> UNITED STATES DEPARTMENT OF AGRICULTURE
>
> FOOD AND DRUG ADMINISTRATION
>
> FOOD ADVISORY COMMITTEE
>
> MEETING ON INFANT FORMULAS
>
> Tuesday, November 19, 2002
>
> 8:15 a.m.
>
> U.S. Department of Agriculture
>
> Animal and Plant Health Inspection Service Building
>
> 4700 River Road
>
> Riverdale, Maryland
>
> PARTICIPANTS
>
> [Temporary Voting Members Present]{.underline}
>
> JAMES ANDERSON, Ph.D.
>
> ROBERT D. BAKER, M.D., Ph.D.
>
> SCOTT DENNE, M.D.
>
> CUTBERTO GARZA, M.D., Ph.D.
>
> JAMES H. HEUBI, M.D.
>
> LAURIE J. MOYER-MILEUR, Ph.D., R.D., C.D.
>
> VIRGINIA A. STALLINGS, M.D.
>
> PATTI THUREEN, M.D.
>
> MARGARET E. BRILEY, Ph.D., R.D., L.D.
>
> [Participating Food Advisory Committee]{.underline}
>
> GOULDA ANGELLA DOWNER, Ph.D.
>
> LAWRENCE N. KUZMINSKI, Ph.D.
>
> MADELEINE J. SIGMAN-GRANT, Ph.D.
>
> [Acting Industry Representative]{.underline}
>
> ROGER A. CLEMENS, Dr.P.H. CNS FACN
>
> [C]{.underline} [O]{.underline} [N]{.underline} [T]{.underline}
> [E]{.underline} [N]{.underline} [T]{.underline} [S]{.underline}
>
> [AGENDA PAGE]{.underline}
>
> Opening Remarks 4
>
> Jose Saavedra, Nestle USA 5
>
> Jon Vanderhoff, Mead Johnson,
>
> Bristol-Myers Squibb 19
>
> Russell J. Merritt, Ross Products
>
> Division, Abbott Laboratories 26
>
> Barbara Heiser, Executive Director,
>
> National Alliance for Breast-
>
> Feeding Advocacy 35
>
> Questions 41
>
> Adjournment 219
>
> [P]{.underline} [R]{.underline} [O]{.underline} [C]{.underline}
> [E]{.underline} [E]{.underline} [D]{.underline} [I]{.underline}
> [N]{.underline} [G]{.underline} [S]{.underline}
>
> DR. GARZA: I want to thank the committee for assembling on time. We
> have a very full schedule this morning, and we\'re going to try and
> conclude by 2:45 instead of 3:00 o\'clock because of some plane
> schedules.
>
> I think we can do this if we all are particularly careful in terms of
> addressing relevant points, if the points have been made, not
> necessarily repeating them, unless there are aspects of it that are
> novel to the argument, and we may have to reduce break times and
> possibly bring your lunch to the table in order to be able to conclude
> by 2:45, but I hope that that latter possibility is proven not to be
> needed.
>
> I think there are no adjustments, other than those, to the agenda. Let
> me check to see if there are other things that anyone else would like
> to raise regarding this morning\'s or this afternoon\'s agenda, so we
> can plan accordingly.
>
> \[No response.\]
>
> DR. GARZA: No? If not, then, let\'s move forward.
>
> I hope that our three presenters for public comment are here, because
> we\'re going to be starting a bit earlier.
>
> I have Dr. Jose Saavedra, Russell Merritt, and Jon Vanderhoof. Are
> they here? I know Russ is, because I saw him. Vanderhoof is here. And
> Dr. Saavedra\--he\'s going to the podium. Very good. Okay.
>
> Again, we\'ll have 10 minutes for the presentation, and the timer will
> warn you when your time is coming to an end. They\'ll be gaveled quite
> strenuously, so I don\'t want anybody to feel picked on if I interrupt
> you after 10 minutes, and then we\'ll go on to questions from the
> committee after that\--after the 10 minutes are up.
>
> Dr. Saavedra is the medical and scientific director with the nutrition
> division of Nestle USA, and the comments are addressing when is a
> clinical growth study needed.
>
> Dr. Saavedra?
>
> DR. SAAVEDRA: Thank you very much.
>
> Thank you very much for allowing us to be here.
>
> I want to thank Dr. Chris Taylor and Dr. Sue Walker for the
> opportunity from the point of view of the agency, and certainly Dr.
> Garza and the advisory committee or this ad hoc committee, for the
> opportunity to be able to address you this morning.
>
> We\'re going to try to make our comments as limited as possible, but I
> do think that it is important that we are able to bring to you a few
> of the points that we think are relevant, particularly from the point
> of view of the industry.
>
> I\'m Jose Pepe Saavedra. I\'m associate professor of pediatric
> gastroenterology and nutrition at Johns Hopkins University School of
> Medicine and School of Public Health, and I\'m here representing
> Nestle.
>
> However, collectively, with Dr. Jon Vanderhoof and Dr. Russell
> Merritt, we hope to bring to you a collective expression of the
> current status from the point of view of when these issues that
> you\'ve been grappling with over the last few days and, actually, a
> few months, are important and how we address them as an industry
> collectively here in the United States, speaking on behalf of the
> manufacturers of infant formula in North America.
>
> So, we don\'t have much time.
>
> I want to go through a particular set of ideas that\--as I
> said\--together with the following speakers will try to give you a
> glimpse of the kind of effort that goes into the development of a
> thinking process and to the determination of clinical trials and how
> we go about that on a regular basis.
>
> And the industry has currently a analysis and a process that is in
> place, that is used, that has been used for years, in collaboration
> with the agency when it comes to documentation and assessment for the
> use of clinical trials in pediatrics and in nutrition, particularly
> when it comes to infant formula.
>
> The industry has a process and, as I said, a history through which it
> considers a change to infant formula for a particular benefit.
>
> Now, we\'re not going to discuss claims, as it was mentioned
> yesterday. We\'re not talking safety. We can address that separately.
> Actually, that would probably be a whole different conference.
>
> But we do have a process of assessment and documentation of all the
> important nutritional\--potential nutritional impacts that any change
> in infant formula will bring about. This process exists and this
> process has been ongoing, and it keeps renewing itself.
>
> Throughout the process and at the end of the process, each one of the
> infant formula manufacturers notifies the agency of all major and
> minor changes and all the rationale behind those changes and
> justifications for them.
>
> Why is that important?
>
> Among other things because we want to determine\--based on the
> potential impact on nutritional adequacy of that change, we need to
> determine the need for clinical trials to confirm if an infant formula
> has and supports\--has the characteristics that support normal
> growth\--i.e., is nutritionally adequate.
>
> Now, it is important to engage in a process that leads ultimately to
> that change, because these clinical trials to be done to demonstrate
> nutritional adequacy, of course, need and should be done every time we
> can reasonably predict that there is a potential nutritional impact
> for that particular change.
>
> On the other hand, I think it behooves us, as people interested in
> children\'s health and people interested in adequate running of trials
> and ethics, that we do not do trials that are not necessary, that are
> not redundant, and that we don\'t engage in the use of trials as a way
> around whatever potential change or potential impact from the industry
> point of view we need to have.
>
> Now, this decision, ultimately, for the use of clinical trials in
> demonstrating nutritional adequacy is based on a very specific
> reasonable and conservative assessment of the potential impact of this
> change on nutritional adequacy, and again, throughout this process
> that becomes transparent between the company and the agency, we are
> always subject to review by the FDA.
>
> Now, the industry holds itself accountable in a number of ways, and
> certainly, one of them is by a regular and clear process of
> notification to the FDA.
>
> This is traditionally done through two types of\--through separate
> types of changes which we divide into major and minor changes. We
> don\'t have time to go into this, and it is not the subject of
> discussion, but these changes, whichever, minor or major, all go
> through essentially the same process of evaluation and clear
> understanding of the impact of that change, with notification to the
> agency.
>
> Only if none of these changes apply then is it that the manufacturer
> continues\--or makes modifications.
>
> In essence, pretty much every aspect of the modification in infant
> formula, as we know it today, truly undergoes a very complex set of
> assessments.
>
> Now, you have this in your hand-out. You may have had a chance to go
> over it last night. If not, you have 10 seconds here to memorize it.
>
> But what basically happens is\--and what this represents here is the
> collective\--the collective decision tree or decision process that
> current manufacturers in the U.S. go through in understanding what
> potential changes, whether minor or major\--and we will focus a little
> bit more on these\--relating to packaging, processing, formulation
> change, or the addition of new ingredients is taken for ultimate
> decision on how this implementation of the change is going to happen,
> what information needs to be done, what documentation needs to be
> present before we do that.
>
> What is a major change?
>
> There\'s a number of ways to address it, but a brief definition is
> that it\'s any change where a whole new infant formula is introduced
> in the United States by a manufacturer that has never produced formula
> or a change in current formula where experience and theory,
> particularly that experience and theory of the manufacturer, predicts
> a possible impact on nutritional adequacy of the product, or a change
> where there is a fundamental change in processing or composition that
> also could potentially impact nutritional adequacy.
>
> Now, that change will lead all infant manufacturers to communicate on
> a regular basis with the agency to document very convincingly to the
> industry itself, as well as to the outside, documentation that
> demonstrates that this formula will support normal growth.
>
> The nature of the change and the scientific rationale is what
> determines how much work needs to go into this process before the
> change is implemented and how much and what kind of supportive data
> are given.
>
> Supportive data is always necessary. There is no change that is
> implemented without a clear process of assessment and understanding of
> what the potential impact of that change might be, and of course, that
> supportive evidence will and sometimes does include clinical trial.
>
> Now, there is a whole process or exercise which is gone through for
> each one of these changes or implementations.
>
> First, of course, we do go through what the published guidelines is,
> and I just do want to echo a couple of speakers yesterday who
> indicated that these guidelines, particularly, and a number of
> regulations need updated.
>
> The industry actually does not necessarily wait for this updating. The
> industry tries to maintain, as much as possible, the scientific
> cutting edge from the point of view of what we understand are, for
> example, nutrient requirements in infants.
>
> We don\'t wait, necessarily, for the final guidelines of somebody to
> show that we need to do one or other.
>
> It was very clear yesterday, for example, that some of these
> regulations regarding nutrient requirements in infants need revision.
> They\'re grossly updated.
>
> But the industry doesn\'t wait for that and, with notification to the
> agency, moves along with these changes.
>
> We also have obviously looked at the literature, and pretty much every
> possible discipline that could in some way modify the change\--or,
> I\'m sorry, modify the conclusions with regards to that particular
> change is reviewed.
>
> We go through all the medical literature, the nutritional literature.
> We certainly bring into bearing all the disciplines, whether it\'s
> chemistry, biochemistry, physical chemistry, microbiology, to
> determine if this particular change might, in some or other way,
> modify what we need to do.
>
> Another critical factor in this assessment is the experience of the
> industry, and sometimes the experience of that particular
> manufacturer.
>
> The manufacturer understands\--and most of them do, certainly here in
> the United States\--understand very deeply their product. They know
> what goes into it. They know how the processing happens.
>
> There is extensive documentation on all the physical, chemical
> changes, adulteration changes that go on in a product that they
> already have and that they have followed historically for years.
>
> There is a historical component of experience that sometimes only a
> particular manufacturer will have on a particular set of nutrients or
> a particular matrix or macro-nutrient.
>
> Certainly every manufacturer carefully measures and knows about its
> ingredients, its batching and packaging processes, knows its nutrient
> stability throughout history.
>
> All this needs to come into bear for understanding the potential
> impact of that particular change that needs to be implemented, and of
> course, each manufacturer also has a history of in vivo and in vitro
> testing in its formula, in each type, in each component, its matrix,
> and of course, they have clinical experience.
>
> They have clinical experience on clinical trials, for example, that
> ultimately will help the manufacturer and ultimately those that are
> participants in the process, in the thinking process, to determine if
> the clinical trials that were done following or prior to this change
> still would support this potential change without the need for other
> assessments.
>
> DR. GARZA: Thirty seconds.
>
> DR. SAAVEDRA: Now, once we go through that large exercise, we also
> then, of course, engage in a very\--sometimes very deep\--just like
> you were discussing yesterday\--very deep discussions as to is this
> going to make a difference or not, and even after that, when we\'re
> not totally sure, then we bring people like you to discuss with the
> industry how do we go about this change, what do we need to do, how do
> things need to move along, are we doing the right thing, is there
> caveats we have not thought about, and again, we communicate these
> back to the agency.
>
> Certainly, if, after looking at this whole process \--
>
> DR. GARZA: I\'m sorry, your time is up. Can you conclude?
>
> DR. SAAVEDRA: Yes.
>
> DR. GARZA: I\'m sorry. You have 10 minutes, and if I give you more
> time, I have to give everybody else more time. We have 10 minutes per
> speaker.
>
> DR. SAAVEDRA: With all respect, what we had requested is a 30-minute
> collective presentation.
>
> DR. GARZA: All right. You can continue.
>
> DR. SAAVEDRA: If, after all this, we are still not convinced, then we
> do go on to the development of clinical trials, and of course,
> clinical trials are necessary.
>
> When we talk about minor submissions over the last 10 years, there\'s
> been approximately 100 minor changes submitted to the agency,
> approximately 360 major changes, and 50 growth studies in more than
> 600 children.
>
> Collectively, the U.S. infant industry has more clinical studies and
> growth studies than any single institution or any single entity that
> we can identify.
>
> Now, what this has done, as mentioned before and in some of your
> papers\--this has produced infant formula that now essentially cannot
> distinguish, in this room, who got infant formula and who got breast
> milk. We\'ve made tremendous strides.
>
> Nevertheless, there is still a lot that needs to be done, and since
> that, here in the United States, with this process in place and with
> this implementation, not a single nutrition-based problem has resulted
> from formulation changes intended and implemented by the industry here
> in the United States.
>
> This is the decision tree you will have. We know we will never be able
> to reproduce breast milk. We\'ll never be able to reproduce the act of
> breast-feeding.
>
> The whole point of this process\--and this is what you went through
> yesterday\--as an exercise, I believe, is try to go through each one
> of these changes so that these changes will apply and allow you to
> make decisions which, again, I think need to be made in the context of
> all this documentation that I mentioned earlier, which makes it very
> difficult to make a decision for everything or make a recommendation
> that is a blanket statement.
>
> I will now ask Dr. John Vanderhoof to continue our presentation. This
> particular aspect will relate to the comparisons and groups that need
> to be incorporated into the measure of clinical trial.
>
> Jon?
>
> DR. VANDERHOOF: Thank you very much.
>
> Until eight weeks ago, I was an academic myself, and now I have this
> new job, and I\'m looking at this from a new perspective, and it turns
> out, I guess, it\'s probably not all that different than how I looked
> at things before.
>
> What I want to do is just tell you very briefly a little bit about the
> \"what\" part of the study process, and then Russ Merritt from Ross
> will tell you a little bit more specifically about exactly how we
> conduct clinical studies.
>
> The first point I want to make is that what we\'ve been doing for the
> past several years, since 1988, is based upon the AAP committee
> nutrition guidelines, and I think these have really served us very
> well.
>
> We\'ve had a longstanding history of producing nutritionally adequate
> formulas, and whenever we do clinical studies, safety is, of course, a
> given.
>
> This is something that\'s well worked out during the pre-clinical
> phases. Those questions have, by and large, been answered, and at this
> point in time, we\'re ready to demonstrate nutritional adequacy with
> our formulas.
>
> As everybody mentioned yesterday, the timing of doing a formula study
> is very critical. You need to do it during the first four months of
> life, when infant formula is the sole source of nutrition for the baby
> and the baby is most vulnerable and its most rapid growth phase, so
> that we do want to study the formula at the time when its performance
> could most likely be critically evaluated.
>
> Weight is the predominant end point that we want to measure. It\'s the
> most sensitive indicator of nutritional adequacy, and it\'s our
> primary outcome variable.
>
> Secondarily, we measure length. One thing I learned from taking care
> of lots of children with chronic liver disease is that weight gain is
> not always a good thing, and so, we have to measure length, as well,
> and I\'ve added head circumference. While we don\'t feel it\'s
> mandatory, it\'s a nice cross-check to have available to us on length,
> and we can address gender differences by co-variant analysis.
>
> There may be some instances when we might choose to look at specific
> laboratory measurements or other body mass indices or something, and
> those are the times when we might want to have a specific nutrient
> change or a specific nutrient that we put into the formula that might
> affect one specific biochemical parameter, and at that point in time,
> we would expect to introduce additional laboratory measurements.
>
> We usually do double-blind, randomized prospective studies in most
> instances. This has been for many years the gold standard for clinical
> research.
>
> You might say, well, why would you want to do this if growth data are
> inherently objective measures and you know how babies are supposed to
> grow.
>
> I think there are a lot of times when we do clinical studies that
> we\'re also interested in looking at some secondary parameters and we
> want to find out if there are differences between the new formula and
> the old formula, and we might also be interested in finding out if the
> incidence of adverse events that might be picked up in the study are
> the same between an old formula and a new formula, and at that point
> in time, we would definitely want to have a control group.
>
> Our studies are powered to detect a mean difference of 3 grams per
> day, and a weight gain is a primary outcome variable. This is based on
> the AAP guidelines, and since this standard was adopted, there have
> been no product withdrawals because of nutritional inadequacy, and we
> think that these guidelines have served us very well in the past.
>
> Presently we\'re facing a bit of a problem in that there are a limited
> number of subjects available because of the increased breast-feeding
> rate and a decreasing birth rate, and we have looked into the
> possibility of powering studies to detect smaller differences.
>
> And if you do the math on this, for example, if you did a study that
> required 500 infants, by the time you looked at the incidence of
> breast-feeding, the patients that weren\'t acceptable, and then the
> number that\--the 10 percent that would actually volunteer and then
> the drop-out rate, you would have to screen 24,000 infants to come up
> with that 500, and at the present birth rate, that\'s about the
> population that you\'d see in new births in a city of 2 million
> people.
>
> So, what other options are there?
>
> Well, there are basically historical controls and reference data. We
> have a large volume of that kind of data available.
>
> The advantage of using reference data is it minimized drift over time
> and identifies it. For example, if you look at formula A and compare
> it to B and then the next study you do is compare B to C and then C to
> D, each one of these formulas are a little bit different, so they may
> statistically come out the same.
>
> But if you compared A to D, you might miss something, and you can pick
> that up when you use historical data, and if you didn\'t have to have
> the control group, then you might be able to power the study at a
> little bit higher level.
>
> Ideally, most of the time when we conduct research, this is what we
> would want to do. We would want to use concurrent controls so that we
> could identify these other things that we talked about, like the
> incidence of adverse events and so forth.
>
> We would want to compare the mean data that we have to the mean
> reference data to make certain that we don\'t have any drift, and the
> vast majority of times, or at least frequently, this is the kind of
> study that we want to do.
>
> So, in summary, we think that the present criteria that we\'ve
> utilized since 1988 provide an ideal balance of allowing very nice
> research to be done on infant formulas and, at the same time,
> protecting too many infants from undergoing formula studies and
> subjecting an excessive percentage of the population to studies.
>
> We think that the present guidelines have resulted in superior infant
> formulas and an excellent record of ensuring nutritional adequacy for
> our population.
>
> Powering the studies according to the AAP guidelines has produced an
> excellent safety record, and we\'re very happy with the results that
> we\'ve had using these guidelines.
>
> Regarding the specific questions that you may be pondering at the
> moment, it\'s our opinion that concurrent controls in formula studies
> are usually desirable but in some instances may be unnecessary, and it
> may be appropriate to use reference data in some form.
>
> We also feel that most of the time the weight and length measurements
> and head circumference measurements that we talked about are the
> primary variables that we want to address, but occasionally other
> biochemical or body mass measurements might be indicated in specific
> circumstances where the particular study might indicate their value.
>
> I\'d like to now introduce Russ Merritt from Ross Labs, and Russ will
> tell us a bit about exactly how we conduct growth studies.
>
> DR. GARZA: Thank you, Dr. Vanderhoof.
>
> DR. MERRITT: Thank you for the opportunity to address the committee
> this morning. I\'m going to pick up where Dr. Vanderhoof left off and
> talk a little bit more about the \"how\" of conducting studies.
>
> The infant formula industry has provided you a sample growth protocol
> for infant growth studies that reflects our experience with conducting
> such studies since before the inception of the Infant Formula Act in
> 1980. I hope you\'ve had an opportunity to review it.
>
> There are a number of specific aspects of this study design that I\'d
> like to call your attention to.
>
> The first is to recognize the purpose of a regulatory growth study.
>
> We need to remember that infant formula is food, food for a vulnerable
> population and, at times, the sole food, but still food.
>
> This food supplies the nutrients required for infant growth within a
> range considered acceptable.
>
> We need to specify testing of new infant formulas that provides
> assurance that they support growth during the fastest period of human
> growth, when it is used as the sole food in the diet\--that is, in the
> first four months of life. After four months of age, the common use of
> other foods in the diet make it much more difficult to assess the data
> in a growth study.
>
> The method of achieving this is to demonstrate that a proposed new
> infant formula performs at least as well as a current commercial
> formula appropriate for the population under study. In some special
> situations, additional claims may be sought and additional studies or
> end points will be needed.
>
> Now, as far as control groups are concerned, accepted clinical
> practices generally require the comparison of a new intervention with
> a standard current of practice\--in this case, a marketed infant
> formula.
>
> To put the growth study in an historical context, the growth data are
> always going to be compared to some reference standard such as the CDC
> 2000, the Iowa data, or internal historical data, which may be more
> extensive than some of the reference databases.
>
> So, in effect, a current control and an historical reference play
> different roles in the growth assessment.
>
> The use of an exclusively breast-fed reference group, historical or
> concurrent, assumes that the group of formula-fed infants should grow
> identically to this group.
>
> As of today, no well-recognized standard for exclusively breast-fed
> infants exists, thus the WHO study we heard about yesterday that is
> underway.
>
> We cannot assert at this stage that we know that the growth of a
> breast-fed and formula-fed infant should be identical or that a
> specific feeding regimen has unequivocally been demonstrated to be
> better than others from the perspective of long-term growth and body
> composition.
>
> Furthermore, different initial growth patterns may turn out to be
> preferable from the standpoint of different clinical outcomes\--for
> example, neuro-development, obesity, cardiovascular risk, etcetera.
>
> We move to one-sided versus two-sided.
>
> One-sided testing addresses the critical question of whether the new
> formula performs at least as well as a current commercial formula.
>
> That\'s the question we need to address, and in contrast, two-sided
> testing, as usually performed, is less sensitive because it dilutes
> the power.
>
> If we look at the sensitivity to measure nutritional adequacy, it\'s
> not certain that very small differences between groups are necessarily
> meaningful.
>
> The existing de facto standard of 3 grams per day, approximately a
> half a standard deviation, appears to have served us well. At this
> stage of our knowledge, we simply do not know the best infant growth
> pattern, especially not for the individual infant in a study.
>
> For context, please bear in mind that studies to define longitudinal
> growth status that are underway\--for example, the WHO multi-center
> study\--are actually smaller than the studies that some food advisory
> committee consultants have suggested to verify that a single new
> infant formula, which will already be known to contain the necessary
> nutrients, supports growth.
>
> So, some of the suggested protocols are actually greater, numbers of
> subjects are actually greater than what is being used in that study.
>
> We\'ve also heard repeatedly from the consultants that it\'s a misuse
> of the available science to pretend we understand the health
> implications of a gram or two of weight gain per day for a short
> period in human life or to define an extraordinarily specific
> statistically-driven definition of a single rate and pattern of infant
> growth as the only one that is normal or even acceptable when testing
> infant formula.
>
> What we\'re trying to get to is an actionable protocol. The growth
> protocol provided by the industry acknowledges the important need to
> continue to provide assurance that new formulas support normal growth.
>
> Although the outline submitted is brief, the actual protocol may
> extend to 80 pages or more, as specific details are filled out in a
> specific instance.
>
> The Infant Formula Act places a responsibility on manufacturers to
> demonstrate that their formulas can function adequately as substitutes
> for human milk.
>
> To date, the manufacturers have met this obligation effectively, often
> through the use of a growth study.
>
> The growth protocol utilizes the current scientific approach of a
> randomized, blinded, control trial in conjunction with
> well-characterized reference data for infant growth.
>
> A couple of comments on the evolving context in which we do these
> studies.
>
> This is not a static environment. The nation is coming closer to the
> Health People 2010 goals for breast-feeding. This will have the effect
> of reducing the number of exclusively formula-fed infants available to
> participate in clinical trials.
>
> In addition, evolving ethical standards may further limit the types of
> studies acceptable in pediatric subjects.
>
> Such changes may make it increasingly difficult to complete even the
> growth study protocol which industry has used.
>
> Thus, rather than moving to more restrictive protocols, other
> approaches regarding study participation, eligibility, and/or fewer
> subjects for the use of historic references may need to be considered
> in the future.
>
> The current system has effectively protected the public health while
> allowing more than 20 new infant formulas to enter the marketplace in
> the last 10 years.
>
> We welcome a more predictable process and regulatory environment, as
> well as the collective expertise which the Food Advisory Committee and
> the FDA have brought to bear here today.
>
> However, in your deliberations on these issues, we do ask that you be
> mindful that more restrictive standards may not achieve any greater
> assurance of nutritional adequacy but could substantially reduce the
> ability of industry to bring the benefits of new science to infant
> nutrition in a timely fashion.
>
> Thank you for the time.
>
> DR. GARZA: Thank you, Dr. Merritt.
>
> We have a choice\--we have one more speaker that has come forward\--to
> hear the additional speaker and then ask questions to all four, or you
> can\--we can take the time now to ask questions to the first three
> speakers. Is there a preference among the group?
>
> Do all four? That would be my sense, as well.
>
> I\'d like to then call Ms. Barbara Heiser\--I hope I\'m pronouncing
> that name correctly\--executive director of the National Alliance for
> Breast-feeding Advocacy.
>
> Ms. Heiser, I\'ll warn you about 30 seconds before your 10 minutes are
> up.
>
> MS. HEISER: Thank you for taking the time this morning to let me speak
> before the committee. My name is Barbara Heiser. I am the executive
> director of the National Alliance for Breast-feeding Advocacy.
>
> I\'m a registered nurse and also an international board-certified
> lactation consultant.
>
> I guess, to start with, yesterday, as I sat and listened from the back
> row, I wanted to stand up as we talked about optimal infant feeding
> and say wait a minute, we\'re mammals, our milk is species-specific,
> human milk for human babies. That\'s optimal feeding.
>
> That doesn\'t mean that the other formulas and all aren\'t important
> and shouldn\'t be good. They should.
>
> But we know optimal feeding is exclusive breast-feeding for six
> months, not even four to six months, six months. That\'s been decided
> after at least\--I\'ve been in discussions internationally for 12
> years on that subject.
>
> It has been reviewed, literature, research, everything, and optimal
> feeding as exclusive breast-feeding for six months has now been agreed
> upon by the American Academy of Pediatrics, by the Surgeon General of
> the United States, as well as WHO.
>
> So, I think that has to be our standard. Does it mean that formula
> feeding has to have the same growth pattern? I don\'t know. But when
> we say there has to be a standard, we should have the standard that we
> know is best for babies.
>
> The other thing that NABA has worked on very hard is speaking for
> breast-feeding moms and babies.
>
> We don\'t speak for any group or professional organization; we speak
> specifically for breast-feeding.
>
> As a mother, I don\'t think the government agencies understand how
> much trust the general public put in you.
>
> When a formula\--when something new comes out, they\'ve heard all the
> reports about how drugs take years and years and years to go through
> testing before they go to the public and they think that\'s true of
> everything.
>
> Recently, with the addition of the long-chain fatty acids\--DHA and
> ARA\--moms think it\'s wonderful.
>
> However, the marketing has been so wonderful that mothers are
> afraid\--well, they\'re happy. They call me up and say which formula
> has the breast milk in it.
>
> And then yesterday I got called\--and you\'ll appreciate this if
> anyone\'s from California. It was from California, and a mother went
> to the WIC program, because they\'re working on contracts right now,
> for the new formulas, and she says whose breast milk is in the
> formula? I want to know, because I want to know if it\'s safe. Okay.
>
> That\'s how it\'s been perceived, and we know that the DHA and the ARA
> that\'s been added is fermented micro-algae and soil fungus, whatever
> it has taken to produce this\--these aren\'t even in our normal food
> chain, and we\'re having a lot of babies have problems with this.
>
> Now, yesterday, one thing that had not come to my attention previously
> was the liability factor as far as hospitals, food poisoning, adverse
> events.
>
> Most of the people working at ground zero with moms and babies don\'t
> know lots of babies have allergic reactions or problems with different
> formulas.
>
> That\'s why there\'s so many out there for them to try and why each
> company makes different kinds.
>
> But we\'re seeing a lot more explosive diarrhea with this, and we\'ve
> been wondering why some of the reports\--in looking at post-market
> surveillance, just in my mind as a mother and an advocate for women, I
> worry that the 4 million babies being born in the United States are
> being guinea pigs for post-market surveillance without the mothers
> knowing that it\'s being looked into if formulas are safe.
>
> They think it\'s already been through 10 or 12 years of testing, and I
> know the companies do a lot of testing, and I appreciate that, and I
> want to say that I believe infant formula is a very necessary part of
> our society. I was a NICU nurse. It\'s very important. But I want to
> make sure it\'s the very best product and it\'s perfectly safe for our
> babies.
>
> Also, as a mother, we talk about easy growth measurements\--height,
> weight, head circumference\--very easy to get, very now, but that
> wouldn\'t be what I want to know about this food to my baby.
>
> I want to know that it\'s giving everything, and we know that the
> important thing for growth for human babies is brain and
> neuro-development, and so, I really ask the committee to look at the
> regular growth parameters. They\'re very important.
>
> But you have to have some looks at the neuro-development, also. It\'s
> been hard to find because of the marketing.
>
> I mean I hear the companies now say that there\'s less totally
> artificially-fed babies out there, formula-fed babies out there, and
> that\'s funny, because we\'ve had the same thing on the breast-feeding
> side.
>
> Because of marketing and supplementation, there\'s been fewer and
> fewer exclusively breast-fed babies out there.
>
> But we need to look at it, and I was excited yesterday, hearing about
> what you\'re doing, because I thought, you know, okay, we know optimal
> breast-feeding is exclusive breast-feeding for six months.
>
> Now, as FDA is doing some studies on new formulas and ensuring, the
> topic was brought up, you know, well, how do we know if a new formula
> starts the growth pattern of a breast-fed baby that it\'s really still
> meeting the nutritional needs? Well, if you\'re doing your study
> right, we\'ll know, and we\'ll have the proof that the formulas are
> just as good as they can be, and I think that would be very important.
>
> The last thing I want to say is, once again, mothers expect safety
> from the government more than you know.
>
> They expect great products from the companies. You have a great
> burden. When a health-care provider gives a mom that discharge bag
> full of the goodies, it\'s like the health professionals are endorsing
> that product to them.
>
> And so, what I ask of you on this committee is, as you deliberate and
> set up growth standards, please know that breast-feeding is optimal
> for six months, and please find out what\'s best for babies on infant
> formula and what\'s the safest for them.
>
> Thanks so much.
>
> DR. GARZA: Thank you, Ms. Heiser. Before you leave the podium, don\'t
> take your microphone off. There may be some questions, and we\'ll take
> questions.
>
> Does the committee have any questions of Ms. Heiser?
>
> Dr. Stallings?
>
> DR. STALLINGS: Thank for being with us.
>
> As a point of clarification, I\'m not sure that the American Academy
> of Pediatrics Committee on Nutrition has endorsed six months of
> exclusive breast-feeding.
>
> MS. HEISER: In their latest statement, they have.
>
> DR. BAKER: I\'m a member of the Committee on Nutrition, and we have
> not. The official policy of the Academy of Pediatrics is still four to
> six months.
>
> There is a new yellow book coming out which will have new
> recommendations, and it\'s not decided yet what that will say.
>
> MS. HEISER: I\'m sorry. I gave that information from the United States
> Breast-feeding Committee on which AAP does sit, and Dr. Larry Gartner
> gave it to us. So, if I mis-quoted, I am sorry, but I had it from a
> primary source.
>
> DR. GARZA: Are there other questions?
>
> Ms. Heiser, you mentioned that there\'s an increased rate of diarrhea
> and other illnesses or intolerance.
>
> Is that from monitoring information that your organization collects,
> or is that based on your professional perception, or can you give us a
> bit more information on that?
>
> MS. HEISER: The information I can give, unfortunately, is only
> anecdotal, but as a organization, we do collect information. We
> encourage mothers to report adverse events via Med-Watch and to report
> to the companies, as we do when we train nurses, etcetera, and we\'ve
> been doing this for the past several months, because initially, when I
> heard of it, I just thought it was one incident, and then I heard it
> again, and we lecture throughout the country, so we have had a pretty
> good report.
>
> The most recent one came from the State of California, the WIC
> program.
>
> A lot of the mothers there were buying formula on their own because
> they wanted the best for their babies, and they reported large number
> of cases of explosive diarrhea, to the point that the WIC director,
> when they were looking at the contracts for the upcoming year, was
> concerned if that was the only product they were going to have
> available to their population.
>
> DR. GARZA: Any other questions?
>
> Dr. Downer?
>
> DR. DOWNER: Thank you for putting a human face to this.
>
> I wanted to find out, with respect to the anecdotal evidence that
> you\'ve been collecting, have you looked at all at how the formula is
> being handled with respect to safety issues, to see if this may be
> impacting on, for example, the explosive diarrhea that you mentioned
> today?
>
> MS. HEISER: Yes, we do question that. We\'ve been asking specifically
> health professionals with babies in NICUs and in the hospital setting
> where we have total control to really look at that issue, so we\'ll
> have some information. As of yet, that hasn\'t been gathered.
>
> But from the general population, we\'re getting more cases of it, and
> these are the same people mixing and doing other formulas, too,
> without it.
>
> So, I see them as their own control group, because they\'re using both
> kinds.
>
> DR. GARZA: Dr. Stallings?
>
> DR. STALLINGS: I was interested in your comment that the public
> perceives infant formulas as, in essence, being managed more like
> drugs than like food.
>
> Could you make a few more comments on that and the basis\--the
> information that led you to make that summary statement?
>
> MS. HEISER: Okay. The reason is, initially, with health-care
> providers, because a lot of the information goes into food and drug
> through Med-Watch and also because of the promotion by the companies
> to hospital personnel, they are treated as vendors on the\--you know,
> as drug vendors more than the PO office for the foods down in the
> cafeteria, okay? So, that\'s the beginning of it.
>
> The other is, as claims come out, health claims and all, as that comes
> out, then people look at formula as more than just a bowl of cereal,
> okay?
>
> They know it\'s important because the Academy of Pediatrics has said
> don\'t give regular milk for one year. You know that the baby needs
> more in its growing time, that it\'s very important that it has this
> thing.
>
> We still have grandmas around that remember pediatricians making up
> their own special concoctions of formula to meet those nutritional
> needs.
>
> So, this is where that perception comes from, that it\'s not just
> something you can go out and get.
>
> DR. GARZA: Thank you very much, Ms. Heiser. We certainly appreciate
> your taking time with the committee this morning.
>
> And I\'d like to ask Doctors Saavedra, Merritt, and Vanderhoof if they
> would please come up, and I think it will be easier for us to ask
> questions if the three of you are up at the podium, assuming that we
> will have some.
>
> Dr. Stallings?
>
> DR. STALLINGS: Thank you gentlemen for being with us.
>
> I\'m interested in having you discuss the issue, really, as the
> one-tailed versus the two-tailed analysis, because I think all of
> us\--and I certainly know, including all of you, are interested in the
> issue of over-nutrition, as well as under-nutrition, and that seems to
> be one of the core issues that we\'re dealing with.
>
> So, could you make a few comments and, in some ways, try not to do the
> practical issue, because I\'m asking you more of the theoretical
> question now.
>
> I know it takes twice as many subjects or almost twice as many.
>
> Thank you.
>
> DR. MERRITT: I\'ll start, since I brought that up.
>
> The historical context has been to assure nutritional adequacy, and in
> that context, if you look at how the study is designed, if you were to
> put all of your power on the lower half of the study, then, in effect,
> you have greater sensitivity to detecting a problem on the low side.
>
> Relative to additional protections on the high side, as Jon and I both
> noted, we not only will generally compare a new formula or a modified
> formula to an existing formula but also then check these data against
> a reference standard, whether it\'s CDC 2000 or Fels, etcetera, and in
> general, what we find is concurrence of the two answers.
>
> I think if you\--if we were in a situation where there was not
> concurrence of those answers, we would, you know, do some additional
> thinking and some additional assessment.
>
> So, I think you have the dual assurance of somewhat greater
> sensitivity on the low side but also the cross-check against your
> historical norms.
>
> DR. GARZA: Dr. Denne?
>
> DR. DENNE: You told us there had been 150 major changes and 50
> clinical studies, and I was wondering if you could tell us\--give us
> an example or two of a major change that didn\'t require a clinical
> study and the rationale behind that.
>
> DR. SAAVEDRA: There\'s a number of examples.
>
> For example\--and there\'s many ways to try to understand the\--I
> think what\'s critical is understanding the process, the thinking
> process, because that\'s really what you\'re all charged with, is
> understanding if that major change\--for example, a particular
> ingredient in a new formula\--is going to be impactful from the point
> of view of nutritional adequacy.
>
> So, a particular ingredient can be added to a formula that has
> slightly changed from the point of view of the manufacturer\'s matrix
> over a period of time, and we add that ingredient, which has already
> been tested, which is already GRAS, which has already been analyzed
> biochemically in terms of nutrient stability, in terms of physical
> chemical stability, in terms of possibility that could adulterate
> other products and so on and so forth.
>
> So, because it is a new ingredient to that particular product\--for
> example, a soy formula versus a milk-based formula\--then that is a
> major change.
>
> However, extensive experience with the basics of understanding of that
> ingredient, as well as the formula, and all the interactions that
> could possibly happen, that we could identify within that\--for that
> change don\'t necessarily mean that you need to study 100 or whatever
> number of children to demonstrate that it is safe and that the formula
> hasn\'t changed from the point of view of providing nutritional
> adequacy.
>
> So, these are major changes, and they\'re classified that, and I
> don\'t think we\'re going to go into the discussion of a particular
> major change.
>
> But this is an example in which a growth study would essentially be
> unnecessary if there has been all the evidence from the point of view
> of the ingredient, from the point of view of the product, and the
> manufacturer\'s understanding\--I think this is critical also to
> understand that each manufacturer knows very well its matrices, its
> proteins, its fats, and every ingredient that goes in there, so that
> this predictability from the point of view of potential nutritional
> impact can be established.
>
> DR. GARZA: Dr. Anderson?
>
> DR. ANDERSON: I\'m going to suggest two criteria for the setting in
> which clinical growth studies are not required and ask you to comment.
>
> The first would be that they would be required only when there is a
> reasonable basis to predict that a change to a formula will materially
> impact nutritional adequacy or otherwise have a significant adverse
> impact.
>
> The second would be that they\'re not required when the preponderance
> of the evidence suggests that a change will not affect the ability of
> the formula to promote normal infant growth.
>
> The emphasis is really on\--I\'ve tried to formulate these in a way
> that\--in the first instance, the assumption is really that the change
> is safe unless otherwise\--unless thought otherwise, and in the second
> instance, one needs to demonstrate safety in order not to proceed with
> a study, and I wondered if you could comment.
>
> DR. VANDERHOOF: I\'ll try that one.
>
> First of all, I think if there\'s reasonable likelihood that\--or even
> a reasonable suspicion that the formula might adversely affect growth,
> we probably would choose not to even test that.
>
> So, we would only want to test a formula clinically that we were quite
> certain was nutritionally adequate.
>
> And then to take that a step further, I think unless we were extremely
> certain that there would be no adverse effects on growth, we would
> want to do a growth study on the babies and particularly any kind of
> an ingredient change or anything that might somewhat affect any
> parameter that involves growth, such as the changes in the hormonal
> milieu or tropic factors or anything like that that could be
> secondarily affected, would certainly trigger a growth study to be
> done.
>
> I think there are other instances, as Pepe mentioned, when certain
> ingredient changes would predict absolutely no effect on growth, and
> in that instance, you may not need to do it if the manufacturer has
> extensive experience in that regard.
>
> DR. GARZA: Dr. Stallings?
>
> DR. STALLINGS: You all were with us yesterday when we had the good
> fortune of having Dr. Fomon recap some of the history that, you know,
> I\'m sure informed the 1980 law and then the 1988 Academy of
> Pediatrics advisory group which put together the things that we\'re
> currently operating under.
>
> And at that point, he was saying that the 3 grams a day, you know,
> basically was an opinion at that point based on those data and a
> little bit of good clinical judgement, which often informs all of it,
> and then yesterday we had, if you will, a group getting together and
> considering the same thing, and my sense of what we heard yesterday is
> that 3 grams a day difference may be higher than it should be and that
> we might be well-informed to reduce it a little bit.
>
> So, I was interested in your comments, knowing all of you have been
> through the opportunity to serve on consensus committees and
> recommendations and that sort of thing, but I think I was hearing that
> that number, which may have served us well in the past, might need to
> be revised.
>
> I\'d be interested in your opinion on that.
>
> DR. VANDERHOOF: I\'ll give you my opinion, and then maybe this is an
> important enough topic that we probably all ought to comment on it,
> but this is an arbitrary number. I think that\'s probably where it
> came from. Somebody had to pick a place to start.
>
> Here you try to strike some kind of a balance.
>
> You know, if you want to do a controlled study with a control group
> and get an appropriate number of babies and whatever and you power it
> to that level, I think it\'s reasonably practical in terms of not
> subjecting too many babies to clinical studies and, at the same time,
> getting the information that you need, and remember, this is where we
> power the study, and in actuality, what happens is that the curves are
> normally quite similar, and that\'s not to say that we expect to see
> that kind of a difference.
>
> I think if you go beyond that, then you have to start looking at other
> situations where you might need to eliminate control groups, and that
> then has a negative on the other side of the equation.
>
> So, there may be instances where it might be necessary to power the
> study differently, but I think for the vast majority of cases, this is
> probably adequate, and it\'s certainly done well for us in the past.
>
> Russ?
>
> DR. MERRITT: I think if we had greater assurance as to what\'s best, I
> could have more enthusiasm for trying to get closer to that standard,
> but in the absence of that knowledge and the history of protecting the
> public health with the 3-gram standard that seems inherently
> reasonable, as well, I\'m not convinced we\'ve made the case that, in
> fact, a different standard will give you additional assurances.
>
> It will certainly increase the time and the number of babies and such
> that will have to be involved in the studies in order to bring new
> formulas or make changes in formulas.
>
> So, I think in the absence of that kind of certainty about the
> standard, it makes it very difficult to rigidly pursue it.
>
> I\'ve looked into, you know, the historical differences that we\'ve
> seen recently, and although we\'ve powered the studies for 3 grams, in
> almost all instances the actual difference is quite a bit less.
>
> DR. SAAVEDRA: I just want to add\--I certainly concur with what Russ
> and Jon said, but I do think that, aside from that\--and certainly
> I\'m trying to understand as best as possible what is ideal, which I
> know none of us can actually say what is ideal.
>
> In the absence of that, it is striking the balance between what is
> practical, what is doable, and what is beneficial.
>
> I mean I think the goal here, if we want to do something that allows
> us to make improvements and enhancements in infant nutrition\--and we
> have\--as we said before, we\'ve come a long way\--it\'s striking the
> balance that we as\--and all of you as academicians have to grapple
> with all the time, and these differences of three grounds that we\'re
> talking about is between the control and the experimental group.
>
> As we discussed, for example, in Jon\'s talk, there can be drift. The
> difference may be 3 grams for that group but may not be with the
> reference population or may not be between two different groups that
> were compared to the reference population.
>
> So, until we know what is the right one that we\'re comparing to, then
> trying to find minute differences and smaller and smaller
> differences\--which, of course, in the ideal situation, in the
> non-human situation, which is the ideal one, it would be doable\--we
> need to do our best to strike that balance, and I do think we need to
> take history into consideration, and I did mis-quote, I said 600
> children instead of 6,000 children, but that\'s the kinds of numbers
> that have evolved into having the kinds of formulas that we have now.
>
> DR. GARZA: Rather than addressing the 3-gram issue, I have a more
> generic question. Each of you referred\--I think each of you referred
> that you would be supplying data demonstrating the support of normal
> growth. What is normal growth, from your perspective?
>
> DR. MERRITT: What I thought I took home from yesterday\'s comments
> here was that there are a lot of opinions based on our scientific
> experience, based on our bias, based on our personal preference, but a
> definition of normal beyond the context of what has historically
> happened is very difficult, and I think the knowledge has simply not
> reached that state.
>
> So, I think we have a default definition of knowledge of normal that
> reflects, for example, in the first few months of life, NCHS or Fels
> or the historical data that are available to us and that, much like,
> you know, an acceptable daily intake, this is the experience that
> appears to be associated with reasonable health.
>
> DR. GARZA: Dr. Merritt, before you pass on the mike, in the absence of
> ideal information, which we often deal with in medicine, we often to
> go to defaults and often in terms of normal physiology and history.
>
> I have not understood the rationale for saying that, in fact, one
> can\'t use, in the absence of whatever one might define as ideal
> information, the growth patterns of breast-fed infants as that normal
> standard, and notice I didn\'t use the term \"reference\" but
> \"standard,\" precisely for the reasons that you\'ve outlined, that,
> in fact, we don\'t have ideal information available to us and that we
> have to depend on some default and that, until proven otherwise, the
> breast-fed infant becomes that standard.
>
> What is faulty with that rationale?
>
> DR. MERRITT: I think we already know that, at some stages, probably
> less in the first three to four months than subsequently, there are
> some differences between the breast-fed and the formula-fed infant.
>
> We\'ve also seen that, by approximately two years of age, they appear
> to come a little closer together, and picking up on something I think
> Jon said earlier this morning, I don\'t think, at 10 years of age, we
> have the ability to look back through the retrospectoscope and say who
> was breast-fed versus who was bottle-fed.
>
> And we certainly, at this stage, do not know the implications for, you
> know, the chronic diseases of later life, as well as even
> neuro-developmental issues, as to what particular mode of feeding or
> combination of foods or combination of breast-feeding with or without
> supplementary foods is truly going to give us a particular outcome at
> some lengthy time point remote from the feeding experience.
>
> DR. GARZA: But if that\'s true\--I need to press this, because it\'s
> an issue that we\'re going to be dealing with once you get off the
> podium.
>
> If that\'s the case, then we have a historical experience of millennia
> with human milk feeding, a rather recent experience with formula
> feeding.
>
> In the absence of that type of information, why not use the breast-fed
> infant as the default?
>
> I mean I am failing to understand the rationale that, because we
> don\'t have information, then, in fact, we have to rely on historical
> information, but if we rely on historical information, then we\'ve got
> the historical information of the feeding patterns for millennia. How
> do we get ourselves out of that bind?
>
> DR. VANDERHOOF: Well, let me make a comment, and then I\'ll turn it
> back to Russ.
>
> As a clinician, we\'ve all had experiences in dealing with
> children\--breast-fed children with failure to thrive, and one of the
> first things that you do is change the mode of feeding and find out
> how well the baby gains weight.
>
> And very frequently, the baby will markedly increase their formula
> consumption and they\'ll gain weight very rapidly, and when you look
> at the feeding patterns for breast-fed babies, I think you have to
> consider that there are probably a fair number of babies in that group
> that are probably not getting as many calories as they might want,
> because the process of feeding the baby is different.
>
> And so, if you simply look at this as a nutritional component problem,
> I think you may be missing the differences in process, that the
> process of breast-feeding, the interaction between the baby and the
> mother, the cues for the baby determining when\--and the mother
> determining when the baby\'s had enough to eat and so forth are all
> significantly different, and so, this factor\--these factors may
> influence the differences in weight gain, as well as nutritional
> factors.
>
> And if we go back\--and then, within infant formula\--I think somebody
> brought this up yesterday\--I\'m not sure who it was\--if we go back
> and try to replicate that by changing the nutrient mix in the formula,
> we may end up depriving the baby of essential nutrients that it might
> otherwise need.
>
> So, I think the problem is there\'s an additional difference in
> process, as well as formula.
>
> DR. GARZA: Without a standard, Dr. Vanderhoof, what prevents the
> formula industry from manipulating the composition to match any other
> standard or any other reference?
>
> If one can do that to, in essence, match the breast-fed infant to
> create the sorts of problems you just described, doesn\'t that argue
> that, in fact, one could do it in the other direction, as well?
>
> DR. VANDERHOOF: We could probably make a formula that could duplicate
> the growth curve of a baby that\'s breast-fed, but you\'d have to do
> it by making a formula with the caloric density significantly lower
> than breast milk, and it\'s been our standard to try to replicate as
> nearly as we can what\'s in breast milk when we create the formula.
>
> So, the only other way to do it would be to feed the baby less milk.
>
> DR. GARZA: In fact, that would not meet the nutritional standards of
> present law if you did that, right, if you manipulated it in that
> fashion.
>
> DR. VANDERHOOF: That\'s right.
>
> DR. GARZA: Okay.
>
> Are there other questions?
>
> Dr. Heubi?
>
> DR. HEUBI: On a totally different vein, the question that was raised,
> I think, by Ms. Heiser this morning was one that I think we addressed
> at our last meeting here, and that was the reporting of adverse events
> related to formulas, and the comment was made\--and I don\'t remember
> who made it in April\--the comment was made, I think, that many
> reports are made to companies that don\'t come to Med-Watch regarding
> adverse events related to formulae, and Ms. Heiser was making this
> comment about introduction of a new formula, and now there are myriad
> complaints.
>
> Can any of you comment about this and how this work vis a vis the
> agency and the individual companies?
>
> DR. MERRITT: In accordance with the Infant Formula Act, we each have
> mechanisms for both recording and assessing all complaints of any type
> relative to infant formulas that are reported to us, and the FDA
> examines those on an approximately annual basis to\--along with
> us\--identify any potential issues that may have emerged.
>
> And we are highly responsive and, I think, responsible in this regard
> in terms of the effort that goes into the record-keeping and the
> assessment of those complaints, and in some instances, for example,
> when a new formula is marketed, we will review those at periodic
> intervals to make sure there isn\'t something happened in the
> marketplace that we had not been seeing previously. So, I think those
> safeguards are in place.
>
> DR. HEUBI: Let me ask one question beyond that, and that is there
> was\--there\'s been discussion, at least at the NIH and other agency
> levels, about having independent monitoring boards, and I know that
> most industry has their own internal, and then there\'s this obvious
> potential for conflict of interest in terms of that particular
> scenario, reviewing your own data, saying, oh, there\'s not a problem.
> Can you comment about that?
>
> DR. MERRITT: I think for a standard growth study of the type that
> we\'re describing here for changes within the realm of a change in the
> formulation but not a dramatic change in claims, for example, on the
> formula, there is enough experience and enough guidance in the form of
> the International Conference on Harmonization and the like relative to
> how these studies are conducted that I think that would be, at least
> in my impression, an unnecessary degree of oversight.
>
> Now, there may be special situations when you\'re studying special
> populations and making more novel interventions when an external
> advisory board may, in fact, be indicated.
>
> DR. GARZA: Dr. Briley?
>
> DR. BRILEY: Yes. I\'d like to ask a question.
>
> I understood that you said that, when you did a product testing such
> as soy, that you knew all the scientific background and all of the
> chemical background, the physiological background, but I guess I
> didn\'t understand or maybe you didn\'t come across\--how would you
> know if that product was absorbed, utilized by the child unless you
> had done a clinical test with that new product?
>
> DR. SAAVEDRA: What I was talking about is, for example, the addition
> of a particular change in a ingredient in a soy product that has been
> used and has clinical trials already.
>
> Of course, a change in the protein, a change in the protein source is
> what would be considered a major change, and actually, that would be a
> very good example of a time where you do need a growth study, if
> you\'re using a protein that has not been used before.
>
> So, from that point of view, absolutely, this would be a very good
> example of one of those situations where a clinical trial is pretty
> much self-evident from the beginning.
>
> DR. MERRITT: Bear in mind, that would be done in the context of what
> was already known, for example, from the animal literature and the
> like that demonstrated the availability of the protein source.
>
> DR. GARZA: We are going to give Dr. Kuzminski the last question, so we
> can stay on schedule.
>
> MR. KUZMINSKI: One of you\--I believe it was Dr. Saavedra\--described
> the use of pre-clinicals, both in vivo and in vitro, prior to clinical
> testing.
>
> Could you provide us with a little bit more detail on what these
> pre-clinicals are and some idea of the reliance on the use of them in
> contrast to going to a full-scale test?
>
> DR. SAAVEDRA: Yes.
>
> The in vitro studies have to do with a number of characteristics of
> the product that relate to chemical, bio-chemical, physical chemical
> studies that are actually done in the product to measure the stability
> of the ingredient, the fact that the ingredients that were previously
> there didn\'t change, didn\'t become adulterated, and so on and so
> forth.
>
> So, there\'s extensive trial work that goes on, typically, at
> the\--what is part of the R&D phase of a particular product to make
> sure that, from the structural, chemical, and physical chemical
> characteristics that might in some way modify a particular or interact
> with another particular ingredient within the formula don\'t happen.
>
> If they do, then, of course, this typically requires further
> assessment to decide if this is even a viable product.
>
> Many times the change is dramatic enough that there is not worth in
> continuing that kind of modification, because the in vitro work
> actually demonstrates that the change is significant enough that it
> might actually have more nutritional impact that you would think.
>
> I do want to emphasize that once we go to the clinicals following
> those studies, it\'s because we have\--for the most part, the industry
> feels very reassured that there is no nutritional inadequacy.
>
> I can assure you\--and I\'m sure you all as clinicians would not test
> a product that you don\'t think is going to be the same or better.
> That happens only after you\'ve gone through this, as I said,
> extensive exercise where you do this kind of testing to understand
> better these changes before you even give them to animals and then
> before you give them to humans.
>
> MR. KUZMINSKI: So, the in vivo part of the pre-clinicals are
> animal-based.
>
> DR. SAAVEDRA: Usually, yes.
>
> DR. GARZA: All right. I certainly want to thank the three of you for
> your patience with the committee and your help in our deliberations.
> Thank you.
>
> DR. SAAVEDRA: Thank you.
>
> DR. GARZA: On the agenda are final questions to invited speakers. I
> don\'t want to\--I think the word \"final\" is perhaps too final. I
> think that most of them have been willing to stay throughout the
> meeting and will be available to us, but having reflected on the
> discussions yesterday, I want to check with each of you to see if
> there are any questions you may have to any of the presenters before
> we continue with question four, where we left off yesterday.
>
> Dr. Stallings?
>
> DR. STALLINGS: I felt like, after yesterday, I had a much better
> understanding of how modern breast-fed and formula-fed infants grow
> compared to the different references, but I didn\'t think I came away
> with quite as clear an idea of how breast-fed and\--modern breast-fed
> and formula-fed babies are growing compared to each other, because a
> lot of the demonstrations we saw were really reflecting the
> idiosyncrasies of the growth grids that we have today and how\--going
> from the \'77 to the new 2000 and potentially to the WHO.
>
> So, I wondered if Ed or someone might be able to address looking at
> that and trying to focus on the difference in growth in the first four
> months or the first six months.
>
> DR. GARZA: Ed, do you have any of those charts with you?
>
> DR. STALLINGS: I don\'t know if it\'s helpful, but that\'s why we had
> the chart brought in.
>
> DR. FRONGILLO: Well, let me tell you what I\'ve done, and you can ask
> me how you want to display it, okay?
>
> Virginia asked me about this first thing this morning, so I was
> sitting here playing with my computer, calculating these rates.
>
> I have brought with me\--happened to bring with me the Iowa data and
> also some data from Newfoundland that Alex Roach and team collected.
>
> The Iowa data are expressed in terms of rates from eight to 42 days
> and then from 42 days to 112 days, and basically, there, in the
> eight-to-42-day period, there is really no difference for males or
> females in rate between breast-fed and formula-fed.
>
> So, in the early period, from eight to 42 days, there was no
> difference, but in the period from 42 to 112 days, roughly a little
> past a month to almost six months, that\--four months, I\'m
> sorry\--that there were differences for weight of about 3 grams per
> day, with the formula-fed being faster, and a difference\--a really
> quite small difference in length, in millimeters per day. It\'s in the
> order of .07 millimeters per day, which is\--I think we can all agree
> is really small.
>
> So, essentially we have differences of\--for males, it was 3 grams per
> day and for females, it was 2 grams per day.
>
> DR. STALLINGS: There was a gender difference in the second interval.
>
> DR. FRONGILLO: Right. Okay. So, that was for the Iowa data.
>
> So, basically no difference in the early period and some difference, 2
> to 3 grams per day, in weight for the second period.
>
> The data in Newfoundland\--those data\--I actually showed some of
> those data in my presentation yesterday.
>
> There were data on breast-fed infants and then three different
> formulas. So, I averaged together all the data from the formulas, so
> we can just have two groups.
>
> And there, it was zero to two months, two to four months, four to six
> months.
>
> There there\'s a different pattern, because in the zero to two months,
> the breast-fed infants for both males and females grew about 3 grams
> per day faster from zero to two months, and then, after that, from two
> to four months, for both males and females, there was a difference in
> the other direction, a large difference in the other direction.
>
> For males, it was about 6 grams per day, and for females, it was about
> 3 1/2 grams per day, and then, similarly, the growth rates are all
> slowing, but there\'s similar differences from four to six months.
>
> So, basically, in the Iowa, there was no difference in the early
> period and a difference afterwards in favor of formula feeding, but in
> the other data, the Newfoundland data, the breast-fed infants grew
> faster in the first two months and then more slowly after that.
>
> DR. GARZA: In the Icelander data, what years were these infants fed?
> Do these come from formulas fed in the \'80s or formulas fed in\--the
> Iowa data, I assume, were formulas in the \'70s, Dr. Fomon?
>
> DR. FOMON: They went from 1968 to 1987.
>
> DR. GARZA: With the predominance being about equally spread throughout
> that period?
>
> DR. FOMON: I don\'t know. There\'s no difference between the earlier
> and the later.
>
> DR. GARZA: Dr. Sigman-Grant.
>
> DR. SIGMAN-GRANT: I didn\'t catch the differences in the four to six
> months. Same direction as the two to four months?
>
> DR. FRONGILLO: In both data sets, in the later period\--so, in four to
> six months for the Roach data\--there was\--the growth rates were
> faster for the formula-fed.
>
> The difference wasn\'t as great as from two to four months, but
> that\'s partly, I think, the rates are just overall lower.
>
> DR. GARZA: Any other questions?
>
> Part of the difficulty that we will face as we go on to the next
> questions is that, as we look at these growth differences, that there
> are other physiological differences between these groups that are
> difficult at least for me to interpret in that when studies had
> looked\--compared breast- and formula-fed infants, there are
> differences in basal metabolic rate, for example, between the two
> groups before even differences in growth rates up here.
>
> There are differences in heart rate, in temperature regulation, energy
> regulation.
>
> So, there seem to be some concrete physiological differences that go
> along with the differences in growth that need to be borne in mind, so
> that whether or not one pattern is consistent with those physiological
> differences, whether they\'re adaptive or not, makes the
> interpretation of this data particularly vexing at times.
>
> Are there any other questions that you all have to any of the
> presenters?
>
> DR. BAKER: I\'m just thinking about this. We\'ve heard that a formula
> wouldn\'t be introduced unless it was going to be better. We don\'t
> know what better is.
>
> We\'ve also established that our best shot at what adequate is is
> growth. That sort of sums up the adequacy of a formula or
> breast-feeding, for that matter.
>
> And then we\'re also saying we don\'t know what the right growth is,
> and certainly we don\'t want babies to grow any faster than
> formula-fed babies are now, maybe a little slower, but we\'ve sort of
> gotten ourselves in a circle here, because in order to show better,
> you\'ve got to measure growth, and growth, you don\'t know whether
> it\'s supposed to be up or down.
>
> So, we can\'t prove that it\'s better. All we can prove is that it\'s
> the same.
>
> DR. GARZA: That\'s been the view of some of the presenters. They
> don\'t necessarily have to be yours.
>
> With that challenge from Dr. Baker, let\'s move on, then.
>
> The sense I had from yesterday\'s discussion is that, if we look at
> question 4A in the abstract in terms of distinguishing values and
> merits of each type of reference, that there was a very clear
> preference that the default option ought to be concurrent controls
> unless otherwise justified, that if one could justify the\--not
> running concurrent controls, that, in fact, one could move to
> reference data such as either the Iowa or the CDC, NHANES, etcetera,
> reference data that were pretty much in the public domain, so to
> speak, and that only under unusual circumstances would one rely on
> historical data.
>
> That was pretty much true for term infants.
>
> For pre-term infants, the group felt that concurrent controls were
> necessary. We didn\'t see a way that one could rely on either
> reference data or historical controls because of the dynamic nature of
> the treatment of these infants and the center differences that exist.
>
> Is that pretty much where we left the discussion?
>
> So, if we move from there to B, which says these reference groups are
> based upon\--please rank these reference groups based upon the ability
> of the respective control population to contribute to an assessment of
> normal physical growth in the population intended to consume the
> formula.
>
> And the reason why it moves us away from the abstract is that now
> we\'re dealing with that phrase that I was pressing the group we just
> heard from, and earlier groups, in terms of normal physical growth and
> whether, in fact, in assessing the normality of that growth, how one
> would do that with concurrent controls and what is that concurrent
> control, and we will be coming to some of that in question 6.
>
> If you use a reference, category number two, you\'re faced with the
> same question which Dr. Baker introduced for us a little bit earlier,
> and if you move to historical controls, I think that\'s possibly the
> easiest, because we can pretty much, I think, from the discussion we
> had, say, well, that\'s not going to give you much help given the
> nature of the way we define historical controls for purposes of this
> discussion.
>
> Who would like to tackle B? How would you rank these in their ability
> to contribute to an assessment of normal physical growth? What would
> be your concurrent controls?
>
> Any takers?
>
> DR. HEUBI: I don\'t think that we\'ve actually\--independent of this
> issue that we can\'t define normal physical growth, which is a real
> problem here.
>
> I think we still are saddled with concurrent controls and longitudinal
> reference data, sort of in that order, and historical controls
> somewhere down the line.
>
> I don\'t think we\'ve changed\--even if you change the verbiage of
> where you put exactly what you\'re comparing it to and knowing that
> this is impossible for us to know what normal really is, I think
> that\'s where we are.
>
> DR. GARZA: I\'d like to challenge the group.
>
> Is that really impossible to discuss? Can it be true that we\'re in
> the 21st century and have to turn to an agency like FDA and say, gee,
> a group of experts can\'t decide what normal physical growth is?
>
> That is a terribly telling comment on pediatrics if it\'s correct.
>
> DR. STALLINGS: I guess I\'m prepared to take Dr. Garza\'s challenge.
>
> I think we have to make a recommendation. That doesn\'t say that that
> will be the same recommendation in 10 years when, you know, this will
> need to be done again, but I think, from the pediatric point of view,
> from a child health and child advocacy point of view, for the purposes
> of the exercise, that a healthy child born to a healthy mother
> exclusively breast-fed for the first four months is our best guess
> today of what normal growth should be.
>
> I\'ll put that out for discussion, in term babies.
>
> DR. GARZA: So, in your mind, a concurrent control would be that, that
> in fact one would have to run a group of breast-fed infants as
> concurrently with whatever you were doing and then make judgements
> based on those comparison.
>
> DR. STALLINGS: Well, it\'s interesting, I think, in my homework last
> night that you sent me home to do, that that became apparent, because
> I changed something of my theory that I would actually be interested
> in knowing how it performed against the current formula, but I also
> wanted to know how it performed against breast-feeding, breast-fed,
> healthy breast-fed babies.
>
> So, I think we\'re entering a time when that may be, in fact, true. I
> look forward to seeing the WHO data and for us to learn about that,
> but knowing\--you know, knowing the process, that won\'t have any
> real-life impact certainly for a regulatory agency until that growth
> grid is out and we\'ve all had a little bit of time to use it, and you
> know, the whole implementation, education, assimilation process that
> goes with such a major change and approach.
>
> So, I think we\'ve got to do something between now and then, and we
> may want to go back to our experts to ask, if we ask the question
> differently, what is the best set of data that we have for breast-fed
> infants in the U.S. currently existing or combinable or whatever,
> could we end up with something that would be a relatively robust
> reference, not a standard, but I don\'t know the answer to that, and
> that might be one of the challenges if this committee or other
> committees works.
>
> But I think we have to take the leap and go with the breast-fed baby
> as the model for normal growth.
>
> DR. GARZA: Let me ask you two questions, Virginia.
>
> Number one, would you then suggest to the group that, in fact, we need
> to have two concurrent controls\--one would be whatever formula plus a
> second group\--or that, in fact, you might use the sort of reference
> that you just described for the comparison or the comparator for the
> breast-fed group, and would an interim use of, for example, the WHO
> breast-fed data set that Ed described that led to the current
> reference and has about 200, 300 children in it from North America and
> north Scandinavia or a Scandinavian country\--would that be a
> sufficient reference?
>
> DR. STALLINGS: I would be willing to consider it.
>
> I think what I would ask is for us to have access to the data and be
> walked through it, you know, in a responsible way, because it\'s not
> at a peer review stage yet.
>
> DR. GARZA: Well, it\'s been published both in the Journal of
> Pediatrics and in the\--and there is a whole booklet out by WHO \--
>
> DR. STALLINGS: Okay.
>
> DR. GARZA: \--that\'s out there.
>
> DR. STALLINGS: So, I would certainly be willing to consider that, but
> it\'s clear from my last comment that I\'m not fully informed.
>
> DR. GARZA: You would consider a reference group rather than two
> concurring groups and someone would have to have three groups in a
> feeding trial.
>
> DR. STALLINGS: Right. I would consider that.
>
> But what I\'m interested in is us having\--instead of showing the
> growth grids that we have been using\--historically, the \'77 ones and
> now the 2000 one\--I would be interested in exploring having a
> breast-fed cohort so that we could start to understand that.
>
> I mean I see this as a process, certainly both for the public health
> interest of the children and for not wanting to take away an important
> product for babies that need it.
>
> So, I\'d like to learn more about that, look at the data, be walked
> through it.
>
> I don\'t think if we\'re changing formulas that we could not look at
> them compared to this history of incrementally-improved formulas,
> which is what industry has done.
>
> I just worry that with each of those steps that we\'ve trapped
> ourselves into the bigger-is-better category and that that\'s what
> we\'re seeing, and I think as was suggested, you know, that it may be
> a fundamental regulatory change, that maybe infant formula shouldn\'t
> be at, you know, .67 calories per cc, that that may not\--in all
> total, that may not be the right thing.
>
> I mean I don\'t know the answer to those things, but I think we have
> to be open.
>
> DR. GARZA: Dr. Stallings has made a suggestion.
>
> Dr. Thureen, do you want to respond to that or make a different one?
>
> DR. THUREEN: No, I think it\'s the same thing, but I want to make sure
> that I understand you.
>
> The current growth standard should be that of the breast-fed infant,
> exclusively breast-fed to four months of age. That\'s the standard for
> normal growth.
>
> As a separate issue, what should we use for concurrent controls? For
> the present time, probably a concurrent group of formula-fed infants
> that doesn\'t have the modification that\'s being studied.
>
> Ideally, in the future, we\'d move towards the second concurrent
> group, that of breast-fed infants, with looking at that as a reference
> standard and maybe with using neuro-development, outcome, etcetera,
> but that\'s a process that would occur over time, so that there would
> be no change in recommendation for the current time of using
> concurrent controls of the same formula without the addition but move
> towards, over time, having a different concurrent control group of
> breast-fed infants.
>
> Is that what you said?
>
> DR. STALLINGS: I think so. This is clearly a thought\--I mean this is
> the part of our work that we need the dialogue for the clarity.
>
> I am very interested in having both\--when working in isolation last
> night, I actually came up with both concurrent control groups, a
> breast-fed contemporary group and the primary formula and then the
> formula with change, when I was looking at what would I really like to
> do. So, that really is an issue.
>
> If we were to go that way, if we use the breast-fed baby as the only
> concurrent control group, we know we\'re going to open up gaps
> immediately, because the growth patterns aren\'t the same.
>
> So, I don\'t have a good idea how to walk through that part.
>
> So, there really are two questions. Is the new formula as good or
> better as the old formula, which is usually our question, and then,
> secondly, how does it compare with breast-feeding?
>
> The challenge that I don\'t know yet is can we create a reference set
> that performs well enough that we wouldn\'t have to have a concurrent
> breast-feeding group.
>
> So, I really offer this to begin the discussions. I\'m very interested
> in other people\'s thoughts.
>
> I do feel strongly about\--that as much as we\--and I know everybody
> in this room would want to do this, certainly protect children from
> unnecessary studies, I think as pediatric health advocates we also
> need to affirm that sometimes we do need to do studies in children and
> not be afraid to do the right ones. It\'s the balance.
>
> So, I\'m not afraid of doing more studies on more children to get the
> right answers.
>
> DR. GARZA: Let me ask the group and possibly our presenters to also
> comment on this, those that presented yesterday.
>
> It\'s my sense, as I look at the literature, that if one looks at the
> growth patterns of breast-fed infants, either historically\--I looked
> at data back as early as the early 1900s and it\'s very sparse, but
> there\'s some there\--and cross-culturally, looking at children, for
> example, in such places like Bangladesh to Norway, the pattern of
> growth is remarkably similar.
>
> They start off at different places, obviously, so that, in fact, the
> children at Bangladesh may start off at minus-3, but if you plot their
> growth\--minus-3 standard deviation\--if you plot their growth against
> the WHO breast-fed data set that Ed showed us yesterday, parallels it
> pretty\--I mean just phenomenally well.
>
> If you look at Norwegian infants, again they\'re much bigger at birth,
> they parallel it pretty well.
>
> Has that been everyone\'s experience, and if true, would studying a
> concurrent group\--would that sort of consistency make as much sense,
> or has it not been your experience so that, in fact, one would need a
> concurrent group to try to be able to overcome the sorts of biases
> that reference data might unintentionally create for us?
>
> DR. STALLINGS: I\'ll make one comment to that, and then, really, I\'m
> very interested in my colleagues\' opinions.
>
> I think, in North America, practitioners have been often frightened by
> the fall-off of breast-fed kids compared to our growth grids. So, the
> truth is I\'m not sure many of us have really looked at that as
> carefully or might be able to express personal confidence.
>
> And then you also\--the people that you have around the room\--often
> our jobs are to deal with children who have failure to thrive. So,
> again, you know, most of us have not been doing general pediatrics
> practice where we\'re seeing the more run-of-the-mill issues.
>
> But the one thing that I am aware of, you know, certainly in personal
> friendship circles and professionally, is until we really became aware
> of there is the natural slowing of growth compared to the current
> growth grids, that a lot of people with breast-fed babies were
> alarmed, and pediatricians caring for them, thinking that we weren\'t
> doing a good job.
>
> So, I think in North America we\'ve got an education piece that\'s
> really just sort of getting out there, and you know, the issue of
> growth charts and the optimal reference, if not standard, is something
> we\'ve been missing for a long time.
>
> DR. GARZA: Let me turn to the group.
>
> Dr. Fomon?
>
> DR. FOMON: I\'d like to make a couple of comments that I think are of
> some practical significance with respect to using the breast-fed
> infant as a reference.
>
> Number one, if we were to analyze the infant formulas on the market
> from 42 to 112 days, almost all of the formulas would be in
> non-compliance, and if we tried to develop formulas that would allow
> us to match the growth of the breast-fed baby, we would have to switch
> formulas at about 42 days.
>
> It would be the only way to do it.
>
> You could not go with the breast-fed babies\' growth and not exceed
> the breast-fed babies\' growth if you stayed with the same formula
> after 42 days.
>
> So, there are some real practical considerations.
>
> The other thing that I think is important in using the breast-fed baby
> as a reference is that most of the studies do not account for
> drop-outs. We account for drop-outs in formula-fed studies, but in
> general, most of the breast-fed studies are breast-fed babies who
> continue to be breast-fed for a certain period of time.
>
> DR. GARZA: Thank you.
>
> Dr. Clemens?
>
> DR. CLEMENS: I\'d like to pick up on a comment that Dr. Merritt made a
> little bit earlier today, and that is, if you were to look at all the
> data that the industry has collected, they, in fact, would have more
> data on breast-fed infants in this country than WHO has collected in
> total, and so, if you were to use that as a standard\--and to go back
> to what Dr. Denne said yesterday\--what is the agency going to do with
> those data if you don\'t match those particular patterns?
>
> DR. BAKER: I\'ve got a question. If you were to try to duplicate the
> growth of a breast-fed baby with your formula, then you would almost
> necessarily have to change the whole character of the feeding trial.
>
> It would no longer be a growth study. You would have to include lots
> of things, because you\'re not really interested in growth at that
> point. What you\'re really interested in is the formula supplying
> everything it needs.
>
> So, you\'d have to look at metabolic things, at neuro-development
> things, at bone accretion. You\'d have to blow it open to a full
> study, a metabolic study, in order to do that.
>
> DR. GARZA: Let me ask the group, because that thought was crossing my
> mind, as well, that the assumption that, in fact, one can look at
> growth in isolation of anything else fails as you try\--at least it
> failed in my mind as I tried to go through it, because in fact, one
> would have to look at the composition of the formula.
>
> One would have to look at some baseline metabolic responses, because
> if not, one could very easily get into a false sense of either
> security or insecurity by relying on any single measure for adequacy,
> one for which we appreciate there is some plasticity.
>
> I can give you a recipe for a small baby. We do it in most of the
> world quite successfully. I can also give you a recipe for a big baby
> and big children. We have been doing that just as successfully for the
> last 15 years in this country.
>
> So that in isolation of intake data and isolation of metabolic data,
> one can decide what the baseline of that information may be, but what
> seems to be coming out of our discussion is that, yes, you may want
> more than one growth comparison, as the way Dr. Stallings described,
> but that those comparisons have to be interpreted in the light of
> additional data than just growth alone, because of that plasticity.
>
> Is that a fair assessment of how the discussion is going, or is that
> unfairly characterizing the deliberation?
>
> Dr. Denne?
>
> DR. DENNE: If I could just maybe digress a bit, I think we\'re talking
> about or at least dancing around trying to develop a formula that
> makes formula-fed babies grow like breast-fed babies, and to me
> that\'s a hypothesis that needs to be tested.
>
> I mean what we know is that formula-fed babies growing like
> formula-fed babies do well, and they do well in the infancy period,
> and as far as we know, all the way through adulthood.
>
> Adjusting our standards to make a formula so that we match the pattern
> of growth of formula-fed babies and breast-fed babies assumes that
> we\'ll get a similar or better outcome, and we have no basis to make
> that recommendation.
>
> It\'s an interesting concept, but in the absence of any information
> like that, I would be reluctant to change that standard.
>
> DR. GARZA: Let me be the devil\'s advocate for just a bit.
>
> Is there any other circumstance in medicine where a significant
> deviation from perceived normal physiology would be interpreted by
> default as acceptable without proving that, in fact, there were no
> problems, where the absence of information is sufficient, rather than
> the presence of information?
>
> DR. DENNE: I think if we were starting today and all we had was
> breast-fed babies and we needed to construct a formula, then trying to
> match the pattern of breast-fed growth would be an appropriate way to
> go.
>
> However, we have, you know, 50 years of formula experience that
> actually is reasonably\--with reasonable good outcomes, again all the
> way to adulthood.
>
> So, given the fact that we have that experience, it\'s difficult to
> radically change the formula in order to just match a pattern of
> growth, which is really all we\'re talking about here.
>
> DR. GARZA: What I was trying to get us to is to the point\--maybe we
> don\'t have to match it but at least be able to explain deviations
> from it.
>
> DR. DENNE: I think it\'s certainly reasonable to compare formula-fed
> babies with breast-fed babies. I mean I think that\'s a reasonable
> thing to do in some sort of academic abstract way so that we know what
> those differences are.
>
> But to act on those differences, I think, is where I\'m less
> convinced.
>
> DR. GARZA: So, your suggestion would be what?
>
> DR. DENNE: I guess I\'m suggesting that, given the fact that we have
> good data on formula-fed babies and the growth of formula-fed babies
> over many years, that that is a reasonable approach to match changes
> in formulas to, rather than a standard of breast-fed.
>
> DR. GARZA: What match would you make, then, to a\--what would be the
> concurrent control? Would it be the Fels data that has some
> formula-fed infants? Would it be a historical? Would it be the NCHS,
> CDC?
>
> What formula would we use as a standard to get that normal growth
> definition?
>
> DR. DENNE: I guess I would use some combination of a longitudinal
> study, Iowa, Fels data, formula-fed infants, probably as a primary
> source, and probably the CDC as a second source, which obviously is a
> mixture, and we understand that.
>
> DR. GARZA: And that would be sufficient without the concurrent
> control?
>
> DR. DENNE: No, that\'s with the concurrent controls. I don\'t think
> this, by any means, replaces the need for concurrent controls.
>
> DR. GARZA: Dr. Clemens?
>
> DR. CLEMENS: It\'s interesting to note that even Dr. Fomon, just
> moments ago, made a comment relative to the duration of kids that were
> on the\--in his studies, and as you look at the data that were
> collected in the \'70s or late \'60s through the data that were
> collected to the mid-\'80s, Dr. Fomon, if I recall what you said
> correctly, that both kids did not differ.
>
> That\'s true if you look at the data that were collected in Iowa. You
> could look at the data that were collected and presented and analyzed
> through the CDC.
>
> Fundamentally, those kids do not differ, that if you look at the
> historical data that the industry has generated in over 6,000 kids,
> all those controls, concurrent controls, mind you, that fundamentally,
> those kids do not differ.
>
> LSRO did a report just a few years and examined the nutritional
> requirements for kids, and if you look at those requirements, that\'s
> exactly where the industry is today.
>
> DR. GARZA: Dr. Clemens, then explain to us the differences between the
> Iowa data and the Roche New Foundland data, because those two differed
> fundamentally in growth pattern, both on formula.
>
> DR. CLEMENS: I can\'t explain that at this time.
>
> DR. GARZA: I think it\'s difficult to say that these patterns have not
> varied, because that statement, I think, is difficult to uphold.
>
> DR. STALLINGS: It sounds like, though, there may be another source of
> data that we haven\'t had the opportunity to see, that if industry
> were able to provide the primary data on the breast-fed infants, you
> know, and the sites, the geography, the males, females, that we might
> have another set of breast-fed babies collected under conditions that
> are common to current infant formula studies.
>
> I\'d be very interested in seeing that, and I think what we\'re headed
> towards is really what the FDA is prepared to do at this point is\--I
> mean some of this is new analysis. I doubt all of the major companies
> have ever combined their data.
>
> DR. GARZA: Dr. Stallings, how would you deal with the problem that Dr.
> Fomon raised, which is a very fair criticism of most breast-fed data
> sets that I know of, and that is that, in fact, you get terrible
> attrition rates, and you have a distillation that gets progressively
> worse.
>
> There\'s only one study that I am aware of that is following all
> children, regardless of whether they adhere to recommendations. That
> was the description that Ed gave us of that WHO study, where they\'re
> following all children to try to see whether there are differences
> between those that quit at three months, four months, five months, six
> months.
>
> DR. STALLINGS: And I think that will be an important issue. I mean I
> would love to see\--I mean it seems a little silly at this point to
> start another major breast-feeding study to answer those questions in
> the U.S. or in North America when we\'re going to have really
> wonderful data soon.
>
> But that is an important question, because we know what it\'s going to
> do, is add to the variability that is artificially low in the
> breast-fed studies now, because it\'s just the compliance-committed
> families.
>
> So, I mean but these are some of the kinds of things that if\--you
> know, if we got great briefing books on those kinds of things, I think
> the way we should head would become apparent.
>
> DR. GARZA: There are some studies in the literature that I\'m aware of
> that have had 3-percent attrition rates for the first four months. I
> mean, so they do exist.
>
> DR. STALLINGS: Right. So, I think that\'s incumbent upon us, if we
> want to consider going down this road, is to really look at that,
> because it\'s not something that\'s been done, and then to be able to
> start to look at what\--I mean we may end up with very different
> sample sizes, requirements, and things like that. It may not be as
> overwhelmingly impossible as it feels, you know, as we\'re going
> through some of this, and to focus on those first four months or maybe
> the first six months.
>
> But I also, you know, agree with Dr. Fomon that one of the challenges
> as we go through this is\--I mean what we now know is the nutritional
> needs of a baby during the first two months are different than the
> nutritional needs after that, and the beauty of it is the breast milk
> supply and composition changes with that and a little bit more than we
> can change a commercial product.
>
> So, then the challenge is what are the windows that we\'d need the
> product to have to perform well on zero to two and two to four or two
> to six?
>
> So, it\'s, you know, a lot of things that might come out of this set
> of questions.
>
> DR. GARZA: Okay.
>
> Dr. Sigman-Grant?
>
> DR. SIGMAN-GRANT: Just to divert the conversation just a little bit,
> if we look into the future at the possible ingredients that might be
> added to formula, we talk about the nutritional needs, and it seems
> that because breast-fed and formula-fed infants do grow and thrive,
> that the nutritional needs are met.
>
> Yet, we\'ve been hinting upon the metabolic changes or differences
> that might exist, which may or may not be reflected by growth, but if
> some of the newer ingredients that might be added to formula may be
> added because of presence, say, in breast milk, because breast milk is
> the standard, does that put a different light and sort of support the
> need for a concurrent breast-fed group in the study, because that
> might be what might be coming down in the future, some of those
> bio-active or other growth substances that are in breast milk.
>
> I mean we\'re trying to set some standards for the future.
>
> DR. GARZA: All right.
>
> I think my read is that we\'ve come to some agreement on 4. Let me see
> if I\'m not being overly optimistic.
>
> We\'ve summarized part A, so we can leave that alone.
>
> In terms of B, the group still feels that, in fact, longitudinal
> concurrent controls of a formula plus\--minus whatever is being tested
> is going to be needed under most circumstances, that we recognize
> there may be some\--I think it was Dr. Baker that described it.
>
> For example, if you\'re doing a series of studies very close to each
> other, that they\'re variations on the same theme, but in fact, one
> might be able to rely on one concurrent control group for multiple
> studies, that it\'s foreseeable that that would work, that, in fact,
> there should be a comparison in addition to that with some reference
> source for the breast-fed infant to try to understand what those
> deviations are from that growth, that there may be instances of the
> type that Dr. Sigman-Grant described where you may want to run a
> concurrent control but that we don\'t envision that necessarily being
> always the case, but at the very least that there ought be some
> reference data set that one ought to be able to make that second
> comparison with the breast-fed population and to be able to identify
> reasons for the deviation, that in fact it may be expected based on
> historical growth patterns from other formulas that this is not
> unusual or that, in fact, it was to be expected because of the nature
> of the change, but that there ought to be some explanatory information
> that comes along with that comparison, but that generally, then, we
> would keep the ranking pretty much the way we described for A, that
> these would be used to assess normal growth in the way that I\'ve just
> described, and so that we\'ve done C in terms of defining the role of
> that reference group, as well.
>
> So, is that a reasonable summary of 4? All right. Then, if it is,
> let\'s take a short break of five minutes to get your coffee, bring it
> back to the table. I have to ask you to bring it back, because we\'ve
> got to go through 5, 6, and 7, and we may not make it, folks.
>
> \[Recess.\]
>
> DR. GARZA: All right. So, we\'re going to go on to number 5, and
> that\'s asking us two questions.
>
> For the purpose of evaluating normal physical growth\--that\'s our
> favorite phrase again\--of infants new formulas, what criteria should
> appropriate infant growth reference groups meet, each or selectively,
> in terms of feeding history, gestational age at birth, sex, racial
> background, socio-economic status, etcetera, in comparison to the
> experimental or study population, as opposed to perhaps the reference,
> and in comparison to the population intended to consume the formula?
>
> I thought the second was surprising, but not so when you stop to think
> that, at our last meeting, we discussed the fact that term infants,
> for example, might be used\--term data might be used to justify
> pre-term feeding, and so, that didn\'t seem so\--such a disconnect
> once I thought about that.
>
> So, in comparison, then, I guess, what similarities exist between the
> study and the control populations, is the way I interpret the first
> bullet, or a reference group, if you\'re using one, or a historical
> group, if you\'re using a historical group.
>
> Now, we might wish to differentiate. For example, if you\'re doing a
> concurrent control, then obviously the idea would be a randomized, so
> that they\'re going to be the same if you randomly assign them.
>
> That would be the intention of that design, at any rate.
>
> Once one gets away from that, then there are criteria that you would
> have to think about in making that match, because you\'re no longer
> dealing with a randomized assignment.
>
> So, I think the first one is easy, unless anyone would take exception
> to that.
>
> Moving past that easy one, then I\'ll turn to the group and ask you to
> address the difficult one.
>
> DR. ANDERSON: I think we want to re-emphasize how important we think
> it is that, in settings where a comparison is thought required, that
> it ought to be done through a randomized trial.
>
> Having said that\--and as I think our recommendations from the last
> meeting implied, the randomized trial ought to be done optimally in
> the population designed to consume the formula, or there ought to be a
> compelling argument that the answer that one gets in a different
> population is the same as one that one would have gotten if one had
> done it in the population intended to consume the formula.
>
> I mean after that, I think the\--any other approach is sub-optimal but
> that the focus ought to be on the kinds of characteristics that we
> recognize from both randomized and follow-up studies predict for the
> type of pattern of growth that one observes.
>
> So, from the discussions here, it seems clear that gestational age at
> birth has a major impact, and to the extent that there are other
> factors that are readily measured that are known to be strong
> predictors, that it would be incumbent on those submitting such
> information to be able to demonstrate that the results that are
> observed, either\--for instance, if they were largely similar, that
> the similarities are not as a result of underlying differences and
> predictors of growth that, if they were adjusted for, would lead to
> very different observed growth patterns.
>
> DR. GARZA: Based on what we\'ve heard, then, one would definitely want
> to see a match on sex, because of differences between boys and girls.
>
> One would want to see a match on gestational age, for reasons that
> we\'ve discussed.
>
> Health\--general health standards would be a third that we talked
> about, that you couldn\'t necessarily extrapolate from one healthy
> population to unhealthy populations, or conversely, and we had
> detailed discussions of that point at the last meeting.
>
> Less clear are feeding history. For example, if, in fact, one was
> comparing two formulas and one formula group was fed human milk or
> some other formula in the early period to a greater degree than the
> concurrent or comparator group, would that present a problem?
>
> I mean how closely do you want\--do you think that one ought to look
> for a match with feeding history? I mean that\'s something that has
> come up.
>
> In terms of racial background, it\'s tough for me to make a point for
> that one.
>
> Socio-economic status\--tough for me to make a point on that one
> either. I mean all kids ought to grow\--I\'ll use the phrase
> \"normally,\" whether they\'re rich or poor. In a society such as
> ours, I don\'t see that that\'s relevant, necessarily.
>
> DR. SIGMAN-GRANT: The feeding history\--you just mentioned formula or
> breast-fed, but I would think you would want to match on introduction
> of solids and other weaning and complementary foods, because we
> haven\'t talked about that, but some of the data from some of the
> years, complementary foods were introduced very, very early, and that
> may have been different for breast-fed and formula-fed babies.
>
> So, I think you would want that in the study.
>
> DR. GARZA: Complementary feeding history?
>
> Other matches?
>
> DR. DOWNER: I was thinking about socio-economic on the grounds that,
> if you don\'t have money to purchase formula and you\'re not
> breast-feeding, that will definitely impact.
>
> I understand that the goal is, regardless of your socio-economic
> status, to make sure that you have the best outcome possible, but if
> we\'re looking at matching, I think that is very important to look at.
>
> DR. GARZA: Okay. I was working under the assumption that, if you were
> doing a growth study, then those factors in terms of accessibility
> would be controlled. Perhaps that\'s too much of an assumption.
>
> Do you feel that SES matches would be necessary, Dr. Heubi?
>
> DR. HEUBI: That wasn\'t what I was going to comment on.
>
> DR. GARZA: All right. Well, let\'s get done with this one, then, on
> SES.
>
> DR. HEUBI: I will comment on it.
>
> I do think it\'s probably important to match as much as we possibly
> can on SES, although I sense that, after having participated in some
> of these trials, that we\'re basically doing that in general, because
> in most cases, you\'re excluding children who are in the WIC programs
> because there\'s no real incentive for them to participate in these
> studies.
>
> DR. GARZA: What is the biological proxy that we\'re using or what is
> the proxy for SES, then, because I\'m trying to understand the
> biological reason why you\'d want to control for SES if you\'re doing
> a growth comparison between two formulas.
>
> Kids that are poor don\'t inherently grow slower. I mean they grow
> slower because they don\'t get food.
>
> DR. HEUBI: I\'ll tell you what my first-blush response to that is, is
> that there are so many other extenuating circumstances in those
> households that may somehow impair their growth and may not make them
> \--
>
> DR. GARZA: Dr. Clemens?
>
> DR. CLEMENS: Actually, demographically, in the control, as well as in
> the study population groups, the intent for the industry is to be
> absolutely identical, and that\'s indicated in the protocol, including
> the SES.
>
> Breast-fed kids are self-select, so it\'s difficult to match SES, and
> it\'s difficult to match some of the other parameters. It\'s difficult
> to match the in-house situations as well, as you probably have
> experienced.
>
> DR. GARZA: All right. So, one would then look at SES but look at
> particular variables, I would imagine, like maternal education, birth
> weight, all the various things that you think would be impacted to
> make sure that, in fact\--that\'s the sense of the group.
>
> DR. CLEMENS: That\'s correct. We do that already. That\'s indicated in
> the protocol.
>
> DR. GARZA: Dr. Heubi?
>
> DR. HEUBI: I think it\'s probably not totally appropriate to be over
> prescriptive about what their antecedent breast-feeding or formula
> history was before they are enrolled.
>
> It depends upon when you want them to be enrolled for the beginning of
> the trial that would determine whether you would restrict what their
> previous feeding history was, and that\'s a piece that I don\'t think
> we\'ve really addressed.
>
> I know there\'s been discussion about trying to enroll age 14 days,
> and Dr. Fomon talked about at age 28 days, and I think that\'s a piece
> that ends up being fairly important, about when you enroll your
> subjects in terms of what their antecedent feeding history truly is.
>
> Certainly in the circumstance where you were studying a soy formula,
> you wouldn\'t suggest that they be switched from a cow\'s milk-based
> formula to soy, and similarly, you wouldn\'t suggest that a breast-fed
> baby would be switched to formula to participate in the study.
>
> DR. GARZA: So, how do we deal with\--what is the match between feeding
> history\--it would just be dependent upon the nature of the study, so
> it\'s very difficult for the group to make a generic comment, other
> than that you ought to think about it. Is that what the group is
> saying?
>
> DR. STALLINGS: Not to directly answer that, but I think one of the
> groups that we have\--often, many of our studies are designed to keep
> people exclusively formula-fed or exclusively breast-fed when, in
> fact, in practice, the third group, the mixed feeding children, are
> really very common.
>
> So, I just bring that up as\--that\'s something that I think we need
> to incorporate, because that really\--when you talk about the
> environment that you\'re really going to use the formulas, as we get
> more and more successful for breast-feeding for the first number of
> weeks or months or however, the other type of complementary feeding,
> when you need the formulas to continue that cycle. So, I just wanted
> to bring that out, and in fact, that was part of the discussion at
> break.
>
> I think it\'s beyond what we can do in this setting to really keep
> detailed history of complementary feeding.
>
> We might be able to say first initiation, because it just gives you a
> time point, and I think that\'s probably accurate, but\--so, my sense
> is I really would not deal much with complementary feeding, other than
> maybe record it.
>
> The feeding history, I think, will be a moot point, because I think
> we\'re going to need to enroll them by eight days or 14 days, and then
> the rest really goes from the protocol inclusion or exclusion
> criteria.
>
> DR. GARZA: Dr. Sigman-Grant, do you want to comment to that?
>
> DR. SIGMAN-GRANT: From the practical standpoint, I really think you
> need to account for complementary feeding.
>
> It\'s so variable. If you\'re not in a hospital setting, the time of
> introduction of cereal varies from\--even now\--from a couple of weeks
> to six months.
>
> So, it\'s so variable, I think you at least have to account for it,
> maybe not measure it but certainly account for it.
>
> DR. GARZA: You would agree that the only thing that you see as
> critical is the age at introduction, not necessarily keeping\--or
> collecting additional information for the amount of complementary
> feeding that occurs, how frequent it is, whether it increases over the
> time of the study, but if you knew, gee, they started at one month or
> two months or four months, that would be sufficient, because I think
> that\'s what Dr. Stallings said, that it\'s the age of introduction.
> Beyond that, it really gets to be impractical.
>
> DR. SIGMAN-GRANT: If you want a true picture of growth, I think you
> need to look at the progression. So, someone who starts complementary
> feeding early tends to progress, so the child gets more and more and
> more, and that might impact the growth study and how much actual
> formula they\'re consuming.
>
> DR. CLEMENS: Actually, if you look at the protocol, first of all, on
> enrollment, we do examine whether breast-fed or formula-fed, they\'re
> not to be exclusively formula-fed, because we do note there is a
> difference at that point.
>
> Secondly, all complementary feeds are, in fact, monitored on a regular
> basis. There is part of the form to examine all of that issue, and
> it\'s part of the compliance.
>
> If, in the estimation of the investigators at hand or the research
> investigators, in fact, that the complementary feeds are out of
> bounds, for whatever reason, then, in fact, those individuals are out
> of compliance and discontinued.
>
> DR. GARZA: So, you\'re suggesting that ought to be made mandatory,
> that the FDA ought to require that information, rather than just
> receive it, because it\'s supplied.
>
> DR. CLEMENS: We already provide the information. In general, the
> industry provides that kind of information.
>
> DR. GARZA: But you think it ought to be required that everybody supply
> that information. Is that what you\'re saying?
>
> DR. CLEMENS: We can work with that.
>
> DR. GARZA: The reason I\'m asking is, if there is a new manufacturer
> that\'s not part of the Infant Formula Council and they choose not to,
> right now there\'s nothing that requires it.
>
> DR. CLEMENS: That\'s right. That\'s not required.
>
> DR. GARZA: And I was asking whether you felt it should be required.
>
> DR. CLEMENS: It should be required, and we do provide those kinds of
> data.
>
> DR. GARZA: Okay.
>
> Any other comments on that?
>
> \[No response.\]
>
> DR. GARZA: All right.
>
> So, in comparison to the population intended to consume the formula,
> how much of a match should there be between your test population\--the
> example that we\'ve dealt with in the past is, can you study term
> infants and then make inferences to pre-term?
>
> Are there other instances where you think that, in fact, if it\'s
> studied, for example, in six-to-12-month-old children, should it be
> used at one to six months?
>
> We had some discussion as to how the nutritional requirements were
> quite different between infants the first three months and the last
> three months of infancy.
>
> So, that\'s another example, I think, that we heard about where there
> should be a match between the study population and the population for
> whom the formula is intended.
>
> Obviously, boys and girls, because it\'s intended to feed both sexes.
>
> Those are the easy ones.
>
> Are there other matches that you feel ought to be made?
>
> DR. DOWNER: Also mention the gestational age.
>
> DR. GARZA: Okay.
>
> DR. DOWNER: And general health.
>
> DR. GARZA: All right.
>
> DR. BAKER: I would say that this\--if I\'m reading this question
> right, it\'s driven by science, and you match you control group to
> your trial group as closely as possible, and if you want to make
> inferences on some other group, that\'s up to you to prove that
> that\'s okay, but you don\'t match your control group to some other
> group.
>
> DR. GARZA: It has to do with a study group, I think.
>
> As I\'m reading the question, they\'re asking, if you set up a study
> group, how closely does that study group have to conform to the
> intended population, so that the external validity issue is the issue
> that they\'re getting at? I think that\'s an external validity issue.
>
> DR. DENNE: I just was going to say I think, you know, at least in some
> sense, this ought to reflect the population of the United States and
> that, although that\'s probably impossible in a relatively small
> study, it shouldn\'t exclusively focus on a specific socio-economic
> group. It shouldn\'t specifically exclude\--explicitly just be white
> or black. It should be relatively representative.
>
> At least that\'s the way I read the intent of the question.
>
> DR. GARZA: Dr. Kuzminski?
>
> MR. KUZMINSKI: My logic takes me just to a very brief answer, and the
> answer it is very closely, because under the criteria, I would have to
> defer to the medical expertise, but if the change is being
> contemplated against an existing formula that\'s out there in the
> marketplace and I would think a manufacturer would want to know how
> that change is going to affect the market for that existing product.
>
> So, whatever medical parameters can be put into the study design are
> the appropriate ones, they should be included, but in terms of the
> context of the question, how closely should the population intended to
> consume the formula be represented in the study, I think very closely.
>
> DR. GARZA: I think that\'s the sense. I don\'t think I could summarize
> the sense of the group any better.
>
> And before I forget, Dr. Kuzminski and I had a discussion during the
> break, and I want to make sure that\--I thought we weren\'t in
> disagreement and that we had not shut the door on the use of
> historical controls or term infant studies in question 4.
>
> We listed it last but recognize that there would be instances where
> that would be appropriate but that that would have to be justified,
> that in fact, because it was the lowest\--the least well-received or
> ranked last, that, in fact, it couldn\'t be used without some
> justification and that we didn\'t see that case with pre-terms but
> with term infants that that might be possible.
>
> Dr. Anderson?
>
> DR. ANDERSON: I think relative to the present question, to the extent
> that the study population differed from the population that intended
> to consume the formula, it would be incumbent on the manufacturer to
> demonstrate that there was no reason to suggest that the findings of
> the study could not be directly applied to the population for which
> the formula was intended.
>
> DR. GARZA: So, you\'d like them to address the external validity of
> their data.
>
> Okay. Well, we\'ve dealt with 5.
>
> Dr. Heubi?
>
> DR. HEUBI: Just as a point of clarification, does the FDA require the
> same kind of demographics as the other PHS agencies for clinical
> trials?
>
> Do they require Hispanics and African-Americans?
>
> DR. GARZA: The answer was no, since the record shows the staff shaking
> their head, and obviously, the sense of the committee was that, in
> fact, those groups ought to be representative in the sense that Dr.
> Denne described. I didn\'t hear any objections to that.
>
> It\'s an important point. I think not many of us have been involved in
> trials.
>
> I remember being involved in one trial where we were told that they
> couldn\'t find African-Americans, and the study was being done in
> Manhattan, which I thought was amazing. I offered to give them a tour
> of the city.
>
> DR. WALKER: You used the word \"require.\" I think it\'s important to
> remember that this is a notification process, not an approval process,
> and we\'re under very different regulations than you would be in a
> drug approval process.
>
> DR. GARZA: Thank you for that clarification. That\'s important.
>
> DR. HEUBI: All I can say is we\'re used to being hammered with this at
> the NIH.
>
> DR. GARZA: All right. Well, let\'s move on to number 6, and I\'m
> actually more optimistic. I thought this was going to take more time,
> but much of our discussion for question 4, I think, might help us deal
> with this one.
>
> So, listed below are examples of control feedings or clinical
> comparators, and then you have six bullets.
>
> You may have other comparators that you would like to present to the
> group.
>
> We\'re being asked what are the most distinguishing values and merits
> of each of these types of comparisons in infant study test formula
> versus a comparative feeding for assessing normal physical growth, and
> there again, we have that phrase of \"normal physical growth\" coming
> back to us.
>
> So, you\'ve got these six bullets. I\'ll read only the first two: a
> current infant formula plus a new ingredient, a current infant
> formula, obviously, with out that new ingredient, and human milk.
>
> So, those are three groups.
>
> We\'ve talked a little bit about how one might use those three groups
> in our discussions of question 5.
>
> A second was only the first two groups that I identified, and then
> there are various permutations through the six bullets which we don\'t
> have to read.
>
> So, who would like to tackle A? And here again, we might want to take
> only those two or three that would be of most value, perhaps have some
> that are moderate value, and those that you would never suggest that
> anybody even consider doing.
>
> Dr. Anderson?
>
> DR. ANDERSON: Well, I\'ll take a shot at this, because I think I\'m
> likely to be somewhat controversial.
>
> I think that the most useful of these is the second one, which is the
> test formula versus the formula without the new ingredient.
>
> In the context of assessing whether a new infant formula is
> appropriate for marketing, I personally don\'t think a concurrent
> cohort of breast-fed infants is relevant, although I do agree that an
> assessment of the growth data to some reference may provide useful
> information.
>
> There\'s an issue that hasn\'t been discussed all that greatly here
> but which I want to raise briefly, is that we\'ve heard this morning
> that there\'s a great deal of historical data available, and I must
> say that my enthusiasm about the use of historical data would depend
> greatly upon what those data look like.
>
> So, for instance, if, of the 60 trials we heard about this morning,
> their observed growth patterns for marketed formulas were all
> extremely similar, so that the variation from one study to the other
> was minuscule, and one came with a single cohort of individuals fed a
> new infant formula which tracked exactly as the others did, my
> enthusiasm for that being sufficient information to conclude that it
> promoted growth consistent with that seen with contemporary infant
> formula would be high.
>
> On the other hand, if the variation from formula to formula was quite
> large, then my enthusiasm for using the historical information would
> be diminished, and as my enthusiasm for tests in populations which are
> not those intended for use is low.
>
> The idea of testing infant formula plus a new ingredient so that that
> new ingredient could be added to some different matrix or some
> different formula would also be low.
>
> DR. THUREEN: The second bullet is sort of number one in preference.
> Then, good historical controls would be number two, then? Or didn\'t
> you even go that far? Bad historical controls would be at the bottom.
>
> DR. ANDERSON: If forced to rate the options, I certainly have no
> objection to the collection of information from breast-fed infants at
> the same time the study is conducted, but I personally don\'t think
> that the information is terribly useful for the purpose that the study
> is being conducted.
>
> So, having said that, the second bullet would be my first and very
> much favored choice of the ones available.
>
> DR. GARZA: What if one were to modify the first bullet to indicate the
> use of reference data of the type that we discussed in question 5?
> Would that be preferable to bullet two?
>
> DR. ANDERSON: Then it would come very closely beyond bullet two, in my
> way of thinking.
>
> DR. GARZA: That would be your favored bullet and having all three?
>
> DR. ANDERSON: No. Two would be first, and one would be very closely
> second.
>
> DR. GARZA: Okay.
>
> So, you would see the comparison with a reference of breast-fed
> children as being less valuable than just the comparison between the
> formula and the formula plus ingredient.
>
> DR. ANDERSON: Absolutely. So, three would be very much below\--in
> fact, I would have three probably below four and five.
>
> DR. GARZA: I was suggesting that the first bullet would be modified to
> not having concurrent children but a reference.
>
> DR. ANDERSON: Right.
>
> DR. GARZA: And then bullet two would be just as it is there, with
> children being\--a breast-fed reference, I\'m sorry. And then number
> three would be a concurrent infant formula plus a new ingredient with
> actually recruiting breast-fed children, so that there would be a
> difference between bullet one and three.
>
> So, with that modification, it would be bullet two that would be your
> favorite.
>
> DR. ANDERSON: If I understood what you said, in the first line, the
> breast milk was meant to mean some reference, then I personally would
> find one and two essentially identical.
>
> DR. GARZA: Okay.
>
> DR. ANDERSON: Three, where there was information on infant formula
> plus a new ingredient and information on either a concurrent
> breast-fed group or a reference would be very much less, because there
> is no either randomized comparison group with the infant formula
> without the new ingredient or some reference to the expectations for
> infant growth when fed what\'s known to be appropriate infant formula,
> so that, to the extent that the references and the historical data
> provide a clear sense of what the expectation would be for the outcome
> when infants are fed an appropriately formulated infant formula, those
> then would become sort of second tier from the first and the second.
>
> DR. GARZA: Okay.
>
> Dr. Sigman-Grant?
>
> DR. SIGMAN-GRANT: I\'ll take a different approach and go from bottom
> up.
>
> Because of the difference in formula matrix, the last one, the infant
> formula plus the new ingredient, versus any of the others, I think
> that should probably be very justified, because like we heard
> yesterday, the composition and the batching and the process may vary
> amongst formula companies, and therefore, needs to be tested within
> each formula.
>
> Currently, I think that, given the data and the status today, just
> having number three, current infant formula plus a new ingredient,
> versus breast milk, would not be appropriate right now, that that
> would not serve as a good comparison.
>
> DR. GARZA: Okay.
>
> DR. SIGMAN-GRANT: The current versus the historical data or the
> current plus the new ingredient versus the reference data\--if you
> look at that, I think comparing it to a longitudinal historical data
> would be preferable over cross-sectional.
>
> So, in other words, the Iowa-Fels would be preferred over, say, the
> CDC\'s.
>
> I have a toss-up between the first two.
>
> I think if you\'re going to have a current formula and adding a new
> ingredient, you must compare it a historical\--the formula without the
> new ingredient. You just have to. It wouldn\'t be appropriate not to.
>
> I would prefer to see a breast-fed cohort or comparison to a
> breast-fed reference standard, so that somehow we can start
> establishing that comparison, because I think we\'ve gone around and
> around and around, and we need to at least start addressing it.
>
> So, this might be a good point in time to recommend that we start
> collecting or compare it to breast-fed babies.
>
> DR. GARZA: Is there anyone that wishes to disagree with that general
> ranking? I\'m not too worried about those that we\'ve ranked at the
> very end, because I don\'t think we would be recommending those to FDA
> anyway.
>
> Dr. Stallings?
>
> DR. STALLINGS: I tried to make myself put them into two categories to
> start, I mean sort of rare to no, that they shouldn\'t be used, and
> this is recognizing that we are shifting, you know, the concept of
> normal physical growth and that the work of the first day and some of
> the others have been that we are concerned about both failure to
> thrive and over-nutrition.
>
> So, my rare to no\'s would be the last one, would be number five,
> which is just the new product versus only reference data. It would be
> number four, which is sort of what would be the new product versus
> other reference data, and when I did that, I also began to feel that
> the number two, which is new product versus old product, with no
> comparison to breast-feeding, would also be rare to no.
>
> So, that leaves me the number one, which is the new product, the old
> product, and reference data for breast-feeding, or number three, which
> is the new product\--no, sorry\--number three would not be good,
> because it doesn\'t contain the old product.
>
> So, I really\--over the process, it really is about old product, new
> product, and either breast-fed babies as a concurrent or breast\--an
> adequate breast-fed reference, which we know we need to work on some
> more, but those would be the two really viable options.
>
> DR. GARZA: Dr. Baker.
>
> DR. BAKER: I agree\--I would list number one as first, but I think
> it\'s\--there is also some use in including other reference standards
> besides the breast-fed baby to avoid formula drift, to make sure that
> you\'re not going in one direction all the time.
>
> So, I think some other references might be appropriate, as well, and
> as I understand it, that\'s not really that hard to do, so we\'re not
> asking a whole lot.
>
> DR. GARZA: Is there a reference that you\'ve heard that you would
> recommend?
>
> DR. BAKER: As I understand it, I think that the Fels data, the
> longitudinal data, would be preferable to the NCS data.
>
> DR. GARZA: Okay.
>
> Dr. Clemens.
>
> DR. CLEMENS: Thank you very much for the opportunity to speak.
>
> Just to make a comment on the matrix, which we don\'t have any food
> scientists in the group, I think Dr. Benton yesterday commented on
> batching\--Madeleine, you made a comment, as well\--historically that
> you look at the worst case scenario, and that is you look at liquid
> processing, usually receives the greatest amount of thermal impact, if
> you will.
>
> That is typically the product that is used for clinical trials, to
> look at protein digestibility, matrix. You could look at available
> leucine, reaction products, all those kinds of things.
>
> That is considered, if you will, the worst case scenario.
>
> That is the product which we evaluate, and that is the matrix which we
> assess at clinical trials.
>
> Based on our clinical experience, based on our food science knowledge,
> and based on our own theory and understanding of food processing, food
> chemistry, we realize that, when you spray-dry a product, it\'s not
> nearly as severe, so hence we do not do clinical trials on products,
> some logistical things, as well.
>
> Secondly, I think it was Dr. Merritt this morning, as well as Dr.
> Vanderhoof and Dr. Saavedra, indicated typically we will conduct
> clinical trials using the\--if you will\--the new product, if you
> will, as well as the old product or the product currently on the U.S.
> market.
>
> However, there are cases, a case-by-case situation, where we, in fact,
> can provide cohort data that we don\'t run a concurrent control.
>
> Also, we have\--in each case, we have data compared usually to the
> Fels, NCHS, or we can, in fact, today compare it to the CDC data.
>
> So, all those are really quite easily done.
>
> I just wanted to reiterate, typically we conduct trials, current
> infant formula, as well as the new product, as well as with the option
> of providing cohort data, which are from clinical trials run in the
> past.
>
> DR. GARZA: Okay.
>
> Dr. Briley?
>
> DR. BRILEY: I would go with the first one as number one, and
> obviously, we have to have the current infant formula with the new
> ingredient, as opposed to testing against the current formula, to see
> what the differences were.
>
> I still think, unless we get reference data on the breast cohort, we
> need to start doing that, and maybe we can get it as a reference.
> Maybe we just have to start collecting it. But I think we need to be
> looking at that.
>
> DR. GARZA: But you would be willing to accept both, either if FDA
> looked at a reference data set or a data set they could use to compare
> breast-fed infants\' growth patterns with these others, that would be
> sufficient, or would you conclude that no, they have to have a
> concurring group of breast-fed infants studied, in addition to the
> other two?
>
> DR. BRILEY: That\'s a pretty hard thing to call in the sense that the
> reference data\--I guess I\'d want to see it to see how well it came
> along and how old it was.
>
> There are a lot of factors in breast-feeding that we can\'t address
> here that make a great deal of difference, and so, I\'m going to opt
> on that one to say reference data for now, until we see it, and then
> go from there to make a decision later.
>
> If it\'s good enough, then fine. If it\'s not, then let\'s go back and
> get it.
>
> DR. GARZA: Okay.
>
> Dr. Thureen?
>
> DR. THUREEN: Well, I don\'t think I fundamentally disagree from
> anybody. I think that the second bullet is probably the most
> practical, current formula versus new ingredient, and running a
> concurrent study.
>
> If you\'ve got the reference data from breast milk, I think that\'s
> great. I wouldn\'t go out and initiate a new study just to prove that
> the new formula is better compared to breast milk. So, one and two
> almost become equal if you\'ve got the data.
>
> Close behind that would be great historical controls. That would be
> number three, but it could almost equal the other two if you had
> really good, nearly concurrent data, and then farther down would be
> the reference group, but I don\'t think there\'s a strong indication
> right now for doing a breast-fed concurrent control with a new
> formula.
>
> DR. GARZA: Dr. Denne?
>
> DR. DENNE: In the interests of time, I would concur.
>
> DR. GARZA: Dr. Kuzminski?
>
> MR. KUZMINSKI: I concur exactly with Dr. Thureen.
>
> DR. GARZA: Dr. Stallings?
>
> DR. STALLINGS: I think what Dr. Baker said was very important, and I
> realized if I were sitting on the other side of the table, I would
> want this information.
>
> So, all of the studies, I think, still would be reported compared to
> the CDC data, because we\'re going to need to know that. All studies
> would have the new ingredient formula, because that\'s why we\'re
> doing it.
>
> Then studies would either have a concurrent old formula group or very
> recent, very comparable historical data, like we did it last year,
> very tight, and then the breast-feeding control group is either
> concurrent breast-feeding group or solid reference data.
>
> So, I think there really are four components to what the regulatory
> agency should be evaluating.
>
> DR. GARZA: One of the things that I heard\--perhaps I heard
> incorrectly\--from Dr. Baker was that a longitudinal component would
> be important.
>
> That\'s missing in the CDC. Would you prefer the Fels, Iowa data that,
> in fact, at least is based on a longitudinal design, as opposed to the
> CDC? Because I thought that\'s what he had said.
>
> DR. STALLINGS: I think you\'re right. If it were my job to make a
> decision whether it was safe or not and all of these things are really
> just data presentation, then Fels, Iowa would be, really a fifth
> component.
>
> Then you would have the longitudinal data. You would have the data
> that all of us see on a daily basis, what is the growth grid that we
> use.
>
> So, then you\'ve basically\--no matter what the question was, you\'ve
> got all of this stuff in front of you, and those are not difficult
> things to provide. Those are just running it on a different growth
> grid.
>
> But I think, then, that puts the regulatory agency in an opportunity
> to see it and to be able to answer all the questions, and certainly
> industry is going to want to know all of that anyway.
>
> I don\'t think any of this would be things that they would not have
> explored.
>
> DR. GARZA: Before I turn to Dr. Clemens, is there any voting member
> that wants to modify what Virginia just said? What she\'s saying is
> she feels that having two concurrent feeding groups, a current formula
> group and a current formula plus new ingredient group, that one would
> then take that data and compare it to at least three different growth
> patterns.
>
> One pattern would be the breast-fed group, wherever that data may come
> from, a second pattern would be the Iowa, Fels longitudinal growth
> pattern, and a third would be the CDC growth grid, but that one would
> want to see how growth compared across those different reference data
> sets and explain deviations from it, either positive or negative.
>
> Dr. Kuzminski, is that what you said?
>
> MR. KUZMINSKI: I think that\'s very thorough, extremely thorough.
>
> DR. GARZA: Is that a code word for not necessary?
>
> MR. KUZMINSKI: I think I anecdotally, to a colleague here, used the
> term \"is that overkill?\"
>
> DR. GARZA: Dr. Briley?
>
> DR. BRILEY: But I would argue you would have those data.
>
> They\'re already there. They\'re in the computer, and each time you
> did a new formula, you would only have to compare it to that and
> explain what\'s going on.
>
> I mean it\'s not like that you have to go back and collect it again.
> There would be a little bit start-up, maybe. Maybe not. I don\'t know
> what they keep now.
>
> DR. BAKER: I\'d agree. I don\'t think that\'s overkill.
>
> We\'re not really asking to do another study, another group. We\'re
> just asking for comparative data that\'s already there.
>
> So, it\'s not a\--that\'s not a big deal, I don\'t believe.
>
> DR. GARZA: Let me ask Dr. Fomon to comment on this discussion.
>
> DR. FOMON: Thank you. I know I\'m not allowed to comment. I appreciate
> it.
>
> I just wanted to make the correction that everyone has been speaking
> on longitudinal data about the Iowa, Fels data. The Iowa, Fels data as
> presented are not relevant to this discussion. It\'s the Iowa data.
>
> The Iowa, Fels data start at birth, which are reported weights and are
> reported for birth to one month, birth to two months, one month to two
> months, one month to three months, and so forth. What you need for
> formula comparison is eight or 14 or 28 days to some later time.
>
> It\'s the Iowa data, not the Iowa, Fels data.
>
> DR. GARZA: Thank you very much for that.
>
> Dr. Clemens?
>
> DR. CLEMENS: Your earlier comment\--compared to the various
> groups\--the question, if you collect data from breast-fed kids, how
> do you compare\--what are the significance of those comparisons? We
> don\'t know that. I think we\'re much too early into that.
>
> Maybe this is an opportunity, frankly, to look at a research
> opportunity and to explore those particular comparisons for future
> application. From a regulatory perspective, it seems in what we\'ve
> discussed so far, the terms concurrent controls, historical controls,
> as well as the Iowa data, would seem to be quite appropriate, but I
> think we\'re much too early in understanding the significance and
> comparison and impact of breast-fed and breast milk to make that
> comparison from a regulatory perspective.
>
> DR. GARZA: I don\'t think anyone suggested that there be concurrent
> breast-fed data collected but that, in fact, since everyone we heard
> from industry indicated they didn\'t know what a normal pattern was,
> then, indeed, making those comparisons seems to make sense.
>
> DR. CLEMENS: What is the significance of that pattern?
>
> DR. GARZA: If you deviate from it, I would imagine you\'d have to
> describe why you thought you deviated.
>
> If, in fact, you deviate\--let\'s assume that you\'ve got two formulas
> and one formula deviates, it goes up or down. Is it good or bad? From
> the old formula.
>
> DR. CLEMENS: From the old formula, it\'s one thing, but deviating from
> breast-fed is another issue.
>
> DR. GARZA: What will it mean if it goes up or down from the old
> formula?
>
> DR. CLEMENS: We can explain those deviations. We just can\'t explain
> the deviations we see with breast-fed kids.
>
> DR. GARZA: I don\'t know.
>
> Is that the sense of the group and, in fact, making that comparison
> makes absolutely no sense?
>
> Mr. Anderson?
>
> DR. ANDERSON: I don\'t think that it makes no sense, but I do think
> that the\--for the purposes of this discussion, the relevant
> comparisons are not to the standard, but to the extent that a new
> formula differs in substantive ways from old formulas in the ways that
> they deviate from breast-feeding, and so, my personal view is that
> these references are useful not for the absolute comparisons but for
> their usefulness as a reference to compare new formulas to old
> formulas.
>
> If, for instance\--and new formula showed note differences in a
> prospective control group, and yet one found differences to the
> standard of, say, twice the increase in weight per day based on the
> breast-fed standard, then it seems to me incumbent that that be
> explained in some way.
>
> DR. GARZA: How would you avoid formula drift of the type we\'ve heard
> is possible if the only two comparisons we make is only with the new
> ingredient formula, so that you could always be drifting in one
> direction without making a comparison to one or the other?
>
> If we just do bullet two, how do you avoid drift?
>
> DR. ANDERSON: That\'s why I thought\--sorry, I wasn\'t clear\--that
> the standards would be important as a reference to which one could
> compare formulas.
>
> I mean on that basis, you could observe drift, that curves were moving
> away from the 50th percentile, for instance, or that there were
> substantial deviations being observed from a breast-milk
> standard\--sorry\--reference.
>
> DR. GARZA: Okay.
>
> So, you still think that a reference\--you were not in agreement with
> Dr. Clemens, then, or you were? I wasn\'t clear. Because he thought
> that all you needed was just bullet two, that doing the third was
> really not going to provide any additional information, as I
> understood his comment.
>
> DR. ANDERSON: I\'ll let him decide whether we\'re in general
> disagreement or agreement.
>
> The references are\--my sense is the references are useful because
> they\'re references and that the useful comparisons are not a formula
> to the reference, because I\'m not sure what that means, but a new
> formula to other formulas based on using the reference, because that
> provides information about how a new formula might\--or a series of
> new formulas might deviate from where we have been in the past or
> recognize that a new formula was substantially different in some way
> to some reference, and in that setting, it would be incumbent to
> attempt to explain what those differences were.
>
> DR. GARZA: Dr. Stallings?
>
> DR. STALLINGS: There\'s some interesting potential new scenarios here.
>
> If we\'re comparing a new to an old formula, a new ingredient, and now
> the growth is whatever the standard is, the 3 grams a day, 2 grams a
> day, now the growth pattern that\'s demonstrated is actually slower or
> less than the old formula but still significantly better than
> breast-feeding, then we may have a chance to make a different kind of
> decision, which is I think the regulatory agency\'s been in a position
> where it had to be comparable or better, and then make a judgement
> decision that we actually could have formulas that are providing
> adequate nutrition that don\'t sustain growth only at a higher level.
>
> And that might be an interesting way to start dealing with some of the
> things that we have probably out of, you know, the last 10 or 15
> product improvements.
>
> So, I think this\--you know, I don\'t think it\'s going to be easy,
> but I think it does open the possibility that we start to have\--and
> especially with this\--we\'ve gone with the incremental data analyses,
> the male/female questions, and the, you know, early enrollments and
> looking at the first 42 days and that sort of thing.
>
> We may actually really be able to tell things in a different way, but
> I think one of the things that might happen is industry might come
> with a formula that they believe is completely adequate from its
> composition and from its manufacturing and it shows growth patterns
> somewhere the old product and breast-feeding.
>
> And with that, you know\--and again, remembering this isn\'t
> pre-approval in the sense of a drug, that they could say, well, you
> know, we think we\'re still right on the nose, that this is a good
> product for all the background physical chemistry and food science and
> nutrient content and bio-availability, we think we\'ve got a good
> product, and because it doesn\'t make it grow better than the last
> one, we are still interested in marketing it, because we think we\'re
> where we want to be.
>
> So, I just wanted to bring that up. When we make it a two-tail test, I
> mean there are some things that even in the inadequate growth, if we
> have had product drift over the last 10 or 15 years, this might be an
> opportunity to start to understand that and potential next steps.
>
> DR. GARZA: We now have three different scenarios.
>
> One is that, in fact, we have a comparison of the two formulas plus
> the three references we described\--the CDC, the Iowa, and the WHO
> breast-fed data set, for example, as a breast-fed group\--a second
> that says no, that really is overkill, let\'s just do the two formula
> groups and one of those three but not necessarily all three,
> and\--well, possibly two more\--a third that says no, let\'s just do
> the two formula groups and a non-breast-fed reference, because we
> really don\'t know much about what breast-feeding will tell you, or a
> fourth that says no, let\'s just compare the two formula groups,
> because that\'s really what\--where our interest lies, just in that
> comparison, as the top.
>
> Now, that doesn\'t discount that you might want to do any of the other
> three, but in terms of a recommendation that that\'s all that we would
> see as absolutely essential.
>
> Now, I think I identified all four positions.
>
> Let me go around the room and try to get a sense of which among those
> four\--and I\'ll say them again.
>
> I\'ll just use the code \"two formulas,\" and we\'ll know what that
> means, all right?
>
> Two formulas plus three references\--and you all know what the three
> references are.
>
> The second is two formulas plus only a non-breast-fed reference.
>
> The third is two formulas plus only a breast-fed reference.
>
> And the fourth is only two formulas.
>
> Now, notice that I left out two formulas plus a concurrent
> breast-feeding group. That was also discussed, but I didn\'t hear much
> enthusiasm for saying let\'s get it on the table. If people want to do
> it, we wouldn\'t object, but those were the four that most individuals
> spoke to.
>
> So, let me go around and ask you to identify your top two choices and
> see if we can get a consensus from that as to which one would
> be\--whether we could agree on one.
>
> Who wants to start?
>
> DR. MOYER-MILEUR: I think that since the data is available, I am most
> comfortable with number one and then would accept number three, as
> well, and again, number two makes me nervous because of the potential
> for drift by constantly comparing formula against formula and
> not\--and I guess I just need to make this comment, that if formula
> manufacturers are using breast milk as their model, then why would not
> the growth of an exclusively breast-fed infant be your standard? I
> guess I\'m confused as a clinician.
>
> DR. GARZA: I think that\'s a rhetorical question.
>
> Dr. Sigman-Grant?
>
> DR. SIGMAN-GRANT: Ditto. How\'s that?
>
> DR. GARZA: Very nice. One and three, with one being your top choice.
>
> DR. SIGMAN-GRANT: Yes. And I would exclude four.
>
> DR. GARZA: And you would exclude four. All right.
>
> DR. DOWNER: I think research is really to fill in the gaps in
> knowledge and also to validate earlier research.
>
> Based on that, I choose four. That would be my first choice.
>
> DR. GARZA: Why would you prefer that to either one or three?
>
> DR. DOWNER: I think if we\'re looking at a current infant formula and
> a new ingredient, look at what the research\--the new research that
> we\'re looking at and do the comparisons within the group.
>
> I think it would be helpful to have other data with which to compare
> and to contrast, you know, the new information with, and that is why I
> say, from the sublime to the ridiculous, perhaps, looking at the
> reference, one, because it\'s already there.
>
> But I\'d like to just look at the essential research, the new formula
> versus the old, and see what we\'re looking at, just get into the meat
> of it.
>
> DR. GARZA: Dr. Anderson?
>
> DR. ANDERSON: I would choose either two or three, and that\'s because
> both of those provide some reference upon which to make comparisons
> among formulas.
>
> DR. GARZA: Would you rank them for us?
>
> DR. ANDERSON: They\'re the same to me.
>
> DR. GARZA: Dr. Heubi?
>
> DR. HEUBI: I would choose one as my first and three as my second and
> probably not four.
>
> DR. GARZA: All right.
>
> DR. HEUBI: Because I think that there needs to be some comparison to a
> standard, and I\'m not entirely certain that I\'m real enthusiastic
> about the CDC standard, but I certainly believe that there should be
> comparison to standards, including a breast-fed reference.
>
> DR. STALLINGS: One and one.
>
> \[Laughter.\]
>
> DR. STALLINGS: You know, I think just from what I would like to see to
> be able to evaluate it, but one is number one, and I think if I had to
> choose another one, it would be number three.
>
> DR. GARZA: All right.
>
> Dr. Baker?
>
> DR. BAKER: I think the real question here is what should the
> recommendation be? What\'s really necessary? And so, the question
> really is should we include references at all, and I believe that we
> should.
>
> I think it should be a recommendation that references be included, and
> I think I would go with number one that all three references ought to
> be included, because I don\'t see how you can decide among the others
> which one you want to do.
>
> DR. GARZA: Dr. Briley?
>
> DR. BRILEY: One. I\'m like Ginny. One. But if I had to go for another
> one, I would go for three.
>
> DR. GARZA: Okay.
>
> DR. THUREEN: I am presuming that, with on-line references, that it
> would be easy to get the three references standardized, accessible,
> and relatively easy to compare data to those, and once you set up the
> databases, that in the future it will be very easy to do, and once you
> get to that point, I don\'t see why you wouldn\'t do one.
>
> The pertinent information for the formula company is primarily the two
> formula comparisons, but the information that could be gained for all
> of us really comes under number one, especially if it\'s not an
> excessive burden.
>
> So, I would say number one, and a distant second would be number
> three.
>
> DR. GARZA: Dr. Denne?
>
> DR. DENNE: One and two, with a preference to one.
>
> DR. GARZA: Okay.
>
> MR. KUZMINSKI: Three.
>
> DR. GARZA: Three and three?
>
> MR. KUZMINSKI: Three and three.
>
> DR. GARZA: All right.
>
> Well, with two exceptions, everyone selected number three. With a few
> more exceptions, one was the next, as I read it, and then two and four
> were less.
>
> Now, with one and three \--
>
> DR. BAKER: I don\'t think you counted right.
>
> DR. GARZA: Well, three was, except for Denne and for Dr. Downer, on
> everybody\'s list, I think. Number one was not as general, but it was
> on most people\'s list but not on everyone\'s list, fewer than number
> three.
>
> So, let\'s go to number one and three, because they seem to be the
> most popular, and I\'ll take a show of hands between one and three.
> You have to select between those two.
>
> So, those that have a preference to one, would you raise your hands?
>
> \[Show of hands.\]
>
> DR. GARZA: Okay. So, we have everybody but two.
>
> And those that would select number three.
>
> \[Show of hands.\]
>
> DR. GARZA: Since number one includes three\--how is that for
> confusion?\--then I think that we\'re somewhat consistent in our
> advice to the agency.
>
> Most people prefer number one. Everyone sees the breast-fed group as a
> necessary reference. There are two individuals who thought that
> perhaps was not necessary but they could live with that.
>
> All right. Well, now, having done this, I think we\'ve done B, but let
> me make sure that you agree with me. We talked about merits and values
> and ranked. All right.
>
> Now we are down to number 7. We could either begin this discussion or
> we could\--I don\'t know whether sandwiches are out there.
>
> You could go now, take 15 minutes, bring your sandwiches is, and we
> could then work through lunch and get through number 7 rather than
> trying to break it up.
>
> So, do you want to do that? Take 15 minutes. Let\'s get back here at
> 11:45. Bring your sandwiches with you, and we will try to get through
> question 7, and what I\'m going to do with question 7 is to ask for a
> volunteer using a specific example of what would trigger a growth
> study and, on the basis of that concrete example, to suggest
> guidelines or criteria that led you to identifying that as an example.
>
> Then I\'ll go down the committee, asking several of you for your
> examples and criteria and guidelines for coming to that example, with
> the hope that soon we will hear echoes of the reasons that led you to
> that, and if we hear echoes, then we should be able to get through
> that discussion fairly quickly, because we would have done A, which I
> think is the\--what we\'re going to be able to do.
>
> I don\'t think we\'re going to be able to identify all of the specific
> changes, obviously, that would lead to that, but we can generalize or
> come up with criteria or guidelines and give examples of how those
> criteria and guidelines, if we use the strategy that I\'m suggesting.
> Is that acceptable to the group?
>
> Dr. Stallings?
>
> DR. STALLINGS: Thank you. I just wanted to make a couple of comments
> that came up during break and to be sure that they\'re part of our
> general discussion, as well, or knowledge.
>
> In talking with Roger, it appears that the industry data on
> breast-feeding babies, which is extensive, might be able to be
> available, you know, in a form that we could all do.
>
> Also, in talking with Dr. Fomon, only about a third of the data on the
> breast-fed infants there have ever been published for them, so there
> might be an opportunity to mine the Iowa longitudinal data set more
> specifically, particularly between the birth and four-month window
> that we\'re looking at.
>
> So, I just wanted to mention those, that there may be better
> information for us in the future, and it represents great cooperation.
>
> DR. GARZA: All right. Very good. All right, then. Let\'s get back at
> about 10 till.
>
> \[Recess.\]
>
> DR. GARZA: I want to thank the committee for being so compliant in
> having such a quick lunch.
>
> So, we\'re on to the home stretch on question number 7.
>
> We\'ve got about two-and-a-half hours to get through it. So, I do
> think that we ought to be able to through it.
>
> Of course, I may have nixed it in the expression of optimism. I hope
> not.
>
> I asked the group to think about this, because I thought it would be
> much more efficient if you had had a chance to reflect last night on
> guidelines and criteria that one can use to determine the need for a
> clinical study intended to provide assurance of normal physical growth
> if one took an example of what, in your minds, would trigger such a
> study, and then, with that concrete example, illustrate for the group
> what general principles or criteria you used in identifying that
> specific example.
>
> Let me ask for a volunteer. Who would like to go first?
>
> You notice that I didn\'t choose anyone, because I want to keep my
> friends.
>
> There\'s this great adage in food and nutrition that friends come and
> go, enemies you accumulate.
>
> No one, huh?
>
> Dr. Stallings, thank you for rescuing me.
>
> DR. STALLINGS: Okay. So, I\'ll\--I\'m sure I don\'t have all the
> details that Bert\'s really going to want, but this will at least
> start the discussion.
>
> So, my proposal was to study term infants, and my question was, on an
> infant\--the term infant formula that has the soy protein\--and one of
> the examples on the table was that there is the potential process for
> stripping the isoflavones out of that, so that you would be taking
> something that we have experience with, which is soy-based
> feeding\--that you would be making a major manufacturing change.
>
> So, in theory, I said it was from the same source, assuming that the
> stripping and all of that would be done by the company but that there
> be an assumption that it may actually have to go to a different
> source.
>
> DR. GARZA: This wasn\'t soy that was grown in a corn field.
>
> DR. STALLINGS: Right. And I was assuming that I would start with the
> idea that the same amount of protein content\--so, the grams per kilo
> for baby, a normal feeding\--I didn\'t have any intent to change that.
>
> So, the inclusion criteria would be term, and I think that\'s been
> described as greater than 37 weeks, or I usually use the 38 to 42.
>
> I stumbled even on the exclusion criteria trying to think about what
> we\'ve all been working on, which is test the new product in the
> population that it will serve, and soy basically has a number of uses.
>
> You know, one is cow milk protein that sometimes is used, although
> there are alternative products, lactose intolerant, and then in real
> clinical practice, it\'s often just used as the formula you try when
> the baby, quote, has \"feeding intolerance,\" so it\'s not really
> coming with a real diagnosis.
>
> So, I decided not to exclude anything. It was the decision.
>
> And then trying to get into a protocol\--I think this kind of a chain
> certainly merits a feeding study, as well as all the pre-clinical work
> that would have been done.
>
> So, again, this was before much of the discussion today.
>
> If I had a wish list, then I would have had, in essence, a four-armed
> study. So, we may have modified that already but that you would have a
> breast-feeding group as sort of a standard, you would have your
> regular soy formula, you would have my new modified soy formula with
> decreased isoflavones, and I was wondering about the strength of the
> data, and it probably could be provided historically, but again, to
> look at the growth of children on cow milk protein versus soy milk
> protein, just to benchmark that difference, as well.
>
> So, then I was trying to think about where would I do the study, and
> as we all know and have talked about, you can\'t exactly randomize
> children to breast-feeding. That has to be a family choice, and
> formula feeding is a family choice.
>
> But then could we have a study where we would have families\' consent
> to be in a study where they were randomized to regular soy protein, a
> new soy protein, or regular cow milk product, whatever the comparable
> product would be.
>
> Then I had the idea that the birth weight would probably be
> historical, because we\'re not enrolling while they\'re in the nursery
> and the stay is so short, and then use the time-line\--and I want them
> enrolled at least by 14 days, preferably by eight but certainly by 14,
> agreed with the work we did yesterday on weight and length and height
> and at the study assessments through six months, and I was actually
> wishing that I could have a 12-month data point for growth.
>
> And then when I looked at, here, growth being your primary outcome,
> trying to follow that, there would be a number of other secondary
> outcomes if we were to take this approach, and those would be really,
> I think, two things.
>
> One, part of the interest in isoflavone-reduced products is that is
> there any indication of estrogen effects on babies during this time?
> So, there could be physical examination and potential bio-markers,
> blood tests that would follow that, and those might be done at one,
> three, six, and 12 months, not at every assessment, and probably the
> three-month is the highest dose exposure of the formula, because it\'s
> before most complementary feeding has started.
>
> So, you know, the one-month, probably the exposure is highest because
> of volume, but I thought those were important.
>
> And then the pre-clinical and the scientific review would have
> given\--and the review of the actual manufacturing would have led to,
> are there any, for example, vitamin and mineral blood tests that need
> to\--are we putting anything at risk by the time we\'ve gone to this
> new manufacturing or new source, so that there might be some other
> biochemical assessments that would need to be done.
>
> So, I came out of it with that kind of a study where growth is still
> the primary outcome, but there would be two types, potentially, of
> secondary assessment that I would be interested in.
>
> One is the estrogen, and I guess the issue there is I know that it
> could never be powered to pick those up, because if they exist at all
> they\'re rare, and the vitamin and mineral data could probably be
> powered reasonably well, I would think, if there were indications from
> the manufacturing.
>
> So, that\'s an overview of things to \--
>
> DR. GARZA: Okay.
>
> As I listened to the design of the study that you were thinking about,
> were the criteria and principles that led you to that\--because it was
> a substantially manufacturing change, I mean the idea that we\'re
> stripping something, that one was dealing with a potential special
> vulnerable population in that these kids, if they\'re generally put on
> soy formula, it\'s a second formula.
>
> It\'s not generally a primary formula that\'s used, but either because
> they were intolerant or developed lactase deficiency or whatever, but
> they were an especially vulnerable population, and that there may be
> the involvement of bio-active factors that could influence growth.
>
> Are those the sorts of criteria that led you to say, well, this is
> what would trigger a growth study, and are there others that one could
> generalize, so that as we look at the example that you gave, and
> others, one would be able to provide some guidance to say, well, if
> the change involves any of these factors, then you probably ought to
> think very carefully about the need for a clinical study or,
> conversely, one that look at growth.
>
> If it doesn\'t meet these, don\'t worry about it.
>
> DR. STALLINGS: I think you captured what I thought of also as my
> general principles. The only thing I realized as I was getting into
> this is, with such a major manufacturing change, you have to do the
> growth study.
>
> If this were to stay a marketable product, I could see there would be
> a time in the foreseeable future where there might be questions that
> wouldn\'t require a whole growth study but might be going back and
> doing biochemical studies, that kind of thing, as we learn more about
> it, or again, you know, maybe there are vitamins, their
> bio-availability, things that change and things like that.
>
> But yes, I think you got the major principles.
>
> DR. GARZA: As I compare those with Dr. Bier\'s guidelines for when one
> would need a clinical study, the one\--I mean and he mentioned others
> that obviously\--that I have not from that example.
>
> The one that didn\'t seem to be covered in his white paper was the
> involvement of a potentially especially vulnerable population, I mean
> that if you\'re dealing with a population such as the one that you
> might expect to be on soy, then you probably ought to have a higher
> bar.
>
> DR. STALLINGS: As a clinician, also, I think the especially vulnerable
> population might be the children with very short gut and the even more
> specialized products.
>
> I think in today\'s environment that the soy product is so\--used in
> so many different indications, many of them are probably not truly
> especially vulnerable.
>
> We use it in that group, but I wouldn\'t want to say that I only want
> to go to children who, you know, had known, for example, protein or
> lactose, because it such a commonly used\--so, I was trying to use
> that idea, where is it really used in modern practice, and this, I
> think, is generally used in many otherwise\--well, in many healthy
> children, not otherwise healthy children, as well as having a special
> place with some specific GI or allergy diagnoses.
>
> DR. GARZA: Do we have another example to help us work through
> identifying criteria or guidelines that would trigger a clinical
> study?
>
> Dr. Heubi?
>
> DR. HEUBI: I have an example, but it\'s pretty esoteric. But it\'s
> fairly relevant.
>
> And that is my suggestion was a infant formula company would decide
> that it was appropriate to include epidermal growth factor in their
> formula for inclusion in a pre-term infant formula because there may
> be evidence that EGF reduces the risk of necrotizing enterocolitis,
> and so, as a consequence, that addition, since it\'s really not been
> tested in humans, ever, as far as I know, in terms of as an enteric
> administration, would require a clinical trial, partly because you
> don\'t know about safety, but also you don\'t know about whether it
> would affect growth.
>
> It may actually have an enhancing quality for growth that we currently
> don\'t know.
>
> So, you would select a population of pre-term infants that would be
> probably 1,500 to 2,500 grams, the group of individuals who would be
> at risk, or even smaller, for NEC, and it would require a large
> population of patients to study to define whether there was really a
> clinically significant reduction in the rate of NEC within that
> population.
>
> It would obviously require a comparison to a comparative formula that
> would be without epidermal growth factor, and your end points would be
> not only measurements of growth but also incidence of NEC, and as John
> presented yesterday, it would require a large sample size to be able
> to answer this question. It\'s a specific health claim, yes.
>
> DR. GARZA: So, what one would be\--you\'re dealing with a factor
> that\'s not been tested in humans before in terms of in a food in an
> especially vulnerable population that might involve growth. That\'s
> one, in addition to the other three we talked about.
>
> Another which I thought was interesting, when you said, well, here\'s
> a factor that\'s in human milk, and Dr. Bier has said, look, the fact
> that it is in human milk doesn\'t necessarily preclude a growth factor
> or a growth study.
>
> Would you entertain the opposite one, to say, well, given the fact
> that any substance, bio-active factor that we don\'t have experience
> with, other than in human milk, should trigger one, because these are
> bio-active factors that act in concert with others, and we\'re not
> quite sure they might act, in isolation of everything else.
>
> Epidermal growth factor is part of human milk, but so are a number of
> other growth factors. If you just provide in isolation, what is the
> outcome?
>
> DR. HEUBI: That\'s a relevant question, too.
>
> It actually sort of begs the issue of would you try to concoct a
> mixture of these to include in infant formula and do a study of that
> nature, but we\'re not designing their study for them.
>
> DR. GARZA: But you\'re saying that anything that\--a bio-active
> factor, whether there is experience\--recognized to be part of human
> milk\--is really irrelevant, I mean, that, in fact, you probably will
> need a study, because we don\'t have an experience with that product
> in isolation.
>
> DR. HEUBI: Yes, this is a circumstance in which a two-tail test for
> growth would be absolutely essential, because you don\'t know whether
> it might have a positive or a negative impact on growth.
>
> DR. GARZA: So, not being tested in humans and its bio-active
> nature\--that second one, I think Dr. Bier had in his paper, as well.
> Okay.
>
> Dr. Clemens?
>
> DR. CLEMENS: Thank you very much.
>
> The hand-out you received yesterday, perhaps in the e-mail, as well,
> talks about the potential change that we might see in the infant
> formula now, and we have experience of what we have gone through, we
> might see in the future.
>
> I think that was a very nice example, Jim, regarding EGF.
>
> You see it as a flow diagram that focuses in the decision, how do you
> get down to the point where you decide to make a clinical trial, and
> that helps us focus on the question of item number 7.
>
> Using Jim\'s example, you can see that perhaps we don\'t have
> sufficient hands-on information at this point in time, even though it
> included a breast-milk, addition that requires a processing change
> under current food science and technology.
>
> That would trigger, automatically, a clinical trial.
>
> So, what I wanted to focus on is the fact that some of the issues
> we\'ll be discussing in the next two hours really go through this flow
> diagram decision tree matrix, and then you will look at the experience
> in a matrix, whether you\'re moving isoflavones from soy, what kind of
> data set are already available in human consumption as well as other
> studies, what processing changes, and maybe it\'s a processing change
> that would dictate initial clinical trials, in addition to
> physiological requirements.
>
> So, look at nutritional adequacy as the bottom line, and if we think,
> in theory or through processing or through whatever change we have to
> go through, the ingredient or through the processing, that would
> dictate we\'d expect a change in growth or impact on nutritional
> adequacy, clearly we would do a clinical study.
>
> DR. GARZA: Dr. Anderson?
>
> DR. ANDERSON: I wonder if I could follow up and ask Virginia some
> questions.
>
> I\'m way out of my content expertise here, so if I say something
> really stupid, you\'ll forgive me.
>
> Suppose, prior to your study, there were two previous studies, one
> done by taking isoflavones\--removing isoflavones in a dietary
> supplement which was directed towards the elderly and the clinical
> trials there were already completed and were found to do what you
> expect dietary supplements in the elderly to do and there were no
> impacts on adverse events.
>
> And suppose, in addition, there was a study in children who, because
> of their medical condition, needed dietary supplements and that study
> had already been done, again with the same processing to remove the
> isoflavones, a appropriately conducted clinical trial showing that,
> in, let\'s say, eight-to-12-year-olds, the product without the
> isoflavones produced the same effect as the product with the
> isoflavones and there were no obvious adverse impacts.
>
> How do you feel now about the necessity for a trial in infants?
>
> DR. STALLINGS: Probably unchanged. The issues of exposure to the
> estrogen component is, I think, very different in the very young,
> growing child.
>
> The per-kilo exposure even in the residual amounts or in the previous
> amounts would be quite different, usually, from the food sources.
>
> So, I don\'t think either of those would be good models to test either
> the growth question, because of the\--in essence, the infant growth
> spurt that we\'ve been talking about, nor optimal for testing the
> question of whether very low bio-active components are having a
> biological effect, and we know in newborns that changes in some
> hormonal\--some enzymes\--that with relatively low amounts of estrogen
> you can estrogenize boys and with relatively low amounts of
> testosterone you can testosteronize girls.
>
> So, there are some things that are fairly unique in that setting, but
> it\'s a good question. But in those two examples, they don\'t meet the
> dose exposure, and neither of these populations would have the growth.
>
> The per-kilo in health infants, the protein intake, you know, is
> probably two to three grams per kilo.
>
> By the time you\'re a 12-year-old, it\'s probably about one gram per
> kilo, and elderly, honestly, we don\'t have as good a handle on, but
> in healthy adults, we tend to think of it being .8 grams per kilo.
>
> So, even the protein sufficiency question, which is inherent to
> changing a protein source\--probably those are not great models.
>
> So, I would be looking for a younger, rapidly-growing group.
>
> DR. GARZA: So, would we then modify one of the criteria that Jim
> introduced to indicate that, in fact, it\'s not enough that it hasn\'t
> been tested in humans but that it hasn\'t been tested in children, so
> that the default ought to be, gee, do you have information that is
> developmentally specific, dose specific, because of autogeny of
> development, etcetera.
>
> Okay. That was very helpful. Thank you.
>
> DR. SIGMAN-GRANT: But didn\'t we say that what we\'d require would be
> that the formula would be tested for the population for which it was
> intended?
>
> DR. GARZA: In terms of triggering that, if you had epidermal\--let\'s
> assume that we had epidermal growth factor data in humans that had
> been safe in the elderly or in an adult population. The fact that you
> didn\'t have it in children would still trigger or be one of the
> factors that at least the FDA would use in determining whether or not
> they would recommend or industry would decide to do a clinical growth
> study.
>
> Dr. Anderson?
>
> DR. ANDERSON: The reason for asking the questions is that I think that
> there\'s probably some continuum, and the particular example here is
> probably not the right one, but I can sort of imagine that there might
> be another instance of a major processing change in which there was
> information from other sources to suggest that the preponderance of
> that evidence would suggest that the change would have no adverse
> impact either on growth or adverse effects, and so, I think we need
> to, you know, test that boundary as we may have these discussions.
>
> DR. GARZA: Knowing full well that this has been a topic of recent
> enormous concern nationally in terms of when you require testing in
> children, I don\'t think we\'ll come to resolution on that one, and we
> probably shouldn\'t try at this meeting.
>
> Okay. Any other examples that will help us go through this development
> of guidelines and general principles?
>
> Dr. Denne?
>
> DR. DENNE: Not so much an example but perhaps a comment on the
> previous AAP guidelines about what might not trigger a growth study,
> and I mean, for example, fairly wide ranges in changes in energy
> concentration and very wide ranges in protein concentration by the AAP
> in 1988 suggested that those didn\'t require growth studies.
>
> I would think that, at present that wouldn\'t be acceptable. I mean a
> change somewhere between two and four-and-a-half grams per hundred
> kilo-calories, according to the AAP, wouldn\'t require a change.
>
> It would seem that, under our revision, that might be different, that
> major changes in macro-nutrient content would require a growth study.
>
> DR. GARZA: This brings to mind the suggestion that was made, I think
> again by Dr. Bier, that we ought to take a look at the LSRO, DRI, and
> other processes to see have those ranges been narrowed by any of that
> information, because those requirements have been looked at, and I
> think you\'re right that we ought to probably go back and get more
> quantitative, then we will have an opportunity to do that here, and
> those may be guidelines that we can use to help determine what would
> be appropriate.
>
> Dr. Thureen?
>
> DR. THUREEN: Yes. I\'d like to know if there\'s any plan to adopt the
> LSRO recommendations by the FDA?
>
> DR. TAYLOR: In order to provide for the final set on nutrient
> recommendations, we, of course, go through notice and comment
> rule-making, and all available data, including that from LSRO, would
> be part of the consideration. So, it will certainly be considered.
>
> DR. GARZA: All right.
>
> Any other examples?
>
> DR. SIGMAN-GRANT: I had an example of adding cholesterol to bovine
> iron-fortified commercial formula.
>
> There are some studies in baboons that suggest\--there\'s some
> previous animal studies that suggest that it, again, is a compound
> found in human milk.
>
> I looked through Dr. Bier\'s criteria, and it will fit under almost
> any one he listed, but I think that would be an example where a growth
> study would be required, particularly since it\'s such a controversial
> sort of ingredient.
>
> DR. GARZA: Did you find any of the general principles or criteria that
> Dr. Bier discussed in his white paper inappropriate in terms of
> triggering the study?
>
> That doesn\'t mean that it would necessarily be exhaustive but that,
> as you went through the cholesterol example in your mind, did they all
> pretty \--
>
> DR. SIGMAN-GRANT: Yeah.
>
> DR. GARZA: \--fit in your mind that that should be looked at?
>
> DR. SIGMAN-GRANT: Almost every one of them. I think addition of an
> entirely new compound, it\'s a formula change. Well, we don\'t have
> nutrient levels established. So, that one wouldn\'t apply to this.
>
> But compound known to affect hormones, growth factors\--I think most
> of them, except for the one where it hasn\'t previously been
> established.
>
> DR. GARZA: As I go through the list in my mind\--and I may not be
> remembering them all\--the only two\--and one could construe, perhaps,
> that some of them would be inclusive in the list that he provided in
> that paper\--is the extra care if the formula is directed at an
> especially vulnerable population and that, in fact, one ought to look
> very carefully at those changes.
>
> Premature might fall into that group, not only the type of infants
> that Ginanne\'s example gave us, and the addition of a new factor, but
> I guess that would be in there, as well, I mean exactly.
>
> So, that may be the only one.
>
> Dr. Heubi and then Dr. Anderson?
>
> DR. HEUBI: My only comment about cholesterol is it actually is present
> in infant formula in varying concentrations, and the reason, actually,
> it would fulfill criteria probably would be it would require a new
> formulation to do this, correct?
>
> DR. GARZA: Dr. Anderson?
>
> DR. ANDERSON: So, perhaps I could ask Roger to comment, because the
> criterion 4 was that a study was required when an entirely new
> compound was added to infant formula, and yet the decision tree chart
> seems to suggest that if the additional ingredient was determined to
> be generally recognized as safe for infant formula, its addition was
> supported by well-accepted scientific rationale and/or experience in
> the manufacturer\'s formulation, I assume other formulations, and
> raised no reasonable expectations of a significant adverse impact,
> that no clinical trial was required.
>
> DR. GARZA: Before he answers, is there a separate GRAS list for infant
> formula? No, there is no special GRAS list for infant formula. So,
> it\'s just\--you\'re suggesting that any GRAS substance \--
>
> DR. ANDERSON: No. I\'m suggesting that\'s what the decision \--
>
> DR. GARZA: I don\'t think any of us would agree with that, but let me
> ask Dr. Clemens. I mean Dr. Benton gave us examples where that could
> be a problem in young infants.
>
> DR. CLEMENS: Even though it\'s GRAS, it may not be appropriate to put
> in infant formula, is the bottom line, and we have to assess the
> science behind putting a particular ingredient in infant formula.
>
> If you want to use the cholesterol issue\--and thank you, Jim, for
> making the comment that all milk-based formulas do, in fact, contain
> cholesterol at some levels, but also the emerging science would
> suggest\--if you want to use that as an example\--suggest there is
> points of addition you want to consider, what happens to instability,
> and a new matrix is not associated with reliable proteins, is not
> associated with microns.
>
> So, how is that metabolized? How does it impact cholesterol
> biosynthesis or degradation? All those things need to be considered,
> and clearly, it\'s likely that we would do not only a growth study,
> Madeleine, but also do a lot of metabolic studies to justify that
> position before presenting it to the FDA.
>
> DR. SIGMAN-GRANT: It was just an example.
>
> DR. GARZA: I do think that it\'s helpful to go back to criteria 4.
>
> DR. HEUBI: It was a good example, and actually, it was a good example
> for maybe the wrong reason, because it actually would require
> reformulation, not because it\'s a new addition.
>
> DR. GARZA: If we go to criteria 4, though, the example that Dr.
> Anderson just gave us about GRAS substances, criteria 4, as suggested
> in Dr. Bier\'s paper, doesn\'t make a distinction between GRAS and
> non-GRAS substances, just as if it\'s a new compound in infant
> formula.
>
> DR. THUREEN: Dr. Garza?
>
> DR. GARZA: Yes?
>
> DR. THUREEN: Maybe I could comment. And this is an example from the
> decision tree paper. They said here are examples of substances that
> may not necessarily require a clinical trial, and it said \"addition
> of minor constituents added for potential nutrient contribution but
> for which there is no reasonable basis to predict that they would
> materially impact nutritional adequacy,\" and the example was
> L-carnitine.
>
> I thought that was a curious example and that that\'s sort of a new
> ingredient that I think has been put in great question, and the
> implication here was that you didn\'t necessarily need to study it,
> because it\'s well enough understood.
>
> DR. GARZA: I think the decision tree is very useful for your
> background, but it\'s not something that is on the table as something
> we\'re going to adopt.
>
> DR. THUREEN: Right.
>
> DR. GARZA: If we start doing that, then we have to go\--also, there\'s
> been another decision tree that was suggested to us by Dr.\--or Ms.
> Heiser to treat it as a drug, and I don\'t want to go down that path.
>
> DR. THUREEN: I didn\'t mean to talk about the decision tree
> specifically. It\'s just that this is a new product that I think
> would, by definition \--
>
> DR. GARZA: It\'s an example like the cholesterol one.
>
> DR. THUREEN: Another example.
>
> DR. BAKER: I\'m sort of\--I\'m going to give another example, and I\'m
> a little bit afraid of what\'s going to happen with this, but looking
> at the decision tree again, to me, it does seem like the decision tree
> does reflect some thinking about what are in the regulations.
>
> So, I think the decision tree is worth looking at.
>
> I do note, however, if you get down into the bottom of these, it
> always comes to a study is unlikely or likely.
>
> You still have to make that decision, and actually, we\'re working
> below the decision tree. We\'re trying to decide how to decide this
> last thing in the decision tree.
>
> DR. GARZA: Well, to the degree, Dr. Baker, that you can take\--extract
> either general principles or criteria that you think the group ought
> to be considering from either that tree or anything else we\'ve heard,
> that\'s fine, but it\'s not the tree we\'re looking at.
>
> DR. BAKER: We are actually looking at the bottom box of this decision
> tree, so that what goes before that is not really relevant. Well,
> it\'s relevant, but it\'s not what we\'re considering at this time,
> and the reason I\'m bringing the example up that I am going to is
> that, if you follow the decision tree and what the industry has given
> us, you probably wouldn\'t have to do a growth study in this case, but
> I think you clearly would if you follow my logic here.
>
> The example\--I don\'t want to embarrass the FDA, but the example is
> boiling water to powdered formula for pre-term infants, and this was
> suggested because\--it was to eliminate contamination in powdered
> formula, and the industry has said, if they have a recommendation from
> an expert body, that they would accept\--would make that change
> without a study.
>
> But it\'s very clear that boiling water to powdered formula changes
> all sorts of things in a formula, and it would definitely\--if you
> were going to actually go through with that\--fortunately, we have
> backed off that a little bit and we\'re not going to go through with
> it, but if you were, it would definitely require a growth study.
>
> DR. GARZA: So, that would be based on the general principle that if
> you\'re going to change the composition\--so, if you\'re going to be
> changing the nutritional composition of the formula\--I think that\'s,
> again, one of the criteria in Dr. Bier\'s paper.
>
> Dr. Downer?
>
> DR. DOWNER: In doing my assignment last night, I looked at iron, and
> we know that most of the formula in the United States do use ferrous
> sulfate, and I wanted to see, if we were to use a different form of
> iron, it might have been interesting to look at, in general principle,
> what some other criteria would be to address this.
>
> Again, this is not factual, just hypothetical. That\'s what we\'re
> going from. And so, in general, I think that would trigger, I
> think\--and essentially what would trigger the growth study would be
> if there were any\--looking at bio-availability.
>
> That would be something that I\'d like to look at.
>
> Also, the impact of this new iron source on the other nutrients that
> would be available. So, how would it impact?
>
> Also to look and see if this new product, whatever this new iron
> source is, how would it perform at least with the old product and also
> against breast milk formula?
>
> I\'d also look for metabolic, physiological, and endocrinologic
> changes in the new formula, and also look to see how this new iron
> formula would impact on growth, particularly the growth parameters
> that we set forth, and of course, taste would be something I would
> look at, acceptability for the infant.
>
> So, those are some of the things that I noted here.
>
> DR. GARZA: So, that would still fall under the new formulation. If
> you\'re going to reformulate it, then for all those reasons, you would
> want to \--
>
> DR. DOWNER: Yes.
>
> DR. GARZA: Okay.
>
> DR. GARZA: Dr. Kuzminski.
>
> MR. KUZMINSKI: Thank you.
>
> We did not collaborate, but I chose exactly the same example.
>
> But I think\--and I was being a little bit more specific, but some of
> the industry may consider a frivolous recommendation of changing not
> just the source but source and type, ferrous sulfate to an
> encapsulated reduced iron, where the new technology may provide
> stability to the reduced iron, and so, we\'re assessing the effect of
> the efficacy of the encapsulation and then also the impact upon the
> other nutritional components of the formulation.
>
> If this is new technology and is driven by supplier problems with the
> traditional source of iron, ferrous sulfate, then a criteria also may
> be the existence or non-existence of internal experience with the new
> component, whereby this particular example may, in itself, not drive
> the need for a growth study but may have an effect on other components
> within the formulation, chemically, organoleptically, for acceptance
> that may drive the need for a confirmatory study, if you will, a
> growth study.
>
> DR. GARZA: So, again, it would be a new formulation, in essence.
>
> MR. KUZMINSKI: New compound.
>
> DR. GARZA: I am not hearing marked deviations from at least the
> background material that we got both from the agency or from Dr. Bier
> or necessarily the general principles that are outlined in anything
> we\'ve heard in any of the presentations.
>
> Is that because it\'s too complex an issue that we can deal with or
> because everybody\'s exhausted, that you gave it enough thought?
>
> How about some of you that have not given us your examples?
>
> DR. THUREEN: I have an example of a pre-term study, which we haven\'t
> addressed, and my example was a new fat gland with possible enhanced
> growth, fatty acid profiles more like infants fed breast milk,
> possible lower cholesterol levels in infancy and possible positive
> effects in neuro-development outcome.
>
> This product has been studied in term infants and shown essentially no
> effect in growth, but there was a slight tendency towards long-term
> neuro-developmental positive benefit, and those studies had only gone
> out to 18 months, and now this was to be studied in pre-term infants,
> though there had been recent reports of increased diarrhea in term
> infants.
>
> So, the objectives were to study this in this new pre-term infant
> population, and what would make it different is that it would be a new
> population, essentially that had not been studied before, a vulnerable
> population.
>
> We\'d want to study effects in neuro-development outcome and look at
> effects on growth, and this would not only definitely require a growth
> study but may require a more detailed study done, both fat digestion
> and level of fat digestion, so we may need nutrient balance studies,
> and maybe micro-nutrient studies in case there was increased fat
> mal-absorption.
>
> You\'d have to look at absorption of other studies.
>
> So, this is in the category of effects on absorption of other
> nutrients.
>
> DR. GARZA: But also, I mean there would be a formula that is now going
> to be intended for a brand new population that\'s never been tested.
> So, in essence, it\'s a brand new formulation.
>
> DR. THUREEN: And new formulation.
>
> DR. GARZA: And that would go ahead and trigger, than, a study, because
> it would be intended now for a population whom it had never been
> evaluated, and I think that\'s not a guideline or a criterion that is
> in Dr. Bier\'s paper. I think it is part of\--maybe not\--of the other
> background material we got from FDA.
>
> Dr. Clemens?
>
> DR. CLEMENS: Actually, I appreciate the comment on iron. I did
> research on iron over 20 years ago, so that\'s pretty close to my
> heart. Actually, ferrous sulfate is a good example, and we\'ve used it
> in infant formula for a lot of years, and if there\'s a change,
> emerging technology, yes, all the studies that have been
> suggested\--metabolic studies, balances studies\--those kinds of
> things are already addressed in the academy guidelines.
>
> In addition to the fatty acid issue that you addressed in pre-term,
> those, too, are addressed in the academy guidelines.
>
> You change the fat source, change the growth profiles that are
> significant based on the scientific evidence, we actually do the
> digestibility issues, we address the balance issues, we look at
> stools, we look at a lot of different things, as you can imagine.
>
> So, both kinds of guidelines were in place, and based on scientific
> background, the knowledge and experience again, we actually won\'t
> trigger clinical trials, because it\'s your point, it makes good
> sense.
>
> DR. GARZA: Dr. Sigman-Grant?
>
> DR. SIGMAN-GRANT: What about an ingredient that\'s, say, genetically
> engineered or produced through a different technique? Would that be
> something that might require a different criterion, if it\'s the same
> ingredient but production is different?
>
> DR. CLEMENS: That\'s a fair question. I can give you two examples.
>
> We look at canola oil, based in Canada. It\'s a low-erucic acid, a
> seed oil, and we\'ve agreed in this country not to use it.
>
> Matter of fact, a number of organizations across the world have agreed
> not to use it because of the presence of erucic acid, and we certainly
> concur with that in the pediatric population, even though Codex, I
> think, agreed that it could be used.
>
> WHO, however, has not agreed that it should be used in infant formula.
>
> In terms of protein, let\'s say, biotechnology, all the soy protein
> used in this country in infant formula is, in fact, Monsanto-derived,
> and it is through years of usage and growth studies, it\'s been deemed
> to be nutritionally adequate.
>
> Now, if there\'s a new ingredient that\'s on the table, in fact, we
> would study it just as rigorously as anything else.
>
> DR. GARZA: Would that trigger a study because it was a new source?
> What that considered a new source of soy and, therefore, a new
> formulation and, therefore, was re-studied when they made the
> transition from traditionally bred to genetically modified soy?
>
> DR. TAYLOR: The answer to your question is a very difficult one,
> because you know, we\'re standing on the precipice of what does that
> mean, and remember, it\'s GRAS for intended use. So, there\'s GRAS for
> whatever the end point is, and I\'m deliberately not going to answer
> your question, because I don\'t think we have a history of knowing how
> to answer your question.
>
> DR. GARZA: All right. The only reason I was curious is because we have
> one guideline that says, if you have a new source\--so, if the new
> source is a new source \--
>
> DR. TAYLOR: What is it? You know, we\'re back to that problem. Is it a
> new source? If it is a new source, it\'s down on path. If it\'s not a
> new source, it\'s down the other.
>
> So, new source, yes, but what\'s a new source.
>
> DR. GARZA: It\'s a good point, because in fact, one looks at the
> criteria that says new source, and it\'s a definition of not what is
> is but what is new and whether, in fact, one would find, if the source
> has been modified in any way, whether that qualifies as new.
>
> Dr. Briley.
>
> DR. BRILEY: I just wanted to ask who identifies whether it\'s a new
> source or not? Does the industry? Who does the identification?
>
> DR. GARZA: Who has the regulatory responsibility to identify if
> somebody switches from one source to another?
>
> DR. TAYLOR: This is a notification process, so the manufacturer comes
> in with a package. We have the right to object or not object.
>
> So, they could assert it\'s a new source or assert it isn\'t a new
> source, and then it comes under our review.
>
> So, it starts with them, and then we, of course, review the package.
>
> DR. GARZA: For example, let\'s assume that BT corn, tomorrow, would
> become a significant source of some unsaturated fatty acids.
>
> It would be the responsibility of the manufacturer to notify FDA that,
> in fact, the source of the fatty acids had now changed from a
> conventional corn to BT corn, or would you be required to identify the
> change by your own monitoring techniques, so it would be the
> manufacturer that\--so, it\'s their judgement as to whether it\'s new
> or not.
>
> DR. TAYLOR: We\'re talking about 412, which is the finished product. I
> want to distinguish between the 409 review, which is the actual
> individual ingredient and its coming in for GRAS, which is a
> preliminary process, separate from the 412, which is once
> everything\--the individual ingredients are deemed safe, once you put
> it together, it works.
>
> Now, that whole notion of working is where new source comes in. So,
> it\'s a very complicated world, but no, we don\'t have a monitoring to
> see what the industry is using for these formulations, if that\'s your
> question.
>
> DR. GARZA: Does that help clarify it? Thank you. Because that\'s very
> helpful.
>
> Dr. Anderson?
>
> DR. ANDERSON: I\'d ask Dr. Thureen to consider the reverse of the
> trial that she suggested.
>
> Suppose that the previous study was done in well preemies and they
> were studied through to six months after expected delivery and that it
> all turned out exactly the way one wanted it to, and now the interest
> is in marketing this to term infants.
>
> Do we need a clinical study?
>
> DR. THUREEN: I think it would require a clinical study, because I
> think you have to assess growth.
>
> It\'s a new formulation in a different population, physiologically
> different population. I think it would need study.
>
> DR. GARZA: Would anyone disagree with that?
>
> So that, as a general principle, anytime you move to a population
> other than the originally intended one, that the default ought to be a
> new study.
>
> Obviously, people can submit information as to why that may not be
> appropriate, but that ought to be a trigger in considering the need
> for one, as a general principle.
>
> Can you think of circumstances where that general principle would
> not\--wouldn\'t even come into play?
>
> Dr. Stallings?
>
> DR. STALLINGS: It\'s hard to think of one that we could do
> theoretically, and I think we\'ve got to remember that, if we use the
> population that you intend to treat, the pre-term infant formula will
> be fed to babies who are still in intensive-care units and are
> generally very sick.
>
> Now, they\'re not so sick that they\'re not getting enteral formula,
> which is a point in the spectrum, but they\'re also capable of getting
> sepsis or any number of other things during that grower and gainer
> phase.
>
> So, I think it is a very different time, and anything designed for
> that and shown safe there actually might have\--might theoretically
> have a different effect in truly term babies without all of the
> stresses of being premature and in intensive care units.
>
> So, I would have\--I\'m sure if we sat and thought, we could think of
> something, but as I go through it, I mean, you know, energy,
> electrolytes, all of those\--osmolality\--all of those things are very
> different from the very young, critically ill\--the small, critically
> ill baby to the term baby.
>
> So, I would be hard pressed to do it.
>
> DR. GARZA: Okay.
>
> Dr. Anderson?
>
> DR. ANDERSON: I can\'t imagine why one would do this, but suppose that
> the study of a new infant formulation was tested exclusively in
> full-term, low-birth-weight children, because there was an available
> source.
>
> Would that be sufficient for marketing to normal term infants?
>
> I\'m trying to stretch the boundaries here.
>
> DR. MOYER-MILEUR: My response would be no, because you\'re again
> looking at a special population that, in utero, has suffered some type
> of nutrient deprivation, even though they\'re born at term, and so,
> then to apply that may work in that population may essentially
> overfeed or over-nourish a healthy population.
>
> So, I still think you\'re working with a different population.
>
> DR. GARZA: We have a number of presenters, and I\'d like to ask
> whether, in fact\--those of you that represented yesterday\--are there
> other criteria or guidelines that, in fact, you haven\'t heard raised
> that you think the group ought to consider in going through this
> discussion?
>
> \[No response.\]
>
> DR. GARZA: Okay. All right. Well, I don\'t know whether we\'re going
> to\--maybe we\'re done.
>
> I don\'t know whether we\'re going to get anymore from the group,
> other than if we look at the guidelines, the criteria that are here,
> the discussion that we\'ve had, I am not sensing that, in fact, we see
> that this is a deficient list in other than the few ways that we\'ve
> talked about, and that is, if you have a potentially vulnerable
> population, that probably that ought to be thought through more
> carefully.
>
> Everything else seems to pretty much under one of the existing
> guidelines or criteria.
>
> The only other issue that\'s come up is that, under criteria four,
> that, in fact, that is a new\--in Dr. Bier\'s paper\--that that is
> under any entirely new compound.
>
> Whether it\'s GRAS or not is seen as irrelevant, that if it\'s new,
> then there ought to be scientific data or something to back it up, but
> it ought to, by default, be considering as triggering a growth study,
> assuming that you had appropriate animal studies and everything else
> that showed that it was going to be safe in this population,
> obviously.
>
> All right. Well, then you\'ve accomplished what I thought was
> impossible, which is very nice, and that is to get through this
> meeting early. I didn\'t think we were going to be doing that. I
> thought we\'d be here till 3:00 o\'clock and that this would elicit a
> lot more debate.
>
> I thought we were going to be there with the genetically modified
> discussion that Dr. Sigman-Grant opened up, and I think that that
> would still fall under the criteria that we now have.
>
> DR. HEUBI: So would pre-biotics, too. So, it\'s actually\--it all
> falls under that category.
>
> DR. GARZA: That\'s right.
>
> DR. STALLINGS: Now that you\'re making us talk about it some more,
> just in the sense of clarification, as I understand it, though, it
> still would be based on industry deciding that changing from
> traditional to genetically modified sources constituted a new source
> versus this soybean or this soybean, that sort of thing.
>
> So, maybe what\--I can go back to Roger and say, does industry
> consider those kinds of\--I mean particularly\--I mean what we might
> have said 10 years ago when we first started thinking about this
> versus where the public interest and elements of trust and all those
> other things are.
>
> So, does industry\--would that merit calling the FDA and saying we\'ve
> just changed growers or our growers changed seeds for the soybeans?
>
> DR. CLEMENS: We may not go back to the growers and say that our
> growers have changed seeds, but we do work\--the industry does work
> very closely with the various suppliers of ingredients, and if they
> change their process, they change their technology, the industry knows
> about it, and they take it very seriously, if, in fact, they believe
> it will change the physical characteristics, as it was mentioned this
> morning, of that particular product, it will impact on nutrient
> bio-availability, if it impact on processing, ultimately will impact
> on growth, and if, under all those criteria, if we feel that it could
> impact negatively in any of those aspects, we will, in fact, do
> additional study, if warranted.
>
> So, they are very, very sensitive to the change of ingredients,
> anything that the suppliers will do. Be assured with that.
>
> DR. STALLINGS: Just to follow up\--but the truth is, many of us think
> that changing the soybean source wouldn\'t do any of those things, but
> yet, we\'ve not had a lot of experience in that.
>
> So, the issue of\--it\'s assumed to\--you know, how are we going to
> make those decisions as some of the new agricultural products come
> down the line?
>
> I mean it really isn\'t like traditional genetic
> engineering\--breeding practices, the old thing, we\'re going to make
> a better soybean\--hybridization, thank you.
>
> So, it still is an issue of a value judgement or somebody going, you
> know, even though this is the commonly used source now, does it have
> any human impact, you know, and maybe the infants will be the canary,
> you know, in the cave, because they are the\--probably among our most
> vulnerable and certainly the most rapidly growing.
>
> So, you know, you guys have a lot of responsibility in this setting,
> because if you don\'t bring it up, the FDA doesn\'t have the authority
> to come and ask you those questions, the way the relationship stands.
>
> DR. GARZA: Well, let\'s not get into this discussion, because we
> won\'t solve it, and it\'s part of 409, as we were told, rather than
> 412, and for those of you that were listening yesterday, that means
> that we\'re dealing with 412 and not 409.
>
> I mean it is a serious issue, but it does come under another section,
> and one has to look at issues that go way beyond what we have time for
> in terms of isoflavone content.
>
> I mean there are lots of things that you would want to think about in
> changing from one formulation to another and potentially bio-active
> products being involved.
>
> So, with that, let me thank everyone, unless there are other issues
> that are outstanding that relate to section 412 that we need to cover
> before we break up.
>
> Dr. Baker?
>
> DR. BAKER: I just have one last\--does this mean that we\'re leaving
> the AAP 1988 guidelines intact?
>
> DR. GARZA: We have not been asked to comment on the criteria. We\'ve
> gone through the seven questions.
>
> I think we\'ve provided the answers that we were asked to give,
> whether it\'s three grams or two grams or one gram.
>
> We can certainly be asked to come back and deal with that issue, but I
> think if we do that, then we need to look at functional outcomes much
> more carefully.
>
> We\'ve had some statistical presentations as to why two may be better
> than three and why even less than two\--I think it was Dr.
> Grummer-Strawn\'s paper that said .2 standard deviations would get us
> to an even smaller\--then there\'s the whole issue of non-linear
> versus linear, does it mean anything to say .3 over the first four
> months or three grams a day when you know you\'ve got a very
> non-linear\--I mean, so\--okay.
>
> Dr. Taylor.
>
> DR. TAYLOR: I\'m going to do a formal thank you, if you\'re ready for
> a formal thank you.
>
> DR. GARZA: Thank you.
>
> DR. TAYLOR: On behalf of the agency, we do want to thank this task
> force very much for their involvement and input and, of course, all of
> the great speakers that we had today.
>
> So, we\'re very pleased. You\'ve provided a lot of food for thought,
> and we look forward to future discussions.
>
> So, thank you.
>
> DR. GARZA: Dr. Anderson.
>
> DR. ANDERSON: At least on behalf of myself, I\'d like to say how very
> helpful the white papers were.
>
> In fact, they were, I thought, extraordinarily well-done, and I think
> that anyone observing the discussions\--our discussions this afternoon
> and today realize how extremely important they were to forming our own
> views about these issues.
>
> DR. GARZA: That\'s very key, and I think one of the reasons we were
> able to get through this as efficiently as we did was because of both
> those white papers and the presentations. So, you know, thank you.
>
> DR. BRILEY: I want to say, on behalf of myself and probably the rest
> of the group, how great you are as a leader, and we appreciate so much
> what you\'ve done.
>
> DR. GARZA: Thank you very much. That\'s very kind.
>
> All right. Well, have a great trip home, and I suspect we\'ll be
> meeting again.
>
> \[Whereupon, at 12:57 p.m., the interview was concluded.\]