> FOOD AND DRUG ADMINISTRATION
>
> FOOD ADVISORY COMMITTEE
>
> \* \* \* \* \*
>
> COMMITTEE MEETING
>
> ON INFANT FORMULA
>
> Friday, April 5, 2002
>
> 8:33 a.m.
>
> Greenbelt Marriott
>
> 6400 Ivy Lane
>
> Greenbelt, Maryland
>
> PARTICIPANTS:
>
> Bert Garza, M.D., Ph.D.
>
> Cornell University
>
> Francis Fredrick Busta, Ph.D.
>
> University of Minnesota
>
> Goulda A. Downer, Ph.D., R.D., C.N.S.
>
> METROPLEX Health and Nutrition Services, Inc.
>
> Johanna Dwyer, Ph.D.
>
> USDA/ARS
>
> Joseph Hotchkiss, PH.D.
>
> Cornell University
>
> Thomas Montville, Ph.D.
>
> Cook College, Rutgers, The State University
>
> Robert Russell, M.D.
>
> Tufts University
>
> Madeleine Sigman-Grant, Ph.D.
>
> University of Nevada-Reno
>
> James Anderson, Ph.D.
>
> University of Nebraska Medical Center
>
> Robert Baker, M.D., Ph.D.
>
> The State University of New York
>
> Scott Denne, M.D.
>
> Indiana University
>
> James Heubi, M.D.
>
> Children\'s Hospital Medical Center-Cincinnati
>
> Laurie Moyer-Mileur, Ph.D., R.D., C.D.
>
> Children\'s Hospital of Philadelphia
>
> Patti Thureen, M.D.
>
> University of Colorado
>
> PARTICIPANTS \[continued\]:
>
> Peter Garlick, Ph.D.
>
> Health Sciences Center
>
> George Giacoia, M.D.
>
> National Institute of Child Health and Human
>
> Development
>
> Robert Buchanan
>
> AAP Liaison
>
> Roger Clemens, DrPH
>
> University of Southern California
>
> [P R O C E E D I N G S]{.underline}
>
> DR. GARZA: If everyone would take their seats, we\'re going to begin
> this morning with Dr. Beth Yetley and Chris Taylor will give us a bit
> of a recap based on their presentations, in trying to clarify some
> issues for the committee, with the hope then that whatever advice we
> might be able to provide at the end of the meeting would be then more
> information. And so we\'re going to take a few minutes, perhaps 15, to
> have them provide some clarification, and then we will return to those
> three questions.
>
> At the present time, we\'ll see how the discussion unfolds. I am
> hoping that we will be finished before 12:00, so we may or may not
> take a break. We\'ll see how the discussion goes and then make our
> decision at that point. You can slip out quietly on your own, and we
> will register your opinions.
>
> \[Laughter.\]
>
> DR. GARZA: We tried locking the doors but I was told that was against
> fire regulations.
>
> Okay, so let\'s begin. I don\'t know whether it will be Dr. Taylor or
> Dr. Yetley. Dr. Taylor? All right.
>
> DR. TAYLOR: Good morning, and thank you very much for the opportunity
> just to do a brief recap. From yesterday\'s discussions, to no
> surprise, somehow the way the statute and the provisions work is at
> times less than clear, so we though we would try once again
> specifically responding in terms of some of the questions we heard
> raised yesterday.
>
> I\'m going to go back in the second slide here to this idea of the
> regulatory boxes. We presented a form of this slide yesterday, and
> based on the discussions, we\'ve added just a few concepts. And it\'s
> a schematic, and the idea that there is a series of components,
> regulatory boxes, for infant formula.
>
> And at the very top here, at the very top here you have the starting
> point of the safety of the ingredients for intended use. It happens to
> be regulated by Sections 409 and 201, which is why you here us use
> those phrases all the time.
>
> But it\'s important to recognize that this has been the classic safety
> issue. It happens to all foods and all food components, and it is
> ingredient specific. It\'s not relative to the product but it\'s for
> the ingredient. And if we follow your Echinacea example through, the
> one that was raised yesterday, Echinacea would start here as safety of
> an ingredient for intended use, in this case being infant formula.
>
> We recognize that as these types of ingredients, the ingredients that
> are of interest in the addition to infant formula, change over time,
> some of them potentially physiologically active. But there are some
> issues here that need to be addressed, and some of you may be aware
> that recently we contracted with the National Academy of Sciences
> Institute of Medicine to explore methods for evaluating the safety of
> new or novel ingredients when intended for infant formula.
>
> So this issue is not on the Advisory Committee\'s plate. It is being
> handled by the Academy, and it\'s the classic issue of the safety of
> the ingredients for intended use.
>
> From this point, this threshold point of the safety of the ingredient,
> you move to formulation and formulating the product. What we have in
> place under so-called Section 412 is a statutory check on the
> formulated product.
>
> It\'s assurances for the specific product, and there are a variety of
> components that come into play, so called tabled nutrients, required
> nutrients, those things that are to be in infant formulas, the listed
> nutrients. There is the series of GMP issues and quality control
> issues, how it\'s processed, how you analyze for the ingredients, the
> nutrients in there.
>
> Those two are part of a whole set of issues that go into providing
> assurances, as is the issue of quality factors. And it\'s highlighted
> here in red because the issue of quality factors is what we\'re
> putting on the Advisory Committee\'s plate.
>
> Quality factors we will talk about again, just to revisit in a second,
> but I noticed yesterday a lot of terms of efficacy and safety came up,
> and I think one way to think of quality factor is that it\'s a
> question of whether the specific product is still providing the
> required nutrients. It\'s a check on that, and in that case there does
> come into play phrases such as efficacy and safety, but it\'s efficacy
> and safety regarding the ability of the required nutrients to perform
> in that specific formulation.
>
> So this is really what this Advisory Committee is all about. Once all
> of this happens and marketing occurs, it is possible to bring into
> play the concept of claims, and I think yesterday perhaps the question
> of efficacy for claims was put on the table.
>
> The issue of truthful and not misleading is where this comes into
> play, Section 403(a). It\'s a post-marketing issue. The manufacturer
> is responsible for determining the substantiation upon which they
> decide to make this claim, and any activities on the part of the
> agency are post-marketing.
>
> But this is perhaps the classic efficacy questions that you folks were
> putting on the table yesterday. They come here post-marketing. Quality
> factors are a different set of issues, and while efficacy and safety
> sometimes come into play conceptually, again it\'s about the ability
> of that particular formulation to provide the require nutrients.
>
> So once again going back to that red box, quality factors, we said
> that the assurances for final product were the first two we talked
> about, and then the quality factors. Is this specific product still
> providing nutrients in a biologically optimal way? The questions of
> interference, interaction, bioavailability, are what this Advisory
> Committee is being asked to address in a somewhat limited way.
>
> Again, you can think of quality factors as being nutrient specific,
> bioavailability, and then the formulation as the totality. At this
> point what we\'re dealing with is normal physical growth. As we heard
> yesterday, other things could be added over time as science evolved
> but, next slide, what we\'re about here is normal physical growth.
>
> As part of this, then, the quality factor component, the issue of what
> is a major change came up yesterday, and to provide just a little bit
> of clarification, generally speaking a major change can fall into one
> of three categories: new manufacturer, a major change in processing,
> or a major change in formulation. That brings into play the concept of
> quality factors.
>
> Some examples of this, new manufacturer to the U.S. market;
> introduction of a new form, for example, a powdered form of something
> that had been marketed previously as a liquid form; significant
> revision, addition, or substitution of macronutrient without prior
> experience relative to that ingredient; new processing in the line or
> in the plant, that constitutes a major change. And then what we are
> increasingly seeing is the use of a new or a novel constituent not
> required by the act.
>
> Now, following up on that, again reemphasizing that quality factors
> are product specific, not ingredient specific, and that they have the
> potential to provide, to impact, to result in a total dietary change,
> one example is a new oil source. That often can be viewed as a major
> change, especially given the vulnerable population and the fact that
> it\'s a sole source issue.
>
> With a new oil source, you would get a change in fatty acid
> composition. You would change the levels and the ratios of the
> saturated fat, the polys, the monos, the Omega-3\'s to the Omega-6.
> Given a target population such as this, the major change would be
> something that would invoke quality factors. There is a change also,
> obviously, in potential for interactions with other constituents.
>
> So this is the kind of thing we\'re talking about when we talk about
> the questions we\'re putting in front of you, as far as how should we
> review these kinds of changes. What is the real bottom line here as
> far as how quality factors operate, is it\'s not a matter of
> experimenting to see how a formula can be improved. That\'s not the
> congressional intent of quality factors, but rather quality factors
> are all about providing assurances for a marketed formula, and it\'s
> all about prior to marketing.
>
> In the next slide we bring home, I think, again another clarification
> relative to yesterday\'s discussions. The whole point of a study is to
> show that there is no adverse effect on physical growth, given the
> current paradigm we\'re operating under, normal physical growth.
>
> The way the process has operated the way we view it at FDA is that the
> end point runs along the route of bioequivalence, so that you\'re
> seeing similar growth. It\'s the proverbial two-tailed test, and in a
> moment I\'ll ask Beth Yetley, who has spent a great deal of time
> working in this area, to clarify for you this concept.
>
> Where I think it\'s traditional to think but it\'s not necessarily the
> way the agency operates, certainly there is room for that, is that the
> end point of the studies does not run necessarily down the beneficial
> route. It has not been historically growth more like breast-fed
> infants, which are a one-tailed test. We have been operating in this
> upper domain of bioequivalence, and I think much of your discussion
> was looking at the lower domain of the beneficial component.
>
> Beth, I know you have done some work, and in fact some of this is
> based on what you have seen, if there is something you would like to
> add as far as clarifying the purpose of this for infant formula
> reviews.
>
> DR. YETLEY: Well, I don\'t have too much to offer. I think that these
> concepts are something that you need to bring back when you talk about
> physical growth next time, because it really gets to the issue of
> whether we have operationalized it correctly and whether or not we
> have an appropriate interpretation. But I thought that part of the
> conversation yesterday was wanting to go to the beneficial arrow, and
> I\'m not sure that we can quite go that far, although equivalence or
> support of adequate physical growth perhaps could be operationalized
> differently.
>
> Part of the confusion I think comes over the\--because of the history
> of this. If you look at the COMA guidelines from \'86 or \'88, they
> really assumed bioequivalence to a comparable formula, and their
> criteria was a one-tailed test, that growth is either equal to or
> greater than, but the adverse effect was a lesser rate of growth. And
> I think what science is saying and what I was hearing yesterday is
> that that\'s not necessarily a valid interpretation. I think what FDA
> has done in recent years is to say a two-tailed test is more
> appropriate, that adversity could be either greater, significantly
> greater weight gain or significantly less weight gain.
>
> I think one of the issues that came up yesterday, and the issue that
> we need to look at more closely at the next meeting, is whether or not
> it should be a one-tailed test and the tail should be in the direction
> of being more like breast milk. But I think those are issues for the
> future, but I thought that perhaps there needed to be some
> clarification, that the purpose of the quality factor study is not to
> find new and improved mousetrap, new and improved formula, but to
> assure that to the best of our ability it is supporting normal
> physical growth.
>
> DR. TAYLOR: Just for clarification, Beth is our lead scientist in
> nutrition, and I have served as office director, so you do see a kind
> of tag-team thing where her science informs our regulatory decisions,
> so she is an excellent source as far as clarifying some of the
> scientific parameters here.
>
> So in terms of just going back to the goals and the purpose, Sylvia,
> if I could have the next slide, please, where we had hoped the
> Advisory Committee or how we hoped the Advisory Committee would
> structure itself, was that we saw you yesterday begin your discussion,
> your general\--your responses to the general question.
>
> And as we indicated, we\'re hopeful that the Ad Hoc Working Group will
> complete these discussions in two subsequent sessions. As we have
> mentioned, we will be contacting the Ad Hoc Working Group to get
> together with dates. Anyone who is a member of the Food Advisory
> Committee, who would like to take part in that, you are certainly
> welcome. And these are public meetings, and we will try to get those
> organized in the near future, as soon as possible.
>
> But as far as this meeting for April 4 and 5, we were asking you folks
> to come to closure on three specific questions by today. We did print
> those out and circulate them. On the next slide, the general question
> that you began to kind of noodle on yesterday, and that will be
> followed up in the future, was the one on your handout about what
> constitutes an appropriate and complete general science-based set of
> guiding principles.
>
> And relative to this, if I could have the next slide, relative to this
> general question, we will use the discussion that we heard yesterday,
> and to the extent it happens today, to create a straw man for the Ad
> Hoc Group for future discussions about quality factors, specifically
> normal physical growth. So we will try to make use of your discussions
> to create a better straw man for your next two meetings. We would also
> ask you what materials would the Ad Hoc Task Force like FDA to provide
> in terms of background, so that we will pull together for you, for
> your next meeting.
>
> And then the next slide, as far as the specific questions for today,
> there were basically three, depending on how you count, three or five.
> One, generalizability relative to population and to product, and then
> the second about adverse events, and the third about attrition rates.
> And again, these were written and handed out yesterday.
>
> If I could have the next slide, in terms of what we need, what would
> be useful, because that did come up yesterday, as far as the
> generalizability question, FDA would need a rationale for the
> responses that the committee members would provide us, and if the
> responses\--it depends, and we put that in there because that seems to
> be the way the discussion was going\--FDA would need criteria for when
> it\'s yes and criteria for when it\'s no and a rationale for that.
> That\'s what would be most useful to us.
>
> And then in terms of the second and third question\--next
> slide\--adverse events, again, FDA would need advice and a rationale
> for that advice, and then the attrition rate, we\'d need the advice
> and the rationale.
>
> So I think that\'s it for the slides. We hope this was helpful.
>
> If I could have the last slide, several of you yesterday requested
> that we provide hard copies of the slides on the comparison of the
> preterm and the term infants, and Sylvia, if you can just flip through
> those very quickly, we did a slide on the adequate intake, meaning
> breast milk, versus the Code of Federal Regulations formula for a
> couple of nutrients.
>
> The next slide\--again, these are in your handout and it I know it was
> the numbers you wanted\--the referenced daily intakes.
>
> Next slide, on the composition of marketed formulas, a comparison of
> preterm to term. Again, this is in your handout.
>
> Next slide, daily intakes for marketed formulas, preterm versus term,
> again in your handout, and then daily intakes for KG body weight,
> again, in your handout.
>
> Several of you had asked for those as hard copies, so we\'ve provided
> them as an attachment. Thank you very much.
>
> DR. GARZA: Thank you. Are there any questions or comments?
>
> \[No response.\]
>
> DR. GARZA: If not, let\'s go back, then, and take up the three
> questions, beginning with the generalizability. I\'d like to ask the
> group if there are any specific points of discussion that anyone would
> like to raise based on yesterday\'s exchanges that would help each of
> us clarify what our individual responses may be when we start going
> around the table.
>
> The plan is that at the end of this general discussion, I will first
> ask the non-voting members of the group to give us responses with
> rationales on all three questions, and then after they have done
> that\--and I will do that in alphabetical order\--then we\'ll go to
> the ad hoc group and then go at the end to members of the Food
> Advisory Committee, the permanent members.
>
> But before we get to that part of the agenda, I want to make sure
> that, in fact, we each have an opportunity either to raise questions
> or make comments on all three questions. So I begin with question one.
>
> \[No response.\]
>
> DR. GARZA: All right. Maybe we\'ll be out of here by nine. I hope we
> get more.
>
> What about question two? Any additional comments or concerns on the
> second question? All right, go ahead.
>
> DR. BAKER: It seems like what the FDA is asking both in this question
> and in the first question is to have some written down rule for how to
> proceed, and I think that may be very difficult. In this question,
> though, we did bring up the possibility of an advisory, or an
> independent board to review adverse events. Would that satisfy the FDA
> as a way of going about things, if you had a board that then would
> review adverse events and report their review to the FDA for a final
> decision?
>
> DR. GARZA: I can\'t\--
>
> DR. BAKER: Would that satisfy that or not?
>
> DR. GARZA: I can\'t speak for FDA. I will not\--
>
> DR. BAKER: Well\--
>
> DR. GARZA: My sense is\--
>
> DR. BAKER: Dr. Yetley, would that?
>
> DR. YETLEY: I have to apologize. Chris and I were trying to figure
> something else out. Can you repeat your question as exactly as
> possible?
>
> DR. BAKER: It appears to me that the FDA is looking for sort of solid
> written down guidelines for how to operate in the situation where
> adverse events are reported, and yesterday we did talk about having an
> independent review board which would review adverse events and then
> report to the FDA. Would that satisfy the FDA as an operating mode or
> would they need more specific things than that? I think it would still
> be up to someone to decide what action needed to be taken about those
> adverse events, none, more review, or accept the report.
>
> So there would still be a decision making thing that would be up to
> the FDA, but it would give them guidelines and evidence and support to
> make their decision. So would that satisfy the criteria or not? I
> mean\--
>
> DR. GARZA: Before Beth answers, as chair, I want to make sure that
> each committee member understands that as a committee member, you are
> free to tell the government whatever you wish, whether it satisfies
> FDA or not.
>
> \[Laughter.\]
>
> DR. GARZA: Our role here is not to bring joy to government
> officials\--
>
> \[Laughter.\]
>
> DR. GARZA: \--but to give them the best advice you have, no matter how
> uncomfortable that advice may be. So I want to make sure that that\'s
> clearly understood before Beth answers because that\'s not\--we can
> say, is that sufficient detail, which is a different question than
> would you find that answer satisfactory. Whether Beth finds it
> satisfactory or not\--I\'m sorry, Doctor\--is irrelevant. So with that
> caveat, I want to make sure the groups understands that, all right,
> otherwise, our independence would be called into question and I
> certainly wouldn\'t want that to happen.
>
> DR. YETLEY: I appreciate your comments, Bert.
>
> \[Laughter.\]
>
> DR. YETLEY: The question that we\'re concerned about is if the data
> that we have available to us has a significant difference in
> adverse\--clinically significant adverse event reports between test
> and control, what do we do? How do we use that data? That is different
> than what should be done if those adverse events occur, and I think
> that gets into study ethics issues and what not.
>
> What would be useful for us is that if we are faced with a situation
> where one of the major pieces of evidence before us is a study that
> has large differences in adverse events between test and control, how
> or should we be using those data, and if you would feel that having an
> independent review to see if they can attribute those adverse events
> to the formula, or if they\'re unrelated to the formula, would inform
> us and make it\--you could then provide some criteria as to whether or
> not those data would then be useful. I don\'t know if I\'m making
> sense, but it\'s what would or should be done to make the data useful
> or are the data not useful.
>
> DR. GARZA: So you\'re talking after the fact. You\'re evaluating a
> study that has adverse events and want to know\--
>
> DR. YETLEY: Right.
>
> DR. GARZA: \--because of the adverse events, does that negate the
> usefulness of the study.
>
> DR. YETLEY: Can that be used to evaluate whether or not that formula
> will support normal physical growth. That does not mean that the
> ethical issues should not be dealt with, but those would be dealt
> with, I think, in a different manner. But that\'s not to say those are
> not serious issues and don\'t need attention also.
>
> DR. GARZA: Up here?
>
> DR. GIACOIA: Yes, a point of clarification.
>
> DR. GARZA: Would you identify yourself?
>
> DR. GIACOIA: George Giacoia. Are you using the same classification of
> adverse events as it is used in drugs, measure versus reporting?
>
> DR. YETLEY: Generally, the concept is clinically significant in the
> context of the infant population that we\'re dealing with.
>
> DR. GIACOIA: Is it well defined? Does it need to be clarified for
> nutritional versus\--
>
> DR. YETLEY: It probably could stand some clarification, yes.
>
> DR. GARZA: Other questions regarding either questions one or two? Dr.
> Dwyer?
>
> DR. DWYER: I don\'t know if there\'s anything we can do about this
> right now, but I\'m still uncertain as to exactly what is required and
> what is usually provided even if it\'s not required in existing
> studies that are being done now.
>
> DR. GARZA: Can you provide a brief summary, either Beth or Chris? The
> question as I understand it is what are companies currently required
> to submit for the assurance factor or quality factors, along the\--
>
> DR. DWYER: What safeguards there are\--
>
> DR. GARZA: But for assurances and under quality factors specifically,
> rather than getting into the other two, and what is normally submitted
> above and beyond what is required.
>
> DR. TAYLOR: We\'ll try the tag team approach on this, as well. There
> are not in place specific check lists for what is submitted. It\'s a
> package that the manufacturer creates to provide assurances. And so,
> assumedly, the manufacturer for clinical trials would follow
> appropriate clinical trial procedures that, as I understand it, are
> standardized with IRBs or whatever.
>
> And so the question of how the manufacturer handles adverse events is
> not one that we specifically provide as a set of check list items, if
> that\'s your question. And consequently, I think there\'s probably a
> range of what happens. Beth?
>
> DR. YETLEY: Well, any of these studies that are done in support of a
> product that\'s to be regulated by FDA would come under both DHHS and
> FDA rules for protection of human subjects, clinical study guidelines,
> and what not. As Chris has indicated, we don\'t have specific
> requirements for X-number of studies of X-type. What we have
> historically relied upon and have been used were the comment
> guidelines for a clinical study to show that the new formula supports
> healthy growth, normal physical growth, and that is basically what
> we\'ve proposed also, although that rule has not yet been finalized.
>
> DR. GARZA: Do you want to follow up on that?
>
> DR. HEUBI: Can I ask you a question? Jim Heubi. If you say they comply
> with DHHS standards, does that mean that all these studies require
> appropriate ethnicity and gender composition for acceptance?
>
> DR. YETLEY: I can\'t give you all of the specifics on it, but any of
> the human subjects protection issues that are covered, and then there
> are some specific\--it primarily comes under human subjects protection
> issues. Maybe we should get back to you on the more specific details
> for the next meeting.
>
> DR. HEUBI: So, I guess, is diversity required for these studies? I
> guess that\'s the question, because\--
>
> DR. YETLEY: Yes, I can\'t\--I don\'t know the answer right now.
>
> DR. HEUBI: Because for NIH, all of us who submit applications now for
> any kind of clinical trial, we have to have composition that mirrors
> the U.S. ethnic population and gender distribution.
>
> DR. YETLEY: Well, the criteria is for the intended population,
> intended use population. The specifics on some of those details, I
> just don\'t know. We can find out and have them for the next meeting.
>
> DR. GARZA: Is it my understand\--I\'m sorry, is there another question
> over here? It\'s my understanding that what is generally submitted,
> from your response, are growth data and supporting biochemical
> clinical sort of screens that are generally done on patients, I mean,
> that you may get serum proteins and electrolytes and cell counts of
> one sort or another, or is the general type of information that you
> see only the growth data with a report of adverse events and those
> adverse events being then defined by the PI and what he or she may
> decide to submit?
>
> DR. YETLEY: I may ask for help from some of the staff, but the
> packages vary considerably. Some have biochemistries in addition to
> the growth data. I\'m not sure that all do. No, all do not. So it\'s
> very variable other than the growth data.
>
> DR. GARZA: Okay. Dr. Dwyer, does that answer the\--
>
> DR. DWYER: Yes.
>
> DR. HEUBI: Let me ask you a question. So the DHA data that was
> submitted to the FDA included growth data and biochemical results?
>
> DR. YETLEY: I need to turn to Sue Ann.
>
> DR. HEUBI: Sorry. I\'m asking too specific of questions.
>
> DR. YETLEY: Okay. She says it varied from manufacturer to
> manufacturer.
>
> DR. HEUBI: Okay. Thank you.
>
> DR. GARZA: Yes, Dr. Busta?
>
> DR. BUSTA: We originally received a Food Advisory Committee Meeting on
> Infant Formula Charges and Questions, and in that was a tentative
> guiding principles for clinical studies. Whose is that?
>
> DR. TAYLOR: That was the one that we put forward for possible
> discussion that you went through yesterday.
>
> DR. GARZA: Those were just the sort of strong recommendations that
> were primarily drawn from the AEP report and the COMA report, but they
> were only intended to initiate discussion by the committee. They have
> no other standing as far as I know.
>
> Now, in the end, we will be asked to make, in the general principle
> part of this discussion, that first question, we will be asked to
> address both the science base and the clinical base, which will then,
> I think, lead to our discussing both the design and the conduct of
> studies. Those discussions clearly got started with the hour and a
> half we had yesterday.
>
> DR. BUSTA: Right. We concentrated on the COMA.
>
> DR. GARZA: That\'s right, and the only reason for doing that was
> because that was the updated report, and as I think it was Dr. Thureen
> who suggested that, in fact, many of those recommendations appear to
> have come from the earlier AEP report and updated to a certain degree.
> But that was only for getting discussions going. That has no other
> bearing and we could end up with a very different list, a partially
> different list. I doubt if we will agree, based on the discussion,
> totally with the COMA report.
>
> DR. BUSTA: Thank you.
>
> DR. GARZA: Yes?
>
> DR. CLEMENS: Rog Clemens. You referred to Johanna\'s comment a moment
> ago. The American Academy of Pediatrics provided some basic guidelines
> in the 1980 report.
>
> DR. GARZA: In the \'88 report or 1980?
>
> DR. CLEMENS: Actually, \'88 report. Thank you very much, Bert. The
> manufacturers follow those basic guidelines and they particularly
> provide body weights and they provide recumbent lengths and they also
> provide head circumference types of data in addition to those interval
> data. They also provide the necessary biochemistries as deemed
> appropriate for that particular trial, and then they also provide
> additional data as, again, appropriate for the hypothesis. I hope that
> helps.
>
> DR. GARZA: But it\'s important, the appropriateness is not determined
> by government or an independent agency. It is a decision of whoever\'s
> carrying out the investigation together with the sponsor.
>
> DR. CLEMENS: The appropriateness is established by the investigators
> and the expert panels, developed by the various manufacturers, the
> manufacturers themselves.
>
> DR. GARZA: Any other\--?
>
> \[No response.\]
>
> DR. GARZA: All right. Then let\'s move on to question three. This has
> to do with attrition, the one that spent the least time yesterday.
>
> \[No response.\]
>
> DR. GARZA: Okay. Then let\'s begin going around the room. I will\--at
> least from my perspective, it\'s very clear that responses to these
> three questions are going to be somewhat difficult because of the
> abstractness of the questions. I don\'t expect that each of you as you
> answer will be able to cover in sufficient detail to provide guidance
> on every conceivable situation or condition that, in fact, the FDA may
> face regarding any of these three questions.
>
> Having said that, try to provide as much guidance as you can, so that
> a simple yes or a simple no at times may be appropriate, and that
> would mean exactly what those words mean, no. So that if, in fact, one
> were to answer that going from a term to a preterm population is never
> indicated, and so that, in fact, that\'s no. That\'s probably one of
> two instances where a simple no should suffice, because I think that
> should be clear to everybody what \"no\" means.
>
> On the other hand, if it is \"depends\" or \"maybe,\" then it would be
> very helpful if one provided some criteria and rationale for, and if
> possible even examples. If it is \"maybe,\" when would it be no and
> when would it be yes? What are the criteria for a yes or a no and what
> would be the rationale for those criteria? If possible, can you
> provide an example of a yes or a no.
>
> The reason for wanting to cover all three questions at one time by
> each individual is to help each of us be as consistent in our
> responses as possible, both as a group and individually. I think it
> would not be as efficient if we were to go around the table three
> times.
>
> So if I don\'t hear any objections to that procedure, then we\'ll
> start.
>
> \[No response.\]
>
> DR. GARZA: Okay. Then let me see if I can get the list. The three
> invited liaisons, non-voting consultants, that I have are Dr. Clemens,
> Garlick, and Giacoia, and then Dickinson and Scholz. I will be going
> to all non-voting members first, so we will begin with Dr. Clemens,
> then Dr. Dickinson, Dr. Garlick, Dr. Giacoia, and then Mr. Scholz. Mr.
> Scholz is not here. Should he come in before, we will surprise him.
>
> \[Laughter.\]
>
> DR. GARZA: Dr. Clemens?
>
> DR. CLEMENS: Do you want to start with question three?
>
> DR. GARZA: Question one, and then question two and then question
> three.
>
> DR. CLEMENS: We have taken the time last evening to prepare a written
> response to get the discussion going. Thank you very much, Bert, for
> the opportunity. There is a handout\--
>
> DR. GARZA: When you say \"we,\" can you\--
>
> DR. CLEMENS: The infant formula manufacturers represented at this
> meeting. I am the representative for those manufacturers.
>
> DR. GARZA: So this is not your personal response but a group response?
>
> DR. CLEMENS: It\'s a group response, yes.
>
> DR. GARZA: Is that appropriate? I don\'t know. Can we have group
> responses?
>
> DR. CLEMENS: I\'m a representative for that group and my name is on
> here, so I\'m accountable for everything that\'s said, so\--
>
> MS. HAYDEN: We know that.
>
> \[Laughter.\]
>
> DR. CLEMENS: Thank you, Linda.
>
> DR. GARZA: I just want to make sure. Thank you.
>
> DR. CLEMENS: There should be three packets going around the room.
> Thank you, Bert. We want to be succinct and direct, perhaps a
> launching pad for the discussion.
>
> Dr. Anderson made a presentation yesterday. She mentioned a decision
> tree process. Dr. Dwyer had indicated what are the components of that
> decision tree process, and I believe Dr. Stallings indicated the same
> thing. So we elected to assemble some brief concept thought or thought
> process which are involved in that decision tree process. We\'ve
> entitled this as a draft, a generalization decision analysis, and in
> this decision analysis we\'ve outlined five basic questions in
> response to your question.
>
> The answer I indicated there at the top in the five bullets. First of
> all, be sure that every ingredient is GRAS or an improved food
> additive for intended use. In this case, the intended use is infant
> formula. Fundamentally, we look at a go/no go operation, as you can
> see here.
>
> Fundamentally, we ask ourselves, what do we know about the digestion,
> absorption, metabolism, and excretion of the ingredients in preterm
> versus term infants and the decision tree is quite clear. Are they
> meaningful or not meaningful, and this is based on our experience and
> in the literature and clinical evidence.
>
> Then looking at the protocol, what is the protocol for a preterm
> study? Again, what do we know? Is the study to be initiated in late,
> preterm, or extended into term? Often, this is the case of preterm
> infants are studied. They\'ll be looking at kids which are
> physiologically mature. These are healthy, preterm infants, if preterm
> infants are to be used.
>
> Often, the case may be that\--or frequently, the case may be that
> preterm infants are started and are at 32 or 34 weeks of age,
> gestational age, and they will continue on into, if you will, 52
> weeks, and so clearly, they will follow that course. Dr. Lien
> indicated that yesterday.
>
> What is the quality of the study, of the data? We emphasize that we
> follow good clinical practice and that includes clinical practice, the
> statistical design, such as those components involving power
> calculations. Relative to statistical analysis, we have to say are
> those data, those practices, and those respective studies which are
> public domain, are they relevant or not relevant? Are they meaningful
> or not meaningful? It\'s part of the decision tree process.
>
> Is a preterm infant consuming more nutrients per kilogram of body
> weight, and again, are the data meaningful or not meaningful relative
> to term? And if so, we ask ourselves, what additional supporting data
> are available, both in-house and outside? Is there a great deal of
> data? Are there international data from which we can glean
> information?
>
> Are there studies and other matrices, whether it be liquid matrix or
> powdered matrix? And certainly, are there clinical studies available
> in the public domain that other manufacturers have provided which
> could be leveraged to use as the total totality of data as indicated
> in the discussion.
>
> I trust that this fundamental review process, at least thought
> process, is of value as we go through the question.
>
> Number two\--
>
> DR. HEUBI: Roger?
>
> DR. CLEMENS: Yes, Jim?
>
> DR. HEUBI: This addresses preterm to term, but there\'s nothing in
> here about term to preterm. Are you basically saying that those
> shouldn\'t be applied in any way to preterm infants?
>
> DR. CLEMENS: Thank you, Jim. This is the most common event here. We
> typically don\'t go backwards because of the unique nutrient
> requirements for those kids. I think Dr. Hierd had indicated yesterday
> that, clearly, the preterm are the most vulnerable. You look at both
> velocities and other issues, and clearly, that makes sense to look at
> it this way as opposed to the other way around.
>
> DR. GARZA: Yes, Dr. Russell?
>
> DR. RUSSELL: Yes, thank you. The other clinical studies and other
> matrices, wouldn\'t it also depend on the similarity of those
> matrices?
>
> DR. CLEMENS: Or even the dissimilarities of those matrices.
>
> DR. RUSSELL: Or the dissimilarity.
>
> DR. CLEMENS: That\'s right.
>
> DR. RUSSELL: So it\'s not just that other studies exist and other
> matrices.
>
> DR. CLEMENS: That\'s correct. We look at the totality of data
> available.
>
> DR. GARZA: Dr. Dwyer?
>
> DR. DWYER: Would the healthy/ill-healthy comparison fit in a similar
> matrix?
>
> DR. CLEMENS: They would fit into this matrix. Typically, we look at
> healthy preterm babies. That\'s the focus of these kind of generalized
> studies. These kids are not compromised other than gestational age.
> That\'s why we emphasize in this case late preterm infants.
>
> DR. GARZA: In clarification on that point, is the mean then of the
> population the 50th percentile when they enter the study, or are they
> significantly below that? Your definition of healthy then is?
>
> DR. CLEMENS: Their Apgar scores are appropriate. I can\'t tell you
> exactly where their percentiles lie here, but\--
>
> DR. GARZA: By healthy, you mean they have no clinical condition\--
>
> DR. CLEMENS: No clinical condition that would predispose them to be
> excluded. Certainly, they\'re typically above the tenth percentile.
>
> MS. GRANT: This is Sigmar Grant. Can I ask a question? Are these
> hospitalized infants or are they infants sent home?
>
> DR. CLEMENS: At 1500 grams, they usually go home. Many of these kids
> are 1500 grams plus. They are ready to go.
>
> DR. GARZA: That\'s all right. That\'s the response. You all may
> respond when you wish.
>
> DR. STALLINGS: I think one of the things, I think one of the hard
> parts that we are grappling with that\'s sort of central to this is is
> there any\--are we really only designing formulas for healthy preterm
> babies, for just sort of the last few weeks of a hospitalization, and,
> in fact, those formulas are necessary to get babies to that point,
> and, in fact, we heard yesterday, maybe given to babies as small as\--
>
> DR. CLEMENS: Four hundred grams.
>
> DR. STALLINGS: \--as 400 grams, which is pushing it, that they even
> have a little intestine to absorb anything\--
>
> DR. CLEMENS: Sure.
>
> DR. STALLINGS: \--but that whole concept really is central to what
> we\'re doing, so I think we have to keep that in mind. I don\'t have a
> lot of answers to that, but talking about\--I mean, it\'s been very
> good for us to realize that these studies are being done on the
> healthiest, most mature preterm babies.
>
> DR. CLEMENS: That\'s correct.
>
> DR. STALLINGS: And I think one of the things that might come out of
> this whole process is, in fact, we are feeding\--these formulas are
> very important to the survival and the growth of those babies at a
> much younger age and under clinical conditions where we would all
> agree that they are not healthy. Consequently, we have no data on
> these products in a place where they\'re also intended and as
> clinicians we desperately need them.
>
> So it\'s an interesting piece that I think has come out of this, and
> except that that\'s where the studies are being done and the inclusion
> and exclusion criteria that we use drive us to enroll those babies in
> these trials. But they\'re not the only intended use.
>
> DR. CLEMENS: You\'re right. Clearly, if you look at the data, very
> young preterm, if you will, the kids less than, say, 32 weeks, even
> much younger than that, 24 weeks, clearly, that\'s a separate set of
> population which may not be applicable, and I think Dr. Lien made that
> presentation yesterday. Clearly, if you look at the healthy term baby,
> it may well be applicable in some cases.
>
> DR. GARZA: Before we move to question two, I want to make sure that
> each of us understands that, in fact, questions regarding clarity so
> that, in fact, you better understand the recommendation or response,
> are fine. But going beyond that, I\'d ask each of you to limit
> whatever comments or answers you would like to provide to the
> questions to when your turn comes. Otherwise, it\'s going to be very
> difficult. It\'s not the time to try to change somebody\'s mind or
> change the nature of their response, but, in fact, to be informed by
> it and then you are certainly free to formulate your own response as
> the time comes.
>
> DR. TAYLOR: Taylor, FDA. Is it okay if I ask a question just for
> clarity?
>
> DR. GARZA: Just for clarity, yes.
>
> DR. TAYLOR: And it is just for clarity. As written, it\'s not clear to
> me how this would be used in a review setting. Should the agency be
> using only the most meaningful? Is the agencies supposed to use
> sometimes most meaningful and sometimes least meaningful? What if
> they\'re mixed? In other words, as a practical tool, I would ask for
> some clarification as to what this means for informing our review
> process and decision making.
>
> DR. CLEMENS: Let me respond to that. I would offer that after this
> meeting, we would do a follow-up and provide documentation to Dr.
> Garza to provide additional detail to this response.
>
> DR. GARZA: Okay. Dr. Dickinson?
>
> DR. DICKINSON: For clarification on the point of what the Infant
> Formula Act and the infant formula regulations cover, I did read the
> regulations before coming to this meeting, and I apologize for not
> being fully familiar with infant formula regulation, but I see that
> there is such a thing as an exempt formula and I\'m wondering whether
> some of the questions about the very sick infants and the very
> seriously premature infants, whether, in fact, they\'re not intended
> to be covered by these regulations and whether those are exempt
> conditions under which a special formula would be prescribed. It may
> be the same formula, but the formula would be selected and prescribed
> by the physician.
>
> DR. GARZA: Or modified at the hospital.
>
> DR. DICKINSON: Yes. In other words, does the regulation and the Act
> cover primarily products marketed for healthy infants?
>
> DR. TAYLOR: My understanding of the regulations is they cover those
> that are not exempt, and exempt formulas are listed. So to the extent
> that these would be formulas intended for non-exempt situations, the
> answer is it still applies, but there are exemptions for PKUs.
>
> DR. GARZA: Any other questions regarding the response to the first
> question?
>
> \[No response.\]
>
> DR. GARZA: Okay. Number two?
>
> DR. CLEMENS: Again in your handout that just went around the table, at
> the top of the handout it says, question two. The question is
> restated.
>
> In response to the question, yes, it is appropriate to use those data
> to support growth. If one is doing an appropriate power analysis for
> growth, the studies are not powered to detect relatively low
> differences in adverse events. However, this does not negate the power
> of the study with respect to supporting growth. If it differs between
> study groups and a number of adverse events is observed, whether or
> not the study has power to detect that rate, the clinical significance
> of the difference must be evaluated through good clinical practice.
>
> DR. GARZA: Any questions regarding this response?
>
> \[No response.\]
>
> DR. GARZA: Dr. Clemens, am I correct then in saying when it reads, if
> a difference between study groups, that you\'re not limiting that
> difference to one that is statistically significant, whether it\'s the
> power is there or not? If there is a difference, then one ought to
> look at it and determine its clinical significance?
>
> DR. CLEMENS: That\'s correct.
>
> DR. GARZA: Any questions, other questions?
>
> \[No response.\]
>
> DR. GARZA: Okay. Number three?
>
> DR. CLEMENS: Again in your handout, the top is indicated by question
> three. The question is stated. I have a rather simple response.
>
> Our typical clinical experience suggests that the normal attrition
> rate in a growth study approximates 25 percent. The assessment of
> physical growth is relatively insensitive to attrition rate. For
> example, study groups with ten versus 20 percent attrition rates do
> not have the potential to sufficiently bias the assessment of physical
> growth rates to change the outcome of the study. This is a matter of
> statistics, and if you\'d like, and perhaps in a subsequent
> documentation, we can go through the mathematics of what it takes to
> shift the apparent growth rate. The bottom line with this is that all
> data are relevant.
>
> DR. GARZA: Any questions? Dr. Heubi?
>
> DR. HEUBI: I guess I have to ask you this question, Roger. If, and
> since you\'re the industry liaison, if a study were powered based upon
> a 20 percent attrition rate, and because of your attrition rate you
> lost more than your 20 percent, what would be the stance of the
> sponsor in terms of would they abandon the study or would they recruit
> additional subjects or what exactly would happen in that context?
>
> DR. CLEMENS: Good point. Good question, Jim. Every manufacturer
> manages that differently and that situation is anticipated at the
> front end of the study, so it\'s not a reactionary approach. Many
> times, you can\'t recruit sufficient subjects or they drop out.
> Additional subjects may be recruited, or, in fact, it may be
> discontinued and then you account for the attrition rate.
>
> The panel on the statistician and the advisory group with which
> they\'re working, they may take either one of those approaches.
> Typically, they account for the attrition rate and they go with it. If
> more than that drops out, still, they look at statistical analysis. Is
> it appropriate? Typically, your dropout receives a normal
> distribution. Clearly, you\'re not going to skew the data because the
> typical dropouts are not at one end or the other end.
>
> So, again, if you look at the mean, the mean is not affected unless
> you skew it by dropping out of the top or dropping out of the bottom.
> So, again, all the data are relevant.
>
> DR. GARZA: Are there any other questions by other members of the
> group?
>
> Dr. Clemens, in reading the question, the question speaks to
> differences in rates between the two groups, not the overall attrition
> rate as the response seems to address. Can you clarify that for me?
>
> DR. CLEMENS: You might say that the ten and 20 percent might be
> perceived as differences in rates, and, in fact, if you look at the
> result of that, of the attrition rate, they do not impact on physical
> growth in this case.
>
> DR. GARZA: So the response is intended to deal both with equivalent
> attrition rates among both groups, where you may then encounter the
> power problem that Dr. Heubi alluded to, as well as to issues of
> randomization when, in fact, you have significantly different\--of the
> magnitude that was discussed yesterday\--between differences, or
> between groups in terms of attrition rates\--
>
> DR. CLEMENS: That\'s correct.
>
> DR. GARZA: \--where you have a four- or five-fold. Okay. Any other\--
>
> DR. DWYER: Maybe this is the wrong time, but couldn\'t that also be
> handled by just doing intent to treat analysis?
>
> DR. GARZA: Well, we went through that. As long as you could follow up
> the reasons why.
>
> DR. CLEMENS: Agreed.
>
> DR. GARZA: But the reason I asked is because, in fact, this doesn\'t
> speak to those issues, at least in my reading of the response, and I
> wanted to make sure that that was clear.
>
> Any other questions?
>
> \[No response.\]
>
> DR. GARZA: Thank you very much, Dr. Clemens.
>
> All right. Then we\'ll move on to Dr. Garlick.
>
> DR. GARLICK: I\'m also speaking for a small group of us who had been
> together yesterday and I think we were all in total agreement on these
> points.
>
> The first one was a general statement, which is that infant formulas
> seem to us to be a special class, more like a drug than a food.
> That\'s just a general statement.
>
> In terms of the individual questions, the answer to the first question
> is presumptively no. We felt that term studies must be done in term
> infants unless there\'s a very strong justification that this is not
> necessary. In these cases, the requirement to do studies in term
> infants could be appealed to the FDA, so we\'d recommend that the
> appeal be reviewed by a panel of experts.
>
> And secondly, ideally, studies that could potentially need to be done
> in both term and preterm infants could be reviewed by the FDA prior to
> initiating any studies, so at least the plan could be designed so that
> they wouldn\'t initially start off in preterms if, in fact, they were
> going to have to be done in terms anyway because that would just
> duplicate the effort.
>
> So that\'s our conclusion on the first point, if there\'s any
> questions.
>
> DR. GARZA: So to the first point, does that mean from one population
> to another or the response to the first question?
>
> DR. GARLICK: That was the response to the first question.
>
> DR. GARZA: Okay. Are there any questions regarding that response? Can
> you elaborate a bit on the rationale for the response, or would you
> prefer that somebody else do that?
>
> DR. GARLICK: The feeling was that term and preterm are metabolically
> different. They handle nutrients differently and, therefore, there was
> no reason\--there was no good reason not to do the studies in the
> group of infants for which the formula was designed.
>
> DR. GARZA: Any questions? Dr. Hotchkiss?
>
> DR. HOTCHKISS: Just a point of clarification. Who is the small group?
>
> DR. STALLINGS: It was our dinner group.
>
> \[Laughter.\]
>
> DR. GARZA: So it was an ad hoc group.
>
> DR. STALLINGS: It was an ad hoc, not bound by anything else other than
> the search for a dinner table.
>
> DR. DWYER: What was that liquid that was on the table?
>
> \[Laughter.\]
>
> DR. GARLICK: Only water.
>
> DR. STALLINGS: It wasn\'t infant formula, though we did use it as an
> opportunity to continue the discussion. So you\'ll probably hear
> modifications, but that was the report.
>
> DR. GARZA: All right. Response to question number two?
>
> DR. GARLICK: We were not able to answer this question definitively. We
> felt that there should be an independent board to monitor and assess
> adverse effects because, potentially, adverse effects do have the
> capacity to influence the outcome if those infant\--in terms of
> growth, because if those infants that were not growing were the ones
> that were showing the adverse effects, then they influence the
> statistics.
>
> We also felt that such guidelines for infant formula studies should be
> created for reference regarding sample size, handling of adverse
> events, et cetera. This is to enable reporting adverse events to be
> much more rigorous and, therefore, the data much more useful. At
> present\--well, if there are no regulations on the\--very strict
> regulations on this, it depends on the individual running the study as
> to just how adverse an adverse effect is and it needs to be more\--a
> more rigorous approach to that.
>
> Also, there needs to be a better established mechanism for reporting a
> post-marketing adverse event because that\'s the time when adverse
> events actually turn up, for the most part. They don\'t usually turn
> up in great numbers at an earlier stage.
>
> We\'re suggesting these measures to protect the industry, basically,
> from any subsequent claims that they might not be reporting adverse
> events appropriately. So that\'s the second question.
>
> DR. GARZA: Okay. Any questions of clarification? Dr. Clemens?
>
> DR. CLEMENS: Jim is smiling, so, yes, I\'ll respond. Rog Clemens. You
> should know that while it\'s not mandated on the AE reporting
> structure what the agency\--that each of the manufacturers in
> compliance with international standards and SOPs has a rigorous
> reporting structure to accommodate adverse events in any clinical
> trial which they conduct.
>
> Secondly, we may not have a post-marketing surveillance program in the
> United States, but we do have a mandated complaint program in the
> United States. It\'s the only one in the world in which customers or
> consumers as well as the medical community can contact the
> manufacturer directly and file either a physical complaint about the
> issue or may file a medical complaint about it, and those medical
> complaints are, in fact, mandated to be reported to the agency. So in
> that regard, there is a sense of post-marketing evaluation involving
> the formulas.
>
> DR. GARZA: So your question of clarification is?
>
> DR. CLEMENS: Dr. Garlick had indicated the required post-market
> evaluation and I wanted to reassure him that, in fact, there is a
> system in place at this point. He suggested that there should be an AE
> reporting system and I wanted to assure him that, in fact, there are
> guidelines set up by the industry that has an AE reporting system in
> place.
>
> DR. GARZA: So you want him to clarify the need for one given what
> you\'ve said?
>
> DR. CLEMENS: I think it\'s assumed\--maybe that\'s not the proper
> word, but that we, in fact, have something in place, even though it\'s
> not mandated by the FDA.
>
> DR. GARZA: Dr. Garlick, do you want to respond?
>
> DR. GARLICK: No.
>
> DR. STALLINGS: Roger\--
>
> DR. GARZA: Dr. Clemens has already spoken, so\--
>
> DR. STALLINGS: Well\--
>
> DR. GARZA: Again, I don\'t want to reopen the issues. That\'s why we
> went through a period saying, now, do you have any other questions or
> comments about these three, because we\'re going to start getting
> people\'s responses. Unless\--that\'s why I asked him specifically. I
> really would like to ask each of us to refrain from commenting\--
>
> DR. STALLINGS: Okay.
>
> DR. GARZA: \--trying to change people\'s minds. There was an
> opportunity to provide as much information given to us in the earlier
> part of the meeting so that, in fact, we can\--I think it would be
> totally appropriate to say, given the structure, why, in fact, have
> you recommended something to replace it? In this case, I might have
> expected Dr. Garlick might have said, well, it\'s not mandatory and we
> think that a mandatory is needed. That would be the difference.
>
> But try to focus on issues of clarification so that you can better
> understand the response, and the only reason for starting with
> non-voting members is that we feel they have a special expertise that,
> in fact, will inform each of us as we formulate our own responses.
>
> DR. GARLICK: As a matter of clarification on my own behalf, I didn\'t
> respond to that question because I thought that my committee, my
> co-members from last night would be in a better position to comment on
> that when they made their own statements.
>
> DR. GARZA: In terms of that, it\'s my understanding that whatever
> happened last night has no bearing in terms of this committee\'s
> decision. You can certainly use it to get new information, to inform
> yourselves, but, in fact, obviously it wasn\'t an ad hoc group getting
> together under the auspices of anything other than having a dinner
> discussion and using that as an opportunity to get better informed.
>
> DR. STALLINGS: Which is all that it was.
>
> DR. GARZA: Thank you.
>
> DR. HEUBI: That\'s absolutely correct. To speak for Peter, because he
> was going to defer to us, I think really what we thought was that it
> would be appropriate to have some mandatory reporting program for
> infant formula like MedWatch that was publicly accessible so that
> under the sunshine laws or whatever they call those things, because
> I\'m not a bureaucrat, that information is available to the public.
>
> DR. GARZA: What I\'m trying to clarify is that what we heard was
> Peter\'s response. This group will expect responses from each of you
> as individuals.
>
> Any other points of clarification for question number two?
>
> DR. STALLINGS: Maybe I can direct this to the FDA, but my question is
> do you see the adverse event reporting in a direct way when you do
> your 90-day review of a study that\'s already been conducted and
> closed?
>
> DR. GARLICK: I\'m sorry, could you clarify that?
>
> DR. STALLINGS: Because I think part of the confusion on my part is
> whether you have access to all of that information to make your own
> decisions as part of your 90-day review or if the decisions are made
> prior to that and it\'s not brought to you in full disclosure.
>
> DR. TAYLOR: Just to clarify, you mean as part of the 90-day package,
> are the adverse event reports made available to the agency?
>
> DR. STALLINGS: I think, if I understand it correctly, all that the FDA
> gets is the information provided by industry for your review as a
> pre-marketing review. I didn\'t know if you\--because I know they\'re
> collected\--
>
> DR. GARZA: It\'s my understanding that, in fact, at least as I heard
> an answer to a previous question, that information is part of the
> packet, but it is there at the discretion of the individual that\'s
> putting the packet together.
>
> DR. STALLINGS: Which would be\--
>
> DR. GARZA: There\'s no check box that says, all adverse events, how
> are they done. There are common practices, good clinical practices
> that govern that, but it is not a mandated statutory, regulatory
> requirement that meets a priori guidelines.
>
> DR. TAYLOR: And after checking with our brain trust to be sure we were
> right, it varies. Some manufacturers provide it. Others do not.
>
> DR. GARZA: The response to question number three?
>
> DR. GARLICK: The presumptive answer is no. As was discussed yesterday,
> high attrition rates maybe should be regarded as an outcome. It\'s
> perfectly possible that a higher attrition rate could result from some
> reaction to an adverse\--a minor adverse reaction to the formula
> itself or some rejection by the infant of the formula. Therefore,
> taking them out of the total group will affect the outcome and the
> remaining infants may well be the same, whereas if they take as a
> total group, it could be possible they could have been different. So I
> think it\'s important that the answer is no.
>
> In addition to this, when possible, the reasons for the dropout should
> be ascertained, because obviously the previous conclusion, which was
> that it could affect the result, is entirely dependent on the reasons
> for dropout. If it\'s to do with acceptability, then, yes, it might
> affect the outcome. But if it\'s because, by sheer chance, parents are
> moving out of the area in different numbers for the different groups,
> then obviously it won\'t. So reasons are an important issue if it\'s
> possible to get them.
>
> It\'s also, of course, presumed that all studies will be powered to
> indicate a typical attrition rate so you know it\'s becoming much
> higher than you expected.
>
> These recommendations are specifically referring to studies with large
> differences in attrition rates, so that it should be possible to
> detect those, to show that those are different.
>
> DR. GARZA: Okay. Any questions?
>
> \[No response.\]
>
> DR. GARZA: Okay. Thank you very much.
>
> We went out of order. I should have asked Dr. Dickinson, perhaps, to
> speak before Dr. Garlick, but I didn\'t have my notes with me. Someone
> whispered Garlick in my ear and I didn\'t look at them.
>
> DR. DICKINSON: If someone had whispered Echinacea, what would you have
> done?
>
> \[Laughter.\]
>
> DR. GARZA: Probably run for the closest herbal food store or
> something, I guess.
>
> DR. DICKINSON: I\'m responding as an industry representative. I have
> 30 years of experience in food and drug regulation issues, but not in
> infant formula in particular, so forgive me if I\'m not up to speed
> entirely on infant formula issues, but I have made an effort.
>
> I\'d like to distinguish on the first question between relevance and
> generalization because I found it troubling some of the discussion
> yesterday seemed to imply that a study done on one population group
> might under some circumstances just be transferred wholesale to a
> different population group. I\'d like to refocus my answer, at least,
> in terms of relevance.
>
> I would say that in response to the first question, study on any
> infant population has very likely relevance to findings that might be
> found in a different population and the degree to which it is relevant
> will depend on some of the things that were outlined in Dr. Clemens\'
> response and also that we heard from several of the spokespeople who
> presented to us yesterday.
>
> It seemed to me in listening to that discussion that there is, at
> least in the case of many nutrients, a good understanding about
> whether there are differences both in requirements and in utilization
> in preterms versus terms or in healthy infants versus non-healthy
> infants and that whole body of evidence will, of course, need to
> inform the decision about whether a study is relevant to the other
> population.
>
> I guess my inclination would be not to focus on the term
> \"generalizing\" but to focus on the relevance of the study, and I
> think that in each of these cases, the responsibility to make the
> argument that it is relevant rests with the manufacturer making the
> submission and that while we\--while you, at least, may wish to give
> the FDA some guidance in terms of what things they would look at in
> making that determination and in agreeing or not agreeing with the
> manufacturer, I would think that in the end, it comes down to a
> requirement that the manufacturer has to make the case in submitting
> this evidence as to whether it does or doesn\'t apply to a different
> population and if it does, why it does.
>
> I would think that between the experts available to the industry and
> the experts available to FDA, that they\'re just going to have to work
> that out. I do not believe there\'s a simple yes or no response to
> this.
>
> DR. GARZA: Any questions?
>
> \[No response.\]
>
> DR. GARZA: If not, let\'s move on to question two.
>
> DR. DICKINSON: I would take question two and question three together,
> and my response to them is similar. I think that, depending on the
> circumstances, there may be conditions under which
> changes\--differences in adverse event rates in the two groups may be
> highly significant, depending on how serious the events are and how
> big the differences are.
>
> And again, my basic take on this as a regulatory issue is that this is
> a matter where the industry will bear the responsibility for making
> the argument to the agency about whether the adverse events are or are
> not relevant in determining whether the findings are meaningful, and
> likewise, whether the attrition rates, if there are differences in
> attrition rates, whether those are relevant or whether they cripple
> the study or do not cripple the study in terms of its relevance for
> the purpose for which it was done.
>
> DR. GARZA: I\'m sorry, I was speaking with Linda and I lost track.
> Were you doing question three or two?
>
> DR. DICKINSON: I was doing two and three together.
>
> DR. GARZA: Two and three together, okay. I understand the response,
> then. That\'s the part I missed.
>
> Are there any questions?
>
> \[No response.\]
>
> DR. GARZA: Okay. Then we\'ll move to Dr. Giacoia.
>
> DR. GIACOIA: I\'m going to be succinct. First of all, it\'s
> usually\--say that the children are not miniature adults. I will add
> that very low birthweight babies are not miniature full term babies.
> In general, I think that clinical trials have to be based on the
> population that it\'s intended to and also that the sample from that
> population must be representative\--it be a representative sample of
> the population.
>
> So if the answer is extrapolated from preemies to full terms, my sense
> is that should not be unless there are very specific circumstances,
> and it would have to be very stiff guidelines, the degree of
> prematurity that will be allowed to represent term babies.
>
> On the issue\--and the same line here, I was somewhat bothered by the
> stratification of low birthweight babies based solely on birthweights
> rather than gestational age. I think here one introduces biases that
> is not done in other studies in this population.
>
> Also, into defining population, if you only define by pure birthweight
> and not other factors, such as socioeconomic factors, that can
> influence outcome, and I think I\'m bothered particularly with the
> idea of study populations which are not representative from the
> population it is intended to. So to just select a group of preemies
> which are very healthy, it would not serve a good purpose.
>
> On the question of the products, I think that I\'m bothered to try to
> think into the future whether changes in formulations will, as science
> advances, will be at this time unpredictable and, therefore, I\'m
> bothered to try to do this type of thing unless we simulate those
> drugs when we have some of the so-called \"me too\" drugs, which are
> not really very much difference between them, in which case an
> exception can be made.
>
> The other issue that bothers me is definitions of healthy and
> diseased, things that are very difficult in the sense that, number
> one, it needs to be recognized where the patient got over the disease
> at the time of the study versus those which continue to be having
> difficulties, such as it be the children that will have significant
> problems. So you take a group of the very\--
>
> DR. GARZA: You mean bronchopulmonary dysplasia?
>
> DR. GIACOIA: Yes, right. So\--
>
> DR. GARZA: I\'ll ask everybody to try not to use acronyms because
> other non-experts may not be\--
>
> DR. GIACOIA: Yes. By the same token, there is a subset of term babies
> who are sick and they\'re not with a metabolic disorder, but they have
> a number of other conditions that might be present.
>
> Now, as far as the question on adverse events, I think the issue here
> is, first of all, the\--
>
> DR. GARZA: Before we move on to question two\--
>
> DR. GIACOIA: Oh, I\'m sorry.
>
> DR. GARZA: \--let\'s see if there\'s any points of clarification that
> people would like to raise to your response to question one.
>
> \[No response.\]
>
> DR. GARZA: Okay.
>
> DR. GIACOIA: As far as adverse events, first of all, we all recognize
> that many of these events are totally unrelated to either a drug or a
> formula and, therefore, it will be important to understand the nature
> of those events. I think that it is important to characterize the most
> degree of severity and I\'d like to see whether the FDA will have some
> criteria that will apply to this particular situation.
>
> I totally disagree with the idea that this is, quote, \"a system is in
> place.\" This has proven to be a disaster as far as drugs are
> concerned, and there, we have high mortality related to that
> particular issue. Voluntary systems have been a dismal failure. Some
> individuals\--for example, in the case of drugs, it has been estimated
> that one physician every 600 years reports an adverse drug event. That
> means that the whole thing is not present.
>
> So the other thing, there\'s a lot of issues related to post-marketing
> unless it\'s starting out and it\'s really looking into detail,
> because I think that, as I said, I doubt very much the situation in
> nutritionals is any better than the situation in drugs. I do support
> the idea of having a DSMB for measure life threatening situations, or
> serious events. I don\'t think they should be across the board for
> anything. That\'s question two.
>
> DR. GARZA: And for clarity, you meant that they were physicians
> reporting, physician years, not individual physicians do this every
> 600 years?
>
> DR. GIACOIA: Yes. I don\'t think they are\--
>
> DR. GARZA: But in terms of a physical definition of physician years,
> yes. All right. Any other points, questions of clarification?
>
> \[No response.\]
>
> DR. GARZA: Okay. We\'ll go to number three. Thank you.
>
> DR. GIACOIA: Number three, again, I agree it\'s a statistical
> situation and I think the rules of the game cannot be changed and
> review statistically and calculate what the attrition rate should be,
> you really do justify why this is beyond that particular rate. And
> also, I\'m very bothered to the idea to have a systematic bias in
> which a bioequivalence that is not present may be demonstrated by the
> difference in attrition rates or whatever situation. So, therefore,
> the composition of those individuals are excluded must be known, and I
> think that will be a situation DSMB would be present to pass judgment
> as to whether it\'s adequate to accept the study.
>
> DR. GARZA: Any questions?
>
> \[No response.\]
>
> DR. GARZA: All right. Then I\'d like to get sort of an informal poll
> from the committee. It\'s ten o\'clock. We can either take a very
> short ten-minute break, because I don\'t want to interrupt the voting
> session. We\'ve heard from FDA, from the non-voting members of the
> committee, and so the information session to guide each of you in your
> responses is now over and so it\'s a nice break point. We can either
> do it now or\--go now? I don\'t see an overwhelming. Do you want to
> break? All right. We will be back at 10:05.
>
> \[Recess.\]
>
> DR. GARZA: It\'s 10:05. If I could ask the committee members to take
> their seats, we will start. I will begin\--
>
> \[Pause.\]
>
> DR. GARZA: We will start with Dr. Anderson, and again, I would ask
> that he take them in order and we\'ll allow some time for
> clarification after each question. Dr. Anderson?
>
> DR. ANDERSON: Generalizations of results from clinical trials of one
> infant formula in a specific population to the same or different
> formula in another population will have to be judged on a case-by-case
> basis. In most cases, results obtained from studies performed in
> healthy term infants will not be adequate to inform what would be
> expected to be observed in preterm infants. Likewise, studies
> performed exclusively in healthy infants or exclusively in those with
> metabolic or disease conditions are unlikely to provide adequate
> information regarding the formula\'s use in another population.
>
> Nevertheless, there are likely to be circumstances where the state of
> knowledge is such that the findings of a study in one group of infants
> would generally be agreed to be directly applicable in another
> setting, although I don\'t feel competent to judge when such
> circumstances may exist.
>
> The FDA may wish to consider the establishment of an advisory panel of
> experts which could advise the FDA during or perhaps before the 90-day
> pre-market notification process period. The panel could be expected to
> assist the FDA to determine in cases where an infant formula
> submission depends in large part on the generalization of data from
> clinical studies in other populations and/or with other formulas
> whether the state of knowledge is such that the formula submission
> should be considered adequate or whether additional information is
> thought to be required.
>
> DR. GARZA: Any questions?
>
> \[No response.\]
>
> DR. ANDERSON: The agency understands the response?
>
> \[No response.\]
>
> DR. ANDERSON: Okay. Comprehensive reports of clinical trial adverse
> events should be part of every 90-day pre-market pre-notification
> packet. There may be cases when clinical studies demonstrate that a
> new infant formula supports normal physical growth under its intended
> conditions of use, but the available data raise clinical concerns
> about the rate of adverse events in those receiving the new formula.
>
> The FDA may again wish to consider the use of an advisory panel of
> experts to make recommendations regarding the clinical significance of
> the observed rates of adverse events. After this review, the FDA may
> choose to consider the formula submission adequate or may request that
> additional information regarding the rate of adverse events associated
> with the new formula be provided.
>
> DR. GARZA: Okay. Any questions?
>
> \[No response.\]
>
> DR. GARZA: All right. Number three?
>
> DR. ANDERSON: When large differences in attrition rates between study
> groups are observed in a clinical trial, one of two situations exists:
> The difference observed is due by chance alone, or the differential
> attrition rates are a direct effect of the interventions. Because
> complete data from those who fail to complete the study are often
> lacking, the benefits derived from randomization and blinding in the
> unbiased assessment of treatment effects will likely be lost in the
> setting of large differences in attrition rates.
>
> Therefore, unless there is compelling evidence that the differential
> attrition can be attributed to factors independent of treatment, such
> studies should not be considered adequate to conclude that a new
> formula supports normal physical growth under its intended conditions
> of use. An advisory panel of experts may be of assistance to FDA in
> its assessment of when differences in attrition rates are, quote,
> \"large,\" and whether the differences can be reasonably be considered
> to be independent of treatment.
>
> DR. GARZA: Okay. Any questions?
>
> \[No response.\]
>
> DR. ANDERSON: Dr. Garza, I have one more thing I\'d like to say, if I
> may.
>
> DR. GARZA: Surely.
>
> DR. ANDERSON: Experience with the use of a panel of experts in the
> review of new infant formula submissions would be expected to develop
> a body of case reviews which should clarify the appropriate
> circumstances where generalization of study results is appropriate,
> clinical concerns regarding adverse events are unfounded, and when
> large differences in attrition rates can be ignored.
>
> In addition, if a panel of experts is to be considered, the 90-day
> pre-market notification process period may be too short to provide
> adequate input from and advice to the FDA. The FDA may wish to
> consider the establishment of a, quote, \"intent to market\" process
> that begins prior to the 90-day pre-market notification process period
> which informs the FDA of the types of data which will be used to
> provide assurances, including whether generalizations of results from
> clinical trials could be a major component of the submission and
> whether any clinical concerns regarding adverse events or major
> differences in attrition rates exist in the clinical trials to be
> submitted in support of the assurance.
>
> DR. GARZA: Any points of clarification regarding that last statement?
>
> \[No response.\]
>
> DR. GARZA: All right. If not, we\'ll go on to Dr. Baker.
>
> DR. BAKER: On the first question, I believe that the answer to the
> first question is that it depends, but I would like to qualify this by
> saying that the modus operandi should be that generalization is not
> allowed and the exception should be that it is allowed. I base this on
> the fact that it\'s wrong not to do a study that\'s indicated, but
> it\'s also wrong to do a study that\'s not indicated. I think that the
> onus on proving the studies are not indicated should fall on the
> industry and that they should provide evidence for that.
>
> In support of not doing a study, I think that all relevant data should
> be submitted and brought into play, and I\'d like to emphasize all and
> relevant, \"all\" meaning data that even though it\'s not generated in
> the general way, in the usual way, it should be admissible, and
> \"relevant,\" there should be some ascertainment of whether a study or
> data is really relevant or not before it\'s taken into consideration.
>
> I\'d also like to emphasize the word \"data\" in that I would say that
> it\'s not necessarily\--this information does not necessarily have to
> be a study but could be experience, for instance. That\'s question
> one.
>
> DR. GARZA: Any points of clarification?
>
> \[No response.\]
>
> DR. GARZA: Dr. Baker\--I\'m sorry, go ahead.
>
> DR. STALLINGS: Dr. Baker, tell me more about the use of the
> experience. How might you envision that, rather than data collected in
> a protocol setting?
>
> DR. BAKER: Just as an example, for instance, the DHA and AA question,
> there is a large body of experience that\'s already available in the
> world that\'s out there. That should be\--
>
> DR. STALLINGS: Not in literature.
>
> DR. BAKER: Yes. The experience in Europe, for instance, it\'s not in
> the literature but it\'s long and fairly extensive.
>
> DR. GARZA: Can you elaborate a bit, Dr. Baker, on the rationale for
> the default being no?
>
> DR. BAKER: The reason for the default being no is that I think, as
> other people have stated, that populations are really not the same,
> that a 24-week gestation preterm is not the same as a 32-week
> gestation preterm and that preterm is not the same as term, and even
> that term is not the same as at six months. So definition of
> population is difficult and needs to be looked at, but certainly
> generalization\--these are different populations and generalization
> should not be assumed.
>
> DR. GARZA: And the difference, I\'m assuming, physiologically or
> metabolically?
>
> DR. BAKER: Right.
>
> DR. GARZA: Are there any other questions?
>
> \[No response.\]
>
> DR. GARZA: If not, let\'s go to number two.
>
> DR. BAKER: Number two, it\'s my opinion that adverse events should be
> taken into account when judging an infant formula. I believe that my
> answer is a part of the clinical study process. If you\'re not going
> to take adverse events into account, why are you tracking them? So I
> think that they definitely need to be taken into account, and as a
> part of this, I think that what other people have suggested, an
> advisory board may be useful to decide whether an adverse event is
> happenstance versus a real event.
>
> DR. GARZA: Any questions?
>
> \[No response.\]
>
> DR. GARZA: Number three?
>
> DR. BAKER: Number three, attrition rates. I view this as largely a
> statistical problem. I believe that attrition rates are important,
> that they are an outcome measure of the study and, therefore, ought to
> be taken into account in assessing the validity of the study. I also
> believe that most of these problems with attrition rates could be
> dealt with a priori via your statistical support.
>
> DR. GARZA: Any questions?
>
> \[No response.\]
>
> DR. GARZA: Thank you very much.
>
> Dr. Denne?
>
> DR. DENNE: In answer to the first question, sort of a strong
> presumptively no. Again, the general principle is that studies ought
> to be done in the population for which the product is designed. There
> are major differences in physiology, metabolism, nutritional
> requirements, and growth, including body composition, between preterm
> and terms, and so they really are not interchangeable and, therefore,
> preterm infants cannot be used, or data in preterm infants cannot be
> used to actually model term infants without some term data.
>
> In addition, this is really not a healthy population. We have talked a
> lot about healthy preterms, which is, frankly, kind of an oxymoron.
> They\'re healthy relative to the ventilated very immature individuals,
> but they\'re certainly not healthy relative to normal term infants.
>
> In addition, nutritional studies in preterm infants really differ in
> design. In particular, there are at least some time periods of
> controlled nutritional intake in preterm studies which really doesn\'t
> mirror the term population.
>
> So under almost all circumstances, I would answer that question as no.
> In the event that preterm data, the industry wanted to substitute
> preterm data for term data, I believe a strong scientific
> justification would need to be made prior to beginning a study in
> preterm infants.
>
> DR. GARZA: Any questions?
>
> DR. BAKER: I have one question. You said that the study, if you wanted
> to generalize to term infants, you needed to say you were going to do
> that at the time you were studying your preterms?
>
> DR. DENNE: Right. I mean that if there was a justification to
> substitute preterm for term, then that ought to be scientifically
> justified before beginning your study in preterm. In other words, just
> having data on preterms isn\'t justification enough. It should be done
> prior to initiating a study.
>
> DR. GARZA: All right. Number two?
>
> DR. DENNE: In response to this question, I\'ll echo most of the
> previous comments, and that is that I think that, in general, this
> needs to be assessed by an independent board and assessed in
> relationship to the severity and frequency of adverse events. The
> board should advise the agency about whether there is concern enough
> to continue or provide additional study or whether some of these
> adverse events could be explained and the product approved. But again,
> I think an independent board, advisory board, may be the mechanism by
> which this could be handled.
>
> DR. GARZA: Any questions?
>
> \[No response.\]
>
> DR. GARZA: Number three?
>
> DR. DENNE: For number three, I think I would like to sign on to Dr.
> Anderson\'s comments. I don\'t think I could say it any more
> succinctly or clearly than he did. The differences in attrition rates
> between groups should be considered as outcomes. They need to be
> evaluated by an outside independent board, and again, presumptively,
> if there are major differences, that should be viewed as an inadequate
> study.
>
> DR. GARZA: Questions?
>
> \[No response.\]
>
> DR. GARZA: Okay. Dr. Heubi?
>
> DR. HEUBI: You don\'t get to go first?
>
> DR. GARZA: I don\'t get to go at all.
>
> DR. HEUBI: The answer to question number one, the answer basically
> categorically from my perspective is no. Under selected circumstances,
> the FDA can convene an expert panel to review requests for formal
> changes based upon studies in one group of infants for comparison to
> another, that is, for preterm to term.
>
> The question of waiving a requirement for study in target populations
> must be based upon strong scientific grounds. This is not different
> from what\'s been said before.
>
> DR. GARZA: Any points of clarification?
>
> \[No response.\]
>
> DR. GARZA: Hearing none, let\'s go on to number two.
>
> DR. HEUBI: Number two, formula studies should not be powered to detect
> differences in adverse event profiles. To ensure adequate protection
> of subjects in trials, independent DSMBs, Data Safety Monitoring
> Boards, should be empaneled to review all adverse events with focus on
> frequent and serious unanticipated events. Post-market surveillance
> should be enhanced to ensure safety, since only with wider use of
> formula after marketing can significant adverse events be identified.
>
> DR. GARZA: Okay. Any questions?
>
> \[No response.\]
>
> DR. GARZA: All right. Third?
>
> DR. HEUBI: Large differences in attrition between study and control
> groups may suggest problems with the study formula and, therefore,
> should be carefully investigated. Studies should be powered for an
> anticipated dropout rate. If rates of attrition in the study group
> exceed anticipated losses for which sample size capture were made, the
> results from the study should be considered suspect.
>
> DR. GARZA: Any questions? Dr. Clemens?
>
> DR. CLEMENS: Rog Clemens. Jim, what would you consider strong
> scientific evidence?
>
> DR. HEUBI: I think strong scientific\--you\'re referring to the
> first\--
>
> DR. CLEMENS: Yes, I am, point one.
>
> DR. HEUBI: I think it would be situations in which there clearly is
> evidence that, as in the case of preterm and term infants, that the
> physiology is virtually identical and that there wouldn\'t be any
> differences in how a preterm versus a term infant would handle a
> modification in the formula.
>
> DR. GARZA: Other questions?
>
> \[No response.\]
>
> DR. GARZA: Okay. Dr. Moyer-Mileur?
>
> DR. MOYER-MILEUR: Okay. In response to question number one, I concur
> that infant formulas are a special class and should be treated more
> like a drug than a food.
>
> In terms of being able to generalize from one population to another,
> the answer is no. Preterm infants or unhealthy infants are a different
> population than a healthy population of term or older infants.
>
> The ability to generalize from one product to another, the answer
> again is no. These products are very different in terms of composition
> and have nutrients that are conditionally essential for specific
> populations and I think we need to keep that in mind, that you cannot
> feed one type of product and look at one nutrient and then apply it to
> a different population. So no to whether or not you can combine this,
> as well.
>
> Again, I believe that, overall, the ability to generalize between
> populations would be an exception and not the rule and that any
> request to do such a thing would require individual review by an
> expert panel from the FDA.
>
> DR. GARZA: Any clarifications as to rationale or content of the\--
>
> \[No response.\]
>
> DR. BAKER: I have just one clarification.
>
> DR. GARZA: Sure.
>
> DR. BAKER: You answered the first question that\--your answer was no,
> and then you said there may be some exceptions, is that right?
>
> DR. MOYER-MILEUR: There is the possibility for an exception, but I
> don\'t think it should be presumed. I think it needs to be\--
>
> DR. BAKER: And the process would be through applying to the FDA?
>
> DR. MOYER-MILEUR: Yes.
>
> DR. GARZA: Number two?
>
> DR. MOYER-MILEUR: Again, there really is no clear answer to this
> question other than to suggest that an independent board be appointed
> to review serious adverse events for their severity and their
> frequency. I think that it is of concern that there\'s variability in
> how the reporting is currently done and that needs to be addressed,
> and that the post-marketing events also are at the discretion of the
> industry to report them to the FDA. So I think that it would be
> helpful if we could set up some guidelines for that. That would
> provide more information.
>
> DR. GARZA: So the safety monitoring board that you are suggesting
> would be appointed before the study got underway or on a post-ad hoc
> basis as required?
>
> DR. MOYER-MILEUR: That you would need one while the study was being
> performed and then also for post-marketing once the product was
> available.
>
> DR. GARZA: Okay. Any questions?
>
> \[No response.\]
>
> DR. GARZA: All right. Number three?
>
> DR. MOYER-MILEUR: And the answer to number three would be, no, that
> attrition rates are part of your statistical analysis, and I
> appreciate the large attrition that does occur with infant studies.
> Wherein a term baby study may find 25 percent attrition, I can
> guarantee you in a preterm study it may be as high as 50 percent and
> those things are taken into account. But if there are differences
> between your treatment groups, that is something that should be looked
> at and divulged.
>
> DR. GARZA: Can you amplify, how would you suggest that this be looked
> at? What do you mean by divulged?
>
> DR. MOYER-MILEUR: That in your study design, you allow for a certain
> percentage of attrition, but in your two treatment arms, if there are
> differences in that rate of attrition, then there needs to be some
> accountability for those differences.
>
> DR. GARZA: Any questions, additional questions?
>
> \[No response.\]
>
> DR. GARZA: We\'ll move to Dr. Stallings.
>
> DR. STALLINGS: Thank you. I think it\'s useful to say, I think out of
> the process, we realize that we\'re all really here to build a better
> formula for the infants and that we\'re operating, in a sense, in an
> environment about 20 years of almost amazing safety, so that the fact
> that the agency brought together both industry and the academics,
> these are the three groups that I think have been working well
> together before.
>
> But I do believe it\'s time for the whole process to change and I
> think that\'s the undercurrent that we\'re dealing with here, so
> really in answer to number one, first recognize what Dr. Dickinson was
> presenting and I think the concept of relevance is probably a better
> word for us to work from than generalizability because that calls the
> science, I think more clearly.
>
> I think that there should be a pre-review process rather than a
> post-review process so that there\'s actually healthy and productive
> interaction between the FDA and industry as they propose studies. I
> believe this would be helpful because industry doesn\'t want to go
> work on something for a number of years and then come and find out
> that they missed one piece that now we believe is there.
>
> So I think we really are looking at an opportunity to completely
> revamp the system so that things would come in for the pre-review,
> there would be a level of understanding of the design and the intent,
> and I think if there were disagreements about, if you will, the
> relevance and the purpose of the study, that the FDA would have the
> opportunity to have an expert panel to work with them in sort of that
> conflict resolution. Obviously, the regulatory agency in the end has
> the right under advisement to make those decisions.
>
> I think this would get us out of a lot of the current concerns, where
> I think the lack of clarity, not intent, but lack of clarity. I
> realize it would take a whole new way of looking at this, but I think
> doing it prospectively rather than in a 90-day window, in fact, after
> all the work has been done, the babies and families have been engaged
> and the money and time spent, would be productive for us all.
>
> So I reduce that really in answer to question one that we would
> quickly get out of this and, as Dr. Anderson said, we would also
> quickly develop a body of case studies that really would inform the
> agency so you wouldn\'t have to keep going back to your committee and
> inform industry about what the current process is and how well it\'s
> working and you would be able to identify the areas of uncertainty
> much more quickly and work on those.
>
> So I believe that there would be a standing review panel so that this
> could be done quickly, because as you all know, it\'s hard to get us
> all in the room at the same time, so that the agency would be able to
> call on people quickly so not to delay the review of proposals and
> science and development.
>
> DR. GARZA: So if you amplify a little bit, because in your preamble
> you said that we had an outstanding safety record. Why, then, the
> added review, the adage of if it isn\'t broken, why fix it?
>
> DR. STALLINGS: Well, I think that\--
>
> DR. GARZA: I didn\'t understand the preamble and then the
> recommendation.
>
> DR. STALLINGS: The answer? That\'s a good question. I think actually
> doing research, and I agree with many of the people who have already
> spoken, I think infant formulas are much more like drugs than they are
> like food and I think we all need to recognize that, so that what this
> is, is putting the whole system in a setting where, in fact, we are
> talking about clinical trials and we\'re managing it with that kind of
> appreciation of safety and design.
>
> I also believe that I\'m recognizing the level of frustration from an
> industry side of not having clarity of what\'s going on. So I think
> it\'s an opportunity to put that on the table, which will add to
> efficiency and getting safe products to the market, which is what the
> agency wants and what industry wants.
>
> So I don\'t think, fortunately, in fact, Dr. Garza, that we\'re here
> today because something awful has happened, which is to all of our
> credits. The last time something awful happened was \'79, \'80,
> something like that, and it really did serve as a wake-up call. But I
> think before something awful happens or just because we\'re doing the
> right thing, it\'s a chance to look at the system in a new way.
>
> DR. GARZA: All right. Any other questions, points of clarification?
>
> \[No response.\]
>
> DR. GARZA: If not, let\'s go to number two.
>
> DR. STALLINGS: Number two is the adverse event question and it goes
> from some of what I just said. I believe that we need to look at this
> very carefully and I would agree that these now are clinical trials,
> and in modern era work that there needs to be an independent review of
> adverse events.
>
> I think there\'s an interesting twist to it, though, because in most
> pharmaceutical settings, we spend most of our time looking at serious
> adverse events, which are things that usually cause death or
> hospitalization or prolonged hospitalization, when, in fact, I think
> many of the adverse events we\'re looking at in an infant formula
> setting may be things historically classified as just regular old
> adverse events, because they\'re GI, they\'re intolerances, they may
> be psycho-social.
>
> So I think there will be a challenge to come up with a new way of
> looking at this and I don\'t have specific recommendations to offer,
> but I think the independent board would meet to be empaneled as a
> study is going on. The serious adverse events, I think would be the
> kinds of things they always are, which would mean you would stop the
> study until you were certain that your study wasn\'t contributing. The
> non-serious events, I think we have to think more about, because I
> think that\'s, in fact, the data that we would want to have.
>
> I also agree that the post-marketing is really there for the
> convenience of the customer and I don\'t see that as a part of the
> safety monitoring plan as it\'s currently conceived, and the data on
> how good doctors are at reporting adverse events speaks for itself. So
> if we want to deal with that, I think we have to be thoughtful about
> how to do it.
>
> My biggest concern is to pick up big things during the course of the
> study and be able to use the GI intolerance kind of data that would
> not rise to a serious level in an effective way.
>
> And I think post-marketing surveillance is a minor part of\--it\'s
> there, but I think we shouldn\'t rely upon it to give us much
> information. The 800 numbers are generally useful for the anxious
> parent and for the companies to get a little feedback on how things
> are going.
>
> DR. GARZA: All right. Any questions?
>
> \[No response.\]
>
> DR. GARZA: I saw several people use the term independent board. Can
> you amplify what independence would mean?
>
> DR. STALLINGS: In this setting, it would be people who had the
> scientific background both in what we\'re talking about, pediatrics
> and particularly in neonatology, in statistics, but not involved in
> the study. So they wouldn\'t have been involved in designing that
> particular study and if it\'s an academic, their home institution
> would not be involved in conducting the study. So that if 20 sites
> were needed to do the trial, the board would need to come from places
> that was not doing the trial.
>
> So, again, there is some art in getting good people to sit on the
> panel. I don\'t think it\'s as much of a challenge in this field
> because we have lots of places where we can do good clinical research
> and lots of places without standing neonatologists. But that\'s what I
> would mean by an independent board.
>
> Now, the agency could decide that the board would have a
> representative, if they thought, from industry, but the model is that
> as the investigator or the sponsor, we would not be at the table when
> safety discussions and infant data were reviewed.
>
> DR. GARZA: So you are suggesting a safety monitoring board for all
> studies, so there would be one group that would be monitoring all
> clinical studies that would be evaluating formulas, or would these be
> independent monitoring boards that would be located within each
> locality?
>
> DR. STALLINGS: I\'m not sure. I would propose that we could set up a
> monitoring board that would serve\--because there are not that many
> studies going on at once and the expertise that you could create might
> be better served by one board that sits. I think then the issues of
> having independence or appropriate disclosure would be very important.
> But you would gain a lot of expertise by there being a sitting board
> and you would get some uniformity of response to industry and to the
> agency, rather than one board sees this as an event worthy of a lot of
> attention and the other board would not.
>
> That\'s not really been done before, but I think in the current
> clinical research environment and with many of us wanting our studies
> to be independently monitored to be sure that everything\'s going
> well, that might be an interesting innovation.
>
> DR. GARZA: Would any of you that have spoken before want to amend your
> recommendation, because I don\'t think I\'ve asked and several of you
> have used the term \"independent.\"
>
> DR. HEUBI: I certainly do, and I would recommend that if we as a group
> believe that an independent board would be appropriate, that it be a
> board that will oversee all sites, that it not be located at
> individual sites, because that\'s one of the issues that we deal with
> on IRBs now because we\'re only seeing part of the elephant, if you
> will. So you want to see data from all the sites to be able to make a
> decision that is thoughtful in terms of determining whether there are
> trends or problems that exist in any clinical trial, whether it be
> formula, drugs, or whatever.
>
> And in addition, I would say that I would exclude members from
> industry and that it would be appointed independent of industry, and
> the reason I say that is for their benefit that it be done that way.
> That way, no one would ever dispute that there was a conflict of
> interest in terms of the review of these kinds of studies.
>
> DR. GARZA: Would anybody else want to amend or ask questions of
> clarification? Mr. Dwyer?
>
> DR. DWYER: I just had a clarification. What is the current process in
> terms of, say, the studies that have been done in the last five years,
> the major studies done by the formula industry? Do they have such
> boards? Are they in place? I don\'t know.
>
> DR. GARZA: I understand from what we\'ve heard that there are some who
> do. Dr. Carlson, for example, indicated that she had. Others have not.
> It\'s been pretty much on an ad hoc basis. If that\'s how\--
>
> DR. DWYER: What about the ones that are multi-site, multi-site ones?
>
> DR. GARZA: That holds for multi-site.
>
> DR. STALLINGS: And most of this work, by its nature, is done at many
> sites, and often just a few subjects at each site because of the
> nature of finding the participants.
>
> DR. GARZA: Do you want to speak to this directly?
>
> DR. CLEMENS: Relative to that point and when following the 1996
> guidelines, which are currently not part of the FDA mandate, the
> clinical studies which we\'ve been involved in for the last ten years
> have included some sort of in-house safety monitoring board, but it\'s
> not gone to outside evaluations.
>
> DR. GARZA: It\'s not been an independent board, then?
>
> DR. CLEMENS: That\'s correct, but we have been doing the safety
> monitoring and reported the AEs, yes.
>
> DR. GARZA: Okay. Are there any other points of clarification that
> speak directly to this point or anyone else that wants to amend what
> they meant when they said an independent monitoring board that would
> be in disagreement with either Dr. Heubi or\--and the major difference
> that I detected there was the presence of industry on such a board.
>
> As a point of clarification\--I\'m sorry, Dr. Hotchkiss?
>
> DR. HOTCHKISS: Joe Hotchkiss. I have served on such a board for GRAS
> substances, not for ingredients, but sometimes those boards are
> appointed by the industry but are independent of that industry, and an
> industry who appoints a board that\'s going to submit information to
> the agency does so at its own peril. In other words, if the agency
> does not accept the independence or the qualifications of the board
> that you have formed, then you\'re probably shot down immediately and
> you\'ve wasted a lot of time and money.
>
> So at least in my experience, most companies are, not because they\'re
> particularly altruistic but because they worry about the agency
> rejecting the qualification of their boards, are usually pretty good
> about the boards that they appoint. So I don\'t have a problem
> with\--this also puts the financial and logistics burden on the
> affected industry, which I think is good, rather than putting it on
> FDA.
>
> DR. GARZA: Let me interrupt you, because you\'ll get a chance to tell
> us your recommendation on that, but in terms of clarity, is there any
> information you want to give the board, Beth, or\--
>
> DR. YETLEY: No. I had a clarification question.
>
> DR. GARZA: Okay.
>
> DR. YETLEY: It seems to me\--I understand the need for an independent
> review board during the course of the study and in terms of human
> subject protection and what not, but I\'m not clear, then, how that
> impacts on the question of if an independent review board had not
> found adverse events to be treatment-related and then the data comes
> in with significant differences in adverse event numbers between the
> two groups, how then do you make the decision about the usability of
> the study in terms of supporting normal physical growth? Do you see
> what I\'m trying to say? It seems to me like there\'s a two-step
> process here.
>
> DR. STALLINGS: And I think you\'re right. The data safety and
> monitoring board really is about safety of adverse events and, in
> essence, signing off on those data. Then it comes to you as an agency
> to review, and if there are differences, I think you still have the
> question of does that influence the acceptability of the data.
>
> The primary outcome data that we\'ve all been talking about is growth,
> and if the growth were not different, that currently being the
> benchmark, and the serious adverse events were not highlighted by your
> safety monitoring board and the non-serious ones were not also, I
> think you would have to move ahead with it was not deemed related to
> the study and move ahead with it.
>
> DR. GARZA: All right.
>
> DR. STALLINGS: I mean, that gets back to randomization work and was
> the study conducted by protocol, and assuming all of those qualifiers
> are met and that the board reviewed both the serious and non-serious
> adverse events and didn\'t act.
>
> DR. GARZA: Let\'s move on, then, to question three. I think we\'re now
> commenting more on the recommendations than clarifying.
>
> DR. STALLINGS: Question three is the issue of attrition rates, which
> was eloquently addressed by Dr. Anderson and I would concur, and I
> agree that I believe in the well-designed, probably randomized study,
> that if you have a big difference in dropout rates, it\'s incumbent
> upon us to know why, and that would be the first step. And then it
> still leaves the judgment step to the agency, but after you have all
> of that information to decide whether you think it invalidates the
> study. If the answers of why are not available, then I think there\'s
> a risk in accepting the data.
>
> DR. GARZA: Okay. Dr. Giacoia?
>
> DR. GIACOIA: I think we have been using two terms interchangeably,
> independent panel of experts and DSMB, and I think we may need, first
> of all, to look at what\'s happening on the other side of the agency
> in CDER, where they\'re coming up with proposed rules for DSMB on
> drugs. I think that the issue, some of it, the recommendations of just
> a priori consultation with the agency, it worked very well in CDER and
> I think you proposed that and I think it\'s a very good idea and
> there, an independent panel of experts would be very helpful.
>
> DR. GARZA: All right. If there are no other questions, we\'ll give Dr.
> Thureen the last word among the temporary members.
>
> DR. THUREEN: Thank you. I assume that much of what I\--I know that
> much of what I say now will be just a reiteration of what\'s been said
> before.
>
> DR. GARZA: That\'s important, so don\'t worry about that.
>
> DR. THUREEN: But when you think about that these recommendations have
> basically been redone every ten or 15 years and trying to project how
> our recommendations now should affect what happens in the next ten
> years, it\'s always difficult to know what\'s going to happen, but I
> would anticipate far more studies are going to be done now at
> developing formulas for high-risk populations, that that\'s a big area
> that we\'re heading into, so that it\'s incumbent on us to try and
> anticipate what will be done and to develop recommendations that will
> support not only the infant and the best research that can be done,
> but really to help support an industry which has done a remarkable job
> to date.
>
> So it disturbs me a bit in that at times it seems like some of our
> comments are adversarial towards the industry and I hope they don\'t
> take it that way at all. In our discussions privately, a lot of what
> we\'ve said is we have to protect an industry that\'s done such a
> remarkable job, so I hope it\'s taken in that spirit.
>
> DR. GARZA: Point of order. Our jobs as committee members here is to
> protect the public. The industry can protect itself. Our main goal is
> the public good, and I want to make sure that all of us recognize that
> even the industry representative, he is on this committee representing
> the public good, not representing this industry.
>
> DR. THUREEN: Regarding question number one, points A, B, and C,
> categorically, theoretically, presumptively, my answer would be no,
> but that there are exceptions. Again, it\'s a basis of physiological
> differences between preterm and term infants, between perhaps one
> product and another, and I think it\'s almost always going to be that
> any study done has to be redone in preterm infants that\'s been done
> in term infants.
>
> Going the other way, I think it has to be considered on a case-by-case
> basis and that a repository of case examples and guidelines, such as
> the industry has already started to develop, would be very helpful to
> provide a framework for answering question and that it may not be one
> single\--and I\'d also recommend that a board be available to review
> studies before they\'re even instituted to help facilitate studies
> being done in a proper manner, and that it might not be one single
> board but a panel of experts that can be available for different types
> of studies that can be called upon that would be willing to make a
> long-term commitment to be on this to facilitate approval of different
> studies and study designs and make commentaries.
>
> Again, I think that these should be reviewed before initiating any
> studies, and I think in many instances, depending upon what the study
> is, available data that might preclude having to redo studies in term
> infants if it\'s felt that there\'s adequate scientific justification
> and other data out there that would make it not reasonable to really
> have to redo this study, that that could be decided by an independent
> board.
>
> DR. GARZA: Thank you. Any questions, points of clarification?
>
> \[No response.\]
>
> DR. GARZA: Thank you. Number two?
>
> DR. THUREEN: In regards to question number two, I struggled with this
> because it seems like a two-part question that\'s not related, sort of
> like the question, is it farther to New York or by water?
>
> \[Laughter.\]
>
> DR. THUREEN: And when I look at this, I think that a lot of studies
> can be concluded to support growth even if there are adverse events.
> The adverse events are a different issue, and I think in the era
> we\'re heading into, the DSMBs are critical to any study that\'s
> conducted and to be able to have the opportunity, with Brad
> Skipperman\'s support, to make really superb independent DSMBs that
> are taken out of the institution for infant formula studies protects
> everyone. So I would strongly recommend that.
>
> The issue on adverse events, I think that they need to be\-- I agree
> with Dr. Stallings that the adverse events of interest may be more
> minor issues and that these all should be addressed as much as
> possible before the study is actually started, but they need to be
> monitored and reported back.
>
> And regarding post-marketing adverse event reporting, I as a
> clinician, and I feel silly not knowing this, I didn\'t know that
> there was really a mechanism for even reporting every time I suspected
> an adverse event, and as a result, I didn\'t even think about
> reporting adverse events that could have been related to formulas, not
> that there ever were any, but it was not even on my horizon.
>
> So I think having the standardized mechanism such as is available for
> drug reporting, to get it to be more of a public issue that most
> clinicians are aware of, would be very helpful.
>
> DR. GARZA: Okay. Any points of clarification, comments?
>
> DR. DWYER: Just a small one, the notion of independent board, whether
> it\'s data safety or whatever. To the best of my knowledge, you still
> have to have the ones in the institutions, so it would be an extra
> one\--
>
> DR. THUREEN: That, I think, is\--you can probably answer it better
> than I can, but at our institution, it doesn\'t have to be an
> institutional data safety monitoring board. It has to be a plan with a
> specific monitoring board, and so in some cases would obviate the need
> for a local board.
>
> DR. HEUBI: I would concur. That\'s correct. That is, if you have a
> DSMB for a multi-center study, centers will accept that as their DSMB.
>
> DR. DWYER: It depends on where you are.
>
> DR. HEUBI: Well, but that\'s generally what\'s accepted in terms
> of\--and we\'ve been in sort of a groundswell of this with the GCRCs
> and that\'s been generally what\'s been accepted.
>
> DR. GARZA: GCRCs are General Clinical Research Centers. Dr. Stallings?
>
> DR. STALLINGS: Clarifying, Dr. Dwyer, if we have these outside boards,
> we\'re still required to notify in the same timely fashion our IRB; if
> it\'s a general clinical research center approved study, them, as
> well. So it doesn\'t obviate the need to report it locally, but you
> don\'t have to have a sitting board for every study. You have to have
> a plan. It used to, like six months ago, you didn\'t have to have a
> plan unless it specifically was called for because of the complexity
> or the funding source. So most studies did not have formal plans.
>
> DR. GARZA: Again, we\'re revisiting ground we should have visited
> earlier. Are there specific\--
>
> DR. THUREEN: And I think it\'s clear, but I think the data safety
> monitoring board is empaneled or used during the conduct of the study,
> perhaps could be extended to the pre-marketing period. Post-marketing
> adverse events may be a central repository of information within the
> FDA or some other board that\'s independent of the data safety
> monitoring board. Their job is done once the study is considered to be
> concluded. So those would be two different mechanisms.
>
> DR. GARZA: Okay. The third question?
>
> DR. STALLINGS: And the third question, again, I defer to Dr.
> Anderson\'s remarks because I think that they were excellently done. I
> think we have to remember that this question deals with large
> differences in attrition rates, that large differences are an outcome
> in themselves, and that this needs to be looked at. I would love to
> have this kind of help in addressing these issues. To have a body that
> would help address these issues for large-scale studies, I think would
> be terrific, and I also think that kind of information would help make
> multi-center studies much more feasible and more acceptable because
> hopefully a lot of these center-specific issues would be addressed by
> looking at attrition rates.
>
> DR. GARZA: Okay. Any questions?
>
> \[No response.\]
>
> DR. GARZA: Would any of the temporary committee members want to amend
> any of the comments they\'ve heard based on information they\'ve
> received from others subsequent to their own recommendation?
>
> \[No response.\]
>
> DR. GARZA: I\'m going to move, then, to the permanent Food Advisory
> Committee members. I understand that some of you do not consider
> yourselves experts in this area. That\'s why they brought in the ad
> hoc group. You do have the option of abstaining on any of these
> questions, but if you do abstain, I\'m required to ask you why.
>
> \[Laughter.\]
>
> DR. GARZA: But you are not required, obviously, to come up with an
> answer that you feel uncomfortable with or that you cannot elaborate
> on.
>
> With that, we tried to keep your interventions to the answer that you
> can be as fully informed by, theoretically, the group of experts that
> was brought in with greater expertise in this area.
>
> So with that preamble, Dr. Busta.
>
> DR. BUSTA: And I think you were specifically referring to me.
>
> \[Laughter.\]
>
> DR. BUSTA: As a non-clinician, I appreciate the education I\'ve
> received in the last day and a half and I think many of you might
> think I\'m presumptuous at even making comments now on this, but I\'m
> going to anyway.
>
> I also appreciated the FDA short course this morning, bringing another
> set of slides and trying to focus us in on what quality factors are. I
> thought that was important because as I see our charge, we are to
> focus on, specifically on quality factors. And then we were told to
> specifically aim at normal physical growth, and I think that Dr.
> Anderson has acquired a charge for all statisticians to give us a good
> statistical analysis on nearly everything that we do, and I would
> think just assessing what \"normal\" is on physical growth would be a
> challenge in itself.
>
> In focusing on that, I thought that we weren\'t giving any emphasis on
> nutrient-specific bioavailability, the various other kinds of
> evaluations that we could do on a formula to determine if it is the
> same. As we were told this morning, a new manufacturer, a major change
> in processing, major change in formulation are the major changes that
> I\'m assuming are evaluated on this and whether something can be used
> in one place or the other in our charge.
>
> In those major change examples, one was a significant revision, and
> again, we have these words of significant, and I don\'t know if
> that\'s statistically significant or just a change. I would appreciate
> someone helping me understand what significant revisions might mean.
>
> I also saw a new processing line as a major change, and to me, I\'m
> not sure what \"new\" means, if it\'s a new process that, in fact,
> changes the product or if it just happens to be a replicated line. I
> have problems with some of those changes to evaluate.
>
> We\'re talking about, as I saw it this morning, providing assurances
> prior to marketing of no changes, and to me, it would seem to me that
> we could have some important, well tested biological analysis that
> would give us results and not necessarily have to do certain clinical
> tests if we could demonstrate that those changes in formulation or
> whatever had not changed the product.
>
> DR. GARZA: Let me clarify. We\'re not being asked right now to comment
> on the adequacy of the quality factors issue that we\'ve heard. It\'s
> these specific questions. I\'m not clear\--
>
> DR. BUSTA: But we\'re being asked to say whether we have a clinical
> trial.
>
> DR. GARZA: No, it\'s questions one, two, or three, and if\--because
> if, in fact, we want to go back to the presentation and ask the FDA to
> clarify, that should have happened earlier this morning. I\'d like you
> to address one, two, and three, if possible. Otherwise, it\'s going to
> be difficult in terms of dealing with the rest of the committee.
>
> DR. BUSTA: All right. I would like to say that one of my favorite
> comments is that no generalization is 100 percent true, and that
> includes the one I just said, and I heard that this morning and I
> think that that is a pretty standard belief and it seems to be
> consistent with my opinion that a generalized approach that is being
> proposed that would cover these changes does not seem to be able to be
> supported, and we\'ve heard all through the last day and a half about
> this is abstract and it\'s conceptual and it\'s non-specific and I
> would guess as scientists, we have a problem with something being
> conceptual and then making a generalized assumption.
>
> My preamble was to indicate that I think to determine whether these
> tests are relevant or not could come in other ways besides the
> clinical to determine if we can make these justifications and make
> these changes, a change in formulation one way or the other.
>
> Consequently, if we\'re talking about when to do a clinical study or
> not, I would say that it needs to be\--it would not be necessary if it
> could be justified in good biochemical, biological, bioavailability
> research. Otherwise, it would need to be assessed.
>
> DR. GARZA: Okay. So that speaks specifically from one product to
> another or from one population to another or both?
>
> DR. BUSTA: Either one.
>
> DR. GARZA: Okay. Any questions of Dr. Busta?
>
> \[No response.\]
>
> DR. GARZA: Okay. Number two?
>
> DR. BUSTA: Number two, I\'d like to state my how far is it to New York
> or\--I\'d go by air.
>
> \[Laughter.\]
>
> DR. BUSTA: I think that the adverse aspect seems important but I
> don\'t know how that is addressed in normal growth. If that\'s part of
> the study and it is the design, then it should be reported and
> included. Otherwise, we\'re talking about another aspect. So, again, I
> would think it could be part of the design, but if it\'s adverse, it
> should be adverse on normal growth because that\'s the charge.
>
> DR. GARZA: Okay. Any questions?
>
> \[No response.\]
>
> DR. GARZA: So the rationale is because of the narrowness of the charge
> in terms of normal growth, not because of other physiological or\--
>
> DR. BUSTA: And\--
>
> DR. GARZA: So it\'s procedural in your mind?
>
> DR. BUSTA: Yes, and the adverse that I heard some people talk about
> was that it influences\--the adverse events influence the normal
> growth. So if that\'s that, then it\'s a part of the study.
>
> DR. GARZA: All right. Number three?
>
> DR. BUSTA: If the study retains its statistical significance, then the
> attrition would have no effect. If you lose the statistical
> significance by attrition, then the study has to be reevaluated.
>
> DR. GARZA: How would you address the issue of randomness that\'s been
> brought up, in terms that it loses its randomness, as well?
>
> DR. BUSTA: Again, if the attrition was matched, then it\'s random. If
> the attrition is abnormal and it loses the randomness, it loses
> statistical design and it\'s hard to make a decision.
>
> DR. GARZA: Okay. With that clarification, are there any other
> questions?
>
> \[No response.\]
>
> DR. GARZA: Let\'s move to Dr. Downer.
>
> DR. DOWNER: Goulda Downer. I guess we recognize that overall health
> issues of the preterm infant with a low post-conceptual age differ
> significantly from those born later and even still those born at full
> term, and so the nutritional, the metabolical, even physiologic needs
> differ, say, from a neonate at 24 weeks compared to one at 30 weeks,
> and even one at 38 or 40 weeks.
>
> Based on that, then, I think it will be difficult in my mind to make
> inferences to such a vulnerable population with regards to the product
> of the population itself. That being said, though, I think that
> perhaps under certain conditions, perhaps with good statistical
> measures and where the clinical trials may not be adverse to the group
> tested that some inferences may be made.
>
> My response is a strong iffy one, not a strong yes and not a strong
> no.
>
> DR. GARZA: Can you elaborate a bit on the criteria that you would then
> advise a strong yes or a strong no?
>
> DR. DOWNER: I think for me a strong yes in terms of, yes, go ahead and
> make the inference, is, for example, if in the preterm infant who
> would need to have\--limited to strong no first. If, for example, in
> the term infant, if additional vitamin A were to be added to a
> formula, I would say no for the full term and yes for the term.
> However, the\--
>
> DR. GARZA: You mean yes for the preterm or\--you said full term and\--
>
> DR. DOWNER: Yes for the preterm. Yes for the preterm. Additional
> vitamin A, yes for the preterm, but for the term, absolutely not.
>
> I think for my strong no, I would have to give that more thought. As I
> read the literature in preparation for this body, I wasn\'t able to
> clearly identify instances where clinical studies that were done on
> term infants, for example, could be\--the information could be
> extrapolated and used definitively in preterm. I\'m not saying that it
> is not possible. There may be studies on it or it may come in the
> future, but so far, I\'m not comfortable saying yes for that.
>
> DR. GARZA: Okay. Any other questions or points of clarification?
>
> \[No response.\]
>
> DR. GARZA: Question number two?
>
> DR. DOWNER: Question number two. I think I concur with the panel in
> that we would need to have some discipline-specific advisory board or
> group to help us identify adverse events. I, too, read this and
> thought these were two questions. It was not just one.
>
> Adverse events may simply mean no additional growth, if that\'s what
> we\'re looking at, to the end would be perhaps death. Along that
> spectrum, what is it we\'re really looking for with respect to adverse
> events? I think we really would need to get a panel together, not
> necessarily for post-market surveillance, but I think, again, as Dr.
> Stallings says, before the study goes even further to the FDA, get a
> body together to define, to identify, to help make sure that we know
> what\'s going on before, because I think when we operationally decide
> and also identify what we\'re talking about where we look at adverse
> effects that it will be much clearer. So I think a panel will best
> serve that question.
>
> DR. GARZA: All right. Any questions or points of clarity?
>
> \[No response.\]
>
> DR. DOWNER: I think everybody said Dr. Anderson answered this question
> well, and I, too, will agree. He gets kudos for that.
>
> I think with all the statistical measures that should go into a
> clinical study\--I\'m talking about the rigorous aspects of it\--that
> the sample size should be large enough at the start of the study to
> ensure that the sample size remains adequate to detect significant
> differences, even with the high attrition as we know with human
> studies.
>
> I think, though, with a large difference in attrition between groups
> that we probably may not only want to look at the design of the study,
> but also look at that again as a possible outcome measure, and again,
> I think a statistical panel would best serve to address that issue.
>
> DR. GARZA: So you\'re suggesting, then, the appointment of two
> separate panels, one to look at safety issues and one the statistical
> rigor of the studies?
>
> DR. DOWNER: I surely do.
>
> DR. GARZA: Okay.
>
> DR. DOWNER: I surely do.
>
> DR. GARZA: Any other points of clarity?
>
> \[No response.\]
>
> DR. GARZA: Thank you, Dr. Downer.
>
> Dr. Dwyer? It\'s nice. This group is sort of lined up.
>
> DR. DWYER: Just to preface, I find it difficult to provide responses
> to general principles and questions that seem to be generated by
> specific cases. It\'s just the way my mind works. I\'m not very good
> at The Ten Commandments and I\'m not good at this, either.
>
> \[Laughter.\]
>
> DR. DWYER: I have a little expertise and only very tentative
> suggestions on processes and panels and the most appropriate ways to
> go from that respect.
>
> In response to the first question, A, B, and C, in general, no.
> Generalization is strongest from clinical studies that are done for
> conditions of intended use, of course, to begin with, and when
> exceptions are made, and I think there should be exceptions, the
> burden of proof rests on the manufacturer. So to protect the public
> health, the answer is, in general, no, but there are exceptions.
>
> The relevance and generalizability depends on a number of factors, the
> type of nutrient and all of the other things we\'ve discussed and
> these need to be considered.
>
> The appropriate generalization depends on the growth response to be
> measured, that is, whether it\'s some kind of a core and very broad
> measure of growth, such as weight, height, head circumference, or more
> specific types of growth measures, such as maturity or visual acuity
> or something that\'s another kind of growth that\'s measured by other
> markers and evaluated by appropriate experts.
>
> The special case of very low birthweight, low gestational age infants
> in non-exempt situations where many may be ill and research on the
> nutritional or growth characteristics associated with various formula
> also needs to be studied, but it seems to me that that\'s at the basic
> research level and that this is a very important question and that we
> need better answers than the idiosyncratic, well meaning but
> idiosyncratic views of the attending physicians that now often govern
> the feeding of those infants.
>
> With respect to growth in height, length, weight, and head
> circumference, generalization, in general, generalization for these
> exceptions when they occur from preterm to term is more likely to be
> appropriate than from term to preterm because of the physiological
> realities that have already been mentioned, as well as the biological
> continuum of sick/well. So comparisons from healthy to ill or diseased
> to healthy seem to be more problematic, but I think it depends on the
> substance that one is talking about. For example, for an emulsifying
> agent or something or a trace element, it might be very different than
> for something else, so it also depends.
>
> DR. GARZA: Any questions, points of clarity?
>
> \[No response.\]
>
> DR. GARZA: Number two?
>
> DR. DWYER: Question two, I think the answer that I can give there is,
> in general, no, but there are exceptions in that the burden of proof
> rests on the proponent, the manufacturer in this case.
>
> In the future, major clinically significant adverse events, and I
> guess the kinds of things\--hospitalizations and deaths, of course,
> but other things, maybe asthma, I don\'t know because I\'m not an
> expert in this field\--are best defined, of course, prospectively and
> monitored as sort of like with an independent data safety and
> monitoring board. What \"independent\" means, I cannot define and I
> leave it to better minds to do that. But the notion is that the people
> are not influenced either way by the results of the trial. They have
> no interest in that on an ongoing basis.
>
> In reviewing existing studies, that is, studies that are already here
> and finished with adverse events, the first thing, of course, is to
> define exactly what\'s meant by that. What are we talking about? Are
> we talking about colic or are we talking about hospitalizations?
>
> And when they\'re disproportionate in the cases, particularly, an
> independent expert review may be helpful in deciding whether and what
> should be done and whether the comparisons have been compromised by
> this. The critical issue is to determine if the adverse events,
> differential adverse events are caused by the food, the formula, and
> how frequent and severe and biologically plausible these explanations
> are.
>
> DR. GARZA: Any questions?
>
> \[No response.\]
>
> DR. GARZA: If not, we\'ll move on to number three.
>
> DR. DWYER: The third question, the answer is, in general, no, but
> there are exceptions, and again, the burden is on the person who
> wishes to sell the food or the formula. Dr. Anderson, I think,
> answered that well. High attrition rates of 25 percent in studies such
> as referred about are troubling and introduce uncertainties and every
> effort should be taken to minimize these by all possible means, and,
> of course, studies should be powered to allow for attrition.
>
> The critical issue is to determine whether the differences in
> attrition are due to the intervention or to other causes, chance or
> whatever. The reasons for attrition and also the characteristics of
> those need to be investigated, and at the very least, it is critical
> to document the reasons for withdrawal to be assured that the
> intervention was not responsible. This kind of judgment is probably,
> again, best made by independent experts.
>
> The other possibility which I throw out in an uninformed way is that
> one could perhaps do intent to treat analysis, but I don\'t know if
> that would get you very far.
>
> DR. GARZA: Any questions?
>
> \[No response.\]
>
> DR. GARZA: All right. Dr. Hotchkiss, question number one?
>
> DR. HOTCHKISS: My opinion on question one is the answer is no. I
> believe that should be FDA\'s default position and the reason for that
> is that as the agency\'s default position, it puts the burden back on
> the industry to argue why that answer should not be no.
>
> In the case of generalization from term studies to preterm studies,
> again, in my view the answer is clearly no, not acceptable. However,
> for other situations, for example, generalizing preterm to term,
> product reformulations, product crossovers, one crossover to another,
> a mechanism ought to be available to the industry to have each case
> reviewed on a case-by-case basis. If the affected industry can
> demonstrate through scientific studies and independent reviews and
> reviews of that data that such generalizations are valid, then FDA
> would be in a position to consider those when it decides whether it
> wants to accept those opinions or reject those opinions. However, FDA
> is ultimately responsible for making those opinions or those
> judgments. However, in some cases, industry should have that option.
>
> DR. GARZA: Any questions?
>
> \[No response.\]
>
> DR. GARZA: If not, we\'ll go to number two.
>
> DR. HOTCHKISS: Again, my answer is no, unless an independent panel
> agrees that attrition is not related to the study and not as\--
>
> DR. GARZA: Attrition or adverse effects? I\'m sorry.
>
> DR. HOTCHKISS: I\'m sorry, adverse effects. Independent review panels
> and FDA should make aware of adverse effects as soon as possible
> during any trial. The independent review panel should be responsible
> for determining if the event is hypothesis related or not. FDA should
> consider the frequency, type, severity of the adverse event whenever
> considering any infant formula.
>
> DR. GARZA: Okay. Any questions?
>
> \[No response.\]
>
> DR. GARZA: If not, number three?
>
> DR. HOTCHKISS: Again, my answer is, no, it\'s not appropriate when
> attrition rates are significantly greater in one group compared to the
> other. It\'s very likely that these attrition rates are hypothesis
> related, and unless an independent review group provides FDA with
> evidence that they were not treatment related, then FDA should take
> these into consideration when considering the issue.
>
> DR. GARZA: Are you suggesting that ought to be the purview of the
> safety monitoring board or independent board or two separate boards or
> two separate groups?
>
> DR. HOTCHKISS: I do not believe that you need two separate boards, but
> I do not have direct or sufficient experience in the area to say
> exactly the mechanism. That should be left to clinicians who practice
> in this area.
>
> DR. GARZA: All right. Any other questions?
>
> \[No response.\]
>
> DR. GARZA: If not, Dr. Montville?
>
> DR. MONTVILLE: I have a qualified no to all of these on the basis of
> sound science, which says you don\'t extrapolate to different
> conditions. However, I do think that there should be mechanisms for
> the manufacturers to state or to make the case that these aren\'t
> different conditions, they\'re really the same, provided that they are
> based on science or physiology.
>
> I agree that a board may be useful here, but would suggest that we
> don\'t mandate a board. Some of these may be so black and white that
> FDA could decide it on its own, so we should empower FDA to make that
> decision.
>
> With regard to question two\--
>
> DR. GARZA: Hold on just a bit. Let me see if anyone has any questions
> on your response to number one.
>
> \[No response.\]
>
> DR. GARZA: All right. Number two?
>
> DR. MONTVILLE: With question two, as has been noted, there are two
> parts of this question. If there are differences in adverse effects,
> those should be examined and followed up and something done about
> that.
>
> However, even given a real difference in adverse effects, if those
> adverse effects don\'t affect normal physical growth, I don\'t see why
> the normal physical growth data would be invalidated by the adverse
> effects, unless I\'m missing something here, okay.
>
> DR. GARZA: Any questions? Yes, Dr. Stallings?
>
> DR. STALLINGS: In response to that, if the adverse events that were
> different were difference in level, say, of diarrhea or food-related
> allergy but the child, because of the intake, was able to growth
> through that and, consequently, the physical growth wasn\'t affected,
> that might be an example of growth going ahead at a normal rate but
> the adverse event might be related to exposure to the study formula.
>
> DR. MONTVILLE: That, I understand, that the adverse events should be
> investigated, but as an adverse effect, not as to relating to physical
> growth.
>
> DR. STALLINGS: I thought when you had closed\--I was just trying to
> come up with an example of where I think children often can growth
> through illnesses\--
>
> DR. MONTVILLE: Right.
>
> DR. STALLINGS: \--and this particular set of events might be related
> to the product that we were examining, just as an example.
>
> DR. MONTVILLE: Okay.
>
> DR. GARZA: All right. Are there any other questions or points or
> clarity?
>
> \[No response.\]
>
> DR. GARZA: All right. Number three?
>
> DR. MONTVILLE: Question three, I also agreed with most of the panel
> that the attrition rates can be an outcome to the study, but there
> should be an opportunity to make the case that they\'re not. If the
> industry can provide data that in this particular case, all of these
> people left town because they worked for the same company which
> closed, then it\'s a no-brainer. That should be acceptable. But
> generally, it has to be, I think, considered that the attrition rate
> is linked to a difference in the formula.
>
> DR. GARZA: Okay. Any questions?
>
> \[No response.\]
>
> DR. GARZA: If not, we\'ll move on to Dr. Russell. Question number one?
>
> DR. RUSSELL: Question one, number one is presumptively no with the
> realization that there could be exceptions. I think the final answer
> on an individual basis could depend on the setting up of a matrix by
> FDA or by a panel of experts that FDA calls together to look at
> possible translatability of the data to other populations. The matrix,
> as I said, should be designed by an expert advisory committee external
> to FDA, and I think it could be set up with recommendations for
> specific scoring cutoffs for use by FDA. It\'s been done before.
>
> DR. GARZA: And that matrix would apply to term/preterm,
> diseased/health, I mean, the various scenarios?
>
> DR. RUSSELL: Yes, but I think the question was really about
> term/preterm. If it\'s late preterm, for example, it might be more
> translatable.
>
> DR. GARZA: Any questions?
>
> \[No response.\]
>
> DR. GARZA: All right. Number two?
>
> DR. RUSSELL: Question two, no presumption of yes or no. The answer
> depends on the judgment of an independent board, which should consider
> factors such as biologic probability, severity and frequency of the
> adverse events and other factors.
>
> DR. GARZA: Can you amplify a bit on what you mean by an independent
> board? Is it pretty much in keeping with what we\'ve heard, or\--
>
> DR. RUSSELL: Yes.
>
> DR. GARZA: Okay.
>
> DR. RUSSELL: And question number three\--
>
> DR. GARZA: No, hold on. Let me make sure everyone is as clear as I am
> on your response.
>
> DR. RUSSELL: Sure.
>
> DR. GARZA: Any other questions?
>
> \[No response.\]
>
> DR. GARZA: Okay. Number three?
>
> DR. RUSSELL: Question number three is presumptively no for the reasons
> also stated by Dr. Anderson.
>
> DR. GARZA: All right. Dr. Sigman-Grant gets the last word.
>
> DR. SIGMAN-GRANT: The last word, okay. I\'m on this panel as a
> representative of the consumer and I take that role very seriously. I
> think a lot of the assumptions are that the caregiver or the person
> feeding the child is going to be the same, and I would suggest that
> preterm infants, even late preterm infants, may not be treated in the
> same manner as term infants and, in fact, that growth can be affected
> by the person who\'s feeding, and if some of the clinical trials are
> done in control settings or with preterm babies, the outcomes might be
> different in a term baby.
>
> So I\'d just like to add that to the presumptive no that everybody
> else has suggested. It\'s something I think that\'s been left out of
> the discussion and needs to be included, and that would refer to
> healthy/diseased, preterm/term, and perhaps even product/non-product
> because of the difference in intended use and the difference in
> treatment between potential populations.
>
> DR. GARZA: So am I correct, then, in assuming that you would agree
> with other reasons that have been given\--
>
> DR. SIGMAN-GRANT: Yes.
>
> DR. GARZA: \--or would that be your only reason\--
>
> DR. SIGMAN-GRANT: No, I agree with the other reasons, but I\'d like to
> include that as an additional reason because I think it\'s
> significant.
>
> DR. GARZA: Any questions for Dr. Sigman-Grant on her response to
> question number one? Dr. Dwyer?
>
> DR. DWYER: So would that imply, Madeleine, that you would like to see
> studies reported, brought in with that information in them?
>
> DR. SIGMAN-GRANT: No, I just think that it\'s two different
> populations\--
>
> DR. DWYER: I see.
>
> DR. SIGMAN-GRANT: \--and that the feeding may very well be different
> and growth is dependent on feeding.
>
> DR. GARZA: All right. Number two?
>
> DR. SIGMAN-GRANT: I think I agree with everything that\'s been said.
>
> DR. GARZA: Could you be more specific?
>
> \[Laughter.\]
>
> DR. SIGMAN-GRANT: No.
>
> DR. GARZA: Does that mean yes or no?
>
> DR. SIGMAN-GRANT: I think there needs to be an independent board. I
> think that what has worked in the past, and the industry has done a
> very good job in monitoring, may not apply anymore because so many
> changes have been made to independent research and to university
> research, that the need for an independent external panel is necessary
> in order to determine how the adverse effects may be different and may
> apply, and the same for number three.
>
> DR. GARZA: Any questions to Dr. Sigman-Grant on her response to
> question number two?
>
> \[No response.\]
>
> DR. GARZA: Number three?
>
> DR. SIGMAN-GRANT: And I, too, would say number three, and refer to
> both Dr. Anderson and Dr. Hotchkiss.
>
> DR. GARZA: Okay. Any questions?
>
> \[No response.\]
>
> DR. GARZA: If not, would any member of the panel, of the voting
> members of the panel, want to amend any of their comments based on
> what they\'ve heard this morning since they voted? Dr. Dwyer?
>
> DR. DWYER: I\'d like to amend mine to endorse Dr. Russell\'s
> suggestion of sort of a checklist, which is what I gather you were
> getting to, rather than always having to convene a group, because
> remember, the only\--if infant formula is like a drug, it doesn\'t
> have the profit margin of a drug so that these things can get rather
> expensive.
>
> DR. GARZA: Okay. Any other comments? Dr. Stallings?
>
> DR. STALLINGS: One clarification. When I had made my suggestion, it
> was that there be the case study and that the independent board be
> there for discussion of situations when after\--it\'s pre-review, and
> after the industry and the FDA did not agree that there would be a
> third body to go to, so that not every proposal would require review
> in a pre-review setting.
>
> DR. GARZA: Okay. Well, I want to thank the group. I hope FDA has found
> these exchanges to be as informative and helpful as I think they have
> been. The group has worked extremely well together. We were able to
> get through the assignment in the prescribed time, and that\'s a real
> credit to both your discipline and the fount of knowledge that you
> bring.
>
> SEVERAL PARTICIPANTS: And the chair.
>
> DR. GARZA: I want to thank you for discharging your duties well in the
> interest of the public, and I assume that the ad hoc group will be
> getting together and will be getting back to you with some straw men
> and possibly some dates in the future.
>
> So with that, unless there\'s any other business to be conducted, the
> committee meeting is adjourned. Thank you very much.
>
> DR. TAYLOR: On behalf of the agency, we\'d like to thank the panel and
> the chair and we did find the discussions very informative. Thank you.
>
> \[Whereupon, at 11:30 a.m., the meeting was adjourned.\]