is current considerations the same as current thinking? A small point, and a little bit facetious.

Alan, as the temporary non-voting and other qualifications that I might not think of industry representative, I have been asked to express a little frustration. And so, since I'm not my own agent at this table, I will do so.

We have no final guidance, no final draft at this point. It's been five months since the discussion at BPAC, almost the same amount of time it took us with the test manufacturers to develop, install, validate, and implement nucleic acid testing. And people are very, very frustrated about that.

We can implement a new nucleic acid assay almost as fast as the agency can provide us what we think should be fairly straightforward guidance. And our problem with that is that it's too late now to apply whatever guidance occurs in the next several weeks, or whatever the interval is for this season under the CGMP processes that we need in order to change the direction of the Titanic, for all intents and purposes.

And also, that we have a continued loss of donors for what we recognized at the time were unvalidated donor history questions, and which we know now from the Red Cross and blood systems data to be ineffective donor screening questions.

So, I think I have made the point that I want to make, and I don't know that I expect a comment. I think we all understand the legal constraints under which FDA operates in terms of talking about the guidance ahead of time. The real issue here is why does it take so long?

DR. ALLEN: That was two points. Was there a third?

DR. KATZ: There was, but I have forgotten what it was.

DR. WILLIAMS: Okay, I'll comment briefly on the first point, maybe very briefly on the second, and Kathleen Swisher from our policy office is here. She may either want to correct me or add something to that. Current thinking is a formal term that is part of GGP. And current thinking, to my understanding, is the thinking that is reflected in a guidance document. Current considerations reflect the considerations that go into policy development before that stage is reached.

In terms of the timeframe, I think the only comment that I can really make is there is a lot of process involved in developing policy, and it competes with many other things that are underway within the office and the center. We are very sensitive to the timing of the upcoming epidemic. The peak period of epidemic still is anticipated to be in the August-September timeframe.

I guess I would be interested to hear why next year would necessary be necessary for a full implementation of policy. But we are sensitive to the concern, and there just is process that needs to be followed.

DR. KLEIN: I would just like to have a follow-up to that. Since we have some relatively new data, at least on the incubation period, and when I say relatively new, as of last October, and on the relevance of some of these questions. Is it not possible for the organizations to put together a policy that the FDA would concur with which would make more sense than some of the current policies that we're using?

DR. EPSTEIN: Well, the agency is always open to suggestion. We call them unsolicited proposals. However, the process for us to establish them as FDA policy is the same under good guidance practice. Namely, we would have to publish it for public comment, simultaneously by all interested parties.

So, it doesn't buy a lot of time at the FDA end. On the other hand, if in this interval the industry went forward with voluntary policies that appear to be in no conflict with what the FDA is considering, probably things will work out fine.

I would also remind you that a year ago we published guidance on implementing the question. I guess that was for 2003, the question about fever with headache. And our guidance published in May for implementation by June, and I know it's a painful exercise, but the industry was able to implement something de novo. Whereas, what we are saying here is basically to back off. So, I would think that by May or June it would be feasible, although I understand it's painful.

DR. KATZ: It's extraordinarily painful. And I'm not convinced even at my center, just a little tiny center out in the middle of nowhere, that those emergency questions where implemented under what I would call CGMP criteria. And so, we would prefer, and particularly if it's not an emergency, to do it very carefully with all the appropriate training and validation.

Would this be an appropriate -- for example, the donor history questions be an appropriate application for a variance, for example, at this early date?

DR. EPSTEIN: I'm not sure how that changes things, Lou. You are saying can you ask now under a variance, to drop the recommended donor question? The answer is yes. But I think that FDA is very mindful that you need to see as soon as possible, at least a draft guidance. And so, we are doing everything we can at the present time to expedite the GGP process. So, I think you will have it in your hands very soon.

And although a draft is a draft and it's not final, mind you final guidance is also not binding on the agency or the industry. So, I think there will be a lot of benefit to see what the agency is currently thinking in the form of draft guidance, and that should happen quite soon.

DR. ALLEN: Other comments or questions? Yes, would you identify yourself, please?

MS. STRAMER: Susan Stramer, American Red Cross.

I would like to complete some of Lou's thoughts for points maybe that he didn't. And first, let me address Dr. Epstein's point. For us to make simple changes, these changes have to go through very well controlled and defined processes. And our documents, including our consent forms through our donor notification letter, and all those processes only come up for renewal at certain time sequences.

So, we have our priorities set, just like the FDA or any other organization. And when there are major changes which have just been introduced in the last couple of days, it's impossible to turn the organization on its ends to have those changes implemented. So, even by the end of the season we have already done investigations, and they can't occur. The next time some of these documents are up for revision won't be until the September timeframe.

So, something as simple as a slam dunk as you would think, eliminating the headache with fever question, the earliest that could be done is in a revision that will only come out in September. For consent forms to be changed, which link the way we do donor follow-up now to reinstatement, not only would those have to be changed, go through the IRB.

But once recognized as formal documents and changed through our system, would have to be trained in tens of thousands of individuals and collection sites throughout the United States. So, clearly these types of changes are very difficult to implement in a very short period of time, which we have now.

And then regarding 56 to 90 days, if we collect a sample for individual donation testing post-56 days, that isn't equivalent to re-entry at 56 days. Donors will not come in on 56 days for a subsequent follow-up sample. And by 56 days, they don't care about a follow-up sample. We have lost the donor at that point to follow-up.

So, a program like this would be tantamount to eliminating follow-up in an investigational protocol. So, not only do we have to bring the donor in at some time post-56 days, by the time you collect consent and collect the sample, send the sample for testing, turn around the test results, notify the region, the region notifies the donor, you are at 90 days.

So, why in the world would we have two tiers? We would just automatically defer everyone to 90 days. And data on follow-up would terminate.

Thank you.

DR. EPSTEIN: Our current consideration is that the donor would be able to give a unit on or after 56 days, provided that that donor has an IDT test. So, we are not thinking of an offline requalification test. We are thinking that the donor could come back as per usual after 8 weeks of donating whole blood. And that as long as the donation is qualified by IDT NAT, that that is a suitable collection.

So, I think that the cycle of testing interpretation, re-entry, and requalification is not really what FDA has in mind. Now, I understand your point that it may be operationally simpler to defer for 90 days, but we are not precluding a collection at the normal 8 weeks. We're just saying do IDT NAT on that unit.

MS. STRAMER: And therein is the rub. For us, when we collect in our system, 22,000-25,000 tubes a day, it's impossible for sample management to flag that sample and say, this one sample goes to individual donation testing while the rest of the units go for pooling. That's operationally problematic, would led to error, and these are all manual processes. In our system, manual processes don't get approved, because they don't work. So, we would be back then to 90 days.

DR. ALLEN: Any other committee comments or to add to that discussion or questions?

I think this is a very important issue in terms of process. It does have a real impact on the blood collection agencies. On the other hand, we want to assure the safest blood possible, but there are lots of practical considerations. I know that the FDA is working on this. The committee has not been asked a formal question on it, but I'm sure that there probably is agreement that we would encourage the FDA to continue to work on this expeditiously with the blood collection industry to try to resolve the issues.

DR. LEW: Just a question. For the 56 day NAT testing, wouldn't that be data that would be quite helpful to us? Because a lot of this data is extrapolated from limited data already. And I can see in a process it might be easier in a large blood collecting facility to go to 90 days.