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October 28, 2010: Transmissible Spongiform Encephalopathies Advisory Committee Meeting Transcript

October 28, 2010

The Holiday Inn Gaithersburg
2 Montgomery Village Avenue
Gaithersburg, Maryland


This transcript has not been edited or corrected, but
appears as received from the commercial transcription service.
Accordingly, the Food and Drug Administration
makes no representation as to its accuracy.

Proceedings by:

CASET Associates, Ltd.
Fairfax, Virginia 22030
caset@caset.net


TABLE OF CONTENTS

     PAGE
Opening Remarks, Chair, TSEAC1
Statement of Conflicts of Interest3
Topic I: Review of FDA's Risk Assessment for Potential
Exposure to Variant Creutzfeldt-Jakob Disease in U.S.
Licensed Plasma-Derived Factor VIII
Introduction: Steven Anderson7
Presentation of FDA Risk Assessment: Hong Yang27
Summary and Questions for the Committee: Steven Anderson50
Open Public Hearing52
Open Committee Discussion55
Topic II: Labeling of Plasma-Derived Products Including
Plasma-Derived Albumin and Products Containing Plasma-
Derived Albumin to Address the Possible Risk of Transmission
of Variant Creutzfeldt-Jakob Disease
Introduction and Rationale for Proposed Labeling Change for
Plasma Derivatives to Reflect vCJD Risk: Dorothy Scott
79
TSE Clearance in Manufacturing of Plasma Derivatives
Albrecht Groener
95
Summary and Questions for the Committee: Dorothy Scott114
Open Public Hearing112
Open Committee Discussion121

PROCEEDINGS
(8:30 a.m.)

TABLE OF CONTENTS

1

Agenda Item: Opening Remarks

DR. HOGAN: Good morning, and welcome to the 2010 Transmissible Spongiform Encephalopathies Advisory Committee meeting. It has been awhile since we had the pleasure of being here. We have a lot to do in two days. I hope you guys are boned up on your math. There is going to be a lot of math this morning.

I think in starting, I would like it if everyone could go around the room and introduce themselves, and tell you name, what you do, and where you currently are located, so that we can introduce some of the newer people.

DR. MC COMAS: I am Catherine McComas. I am an associate professor of communications, specializing in risk communication at Cornell University.

DR. GESCHWIND: Michael Geschwind, associate professor of neurology, UCSF Medical Center. I probably see about a quarter of the patients with prion disease in the U.S.

DR. KREINDEL: Sylvia Kreindel, senior staff at the USDA National Center for Import-Export.

MS. BAKER: Hi, Judith Baker. I am the Administrative Director for the federal hemophilia treatment centers in Region 9. I am based at UCLA.

DR. BARRAJ: I am Leila Barraj. I am a statistician with a consulting firm in Washington, D.C. I am responsible for statistics and risk assessment exponents.

DR. HOGAN: Good, we will need a math expert today. I am Nick Hogan. I am an associate professor of ophthalmology, neurology and neurosurgery. I do neuro ophthalmology and ophthalmic pathology in Dallas, Texas at the University of Texas-Southwestern.

MR. EMERY: Good morning. My name is Brian Emory. I am the designated federal official.

DR. MONROE: Good morning. Steve Monroe from CDC, Atlanta. I am Director of the Division of High Consequence Pathogens and Pathology, and our division has the Prion Disease Surveillance program at CDC.

MR. BIAS: I am Val Bias. I am the CEO for the National Hemophilia Foundation. I am located in New York.

DR. MANUELIDIS: Hi. I am Laura Manuelidis. I am professor and Head of Neuropathology at Yale in the Department of Surgery. I suppose I have been in this game for a very long time.

DR. GUO: Good morning. I am Chuanfo Guo from the USDA Safety and Inspection Service in the Risk Assessment Division. I do risk assessment there. Thank you.

DR. PRIOLA: Sue Priola. I am a senior investigator studying prion diseases at the NIH Rocky Mountain Laboratories.

DR. HOGAN: Good morning. Thank you all for coming today. Lieutenant Commander Emory is going to give us a little bit of information pertinent to this morning.

TABLE OF CONTENTS

3

Agenda Item: Statement of Conflicts of Interest

 

MR. EMERY: Good morning. The Food and Drug Administration is convening the October 28-29, 2010 meeting of the Transmissible Spongiform Encephalopathies Advisory Committee under the Federal Advisory Committee Act, FACA, of 1972. With the exception of the industry representative, all participants of the committee are special government employees or regular federal employees from other agencies, and are subject to the federal conflict of interest laws and regulations.

The following information on the status of this Advisory Committee compliance of federal ethics and conflict of interest laws, including but not limited to 18 USC Section 208 and 712 of the Food Drug and Cosmetic Act are being provided to participants at this meeting and to the public.

FDA has determined that all members of this Advisory Committee are in compliance with federal ethics and conflict of interest laws under 18 USC Section 208. Congress has authorized FDA to grant waivers to special government employees and regular government employees who have financial conflicts, when it is determined that the agency's need for a particular individual's service outweighs his or her potential financial conflicts of interest. Under 712 of the Food Drug and Cosmetic Act, Congress has authorized FDA to grant waivers to special government employees and regular government employees with potential financial conflicts when necessary, to afford the committee their essential expertise related to the discussion of this meeting. Members and consultants of this committee have been screened for potential financial conflicts of interest of their own as well as those imputed to them, including those of their spouses or minor children and for the purposes of 18 USC 208, their employers. These interests may include investments, consulting, expert witness testimony, contracts and grants, CREDAs, teaching, speaking, writing, patents and royalties, and also primary employment.

For topic one, the committee will review FDA risk assessment for potential exposure to variant Creutzfeldt-Jakob disease in U.S.-licensed plasma derived Factor VIII. This is a particular matter of general applicability.

For topic two, the certain will discuss labeling of plasma-derived products, including plasma-derived albumin and products containing plasma-derived albumin, to address the possible risk of transmission of variant Creutzfeldt-Jakob disease. This is a particular matter of general applicability. The committee will also hear an informational presentation on FDA's geographic donor deferral policy to reduce the possible risk of transmission of Creutzfeldt-Jakob disease and variant Creutzfeldt-Jacob disease by blood and blood products and human cells, tissues and cellular and tissue-based products. The committee will also hear an update on recent advances in development of devices to remove TSE agents from blood components. The information, presentation and update sessions are not for discussion by the committee and therefore, committee members who are not screened for financial interests related to their presentation and update.

Based on the agenda and all financial interests reported by members and consultants, no conflict of interest waivers were issued under 18 uniformed code 208b3 and 712 of the Food Drug and Cosmetic Act.

There may be regulated industry and other outside organization speakers making presentations. These speakers may have financial interests associated with their employer and with other regulated firms. The FDA asks in the interest of fairness that they address any current or previous financial involvement with any firm whose product they may wish to comment upon. These individuals were not screened by the FDA for conflict of interest.

The conflict of interest statement will be available for review at the registration table. We would like to remind members, consultants and participants that if the discussions involve any other products or firms not already on the agenda for which the FDA participant has a personal or imputed financial interest, the participants need to exclude themselves from the discussions, and their exclusions will be noted for the record. FDA encourages all other participants to advise the committee of any financial relationships that you may have with the sponsor, its product, and if known, its direct competitors.
Thank you.

DR. HOGAN: Thank you. So I think we will go ahead. It is going to be an interesting morning. The staff has done an awful lot of work in getting this meeting put together.

We will begin on topic one, which is a review of FDA's risk assessment for potential exposure to variant Creutzfeldt-Jacob disease in U.S.-licensed plasma-derived Factor VIII. Dr. Anderson.

Excuse me. Before we start that, we have one other comment here.

MR. EMERY: I was also going to say that Miss Janice Hamilton and Dr. Douglas Lee are unable to attend today's meeting. Dr. Lee serves as the industry representative for the committee, and due to an unforeseen family situation is not able to participate. Every effort was made to find another suitable industry representative appointed to serve. However, due to the late notice, we are unable to find an acting industry representative for today's discussions.

For tomorrow's discussion, Dr. Kelso Bianco from America's Blood Centers will serve as the acting industry representative.

I'm sorry he couldn't be with us today. I would also like to make an announcement that Dr. Paul McCurdy, who used to be a member of this committee, died about three months ago. He served long and well.

TABLE OF CONTENTS

Agenda Item: Topic I: Review of FDA's Risk Assessment for Potential Exposure to Variant Creutzfeldt-Jakob Disease in U.S. Licensed Plasma-Derived Factor VIII

DR. HOGAN: Thank you. Dr. Anderson.

7

Agenda Item: Introduction

DR. ANDERSON: Thank you. I am going to start with topic one, as has been announced.

I thought what I would do is give you a thumbnail sketch of the session that you are going to hear presentations from. There are going to be three presentations. The first presentation is mine. I am going to talk to you a little bit about some of the background of the risk assessment, going back to 2006, and provide you with some of the summaries of discussions that occurred during previous Advisory Committee meetings, then give you a little bit of background on the risk assessment from a higher level perspective. Then the second presentation will be given by Dr. Hong Yang in our group. She is going to give you a background of the risk assessment as well, probably more in depth than I am going to go into, and then she is going to present results from the risk assessment, and some basic summary conclusions.

The third presentation is, I will come back to you with some summary conclusions from this session and from the risk assessment, and then follow that with the questions to the committee for discussion, comment and voting.

Just to remind you, my name is Steve Anderson. I am the Deputy Director in the Office of Biostatistics and Epidemiology. This is an introduction background to the risk assessment for potential variant CJD risk for plasma-derived Factor VIII products licensed in the United States.

The first question that comes to mind is, why are we here, and what is different from what we have done before.

What we are doing today is, we are reviewing the FDA 2010 risk assessment. Again, what we are delivering to you is the completed risk assessment report. That is in the committee's folder packet. They have seen the report. That is also going to be posted in the future on the FDA website.

I want to emphasize that this FDA 2010 risk assessment report is based on the FDA 2009 model that we presented at the June 2009 TSEAC Advisory Committee meeting.

Since that time, we have done several quality control measures on the model, and then generated the documentation. For instance, we have generated extensive analyses of the model stability of the results, running one million iterations. Actually we have done that several times, just to look at the results. Dr. Yang is going to go into more detail about that in her presentation.

We have had additional quality control checks by three FDA staff that have gone through the model since 2009. Then we have had external expert review by a TSEAC member up here at the table, Dr. Leila Barraj.

 

All of these comments were taken into the risk assessment report, but there weren't any changes to the model based on any of the comments or any of the reviews that we have conducted. So essentially we are using this 2009 model.

So based on the 2010 risk assessment result, there has really been minimal change in the outcome since 2006. So based on those results, we continue to believe that the risk for variant CJD to patients who receive U.S.-licensed plasma-derived coagulation Factor VIII products is likely to be extremely small, although we don't know the risk with certainty. So why we are here is to invite committee discussion and comment on the input to the risk assessment and then FDA's interpretation of the risk.

I wanted to step back and talk about the June 2009 meeting, and also some of the activities in 2009 related to the risk assessment.

We updated the model in 2009. Our activity was prompted by this report in February of 2009 of a vCJD infection in a 73-year-old man with hemophilia in the United Kingdom. From information from this publication, we know that the patient had no signs of neurological disorder. The autopsy found spleen that was positive for vCJD agent. That patient received several blood and plasma products, including the products listed here, 400,000 units of plasma-derived Factor VIII. There were 9,000 units that the patient received from two implicated batches of plasma, meaning patients with variant CJD and diagnosed with variant CJD at a later time had contributed plasma to some of these batches that this product was derived from. Fourteen units of red blood cells. They had also undergone several surgical and endoscopic procedures.

In 2009, what had changed since 2006? Obviously this variant CJD transmission through plasma derivatives made the risk no longer theoretical, but probable. There was additional consideration of epidemiological data. In this case, what that means is that we have expanded our risk estimates to include the risk for all genotypes. I will explain that a little bit more later, but in 2006 we accounted for just individuals in the MM genotype, which represented about 40 percent of the population. In 2009, based on emerging information in the literature -- that meant information was already emerging in 2006, by the way -- we decided to expand the model to include all genotypes, so assumed that the entire population was potentially at risk for variant CJD infection.

Also, it is important to note that infections in the non-MM genotypes can be subclinical. They are assumed to have longer incubation periods than the MM genotypes.

Another important consideration is that there have been on known clinical cases of persons with vCJD that have the non-MM genotypes. I will explain a little bit more about this.

As far as the updates to the risk assessment model in 2009, you have seen this information before. We had two updated inputs basically in the model, where we updated prevalence estimations to the U.K. population, the time during the incubation period when the infectivity was in blood. These new inputs represent our expanded view that everybody in the population was susceptible to the disease, and not just individuals of the MM genotype.

We did three adjustments to include that assumption in the model. Then our interpretation of the risk hadn't changed since 2006. That is, the variant CJD risk from U.S.-licensed Factor VIII is likely extremely small.

Moving forward, I am reminding you that the questions to the committee at that time were, does the committee agree with the updated and new inputs. That was a discussion question. Should the reported variant CJD case in hemophilia patients alter the interpretation of the risk, and that was a voting question.

The summary of the discussion was that our updates and the new inputs were reasonable, although acknowledging that there was considerable uncertainty in several of the input parameters in the model, for instance, prevalence, and then the time that the agent is present in blood, and other factors.

Also at that meeting they suggested increasing the number of simulations to improve stability of the model outcomes. Hence, we bumped up our simulations to a million, and that was up from 10,000 that we had done in 2009.

The outcome of the committee vote was, 15 out of 15 voted for no change in FDA's interpretation of the risk.

Moving on, I thought I would just provide you with a little reminder about what we are talking about when we are talking about MM genotype and the non-MM genotypes. These are persons who are methionine homozygous at the PRNP codon 129, and the MMs represent 40 percent of the population in the United Kingdom.

To date, all persons with variant CJD clinical cases are of the MM genotype, although there is one case that is possibly of another genotype, but that case hasn't been verified formally.

The non-MM genotypes fall into methionine valine at the codon 129 and then valine homozygous. The methionine valine represent 50 percent of the population, valine homozygous represent ten percent of the population, and the incubation periods around these are estimated to be 32 years. That is a total estimate based on results from Dr. Nasir Ghani's group in the United Kingdom. I wanted to remind people that the incubation period for the MM homozygous is estimated at 12 years.

There is more certainty around this estimate. There are extremely high degrees of uncertainty around these estimates of 32 years, so use extreme caution when you are thinking about those estimates of the incubation periods for these two particular genotypes.

This slide is representing the distribution of cases known of MM and MV and VV genotypes. As you would assume, the majority of cases are MM that have been diagnosed. This is greater than 120 because obviously all the patients in the U.K. and other parts of the world have not been genotyped, but just trying to represent the overall magnitude, so a very large number. There are relatively small numbers, in this case three, MVs that are known and have been typed, and then two VV's that have been typed.

What I want you to look at is the relatively small numbers here. That doesn't mean that there aren't large numbers of patient populations in these two genotypes. That just means that we haven't really detected. These are all what you would consider incidental findings, and because these patients don't develop clinical disease, it is very hard to identify these patients or the persons infected with these genotypes.

Going all the way back to the 2006 risk assessment, which the title is up here, our interpretation of the risk is, it is impossible to precisely estimate the variant CJD risk for the licensed product plasma-derived Factor VIII. The risk is likely extremely small, but not zero, and highly uncertain.

I wanted to remind people that earlier iteration was peer reviewed by three external experts. It was presented at the December 15, 2006 TSEAC meeting, and then posted on the FDA website. It was also accompanied by a risk communication plan.

What I also wanted to point out that is important is that these models have as you will see a fair amount of external peer review associated with them. This model in 2009 is an iteration of the earlier model in 2006, so if you combine all the expert peer review, we have had this reviewed by four external reviewers, and then numerous times by internal FDA reviewers as well. So we are confident at least for the time being that this model is as robust as it can be, just based on the comments that we have received and incorporated into the risk assessment.

Moving on, the results from the December 15 TSEAC meeting in 2006. The question to the committee at that time, were there any comments on the technical aspects of FDA's risk assessment, including risk estimates and uncertainties for plasma-derived Factor VIII from U.S. donors.

The summary of the discussion at that time was, the overall approach and the assumptions were scientifically sound. The committee agreed with the conclusion that the vCJD risk from U.S.-licensed product was very small. There was this concern about considerable uncertainty associated with several elements in the risk assessment or inputs into the risk assessment.

Then the request that the FDA should revisit the risk assessment when the information became available. Obviously we have done that in 2009 and 2010, that we are bringing you today. They agreed with the FDA communication strategies.

Jumping into some of the background on variant CJD and BSC. This is a slide that I borrowed from Dr. David Asher of CBER. You will be seeing this slide tomorrow as well. What we are showing is the distribution of the BSE epidemic and the variant CJD epidemic in the United Kingdom.

On the right and on the scale here are the BSE deaths. These represent the distribution of those deaths, starting from 1987 through present day. I'm sorry, this is the left, this is the right. Variant CJD deaths on these side and then this linear graphic represents that distribution of cases.

For instance, the cases of BSE started in '87, peaked in 1992. The cases of variant CJD started in '95, peaked in 2001, and then have fallen significantly. One other important point is, there is about a nine-year difference between the start of the BSE epidemic and then the start of the human epidemic for variant CJD. Peak to peak it is about a nine-year difference as well.

One other thing I wanted to point out were the time points for the transfusion transmitted cases, the first one starting in December of 2003 and the last one was reported in January of '07. Then this is the time point for the February 2009 case in the UK hemophilia patient.

That gives you an overall general feel for the epidemics of both BSE and variant CJD. Now we are moving on to the variant CJD cases known worldwide. The total cases estimated as of June 2010 are 221 cases, of which 175 in the United Kingdom, 25 in France, 16 in other countries in Europe. Then there are non-European countries as well. What you will notice is that several of these individuals lived for long periods of time in the United Kingdom and could have acquired disease there.

The other thing I wanted to point out as you look at this is, the risk resides a lot in this European region. That is really the focus of the risk assessment in the model, so we are looking at honors who traveled to U.K., France and other countries in Europe in this model, because we believe that is where most of the variant CJD risk is for blood donors that could potentially be transmitted through the Factor VIII product.

Let me launch into the updated risk assessment. I am going to give you a high level view, as I mentioned. The risk assessment framework that we are using was published by the National Academies of Science in their report in 1983, It is a four-part framework. Many of the committee members have seen this before.

What I wanted to draw your attention to was stage three or component three, which is exposure assessment. This is where most of the modeling is being done. I am going to show you an overall view of the model in just a second.

What we get from this part of it is the dose of variant CJD infectivity that a patient could potentially exposed to, then based on that potential dose we do the risk characterization about what is their potential risk. Those are going to be in the tables that Dr. Yang is going to show you in her presentation.

Here is the exposure assessment component, which is a diagram of the model. I am not going to go in depth into this model. The overview is here for your reference. It is a four-component model. We are interested in prevalence, especially prevalence of vCJD in U.S. donors.

There is an important impact effect of processing of the Factor VIII product which we believe leads to reduction in the quantity of infectious agent if it is present in the product. Then finally, utilization of Factor VIII by patients. If the patient chooses high quantities of the product, if the agent is present, then presumably they will be at greater risk than patients that use smaller amounts of product. Ultimately we are looking for the dose of variant CJD agent to which Factor VIII recipients may be exposed to in this exposure assessment model.

There are several things I am going to talk about in the next few slides. Prevalence is an important factor on risk in the model, as well as manufacturing, which I mentioned, and then utilization is another important part of that risk picture.

There is significant uncertainty, first off, in estimating UK vCJD prevalence. That was reflected in the way we did our modeling. You will notice in the results that we stratified our results by a lower estimate and then a higher estimate.

The lower estimate is what we are calling a case prevalence estimate. That was based on work that we expanded on done by Paul Clark and Azer Ghani in the U.K. in 2005. From that estimate we estimate that the prevalence is 4.5 per million.

There is a second approach that we used to estimate the higher infection prevalence estimate. This is infections versus cases. Our estimate from this Hilton et al. tissue surveillance study, they found three positives appendices in 12,600 samples, which gave us an estimate of one in 4,225 for prevalence.

When you look at this estimate versus this, I dropped out the number, but this equates to about 247 cases per million. So there is a two log difference between these two estimates, or about a 100 fold difference between these two estimates.

One more thing. In this previous slide we are talking about a tonsil/appendix study. There was a follow-on study, and the positives were found in appendices. What I wanted to mention was, there was a follow-on study that looked just at tonsil pairs, 63,000 pairs, and they found no prion agent in those samples. So trying to look at that data is a challenge. You can either look at this data and say there is zero prevalence, you can look at the other and say there is one in 4,225, or you can combine the data.

What we decided to do was stick with our prevalence estimate from previously, which was one in 4,225. The U.K. SEAC or Spongiform Encephalopathy Advisory Committee, released a statement indicating that they agree with that approach too, that it would be prudent, and it is prudent and reasonable to use the appendix survey as an estimate of prevalence. That is a cautionary or precautionary estimate of prevalence.

Talking about clearance. I am not going to go too much into clearance, except to say there is a fair amount of uncertainty when we are talking about clearance and the precise level of clearance for a Factor VIII product. Because of that uncertainty we stratified our results into two ranges, seven to nine logs and then four to six logs. What we assume is that most products in the United States that are U.S. licensed likely have greater than four logs of clearance.

Finally, in our elements of risk assessment, utilization and patient use of Factor VIII for treatment is a very important factor in risk and contribute to risk. So patients with hemophilia, there is approximately 17,000 patients with hemophilia in the United States. Our model specifically is focusing on 1800 patients who have severe hemophilia disease or disorder. The annual usage per person ranges in those patient populations from 5,000 units to 1.6 million units, based on the data that we had from CDC.

It is important to note the huge difference here, which is about a 300 fold difference, so about two log orders of difference. For von Willebrand's disease, this is a deficiency in von Willebrand factor, we assumed that approximately 250 patients with severe van Willebrand's disease are in the United States being treated with plasma-derived Factor VIII, and the range for annual usage among those patient populations ranges from 1,000 units up to 600,000 units. The math here is pretty easy. It is a difference of 600.

Not any difficult equations. We are not going to bore you with too much of the math.

As far as the FDA 2010 risk assessment, what are the greatest sources of risk that we considered in the model? The major source of risk is for donors who spent large amounts of time in U.K., France and other countries in Europe. There was the potential to consume BSE contaminated beef during those extended periods of travel or residency.

So that is the major assumption in our model, that this is the major contributor to risk. We also looked at dietary exposure in the U.S. We found that to be negligible based on our modeling, because there were only three reported BSE cases in the U.S. One of those was imported.

The three vCJD cases in the U.S. likely were not acquired in the United States. So we assume this domestic exposure from U.S. sources to be negligible. We included that in the model, but it had a negligible effect.

Another factor that contributes to risk and risk reduction is our current donor deferral policy. When I look at these two things, I see there is a considerable amount of risk reduction. The range that we put in the model on that risk reduction is 85 percent to 99 percent. If you subtract those numbers from 100 percent you get the residual risk, which is assumed to be anywhere from one percent down to 15 percent.

So there is residual risk, and where that risk may lie as well is from persons who fall outside of these guidelines. So if somebody was in the U.K. for two months but still was exposed to the agent and infected, the current donor deferral policy would not exclude those individuals from donation. You can go through the same criteria as well and find exclusions for those individuals as well. So there are limitations to the current donor deferral policy.

In the final couple of slides for this sector of the presentation, what I wanted to do was talk about model based estimations of variant CJD risk to give you some comparisons for the U.K. case in 2009 in the hemophilia patients, this information appears in the literature, and then what estimates are showing.

This is a table based on a publication in 2010 concerning the 2009 U.K. hemophilia patient. We are looking at the different exposure routes. As you will recall, I mentioned that the patient received 400,000 units of plasma-derived Factor VIII. They received 9,000 units from implicated batches. They received RBCs. They obviously have a background risk which is a potential dietary exposure, and then risk from multiple medical procedures, endoscopy among them.

These are the exposure routes listed here, and then the infection probabilities. Not to draw on these, but these infection probabilities are extremely high and of some concern. The estimate in the publication was, the patient just from non-implicated plasma-derived Factor VIII had received greater than two ID-50s, which makes infection probable.

I wanted to remind people, the reason that is, is because if you are looking at a high number of individuals, if you are looking at the high estimates, one in 4,000 individuals in the U.K. that may be infected, if you look at the percentage of plasma batches that may contain BSE agent in that case, it is something like 95 percent or more of the plasma batches would have been predicted to contain vCJD agent. So that is why this estimate is so high.

These estimates are compared to the next one down, ten to 30 percent from the implicated product, compare that out to the estimates that we are getting from our models. For some of the higher estimates, I pulled out a sector of the table where we had the highest estimates of risk. For patients who are on prophylaxis who have severe hemophilia A, this is the four to six log reduction for the products, for the higher prevalence estimate of one in 4,225.

Patients on prophylaxis who have inhibitor and immune tolerance, these are the patients that are going to receive that high end, like 1.1 million or more units of product in a year. There aren't many of those patients, but there are some. Even at that level of product consumption, the risk was predicted to be one in 18,000. So contrast that to the previous estimates; our estimates are smaller by comparison for the risk.

I wanted to acknowledge the number of people that helped in doing this risk assessment. Hong will also acknowledge these, Hong Yang, Rich Forshee and Mark Walderhaug in our group, and then David Asher, Jay Epstein and a number of people in the Office of Blood Research and Review contributed to this work.
With that.

DR. HOGAN: Thank you very much, Steve. That is a lot of information in 30 minutes. Are there any questions for Dr. Anderson, just questions, not discussions?

I only had one question. Do you know what the genotype at codon 129 was for the 2009 hemophilia patient that had vCJD?
DR. ANDERSON: Yes, that is in the slide. The one patient was MV.
DR. HOGAN: Thank you. Laura, quick question.

DR. MANUELIDIS: The people who were in the United States and they got vCJD when they were in the U.K., how long were they living in the U.K.? Was it six months or was it a year or two years? What was the exposure time in the U.K. for those patients?
DR. ANDERSON: Many years.

DR. GESCHWIND: You mentioned somewhere about 98 to 99 percent effectiveness of the policy? Where did you get that? Then you said subtracting that gives you one percent remaining risk or something. I didn't understand where you got the 98 percent.

DR. ANDERSON: I need to walk you through that. The effectiveness of the policy was 99 percent. We got the higher end estimate from research that was done for other diseases. There hasn't been a study looking at the particular effectiveness of this vCJD donor deferral policy. So we used data from studies on HIV deferrals, and I believe hepatitis as well, other infectious diseases that inferred up to a 99 percent effectiveness of the deferrals.

So if we remove 99 percent of the risk, what remains is one percent of the risk.
DR. GESCHWIND: My question had to do with, how did you get the 99 percent? Thanks.
DR. HOGAN: Dr. Epstein, do you have something to say?
DR. EPSTEIN: I can speak to this point. I have another comment to make.

We have looked at other donor deferral criteria and tried to estimate how effective they are. So if you say look at behavior exclusions or you look at medical risk exclusions, and from those databases we estimate that the effectiveness of the deferrals, the questions you ask the donors is in that range of 85 to 99. Obviously we have no direct information on the effectiveness of the exclusion for variant CJD risk, so it is imputed from other data.

The point I wanted to make just for completeness, we are aware that there is a report in August 2010 of one positive tonsil in a cohort of about 9,600 tonsils from individuals in the birth cohort 1961 to 1985. David will correct me if I've got that wrong. That leads to a prevalence estimate of about 109 per million, which is statistically in the same range as the appendix-based estimate. So even though that information came very, very late in the game in terms of finalizing the model, we don't think that it perturbs the high risk estimate, which is of course driven by the appendix findings, three of 12,000.

So just so the committee knows, yes, we do know that there was that one more case.

DR. HOGAN: Thank you. We will go ahead now. Dr. Yang will talk to us about the model in more detail.

TABLE OF CONTENTS

27

Agenda Item: Presentation of FDA Risk Assessment

DR. YANG: Thank you. Dr. Anderson just give you a general introduction and the background on the FDA risk assessment for the potential vCJD risk of plasma-derived Factor VIII. In my presentation I am going to go through FDA 2010 updated risk assessment in more details.

First I would like to remind you that the history of the FDA risk assessment development and the revisions. FDA's risk assessment was first developed in 2006. The risk assessment was revealed by three outside experts. The result in the model was presented in 2006.

In 2009 FDA updated the risk assessment model to include wider population for being susceptible to vCJD infections. The updated risk assessment model was presented in 2009.

After 2009 set, FDA conducted internal model auditing on the updated risk assessment model. The model also reviewed by one external expert. We also increased the number of iterations for the model run to generate more stable model output. We also generated a updated 2010 risk assessment report.

Next I am going to go through the FDA 2010 updated risk assessment. First, for the model structure modeling approach in the assumption. I want to remind you again that this part of the information we have present in previous TSEAC meeting. The model structure and modeling approach and assumption has not changed since 2009.

What is the scope and the general approach of the FDA's risk assessment? FDA's risk assessment mainly focus on two groups of patients with the most extensive usage of plasma-derived Factor VIII. They are severe hemophilia patients and the severe von Willebrand disease patients.

We estimated the vCJD risk for these patients for a one-year window in 2002, because 2002 is the year the final FDA guidelines on donor deferral was published. We assume the vCJD risk after 2002 are either similar or lower than the risk in 2002.

FDA developed a computer simulation model to estimate the risk. I want to point out here that both model input and output generated by the model are statistical distributions. However, in this presentation and risk assessment document, we only present the mean 95th percentile.

Dose response is an important component of the risk assessment, because there is insufficient data from human. Therefore FDA's risk assessment use animal dose response data represented by ID-50. We assume linear dose response, assume the FDA accumulated in human. However, the major challenge for the dose response is, animal model may not be a good representative of human.

This slide give us a overview of the structure of the FDA's risk assessment model. The model include four modules. Module 1, vCJD prevalence in United Kingdom. We used U.K. vCJD prevalence to estimate the vCJD prevalence in other vCJD countries, also later the prevalence in U.S. plasma donors.

Module 2, vCJD prevalence for U.S. donors. In this module, we estimate the vCJD risk for the U.S. donor based on donor travel history.

Module 3,Factor VIII processing. In this module we consider pooling of the plasma from thousands of donors. Also we are considering the potential infectivity occurrence during the manufacturing.

Module 4, utilization of Factor VIII. In this module we incorporate individual patients' Factor VIII usage data to estimate the individual accumulated annual exposure to the vCJD agent through the plasma-derived Factor VIII.

I am going to go through module one by one. Module 1, prevalence of vCJD in the United Kingdom. As Dr. Anderson already mentioned, because of uncertainty in estimate the U.K. prevalence, FDA's risk assessment uses two different prevalence estimates. One estimate is based on epidemiological monitoring of vCJD in clinical cases. Using this approach, FDA estimates the U.K. prevalence of about 4.5 per million. This estimate derived after the adjustment to include all genotypes.

The second estimate is based on tonsil/appendix tissue surveillance data in the U.K. This study generated a prevalence of 237 per million.

However, there is uncertainty associated with both prevalence estimates. For example, for the estimate based on epidemiological modeling, the estimate is heavily dependent on many model assumptions. The estimate based on tissue surveillance study is highly uncertain because there is a lot of caveat associated with this tissue study.

Module 2, vCJD prevalence in the U.S. plasma donors. In this module we tried to estimate the potential number of vCJD infected donors and donation in the United States. We used blood donor travel survey data collected by American Red Cross to estimate the travel risk for the U.S. plasma donors.
We also are considering the efficiency of our current donor deferral policy in risk reductions.

However, there is uncertainty. Maybe it come from the blood donor travel data. The travel pattern for blood donor may not represent the travel pattern for the plasma donors. We know plasma donor usually younger and maybe they have less trouble.

Also, as Dr. Anderson just discussed, the assumption FDA used for the efficiency of donor deferral also may have uncertainty, because this assumption is based on the donor deferral data for other infectious disease. There is no data for donor deferral for vCJD risk.

Module 3, Factor VIII processing. In this module we have two output. One is the percentage of products that may contain Factor VIII agent because of plasma pool contamination from infected donors. Another output is the quantity of Factor VIII agent in those contaminated products.

In FDA's risk assessment we are consider the impact of the plasma pool size on the probability of contamination. Recovered plasma has a larger pool size, therefore has a higher chance to contain contamination from infected donors.

FDA risk assessment also is considering the infectivity occurrence during manufacturing. We believe U.S.-licensed Factor VIII products has at least more than four log clearance. However, exposure because there is no product specific data available, therefore FDA model two clearance range. One is seven to nine log represent high clearance, and another one is the four to six log represent intermediate clearance.

Module 4 is utilization of Factor VIII. In this module we generated the final out of the model. The individual accumulated annual exposure represented by ID50. The Factor VIII usage data is coming from a CDC sponsored hemophilia surveillance study from 1993 to 1998. Updated risk assessment considering the variation in the usage of plasma-derived Factor VIII among the patients with different disease condition and different treatment regimens.

A major problem from this usage data is, the Factor VIII usage by hemophilia A patient or von Willebrand disease patients, the current usage may be really different from the usage in 1998. This data is relatively old. Therefore, the treatment regimen may have been changed since 1998. But we don't have other more updated data.

This table summarizes the update and the new improved in 2009 update risk assessment model. I want to remind you, this information summarized in this table has already been present in 2009 TSEAC meeting. So I think it will be helpful to present it here again to help you refresh your memory, because at the end FDA will again ask the committee to comment on this update in the 2009 updated risk assessment model.

In 2009 updated risk assessment model, we updated two improved variables and added three new improved variables. One updated improved variable is lower case prevalence estimate. This is the prevalence estimate based on epidemiological modeling of the clinical cases.

In 2006 we used an estimate of 1.8 per million. This estimate is based on the modeling of clinical cases, but because all the confirmed clinical cases reported so far are all associated with MM genotype, this estimate is the prevalence model in the MM population.

In 2009 we tie 1.8 by a factor of 2.5 to incorporate potential infection from MM genotype. For the time when infectivity present in the blood, in 2006 risk assessment model we assume the infectivity present at the last 50 percent of incubation period. In 2009 we updated this input by assuming the infectivity present in the last 75 percent of incubation period.

In the 2006 model we added in a new improved for the proportion of PRNP genotype. In 2006 model we didn't model by genotype, but in 2009 we added in different genotype.

In the 2009 model we also added the incubation period for non-MM genotype. We assume the median incubation period for a non-MM genotype is 32 years because currently there is no clinical cases, confirmed clinical cases coming from non-MM genotype, so this is solely an assumption. There is no data to estimate the incubation period for non-MM genotype.

We also updated the input variable for the age distribution of asymptomatic infections. In the 2006 risk assessment model, we assume this age distribution is the same as the age distribution for the clinical onset. In 2009 after additional consideration, we adjusted this age distribution for the incubation period.

Next I am going to present you the result from FDA 2010 updated risk assessment and the conclusion.

In 2009 TSEAC meeting, the committee asked FDA to examine the stability of the model output. The major concern is, vCJD infection is a low prevalence event. There is a lot of uncertainty associated with FDA's risk assessment model. Therefore, the committee considered the 10,000 iterations we used in 2009 risk assessment may not be enough to obtain a stable model output.

So based on TSEAC's suggestion, FDA conducted a convergence analysis on the model output. This slide gives us the result of the convergence analysis. The horizontal axis here represents the risk output mean ID50. Here vertical axis represent the number of iterations. From here, we can see, when we have iteration of 10,000, we can see a considerable variation in the mean ID50. When we increase the iteration to 100,000, we start to see the mean ID50 converge. Here one million iteration is what we currently use in the FDA 2010 risk assessment model.

This table summarizes the model output for the individual vCJD risk for the severe hemophilia patient. In this table the lows represent the different patient groups with the different treatment regimen and different inhibitor status.

The column for the output was divided into two blocks. One block presents the risk estimate based on assumption of lower vCJD prevalence for the UK population. This block represents the result and the assumption of higher vCJD infection prevalence.

So we have generally two different model outputs. One is accumulated individual annual exposure represented by accumulated ID50. Then based on this accumulated ID50, we calculate the probability of infection.

Here I want to emphasize again, the model output are actually statistical distribution, but here we only represent the mean 95th percentile.

This table is from a paper I just presented in the previous slide. To make you see clearly I only include the risk output and the assumption of lower vCJD case prevalence. From this table I want you first to see, this group of patients has the lowest risk among the severe hemophilia patients. This group is the patients with episodic treatment with no inhibitor.

This patient group is the group that has the highest risk. They are patients with prophylaxis treatment and have both inhibitor and immune tolerance.

Another thing I want to draw your attention to is, look at the 95th percentile for all patient groups. Here it is zero to zero. What that zero to zero means, it means in at least 95 percent of the iterations, there is zero exposure. So what we present here, the mean exposure, is driven by the small number of the iteration that has exposure.

From here our interpretation is, the vCJD risk for the severe hemophilia patient is very low, under the assumption of lower vCJD case prevalence.

What is the uncertain range for the individual vCJD risk of the severe hemophilia patient if we consider in the uncertainty in estimate the UK prevalence. We take the risk estimate for the patient group with the highest risk and the lowest risk, and then this is the lowest risk estimate.

This is the highest risk estimate. The lower end of the risk estimate is coming from the low risk patient group under the assumption of the lower vCJD prevalence assumption. The highest end of the risk range is coming from the high risk patient group under the assumption of higher vCJD infections prevalence. So the difference between these two group, the risk difference between these two groups is about 400 times difference.

What is the uncertain range for the individual risk of severe hemophilia patient if we further include the uncertainty and estimate the infectivity clearance? This is the lowest estimate, and this is the highest risk estimate. This lower end of the risk estimate is coming from the patient group has the low risk, under the assumption of seven to nine log reduction and low vCJD case prevalence.

This is the highest risk estimate coming from the patient with the high risk under an assumption of a four to six log reduction and the higher vCJD case infection prevalence.

Another key question is, is there any difference between the result of 2006 and 2010 FDA risk assessment. We still take the risk estimate for the patient group with the highest risk and the lowest risk to do the comparison.

From this table we can see the big difference is here under the seven to log reduction and the lower vCJD case prevalence estimate. The result from 2010 for the patient group that have high risk is one in 1.1 billion. The result for 2006 is one in 551 million. So the difference is roughly about two times difference. So similar here for the lowest risk patient group. So we can see this difference is very small, given such a small overall vCJD risk.

This is the table we compare result from 2002 to 2006 for the vCJD risk for the young severe von Willebrand disease. From here we can also see the result from 2010 and 2006 is very close.

In FDA 2010 risk assessment, we also conducted an important analysis, tried to identify the key input for the vCJD risk. The result of analysis indicate the infectivity clearance during manufacturing is still the most important input in the model. This is consistent with the result from 2006.

This graph showed the result for important analysis. This longest bar is infectivity clearance during manufacturing.

In summary, there is no significant change in the risk estimate from FDA 2010 updated risk assessment compared to the older version of risk assessment in 2006. FDA's interpretation of the risk in 2010 remains same as 2006. The important analysis indicate infectivity clearance during manufacturing is the most important factor for vCJD risk for U.S.-licensed plasma-derived Factor VIII.

Finally, I would like to thank my colleagues from the Office of Biostatistic Epidemiology. They made a great contribution in model auditing and document revision. I also would like to thank our colleagues from the Office of Blood Research and Review. They worked with us very closely throughout the whole process of model development and the revision, and provided us a lot of valuable advice in many subject-specific areas.
Thank you.

DR. HOGAN: Thank you very much, Dr. Yang. Are there any questions for Dr. Yang? We can discuss them later, but are there any direct questions now while the data is fresh?

DR. GESCHWIND: Yes, I just had a quick question. I was a little confused about four tables back. It looks like the risk in 2010 is less than 2006. Yet with all the inputs in the model, I would have expected the opposite to have occurred.

DR. YANG: There is one confounding factor here. You remember, I showed you, we checked the stability of the model output. In 2009 and 2006 we only have 10,000 iterations. So at that time the output may not be that stable. It can go either way, lower than the expected mean value or higher than the expected mean value. So this is confounding with other updates.

DR. GESCHWIND: Related to that, with that many iterations, there was so much uncertainty at 10,000 iterations. So the uncertainty got much narrower. Is that something you would have expected for such an uncertainty, that at 10,000 to completely disappear? It was well even before a million iterations that you narrowed. Is that something that was expected? It is variability, I should say.

PARTICIPANT: Could you go back to the convergence slide? I want to distinguish between the remaining uncertainty, because of the parameter inputs and the convergence of the models as we add more iterations.

What we are seeing in this slide is the percentage change in the overall mean result for the model as we add more iterations. So each one of the points on this graph represents the percent change in the mean as we have added 500 more iterations. So down here when we were at 1,000 iterations, when we went from 500 iterations to 1,000 iterations, there was about a 40 percent change in the mean between what the mean was at 500 and what the mean was at 1,000.

So this is showing that because this is such a rare event, we were seeing the mean jump around a lot when we only had 10,000 iterations in the model. By the time we were getting up to 100,000, 500,000 and a million, the mean estimate from the model had converged to a stable result.

Now, there was still uncertainty around this mean, and we did this convergence analysis for the standard deviation and the 95th percentile as well. So this doesn't mean that the overall uncertainty of the model had shrunk, but rather that by going to a million iterations we were now getting stable estimates for the mean, the standard deviation and the 95th percentile, compared to when we were only using 10,000, we had not gotten to a stable result at that number of iterations.

DR. GESCHWIND: So if you take that fact into account and balance that with the increased risk, does that make sense that the actual estimates of the number of cases would have decreased?

PARTICIPANT: Yes. We believe that because there was this significant instability when we only had 10,000 iterations, that the results that were reported earlier, just because of the chance, whether we got more or fewer infected individuals in that year, could lead to either a higher or lower estimate. So in this case we think that the new estimates are much more stable and are the best estimates that we can have from those results.

DR. HOGAN: Just to dissuade you thinking this is easy, I understand that to do a million iterations takes about 72 hours of computer time?

PARTICIPANT: With this particular model, yes, it was taking about 72 hours for each runs.

DR. HOGAN: There is one other clarification I wanted to mention, because it was unclear to me on the slide. When you talk about the time of blood infectivity as being 75 percent, you mean it doesn't appear until 75 percent of the incubation period has elapsed, is that correct?

DR. YANG: No, no, no. What I mean is, in the later 75 percent, so after the 25 percent of incubation is started here.

DR. HOGAN: That is not what is printed in your model. That is important, because that is what you are asking us. On page 36 it says, the vCJD agent is assumed to appear in the blood of infected persons most likely after 75 percent of the incubation period of the disease has elapsed.
Those are different. Am I wrong?
Anyway, we can talk about that later, but that is two very different statements.
DR. GESCHWIND: Page 36 of which?
DR. HOGAN: It is on the next to the last bullet on page 36 of the model assessment printout.

DR. PRIOLA: It is actually referred to correctly on the page before. They refer to it both ways.

DR. ANDERSON: We will correct the document. You are absolutely right that that is an error. So we will correct that?
DR. HOGAN: So it is 25 percent?

DR. ANDERSON: But it does appear after the first 25 percent has elapsed, and it is present for the remaining 75 percent. So we will correct that.
DR. HOGAN: That is based on what information?
DR. YANG: That is based on the animal data.
DR. HOGAN: Thank you.

DR. ARIGOTI: I am Louise Arigoti from OBR. The 75 percent number came from the sheep data, the sheep infectivity data that was published by Fiona Houston a few years ago.
DR. HOGAN: Sheep in what disease?
DR. ARIGOTI: It is BSE and natural scrapie.
DR. HOGAN: Thanks.

MS. BAKER: Thank you for these presentations. For your module four, where you focus on utilization, you refer to the CDC articled published 1993-1998 data. Was that the only data source used for this utilization in nodule four?
DR. YANG: Yes. This is the only data we used.
MS. BAKER: Thank you.

DR. BARRAJ: I want to go back to the question that was asked earlier about the 2006-2010, and ask one more question. For the 2006-2010, the change in the parameters, we would have expected the risk to increase in 2010. I understand we tried all these iterations, but one way to put this thing to rest completely is to take for instance 2006 and simply change those parameters around them at the 1,000 iterations and see what you see there. I am not going to make you run the 2010 at a million iterations, but just doing that you could see whether you do see that increase, or how much variability you are seeing. That is one.

The other question that I had was about the difference for the MM and the other genotypes, the non-MMs, we are moving the incubation periods from 15 to 32. Where did you come up with this estimate to move from 15 to 32? Or were there any data?

DR. YANG: We don't have the data, but just based on country, the first case of the MM genotype appeared is in 1993. But by now we haven't seen any cases of non-MM. So we are thinking about this that there is from 1993 to now should be around 20 years, so we just make assumptions that the non-MM genotype has an incubation period that is 20 years longer than the MM genotype.

DR. ANDERSON: We haven't seen any cases in the non-MM. So if you take the start of the cases for MM starting in '95, you would assume that they were infected perhaps ten years earlier, let's say. So it has been 25 years at least.
So we assume that it is at least 25 years, so that is represented in the model.

DR. YANG: The assumption we used is, the median for non-MM is 32 years, but the confidence interval --
DR. ANDERSON: Is large.
DR. YANG: Yes, right.

DR. MONROE: One further clarification while we are looking at the convergence model data. The arrow there says the 2006-2009 models, but the scatter there is actually the 2010 model run at the same number of iterations as the 2006 and 2009 models, is that correct? That is, the actual data that is presented is the 2010 model at that number of iterations, not the 2006 model.
DR. ANDERSON: Yes.

DR. MONROE: One clarifying point. In the introduction, I believe you said -- maybe I heard this wrong -- that there were no subclinical cases in MM. But I think what you mean is that based on the tonsil and the appendix data, no cases have been identified, but clearly the model accounts for the infectivity if there would have been subclinical cases.
DR. ANDERSON: Absolutely, and the model does account for that.

DR. MANUELIDIS: I need a clarification about the infectivity studies. In the first talk, I heard that there was no prion agent, and that meant that there was no PrPFC visible. I think that is problematic.

But you mentioned infectivity studies. I would like to know what the animal model was, whether vCJD was used, whether brain was used, and how sensitive the model was for detecting infectivity.

DR. YANG: Could you answer this question? DR. HOGAN: Do we have that information available to us, or can we get it and come back to it?
We will come back to that.

DR. GESCHWIND: Just a quick point of clarification for Dr. Anderson. You mentioned a couple of times that there were no non-MM cases, but there is the probable case, right? Are you not considering that a case?
DR. ANDERSON: I'm not sure it is verified. The non-MM case, it appeared in the press, but has it been verified?
DR. HOGAN: There was no pathology done.
DR. ANDERSON: There was no autopsy done.
DR. GESCHWIND: But it is still a probable case. I think you have to assume that it is a case, even though it is probable.
DR. ANDERSON: We didn't really place that in the slides, but it is --

DR. YANG: Even if we see there are cases for MV genotype, because currently our models already include all three genotypes. So it will not change our model.

DR. ANDERSON: But you're right, we still acknowledge that. It is a probable-possible case.

DR. EPSTEIN: Could I just try to clarify, Dr. Manuelidis? Your question is, what data source did we use for estimating the infectivity in plasma, right? We were asserting that infectivity was based on animal models, and you wanted to know which data did we use, is that correct?

DR. MANUELIDIS: Actually I wanted to know a couple of things. It was very unclear to me whether you are using human material, and if so, how are you measuring infectivity in the human material, and what kind of animal model. Or second, in the spiking and other things, what kind of vCJD material are you using? Are you using brain, are you using plasma? And what is the sensitivity of the infectivity, especially if you are going cross species?

I just think that that is another problem in terms of estimating things, how infectious something is, if you don't have a model that is quite sensitive.

PARTICIPANT: If I understand your question, how we determined the level of infectivity in blood to put in the model, right?

DR. MANUELIDIS: No. I was unclear. I thought that you were speaking about what was in the plasma extract, and that you had looked at infectivity in the actual plasma olfactory extracts.

PARTICIPANT: I believe the model doesn't distinguish if the infectivity is in plasma or blood. We are just talking about infectivity in blood as we measured it as whole blood. I don't think it was distinguished -- it didn't distinguish what is in plasma and what is in the whole blood.

DR. MANUELIDIS: Is this human blood or is it some model of vCJD? Then what is the animal model that you are using to assess the infectivity?

PARTICIPANT: No, it is not in human blood. It will be in animal models. We used the hamster animal model. We used the mouse animal model. Those are basically the two models for which we have a quantitative analysis of the level of infectivity in blood.
DR. MANUELIDIS: But that is not vCJD, and there are animal models of vCJD.

PARTICIPANT: Well, but those animal models, the studies don't give us an infectious dose, so we can't really use it. In any case, we also looked at -- we started with one value and we put a range between infectious dose per ml. We go from .1 to 100 infectious dose per ml.
DR. HOGAN: Dr. Asher, did you have some clarification?

DR. ASHER: Steve might explain what was done. We had a question of how to model infectivity in human blood, which has never been detected experimentally, even though we know from the transfusion cases that it has to be there in human blood. But we had to have a number.

So what was done, and this was done after discussion with TSEAC Advisory Committee, was to use a triangular distribution, taking somewhere between .1 and 100 doses per ml as being most likely. The far points of the --
DR. ANDERSON: The tail went out to --

DR. ASHER: Went out to 1,000. You have to take some number, and there is no direct measurement of the infectivity in human blood in variant CJD. So everything has to be based on an animal model plus allowing for the uncertainty, the probable variability, plus a cautious margin of error, that is, taking something that is a realistic worst case, and the specific details of how the triangular distribution was set up.

That is done by the way for most of the assumptions in getting ready for a Monte Carlo analysis, which is what this model was based on. So unless you are absolutely certain that you have a point estimate, you have to take some sort of distribution, and the triangular distribution is a reasonable way of approximating the normal distribution. You have to base it on whatever little information you have. The only information that was available was from the hamster model.

DR. HOGAN: That's fine. I think we are going to go ahead with the questions so we can discuss this when we discuss the model. But that gives us some information about how the model was generated.

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Agenda Item: Summary and Questions for the Committee

DR. ANDERSON: I am going to start with some of the conclusions once this slide comes up on the risk assessments, and then move on to the questions.

Moving on to the conclusions of the risk assessment, this is really summing up many of the things that you heard today. Updates to the 2009 model, to account for the susceptibility of the entire population really weren't hypothesized to cause a significant change between the estimated risk between 2006 and 2010. That really is what we found. The results from the models indicated that the estimates for potential risk in 2010 were of course very similar to those from 2006, which you have heard already.

This doesn't substantially change FDA's interpretation of the risk, since it was based on estimates using the higher vCJD prevalence, that the risk is extremely small but uncertain. Again, accordingly as in 2006 we assume the current vCJD risk from U.S.-licensed plasma-derived product may not be zero, but it is likely extremely small, but we don't know the risk with certainty.

Some conclusions from 2006, that are really valid for today's meeting as well. It is not possible to precisely estimate the variant CJD risk. This is getting at the underlying uncertainties of the model, so estimating potential risk is really difficult, and we acknowledge that. Variant CJD risk from the use of U.S. licensed, the risks are assumed to be non-zero, but extremely small.

The next two points get at risk reduction measures. That is, the questionnaire and the current donor deferral policies have reduced risk considerably. Then another factor that is important in reducing risk is clearance during manufacturing processes. Both of these elements have significant impact on reducing risk, as predicted and shown in the sensitivity analysis.

Getting to the questions for the committee, does the committee agree with the inputs, either updated or new, to the 2009 FDA risk assessment model for U.S.-licensed plasma-derived Factor VIII. I am also reminding you of what those inputs were here. We will come back to that question. I wanted to get to the second question as well, and then we will go back and discuss.

The second question is, based on the 2010 updated risk assessment, FDA continues to believe that the risk of variant CJD, variant Creutzfeldt-Jakob disease to patients who receive U.S.-licensed plasma-derived coagulation Factor VIII, plasma-derived Factor VIII products, is likely to be extremely small, although we do not know the risk with certainty, and does the committee agree with that statement.

DR. HOGAN: We are about a half hour ahead. Do you want us to go ahead and have a break now, or to discuss it and vote?

DR. EPSTEIN: It is probably best to take a break, because we usually do open public hearing when it was scheduled. So we can just do a slightly longer break.

DR. HOGAN: We are scheduled for 10:45. That is a 45-minute break. I have never been ahead in this committee.
DR. EPSTEIN: Let's wait until 10:30. I think that is a fair compromise.
DR. GESCHWIND: Are we going to have time for more questions?
DR. HOGAN: Yes. So everybody come back at 10:30. Thank you.
(Brief recess.)

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Agenda Item: Open Public Hearing

DR. HOGAN: Welcome back. Round two. We are going to have the open public hearing session now. I need to read this into the minutes.

Open public hearing announcements for particular matters of general applicability meetings.

Both the Food and Drug Administration, and the public believe in a transparent process for information gathering and decision making. To insure such transparency at the open public hearing session of the Advisory Committee meeting, FDA believes that it is important to understand the context of an individual's presentation. For this reason, FDA encourages you, the open public hearing speaker, at the beginning of your written or oral statement to advise the committee of any financial relationship that you may have with any company or any group that is likely to be impacted by the topic of this meeting. For example, the financial information may include the company's or group's payment of your travel, lodging or other expenses in connection with your attendance at the meeting. Likewise, FDA encourages you at the beginning of your statement to advise the committee if you do not have any such financial relationships.

If you choose not to address this issue of financial relationships at the beginning of your statement, it will not preclude you from speaking. That said, we have nobody who is pre-registered to address the committee at this time. Is there anyone in the audience that would like to make any kind of statement? Dr. Robert Rohr.

DR. ROHR: I would like to make a couple of ad hoc remarks based on this morning's discussion. By way of disclosure, I am a TSE investigator of about 30 years standing. I do have a number of conflicts. I have consulted for a number of companies in the plasma industry, and I am one of the developers of the prion removal filter that you will hear more about tomorrow.

The main point I want to make is that in the sensitivity analysis which Steve was calling something else, but anyway, the two major factors are removal and prevalence. They both have major issues in my mind, the removal, because almost all of these things have been done, all of them as far as I know, have been done with brain homogenous spikes, which is a vulnerability. We don't know how well that represents TSE infectivity in blood.

The second point is the one I want to talk about now, and that is the prevalence. You are taking as your upper limit for prevalence the Hilton study. The point I want to make about the Hilton study is, the Hilton study is based on an analysis of a Western blot signal in spleen or tonsils from various patients. They found three cases in their series of several thousand.

The vulnerability of that analysis is that we have no idea what the ascertainment rate is for that type of surveillance. It may only be ten percent, one percent. There is really no control. There is no way of knowing what it is. If they are off by a factor of 100, it can have a huge impact on the analysis, or at least I suspect it would.

I would be very interested to know if Steve has looked at something like that and whether you have taken that type of thing into consideration.

The main point is though, I think it is a mistake to consider that as the upper limit. It can't possibly be a 100 percent ascertainment rate. It has got to be something less than that. That should at least be taken into account.
Thank you.

DR. HOGAN: Any comments? We can wait. I think part of the issue, at least for me, and I have problems with it as well, but I think it is the only bit of information that we have on prevalence. If you are going to base it on something scientific rather than just finding a number out of the air, I don't know what else you guys have looked at.

I think what Bob is asking is whether or not you have run this using higher numbers than the one in 4,000 for prevalence. We can address that at some point.

Is there anyone else in the audience that would like to address the committee? I don't see anyone, so we will open this discussion based on topic one information that you can see on the slide.

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Agenda Item: Open Committee Discussion

DR. HOGAN: Just to reiterate, does the committee agree with the inputs, either updated or new, to the 2009 FDA risk assessment model for U.S.-licensed plasma-derived Factor VIII? I would just like to remind everyone that in the 2009 meeting, we have already agreed that these inputs were reasonable. They have just been updated, although there are some new inputs as well. So is there any discussion on these points, any questions, comments?

DR. MANUELIDIS: I would just like to make sure that the record explains on the input -- something referring to what Bob says also -- that PrPSC is not equivalent to infectivity. There are certainly models where you have very little PrP and no PrPSC where there is high infectivity. There are lots of animal things in spleen, where you can inject the spleen. It is highly infectious, like sporadic CJD in hamsters, and it is infectious.

So I think that you have to give a caveat when this is written to say that this is PrPSC, which is not equivalent. The numbers may be higher in terms of infectivity.

DR. HOGAN: Well said. I think that the FDA staff has taken that into account. We are still waiting for Dr. Geschwind. Could somebody see if he is out in the hall? Thank you.

In the Hilton study they were looking at immunohistochemistry blots on lymph reticular tissue in spleen and tonsils. So they were looking for PrPSC after proteinase K digestion, and the staining in all those three samples was not the same. In only one of those samples was the staining similar to that seen in natural vCJD. The other two cases were different in terms of their appearance. So there is even more uncertainty about those numbers.

Any other comments?

 

DR. MONROE: To the question about the one in 4,000, in the model that was also a distribution, or that was a point estimate?
DR. ANDERSON: The question is, the one in 4,000, was it a point estimate?
DR. MONROE: Yes, or if it was a distribution, what are the bounds on the distribution that was used?
DR. HOGAN: Do you mean for the Hilton study?
DR. YANG: From that study they gave a mean of 277 per million, but there is a 90 percent confidence interval also.

DR. ANDERSON: We think the lower end estimate of that is about 40 per million, the upper estimate is about 650 per million. So we used a distribution, so that is the answer. DR. MONROE: And that distribution is based on the data that was presented in the -- DR. ANDERSON: Correct, and then the analysis within the paper.

MS. BAKER: Thank you for all this good work. I am concerned again about module four. The only article cited as the basis for the utilization was the wonderful article by Dr. Michael Soucie at the CDC.

That was a six-state surveillance study. The data period for that study was not 1993 through 1998 as referenced several times in these documents, but the data collection window was 1993, January through December of 1995.

I am concerned for a variety of reasons. It is old data for these purposes in terms of utilization for a number of reasons. Number one, HIV was cleaned from the blood supply at the end of the 1980s. So the youngest patients enrolled in that study would have been eight years old.

Now, in 2007 Dr. Marilyn Macon Johnson et al. and colleagues came out with a randomized clinical trial showing the positive results of prophylaxis in children with hemophilia. So treatment between prophylaxis and episodic has changed. There is much more prophylaxis being used.

In Dr. Soucie's subsequent studies, there is another whole database that I am wondering if the CDC consulted, and that is the universal data collection study that has been ongoing through 1998 through current prospective data in 130 federally supported hemophilia treatment centers, versus Dr. Soucie's data referenced here, which was the wonderful six state surveillance study. But those six states were not necessarily representative of the entire United States, and I am familiar with which states those are, but rather the universal data collection study that the CDC has sponsored prospectively since 1198 in 130 hemophilia treatment centers, that is much more representative data, and current data showing current treatment patterns, and that data is over 18,000 unduplicated individuals with hemophilia A, B, von Willebrand disease and other inherited disorders. There is data collected on treatment regimens, so episodic versus prophylaxis also by age.

We do know from that data that there is much more prophylaxis among the younger patients than the adults, but we do have -- that data could perhaps inform module four of the risk assessment.

So I am concerned about that, because prophylaxis has been increasing in a particular sense the 1007 Dr. Mako Johnson study. Dr. Soucie has shown since before and after that study was published, that individual treatment centers, the rates of prophylaxis have indeed gone up. So that is another consideration I have.

Also, there is some recent data published by Tom Howard in the New England Journal of Medicine in 2009. He is looking at different -- that African-Americans with certain genotypes have increased risk of inhibitor development. That data is now being confirmed. His work is at the Veterans Administration over in Los Angeles. I just talked to one of my colleagues there during the break.

So in terms of inhibitor development, the six state surveillance study may not have been representative -- I know it wasn't -- of African-Americans. So in terms of inhibitor development, immune tolerance, Dr. Carol Casper, who I just spoke with, she did confirm that some individuals with hemophilia who do use immune tolerance for their inhibitors, are indeed using plasma-derived product. There is another trial going on, I believe an individual trial, of immune tolerance failures on recombinant. People are switching to plasma-derived product for their immune tolerance, because that may be more effective.

So there are a variety of concerns that I have about using only Dr. Soucie's six state surveillance study as the input for utilization. Also, the universal data collection study from the CDC does have product usage and utilization.

There is another study that I am involved in, the hemophilia utilization group study, that is based at University of Southern California, that is a prospective study of Factor VIII usage of clotting factor concentrates. That could also be another potential source of data that the CDC could tap into, to help re-look at the model.
Thank you.

DR. HOGAN: I think that part of what you are going to hear from the committee today is, as new data comes in such as what you have just described, the model needs to be readdressed using better data, up to date data, so you can have better iterations and more up-to-date information.

DR. ANDERSON: We did work obviously with Mike Soucie with the data set that we had in hand. That was more than 17,000 patients or 17,000 entries over the period 1993 to 1998. The data set we had was from '93 to '98, I believe. That is what was shared from CDC.

So there are a lot of complexities here too, that we have to acknowledge. Younger patients now we presume are mostly going with recombinant products, so that is one issue.

So you are right, there are a lot of complexities and a lot of updating that we really should look at on utilization, and a lot of considerations. We have done that to some extent, but we haven't done it to the full extent that you describe, actually. DR. HOGAN: That is obviously a lot more work, but I am hoping you are going to do it.
That is a good point.

MR. BIAS: Just to echo what Dr. Baker is saying, treatment has evolved, and it has changed greatly over the last ten years. There has been a significant number of patients who have moved to recombinant treatment based on the prophylaxis study.

My suggestion would be, especially since you list inhibitors as one of the high risk populations that you are looking at, is to see what kind of data can be contrived or considered from what is going on with that world study, where you are actually going to have some patients who are coming out of the UK and Europe, who may have a different exposure. It might enhance the data that we are trying to use to assess the risk here.

Also, in the United States, although Factor VIII plasma-derived products are being used for immune tolerance, we are also now seeing a trend of this combination of therapies, where you do see kids who are trying to tolerize on recombinant products. You see kids who are tolerizing between a bypass product and a plasma VIII product.

All of those things will have an impact, I would think, on your model to some extent, if that is a patient population. We are all concerned within the bleeding disorder community of the prevalence of inhibitors that we are now seeing. So if that is a high risk point of the model, then perhaps some adjustment in the data should be looked at.

DR. YANG: I want to add in some information. When we developed the model, we do concede the universal data collection program. But the problem is, at that time we could only get population-based information, like how many patients in which patient group, what is the average usage. But we are not able to get individual patient usage data from universal data collection. We want to catch the variability among the patients. So we want to get individual patient usage data. So that is why we used the CDC sponsored six state data.

DR. MC COMAS: I have a q about the donor deferrals, so it is taking us in a different tack. It comes back to one of the conclusions, current donor deferral greatly reduced the risk by deferring individuals with a history of extended travel, et cetera. Looking through the data, how can you be sure that it reduced the risk? There is no data necessarily. Was that tested as an assumption?

DR. ANDERSON: That is a model based result and conclusion. So you are correct, we don't have any physical evidence of that. We don't have any verifying.

DR. MC COMAS: As you are pointing to what has been effective and what has been not, with granted what seems to be a fairly low risk, it is still a question of, to what extent is the donor deferral policy doing something, could it be improved.

DR. ANDERSON: We need to get a better handle on the extent of the effectiveness. We know that is affecting prevalence obviously, because we are removing people that potentially have the disease. So we are lowering the prevalence of the donor base. But again, we don't have those exact numbers, so that is why we have that wide range of the effectiveness of the deferral policy.
DR. MC COMAS: And the deferral policy was put into place in '96 in relation to vCJD?

PARTICIPANT: I believe it was in August of 1999, the first draft guidance. Recommending these deferral policies was put into place later. The UK deferral policy at six months was more stringently reduced to three months.

I would also note though that several of the vCJD cases that were identified in the U.S. would be people who would have been excluded from donation based on that deferral policy. And we have not had any post donation information reports of a vCJD case.
DR. MC COMAS: Thanks.

DR. GUO: The 2006 model and the 2009, that is, the current model, and the 2010 report is based on the 2009 model. We learned from the presentation that they (?). The slides presented that the lower prevalence is one scenario of five per million.

My question is, how do you look at the other scenario to do a similar analysis to study, to show the model's stability, since people are interested in the higher prevalence (?). Also, the estimate used the index year, 2002, for the annual risk estimate. So both the 2006 and the 2009 I believe use the same index year, is that correct?

DR. ANDERSON: The answer to at least the index year is, both models used 2002. The reason we chose that was, that was near the time that the new guidance policy for deferrals was implemented. We think the risk since then has decreased, and we can go and look at that a little bit more. But we just locked in on that 2002. We think if anything, the risk is decreased. We don't think the risk has really changed appreciably. So that is why we are still locked in in that 2002.

PARTICIPANT: With regards to the convergence analysis, we did run the same convergence analysis for low and high prevalence and for all the different usage categories that we had. All of the models showed great stability by the time we got up to a million iterations, and showed similar patterns in terms of the rate at which they reached convergence.

DR. HOGAN: Thank you. Any other comments? One thing I was thinking about -- I'm sorry, go ahead, Dr. Manuelidis.

DR. MANUELIDIS: Sorry for speaking so much. One other issue we should come back to which was mentioned by somebody else. That is the MM versus MV and VV prevalence.

I think that there is an assumption, based on the work of Collins, that only people with MM, because of these cases that appeared, would be susceptible to the vCJD agent. But in fact, experimentally, you can put vCJD into a mouse which is not MM, just an ordinary mouse, and it will take better than it will take in a PrP humanized mouse with MM. In fact, many people have made that model and have been unable to get it to go. It will go into a BSE PrP cow mouse.

So I would just say you may want to have a caveat about the assumption that people will get this disease very, very late if they are not MM, rests on the assumption that one is looking only at PrP. There are probably other factors in susceptibility.

I think that is important to put into your report. Just concentrating on this MM versus MV versus VV may be a very one dimensional type of analysis, and may not be correct ultimately.
DR. HOGAN: I think the staff heard you on that.

DR. ANDERSON: Yes, we did. I think within the current document we have assumed both populations are at least equally susceptible. But it merits further consideration. DR. HOGAN: What I was going to say is exactly on that point. As we get more information about the non-MM patients in terms of clinical disease, autopsy data, that will be important to add to the model. Rather than just assuming it, you will have some data.

DR. EPSTEIN: I would like to ask Dr. Manuelidis to comment. Whereas we have assumed that all genomic variants are susceptible, equally susceptible to infection, we have modeled a different incubation period for the non-MM. So do you think that that remains valid in the model or not?

Of course, the actual number chosen is somewhat arbitrary for lack of data, but do you think that concept is wrong? Essentially it is based on the absence of clinical cases.

DR. MANUELIDIS: That is just too speculative for me. I almost would say we just don't know at this point. These cases have not appeared, we don't know when they will appear. I wouldn't like to put a number on it, like 36. I don't have that kind of Delphic oracle ability at this particular point.

Why put a number in? All you can say is, so far the cases have shown more of a prevalence in MM human beings, but that may not be the only factor involved, and you don't know what will happen.

DR. GESCHWIND: If I recall, there is data from the mice data showing that there are different incubation periods. So at least there is some data that suggests that the incubation period would be longer for the VV or MV than the MM.

Right now, since we don't have data on the other cases on humans, I think you have to assume that it is longer, but how much longer --

DR. ANDERSON: Assuming a longer incubation period is actually more public health protective. If we just assumed a very short period of time, 75 percent of that is not as -- we would generate lower risk estimates than if we assume a longer incubation period; 75 percent of that period potentially has agent in the blood. So I think that is an important issue.

DR. MANUELIDIS: I just want to add a correction to that. I think that you are speaking about a particular model of a transgenic mouse. I am talking about ordinary mice plus mice that have high murine PrP. They are actually more susceptible when they go down to an incubation time of 130 days.

Also, the English group, Jean Manson, has in wild type mouse of a different type also eventually a very short incubation time, which is much better than what you get with the humanized PrP mice with the MM. So I think in terms of the incubation time, that may not be a correct statement in terms of the experiments.

DR. ANDERSON: But I just wanted to close the loop on this discussion about how we have been dealing with the non-MMs. We have struggled how to do that as modelers and within the center. In 2006 we decided there was emerging information, but not enough that we could put that into the model. Now we are putting these assumptions in, and we are trying to address it as best we can with the current data.

So yes, we are watching the situation. We are updating the model as need be. We made assumptions that we believe are public health protective. So if you have comments, we appreciate any comments or input, or pointing us to new information that we haven't included in the model.

DR. BARRAJ: I want to go back to the deferral policy and whether it is working or not working, and how we could potentially measure that.

By reducing the duration from six months, the minimum duration in the UK from six months to three months, the change that happened with the policy, you could put that in the model and say what is happening now with three months, how many cases am I avoiding by doing this, versus my six months. That could give you some estimate about how efficient --

DR. ANDERSON: We have actually evaluated that. We have evaluated six months, three months, and I believe 30 days. I don't have that information here, but we have done that exercise.

DR. BARRAJ: It might answer some of those questions we had before about the policy. DR. ANDERSON: But again, I think the decrease in risk as you go to 30 days, there is some, but I don't recall what that is.
DR. HOGAN: Wasn't the Japanese case only in the UK for 24 days?

DR. ASHER: I think of the three patients with variant Creutzfeldt-Jacob disease in the United States, none was a blood donor. But had they attempted to donate blood, two would have been unsuitable and one would have been a suitable donor. If the Canadian patient had attempted to come south and give blood, she would have been an unsuitable donor.

So we think that at least as far as empirical data are arriving, it has had a reasonable effect in reducing risk, but it was never claimed to be a risk elimination measure.

As for the incubation period, of the 174 cases in the United Kingdom, I don't know what fraction have been genotyped, but all the cases that made the case definition of confirmed cases have been MM.

The first case would have become ill in 1993 or 1994. Taking the case reported recently by Diego Caskey in a person who was heterozygous as being a probable case that will never be confirmed because there was no tissue, that person would have become ill in about 2008. The two persons with positive PrPSC in their appendices who were found to be homozygous for valine, neither one of those cases has appeared in the vCJD surveillance unit of positive patients.

So it does appear that the incubation periods in people with other than the codon 129, methionine and homozygous genotype, will have a longer incubation period. In the midst of so much uncertainty, I think that is one thing that we can be reasonably certain of. We don't know how many will come down, hopefully few, but of those who don't come down with clinical disease, we still don't know how many people will be silently incubating the disease and may have infectious agent in their blood.

But their incubation periods taken at the time of diagnosis in the first case in each genotype, the incubation period in those genotypes is clearly going to be longer than it was in methionine homozygous patients.

DR. HOGAN: I feel pretty certain that if those two valine-valine patients come to clinical disease, that thanks to Dr. Bob Wills' excellent work at the best surveillance unit in the world, they will find them.

DR. MC COMAS: Just a follow-up to that. So what you are saying is that the donor deferral policy would have worked in two out of three of those cases. So 66 percent of the time should we assume a perfect response that the donor was giving the correct answers, et cetera? That doesn't sound so great.

DR. HOGAN: We had to close the public hearing early. In the interest of getting as much information as we can, I am going to recognize a speaker at the microphone, if you would please introduce yourself before you speak.

DR. CERVENAKOVA: My name is Larisa Cervenakova. I am a senior scientist at the American Red Cross, and I work on prion diseases since 1991.

I would like to make a comment in regard to incubation period. Whatever Dr. Manuelidis said is true, that the mouse model of transgenic mice is not very susceptible. But we do have two examples which we are forgetting about. It is scurus and it is growth hormone patients as well.

The incubation periods in these populations of people which were affected with scurus and growth hormone were much larger in the population who didn't carry methionine homozygous gene. It means that we can, as Dr. Asher said, truly believe that people with known methionine-methionine genotype will have longer incubation period comparing to people who do methionine-methionine genotype. If this is 32 years, I am not sure about that, if you can put number on that, but definitely we would expect that the incubation period will be much longer in other populations than methionine-methionine homozygous. Thank you.

DR. HOGAN: Thank you very much for your input. Any other comments on this at the moment? We have talked about vCJD prevalence estimates estimate input, incubation period input, the proportion of genotype input, distribution of incubation periods for people of different genotypes, and prevalence of vCJD based on age distribution of asymptomatic vCJD in patients.

So I think if there is nobody else that wants to say anything, we probably can -- we will vote for number one and number two separately, is that correct?

So the question is, based on the FDA 2010 updated risk assessment, the FDA continues to believe that the risk of variant CJD to patients who received U.S.-licensed plasma-derived coagulation factor products is likely to be extremely small, though we do not know the risk with certainty. Does the committee agree with that statement, and agree with the inputs, either updated or new, to the risk assessment model for plasma-derived Factor VIII?

We are going to vote yes or no or abstain. We will just go around the room. Wait, you have a comment first?
MS. BAKER: Yes. Those are two different questions. We are only allowed to have one vote on both questions, and what if you differ on the two different --

DR. HOGAN: We can separate them out, I believe. So how would you propose doing it, the updated and then the new, as two different questions?

MS. BAKER: No, rather that, do we agree with the interpretation of the FDA regarding the analysis being small, as separate from, do we agree with the inputs.

DR. ANDERSON: So question one voted on in its entirety as one vote, question two as a second vote.

DR. HOGAN: I haven't gotten to question two yet. Well, question two is a little different. So we will just do question one now, is that okay with you? I don't understand what you are saying.

DR. MANUELIDIS: I can't understand, either. Could we have a vote on, if we agree if the inputs are updated, I think the first thing, would we like the inputs updated. Then I think we can vote on the question and say, yes, we agree.

DR. HOGAN: We have all sort of said we want them updated, but I suppose we could vote. Is there anybody that disagrees with wanting to have the data updated? Is there anyone who does not think they need updating?

DR. EPSTEIN: Could I perhaps clarify the situation that we are dealing with? The model updates were discussed in June 2009. What has happened is, we have gone ahead and completed the model based on those updates.

Now, everyone understands that there is a need periodically to update the risk assessment in its entirety. I think we have heard the sentiment of the committee that for certain parameters, specifically product utilization, that is warranted. So we understand that. But what we are really asking is, can we regard this piece of work as conceived in 2009 as done, recognizing that in a year or so maybe we should do it again?

I don't have a problem if the committee wants to stratify voting according to the various inputs. But remember, the committee endorsed them in June 2009, and we are just telling you, how we have completed the work, do you think we got it right.

We have heard committee members remark that there are new data and we should consider another update, but that would be yet another update. So really what you are saying, if you think that it would be in some way misleading to the public or the user community to finalize this update with the inputs that were previously discussed, then you should vote this down. But what that means is that we don't accept this as a final risk estimate.

DR. MANUELIDIS: Isn't there another way, just to add some of the caveats to the model that you currently have, and some of the questions or some of the additional data, without necessarily rejecting the low risk estimate that you have? In other words, one could vote yes for the model, but say that it has certain caveats, and that has to be in the report.

DR. EPSTEIN: I think we would be very receptive to a more detailed review and commentary on the report, and certainly could have a more robust discussion of caveats and limitations in the report. We could certainly accept specific comments from committee members on the text of the report. I appreciate that comment, because that is very helpful, finishing the model from giving a better discussion in the report. We would welcome that.

DR. HOGAN: Good. I think that addresses your comment too, Dr. Baker, because it would be updating.
MS. BAKER: Yes, thank you.

DR. HOGAN: I am told we can all just vote simultaneously and then if you have any caveats to your vote, then you can be recognized and bring those up.

So we are voting now. Do you accept the model as it is finalized now, yes or no, given all the discussion that we have already had.
(Whereupon, the committee cast its votes.)
DR. HOGAN: It is unanimous. Moving on to number two.

MR. EMERY: I would like to read the voters. Dr. Hogan voted yes. Dr. Barraj voted yes. Dr. McComas voted yes. Dr. Kreindel voted yes. Dr. Monroe voted yes. Dr. Geschwind voted yes. Dr. Priola voted yes. Val Bias voted yes. Dr. Manuelidis voted yes. Dr. Guo voted yes. Judith Baker voted yes. There were no votes for no, and there were no votes for abstain.

DR. HOGAN: Great. Moving on to number two. Based on the FDA 2010 updated risk assessment, FDA continues to believe that the risk of variant CJD to patients who received U.S.-licensed plasma-derived coagulation Factor VIII products is likely to be extremely small, although we do not know the risk with certainty. Does the committee agree?

Is there any discussion on that before voting yes or no? I think we have already discussed that. So once again, we will vote yes or no on that. So do you agree with that statement, yes or no?
(Whereupon, the committee cast its votes.)

MR. EMERY: For topic one, question two, the votes were unanimous for yes. Dr. Hogan was yes. Dr. Barraj was yes. Dr. McComas was yes. Dr. Kreindel was yes. Dr. Monroe was yes. Dr. Geschwind was yes. Dr. Priola was yes. Val Bias was yes. Dr. Manuelidis is yes. Dr. Guo is yes. Judith Baker is yes. There were no votes for no, and there were no votes for abstain.

DR. HOGAN: That concludes the morning issue. We are quite early, which is amazing. So I was going to ask, do you want us to come back earlier? We will come back at 12:30. This meeting will start at 12:30 rather than 1:45. Thank you. Have a good lunch. (Whereupon, a luncheon recess was taken at 11;17 a.m.)

AFTERNOON SESSION (12:35 p.m.)

DR. HOGAN: Welcome to the afternoon session. We have a new member here with us today, Dr. Jose Romero. He will tell you a little bit about himself.

DR. ROMERO: Thank you. Good afternoon. I am Jose Romero. I am Section Chief of Pediatric Infectious Diseases at the Arkansas Children's Hospital and the University of Arkansas for Medical Sciences. I am also a member of the Vaccines and Related Biological Products Advisory Board of the FDA.

TABLE OF CONTENTS

Agenda Item: Topic II: Labeling of Plasma-Derived Products Including Plasma-Derived Albumin and Products Containing Plasma-Derived Albumin to Address the Possible Risk of Transmission of Variant Creutzfeldt-Jakob Disease

DR. HOGAN: Welcome. We are going to talk this afternoon about topic two, which is labeling of plasma-derived products, including plasma-derived albumin and products containing plasma-derived albumin, to address the possible risk of transmission of variant Creutzfeldt-Jacob disease. Dr. Dorothy Scott will give us an introduction and information.

TABLE OF CONTENTS

79

Agenda Item: Introduction and Rationale for Proposed Labeling Change for Plasma Derivatives to Reflect Possible vCJD Risk

DR. SCOTT: Thank you very much. We will now begin the second topic. You have already heard the title of the second topic, but I do want to point out that we have had labeling of plasma derivatives for the potential risk of classical CJD recommended for plasma derivatives since 1999. So what is really new about this topic is the inclusion of variant CJD as a possible risk from plasma derivatives

This is the rationale for updating the package insert warning statements to address variant CJD risk. First of all, you have already heard at the beginning of this talk from Dr. Anderson -- at the beginning of the first session from Dr. Anderson, that vCJD infection was likely transmitted by a UK plasma derivative made from the plasma from donors from the United Kingdom, and that that recipient had hemophilia and received UK plasma-derived Factor VIII. He died of unrelated causes, and there was no evidence of neurological disease, but there was evidence of variant CJD infection in the spleen by western blot.

The risk was most likely from receipt of Factor VIII products. This is the 8Y product, the previous version of their Factor VIII product. He received two lots that contained plasma from the same donor, who later developed variant CJD, but he also received many, many units from non-implicated lots, which in fact when you add it all up and you consider the possible prevalence of variant CJD at that time in donors in the UK, those might have been responsible. For us it doesn't really matter. What happens is that it happened.

In addition, the U.S. risk assessment for U.S. plasma-derived Factor VIII shows that the risk is extremely small for variant CJD. But we know now from this that the risk is no longer theoretical. The risk for other plasma derivatives is likely to be even less, and I will show you why that may be the case, at least with respect to the initial fractionation products of plasma.

There is also a comparatively greater risk of variant CJD transmission by blood than for vCJD. This is a slide borrowed from Drs. Asher and Gregori. It depicts the recipients surviving greater than five years post transfusion of labile blood components and not plasma derivatives, from donors who later developed variant CJD in the UK or CJD. This is from the U.S. look-back study, the CJD information.

But what you can see is really quite clear, that of the 32 known recipients of labile blood components from donors that later came down with variant CJD, four of these have been diagnosed with variant CJD infection. The case is somewhat different for classical CJD in the U.S.; out of 144 recipients surviving who received components from these donors that later came down with CJD, none of them have been diagnosed with infection.

Statistically speaking, it makes it very likely that variant CJD in fact is transmitted at a much greater rate, and that classical CJD is transmitted if at all at an extremely low rate. There are no reports of human to human transmission of classical CJD by blood components or plasma derivatives.

Before we go any further with plasma derivatives, I want to point out that we already have risk labeling for variant CJD and classical CJD for blood and blood components. That was put into place by a guidance recommendation in October of 2009. This states, because whole blood and blood components are made from human blood, they may carry a risk of transmitting infectious agents, e.g., viruses, bacteria, parasites, the vCJD agent and theoretically the classical CJD agent. This is not the focus of our discussion today, but I just wanted to for the sake of completeness show you that this labeling has already been recommended.

The current safeguards to lower the likelihood that any variant CJD infectivity could get into plasma derivatives include, as we have already talked about, the donor deferrals for variant CJD risks which include travel to many BSE endemic countries, certainly including the UK, France and other European countries. In addition, if we had such a report, we have a recommendation in place to withdraw the plasma derivatives that contain donations from an individual with variant CJD. It hasn't happened here, thankfully.

Finally, you have seen from the sensitivity analysis that Dr. Anderson showed you that manufacturing processes might be the most important way to reduce risk of transmission by plasma derivatives of any kind of transmissible spongiform encephalopathy. We do know from a great deal of evidence that manufacturing processes for plasma derivatives can reduce TSE infectivity in laboratory scaled-down experiments that replicate manufacturing steps.

Dr. Groener is going to speak with you about this at length, and show you some very detailed information, but some of the very common steps used in manufacturing plasma products are the ones that happen to reduce TSE infectivity in these experimental studies. They include precipitations, depth filtration, column chromatography and NF filtration.

To talk about the labeling, I am going to subdivide it into two categories. One is plasma derivatives other than albumin, so that is everything but albumin. You will be seeing what some of those are in just a minute, and albumin in products containing plasma derived albumin as excipient or leftover manufacturing reagents.

The reason for separating these is that historically for classical CJD, the labeling for albumin and products containing albumin has been somewhat more reassuring even than for the other plasma derivatives. But we are going to talk about the other plasma derivatives.

The current labeling states, and this is in the warning section, because this product is made from human blood, it may carry a risk of transmitting infectious agents, e.g., viruses and theoretically the CJD agent. So obviously this does not address the no longer theoretical risk of human to human transmission of variant CJD by plasma derivatives.

This is that same statement I just read to you. I put it up there so you could contrast it with the proposed statement. This is what we are proposing for the committee's comments. Because this product is made from human blood, it may carry risk of transmitting infectious agents, e.g. viruses. That has not changed, the variant CJD agent and theoretically the classical CJD agent.

Part two, albumin. Albumin is directly infused as a treatment typically for hypovolemic shock and some other indications, or it is used as an excipient or in manufacturing of other products. It has been believed that there is an extremely remote likelihood of vCJD of CJD transmission by albumin, based upon the lack of any epidemiological evidence in the UK or the U.S. for CJD or vCJD transmission by albumin or products containing albumin. Additionally, TSE clearance by precipitation processes for albumin exceeds that of other plasma protein fractions. Just to illustrate what I mean by this, I am going to show you a highly oversimplified depiction of plasma fractionation. This would be typical, but of course there are many variations that manufacturers use.

Basically you begin with plasma. The goal is to separate out and purify proteins that are medical therapies. So first we have cryoprecipitation. The cryoprecipitate results in Factor VIII products. Then the cryoprecipitate supernatant is separated into -- this fraction I here, you end up with fraction II plus III, and it goes on and on and on. But what you really want to see is that some time after cryoprecipitate, you have immunoglobulins coming off, alpha-1 proteinase inhibitor, also antithrombin, and finally at the end of all this, albumin. You have a supernatant here, a supernatant here, a supernatant here, a supernatant here, a supernatant here, and here is albumin. So a lot of stuff got precipitated out over here.

That is really the only point I especially want to make on this slide, that it is at essentially the end of the plasma fractionation process.

In the first published study of TSE clearance in albumin, where an experimental model of plasma fractionation was set up, what I am telling you about albumin seems to have been fairly well borne out. There are many studies that have occurred since this that have supported it, both published and unpublished.

But in this, Paul Brown and his group looked at an endogenous infectivity model of TSE. So obviously this has to be done in animals. He took mice infected with PUKA-1 (?) strain that were also symptomatic, and he bled many mice and got their plasma. So this is infected plasma. Then he put it through a fractionation scheme, something like this. He looked at the fractions that would be destined normally to become products, including cryoprecipitate which would contain Factor VIII and von Willebrand factor, the IGIV fraction, the alpha-1 proteinase inhibitor fraction, and finally way down here for those of you who can see it, take my word for it, here is albumin.

He took that fractionated plasma and he injected about 30 to 40 percent of the fraction that he obtained into weanling mice intercerebrally, and then he waited and found out how many animals developed disease or did not. You can see that in cryoprecipitate, about 50 percent of the animals became ill. In the fraction that becomes IGIV, and believe me, it is only this part, fraction II, that really is IGIV, you have a much lower rate of infection. For these other fractions that come off later, you have an even lower rate. We don't know if he had used more animals if we would see anything here or even here.

The real point I wanted to make is that your possibility of infectivity goes down in this endogenous infection model.

There are many other studies that support this effect of sequential precipitations. I have listed some here, but I probably have fewer than half of those studies. A nice one to look at is Dr. Foster's review, but many of these are very interesting and informative papers if you want to think about how plasma fractionation and other plasma process and methods remove TSEs.

I'm afraid the current warning statement for albumin and the new proposed one are very long, so I have to put them on separate pages, but this is the current warning statement since 1999. This product contains albumin, a derivative of human blood, or in the case of albumin for infusion, it will say albumin is a derivative of human blood. Based on effective donor screening and product manufacturing processes, it carries an extremely remote risk for transmission of viral diseases. A theoretical risk for transmission of CJD is also considered extremely remote. No cases of transmission of viral diseases or CJD have ever been identified for albumin.

I have underlined what is new here. All of this is old, about albumin and the remote risk for transmission of viral diseases, but then we add in with viral diseases as having an extremely remote risk, or variant CJD. Then a new sentence which still conveys very similar information about classical CJD. There is a theoretical risk for transmission of CJD, but if that risk exists, the risk of transmission would also be considered extremely remote. Then the final statement that no cases of transmission of viral diseases, variant CJD or CJD have ever been identified for albumin.

I think before I yield the floor to Dr. Groener, I will just remind you what our questions are, so that you can ponder these in the context of his presentation as well.

There is one question and one comment period. The question is, given the evidence of variant CJD transmission by non-leukoreduced blood and plasma-derived Factor VIII in the United Kingdom, does the committee agree that labeling for the potential risk of variant CJD is warranted for the following products: plasma derivatives other than albumin and plasma-derived albumin in products containing plasma-derived albumin.

We very much appreciate if you wish to comment on the proposed wording for the warning statements for both of these scenarios.

I guess if there are any questions, I could go ahead, then we will hear from Dr. Groener.
DR. HOGAN: Does anyone on the committee have any questions?

DR. GESCHWIND: I guess one issue that has come up in discussion with others that I brought up is an issue of terminology. I'm not sure what the best answer is. I deal a lot with patients with prion disease, and the terminology for how to call their disease has been confusing. I think most people in the field use the term prion diseases to refer to sporadic CJD, variant CJD and the genetic cases.

One of the things that I see missing here are any reference to the genetic cases, which are not technically classic CJD. I brought this up to the people at the Red Cross, too. I follow more than 100 families of genetic prion disease, and my GSS families have been donating blood for years prior to coming to visit me. They said, it is okay, because we go to donate at the Red Cross and it is very explicit. It says, if you or a family member has CJD. It doesn't mention Gerstmann-Straussler-Scheinker, so it is okay for us to donate blood.

So I think that we have to have a more general term. I'm not sure if it applies to this specific for a safety comment for albumin, but just the notion that we are limiting ourselves if we just use the term CJD or classical CJD. I would prefer a term like prion diseases. It is a little more updated. I prefer that to TSEs as well, even though I know this is a TSE committee.

DR. HOGAN: You are talking politics here. I think it is a good comment. We will think about it. Is your point on target?
DR. CERVENAKOVA: Yes. I would like to comment on the table.
DR. HOGAN: Would you like to tell us who you are again?

DR. CERVENAKOVA: Yes, I am Larisa Cervenakova, Senior Scientist from the American Red Cross. The table, TSE clearance, albumin interruptions, this one, I don't understand how you come up with negative animal numbers. I was part of this study, and we never inoculated 94 animals. This should be somehow explained, how you did come up with this number of animals.

DR. SCOTT: Actually I came up with it from one of Paul Brown's papers, so maybe when this session is over, we can look at the paper and figure out which number is correct.

I was interested to see that you all injected more from the fractions that came down later, in an attempt I think to determine if there were any infectivity, but albumin had the most. So we can straighten it out, and if I need to make a correction, I will.

DR. HOGAN: I think she was actually second author on that paper.
DR. SCOTT: Yes, I know. So there is a greater chance that she is right than that I am right. But the point you would say still stands.
DR. CERVENAKOVA: The point stands, but just for clarification of the table.
DR. SCOTT: Thank you very much.

DR. MANUELIDIS: You mentioned that there are no cases of human CJD that have been transmitted from blood. There is a Lancet paper from our lab in 1985 that says human transmission of sporadic CJD to hamsters.

I don't like the word theoretical. I just would put everything into a very low or negligible risk. I don't think there have been a lot of experiments on transmissions from blood or my blood cells, we did it from my blood cells, from sporadic CJD, and probably the best model might be primates, but that is very expensive to do. Most people use mice. Mice are not susceptible. That particular agent is very avirulent for mice. It is much more virulent for other species.
So I wouldn't separate them that way. In that way I agree with Dr. Geschwind.

To be fair, rather than be political about it, why not say transmissible encephalopathies, prion diseases, Creutzfeldt-Jakob disease, just be inclusive about it. Just add the terminology, because that way it will get to all doctors and that is what we want to do. We don't want to have a political discussion about what the agent is.

DR. HOGAN: I think your point is well taken. I am hoping that the staff is taking -- we are putting the cart before the horse a little bit, but I see them taking notes. Anything else, Dr. Geschwind?

DR. GESCHWIND: No, I think that is a great idea. DR. SCOTT: I think we would be interested to understand from the risk communication standpoint, and you all might want to help us out with this in the discussion, the extent to which patients and physicians reading any of this terminology other than variant CJD or CJD are going to have a clue of what we were talking about. That is the only thing that we were worried about. I agree, it is an oversimplification, there is no question.

Also, in terms of the Gerstmann-Straussler-Scheinker patients who were donating blood, I think that is the kind of thing that needs to be fixed on the donor deferral level. It is a very important thing for us to think about.

DR. MC COMAS: Just a quick point of clarification. Have you done any testing or focus groups with physicians or patients on these messages?

DR. SCOTT: I would say that what we have done is, initially we had the draft guidances. We are aware that blood centers and plasma centers in a sense tested out some of these questions and initially came back to us with more questions. I think they became more comfortable with explaining to people what this meant. But did they do any focus groups? To my knowledge, no.

Jay, you might know if the UDHQ did anything with TSE, but I don't think that they did. When the universal history donor questionnaire was designed, I think this came late in the game in that design, and so there weren't groups dedicated to addressing the comprehensibility of those questions.

DR. EPSTEIN: These questions would have been part of the focus group analysis of the donor history questionnaire, which is now part of the standards for the AABB. But I don't recollect whether there was specific attention to this question as part of that. I just can't answer that. It is knowable, but I just don't know it at the moment. There were focus groups that looked at the donor questionnaire, including CJD related risk questions.

DR. HOGAN: Anything else? Anyone else have any comments? Because we have a lot of time, I am going to recognize the lady at the microphone back there.

DR. CARGREW: I am Aline Cargrew with AABB. I do work with the Donor History Questionnaire Task Force that Jay just referred to.

The question did not get a lot of extensive work. We basically just followed the guidelines that have been in the guidance documents that came out, and it just uses the disease by name, Creutzfeldt-Jakob disease. If there is an understanding of the disease, that is basically how the donor is captured.

But I just made a note about the other disease, the letters that were thrown out, so we can go back to the task force and inquire about that. I am listening to those questions, these things that were brought up. But there was not extensive, beyond the information that was in the guidance document.

DR. HOGAN: Thank you. Does anybody know if there is infectivity in GSS blood? Okay, I guess we don't.

DR. MANUELIDIS: I should say, what you get out of GSS patients is, you get a sporadic CJD agent in Western Europe and the United States. In Japan you get a Japanese agent, which is quite different.

DR. ASHER: The Fukuoka-1 strain of TSE agent was derived originally from a patient that was initially diagnosed with familial CJD, but was later re-diagnosed as having GSS.

From the very beginning, I have not been comfortable with making a firm distinction between familial CJD and GSS. I'm not convinced that making that distinction has produced a public health benefit. In addition, there appear to be certain patients with a diagnosis of GSS from which transmissible agent has not been demonstrated, so it is an additional consideration.

DR. HOGAN: Thank you. We can come back to this at the discussion point. Is there any other comment? Dr. Groener is going to speak to us now about TSE clearance in manufacturing of plasma derivatives.

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Agenda Item: TSE Clearance in Manufacturing of Plasma Derivatives

DR. GROENER: Good afternoon. My name is Albrecht Groener. I am working for CSL Behring, and I am head of the Pathogen Safety Department. Here I am now presenting data on behalf of PPTA.

We had this morning a discussion on the risk assessment. I would just focus on that. One major aspect is the epidemiology in the donor population. We have our donor deferrals for variant CJD risk is instituted in 1999, and continue to be updated, and the last update is 2010.

One other aspect is the prion load in the incubation period in an infected subject. We can consider that the prion load is very low in blood, or especially in plasma, based on animal studies and in transfusion incidence in U.K. Very low is at least in relation to the known blood transmissible viruses.

I will now discuss the prion reduction capacity of the manufacturing processes of plasma-derived medicinal products, because that is also based on the risk assessment the major driver for the low transmission risk of variant CJD plasma derivatives. Last but not least, the risk assessment was discussed.

When I was here one and a half years ago roughly, we discussed that prion reduction studies were performed, several considerations has to be taken into account. That is first of all, we need to have a valid downscale of the manufacturing process. Only then we have demonstrated that our laboratory scale is predictive for the manufacturing scale and is mimicking it very closely. The reduction factors we have demonstrated are predictive for the manufacturing scale.

Then we may have to discuss the choice of prion spiking agent, the preparation of the spiking material, the choice of assays for the quantification of the spiked material, and whether conditioning of the spiking material by the manufacturing process will have an impact on the overall reduction capacity. Therefore we come to the conclusion at that time, based on our model and ten years' experience with prion studies, that the prion material derived from different species had no impact on different reduction factors. That means they have comparable reduction factors.

If we would concentrate on induction activity to spike plasma intermediates, then we would alter significantly the physical-chemical properties of such a preparation and it would not any longer intouch(?) infectivity.

We also discussed, and I will show it again, that biochemical serological assays as well as bioassays reside in a comparable reduction factor. Then when we add up the reduction factors of individual spiked manufacturing process steps, then we can demonstrate that in most cases the sum of the individual reduction factors are comparable to the reduction factor if you would have a combined step approach.

Here I now show you some data. Most of them you have seen already last year. These are U.S.-licensed Factor VIII products anonymized for the different companies, where used in brain homogenate. You should clarify brain homogenate by low speed centrifugation or microsomal fractions, used in bioassays or western blot, different manufacturing steps, and we were coming up to 8.1 log, four log, 4.2 log, or different products, slightly different slide preparation, western blot and bioassay studied in parallel, coming up with very close reduction factors.

Here, another product we were using the western blot, but in CDI as well as in bioassay, and despite material was either a microsomal preparation or a purified non-membrane associated PrPSC, the reduction factors were lowest for these two preparations and especially very close where we determined the reduction factor by CDI or by bioassay.

Now I will show you three non-U.S.-licensed Factor VIII products. Here again, detergent treated brain homogenate or microsomal fractions, western blot here, also western blot or here CDI, again microsomal preparation and the purified non-membrane associated PrPSC. 5.5 log overall here, 6.5 log overall here. It was studied yearly, the whole process of the manufacturing for these Factor VIII products, resulting in a four to nearly five log reduction, depending on the spike material.

I now summarize our experience with plasma-derived Factor VIII products. We can say that all products had at least a four log reduction capacity for the Factor VIII products licensed in the United States, but also outside the United States. Therefore, when we take together these data in the FDA guidance on donor deferral based on the geographic risk, then we can conclude -- and are definitely in agreement with the risk assessment, which you heard just this morning -- that the risk to transmit variant CJD via plasma-derived Factor VIII products is extremely small.

I would now like to update you a little bit on other plasma derivatives. We as other companies diligently assess the prion reduction capacity also of other plasma-derived products on an ongoing basis.
Here I show you some data on immunoglobulins, again Company A and B. Brain homogenate, bioassay study, excellent, very, very high reduction factor.

Here, Company B, brain homogenate in bioassay, the microsomal fraction, purified PrPSC by CDI, coming up also with very high reduction factors.

Other products C and D, bioassay again. Here is only one combination studied of a huge variety of other manufacturing steps which were not studied, coming up with more than 6.6 log. The company or product D is also selected manufacturing steps, not the whole manufacturing step, BEG precipitation followed by depth filtration, and currently so-called -- filtration, which should be called according to my knowledge -- filtration, 35 millimeter (?) very high reduction factor as you see here. The difference in reduction factor is based on -- the western blot is much less sensitive than the infectivity assay. That is the only difference.

When we are now looking for hybrid immunoglobulins, we come up here with a bioassay with a high reduction capacity, at least according to the risk assessment for Factor VIII, more than 46 log. Or here, product B, again in bioassay, that is in CDI, again more than four to six log for the hybrid immunoglobulins, for antithrombin 3, a product from Company A or B, six log, five to 6.6 log.

When we are now looking for albumin, you just heard that albumin is a very safe product. The assessment that it is a very safe product, I can only support. There are several manufacturing steps, but not all manufacturing steps you just saw about these different increasing ethanol concentration steps, not all there studied.

We got here six log or five to six log or more than seven log. We also have other products, alpha-1 proteinase inhibitor, C1 inhibitor or prothrombin complex concentrate, just to show you they were all at least in the range of four to six log you just learned about the Factor VIII product.

Then we now conclude. We can say in our opinion for albumin as well as for other plasma-derived products, definitely immunoglobulins, the manufacturing process step demonstrated very high level of prion reduction, and the risk of transmission of variant CJD is extremely remote, especially when we are considering the yield of the product, which is higher than for Factor VIII products, and the usage of the product is usually also based on a per liter plasma starting material, lower for the other products than for Factor VIII product. Therefore, the risk is even smaller for these products than for Factor VIII product. It would have to be calculated, but as a rough assumption I would make that statement.

I now conclude. I would like to say that we assure the highest level of safety for our products by continue to adhere to the regulatory guidance. That means primarily donor deferral and donor management, and only donors from U.S. FDA-licensed donor centers are allowed to be used for the product of U.S.-licensed products.

We continue to improve the understanding of the prion reduction capacity of manufacturing processes for products, both licensed and under development. We also continue to invest in the research in the field of prions. Thank you.

DR. HOGAN: Thank you very much, Dr. Groener. Are there any comments or questions from committee members? Most impressive data.

DR. MANUELIDIS: I just have a quick question. I am very curious. The detergent treatment, can you tell me what detergent it is, number one, and number two, if this is what you use when you are going to do these things for the product. Number three, what happens if you don't use detergents, something about the clearance?

DR. GROENER: That is a very good question. I have to admit, I don't know all the answers because these are anonymized data, and I just present them so to speak. But nevertheless we have experience.

The detergent material will be isoliso -- all ST rated, because the ST treatment is part of the manufacturing process of some or several of the factors, Factor VIII products; there are other products. In some companies we are using different preparations, I forgot to point it out, depending on the manufacturing step where they spiked, when they spiked in the ST treated, intermediate or (?) intermediate were used in detergent treated product.
Excuse me, the second part of the question was?
DR. MANUELIDIS: I just asked what is the clearance like if you don't use detergent.

DR. GROENER: Based on our own experience when we were using microsomal fraction without any detergent, or these purified PrPSC, and all the membranes were removed and high speed concentrated, then you saw that the microsomal fraction and the PrPSC spiking material was comparable in the overall reduction capacity. Therefore, it doesn't seem to have a huge impact whether you treat it or not treat it. We have to consider of course that we have a process which is using not normal blood conditions. We have either fairly high concentration of ethanol or very high concentration of ethanol. We have different pH values. We have different tonic strengths, significantly different tonic strengths than in blood. So the experience which is based on blood or plasma may not be always relevant for plasma-derived intermediate.

DR. MONROE: I agree that in aggregate, this is pretty impressive data. I am just trying to make sure I understand. I realize there is a little bit of comparing apples and oranges here, that things are spiked at different points and whatnot.

But given the flow chart that we saw from Dr. Scott showing that albumin was one of the more downstream products if you will, you have some data, for instance the ID data, which have these remarkable seven to eight to 11 log reductions, versus the albumin, which are still very good, but five logs or four logs less than that.

Does that reflect that things were spiked at different points in the process, and you are only looking at -- each data is only looking at some subset of the total manufacturing steps?

DR. GROENER: Here you see the major manufacturing steps, fractionation steps, depth filtration and virus filtration , or here again, aktanoid(?) depth filtration and virus filtration we used in that case, filled with a pore size on the order of 20 nanometers.

Here we have tested three, at least three manufacturing steps. When you are looking for the albumin, it is one or two manufacturing steps we just studied.

DR. MONROE: So it is fair to say that these represent the minimum values of the reductions that are occurring in the total manufacturing processes?

DR. GROENER: Yes. For instance, we have published data. When we were using three or four manufacturing steps, we had depending on the spiking material, between more than seven log and more than 11 log.
DR. MONROE: Thank you.

DR. PRIOLA: With regard to this, I think it is important to remember, these overall reduction factors that you list aren't related to how much infectivity is present in the initial spike, because no infectious spike has 15 logs of infectivity.

So it is best to look at these steps individually. The overall reduction I don't think is a valid number, but the reduction levels for the individual steps, I think that is fine, is that correct? You are just basically adding up.

DR. GROENER: We are adding up, and that is the way it is done at least for virus validation studies. It is also a (?) to make the risk assessment. These four to six logs or seven to nine logs are based on the overall reduction demonstrated by adding up the reduction factor for individual steps or sometimes using a combined step approach where several steps were combined right at the beginning and tested at the end of two, three, four manufacturing steps.

DR. PRIOLA: It is very impressive that you bioassayed these individual steps, but there is no way that you can combine them and get a 15 log reduction when the most you can be starting out with is -- and I am being generous -- ten logs.

DR. GROENER: No, I agree, but we don't say we would be able to demonstrate a 15 log reduction from spiked material. What we can only say is, we have a huge capacity of reduction, and the risk assessment is also based on the probability of the concentration of prions in the starting material in plasma, and then the yield, how many units you get out of one liter of plasma, and take into consideration the reduction capacity.

At least for viruses, you are expending to have -- no, you are on a very safe cycle that way, and you can demonstrate a four to six log safety margin. That means when you have your reduction factor subtracted from the potential maximum load in your amount of plasma to produce one vial of product, then you will still have a six log safety margin. When you reach that six log safety margin, you are definitely on the very, very safe side, because this six log is derived from the sterility assurance level for all pharmaco PIs I know of. DR. HOGAN: I think I would call a 15 log reduction sterilization.

DR. ROMERO: I have to say that the data is extremely reassuring. This is also for the committee, if anybody knows this information. I am looking for some additional real world support of this.

There is a congenital condition called X-linked agammaglobulinemia, in which children are born without B cells. These individuals get chronic and/or viral infections in primarily the central nervous system.

One of the therapies for this, it is not practiced very often in today's world but was used in the past, was intrathecal administration of intravenous gamma globulin. Do we have any information, looking back at those patients, regarding the presence of prion disease, either in the brain or spleen or other organs of those individuals?

It is possible it has never been done, but I am throwing out it for experts in the committee, if you would know about that.

DR. HOGAN: I don't know of any intrathecally transmitted cases using IVIG. But it is important to watch. Any other comments?

DR. GESCHWIND: Getting to Dr. Priola's comment, these overall reduction factors really are a theoretical overall reduction factor. They are not actual. Each individual one might be actual, but to sum them up is not real. It is theoretical that if you actually started with a 15 log, which you don't, level you would reduce them. So this really is a theoretical number. I think that is my first point.

The second is, are these data -- have they been published, have they been peer reviewed? Who did all these analyses? It sounds like each company did their own internally and they provided you the data, is that correct?

DR. GROENER: That is correct. The data are partly published, partly they are not published, partly they can be extracted to a certain degree from the package insert of U.S.-licensed product, but only to a certain degree. Some data are currently not published, at least not in a peer reviewed journal.

DR. GESCHWIND: I would certainly feel more comfortable if the FDA were using data on peer reviewed literature.

My second point would be, your second slide, you mentioned prion load during incubation period in infected subjects, prion load very low based on animal studies and transfusion incidents in the U.K.

Maybe it is an issue of definition, but whether it is high or low, it is certainly sufficient, the prion load is sufficient during the incubation period to cause transmission.

I am forgetting all the numbers, maybe somebody else on the committee or Professor Will will have more information on this, but if you think about the three or four cases that did come down with variant CJD, and you look at the total number of patients who are exposed, that seems to me to be a pretty high number. It is not very low.

It seems like the prion load is sufficient to cause disease. My recollection was that there might be 60 patients. Maybe those were only 60 patients still surviving who have been exposed to contaminated product. But I can't remember the number who had died. Most patients who get particularly blood products, not these other products, most of them have a pretty short life span anyway because they are so ill. But to have three or four cases to me seemed pretty high. So to say that it is very low, I'm not sure I agree with that.

DR. GROENER: This very low is based in comparison to viruses which can be transmitted by a blood transfusion, as HIV, HPV, HCD. These are really high. These are several logs, six, seven, eight, nine logs per millimeter.

Here we are discussing the order of ten. As you just heard of the risk assessment, nobody knows exactly how high it is, but it will be most probably not exceeding three log. That three log is based on the -- if I recall it correctly, based on the detection limit of an assay by western blot, the detection limit for 1,000 IUs, in that order of magnitude, 1,000.

So the very, very, very conservative approach, the risk assessment that was done by the FDA was up to 1,000, between point-something up to 1,000, and the mean would be ten, the triangular distribution used in the probabilistic model. That is the one topic.

The other topic is, you are correct. We don't know exactly, but it is not zero, no question about it, it is not zero, but it is low. Therefore when I had the animal studies between two, ten, maximum 30 infectious doses per milliliter, and the transfusion incidence, you just saw from Dr. Scott, the table, 18 transfused and four transfusion cases. That means per transfusion, when you take all together, is less than one infectious dose in transfusion, which may be -- no, not only may be, is under certain conditions sufficient to transmit the disease.
DR. HOGAN: Dr. Scott, did you have something else to say?

DR. SCOTT: I have a lot to say, but I will only say some of it right now. It was four out of a total of 32 identified transfusion recipients of blood or components that were donated by someone who came down with variant CJD within five years. I'm sorry, where the recipient lived at least five years. Actually, the donations went back a little further.

With respect to the comment about FDA reviewing peer reviewed literature, the peers who review it, I didn't include this in my talk, but actually we have allowed companies to come in and present us with all of their data for these studies in support of a labeling claim.

So we see not only what somebody would see who is reviewing the literature, we see all of the raw data. We see every aspect of the experiments. We see the spike characterization. So for those labels for which we have approved TSE clearance labeling, we have seen all of that. That isn't comprehensively everything that you have seen here, and I think many of these studies are recent or in progress, but some of them we have reviewed in a lot of labeling claims.

The second part of that is, we allow the company to state what steps they removed how many logs for, but we don't put a sum in that labeling claim. So we have diverged from how the labeling claim appears for viral reduction.

Nevertheless I think it is reasonable to imagine that in steps that are likely to be non-similar with respect to how they remove the TSE, you might have an additive effect, but you can't measure that, as you say, because you can't get a spike high enough to do that.

DR. GESCHWIND: I think the last point you brought up is a good one, and related to what Dr. Priola was saying. If you get a four log from three different steps and three different experiments, the techniques might be identical. So you are still getting the same -- you can't total them up.

DR. SCOTT: The mechanism of removal might be identical. So where we have companies that want to claim two steps that are very similar, even the same, what we ask them to do to get a claim at all is to do a throughput experiment where they perform those steps in their proper sequence that replicates manufacturing. Sometimes you remove more and other times you don't.

There are other caveats to that obviously, and these are scaled-down experiments, you can't be perfect when you are replicating manufacturing. But they use real manufacturing intermediates. We encourage conditioning of the spike, so something that is solvent detergent treated upstream, we want that same intermediate, the solvent detergent treated upstream, to be run through the step that they are studying.

It is about as rigorous as we can get within the limitations of how you can do these studies.

DR. HOGAN: Thank you. Anyone else have anything to say right now? Thank you very much, Dr. Groener. Dr. Scott will come back to the questions again for us.

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Agenda Item: Summary and Questions for the Committee

DR. SCOTT: This isn't so much about the questions. Earlier Dr. Cervenakova -- we spoke about one of the slides in terms of how many mice were injected and how many were infected. The good news is that we are both right, impossible though it may seem. I was using the information from Paul Brown's first paper in Transfusion on endogenous infectivity, and in the second paper on which Dr. Cervenakova was the co-author, they may well have injected fewer mice, but they replicated those experiments of endogenous infectivity. So I hope that clears things up.

DR. HOGAN: Dr. Scott, at this point on the agenda you are going to discuss the questions. You have already done that. Is that something you want to reiterate? Then we are going to break. We are about an hour ahead. Perhaps it would make more sense if we took the break and then you did it.

The public hearing is scheduled to occur at 3 o'clock, and it is 1:35. So Jay, give me some direction.

 

DR. EPSTEIN: We have no requests for speaking in the open public hearing for this segment, so I would assume that any interested parties came here. So at whatever point is convenient for the Chairman, you can have an open public hearing.

 

DR. HOGAN: Why don't we take a half hour break, then everybody come back at 2 o'clock.
(Brief recess.)

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Agenda Item: Open Public Hearing

DR. HOGAN: While people are getting seated, in the interest of keeping the momentum going, in a moment I am going to ask if there is anyone who wants to speak at the open public meeting. No one has pre-registered, but if you want to speak, now would be the time. But first I have to read this announcement again that I read this morning.

Both the Food and Drug Administration and the public believe in a transparent process for information gathering and decision making. To insure such transparency at the open public hearing session of the Advisory Committee meeting, FDA believes that it is important to understand the context of an individual's presentation. For this reason, FDA encourages you, the open public hearing speaker, at the beginning of your written or oral statement to advise the committee of any financial relationship that you may have with any company or any group that is likely to be impacted by the topic of this meeting. For example, the financial information may include the company's or group's payment of your travel, lodging or other expenses in connection with your attendance at the meeting. Likewise, FDA encourages you at the beginning of your statement to advise the committee if you do not have any such financial relationships.

Should you choose not to address this issue of financial relationships at the beginning of your statement, it will not preclude you from speaking.

So would anyone like to say anything relevant? I see no one, so we will move ahead. We have people we have to wait for, so talk among yourselves.

Dr. Scott, would you mind re-presenting the questions to us, please?

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Agenda Item: Summary and Questions for the Committee

DR. SCOTT: The question followed by our request for comments. The first question is, given evidence of vCJD transmission by non-leukoreduced blood and plasma-derived Factor VIII in the United Kingdom, do you agree that labeling for the potential risk of variant CJD is warranted for the following products, subdivided into plasma derivatives other than albumin, and plasma-derived albumin and products containing plasma-derived albumin?
DR. HOGAN: Do you want us to consider those separately? Yes?
DR. SCOTT: I would ask yes.

DR. HOGAN: So two votes. So we will just stick with number one for now. Comments and discussion among the committee members relative to the labeling issue for plasma derivatives other than albumin? No one.

One of the questions that I have asked a couple of people that nobody is able to give the answer to because it is so complex is, a lot of this is based on the case of the hemophiliac who came down with vCJD that was reported in 2009, from an implicated vCJD plasma donor pool.

My question was, how many people received components from that pool, other than the index case. I am told that getting that data is nearly impossible because of the complexity of recordkeeping. There really is no idea how many there might have been. I asked an informed individual, and they couldn't even tell me whether it was hundreds versus thousands or tens.

But I think that is an important issue, since there is no one else that has come down in the United Kingdom to date. But anyway it does warrant from a public health standpoint being careful, since that certainly is implicated as being a true case.

That said, does anyone else have anything to say about the labeling issues? We can talk about the language in a moment. No?

DR. MANUELIDIS: Again, I just don't understand. Is this going to be just for vCJD and then we are going to discuss the others?

DR. HOGAN: Yes, it is just for vCJD. Given evidence that the vCJD seems to be transmissible to hemophiliacs in this context, does the committee agree that labeling for the potential risk of vCJD is warranted for plasma derivatives other than albumin. No discussion, so let's go ahead and vote. Sorry, Dr. Monroe.

DR. MONROE: I would just like clarification on why the FDA -- I understand the logic for why there is a so-called non-theoretical risk for vCJD from plasma components, but since there is no demonstrated cases resulting from albumin, why FDA thinks it is a non-theoretical risk for albumin specifically. I guess that is 1B.

DR. HOGAN: Given the data we saw on clearance, one would question whether albumin would be necessary to be labeled, unless you are just being very conservative and careful. People may agree and want to vote on that. However, we can discuss it and they can understand how we are voting. Any other comments? Your point is well taken.

Right now we are not dealing with the albumin. We are dealing with derivatives other than albumin for the next vote.

DR. EPSTEIN: I think the way we look at it is that the data on clearance of infectivity and/or PrP are model data. We don't know what actual infectivity or actual clearance are. So we are looking at this as relative risk.

But we are saying there is a new context here, because there is the highly probable case of transmission from a plasma derivative, which confirms that there is infectivity in plasma which might end up in some end products.

So what we are trying to put together here is on the one hand the finding of an actual case, which we believe to be real. So it is no longer a theoretical infectivity in plasma or derivatives, and then the relative risk.

So that is what underlies the notion that this should potentially apply to all derivatives, but we are trying to recognize relative risk.

DR. HOGAN: Thank you very much. We will go ahead and vote on this then. It will be yes, you agree with the need for labeling about vCJD or no, or abstain.

(Whereupon, the committee cast its votes.)

MR. EMERY: Everyone has voted for topic two, question one. Dr. Hogan voted yes. Dr. Barraj voted yes. Dr. McComas voted yes. Dr. Kreindel voted yes. Dr. Monroe voted yes. Dr. Geschwind voted yes. Dr. Priola voted yes. Val Bias voted yes. Dr. Manuelidis voted yes. Dr. Romero voted yes. Judith Baker voted yes. There were no abstentions and no no's.

DR. HOGAN: Thank you, sir. We will move ahead to part B. Does the committee agree that vCJD labeling is necessary for albumin and products containing plasma-derived albumin?

DR. PRIOLA: Dr. Epstein just talked about relative risk with regard to albumin and non-albumin related products. You brought up the manufacturers' data. How do you factor in the data from Paul Brown and Larisa, where they show that there is no infectivity in the albumin from an animal model, but there is infectivity in the cryoprecipitate that contains Factor VIII.

So that is relative risk and it seems much higher for Factor VIII than albumin, where they detected nothing. So how does that weigh into your relative risk assessment?

DR. SCOTT: I think we would say relative risk is lower, but you have to consider that these are very small scale experiments. Even though he injected 94 mice with the albumin product, that still only was about 30 percent or so of the amount that he got. Overall, the experiment is small scale. So if there is a chance of little infectivity trickling through, this experiment is not on a scale where you can understand that that could happen.

The other thing is, you are only starting out probably with a few infectious units per ml anyway, so you don't really have the ability to see the broad possibilities of how much infectivity truly could be removed by that process, because you are going to remove all that infectivity if you only have a very little amount at the beginning. If you were able to spike let's say 15 logs of infectivity that was endogenous infectivity or halve 15 logs of that, you might see something at the end.

So I can't think of any experiments in the lab so far that you can do that really replicate the full-scale human situation. That is a problem with all of these. That is one of the reasons that in spite of a lot of reassuring data, we still feel the need to communicate a possibility of risk.

It is also the case that in some spiking studies, I believe it has been shown that you can get a tiny amount of infectivity in the albumin fraction.

A second caveat I wanted to mention, or something that can be confusing about the way -- we had to present these studies rather quickly. What I talked about was what we call the fractionation trunk, where you are pulling off semi-purified fractions that contain certain products of interest. After that, many manufacturers do additional viral clearance methods such as nano filtration, additional column chromatographic steps, what they call polishing steps, but which also happen to have the capacity to remove a spike.

So that is why you see sometimes in the information that Dr. Groener presented what looks like it might be higher clearance for a non-albumin product than an albumin product. But that is a function of the specifics of that manufacturing process. And of course the spiking model has many caveats that we have talked about in previous sessions. I recognize that quite a few of you weren't here, because previous sessions go a number of years. But the fact is, we don't have a perfect model. We don't have perfect surveillance, so we can't completely assure ourselves that the risk is --

DR. PRIOLA: What level of sensitivity are you asking for? Or what level of sensitivity did Dr. Brown and Dr. Cervenakova have in this experiment? How much infectivity could they detect using this approach, where they inoculated 30 percent of the fraction into a total of 94 mice? What number of infectious units would you be expected to detect under those conditions?
It seems to me that is important in thinking about what you might be missing.
DR. SCOTT: I can't do all the math in my head.
DR. PRIOLA: Neither can I. That is why I am asking.

DR. SCOTT: I think the scale is such that you can't completely reassure yourself even about that process. You are asking for the sensitivity of the method, and I can't give you that off the top of my head. I don't know if anyone else in the audience has some thoughts about that.

DR. HOGAN: No, but we had that meeting where we discussed these clearance issues. That point was brought up, that sensitivity in some of these assays is not perfect. But I don't remember specifically Paul's.

What I understand from industry and from other individuals is, there is ongoing research on these clearing steps for albumin, et cetera. So if there is some data in the future, you might be able to give us more information. We could perhaps rescind labeling restrictions if we go ahead with that today. So people are working on this? Yes? No? Yes.
Any other comments?

DR. MONROE: Just a procedural question. We voted on 1A. For 1B we are voting on the yes-no question of, do we think that labeling is warranted, and then in two, which is labeled as a question but it really is a comment, it would be a chance to comment on specific wording of the labeling that we vote yea or nay on in 1B, is that correct?

DR. HOGAN: What you said is correct. We are voting only on albumin and plasma-derived albumin products, yes or no, labeling in vCJD.
Why don't we go ahead and vote, yes or no.
(Whereupon, the committee cast its votes.)
The yes have it; 11 yes.

MR. EMERY: For the next one, all voters voted yes. Dr. Hogan voted yes. Dr. Barraj voted yes. Dr. McComas voted yes. Dr. Kreindel voted yes. Dr. Monroe voted yes. Dr. Geschwind voted yes. Dr. Priola voted yes. Val Bias voted yes. Dr. Manuelidis voted yes. Dr. Romero voted yes. Judith Baker voted yes. There were no abstentions and no no's.

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Agenda Item: Open Committee Discussion

DR. HOGAN: The last portion of this afternoon's meeting then is commenting in a discussion fashion, there will be no voting, on the proposed wording for the warning statements for both plasma derivatives other than albumin and plasma-derived albumin in products containing plasma-derived albumin. The proposed changes were a little bit different for those two, right, Dorothy?
DR. SCOTT: That is correct.

DR. HOGAN: As you can see on the screen, this is one of the proposed -- let's do albumin first, because that is the one we have up there.
DR. SCOTT: That was the other than albumin.

DR. HOGAN: Okay, whichever one. This is other than albumin, so we will do other than albumin first. Does anybody have any comments about proposed labeling wording, understanding?

DR. MANUELIDIS: I will just repeat again, I think I wouldn't like the word theoretically for classical Creutzfeldt-Jakob disease. I agree with Dr. Geschwind that we should say Creutzfeldt-Jakob disease, human transmissible encephalopathies, prion diseases, and just have it as that label.

DR. PRIOLA: Could I just ask, why is it that you are so general when it comes to referring to viruses, and you say there is a theoretical risk of transmitting infectious disease, for example, viruses, which there are a lot of, and only some are transmitted through blood, but you are so specific about a TSE agent? Why can't you be more general?

You are not singling out HIV or hepatitis for the viruses. I think this was alluded to by both Dr. Geschwind and Dr. Manuelidis; just say viruses or transmissible spongiform encephalopathy agents, prions in parentheses, and leave it at that? Why so specific?
DR. SCOTT: I think for comprehension, really.

DR. PRIOLA: I guess that is my point. You have got -- in these two different labels, this one and the one coming up, you have variant Creutzfeldt-Jacob, Creutzfeldt-Jakob and classic Creutzfeldt-Jakob. Nobody is going to know what the differences between those three are, so are you really giving more information, more useful information, by being so specific?

DR. SCOTT: I guess it is good to hear your comments, first of all, we will take those into consideration. I guess we thought, how great was the -- originally when we did this in 1999 we thought, how likely is it that people are going to know what a transmissible spongiform encephalopathy is versus Creutzfeldt-Jakob disease. It may be the same thing, but we were hoping, based on publicity, where publicly these are called CJD or vCJD, that it would be helpful.

But to my mind, that is what I recollect as the main reason, simplicity, potential of greater comprehension. We have learned of course that people with GSS don't consider that they have this kind of disease, some. I think that we will never get 100 percent comprehension, no matter what we do. The question is, is there a way to do it better.

DR. PRIOLA: So is it possible to do some forms of Creutzfeldt-Jakob disease? It is bigger. It still keeps in the reference to CJD, which some people may recognize.

All I know is that when people ask me what I do and I respond to them, I either say I work on prions, and sometimes I get a blank look, and I say, I work on TSE, I don't get a blank look. Everybody knows what that is. Very few people know what CJD is.
DR. HOGAN: But more people know what CJD than Creutzfeldt-Jakob disease.
DR. PRIOLA: Probably yes, that is true, too.

DR. GESCHWIND: What everybody is saying makes sense. I certainly understand why you want to list some of the names out, because there is that risk of confusing people by giving so many complicated names. On the other hand, this GSS example I gave is an area in which, if you hadn't listed it out, people wouldn't realize it.

If you just say Creutzfeldt-Jakob disease, that might limit it. So maybe prion diseases, transmissible spongiform encephalopathies, or maybe you can say CJD and other forms of TSEs and prion diseases, something like that.

DR. SCOTT: I think it is also important to keep in mind that there is a relative dissociation in how we are expressing the risk of variant CJD and other forms of CJD. So to keep that distinction is theoretical or maybe not quite so theoretical. We probably need to mention both types of agents. DR. MC COMAS: I think that this has been an informative discussion. I have got a few points to raise.

I think one of the things that we are hearing a lot is that we are guessing what should be in there and what shouldn't be in there. I don't think we have even defined who the target audience is for this message. Is it physicians, is it caregivers, is it patients? Where are they getting that information? Where are they seeing that information? What sort of supplemental information is there? Is somebody there to talk to them about it, et cetera.

So I am viewing this outside of a context, which is very hard to assess the effectiveness, not to mention the fact that there is no evaluation of the effectiveness. I say again to the FDA that if you can encourage social science research, there are scientists out there whose area is to test message effectiveness, through focus groups, through experimental design, but you have to again have determined what your objective and who is your target audience. I am not clear what the objective is from these messages.

That is why I also had a little bit of trouble with the earlier conversation of, should we label the relative risk of albumin. it is important to have that out there for transparency's sake for FDA's credibility, but what do you want people to do with that information? So you ask from a risk communication perspective.

I put down some possible objectives of your labeling. Provide information, increase awareness of a risk, increase or decrease concern about a risk, increase information seeking about a risk, a change of behavior, a change of therapy treatments, talk to your doctors. What should people do with this information?

That comes back to who are the people that you are targeting with this information. One of the dangers is to provide information that raises concern without providing information as well that tells people what they can do about it.

So if this is just out there to raise awareness about it, that is one thing. Then you have at least set it out there. You can't say that people weren't told that there was a risk. But that more protects you. Now you have told them that there is a potential risk, what should they do.

I haven't heard much, and maybe we are going to hear some tomorrow, but there really doesn't seem to be much of an alternative. If somebody needs this product, they are going to have to take that product.

So you have raised the concern about it, but yet they don't have anything that they can do to lessen that concern.

So I guess I would just say that once you start to unravel these things -- and I have got little comments on the wording, I think we all probably do, but it is a large fundamental issue of what is the purpose behind these, and who is it targeting, and how are you dealing with these other factors.

MR. BIAS: A lot of great points raised about the language. The only individual responsible at the end of the day based on usage of these products is the end user, the patient who ends up taking this product. They are the ones who have to live with whatever consequences.

There are a group of patients that exist who are going to be reliant on these products, no matter what, but there is also a group of patients who have some limited choices. There is a group of patients who choose plasma products over recombinant products because they feel the plasma products work better in their systems. It is a shrinking group of people, but speaking as one of them, they would rather know. They do follow these issues quite closely. They do weigh them in terms of their own care and the future generations of their families.

This whole process that we all exist in in terms of the advisory committees, consumers being present on the advisory committees, is because over the years since our experience with the '80s we have chosen to inform and take caution and provide that information to the public, whatever their level of understanding is. It is for us to provide the warning and for people to do what they deem best for themselves, for their families and for their own knowledge base.

So I would err on the side of expanding the definition, and let people choose to do what they can with that information. One of the things that we try to teach our patients is, you must always be vigilant, because these are not static issues. They continue to move and grow as we develop new generations of these products. They continue to provide us challenges that we have never seen before.

One of the scary parts about where we are at today, because we have made so much progress in the last four years or so, is that the number of vigilant patients today has shrunk because the products seem to be so safe.

So I would expand the definition and let people use the information as they see fit. I don't think there is any reason not to. I think you have to list CJD and variant CJD because unfortunately we live in a reality of a media, and that is what they understand is the problem, so you have to list those. But I think the expansion of TSE is going to be to the benefit of that patient group, and may inform a larger audience as we go forward.

DR. MC COMAS: Just as a follow-up, I certainly hope that you didn't take that I am saying don't provide that information.

But just to follow up on your point also in terms of another question of consistency throughout. There is some inconsistency of information, not necessarily contradictory, but inconsistent, between what you say about the blood components, as containing blood components versus albumin, that there has been no shown case and those sorts of things.

I am wondering about that. I was also looking at, in terms of what we include and don't include. One of your handouts on the guidance for industry and acceptable circular of information. Here in this, because whole blood and blood components are made from human blood, they may carry a risk of transmitting infectious diseases, e.g., viruses, bacteria, parasites, the variant CJD and theoretically the classic CJD.

So if we are going to talk about adding additional things, here is one where you also talk about bacteria and parasites. We can make this list longer and longer and longer. The question is, where is this going? If we can include it all there, because we are limited by a bit of space, what is this supplemental information that is going to provide the additional details to help somebody make an informed decision about their treatment or how they move forward.

DR. SCOTT: I think I will start with the beginning, who do we want to address. I would say ultimately the patients and secondarily the other people that may help the patients make those decisions, the health care providers, to increase awareness and to provide transparency.

But it is true that in some cases for Factor VIII where there exist plasma-derived and recombinant products, there may be the ability to choose a product that could have even a lower risk. It is not only true though for Factor VIII; it is true for some other factor products, and it is also true for products where there are options for therapy.

For example, some of the off label uses for immunoglobulin, you could use another therapy like plasma exchange in certain conditions or immunosuppressants in certain conditions. So there are options there. Also with respect to albumin and treatment of hypovolemic shock there are also some other options, not that anyone in hypovolemic shock will be reading the package insert.

But the general point is that there are choices in some cases that can be made. Obviously in some cases people have an obligate need for a plasma-derived product, and it does them a great deal more good than this possibility of harm, it is generally believed.

Then Mr. Bias spoke. I really appreciate that, because you are on the ground level, and you know how people perceive this. One thing you brought up is, by having this transparency or this awareness, if there were such a case to occur, if somebody is an obligate user of a plasma derivative, develops a neurological disease that looks like a spongiform encephalopathy or gets that diagnosis, I believe we are more likely to hear about it. I can't prove that, though. But there is at least the concept that increasing awareness might in some small way potentially increase our chances of capturing such a case, should it occur.

Then with respect to bacteria and parasites, the use of alcohol and the procedures of fractionation obviate that possibility, because of the manufacturing. The only cases of bacterial transmissions involve inadvertent contamination of vials that were filled. So they didn't occur because the starting plasma was problematic. Those are extremely rare, but have occurred.

DR. MC COMAS: It just seems strange to have it in some and not in the other. That is what I was pointing out.

Just as a quick follow-up, I think what you said in relation to the intent of this, would it be impossible to include a line at the end of the warning saying users of this product are encouraged to talk to their physician about available choices for treatment, something that tells people what to do with this information that you have now given them. If indeed talking to their doctors about choices is an important objective, then I think you need to come full circle and say that.

DR. GROENER: May I just add to the parasites and bacteria one issue. For plasma-derived proteins which are parenterally applied, there has to be validated sterile filtration in place which takes care of the bacteria, fungi and parasites. Therefore, that is for plasma-derived proteins no issue, which may be in contrast to blood for transfusion.
DR. HOGAN: Thank you.

DR. MONROE: This discussion is fairly high level. I was stumbling over the specific word theoretical. I have a question to risk communication and then to the patient group. Do people make a distinction between something that is a small demonstrated risk versus a small theoretical risk? I understand what it means, but maybe in the context of how it is being used, it doesn't really matter.

DR. MC COMAS: I would say, without having done an evaluation, no. That is looking at the audience. Why are we saying an extremely remote risk and not just say small? Let's simplify the language and take out some of these terms if it is for the patient, and then test to see whether or not that group is getting the message.

DR. MANUELIDIS: I would like to go back to something very simple. The current description to me seems very straightforward, except I would take out the word theoretically. I wouldn't talk about the degree of risk, if you want to put in something like CJD and other prion diseases.

I get calls from all of the CJD family things because I am on the NIH list. People call me up all the time. They have a very active group. They go on the web. They know what CJD is. People call me up, they tell me they have familiar CJD, et cetera.

I think that within that, CJD and other forms of the disease, or whatever you want to say. I just think it gets very complicated if you are going to call things classic CJD, whatever the hell that is, sporadic CJD in the Western Hemisphere.

I think all of these words and classifications take away from the message, which should be very simple. It says carry a risk, it doesn't say what the degree of risk is. So then people are aware that this is something that may happen, and they can find out about how big or small the risk is. You have already said it in the first part, that it is a small risk.

MR. BIAS: I would agree with her. I think the simpler the explanation, the better. I think what you want to communicate to the patient is that there is risk, and then have them take it to the next step.

Small gives people comfort level. Theoretical gives people -- I don't know what that means to people. I don't think it means much to people, but small does give people some level of comfort. But from the FDA's point of view, they want to hear about these cases if one should occur, and they can be missed, depending on how sick the patient is and whether somebody actually makes the connection between how sick the patient is and what else they are afflicted with. That could be an underlying reason why we are not seeing so many cases, because if you get a really sick person and they die, you don't question so much how they died.

DR. GESCHWIND: Not to play devil's advocate here, but I am trying to think what you just said, Dr. McComas, about who the audience is. I thought the doctors at some point can be the audience, because either the doctor is going to read it or the nurse is going to read the label instruction or the patient.
But at some point, any of those people are going to ask the doctor, what does this mean.

I write consent forms all the time for my research studies, and a small risk might be a small percent, five percent, one percent. But what we are talking about here is much, much less than that.

So I just want to weigh this with who is the audience that we are trying to approach. If a patient is going to ask a doctor, small doesn't really tell me that much. I would think small would be five percent or less than one percent, and it is not, it is much less than that. So that is one issue.

The other issue is theoretical. To me, coming from a doctor trying to explain this to a patient, I would explain that theoretical means it has never been proven in people, but in theory it could happen, maybe because of animal data, maybe because we know that Factor VIII or whole blood has done it. Whereas small almost implies -- and again, this is just my opinion, that it has been shown, but it is really, really rare.

So there is a difference between theoretical and saying something is very small. To me, theory means it has never been shown, it is a theory. So I think there is a distinction from a medical perspective, trying to explain it to a patient. So I understand how that might be complex to a patient. DR. HOGAN: Anyone else to make any comments? All really good comments. You guys took your notes, I think. This is covering the other than albumin.

DR. EPSTEIN: I think the problem is that we are hearing a very wide spectrum. That is perhaps not surprising. One the one hand there is advocacy for simplification, single common term, something more akin to small versus extremely remote. On the other hand, we are hearing that there are good arguments for listing, for being more complete, and for using a more complicated term that better reflects the actual risk estimate.

So this is a lot to reflect on. We have heard everything. We are taking a lot of notes, and there is a transcript, but I'm not sure that there is a sense of the committee. I think that what we are dealing with is a spectrum of opinion which is the entire gamut of the issue. That just may be the state of play and we just have to decide whatever.

DR. MC COMAS: I was just going to say, I think the problem is that those are two target audiences, physicians versus patients. You can't develop one set of messages and expect to meet both of those needs when they are likely very different demographics and user needs.

DR. EPSTEIN: We do have physician labeling and patient labeling. Perhaps we can begin to think about differentiation of this message in those two contexts.

DR. HOGAN: Sense of the committee. What I have heard is that being a little more inclusive about the description of the diseases that we are discussing is important. What I have heard is using the word theoretical only when it is theoretical, not small or extremely small or whatever, and trying to get simple but complete.

I personally think that what you have proposed is fine. It doesn't include TSEs or prions. If anyone disagrees, I don't want to summarize for everyone. Does anyone have anything else that we have discussed that you think they ought to take home from this discussion?

DR. PRIOLA: I think you could find a middle ground to do this. You can keep Creutzfeldt-Jakob in the label. Use a phrase like extremely remote. Have the extra information.

To me, what struck me about the label was, there were three different mentions of CJD, variant, classic and then just plain old CJD. I think you just don't need all that. If you just had CJD in there, there is an extremely remote risk, I think that would be okay. You can't use theoretical because that excludes variant CJD, I don't think any of us consider that theoretical anymore. So if you were to make it general, it would be, extremely remote chance of CJD and leave it at that.

DR. GESCHWIND: A question that I have for the FDA is, if we are trying to focus on variant CJD, then yes, I think we need to mention it and mention its risk and to actually say it. Whereas, with all the other forms, it is essentially theoretical.

So that is a distinction I personally would understand, if the FDA wanted to make. It would certainly be clearer for the physician. For the patient, I'm not sure.
DR. HOGAN: So the placement of the word theoretical is important in the sentence.

DR. GESCHWIND: Yes, because I think for the non-variant forms of CJD, most people would agree that it is still theoretical in people.

DR. MANUELIDIS: I don't think that if you have a transmitted case it is theoretical, number one. I don't think if you have a transmitted case from human blood, it is theoretical. I don't think you can do the experiment in people. Just like HIV, you can say HIV is not causing the disease because we can inject it into people and find out.

There is a case that was reported where it goes into animals, and nobody has tried to replicate it. So I don't want the word theoretical. I think that is misleading.

I think one way to resolve it is to have two separate things. One is to say CJD including variant CJD, whatever you want to say, and then for physicians you can have a different label which says, these are also known as GSS, prion diseases, transmissible encephalopathies, et cetera. That can be for the physician's label. But I think for patients, they know what CJD is. How else would you explain it? CJD related to non-cow disease, then everybody knows what it is. This is just much too inflammatory, in a sense.
DR. HOGAN: Does that give you a sense of the committee or not?
DR. EPSTEIN: No.

DR. PRIOLA: Can I ask Mr. Bias, when patients read these warning labels, all these drugs also come with inserts, right? Do the patients who want to be really well informed -- because I have seen these inserts and I go, oh my God, I'm not reading this. Do they read it very carefully? Because that would be a place where you could put in these extra details about GSS and really go into detail there. So if they were worried from the label, would an informed patient then go to the insert?
DR. EPSTEIN: We are talking about the product insert.
DR. PRIOLA: Oh, excuse me.

DR. EPSTEIN: We are talking about the warning section of the product insert here. What I think we heard pretty clearly from the committee is that we might want to craft simpler messages for patient information. There is patient product labeling now which FDA reviews and recognizes, independent of the package insert. But what you have been hearing about is the package insert.
DR. HOGAN: Any final -- go ahead.
DR. MC COMAS: Just a question for clarification and perhaps consistency, to return to that.

One thing that is not added onto the end of this one which is at the end of the albumin, in the albumin it says no cases of transmission of viral diseases, vCJD or CJD have ever been identified for albumin. Why is there not a similar statement at the end of this saying that no cases of transmission of CJD has ever been identified for human blood? Is that correct?

So I come back to this idea of how we understand theoretical or not. The information that we are providing in one context but not in the other. Just a question of, might you consider adding a statement like that as well, but again, to what effect.

MR. BIAS: Two things, one to answer your question. When I give a blood safety talk, I encourage families to make an annual event out of reading their label, just like a holiday. Take out the label and read it as a family and try to understand what is in there. That is just part of keeping it alive.

I wish I could get manufacturers to put a little label on the box that said, we have changed the label. But we are not there yet. That will happen.

I think sometimes we have to rely on animal models. We are not going to see it in a human model. So I would hate to see the label be limited to human transmission, because that would disavow the animal models, where we have been able to do some of these experiments. So I think it is important, if we have it in an animal model, because these cases are so rare, that we give it the weight.

That is why we continue to meet, because we are waiting for that human case. It took us a long time to get to that new variant case, but it eventually came, and it was because we were all hanging around and continuing to meet, and it eventually came. We knew it would come. Someday the human case will come. That is why we keep meeting. So I wouldn't take that one out. I wouldn't change that part.

DR. HOGAN: Why don't we move now to the issue about albumin, since that was plasma derived. The question now is, the proposed revised warning with all of this yellowed-in stuff, which is even more complex than it was for the plasma-derived products, and with perhaps less risk of transmission. Any comments or thoughts about this one?

DR. MC COMAS: My comments were pretty much for both.
DR. HOGAN: For both. I think we perhaps covered them for both. Does anyone have anything specifically here? It is awfully long. It is again extremely remote, but it does tell a story.
Are we giving you enough from this entire discussion for both topics?

DR. EPSTEIN: I think so. I think what we are hearing is, be inclusive but don't use a lot of technical terms. Try to simplify the risk message, and consider developing more targeted information for patients. That is good advice.
DR. HOGAN: One additional issue is, perhaps doing some study to see how the information is understood.
DR. EPSTEIN: And that in particular, the term theoretical may not have value in the direct patient communication, but to be determined.
DR. HOGAN: That's good. Anything else? Anything else that anyone would like to say?
MS. BAKER: Just briefly, to be aware of the reading level of the average American, and translation of this to appropriate literacy levels.

DR. HOGAN: You get the last word, except that I would like to thank everybody for coming today. We are leaving an hour and a half early, but you still have to pay us for the whole day.

Thank you very much. We will see everybody tomorrow morning at 8:30. Thank you. Have a good evening.

(Whereupon, the meeting was recessed at 2:55 p.m.)