1 
 
                 DEPARTMENT OF HEALTH AND HUMAN SERVICES 
 
                       FOOD AND DRUG ADMINISTRATION 
 
               CENTER FOR FOOD SAFETY AND APPLIED NUTRITION 

 

 
 
                  FOOD BIOTECHNOLOGY SUBCOMMITTEE (FBS) 
                                  OF THE 
                         FOOD ADVISORY COMMITTEE 

 
 
                        Wednesday, August 14, 2002 
 
                                8:30 a.m. 

 

 

 

 
                     Harvey W. Wiley Federal Building 
                        5100 Paint Branch Parkway 
                      College Park, Maryland  20740 

 
                                                                  2 
 
       PARTICIPANTS 
 
       Edward N. Brandt, Jr., M.D., Ph.D., Acting Chair 
       Dr. Margaret Cole 
 
       MEMBERS 
 
       Fred McDaniel Atkins, M.D. 
       James Astwood, Ph.D., Industry Special Liaison 
       Bob B. Buchanan, Ph.D. 
       Francis Fredrick Busta, Ph.D. 
       Anne E. Kapuscinski, Ph.D. 
 
       TEMPORARY VOTING MEMBERS 
 
       Jonathan Arias, Ph.D. 
       Douglas Gurian-Sherman, Ph.D. 
       Samuel Lehrer, Ph.D. 

 
                                                                  3 
 
                             C O N T E N T S 
 
       Call to Order 
         Dr. Edward Brandt                                        4 
 
       FDA Food Biotechnology Update 
         Dr. James Maryanski                                      4 
 
       Questions of Clarification                                21 
 
       Public Comment 
         Dr. Sue MacIntosh                                       35 
         Dr. Michael Hansen                                      46 
         Dr. Gary Bannon                                         55 
         Mr. Bill Freese                                         65 
 
       Summary 
         Dr. James Maryanski                                     71 
 
       Questions and Discussion                                  74 

 
                                                                  4 
 
   1                      P R O C E E D I N G S 
 
   2                          Call to Order 
 
   3             DR. BRANDT:  Members of the Subcommittee, 
 
   4   you have on your table copies of the slides from 
 
   5   the presentations yesterday, as well as copies of 
 
   6   slides from two of the presenters today. 
 
   7             I will remind the four public speakers 
 
   8   that we are going to begin at 9:45 with Ms. 
 
   9   Macintosh followed by Michael Hansen, followed by 
 
  10   Gary Bannon, followed by Bill Freese.  I would 
 
  11   remind all of them they have 10 minutes, period, at 
 
  12   which point I bang on the gavel and the trap door 
 
  13   opens and you wind up in contaminated food. 
 
  14             DR. LEHRER:  Is there any opportunity to 
 
  15   ask questions or not? 
 
  16             DR. BRANDT:  No.  If you are going to ask 
 
  17   questions, we have a break right afterwards.  You 
 
  18   can talk to them during the break. 
 
  19             Dr. Jones is apparently ill and isn't 
 
  20   here, and so she is being more or less replaced by 
 
  21   the inimitable Dr. Maryanski, whom I am told will 
 
  22   be very brief. 
 
  23                  FDA Food Biotechnology Update 
 
  24                       Dr. James Maryanski 
 
  25             DR. MARYANSKI:  Good morning, Mr. 

 
                                                                  5 
 
   1   Chairman. 
 
   2             Yes, Dr. Jones cannot be here today, so we 
 
   3   are going to do a slight modification of her 
 
   4   presentation, but I think we will still cover the 
 
   5   issues for you and give you plenty of food for 
 
   6   thought, so to speak. 
 
   7             I am going to do two things this morning 
 
   8   in a briefer amount of time than was scheduled for 
 
   9   this presentation.  One, I am going to spend just a 
 
  10   few minutes giving you a little background on some 
 
  11   of the recent events and things that are happening 
 
  12   now relative to biotechnology at FDA. 
 
  13             This is just part of our attempt to give 
 
  14   you background information to help you understand 
 
  15   who we are, what we are doing. 
 
  16             [Slide.] 
 
  17             There have been several activities 
 
  18   recently, some of which are completed, one of which 
 
  19   is completed, others are just beginning, so we 
 
  20   thought that it would be useful to tell you about 
 
  21   some of these very briefly, not going into any 
 
  22   detail, but the idea is to let you know about these 
 
  23   activities because it is quite likely that there 
 
  24   will be aspects of some of these activities that we 
 
  25   will want to discuss with the subcommittee at some 

 
                                                                  6 
 
   1   future time. 
 
   2             The General Accounting Office, GAO, did a 
 
   3   study on FDA's procedures for evaluation of 
 
   4   bioengineered foods over the past year and they 
 
   5   have published the findings of their report May 
 
   6   23rd.  That report is available on the GAO web 
 
   7   site, and we can, of course, give that information 
 
   8   to you. 
 
   9             The interesting thing about the report, 
 
  10   they looked very carefully at our procedures.  They 
 
  11   actually went through a number of files word by 
 
  12   word.  They also talked to various individuals both 
 
  13   inside and outside of FDA, and the object was to 
 
  14   see if we were basically following the procedures 
 
  15   that we have set out for these foods and if those 
 
  16   things would be reasonable. 
 
  17             I think they found that overall, we 
 
  18   actually were doing a good job.  They did, of 
 
  19   course, make some recommendations, and that is the 
 
  20   part of the report that you will find most 
 
  21   interesting. 
 
  22             They were basically a recommendation, one 
 
  23   recommendation is that FDA, of course, does not 
 
  24   receive all of the information about these 
 
  25   products, and they thought that it might be a good 

 
                                                                  7 
 
   1   idea if at least on some basis, FDA would go out 
 
   2   and actually visit a company or request all of the 
 
   3   information from the company and actually check it 
 
   4   to be sure that the information did support the 
 
   5   conclusions that had been given in the 
 
   6   consultation. 
 
   7             We agree with that recommendation.  We 
 
   8   actually had a similar thought in our proposed 
 
   9   notification rule, so that is something that we 
 
  10   feel would be useful. 
 
  11             Their second recommendation to FDA was 
 
  12   that they felt that our memos that we place on the 
 
  13   web now, that describe our evaluation of the 
 
  14   products, could do a better job of explaining to 
 
  15   the public what our decision is, and we also think 
 
  16   that that is a reasonable recommendation and will 
 
  17   be looking at that. 
 
  18             So, we have these two recommendations from 
 
  19   the GAO that we will be looking at.  I think that 
 
  20   is something that you may find that report 
 
  21   interesting. 
 
  22             Just on August 2nd, the Office signed some 
 
  23   technology policy, announced new work basically. 
 
  24   They announced that the federal agencies were 
 
  25   initiating some actions to look at field testing 

 
                                                                  8 
 
   1   requirements and early food safety reviews for 
 
   2   crops that are under development. 
 
   3             These are crops that are in the early 
 
   4   stages of development, they are not through all of 
 
   5   the regulatory steps, but because of pollen 
 
   6   transfer or because of seed mixing, it is possible 
 
   7   that these crops that have not been through the 
 
   8   full regulatory process could become components of 
 
   9   food at some point on an intermittent basis. 
 
  10             So, the agencies are proposing steps to 
 
  11   deal with that issue, and FDA's piece of that is 
 
  12   that we will be developing draft guidance for crops 
 
  13   that are intended for food use for developers to 
 
  14   come in for an early food safety assessment, and 
 
  15   that assessment will focus on the proteins that are 
 
  16   new in the foods particularly with respect to 
 
  17   potential allergenicity because, as you heard 
 
  18   yesterday, we can't set a threshold for a low level 
 
  19   of a protein that would be safe, and so we want to 
 
  20   make sure that even these intermittent low levels 
 
  21   of proteins would be safe in food and there will be 
 
  22   no disruption of the food supply because small 
 
  23   amounts may be detected in some foods at some 
 
  24   particular time. 
 
  25             So, that is something we will be doing 

 
                                                                  9 
 
   1   will be developing that guidance over the next 
 
   2   several months. 
 
   3             Another study which is just underway is a 
 
   4   study that is initiated by the National Academy of 
 
   5   Sciences National Research Council, and the council 
 
   6   has a Committee on Agriculture, Health, and 
 
   7   Biotechnology, and that committee is initiating a 
 
   8   study sponsored by FDA, EPA, and USDA on unintended 
 
   9   effects that occur in plants and their possible 
 
  10   implications for the food, so this is getting at 
 
  11   this question of can something unexpected happen as 
 
  12   a result of the genetic modification, what are the 
 
  13   steps being taken to ensure that those do not 
 
  14   result in public health problems in the food and 
 
  15   are there ways that that process could be improved. 
 
  16             So, they will be looking at recombinant 
 
  17   DNA-derived plants in comparison to conventionally 
 
  18   derived plants to try to sort out this issue of 
 
  19   unintended effects. So we think that is a very 
 
  20   important study and that will be ongoing probably 
 
  21   for the next year or so. 
 
  22             We have already discussed the other items 
 
  23   on this slide, so I think my purpose here is just 
 
  24   to kind of give you a heads-up of some other things 
 
  25   that we are working on that you may be hearing 

 
                                                                 10 
 
   1   about, so you are not surprised about these things 
 
   2   if they show up in the news or you hear about them. 
 
   3             DR. BRANDT:  Do you want to go ahead and 
 
   4   do your summary? 
 
   5             DR. MARYANSKI:  You want me to do my 
 
   6   summary?  I have another slide, sir, that I need to 
 
   7   do. 
 
   8             DR. BRANDT:  Oh, before that? 
 
   9             DR. MARYANSKI:  Yes. 
 
  10             DR. BRANDT:  Okay, I am sorry. 
 
  11             DR. MARYANSKI:  How about three slides, 
 
  12   can I squeeze three slides in, Mr. Chairman? 
 
  13             DR. BRANDT:  Yes, sure.  I am just going 
 
  14   by what you told me. 
 
  15             DR. MARYANSKI:  I know, I have to be very 
 
  16   careful here. 
 
  17             [Slide.] 
 
  18             The presentation that was scheduled for 
 
  19   this morning by Dr. Kathleen Jones was one where we 
 
  20   were going to talk to you in more detail about some 
 
  21   of the issues that are being discussed in the 
 
  22   scientific committee related to the assessment of 
 
  23   allergenicity, and these are issues that we will 
 
  24   have to be taking into account, as well. 
 
  25             These are issues that deal with how we 

 
                                                                 11 
 
   1   assess the sequence of the protein, the issues 
 
   2   around serum testing, the use of animal models, the 
 
   3   use of degradation of these parameters.  I think 
 
   4   you have heard a good deal about these already. 
 
   5   They are also discussed in the background paper, 
 
   6   which is in your packet.  I believe it is No. 6. 
 
   7             This is the paper that FDA has prepared 
 
   8   and Kathleen was the primary drafter with a lot of 
 
   9   help from various scientists in the center, but the 
 
  10   second half of this paper deals with issues that we 
 
  11   will have to be thinking about as we develop our 
 
  12   draft guidelines. 
 
  13             I thought that instead of going through 
 
  14   her talk before you, because I am not an 
 
  15   immunologist as she is, so I think that what I will 
 
  16   do is go back to the decision tree that Dr. Mayers 
 
  17   showed yesterday to give you a sense of our 
 
  18   thinking about the decision tree, so that you have 
 
  19   a little bit better understanding of how we have 
 
  20   come to where we are in the Codex and what our 
 
  21   current thinking is, so that it will help you in 
 
  22   your discussions. 
 
  23             If you recall, this is the decision tree 
 
  24   that was evolved by the task force in Codex based 
 
  25   on the earlier information and other decision trees 

 
                                                                 12 
 
   1   that had gone before.  I am sorry, I want to back 
 
   2   up, that is not correct.  This is the Expert 
 
   3   Consultation decision tree, because we do not have 
 
   4   a decision tree as part of the Codex guidelines. 
 
   5             But this is the decision three that was 
 
   6   developed by the Expert Consultation that was used 
 
   7   in developing the Codex guidelines. 
 
   8             The decision tree was first published by 
 
   9   ILSI, as you may realize from the background 
 
  10   papers, so decision trees have been part of this 
 
  11   thought process for some time, and I think, as Paul 
 
  12   alluded to yesterday, we do like to have a visual 
 
  13   kind of representation as a key to help us in our 
 
  14   work.  So, there was a lot of interest in 
 
  15   continuing the idea of the decision tree. 
 
  16             One of the things that we felt was that it 
 
  17   is useful to have a decision tree, and we are 
 
  18   certainly not opposed to it.  What we found is that 
 
  19   there are certain things that have not made us feel 
 
  20   comfortable about any of the decision trees we have 
 
  21   seen to date, and I will explain some of those to 
 
  22   you. 
 
  23             When we decided to initiate the Codex 
 
  24   work, we thought that the priority, the first work 
 
  25   should be given to developing the text of a 

 
                                                                 13 
 
   1   guideline, put down on paper what we think is the 
 
   2   best guidance based on the science as we understand 
 
   3   it. 
 
   4             Then, if we can derive a decision tree 
 
   5   from that, then, we would do that.  Now, we did not 
 
   6   have time in the Codex process to get to working 
 
   7   out a decision tree based on the guidance, so the 
 
   8   sense I am trying to convey to you is FDA is not 
 
   9   opposed to a decision tree, nor do we think it is 
 
  10   necessary to have one, but it could be useful if 
 
  11   one could construct one that would work in a way 
 
  12   that would satisfy the needs for providing 
 
  13   guidance. 
 
  14             Let me be a little more specific then 
 
  15   about some of the things that we observed in this 
 
  16   particular decision tree.  One of the things that 
 
  17   it does is that this consultation resolves some of 
 
  18   the problems that had been in earlier guidance 
 
  19   documents and decision trees. 
 
  20             For example, it gets away from the idea of 
 
  21   what is a common food allergen versus a less common 
 
  22   food allergen.  We don't have to address that issue 
 
  23   anymore, and that is very helpful. 
 
  24             The other thing this decision tree does is 
 
  25   it gets away from the idea of directly addressing 

 
                                                                 14 
 
   1   human challenge studies, and that is something that 
 
   2   is very problematic in many circumstances.  For the 
 
   3   large part, people are really not inclined to want 
 
   4   to use those studies on a routine basis, so it gets 
 
   5   away from that. 
 
   6             So, there are a number of things that the 
 
   7   expert consultation did that resolved issues that 
 
   8   it was asked to look at.  When we look at this, you 
 
   9   can see there are a lot of yes or no's here in 
 
  10   terms of what one would decide and even early in 
 
  11   the process, leads you to conclusions about 
 
  12   something being likely allergenic. 
 
  13             When we make evaluations, I think it is 
 
  14   more like we don't have a litmus test.  You know, 
 
  15   it would be nice if we did, we could just put the 
 
  16   piece of paper in, it would turn either pink if 
 
  17   it's a no and blue if it's a yes.  We would like 
 
  18   that.  We don't have that.  We have to make 
 
  19   judgments, and in something like that, 
 
  20   digestibility, there is always a question of how 
 
  21   digestible and what are the conditions, and so 
 
  22   forth. 
 
  23             So, we find that that is the reason for 
 
  24   wanting to take into account a number of different 
 
  25   kinds of information and to have some flexibility, 

 
                                                                 15 
 
   1   and not to necessarily just stop at the point where 
 
   2   something about the sequence seems to be similar to 
 
   3   an allergen, and not ask any further questions, so 
 
   4   we felt that that was too rigid in the sense of the 
 
   5   decision tree. 
 
   6             The other thing that is in the decision 
 
   7   tree are some new things.  We have here targeted 
 
   8   serum and the use of animal models as for example, 
 
   9   and things that we know are under development and 
 
  10   there is a lot of interest in that, and we are 
 
  11   interested in those areas. 
 
  12             Our sense has been up until now, is that 
 
  13   these have not been fully worked out in terms of 
 
  14   development, in terms of research, to the point 
 
  15   where we can use them for regulatory purposes. 
 
  16             We were a little uncomfortable with 
 
  17   actually having a decision tree where things flow 
 
  18   through these where there is an expectation that 
 
  19   one would always do these for every protein.  We 
 
  20   have seen, of course, almost 20 proteins to date. 
 
  21   We are confident about the evaluations that have 
 
  22   been done by those, that have not gone through some 
 
  23   of these steps. 
 
  24             It is not clear to us whether those would 
 
  25   add, whether they would be necessary, and I am not 

 
                                                                 16 
 
   1   trying to make judgments.  I don't want to make 
 
   2   judgments here about this, I am just trying to 
 
   3   convey to you what our discussion was in looking at 
 
   4   these decision trees. 
 
   5             So, that was the reason that we thought, 
 
   6   well, let's set the decision tree aside.  We are 
 
   7   not rejecting it, but let's set it aside, let's go 
 
   8   back and look at all the information and experience 
 
   9   that we have had and then work in the Codex process 
 
  10   to develop the text, and then from that text, then, 
 
  11   we can derive a decision tree, that would be even 
 
  12   more helpful, but we only have so much time in the 
 
  13   Codex, and so we didn't get as far as a decision 
 
  14   tree. 
 
  15             But I hope that gives you at least a 
 
  16   little sense of how we have looked at this. 
 
  17             I just want to say a little bit about the 
 
  18   issue of weight of evidence, because we are aware 
 
  19   that there are already beginning to evolve 
 
  20   different interpretations of this and it's no 
 
  21   wonder, when you think about the words one can see 
 
  22   that there is a potential for that, and we would 
 
  23   like to avoid confusion.  We would like to have it 
 
  24   be clear what we mean if we use that term. 
 
  25             We had confusion on a term we used in the 

 
                                                                 17 
 
   1   past, "substantial equivalence," that some of you 
 
   2   may be familiar with, and there was a meaning that 
 
   3   was associated with it, but, in fact, if things are 
 
   4   not really clear, people will interpret them 
 
   5   differently and understand them differently. So we 
 
   6   would like to have whatever draft guidance we 
 
   7   develop be as clear as possible. 
 
   8             Weight of evidence in our mind is 
 
   9   something we do all the time in the food safety 
 
  10   assessment arena.  When we are asked to evaluate 
 
  11   something, it kind of gets back to the litmus test, 
 
  12   we don't have a litmus test for most things.  We 
 
  13   have to evaluate a number of different kinds of 
 
  14   information. 
 
  15             That does not mean that if there is one 
 
  16   test that suggests that something is an allergen, 
 
  17   and there are three or four tests that suggest that 
 
  18   it is not, that we say, well, the weight says that 
 
  19   it is not.  That is not the way we would make the 
 
  20   judgment, we simply would not do that.  One test 
 
  21   could be the one that would sink the ship, so to 
 
  22   speak. 
 
  23             What we do have to do is make a judgment 
 
  24   about whether any data that suggests something 
 
  25   could be an allergen, is strong enough and 

 
                                                                 18 
 
   1   meaningful enough, and we realize that that is not 
 
   2   the sort of kind of digital answer that would make 
 
   3   us feel most comfortable, but most of the things we 
 
   4   do in food safety and biological science is we wind 
 
   5   up having to make judgments. 
 
   6             So, that is really what we mean by "weight 
 
   7   of evidence," it is more taking into account all 
 
   8   the information, and that is why the Codex is 
 
   9   structured in a way that there usually are certain 
 
  10   numbers of tests that are done in the first 
 
  11   evaluation.  We don't just do the sequence and stop 
 
  12   there. 
 
  13             So, the idea is that there will be several 
 
  14   different pieces of information, and that one 
 
  15   should look at all of that.  Any one of those might 
 
  16   be enough to say no, it's time to stop here, this 
 
  17   is possibly an allergen, but it may be that that 
 
  18   would not be the case. 
 
  19             In terms of developing our draft guidance, 
 
  20   then, this is draft guidance and what we will be 
 
  21   thinking about is developing a document that will 
 
  22   put forward what we think are the practices based 
 
  23   on current science, that will provide industry with 
 
  24   the guidance to address this issue in a way that is 
 
  25   scientifically adequate to assure the safety of 

 
                                                                 19 
 
   1   these products. 
 
   2             This is guidance, this is not a 
 
   3   regulation.  In regulations, we codify something, 
 
   4   we put down the specifications for safe use.  It is 
 
   5   very rigid, it is very difficult to change. 
 
   6             Guidance is different.  Guidance is non-binding on 
 
   7   the agency, it is non-binding on 
 
   8   industry, and it is written therefore in a way that 
 
   9   does not say thou shalt do this particular test. 
 
  10   So, we will use words in guidance that bother Dr. 
 
  11   Metcalfe. 
 
  12             He has said quite clearly that the Codex, 
 
  13   for example, bothers him because it says "may" in a 
 
  14   number of places, but that's a guidance document, 
 
  15   Codex is also guidance, it is not binding on 
 
  16   countries. 
 
  17             So, what will happen is for each country, 
 
  18   we will examine the Codex guidance and will develop 
 
  19   its own use of that guidance or not use depending 
 
  20   on the case, but the goal, of course, is to put out 
 
  21   something in guidance that people do agree to, at 
 
  22   least generally, so that there will be some 
 
  23   uniformity in the approach and therefore an 
 
  24   understanding among countries about how to approach 
 
  25   a particular issue in this situation, the 

 
                                                                 20 
 
   1   assessment of potential allergenicity. 
 
   2             When we develop our guidance, it also will 
 
   3   be a document that is not as rigid as a regulation. 
 
   4   It is something that will go out for public 
 
   5   comment, that is part of the process, and at some 
 
   6   point we could make it final or it can just remain 
 
   7   as draft guidance. 
 
   8             This is an area where we all know the 
 
   9   science is evolving, that thinking is evolving.  I 
 
  10   will be very surprised if the issues that we are 
 
  11   thinking about today are resolved before I retire 
 
  12   from FDA.  I don't think that is going to happen, 
 
  13   but I think what we need to do is come to a point 
 
  14   where we can at least say this is our current 
 
  15   thinking, and that is what guidance is from FDA. 
 
  16             It is our current thinking at the time, 
 
  17   and we issue guidance, so that industry has the 
 
  18   benefit of our thinking and the public understands 
 
  19   what our thinking is, and the guidance has the 
 
  20   advantage that we can modify it fairly easily 
 
  21   through the public comment process if we feel that 
 
  22   we need to in the future. 
 
  23             So, that is the goal that we are here for 
 
  24   and I think that is the comments that I would like 
 
  25   to make this morning, Mr. Chairman, if you want to 

 
                                                                 21 
 
   1   entertain questions now or later, it is up to you. 
 
   2             DR. BRANDT:  Any questions, anybody?  Yes, 
 
   3   sir. 
 
   4                    Questions of Clarification 
 
   5             DR. GURIAN-SHERMAN:  I guess that I want 
 
   6   to start with the GAO report, which I think I would 
 
   7   like to clarify something about it because I was 
 
   8   one of the consultants on that report and I think 
 
   9   it is frankly quite misleading in terms of the 
 
  10   representation on that report. 
 
  11             Most of the people that were consulted are 
 
  12   four companies.  There were two consumer groups 
 
  13   supposedly consulted.  I know the other consumer 
 
  14   group had very little input, and most of our input 
 
  15   was ignored. 
 
  16             We have made that clear in other fora, but 
 
  17   I think that anybody who reads that report should 
 
  18   understand, at least from our perspective, as well 
 
  19   as consultants on that report, that it did not 
 
  20   adequately represent consumer opinion. 
 
  21             I am sure beyond the couple of consumer 
 
  22   groups that were consulted to some extent, there is 
 
  23   a lot of opinion from other consumer groups that is 
 
  24   nowhere in that document.  So, I think if you read 
 
  25   that document, you should read it with that 

 
                                                                 22 
 
   1   perspective. 
 
   2             There are a couple other issues.  One of 
 
   3   the things that you mentioned in that report was 
 
   4   that the GAO reviewed several of the submissions. 
 
   5   I think they said they reviewed five of them. 
 
   6   They, by their own, at least in discussions with 
 
   7   me, admission are not experts on the process. 
 
   8             I am not sure exactly how they reviewed 
 
   9   those, but I will say that we now are in the 
 
  10   process of reviewing 14 of those reports, and 
 
  11   frankly, come to a pretty different conclusion. 
 
  12   Some of those reports are not several hundred 
 
  13   pages, as you said.  We have several that are 10 or 
 
  14   20 pages, are very cursory. 
 
  15             Right now there is no standards as far as 
 
  16   I can see in terms of what is submitted to FDA. 
 
  17   Some of them did no statistical analysis for many 
 
  18   things.  You mentioned stability yesterday.  One 
 
  19   typical way of looking at stability over several 
 
  20   generations is to do chi-square analysis. 
 
  21             Many, most of them did no chi-square 
 
  22   analysis, several did, by contrast.  Some of the 
 
  23   companies are doing a more thorough job than 
 
  24   others, but there is really no standard, and I 
 
  25   think we need to give FDA a lot of detail about how 

 
                                                                 23 
 
   1   they should do these tests. 
 
   2             I think from a scientific perspective, you 
 
   3   know, we only have to look at Starlink.  What 
 
   4   happened with Starlink through the SATs is that the 
 
   5   company that presented that data was criticized for 
 
   6   the way they did a lot of the analysis, and I was 
 
   7   personally involved in some of that analysis. 
 
   8             They used monoclonal antibodies instead of 
 
   9   polyclonal, so you might not pick up fragments that 
 
  10   are digested.  They didn't look closely at 
 
  11   glycosylation or some issues about whether the 
 
  12   protein was glycosylated that were not resolved. 
 
  13             There are a number of things in the 
 
  14   procedure.  I think, as scientists, we all 
 
  15   understand that those can make huge differences in 
 
  16   your outcome.  I think the process right now is so 
 
  17   vague and so open-ended that you can't draw 
 
  18   conclusions about a lot of the data that is 
 
  19   submitted.  It is actually most of the time not 
 
  20   data, and I think you only have to look closely at 
 
  21   those studies to see the tremendous amount of 
 
  22   variation in the quality of the submissions. 
 
  23             For the most part, you know, we have also 
 
  24   looked at FDA responses to those, and there is very 
 
  25   little response from FDA to a lot of those issues, 

 
                                                                 24 
 
   1   and I can discuss a number of them. 
 
   2             So, I think that really has to be taken 
 
   3   with a big grain of salt, and I think without an 
 
   4   actual approval process, I am not sure how much can 
 
   5   be done because the agency does not approve of the 
 
   6   safety of these products, but I think as an interim 
 
   7   step, the agency needs to have a tremendous amount 
 
   8   of guidance wherever we can. 
 
   9             I mean there are some areas that are just 
 
  10   not resolved in terms of protocols, but also in 
 
  11   terms of decision tree, I can appreciate the desire 
 
  12   to have flexibility, but again because there is 
 
  13   uncertainty about what the results mean, I think 
 
  14   there should be some clear stops here. 
 
  15             I appreciate what you said about 
 
  16   digestibility, for instance, and there may be 
 
  17   situations where you have an ambiguous result, but 
 
  18   even from the studies that have been presented, 
 
  19   Jim's work in '96 and subsequently, several of 
 
  20   those that are considered stable under those tests 
 
  21   were digested after two minutes or eight minutes. 
 
  22             I think those kind of things need to be 
 
  23   built in as explicitly as possible into the 
 
  24   guidance, and granted they are not written in 
 
  25   stone, but without it, the companies are largely 

 
                                                                 25 
 
   1   determining the process of how this is done, and 
 
   2   they may do a good job in many cases, they may make 
 
   3   mistakes in others, and I just don't think it gives 
 
   4   them enough detail, and I think we should be doing 
 
   5   that or at some point in this process. 
 
   6             DR. BRANDT:  Other questions? 
 
   7             DR. ARIAS:  I have a question.  The power 
 
   8   of any good predictive model, such as I assume that 
 
   9   this decision tree is, is reflected in the outcomes 
 
  10   that have been tested in some type of real-world 
 
  11   situation. 
 
  12             Now, it is clear that no one is going to 
 
  13   test prospective allergens in a human population, 
 
  14   but given the discussion that I have heard over the 
 
  15   last day, there are at least some animal models for 
 
  16   potential allergenicity. 
 
  17             So, I am wondering had this model actually 
 
  18   been tested and validated for its predictive power 
 
  19   using prospective candidates through an animal 
 
  20   model system to see whether predicted outcomes 
 
  21   actually correspond to what the model says they 
 
  22   should. 
 
  23             DR. MARYANSKI:  That's a good question.  I 
 
  24   am not aware that anyone has actually done that 
 
  25   specifically. Certainly, this is very new as you 

 
                                                                 26 
 
   1   can see, 2001, so this process, I am not aware of a 
 
   2   lot of things that have been run through this. 
 
   3             DR. BUCHANAN:  Actually, with Syngenta, 
 
   4   with one of their genetically modified products 
 
   5   over a two-year period using our system, and with 
 
   6   the dog, which as I mentioned yesterday, there is a 
 
   7   hierarchy of response. 
 
   8             It was an interesting study, and the 
 
   9   results turned out suggesting that it is not an 
 
  10   allergen. 
 
  11             DR. LEHRER:  I had a question.  You talked 
 
  12   about the decision tree versus the weight of 
 
  13   evidence, and it seems to me that some aspects of 
 
  14   the decision process lend themselves, our decision 
 
  15   tree lends itself well to that, whereas other 
 
  16   aspects may fit in better with the weight of 
 
  17   evidence. 
 
  18             Do you think that some type of combination 
 
  19   of these processes, of these approaches is 
 
  20   reasonable? 
 
  21             DR. MARYANSKI:  I would not want it to 
 
  22   come down to a question of should we have a 
 
  23   decision tree or not have a decision tree.  I was 
 
  24   one of the skeptics back in 1992 when Dr. Call from 
 
  25   our center, when we were putting together the '92 

 
                                                                 27 
 
   1   policy, said hey, we can do some decision trees to 
 
   2   explain this guidance we are developing. 
 
   3             Another colleague and I thought, oh, no, 
 
   4   we will never be able to do that in a way that will 
 
   5   not raise the kinds of issues that--but she 
 
   6   managed, and obviously, by the time we all pitched 
 
   7   in, we have decision trees in the '92 policy, I 
 
   8   think that they have been useful, so I do think 
 
   9   decision trees can be useful, and it could be that 
 
  10   either aspects of this could be done as a decision 
 
  11   tree or all of it depending when one has the 
 
  12   opportunity to really sit down and think about it. 
 
  13             DR. LEHRER:  Also, do you know why 
 
  14   sequence homology was put first in this process as 
 
  15   opposed to using specific serum testing? 
 
  16             DR. MARYANSKI:  I was not involved.  This 
 
  17   is from the expert consultation, so Dr. Metcalfe 
 
  18   would be a better person to answer that.  I really 
 
  19   can't answer that. 
 
  20             DR. LEHRER:  One last point that Jonathan 
 
  21   asked concerning animal models, I think you raised 
 
  22   a good point.  I think that the problem is that 
 
  23   these models are currently being validated.  You 
 
  24   really need to validate them before you take it to 
 
  25   that step, and I would imagine or I would hope soon 

 
                                                                 28 
 
   1   that some of them will have reasonable validation 
 
   2   in terms of reflecting the human experience, so 
 
   3   they could be used for that. 
 
   4             DR. ARIAS:  May I make a comment?  My 
 
   5   understanding is that the cosmetic industry for 
 
   6   many years has been validating animal models for 
 
   7   allergenicity and for organic materials now.  I 
 
   8   don't know if that would be consistent with the 
 
   9   proposed expression of transgenic proteins, but 
 
  10   nonetheless, animals have been looked at. 
 
  11             In regards to my specific comment here, is 
 
  12   that if we are considering adopting as part or at 
 
  13   least recommending the adoption to FDA of part or 
 
  14   all of this decision tree-- 
 
  15             DR. BRANDT:  We don't have to do that 
 
  16   today. 
 
  17             DR. ARIAS:  Yes, I realize that, but I 
 
  18   mean if that is one of the issues on the agenda, 
 
  19   then, clearly we need to know more about the 
 
  20   issues, the power of this model and whether it is 
 
  21   predictive.  I think that is going to be a key. 
 
  22   You can't adopt a model without knowing its 
 
  23   potential predictive outlook. 
 
  24             DR. LEHRER:  They may have been using 
 
  25   animal models for many years.  There is a lot of 

 
                                                                 29 
 
   1   question about the validation of those animal 
 
   2   models frankly, and particularly for allergy and 
 
   3   especially IgE antibody responses that we are 
 
   4   looking at.  I think they look at irritant type 
 
   5   responses.  They may call it validation for 
 
   6   allergy, but I am not so sure it is. 
 
   7             DR. KAPUSCINSKI:  I guess I would like to 
 
   8   make three comments.  Last night I sort of 
 
   9   revisited all these documents again and one thing 
 
  10   that really struck me when I read the entire 
 
  11   FAO/WHO joint report is that we really can't look 
 
  12   at this decision tree just alone, we really do need 
 
  13   to read all the supporting documentation. 
 
  14             When you read that, you see that this is 
 
  15   really meant to be a guide for sort of thinking 
 
  16   through systematically and also in what order you 
 
  17   consider doing these tests, but then the supporting 
 
  18   documentation is really critical and I would argue 
 
  19   that it is very similar to what I imagine you would 
 
  20   be looking for in the guidance document. 
 
  21             It has all the caveats, all the 
 
  22   suggestions about, you know, it lays out the pros 
 
  23   and cons of the different methodologies, different 
 
  24   in terms of the state of the art, suggestions about 
 
  25   ways to address them. 

 
                                                                 30 
 
   1             I think that is that, I mean from my 
 
   2   perspective and from my experience with risk 
 
   3   assessment methodologies and a lot of other areas, 
 
   4   not only in other aspects of biotechnology, but 
 
   5   also other technology assessments, this is a pretty 
 
   6   proven way of moving forward. 
 
   7             I don't actually think that there is this 
 
   8   big a disjunct between this decision tree and 
 
   9   starting off with writing a guidance document.  It 
 
  10   seems to me that expert consultation would probably 
 
  11   use that integrated approach, and it really comes 
 
  12   out clearly when you read the entire document 
 
  13   rather than looking at the decision tree alone. 
 
  14             My second comment is that it struck me as 
 
  15   I was looking at the righthand side of this 
 
  16   decision tree last night and then again hearing you 
 
  17   talk this morning, that what I am sort of hearing 
 
  18   you say is that you would like to have the 
 
  19   flexibility to, for example, not just stop if you 
 
  20   get a positive response in the sequence homology, 
 
  21   and I have to just stop there and go automatically 
 
  22   to that decision of likely allergenic, but like to 
 
  23   have the flexibility to do other testing. 
 
  24             That would be a very easy thing to do, a 
 
  25   fairly simple modification of the decision tree, 

 
                                                                 31 
 
   1   but still be able to hold onto I think some of the 
 
   2   elegance of what is in here right now, and would 
 
   3   simply be to create another arrow and give the 
 
   4   option that you can either, after doing the 
 
   5   sequence homology, choose to reach the decision 
 
   6   that it is like allergenic or proceed to the next 
 
   7   test, which would be targeted serum screen, and you 
 
   8   could also add another arrow between targeted serum 
 
   9   screen and the last box, which combines pepsin 
 
  10   resistance and animal models. 
 
  11             Again, if you look through the published 
 
  12   literature on risk assessment methodologies, 
 
  13   decision trees are often designed, so that there 
 
  14   actually is an option in the sense that burden is 
 
  15   placed on the user of the tree to decide how much 
 
  16   more testing do they want to do, and if you gave 
 
  17   that option, I think it would also fit with the 
 
  18   notion that FDA may want to come out at the end, in 
 
  19   the guidance document, saying if any one of these 
 
  20   tests gives a very strong positive signal, that is 
 
  21   enough to sink the ship, but give the users the 
 
  22   flexibility of combining tests. 
 
  23             My final comment has to do with this 
 
  24   concern that all these methodologies are still 
 
  25   being developed, there is a need for improved 

 
                                                                 32 
 
   1   validation, et cetera.  Again, that is not unusual 
 
   2   to this particular area.  We deal with this in risk 
 
   3   assessment all the time. 
 
   4             I would argue that that is exactly the 
 
   5   reason that we need, number one, a fairly 
 
   6   systematic methodology that everyone can look at 
 
   7   and say, oh, yes, this is the steps we should go 
 
   8   through with all this documentation to kind of add 
 
   9   the devil in the detail stuff. 
 
  10             Then, we do need some sort of surveillance 
 
  11   and ongoing research after things get approved, so 
 
  12   that we can learn and, over time, improve the 
 
  13   methodology, but we obviously can't just stop in 
 
  14   our tracks and not do anything until the 
 
  15   methodologies get improved, but I think this 
 
  16   actually gives you, using this tool combined with 
 
  17   surveillance on any kinds of products that get 
 
  18   approved where there may still be some questions 
 
  19   and combined with research, is the way to move 
 
  20   forward. 
 
  21             DR. ARIAS:  Another question regarding the 
 
  22   decision tree, analyzing some of the same documents 
 
  23   that Anne mentioned in more detail last night, as 
 
  24   well, I came across the issue that right now 
 
  25   perplexes me, and that is, looking at the decision 

 
                                                                 33 
 
   1   tree, it is apparent that a prospective allergen 
 
   2   that has not been previously characterized and has 
 
   3   not been identified in a population, because 
 
   4   apparently this hasn't been studied extensively for 
 
   5   large numbers of allergens systematically 
 
   6   throughout different geographical and ethnic 
 
   7   populations, might very well slip right through the 
 
   8   screen particularly one that didn't have the 
 
   9   anticipated resistance to pepsin that not all 
 
  10   allergens have. 
 
  11             So, since our knowledge, as I gathered 
 
  12   from expert testimony and these documents, is less 
 
  13   than perfect on what constitutes an allergen, and 
 
  14   there is many exceptions to these rules, I think we 
 
  15   might want to be careful that we don't place too 
 
  16   much weight in this decision tree, and as Anne 
 
  17   mentioned, make sure that there are other facets 
 
  18   that go into the evaluation. 
 
  19             As I mentioned before, I think certainly 
 
  20   we want to try to validate as many of the 
 
  21   predictions of this model, but one just looking at 
 
  22   it, which is obvious, is that type of allergen that 
 
  23   goes right through your screen and never be 
 
  24   detected, right through the decision tree. 
 
  25             So, just multilevels are very important 

 
                                                                 34 
 
   1   for enhancing confidence, but each one of these 
 
   2   really intrinsically is flawed, and I think we all 
 
   3   recognize there is no probability coefficients 
 
   4   assigned to any of these, there is no quantitation. 
 
   5   In fact, I am not even convinced, in talking about 
 
   6   sequence homology the other day, a contentious 
 
   7   issue, where the cutoff is. 
 
   8             It sort of reminds me of looking at 
 
   9   microarray expression data, you know, what is a 
 
  10   clear difference in gene expression.  Some people 
 
  11   say 2 standard deviations, some say 3.  It is 
 
  12   really flipping a coin in some regards.  The same 
 
  13   things holds true here. 
 
  14             The variety of epitopes that may be 
 
  15   present, for instance, in a specific allergen, that 
 
  16   are only recognized, say, by a subpopulation of 
 
  17   reactive individuals, may not necessarily be 
 
  18   predictive for the other allergen epitopes that 
 
  19   are, for instance, present in a novel protein, 
 
  20   perhaps a transgenic one, so we can't necessarily 
 
  21   rely on that, and then we have to use ridiculously 
 
  22   large numbers of sera in order to enhance our 
 
  23   confidence. 
 
  24             I think these are excellent beginnings, 
 
  25   but I think we have to recognize there are 

 
                                                                 35 
 
   1   limitations.  There is no assignation of 
 
   2   probability or quantitative outcomes in this 
 
   3   decision tree.  So, as long as we recognize that 
 
   4   and proceed, I think it acts as a good nucleus, but 
 
   5   clearly, lots more needs to be done. 
 
   6             DR. BUCHANAN:  For the record, I want to 
 
   7   mention a workshop that was held last year in North 
 
   8   Carolina.  I don't believe we have heard about 
 
   9   that.  That was dedicated to animal models.  It was 
 
  10   organized by Dr. Germolec at NIEHS, and I 
 
  11   understand that that summary will soon be 
 
  12   published, and I think all of the candidates were 
 
  13   covered at that time. 
 
  14             DR. BRANDT:  They must have pushed dogs. 
 
  15             DR. BUCHANAN:  In this case, the rats were 
 
  16   ahead. 
 
  17             DR. BRANDT:  Do you want to do your 
 
  18   summary now? 
 
  19             DR. MARYANSKI:  I think I am done for now. 
 
  20             DR. BRANDT:  You are done for now. 
 
  21             Folks, we are ready for a break.  We will 
 
  22   take a break and then we will start you all off in 
 
  23   15 minutes. 
 
  24             [Recess.] 
 
  25                          Public Comment 

 
                                                                 36 
 
   1             DR. BRANDT:  Sue MacIntosh from Bayer Crop 
 
   2   Science. 
 
   3             DR. MacINTOSH:  Thank you.  I am Sue 
 
   4   MacIntosh and I am from Bayer Crop Science, but 
 
   5   today, I am actually representing ILSI.  In 
 
   6   particular, I am the chairman of the Protein 
 
   7   Allergenicity Technical Committee.  In the next 10 
 
   8   minutes, I would like to share with you a little 
 
   9   bit about ILSI and about some of the work that we 
 
  10   have been doing over the last couple of years since 
 
  11   ILSI was formed. 
 
  12             I will start out by giving you just a 
 
  13   little bit of background on ILSI, if you are not 
 
  14   familiar with this organization, because I think it 
 
  15   is a rather unique organization. 
 
  16             [Slide.] 
 
  17             ILSI is a nonprofit, worldwide foundation 
 
  18   established in 1978 to advance the understanding of 
 
  19   scientific issues relating to a wide range of 
 
  20   different topics, nutrition, food safety, 
 
  21   toxicology, risk assessment, and the environment. 
 
  22             Also unique to this group is that it 
 
  23   brings together scientists from all realms, from 
 
  24   industry, from government, from academia, and also 
 
  25   from the public sector to solve problems with broad 

 
                                                                 37 
 
   1   implications for the well being of the general 
 
   2   public.  Thus, the funding also comes from those 
 
   3   same groups, from industry, from government, and 
 
   4   also from foundations. 
 
   5             [Slide.] 
 
   6             I am not going to go into this mission 
 
   7   statement because I am short on time, but this just 
 
   8   focuses on HESI, which is where the Protein 
 
   9   Allergenicity Committee resides, is on the HESI 
 
  10   side, which is focused more on the environmental 
 
  11   aspects and health. 
 
  12             [Slide.] 
 
  13             Finally, the Protein Allergenicity 
 
  14   Technical Committee, the goal there was to advance 
 
  15   the scientific understanding of different relevant 
 
  16   parameters for characterizing the allergenic 
 
  17   potential of novel proteins and biotech products. 
 
  18             [Slide.] 
 
  19             On this slide, you know, we have a lot of 
 
  20   decision trees and a lot of discussion about 
 
  21   decision trees, but I only have it here to really 
 
  22   point out that we wanted to look at each of these 
 
  23   different boxes, evaluate the issues surrounding 
 
  24   those, and see what we, as a group, could try to 
 
  25   understand or maybe clarify using some various 

 
                                                                 38 
 
   1   scientific aspects. 
 
   2             In particular, we were interested in 
 
   3   trying to validate various methods as the 
 
   4   discussion earlier this morning.  There are many 
 
   5   methods out there, different companies are using 
 
   6   different methods, and when we put our heads 
 
   7   together, we realized this and wanted to try to 
 
   8   develop some protocols that could be validated and 
 
   9   could be uniformly useful, not only within the 
 
  10   U.S., but globally. 
 
  11             [Slide.] 
 
  12             So, what we have done is we have convened 
 
  13   several different expert panels with many different 
 
  14   academics  and government people and also public 
 
  15   sector, and we have come up with this set of 
 
  16   different issues that we identified that was the 
 
  17   starting point of then narrowing down into specific 
 
  18   projects. 
 
  19             [Slide.] 
 
  20             I will just run through these.  The first 
 
  21   was the need for standardization of the methods for 
 
  22   amino acid sequence analysis, and I don't think any 
 
  23   of these are going to be strange to you.  These are 
 
  24   all topics that have been brought up over the last 
 
  25   day and a half. 

 
                                                                 39 
 
   1             Uncertainty regarding whether IgE epitopes 
 
   2   are missed by the current sequence comparisons. 
 
   3   The need for standardization of the in vitro pepsin 
 
   4   digestion assay.  The need for scientific consensus 
 
   5   on additional information necessary for proteins 
 
   6   that would be stable to digestion. 
 
   7             The need for scientific consensus 
 
   8   regarding usefulness of using broad serum IgE 
 
   9   screens to provide a more complete allergenicity 
 
  10   assessment.  Finally, the need for more research to 
 
  11   evaluate and validate animal models currently 
 
  12   available for human allergenicity assessment. 
 
  13             [Slide.] 
 
  14             Now, from that group, we came up with five 
 
  15   different project areas.  One was molecular 
 
  16   characterization, which includes the digestibility 
 
  17   stuff.  The sequence homology and bioinformatics, 
 
  18   another project. Animal models to predict human 
 
  19   food allergy. 
 
  20             The last two, we haven't gotten very far 
 
  21   in those, but I want to name them anyway, because 
 
  22   they have been identified by our group.  Effect of 
 
  23   protein prevalence in food, and that is that 
 
  24   threshold question, and finally, the development of 
 
  25   sera bank, another topic that was also raised 

 
                                                                 40 
 
   1   yesterday.  Again, we have focused on the top three 
 
   2   so far in the last couple of years. 
 
   3             [Slide.] 
 
   4             Now, I will go through each one and kind 
 
   5   of give you an update on where we are. 
 
   6             The first on the molecular 
 
   7   characterization, we held an expert panel, and 
 
   8   those experts recommended that we develop a 
 
   9   standard digestibility protocol, and that we then 
 
  10   take this protocol and conduct a ring test at 
 
  11   multiple labs with multiple proteins, which is the 
 
  12   typical way that we validate an assay, an 
 
  13   analytical assay. 
 
  14             Of course, the second item, which you saw 
 
  15   in the previous slide, was expand the abundance 
 
  16   comparison and evaluation to really understand 
 
  17   thresholds and if we can come up with a threshold. 
 
  18             [Slide.] 
 
  19             Now, the in vitro gastric stability, we 
 
  20   actually have now carried out an international ring 
 
  21   study at the labs listed on the righthand side. 
 
  22   You will see that aside from the tech providers, 
 
  23   which obviously would be very interested in this 
 
  24   process, we also had a couple other labs, the 
 
  25   National Center for Food Safety and Technology, and 

 
                                                                 41 
 
   1   actually a couple of the FDA people are here that 
 
   2   conducted that study, and also the CLB Department 
 
   3   of Allergy, which is in the Netherlands, and then 
 
   4   the National Institute of Health Sciences in Japan. 
 
   5             So, it really was a very large study. 
 
   6   This now has been completed, the ring study has 
 
   7   been completed, the data is being collected at this 
 
   8   point, and we are now working on a paper that would 
 
   9   incorporate, of course, all the people who 
 
  10   performed this study. 
 
  11             [Slide.] 
 
  12             Just a little bit looking on the results, 
 
  13   in general, we saw very consistent results, in 
 
  14   fact, we actually were pretty surprised because 
 
  15   usually, a ring study like this is not an easy one 
 
  16   to do if you have ever carried one out for an 
 
  17   analytical study, but they were fairly consistent 
 
  18   in the laboratories around the world. 
 
  19             We did digestions of a standard set of 
 
  20   proteins at two different pH's, pH 2 and pH 1.2, 
 
  21   and while we saw a bit slower rate of degradation 
 
  22   at the pH 2 than at pH 1.2, it did not alter the 
 
  23   overall apparent sensitivity of the protein to 
 
  24   digestion. 
 
  25             One aspect was the gel fixing and staining 

 
                                                                 42 
 
   1   procedures may affect the visibility of certain 
 
   2   fragments, but again the apparent sensitivity of 
 
   3   the protein to digestion was similar. 
 
   4             We feel we have been successful 
 
   5   establishing a general protocol, and like I said, 
 
   6   we are writing up the paper and we will go to an 
 
   7   external peer-reviewed journal to work that 
 
   8   through. 
 
   9             [Slide.] 
 
  10             Now, in the sequence homology expert 
 
  11   recommendations, we had several different 
 
  12   recommendations focused on databases to encourage a 
 
  13   clear set of criteria and definitions for allergens 
 
  14   that would be placed in such a database, and 
 
  15   convene an expert group to actually define what 
 
  16   that criteria would be. 
 
  17             Identify all available databases with a 
 
  18   view towards synthesizing all information including 
 
  19   specialized databases, such as when we start to 
 
  20   understand more about T cell epitopes, perhaps a 
 
  21   database could be developed with those epitopes and 
 
  22   we could screen against that, and not just whole 
 
  23   protein or sequences of protein. 
 
  24             We also want to encourage the development 
 
  25   of database or databases that have links and 

 
                                                                 43 
 
   1   annotations to support that data.  Right now, most 
 
   2   of the databases don't have links, so you are not 
 
   3   really sure why that protein was put in the 
 
   4   database, and we would like to see a link to the 
 
   5   literature. 
 
   6             Finally, utilization of 3-D structural 
 
   7   data could be informative, and the exploration of 
 
   8   this aspect should be encouraged, and, of course, 
 
   9   again, we have talked about the sequences, linear 
 
  10   sequences versus 3-D structures, and as 3-D 
 
  11   structures become more apparent and we get a wider 
 
  12   range of them understood on different allergens, 
 
  13   then, I think this would also have some value. 
 
  14             [Slide.] 
 
  15             Now, we have worked actually with ECVAM, 
 
  16   which is European Commission for the Validation of 
 
  17   Alternative Methods, and they convened a group last 
 
  18   year to try to develop this ultimate allergen 
 
  19   database. 
 
  20             They are at the point right now of trying 
 
  21   to determine funding for that data base, which of 
 
  22   course, as you can imagine, is not just the expense 
 
  23   of setting up the database, but maintaining it and 
 
  24   continuing to add allergens into that database in a 
 
  25   very structured fashion is also a very expensive 

 
                                                                 44 
 
   1   proposition, but I think it is an important thing 
 
   2   for all of us to have a publicly available database 
 
   3   for allergens. 
 
   4             [Slide.] 
 
   5             The final aspect, which we have just 
 
   6   started really in the last year, was the expert 
 
   7   panel that recommended that we needed a comparative 
 
   8   assessment of animal models with allergens and non- 
 
   9   allergens, which is often the part that is usually 
 
  10   left out.  It is using a variety of exposure 
 
  11   scenarios. 
 
  12             So, we initiated the evaluation of a 
 
  13   rodent model for human allergenicity prediction 
 
  14   with a standard set of proteins using different 
 
  15   mouse strains, comparing IP to oral routes of 
 
  16   sensitization, evaluating results with and without 
 
  17   the use of adjuvants, and also comparing different 
 
  18   sensitization and challenge protocols using 
 
  19   bioactive IgE as the primary endpoint, which is 
 
  20   another very important thing that we felt was very 
 
  21   important in an animal model. 
 
  22             [Slide.] 
 
  23             Of course, in order to even start that 
 
  24   work or think about the work, is proteins, and that 
 
  25   is a very expensive and difficult aspect is to get 

 
                                                                 45 
 
   1   a good supply of pure proteins. 
 
   2             We have now hired a lab in Europe, and we 
 
   3   are now having purified proteins made there.  We 
 
   4   have chosen actually two positive controls or what 
 
   5   we would have as known allergens Ara h1, Ara h2, 
 
   6   and also beta-lactoglobulin, and then we also have 
 
   7   a couple known non-allergens RUBISCO and Soy 
 
   8   lipoxygenase, and these are being purified as we 
 
   9   speak, and we should have them available in the 
 
  10   next six months to a year. 
 
  11             [Slide.] 
 
  12             Finally, in conclusion, allergenicity 
 
  13   assessment for novel proteins and biotech projects 
 
  14   should encompass a comprehensive evaluation--I 
 
  15   think we all agree on that--that assesses a variety 
 
  16   of parameters. 
 
  17             To date, no single factor has been 
 
  18   recognized as the primary determinant for 
 
  19   allergenicity.  So, instead, our scientific 
 
  20   guidance has been to utilize a holistic, weight-of-evidence 
 
  21   whether you use a decision tree or not, it 
 
  22   still has to be a weight-of-evidence of all the 
 
  23   different pieces of data that you have, that 
 
  24   accounts for a variety of factors and experimental 
 
  25   approaches for an overall assessment of the 

 
                                                                 46 
 
   1   allergenic potential of the new protein. 
 
   2             Thank you for your attention and I really 
 
   3   appreciate having the opportunity to share what 
 
   4   ILSI has been doing, and if you have any other 
 
   5   questions, don't hesitate to come to me and I can 
 
   6   give you more information, and also Carlos Thomas, 
 
   7   who is our scientific director at ILSI for this 
 
   8   project, either one of us can certainly help and 
 
   9   answer any questions. 
 
  10             Thank you very much. 
 
  11             DR. BRANDT:  Thank you for being here. 
 
  12             Dr. Michael Hansen of Consumers Union.  I 
 
  13   think we have a handout from him. 
 
  14             DR. HANSEN:  Unfortunately, I don't have 
 
  15   any slides or anything.  If I would have known I 
 
  16   could use them, i would have. 
 
  17             Anyway, thank you very much for the chance 
 
  18   to present the views of Consumers Union, which is a 
 
  19   publisher of Consumer Reports, to this 
 
  20   subcommittee.  We feel that the Food and Drug 
 
  21   Administration is taking a very positive, 
 
  22   important, and much needed step by undertaking an 
 
  23   effort to develop a protocol for assessing the 
 
  24   potential allergenicity of engineered foods. 
 
  25             We have already seen an example with the 

 
                                                                 47 
 
   1   Brazil nut allergen that was successfully 
 
   2   identified and removed from and development 
 
   3   stopped, so it never made it on the market. 
 
   4   However, with that case and also with the 
 
   5   subsequent case of Starlink corn, whose potential 
 
   6   allergenicity was much more difficult to predict, 
 
   7   these underline the need to have a sound, 
 
   8   consistent, and comprehensive assessment protocol 
 
   9   which, when scientific data is incomplete, errs on 
 
  10   the side of protecting consumer health, to be used 
 
  11   by all companies developing protocols and by all 
 
  12   the agencies regulating them. 
 
  13             We feel that the guidance should be 
 
  14   incorporated in the rule on Pre-Market Biotech 
 
  15   Notification, which FDA has under development.  Our 
 
  16   comments are going to focus primarily on the 
 
  17   specifics of what the assessment should contain and 
 
  18   how it should be conducted. 
 
  19             As I note in my paper that I handed out, 
 
  20   we think the FDA can profitably draw on several 
 
  21   excellent bodies that have already given 
 
  22   consideration and thought to the difficult question 
 
  23   of allergenicity assessment. 
 
  24             I want to bring special attention to the 
 
  25   global expert consultation that was a joint FAO/WHO 

 
                                                                 48 
 
   1   that was held in 2001 and chaired by Dr. Dean 
 
   2   Metcalfe of the National Institute of Health, to 
 
   3   the Annex on Allergenicity to the Guidelines for 
 
   4   Assessment of the Safety of Recombinant DNA Plants, 
 
   5   that Paul Mayers talked about yesterday, and to the 
 
   6   work that the Environmental Protection Agency's 
 
   7   FIFRA Scientific Advisory Panel.  Their report on 
 
   8   charging them with developing mammalian toxicity 
 
   9   assessment guidelines for protein plant pesticides 
 
  10   and with assessing the human safety of Starlink 
 
  11   corn. 
 
  12             The key points that I would like to 
 
  13   quickly go through is, first, we urge FDA, we think 
 
  14   that the protocol should be a rule, and not a 
 
  15   guidance.  We feel that it needs to be mandatory 
 
  16   and not voluntary. 
 
  17             Related to this, we also think that it is 
 
  18   very important to have a decision tree because we 
 
  19   think that in both of these cases, if you want the 
 
  20   confidence of the public, they need to have some 
 
  21   kind of sense that there is a clear-cut pathway 
 
  22   that the companies have to follow. 
 
  23             A problem with having guidance, which is 
 
  24   not binding on the companies or with having a 
 
  25   general weight-of-the-evidence approach which says 

 
                                                                 49 
 
   1   you weigh these various things, that, to the public 
 
   2   looks like that there isn't a clear pathway. 
 
   3             That is why we think it is important they 
 
   4   actually have a decision tree, so it is very clear 
 
   5   what data has to come in and what you will conclude 
 
   6   based on those data.  So, we do think it is 
 
   7   important that you require the companies to 
 
   8   actually do these tests, so that means rather than 
 
   9   a guidance, it should be a proposed rule, so it is 
 
  10   mandatory and that there is the use of decision 
 
  11   trees. 
 
  12             We actually recommend that the decision 
 
  13   tree to be used is the one from the Expert 
 
  14   Consultation.  We also view that all allergens, 
 
  15   whether food, dermal, or inhalant allergens, should 
 
  16   be used in the amino acid sequence homology 
 
  17   searches.  This is actually recommended in the 
 
  18   Annex to the Safety Testing Guidelines that Codex 
 
  19   put out. 
 
  20             We also think that all the assessment 
 
  21   criteria that the Science Advisory Panel, that the 
 
  22   Expert Consultation, and that EPA has suggested, 
 
  23   that is, looking at amino acid sequence homology, 
 
  24   digestive stability, heat stability, animal models 
 
  25   and certain physical characteristics should all be 

 
                                                                 50 
 
   1   looked at, and as I said, these should be 
 
   2   integrated into a decision tree. 
 
   3             We also feel that you should conduct tests 
 
   4   on all, quote "all," quote "newly-expressed" 
 
   5   proteins.  That is language from Annex 1 of the 
 
   6   draft safety assessment guidelines for rDNA plants 
 
   7   that Codex has, and that means not just the 
 
   8   intended transgene product, but also would include 
 
   9   all unintended newly-expressed proteins, that is, 
 
  10   the process of genetic engineering may turn on 
 
  11   genes in a plant or animal that have been 
 
  12   previously turned off, or the transgene protein 
 
  13   could interact with the complex metabolic pathway 
 
  14   to create new proteins, so all of them, whether 
 
  15   intended or unintended, need to go through the same 
 
  16   testing protocol. 
 
  17             We also believe that you should require 
 
  18   that proteins be tested in both the purified form 
 
  19   and as they exist in the food that will be sold, so 
 
  20   also within the food matrix.  We believe that the 
 
  21   purified protein should be extracted from the plant 
 
  22   from which the food will be derived. 
 
  23             We do not think the FDA should allow a 
 
  24   company to test a protein as it is expressed in a 
 
  25   bacterial or other microbial source because there 

 
                                                                 51 
 
   1   can be differences.  For example, E. coli does not 
 
   2   glycosylate whereas plants often do. 
 
   3             So, I quickly just want to make a few 
 
   4   comments on the key assessment techniques for the 
 
   5   amino acid sequence homology.  I would just like to 
 
   6   point out that the old decision tree that ILSI had, 
 
   7   the Expert Consultation, they came up with a 
 
   8   standardized methodology, and that is actually 
 
   9   another important point is for all these assessment 
 
  10   criteria, there need to be standardized 
 
  11   methodologies and protocols. 
 
  12             For the sequence homology, what the Expert 
 
  13   Consultation did is they started with the ILSI 
 
  14   decision tree and then they updated it based on new 
 
  15   scientific information.  What they suggested is 
 
  16   that rather than use the eight identical contiguous 
 
  17   amino acids, and using a global alignment, the 
 
  18   Expert Consultation recommended that you could use 
 
  19   sequence identify of six rather than eight 
 
  20   identical contiguous amino acids. 
 
  21             They also suggested using local alignments 
 
  22   rather than global alignments when you are 
 
  23   comparing unrelated proteins.  They also suggested 
 
  24   additional criteria, such as that 35 percent 
 
  25   overall amino acid sequence homology is a cause for 

 
                                                                 52 
 
   1   further concern, and suggested development of 
 
   2   databases and methods to test for discontinuous 
 
   3   epitopes including those change by glycosylation 
 
   4   patterns.  They suggest that a very specific 
 
   5   methodology, which I outlined. 
 
   6             I also would like to bring up the work, 
 
   7   since they do refer to it, of Dr. Steven Gendel, 
 
   8   who argued persuasively for the use of local 
 
   9   algorithms rather that global algorithms when 
 
  10   assessing allergenicity of novel proteins because 
 
  11   those proteins are not evolutionary related. 
 
  12             DR. BRANDT:  Three minutes. 
 
  13             DR. HANSEN:  He goes on to develop what he 
 
  14   calls a "biochemical similarity matrix," which 
 
  15   divides amino acids into six classes based on 
 
  16   biochemical characteristics, for example, 
 
  17   hydrophilic acid, amino acids, hydrophilic basic 
 
  18   amino acids, et cetera, and then the alignment of 
 
  19   members of the same class is scored as a match. 
 
  20             The realignment was then confined to 
 
  21   regions of 15 to 20 amino acids in each case to 
 
  22   preserve the previously located identities.  He 
 
  23   actually found by doing this that there was 
 
  24   significant sequence homology between beta-lactoglobulin and 
 
  25   the Cry3A, which is found in Bt 

 
                                                                 53 
 
   1   potatoes, and between Cry1Ab and Cry1Ac and 
 
   2   vitellogenin, and he concludes, "although it is 
 
   3   clear that some amino acid residues are critical 
 
   4   for specific binding, some conservative 
 
   5   substitutions may not affect allergenicity. 
 
   6                                 Therefore, it may be 
 
   7   prudent to treat sequence matches with a high 
 
   8   degree of identity that occur within regions of 
 
   9   similarity as significant even if the identity does 
 
  10   not extend for eight or more amino acids.  For 
 
  11   example, the similarity between Cry1Ab and 
 
  12   vitellogenin might be sufficient to warrant 
 
  13   additional evaluation." 
 
  14             So, we think FDA should use the WHO 
 
  15   protocol as modified by Dr. Gendel. 
 
  16             The only other comment I wanted to make, I 
 
  17   will flip over to heat and digestibility because 
 
  18   those are laid out, and I just want to, for animal 
 
  19   models, bring people's attention to the meeting on 
 
  20   Assessment of the Allergic Potential of Genetically 
 
  21   Modified Foods, which was held in Chapel Hill last 
 
  22   November. 
 
  23             I want to point out that one of the people 
 
  24   that presented there was Dr. Katherine Sarlo, who 
 
  25   is a scientist at Proctor & Gamble.  It turns out 

 
                                                                 54 
 
   1   Proctor & Gamble, when they first started using 
 
   2   enzymes in their detergents in the mid-1960s, they 
 
   3   had huge problems with workers developing 
 
   4   allergies, up to 50 percent of the workers in the 
 
   5   plants were developing allergies. 
 
   6             So, what they did is they were able to use 
 
   7   certain strains of guinea pigs and certain strains 
 
   8   of mice, and the particular strains that they used 
 
   9   were ones in which there was a direct correlation 
 
  10   between the responses of the animals and the 
 
  11   responses in the workers.  Over the years, using 
 
  12   those particular animal models, combined with 
 
  13   medical surveillance of the workers and 
 
  14   modification of the environment, they were able to 
 
  15   drastically reduce this problem, so that the rate 
 
  16   of sensitization dropped to less than 3 percent. 
 
  17             So, I think the experience of Proctor & 
 
  18   Gamble shows that animal models can indeed work, 
 
  19   and they can work with humans.  We suggest that 
 
  20   perhaps the exact strains of guinea pigs and mice 
 
  21   that were successful surrogates for humans when 
 
  22   predicting inhalant allergy of proteins, may be 
 
  23   successfully used to predict food allergy. 
 
  24             We would suggest that if it hasn't been 
 
  25   done, that FDA begin such research with known food 

 
                                                                 55 
 
   1   allergens with these particular strains of guinea 
 
   2   pigs and mice. 
 
   3             DR. BRANDT:  Your time is over. 
 
   4             DR. HANSEN:  Thank you. 
 
   5             DR. BRANDT:  Thank you, sir. 
 
   6             Dr. Bannon from Monsanto. 
 
   7             DR. BANNON:  I certainly appreciate the 
 
   8   opportunity to come and address the FDA on such an 
 
   9   important topic and one that is near and dear to my 
 
  10   heart, the protein allergenicity. 
 
  11             I come to you probably with somewhat of a 
 
  12   unique perspective, and the unique perspective is 
 
  13   due to the fact that I was an academic for 17 years 
 
  14   working on food allergy, and now I am on the other 
 
  15   side and working with industry, working on the same 
 
  16   thing, allergenicity, and it gives you a fairly 
 
  17   good perspective on what is going on and the 
 
  18   science that is involved. 
 
  19             [Slide.] 
 
  20             To frame this for you, that you already 
 
  21   are aware of, there are many issues that impinge on 
 
  22   allergy research and allergy in general.  As we 
 
  23   have already heard, it is a fairly emotional topic. 
 
  24   The numbers I have heard thrown around is in 
 
  25   surveys, that 25 to 30 percent of people contacted 

 
                                                                 56 
 
   1   indicate that they or a family member think they 
 
   2   have a good allergy. 
 
   3             Of course, the reality of that is quite 
 
   4   different.  We have heard that 1 to 2 percent of 
 
   5   adults, approximately 4 to 6 percent of children 
 
   6   actually have IgE-mediated food allergies. 
 
   7             Mixed into this, the fact that children do 
 
   8   have allergies and can die from these allergic 
 
   9   reactions, you have a very emotional topic that can 
 
  10   sometimes overwhelm the science and cause bad 
 
  11   science to be done. 
 
  12             Additionally, there are many stakeholders 
 
  13   in this particular argument - industry obviously, 
 
  14   allergists, scientists, regulators, food producers, 
 
  15   and public, and they all have different 
 
  16   perspectives and they all have something 
 
  17   significant to contribute to the argument, but they 
 
  18   come at it with viewpoints. 
 
  19             Also, we are in essentially a hazard ID 
 
  20   mode at this point in terms of our decision tree 
 
  21   and in terms of our determining whether a protein 
 
  22   is an allergen or not, and we think that the hazard 
 
  23   ID mode has worked very well, but we would like to 
 
  24   see it move to more of a risk assessment mode, 
 
  25   which I will talk to you about in just a minute. 

 
                                                                 57 
 
   1             Finally, and most importantly, the science 
 
   2   of allergy is still evolving.  Even though we have 
 
   3   been doing immunotherapy for allergic disease for 
 
   4   almost 100 years, there are still basic mechanisms 
 
   5   that are lacking that we don't know, and it is 
 
   6   still evolving, which is why we are here today. 
 
   7             [Slide.] 
 
   8             As most of you know, there is eight foods 
 
   9   or food groups that account for greater than 90 
 
  10   percent of the allergies.  They are listed on the 
 
  11   slide.  The biggest take-home message from this 
 
  12   slide is that as you have already heard, the only 
 
  13   way to treat this particular disease is by 
 
  14   avoidance of the food, and therefore, that is 
 
  15   paramount in our mind at Monsanto.  We do not want 
 
  16   to put allergens into food crops and put anyone at 
 
  17   risk. 
 
  18             Of course, the U.S. policy designed to 
 
  19   prevent that unwanted or unexpected exposures to 
 
  20   offending allergens, and they do that by preventing 
 
  21   transfer of existing allergens or likely allergens 
 
  22   via biotechnology or other processes, and, of 
 
  23   course, there are comprehensive labeling laws for 
 
  24   all foods. 
 
  25             [Slide.] 

 
                                                                 58 
 
   1             Now, even though that is one big category, 
 
   2   there are other categories.  The first one 
 
   3   obviously would be hidden allergens, as I have just 
 
   4   described.  The other category is alteration or 
 
   5   quantitative increase of endogenous allergens, and 
 
   6   finally, the big bugaboo, creation of food allergen 
 
   7   de novo, new ones, and that is where the technology 
 
   8   is lagging behind. 
 
   9             [Slide.] 
 
  10             We have many tools currently to detect 
 
  11   known and potential allergens, and I have split 
 
  12   them into two categories where we look at both 
 
  13   known or cross-reactive allergens using 
 
  14   bioinformatics, and you have heard a lot of 
 
  15   discussion about sequence homology, six or eight 
 
  16   amino acid window searches. 
 
  17             For potential allergens, we really have 
 
  18   three tools - pepsin digestive fate, in vitro and 
 
  19   in vivo IgE binding assays, and animal models, the 
 
  20   last one of which is still under development. 
 
  21             [Slide.] 
 
  22             The tools to identify known allergens, 
 
  23   bioinformatics, are really dependent upon the 
 
  24   availability of high-quality clinical data 
 
  25   describing the offending food and other allergens, 

 
                                                                 59 
 
   1   and that is absolutely paramount, and that 
 
   2   information must be available to everyone, so that 
 
   3   known allergens, proteins have been identified as 
 
   4   allergens can be put into the appropriate 
 
   5   databases. 
 
   6             Accessibility of that data, such as the 
 
   7   gene or protein sequences, to assess allergenicity 
 
   8   is also paramount, and I have given you an example 
 
   9   of a web site, Allergenonline.com, which contains 
 
  10   one of the more significant databases on allergens. 
 
  11   It is curated on a yearly basis, and is housed out 
 
  12   of the University of Nebraska at Lincoln. 
 
  13             Finally, there is another allergen 
 
  14   database out of Europe, you have heard Dr. 
 
  15   MacIntosh talk about that a little bit, that 
 
  16   attempts to synthesize the clinical and structural 
 
  17   biology data of what is a food allergen, and it is 
 
  18   still under development. 
 
  19             [Slide.] 
 
  20             The bioinformatics, we have heard a lot of 
 
  21   discussion about what that is and how to do it. 
 
  22   The source of the gene is very important, very 
 
  23   important to us, known allergen source, such as 
 
  24   Brazil nut, we have heard an example of that versus 
 
  25   a non-allergenic source will really determine, by 

 
                                                                 60 
 
   1   and large, what path you go down on the current 
 
   2   decision tree, and will decide what tests are 
 
   3   appropriate. 
 
   4             The appropriate search criteria.  You hear 
 
   5   Mr. Hansen talk about the global search, if you 
 
   6   will, over the entire protein, and there are 
 
   7   certain requirements that are already recommended, 
 
   8   that is, greater than 35 percent identity over 80 
 
   9   amino acids. 
 
  10             The other is a small-scale search with 
 
  11   defined amino acid window.  We have heard a lot of 
 
  12   argument about six versus eight amino acid sliding 
 
  13   window.  You should be aware that there are data 
 
  14   out there, excuse me, that will be published this 
 
  15   August in the International Archives of Allergen 
 
  16   Immunology, that points to the eight amino acid 
 
  17   window as being the preferred in the sense that six 
 
  18   gives many false positives and the eight appears to 
 
  19   include known allergens using the corn sequence 
 
  20   database.  That should be coming out, out of IAAI 
 
  21   this month. 
 
  22             [Slide.] 
 
  23             Well, what do we need to do?  We need to 
 
  24   standardize our tools for predicting potential 
 
  25   allergens, need to standardize the characteristics 

 
                                                                 61 
 
   1   of clinically relevant patient sera.  It amazes me 
 
   2   many times, looking at particular sera and how they 
 
   3   are categorized as an individual being sensitive to 
 
   4   a particular food. 
 
   5             There is not a common way of doing that at 
 
   6   this point, although there is a best practice way, 
 
   7   although it is not always utilized, and you see the 
 
   8   problems with using a non-clinically relevant sera 
 
   9   all the time. 
 
  10             We need to standardize our in vitro IgE 
 
  11   binding assays.  In the literature, you will find 
 
  12   many different ways of doing our in vitro IgE 
 
  13   binding assays and many ways in which it 
 
  14   interpreted positive versus negative.  That needs 
 
  15   to be standardized. 
 
  16             Finally, we need to standardize our 
 
  17   prospective standardization predictions.  That 
 
  18   means we need to look at the standardization of in 
 
  19   vitro pepsin digestion assay and the animal models 
 
  20   of oral sensitization. 
 
  21             [Slide.] 
 
  22             In terms of the pepsin digestive assay, 
 
  23   you heard Dr. MacIntosh talk about the ILSI ring 
 
  24   test.  That addressed a couple of issues.  One was 
 
  25   some variables, such as the pH of the assay, and 

 
                                                                 62 
 
   1   the other was the reproducibility of the assay. 
 
   2   Dr. MacIntosh did a great job of describing that, I 
 
   3   won't go into that further. 
 
   4             The other question that has been brought 
 
   5   up about the pepsin digestion assay is the 
 
   6   biological relevance of that assay, and a recent 
 
   7   publication out of my laboratory before I joined 
 
   8   Monsanto indicates that stable fragments of food 
 
   9   allergens contain some of the immunodominant IgE 
 
  10   binding epitopes lending some biological relevance 
 
  11   to the fact that the pepsin digestion assay appears 
 
  12   to be able to identify fragments that will cause 
 
  13   etiology of this disease. 
 
  14             [Slide.] 
 
  15             Validation of the oral sensitization 
 
  16   models.  I have been involved prior to joining 
 
  17   Monsanto with the development of two animal models, 
 
  18   a mouse model and a swine model.  They used an 
 
  19   intragastric sensitization protocol or an IP, 
 
  20   intraperitoneal protocol. 
 
  21             What we need to do are listed on this 
 
  22   slide.  We need to have a high positive and 
 
  23   negative predicted value, i.e., clinical accuracy. 
 
  24   We need high correlation to clinical manifestations 
 
  25   of food allergy. 

 
                                                                 63 
 
   1             We need relevance to the oral route of 
 
   2   sensitization.  That doesn't mean that it has to be 
 
   3   an oral route, but has to have relevance to the 
 
   4   human condition. 
 
   5             We need to be able to distinguish between 
 
   6   complete and incomplete allergens.  What that means 
 
   7   is an incomplete allergen being one that can only 
 
   8   elicit whereas, a complete allergen is one that can 
 
   9   sensitize and elicit, and we need to be able to 
 
  10   validate and have available test materials to 
 
  11   validate those animal models. 
 
  12             My experience in the academic world is 
 
  13   most of these animal models were developed to look 
 
  14   at the mechanism of food allergy, not for what we 
 
  15   need in the industry in terms of predicting whether 
 
  16   a protein is a potential allergen. 
 
  17             [Slide.] 
 
  18             We believe that there is an opportunity to 
 
  19   improve the current allergy assessment.  We can do 
 
  20   that by applying a risk assessment mode, something 
 
  21   that toxicologists have been doing for quite some 
 
  22   time, to the decisionmaking process in terms of 
 
  23   allergenicity. 
 
  24             To do that, we need more data.  We are not 
 
  25   up there yet.  We have to have threshold levels in 

 
                                                                 64 
 
   1   terms of at least elicitation, how much exposure 
 
   2   there is, and assign some type of hazard ID to 
 
   3   particular outcomes of the assays that I have 
 
   4   already described. 
 
   5             The exposure validations should provide, 
 
   6   then, a context against which risk managers can 
 
   7   make decisions benchmarking against known food 
 
   8   allergens. 
 
   9             [Slide.] 
 
  10             Finally, I believe we have excellent 
 
  11   methods for identifying known allergens and 
 
  12   preventing those transfers to food crops.  We can 
 
  13   do that very well. 
 
  14             We are refining, if you will, the old 
 
  15   methods for predictive like pepsin digestion, as 
 
  16   you have heard, et cetera, and developing new ones, 
 
  17   hopefully animal models, but that are not yet 
 
  18   validated, to predict potential allergens, and we 
 
  19   have the opportunity to improve allergy predictions 
 
  20   by incorporating risk assessment strategies to 
 
  21   already available hazard identification methods. 
 
  22             Thank you. 
 
  23             DR. BRANDT:  Thank you, sir. 
 
  24             Now, Bill Freese from Friends of the 
 
  25   Earth. 

 
                                                                 65 
 
   1             MR. FREESE:  I am Bill Freese, policy 
 
   2   analyst, Friends of the Earth.  We appreciate the 
 
   3   opportunity to present comments today. 
 
   4             It goes without saying that the FDA's 
 
   5   assessment of the potential allergenicity of novel 
 
   6   proteins is only as good as the data on which it is 
 
   7   based.  In order to be truly science-based, any 
 
   8   given assessment procedure must rest on data that 
 
   9   are both accurate and adequate to the assessment 
 
  10   task.  Without such a foundation, even the best 
 
  11   approach isn't worth too much. 
 
  12             What I would like to do is, in contrast to 
 
  13   the kind of broad-brush treatment we have had about 
 
  14   FDA's regulatory approach, I would like to look in 
 
  15   detail at two consultations.  I have distributed 
 
  16   both my comments plus the two consultations.  You 
 
  17   should have those. 
 
  18             The first has to do with Monsanto's Bt 
 
  19   corn event, MON810.  If you would turn to Appendix 
 
  20   2, what I have basically done there is compare the 
 
  21   FDA's Note to the File that is the consultation 
 
  22   document on MON810, and molecular characterization 
 
  23   study that was submitted by Monsanto to the EPA. 
 
  24   This is an unpublished study, which only the EPA 
 
  25   has seen. 

 
                                                                 66 
 
   1             First of all, I recognize that the EPA has 
 
   2   responsibility for the--I am looking at the 
 
   3   allergenicity of Bt proteins, but as Dr. Maryanski 
 
   4   mentioned yesterday, the FDA also has a role, and 
 
   5   that is to look at other possible alterations, for 
 
   6   instance, unintended effects or nutritional 
 
   7   differences, and that is why Monsanto also 
 
   8   conducted a consultation with the FDA on this crop 
 
   9   even though it's a pesticidal protein. 
 
  10             Basically, you can see in Appendix 2, 
 
  11   there are three basic errors in the FDA's Note to 
 
  12   File on MON810.  I will just go through this real 
 
  13   briefly.  The first one is that the FDA assumes 
 
  14   there is a complete copy of the Cry1Ab gene in the 
 
  15   corn, whereas, Monsanto's study shows clearly it is 
 
  16   only a partial gene, and what apparently happens is 
 
  17   there was the transformation vector ruptured during 
 
  18   the transformation process and only a partial gene 
 
  19   was incorporated. 
 
  20             Secondly, the FDA assumes that there is a 
 
  21   NOS termination sequence in MON810, and, in fact, 
 
  22   Monsanto's study shows pretty clearly that that 
 
  23   determination sequence did not make it into the 
 
  24   corn. 
 
  25             It is interesting here to note that this 

 
                                                                 67 
 
   1   NOS might have played a role, according to the FDA, 
 
   2   in directing messenger RNA adenylation, so the 
 
   3   absence of that NOS sequence might have some 
 
   4   implications. 
 
   5             Third, the FDA assumed that the protein 
 
   6   was nature identical, that is, identical to the 
 
   7   native protein found in the Bt microbe, whereas, in 
 
   8   fact, what we have is it looks like an odd-length 
 
   9   protein about 92 kilodaltons, about 70 percent of 
 
  10   the folic protoxin. 
 
  11             I think what this example shows is the 
 
  12   need for the FDA to demand original studies, not 
 
  13   summaries, and in every case, not just in random 
 
  14   spotchecks, as was suggested earlier. 
 
  15             The second example has to do with Aventis' 
 
  16   male-sterile corn.  Basically, it produces barnase, 
 
  17   and barnase is expressed in the pollen and causes 
 
  18   the pollen to be sterile, but as we know, even with 
 
  19   tissue-specific promoters, you often have weak 
 
  20   expression.  The barnase could possibly end up at 
 
  21   low levels in other tissues of the corn. 
 
  22   Apparently, Aventis looked at this. 
 
  23             Their method for looking at this was to 
 
  24   say basically, was to assume that any level of 
 
  25   binding expressed in tissues other than the anther 

 
                                                                 68 
 
   1   would result in "abnormal plant growth."  So the 
 
   2   test was basically to look at the corn and see if 
 
   3   there were any abnormalities, and that was 
 
   4   basically their test to see if barnase was 
 
   5   expressed in other plant tissues. 
 
   6             It seems to me that the FDA should have 
 
   7   clearly demanded at least an ELISA assay to test 
 
   8   for barnase.  That doesn't seem like it would be so 
 
   9   difficult to do, and it would provide better 
 
  10   information.  By the way, barnase is a toxin.  It's 
 
  11   a ribonuclease which breaks down RNA. 
 
  12             That is a second example, in this case, 
 
  13   where the FDA perhaps could have demanded better 
 
  14   data. 
 
  15             A second point I would like to make, I 
 
  16   think this has been brought up a little bit, Doug 
 
  17   Gurian-Sherman mentioned it.  The FDA does not 
 
  18   reach any independent conclusions regarding the 
 
  19   safety of a genetically engineered crop. 
 
  20             If you look at the two Notes to File that 
 
  21   I have given you, if you look at the conclusions, 
 
  22   basically, the FDA merely conveys the notifying 
 
  23   company's conclusion that the crop is not 
 
  24   materially different than their conventional 
 
  25   counterparts, and then says basically that the 

 
                                                                 69 
 
   1   consultation is ended.  There is no affirmation 
 
   2   that this crop is safe, no affirmation by the FDA 
 
   3   that this crop is not materially different, only 
 
   4   conveying the company's conclusion that this is the 
 
   5   case. 
 
   6             I think that is not at all what most 
 
   7   laymen think when they think of the FDA and their 
 
   8   evaluation of genetically-engineered foods, and I 
 
   9   think we really expect more from the agency.  They 
 
  10   should take a close enough look at these crops to 
 
  11   be able to say with confidence that they are safe 
 
  12   or at least not materially different. 
 
  13             Perhaps one of the reasons the FDA has 
 
  14   been willing to say that is because they do only 
 
  15   collect summary information and perhaps don't feel 
 
  16   confident in making the affirmation.  Again, that 
 
  17   gets to the need to demand original studies instead 
 
  18   of the summary information. 
 
  19             The final point I would like to make is 
 
  20   about the examples of lack of coordination under 
 
  21   their coordinated framework.  Basically, I will 
 
  22   again use the example of MON810 since that is one I 
 
  23   am quite familiar with. 
 
  24             Basically, we have lack of information 
 
  25   flow in two directions.  One, that FDA could have 

 
                                                                 70 
 
   1   avoided the errors in its Note to File if it had 
 
   2   just consulted with the EPA, which, as I said, add 
 
   3   this molecular characterization study, so it would 
 
   4   have been very easy. 
 
   5             The FDA wouldn't even have had to go to 
 
   6   Monsanto to request this study.  It could have 
 
   7   gotten it from EPA, but apparently didn't do that. 
 
   8   The EPA, in turn, should have consulted with the 
 
   9   FDA during its assessment of the Cry1Ab protein 
 
  10   expressed in Monsanto's MON810 and also Syngenta's 
 
  11   Bt11 corn events. 
 
  12             DR. BRANDT:  Three minutes. 
 
  13             MR. FREESE:  As Dr. Hansen mentioned, 
 
  14   Steven Gendel, who is here, has studied Cry1Ab and 
 
  15   found similarity, sequence similarity between 
 
  16   Cry1Ab and the vitellogenin and egg yolk allergen, 
 
  17   and he found the similarity.  He thought it might 
 
  18   be sufficient to warrant additional evaluation, and 
 
  19   unfortunately, it doesn't appear as if the EPA has 
 
  20   taken that under consideration. 
 
  21             So, it seems like there is a lack of 
 
  22   information flow in both directions, at least in 
 
  23   some cases, and that clearly needs to be worked on. 
 
  24             So, just to sum real briefly since I have 
 
  25   about  minute, I guess, I would say demand original 

 
                                                                 71 
 
   1   studies, not summaries.  Errors can happen. 
 
   2   Companies can either conceal information or perhaps 
 
   3   just fail to report things.  Adequate testing 
 
   4   should be performed, and I don't think, well, again 
 
   5   the barnase example I think shows that. 
 
   6             Then, we need coordination between the 
 
   7   various agencies involved in looking at the safety 
 
   8   of these crops and potential risks. 
 
   9             Thank you. 
 
  10             DR. BRANDT:  Thank you very much, sir. 
 
  11   Thank you for coming and for the material.  All of 
 
  12   you had all this material from all four speakers. 
 
  13                             Summary 
 
  14                       Dr. James Maryanski 
 
  15             DR. MARYANSKI:  Thank you, Mr. Chairman. 
 
  16             I will be very brief.  Again, we would 
 
  17   like to thank the committee members for joining 
 
  18   this committee.  We think that we are going to have 
 
  19   a lot of work and interesting topics to do over the 
 
  20   next couple of years, and we welcome this as the 
 
  21   beginning of that process. 
 
  22             I think you have gotten the sense, if 
 
  23   nothing else, over the past day and a half, that 
 
  24   there are quite a few issues here.  We brought one 
 
  25   to you actually in terms of what we are actually 

 
                                                                 72 
 
   1   asking you to took at. 
 
   2             We brought one issue to you, but I think 
 
   3   you have got an inkling that there are probably 
 
   4   some other issues that you may want to discuss 
 
   5   among yourself and with us, and that we are likely 
 
   6   to ask you about over the course of the next 
 
   7   several months and years.  I hope that has been 
 
   8   instructive. 
 
   9             We have not asked you to look at our 
 
  10   policy per se or our procedures, but it is likely 
 
  11   that we will be asked for that, that we will be 
 
  12   discussing as things go forward.  We have a process 
 
  13   that has been through much the same kind of process 
 
  14   we are having here in terms of vetting it before an 
 
  15   advisory committee before we take it forward, and 
 
  16   there are things about that, that some people like 
 
  17   and some people don't like. 
 
  18             It is an interesting process because we 
 
  19   don't use a process for these products that is a 
 
  20   full, comprehensive scientific review for every 
 
  21   single product, and that was a decision that we 
 
  22   made in 1994 based on the kinds of products and the 
 
  23   characteristics of those products. 
 
  24             So, it is very different than a food 
 
  25   additive approval and the process, and that is 

 
                                                                 73 
 
   1   something that you will have more opportunity to 
 
   2   learn about. 
 
   3             So, it is something that I think you need 
 
   4   to look carefully at down the road.  We hope that 
 
   5   today you can focus on the issue of our project, 
 
   6   that we are really beginning in the sense of 
 
   7   developing draft guidance now on allergenicity and 
 
   8   give us your thoughts to help us get started based 
 
   9   on what you have heard. 
 
  10             As we have told you, our intent is then to 
 
  11   go back to work to develop a draft guidance 
 
  12   document that we will bring back to you before it 
 
  13   goes public. 
 
  14             We wish you well.  We look forward to your 
 
  15   input, and we certainly again thank you very much 
 
  16   on behalf of all of us at FDA that you are willing 
 
  17   to engage in this process. 
 
  18             Thank you, Mr. Chairman. 
 
  19             DR. BRANDT:  Let me make a couple of 
 
  20   announcements first.  This is a process that is 
 
  21   just starting and all of you, but not me, will be 
 
  22   able to carry this forward.  I am just here for 
 
  23   this one meeting as far as I know.  I go back to 
 
  24   the bench now. 
 
  25             Second, taxicabs to all three airports 

 
                                                                 74 
 
   1   will be out in front at 3:15, those you that need 
 
   2   transportation.  I know there is at least one, to 
 
   3   Reagan, one to Dulles, and one to BWI.  The rest of 
 
   4   you are on your own. 
 
   5                     Questions and Discussion 
 
   6             DR. BRANDT:  You have the three questions 
 
   7   we have been asked to address, and then we begin 
 
   8   with Question No. 1, which has to do with the 
 
   9   priorities, emphases, et cetera, that you think the 
 
  10   FDA should be taking into consideration in their 
 
  11   material as it comes from the Codex material that 
 
  12   you saw yesterday and that you have a copy of. 
 
  13             One other thing, all of you should have 
 
  14   gotten the extent of reimbursement, a very valuable 
 
  15   document, so if you don't fill it out and sign it, 
 
  16   you can't get paid. 
 
  17             The floor is now open.  Are there 
 
  18   particular aspects of this international document 
 
  19   that you think FDA should particularly emphasize? 
 
  20   Go ahead. 
 
  21             DR. ARIAS:  After reviewing the Codex 
 
  22   document, it was clear that there is a substantial 
 
  23   investment of attention to issues that have not 
 
  24   been amply discussed at this particular meeting in 
 
  25   regards to GM plants, and that is, the 

 
                                                                 75 
 
   1   transformation process itself and so for unintended 
 
   2   consequences. 
 
   3             I would note that there were several 
 
   4   sections in particular that amply described some of 
 
   5   those potential unintended consequences we have 
 
   6   heard through some of the talks today, some of the 
 
   7   implications of that. 
 
   8             I would like in particular to address the 
 
   9   questions of unexpected allergenicities as a 
 
  10   consequence of gene insertion.  It is, of course, 
 
  11   in the hypothetical since there are no specific 
 
  12   examples that can be brought to bear on this 
 
  13   question. 
 
  14             Yet, I think in any assessment of the 
 
  15   prospects of using GM foods, I believe that the 
 
  16   issue of the insertion of the transgene, its 
 
  17   unintended consequences on local expression of 
 
  18   neighboring genes, as well as the potential for 
 
  19   altering global expression patterns throughout the 
 
  20   plant have to be at least addressed at some level, 
 
  21   and the Codex document does stipulate the number of 
 
  22   specific steps in this process that should be 
 
  23   examined. 
 
  24             In particular, the concern here is that 
 
  25   insertion of a gene can influence the effects of 

 
                                                                 76 
 
   1   neighboring genes and since the process of 
 
   2   transgenic insertion is, by and large, a random 
 
   3   event, although there is some bias towards 
 
   4   insertion actually into transcriptionally active 
 
   5   regions of the genome, and, of course, the 
 
   6   attendant possibilities for how that might in a 
 
   7   number of cases create problems.  It is yet unclear 
 
   8   to me what the actual examples are currently 
 
   9   through industry for how those insertion events are 
 
  10   monitored vis-a-vis the Codex guidelines. 
 
  11             For example, I would assume that all genes 
 
  12   are mapped to a specific locus and site in a crop 
 
  13   plant when they are put into commercial production, 
 
  14   however, it is less clear to me, as a consequence 
 
  15   of that, how thoroughly the expression pattern of 
 
  16   neighboring genes that could be affected by the 
 
  17   insertion of a strong promoter element, for 
 
  18   instance, like the cauliflower mosaic virus 35S 
 
  19   promoter, which is widely used in the genetic 
 
  20   engineering plants, might affect neighboring genes. 
 
  21             One, for instance, could envision such an 
 
  22   insertion as affecting a gene that is involved in 
 
  23   transcriptional control and thus having very 
 
  24   significant effects throughout the plant, that may 
 
  25   not necessarily show up as an effect on phenotype 

 
                                                                 77 
 
   1   or on development or on fertility. 
 
   2             Moreover, it is also clear to me, having 
 
   3   come recently from the meeting of the American 
 
   4   Society for Plant Biologists that was held in 
 
   5   Denver last week, that the state of the art of 
 
   6   looking at metabolic profiles of plants is still in 
 
   7   its infancy.  Because of this, it would be 
 
   8   unrealistic to expect at present that we could look 
 
   9   at global patterns, for instance, of various 
 
  10   metabolites that might conceivably be affected by 
 
  11   insertion of the transgene or expression of that 
 
  12   transgene and its effect on metabolism. 
 
  13             Yet, I would think that in crafting any 
 
  14   guidelines for future, we should certainly consider 
 
  15   the prospects that unintended consequences of 
 
  16   genetic engineering should be examined and 
 
  17   thoroughly characterized within the state of the 
 
  18   art, clearly can't ask industry to be held to 
 
  19   standards that technologically are not available, 
 
  20   for instance, metabolonics, looking at metabolic 
 
  21   profiles. 
 
  22             Yet, the Codex document certainly does put 
 
  23   a rather strong emphasis on this issue, and I think 
 
  24   it should be one that we should deliberate on 
 
  25   further. 

 
                                                                 78 
 
   1             DR. ASTWOOD:  I just wanted to pick up on 
 
   2   Jonathan's suggestion.  One of the things that was 
 
   3   not clear to me in our charge from the FDA is 
 
   4   whether the scope of the activities strictly 
 
   5   focused on the protein or whether we should also 
 
   6   consider recommending back to the FDA, the need to 
 
   7   develop guidelines on how to do the exact kind of 
 
   8   assessment focused on allergy that Jonathan really 
 
   9   suggests. 
 
  10             There are suggestions in the literature 
 
  11   about how to do that.  There are examples in the 
 
  12   literature of how to do that, but I am not aware of 
 
  13   any specific guidance on how to evaluate whether 
 
  14   there have been changes in endogenous allergens in 
 
  15   the target crop, obviously, would be crop specific. 
 
  16             So, whether that is something that would 
 
  17   fall within our charge or not may need 
 
  18   clarification.  I think it is certainly an 
 
  19   important topic. 
 
  20             DR. BRANDT:  As far as I am concerned, it 
 
  21   is certainly mentioned in the Codex.  I don't see 
 
  22   why it is outside our charge by any means. 
 
  23             DR. GURIAN-SHERMAN:  To pick up on that, I 
 
  24   know of at least one case in the literature where 
 
  25   the different levels of endogenous allergens have 

 
                                                                 79 
 
   1   been measured.  There is case with pepper, where 
 
   2   some varieties don't even have the assayed allergen 
 
   3   and other levels, so there is some beginnings of 
 
   4   that, and I think it is something that certainly 
 
   5   should be considered especially in the context 
 
   6   similar to what Dr. Metcalfe was discussing 
 
   7   yesterday about although we can't determine clear 
 
   8   levels of sensitization or response, there is some 
 
   9   dose response issue. 
 
  10             So, in that context, I think that should 
 
  11   definitely be considered as part of FDA's task. 
 
  12             DR. ARIAS:  I would like to point out that 
 
  13   it is not that genetic engineering per se has, as 
 
  14   far as the scientific community knows, any special 
 
  15   risk associated with it compared to other methods, 
 
  16   for instance, traditional plant breeding, which as 
 
  17   you mentioned, Dr. Brandt, yesterday, can bring 
 
  18   together various combinations of genomes or genes 
 
  19   that can sort themselves out in rather dramatic 
 
  20   ways. 
 
  21             In fact, the evidence to date shows that 
 
  22   the only known unintended deleterious effect of 
 
  23   moving genomes has, in fact, been observed in 
 
  24   classical breeding situations where, for instance, 
 
  25   glycol alkaloids have been detected in potatoes 

 
                                                                 80 
 
   1   that were made by standard crop breeding 
 
   2   strategies. 
 
   3             So, I want to point out that I don't think 
 
   4   that genetic engineering per se has any higher 
 
   5   degree of risk, however, since we are putting 
 
   6   together a guidance document that should I think 
 
   7   encompass both intentional protein expression and 
 
   8   its allergenicity, as well as any unintended 
 
   9   effects, I think this would certainly be reasonable 
 
  10   in its scope. 
 
  11             DR. BUCHANAN:  In the experiment I 
 
  12   referred to earlier, that we did with St. James 
 
  13   preparation, we asked three questions - is the 
 
  14   protein of interest an allergen, has the protein of 
 
  15   interest become an allergen, and has the 
 
  16   transformation process somehow created an allergen 
 
  17   in another way, and that is an unlikely event, we 
 
  18   felt, but possible. 
 
  19             In this experiment, we were able to 
 
  20   provide the no answer to each of those questions. 
 
  21   So, I think with our protocol with the dog, we are 
 
  22   able to address those areas, and I wonder if it may 
 
  23   not be possible also with rodents, that just one 
 
  24   has to plan the experiment properly, but we were 
 
  25   certainly able to do that. 

 
                                                                 81 
 
   1             DR. BRANDT:  Other comments about Question 
 
   2   1? 
 
   3             DR. GURIAN-SHERMAN:  I just would make a 
 
   4   general comment, reiterate a point, and it has been 
 
   5   brought out by several speakers and others about 
 
   6   how FDA should look at the guidance, and I think 
 
   7   the FAO consultation has a lot of value.  Some 
 
   8   other points that have been brought out I think 
 
   9   have a lot of value. 
 
  10             The FAO, for instance, cites the Dr. 
 
  11   Gendel's work in its guidance as something that can 
 
  12   be looked at further, but I guess I would just, in 
 
  13   this context, want to reiterate that given the 
 
  14   uncertainties of some of these tests, we should err 
 
  15   on the side of caution in making our decisions, and 
 
  16   I think that while I again understand FDA's desire 
 
  17   for flexibility, until we have more certainty, when 
 
  18   we get certain results from some of these tests, 
 
  19   and I am think Maryanski indicated that that would 
 
  20   be the case, that the product should not go forward 
 
  21   even though there is some uncertainty. 
 
  22             If you get a result in the digestive assay 
 
  23   that considers a protein to be stable, there is 
 
  24   uncertainty about whether it is actually an 
 
  25   allergen, but there is at least a reasonable chance 

 
                                                                 82 
 
   1   it could be, and unless there is something 
 
   2   definitive that suggests that it is not an 
 
   3   allergen, I think there should be some again clear 
 
   4   stops in the process. 
 
   5             I think that needs to be spelled out for 
 
   6   reasons that have been discussed already about the 
 
   7   uncertainties of industry and the public about how 
 
   8   to proceed. 
 
   9             DR. BRANDT:  Other comments about Question 
 
  10   1 and the Codex? 
 
  11             DR. LEHRER:  I agree that there probably 
 
  12   should be some stops, but I would hope that we 
 
  13   would be able to have several criteria rather than 
 
  14   just one.  I think that is the problem in the past, 
 
  15   and I think the technology is moving along and our 
 
  16   knowledge of allergens is moving along, so 
 
  17   hopefully, we would have several criteria. 
 
  18             I think also that we need to have a 
 
  19   balance in looking at these different documents in 
 
  20   which some aspects are highly detailed and others 
 
  21   are too vague, and I think that that is going to be 
 
  22   an important challenge to us, that we need to have 
 
  23   structure and some detail in terms of having 
 
  24   similarity, but on the other hand, I think we have 
 
  25   to have some flexibility. 

 
                                                                 83 
 
   1             DR. KAPUSCINSKI:  I guess I would like to 
 
   2   briefly reiterate the point I made earlier this 
 
   3   morning, but this time in response specifically to 
 
   4   Question 1 and our charge, and that is, that I 
 
   5   support trying to develop a guidance document that 
 
   6   would contain a decision tree and then would have a 
 
   7   lot of guidance text that would lay out, at the 
 
   8   very least, options for different methodologies 
 
   9   that seem to stand up to the current state of the 
 
  10   art of the science. 
 
  11             One way that flexibility can be built in 
 
  12   is to also provide the option that if a company 
 
  13   thinks it has come up with a better methodology, it 
 
  14   can present results from that and make a scientific 
 
  15   case for why that is a better methodology, and that 
 
  16   is a way that we can kind of keep building as the 
 
  17   science is progressing, but I want to stress really 
 
  18   strongly that the power of having a decision tree 
 
  19   approach has really been pretty well proven 
 
  20   throughout the field of risk assessment in 
 
  21   assessing many kinds of technologies, and I think 
 
  22   we should take the wisdom from that and build on 
 
  23   that. 
 
  24             It gives you a systematic way of thinking 
 
  25   clearly about which test you should do first.  It 

 
                                                                 84 
 
   1   makes it easier to explain the rationale to 
 
   2   outsiders including consumers.  It has the power 
 
   3   that if different companies are using the same sort 
 
   4   of systematic structure, it will be easier for us 
 
   5   to be generating data that then will be easier to 
 
   6   compare, which will again help us to improve the 
 
   7   state of the art. 
 
   8             I mean I think we need to recognize that 
 
   9   one way we are going to move the science forward on 
 
  10   this, it is not only going to be through 
 
  11   traditional kinds of research, but it is also 
 
  12   through well documented gathering of the actual 
 
  13   empirical data that you gather when you do risk 
 
  14   assessment, and if you can both have that well 
 
  15   documented and if you are using procedures that are 
 
  16   relatively standard, as much as they can be across 
 
  17   the board, then, you can compare the data from 
 
  18   that. 
 
  19             So, the data that is actually being 
 
  20   gathered in risk assessment itself can contribute 
 
  21   to moving the science forward, and that will be one 
 
  22   of the real powers of relying on some kind of 
 
  23   decision tree methodology. 
 
  24             Finally, as I pointed out this morning, I 
 
  25   think some thought could go into considering 

 
                                                                 85 
 
   1   whether it be worthwhile to add some additional 
 
   2   arrows that would allow, if we look at the 
 
   3   righthand side of that decision tree that was shown 
 
   4   to us this morning, allow the developer or the 
 
   5   company to do more than one of the tests if they 
 
   6   want to. 
 
   7             I think that could be done and still have 
 
   8   some clear endpoints.  Finally, I would agree with 
 
   9   Doug that given the uncertainty in some of the kind 
 
  10   of information that gets generated right now, we do 
 
  11   need to be careful and err on the side of caution. 
 
  12             DR. BRANDT:  Go ahead, Dr. Astwood. 
 
  13             DR. ASTWOOD:  Thank you.  I had a question 
 
  14   for Dr. Kapuscinski about I was very intrigued by 
 
  15   your suggestion this morning again as you 
 
  16   articulated it, and I was wondering if one thing 
 
  17   for the drafters of the guidelines to consider 
 
  18   would be a tiered approach, which is a common 
 
  19   mechanism in risk assessment, where the 
 
  20   methodologies, you basically have a decision 
 
  21   process, but some studies are essentially triggered 
 
  22   by data development in previous studies. 
 
  23             DR. KAPUSCINSKI:  Yes, and that is very 
 
  24   common. 
 
  25             DR. BRANDT:  None of that is going to get 

 
                                                                 86 
 
   1   captured if you don't talk into the microphone. 
 
   2             DR. KAPUSCINSKI:  That kind of tiered 
 
   3   approach, as long as it is structured and you can 
 
   4   again, if it is thought through clearly, you should 
 
   5   be able to capture it in a visual decision tree, 
 
   6   and that is the power of those, that they are a 
 
   7   representation of really clear thinking and 
 
   8   systematic thinking, and tiered approaches are very 
 
   9   common in risk assessment. 
 
  10             Now, I think some thought has to go into 
 
  11   the details of that.  I am not blanketly saying any 
 
  12   tiered approach would work.  We would want to look 
 
  13   at how that actually gets developed, but 
 
  14   conceptually that is a very powerful way to go, and 
 
  15   it has worked very well in other areas. 
 
  16             DR. BRANDT:  Other comments about Question 
 
  17   1? 
 
  18             [No response.] 
 
  19             DR. BRANDT:  We will move on to Question 
 
  20   2. 
 
  21             Are there areas that you believe would 
 
  22   contribute, that is, areas of research to this 
 
  23   whole process of allergenicity determinations?  Now 
 
  24   is your chance.  Yes. 
 
  25             DR. GURIAN-SHERMAN:  First, there is a 

 
                                                                 87 
 
   1   recent study that probably a lot of you are aware 
 
   2   of, that I think bears examination, a Pugh forum on 
 
   3   biotechnology, did an assessment of federal 
 
   4   programs on research in allergenicity and found 
 
   5   several significant problems, one, minimal funding, 
 
   6   inadequate funding, lack of clear goals, lack of 
 
   7   coordination between agencies, and I think, as we 
 
   8   saw yesterday, some of the agencies have somewhat 
 
   9   different goals. 
 
  10             NIH is looking more at basic research. 
 
  11   That is where a lot of the research is going on. 
 
  12   FDA and EPA have very small budgets and they need 
 
  13   more targeted research to help them look at how 
 
  14   they can implement their guidelines, how they can 
 
  15   best do the tests, validations of tests, those kind 
 
  16   of things, and there is very little funding in that 
 
  17   areas. 
 
  18             So, I would first recommend that FDA look 
 
  19   at that.  There needs to be a coordinating body.  I 
 
  20   guess FDA and EPA's Office of Research and 
 
  21   Development need more funds to apply to research, 
 
  22   but there needs to be some mechanism to try to 
 
  23   coordinate that research and to get more research 
 
  24   addressing the specific applications.  So, I think 
 
  25   that would be a start. 

 
                                                                 88 
 
   1             DR. BRANDT:  My observation about 
 
   2   coordination among federal agencies, that that is 
 
   3   an unnatural act. 
 
   4             [Laughter.] 
 
   5             DR. BRANDT:  But there might be a 
 
   6   mechanism for doing it, but certainly during my 
 
   7   years up here, I have never figured it out at least 
 
   8   how to do it.  You know, it is kind of like getting 
 
   9   two departments in a university to coordinate their 
 
  10   activities.  As long as you put one in charge, they 
 
  11   are happy to coordinate, but you have got to have 
 
  12   somebody in charge, that's the problem. 
 
  13             Yes, sir, go ahead. 
 
  14             DR. BUSTA:  I am not sure if this is part 
 
  15   of the last question or this one. 
 
  16             DR. BRANDT:  It doesn't make any 
 
  17   difference, you can go ahead.  We will let them 
 
  18   sort it out. 
 
  19             DR. BUSTA:  I think that in needs of 
 
  20   research and under other considerations in the 
 
  21   Codex document, I think the effects of food 
 
  22   processing, the processing treatments, and the 
 
  23   whole sequence of how these products are going to 
 
  24   be handled should be taken into consideration, 
 
  25   because they either enhance or generate potential 

 
                                                                 89 
 
   1   problems, or they may, in fact reduce them or 
 
   2   eliminating them. 
 
   3             I think that the ultimate use of these 
 
   4   items as a food are essential considerations. 
 
   5             DR. BRANDT:  Yes, sir. 
 
   6             DR. ARIAS:  I think in thinking of the 
 
   7   future, the FDA might consider linking efforts, 
 
   8   pre-existing efforts, with other federal agencies, 
 
   9   such as the National Science Foundation, U.S. 
 
  10   Department of Agriculture, DOE, et cetera, who are 
 
  11   already looking at functional genomics of crop 
 
  12   plants in a very systematic way, in particular, the 
 
  13   sequencing of plant genomes for a number of crops 
 
  14   will be I think greatly useful in regards to some 
 
  15   of the points that I raised earlier in regards to 
 
  16   the transgenic process itself, as well as leading 
 
  17   ultimately beyond functional genomics, the 
 
  18   expression of various genes in plants and the 
 
  19   influence perhaps of the transgenic process itself 
 
  20   will lead to more systematic efforts in the field 
 
  21   of metabolic profiling, which I think also is 
 
  22   likely to be the future in regards to nutritional 
 
  23   compositions and effects of transgenic expression 
 
  24   of various substances in crop plants. 
 
  25             Since these efforts already are underway 

 
                                                                 90 
 
   1   by a number of federal agencies, it is seems to me 
 
   2   integration of such approaches would be a very 
 
   3   powerful tool to exploit that information in 
 
   4   databases that are being created. 
 
   5             I feel also that it is unreasonable to 
 
   6   expect industry to adopt the burden of having to 
 
   7   pull a sequence and characterize crop genomes 
 
   8   although certainly that has been done by Syngenta. 
 
   9   I think the ultimate outputs of those data are much 
 
  10   better served when they are in the public database 
 
  11   and have broad utility for a large number of 
 
  12   questions that address not only the scope of this 
 
  13   meeting, but I am sure many other issues that will 
 
  14   come onboard to FDA in the future. 
 
  15             DR. LEHRER:  I just want to respond to 
 
  16   point 2. Absolutely, yes, there are areas of 
 
  17   allergy research I think that FDA can help further, 
 
  18   and I would say yes to all of the issues that were 
 
  19   raised.  We know very little about the some of the 
 
  20   basic mechanisms.  Food allergy, we don't even know 
 
  21   the nature of the components that are stimulating 
 
  22   food sensitization or even in some cases eliciting 
 
  23   a food allergic response. 
 
  24             Digestibility has been discussed.  I would 
 
  25   encourage looking at real life situations, that is, 

 
                                                                 91 
 
   1   old foods in terms of stability or lack of 
 
   2   stability of proteins. 
 
   3             We want to make the assays to be as 
 
   4   similar as possible to human exposure.  Animal 
 
   5   models are essential.  I have been encouraged over 
 
   6   the last couple of years in that there are several 
 
   7   groups that are moving in this direction, and I 
 
   8   think that we will see useful animal models in the 
 
   9   not too distant future. 
 
  10             Although an animal model of complete food 
 
  11   allergic response would be wonderful to have, I 
 
  12   think that it probably would be somewhat of an 
 
  13   impossible goal to have something without any type 
 
  14   of experimental manipulations, as has been 
 
  15   mentioned earlier, and I think that it is more 
 
  16   important for our discussions to have a model of 
 
  17   allergenicity at this point although it is 
 
  18   difficult, it would have to be balanced somewhat 
 
  19   with knowing the unique type of exposures that one 
 
  20   has to food allergens. 
 
  21             Serum testing again I think is important. 
 
  22   It has been talked about developing serum bank.  I 
 
  23   think that would be very useful in terms of 
 
  24   standardizing and making available the right types 
 
  25   of serum to be used in the assays, and then 

 
                                                                 92 
 
   1   certainly sequence homology I believe can be very 
 
   2   useful. 
 
   3             I think it is very important how this is 
 
   4   defined.  I think there is emerging information 
 
   5   about epitope sequences and substitutions of these 
 
   6   sequences that you can have one amino acid that 
 
   7   will actually enhance IgE binding to an epitope, 
 
   8   and if one was using the strict rule of sequence 
 
   9   evade amino acids, or so on, this would be 
 
  10   rejected, whereas, it could be a very potent or 
 
  11   potentially a potent reaction. 
 
  12             In terms of how FDA should implement all 
 
  13   of this, it really is certainly a challenge I think 
 
  14   to FDA and to all of us, because of the way monies 
 
  15   are distributed by the government in terms of 
 
  16   research, and unfortunately, you almost get a 
 
  17   runaround in terms of that. 
 
  18             The agencies that are interested in this, 
 
  19   such as the FDA and the EPA, don't have a whole lot 
 
  20   of money to support research.  USDA, I think has 
 
  21   more funding, but I don't know that they have 
 
  22   funding directly for allergenicity.  There may be 
 
  23   some available. 
 
  24             NIH certainly has the vast majority of 
 
  25   funds available, yet, to my knowledge, they haven't 

 
                                                                 93 
 
   1   directed funds in this area, and I think that that 
 
   2   would be the best source of funding if one can not 
 
   3   only convince them to have directed funding for 
 
   4   this area, but also have study sections of 
 
   5   individuals that are knowledgeable about these 
 
   6   problems. 
 
   7             You can have money directed to a certain 
 
   8   area.  I have seen this in AIDS, for example, where 
 
   9   they have put millions and billions of dollars into 
 
  10   funding, but then if you have study sections that 
 
  11   are basic immunologists, composed of basic 
 
  12   immunologists, you are going to see money going 
 
  13   toward projects that may not necessarily the 
 
  14   questions that we are interested in. 
 
  15             I think all of these issues certainly need 
 
  16   to be addressed and would help further our 
 
  17   knowledge and allow us to make better decisions 
 
  18   concerning the allergenicity of these products. 
 
  19             DR. KAPUSCINSKI:  Just to add a little bit 
 
  20   to the end of what Dr. Lehrer was just saying, my 
 
  21   thoughts when I looked at this question last night 
 
  22   was recognizing the difficulty of agencies 
 
  23   cooperating. 
 
  24             I do know of some recent cases where an 
 
  25   agency with regulatory responsibility, in this 

 
                                                                 94 
 
   1   case, a subcomponent of Department of Commerce 
 
   2   actually collaborated I believe with NSF to develop 
 
   3   a very applied competitive research grant program, 
 
   4   and so it seems like it might be possible for FDA 
 
   5   to do something like that in concert with NIH. 
 
   6             It may be very helpful to generate some of 
 
   7   this research through a competitive grants program, 
 
   8   which is pretty well shown to help get results 
 
   9   fast.  It would be just simply because of the 
 
  10   competition and the pressure on researchers to get 
 
  11   stuff published. 
 
  12             It is also a good way of having a lot of 
 
  13   transparency in the research results, so that may 
 
  14   be able to piggyback on some of the comments that 
 
  15   Dr. Lehrer just made at the end of his comments. 
 
  16             DR. BUCHANAN:  Yes, I would certainly 
 
  17   support the need for additional support, and I 
 
  18   think that the dogs eat 12 months, you know, day-in 
 
  19   and day-out whether they are busy making IgE or 
 
  20   not.  So, it has certainly been a major factor in 
 
  21   our operation to keep that going for the last 22 
 
  22   years. 
 
  23             But I think that my impression is that one 
 
  24   of the goals of that North Carolina conference was 
 
  25   to at least support for animal models in 

 
                                                                 95 
 
   1   interesting other areas, and I think it is needed, 
 
   2   not just for animal models where it is sorely 
 
   3   needed, but also for proteomics.  I think we need 
 
   4   to look at the proteomics in addition to the things 
 
   5   that Jon has been mentioning. 
 
   6             I am involved currently in various 
 
   7   projects on proteomics of chloroplasts and of 
 
   8   wheat, and I think if we can look in the future and 
 
   9   apply that to allergens, allergenic foods, that the 
 
  10   future will just be very, very great, I really 
 
  11   believe that. 
 
  12             DR. BRANDT:  Well, I heard the word 
 
  13   challenges used twice, and it reminds me of a 
 
  14   former Secretary of Health and Human Services, then 
 
  15   called HEW, and after about a month on the job, at 
 
  16   a press briefing, he was asked what do you think 
 
  17   about your job, and he said, well, what I have been 
 
  18   faced with are some unsolvable problems cleverly 
 
  19   disguised as challenges, so there are some of those 
 
  20   for sure. 
 
  21             I mean there are examples of NIH and FDA 
 
  22   doing some things together in the past, and I would 
 
  23   suspect that this is an area that certainly could 
 
  24   be explored.  The lack of a commissioner may hinder 
 
  25   some of that at the moment, but some of it 

 
                                                                 96 
 
   1   certainly could be approached, and I think without 
 
   2   doing that, it is going to be very difficult for 
 
   3   some of this research to really get done frankly, 
 
   4   because I think the odds of FDA getting big chunks 
 
   5   of research money are pretty slim for a while at 
 
   6   least. 
 
   7             Any other comments about Question 1 or 2? 
 
   8   We are going to finish here by lunch at the rate we 
 
   9   are going. 
 
  10             All right.  Development of draft guidance 
 
  11   that may aid in enhancing public understanding. 
 
  12   Now, there is a real challenge to get across.  So, 
 
  13   there we go.  Go ahead, sir. 
 
  14             DR. ARIAS:  I think it is apparent from 
 
  15   discussions in the documents that there is a lack 
 
  16   of an absolute standard even in the best case for 
 
  17   analysis and determination of allergens, and so I 
 
  18   think clearly what the public will want to be 
 
  19   apprised of is this lack of absolute standards 
 
  20   despite the fact that the decision tree gives a yes 
 
  21   or a no, of course, it doesn't integrate 
 
  22   probabilistic issues, which I think are intrinsic 
 
  23   to the risk analysis. 
 
  24             So, we really can't talk about a lot of 
 
  25   risk or a little risk.  We can only say there may 

 
                                                                 97 
 
   1   be or may not be.  I think that has to be defined. 
 
   2   Also, the concept of substantial equivalence, which 
 
   3   I think is in some regards going to be a slippery 
 
   4   one for the public.  I know it has been in part for 
 
   5   me to define what types of terms we can use to best 
 
   6   describe the model systems and the outputs that we 
 
   7   are comparing. 
 
   8             Third, I think the public, in general, has 
 
   9   a great degree of confidence in U.S. regulatory 
 
  10   agencies.  I think they have, in the main, 
 
  11   performed admirably, at least as a member of the 
 
  12   public I am speaking, and the FDA in particular I 
 
  13   think is obviously showing a high degree of 
 
  14   sensitivity by this in other fora in trying to 
 
  15   address those concerns and by the public comment, 
 
  16   for example, and input. 
 
  17             I think what the public wants clearly are 
 
  18   the facts and the truth.  If we are ambiguous about 
 
  19   our determinations, we should probably make it 
 
  20   clear that those models and the improvement, the 
 
  21   state of the art, this is the best we can say.  I 
 
  22   think if we go beyond that, we might very well wind 
 
  23   up in the case of like the British public and their 
 
  24   apparently lack of confidence in British health 
 
  25   administrators vis-a-vis the bovine spongiform 

 
                                                                 98 
 
   1   encephalitis epidemics, the French Red Cross, and 
 
   2   many others where public confidence has plummeted 
 
   3   because people assured the public of risks that, in 
 
   4   fact, did exist, but did not really communicate 
 
   5   that effectively. 
 
   6             I think the public in the United States 
 
   7   will tolerate some ambiguity as long as we are 
 
   8   front and center on that. 
 
   9             DR. LEHRER:  Also, I think it is very 
 
  10   important that the public first understand what 
 
  11   allergy is and the risk of allergy from their food 
 
  12   supply, because I think that there is some 
 
  13   confusion, as has been mentioned I think in the 
 
  14   lectures yesterday, a much larger percentage of the 
 
  15   population think they have allergies than really 
 
  16   do. 
 
  17             Also, there are a variety of types of 
 
  18   reactions or symptoms that are really not related 
 
  19   to allergy, that they may attribute to that.  So, I 
 
  20   think that if in some way they can be better 
 
  21   educated with regard to that. 
 
  22             Also, in dealing with allergists, I felt 
 
  23   in some ways they might be one of the first lines 
 
  24   of inquiry or individuals who may have reactions, 
 
  25   and one of the things that we have tried to do at 

 
                                                                 99 
 
   1   the American Academy of Allergy is have sessions, 
 
   2   so they better understand the process and also the 
 
   3   assessment of them. 
 
   4             I would encourage that to go further 
 
   5   because a lot of the folks that may be having 
 
   6   reactions or think they have a reaction, if there 
 
   7   is one, may go to their allergist and a lot of 
 
   8   times they may not know how to deal with it or even 
 
   9   how to discuss it with their patients. 
 
  10             DR. GURIAN-SHERMAN:  I would like to 
 
  11   reiterate and endorse a lot of what Dr. Arias said, 
 
  12   and I think one of the ways to enhance consumer 
 
  13   confidence is to lay out in as much detail as we 
 
  14   feel is warranted by the science, what FDA is doing 
 
  15   and how they are doing it, and what their criteria 
 
  16   are. 
 
  17             I think a lot of the ambiguity and 
 
  18   vagueness in the current process only lends itself 
 
  19   to more consumer skepticism when it is examined 
 
  20   closely.  So, again, I would make a plea for as 
 
  21   much detail as we can put in the process and to 
 
  22   make it as mandatory as we can. 
 
  23             I know our charge here is to discuss it 
 
  24   within the framework, but I that especially given 
 
  25   the fact that there is not a natural pooling 

 
                                                                100 
 
   1   process, makes it even more important to be as 
 
   2   thorough and specific as possible in laying out the 
 
   3   process. 
 
   4             DR. KAPUSCINSKI:  I will just add that I 
 
   5   think that if you actually intelligently present 
 
   6   the decision tree picture, then considering the 
 
   7   comments that others have made here, that is 
 
   8   actually a really nice way to be able to explain to 
 
   9   the public what FDA is doing. 
 
  10             People will be able to relate to that 
 
  11   better, and I think it actually gives you an 
 
  12   opening to communicate the message about ambiguity 
 
  13   in a way that that will sort of make sense to 
 
  14   people, because they will see that yes, there is 
 
  15   these ambiguities, but instead of just being 
 
  16   paralyzed by it, we are trying to move forward in a 
 
  17   systematic way, and I think if it is articulated 
 
  18   well, it will be easy to explain, to convince 
 
  19   people that this is the best that we can do at this 
 
  20   time, this is the state of the art. 
 
  21             I think again specificity can be in the 
 
  22   more detailed text that maybe not every consumer 
 
  23   will read, but it is there for the people that are 
 
  24   more interested and want to read that.  So, I think 
 
  25   that the more you can show that the FDA is taking a 

 
                                                                101 
 
   1   systematic, structured approach  it is expecting 
 
   2   across the board, the easier it will be to address 
 
   3   Question 3 about enhancing public understanding. 
 
   4   People are just going to be more comfortable with 
 
   5   that. 
 
   6             DR. BRANDT:  Other comments? 
 
   7             DR. BUCHANAN:  I think it has been said 
 
   8   before, but, but I will just say it another way.  I 
 
   9   think that certain of these technologies and 
 
  10   protocols for testing really have to grow up as the 
 
  11   field develops.  That would include not only animal 
 
  12   models, but the serum bank and perhaps other 
 
  13   aspects of the decision tree. 
 
  14             I am optimistic if the work in the field 
 
  15   or research in the field can parallel the 
 
  16   development of regulatory policies, otherwise, 
 
  17   this, as has been said before, it will just stop 
 
  18   and anything would be terrible, that would be the 
 
  19   stop. 
 
  20             DR. ARIAS:  I think also it does the FDA 
 
  21   no good to bury its recommendations in obscure text 
 
  22   like the Federal Register and such, which the 
 
  23   majority of people don't read every day.  I think 
 
  24   there are a number of venues for the FDA to more 
 
  25   amplify their message to the general public in 

 
                                                                102 
 
   1   particular, for instance, societies that deal with 
 
   2   plants and plant biology, such as the American 
 
   3   Society for Plant Biologists. 
 
   4             There are a web sites, of course, that 
 
   5   deal specifically with information to the public on 
 
   6   GM crops.  I think the FDA should take a more 
 
   7   active role in making that information available 
 
   8   either directly or through links, so that the 
 
   9   general public can begin to access such 
 
  10   recommendations. 
 
  11             DR. BRANDT:  How accurate are those?  I 
 
  12   mean I have reviewed just recently web sites having 
 
  13   to do with medicine.  Ninety percent of the stuff 
 
  14   that is in there is wrong. 
 
  15             DR. ARIAS:  I can state for the record how 
 
  16   many there are that are accurate enough, but there 
 
  17   are web sites that do promote accurate 
 
  18   dissemination of information on GM crops.  I have 
 
  19   no doubt there are some that are self-serving, 
 
  20   particularly in the farm and nutritional area, 
 
  21   there is a lot of phenomenology, but I think that 
 
  22   certainly through the societies, the scientific 
 
  23   societies would be a good start to link, at least 
 
  24   link that information to information that is 
 
  25   already being disseminated by those groups for that 

 
                                                                103 
 
   1   very same purpose, to better educate the general 
 
   2   public on the issue of GM crops. 
 
   3             So, I have noted a conspicuous absence of 
 
   4   regulatory agency links through such sites, but I 
 
   5   am sure the societies would be delighted to get 
 
   6   that type of input. 
 
   7             DR. BUCHANAN:  I am glad you mentioned 
 
   8   that.  The American Society of Plant Biologists is 
 
   9   a major activity in educating the public.  It is 
 
  10   just one of the things that is right at the top of 
 
  11   the agenda.  I know because I was president of the 
 
  12   society a few years ago, and it continues to put 
 
  13   resources and effort into that arena, what you 
 
  14   consider is very, very important. 
 
  15             DR. BRANDT:  Everybody suddenly went 
 
  16   quiet. 
 
  17             DR. BUSTA:  I think that with all of the 
 
  18   communication, an item that was publicized 
 
  19   yesterday and brought up today, as well, is that 
 
  20   communication should not generate extensive 
 
  21   responses and make the public more concerned about 
 
  22   allergens than they are, and actually exist. 
 
  23             If a lot of the public feels that they are 
 
  24   allergic to food, and are not, I think that part of 
 
  25   the education process, in addition to saying what 

 
                                                                104 
 
   1   FDA is doing, is to alert the public to the actual 
 
   2   incidence, and not cause a major response beyond 
 
   3   what is necessary.  Maybe the allergen societies 
 
   4   could do that. 
 
   5             DR. BRANDT:  Dr. Maryanski, have you got 
 
   6   all the advice you can handle or you want more? 
 
   7             DR. MARYANSKI:  I think you have a lot of 
 
   8   good ideas. 
 
   9             DR. BRANDT:  What we can do, all of you 
 
  10   have ordered your lunch.  Perhaps after lunch, over 
 
  11   lunch, some of you may have other ideas, we can get 
 
  12   them discussed, and then we can all go home. 
 
  13             DR. KAPUSCINSKI:  I was wondering, since 
 
  14   we have a little bit of time, if we could maybe get 
 
  15   a little more detail from Dr. Maryanski about 
 
  16   exactly how we are going to proceed in the next 
 
  17   step.  For example, yesterday, there was some 
 
  18   mention that the agency would like now to try to 
 
  19   develop draft guidance and then run the draft by 
 
  20   the committee. 
 
  21             I am wondering how is that going to 
 
  22   actually happen, are we going to reconvene as a 
 
  23   committee, meet face to face and discuss the draft 
 
  24   or are we going to each receive it individually and 
 
  25   be asked to sent in comments? Is there any general 

 
                                                                105 
 
   1   idea of when the next meeting might be and things 
 
   2   like that? 
 
   3             DR. MARYANSKI:  It is a good question and 
 
   4   I think it actually gives me an opportunity to give 
 
   5   you a sense of what our expectation is.  This whole 
 
   6   idea of the subcommittee, did we actually explain 
 
   7   to you that this is one of actually six 
 
   8   subcommittees that we are forming? 
 
   9             DR. KAPUSCINSKI:  No. 
 
  10             DR. MARYANSKI:  Then, let me back up since 
 
  11   we have a few minutes. 
 
  12             DR. KAPUSCINSKI:  A little more context 
 
  13   would help. 
 
  14             DR. MARYANSKI:  We have had for a number 
 
  15   of years a standing Food Advisory Committee, which 
 
  16   is the full committee.  This is now a subcommittee. 
 
  17   Dr. Brandt in the past has been chairman-- 
 
  18             DR. BRANDT:  Eight long years. 
 
  19             DR. MARYANSKI:  Eight long years he 
 
  20   served, yes, and very admirably, I must say.  In 
 
  21   fact, he did manage to weave through the mine 
 
  22   fields on the first biotech issues for us quite 
 
  23   admirably. 
 
  24             But we have a Food Advisory Committee and 
 
  25   what we have now done to give us really more 

 
                                                                106 
 
   1   focused scientific input is to establish, I think 
 
   2   the number is now up to six subcommittees under the 
 
   3   Food Advisory Committee, so these are established 
 
   4   as subcommittees of the full Food Advisory 
 
   5   Committee, and they are all designed to look at 
 
   6   specific topics. 
 
   7             This one, of course, is food 
 
   8   biotechnology.  We have other committees, one that 
 
   9   looks at food additives, one that looks at 
 
  10   contaminants, one that looks at dietary 
 
  11   supplements, and there are some others that I don't 
 
  12   off the top of my head have the complete list for 
 
  13   you, but you get the sense that we have now a 
 
  14   number of subcommittees under this committee. 
 
  15             What the goal is, is to have these 
 
  16   committees really be essentially working committees 
 
  17   that work on primarily scientific issues for us, so 
 
  18   that they are focused on particular topics.  Those 
 
  19   committees, the work of those committees then would 
 
  20   be reported back to the full committee, and in some 
 
  21   cases, issues that are discussed in the 
 
  22   subcommittee may also be addressed through the full 
 
  23   committee, but basically, this is a subcommittee of 
 
  24   the full committee. 
 
  25             So, our goal, once we have this up and 

 
                                                                107 
 
   1   running, is to have probably two meetings a year of 
 
   2   this subcommittee, so this will be a fairly ongoing 
 
   3   process in that sense. 
 
   4             It does take a couple months to put 
 
   5   together a committee meeting.  It is not an easy 
 
   6   process usually.  We are hoping that the next few 
 
   7   will be a little easier than the rest one has been, 
 
   8   and we certainly will be looking. 
 
   9             We plan to look at all of the aspects of 
 
  10   this committee meeting in terms of the logistics, 
 
  11   and so forth, for the planning for future meetings, 
 
  12   so this is the beginning of an experience here at 
 
  13   the Center for Food Safety and Applied Nutrition. 
 
  14             We have not had these subcommittees 
 
  15   before, and we have not been in this building 
 
  16   before, but I think in terms of the work, I am 
 
  17   certainly very pleased with the discussions that we 
 
  18   have had. 
 
  19             Our expectations were not real high in the 
 
  20   sense that we did not want this subcommittee to 
 
  21   feel that we were bringing them in here to present 
 
  22   this issue and expect you to give us some 
 
  23   definitive answers about how to assess 
 
  24   allergenicity, for example.  That would not have 
 
  25   been fair to you, it would not have been a proper 

 
                                                                108 
 
   1   expectation for us. 
 
   2             But we think this is a good start.  You 
 
   3   now know a little more about who we are, and I 
 
   4   would encourage you, if you feel that there are 
 
   5   other aspects of what we do as FDA, that would be 
 
   6   helpful to you in doing your work, that you let us 
 
   7   know that, because we have been listening over the 
 
   8   past two days for things that might be helpful to 
 
   9   you in terms of doing your work, thinking about 
 
  10   that, as well outside of just the biotechnology 
 
  11   aspect. 
 
  12             We want you to be able to understand what 
 
  13   we do, what we can do, what we can't do, as well as 
 
  14   the issues around biotechnology. 
 
  15             In terms of the actual work here now, we, 
 
  16   of course, now have suggestions, probably you have 
 
  17   things to think about as we now proceed to develop 
 
  18   the draft guidance document.  When we speak of a 
 
  19   draft guidance document, it is a document that we 
 
  20   have special procedures for, and we do, once a 
 
  21   document is developed, we do put it out for public 
 
  22   comment. 
 
  23             As you heard Mr. Lake say yesterday, out 
 
  24   intention in this process, for this particular 
 
  25   document, is to bring it back to you as a 

 
                                                                109 
 
   1   subcommittee before we actually put it out for 
 
   2   public comment, so you will have another chance for 
 
   3   input on that document before we actually publish 
 
   4   it for another round of comments from the broader 
 
   5   public. 
 
   6             My expectation would be the normal process 
 
   7   for putting together a committee is to prepare the 
 
   8   background information ahead of the meeting and 
 
   9   make that available to you, so that you have a 
 
  10   chance to read that and study it before you come to 
 
  11   the meeting. 
 
  12             So, my expectation would be that we would 
 
  13   do another meeting when we do a meeting on the 
 
  14   draft guidance once we have it, would be to make it 
 
  15   available to the subcommittee members before the 
 
  16   meeting, and at the same time, I believe, Margaret, 
 
  17   we would put it on the web.  How are we doing that, 
 
  18   how are we doing background documents? 
 
  19             DR. COLE:  I am not entirely clear on that 
 
  20   yet. 
 
  21             DR. MARYANSKI:  We are working out a 
 
  22   process here with the new subcommittee, but the 
 
  23   idea here is that the document should be available 
 
  24   to you before you have to come in and discuss it. 
 
  25             DR. KAPUSCINSKI:  And your impression is 

 
                                                                110 
 
   1   that at that point, the document is public or is it 
 
   2   something that we would have a closed meeting 
 
   3   about? 
 
   4             DR. MARYANSKI:  Once we give the document 
 
   5   out to the subcommittee, it is, in fact, a public 
 
   6   document. 
 
   7             DR. KAPUSCINSKI:  That is what I was 
 
   8   guessing.  And then you would get our comments, you 
 
   9   would use that to rework the draft and then publish 
 
  10   it officially in the Federal Register for public 
 
  11   comment? 
 
  12             DR. MARYANSKI:  Well, the way it works is 
 
  13   what we would do is take the comments from whatever 
 
  14   the subcommittee provides us, we would make 
 
  15   whatever modifications we felt were appropriate to 
 
  16   the draft guidance. 
 
  17             We would then publish an announcement in 
 
  18   the Federal Register of the availability of the 
 
  19   draft guidance, and would then at the same time 
 
  20   place it on the web, so it is available then for 
 
  21   all interested parties to comment. 
 
  22             DR. ARIAS:  Can I ask a question in 
 
  23   regards to sort of the more global perspective of 
 
  24   the focus of the group and ultimately how that may 
 
  25   impact agricultural policy down the line.  In 

 
                                                                111 
 
   1   particular, I am thinking that this panel, I think 
 
   2   works on the assumption that these guidelines are 
 
   3   targeted towards national agricultural industries, 
 
   4   and since agriculture is obviously an international 
 
   5   commercial enterprise in the United States, we 
 
   6   export, we import. 
 
   7             How would these guidelines affect those 
 
   8   types of relationships and what would ultimately be 
 
   9   expectations there in terms of the global 
 
  10   perspective? 
 
  11             DR. MARYANSKI:  Well, of course, we are 
 
  12   often asked by countries about our procedures and 
 
  13   policies, and it has been our position to, when 
 
  14   other governments ask for advice from FDA, that we 
 
  15   make every attempt to respond to that, and that may 
 
  16   be sharing our guidance documents or explaining our 
 
  17   evaluation process or whatever seems to be the need 
 
  18   for the other government. 
 
  19             We are most effective in talking to other 
 
  20   countries when we are talking to our counterparts, 
 
  21   in other words, those officials who make decisions 
 
  22   about the safety of foods and food ingredients.  We 
 
  23   are not effective in talking to the public, that is 
 
  24   not our role to talk to publics in other countries 
 
  25   or even the people primarily interested in trade. 

 
                                                                112 
 
   1             We do provide information, and that is one 
 
   2   of the reasons for our web site, to make sure that 
 
   3   everyone has access, but it is very important for 
 
   4   us to communicate with other governments, and that, 
 
   5   of course, is the reason we work in the Codex 
 
   6   process. 
 
   7             We also work in another international 
 
   8   organization called the OECD, which is the 
 
   9   Organization for Economic Cooperation and 
 
  10   Development.  That organization has a task force on 
 
  11   novel foods and feeds, and Dr. Paul Mayers is the 
 
  12   chair--well, he was the chair, I have to correct 
 
  13   myself, up until now he has been the chair of that. 
 
  14   Because of new responsibilities in Canada, he has 
 
  15   stepped down from that. Dr. Kelly from Australia is 
 
  16   the current chair of that committee. 
 
  17             But you probably will be hearing from us 
 
  18   about some of the work that we are doing in that 
 
  19   task force also.  The international activities are 
 
  20   things that I think this subcommittee probably is 
 
  21   going to be hearing about along with other issues 
 
  22   that we are working on internally, as well. 
 
  23             We actually see this as a working 
 
  24   subcommittee.  We want to be able to discuss issues 
 
  25   with you that relate to our everyday work.  The 

 
                                                                113 
 
   1   reason I say that is that most of the time in the 
 
   2   past, in this center, when we have used advisory 
 
   3   committees, it has been for something that is very 
 
   4   much in the public interest.  The Flavr Savr 
 
   5   tomato, of course, is the one that I am most 
 
   6   familiar with, but we have had other issues that 
 
   7   are very much in the public interest, and we will 
 
   8   do that, too, here, but we really want to also use 
 
   9   this opportunity to gain your suggestions about 
 
  10   things that relate more to our everyday work, as 
 
  11   well as these more sort of noticeable issues. 
 
  12             So, we are expecting a lot actually in 
 
  13   that sense, but as I have said, if you have any 
 
  14   suggestions about things that you think it would be 
 
  15   useful to discuss, we would certainly be interested 
 
  16   to hear that.  We will be, of course, thinking 
 
  17   about issues to bring for the agenda for these 
 
  18   meetings on the basis of what we feel are the 
 
  19   priorities at the time. 
 
  20             You have now gotten one of my really long-winded 
 
  21   answers to your question. 
 
  22             DR. KAPUSCINSKI:  Thank you. 
 
  23             DR. BRANDT:  I have to say that scary part 
 
  24   is that they listen to you, and also sometimes even 
 
  25   implement things that advisory committees 

 
                                                                114 
 
   1   recommend, so I mean it is taken serious and it is 
 
   2   worth your time and your effort, so I would commend 
 
   3   all of you for doing it. 
 
   4             Next time you meet--you have three members 
 
   5   missing today--I presume they will be here 
 
   6   including your chair, Dr. Archer from the great 
 
   7   State of Florida.  He is probably down there trying 
 
   8   to get mercury out of fish, but in any event, I 
 
   9   presume he will be here next time, and I won't be. 
 
  10             The reason his expectations were so low 
 
  11   was because he knew they were running me in as a 
 
  12   last-minute substitute, but anyway, it has been a 
 
  13   real pleasure for me to get to meet all of you and 
 
  14   talk to you, and I hope that your work is 
 
  15   satisfying on this subcommittee, and so forth. 
 
  16             Thank you very much. 
 
  17             [Whereupon, at 11:20 a.m., the meeting was 
 
  18   concluded.]