> UNITED STATES DEPARTMENT OF AGRICULTURE
>
> FOOD AND DRUG ADMINISTRATION
>
> FOOD ADVISORY COMMITTEE
>
> MEETING ON INFANT FORMULAS
>
> Monday, November 18, 2002
>
> 8:20 a.m.
>
> U.S. Department of Agriculture
>
> Animal and Plant Health Inspection Service Building
>
> 4700 River Road
>
> Riverdale, Maryland
>
> [Temporary Voting Members Present]{.underline}
>
> James Anderson, Ph.D.
>
> Robert D. Baker, M.D., Ph.D.
>
> Margaret E. Briley, Ph.D., R.D., L.D.
>
> Scott Denne, M.D.
>
> Cutberto Garza, M.D., Ph.D., Chairman
>
> James E. Heubi, M.D.
>
> Laurie J. Moyer-Mileur, Ph.D., R.D., C.D.
>
> Virginia A. Stallings, M.D.
>
> Patti Thureen, M.D.
>
> [Participating Food Advisory Committee]{.underline}
>
> [Members Present]{.underline}
>
> Annette Dickinson, Ph.D.
>
> 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
>
> FOOD ADVISORY COMMITTEE ON INFANT FORMULAS
>
> [AGENDA]{.underline}
>
> Welcome, Introduction and Charges
>
> Christine J. Taylor, FDA 4
>
> Administrative Issues \-- Cathy DeRoever,
>
> Mary Ann Killian and Jeanne Latham, FDA 7
>
> Regulatory Background
>
> Christine J. Taylor, FDA 23
>
> Remarks by Chairperson, Cutberto Garza 32
>
> Presentations by Invited Speakers
>
> Physical Growth Measurements
>
> W. Cameron Chumlea 43
>
> Body Composition, Kenneth J. Ellis 72
>
> World Health Organization Growth
>
> Reference, Edward A. Frongillo 103
>
> National Center for Health Statistics/
>
> Centers for Disease Control and
>
> Prevention Growth Charts, Lawrence M.
>
> Grummer-Strawn 127
>
> Iowa and Iowa/Fels Growth Data
>
> Samuel J. Fomon 152
>
> Growth Data for Preterm Infants
>
> Jon Tyson 169
>
> Analytical Issues, Edward A. Frongillo 202
>
> Questions to Previous Speakers
>
> Clinical Studies \-- Product Composition
>
> Considerations, Duane Benton 228
>
> Clinical Studies \-- Clinical
>
> Consideration, Dennis M. Bier 259
>
> Questions to Speakers 283
>
> Preliminary Discussion of Issues by Committee 313
>
> Concluding Remarks 383
>
> [P]{.underline} [R]{.underline} [O]{.underline} [C]{.underline}
> [E]{.underline} [E]{.underline} [D]{.underline} [I]{.underline}
> [N]{.underline} [G]{.underline} [S]{.underline}
>
> DR. TAYLOR: I\'m Christine Taylor, and I\'m director of Office of
> Nutritional Products Labeling and Dietary Supplements at FDA\'s Center
> for Food Safety.
>
> We will be this morning going through a series of conversations, and
> what you\'ve got right now is our overview. So given the fact that we
> started just a few minutes late, we\'ll go ahead and try to shortcut
> this overview.
>
> In the next few minutes, we\'ll do a brief overview for this Food
> Advisory Committee meeting. We\'ll review a couple of the
> administrative issues, which will be focused on ethics and conflicts
> of interest. We\'ll spend some time on regulatory context for this
> meeting, and then we will begin the meeting per se with Dr. Bert Garza
> serving as chair.
>
> During the meeting, there will be a series of presentations and white
> papers, which we have provided as background information for the
> committee. There will be some discussion, and then beginning tomorrow
> there will be public comments, more discussion, and response.
>
> We\'re going to spend just a very few minutes this morning going over
> the role and expertise of the task force members, and I think the key
> point to be recognized is that there are several different kinds of
> members sitting with us today.
>
> FDA considers a number of factors in selecting individuals to serve on
> the Food Advisory Committee, including their scientific expertise, as
> well as issues related to conflict of interest.
>
> We also have sitting with us a consumer representative. This person is
> a voting member of the Committee and represents the consumer
> perspective on issues and actions that come before the Committee.
>
> We also have an industry representative sitting with the committee.
> This is a nonvoting member, and they\'re responsible for representing
> all members of the industry, and not any particular association,
> company or product.
>
> Basically, the kinds of members we have on this committee are
> temporary voting members, as well as some members of our larger Food
> Advisory Committee. As I mentioned, we also have consumer reps and
> industry reps.
>
> What I\'d like to do, at this point, starting with Dr. Baker, if you
> will, Dr. Baker, just so we can get used to using the microphones, if
> you would let us know your name, where you are, and if you\'re too
> modest, I have a listing of your expertise.
>
> DR. BAKER: Robert Baker from Buffalo, New York. I\'m a pediatric
> gastroenterologist, and I have a Ph.D. in biochemistry and in
> nutrition.
>
> DR. STALLINGS: I\'m Virginia Stallings, from Children\'s Hospital in
> Philadelphia. I\'m the head of the Nutrition Section there, and I do
> work in healthy children and children with chronic disease related to
> nutrition.
>
> DR. HEUBI: I\'m Jim Heubi. I\'m a pediatric gastrologist, as well.
> I\'m the program director for the GCRC, the General Clinical Research
> Center at the Children\'s Hospital in Cincinnati, and I have a
> longstanding interest in nutrition relating to infant nutrition bone
> disease, cholesterol, metabolism, you name it, there\'s a variety of
> things.
>
> DR. ANDERSON: I\'m Jim Anderson. I\'m at the University of Nebraska
> Medical Center in Omaha, Nebraska. I\'m chairman of the Department of
> Preventive and Societal Medicine, and I\'m a biostatistician by
> training.
>
> DR. DOWNER: I\'m Goulda Downer, a doctorate in Human Nutrition, with a
> residency in pediatrics at Georgetown. Currently, I\'m a clinical
> nutritionist with my own practice, and I\'m also on faculty at George
> Washington University.
>
> MS. SIGMAN-GRANT: I\'m Madeleine Sigman-Grant. I\'m a maternal and
> child nutrition specialist at the University of Nevada Cooperative
> Extension.
>
> DR. MOYER-MILEUR: I\'m Laurie Moyer-Mileur, from the University of
> Utah. I\'m a registered dietician with a doctorate in exercise
> physiology, and I have over 20 years of neonatal nutrition experience.
>
> DR. GARZA: I\'m Bert Garza. I\'m a professor of nutrition at Cornell
> University. I\'m both an M.D. and have a Ph.D. in nutritional
> biochemistry and metabolism, and my primary interests have been in
> maternal-child health, with interests in growth, and protein and
> energy metabolism.
>
> DR. KUZMINSKI: I\'m Larry Kuzminski. I\'m from Duxbury, Massachusetts.
> I\'m retired from the food processing industry, having R&D
> responsibilities and operations responsibilities with the Kellogg
> Company and with Ocean Spray Cranberries.
>
> DR. DENNE: I\'m Scott Denne. I\'m from Indiana University. I\'m a
> pediatric neonatologist. I have a longstanding interest in neonatal
> nutrition, specifically, and protein and energy metabolism.
>
> DR. THUREEN: I\'m Patti Thureen, a neonatologist from the University
> of Colorado in Denver, and my particular interest is in protein and
> energy metabolism in the extremely low-birth-weight neonate.
>
> DR. BRILEY: I\'m Margaret Briley from the University of Texas at
> Austin, and my expertise has been in nutrition of children and child
> care.
>
> DR. TAYLOR: If we could just stop right there. Margaret is our
> consumer rep, and on our right we have Dr. Roger Clemens, who is
> substituting for Annette Dickinson, who is our industry rep.
>
> I\'ll go to the next slide and just give a minute or two about the
> staff you have sitting at the table with you. As I\'ve mentioned, I\'m
> with the Office of Nutritional Products Labeling and Dietary
> Supplements.
>
> We also have Dr. Susan Walker, who is our associate director for
> Clinical Affairs, as well as Dr. Beth Yetley, who\'s the lead
> scientist for nutrition.
>
> Jeanne Latham, who is sitting next to Dr. Bert Garza, is our executive
> secretary, and we\'re being joined today by Ms. Mary Ann Killian, who
> is program integrity adviser at the Office of Human Resources at FDA.
>
> Let me just spend a very quick minute, and then we will return with a
> regulatory context. I think in terms of mechanics, we need to
> understand kind of where we are in the process. Currently, we are
> operating as an ad hoc task force to the Food Advisory Committee. In
> the very near future, we will constitute an Infant Formula
> Subcommittee of the Food Advisory, but currently we are still in the
> ad hoc mode.
>
> The current focus of the Infant Formula Advisory Meetings is to obtain
> scientific input for evaluating whether new infant formula supports
> normal physical growth of infants. This comes under Section 412 of the
> Food, Drug, and Cosmetic Act, which in a few moments we\'ll come back
> to in more detail. We\'re looking basically for scientific input,
> which eventually will inform the Agency relative to regulatory
> efforts.
>
> What we\'re undergoing currently is a series of meetings, and I\'m
> sure most of you remember that last April we held our first meeting on
> this issue of normal physical growth. It included a somewhat general
> discussion, an effort to understand the regulatory context, as well as
> a few specific questions about extrapolation and attrition in the
> study.
>
> This is the second of this series, and the general scientific topics
> for today fall into three categories: Growth Measures and
> Methodologies, the Role of Such Measures and Methodologies in
> Demonstrating Normal Physical Growth, and then, finally, Principles
> and Criteria to Determine the Need for a Clinical Study to Provide the
> Agency an Assurance of Normal Physical Growth.
>
> It\'s always helpful to be clear about what\'s not on the table. There
> are so many issues in the area of infant formula, normal physical
> growth, other issues related to the Agency\'s regulatory purview that
> sometimes it\'s important to realize there are things that are of
> great interest, but are not on the table for discussion.
>
> This lists a few, probably the ones that our discussions will most
> likely tend to gear toward. The design and conduct of studies is not
> on the agenda today, other endpoints of clinical studies is not on the
> agenda. What constitutes major and minor changes is not on the agenda.
> That\'s, of course, for those of you that are intimately involved in
> the regulatory, you understand that that has regulatory meaning. The
> nutritional impact or efficacy of formulas, the safety of individual
> ingredients and specific regulatory decisions are not topics for
> today.
>
> We have provided specific background for the committee in the form of
> white papers. We have a total of nine white paper which, as Dr. Garza
> will explain in a few moments, we\'ll go through this morning. Each of
> the papers will be introduced by an expert, and then of course
> discussed by the committee as appropriate. Those related to the
> assessment of normal physical growth are listed here, and then for our
> second topic, changes warranting a clinical study, we have two white
> papers. Those should be in your notebooks and available for further
> discussion.
>
> Now, the Agency\'s role is to give you specific charges that are to be
> accomplished by the end of the meeting on Tuesday, and those charges
> are in your notebook in the form of seven questions, and I won\'t go
> through them now. I think Dr. Garza will take the time to do that with
> you later on, but they fall into basically four categories: Metrics
> for evaluation of growth, which is Questions 1, 2, 3A and 3B;
> questions about comparators, Questions 4 and 5; controlled feeding
> parameters, Question 6; and then changes in composition, Question 7.
>
> Just for the group of us here, the summary of the charges fall into
> two categories: The criteria for adequate evaluation of normal
> physical growth during the first six months, and here are several
> substantive ones. Again, they are specifically it in your questions;
> and then, secondly, the type of changes in infant formula that should
> warrant a clinical study. Again, those are the remaining questions in
> your notebook.
>
> Just in terms of the mechanics, this morning, next, we\'ll cover the
> administrative issues, Jeanne Latham, as assisted by Mary Ann Killian,
> will go through that with you.
>
> I\'ll return, and with the help of Dr. Walker and Dr. Yetley, give you
> some regulatory context and then the actual task force meeting will
> begin.
>
> What we\'ll do is hold questions until after the administrative
> component, and then again after the regulatory context, and then we
> should be on our way.
>
> So, Jeanne, I\'ll turn the meeting over to you, and dutifully return
> for the next part. Thank you.
>
> MS. LATHAM: Good morning. I\'m Jeanne Latham and, first of all, in
> terms of administrative issues, we wanted to have Cathy DeRoever\'s
> statement read into the record, and Dr. Garza will take care of that.
>
> Thank you.
>
> DR. GARZA: Catherine DeRoever, the executive secretary of the Food
> Advisory Committee, was asked to take a few minutes to refresh
> everyone\'s memory about a few of the rules of the road, in terms of
> Advisory Committee operations, so I\'m going to be reading her
> statement.
>
> It is my understanding that all committee members have been provided
> with a copy of a Committee Member Guide to FDA Advisory Committees and
> a video. The video\'s title is \"A Panel Member\'s Responsibility.\" I
> believe there are copies of the Member Guide available at the
> registration desk for anyone who may be interested. The Committee
> Member Guide is in need of updating but, by and large, it provides a
> good operational overview.
>
> FDA relies on its Advisory Committees to provide the best-possible
> scientific advice available to assist us in making complex decisions.
> Our goal is to do this in as open and transparent a manner as
> possible. Part of that openness carries with it a request that the
> members try to avoid even the appearance that issues are being decided
> or conclusions are being reached outside the actual meeting.
>
> We understand that issues raised during the meeting may well lead to
> conversations over breaks or during the meal. In fact, we hope the
> discussions are thought-provoking. We have had instances where the
> members have come back from a break and said, \"You know, we were
> talking over break, and we would like to request that FDA provide us
> some additional information so we can better understand thus and
> such.\" This is perfectly acceptable.
>
> What we don\'t want is to have a situation where after the break the
> members come back and say, \"We were talking over break, and we
> decided that the answer to Question 1 is\...\" From our perspective,
> that would be particularly troublesome because neither the Agency, nor
> the public, would have had the benefit of listening to the entire
> discussion, the questions raised, the responses, et cetera.
>
> In fact, FDA has recently adopted a policy that only matters that can
> be decided by a show of hands are procedure matters, for example,
> break times. I\'m not sure I understand that.
>
> \[Laughter.\]
>
> DR. GARZA: All other votes and comments must be placed on the record,
> attributed to the member making the statement. The policy goes even
> further. If a member has to leave the meeting early, that member
> waives the right to vote. You may wonder why would the person lose
> their right to vote, but the answer is fairly simple. FDA believes all
> parts of the meeting and the discussions are important. Consequently,
> voting on issues without having the benefit of all of the discussion
> would be premature.
>
> The issue of openness is larger than what transpires during the course
> of the meeting. I would like to call your attention to the section in
> the Members\' Guide, titled, \"Member Interaction Before, During and
> After a Meeting.\" In essence, this section underscores the fact that
> all communication with the members should be routed through the
> Committee\'s executive secretary. No one, not even FDA staff, with the
> exception of the executive secretary, should be contacting the members
> about upcoming meetings, topics, et cetera.
>
> This same guidance applies to consultations between members prior to a
> meeting. If a member receives an inappropriate contact, the members
> should feel free to notify the executive secretary and/or refer the
> person making the contact to the executive secretary. Our goal in
> having all contacts routed through the executive secretary is to
> minimize any situation that could be misinterpreted.
>
> Appearance issues are always difficult because, as is true of many
> things, appearances can be deceiving. We ask that our members, guest
> speakers, and everyone attending the meeting be mindful of how an
> interaction between a member and anyone, for that matter, might be
> perceived.
>
> Please let me be clear it is not my intention to question anyone\'s
> motives or integrity, but I am very sensitive to the issue because I
> have, and imagine so have you, seen highly respected individuals
> become the object of negative attention based on a misperception, and
> I certainly wouldn\'t want anyone in this room to become such a
> target.
>
> I am confident that everyone here is sensitive to these issues and can
> appreciate that my comments are intended as a gentle reminder.
>
> Thank you.
>
> Any questions? Which I will refer to Ms. Latham.
>
> \[Laughter.\]
>
> DR. GARZA: From any of the committee members? Is all of that clear?
>
> \[No response.\]
>
> DR. GARZA: Thank you.
>
> MS. LATHAM: Good morning. I am Jeanne Latham, the executive secretary
> for the FDA\'s Food Advisory Committee on Infant Formula. I want to
> welcome everyone, and I\'d like to read the conflict of interest
> statement for the record.
>
> The following announcement addresses the issue of conflict of interest
> with respect to this meeting and is made a part of the record to
> preclude even the appearance of such at this meeting.
>
> By the authority granted under the Food Advisory Committee Charter of
> July 2002, the following individuals have been appointed as temporary
> voting members by Joseph A. Levitt, director, Center for Food Safety
> and Applied Nutrition:
>
> James Anderson, Ph.D; Margaret Briley, Ph.D.; Robert Baker, M.D.,
> Ph.D.; Scott Denne, M.D.; Cutberto Garza, M.D., Ph.D.; James Heubi,
> M.D.; Laurie Moyer-Mileur, Ph.D.; Virginia Stallings, M.D.; Patti
> Thureen M.D.
>
> The issues to be discussed at this meeting are issues of broad
> applicability. Unlike issues in which a particular sponsor\'s product
> is discussed, the matters at issue do not have a unique impact on any
> particular product or manufacturer, but rather may have widespread
> implications with respect to all infant formulas and their
> manufacturers.
>
> To determine if any conflicts of interest exist, the committee
> participants have been screened for interest in companies that make
> infant formula. As a result of this review, in accordance with 18
> United States Code, Section 208(b)(3), Dr. Cutberto Garza has been
> granted a particular matter of general applicability waiver that
> permits him to participate fully in the matters at issue. A copy of
> the waiver statement may be obtained by submitting a written request
> to the Agency\'s Freedom of Information Office, Room 12A30 of the
> Parklawn Building.
>
> With respect to FDA\'s invited guest speakers, there are reported
> interests that we believe should be made public to allow the
> participants to objectively evaluate their comments.
>
> Dr. W. Cameron Chumlea has a grant from Nestle to serve as a
> coordinating center for a nutritional study of Chinese elderly.
>
> Dr. Samuel Fomon previously consulted with firms that make infant
> formula and is likely to do so in the future.
>
> Dr. Duane Benton owns stock in Abbott Laboratories, and he receives
> retirement benefits from Abbott.
>
> Dr. Dennis Bier\'s employer, the ARS Children\'s Nutritional Research
> Center, recently received the Bristol-Myers Squibb-Mead Johnson
> nutritional 2002 unrestricted nutritional research grant. As Center
> director, Dr. Bier is named as the principal investigator, although no
> funds come to him personally or for his personal research.
>
> We would also like to note for the record that Dr. Roger Clemens is
> participating in this meeting as the acting industry representative
> and a nonvoting member of the Committee.
>
> In the event that the discussions involve any other issues not already
> on the agenda, for which FDA participants have a financial interest,
> the participant\'s involvement and their exclusion will be noted for
> the record.
>
> With respect to all other participants, we ask, in the interest of
> fairness, that they address any current or previous financial
> involvement with any firm that makes infant formula.
>
> Thank you.
>
> With that, I will turn the program back over to Dr. Taylor.
>
> DR. TAYLOR: Thank you very much, Jeanne.
>
> Our goal for the next 15 or 20 minutes is to set the regulatory
> context for the discussions we\'re having today. For those of you that
> remember the spring meeting, we did spend some time on that, and
> hopefully most of this is a review, and all we have to add is an
> additional focus relative to the topic for today. As I\'ve mentioned
> earlier, this is an ad hoc task force of the Food Advisory Committee,
> addressing infant formula issues.
>
> Obviously, we have statutory authority relative to infant formula, and
> its long history goes back to 1980, at which time Congress passed
> special legislation that amended the Food, Drug, and Cosmetic Act. We,
> in the Agency, try to avoid throwing numbers, and clauses and phrases
> around, but it\'s almost impossible not to, and the key phrase is that
> it provided Section 412 to the Food, Drug and Cosmetic Act.
>
> In 1986, Congress had an interest in adding to this, providing more
> statutory authority, and so there were some additional amendments in
> 1986.
>
> I think what we have to keep in mind is that the infant formula
> legislation happened for a very specific reason. Infant formula is
> unique from other foods. It is the sole source of nutrition for a
> vulnerable population. In Congress\'s mind, it therefore warranted a
> special set of provisions for regulation.
>
> It\'s clear that the intent and outcome of this action was the
> following statement from Congress. It should not only be safe, which I
> would point out is handled in separate sets of provisions than what
> we\'re addressing today and contain all of the necessary nutrients,
> which again is the separate set of provisions which are not on the
> table for today, but also should provide those nutrients in a
> bio-available form to ensure that the infant formula were to support
> optimal infant growth and health. That\'s what we\'re about today in
> some respects.
>
> This chart is a little complicated at first, but I think it sets the
> context for what we call to be regulatory boxes, and really what\'s on
> the table today is this particular component, but all of this is the
> regulation of infant formula. The safety of the individual
> ingredients, the classic safety considerations are handled under a
> separate set of provisions, the so-called Section 409. So ingredients
> for intended use, that\'s where most of your classic safety reviews
> come in.
>
> Section 412, as provided for by Congress in 1980, is really a
> statutory check on a particular formulated product. In providing those
> assurances, companies consider the required nutrients that have to be
> in the formula, the good manufacturing practices or GNPs and quality
> controls, and then quality factors.
>
> Today, we are focusing on quality factors. These assurances are
> provided prior to marketing, and once marketing occurs, in the world
> of infant formula, the claims then come in, as far as efficacy,
> truthful, and not misleading, again, a separate set of provisions.
> I\'ll come back to this in a moment, but the key component is that
> we\'re here taking a look at that.
>
> Now, as mentioned just a second ago, in order to provide these
> assurances, manufacturers submit a notification to FDA 90 days prior
> to their intention to market that particular infant formula. Again, as
> I mentioned, it\'s specific to a finished product. The Agency reviews
> it, again, as I just mentioned, for those three components, and it\'s
> here, hopefully, highlighted in red that our questions today will
> focus.
>
> The definition of quality factors is not precise. They certainly do
> offer the opportunity of expanding, as needed. There is language from
> a 1980 discussion in the House Committee, and their references to
> quality factors focus on things such as pertain to the bioavailability
> of a nutrient and the maintenance of levels or potency. They discuss
> at great length the growth of infants during the first few months of
> life, and they discuss the concept of healthy growth, the idea being
> that once you\'ve formulated a product, it needs to support healthy
> growth. So, in its simplest form, quality factors are a check on the
> concern that once you get the entire product put together it works
> appropriately.
>
> Now the types of quality factors could be many. At this point, we
> basically have two. In the realm of nutrient-specific, we have
> provisions for protein efficiency ratios, protein per se, but over
> time, others could be put in place. In the world of the formulation
> itself, the totality of the formulation the quality factor we address
> is normal physical growth, and, again, others could be put in place
> over time as needed.
>
> So, for today, normal physical growth as quality factor is what\'s on
> the table.
>
> The scientific questions that will come through as you read the
> charges are basically twofold. How do you measure and affirm normal
> physical growth and how and when should assurances of normal physical
> growth be appropriately provided?
>
> Going back to that again, this particular slide, quality factors,
> normal physical growth, assurances for a specific product, along with
> other components of these assurances.
>
> Now, just so that we\'re sure how it works from a regulatory
> perspective, we\'ve put in this slide, but I think it\'s redundant to
> what we\'ve said before. In order to provide assurances, vis-a-vis
> Section 412, the manufacturer submits a notification 90 days prior to
> marketing. FDA reviews the notification package, taking into all of
> the components, nutrients, GNPs, quality control and quality factors,
> and if assurances are adequately provided, FDA does not object to the
> marketing of the formula.
>
> If, in the Agency\'s opinion, assurances are not adequately provided,
> FDA does let the company know that it objects to the marketing of this
> particular formulation. It\'s important to note, from a regulatory
> perspective, that this is not a premarket approval process, so
> manufacturers do have the right to go to market over FDA\'s
> objections.
>
> The scientific input we get from you folks today and tomorrow will
> certainly guide our thinking about the evaluation of normal physical
> growth when infants are fed a new formula. We\'d like to point out
> that it certainly helps us, but it\'s also helpful to stakeholders in
> that what is expected becomes clear to them. It\'s not as much of a
> black box if it\'s quite clear how FDA\'s scientific considerations
> are handled.
>
> It\'s also going to guide our thinking about when clinical studies
> should accompany formulation of processing changes in infant formulas,
> and again it\'s helpful to us, but it\'s also helpful to our
> stakeholders.
>
> The outcome of today\'s discussions can be used to inform our ongoing
> reviews, but we do need to talk a little bit about current rulemaking,
> in that discussions today have the opportunity or the possibility of
> impacting on current rulemaking activities. The current state of our
> rulemaking, as probably many of you know, is that in 1996, we proposed
> a rule to implement parts of Section 412, and in that was included the
> implementation of quality factors.
>
> That final rule has not been issued, so we are still in the process of
> what\'s known as rulemaking. If input from this Committee is relevant,
> and it may or may not be, but if input from this Committee is
> relevant, there would need to be an opportunity to comment on that,
> and we would, of course, reopen the comment period on this rule for
> that purpose. So we retain the option of reopening the comment period.
>
> So, again, just to review, you\'ve seen this before, today\'s
> discussions, vis-a-vis the charges, our growth measures and
> methodologies, the role of such measures relative to normal physical
> growth, and the general principles and criteria to determine the need
> for a clinical study to provide assurances of normal physical growth.
>
> I think we\'ve gone over topics not under discussion, so I\'ll mention
> these only in passing, and then again remind you that the specific
> charges from the Agency to the Committee are the seven questions in
> your notebook, and I\'m sure Dr. Garza will go over those with you in
> some detail.
>
> I do want to introduce Dr. Susan Walker, who\'s at the table here, our
> associate director for Clinical Affairs, and Dr. Beth Yetley, who\'s
> our lead scientist, and the agreement we have is if you have
> questions, I will go join them, and we will answer them as a troika.
>
> Thank you very much.
>
> MS. LATHAM: Are there questions?
>
> DR. GARZA: Are there any questions to Dr. Taylor?
>
> \[No response.\]
>
> DR. GARZA: Thank you very much. That is clear, judging from the lack
> of questions from the Committee. I do want to take this opportunity to
> welcome the Committee members, and guests, and staff that have joined
> us, and to thank Dr. Taylor because we\'ve made up the lost time. I
> was concerned that we would be running late, but we\'re doing all
> right in terms of time.
>
> We have a very full agenda and would like to begin by asking the
> Committee members if, in fact, they have any questions about the
> agenda.
>
> \[No response.\]
>
> DR. GARZA: Very quickly, just to review the procedure, we\'re going to
> be launching into one of the major segments of the Committee meeting
> in just a few minutes, and that is nine presentations, based on the
> nine background papers which were sent to each of us several weeks
> ago. Only Committee members have the privilege of asking questions to
> any of these presenters. We will try to hold presentations to about 15
> minutes. Someone will be helpful in alerting the speakers when I think
> there is about three minutes left in their presentations to help them
> allocate their time appropriately, and then we will have about 10
> minutes of questions from Committee members to each of their
> presenters.
>
> You also will have the opportunity to ask questions of those that make
> comments in the public comment period tomorrow, and we will have
> blocks of time then to come to some consensus on the seven questions
> that you have been sent as well.
>
> It\'s going to be very important that we address each of those
> questions carefully, and therefore I\'d like to make sure that each of
> you has a chance to review those questions because I will be proposing
> time limits to assure ourselves sufficient time to deal with each of
> them in a way that doesn\'t shortchange any of them, and so we\'ll be
> trying to deal with that time allocation later this afternoon.
>
> All experts, I am told, will be able to stay throughout today and
> tomorrow for those questions and answers to that if, in fact, in those
> blocks of time when we\'re dealing with any of those seven questions,
> any of the committee members would like to address any questions to
> any of the presenters, and then obviously that\'s going to be possible
> as well.
>
> You have seven questions. They have been divided for us in four
> sections. One of those sections is on metrics for the evaluation of
> normal physical growth, a second section deals with comparators for
> the evaluation of normal physical growth, and a third is on controlled
> feeding comparators, and the fourth is on changes in infant formula
> composition.
>
> Rather than reading each of the seven questions, I\'d like to take
> just a few minutes to ask committee members if you have any questions
> about the issues that we\'ve been asked to consider under each of
> these sections so that, in fact, we can be clear what we\'re being
> asked to do, and you can have those clearly in mind during the
> presentations.
>
> So let\'s begin with the first in terms of metrics for the evaluation
> of normal physical growth. There are two questions under that section.
> Do any of the committee members have any questions about points that
> you\'re being asked to address? I\'ll give you a few minutes to review
> those, and we can ask the troika to clarify those for us. I think
> that\'s the way you were described. That was not my word.
>
> Having had the pleasure to work with them, you\'ll get informative
> responses to your questions, I\'m sure.
>
> MS. LATHAM: At the end of last week\--this is Jeanne Latham, the exec
> sec\--we e-mailed to everyone the updated questions, and I just wanted
> to make sure that you all have those, and if you don\'t, we will get
> them to you. You\'ve got them. . Anybody that doesn\'t have them?
>
> \[No response.\]
>
> DR. GARZA: I think they were in the packets today, again, in case you
> didn\'t bring them with you.
>
> Would any member of the staff want to address any questions in this
> section?
>
> \[No response.\]
>
> DR. GARZA: I take it, then, that they\'re clear\--Dr. Thureen?
>
> DR. THUREEN: Yes, I have one question. These are metrics for the
> evaluation of growth between birth and six months of age. We will be
> dealing with both term and preterm infants, I presume. Should they be
> handled separately? Because the preterm infants we are discussing I
> believe growth after post-conceptional age birth to six months, so
> should they be handled separately or should we just do a general
> assessment of these evaluations, presumably for term infants, with
> maybe later adjustments for preterm infants?
>
> DR. GARZA: No, I would assume that we will take those separately, but
> let me ask the staff if they would object, if there\'s any reason why
> we shouldn\'t take them separately?
>
> Committee members? So we\'ll probably do A and B. Thank you. That\'s a
> good clarification, with preterm being all preterms, low birth weight,
> very low birth weight, and extreme low birth weight.
>
> Any other questions, then, on this first section?
>
> \[No response.\]
>
> DR. GARZA: Then, on the second, on comparators for the evaluation of
> normal physical growth, let me give you a few minutes to review those
> two questions and see if there are any issues that need to be
> clarified.
>
> \[Pause.\]
>
> DR. GARZA: Any questions on either of those?
>
> We have one question on the control feeding comparators. Let\'s take a
> look at that and see if that\'s clear.
>
> DR. ANDERSON: This is Jim Anderson.
>
> I wonder if I could get a clarification of the difference between the
> current infant formula plus new ingredient that\'s listed on the first
> bullet and the infant formula plus new ingredient with the asterisks
> on the last of the bullets.
>
> DR. GARZA: On the last bullet, right? So it\'s listed below are
> examples of controlled feeding clinical comparators, and I believe the
> question is can you clarify the distinction between the first and the
> last bullets.
>
> DR. TAYLOR: We\'re working on it.
>
> DR. GARZA: I gather what it meant was that it was a study in which the
> new ingredient would be used with some infant formula, but that the
> intention was to market the new ingredient as a component of some
> other infant formula.
>
> DR. GARZA: That was mine or a generic infant formula, where that new
> ingredient might be added to any formula, so that it would be a
> generic comparison was the way I read that. Am I not clear of that? If
> my interpretation is correct, so it\'s a generic\--
>
> DR. WALKER: Your interpretation is correct.
>
> DR. GARZA: So it\'s a generic endorsement of the ingredient.
>
> DR. WALKER: Right.
>
> DR. GARZA: Does that clarify it?
>
> Dr. Walker, would you\--
>
> DR. WALKER: The instance in which the generic ingredient is added to
> the new infant formula and the way that you discussed there, Dr.
> Garza, is a correct interpretation.
>
> DR. GARZA: So it\'s more an endorsement of the ingredient itself, with
> a test formulation, but as opposed to a specific formula that had been
> marketed in the past, where a new ingredient would be added. I
> understood it to mean a more generalized evaluation, rather than a
> specific one.
>
> DR. WALKER: I think after we have some of the discussions, some
> specifics of these will be made much more clear. I think the speakers
> will address a lot of these issues in detail, and then we can have
> more questions.
>
> DR. GARZA: And I\'ve been reminded that we must each identify
> ourselves before we ask questions. I will try to remember, but I\'m
> probably the guiltiest of all. I would hope that they would recognize
> my voice before this meeting is over.
>
> The statement I was supposed to read said, \"I am Cathy DeRoever.\" I
> thought I better not say that.
>
> \[Laughter.\]
>
> DR. GARZA: It would confuse people, and obviously embarrass Dr.
> DeRoever as well.
>
> Are there any other questions on this third section?
>
> \[No response.\]
>
> DR. GARZA: If not, then, the fourth one is the last. It is also one
> question with two parts, A and B. The table that is attached,
> obviously, is quite informative, so I would ask you to take a few
> minutes to look at Question 7, along with Table 1, see if there are
> any questions.
>
> \[Pause.\]
>
> DR. GARZA: Are there any questions related to this section?
>
> \[No response.\]
>
> DR. GARZA: If not, what I propose is the following; that you think
> about 30 minutes for each of the first six questions, approximately
> 120 minutes for the seventh question. If we don\'t need the entire two
> hours for the last question, we can always come back and address
> issues that perhaps we might have felt were not completely resolved.
>
> Obviously, if it\'s clear that we need more time with any specific
> question, as the discussions evolve, then we can always go back and
> try to reallocate them, but we will come to some agreement on how much
> time to spend with each before we start the discussion this afternoon.
> But as you\'ve had a chance to review them, see if, in fact, you feel
> comfortable beginning with that type of allocation for the various
> questions that we\'re being asked to review.
>
> I don\'t think that all first six would necessarily take 30. Some may
> take a bit longer, and some will take less, but I want to make sure
> that we don\'t shortchange, as I said, any specific question, and so
> we can get agreement on that as a group, going through the discussion
> and developing some information that would be useful to the FDA I
> think is more likely.
>
> Are there any other questions regarding procedures or the charge to
> the group that either staff or I have failed to clarify for you?
>
> \[Pause.\]
>
> DR. GARZA: If not, then why don\'t we begin with the presentations. I
> know that Dr. Chumlea was on the bus, so I assume he\'s here. We\'re
> starting a bit early, but I think that\'s fine. I will just introduce
> each speaker as they come forward.
>
> Dr. Cameron Chumlea is a Fels Professor at Wright State University
> School of Medicine in Ohio. And for those of you in the field of
> anthropometry, I don\'t think Cameron needs any introduction. For
> those that may not be familiar with his work, we don\'t have time.
>
> \[Laughter.\]
>
> DR. GARZA: It has been quite extensive, and he\'s certainly recognized
> throughout the world for his work in this area.
>
> Thank you very much for the white paper and for joining us this
> morning, Cameron.
>
> DR. CHUMLEA: Thank you very much for the introduction. It\'s a
> pleasure to be here this morning, and I hope I can provide the
> committee with some information that\'s appropriate.
>
> First, I\'d like to just simply recognize my co-author, Dr. Shumei
> Sun, who I know is familiar to many of you and point out that she has
> just recently become Wright State\'s Brage Golding Distinguished
> Professor of Research.
>
> So, first of all, I\'d just like to point out that growth is relative,
> as you can see from the slide here, it says, \"I keep track of my
> son\'s growth, which is going up the vertical scale, and my husband\'s
> growth. Frank is age 30, 33, 35, 40.\" So growth goes in various
> directions for all of us here.
>
> The second thing here is that we\'re dealing with infants. Of course,
> there\'s our perspective of what infants are, but there\'s also a
> public perspective, and I saw this checking out the groceries and
> decided it really deserved a slide because clearly this, to some
> degree, is maybe the public\'s viewpoint, which you can clearly see.
> It\'s amazing what you can do with PowerPoint these days and some
> slides that are available.
>
> So what I\'m going to do this morning is just basically cover some
> brief information that\'s probably familiar to everybody, so that we
> can just kind of all come up to speed. Clearly, infancy is a period of
> rapid growth, and to some extent, this is probably the most difficult
> group of individuals to measure. The only other group that\'s equally
> difficult is at the opposite end of the age range, but this is
> generally a very difficult group, but it\'s also easy in the sense
> that there\'s also very few actual measurements that can be collected
> from them that are really going to be useful. Weight, recumbent weight
> and head circumference are the three that are the most important and
> the ones that should be taken.
>
> Just to review, weight clearly measures the growth of all body
> tissues, recumbent length describes the amount of linear growth
> because we\'re dealing with both increase in mass and increase in
> size, and then head circumference reflects brain growth because this
> is the period of time, the first few years of life, when the brain
> actually does the majority of its growth.
>
> This is a period of time when body dimensions increase at a greater
> rate than in any other period in life. Weight increases between birth
> and six months about 115 percent, length increases about 34 percent,
> head circumference increases 22 percent on average. The rate of growth
> in weight ranges from about 1.1/1.2 kilos for boys or girls at one
> month of age, but then we have to remember that we\'re on a growth
> curve here, and then it, of course, starts to slow down, and by six
> months it\'s running around a half a kilo a month for boys and girls
> at six months of age.
>
> The rate of growth in length is about 3.5 to 4 centimeters per month
> for boys and girls, and it slows to about 1.5 to 2 centimeters a month
> for girls and boys at six months. Just as a reference, the adolescent
> growth spurt between, say, you know, 12 to 16 years of age, the
> maximum amount there is only somewhere in the neighborhood of 5 to 8
> centimeters a year. So here we\'re looking at 3 to 4 centimeters a
> month. So they can just put that in comparison because everybody kind
> of focuses and remembers how much growth their kids did when they were
> adolescents. They frequently forget that that rate was a fraction of
> what they were really doing in the first few years of life.
>
> The assessment of status, once we\'ve collected measurements, we
> really need the measurements to be accurate and reliable, and this is
> really a very critical point, particularly in this particular age
> range.
>
> The measurements are really not difficult to take, and there are a
> variety of mediums in which they\'re now described. NCHS produced a
> video at the end of NHANES III that describes these and all of the
> measurements that were used in NHANES III on that videotape. WHO has
> an in-house video that describes the measurements that are being used
> in their multi-center growth reference study. I don\'t think that one
> has really actually been distributed yet, but it is available if you
> can talk to the right people.
>
> These are also all very similar techniques. They are also probably
> being what\'s currently being done in the current NHANES, and they\'re
> all the ones that have come out of the [Anthropometric Standardization
> Reference Manual]{.underline} from 1987, by Lohman.
>
> When we collect the measurements, this is a point where frequently
> things get skipped over, and the reason things get skipped over is
> because there\'s lack of time, money, personnel, et cetera, but it\'s
> the part that\'s really very important, in terms of collecting the
> information because, one, we\'re going to either plot those on a
> growth chart or refer to status, and the other aspect is what\'s very
> important here is we\'re going to calculate increments of rate of
> growth, and there you\'re compounding your measurement errors.
>
> It really takes two people to measure an infant appropriately. I\'m
> sorry, folks, but that\'s really the correct way to do it. It can be
> done with one, but that\'s going to add to the errors that are going
> to be involved. You need an examiner who\'s going to position and take
> the measurements, and you need a recorder who\'s going to be writing
> down the measurements because one person is holding the infant and
> trying to do the measurements, and they really don\'t have time to
> write anything down, and then they need to switch roles because we
> need to take double measurements here so that we can get as much
> information as possible.
>
> Also, what we\'d like to do is have the technicians compare their
> values. One, this just simply catches transposition errors that occur
> frequently because people write down numbers in different ways
> sometimes. All of the studies that I\'ve described to you have
> allowable differences between what the measurement values can be
> between the technicians, again, to control for errors and just to
> control for variabilities that can occur.
>
> Did I skip one? How do I go back on this?
>
> \[Pause.\]
>
> DR. CHUMLEA: Weight. An infant can be weighed alone or they can be
> weighed while the mother is holding them. It depends a little bit on
> the situation, but, frankly, I would prefer that the mother hold the
> infant. You can weigh the mother, weigh the mother holding the infant,
> take the subtraction and you\'re going to get the weight. The reason I
> like the idea is it keeps the baby calm, and it provides for a very
> stable piece of information.
>
> The infant can be weighed alone, and there are a variety of electronic
> scales, but pretty much once you take the baby out of the mother\'s
> arms and you place it on something else, it starts moving around.
> Fortunately, the manufacturers of several of the scales now can
> compensate for this weight so the stability of the measurement is much
> better than it used to be.
>
> It\'s best that they be weighed nude. Blankets, et cetera, are
> available. However, if they are going to be in undergarments, I think
> NCHS subtracts about a tenth of a kilo from that for the readings, and
> spring-type scales and beam balance scales are simply not appropriate
> for use any more. The electronic scales are much more available.
>
> There\'s a company called Seca that makes some very good scales.
> We\'ve used those. WHO has a really nice platform scale that actually
> pares the mother\'s weight. I don\'t know exactly what the
> manufacturer is, but it\'s a really excellent device. I think it\'s
> been specially made for them, but there are a variety of scales that
> are available for use, but my preference is that the infant should be
> held with the mother or the caregiver, whoever is there, and then
> subtract the weight, if that\'s possible.
>
> This is the one nobody really likes. It\'s recumbent length. It takes
> two people to do it, again. A variety of different pieces of equipment
> that are useful for doing this.
>
> It requires one person holding the infant\'s head. It requires the
> mother, the caregiver standing there beside the infant reassuring them
> that nothing is going to happen, and it takes a third person then to
> position to footboard up against the soles of the foot of the infant.
> You\'re holding the head so the child is looking straight up in a
> vertical Frankfort plane, and it takes then another person to hold the
> legs, both legs, for the infant, if it\'s very small, and get the
> length, and by the time they\'re six months, generally, the best you
> can sometimes do is grab one leg and try to hold the other one with
> your little finger and get it. It\'s not easy to do, and it\'s one
> that can be particularly prone to error, and it\'s also important that
> the kid stays straight down the table. I think I\'ve covered what\'s
> there.
>
> This simply gives you a description. I think this child is about two,
> the age there, but again positioning the head up against the
> headboard, keeping the legs straight and keeping the feet straight up
> in terms of taking the measurement, but clearly it takes two people to
> do.
>
> Head circumference, it should be measured with an inelastic tape of
> fiberglass, metal, something like that that\'s good. It\'s really best
> that the infant is seated in the mother\'s lap. I don\'t like it being
> done with the infant. I\'ve seen that done. I like the kid up in the
> mother\'s lap, which requires then the person getting, who\'s taking
> the measurement, to get down beside the mother. This allows the mother
> to cuddle the infant, keep him quiet, and you can slip the tape over
> their head and get the measurement before they pretty much know what
> happened to them.
>
> It\'s placed right across the front of the skull, and it can be
> quickly moved up and down the back of the skull. The insertion tape is
> a nice piece of equipment that\'s useful for doing this until you find
> the greatest circumference, and then you pull the tape tight, and this
> is something we have to coach people in because it doesn\'t hurt the
> infant. There\'s no pain involved with it. They feel a little
> pressure, and they want to kind of shake it off, but it does need to
> be tight.
>
> And you can see here it\'s just anchored really right over the kid\'s
> eyebrows, worked up and down. Most kids at this age aren\'t going to
> have quite this much hair, and so it\'s generally pretty easy to get
> this one from them, particularly, again, with the child being
> comforted by the caregiver.
>
> Now, what are some other measurements that could be taken? Well,
> there\'s really a bunch of them, but I don\'t think those are really
> going to be really appropriate in the instance here. Crown-rump length
> is sitting height. Crown-rump length, I think that was pretty only
> used in children with special cases. Chest circumference, limb
> lengths, one that\'s potentially possible is skinfold thicknesses.
>
> The problem with all of these measurements is they really kind of have
> a restricted utility in terms of describing normal or healthy growth.
> They\'re frequently prone to high measurement errors, and there\'s
> really a limited amount of reference data available for all of these
> measurements pretty much within the age range that we\'re looking at,
> six months.
>
> If you\'re going to do something like a skinfold. The skinfolds
> you\'re going to take are going to probably be triceps and
> subscapular. Now, again, you\'re bringing two people into the program,
> if not three, and you\'ve got to go to landmarks, and to do a triceps,
> you\'ve got to find the midpoint of the arm, which means you\'ve got
> to measure it, and make that determination, and you can see clearly
> it\'s requiring one person is holding the child and the other person
> is taking the measurement, and then you\'re going to have to go and
> take the measurement.
>
> The question comes up there in terms of equipment. Skinfolds are
> dependent upon the type of caliper you\'re using. There\'s two major
> brands, really. There\'s a Lang and a Holtain, which you see here.
> NCHS and WHO are both using the Holtain caliper. I think the Lang is
> still used out there, to some degree, but I\'m not that familiar with
> it any more. There are differences there.
>
> Really, if you\'re wanting to do skinfolds, the question is what do
> you want to get out of that? And probably what you wanted to get is
> total body fat, and there\'s probably, I think Dr. Ellis is probably
> going to talk about better ways of doing that today than taking
> skinfold measurements. I don\'t really feel comfortable in doing it on
> anybody until they\'re about two years of age. It\'s just difficult to
> do.
>
> Now, there\'s indices that can be used from the information that\'s
> collected. BMI is the one that we all get informed, and just for your
> information, I\'m 28, so you can kind of put that in reference. I
> always think everybody should, when we have meetings like this, they
> should always walk around with their BMI on it, so we\'ll all be
> honest about this folks.
>
> \[Laughter.\]
>
> DR. CHUMLEA: The problem with BMI is that, in infants, you\'ve got
> 25-percent body length is composed of the head, so that throws off the
> proportionality aspect. The relation of BMI with direct measures of
> body composition in infants hasn\'t really been established. Weight
> for length is probably a better descriptive indices of relative
> leanness adiposity within children.
>
> Measurement error is very important and needs to be paid attention to.
> The catch here is that the error which may be small is actually going
> to be very large because of the small size of the child that you\'re
> measuring. So you really need to pay a tremendous amount of attention
> to error in measuring infants. Of course, they can have a tremendous
> impact on the interpretation, if you\'re going to go growth
> increments.
>
> We need to get good-quality equipment. Measurements should be taken.
> If they\'re taken on a daily basis, the equipment needs to be
> calibrated. That includes scales. People forget that scales can go out
> of calibration, and then particularly the technicians need to be
> trained in a standardized way of taking the measurements.
>
> We need to collect inter- and intra-observer reliability. Quality
> control is really important, particularly if there\'s going to be more
> than one center used to collect information because we need to control
> for inter-site differences.
>
> Measurement schemes. You need baseline, an interim and a final. I
> really like something that\'s going to be getting a measurement at 1,
> 2, 4 and about 6 months of age is my preference for collecting things,
> generally, starting after about 10 to 14 days. With measurements at 1,
> 2, 4 and 6 months, you\'re going to get a good accountability of
> weight measurements over that period of time. Clearly, if you can
> collect more measurements, the more measurements the better. I\'d be
> very happy to have those.
>
> I\'m going to cover just very briefly growth increments, which are
> going to be calculated from the repeated measures of growth, and there
> are charts that these can be plotted on from birth to 12 and 3 to 6
> months of age, which are examples here.
>
> These are from Fels data, and just contrary to popular opinion, the
> majority of Fels infants were breast fed for at least three months,
> exclusively, so that has been reported. We tend to not get a good
> press on that. I just want to kind of correct that.
>
> In terms of growth velocity data, there\'s the Fels data. Also, I\'d
> like to point out that WHO is collecting longitudinal data from its
> multi-center growth reference study, but this data and report from
> that study has not been available, and that\'ll probably be given
> later.
>
> So recommendations, from what I\'ve just described to you, weights
> should be measured I think at 1, 2, 4 and 6 months. I\'d like to see
> recombinant length and head circumference at the beginning and end
> because it just gives you additional information on the quality of the
> size of the infant. Close attention needs to be given to methodology
> and errors. Two technicians are really important and reliability data
> needs to be collected, and use of existing increment charts until the
> WHO charts are available.
>
> So thank you very much. I\'d just like to say, personally, the last
> time I had to give a paper in front of Dr. Briley, she gave me a B\--
>
> \[Laughter.\]
>
> DR. CHUMLEA: \--which is about 25 years ago. So I hope I did at least
> that good this time.
>
> Thank you.
>
> DR. GARZA: We\'ll take that up at the break, I guess.
>
> DR. CHUMLEA: Okay.
>
> \[Laughter.\]
>
> DR. GARZA: Thank you very much, Dr. Chumlea.
>
> Are there any questions?
>
> DR. SIGMAN-GRANT: Sigman-Grant. I have a question. You recommend
> weight starting at one month, and you talked about the regain from the
> loss from birth weight. So much is happening in that first month. Why
> don\'t you measure it before\--
>
> DR. CHUMLEA: I said that, really, as early as, say, 10 to 14 days. I
> would like to see it done that way, but within no later than one month
> of age. So let me kind of restructure that between\--
>
> DR. SIGMAN-GRANT: Why not between\--why not the first week, instead of
> 14 days?
>
> DR. CHUMLEA: Well, there\'s a shift in weight, as far as I\'m familiar
> with, that\'s supposed to occur after birth, and so I think, just my
> understanding is, that there\'s a period of time within the first week
> or State or local that the infant basically kind of stabilizes after
> the birth experience. Now, Dr. Fomon, I\'m sure, could give you more
> information on that, if I\'m incorrect on that.
>
> The more measurements you can get out of this, the better. I was
> being, trying to give you what I think is the very minimum that you
> have to collect there. You can measure them every week. That would be
> fine with me.
>
> DR. DOWNER: Goulda Downer. I understand, when you talked about
> examiner variability and possibly downright error, but can you talk a
> little bit more about why you don\'t think that subscapular skinfolds
> and triceps skinfold are important\--
>
> DR. CHUMLEA: Useful information?
>
> DR. DOWNER: Yes, at this juncture, because I think it is.
>
> DR. CHUMLEA: The reason I don\'t like them is this. First of all,
> they\'re extremely difficult to collect in children at this age, so
> the amount of error that\'s in the measurement is extremely high. The
> question I would have is that what information are you going to get
> out of this particular measurement that you\'re not going to be
> getting by bodyweight alone? Because if weight is going up, the
> skinfolds are going to go up; if the weight is going down, the
> skinfolds are going to go down.
>
> So the question that you\'re really interested in is total body fat,
> and, yes, 90-some-odd percent of total body fat in a child is
> principally subcutaneous; that if you want to go total body fat, there
> are now better ways of doing that, such as DXA, that I think are going
> to give you the information that you really want.
>
> If you do go and collect the skinfolds, then you\'re faced with some
> reference values that are useful. There\'s only two that are out there
> that are fairly good\--what\'s available from NCHS and NHANES III, and
> then Dr. Fomon\'s data on skinfolds. But outside of that, there\'s
> really little other reference data that\'s available.
>
> So I guess if I\'m going to, what I want to know is total body fat,
> and if I want to measure total fat, I\'ll go measure total body fat
> with something that\'s going to give me I think better, and more
> accurate, and reliable information about the child than I\'d get from
> the skinfold.
>
> DR. HEUBI: Jim Heubi. I don\'t want to misunderstand what you\'re
> saying, but you\'re not recommending that people weigh infants in
> garments and subtracting\--
>
> DR. CHUMLEA: I\'m sorry, what?
>
> DR. HEUBI: You\'re not recommending that people weigh infants in
> garments and then subtracting one-tenth of a kilogram for the\--
>
> DR. CHUMLEA: I would prefer they be weighed nude, yes.
>
> DR. STALLINGS: Stallings. To follow up a bit on the other question.
> We\'re beginning to think I think about looking at infants who are
> growing too slowly as the historical way of the failure to thrive
> related to this, but the issues of growing too fast are also of
> concern.
>
> So, to go back to the question, could we get most of that information
> with weights and heights, and weights for heights, rather than looking
> for data related to adiposity, or if we were looking for excess
> growth, whatever that concept means, what would you recommend, derived
> values from the anthropometry or DXA?
>
> DR. CHUMLEA: I think\--we\'re still sticking between this birth and
> 6-month range, and I think if you\'re getting excess growth, you\'re
> going to, you may need to take more frequent measurements so that you
> can plot and get a better description of the curve as what\'s going on
> there. And if you have more information, then you can discriminate
> between the children who have excess growth and those who don\'t. So
> that\'s I think something that\'s important to consider.
>
> I think you will get everything you want from weight and length. If
> you go to DXA with a child at this age, and Ken will address this more
> I think in his talk, you\'re going to get, you know, fat, lean and
> bone, and the fat is probably the most important aspect here that
> you\'d be concerned about for excess growth, but it\'s going to be
> described in weight, also.
>
> So unless you\'re wanting to tease a tissue out and say, okay, we\'re
> really concerned about the increase in fat here, in addition to the
> increase in weight, then, yeah, then something like DXA I think would
> be important.
>
> DR. STALLINGS: Follow-up. The velocity, then, would be what we would
> be looking at, more than just attained weight?
>
> DR. CHUMLEA: I think you have to do both of them.
>
> DR. STALLINGS: We, historically, are always looking I think at the
> attained weight.
>
> DR. CHUMLEA: Yes, and you\'d have to include the velocity in there
> because the velocity would, these children should, I think,
> potentially have much higher velocities.
>
> DR. STALLINGS: And that might be a way of discriminating between the
> concept of normal growth and excess growth?
>
> DR. CHUMLEA: Yes, right. You could have children, let\'s put it this
> way, who have, say, after, say, three or four months, when their
> velocity should be declining, these children might not be declining as
> what the average is, so they\'re still obtaining a rather high
> velocity of growth at that point.
>
> DR. THUREEN: Thureen. I would argue that DXA is not a very useful body
> composition measurement for most studies because it\'s not that
> readily available, especially as a field tool, and I think that a lot
> of people are now starting to do more caliper measurements for
> assessment of body fat, even in very tiny infants. And certain people,
> like Suda Kashyap, have gotten very reliable measurements over time.
>
> Do you think that the data from the NHANES study on body composition,
> using anthropometric measurements of body fat, was not useful or do
> you think it is useful? And if you want to do large population
> studies, do you think that there is a future for caliper measurements?
>
> DR. CHUMLEA: The DXA thing you can talk to Ken about. I\'ll let him
> address that when he gets up here.
>
> There\'s two issues here, whether we\'re talking about small studies
> or large studies. If you\'re wanting to do large-scale studies,
> population studies, like NHANES has done with NCHS, then collecting
> caliper information is going to be what you can do because there can
> be limits to what you can collect for DXA, particularly because of the
> issue of radiation exposure, although it\'s very minimal, even within
> the current NHANES, where they have DXA machines in all of the
> trailers, I think the limited age there is Age 8, from what they\'re
> collecting, although they technically have the availability of doing
> it in those particular studies. Other people clearly don\'t have
> access to such expensive pieces of equipment.
>
> If you don\'t have access to that, then I\'m not opposed to collecting
> the skinfold data. The issue comes up that it is extremely difficult
> to collect accurately and reliably, and so, I guess, I kind of am in
> favor sometimes of no data is better than bad data, and I know that,
> in collecting it, it is something that people have to pay very close
> attention to, the technicians have to be very careful, and this is
> frequently something that in the course of studies, we pay lip service
> to it, and there\'s good attention, but these things do tend to fall
> out.
>
> Now, in smaller scale studies, this is something that can be done, and
> the information can be collected. Overall, I\'m just not that happy
> with the information. Yes, there are studies where it\'s been done
> very well, and so I\'m not putting those studies down at all. I\'m
> just talking about, in general, my experience has been, in collecting
> from infants in this age range, that this is really hard to do, and
> when it\'s something that\'s hard to do, it doesn\'t sometimes always
> get done the best way.
>
> DR. THUREEN: Thureen, one more question.
>
> In your opinion, if you\'re looking at a growth outcome study, do you
> think incremental data are the gold standard\--growth data are the
> gold standard, attained growth are both critical to an outcome study?
>
> DR. CHUMLEA: I\'m assuming, when you say a \"growth study,\" you\'re
> going to be collecting repeated measurements from the same children,
> so you\'re going to have both pieces of information available there.
>
> The status value simply describes where the children are in reference
> to whatever reference values you\'re using for peers at that age. That
> simply tells you that they\'re at certain percentile levels, but at
> the same time children also grow at different rates, and so there\'s a
> distribution of the rates at which they grow.
>
> So children who may appear to be at one percentile level, their rates
> of growth can be a different percentile level, so it gives a much
> clearer picture upon what\'s available. And since any study where
> you\'re going to collect repeated measurements, you\'re going to have
> all of that information available to you. So I would take advantage of
> it. Again, the errors are difficult to control and need to be paid
> attention to for collecting it.
>
> DR. GARZA: Cameron, I have two questions. Given the fact that we are
> going to be providing advice to the FDA on the approval of specific
> formulas, how many measures do you recommend be taken if, in fact, one
> has an interest in the pattern of growth?
>
> DR. CHUMLEA: If I was going to design the study, and you\'re not going
> to restrict me to what I want, okay.
>
> DR. GARZA: From your perspective, if you\'re going to be protecting
> the public health and infants\' health, what should the American
> public ask?
>
> DR. CHUMLEA: I\'d want a birth weight.
>
> DR. GARZA: Birth weight.
>
> DR. CHUMLEA: Clearly. I would like it at, say, two weeks, one
> month\--I\'d like it again at two, and then at four, five, and six
> maybe, something like that. The more measurements I could get out of
> the thing the better.
>
> DR. GARZA: But you think that with seven measurements, one would be
> able to assess both the pattern of growth, as well as velocity of
> growth, at those specific time periods.
>
> DR. CHUMLEA: Yes.
>
> DR. GARZA: And you mentioned there were various sources of error. Is
> there any consensus that FDA could rely on that deals with the nature
> of the equipment, the type of calibration that should be insisted
> upon, the training that obtaining the measures should be able to
> obtain and document, and the\--those would be the three: equipment,
> calibration and the training of the technicians.
>
> DR. CHUMLEA: There\'s a little bit of information about equipment
> errors and a little bit of information about the inter- or
> intra-observer errors for collection of measurements in the
> [Anthropometric Standardization Reference Manual]{.underline} that\'s
> collated in one location.
>
> There\'s other pieces of information that are clearly scattered around
> the literature that are available. From NCHS, there\'s really a
> limited amount of information. There was really limited error data
> that was collected in NHANES III. What\'s available from NCHS is
> principally from the earlier NHANES studies, and NHES. So there\'s not
> much there.
>
> The techniques are described in a variety of locations, but there\'s
> not really anything that I know of that\'s really written down that
> says, okay, you can refer to here, and this is what you should do, in
> terms of training, collecting the measurements, et cetera, in one
> central location, no.
>
> DR. GARZA: Any other questions or comments?
>
> \[No response.\]
>
> DR. GARZA: Thank you very much.
>
> DR. CHUMLEA: Thank you very much.
>
> DR. GARZA: We\'ll move on, then, to the next presentation. It\'s a
> topic that has already come up, body composition assessment in early
> infancy. Dr. Ken Ellis, from the USDA/ARS Children\'s Nutrition
> Research Center, with Baylor College of Medicine.
>
> Again, Dr. Ellis, thank you very much for joining us.
>
> DR. ELLIS: Thank you. What I\'m going to present today is a probably a
> little different from what most people have had experience seeing.
> Some of this\--in fact, all of this is going to be body composition
> beyond simple weight. If one was interested in what the composition of
> weight is\--let\'s see. Which button do I\...this is the laser, okay?
> And which one of these is\--can you hear me now?
>
> \[Pause.\]
>
> DR. ELLIS: This is supposed to move the slides, she said. I\'m so used
> to pointing to the screen these days, so it\'s my fault.
>
> As you already heard, most people\--or most of the work, at least in
> infants, has been with weights and heights, all kind of weights and
> heights charts. But body composition, at least the first models that
> were attempted, the basic classic 2-compartment model is to
> measure\--is divided in two compartments, fat and non-fat. The direct
> measurement of body fat is really very difficult to do. It\'s not an
> easy process to do that. And so for many years what we did was we said
> that if we could measure precisely some parameter of the body that
> would represent the fat-free mass, then subtraction of the fat-free
> mass from the total weight would give us a measure of the fat mass.
>
> Part of the problem with that is that all the years in the (?) scale
> for the fat-free mass translate directly to the fat mass, and you\'ll
> see what I mean by that in a few minutes.
>
> Three classic methods that have been used for 50 years, or maybe even
> longer: underwater weighing in adults\--you can\'t do this in babies
> and infants. Practitioners as well as parents tend to object to
> holding babies underwater. Hydration, this is probably the more common
> thing you\'ll find in the literature that is done. It\'s the dilution
> technique. You give a tracer, collect the blood sample or some fluid
> sample several hours after that, then do some manipulations on that,
> (?) space to get water, and make some assumption about how much water
> there is in the fat-free mass. And as we all know, hydration content
> of the fat-free mass in children at very early ages changes
> dramatically. So depending upon what you assume, you can then quickly
> be off in your estimate of the fat.
>
> Whole-body counting is another method used to measure potassium
> content, primarily the body cell mass. And, again, how much that
> relates to the\--how much of that is a constant fraction or not of
> fat-free mass at these ages has also been questioned.
>
> So, again, like I said, the difficult underwater weighings, difficult
> to do the infants. For the water measurements, they must swallow all
> the tracer, collect some kind of fluid sample. Plasma is your best
> choice.
>
> The problem with this is you can\'t repeat it. If you want to do the
> trial a week or so later, you can\'t. You need to leave a sufficient
> amount of time for the previous tracer to clear, or you start
> increasing the doses of the tracer to compensate for that. And, again,
> in the past, the most accurate assays required one to have a mass spec
> or availability of a mass spec, which is not in everyone\'s laboratory
> or garage, as I usually say.
>
> Whole-body counters, the problem with those have been over the years
> really they haven\'t been designed for infants. They\'re really
> designed for adults. There are a few of us who have done this, but in
> general they simply don\'t exist. And even if you do have a whole-body
> counter available to you, most of the time it\'s not in a clinical
> setting. You\'re going somewhere else to get the measurement done.
> Again, the reason that tends to exclude it, at least for infants and
> children. But one nice feature is you can repeat this as often as you
> wish, and so you could do it on a daily basis if one chose to do that.
> So if you have access to a counter, one can count these infants as
> frequently as one chooses.
>
> And because of the way in which the counting procedure works, there
> doesn\'t have to be any really significant constraints. They can move
> around and be\--it will not really affect the results that much.
>
> Now, I looked at the various things that we received in reference to
> this meeting, and there\'s the document in there from the American
> Academy of Pediatrics where there\'s one little paragraph on body
> composition. This was in June of \'88. And it says, \"Normal growth
> implies appropriate composition of the increment in body weight.
> Sequential measurement of various aspects of body composition\"\--such
> as water, fat and bone\--\"have the potential for defining changes in
> body composition.\" However, at that time the opinion of the Task
> Force was that such measurements have not yet reached the stage of
> precision, non-invasiveness enough, and they\'re not that very
> convenient, and which I\'ve just showed you that sort of in the three
> previous procedures, which I would agree in 1988, I would agree with
> that statement.
>
> That gives us a quick summary of that. It just says you want to be
> able to\--that the weight is appropriate composition, you will be able
> to do longitudinal measurements. Again, for clinical testing, the
> precision, noninvasiveness, and convenience are the issues that they
> put out.
>
> Again, the 2-compartment model, I quickly talked about the
> limitations. The density is not constant. The hydration is not a
> constant. Extracellular and water ratio is not constant. Bone
> accretion is not constant. Basically babies aren\'t constant. We know
> that, right? Because we know that when the baby comes back a month
> later, it\'s not the same baby we saw a month before. It\'s a whole
> different child totally, at least from a body composition point of
> view, unlike adults, which really change very slowly over time.
>
> Now, so what\'s happened in pediatric body composition research since
> 1988? There are sort of three general areas where there have been
> advances made. One is bioelectrical techniques. In pediatrics, I want
> to take a broad sense of pediatrics. That\'s anybody under the age of
> 18. And there\'s been quite a bit of work used with this technique in
> older children. When it has been tried or used in infants, it has not
> been very successful at all. In fact, in general, most conclusions
> with this technique\--I should say the first two techniques, the
> bioelectrical impedance and the bioelectrical spectroscopy, which is
> the same as this but at two frequencies, have been that the
> information gained from those two techniques really hasn\'t been much
> more than you already knew when you had just simply weights and
> heights with these individuals.
>
> TOBEC, on the other hand, has been more successful, but the problem
> with TOBEC is that these machines are very\--they\'re not common,
> there are not many out there. There\'s probably not more than a
> dozen\--a half a dozen, in fact, for infants. And so, again, this is a
> technique that holds promise or has held promise, but, again, it\'s
> not a technique that is widely available at all.
>
> Absorptiometric techniques, DXA. Remember that Academy of Science
> report? It was in 1988. Well, in 1993, the world of X-ray
> absorptiometry changed because at that time it went to what\'s called
> DXA. It went to X-ray sources, different detectors. The whole
> technology advanced substantially such that one could now consider
> this technology for whole-body measurements in infants, and one can do
> a localized region, such as the spine, if that\'s specifically what
> one would want to do.
>
> Another area, body volume measurements. Remember, underwater weighing
> doesn\'t work. This is an air displacement plethysmograph technique
> now, which is just actually started this year, so maybe in another few
> years, when this committee reconvenes, we\'ll be able to talk more
> about this.
>
> I\'m going to basically focus on the absorptiometry or DXA or DEXA
> methodology because that right now holds the best promise for this
> kind of broad application.
>
> So the basic model, again, in 1988\--I mean, there are more models,
> but the very basic model, again, we\'re talking about fat and fat-free
> mass. And today, when one talks about body composition, one is almost
> forced pretty much to really address this kind of a model over here,
> 4-compartment model: fat, bone mineral, mineral composition, ash, the
> water, and protein content. And, in fact, it is these compartments
> that we\'re interested in when we look at body composition at any age
> and look at change in body composition at any age.
>
> So that 4-compartment model is now shown on your left, and what does
> DXA provide us? DXA provides us\--the only method we have that
> provides us a 3-compartment model for a single measurement. We have a
> measurement of fat, which is directly the fat. We get a measurement of
> BMC, which is bone mineral content, which is for the mineral
> compartment. Eighty percent of this is this; there\'s another 20
> percent which is distributed in the non-mineral, non-osseous
> compartments. Then a third large compartment called the lean tissue
> mass, which is the non-bone, non-fat compartments.
>
> So when we do a DXA measurement of anyone at any age, we get this
> basic model, which has been a huge advance.
>
> This is what an image looks like in a child. Most of the time people
> show images of adults. Adults are very nice. They hold their arms
> right. They put their legs down straight. Children, amazingly, 14
> years of age, haven\'t learned how to do that yet, have they? So they
> tend to lay the way they want to. We do make measurements in children
> at our place. We\'ve done probably, I don\'t know, 600, 700 DXAs, at
> least. Maybe a thousand. I really don\'t know the number these days.
> Quite a few studies.
>
> Let me show you, again, if one is interested in just the spine, this
> is not an infant spine. It happens to be an adult image there. But one
> can localize and make a measurement just at the spine for bone. But
> for body composition work, we do total body measurements, which is
> shown here. I think you can get an idea of the skeleton seen. I think
> you can see the soft tissue parts that are obviously not the bone, and
> we can then get that information.
>
> Now, as you heard earlier, the BMI in terms of the height of heads, if
> one chooses to, one can actually decapitate the image and just worry
> about this part if you\'re concerned about how does the head
> contribute to all this information. So it is possible to do that kind
> of stuff.
>
> By the way, the time it takes us today\--in 1988, if you attempted an
> infant, which you would never be successful at, it would be 25
> minutes. Today we do an infant in less than 3 minutes with the newer
> scanners.
>
> So DXA, what are the advantages and some of the disadvantages? First,
> DXA has almost achieved a reference status within the body composition
> field. It still has some improvements to be made, but, again, in terms
> of everything else, it is the better technique that we have.
>
> Advantages, it does give us good precision and accuracy. It is the
> only technique for a single assay that gives us basically a
> 3-compartment model: bone, fat, and lean. As you can see from that
> image, we can get some regional information if we choose to do that.
> It has a very low exposure risk. There\'s a very minimal amount of
> that. And there are more the reference populations out there for
> adults, for children, and they are being developed, and several for
> infants, if you know the references to look for.
>
> The disadvantages, very low exposure risk, the same thing. One could
> argue whether it\'s an advantage or disadvantage. One of the ways I
> talk about this\--in fact, I just thought about it coming over here
> yesterday on the plane\--was on the flight I was on, there was at
> least five children under the age of 2 on that flight with me, and the
> radiation dose they got on that flight exceeds what you get from the
> DXA. In fact, it\'s two to three times higher. So there\'s an idea
> what the risks are involved.
>
> Scanners are not optimized for infants. If you get a scanner, it\'s
> adult size. They have not\--the industry has tended to resist this,
> primarily because of the market that they are focused at, which is
> osteoporosis in older women.
>
> It doesn\'t give us a 3-D image. You saw that 2-dimensional image. It
> gives us 2-D not 3-D imaging. That\'s what I call boot-strapped 3-C
> model. It\'s not a perfect 3-C model, but it\'s not bad. And the one
> different problem has been that the results differ between
> manufacturers, so that if you do a study\--a multi-site center study,
> you want to stay with the same instrument, same software.
>
> Okay. Precisions and accuracy of different body composition
> measurements and the minimal detectable change in an infant. For this
> I chose basically a full-term infant and made the assumption it\'s 15
> percent body fat.
>
> If you look at these methods, the water, the dilution method, or the
> bioelectrical impedance method or TOBEC, this is the potassium one
> here. DXA, the bottom three, the fat, fat-free, and the bone,
> precisions, these are optimistic. Precisions tend always to be a
> little bit better than\--whenever you do a precision measurement
> study, they always do much better than they do random. I\'ll guarantee
> that.
>
> This shows you the precision measurements here. This is generally the
> accuracy. Precisions are, let\'s say, in the 1 to 5 percent range or 2
> to 5 percent range. Accuracies tend to be in a 3 to 5 percent range.
>
> If you take these, this information, and take this size of an infant
> and you translate those into one of the minimum detectable changes for
> that infant, the values are shown here, the last column on the right.
> And the percents are those percents of what that person had in terms
> of the composition at that age.
>
> So one can measure water, changes at 5 will start to show up. If you
> use (?)-ium, they can get worse, TOBEC or BIAs. Fat-free mass, 125
> gram changes, only about 5 percent of the total fat-free mass. Forty
> grams of fat, if that starts to change, it\'s 8 percent of that to
> implement this weight and composition. You can start to see changes
> relatively quick with the single input.
>
> This shows the relationship between precision of the methods and what
> kind of a change, minimal change is required for that to become
> statistically significant, at the 5 percent level and a power of 0.8.
>
> I call this the clinical application in individuals, what I consider
> to be a clinical application, what\'s changed in that individual. And
> if you look, for example, this is the relationship that the minimal
> detectable change\--this is approximately 3 times the precision. And
> so that if our precisions for BMC are somewhere around 2.5 percent, 6
> percent change would occur, lean tissues at about 10 percent, and
> fat-free mass at around\--if the precision is 4.5 to 5 percent, we\'d
> have to see changes in the range of about 14 percent to be significant
> for that individual.
>
> Now, this I show you because this is the difference between 1988 and
> today. I only got 30 seconds left? Oh, well. Well, okay. Very quickly,
> this shows you the methods. This shows you what the precisions are for
> FFM, fat-free mass. If you translate those into fat-free mass, this is
> the tail here. The top three were in 1988. That\'s why you couldn\'t
> do it. DXA is hugely improved since then. This shows you the kind of
> weight gains that would have to occur in infants at, I guess, again,
> the standard term infant here, very small weight change with DXA,
> large weight changes for\--I\'m out of time. She says zero. Anyway,
> the\--I\'ll keep on going anyway. And the number of weeks would have
> to be changed in that individual.
>
> I can\'t believe I\'ve taken up all the time already.
>
> This just shows you the rates of change that occur with age. You can
> find this from several different sources.
>
> This shows you the first six months where you have to figure out what
> the rates of change are in the composition, and here\'s a series of
> papers that are on infants. There\'s one on TOBEC. This one used a
> series of methods which we can do. All the rest you\'ll notice, with
> the exception of one here and dilution, were done with DXA. The weight
> ranges are shown here. The number of infants are shown over here. We
> are now doing a meta-analysis to bring this together into one common
> reference database.
>
> And I want to just quickly go through these, again, precisions, 2
> percent, 3 percent, 6 percent reported here. And if you did a
> calculation\--this is an interesting study in twins. They looked at
> the weight difference, which is about 14 percent, and they calculated
> again with these alpha-5, power of 0.8, 40 to 45 infants would be
> needed to detect a 15 percent difference in one or more of any of
> these three compartments.
>
> Another paper here, let\'s see, this particular paper does give
> percentile curves for each of these values as a function of weight.
> And, again, what I\'ll point out here is that even though you may have
> a 3.5 kilogram weight infant, the fat range can range from 10 to 26
> percent. By the time they\'re 10.5 kilograms of weight, it can range
> from 22 to 23 percent. So weight does not represent fat.
>
> This paper is another one that has percentile curves of each of these
> compartments versus weight. Again, comparable to the other one,
> actually these are lower fats. Interesting, this is an European study.
> The previous one was a U.S. study.
>
> And I want to show you\--this is the last one, slide here, and I\'m a
> minus five I think now. But here this shows the changes\--total body
> DXA. These were preterm infants. Initial weights were about 17\--under
> 1750. This was fortified human milk formula, and this was a preterm
> infant formula. And the baselines are measured at 3 weeks of age,
> repeated again at approximately 3 to 4 weeks later. And this shows the
> statistical ability to measure changes in body weight, for example,
> and in the fortified human milk you can make\--you can change\--see
> the difference at this level. And the preterm formula, it\'s about
> 19.9 grams per kilogram per day. Differences were four, and this is
> statistically different. You can see these\--in other words, you can
> compare in groups of 20 versus 30, you can see differences in weight,
> you can see differences in lean mass and fat mass and bone mass by DXA
> at three weeks between these two groups of children. So it is possible
> with DXA to measure not only weight but the composition of that weight
> change in relatively small sample sizes.
>
> And if you want to convert those to growth kind of numbers, this
> represents about 2.3 grams per kilogram per day in terms of growth,
> and that\'s about 12 percent of the mean weight gain in terms of
> composition. This again is 2.1 grams of lean mass per kilogram per
> day, 15 percent, about 1.2 grams per kilogram for fat mass and 76
> milligrams per kilogram per day for the BMC.
>
> So the point here is that we can measure\--I think there was a
> question, could we measure changes of composition that would be
> comparable to 3 grams per day? The answer is\--from this study the
> answer would be yes, we could do that. Again, relatively small sample
> sizes of 25 to 30 children.
>
> I\'ll end there. Thank you.
>
> DR. GARZA: Thank you very much.
>
> Any questions or comments?
>
> DR. MOYER-MILEUR: I have a question. When you do your measurements in
> your babies, are they sedated? Because we find that we require
> sometimes more than two technicians to keep a baby quiet to minimize
> the movement artifact.
>
> And my other question is, with preterm babies, we found it somewhat
> difficult to do early measurements because of equipment artifact, that
> they have leads and monitors on that make it very difficult to get a
> true assessment using DXA.
>
> DR. ELLIS: Yes, two things. One, none of the infants that we measured
> and none of the infants that any of these studied were sedated. These
> are\--again, they\'re all healthy children.
>
> Our experience has been if you feed them right before you want to do
> the measurements, they tend to be rocked in the chair by the mother or
> someone, they go out, and then you can make the measurement pretty
> easily.
>
> I don\'t know which machine you were using. Was it a 4500A or 2000
> or\--
>
> DR. MOYER-MILEUR: We have a 4500A, and we also have\--
>
> DR. ELLIS: You should do it in three minutes or less. You do have to
> work at it. I mean, normally with older children who will cooperate,
> that could be anywhere from age 5 to 18, depending upon what you\'re
> looking for. But those children can get on a bed and will cooperate
> and can be\--and they\'ll do it.
>
> Here you can do the whole procedure in ten minutes or less. Here
> sometimes you have to spend as much as an hour to get the one
> measurement done. You have to work at it. But none of these children
> were sedated. We don\'t sedate any children in any of our studies.
>
> DR. MOYER-MILEUR: Yes, and I just, you know, would caution DXA in the
> infants in that it requires people with specialized training so that
> you can\'t just\--
>
> DR. ELLIS: Yes, yes.
>
> DR. MOYER-MILEUR: \--go to a community hospital and get their\--
>
> DR. ELLIS: Yes, you can\'t\--you cannot send these children to a
> radiology department even with the hospital because they simply are
> not experienced with measuring children. They just don\'t like it when
> children show up. They don\'t have\--infants, they basically will send
> them back. They will not\--they will not take that hour, hour and a
> half to do it in. It takes effort sometimes. Sometimes they go right
> on the bed and out. It\'s always the ones that show up at 4:30 that
> take the hour and a half to two hours, though.
>
> As far as the artifacts, you\'re right. You have to be careful about
> artifacts. You can delete those off the images, though, pretty well.
> If you take leads out, for example, out to the side, you can delete
> those right off the images. And so that\'s a minor effect if you deal
> with it right.
>
> DR. GARZA: Dr. Denne?
>
> DR. DENNE: I was wondering if there are any direct comparisons in
> infants between skinfold thicknesses and DXA for fat mass.
>
> DR. ELLIS: There may be a few, but, again, the issues have been that
> skinfolds are probably more difficult to get than the DXA. We have
> skinfolds in some of our kids, but we just don\'t rely upon them for
> anything.
>
> DR. DENNE: It would be an interesting comparison to make. You know,
> relative difficulty depends on what you\'re actually used to doing.
>
> The other question is: How is DXA validated in infants? I mean, most
> of this body composition, you know, was validated against the other
> techniques which all have their own sets of issues.
>
> DR. ELLIS: Yes. The validation of DXA are done two ways. One is with
> animals, small animals have been done. We have done 73 piglets under
> the weight of 10 kilograms. Other people have done comparable size
> piglets. And probably if you add everything up, it\'s probably about
> 200 pigs have been done over the years at different centers with
> different machines.
>
> The pig is not the best of models because, for example, its bone is
> more mineralized than infant\'s. Weight-wise, composition-wise, soft
> tissue is not that bad.
>
> The other way we\'ve done it is we actually built phantoms. We\'ve
> actually fabricated mock-ups of the human body with parts made from
> polyester resin, doped with calcium and phosphate\--phosphorous
> compounds to simulate that. But that\'s how it\'s done.
>
> I have also done cadaver work. The problem\--not the problem. The
> situation is that, unlike Elsie Widdenson, today\'s environment would
> not allow one to chemically digest the infant body, so we have done
> that in about 30\--more or less 30\--these are all preterm infants,
> and we did that by a technique called neutron activation analysis
> where we do a nuclear, chemical\--nuclear chemistry technique where
> you measure calcium, phosphorous, sodium, chlorine, phosphorous,
> manganese and magnesium and potassium.
>
> And so if I look at the BMC bone versus fat, and if I look at the
> other ones and make some model\--I have to make some modeling
> assumptions now about how much sodium is in the water, extracellular
> water and so forth, but they come out pretty well, with the 5 percent
> kind of accuracies.
>
> DR. THUREEN: In the past several years, it\'s been recommended that at
> different centers, even if you have the same type of machine, you
> should do your own phantoms. Do you think there\'s enough phantom data
> out there now that that doesn\'t need to be done? Or if you\'re going
> to do a multi-center study, do you think that needs to be done?
>
> DR. ELLIS: Well, for the multi-center study, there should be at least
> a common phantom that is going around to all those sites. One, to do
> the initial calibration to be certain everybody is within reason of
> the numbers, and then continue on throughout going for the study.
> That\'s typically what we do in all studies at all ages, whether it\'s
> infants, children, or adults. That\'s what we do these days. For
> multi-site studies, there\'s a common set of phantoms that go around
> all the time.
>
> DR. GARZA: Dr. Stallings?
>
> DR. STALLINGS: I\'m one of those other six people in the world that\'s
> got the TOBEC, so I agree those, you know, have tremendous advantages.
> But I don\'t think that we would be able to use them. So I think, you
> know, bringing us to issue with DXA and how we could use it is an
> important question.
>
> Laurie asked one of the big questions that I\'m always asked, which is
> about sedation, and I would agree that, you know, natural sleep and
> that sort of thing and working in the research setting.
>
> The other question sometimes is: How many images do you really have to
> take to get the one right? I even noticed on your slide the hand is\--
>
> DR. ELLIS: The hand was a little off.
>
> DR. STALLINGS: And I just spent last week working with DXA and trying
> to figure out which one had all the body parts there and minimal
> movement.
>
> But would you share with the group, you know, how frequently do you
> need to do two scans or you get halfway through a scan and then you do
> it again to get a good research quality measurement?
>
> DR. ELLIS: I would say it\'s definitely less than 10 percent that we
> have to repeat the scans. It\'s like you say, there\'s a technician
> there. The image is being acquired while the scan is being done, and
> you can stop it immediately to start again, as you well know.
>
> We have some\--we have looked at some scans where the infant has
> moved, but we finish the scan and then repeat the scan again and
> looked at those. It has a lot to do with what kind of movement you
> have. As you well know, you can\--if the child\'s arm is here\--or say
> here when it starts and here when it ends, you have a three-armed
> child in the image you end up with, because it was here the first time
> you scanned through and caught on the second, on the lower case.
>
> We have found that if we have motion in this direction, there tends to
> be a minimal effect because you\'re not changing anything. You\'re
> just moving the slice over a little bit here. But it\'s when there\'s
> movement like this, a flapping of the arms or kicking of the legs, if
> they\'re doing that, we don\'t scan them. We stop. But that\'s usually
> what happens, they wake up or something. Less than 10 percent.
>
> DR. GARZA: Any other questions?
>
> \[No response.\]
>
> DR. GARZA: I have two, Ken. How well described are the specs of
> equipment that one would need to be able to measure infants reliably?
> Is there pretty much a consensus on the quality of the equipment, the
> DXA equipment that would be needed?
>
> DR. ELLIS: You\'d have to have something that\'s equivalent to what\'s
> called\--there\'s basically two manufacturers in this country. One is
> Lunar, the other one\'s Hologic. You have to have at least the DPXL
> for the Lunar at least the 4500A or DelphiA for the Hologic.
>
> We always use Hologic\'s, and, in fact, we, you know, are constantly
> trying to improve those machines. I\'m not going to tell you they\'re
> perfect, but they\'re the best thing we have. I think they could make
> them better.
>
> DR. GARZA: You also indicated that individuals or personnel had to be
> specialized or had to be highly trained. How much training do
> individuals need to be able to use this equipment reliably, or was the
> training in reference to just training and dealing with pediatric
> populations?
>
> DR. ELLIS: It\'s more dealing with the pediatric populations. It\'s
> more of that than it is simply for this, because once they
> understand\--basically what you want to do is you want to minimize
> motion and have them in the right position and things like this. But
> it\'s more dealing with the pediatric population, dealing with a child
> that may want to cry for 20 minutes or something, or a mother that
> could be apprehensive when she hears the child crying. It\'s more that
> issue than it is anything else.
>
> DR. GARZA: Dr. Stallings?
>
> DR. STALLINGS: I just want to ask a little bit what Bert was doing. If
> we were doing such a study, a multi-center study, what would your
> advice be about centralized reading of the scans, the technician at
> the instrument site?
>
> DR. ELLIS: It is a good point. These days, again, it is common
> practice now to send all the scans to a common central reading site
> because at least what happens there\--well, I\'m thinking more of the
> adults. If there is any kind of bias\--in adults you set regions of
> interest. In the infants, it\'s a total body scan. There\'s no region
> of interest set. So it\'s less of an issue there.
>
> But, again, the judgment about good scans or bad scans would come from
> one source and not from different sources. So it would be a reasonable
> thing to do.
>
> DR. GARZA: Any other questions?
>
> \[No response.\]
>
> DR. GARZA: Thank you very much, Ken.
>
> DR. ELLIS: Sure.
>
> DR. GARZA: Committee members and guest speakers are invited next door
> for coffee. We\'re going to break right now, instead of at 10:35 as on
> your schedule, so that we don\'t break up the following three
> presentations. But I will ask everyone to try to get back here at
> about 10:25, 15 minutes from now, so we can assure that we don\'t eat
> into any discussion time with either the speakers or anyone else.
>
> Everyone else that is not a speaker or on the committee is invited to
> the cafeteria. These are federal rules. I didn\'t make them.
>
> \[Laughter.\]
>
> \[Recess.\]
>
> DR. GARZA: The committee is seated at the table. If I can have our
> guests please take your seats, we\'re ready to start.
>
> Our next speaker is Dr. Frongillo. Dr. Frongillo is an associate
> professor in the Division of Nutritional Sciences at Cornell
> University, and he\'s going to give us an overview of the World Health
> Organization Growth Reference Study that was referred to a bit earlier
> by Dr. Chumlea.
>
> DR. FRONGILLO: Good morning. I\'m going to stand here in the middle
> and use this archaic technology. It might help if we could dim the
> lights up at the front here a little bit.
>
> These are some growth data from a single child, and you can tell what
> country they\'re from if you look at the units of measurement in
> pounds. And if we plot the data, it\'s actually more interesting to
> look at. We see a trend like we expect. But to try to really discern
> anything about what the pattern is, it\'s helpful to compare it to
> something. And so this is a graph\--this is the old U.S. reference,
> the 1978 reference, and this is the same child. And you can see this
> graph on the left, the child started off at the bottom of the
> distribution and then seemed to climb into the chart a bit, and then
> at about four months or so started to really\--three to four months in
> there, started to really\--its trajectory is now falling well below
> the chart. And eventually by\--this is about two years where you see
> it comes back onto about the same percentile where it originally
> started.
>
> This discrepancy that we see is either telling us something about this
> particular child or it\'s telling us something about the reference.
>
> Well, it turns out it\'s telling us something about the reference
> because that\'s a breast-fed child. And if we look at a data set, this
> is a comparison that the WHO infant growth\--an analysis that was done
> in the early 1990s, and what it shows is that, if you look on the left
> here, this is for boys, this is weight in kilograms and age going up
> to 12 months. And the dotted line to the 1978 U.S. reference which was
> adopted about that time, just after that by WHO, is the international
> reference. And the breast-fed data set, these are infants who were
> exclusively breast-fed for four months and then continued breast
> feeding through the first year.
>
> And you can see again that about four months you start to see the
> solid curves deviating from the dotted lines, which is the same
> pattern that we just saw. And so this is showing that in a sample of
> about 426, I think it was, infants epidemiologically what we just saw
> in that individual child.
>
> And a similar pattern was seen for girls. We can amplify this in a way
> by\--what I\'ve done is just simply take the current reference, the
> current international reference, the 1978 reference, and that\'s what
> would be at zero. So if these children were growing exactly like the
> reference, there\'d be a horizontal line right at zero here. But what
> we can see is that this breast-fed set seemed to grow, if anything, a
> little bit faster at first, and then by the end of the first year had
> increased their weight substantially less than the U.S. set.
>
> In fact, if we calculated the difference in rates for these two groups
> from zero to 12 months, it\'s about 2.7 grams per day. So this is
> something to keep in mind for later when we\'re thinking about how big
> our meaningful difference is.
>
> The difference from about one month, which is at the top there, from
> the maximum to the minimum at 11 months is about five grams per day.
>
> So that was for weight. If we calculate a z-score\--and we\'ll
> have\--I\'ll put this up here because we\'re going to hear about
> z-scores at various points. A z-score is where we take a particular
> measurement for a child and compare it to a reference median, whatever
> the reference is, and then divide it by a reference standard
> deviation. So the graph I just showed you just showed the numerator
> there, but for a z-score we also divide by the standard deviation. And
> the reason we do that is because then it\'s easy to imagine that the
> growth of a, quote, normal population would fall between about minus
> two and plus two z-scores. About 95 percent of the distribution would
> fall there.
>
> So if we look at z-scores for this breast-fed set, then what we saw
> was that, regardless of the index that was used, whether it was
> length-for-age, which are the triangles, which is the curve near the
> bottom, whether it was weight-for-age, which is the circles, or
> weight-for-length, which is the squares, we saw a very similar pattern
> with this breast-fed set in comparison to what was then the U.S. and
> international reference.
>
> So this discrepancy, along with other information that was obtained
> during the review that the Infant Subcommittee made during the early
> 1990s leading up to the WHO publication in 1995 of the uses and
> interpretation of anthropometry, the recommendation was made that
> consideration should be given to making a new international growth
> reference.
>
> The justification for having an international reference is, first of
> all, that it allows cross-national comparisons to be made that
> otherwise couldn\'t be made; and since there\'s been an international
> reference since the late 1970s, it\'s allowed us to do some things in
> a comparative way globally that we weren\'t able to do before. For
> example, this is a graph from a WHO publication that was in the
> bulletin of the WHO showing that the trends that have occurred from
> 1980 to about now so that we could actually look at the progress in
> Africa on the left, the very rapid progress that occurred in Asia.
> This is in percentage\--the percent of the population that\'s
> stunted\--and the rapid progress that was made in Latin America and
> the Caribbean region.
>
> This kind of comparison has been made possible because there is a
> common reference being used throughout the world.
>
> In addition, we know that it\'s very expensive to make local
> references, and also that in developing countries where there\'s still
> a very strong cyclical trend in growth, if a local reference were
> made, it would have to be revised very quickly because of changes that
> are occurring.
>
> The justification for having an international reference goes back to
> work that was done in the early 1970s. This is a well-known graph from
> a well-known paper, in \'74 I think it was, showing that these curves
> right here were all curves of high SES children in well-off countries,
> whereas the ones that were down here were children in developing
> countries that were not so well off. And so the fact that these were
> all so close together meant that growth roughly from one place to
> another where children are growing in conditions that are favorable to
> growth tends to be roughly about the same.
>
> Some work that the WHO has done with a cross-national data set
> collected by the Human Reproductive Program recently shows that\--this
> is for girls\--across a number of different countries, these are
> children who were reasonably well off SES, not necessarily the highest
> SES, showed basically that, with the exception of this lower curve,
> which is in China, that these other curves all pretty much are very
> close together. Again, giving more recent evidence of the idea that it
> was reasonable to make an international reference where data from
> multiple countries could be combined.
>
> So let me tell you, then, a little about the effort that\'s underway
> in the Multi-center Growth Reference Study.
>
> First of all, I wanted to point out that a reference\--the idea of a
> reference is that it\'s a tool for providing a common basis for the
> purposes of comparison. So we\'re interested in references because it
> allows us to compare as opposed to a standard which then involves a
> judgment. So here we\'re talking about making a reference, and during
> the early 1990s, both the U.S., in preparation for the revision of the
> U.S. reference, and also WHO examined the current reference which was
> being used in both the U.S. and internationally. And the sample that
> had been used for the early infancy especially was from Fels, which
> was one particular place in Ohio. The measurements were taken every
> three months, and in the very early period we might wish for more than
> that.
>
> There were very few infants that were breast-fed for an extended
> period of time, and at the time that this reference was made, there
> simply wasn\'t the technology to do curve-fitting that we now have.
>
> So those reasons, plus the main factor that the breast-fed infants
> seemed to grow differently than infants who were not necessarily
> breast-fed according to feeding recommendations, drove the decision to
> make a new reference.
>
> At the time the WHO feeding recommendation was that infants should be
> breast-fed exclusively from birth up to about four to six months, and
> then after that they should continue to be breast-fed for up to two
> years or beyond. You may know that WHO recently\--I guess about a year
> and a half ago\--revised this to be from birth to about six months for
> exclusive breast feeding.
>
> So the objective of the Multi-center Growth Reference Study that WHO
> is doing is to build a set of growth curves for all children under age
> 5 years to be adopted as a new international reference for assessing
> the growth and nutritional status at both the population and
> individual level.
>
> When this effort was started, it was clear that there were a couple of
> conceptual issues that needed to be thought through. One was that some
> references have been constructed, especially, for example, in the U.S.
> or in England, to take two examples, have been constructed to be
> descriptive references, meaning that they were intended to describe
> the growth of the population at a particular time.
>
> This is different than what\'s going on in the Growth Reference Study,
> the WHO Multi-center Growth Reference Study, which we can think of as
> perhaps a prescriptive reference, meaning that it\'s meant to be a
> reference that depicts the growth of infants who were fed according to
> current recommendations for how children should be cared for during
> infancy.
>
> The other issue had to do with maximal growth versus optimal growth.
> In the past, we\'ve had a tendency to think that maximal growth and
> optimal growth are the same thing. The graphs I just showed you
> indicate that when infants are breast-fed, at least during the first
> year, and perhaps into part of the second year, they are not the
> maximum size they would be if they were breast-fed, but we think that
> because they\'re fed following feeding recommendations that that
> corresponds to optimal growth.
>
> So the design of the study involves multiple geographically diverse
> sites. There\'s a longitudinal component which goes from zero to 24
> months. And each site was asked to recruit about 300 infants per site
> in the hopes that at least 70 would be available for inclusion in the
> final reference. We\'ve actually done better than that because the
> compliance with the feeding recommendations by the mothers and infants
> has been much higher than the 25 percent that we feared might be
> there. So we\'ve actually ended up with quite a bit more than 70
> percent. And then very frequent measurements, I\'ll show in a minute,
> and then there\'s a cross-sectional component which overlaps the
> longitudinal component. It starts at 18 months, goes up to 71 months,
> past 5 years, to make sure we have enough data on the right-hand side
> to be able to characterize growth well up to at least 5 years. And
> sites were asked to recruit about 1,400 per site, which, again, would
> give a minimum at each age of about 70.
>
> In the longitudinal component, which is a very demanding part of this
> study, measures of weight, length, and head circumference are
> collected frequently during the time. At birth, there\'s one visit, of
> course, and then in months 1 to 2 they\'re biweekly. So there\'s four
> visits there. In months 3 to 12, measurements are monthly, so there\'s
> 10 visits for that. And then in roughly the second year, they\'re
> bimonthly, which is six visits during that time. And then arm
> circumference and skinfold measurements are also taken in the same
> schedule, starting at 3 months, as in the other measurements.
>
> Now, the way the study was constructed, there were a set of criteria
> at the population level and then a set of criteria at the individual
> level. So at the population level, the idea was to find populations of
> infants who did not have socioeconomic constraints on growth, where
> mobility would be low so that they could be followed, where at least
> 20 percent were willing and able to follow the WHO feedings
> recommendations, with support, so there had to be existence of or at
> least the ability to build breast-feeding support systems; and then
> there had to be local presence of collaborative institutions who were
> capable of carrying out this kind of exacting work.
>
> Then at the individual level, individual criteria were set that there
> was an absence of health, environmental, economic constraints on
> growth; the mother was willing to follow the WHO feeding
> recommendations; that the mother was a non-smoker; that gestational
> age would be at term, which we defined to be 37 to 42 weeks; and that
> the infants wouldn\'t have any severe illnesses that would be expected
> to affect growth.
>
> The protocol for the study site selection then applied to
> subpopulations the fact that socioeconomic status did not constrain
> growth, it was low altitude, low mobility, the minimum of the 20
> percent, existence of breast-feeding support systems, the local
> institutions. We looked at the rate of hospital deliveries because we
> had to know that there were enough infants being produced quickly
> enough that they could be enrolled in the study so we could get the
> study done sometime in our lifetime; that there would be sufficient
> numbers of eligible birth; and that it was feasible within those
> locations.
>
> In some places, for example, in a really huge city of 10 million,
> it\'s just not feasible to do a study like this. The logistics are too
> difficult.
>
> The Steering Committee also considered some other factors in its
> thinking about in looking at mean birth weights, maternal heights,
> complementary feeding practices, health-related behaviors, and the
> existence of environmental hazards. The Steering Committee looked at
> geographic distribution. It\'s a global reference, so WHO tried very
> hard to have geographic representation throughout the world, and
> funding issues, because it\'s expensive to do this kind of study and
> we had to think about where the funding would come from and how that
> could be arranged.
>
> The protocol was developed by this set of characters here. The main
> reason I put it up here is to show you that it\'s a multidisciplinary
> set of people representing a diversity of backgrounds and
> institutional relationships. So this group put together the protocol
> roughly in the \'95, \'96 time frame. And then the study is being run
> now with an advisory group: Cameron Chumlea, Tim Cole, myself; Ray
> Martorell is the Chair of this group; John Van den Broeck, who
> recently moved to South Africa; senior scientists representing CDC and
> UNICEF, previously was Roger Shrimpton in UNICEF; and then WHO, the
> day-to-day work gets done at the sites and at WHO Secretariat.
> Mercedes de Onez coordinates all of this with her staff there. A very
> dedicated group of people.
>
> The sites that have been selected are the following: in Pelotas,
> Brazil, in the south part of Brazil near the coast; Victoria is the PI
> with Cora Post; in Oslo, Norway; in the U.S. at Davis; in Muscat,
> Oman; in Accra, Ghana, the capital of Ghana; and in New Delhi, India.
> These are the six sites. Each of these sites represents very differing
> and very large challenges to carrying out this study. And it couldn\'t
> be done without the commitment of the teams there who are doing the
> work on the ground.
>
> The Steering Committee is chaired by Cutberto Garza representing UNU.
> Data management is done by local data entry and checking at the local,
> each site, and then the data are shipped to the WHO Human Reproductive
> Program. They have extensive experience in handling large,
> multi-country data sets, and they\'ve done a fantastic job in
> coordinating all of this and in helping to ensure data quality.
>
> The decisions and information about the study, there was a working
> group on the growth reference protocol. We have Steering Committee and
> Advisory Committee meetings periodically, other meetings. Particular
> tasks are handled by other meetings. We do a lot through electronic
> mail. Various site visits are made, were made before the study started
> in preparatory work and are made throughout the study, and rapid
> surveys were done at the beginning to get information that was needed
> to actually do the planning for the data collection in the particular
> sites.
>
> To give you an idea of what\'s involved, I just made a list here of
> sort of the documentation that\'s been produced, which will give you a
> feel for what was necessary to carry this off at the level of
> scientific quality that was being strived for. The protocol was
> developed, a measurement of standardization protocol was developed. A
> manual of operations, a generic manual of operations was produced, and
> each site had to adapt that for its particular location.
>
> There was a protocol for the 12-month visit. A special effort was made
> throughout this study on the epidemiological quality of the study to
> follow all infants. Even if mothers wanted to drop out or weren\'t
> complying, an effort was made to follow them as much as possible so we
> could keep measurements for every infant even if they weren\'t exactly
> following the feeding recommendations.
>
> In particular, we had an effort made that at 12 months we could go out
> and get at least some measurements on all those who were not willing
> to continue.
>
> There were guidelines for complementary feeding. A protocol was
> developed for assessing diet, for the cross-sectional study, for data
> management, and then questionnaires were produced for both the
> longitudinal and the cross-sectional study. And if any of you have
> been involved in questionnaire production, you can imagine what those
> meetings were like as people argued about the exact wording of every
> question and every answer.
>
> So that\'s an overview of the study. Basically where we are now is
> that the last site\--the sites have been selected over time. Some were
> able to start earlier than others. Some had technical challenges that
> took longer than others. So in the next few months we\'ll be finished
> with data collection. There\'s a meeting coming up to look at and try
> to decide on the final methodology for analysis. Some preliminary work
> is underway. So this will be proceeding, and we\'re talking about
> having a reference be available in the 2005 year.
>
> There\'s a lot of work that needs to be done in order to prepare for
> not just producing the reference but preparing for how it will be
> depicted and how it will be used and testing that will have to be done
> with the reference under the auspices of WHO.
>
> DR. GARZA: We have about five minutes left for questions. We might be
> able to go over.
>
> Dr. Stallings?
>
> DR. STALLINGS: Well, one, to compliment the group. This is an
> extraordinary effort and an extraordinary study. But to cut to the
> chase, do you think that we will see this used in the U.S. as the
> growth standard for infancy through 5 years or even infancy through 3
> years with what we think of now as our traditional infant chart? So
> I\'d be interested in your opinion and certainly in relation to what
> we\'re here for, which is to start to understand the best comparison
> group for children in the U.S. who are taking infant formula.
>
> DR. FRONGILLO: Okay. Well, I think I\'ll probably not try to answer
> your question so directly. Let me just say that I think the advantages
> of this reference will be that it\'s longitudinal, that the
> longitudinal data in the first couple of years will have the ability
> to look at\--to have a reference, a velocity reference, and so a
> judgment will have to be made whether that\'s better than, for
> example, the Iowa/Fels data that are available.
>
> The second thing is that we know that infants who are fed following
> the breast-feeding recommendations will show a different pattern of
> growth than formula-fed infants. So to the extent to which it\'s seen
> as desirable to have a reference which fits that growth pattern for
> infants who are being breast-fed, then I think that would certainly be
> the advantage of the new reference.
>
> DR. GARZA: It may be useful to describe the references that are going
> to be available. Is it just weight and length, or are there others?
>
> DR. FRONGILLO: Well, those reference data will be available for all of
> the measures that I showed, so we will have data on weight and length,
> head circumference, arm circumference, and skinfolds.
>
> DR. GARZA: Any other questions?
>
> DR. THUREEN: Why did you choose to include skinfold measurements, and
> what kind of information did you hope to get from that?
>
> DR. FRONGILLO: Well, I think that there was a debate about, you know,
> the importance of this and when it should be started, and I think the
> lack of reference data on skinfolds was very compelling and it was
> thought that, given the potential usefulness of that information in
> the future, that while a study of this effort was\--while this large
> effort was being made, it would be important to have that kind of
> information available.
>
> DR. GARZA: Dr. Baker?
>
> DR. BAKER: I have a question about the prescriptive nature of this. If
> you\'re going to do a study like this using a prescription, it assumes
> the prescription is right. It also assumes that it also would change,
> presumably, if the prescription changed.
>
> Now, the WHO has changed it since this study was done. Does that make
> a difference?
>
> DR. FRONGILLO: Well, certainly we thought about this a lot during the
> time in which the study was being planned. I don\'t think anyone
> imagined that the basic recommendation about breast feeding and
> complementary feeding is going to change appreciably, and at least not
> for quite some time.
>
> Now, if it does, one of the things we wanted to do and part of the
> reason for the intensive follow-up even for infants who didn\'t
> exactly follow the current feeding recommendation was that it allows
> us to have the information available so that if 15 years from now we
> have new knowledge and decide that some slight revision of the feeding
> recommendation is made, anybody who\'s ever thought about changing the
> feeding recommendation will run after that possibility.
>
> But, anyway, if anybody gets brave enough to try to do that, we will
> have the information available from the cohorts in the six sites so
> that one could conceivably reconstruct the reference to conform with
> that.
>
> DR. GARZA: Yes?
>
> DR. DOWNER: Have you decided exactly which tool you will be using to
> do the skinfold measures? And my second question is: Because what we
> consider SES for different world populations differ so widely, how are
> you going to decide on what to use in this study?
>
> DR. FRONGILLO: Okay. The skinfolds, which tool, do you mean which
> skinfold caliper? Basically I think\--and Cameron can comment on this
> because he\'s the expert here. But my experience is that it\'s not the
> caliper that makes much\--any difference at all in the measurement.
> It\'s the quality of the enumerator and their training in using the
> instrument. So that\'s not going to make any difference.
>
> DR. DOWNER: What instrument have you planned on using?
>
> DR. FRONGILLO: The instrument we are using is\--what is the instrument
> we\'re using? Holtain, right. Okay.
>
> And the second question? I\'m sorry.
>
> DR. DOWNER: The SES.
>
> DR. FRONGILLO: Oh, the SES. In each site, a survey was done before the
> study began, the main study began, to actually look at the
> relationship between socioeconomic status and growth so that we could
> develop in each site exactly what the criteria needed to be from a
> socioeconomic standpoint in order to ensure that the population of
> infants selected was at high enough SES to not constrain growth. So
> that was done separately in each of the sites, and some of us traveled
> around to different sites to help them actually carry that out. And
> you\'re right, in each site different criteria were needed because the
> conditions were different.
>
> DR. GARZA: Any other questions?
>
> \[No response.\]
>
> DR. GARZA: All right. Thank you very much.
>
> We\'ll move on then to Dr. Larry Grummer-Strawn, who is the branch
> chief of the Maternal and Child Nutrition Branch at CDC, and he will
> tell us about the NCHS/CDC\'s growth charts.
>
> DR. GRUMMER-STRAWN: Good morning. If we can figure out how to forward
> this? Which one? Just here? Okay. Thank you.
>
> This morning I want to give kind of an overview of the new growth
> charts and contrast them to the old NCHS growth charts. I\'m going to
> start off with kind of a historical perspective. I\'m sure many of you
> know the history but to kind of just set a context for all of us, do
> some comparisons of differences and similarities between the old and
> the new, and then go into some of the differences a little bit more
> explicitly, and then finally end with some analytic issues that the
> charts pose for us.
>
> The original NCHS charts were released in 1977. Those charts were only
> percentile curves. They were published by Hamill, et al., really
> became the standard of reference for all U.S. infants.
>
> Subsequent to that, there was a normalization of those curves at CDC.
> Those were actually published in 1987, but were actually available for
> use long before that. So people who were interested in normalized
> curves had access to them earlier. And, finally, the WHO adopted those
> curves as being the international reference, really referring to the
> normalized curves. The adoption by WHO actually came prior to the
> publication of the normalized curves.
>
> The reason that I point this out is that those curves never became one
> and the same. The percentile curves never matched with the normalized
> curves, and so someone who was using clinical charts that actually saw
> the graphs in front of them was not necessarily using the same cut-off
> points as someone who was using computer software or might be
> analyzing data sets. They were very similar to one another. They were
> analyzed off of the same data, but were slightly different from each
> other. And then, finally, in May of 2000, CDC released a revision to
> these charts.
>
> Now, at the time that the original charts were created, NCHS was a
> separate agency, and so they were referred to as the NCHS Growth
> Reference. When people talked about the normalized curves and put them
> in an international context, they might have referred to the
> NCHS/CDC/WHO because of the separate role each of those agencies
> played.
>
> Subsequent to 1977, NCHS was actually incorporated into CDC, and so
> the new charts are referred to as CDC charts. That does not mean that
> NCHS was not an active player. They actually were the progenitors that
> moved the new charts forward. But it was in a larger context of CDC,
> and other parts of CDC were also involved.
>
> So what are some of the similarities? First of all, both sets of
> charts are looking at the same indicators. We have weight-for-age,
> length-for-age, weight-for-length and head circumference-for age. Both
> sets are sex-specific. In neither case did we have any separation
> according to the parental anthropometry, race, ethnicity, infant
> feeding mode, different things that might impact on the growth of the
> infants.
>
> Ed just described for us kind of the difference between the idea of a
> reference and a standard or a descriptive reference and a prescriptive
> reference. These clearly are references, not standards. The only kind
> of movement toward a standard is that very low birth weight infants,
> that is, less than 1,500 grams, were not included in the new charts,
> the CDC 2000 charts.
>
> These charts reflect attained size, not incremental growth, and in
> both cases, we have accessibility of percentile scores and z-scores.
> In the new charts, the z-scores are one and the same.
>
> The differences between the old and the new are, first of all, that in
> the 2000 charts, the data for infants are now nationally
> representative. These represent a broader spectrum of race and
> ethnicity across the United States, a broader spectrum of
> socioeconomic status, and there\'s an increased representation of
> breast feeding in the charts. That doesn\'t mean that they are
> primarily breast-fed children, but there\'s a mixture of formula-fed
> and breast-fed children.
>
> The 2000 charts are based on a pooling of several data sets coming
> together, whereas the 1977 NCHS charts were all based on the Fels data
> set.
>
> There were some minor changes to the smoothing techniques, which I
> will mention briefly. As I said, the z-scores now are one and the same
> as the percentiles. There\'s a one-to-one match on those, so it
> doesn\'t matter whether you use computer software or you\'re using
> printed charts. You\'re going to be looking at the exact same cutoffs.
>
> Another minor difference is that the length now extends down to 45
> centimeters rather than 49 centimeters when we\'re looking at
> weight-for-length, and when ow have on the clinical charts the
> accessibility of 3rd and 97th centiles. Of course, based on normalized
> curves, you can get any kind of centile that you\'re interested in,
> but the difference is that the clinical charts that are produced
> actually do extend out to the 3rd and 97th percentiles, and the
> smoothing-out rhythm is intentionally extended out to those centiles
> to make sure that we\'re incorporating the original data out that far.
> And, finally, as I mentioned before, very low birth weight infants are
> excluded.
>
> So what are the data sources? Well, in 1977, I\'m sure you\'re all
> familiar with the Fels Research Institute study. It was done in Yellow
> Springs, Ohio, primarily represented Caucasian, middle-class families.
> And while not exclusively formula-fed, this group is considered to be
> almost all formula-fed infants.
>
> There was a longitudinal follow-up study. The children were followed
> from birth, 1 month, 3 months, 6 months, and at three-month intervals
> after that, but we\'re focusing on the first 6 months today. The data
> were collected between 1929 and 1975, and there were a total of 867
> infants.
>
> Now, the data for the CDC 2000 curves, as I said, represents a number
> of different data sources. What I\'ve put up here is a graphic showing
> you how at different ages, different data sets come in. I\'m going to
> talk about kind of these different data sets at different points.
>
> The primary data source is the NHANES III data here when we\'re
> talking about children birth to 6 months of age.
>
> Now, this is represented by the long line here in light blue. The
> NHANES III was the only data set for which we had nationally
> representative data prior to 6 months of age. Starting at 6 months,
> the NHANES II data were also available, and starting at 12 months the
> NHANES I data were also available.
>
> Now, the reason that these are important for us today is that because
> we\'re smoothing these curves across age, the influence of those older
> data sets does come in at 6 months of age and at 12 months of age. The
> smoothing is across all ages, and so the curves below 6 months are
> also affected by those other data.
>
> However, the NHANES III data started at 2 months of age, and among
> 2-month-olds, it was a fairly small sample size. In order to extend
> these curves down to birth, we had to look to other data sets. And in
> each case, whether we\'re talking about head circumference-for-age,
> length-for-age, weight-for-age, weight-for-length, in each case we
> have to turn to different data sources.
>
> I\'m going to start in the middle here to talk about in the
> weight-for-age. In this case, it was fairly straightforward to use a
> birth point coming from the national birth certificates. We had all of
> the birth certificates during the years that the children in these
> NHANES surveys had been born and had the birth weights available on
> all of those. So it\'s a huge sample size, a very precise point that
> is truly not only nationally representative but a census of all births
> in the United States. And so in creating the curves, we were able to
> connect that particular point, actually anchored the curves to that
> point, and then smoothed it with the data starting at 2 months of age
> from the NHANES.
>
> However, we don\'t have national data on any of the other indicators,
> head circumference or length. With regard to length, we did find that
> there were two states that routinely collect length data at birth in a
> representative fashion. We analyzed the data in those states for their
> birth weights against the national birth weight distribution and found
> that they were quite representative\--those states were Missouri and
> Wisconsin\--and felt that because the birth weight distribution
> matched the national distribution, we could expect that they should
> represent the national birth length distribution, even though we do
> not have data on the national birth length.
>
> So when we looked at the weight-for-length curves, those are based on
> connecting the dots between the Missouri and Wisconsin data on
> weight-for-length versus the NHANES III data weight-for-length, and
> those curves were connected together.
>
> Initially, we intended to do the exact same thing with length-for-age,
> use only the data from Missouri and Wisconsin to connect these curves
> across age and with the NHANES III data. We did that in our first pass
> but analyzed\--as we were evaluating the curves against alternative
> data sets, we found that we were comparing against the Chicago data
> set, the WHO pooled data set that Ed just described for us, as well as
> some of CDC\'s surveillance data, and found a common pattern in all
> three of those that the curvature between birth and 6 months did not
> match what we found in external data sets and felt that this was
> partly an artifact of the fact that we only had about 35 infants from
> the NHANES III data that clearly were not matching the normal pattern
> of growth. And so the curves were being pulled in the direction of
> those NHANES III data from a very small sample size.
>
> So what we opted to do was to choose an additional data set to add in
> here between just beyond birth\--these were not birth points, but at
> the first visit to a clinic\--up through 5 months of age from the
> CDC\'s Pediatric Nutrition Surveillance System.
>
> These are data on low-income infants. However, we didn\'t use a
> representative sample of low-income infants. Instead, what we did is
> we chose clinics that matched the national distribution in terms of
> their mean, standard deviation, and skewness at each age from
> birth\--from 3 months of age through 11 months of age compared to the
> NHANES III data. So we were pulling out clinics that the children in
> that clinic happened to look exactly like the national distribution
> and chose those clinics and assumed that they would also look like the
> national distribution would have looked between birth and 3 months,
> and then added those data to the curves here and connected using the
> Missouri and Wisconsin data, the CDC nutrition surveillance data, as
> well as the NHANES III, and continued the curves using that.
>
> Finally, for head circumference, we had no national data, and we
> returned once again to the Fels Institute data for the head
> circumference at birth point and, again, connected that with the
> NHANES III data.
>
> So you see the picture here is one of bringing together multiple data
> sets. We had a number of comparisons to try and make sure that these
> were valid comparisons to make, but it certainly leaves us with a
> difficulty using multiple data.
>
> So what are some of the other differences? First, with regard to the
> smoothing, the old curves were smoothed with cubic splines, with knots
> at birth, 6 months, and 18 months, for those of you who work on these
> statistical arenas. What that meant for us was that there were six
> independent parameters that characterized growth between birth and 3
> years of age.
>
> In the CDC 2000, a completely different approach to smoothing was
> applied. Here we used fractional polynomials that had been used
> previously in other growth studies, primarily used in the Fels data as
> well as some Canadian data. And so they had kind of been proven
> methodologies for assessing growth during the first three years of
> life. However, there were a smaller number of parameters that
> described growth, really just three independent parameters\--roughly
> three, because there were some other things that were done to the
> curves to get them to fit.
>
> Finally, on weight-for-length, there were no set models, and so we
> used a 5th degree polynomial to maximize the flexibility of the curves
> there.
>
> I mentioned before that in 1977 the standard deviations were estimated
> as a separate path and created a separate set of curves. In that case,
> we had two different standard deviations. There was a standard
> deviation above the median and a standard deviation below the median.
> And so if you think about kind of plotting the standard deviation as
> it goes across the curve, it was a low standard deviation that
> instantaneously at the median rose to a higher level.
>
> We calculated these scores in the normal way, taking the measure minus
> the median divided by the standard deviation.
>
> In the CDC 2000, this kind of immediate change in the standard
> deviation at the median was thought to not be desirable, and so
> instead we had a more continuous change in the standard deviation. In
> this case, we transformed the data with a Box-Cox transformation, a
> power transformation. People understand how you take the log
> transformation of a data set or a square root transformation. The
> Box-Cox is a continuous set of transformations that you can then
> choose a parameter to say how much you want to transform that data to
> make it symmetrical. And then once it is symmetrical, you can fit
> parameters to normalize that curve.
>
> Some other differences, clearly this group would be interested in the
> differences between the infant feeding in the groups. As I mentioned
> before, the old charts were virtually all formula-fed infants. The
> quality of the infant formula across that time, of course, has
> changed, so it is a mixture of a number of different kinds of feeding
> across those year \'29 through \'75.
>
> In the CDC 2000, we have a mixture of breast feeding and formula
> feeding, but it still is primarily a formula-fed group. At 2 months of
> age, about half were formula-fed, half breast-fed, but by 6 months of
> age that was down to 28 percent currently being breast-fed. And we\'re
> not talking about exclusive breast feeding. As you can see, the
> exclusive breast-feeding rates are much lower than that. Down to less
> than 10 percent by 6 months of age were exclusively breast-fed.
>
> If I can just take a couple of minutes to show you a comparison
> between the old and the new curves with regard to breast feeding, and
> we\'ll stop there, Ed showed a number of things as to how the old
> curves performed against WHO pooled breast-feeding data set. We did
> some additional comparisons seeing whether the new curves have
> actually improved that situation. So we\'ve compared the WHO pooled
> data set that came together from six different studies of exclusively
> breast-fed children and pooled those data together. And instead of
> plotting the means, which is what Ed was showing us, here I\'m going
> to show the percent below the 10th percentile using the old curves
> versus the new curves.
>
> When we\'re looking at weight-for-age, you can see that there really
> has not been much of a change between the old curves and the new
> curves. We have this same problem that as children get older, we\'re
> going to diagnose more of them as being underweight. Just as Ed was
> showing us that the means go down, the percent that would be low is
> going to get higher. And we still have that problem with the new
> curves, that it is considerably\--we would have considerably more
> older children being considered underweight in this breast-fed data
> set compared to the younger children.
>
> However, with regard to height for age, we\'ve improved the situation
> somewhat. With the newer curves, there still is a tendency toward
> increasing the percentage that would be considered low as we get to
> older infants, but it\'s not as steep a trend as we had with the older
> curves.
>
> And, finally, with regard to weight-for-height, whereas the old curves
> showed that same pattern of worsening nutritional status over the
> first year of life, on weight-for-height the new curves have pretty
> much wiped out that problem. We see a much flatter distribution across
> age.
>
> I\'m going to skip over these because Ed is going to come back to many
> of these points in his description of the analytic issues.
>
> Conclusion: The interpretation of the new charts is really not widely
> different from the old charts. We\'re still using the same kind of way
> of thinking about growth and the way we analyze growth as very similar
> in the old curves to the new curves.
>
> There are a number of enhancements that argue for changing over to the
> new curves. I\'m not arguing that we haven\'t made enough of a
> difference to adopt these new curves. However, I do think that the WHO
> reference that Ed has described would relate to a more substantive
> change in our interpretation of growth parameters, and we really need
> to give much more thought to different ways of thinking about growth
> than we have so far.
>
> Thank you.
>
> DR. GARZA: Thank you very much, Larry.
>
> Any questions? Dr. Stallings?
>
> DR. STALLINGS: I actually have a series of questions, lots of things
> jotted down. One, also, thank you and your team for doing this. It was
> a monumental change to give us this from the clinical point of view.
> It\'s wonderful to have the charts revised.
>
> In that last set of slides where you were showing the less than 10th
> percentile, just so I\'m thinking about it correctly, the perfect
> outcome would be 10 percent would be less than the 10th percentile,
> because if we were looking at a population study, would you by
> definition expect 10 percent to be less than the 10th percentile?
>
> DR. GRUMMER-STRAWN: Yes. What I\'m more concerned about is the pattern
> of growth there than the actual level. We\'re comparing curves that
> are based on formula-fed infants mixed with some breast-fed infants
> against a group of breast-fed infants. And so I wouldn\'t have been
> surprised if the level was somewhat different in a group of breast-fed
> children that might have less malnutrition than a general U.S.
> population. But I would expect the pattern should be representative of
> the pattern of growth.
>
> DR. STALLINGS: But, still, when I was looking at it, when there was
> almost zero less than the 10th percentile, I saw that as unusual as
> when we have 20 percent less than the 10th percentile, that that\'s
> sort of the concept. If we were getting\--whatever right is, but if we
> were getting it right, the population would go along that.
>
> While we have all the experts in the room, we\'ve heard three
> different people say three different things about whether the Fels
> data included a lot of breast feeding or not. And before you guys
> leave today or tomorrow, I\'d like that to be readdressed. You know,
> you were very helpful in showing in your slide the percentage of
> children who were breast-fed and then exclusive, and so obviously
> it\'s not one number. Where you are at 2 weeks of age is different
> from 6 months. But I think it would be helpful for the committee and
> for the FDA to have an understanding of what we believe the Fels data
> represented as exposure to breast feeding and what you believe your
> 2000 charts represent. This is\--
>
> DR. GRUMMER-STRAWN: I\'d like to have that, too, because I
> certainly\--
>
> DR. STALLINGS: Okay. Well, then, you guys aren\'t leaving until we get
> this right.
>
> \[Laughter.\]
>
> DR. STALLINGS: The other part of that is I think getting a handle on
> that will be even more important as the WHO new charts come out and
> those data are there.
>
> My last question, which really is a question, is: If I understand,
> then breast-fed babies grow faster during the first 4 months of life
> compared to our usual reference data and more slowly between 4 and 6
> months, if we were to look at the zero to 6-month period that we\'re
> really supposed to be focusing on.
>
> DR. GRUMMER-STRAWN: I think it\'s more like around 3. Is that about
> the peak? Three months of age. So faster in the first 3 months of life
> and slower after.
>
> DR. STALLINGS: So that\'s part of the pattern that we\'re trying to
> capture that has made individuals difficult to look at.
>
> Thank you.
>
> DR. GARZA: Any other questions?
>
> \[No response.\]
>
> DR. GARZA: I have two. In thinking through the reasons why the WHO
> took more frequent weight measurements, one of the principal things
> that drove that was that very often the pattern of growth was used to
> assess the nutritional management of infants, the first 3 to 6 months.
>
> To what degree can the present reference between used with that amount
> of detail, the first 3 to 6 months? Were the smoothing techniques in
> your judgment sufficient to capture the differences in growth patterns
> that Ginanne just described? Or did the smoothing eliminate much of
> that?
>
> DR. GRUMMER-STRAWN: First of all, you have the whole difficulty of
> dealing with the cross-sectional data as opposed to longitudinal data.
>
> DR. GARZA: I know. That was Part B to 1.
>
> \[Laughter.\]
>
> DR. GRUMMER-STRAWN: So all of those issues come in there. You have not
> a very large sample size in that age range, and so there is a fair
> amount of noise.
>
> In addition to that, you\'re fitting basically a three-parameter model
> to the first three years of life. That doesn\'t give you a whole lot
> of degrees of freedom to really let that first few months take on a
> particular shape.
>
> That said, we did examine what the curves were doing in that age
> range, and they looked like they fit fairly well. But there\'s a large
> amount of noise in the cross-sectional data that bounces from month to
> month, and you look at the curves and say, you know, I think we did
> the best we can given the data that we have.
>
> So I don\'t want to blame the three-parameter model, but I would say
> that if one had better data and wanted to capture really what is the
> pattern of growth in the first year of life, I probably would not do
> the smoothing in the way that it was done.
>
> DR. GARZA: And the second, since you answered Part B of 1, we\'ve been
> asked to look at various control groups, either historical or using
> specific references as controls in clinical studies. You also make the
> distinction between standards and reference. To what degree can, in
> fact, one use the present reference in making judgments, value
> judgments for clinical studies and making comparisons between feeding
> groups that might be placed on new formulas and the current CDC
> reference? Is it sufficiently robust to be used as a standard in
> making that clinical judgment that control groups normally play in
> clinical studies?
>
> DR. GRUMMER-STRAWN: I think the question is one of what do you want to
> compare to. What is right? In comparing to these curves, you are
> implicitly saying I am comparing this child\'s growth or this group of
> formula-fed infants\' growth to the way children have grown in the
> United States essentially over the last 10 years, maybe 15 years. Are
> you comfortable with that kind of a comparison?
>
> You would say based on formula\--in assessing a formula, you are
> saying this particular formula that we are evaluating generates a
> pattern of growth similar to the way children grow in the United
> States, whether they are formula-fed or breast-fed, fed on all kinds
> of different formulas, mixtures of solid feedings coming in at various
> ages. If you are comfortable with that kind of a comparison, this
> formula produces a pattern of growth like children in the United
> States, like a cross-section of all the children in the United States,
> then I say yes, this is a perfectly fine comparison to make.
>
> If you want more of a prescriptive statement that this formula
> produces a pattern of growth that is the most healthy, I don\'t think
> that you can say that. I don\'t think that we can infer that a
> cross-section of infants from the United States with all of the
> variety of primarily infant feeding patterns\--there are also
> varieties in terms of socioeconomic status, the kinds of conditions
> children are running up against. I think that in terms of the impact
> of those on these curves, those are not as great. But the variation in
> feeding patterns, I don\'t think that we can say that we have the best
> pattern of growth here.
>
> DR. GARZA: Any other questions?
>
> \[No response.\]
>
> DR. GARZA: Thank you again.
>
> We\'ll move on to the next paper. I don\'t think Dr. Fomon needs an
> introduction. I can\'t think of a more senior person in pediatric
> nutrition than Dr. Fomon, and I\'m very pleased that he was able to
> join us today and was willing to leave lovely Texas for Washington for
> this purpose, from one native Texan at least. And he will be
> addressing the Iowa data and the Iowa/Fels growth data.
>
> Thank you very much for joining us, Dr. Fomon.
>
> DR. FOMON: As the most senior member of the presenters, I\'d like to
> make a statement for the presenters that we were asked to prepare a
> 20-minutes presentation, and if we run over and get the zero sign at
> 15 minutes, we\'re not very apologetic.
>
> \[Laughter.\]
>
> DR. FOMON: First I want to get out of the way what are the Iowa data
> and what are the Fels data, and then we can talk about more
> interesting things. The Iowa and the Iowa Fels data, Iowa Fels data is
> published by Guo, et al. Term infants measurements all made with
> highly quality controlled efforts. Caucasian, we were able\--and I
> will show you that\--no, but it\'s in my paper\--that the length and
> weight of the Fels and the Iowa series were very similar at three
> months, which gave us some encouragement in combining them.
>
> Iowa data. There are other Iowa data, but I wanted to first speak
> about 8 to 112 days. These were all formula fed infants, 380 males,
> 340 females, and mostly infants of upper socio status, but not
> necessarily economic, because they were mostly UI personnel,
> University of Iowa faculty and students.
>
> They were measured within 4 days of 8, 14, 28, 42, 56, 84 and 112
> days. No exceptions. And the age of measurement by interpolation or
> extrapolation was made to the target age. So we adjusted if a baby was
> measured at 16 days. We used the 28, 16 and 8-day measurements to
> compute a 14-day measurement. It was fully longitudinal. There is no
> one of those 380 males or 340 females who was not measured at every
> time. This is published, so you can read about it in books.
>
> Then we did also measure a number of infants from 112 to 196 days of
> age, and they were 165 males, 188 females, and there was a subsample
> of these that were also in the other group that I talked about. There
> were 63 males and 74 females who went from 8 to 196 days. We have many
> more now, but it\'s too expensive to do the analysis.
>
> The Fels data, there are a lot of Fels data. The Fels data that I\'m
> talking about are the Fels data that are included in the Guo, et al.
> paper, and that included 240 males and 236 females, wide range of
> socioeconomic status, few measurements during the first 3 months. The
> target ages were 1, 3, 6, 9, 12, 18 and 24 months. Most of the
> children were measured within 3 weeks of the target ages, and there
> were some missed points, and they arrived at these ages by mathematic
> curve fitting. And there are other people who know a lot more about
> that here than I know.
>
> So the Iowa Fels data, we ignored the Fels data during the first 3
> months, so it doesn\'t matter whether they were breast fed or formula
> fed. There were, for the first 3 months, just Iowa data, 580 males and
> 562 females. The reason that\'s bigger than the numbers I showed you
> before was what I showed you before was formula fed. We included
> breast fed in this, and I\'ll tell you why.
>
> Then we used both Iowa and Fels data, having established that the Iowa
> Fels size at 3 months was very similar. We used both for 3 to 6 months
> of age, and then we used only Fels data for 6 to 24 months of age.
>
> So those are the Iowa data and the Iowa Fels data.
>
> The Iowa data and the Iowa Fels data and most other referenced data,
> except those for international comparisons, have been developed to
> detect abnormalities of infants, of individual infants, and to detect
> abnormalities of individual infants you have greatest interest in the
> outlying centiles. The more individuals you have, the more confidence
> you have in those outlying centiles. What you want is early detection
> of growth abnormalities. Growth will not tell you whether a child is
> normal or not, but it gives the most important single clue to telling
> you that that baby is one that needs closer attention than the general
> garden variety baby.
>
> And for that reason, weight gain is more important than length gain,
> and that\'s because it gives you this clue much earlier than change in
> length. I think I have that on the next slide. And you need data for
> at least the first 2 years. Iowa data are only good, up to at best,
> 196 days.
>
> I have to go back, but I don\'t know how to do that, so I\'ll tell you
> that\--can you go back? Just go on back.
>
> The weight gain is more important than length gain because as I said,
> weight gain gives you the clue earlier. Length gain is very difficult
> to measure accurately enough to be useful for determining changes in
> length the way it is done in hospitals, clinics and doctors\' offices.
> So length is not really a very feasible way, and moreover, there are
> very few instances in which length gain will be abnormal and weight
> gain normal. So weight is the most important thing.
>
> Now, when you evaluate an infant formula\--we didn\'t think about this
> until much after we published most of the Iowa growth data\--you have
> different criteria for what you need as reference data, and the
> characteristics are it should be longitudinal. It\'s difficult for me
> to agree that you can use cross-sectional data as a sensitive way of
> analyzing longitudinal data. If you\'re doing an infant formula study,
> you\'re examining how the infants grow over the period of study. For
> that you need longitudinal reference data. It should be gender
> specific. I haven\'t heard any argument about that.
>
> The study integral must include at least part of the neonatal growth
> spurt, should include all of it or most of it. Neonatal growth spurt
> is from 8 to 42, maybe 8 to 112 days of age. After 112 days of age
> growth rates are substantially less, and we\'ll come back to that. And
> you need length data as well as weight data because it is possible
> that you would find\--and I\'ll give you an example of this\--a
> situation in which babies would grow normally in weight or maybe super
> normally in weight, and the weight to length would be outside of what
> we see with usual infant formula, suggesting that maybe this formula
> is not fully adequate.
>
> The reference population should be similar to the study core, and
> that\'s always going to be a problem. It will never be exactly like
> the study core, but the question is, how close can you get and how
> close do you need to get?
>
> I missed the last one. If I knew how to use this, probably I\'d know
> how to use my camera too.
>
> \[Laughter.\]
>
> DR. FOMON: The duration of study should be at least 84 days. That\'s a
> new minimum length. I made up the old 3 months minimum length that\'s
> in the AAP report, and I didn\'t have any good basis for that, but I
> think that maybe you can agree to 84 days as well as you can agree to
> some slightly longer figure, and we\'ll come back to it.
>
> I said this. The most sensitive evaluation of the longitudinal growth
> study of a cohort in the longitudinal growth study requires
> longitudinal reference data. I don\'t say that this is gospel. It\'s
> just what I believe. Gains in weight and length are more rapid in
> infant males than in infant females. The formula may be adequate for
> females but not for males. Nobody\'s arguing about the gender anyway.
>
> The study integral must include at least part of the neonatal growth
> spurt. A formula may be adequate for older infants but not for younger
> infants. The reason is that during the period of most rapid growth the
> ratio of specific nutrient to energy is highest, and if you get beyond
> that period, the ratio of protein or calcium or whatever to energy may
> be down at a lower level. So if you start a study at 4 months and you
> get 4 or 5 months of additional data, the formula may be fine, but it
> doesn\'t tell you that it will be fine starting at 8 days or at birth.
>
> Here is an example. These are males, and this is weight gain from 8 to
> 56 days, and we did a study of a relatively low protein diet based on
> isolated soy protein with or without a methionine supplement. We were
> interested in getting a fix on the requirements for sulphur containing
> amino acids. And with the methionine supplement the gain was 42.3
> grams per day, and with no methionine supplement it was 38.8 grams per
> day. Compared to the reference data, 8 to 56 days, this was not
> significant and this was significant. From 56 to 112 days there was no
> difference.
>
> I wish I had 3 or 4 more studies to demonstrate this, but this
> suggests at least that you need to have an early portion where you
> have the maximum postnatal growth included in your evaluation of a
> formula. You need data on length as well as weight, and this was the
> best example. I think if I spent more time I could find more examples
> and then it would be more convincing, but I couldn\'t do that, because
> I had to work in my yard.
>
> \[Laughter.\]
>
> DR. FOMON: These are males and this is the BMI, and this is a
> low-protein formula and this is the reference. And at 8 days, when we
> enrolled them, the low-protein, the cohort receiving the low-protein
> formula had a BMI of 13. That was significantly less than the
> reference data. At 112 days the low-protein cohort had a BMI of 18.6
> which was significantly greater than the reference data. And all our
> data, including\--if you pardon my expression\--skinfolds, indicated
> that these babies were fat. And what we speculate is that they
> were\--and they took more volume. We, in all our studies, record how
> much the babies eat. We weigh the bottles in and the bottles out, and
> they took more energy in and they gained more weight, and we
> speculated that they ate more because of the low-protein content. They
> were eating\--I don\'t know how they knew how to do it\--but they were
> eating more to make up for the low-protein concentration in the diet.
> They got enough protein. They grew normally in length.
>
> The study cohort must be similar to the reference cohort. They should
> be healthy, that is they shouldn\'t include babies with illness. They
> should be term if what you want to know is, is your formula going to
> be adequate for term infants. You don\'t want to increase the noise in
> your experiment by adding preterm infants. And then the question of
> ethnicity, terribly important in international studies, may not be so
> important in the United States where you\'re comparing what seems to
> be similar groups, but that\'s a question that needs to be carefully
> examined for each study.
>
> So the duration of study should be at least 84 days. I think that 8 to
> 112 days, which is why our data are mostly 8 to 112 days, or 14 to 112
> days, almost as good I think. At 8 days, there are great advantages of
> 8 days. Most formula-fed babies have regained their birth weight. You
> can get a really good measurement of length at 8 days. You\'re not
> there to get it when the baby is born, and even if you are there, the
> hardest time to get an accurate measurement on a baby is at birth.
> Howard Meredith, many years ago, showed me some publications on how
> very hard it was to get an adequate length at birth.
>
> Now, I think that in the current U.S. climate, where you can hardly
> recruit any formula-fed babies before 42 days of age, which is still
> fairly easy, but you may be able to recruit them at 28 days. Later
> than 28 days you miss too much of the postnatal growth spurt. Earlier
> it\'s too hard to recruit, so maybe 28 days is the most feasible, and
> 28 to 112 is 84 days, and that\'s how I came to 84 days.
>
> Now, if I give you my recommendations to the FDA, straight out, no
> hedging, I would say that size data are not relevant. I mean I know
> half the people in the audience hate me. Size data are not relevant.
> Data over 6 months of age are not relevant. I\'m not even sure that
> data over 4 months of age are relevant. Breast-fed babies are not
> relevant, but that\'s not so serious because during the period we talk
> about they gain about the same. I just don\'t like to muddy up a study
> of formula-fed infants with a mixed group that I can control. And
> unless you have\--you must match the cohort with the reference group.
> If your reference group consists of term infants, then you can\'t
> muddy it up by including infants, preterm infants in any number that
> they might be present.
>
> So those are my messages and I\'m willing to take the flak because
> I\'ve done it before.
>
> DR. GARZA: Thank you very much, Dr. Fomon. I regret the
> miscommunication between FDA and the speakers. We\'ll try to get that
> resolved for you in terms of the 20 versus 15 minutes.
>
> Are there any questions? Dr. Anderson?
>
> DR. ANDERSON: Anderson. I understand that the Iowa Fels data are
> longitudinal data.
>
> DR. FOMON: Absolutely.
>
> DR. ANDERSON: And that the recently published CDC standard is largely
> from cross-sectional data.
>
> DR. FOMON: Absolutely.
>
> DR. ANDERSON: To what extent do the percentiles generated from the two
> sources differ in substantive ways?
>
> DR. FOMON: I don\'t know that offhand. I think from the point of view
> of infant formula evaluation, that it\'s not relevant because you
> can\'t get good analysis of longitudinal data from a cohort under
> study by comparing with size data. In 1976, just to prove my
> seniority, I had a dialogue with Peter Hamill \[ph\] over about 9
> months, trying to convince him to call the NCHS charts size charts so
> that people wouldn\'t be confused by thinking that they\'re growth
> charts, but I lost that argument.
>
> DR. GARZA: Dr. Stallings?
>
> DR. STALLINGS: Dr. Fomon, I\'m interested in your opinion of a couple
> things. One, the need for a control group, a contemporary control
> group when you\'re actually doing a study, you know, particularly for
> the kind of things we would be looking at, a change in formulation.
>
> And secondly, when you said that you thought the breast-fed baby
> didn\'t have any role in thinking about evaluation of formula-fed
> babies, I think rather than is breast feeding\--the growth pattern of
> breast-fed babies a pattern that should be strived for with
> formula-fed babies?
>
> DR. FOMON: Well, let\'s see, question number 1. Tell me question
> number 1 again.
>
> DR. STALLINGS: About a contemporary control group.
>
> DR. FOMON: I think there are circumstances under which a concurrent
> control is essential, and one was the study that I mentioned to you,
> where we had a formula, a low-protein formula fortified with
> methionine or not fortified with methionine. In that case we had to
> demonstrate that with methionine it maps the reference group. But I
> think in general it\'s probably not really essential if you have good
> reference data for comparison, don\'t think it\'s really essential to
> have a concurrent control. It greatly increase the number. The number
> that you need to compare one cohort with the reference data is
> considerably less than the number that you need if you\'re going to
> compare it with a concurrent control.
>
> So just from the practicality of making it possible at all to study
> new formulas, I think it\'s a reasonable compromise not to require a
> concurrent control unless something about the ingredient change or
> whatever suggests that a concurrent control would be valuable.
>
> And on the other question, should a cohort fed a new infant formula be
> compared to a breast fed control reference group, I think that\'s more
> a philosophic matter than a scientific matter, and my own conclusion
> is that if you want to study a new formula, you should study it in
> comparison with old formulas, and not with some group that we think
> might represent ideal growth. That\'s just what I think. Other people
> think other ways.
>
> DR. GARZA: Any other questions?
>
> \[No response.\]
>
> DR. GARZA: Thank you very much.
>
> It is 5 minutes to 12:00. We\'re going to try to make up the 20
> minutes from this afternoon\'s schedule because we\'ve been running a
> bit over time in the presentations, so that rather than coming back at
> 1:35 as the schedule suggests, I\'m going to ask people to come back
> at about 1:10. So that we can make sure we can started by that time,
> having everybody here at 1:00 o\'clock would be ideal. So we will ask
> the Committee to reconvene at 1:00 and we\'ll get started after that
> as possible.
>
> Lunch for the Committee and the speakers is in the room where you had
> coffee, and the cafeteria is available to everyone else. 1:00
> o\'clock.
>
> \[Whereupon, at 11:57 a.m., there was a luncheon recess.\]
>
> **A F T E R N O O N S E S S I O N**
>
> (1:07 p.m.)
>
> DR. GARZA: We can get started. Our next speaker\--can I have all our
> guests please take their seats? I think the Committee is at the table.
>
> Our next speaker is Dr. Jon Tyson, who is a professor of pediatrics,
> obstetrics, internal medicine and epidemiology at the University of
> Texas Medical School in Houston and the School of Public Health. Dr.
> Tyson will not be able to stay with us tomorrow, so I want to make
> sure that the Committee members ask all questions or clarify any
> outstanding issues that they might have related to the topic of growth
> data for preterm infants, because in fact Jon will be leaving soon
> after his presentation. So it\'s important that you try to get your
> questions to him before he returns to Houston.
>
> Jon, thank you very much for coming.
>
> DR. TYSON: Thank you very much.
>
> Well, as a neonatologist and epidemiologist, I\'m going to try to make
> the case today that if what you mean by normal growth is desirable or
> healthy growth, that the evaluation of early growth in preterm infants
> will necessarily involve evaluation of health and development. I\'m
> going to try to go through this in a orderly fashion to promote a
> rational and evidence-based decision making.
>
> The first question is: can the growth rate sustained by a new formula
> be adequately assessed using published growth norms?
>
> This is a growth curve from the Neonatal Research Network, observed
> rates of growth, are weight\--sizes, Dr. Fomon would say\--in babies
> according to their birth weight. Throughout their hospital stay there
> is serial information assessed. Also in length and head circumference
> and mid-arm circumference for these babies. There\'s no data for
> babies greater than 1,500 grams and no data beyond discharge. I would
> add that there in my little handout, there\'s a website that you can
> go to where you can, for an individual baby, enter the measurements at
> birth, and print out a growth curve for that particular baby.
>
> For preterm babies beyond discharge, this shows what I think is the
> best available data from the Infant Health and Development Program
> which had 985 preterm babies, and it provides data for 3 groups: 2,000
> to 2,500 grams, 1,250 to 2,000 grams, and less than 1,250, plotted
> according to post-conceptual age\--I think that\'s really
> post-menstrual age\--up to 3 years of age.
>
> Now, do these both norms describe normal growth? And I think we have
> to be really careful what we mean when we say normal values, because I
> think that\'s a term that often causes confusion. I actually try to
> avoid that word. I see it used sometimes as referring to values that
> are expected or typical, typical values, values that are not
> associated with adverse outcomes or low-risk values, values that do
> not cause adverse outcomes, healthy or optimal values, and values for
> which intervention has not been demonstrated to be beneficial. I think
> it\'s really important that we keep clear what we\'re talking about.
> At best these growth grids describe what are typical values.
>
> How should they be used? I think that they\'re a useful clinical tool
> to assess the growth pattern of individual babies. Whether they are
> appropriate regulatory standard to evaluating the formula, I\'m sure
> the answer to that is no. They provide neither the optimal values nor
> an adequate basis to compare the growth with new formula to
> conventional formulas.
>
> As I\'ve spelled out in the handout, if you compare the growth for the
> new formula to one of these growth grids, what you describe as an
> effect on growth might be due to any of a large number of factors,
> including intervening changes in care and outcome since the growth
> grid was developed, the fact that in most studies you\'re using
> selected patients, whereas the growth grids are based on all patients;
> a myriad of differences between centers, and the opportunity for bias
> in patient care, selection, care and assessment in evaluating new
> formulas. And I think it\'s particularly important when the sponsor or
> the investigator has a financial or even a professional interest in
> the outcome of the studies to attempt to avoid bias.
>
> I think we also have to ask ourselves whether the statistical tests
> that are commonly done in evaluating growth studies are misused and
> then misinterpreted in assessing interventions using historical
> controls. The babies in feeding studies and the babies in these norms
> that we see for preterm babies and for term babies, are clearly not a
> random or even a representative population of the sample of the same
> population. Moreover, a p-value of less than .05 is often taken to
> mean that the difference is due to the intervention, when it may be
> due to any of a number of factors a difference in population,
> differences in the way the populations are assessed, et cetera.
>
> So I think we should be asking the question, why use historical
> controls at all to evaluate new formulas for preterm infants or for
> term infants as well. For every other intervention that we talk of in
> medical care, the randomized trial is the gold standard. The
> concurrent cohort, carefully done, carefully studies, is a silver
> standard. Historical control is a bronze standard. Why do we want to
> use the bronze standard? And these are also issues in concurrent
> controls as well.
>
> Should carefully designed randomized trials be required? I think the
> answer to that is clearly yes with a number of other features designed
> to minimize random error or systematic error and increase the
> signal-to-noise ratio, which would include mass caregivers and
> evaluators, well-standardized evaluations shown to be reliable by the
> people who do the assessments in the study, effective procedures to
> avoid attrition, and intention to treat analysis predefine stopping
> rules in an adequate sample size. And I would add to that I think a
> commitment to publish the data at least on the website, no matter what
> the data show.
>
> Now, there has been opposition to the use of clinical trials by
> formula companies that would be charged with this responsibility, and
> I think part of that opposition is the expense and the feasibility of
> such trials, and I think with the progress in organization of research
> effort, that this is more feasible now with lots of neonatal research
> networks out there, some that already include follow up evaluations in
> at least some if not all the centers, and by the recognition that you
> don\'t\--you need only do simple management trials.
>
> Most people, when they think about randomized trials are very
> expensive, are thinking about the usual traditional kind of
> explanatory trial, which are designed to determine whether therapies
> work in ideal or restricted circumstances, or that are designed to
> define the mechanisms of action. Management trials, on the other hand,
> or so-called effectiveness trials, are designed to determine whether
> therapies work under routine clinical circumstances, so all the effort
> that goes into trying to control all the co-interventions in
> explanatory trials is inappropriate in a management trial.
>
> Who should be enrolled? Who should be excluded? I think you want to
> enroll representative sample of the babies for whom the formula is
> intended or at least the highest risk group. So you want to include
> any babies who make up an important part of that population, small for
> gestational age babies, very sick babies, twins, et cetera. You would
> want to exclude relatively few infants, say the babies who have major
> congenital anomalies or overt nonbacterial infections.
>
> Should infants fed their mothers\' milk be included? I don\'t think
> it\'s absolutely necessary, but I think it\'s highly desirable to
> increase the generalizability of the results of the trial because a
> large proportion of all preterm babies are fed at least some of their
> mother\'s milk, and also to help identify limitations of the formula,
> and areas for potential advances based on the benefits of mother\'s
> milk over formula after adjusting as best feasible for other factors.
>
> What assessments should be performed? I think, obviously, body
> composition or biochemical, physiologic or functional variables need
> be considered, but most of the time those would have been studies in
> prior explanatory trials. There might be some need to get some of that
> in some of the patients though.
>
> What about health outcomes? Well, I think one variable that has to be
> considered is the percent of infants with necrotizing enterocolitis.
> This is a serious disorder with a mortality exceeding 50 percent in
> surgically treated extremely low-birth weight babies, and it may well
> be related to feeding. Death is a competing variable for necrotizing
> enterocolitis. You have to live long enough to get NEC, so you would
> need also to look at the composite outcome of death or necrotizing
> enterocolitis. We also have to be worried when we feed babies with
> chronic lung disease that rapid growth may not be attainable or even
> desirable. If you have marginal pulmonary sufficiency, how fast do you
> want that baby to grow? So you would like to know about the
> combination of death or prolonged mechanical ventilation.
>
> Neuro developmental outcomes I think are at least highly desirable if
> not mandatory, because first growth and development may be
> differentially affected. You need to exclude adverse outcomes on
> development, even in the presence of good growth rates. I think also
> we need this information to better define the optimal growth rate and
> the appropriate goals for growth rates sustained by formulas for
> infants with or without serious illness.
>
> While growth assessments, weight, length, head circumference and
> weight-length ratio I think are essential, there may be others as
> well. What minimum period of assessment is needed, I think we should
> remember that a reliable identification of major neural developmental
> impairments is probably not possible any earlier than 18 months
> adjusted age, that is, post term, and this would allow evaluation of
> potential late effects beneficial or hazardous on time-limited
> interventions given in the NICU or later.
>
> What standard should be used in judging the growth of preterm infants
> fed new formula? The American Academy of Pediatrics has said that the
> goal should be to achieve rates in an extrauterine environment like
> those that would have been achieve in utero had the baby not been
> delivered early. But we have to wonder if this is really the right
> goal. We have some uncertainty about what this rate is currently and
> we can discuss why. If we can only measure gestational age well, we
> could do this better. Currently we think that it\'s about 15 to 17
> grams per kilo per day weight gain, about 1.1 centimeters per week in
> length, and about .7 centimeters increase in head circumference. We
> again need to ask is this an appropriate goal for infants with severe
> lung disease, and we also had this observation of persistent growth
> deficits after reaching full feedings. So even though we can get
> babies to grow rapidly, once they get to full feedings, there\'s this
> long period of time when they\'re growing poorly as they recover from
> illness after birth, and this shows you data for the neonatal research
> network for babies of different gestational ages, 24 to 25 weeks, 26
> to 27 or 28 to 29 in relationship to a so-called growth grid that
> Alexander published. And you can see that the babies don\'t do that
> bad once they start growing and taking a full intake, but they end up
> with most of them smaller than the 10th percentile for babies
> developing in utero with the same gestational age.
>
> Whatever goal we try to take we have to think of it as provisional,
> but we could ask, should the current standard for judging preterm
> formulas be the formula that sustains the best catch-up growth, and
> that could be that the weight, length and head circumference and the
> body proportions would be most like that of term infants of the same
> adjusted age, providing there were no adverse effects on the health or
> development through 18 months as identified in a well-designed trial.
>
> How many infants would you need to study to assess a new formula? This
> is a really complex and important generic issue in assessing
> intervention, any intervention where there may be an uncommon but
> serious potential hazard like necrotizing enterocolitis, and I\'m
> going to spend some time on this even though this may seem to you like
> a statistical issue only, I think it\'s an important practical issue,
> because the kind of things I\'ve said would make feeding studies so
> large that formula companies or indeed the NIH may be unwilling to
> fund these. So I want to try and see if we can find some way to
> address this.
>
> So somebody may say, well, wait a minute. The old formulas have not
> actually been tested that well, and I\'ve got a new formula here that
> has strong a priori evidence and rationale for using it. Say it has a
> component that\'s provided before birth across the placenta and in
> human milk after birth, not given in prior formulas. It\'s not well
> synthesized from precursors in preterm babies. And we think it\'s
> important for healthy development.
>
> I think even in that circumstance you still need to rule out the
> possibility that there are important unrecognized hazards of this
> formula and I\'m going to try to list what I think those are or the
> most important.
>
> The first would be an absolute increase of at least 3 to 7 percent or
> more in major adverse neonatal outcomes, particularly necrotizing
> enterocolitis. A 3 percent absolute increase corresponds to what\'s
> called the number needed to treat of 33. That is, for every 33 babies
> that you this formula to, you would cause one baby to have necrotizing
> enterocolitis. I think that would be unacceptable even if all the
> other babies benefited in growth or perhaps even in development.
>
> A second would be a reduction in developmental quotient at 18 months
> of a quarter of the standard deviation or more. That\'s the mean
> developmental quotient of 18 months and reduction of a quarter of a
> standard deviation or more. If you observe that, that would
> substantially increase the number of preterm infants with a deficient
> or marginal IQ that would be eligible later for educational
> intervention programs. In the neonatal network this would correspond
> to a reduction of almost 5 points on either of the Bayley subscores.
>
> Third would be a reduction of a quarter of a standard deviation in
> length or head circumference at 18 months. And this of course is
> arbitrary, but at least after recovery from serious illness, there\'s
> no apparent benefit of slow growth so that I would think a modest
> decrease in length or head circumference, if not weight, could be seen
> as presumptive evidence of harm. And this would correspond in the
> neonatal network in 18 months to about 250 grams in weight, 1-1/4
> centimeters in length and a half a centimeter in head circumferences.
>
> Now, you may think that this is too small to look at, but I would
> reassure you that the sample size needed to assess necrotizing
> enterocolitis, if you use a sample size that\'s large enough for that,
> you can evaluate very small effects on growth.
>
> Now, if you take a conventional approach to sample size, you would
> need 315 per group to have 80 percent power to identify a quarter of a
> standard deviation difference in either development or growth or size
> at 18 months, and an alpha error of .05, assuming you lose fewer than
> 20 percent of kids to follow up. The power to identify an increase in
> necrotizing enterocolitis would be 78 percent, for a large increase, 7
> percent, that would be a doubling of the right of necrotizing
> enterocolitis in the neonatal research network. It would fall to only
> 22 percent for a 3 percent increase, so a really small power to look
> at a clinically important increase. If you said you\'d like 90 percent
> power to identify a quarter of a standard deviation difference of 18
> months, you\'d need 421 per group. Your power to identify an increase
> in NEC would still be only 30 percent for a 3 percent increase in NEC.
>
> What can you do about this? One potential way to address this is a
> non-inferiority trial. For the sake of time I\'m not going to talk
> about that.
>
> Another, and I think this is, practically speaking, the most
> attractive option, is to increase the p-value considered statistically
> significant in evaluating a serious hazard. As you know, the same
> p-value, usually p less than .05 is used for benefits and hazards in
> studies, and this is an arbitrary and not well justified practice. For
> a serious hazard like necrotizing enterocolitis, a higher p-value
> might be justified on multiple grounds. First is, we know in clinical
> studies the direction of bias is toward finding benefits rather than
> looking for harms. There\'s a lot more effort put into it in general,
> and the studies are powered to evaluate benefit rather than harm
> usually. But the hazard may be much more important than the benefit.
> And as pragmatic evidence, we know that data safety monitoring
> committees that review the accruing evidence in clinical trials will
> stop a clinical trial at a much higher value of p for hazard than for
> benefit.
>
> The appropriate p value shouldn\'t depend in part on the cost of
> drawing the wrong conclusion. For a serious hazard like NEC, I would
> contend that we might select a p less than .30. That would still
> result in a 70 percent chance or higher that a difference of that
> magnitude would not occur by chance under the null hypothesis. If you
> did this, what you\'re doing is you\'re increasing the risk of a false
> positive conclusion, that is, that you would conclude that the formula
> causes NEC when in fact it doesn\'t. In order to reduce the risk of a
> false negative conclusion, that is, a conclusion that the formula
> doesn\'t cause NEC when in fact it does.
>
> So if we go back to the numbers we calculated before for benefit, at
> 315 infants per group, again, that was for 80 percent to look at a .25
> SD difference, the power to identify an increase in NEC would be 96
> percent very high power for a large increase, 58 percent for a 3
> percent increase. So you\'re slightly more than 50 percent likely to
> identify it. If you use 421 per group, you then get down to a power of
> about 2 in 3 to identify a 3 percent increase.
>
> If you found hazards at a p of .30 and benefits at a p less than .05,
> what would you do? Well, I think you wouldn\'t recommend the formula,
> you\'d recommend further study, and that would be a departure from
> what has been done in usual practice.
>
> I\'m going to skip that one, and just conclude by saying that I hope
> I\'ve convinced you that the growth of preterm infants should not be
> assessed in isolation from effects on health and development, that a
> large trial evaluating growth health and development to 18 months or
> more is needed to assure that the benefits of any new formula outweigh
> any hazards in preterm babies and to better define the effects of
> different growth rates, and the growth rate that we should be looking
> for in deciding how to design preterm formulas.
>
> Thank you.
>
> DR. GARZA: Thank you very much. Questions or comments? Dr. Stallings?
>
> DR. STALLINGS: It sounds like you\'ve silenced us pretty well. You
> know, we at the beginning, talked about dividing up preterm from term
> infants completely, and it sounds like, from your presentation, that
> you really, in the area of growth, that there really isn\'t anything
> you learned from term studies that would influence you on preterm.
> Would that be a fair\--
>
> DR. TYSON: Well, I wouldn\'t say wouldn\'t influence you, but I don\'t
> think you can determine whether a new formula is appropriate for a
> preterm infant based on observations in term infants.
>
> DR. STALLINGS: The other thing I\'d like for you to elaborate on a
> little bit is I think it\'s often that\--you were telling us a bit
> about who the sample should be, and in essence, the
> inclusion/exclusion criteria. Which infants, if you elaborate, which
> infants should not be in a growth study? Which preterm infants should
> not be in a growth study of preterm?
>
> DR. TYSON: Well, I think it would be babies with the kind of problem
> that\'s very unusual, and that\'s going to have an overwhelming effect
> on growth like trisomy 13, growth and mortality, nonbacterial
> infection. Other than those things, I think you\'re talking about 3
> percent of babies or something. The rest of them I would vote to
> include.
>
> DR. THUREEN: Thureen. Dr. Tyson, I know that in your paper you said
> you would include growth restricted infants as part of this because
> they\'re such a large portion of the population, but that you would
> substratify those infants for further analysis.
>
> DR. TYSON: Yes, right. You can of course include explanatory
> evaluations within a management trial, so it might be that that
> formula has a different effect on those babies.
>
> DR. THUREEN: In terms of neuro developmental outcome, do you think it
> would be fair to exclude infants who had had very high risk factors
> for significant neuro developmental outcomes, such as intracranial
> hemorrhage, prolonged asphyxia, evidence of white-matter disease,
> before the trial even started?
>
> DR. TYSON: If the formula is going to be fed to babies with severe
> asphyxia, then I think you would want to test it in those babies. For
> some of those conditions you had mentioned, they would occur after you
> started the feeding, so like cystic white matter disease you might not
> identify till 36 weeks post conceptual age or something, and that\'s
> really, that\'s potentially an outcome variable.
>
> DR. THUREEN: Would you pair match those infants then at all with other
> infants who had similar risk factors or known disease that affects
> neuro developmental outcome, or would you just do a purely prospective
> randomized trial?
>
> DR. TYSON: If you do a large randomized trial, first of all, it gets
> really cumbersome to try and pair anybody at birth. As long as you\'re
> stratifying by center and maybe a couple of other things like birth
> weight less than 750, 750 to 1,000, something like that, that you will
> end up with an approximately equal number of those babies in the two
> groups, and then you can go back and do an analysis. If you try to
> stratify for birth weight, SGA, gender, birth asphyxia, et cetera, you
> end up with so many huge strata that the study gets really complicated
> to do. And I don\'t feel as strongly about that as most statisticians,
> but my understanding of the school, most statisticians are towards the
> minimal prognostic stratification at randomization, and more toward
> post hoc looking at individual groups who should have been predefined
> ahead of time which group you were going to look at. Does that answer
> your question?
>
> DR. THUREEN: That makes sense. And would you change any of your ideas
> about how to conduct a study if you are going to look at patients who
> this is their exclusive formula fed from initial feeding versus
> studies started when infants really attained full feeding? Do you
> think that it makes any difference on how you conduct the study if
> you\'re looking at those two issues? Did that make sense? Because
> yours sound like you\'re referring to infants who may start minimal
> enteral feedings with the study of formula, rather than waiting until
> they attain full feeding and then starting from that standpoint? Do
> you think it\'s preferable to do one or the other, or do all of your
> idea really apply to\--
>
> DR. TYSON: It depends on when the formula is going to bed. If it\'s a
> formula that\'s going to be fed in the first week or something like
> that, I think you want to test it as it\'s going to be used. Let\'s
> say that it was a formula that was recommended for us from the first
> feeding. Let\'s say for the sake of argument that it cause necrotizing
> enterocolitis, and you didn\'t enroll baby, and you didn\'t start that
> formula until 3 weeks of age or something, or at a point when the
> babies were on full feedings, you might miss that effect, so you want
> to test it as it\'s going to be used in the real world. Does that make
> sense?
>
> DR. THUREEN: Yes. And then lastly, do you believe that there are
> really no good reference standards for growth in the preterm infant or
> at least a certain subgroup of preterm infants that may be extremely
> low birth weight?
>
> DR. TYSON: In the Neonatal Research Network, we have research nurses
> that are doing standardized\--that have done standardized evaluations
> of anthropometry in intervals. There are huge center differences. If
> you try to take the data from any center to apply it to another
> center, you could easily be mislead just by the center differences. So
> I don\'t see why you would want to use comparisons that would involve
> center differences or time differences. This was gathered data 3 years
> ago when they were using steroids, postnatal steroids more often or
> less often than they are now. Why not randomize and get the
> cleanest\--I think the belief that you don\'t have to use controls,
> you don\'t have to use randomized controls, that you can answer the
> question with fewer patients is an illusion, that at a given number of
> patients your ability to get a unbiased answer to the question is
> going to be greater with randomized controls than with historical
> controls.
>
> DR. THUREEN: Thank you.
>
> DR. GARZA: Heubi?
>
> DR. HEUBI: I think, Jon, this is all very interesting. I wanted to
> actually ask you a couple of questions, and you\'d have to follow my
> line of thought here.
>
> The number of subjects that you would entertain as being appropriate
> for a study is about 10 times what a typical current formula study
> would be.
>
> DR. TYSON: Right.
>
> DR. HEUBI: With that in mind, knowing what you knowledge is of the
> Neonatal Network, would the Neonatal Network sponsor studies like this
> because this is specific to preterm infants and it would be a
> potential rationale to study with partnering between industry and NIH
> money to do studies like this?
>
> DR. TYSON: The Neonatal Network has a protocol review committee and
> standard procedures for\--there\'s no reason that couldn\'t be
> proposed and seriously considered or accepted if it went through all
> those things. There are lots of networks out there. In Texas we\'ve
> started a Texas network, and there\'s an Oxford network, and the
> Canadians have a network, and the Australians have a network, and I\'m
> sure there\'s networks developing in the United Kingdom if they\'re
> not already in place. So there are a lot of people willing to do this.
> The hardest part is going to be the 18-month follow up. That\'s a lot
> harder than studying NEC, but as more and more people say, \"If I\'m
> going to take care of babies this size, I need to know how they turn
> out. That means I have to have a really well functioning follow up
> system. So I think there are going to be people out there that can do
> it at much lower cost than if you just went to them on day one and
> said, \"We\'re going to fund your whole follow-up effort in order to
> answer this one question.
>
> DR. HEUBI: But I was looking at it from the standpoint of it being
> economically more attractive to industry to do studies through the
> network that exists through the NIH because some of the infrastructure
> already existed and was already being paid for in part by federal
> money.
>
> DR. TYSON: Right. Kathleen Kennedy and I proposed to the network a
> feeding study, and one of the things\--and I\'m glad I was involved in
> this effort\--the business about the p-values that I presented today,
> that was aware stumbling block to us when we got to the\--the
> reviewers really liked it and the statisticians said, \"Well, you\'re
> going to have to study 6,000 babies or something,\" and I was working
> under the same mindset I had been before, well, that\'s if you want to
> look at a p less than .05. But why not accept a higher p-value, or as
> I was going to say on the last slide, predefine what you think is an
> acceptable ratio of the number of babies who benefit to the number of
> babies that are going to be harmed, and then test that and say, does
> the number of babies who are helped by improved growth or development,
> relative to the number who are harmed by NEC or worsening BPD, if
> indeed that\'s a hazard, is that an acceptable ratio or not? And try
> to design studies not to look at one outcome variable but at the
> relationship of one or two variables or perhaps even more. And I think
> that\'s a cutting edge issue in the experimental design that the time
> is ripe to do now.
>
> DR. HEUBI: And this is a circumstance where clearly DSMB or some
> monitoring board, during the\--
>
> DR. TYSON: Yes.
>
> DR. HEUBI: \--would be pretty accepted.
>
> DR. TYSON: Right.
>
> DR. DENNE: Jon, you\'ve made an argument about following preterm
> infants out to 18 months for neuro developmental outcome and I
> understand the rationale for that argument. How do you feel about
> similar studies in terminants?
>
> DR. TYSON: Do you mean randomized trials or\--
>
> DR. DENNE: No. I mean the necessity for evaluating neuro developmental
> outcome at 18 months in studies of new term formulas?
>
> DR. TYSON: I don\'t see why not. I mean everybody in this room thinks
> nutrition\'s really important. You take these formulas and you feed
> them to millions of babies. Why test it in only 50 or 60 babies? Why
> allow it to go on the market without knowing does it have beneficial
> or harmful effects as far as you can tell with an appropriate sized
> study in term babies?
>
> DR. ANDERSON: Anderson. In your discussion of NEC much of the
> calculations were done based on a baseline rate of 7 percent. How
> would you feel about some of the adverse event monitoring being done
> not necessarily in the context of a randomized clinical trial, but
> against some fixed standard? That is an infant formula would be
> unacceptable if it produced a rate of NEC above 10 percent.
>
> DR. TYSON: There are several problems with that. One is there is a lot
> of institution variation in NEC and with any institutions, there are
> periods when the NEC rate really goes up, and when it comes down,
> nobody quite understands that.
>
> And finally you have the potential problem of bias. There have been
> studies, for example, they took x-rays of kids with NEC and x-rays of
> kids thought not to have NEC, going to every pediatric radiologist in
> California, and they found this incredible variability in what was
> called NEC and what wasn\'t. And so when you\'re in the context of a
> study like that, I just think the opportunity for bias is there, and
> that your ability to relate that to some other institution in a
> different point in time I just don\'t think is worth the effort.
>
> DR. STALLINGS: Stallings. A slightly different angle. And we talked
> this morning a little bit about, or inferred a little bit about term
> babies growing too fast, and you know, that\'s of concern, but
> certainly for my clinical time, the worry over preterm babies growing
> too fast, and I can remember bedside debates about too fast and it\'s
> only fat and it\'s no brain and it\'s no muscle and all of that. I
> don\'t think we have nearly as good a handle on the body composition
> component of the preterm babies. And then you add to all of that the
> concerns that we\'re all reading more and more about, is early
> postnatal growth a very\--I mean we know it\'s an important time, but
> a differently very important time in lifelong health. Would you make a
> few comments? I know you made the caveat about babies with really
> chronic lung disease and concern, and that\'s really related to CO~2~
> retention, but put those babies aside, and can we grow preterm babies
> too fast, and how do we determine when we\'re approaching that?
>
> DR. TYSON: Well, I clearly don\'t have the answer to those questions.
> It seems to me the only way we can get it is to randomize babies to
> different feeding regimens that produce different growth rates and see
> who turns out to have the best health and development. That might be a
> different answer for the really sick babies and the healthy babies.
>
> DR. GARZA: In terms of randomized trials, the implicit assumption is
> that in fact it will be a concurring group of formula-fed infants. The
> other control group that\'s been discussed by this committee in using
> breast-fed infants, in this case perhaps infants fed human milk that
> may be fortified or enhanced with other nutrients, what\'s more
> important in your perspective, a randomized trial, which obviously you
> can\'t do unless you\'re willing to go down the hospital hallway and
> say, \"Are you going to breast feed or are you going to bottle feed,\"
> which obviously is not feasible.
>
> DR. TYSON: So among those whose mothers commit to breast feeding those
> babies to randomize them to the new formula versus the old formula for
> supplementation, when they need supplementation, so you can stratify
> pre hoc for intent to breast feed or not. Then randomize within those
> strata.
>
> DR. GARZA: And then use the amount of formula you\'re feeding them as
> part of the co-variants in that?
>
> DR. TYSON: Yes.
>
> DR. GARZA: Any other questions?
>
> \[No response.\]
>
> DR. TYSON: Thank you.
>
> DR. GARZA: All right. Thank you very much, Jon.
>
> DR. GARZA: We\'re going to move from preterm infants to generic
> analytical issues. And Dr. Frongillo, who you\'ve met before, is on
> next. I remind everybody Ed is from Cornell University Nutritional
> sciences.
>
> \[Pause\]
>
> DR. FRONGILLO: So I was asked to look at analytical issues related to
> the evaluation of formula, and I was asked to look at 5 issues, the
> sensitivity and usefulness of several types of comparisons, the
> potential for evaluating a meaningful difference in the growth
> increments per day, the impact of transformations of raw data
> measurements into normalized indices, advantages and disadvantages of
> comparing with various reference data sets, and finally, circumstances
> that might favor one type of comparison to another.
>
> So the first issue is sensitivity and usefulness of several types of
> comparisons. In 1988 the Academy of Pediatrics had issued some
> guidelines for determining physical growth, for evaluating new infant
> formula, and just to remind you, the suggestion there was to look at
> weight gain over the first 4 months, to look at measurements at 14, 60
> and 120 days, and to look at rates of weight gain in grams per day
> over the intervals that are implied by that, 14 to 60, 60 to 120, and
> then the whole period 14 to 120.
>
> Some possible comparison groups to infants who are receiving new
> infant formula would be infants who are randomize to receive a
> standard established infant formula or alternately infants whose
> growth is represented in a reference, infants whose measurements are
> in a currently available data set, and finally, another possibility,
> infants whose measurements are in a historical data set. So I\'m going
> to go through each one in turn.
>
> The advantages\--I\'ll use pluses for advantage and negatives for
> disadvantages. So in terms of advantages for randomized clinical
> studies, is first of all theoretical close control of the factors that
> might influence the outcome, in this case, weight gain as an example,
> the incorporation of design feeders to minimize known sources of bias.
> This might be something like doing stratification based on certain
> characteristics of the infant, perhaps size at birth or something like
> that, and that the probability statement is justified\--this gets to
> sort of statistical philosophy here\--but that the probability
> statement is justified on the design itself as well as the statistical
> model that\'s used.
>
> And these issues are important, especially the first one in light of
> the fact that we might expect that, for example, if there was
> challenges in recruiting infants into a study, if it was difficult to
> recruit infants into a study whose caregivers are interested in
> formula feeding, we might be concerned about selection biases or the
> differential characteristics of people who agree to participate in
> such a study. And so being able to control for those would be
> important.
>
> The disadvantage is that the sample size is going to be larger than in
> the other approaches. I\'ve said here the sample size would be twice
> as large. That\'s under the assumption that the other data set that
> one might be compared, whether it\'s a reference or a historical
> control, contributes no sampling variability. It\'s even larger if
> we\'re willing to assume that, for example, a reference has no
> sampling variability. And then it might be as great as a difference of
> a factor of 4. So the sample size then in a randomized control study
> would be potentially much larger than if we didn\'t do that. If we
> compare it to a reference the advantages would be that we can compare
> to a known established reference, something we know and love. One
> group of infants would be measured. Therefore, saving on sample size
> and work. The negatives would be that the new cohort on new infant
> formula may be different in some important ways from the reference
> sample, and that the reference may exhibit somewhat different
> characteristics in terms of the growth patterns from the new cohort.
> And I already showed you an example of that earlier when I was talking
> about WHO growth reference, and we know breast-fed infants grow
> differently than formula-fed infants, and we might be concerned about
> whether the reference is the appropriate sort of comparitor for the
> current cohort.
>
> And in relation to the current U.S. reference, it\'s a cross-sectional
> reference, and if our interest is in growth increments, we would like
> something that would characterize the variability in growth
> increments.
>
> And then finally, reference data are not free of sampling error.
> Reference data have a finite number of infants measured in any
> particular time, and if we\'re doing a comparison between a new cohort
> and a reference, we really should be taking into account the sampling
> error that\'s present for both.
>
> And the other choices had to do with use of currently available or
> perhaps historical data. These are data that\--existing data that are
> collected earlier in time, so I\'ll consider those together, obviously
> advantages if this minimizes data collection, but the disadvantage
> would be that the characteristics of this new cohort might differ from
> the current cohort in some important ways.
>
> The second issue was the potential for evaluating a meaningful
> difference in growth increments per day. So I want to talk about what
> I call the smallest meaningful difference, abbreviated SMD. This is
> not the difference expected or what\'s previously been found. What it
> is, is the smallest difference that we think would be substantively
> important. It\'s a judgment about what do we think is the smallest
> difference that would matter. And this is inherently\--we should be
> thinking of this as a population rather than individual
> characteristic. In other words, the population perspective is most
> salient. We\'re not trying to judge whether one infant is growing
> differently than another. We\'re trying to judge whether a whole group
> of infants, potentially a large group of infants fed on an infant
> formula would grow differently than a group or population of infants
> fed on some other means.
>
> The previous recommendation from that 1988 guideline was 3 grams per
> day, which amounts to 318 grams over the 14 to 121-day period. And I
> tried in the background paper to sort of get some perspective on how
> big is this difference. So if we look at the increments in the Iowa
> and Fels data, this difference here is about the same difference in
> those reference data between the 25th and the 50th or the 50th and the
> 75th percentile, to give you an idea of how big that is. If we think
> about high and low altitude, which is one of the factors that causes
> the largest differences in birth weight, differences at high altitude
> are in the order of 350 grams or so. So that difference is about the
> same or a little bit bigger than this.
>
> And we\'re always concerned about the effect of smoking on birth
> weight, and this difference of 318 grams is about 50 percent larger
> than that difference.
>
> Another perspective we can get is if we look at some prior results.
> These are some results from a paper by Roche, et al. in 1993. They
> compared for males and females growth on 3 different infant formulas.
> They also had breast-fed infants that\'s in the paper, but I left that
> out here for simplicity. And this is the growth that occurred from
> zero to 4 months, and the total number of infants was about 260. And
> so these are the values of growth that occurred during those periods
> for male and females. What I was particularly interested in was having
> us look at the differences.
>
> So the differences among those 3 groups, for males were 210, 270, and
> 480, and for females were 110, minus 10 and then 100. So you can see
> that first of all the differences for the males are much larger than
> the difference for females, and these differences here are smaller
> than the 318 grams over roughly the same period, and this difference
> is quite a bit larger than that.
>
> And so it seemed to me, just from looking at this, we might say, well,
> these differences maybe aren\'t too big, but my guess is most of us
> would be concerned about differences of around 200 grams over this
> period.
>
> The previous recommendation for sample size that was needed per group
> for the smallest meaningful difference was based on 80 power, testing
> at .05, a one-tail test and this standard deviation. And the result
> that was given was for 3 grams per day, a sample size of 28 was
> needed. So I wanted to comment on this.
>
> First of all, as Jon Tyson pointed out in the talk just before, we\'re
> trying to do what\'s like a bio-equivalence. We\'re trying to make a
> judgment whether things are really producing about the same effect or
> whether there\'s evidence that something is really different. In that
> regard we\'re particularly concerned about power, because if there was
> a real difference in growth, the power represents the probability that
> we would find that difference. And 80 percent power means one fifth of
> the time we wouldn\'t detect the difference that was really there. My
> guess is that\'s a risk that we\'re probably not willing top take. And
> so I\'ll argue that 90 percent power is probably better.
>
> Also this used a one-tail test and there\'s already been comments this
> morning that we\'re probably concerned about differences in growth
> that are in either direction, whether infants grow too slowly or
> whether infants are growing too quickly in terms of weight, so a
> two-tail test is probably more appropriate. And finally, this figure
> was based on a personal communication with one of the investigators at
> the time, and since then a larger standard deviation has been
> published. So if we go to 90 percent power, the same test for the
> p-value, a two-tail test and a slightly higher standard deviation,
> then I\'ve given a table here. In the background papers there\'s even
> more variance of this.
>
> But this shows that first of all at 3 grams per day, we would need 67,
> not 28 under these parameters. And then if we go, obviously, to
> smaller and smaller meaningful differences, then we\'re going to need
> larger and larger samples to be sure that we would detect them.
>
> The third issue was the impact of transformations if we go from raw
> data to normalized indices. The idea of Z-scores is that we match
> measurements with reference values for age and sex. The Z-scorer then
> takes that measurement, compares it to the reference median for that
> age and sex, divides by the appropriate standard deviation. The
> primary purpose for Z-scores is descriptive. It allows combining
> together ages and sexes so that we can get one overall description of
> a where a population is or a group is. This assumes that the pattern
> of growth in the sampled population is expected to be the same as in
> the referenced population.
>
> In terms of the application of this to evaluating new infant formulas,
> first of all, age adjustment would usually not be needed if the
> measurements are taken at the prespecified ages, and I think Dr. Fomon
> gave us the motivation and the example we need as to how you do that
> in getting measurements within plus or minus 4 days, which is
> remarkable. If we can do that, then we really wouldn\'t need to do age
> adjustment. And then if age adjustment was needed\--because we\'re all
> not that good\--what we would probably prefer to do is include
> co-variates for age or interpolate and extrapolate the time series
> rather than converting to Z-scores as a means to deal with this.
>
> And finally, as I\'ve already said, males and females would typically
> be analyzed separately because there are sex differences in the growth
> response. So the need to do sex adjustment from Z-scores isn\'t even
> there.
>
> The fourth issue was advantages and disadvantages of comparing with
> the various reference data sets. References are a tool to provide a
> common basis of comparison, and as I said before, the referenced
> population should reflect the growth that\'s expected for the children
> that we have under study. The reviews that were done by NCHS and CDC
> and also be the WHO in the early \'90s, led to the development of new
> references, and so we need to consider this in the context of those.
>
> I\'ve made a table here which shows what the possible references might
> be. The CDC 2000 reference has both breast-fed and formula-fed
> infants, but it\'s cross-sectional, which is a limitation in its
> application for this particular purpose. The WHO data has breast-fed
> infants. It\'s longitudinal, which is good, but besides having
> breast-fed infants, it won\'t be available for a while. The Iowa data
> and Iowa Fels data combine together breast-fed and formula-fed infants
> in a longitudinal, and so probably at the current time, if we had to
> do this today, we\'d probably choose to use this as a reference if we
> wanted to make a comparison for descriptive purposes.
>
> And then finally circumstances favoring one type of comparison to
> another, it seemed to me that we would probably want to consider using
> currently available data if we wanted to test several new infant
> formulas nearing us in time. If we were doing a set of tests over some
> period of time that\'s relatively close, then perhaps it would be
> efficient to sample from the same population for the whole series of
> studies, but without having to do repeated sampling for a comparison
> group. The concern always will be that the characteristics of later
> samples might differ from the earlier samples.
>
> So in summary, this review suggests the for primary analyses, the main
> analyses to answer the question, that it probably is appropriate to
> choose a design with a randomized concurrent comparison group.
> Otherwise, we\'re not going to be really sure that the growth of the
> infants on the new formula would really be expected to be the same as
> from some previous comparison, and this is of a concern about the
> characteristics of the samples and the populations, and it\'s
> particularly concerned potentially because of selection issues as to
> who actually gets into and agrees to be in the study.
>
> For descriptive purposes, it would be useful to compare the attained
> weight for all groups at each measured age with the current U.S.
> reference, the 2000 reference, and to compare for descriptive
> purposes, rates of weight gain with the Iowa or Iowa Fels data.
>
> And then continuing the summary, the sample size per group of 28 is
> clearly, in my view, without sufficient power for meaningful
> differences of even 3 grams per day, and a larger sample size is
> needed even if we stay with that guideline. The smallest meaningful
> difference might be smaller than that. It might be perhaps 2 grams per
> day. I think some might argue for something smaller than that,
> something larger than that. That\'s something that would have to be
> considered, but in any event, this would imply a much larger sample
> size, and determining the smallest meaningful difference should be
> based on the best understanding we have of the biology, but also on
> the required regulatory, clinical and public health decisions that are
> going to be made with this information.
>
> And finally, to Anna Milman, who\'s an undergraduate at Cornell who
> helped me in the preparation of the paper.
>
> DR. GARZA: Any questions or comments? Dr. Stallings?
>
> DR. STALLINGS: Talk tome a little bit about the\--we heard some of
> this in the other talk to, the differences in comparing just the needs
> and medians and in growth studies looking at the number of children
> that would be, for example, less than the fifth or less than the
> third, some cutoff that we also think of? I\'ve been\--you know, we
> tend to analyze the data just looking at the group means and
> differences, rather than a secondary analysis, or often we do these
> things that we don\'t have any idea because of the way the data
> presented, how many children, how many infants might have been in the
> tails of the extreme. Any thoughts on that from a statistical point of
> view or an approach to believing that a formula supporting growth
> properly?
>
> DR. FRONGILLO: No, that\'s exactly right. This whole discussion that
> I\'ve just given is based solely on the idea that under a new formula
> as opposed to an existing formula, say, that what we would be looking
> for and all we would care about is shifts in the whole distribution
> that could be captured by differences in the mean. Now, if there are
> differences of other kinds like differences in the variability or that
> if there was concern that maybe with a new formula for most infants it
> does fine, but there is a small subset of infants that don\'t do well
> at all, this approach is not designed to detect that. And Jon Tyson\'s
> thoughts about that I think are important, in that if we\'re concerned
> about what\'s happened at the extremes, that\'s going to inevitably
> require much larger sample sizes.
>
> We know that any time we, for example, categorize infants into whether
> they\'ve done okay versus not done well at all, and we have binary
> data, the sample sizes go way, way up, because in essence we\'re
> looking for those rare, rare events.
>
> DR. GARZA: Ed, a related question to the one just asked by Dr.
> Stallings. In a clinical study one might be interested in individual
> outcomes, so that one doesn\'t have to wait until the end to decide
> that the child did not grow well. What sort of analytical issues would
> this present when you want to be able to monitor for safety reasons
> the ongoing growth of infants, of individual infants?
>
> DR. FRONGILLO: You mean during the conduct of a trial perhaps?
>
> DR. GARZA: During the conduct of a trial.
>
> DR. FRONGILLO: Well, surely, you would want to have some guidelines in
> place so that if a child is growing extremely poorly, that some
> intervention is made. If you\'re starting at 14 days, you\'re not
> going to want to wait until 120 days to intervene, to decide that this
> child just is not thriving at all. So that would have to be built in.
>
> DR. GARZA: With that thought in mind then, you talked about perhaps 3
> grams being\--sample size of 28 for 3 grams being definitely
> inappropriate or 2 grams obviously more so. But that assumes a linear
> rate of growth through this period, which several speakers have
> described as highly nonlinear. Should we be looking at narrower
> periods and different amounts of growth during those narrower periods
> than 2 or 3 grams over that longer period, where one assumes then the
> linear pattern that doesn\'t exist?
>
> DR. FRONGILLO: Yes, I would say so. And the 1988 guideline has
> suggested that, what was it, 14 to 42\--now I can\'t remember\--that
> intervening interval would be looked at. The standard deviations there
> are a little bit higher. The growth rates on average are higher, and
> there are also more variables. So if one was particularly concerned
> about say the earlier part\--if there were three measurements and one
> was concerned about the earliest period, he\'d need slightly larger
> sample sizes based on that. But, yes, one would certainly want to be
> able to evaluate growth. And I think Dr. Fomon\'s admonition that
> it\'s the earliest\--the time when probably most concern and maybe
> most sensitive to different formula characteristics may be the period
> when the fastest growth is occurring, and that would be the earlier
> part of that period.
>
> DR. GARZA: And yet\--with that idea in mind then, when do you have to
> worry about regression towards the mean? I mean, so that in fact if a
> child is born large, do they begin to downsize immediately, or is that
> not a phenomena that we should worry about in the first 3 months of
> life?
>
> DR. FRONGILLO: No, I think that is a phenomena we should be worried
> about, and that ties to what I was saying about selection issues. If,
> for example, for whatever reason, the parents who agree to enroll
> their infant into a trial are parents whose infants tend to be small
> or have lower birth weights, for example. We would expect infants with
> lower birth weights to grow faster. That\'s what we know, and if
> they\'re at the high end of the birth weight distribution, they\'re
> going to grow more slowly, and so one of the important advantages of
> having the concurrent randomized comparison group is if any regression
> that occurs because of that kind of selection, that will be common to
> both groups. Any other way of doing it won\'t be guaranteed to pick
> that up.
>
> DR. GARZA: Any other questions? Dr. Stallings?
>
> DR. STALLINGS: One last technical question while we have you here.
> Like Bert was saying, maybe the 2 grams across the whole period is an
> optimal. Should we consider different rates for the gender since
> that\'s a pretty well appreciated fact as well to do sample on boys
> versus girls, different sample sizes in designing the study, or is
> that not\--
>
> DR. FRONGILLO: I guess my initial reaction is figuring out what the
> smallest meaningful difference once is going to be difficult enough.
>
> DR. STALLINGS: Forget it, okay.
>
> \[Laughter.\]
>
> DR. FRONGILLO: And now you want to do it twice.
>
> DR. STALLINGS: I was just thinking about how if we were, if we got to
> design sort of perfect studies in the young group, the youngest age
> group, and thinking about what we heard this morning, where there\'s
> at least one good example where the boys didn\'t try it as well as the
> girls, and that if we had been in that unique place where it had been
> a balanced gender sample, we might have missed the boys. Anyway, I was
> just\--
>
> DR. FRONGILLO: That\'s right. I mean from data I\'ve seen, from the
> Iowa Fels data the girls are slightly less\--their growth rates are
> slightly less variable than the males. On the other hand, at least
> that example from the Roche, et al. data\--others have far more
> knowledge than I do\--suggest that males are more differentially
> responsive to differences in feeding mode, so if both of those are in
> place, that suggests that on the grounds of variability, a smaller
> sample size would be needed for females, and on the grounds of
> variability, a larger for males. On the other hand, the differences we
> see for males might be larger than the important differences we see
> for females. So some thinking about that is probably\--certainly would
> be helpful.
>
> DR. GARZA: Dr. Denne then Dr. Heubi.
>
> DR. DENNE: I just wanted to clarify what you said about the growth of
> large infants and small infants, that larger infants grow more slowly
> and smaller infants grow more quickly. My understanding of the growth
> curves is that the 10th percentile and 90th percentile are fairly
> parallel in terms of their slope. So I guess I\--
>
> DR. FRONGILLO: On a population basis infants who are born at high
> birth weights tend to grow a little bit more slowly than infants who
> are a low birth weight, so you actually see a convergence of the
> distributions a bit. So that the variability at birth tends to be a
> little bit larger cross-sectionally and little variability after that.
> It\'s not a factor that comes into play anywhere after the immediate
> neonatal period. But for this purpose that\'s relevant.
>
> DR. GARZA: Heubi.
>
> DR. HEUBI: You showed us an example of a circumstance of where the
> smallest meaningful difference was in fact probably too large. I guess
> the question I have is do we know from formulas that are currently on
> the market, how many of them would have fallen out if you\'d applied
> more strict criteria to them in terms of their trials?
>
> DR. FRONGILLO: I asked exactly that question at lunchtime, and at
> least the people at my table didn\'t know the answer to that.
>
> \[Laughter.\]
>
> DR. HEUBI: So we don\'t know the answer to that question.
>
> DR. FRONGILLO: I think that it would be helpful to have an idea of how
> often is it that we see differences that are larger than whatever the
> smallest meaningful difference we happen to be fixated on at the
> moment, how often is it that when trials are done do we actually see
> differences that exceed that and therefore would cause worry? So
> knowing something about the distribution of the differences that are
> seen when studies are done would probably be helpful. The answer I got
> was that\'s not something that has to be publicly reported, and so we
> don\'t have a database of information available.
>
> DR. HEUBI: And I guess my follow up question was, I\'m actually
> surprised that they agreed to a one-tail test to begin with when they
> actually made these recommendations. Do you have any comment about
> that?
>
> DR. FRONGILLO: On why they agreed to that?
>
> DR. HEUBI: Why they decided that one-tail T-test was adequate.
>
> DR. FRONGILLO: Well, I think that if your concern was we have
> currently available formula that are fine and you\'re introducing a
> new formula and you\'re concerned about under nutrition, that it
> doesn\'t meet the infants\' nutritional needs, then it would sense to
> have a one-tail test because you\'re concerned about deviations that
> are in one direction. I guess I\'m suggesting that where we are now in
> the public health concerns we have about obesity, it\'s probably the
> case that we would be concerned in either direction. So at the time it
> may have been a perfectly reasonable conclusion that isn\'t
> necessarily the one we should reach now.
>
> DR. HEUBI: I guess it\'s just been pounded in me so often not to use a
> one-tail test for anything, that it just seems like it makes no sense.
>
> DR. GARZA: You don\'t have to answer that.
>
> \[Laughter.\]
>
> DR. GARZA: Any other questions?
>
> \[No response.\]
>
> DR. GARZA: All right. Thank you very much. You may not want to leave
> the podium just yet.
>
> We have next on the agenda is an opportunity to bring all the previous
> speakers forward for a question and answer period. And what I\'d like
> to ask the Committee is whether you would find that helpful or whether
> we should just move on to the next two talks and thus bring everybody
> up at one time. I need a sense from you as to what you would find most
> helpful.
>
> On with the speakers? Is that the consensus. And then we\'ll just ask
> everybody to come up. Is there anyone objecting to that on the
> Committee?
>
> \[No response.\]
>
> DR. GARZA: If not, Dr. Benton? Dr. Duane Benton, who is retired. I
> don\'t know whether there is an emeritus ranking within industry, but
> certainly you would merit that title if it existed. So we will refer
> to him as an emeritus industry representative, at least as an industry
> employee in the past, but one of high distinction. And he will be
> talking about product composition considerations, clinical studies.
>
> DR. BENTON: I want to make sure you can hear and other things. One,
> I\'m not going to\--at my age and my position, I\'m not going to try
> to impress you with how fancy I can make slides. So we aren\'t going
> to have any. I hate to a slide, to a screen.
>
> Also I think all I\'m going the be doing is a critique of my own talk,
> so I\'ve got some things here I don\'t want you to forget. I enjoy
> looking at the audience and if you\'re falling asleep, I\'ll start at
> you, something like that.
>
> Now, you should have background of why am I up here. Well, one of my
> various qualifications is, as Bert said, I\'m retired, and they
> somehow felt that would reduce the conflict of interest. Obviously one
> of the senior people. Sam\'s a little more senior than I am.
>
> But in this, what I am drawing from is 25 years when I was director of
> nutritional research with the Ross Products Division of Abbott
> Laboratories. And when I refer to my company, then I\'m referring
> to\--some of you used to know it as Ross Labs back in the good old
> days, and it is now Ross Products Division.
>
> It was a very good company to work for. It may not be representative
> of the industry in its attitude toward physical growth studies, and in
> fact what I say may not be representative of what the industry or the
> Ross Products Division presently do. In other words, when I went into
> this, I asked the people at Ross. They were calling me up because Bert
> couldn\'t find me, because I was wandering around out in Kansas. And
> so they called me up and said, well, wouldn\'t you do this? And I
> said, \"Do you want me to? I could be kind of a loose cannon.\"
>
> \[Laughter.\]
>
> DR. BENTON: And they said, \"Oh, yeah.\" The people on the Infant
> Formula Council said, \"That\'s a great idea.\" We\'ll see.
>
> \[Laughter.\]
>
> DR. BENTON: Because these are my opinions. This is not edited
> material. I really sort of identified when Benjamin Franklin was asked
> whether he would write the Declaration of Independence, and he said he
> made it an issue of point, that he did not write material to be edited
> by other people. I can understand that now that I\'m in my\--other
> than my wife did try to read it through and tried to figure out
> whether it made any sense at all.
>
> Now, the issues in here are, in my 25 years at Ross I was doing all
> kinds of different things. I\'m a biochemist by training. I worked in
> nutrition throughout my professional career, and I was very concerned
> about safety of our products. Now, in this we\'re not supposed to be
> talking about safety. We\'re talking about nutritional adequacy. When
> you are in the position that I was in for 25 years you don\'t know how
> to draw a line between those. You remember back when you were a
> graduate student and there was SMA out on the market that was vitamin
> B-6 deficient? And that company was\--well, it was a real blow. Rudy
> Tomarelli told me that he spent through his whole career going into
> court cases in relationship to that. That\'s the one thing you don\'t
> want to do if you are in the position I am.
>
> So, safety, nutritional adequacy, et cetera, there is no
> discrimination in there. The formula has to be good, and you\'ve got
> to somehow figure out whether it is or it isn\'t, and if it isn\'t,
> you\'d better do something about it very fast.
>
> I was in a company where the aspect of a physical growth study was
> something that was assumed. When we were in a meeting and they were
> talking with the president about, \"Are we going to introduce this?\"
> You know, the answer was, \"Where are the growth studies?\" You
> didn\'t want to be in the position of not having that kind of
> information because that was sort of viewed as something not right
> with it, and we\'re not going to get out there, and we\'re not going
> to be hit with something very undesirable.
>
> So it\'s also very helpful to see what I\'m saying here and what I\'ve
> written in the paper, and I\'m going to be talking basically to the
> paper, is directed toward that. Now, it is not an aspect of you
> saying, \"Oh, well, this didn\'t sort of turn out right and maybe we
> ought to do this and a little more of that.\" Within the company,
> clearly, they want to do something. You can tell them, \"No way. This
> stuff doesn\'t look like it\'s safe.\" But tell them, \"Oh, we
> haven\'t got that done yet, or \"We haven\'t looked into that,\" or
> something like that. You better have looked into it. You better know
> what you can as far as the answers to it.
>
> Now, what we\'re basically saying about a physical growth study, from
> our point of view, is that if there were a nutritional deficiency of
> any sort, some slight depletion of an essential nutrient, that the
> first thing we would expect to show up would be a diminution in weight
> gain. Now, the other thing that in many cases we would expect to see
> would be a diminution in intake of the formula. Dr. Fomon did address
> to a degree the intake of formula. Most of the other things are
> talking about growth of infants and things you can measure on infants
> and so forth.
>
> In my evaluation, really, wherever I could, wanted to see if the kids
> really did take in the formula and would continue to do that, and if I
> could work that into a study I would. It\'s hard. It\'s very hard
> work, but there are ways to find out that you can do that.
>
> Now, when we progress into\--and you now, I\'m talking about the
> studies as such. Before I talk about the formula and the ingredients,
> although my job was formula ingredient, I\'ve got to talk about the
> studies to the degree of what can we expect from them, because it
> isn\'t going to make any sense why I would want to run them if I could
> expect\--if I didn\'t have in mind clearly what we can expect from
> them and what we cannot expect from them. And one point that I have
> tried to make in here, those things that we can measure in a physical
> growth study, and clearly you\'ve outlined most of them that could be.
> I mean we could do innumerable measurements on these infants. But our
> attitude, or at least mine was then\--I may find somebody that would
> disagree with me\--are that growth is a combination of responses,
> thousands of them, and those might or might not be measured. But we
> need the most sensitive measure of how an infant is growing to detect
> in this short period of time, and with as small a number of infants as
> possible, that nothing is going wrong. And therefore we need the most
> sensitive, sensitive response within the study.
>
> With that, one of the things that you people are addressing is, well,
> shouldn\'t we use a breast-fed group as the control? This just sort of
> knocks me off my seat to think of that. We know that those breast-fed
> infants grow differently than any other infants fed on infant formula,
> that there are real differences of what we can measure as far as
> growth. And I\'m trying to answer one question. I\'m trying to answer
> the question, should we put this formula on the market? I may have
> made a bad infant formula, and now they do go over\--they gain weight
> or length or whatever at the rate that a breast-fed infant does. That
> may be a bad situation. It\'s not because the growth of a breast-fed
> infant is bad. It is that I may have gotten there for a very, very
> different reason. I may have depleted a nutrient. I may have caused a
> metabolic imbalance. I may have done a whole bunch of things because
> you cannot equate a weight gain or a body weight or something like
> that in a infant and say, \"These two are the same. Therefore, their
> metabolic patterns are the same. Their nutrient contents are the
> same.\" No, they\'re not.
>
> If I get one that is like a breast-fed infant, I would probably
> conclude that there was something wrong with my formula, and that\'s
> basically what we do. I mean we look at all of the information that we
> can collect and is practical from that point of view. When you come
> down and you make a decision and you\'re going to make advice to your
> company, you\'re saying, \"Is this safe when you compare it to a
> present formula that we believe is safe, and we have long
> experience?\" If it isn\'t, you don\'t have a formula, and the issue
> is that you\'re going to go back there and you\'re going to change the
> formula so you fit into that.
>
> Now, clearly, there are innumerable research studies that can be done,
> and you people would probably look at the budgets that we\'ve used for
> our research studies over the years because there are extensive ones,
> and you\'d think, \"Hey, that\'s a pretty good looking budget.\" That
> wouldn\'t even come close to trying to answer the question that you
> are posing in the sense of can we somehow make infant formula feeding
> similar to that of the breast-fed infant. That is an enormous research
> project. I\'m not really sure how I would try to undertake it if I
> were forced to try that. I\'m sort of glad I\'m not.
>
> The other thing I\'m going to say here is that I\'m not going to
> discuss the premature infant. Dr. Tyson gave a very good talk about
> the aspect of doing that. I guess I would say that if he were to
> implement and be able to implement his thing about the risk of
> necrotizing enterocolitis, all of our formula bottles would say the
> surgeon general has determined that this formula may increase the risk
> of necrotizing enterocolitis, because I have not seen a formula that
> in some way or other didn\'t appear in a particular nursery to
> increase the risk of NEC.
>
> Now let\'s proceed on with this, and another thing that I wanted to
> address, and Dr. Fomon introduced me to that in his paper and in his
> talk. He said that these days it\'s going to be very, very difficult
> to start a study with formula fed infants before 28 days. This is
> very, very serious from my point of view. We really depended on Sam
> for our work, and he started those infants\--well, it was not within
> the first week, but certainly the end of the second week. and if we
> had some kind of a nutritional inadequacy which represented the
> depletion of a nutrient, or I guess you could even say accumulation of
> a toxin. Those very early part of the growth would be a very serious
> loss of that period, would be very, very serious in trying to detect a
> deficiency, because sometimes around 4 months or 3 months or 4 months,
> solid foods are going to be introduced, the proportional growth rate
> is decreasing. If you had had 3 weeks of feeding of a formula or
> breast feeding, you might have depleted or repleted stores of a
> particular nutrient, and I\'m not certain that I wouldn\'t miss a
> serious problem.
>
> One of the things that I always fall back on is saying that when I was
> director I was referring to the vitamin B-6 deficiency in a formula.
> Would I have been able to detect that in a clinical study? I seriously
> doubt if an infant had been fed for 28 days on a totally adequate
> infant formula that had been fortified with vitamin B-6, that at the
> 4-month period of time whether you would be able to detect a weight
> gain difference, you know, using that formula, because they would have
> received enough Vitamin B-6 that it pretty might likely have carried
> them through that deficiency, and we would have never known. And we
> well know what happened when it really went out on the market and
> infants were really fed on that product as the sole source of food
> from birth. So I think it will be a great loss if we cannot introduce
> our infants quickly into the formula feeding when we\'re testing.
>
> Another thing that I would point out, at least in our studies\--and it
> was tremendously important to our work with Dr. Fomon and most of our
> other centers\--they had an expert nursing staff. They observed the
> infants closely, just as the pediatricians observed the infants
> closely. They talked with the mothers. They resolved observations that
> the mothers had and so forth. And I personally believe that
> nutritional or other types of problems will probably be detected by
> the nursing staff before we get statistically significant weight
> differences, which, from our point of view, would be important to be
> able to stop a study where something was going wrong. And we have had
> studies where\--that were stopped, anyway. I don\'t know whether you
> would statistically ever have found out whether something was going
> wrong or not. We didn\'t want to know.
>
> One of the things that is in here and that I have not really
> discussed, but I would just want to mention in this, there are
> situations where claims are going to be made for infant formula. And,
> yes, if someone is making a claim for infant formula, a growth study
> is important. It\'s my personal opinion that there\'s an awful lot
> more research that is needed to go out and make some kind of a claim
> for an advantage or disadvantage of an infant formula. And no one has
> ever regulated that. I certainly would hate to see claims that I see
> at the health food store for other foods.
>
> Now, when I went through here, I gave you on page 2\--I tried to break
> down the aspect of, you know, how we make an infant formula, what the
> steps are in it, and then we\'ll try to discuss how those go into the
> aspect of our evaluation. Certainly the ingredients, which we have had
> discussions of, and they\'ve asked me to try to discuss all of the
> other various ones.
>
> But the aspects of things like batching, in other words, this is where
> you\'re going to put together all the ingredients, they have to be put
> together in a specific order, specific manner, specific temperatures,
> and specific times of what is going on in there, and it can make
> tremendous differences in the stability of nutrients, interactions
> between nutrients, a lot of other things that are involved here. And
> we will say later on, you know\--and someone mentioned before, hey, we
> could just test this ingredient in an infant formula someplace, and
> then everybody could use it. Well, I have serious doubts about that,
> and I will try to address those as I have time here.
>
> Certainly heat processing is very, very important in the interaction
> between the various ingredients, and, therefore, we\'re going to have
> to always think about how much heat processing a particular product
> has received. But that heat processing is going to interact with all
> of the other aspects of things that I\'m talking about here. And it
> has to do with, you know, aspects of how we get the product into the
> container, how it\'s going to hold up over shelf life, innumerable
> aspects of that.
>
> Now, let\'s just go down through and look at a few things in
> relationship to proteins. Dr. Fomon addressed it. Maybe I better not
> spend too much time on it. But, clearly, if you think you\'re going to
> measure the protein quality of an infant formula as to its adequacy,
> you must feed a very, very low protein feeding. In fact, Dr. Fomon,
> just a little lower than you dared feed in those studies that you
> showed them here.
>
> Certainly when you want to use a rat to study protein quality, you get
> half its maximum growth rate. I don\'t think you\'d like that for a
> clinical study on infants. So if you want to answer about protein
> quality, you\'re going to have to do other types of research. There
> are such studies that are very, very complicated.
>
> I also make reference in here to the PER. This is a rat study. From my
> point of view, it has almost nothing to do with how acceptable a new
> protein source is for the quality of an infant formula because the
> amino acid requirements of an infant, as far as, say, patterns of
> amino acids, however you want to address it, are very, very different,
> certainly must be very, very different between the rat and\--but it is
> a very useful test. It is useful in the sense of if a formula is
> different, in other words, if I have done different heat processing, I
> have an ingredient that\'s interacting with the protein or something
> like that, it will tell me that something has changed in relationship
> to the protein in a PER study. And you better watch out. It is just
> like our attitude on the clinical growth study. It is a very sensitive
> test, but it is very non-specific. It doesn\'t tell you what is wrong.
> It says something is wrong. And that is very important to our work.
>
> I gave you some interesting examples in here in relationship to why I
> think we\'re a clinical study, and one of them I should mention
> because it got tossed into that, goat\'s milk. Goat\'s milk is a high
> quality protein. Why would somebody run a clinical study if you made
> an infant formula with it? Some of you even wondered.
>
> Well, from my point of view, it is certainly different from bovine
> milk. It certainly can interact, as the protein mixtures always
> will\--protein mixtures are complex mixtures, and they have a
> potential to interact with other ingredients, possibly to produce
> unsafe material or to change the quality of the protein. Our feeling
> would be that we would have to run a clinical study.
>
> I tried to think through and look at examples of ones that you might
> look at in relationship to protein quality, and they posed the
> question of: What if you used ultra-filtration to clean something out
> of soy protein isolate? Well, I said that wouldn\'t really need a
> clinical study. It certainly doesn\'t damage the soy protein isolate.
> It doesn\'t remove anything that you normally think of as nutrients.
> It removes phytoestrogens and assorted other materials. And so I think
> you could justify that you didn\'t need to run a clinical study.
>
> If we were faced with that situation, would we run a clinical study?
> Yes. I think so, Ross. You just wouldn\'t want to be sitting out there
> without it.
>
> I also made some derogatory remarks about protein hydrolyzates. They
> scare me to death because it makes\--and that\'s not the mild protein
> hydrolyzates. Some of you are smiling. These are the highly hydrolyzed
> mixtures that taste like mud and so forth. But they have a very
> definite use.
>
> The interaction of those with other ingredients in the formula is
> unbelievable. Certainly you would run a growth study of anything, you
> know, that received that kind of treatment.
>
> I think my time is running a little short. Let\'s go through\--because
> you can ask in questions if you have anything about carbohydrate
> sources, minerals, et cetera. To me they are relatively
> straightforward vitamin mixtures.
>
> Food additives is something that has bothered me, always has, the
> aspect of how you approve food additives. One of them\--probably the
> only one that has been studied adequately for an infant formula from
> my point of view is carrageenan. I\'m sure there are people that will
> argue with me about that. I spent my whole career working with
> carrageenan.
>
> Other additives, however, are based on are they safe for adult
> population at a level that they would be fed there. The intake in an
> infant can be so much greater and where it\'s the sole source of\--I
> put one example in here that I just wanted to show you of a product
> that is generally recognized as safe, or GRAS, as far as the Food and
> Drug Administration. It\'s considered to be perfectly safe to add to
> any food. FDA may disagree with me on that.
>
> But when we went into using this food additive, we found out that we
> knew nothing about its metabolism. We didn\'t know that the infants
> were going to be excreting large amounts of organic acids that we knew
> absolutely nothing about. And so we started out with rat studies and
> with labeled compounds to try to find out what in the devil was
> happening to\--in this case it\'s octenyl-succinic-anhydride-treated
> starch. And we found out that there were these organic acids that were
> being excreted in the urine, and I was proposing some rather extensive
> animal studies and hopefully to go into the studies later on. And
> after a while, the people in companies ended up spending quite a bit
> of money. They said, Do you think you\'re ever going to convince
> yourself these are safe? And they decided, oh, let\'s not keep dumping
> money into a hole.
>
> So as far as I know, our company did not use that additive, at least
> in the way we were talking about. But it was certainly one that there
> was no legal bar to its use, and I felt that there was an awful lot
> that had to be studied about what the material was.
>
> I also have the situation where at some time people came to me and
> said we think you have this horrible hydrolyzate formula, and we think
> it would be a wonderful idea if we could improve the flavor of it
> because the infants would consume more of it and grow more happily.
> Well, one, their food consumption was very good on it, even though it
> tasted\--I mean, you would never drink it. But you probably would have
> a hard time when the formula bottle was open and be in the same room
> with it.
>
> But, anyway, they wanted me to evaluate flavors and the possibility of
> feeding it to infants. And there are more than 2,000 flavoring
> compounds that are perfectly legal to use in foods, and I spent a lot
> of time looking over those. And where I could learn the information I
> needed about the metabolism and so forth, I had some serious
> reservations. Many of them I couldn\'t even find out what happened to
> the\--what would\--how they would be utilized.
>
> I don\'t know that we have flavored any infant formula\--I hope we
> don\'t, or I hope somebody around there goes back and does that over
> again, because I wasn\'t too happy with it.
>
> Now, I was asked to try to get criteria for the aspects of how you
> would evaluate whether a clinical study would meet\--it\'s right at
> the end of the paper. There are five aspects that we have here, and I
> guess it at least shows that I\'m a chemist because I feel I have to
> know the chemistry and the reactivity of anything that I put into an
> infant formula. And if somebody can\'t explain to me what it\'s going
> to interact with, what it\'s going to do, you know, I can\'t approve
> it going in there.
>
> Then you start proceeding to how is the infant going to metabolize
> this and do we know anything about that. And I think we ought to have
> some data, even before you go into a clinical study, but have a
> reasonable idea of the metabolism.
>
> Now, some of these things are easy. Sure, we use mono- and
> diglycerides as a multiplier in infant formula. Those are natural
> products of the digestion of fat. That\'s easy, both in the chemistry
> and the metabolism. But there are other things that are much more
> complex and sometimes require important research studies.
>
> Then you\'ve got to go through and evaluate your whole process, and
> this is something to get you to realize that the aspect of the
> clinical study is something that\'s going to come last. All of these
> things are going to be done. All of the chemistry, all of the stuff
> that\'s done in the pilot plant, is going to have to be worked out
> before anybody thinks about, you know, feeding it to an infant. And I
> think with good reason.
>
> But any change that we have made in the formula has to be thrown into
> the mixture and say how could it have changed some nutrient, some
> interaction of ingredient, or something like that, to damage it? We
> certainly have tremendously sophisticated chemists these days that can
> go in and tell us just an awful lot of things about what has happened
> when a nutrient is\--the state it is in a particular formula.
>
> And if we started to find out that it was very different from what was
> in existing formulas, I would have concerns and feel that you have to
> have it resolved even before you went into the clinical.
>
> Also, you should know whether you have any historical experience with
> similar formulas. In other words, if somebody\--you know, we need a
> new formula or marketing people have some idea that there\'s reason
> for one, and you adjust the amount of milk protein down a little and
> the whey protein up a little, and you, you know, shift a little in the
> amount of fat and some of these things, you can visualize, well, you
> know, gosh, we\'ve got all these clinical studies, and we\'ve done
> things almost identical with that. Why do you want to run a clinical
> study? And it\'s right. There isn\'t any reason if you have historical
> experience in clinical studies or experience out in the market that a
> very similar formula was the same way.
>
> But if you find that, no, it is very different, then you\'ve got to
> proceed to these other issues and try to answer the question of, you
> know, do we have enough knowledge to not run a clinical study? It\'s
> asking a negative. And it has to be that way.
>
> You also should ask yourself the question of whether there are going
> to be physiological effects, and as I note in here, people are always
> coming to us with marvelous ideas about some fancy carbohydrate that
> we can add or a new fat or something like that, and it\'s going to
> have some remarkable physiological effect. Well, it is?
>
> From my point of view, that means that\'s it. We certainly must at
> least run a growth study. No way are we going to, you know, not have
> that. But we also ought to be able to within that study try to
> understand\--try to measure something that will tell us whether it has
> that physiological effect, or any, and can it in any way be injurious?
> And don\'t tell me that, aw, but it\'s more like human milk. I do not
> think that human milk would be safe to feed to an infant if we
> processed it in the manner that we process infant formula. I don\'t
> think any of you can make it into a product that would be safe.
>
> Now, that\'s just something to remember in this. I\'m not saying
> anything against human milk or breast feeding at all. I\'m just saying
> we are tough on the stuff that we\'ve put into those bottles. And,
> yes, I know you give some heat treatment to the human milk that
> mothers collect and bring into the hospital. But you don\'t give it
> the kind of heat treatment we give it. No way.
>
> So these are the kinds of things that we have to do, and if you do get
> down through all of those and you\'re confident of all of these
> things, then you can draw the conclusion that, well, there isn\'t any
> real reason that you have to run a growth study. The likelihood of it
> is small. And often within our company, the consequence was, aw, run
> it anyway, even though it\'s expensive, because the last thing you
> want to do\--as I say here, one should use caution in drawing this
> conclusion. Why? Because if you\'re out there with the product and it
> doesn\'t perform the way you want it to, life will be unbearable.
>
> Can I answer questions?
>
> DR. GARZA: Thank you very much. Yes, I\'m sure you will.
>
> \[Laughter.\]
>
> DR. GARZA: Any questions? Don\'t make me\--Dr. Heubi?
>
> DR. HEUBI: Can you comment about pre-biotics and pro-biotics and what
> you would think a company would require in terms of proof that
> they\'re safe and potentially efficacious?
>
> DR. BENTON: Whew.
>
> DR. HEUBI: It would take an hour, huh?
>
> DR. BENTON: Well, I\'ve thought about the subject. It is scary. It
> probably could be done. You\'re dealing with types of materials that
> in most cases are going to be reactive, that you have no experience
> with intake of these materials at the kind of intakes that an infant
> is going to have. You really ought to be looking for various
> kinds\--for innumerable different effects that you would have on the
> infant or could have on the infant.
>
> I would have to have an individual example to try to deal with, and
> I\'d probably spend the next month in the library, at least, because
> it\--those are hard questions.
>
> DR. GARZA: Dr. Baker?
>
> DR. BAKER: You, I think, have made the best argument I\'ve heard for
> not including a breast-feeding control in infant trials. But I still
> have a little bit of a problem with the issue of a baby who\'s growing
> too fast. I think that we all agree that there are times when babies
> are growing too fast. How are you going to differentiate\--how are you
> going to tell whether your formula is giving optimal growth as opposed
> to good growth?
>
> DR. BENTON: Well, I think you can tell, one, I\'m not going to. But
> even back in the days when, you know, I would have been involved in
> any decision within the company trying to address that issue, it would
> have been an awesome process because I really view growth as a very,
> very complex thing. I mean, it\'s not a maximum thing of how much fat
> do you have in the baby and, you know, what muscles. I mean, it\'s
> down to the cellular level. It is innumerable things. And to say what
> is the right growth, you\'re going to have to look at those things at
> least to some degree, and you\'re going to have to have follow-up for
> a long, long time, you know, to draw that conclusion.
>
> DR. BAKER: I think some of us in this room would say that formula-fed
> babies are too fat or too big, and so we\'re trying to figure out is
> there a way to feed babies with formula just right. I think that\'s a
> real issue.
>
> DR. BENTON: Oh, well, Dr. Fomon did a series of studies at different
> caloric intakes, and these are perfectly adequate formulas. They just
> have a little more water added to them. And he was able to get down to
> a level that even scared him. He got down to 11 calories per ounce
> from 20 calories per ounce. And you\'ve got a different growth rate.
> At that point he was a little scared, and we did quit on some of those
> things.
>
> I was scared, too. But we could reduce the caloric concentration on
> the formula, and the way mothers would feed it, you would get a slower
> growth rate.
>
> I\'m fairly confident you probably would reduce the body fat some,
> although I\'m not so sure of that. Certainly the relationship of
> growth to body fat and so forth is a very, very complex issue. Long
> ago, when I was at Cornell, we studied that in the rat, and we could
> do tremendous things, although usually the rat followed constant
> increase of fat increase with time no matter the crazy things that we
> did to the poor creature. That relationship seemed to stay constant.
> But you would have to address it and do that.
>
> Of course, you could also reduce it by reducing the protein content of
> the feeding. I get scared of that, too. I guess you would say, hey, he
> gets scared awfully easily.
>
> DR. BAKER: But you wouldn\'t claim that that was optimal growth?
>
> DR. BENTON: I have no idea. I have no idea of what\'s optimal growth.
> I know that I have to sell an infant formula\--well, when I was out
> there, we had to sell an infant formula next week, and so we could not
> shut down and say, well, when we\'ve got an optimum formula and an
> optimum feeding pattern and an optimum\--got everything arranged, then
> we\'ll start, you know, introducing feeding again.
>
> I think our company would be very\--Ross Laboratories, my ex-company,
> would be very interested in participating in studies of that. The idea
> that as a stockholder in Abbott Laboratories I don\'t think they could
> afford it to fund the whole thing because it is an enormous project.
> But it might be possible to do it.
>
> But if, you know, somebody comes to you and says, well, that\'s easy
> to do, I don\'t think they understand the situation.
>
> DR. GARZA: We\'ll take one more question, if there is one more.
>
> DR. DOWNER: Thanks for such an interesting presentation. Did I hear
> you correctly in saying that in your opinion you didn\'t think that
> clinical trials were indicated as this time for the matter at hand?
>
> DR. BENTON: For what? Pardon?
>
> DR. DOWNER: Did I understand you to say that clinical trials in your
> opinion would not be indicated for the matter that we\'re discussing
> at hand?
>
> DR. BENTON: For formula we were discussing?
>
> DR. DOWNER: Did I understand you to say that you did not agree that
> clinical trials were needed at this time for the matter that we\'re
> discussing? You didn\'t say that then? Okay.
>
> DR. BENTON: No, I don\'t think so. Our comparisons would always be to
> an infant formula.
>
> DR. GARZA: I\'m sure we\'re going to come back to that during the
> general discussion, Duane, but let\'s move on to the next speaker.
> Thank you very much.
>
> The last presentation before we move on to that discussion is Dr.
> Denny Bier, who directs the ARS/USDA Children\'s Nutrition Research
> Center at Baylor College of Medicine, where he is professor of
> pediatrics. And he will be discussing clinical consideration in
> determining the need for clinical studies. Dr. Bier?
>
> DR. BIER: Okay. Duane said that the clinical studies come last. Well,
> here I am.
>
> Whereas I\'d like to make a few disclaimers, first, I was fed on
> evaporated milk formula.
>
> \[Laughter.\]
>
> DR. BIER: So if I say anything dumb, that\'s the reason.
>
> DR. GARZA: Should we add that your Dad was six feet tall?
>
> \[Laughter.\]
>
> DR. BIER: Right. And my mother won the Nobel Prize.
>
> Two, whereas I did nose around among my knowledgeable friends for
> opinions, although the ones I express here are my own, and Duane and
> Sam said they could say what they want because they\'re retired, and
> I\'m a director and my faculty thinks I\'m retired, so I can say
> anything I want here. Let\'s see. Forward, if I can figure it out. The
> round button? Okay.
>
> General operational principles for this talk are that as far as I can
> tell, today\'s formulas all contain\--contain all of the known
> essential nutrients, and we don\'t find nutritional deficiencies that
> we know about, and for this reason new additions to formulas are
> likely to be those which have other purposes besides simple
> replacement of nutrient deficiencies. And I have not considered things
> like\--no, no, that\'s not it. Okay.
>
> \[Laughter.\]
>
> DR. BIER: I\'m not going to press it again.
>
> I have not considered these things which we heard about this morning.
> That was good because we weren\'t supposed to consider them. I did
> leave out one important thing here, which is political considerations,
> which are certainly going to enter into whatever happens here later, I
> would assume.
>
> Okay. Real-life Investing 101. When the energy and metabolism bills
> are paid, Mother Nature makes a contribution to a growth fund. This is
> why measuring growth is so important, because it occurs when all the
> maintenance needs are met. So it\'s a fundamental indicator of
> adequacy. And many people have talked about this, but growth
> measurements are advantageous because they\'re simple, they can be
> measured accurately, precisely. They\'re not invasive. And, most
> importantly, they\'re non-specific, that is, they\'re the best generic
> indicator of the fact that something unanticipated may have gone wrong
> or may have happened.
>
> Factors controlling linear growth are different from those responsible
> for body weight accretion. For this reason, I think it\'s important to
> measure linear growth. Now, we had some discussion of this in various
> ways this morning, but the genetics that control linear growth is
> different than the genetics that controls accretion of body fat. The
> hormones and things and growth factors that control linear growth are
> different. So I think if we\'re talking about growth as a whole, we
> have to measure both weight accretion and linear growth.
>
> I do not believe that body composition measurements are mandatory for
> a clinical study today, for a formula study, because the relationships
> among body components and childhood\--infant, childhood, and adult
> outcomes are really not well established. And for that reason I would
> say it\'s nice to measure body composition. It\'s very important for
> research purposes, but it\'s not mandatory for routine clinical
> formula evaluation.
>
> My next guideline is that animal studies are never a sufficient
> substitute for human growth studies. Several people have addressed
> this today. Animal studies are necessary for proof of principle, for
> preclinical assessments of safety, for all sorts of other things. But
> the rat stops there, or the pig or the mouse or whatever.
>
> Species differences in all sorts of events that deal with growth and
> developmental characteristics, the hormones, growth factors, metabolic
> differences among animals, and the species-specific characteristics of
> milk components and how they respond to them just make it not
> realistic to substitute animal growth data for human growth data.
>
> Guideline 4 is that the presence of a substance in human milk is not
> sufficient in itself to eliminate the need for a human growth study.
> First, as I opened with, current formulas are nutrient sufficient, at
> least as far as I\'m concerned. The non-nutritive components of milk
> are not well characterized. Some enter milk passively. They come along
> with the movement of fluid and water and electrolytes. Many don\'t
> have any established purpose, and some have profound biological
> activity but their role in human growth and development is not well
> understood, for example, all the growth factors in colostrum.
>
> So another way of saying this would be that the non-nutritive
> components of breast milk, what their function is in humans today,
> many of those are hypotheses, and because they\'re hypotheses, they
> deserve to be tested. And then I\'d just like to remind you that there
> are compounds in human milk that you don\'t want there. For example,
> the infant\'s largest source of dioxin is breast milk. Now, that\'s
> not the mother\'s fault. But the infant\'s least source of dioxin is
> infant formula. There\'s no dioxin in infant formula. There\'s dioxin
> in breast milk and, therefore, we shouldn\'t use\--I\'m not trying to
> imply that anybody wants to put dioxin in infant formula. But it\'s
> just an indicator of the fact that its presence in human milk doesn\'t
> mean that it\'s necessarily safe or should be there.
>
> Guideline 5, I don\'t believe that data from post-marketing
> experiences elsewhere are really sufficient to substitute for a
> pre-market growth study. Post-marketing surveillance is largely an
> uncontrolled, anecdotal experiment. The validity of post-marketing
> data is heavily dependent upon the reporting of adverse events, and I
> think there are well-established and documented cases for reasons why
> people don\'t report adverse events. Sometimes they don\'t see them.
> They frequently attribute them to another causes. Sometimes they
> don\'t talk about them because of potential liability issues. And then
> they don\'t like to fill out the paperwork or get involved in
> answering questions about this. So there\'s a significant
> underreporting.
>
> I also don\'t believe that post-marketing surveillance is likely to
> detect subtle growth effects because of the range of normal infant
> growth and development and length, some of the things we heard about
> earlier, and then the various confounding effects that occur in
> routine clinical practice, and these are not going to be helpful, I
> think, in understanding control differences in new formula.
>
> Okay. Those are sort of guiding principles, and we were asked to
> provide criteria, and my first criterion is that an infant growth
> study is required if a substance is being added to human milk for the
> purpose of influencing human growth. Given all the things that
> are\--just, for example, colostrum growth factors, these sort of
> things that might someday be added to infant formula.
>
> If the stated purpose is because this material influences human
> growth, well, it seems to me you need a growth study. Now, this is a
> subset of a more generic question, and even though\--I forget who this
> morning said\--these are not on the table, I\'m going to throw in a
> few gratuitous comments. If one claims an effect or benefit for a
> material added to the formula, then you have to demonstrate the
> claimed effect or benefit. I think that should be a fundamental
> principle.
>
> The Working Group on the Nutritional Assessment of Infant Formulas of
> the Committee on Medical Aspects of Food and Nutrition Policy in the
> U.K. recently issued a statement which said \"the goal should be an
> hypothesized functional or clinical benefit based on defined outcome
> measures.\"
>
> \"Any modification which is hypothesized\--this should be \"or,\" I
> guess\--\"or claimed to have significant advantages should be subject
> to clinical trial.\" This is basically sort of the same generic
> principle.
>
> Okay. The sort of complement to that principle, Criterion 2, is that
> an infant growth study is required for macronutrients or other
> components that are known to affect the hormones, growth factors,
> genes, or metabolites that control human growth. So we have, you know,
> a variety of examples of that, things that, you know, for example,
> growth\--amino acids that are growth hormones, secretagogues. We have
> fatty acids that are known to have gene regulatory effects, things of
> this sort. And if that\'s the case, then one needs to do a growth
> study.
>
> Criterion 3, I would suggest that an infant growth study is required
> for formula changes that result in nutrient levels that are outside of
> established ranges. Now, I didn\'t quite know how to say this and it
> make sense, so I\'ll explain to you what I was thinking.
>
> First, I think it\'s time to update CFR 107 because it talks about, as
> I recollect, minimum levels of 29 nutrients, maximum levels of only
> 10. It exempts a variety of others, and I think we now have LSRO
> reports on term infant formula, preterm infant formula, and the new
> DRIs. And I think it\'s time to start establishing a new set of
> consensus ranges for term and preterm infant formulas. And that would
> also require addressing the exemptions that currently exist for
> preterm formula. Should it still be exempt? I mean, these are legal
> questions and regulatory issues. I don\'t know, but I think it\'s time
> to look at them again. And I think its time to address the issue of
> the various non-nutritive substances that people are considering or
> talking about may have benefit in infant formulas.
>
> Once that\'s done, you would have consensus ranges. You know, they
> might turn out to be regulations. I don\'t know. But you would have
> some relative established ranges. If they became statute, then it
> would be illegal to actually manufacture or to sell a formula that was
> outside those ranges. But hopefully science changes along the way or
> we advance in some way, and there will be a time when someone wants to
> test things that are outside of those ranges. And I think growth
> studies or studies of effect would be required for any proposed
> formulas that fall outside those ranges. And this is, in fact, you
> know, equivalent to the opinion of a recent workshop report from the
> European Society for Pediatric Gastroenterology, Hepatology, and
> Nutrition.
>
> Criterion 4, addition of an entirely new compound to formulas requires
> a clinical growth study. I also sort of slipped away from trying to
> define what I mean by an entirely new compound, but I mean things that
> haven\'t appeared in formula before.
>
> Now, as I mentioned, substances that are present in human milk, in my
> opinion, is not a sufficient reason for an exemption from this.
> Substances not present in human milk, again, for reasons we talked
> about earlier, animal studies are insufficient for establishing either
> safety or efficacy. A human study is required. If a human study is
> required, it contains several endpoint variables. One is growth as the
> non-specific variable of overall adequacy or identification of
> untoward effects, and then some primary endpoint variables that are
> relevant to testing the hypothesis of why you added this material in
> the first place.
>
> Criterion 5, all entirely new formulas require a growth study, and,
> again, I\'m not talking about legal definitions here. These will have
> to become legal definitions, but formulas that are not simply
> modifications of products already marketed in the U.S. For example, if
> one has a marketed formula and one changes the composition in a modest
> way\--and I don\'t want to try to define that here\--that would not
> necessarily fall into this category. But if an entirely new company is
> formed that\'s marketing an entirely brand-new formula that\'s never
> been marketed here before, even though they\'ve stolen it from Ross or
> Mead Johnson or somebody else and are now making it themselves, they
> would have to establish the proof of nutritional equivalency
> or\--equivalency to or superiority to marketed formulas because of the
> things we just heard about from Duane, that is, the different types of
> ingredients, ingredient sources, production and processing variables,
> matrix interactions, differences in absorption, bioavailability, et
> cetera. This coincides with the 1988 Academy of Pediatrics Task Force
> position.
>
> Then, finally, the last criterion is that formula alterations that are
> likely to affect GI function or nutrient bioavailability require a
> growth study, and it seems to me this is, again, sort of a fundamental
> axiom. I mean, the gastrointestinal tract is required to assure
> bioavailability. And if you put something into the gastrointestinal
> tract that affects the function of the gastrointestinal tract, you
> have to show me that the function is still adequate. There are known
> matrices that are more or less difficult to extract nutrients from,
> changes in macronutrient composition that affect absorption, for
> example, different types of fatty acids, enterocyte function,
> nutrients that react with enterocyte receptors and, in particular,
> gastrointestinal flora that have effects both among what the flora do
> in the intestinal lumen and how they interact with enterocyte
> receptors.
>
> Then, finally, something we didn\'t talk about at all here today that
> I recollect, things that might affect gastrointestinal motility that
> may affect the ability to absorb nutrients.
>
> So, with that, I will close and answer any questions.
>
> DR. GARZA: Thank you, Dr. Bier.
>
> Any questions? Dr. Stallings?
>
> DR. STALLINGS: Thank you. There were two things that I thought about
> while I was listening. Early on you were discussing body composition,
> and, you know, that\'s one of the things I think as a committee we\'re
> thinking about, the role that might play. And you made the distinction
> between body composition measures being appropriate for research and
> not appropriate\--and suggesting not appropriate or necessary for
> these infant feeding studies.
>
> And I think as I\'ve thought about this over the last, you know, few
> months that we\'ve been doing this, part of it is what is the quality
> of the research that\'s going to be required to bring products to
> market.
>
> So I\'m not trying to put you on the spot. Clearly, you\'re hearing
> some of that, too, that what we might be doing in our laboratories
> under protocols that we derived and are those really\--should those be
> different, we\'re trying to get at the same thing. So just maybe
> elaborate on that in that context.
>
> DR. BIER: Well, first, if someone wants to add body composition
> measurements to studies for licensing of a formula, I think that\'s
> entirely appropriate because I think we need far more information
> about what body composition means.
>
> Right now I don\'t know what to do with the data, so if you gave me an
> old formula, Formula A that\'s marketed and now you test Formula B and
> it has slightly more fat and whatever, I don\'t know what to do with
> that information. Does that make it better? Does that make it worse? I
> don\'t know. Certainly a lot of people would say, well, if the infant
> is slightly fatter, well, that makes it worse because they may be
> fatter later, and I would say that\'s an hypothesis that we certainly
> need to test a little bit more. So I\'m not sure I know what to do
> with the data. Once I understand from the research studies what to do
> with the data, then I think it might be required, you know, for a new
> formula. But right now I just don\'t the information\'s adequate.
>
> DR. STALLINGS: But you\'re making a bit of a distinction between the
> research and the activities the companies are doing\--
>
> DR. BIER: Okay. What we call research\--okay. You know, yes, I\'m
> talking about research for a primary scientific purpose as opposed to
> research for a licensing.
>
> DR. STALLINGS: Well, that leads nicely into the other question.
>
> DR. BIER: Good. I\'m glad I\'m baiting you.
>
> DR. STALLINGS: You did fine.
>
> \[Laughter.\]
>
> DR. STALLINGS: But the other thing you\'ve heard us contemplate here
> is what is the role of the pattern of growth of modern-day
> contemporary breast-fed babies and looking at if not optimum but
> desirable, or whatever we want to call it, what are your thoughts on
> that, because we have had 20 years of\--
>
> DR. BIER: I don\'t know what optimal is, and I know if I want to test
> a formula and know that it\'s adequate, I need to test it against
> other adequate formulas, not against breast milk, because I know it\'s
> going to be different than breast milk. And I think it was Duane who
> just said we may be able to produce formulas that are equivalent to
> breast milk, and until someone shows me that they are better in some
> long-term way, I don\'t know what that means.
>
> DR. STALLINGS: Thank you.
>
> DR. GARZA: Any other questions?
>
> \[No response.\]
>
> DR. GARZA: Taking Duane\'s suggestion that, in fact, because one can
> manipulate formulas in a variety of ways, theoretically at least, to
> be able to achieve a growth pattern that would be comparable to human
> milk, what formula would one use as a standard against which to judge,
> given the fact that formulas are evolving and changing over time?
>
> DR. BIER: You mean any new formula with regard to another formula?
>
> DR. GARZA: Yes. And if they\'re different, how do you decide if it\'s
> an improvement? Does following growth then become a moot point?
>
> DR. BIER: If it\'s an established\--if you\'re making a change in a
> formula that\'s compared to an established formula, then the
> established formula becomes one. If it\'s not, then I think what you
> have to resort to minimally are growth data from, you know, formula
> that babies, not breast-fed babies\--
>
> DR. GARZA: Does that in essence then become the desirable growth
> pattern? And what evidence is there that that, in fact\--
>
> DR. BIER: I don\'t know what a desirable growth pattern is, Bert. Can
> you tell me what that is?
>
> DR. GARZA: No, but\--well, I was trying to follow up.
>
> DR. BIER: Well, tell me. I don\'t know. I mean, I think that\'s what
> we struggle with.
>
> DR. GARZA: That\'s right. The logic of the proposition that, in fact,
> if one were to use a formula, then you have to choose the formula that
> you\'re going to be using to compare it with. And if growth is going
> to be the criterion and that becomes the control or the standard,
> then, in fact, a priori, one has decided what is the control or
> what\--a value judgment has been made.
>
> DR. BIER: I think that\'s a fair question, and I\'m not sure I, you
> know, know the answer. I think now we have a variety of infant
> formulas that at least by all nutritional criteria are adequate. I
> honestly don\'t know if we have the data sets that allow us to compare
> those to each other in these critical periods of time to determine
> what the noise is if we use any one versus the other. Perhaps the
> industry people can tell me that. But that would be something that
> would have to be established.
>
> DR. GARZA: The other implicit assumption is that one would use growth
> in isolation of any other information to be able to assess
> manipulations in a formula that would achieve a growth that\'s coming
> from human milk. One could use body composition or one could use
> growth rates at different periods, or one might be able to use
> metabolic indicators for adequacy to make sure that nothing was
> limiting growth in an adverse way.
>
> Among those three, which would you think would be the most relevant or
> which others?
>
> DR. BIER: Well, I was asked to talk about growth, so that\'s why I
> focused on that. I mentioned body composition because I don\'t think
> it\'s necessary. I think in the case of many of these ingredients, one
> would have to have a metabolic measurement. So if you\'re changing the
> iron content of milk, for example, you would certainly want to know
> what serum iron is or ferritin or something like that.
>
> I mean, I think it depends on what you\'re adding, and you have to add
> other components that allow you to test what the functional changes in
> the formula are.
>
> And, by the way, there maybe\--you know, I think your question also
> has in it this generic issue of if we re-establish what the minimum
> requirements are for testing formulas, which I understand the
> committee is now going to expand into those questions over time, yes,
> what besides growth is necessary and what are some of the fundamental
> things? We heard about neural development earlier. That\'s obviously
> terribly critical in formulas, and as you know, the latest additions
> to formulas, the LC PUFAs are in some degree based on changes that
> might occur in neural developmental outcome.
>
> DR. GARZA: We heard about Einstein formulas last time.
>
> Okay. Any other questions?
>
> DR. KUZMINSKI: I listened to your presentation, Dr. Bier, and to Dr.
> Benton\'s, and I\'d link\--both of which I appreciated very much. And
> I try to link material that I\'ve heard and read with the material
> presented in Table 1 that was presented to us right up front this
> morning and, coming out of that, conclude that there are very few
> instances where a change in formulation does not necessitate a growth
> study to validate the change effectiveness, the effectiveness of the
> change.
>
> And I guess I reflect a little bit that this is going to cause\--this
> is a gray area. I hear comments like depending upon the experience,
> internal experience of the manufacturer, the experience at the
> clinical testing organization, that would conclude that a growth test
> is needed or not, is it a serious change, is it a significant change?
>
> I guess I finally get to my question, that I suspect that this will
> cause difficulty for the agency to try and put a rope around to try
> and harness what is a significant change. What is a significant amount
> of internal experience that leads a manufacturer to judge that no
> trial, no growth trial is necessary?
>
> I\'d be very interested in your comments and Dr. Benton\'s comments on
> that observation.
>
> DR. BIER: Well, you noticed I avoided all of that in my talk.
>
> \[Laughter.\]
>
> DR. BIER: No, I mean, that\'s the nitty-gritty. I mean, we\'re going
> to\--there\'s going to be cases when you\'re doing something that\'s
> so outside of prior conventional practice that everyone will agree
> that you need a study. And then there are going to be minor
> modifications to formulas which I think most everyone in the room,
> including myself and people who think you need growth studies, will
> agree it\'s almost certainly unnecessary in this case if some
> information X, Y, and Z is established. That\'s where, you know, the
> FDA and the infant formula manufacturers and whoever address this will
> come to some functional rules. And I don\'t think they\'re going to be
> very easy to find. I just don\'t know\--you know, I don\'t think
> there\'s any simple rule. Well, the simplest rule is to say yes, any
> change of an infant formula requires a new study. That\'s the easy
> rule. But that\'s probably not going to be the functional.
>
> DR. GARZA: All right. Thank you very much, Denny.
>
> We\'re going to take a break now and come back at 3:45 and then have
> the speakers all come to the podium at that time for a more general
> discussion. Thank you.
>
> \[Recess.\]
>
> DR. GARZA: If we can get all the speakers to come up to the podium?
>
> We will try to go no later than 4:30 with the panel\--I\'m sorry, no,
> that\'s not the whole committee. Sorry about that.
>
> \[Laughter.\]
>
> DR. GARZA: We are good, but I fear we\'re not that good. We now have
> everyone assembled, so let\'s start with questions.
>
> Maybe we will done by 4:15.
>
> \[Laughter.\]
>
> DR. GARZA: Dr. Anderson?
>
> DR. ANDERSON: Imagine that I\'ve taken a marketed infant formula and
> added to it a new substance and that the only information that I have
> subsequently beyond safety is that in a clinical growth study the
> children who were first measured at 14 days had a distribution which
> was set right at the median of the CDC 2000 standards, and when
> measured at 1 months, 2 months, 3 months, and 6 months the
> weight-for-age, length-for-age, weight-for-length and head
> circumference was all centered at the 50th percentile with\--let\'s
> suppose that there were 100 such infants, and 2.5 percent of them were
> above the 97.5 percentile and 2.5 percent were below the 2.5
> percentile at each of the measurement points. Tell me why that
> particular formulation should not be approved for marketing.
>
> DR. FOMON: Because the ingredient that you\'ve added was supposed to
> be added for some purpose, and if it didn\'t accomplish that purpose,
> there is no point in approving the formula. If you\'re going to add
> something to a formula, you have a reason for adding it. If that
> reason is not substantiated, I don\'t think we\'re going to let you do
> it.
>
> Anybody else?
>
> \[No response.\]
>
> DR. GARZA: Do you want to follow up?
>
> DR. ANDERSON: Yes. So a natural consequence of that would be that a
> double-blind, randomized, controlled clinical trial that wasn\'t
> focused on\--that showed that there was no difference in growth
> between the new formula and the standard formula, in the absence of
> any measurements demonstrating that the additive had a desired effect
> would mean that such a formula would be inappropriate for marketing?
>
> DR. FOMON: As a member of the FDA decision team, I say you\'re right,
> it would not be appropriate to market it. There\'s no point in putting
> out just a whole series of formulas that are going to be marketed
> because of some proposed advantage if that advantage isn\'t present.
>
> DR. GRUMMER-STRAWN: Let me address that in a couple of directions.
> First of all, you haven\'t given us enough information to say whether
> we would want to approve it or not, because all that we\'ve looked at
> is the growth data. There may be other purported effects of this new
> additive that may have been demonstrated to be there. There may have
> been particular marketing reasons that the company feels is important.
> Those need to be evaluated, so there\'s a whole set of other
> characteristics that we might be interested in other than the growth
> data.
>
> But with regard to the growth data, how do we interpret that movement
> along the 50th percentile as the group mean? Really getting back to
> the discussion that I had with regard to Bert\'s question, the
> question is: What is the appropriate reference? What you have
> demonstrated to me is that this new formula leads children to grow in
> the way that they grow across the United States. Does that mean that
> it\'s a good formula? I don\'t know.
>
> Suppose that the previous formulation prior to adding this new
> ingredient had children growing starting at the 50th percentile and
> then falling off to the 25th percentile, and this new additive now has
> caused them to have a more rapid growth? Is that a good thing? I
> don\'t know. Back to the question Dr. Baker was asking. As we\'re in a
> situation in the United States with a growing epidemic of obesity,
> starting in young children, is it a good thing to have faster growth
> in the first 6 months of life or in the first 9 months of life? I
> don\'t know. But certainly I would question whether the way children
> are growing right now in the U.S. is the optimal set of circumstances.
>
> DR. GARZA: Dr. Bier? And please identify yourselves as you answer
> because whoever is recording this will have difficulties.
>
> DR. FRONGILLO: Ed Frongillo. Just to add to that, I guess a concern
> would be that, for example, the 2000 CDC reference has an admixture of
> infants who were fed in different ways, and we know that breast-fed
> infants, at least who have been intensively fed for some time
> exclusively on breast milk for some time, for a few months, grow quite
> differently. And the results that we looked at earlier showed that
> this has been replicated many times. In the Euro growth study, they
> show differences that are similar, not quite as large but very similar
> in pattern, and that\'s from a large, multi-country data set.
>
> So I think one of the concerns\--I mean, I think to me there\'s two
> parts to your question. One is you seem to be trying to push our
> thinking about are there any circumstances when an existing reference
> might be used as a comparator rather than, for example, a randomized
> clinical trial. And I think we should probably consider that part of
> the question.
>
> The other part is then what\'s the appropriate reference if you\'re
> going to use a reference. I would say the 2000 CDC is probably not the
> appropriate reference because of the admixture of breast-fed and
> formula-fed infants. If there was a reference group of formula-fed
> infants, one could maybe take up your question and think about are
> there circumstances when that\'s a good enough comparator that you
> would avoid the trouble of doing a randomized clinical trial. Well, I
> argued in my presentation that it would be hard to justify doing that
> because in this particular case, things kind of came out nicely. But
> when we do the study, we don\'t necessarily know how it\'s going to
> come out.
>
> DR. BIER: I\'d just like to go back to our mystery formula.
>
> You know, when you put a new ingredient in infant formula, you\'re
> doing a very big experiment on some number of children. And I think
> one of the fundamental principles of experimenting on children is
> there has to be a significant benefit-to-risk ratio or an
> insignificant risk-to-benefit ratio. Well, if you don\'t tell me the
> benefits, then the risk becomes infinite, or at least incalculable
> mathematically if you\'re dividing by zero.
>
> You know, it\'s almost impossible to prove that what you\'re going to
> add is infinitely safe. So it has to have, you know, the potential for
> some risk, and until you give me a reason for saying that the benefit
> outweighs the risk, I\'m reluctant to take the chance.
>
> DR. BENTON: Duane Benton. I guess I should comment on it. I certainly
> agree, I think, with all of the things that have been said. There
> isn\'t anybody in the industry that wants to get an ingredient in
> there that isn\'t there for some purpose. I mean, that\'s just going
> out there and looking for trouble. Every ingredient is trouble, and
> you\'re certainly not going to put something in that you can\'t find
> some kind of benefit for.
>
> Now, if, you know, a regulatory agency were to look at this and think
> that some marketing people had cooked up something that was off the
> wall for a so-called benefit, I think they\'d be highly justified in
> saying, Forget it, this doesn\'t even justify a clinical study. Don\'t
> come back to us and talk to us about it until you can tell me why
> you\'re adding it and what the benefit is.
>
> DR. GARZA: Dr. Stallings?
>
> DR. STALLINGS: To come back to one of the issues I think I\'ve been
> trying to get us to think of, and as our consultants, I want to pose
> it in a little bit different way. I\'m still intrigued by the idea of
> what the standard should be and knowing that none of us at this point
> in time know what\'s optimal. But if we weren\'t in the current
> environment where we didn\'t have the history of the current
> regulation and the history of a very successful program of, you know,
> the additive tests, the previous formula, and it was 2002 and we knew
> the epidemiology of growth in this country, if we were just starting
> from scratch, what would we think of as a good way to say what the
> normal pattern of growth is? Because I think we\'re struggling with
> two different things. One, we have a history of something that\'s been
> working pretty well, and in many ways it protects the population, and
> it\'s given industry a framework. But part of what we\'re being asked
> to do is to come back and really potentially look at it very freshly.
> And I think that\'s where I keep coming back to is the pattern of
> healthy children born to healthy mothers who are exclusively
> breast-fed, say, for the first 4 months of life, is that something as
> experts in pediatric nutrition and growth and statistics and\--you
> know, is that\--would that be a place to start if we didn\'t have the
> history that we\'re currently working on, and the pros and cons of
> that. I think it would be helpful for the committee to hear some of
> this.
>
> DR. CHUMLEA: Okay. I\'ll take a whack at that. You said\--
>
> DR. GARZA: Please identify yourself, Cameron.
>
> DR. CHUMLEA: I\'m sorry. Cameron Chumlea. You said, okay, basically in
> 2002 we\'ll start from scratch or we\'ll reinvent the wheel here.
> Okay. And then from whatever information we collect, we would be able
> to determine what optimal growth is. Is that\--
>
> DR. STALLINGS: I have a standard\--
>
> DR. CHUMLEA: I have a standard which we could do. Okay. We could do
> that, and we would find out basically pretty much that\'s what we did
> with NHANES III. It was a study just recently done of children,
> collect information, gives us status information.
>
> And if that was where we started, we wouldn\'t know that we have a
> problem of obesity because it\'s the previous studies that kind of
> gave us that. So we\'d be starting off with potentially false
> information or bad information.
>
> DR. STALLINGS: Four months. First 4 months of life.
>
> DR. CHUMLEA: Okay. In the first 4 months of life. So if we want to do
> this again, it will give us what is currently right now. Okay? If we
> did this in 1940, we would have gotten what\'s then, or 1929, or
> whatever. Each of those would be what was at that present time, and
> they\'re correct for the present time. But whether that\'s really the
> best or the end to meet all ends, none of us particularly know that.
>
> So if I was going to want to do that and to come up with the
> information and assuming that the federal budget is not an issue and
> we have plenty of money, you could do this by creating a sufficiently
> representative sample of children, multi-ethnic, both sexes. It would
> be very intense to collect the information. And we could collect,
> starting from birth and a multi-center study, the information that
> would give us both status and rate of growth from birth to 6 months.
> But you\'re talking lots and lots of money\--well, relatively.
>
> DR. FOMON: Okay. It\'s 2002, and we\'re throwing out everything we
> thought we had and starting over. And now we have ease of recruiting
> breast-fed babies. We know that they don\'t grow appreciably
> differently than formula-fed babies, providing we start at 14 days,
> because it takes the breast-fed baby a little longer to get on that
> post-natal growth spurt. So if you start at 8 days, then the
> breast-fed babies grow faster between 6 and 14 days because they\'re
> still in catch-up.
>
> So we start at 14 days, and we compare breast-fed babies and
> formula-fed babies, and there\'s nothing too much the matter with
> that. And if we demonstrate that we can\--that the growth of
> breast-fed babies now is the same as it was during the past 20 or 30
> years, we can use our big cohort of reference breast-fed babies. We
> have to\--if we\'re going to do it for a 4-month study, then the
> breast-fed babies presumably should have some rules like they\'re all
> solely breast-fed, and the formula-fed babies should have some rules
> like they don\'t get anything else except formula. But that would be
> feasible. I mean, I can\'t argue against that just because we\'re
> comparing formula-fed with breast-fed babies. For 4 months\--between
> 14 and 112 days it really doesn\'t make that much difference.
>
> DR. GRUMMER-STRAWN: Larry Grummer-Strawn. I think that the appropriate
> reference is largely as you described it, that I think we need to have
> a real prescriptive reference. I disagree with Cameron in terms of we
> could do this based on going out and sampling the U.S. population, not
> only because of the problem of obesity but because we have an
> admixture that Ed was talking about of a variety of ways of feeding,
> and we cannot conclude that somehow mixing all of that together is
> going to give us what\'s optimal.
>
> I think that in developing formulas, if we\'re starting from scratch
> and we don\'t have them in front of us, if we\'re developing formulas,
> we would want to develop those formulas to best match what Mother
> Nature offers us and what we have defined at this point in time as
> optimal feeding.
>
> It is true that 50 years from now we might think differently of what
> is truly optimal and we will have to re-evaluate that decision. But
> that is the nature of public health, that we always work with the best
> information that we have available to us. So I think the appropriate
> reference is to find the population that is feeding in the way that we
> currently think is the best way to feed.
>
> How we get there from where we are now I think is a very difficult
> question. I think we\'ve raised interesting issues in terms of we
> already have a formula that is producing a different kind of growth.
> It is not automatically better to\--any formula that moves in the
> direction of breast feeding is the right formula. So we can\'t
> immediately assume that that is a better formulation. But I think that
> somehow we need to figure out how to get back onto the track that
> Mother Nature would have us on.
>
> DR. BIER: Dennis Bier. I thought Sam was going to give us the history
> of this in the 20th century and it would save my guessing at it,
> because he was there, you know.
>
> \[Laughter.\]
>
> DR. BIER: I only guess. And my guess is we started out the 20th
> century with infants who were formula-fed, you know, not doing as well
> as breast-fed infants. And people developed the formulas, and, in
> fact, what they used as their standard was the health and growth of
> the breast-fed infant. And at some point in the middle of the century
> or slightly thereafter, they found out, yes, by God, we can make
> infants grow just as well and be just as healthy as breast-fed
> infants, in fact, even a little bit better.
>
> Now, if we weren\'t concerned about the hypothesis that these infants
> have more fat, maybe, and are getting fatter on that basis later in
> life, the hypothesis that this is true, what would be arguing about
> here as far as breast and formula feeding? They\'re as healthy. They
> grow slightly better, if not the same or slightly better. So, you
> know, our concern here about too much growth is based on accretion of
> body fat. And any standard relative to that is going to be an
> arbitrary number based on someone\'s belief at this moment, in my
> estimation.
>
> DR. FRONGILLO: Ed Frongillo. Virginia, if I understand the question
> you were asking, if we could start over and dismiss the 20th century
> and we\'re now in the 21st century, what would be an appropriate
> reference? But then I think that begs the question of: For what
> question, for what purpose? What is one trying to evaluate?
>
> For example, if our only concern is are the nutrients adequate and
> we\'re not really interested in growth itself but we\'re interested in
> the fact that growth represents the summation of a whole series of
> processes that include having adequate micro- and macronutrients,
> that\'s one question. That\'s a very different question than does it
> lead to growth per se that we think is optimal. And even that could
> have a time frame of the first 4 months, say, or first 6 months, or it
> could have a much longer time frame. I mean, there is some
> evidence\--I don\'t think it\'s terribly compelling yet in its
> magnitude, but there\'s certainly evidence that exclusively breast-fed
> infants tend to be less obese later one.
>
> Now, one could pose a question that we would like to have the growth
> that sort of represents not just satisfying the nutrient needs of the
> infant and some pattern of growth that we think represents optimal for
> now, but something that tells us something about what\'s going to
> happen with this infant in the future. And so how we think about will
> probably determine what choice we make of the reference.
>
> I think Sam is right in the sense that there are certain windows\--if
> you took perhaps the mid maybe 1 month to 4 months\--I don\'t know
> exactly, somewhere in there\--you\'d probably find on average that the
> amount of growth of breast-fed infants and formula-fed infants, the
> growth that\'s accrued during that time is about the same. They
> probably got there differently over that period. If you extend it to 6
> months, you\'d probably find out they\'re not quite the same.
>
> One of the things that we should recognize is that there\'s been lots
> of studies done now that have shown that breast-fed and formula-fed
> infants don\'t\--their pattern of growth isn\'t the same through the
> first year. Everything we know tells us that by 24 months they\'ve
> come back together. But those studies have been done. A lot of that
> has been motivated by\--and I should have said this when I talked
> about the WHO Multi-center Growth Reference Study this morning\--has
> been motivated by the management problems that have resulted from this
> discrepancy and pattern so that the concern has been that infants who
> are breast-fed appear to be faltering relative to the current
> international previous U.S. reference. That management problem has
> been a major motivator in going ahead with a breast-fed based
> reference.
>
> So many of the studies have examined the differences in patterns in
> light of that question. Here we\'re asking a different question. And
> it may be that some effort to evaluate perhaps the Iowa data that have
> infants from both feeding modes might tell us something about this
> question that we\'ve kind of overlooked in asking a different
> question.
>
> DR. GARZA: A related question that is useful for the panel to discuss
> relates to Virginia\'s question. Given the fact that we don\'t have
> long-term data to try to assess the functional consequences of
> different growth patterns in the first year of life, where should the
> burden of proof lie in terms of should we assume than that
> differences, until proven otherwise, are significant? Or should we
> assume that differences, until proven otherwise, are not?
>
> DR. FRONGILLO: Can I just ask, for my benefit, at least, for
> clarification? Differences from what to what?
>
> DR. GARZA: Growth patterns, the first year of life, breast versus
> formula, I mean, or one formula versus another formula.
>
> DR. STALLINGS: But you\'re getting into long-term\--
>
> DR. GARZA: Long-term\--given the fact that we keep referring to the
> fact that we can\'t\--we don\'t have long-term data that try to assess
> the functional consequences of growth differences in the first year of
> life\--
>
> DR. CHUMLEA: What\'s long term?
>
> DR. GARZA: Seven years, 15 years, 30 years, I mean, however you choose
> to define it, there are data, for example, now suggesting that certain
> growth patterns may predispose children to obesity.
>
> DR. FRONGILLO: But I think\--I\'ll turn this to somebody else who has
> an answer, because I don\'t, but\--
>
> \[Laughter.\]
>
> DR. GARZA: We agree to do the difficult, the impossible, but we\'re
> contracting out to you guys.
>
> \[Laughter.\]
>
> DR. FRONGILLO: But it seems to me that question you\'re asking, Bert,
> there\'s at least two aspects to the scope of that. One could be\--has
> to do with formulas versus breast feeding, and if we started again at
> the 21st century, would we ever agree to have infants fed on any
> formula? That\'s a very different question than saying given that
> we\'ve already accepted that infants can be, should be in many cases
> fed on formula, about differences among the formulas. Those are
> different issues.
>
> DR. BENTON: I may be sort of throwing a question back at you instead
> of trying to answer it. But I am really perplexed in the sense that
> you people seem to think that what you are seeing in difference in
> growth patterns has something to do with nutrition. And I have no
> confidence in that at all. I mean, clearly, breast feeding is an
> interaction between the mother and the infant. And what the infant
> consumes is very determined in that process. And if that is the case,
> what is changed is in the breast-feeding process and how it changes
> the baby and how it changes the mother and her outlook on feeding and
> so forth. Our fooling around with formula to try to duplicate that is
> utterly hopeless.
>
> Now, clearly, if you want to have studies to do this, you\'re going to
> have to have randomly assigned feedings. And you know\--
>
> DR. ANDERSON: Yes.
>
> \[Laughter.\]
>
> DR. GARZA: Are you saying, Duane, just so I understand, that you think
> it\'s due to feeding behaviors between\--differences between the two
> groups?
>
> DR. BENTON: Because \[inaudible - off microphone\] I mean, they\'re
> not at that critical \[inaudible\]. It is later you\'re seeing the
> striking differences. And that is the point at which, you know, it\'s
> the mother and the infant and how they\'re interacting. I guess the
> other way you study it is you trade in \[inaudible\] mothers.
>
> \[Laughter.\]
>
> DR. GARZA: You think that would be true cross-culturally, I mean, the
> fact that these differences are seen in all settings, that, in fact,
> it still reflects behavior. Okay.
>
> DR. FOMON: Fomon. First time. Bert, in answer to your question, and
> putting it, if I may, in the context of testing a new formula, if we
> don\'t know the consequences of more or less rapid growth during the
> first 4 months, all we have left is the comparison of how they grow in
> the first 4 months. And that\'s all we can do now. Either they grow as
> we anticipate on the basis of a cohort of breast-fed babies or a
> cohort of formula-fed babies, or they grow the same, and that\'s all
> we can do. There is very little in the literature that tells you how
> growth during the first 4 months relates to any subsequent time.
>
> DR. GARZA: Let me follow up because you\'ve made an important point.
> Let\'s assume, then, that one can\--given the fact that in Duane\'s
> presentation, he clearly pointed out that one can manipulate growth in
> a variety of ways by formula changes. How useful would body
> composition be in assessing both differences as well as similarities
> in growth pattern given what we heard in Dr. Ellis\' presentation and
> DXA? Would that be of any use in helping assess the nature of the
> differences or similarities, or do you feel that that would be either
> trivial or not very useful?
>
> DR. FOMON: I think it would give you very little information at
> considerable cost in what you would get from measuring length and
> weight, if done properly.
>
> DR. FRONGILLO: Ed Frongillo. Comments to add to what Duane said. I
> think that we know\--Bert knows this more than just about
> anybody\--that human milk is a biologically active substance. There
> are regulatory factors there that we don\'t really understand very
> well. So in addition to the perhaps maybe behavioral differences, it
> could be that some of the hormonal substances in milk play some role
> in determining the pattern that ensues after that.
>
> And then in response to your last question, I agree with Sam that for
> the kinds of questions that are being asked, it seems that having both
> weight and length information would be important. Whether\--
>
> DR. GARZA: No one argues with that. Body composition\--
>
> DR. FRONGILLO: And whether or not there\'d be any additional value of
> body composition on top of that, I would be skeptical that that would
> bring much more information relative to the work that would be
> required.
>
> DR. CHUMLEA: I\'d just add, going back one question, to the effects
> within the first 4 months on some subsequent event, since we have
> recorded information rather than anecdotal information, and the issue,
> say, 15 years ago was that babies became fat adults type thing. In the
> analysis of Fels data, there was no indication that anything before,
> in terms of skinfolds and weight before 2 years of age had any impact
> upon subsequent levels of obesity by 5 or 6 that did affect, and, of
> course, Sun\'s been happily able to show that changes in weight
> stature, BMI stature are very predictive of\--in childhood and
> adolescence are very predictive of subsequent risk for obesity in
> adulthood, but nothing that shows up within the first 2 years. Going
> to kind of what\'s called the Barker hypothesis, we\'ve got blood
> pressure. We\'ve looked at birth weights. There\'s nothing within Fels
> where we actually have recorded information and any information of
> adulthood that has any link whatsoever.
>
> From a nutritional standpoint, we actually have seven-day dietary
> records that were collected from the children. What we have noticed in
> the preliminary analysis of that is that nutrition potentially in late
> childhood, say 8 to 12 years of age, and early adolescence, 12 to 16,
> does have predictive values on bone mineral density in terms of milk
> consumption in adulthood. But nothing before that has any
> relationship\--and we\'ve got dietary records back as early as 6
> months of age. So nothing there links up. So I think frankly that the
> infant is extremely plastic and can absorb a lot of insults or
> whatever that goes on and nature has it so that pretty much it can
> take whatever abuse we\'re going to give them, and they\'re still
> going to probably turn out pretty good.
>
> \[Laughter.\]
>
> DR. ELLIS: It\'s just like we\'re saying, that we don\'t know what the
> translation is at this point for babies between, say, in the first 4
> months or 6 months of life really what that translation is down the
> road. We do know that, like Cameron has said, when you get to age 3,
> that there are relationships. Of course, the closer you get to
> adulthood, the stronger the correlations would be, which is
> understandable. Of course, again the 3 to 5, whatever, the main
> factors going between the first 6 months and there, environmental,
> genetic issues, even behavior issues and so forth, that are going to
> compound a simple relationship between what goes on the first 6 months
> and later.
>
> However, most people do argue that unless there\'s something unusual
> about a child, they tend to track along the same percentile. And so
> presumably then if you have a high percentile, in terms of being
> percentiles, you\'re a high fat baby or a high probability of any
> increased fat, and, therefore, presumably those are the ones who also
> appear in the higher percentiles later on.
>
> Again, today can you say for certain a baby was 30 percent fat versus
> one who\'s 15 percent fat, that he or she has a higher probability of
> developing cardiovascular disease or obesity or diabetes? The answer
> is no, we don\'t know that.
>
> DR. SIGMAN-GRANT: Sigman-Grant. My two questions are going to just
> demonstrate my ignorance, but be that as it may, nobody mentioned head
> circumference. Is there any difference between, say, formula-fed and
> breast-fed babies in relationship to head circumference?
>
> DR. FOMON: Head circumference in a normal baby is proportional to
> length. And head circumference\--increase in head circumference is
> proportional to increase in length. The value of head circumference is
> in detecting discrepancy between gains in head circumference and gains
> on length, which has neurologic, diagnostic implications.
>
> DR. SIGMAN-GRANT: And my other question is: Is there any difference in
> organ weight betweens breast-fed babies and formula\--and I know that
> there\'s only one way to look at that. However, I\'m just curious
> because we talk about gross\--you know, gross weight and gross percent
> fat versus\--I know, but that\'s\--the reason I ask that is because of
> the potential bioactive compounds in human milk and its relationship
> to stimulating GI growth and that kind of thing.
>
> DR. FOMON: I can answer that question.
>
> \[Laughter.\]
>
> DR. FOMON: The answer is I don\'t know.
>
> \[Laughter.\]
>
> DR. FOMON: And I don\'t think anybody knows.
>
> DR. GARZA: Although there are some scattered reports at least that
> have been done with sonography for thymus differences. But I don\'t
> know whether they\'ve been replicated, and for thyroid, I think as
> well. But I don\'t think those have been replicated, and they\'ve been
> done indirectly rather than by direct examination.
>
> DR. SIGMAN-GRANT: Well, I bring that up not to be facetious. It\'s to
> ask a question. There\'s just another thing we don\'t\...
>
> DR. FOMON: Any other questions that none of us can answer?
>
> \[Laughter.\]
>
> DR. GARZA: Is their pay dependent upon whether they can answer these
> questions?
>
> Any other questions from the group? This group will be here tomorrow,
> but we should not be shy. Dr. Anderson?
>
> DR. ANDERSON: Supposing the development of the infant formulas
> containing very long chain fatty acids, no growth studies have been
> done, but there was evidence of the benefit of neurologic development
> at 24 months or 36 months and the additives were generally recognized
> as safe. Anybody willing to proceed without a growth study?
>
> DR. BIER: No, because there is a priori evidence that fatty acids,
> particularly polyunsaturated fatty acids, can have effects on
> acosinoid (ph) metabolism. They have effects on activating fatty acid
> oxidation genes, you know, reducing fat synthesis genes. So we have a
> lot of a priori information that suggests we should do a growth study.
> So the answer would be no.
>
> DR. GARZA: I certainly want to thank each of you for being so patient
> with this committee and its unreasonable demands of you.
>
> \[Laughter.\]
>
> DR. GARZA: But we will continue being unreasonable. I hope that each
> of you can join us tomorrow.
>
> We\'re going to turn now\--and you are certainly welcome to join us as
> we begin going through the seven questions. You all have these in your
> packets. I\'d like to see if we could get through the first section on
> metrics for the evaluation of normal physical growth before we
> adjourn, and if possible, to take on at least part of No. 4 and 5.
>
> Before getting into that discussion, though, there is one item of
> take-home work for each of us, unless you can figure out a better way
> of doing it. That is, if you look at Question 7, what I\'d like each
> of you to try to do this evening\--on your own, it doesn\'t have to be
> done as a group activity\--is to\--well, it can\'t be done as a group
> activity, anyway\--is to look at some specific\--pick one or two
> specific changes in infant formula that you think would reasonably be
> expected to be accompanied by a clinical study. That is Part B to that
> question. And then use that as a basis for trying to come up with
> general principles and criteria that led you to that decision. Or you
> can do it in reverse, but if you can choose a specific example and
> guidelines and criteria, I think that if each of us brings those to
> the table tomorrow, then we might be able to agree on general
> principles or criteria that we would be able to answer Question 7
> within the time frame that we\'ve got.
>
> In the absence of that preparation, I think it may be more difficult
> for us to get there.
>
> You can pick an original one or go to Table 1. It\'s whatever\--so
> that if I want to deal with it in less than the abstract\--Roger?
>
> DR. CLEMENS: Roger Clemens. To that point, Item 7, first of all, I was
> a 17-kilo baby at 12 months. And you\'d probably say I should have
> been very big right now.
>
> DR. GARZA: Well, you do look big.
>
> \[Laughter.\]
>
> DR. CLEMENS: I must admit, I am taller than anyone in my family, if
> that has any merit. Just to help with Item 7, the IFC, the
> International Formula Council, provided each member here on the panel
> with a diagram\--a decision tree for documentation of nutritional
> adequacy. This was to have been mailed out to everyone, but I wasn\'t
> certain that everyone received a copy.
>
> DR. GARZA: We received it about a week ago.
>
> DR. CLEMENS: That\'s great, because I did not, Bert.
>
> \[Simultaneous conversation.\]
>
> DR. CLEMENS: \--copy of that decision tree. Thank you very much. I
> appreciate the fine work that Jeanne has done on that point.
>
> Also, just a comment, because Moski (ph) had made a comment from the
> CDC on examples that would not necessarily require clinical trials.
> Again, on the handout that was provided on the clinical protocol that
> has been followed by the IFC members for the last 20 years,
> fundamentally, you\'ll see that on page 6 there is a list of about
> eight items, of which under the current regulatory guidelines do not
> require additional clinical trials. That doesn\'t mean that the
> companies won\'t do them. It just says they\'re currently not
> required. I just want to bring that to light to everyone.
>
> DR. GARZA: If some of you did not get the e-mail, you should let\--
>
> DR. CLEMENS: They were all distributed. It\'s just a case of
> e-mails\--
>
> DR. GARZA: If you haven\'t received that type of information, then
> either the e-mail system is not working\--but it was sent out. I know
> that I received it about a week ago along with three or four other
> items on the attachments.
>
> DR. CLEMENS: I appreciate that, Bert. I just bring out No. 7 in
> particular because you talked about the items, and I want to be sure I
> have that as a guideline because it talks about those changes, what
> changes would require clinical trials under this current environment
> versus those which would not.
>
> DR. GARZA: I\'m glad you raise that. I\'m just more concerned about
> whether information committee members may not have received that was
> shared\--
>
> DR. HEUBI: I have this letter from IFC but didn\'t get this document.
>
> DR. CLEMENS: See, that was my fear that they did not receive all the
> documentation. Thank you for the opportunity to share that.
>
> DR. GARZA: All right. Then is dealing with Item 7 in the way that
> I\'ve described acceptable to the group so I don\'t surprise you
> tomorrow morning? I\'ll turn to each of you and say no.
>
> All right. Then with that housekeeping item, let\'s turn to
> Question 1. And we agreed that we would do this for term and preterms
> this morning as we reviewed the questions. It\'s asking us to group
> the following metrics in terms of clinical usefulness as endpoints,
> and I would suggest that we try a grouping scheme that says extremely
> useful or mandatory or whatever, of moderate use, C, of no use, or, D,
> it\'s still in the research area and we really can\'t comment on
> whether it\'s of high, medium, or no use without additional research
> because there\'s enough biological plausibility or there\'s enough
> potential interest in the item that we would want to get it, but we
> just don\'t have enough information to make a judgment.
>
> That\'s one suggested grouping. I don\'t know whether you may\--and it
> doesn\'t mean that we need to fill in each of those cells. But that\'s
> the grouping that came to my mind as I reviewed this question when
> they were first sent.
>
> Is that acceptable to the group? Okay. Then would you like me to call
> on each of you, or do you want a period of discussion before we do
> that? All right. Then why don\'t I start with Dr. Baker. Is that all
> right?
>
> DR. BAKER: Let\'s see if I\'ve got this charge properly. You want me
> to go through each of these measures and say whether they\'re
> mandatory for a growth study, whether they would be useful for a
> growth study, or not so useful, and then if they are experimental and
> not\--
>
> DR. GARZA: Without further research, you really can\'t put them in any
> box, but of interest, but, in fact, the research should be done.
>
> DR. BAKER: Well, I think the first two should be mandatory without a
> doubt. The third, head circumference, it\'s certainly not in the
> experimental stage. I think it\'s accurate, but I don\'t see where
> it\'s useful for a growth study alone. So I would say it would be
> helpful but not mandatory.
>
> I think the same thing goes for skinfold thicknesses. I think that the
> major amount of information would be\--is obtained through the body
> weight and length. Skinfold thicknesses would be additional
> information that\'s useful. The accuracy is somewhat less, and I would
> say it\'s probably not mandatory.
>
> Bioelectrical impedance, I don\'t think it\'s a stage where you can
> clinically use it, so scientifically I don\'t think it\'s appropriate
> yet.
>
> Stable isotopes\--
>
> DR. GARZA: I\'m sorry. Would you put that in the third category, No.
> 3, research?
>
> DR. BAKER: Research. Stable isotopes I think are at the stage where
> you can use them but not practical, so I would put that as\...
>
> DR. GARZA: Can you define \"practical\" for the group?
>
> DR. BAKER: It\'s not practical in terms of the money that it would
> require, the testing, the exposure, the instrumentation, the\--
>
> DR. GARZA: Is that relative to the benefit?
>
> DR. BAKER: \--the repeatability of the study, so I don\'t think it\'s
> practical to use it for a growth study.
>
> The final one\--
>
> DR. GARZA: DXA is\--
>
> DR. BAKER: DXA. DXA I think is\--would be in the category of very
> helpful but probably not required. Again, I think it relates to the
> feasibility of doing it, the availability of the testing, the time
> that\'s required, and, therefore, the money that\'s involved.
>
> DR. GARZA: Any other physical body measurements or body composition
> measurements that are not in that list that you would like to add?
>
> DR. BAKER: I\'m not coming up with any. Underwater weighing\--
>
> \[Laughter.\]
>
> DR. GARZA: Mothers may object. Okay. Dr. Stallings?
>
> DR. STALLINGS: Body weight and recumbent linked, would those be
> essential? I have more interest in head circumference, and so I put
> that in the second category of moderate interest.
>
> The two skinfolds that we discussed, triceps and sub-scapular, I would
> put in moderate interest. I think bioelectrical impedance will not
> play out, so I have it in no use in the age group we\'re looking at.
>
> Stable isotopes research, DXA in moderate interest because I think it
> may be a method that will help us in the future if we go down that
> way.
>
> And the only other physical measurement that I felt like was missing
> would be the mid-arm circumference, and there\'s a history in neonatal
> care of using a head circumference, mid-arm circumference measurement
> that at times has been helpful in the research. So I would put that
> with the skinfolds under research interest.
>
> DR. GARZA: Can we get that down? Dr. Heubi?
>
> DR. HEUBI: Can I say \"ditto\"?
>
> \[Simultaneous conversation.\]
>
> DR. GARZA: \--literally with everything, but\--
>
> DR. HEUBI: I don\'t have really much\--
>
> DR. GARZA: But who\'s ditto because they differed a little bit?
>
> DR. HEUBI: Ginanne\'s.
>
> DR. GARZA: Okay. I think I almost totally agree with what she said. I
> don\'t know that I\'ll add much by making any more comments than that.
>
> DR. GARZA: That\'s fair. Dr. Anderson?
>
> DR. ANDERSON: Obviously, this is not an area of expertise for me, but
> based on today\'s discussions\--
>
> DR. GARZA: This is for term infants. We\'re going to do this again for
> preterm, so I just want to make sure everybody understands that.
>
> DR. ANDERSON: It seemed to me that my enthusiasm for head
> circumference is somewhat greater than what I\'ve heard so far in
> light of what we heard about the relative correlation of length to
> head circumference and its ability to potentially identify deviations
> from standard neurologic development. Beyond that, I don\'t have
> anything to add.
>
> DR. GARZA: You would classify head circumference then in the
> necessary\--
>
> DR. ANDERSON: Yes.
>
> DR. DOWNER: Body weight, recumbent length, and head circumference
> would all be mandatory. Skinfold thickness I would put moderate.
> Bioelectrical impedance, do some more research on that. Stable isotope
> as well as the DXA, additional research. And for other physical body
> measurements, I too think that arm circumference may be of interest.
>
> DR. GARZA: And you would put it in which category?
>
> DR. DOWNER: Not moderate, but additional research. Additional
> research.
>
> DR. GARZA: All right. Thank you.
>
> Dr. Sigman-Grant?
>
> DR. SIGMAN-GRANT: The first three essential, body weight, length, and
> head circumference. Skinfold thickness, I think it\'s moderate
> interest at this point. Bioelectrical impedance, I\'d say no. Same
> thing for stable isotopes. It\'s a research, but it wouldn\'t be
> mandatory. I think there\'s potential in DXA, and I can\'t think of
> any other physical body measurements, but I think we should start
> thinking about getting out of the box, and maybe there could possibly
> be.
>
> DR. GARZA: Any examples?
>
> DR. SIGMAN-GRANT: Nothing that wouldn\'t be like MRI or\--I don\'t
> even know, echograms or something like that. We can look at\--but
> it\'s not my area particularly.
>
> DR. GARZA: All right. Yes?
>
> DR. MOYER-MILEUR: Moyer-Mileur. I would agree that the first three,
> body weight, recumbent length, and head circumference, should be
> mandatory. Skinfold thickness would be of moderate use. Bioelectrical
> impedance I don\'t think has a valid reason for use in infants. Stable
> isotopes for research, DXA I think would\--could prove to be very
> useful with a number of caveats. And then there are other physical
> body measurements such as air displacement and TOBEC that potentially
> would be of moderate usefulness.
>
> DR. GARZA: Okay. Dr. Kuzminski?
>
> DR. KUZMINSKI: Sure. Thank you. Kuzminski. Again, this is not my area
> of expertise. I only know what I\'ve read in the book and what I\'ve
> heard in the discussions today. As mandatory, I would think body
> weight, recumbent length, and head circumference. Interesting, but not
> mandatory, certainly, skinfold thickness, but interesting.
>
> I agree with the comment of looking towards the future, thinking out
> of the box in terms of traditional measurements, and maybe DXA falls
> into that category. And the others I would classify as research.
>
> DR. GARZA: So you would put DXA into the research category or into a
> category that ought to be requested or\--I\'m\--
>
> DR. KUZMINSKI: Useful category.
>
> DR. GARZA: Okay. Now, just to help the recording, it may be difficult.
> We\'ve got, gee, it should absolutely be of use, moderate, might be
> useful, so you would put it in that second category then, DXA, along
> with skinfold thickness? Okay. Good. I wanted to make sure I
> understood that. Thank you.
>
> DR. DENNE: Denne. I would also include body weight, length, and head
> circumference as mandatory, and I would put head circumference there
> because it really is our only surrogate measure of neurologic outcome
> and reflective of brain growth. So I think it belongs there.
>
> Skinfold thickness is sort of moderate. Bioelectrical impedance, as
> discussed before, probably not useful, and the other techniques,
> research.
>
> DR. GARZA: Okay.
>
> DR. THUREEN: Thureen. I agree that the first three are essential.
> Skinfold thickness is of moderate interest, and I always do mid-arm
> circumference with skinfold, so I\'d put those in the same group.
>
> Bioelectrical impedance I think is probably of no use at this point.
>
> Stable isotopes and other physical measurements are research tools,
> and DXA I have mixed feelings about because I think in most instances
> it\'s a research tool because it\'s not widely available. On the other
> hand, I think it\'s probably going to be of some significant use in
> the future, so it\'s kind of between the second and fourth category
> for me, but at this point I guess I\'d call it a research tool.
>
> DR. GARZA: Okay. Thank you.
>
> Dr. Briley?
>
> DR. BRILEY: Briley. The first three I think are of great use, skinfold
> thickness moderate, and the bioelectrical impedance, not yet. And the
> isotope and the DXA are research tools. I just wish that industry
> could get it down to it would be less costly piece of equipment. And
> the last is research also.
>
> DR. GARZA: All right. Roger, would you have any comments?
>
> DR. CLEMENS: I certainly agree with the \[inaudible - off
> microphone\]. I certainly agree with the rest of the \[inaudible\]
> research tool \[inaudible\] more cost-effective, technology will
> change \[inaudible\].
>
> \[Laughter.\]
>
> VOICES: Say it again.
>
> DR. GARZA: No, we won\'t ask him to do that. That\'s all right.
>
> There is a fair consensus on the first category in terms of body
> weight, recumbent length, and head circumference. I realize that it
> isn\'t unanimous, but generally as close as we come. Would anyone like
> to object to it being characterized in that way on the committee? With
> skinfold thickness as being of moderate interest, DXA at times was
> placed there, at other times it was put with research, but
> predominantly as a research tool. Is there any objection if the
> minutes record that in the end the discussion said, well, it\'s more
> of a research tool right now but one that we would recommend highly to
> FDA to get more information on because of its potential usefulness in
> future assessments? Or do you want to say no, it\'s of moderate
> interest? Ginanne?
>
> DR. STALLINGS: I\'d\--
>
> DR. GARZA: You need a mike. I\'m sorry. Otherwise\--I may get away
> with not asking you to repeat once, but possibly not twice.
>
> DR. STALLINGS: Stallings. I\'d like to pause and have a little bit
> more discussion of that, because I think it is going to be very
> available and is in most centers\--and if you do some of the study
> kinds of things, like having the phantom and centralize the assessment
> and that sort of thing. I think it\'s moving forward fairly quickly.
> So I\'m lobbying to keep it on the\--out of the research only and into
> the moderate. Certainly it might not be appropriate for everything
> we\'re doing, but there\'s so much interest both in body fatness and
> the childhood issues related to osteoporosis that I think those
> two\--this is the measurement that give you some assessment of bone
> health and some assessment of body adiposity. So that was why I was
> putting it in the moderate rather than research only.
>
> There\'s a comment from the floor. I don\'t know if that\'s not
> possible at this point.
>
> DR. GARZA: Not unless you want to ask them a question.
>
> DR. STALLINGS: I don\'t.
>
> \[Laughter.\]
>
> DR. STALLINGS: I don\'t want to break the rules.
>
> DR. GARZA: That\'s certainly within the procedure. You can ask if you
> want.
>
> DR. STALLINGS: So that was why I put it in\--sort of started that.
>
> DR. BRILEY: Could I ask you a question?
>
> DR. GARZA: Yes, Dr. Briley, that is certainly within the procedure.
>
> DR. BRILEY: What percent of the centers in the United States currently
> have access to this kind of equipment? This is not something I know
> about, so kind of fill me in about how many are already using it.
>
> DR. STALLINGS: Well, it\'s like what we\'ve been doing today. You\'ll
> have to define \"centers.\"
>
> DR. BRILEY: Whatever you\--
>
> DR. STALLINGS: But I think most children\'s hospitals are going to
> have them or have them. I think that Level 3 nurseries, which is where
> a lot of the sicker babies are often at adult hospitals, and they
> certainly have them. We will probably never see, you know, private
> pediatric practices having them, but they would have access to them in
> their community, generally under the auspices of women\'s health
> centers and things like that. But you\'ve heard all the caveats about
> if you really are going to do this, you have to have a technician, an
> operator who\'s really good with kids and moms, and so they\'re all
> things that flow from that.
>
> But the current DXA technology is fairly widely available in
> middle-size towns and up and in all major medical centers.
>
> DR. GARZA: Virginia, related to that, what percentage of centers that
> have an interest in doing growth or nutritional studies to you
> estimate now have DXA? Is that more than half or less? In terms of
> groups that might be engaged in this type of assessment.
>
> DR. STALLINGS: Well, I think the groups that really define themselves
> as interested in growth, both in little\--you know, failure to thrive
> and obesity, are going\--either have it or are approaching 100
> percent, because it is\--it was a breakthrough technology in childhood
> body composition and growth studies. So I think if they don\'t have
> them, it will be hard to stay in the field, and most of us who have
> gone from a lot of stable isotope work to this find this a much easier
> technology to work with with children of all ages.
>
> DR. GARZA: Dr. Heubi?
>
> DR. HEUBI: My comment was, although this is widely available, not
> everybody has pediatric software, and that becomes a bit of an issue.
> But Ginanne is absolutely\--she\'s absolutely correct about it. Most
> centers that have GCRCs that are in pediatric centers have them, and
> they\'re broadly available. And they\'re often free and at low cost in
> the GCRC\--
>
> \[Laughter.\]
>
> DR. GARZA: That sounds like a paid political announcement.
>
> DR. HEUBI: This is an infomercial.
>
> DR. GARZA: An infomercial, that\'s right.
>
> DR. STALLINGS: He\'s the center director.
>
> \[Laughter.\]
>
> DR. HEUBI: But it\'s true that most of them have\--actually, I\'d
> say\--there are eight pediatric centers in the country, and I\'d say
> pretty uniformly they all have them. So it\'s widely available.
>
> DR. GARZA: Would anyone like to speak against Ginanne\'s proposition?
>
> DR. DENNE: I guess I\'d just want to raise the question about what are
> you going to do with the data. You know, how are we going to interpret
> the DXA scans? Again, I\'d love to have that as a reference, but how
> are we going to, in the context of a formula study, interpret the
> results?
>
> DR. STALLINGS: Well, you know, we all can see that we don\'t have
> great reference data right now. And, in fact, there\'s a major
> NIH-funded study looking at reference data down to a certain age
> that\'s going to address that in older children. And I think one of
> the gaps that remains is having similar quality\--I think it\'s a
> five-center study? I think one of the challenges that remains is the
> reference data, but I would propose this would be used in the
> randomized trial setting where you would have enrolled groups
> randomized, and then you really could start to see are we having
> differences.
>
> My interests really are in all three compartments, actually,
> that\--are we making children fat to the detriment of the fat-free
> mass? Or are we making them fat and fat-free mass is fine? And there
> are a number of issues that are coming along in the infant formula
> world and in the antecedents of osteoporosis that really directly have
> to do with bone mineral accretion.
>
> Now, it would be completely misrepresenting it to say that what goes
> on at 4 months we know has something to do even with 2 years being now
> ambulatory or at 7 or at that critical time sort of 10 to 14.
> So\--but, I mean, it is, I guess from the committee point of view, you
> know, it\'s futuristic, but I\'m already pleased that we\'ve added
> length to this. You know, so we are trying to think about where do we
> want to go in the future.
>
> So, to me, the big deal is we\'ve changed from just worrying about
> children not growing, which is failure to thrive, to trying to look at
> both sides of the growth spectrum.
>
> DR. DENNE: And, again, I don\'t have\--I think that data would be
> useful, but specifically if you find a difference in one compartment
> or another, what is it that you will do with that between formula?
>
> DR. HEUBI: I think what it\'s going to require is the more
> longitudinal view, because one of the comments was made about not
> knowing anything below age 2 in terms of what its relationship to
> adult obesity is. This would give us an opportunity to actually go
> another step further with follow-up studies in the future. Again, it
> would require probably out of the scale of an infant formula trial but
> would be some information that could be added as added knowledge.
>
> DR. THUREEN: Thureen. I agree with what you said, the usefulness as a
> tool. I just don\'t want to\--this committee\'s recommendation come
> across as meaning that unless you have a DXA you shouldn\'t be
> involved in formula trials. And I\'d hate to see that happen because I
> know at most centers, pediatric GCRCs are at most children\'s
> hospitals, but there are still a lot of people out there who don\'t
> who have been involved in formula trials. So I think we have to make
> it very clear that this\--when we say moderately useful, it shouldn\'t
> be looked on as that kind of a center would have a preference for
> doing these types of studies if they had a DXA machine, because I
> don\'t think at this point in time that\'s realistic.
>
> DR. GARZA: Okay. There is still is somewhat of a split, is my sense,
> but if it\'s not required, then I think we\'ve given the FDA a
> sufficient breadth of views on this that prolonging the discussion
> probably will not be very useful. I don\'t think that there is a
> fundamental difference in how this technique is viewed, but where it
> might be placed.
>
> Okay. Bioelectrical impedance was pretty much put into the useless
> category for right now, and with stable isotopes also being in the
> research category, and arm circumference possibly being placed
> alongside with skinfold thicknesses as of moderate use. Is that\...any
> objections to that summary?
>
> \[No response.\]
>
> DR. GARZA: All right. Then we\'re done with terms. We\'ll start with
> preterms, and I\'m trying to find\...
>
> Dr. Thureen, would you like to start?
>
> DR. THUREEN: Yes, I will start. I think that body weight, recumbent
> length, and head circumference are critical. I think that skinfold
> thickness and DXA are of moderate interest, but are of less use at
> this point in time than they actually are in terms infants because of
> the technical difficulties in using them. And I think there is no role
> for bioelectrical impedance. I think that stable isotope and other
> physical body measurements are not indicated at this time, are really
> in the research area.
>
> I do want to stress that in this age group, I think head circumference
> is critical because we use head circumference frequently for detecting
> significant abnormalities in growth, and it is a major way of looking
> at\--or at least suggesting long-term neurological growth.
>
> DR. GARZA: Okay. Thank you.
>
> Dr. Denne?
>
> DR. DENNE: I don\'t think I would add anything different to that. That
> seems a reasonable position.
>
> DR. GARZA: Okay. Dr. Kuzminski?
>
> DR. KUZMINSKI: I have to defer to the experts on this and agree to the
> same thing.
>
> DR. GARZA: Dr. Moyer-Mileur?
>
> DR. MOYER-MILEUR: I would just concur for preterm babies that head
> circumference is probably more critical than recumbent length and
> easier to obtain.
>
> DR. GARZA: I didn\'t sense in the previous discussion\--just to make
> sure that the minutes reflect the group\'s sentiments correctly\--that
> head circumference, recumbent length and body weight were prioritized.
> We said all three are required at the same time.
>
> DR. SIGMAN-GRANT: I agree with everyone else so far.
>
> DR. GARZA: Sigman-Grant.
>
> DR. DOWNER: Downer. Ditto for me, too.
>
> DR. GARZA: And that\'s Dr. Downer.
>
> DR. ANDERSON: Anderson. The same.
>
> DR. GARZA: We\'re on a roll.
>
> DR. HEUBI: Heubi, except that I do want to say I\'m glad that Patti
> came around to thinking that DXA was of moderate importance.
>
> \[Laughter.\]
>
> DR. STALLINGS: And I would agree, and I was one of the ones who
> didn\'t put head circumference in priority for term, and I agree
> completely it\'s essential for preterm. And I was just trying to have
> some distinguishing characteristics.
>
> DR. GARZA: Okay. Thank you.
>
> DR. BAKER: I think I agree with everyone. I would vote for head
> circumference being essential for preterm growth studies.
>
> DR. GARZA: All right. Dr. Briley?
>
> DR. BRILEY: I agree with Patti.
>
> DR. GARZA: All right. Thank you.
>
> Roger, would you like to make any comments?
>
> DR. CLEMENS: I certainly concur with the group.
>
> DR. GARZA: Okay. Well, gee, all right.
>
> \[Inaudible comment off microphone.\]
>
> DR. GARZA: You can repeat it this time.
>
> DR. CLEMENS: Officially, yes, I concur with the group.
>
> DR. GARZA: You have to identify yourself.
>
> DR. CLEMENS: Roger Clemens. I\'ll get it out yet.
>
> DR. ANDERSON: Then I think we\'ve answered Question 2 in the way the
> groupings were made. Does anyone want to address any aspect of two
> that you don\'t think we\'ve addressed?
>
> DR. ANDERSON: On behalf of the group, I say no.
>
> \[Laughter.\]
>
> DR. ANDERSON: This is Jim Anderson.
>
> DR. GARZA: Thank you, Dr. Anderson.
>
> All right. Then let\'s move on to No. 3, and 3A is that the metrics
> above can be evaluated as either retained or absolute growth or
> velocity, rate of change. Comment on the distinguishing values and
> merits of each static or variable method in the assessment of normal
> physical growth. I\'m going to limit the discussion to body weight,
> recumbent length, head circumference, skinfold thickness, because, in
> fact, none of the others were either recommended or seen as useful, so
> I don\'t see much point in our discussing each of those.
>
> Who would like to start? Dr. Stallings?
>
> DR. STALLINGS: I think that both attained growth and velocity are
> essential for the first three, for weight, length, and head
> circumference. I think velocity would not be helpful in skinfold
> thickness because of the very small magnitude that we\'re moving
> through. And in the age range we\'re looking at, I honestly don\'t
> know about mid-arm circumference since we\'ve clustered that one. I
> think the change is relatively modest, but I\'ll defer on that one.
>
> I think that covers it.
>
> DR. GARZA: Well, the only other thing that might be useful, although
> it may be frosting on the proverbial cake, is whether you feel that
> velocity, since you said that it would be helpful for body weight,
> recumbent length, and head circumference, should all be obtained with
> the same frequency or whether you want to suggest any frequency of
> measure to be able to accurately reflect velocity.
>
> DR. STALLINGS: Well, there are two issues here. I\'m still of the mind
> that most of the things that merit growth study would have a
> contemporary, comparable group, so that I would be measuring them\--if
> you were going to existing data, I think the velocity curves are 1
> months at this\--birth to 4 months?
>
> DR. GARZA: I just meant in terms of how often would you want measures
> of body weight, recumbent length, or head circumference obtained to be
> able to define velocity.
>
> DR. STALLINGS: In a study\--
>
> DR. GARZA: In a study population. Are three measurements sufficient,
> or do you want more frequent measurements?
>
> DR. STALLINGS: A baseline and\--well, baseline, and then assuming that
> was before 1 month, because everything we\'ve heard said that that
> should be, and then 1 month, 2, 3, and 6. Again, I guess I don\'t
> understand how long we\'re planning to run this. A 4-month study?
>
> DR. GARZA: Four to six months would be my\--
>
> DR. STALLINGS: Okay. So baseline, 1 month, 2 months, 3, 4, and 6.
>
> DR. GARZA: I\'m just basing that on the previous question that said
> birth to 6 months.
>
> DR. STALLINGS: Right. Good.
>
> DR. GARZA: I\'m sorry. Could you repeat that again? You said birth\--
>
> DR. STALLINGS: Baseline\--well, birth, the 14-day, then 1 months, 2
> months, 3 months, 4, and 6.
>
> DR. GARZA: So, in essence, monthly for the first 4 months, and then 6
> months, the first month having measures at birth and at 2 weeks.
>
> DR. STALLINGS: Right, or whatever that earliest\--but something\--I
> was calling it baseline.
>
> DR. GARZA: Between 1 month and birth.
>
> DR. STALLINGS: Right. But something before\--at 14 days as your
> baseline, and then again at 1 month.
>
> DR. GARZA: Okay.
>
> DR. STALLINGS: So that might be a 28-day or a 14-day measure.
>
> DR. GARZA: I don\'t know that we have to be that exact, but it gives
> people a sense of how velocity would be obtained, or measured, at any
> rate.
>
> Dr. Heubi?
>
> DR. THUREEN: Dr. Garza, can I make a comment?
>
> DR. GARZA: Sure.
>
> DR. THUREEN: I\'d like to ask the committee if they\'d agree on the
> time points that Dr. Fomon suggested this morning, the seven time
> points over the first 6 months of life, because I think that\'s what
> you\'re referring to. And unless there\'s dissension from that, which
> I suspect there\'s not but I\'d like to ask the committee, that those
> may be the time points that we\'d recommend for longitudinal studies.
>
> DR. GARZA: They pretty much coincided with those.
>
> DR. THUREEN: But we could just call it the Fomon criteria from now on
> rather than\--
>
> DR. GARZA: That sounds good. Thank you, Patti.
>
> Dr. Heubi?
>
> DR. HEUBI: If you\'ll give me one moment, I just want to see what he
> actually said.
>
> DR. DENNE: This is Denne. I think it was Dr. Chumlea who suggested
> that time frame. I think Dr. Fomon was sort of talking about 4 months
> as the criteria.
>
> DR. HEUBI: I think birth, 2 weeks, 1, 2, 4, 5, and 6 months.
>
> DR. GARZA: So the third month was omitted. I think that\'s\--we just
> need a general idea. I don\'t know that we have to come up with the
> exact metrics or exact time points. That\'s close enough. There\'d be
> some wobble.
>
> DR. SIGMAN-GRANT: This is Sigman-Grant. Is there any advantage to
> having a measure between birth and 2 weeks?
>
> DR. GARZA: Between birth and 2 weeks, is there any advantage? There is
> quite a bit of wobble, is the sense that I\'m getting from the group
> again at the table because of weight loss during\--
>
> DR. SIGMAN-GRANT: But is that an important measure?
>
> DR. GARZA: There are no standards that I\'m aware of.
>
> DR. STALLINGS: Right. I think what you would end up there mostly would
> be with the individual variation and hydration and immediate
> pre-partum kinds of things, which wouldn\'t reflect the feeding
> experience as much.
>
> DR. SIGMAN-GRANT: Okay.
>
> DR. STALLINGS: And, also, just\--I mean, I don\'t want to talk about
> practicality, but, you know, there is the issue of if we could get a
> birth, true birth measurement, and then 14 days or something like
> that, that would be great. But I think what we\'re doing is just
> skipping the variability of when you regain your birth weight and
> establish full feeding.
>
> DR. GARZA: In the interest of time, while Dr. Heubi\'s getting these
> things together, would you\--maybe we can take both preterm and term
> together? Would you change any of those recommendations for the
> preterm, or would you leave them pretty much the same for both term
> and preterm?
>
> DR. STALLINGS: I think I would leave them pretty much the same, again,
> just recognizing the preterm\--that the physical measurements on the
> preterm are more stressful, but we still have to have them to be able
> to make the decisions we need.
>
> DR. GARZA: Would you recommend\--well, going to 6 months
> post-conceptional equivalency or-
>
> DR. STALLINGS: Yes, I would.
>
> DR. BAKER: I think that both the static and the velocity measurements
> should be obtained for weight, length, and head circumference. I
> don\'t think velocity is necessary for skinfold thickness or mid-arm
> circumference. And I would agree with the time points as Ginanne said
> them, and I also think that it would be useful for both full-term and
> premature babies.
>
> DR. GARZA: Okay. Thank you.
>
> Dr. Heubi?
>
> DR. HEUBI: Well, after all that, I don\'t think that I disagree.
>
> \[Laughter.\]
>
> DR. HEUBI: I was looking very feverishly for this information. I think
> Jim showed it to me. So I don\'t think that\--I think that I would
> agree with the same time points and the same measurement parameters
> would be quite appropriate, and for preterm infants, I think it would
> be 6 months post-conceptional age. I think that\'s the issue that has
> to be addressed, and I think that should be left up to Dr. Denne and
> Dr. Thureen.
>
> DR. GARZA: All right.
>
> DR. ANDERSON: Anderson. Agree.
>
> DR. DOWNER: Downer. I, too, agree. Body weight, recumbent length, and
> head circumference at birth, 2 weeks, 1 months, 2, 3, 4, and 6 month
> intervals. I\'d also agree that skinfold thickness and mid-arm
> circumference, the velocity for that is not important here.
>
> DR. SIGMAN-GRANT: Sigman-Grant. Ditto.
>
> DR. MOYER-MILEUR: Moyer-Mileur. I agree for the term infant on the
> attained and velocity measures as well as the measurement periods. But
> for the preterm baby, I think we need to keep in mind that some of
> these studies will be done in-hospital versus post-discharge, and I
> think in the hospital that your intervals need to be different. And so
> it would be wherever\--a set baseline, and then probably every two
> weeks until that child is discharged, and then go into the 1-month
> interval to 6 months post-conception age.
>
> DR. GARZA: Okay. Dr. Kuzminski?
>
> DR. KUZMINSKI: Thank you. I agree.
>
> DR. DENNE: Yes, I would agree for the\--
>
> DR. GARZA: Dr. Denne?
>
> DR. DENNE: I\'m sorry. Yes, I would agree for the term, and also agree
> that preterm needs more frequent measurements in-hospital, probably
> every 2 weeks, every week to 2 weeks, something like that.
>
> DR. GARZA: Dr. Thureen?
>
> DR. THUREEN: Thureen. I agree on the term infant, and, again, the
> preterm infant, it\'s going to be really critical looking at what
> their growth rate is over their hospitalization period, especially
> when they\'re sick. So initially it may need to be every week, but
> probably no less than every 2 weeks during hospitalization.
>
> DR. BRILEY: And I agree.
>
> DR. GARZA: I\'m going to ask the group the question of whether
> somebody is willing to comment on the merits and value of having both
> static and velocity measurements. I think we\'ve got fairly good
> agreement, other than on the number of measurements, and the frequency
> of measurements of premature. Would there be any objection if we
> summarize it? In fact, the in-hospital phase of the premature
> management should probably be more frequent. Every two weeks seems
> appropriate.
>
> DR. STALLINGS: That was actually part of my question because
> the\--Stallings. I think the question you bring up about weekly
> measurements, while hospitalized\--
>
> DR. GARZA: She said every two weeks, I think.
>
> DR. STALLINGS: No, it was\--
>
> DR. GARZA: Is it weekly or\--weekly.
>
> DR. STALLINGS: Both neonatologists considered weekly measurements, so
> that was why I wanted to bring that back up because I would agree with
> that, if you think it\'s merited, because things are happening so
> fast, and they could either be in a rapid rate of growth or a very
> clear static phase. So I was asking the two neonatologists to comment
> on one versus two weeks, and then the measurement error and all of the
> things that go from that.
>
> DR. THUREEN: This is Thureen. I would advocate for one week because
> the fastest rate of growth is actually the in utero rate of growth,
> and so potentially, if these infants are growing at the in utero rate,
> you\'ve got it higher than you have during the growth spurt
> post-natally? So I think that there are going to be dramatic changes
> even over a week period, and I would advocate for weekly measurements.
>
> DR. DENNE: Yes, I would basically agree. It depends a little bit on
> the study design, and when patients get entered and those kinds of
> things. I guess the principle would be more weekly measurements early
> and spacing out later, but\--
>
> DR. GARZA: Dr. Anderson?
>
> DR. ANDERSON: I would only ask that we consider the distinction
> between what\'s required, for lack of a better term, good patient
> care, and what\'s required for the purposes of documenting normal
> infant growth in the setting of an infant formula study. I wonder
> whether, in the latter, every two weeks might not be sufficient.
>
> DR. THUREEN: Thureen. I think pretty much every neonatal unit measures
> these parameters on a weekly basis anyway. Whether the actual research
> measurement would be more destabilizing I think is difficult to say.
> I\'d also say that in most units, if your patient is unstable, you
> don\'t even do your routine measurements. You just have to have some
> latitude for those kind of decisions, so ideally every week, but if
> the patient is not stable or if it appears to be a difficult
> measurement for a patient, then I think you may have to be a little
> bit more flexible.
>
> DR. DENNE: Yes, and obviously that partly depends on the study design,
> but things do happen quickly over a week. These measurements are
> clearly possible over a week, as opposed to later on when it\'s tough
> to make that difference over a week.
>
> DR. GARZA: Roger?
>
> DR. CLEMENS: I do want to refer to that. In terms of body weight and
> length, we do, the infant formula manufacturers, do conduct these
> studies, and when they do, they measure length and weight at the 14,
> 28, 56, 84, 112 days. Clearly, the Fomon formula, if you will, when we
> conduct four-month studies, and certainly to include two more data
> points would not be a big deal if required by statute to go on to six
> months for these kinds of growth studies.
>
> We do collect skinfolds, but not as frequently at this point in time.
>
> DR. GARZA: Any other comments regarding the one or two weeks for the
> prematures?
>
> \[No response.\]
>
> DR. GARZA: All right. What about the values and merits of attained and
> velocity, does anyone want to speak to those any more than you may
> have in your comments?
>
> Dr. Anderson?
>
> DR. ANDERSON: Perhaps I\'m not thinking of this correctly, but it does
> seem to me, if we have the data points at the specified times that
> we\'ve talked about, then the data can be presented, in either way,
> simply through a data transformation. And so if people are normally
> used to thinking about velocities, they can be recorded as velocities,
> and if they\'re used to thinking about weights and specific I points,
> they can be recorded that way.
>
> DR. GARZA: Any other points that anyone wishes to make in response to
> that request from the Agency?
>
> \[No response.\]
>
> DR. GARZA: Then why don\'t we move on to 3B, and here again I think we
> can take both the preterm and the term together. The outcomes above
> can also be evaluated as individual infant data or as group
> comparative data, comment on the values and merits of using individual
> or aggregate data in the assessment of normal physical growth.
>
> DR. DENNE: Dr. Garza, before we start, I\'m not sure I understand that
> question.
>
> DR. GARZA: I think what they\'re asking is should the Agency be
> presented with the individual growth data for individual subjects or
> just the aggregate data for the entire group.
>
> DR. DENNE: So in terms of what\'s actually submitted to the Agency.
>
> DR. GARZA: Or here it\'s phrased, in terms of the values and merits of
> each one, but I suspect that that\'s why they\'d like to know that.
>
> Is there value in submitting both and or merit, and would one or the
> other suffice?
>
> Dr. Anderson?
>
> DR. ANDERSON: I think that either would suffice. For longitudinal data
> like this, there\'s often a choice in terms of how one both presents
> and analyzes such data, and it reflects essentially the question here;
> that is, one can analyze parameters at the patient-specific level and
> then estimate population parameters, considering the patients as
> random realizations from that population, so each patient would have
> specific parameters, some showing a strong growth tendency, others
> less so, and that the parameters, the estimates would be the average
> of those parameters in the population or one could take what\'s often
> called a population-average approach, which is essentially one is not
> interested in the parameters of individual subjects, but how they\'re
> realized in the observed population, and there the focus is more
> naturally on the population values that are observed at individual
> time points.
>
> My own personal view is that the answer that you get from the two
> approaches are oftentimes largely the same, and that I would think
> that either approach here would be acceptable.
>
> DR. GARZA: But what sort of information would you recommend be
> obtained if population or group data are being submitted that would
> describe the distribution? Would a mean and standard deviation be
> sufficient or do you think we ought to look at \"skewdness\" or
> whether, in fact, it\'s normally distributed? Can you elaborate a bit
> on what you think would be the essential information you would need to
> assess the distribution?
>
> DR. ANDERSON: Well, we\'re largely getting ahead of ourselves because
> we haven\'t talked about what we would be comparing things to.
>
> DR. GARZA: Assuming only one group, and you\'re going to look at
> individual data versus group data.
>
> DR. ANDERSON: If it was a single group, I would think that you would
> want more than simply means and standard deviations because, as we\'ve
> seen from the, from the growth charts, the data can be somewhat skewed
> at various time points, and so either some summary of the data
> reflects a transformation towards normality at each of the time points
> or some other type of display which allowed one to see not only the
> measure of central tendency, but also a sense of the general
> distribution at the times when the data were collected would be
> appropriate.
>
> DR. GARZA: Drs. Heubi or Downer, would either one of you like to go
> next?
>
> It looks like you\'re the winner, Dr. Heubi.
>
> DR. HEUBI: Did I win? And it\'s still on.
>
> I tend to think that it probably would be appropriate to submit all of
> the data showing individual data points, in addition to some summary
> data, just because it looks to me like based upon the size of these
> groups are likely to be such that it would be a value to see what the
> distribution looks like, in addition to the summary statistics.
>
> DR. GARZA: Can you elaborate a bit on the value of seeing both?
>
> DR. HEUBI: It would allow someone to look at how normally distributed
> the data was and how whether there were outliers that were not
> reflected by the summary statistics.
>
> DR. GARZA: Dr. Stallings?
>
> DR. STALLINGS: Stallings. I would like to see both. The reason for the
> individual data I think is important to, I mean, I can\'t give us a
> good example of what\'s happened historically, but I think it would be
> important to see a group of children that would be on both ends of the
> distribution, and again particularly also by gender. I mean, I think
> there are some different things going on, so I\'m assuming we get the
> different segmental analyses that we had talked about.
>
> So I would be really interested in seeing how many individual babies
> fell out less than a fifth, less than a third greater than the 95th.
> Now, the logical question is exactly what am I going to do with that
> data, and I don\'t really know that, except that I think if I were in
> a regulatory environment and I saw that, yes, most of the kids were
> doing just fine, but there really was a group that wasn\'t, I would
> want to explore that more, and that might start the dialogue to find
> out more about that.
>
> DR. GARZA: Dr. Baker?
>
> DR. BAKER: I would certainly want the individual data I think, just
> thinking about the same sort of things that there are a possibility of
> outliers that would trigger you to think more about the whole problem.
> I don\'t think we can give guidelines about what exactly you would do,
> but I certainly think it\'s worth looking at.
>
> I think some group data would also be useful sort of, but I think
> certainly the individual data and a good bit of the group data would
> be useful.
>
> DR. GARZA: Dr. Clemens?
>
> DR. CLEMENS: Clemens. You caught me early.
>
> DR. GARZA: I called you earlier, that\'s right.
>
> DR. CLEMENS: I appreciate that. Actually, the pro forma to
> manufacturers provide all of the data, to provide individual data, as
> well as group data, and so they can clearly see, to your comment
> there, Ginanne, they can determine if there\'s any outliers, if you
> will. Also, if there are any outliers, potential outliers, as there is
> in any population group, then, actually, the clinical or the medical
> director provides clinical comments, as well as to the principal
> investigator, to provide clinical comments specific to that particular
> child, so you get here exactly each child.
>
> DR. GARZA: Thank you.
>
> Dr. Downer?
>
> DR. DOWNER: Thank you. I\'m still pondering this. I think both data
> sets would be important. As Dr. Stallings said, I\'m not sure what we
> would do with the individual data, from a group perspective, but it
> would provide some information on the substance within the group, and
> that\'s important. So I think both data sets would be important.
>
> DR. SIGMAN-GRANT: Sigman-Grant. I think both sets are important. I
> think, if you look at individuals, you might see clustering, perhaps
> by ethnicity or something else that you might not see if you only saw
> population data, and that might be helpful information. So that\'s
> like clustering of individuals.
>
> DR. GARZA: Dr. Moyer-Mileur?
>
> DR. MOYER-MILEUR: Moyer-Mileur. I would agree that both individual and
> summative data is important.
>
> DR. GARZA: Dr. Kuzminski?
>
> DR. KUZMINSKI: Both data, please.
>
> DR. DENNE: Denne. I would concur with the previous comments.
>
> DR. GARZA: Both in terms of the\--
>
> DR. DENNE: Yes.
>
> DR. THUREEN: Thureen. I would concur. I have nothing to add to the
> comments that have been made from that side of the table.
>
> DR. BRILEY: Briley. I would concur. I also think about this might be
> the first time that we have these data, and the next time around, it
> would be nice to do some comparison with it. So it would be nice to
> have both.
>
> DR. GARZA: All right. Does anyone want to add any comments to what you
> may have said earlier on this question?
>
> \[No response.\]
>
> DR. GARZA: If not, there seems to be a consensus that both individual
> and group data should be evaluated, and the values and merits, having
> to do with the ability to assess the distribution and potential
> outliers, et cetera, in a way that perhaps summary statistics may not
> lend themselves to easily.
>
> It is 5:30, almost. We can go ahead and try to do the next one or two
> questions, if you\'re up to it, or we can try to get the van here by 6
> o\'clock, and we will still be here. Let me confer a bit. It\'ll be
> here at 6:00, so why don\'t we go ahead and do the next one.
>
> DR. SIGMAN-GRANT: It\'s a really big one.
>
> DR. GARZA: It is a big one, you\'re right.
>
> Dr. Briley?
>
> DR. BRILEY: Don\'t you think we can do the question now and not have
> to do the work tonight? Would that be a trade-off you\'d allow?
>
> \[Laughter.\]
>
> DR. GARZA: Oh, that doesn\'t buy us more time, Dr. Briley.
>
> DR. SIGMAN-GRANT: This is Sigman-Grant. I think both of these require
> a lot of, it\'s going to be a lot of discussion, the difference
> between reference and standards.
>
> DR. GARZA: You notice that I said it with some trepidation, and
> you\'re absolutely right. I\'m trying to think how one could use the
> next 30 minutes most productively, given the fact that the idle mind
> tends to be the devil\'s workshop.
>
> Why don\'t we then work on Question 7 on your own, as Dr. Briley
> suggested.
>
> Dr. Denne, did you\--
>
> DR. DENNE: Well, I just wonder whether Question 4, whether there
> wouldn\'t be reasonable consensus about the answer to that question. I
> mean, my sense is there might be, but\--
>
> DR. GARZA: We have one potential masochist in the group.
>
> \[Laughter.\]
>
> DR. GARZA: Do I see another one that\'s willing to start with No. 4?
>
> DR. STALLINGS: Take Question 5.
>
> DR. GARZA: Well, 5 might benefit from having 4 in the discussion, and
> that\'s why I didn\'t want to take them out of order. I thought of
> that, and so why don\'t we begin and then see whether, in fact, we are
> making progress, and we don\'t have to come to a forced conclusion
> because Dr. Sigman-Grant is right, it\'s probably going to take quite
> a bit of discussion, but Dr. Denne may prove us wrong, in the fact
> that we can come to a consensus in 30 minutes, and that would save us
> an enormous amount of time tomorrow.
>
> So let\'s, since the bus can\'t pick us up until 6:00, let\'s try and
> do 4:00. It\'s for adequate evaluation of normal physical growth.
> Below are examples of clinically distinct reference groups, and we
> really have three. One, our concurrent controls, a reference data uses
> a control, and historical control, and I\'m assuming that by
> reference, what is meant is a more comprehensive data base with
> historical controls, perhaps referring to a specific formulation that
> might have been looked at in the past, but not necessarily information
> that may be in the public domain. Is that an accurate interpretation
> of that? Dr. Walker is saying yes.
>
> So a reference data, think of it as something that is in the public
> domain that is quite extensively documented, as opposed to a
> historical control that might be more limiting in that it may just be
> either proprietary information or information that relates to a
> specific formulation from a specific one single article or one single
> study.
>
> So it might be seen as a historical control, but not necessarily as a
> reference. I\'m at a loss as to what other groups, but let\'s get
> those on the table.
>
> DR. HEUBI: I guess it\'s possible that that is referenced as
> longitudinal data, as opposed to other, which might be
> cross-sectional. That would be another option for other.
>
> DR. GARZA: You mean that would be under reference or historical that
> it could be either longitudinal, the substance of those?
>
> DR. HEUBI: Well, I\'m saying reference data used as controls would be
> things like the Fels-Iowa data, as opposed to the CDC data for other
> as cross-sectional.
>
> DR. GARZA: I\'m sorry. In my description, I meant to include both Fels
> and CDC, for example, as reference data.
>
> DR. STALLINGS: So not just longitudinal\--
>
> DR. GARZA: And subsets of that. It could be cross-sectional.
>
> DR. HEUBI: it would be relatively easy to rank these if you separate
> those out and make it the other way, so it\'s cross-sectional being
> your last category.
>
> DR. GARZA: Okay.
>
> DR. HEUBI: Because that\'s the least desirable.
>
> DR. GARZA: So you would say cross-sectional, and we would interpret
> concurrent controls, reference data, and historical as longitudinal,
> and then other would be cross-sectional or would you prefer seeing six
> cells with concurrent controls being longitudinal or cross-sectional?
> No?
>
> DR. HEUBI: This may be a long time.
>
> DR. GARZA: That\'s more complicated, but I think it\'s going to be
> complicated by just saying all of the above is cross-sectional, but
> let\'s try it.
>
> Yes?
>
> DR. SIGMAN-GRANT: I have a question.
>
> DR. GARZA: Sure.
>
> DR. SIGMAN-GRANT: Sigman-Grant. Are we referring to this as reference
> or standard?
>
> DR. ANDERSON: This is Anderson. I think we can\'t do anything other
> than refer to this as reference because that\'s what they are.
>
> DR. GARZA: So that the implication of that is that you\'re not going
> to be making any value judgment on the basis of the comparison, but
> that you\'re suggesting we limit the discussion to just the fact that
> if it\'s going to be a comparison, it\'ll be more or less, not better
> or worse. Is that clear to everyone? Because it\'s an important
> distinction.
>
> Now, we may want to take up the issue of standard in number five, but
> for right now we would limit this to a reference, and so that what one
> would say is more or less, not better or worse.
>
> Dr. Anderson?
>
> DR. ANDERSON: With the permission of the chair, let me take a stab at
> this.
>
> DR. GARZA: Yes, please do.
>
> DR. ANDERSON: My own personal view is that the least helpful of what
> we\'ve discussed are historical controls, largely because they tend to
> be small populations collected in a process which is often difficult
> to describe, and the temporal changes that can occur make it highly
> likely that historical controls will\--it will be extraordinarily
> difficult to convince individuals that the historical control
> accurately reflects an appropriate comparison group.
>
> And then notwithstanding my attempting to push the envelope during the
> discussion today, I think that using reference data is not that much
> better, largely because it\'s just that. It\'s reference data, and so
> as a result of the conduct of a study, we can say that the results
> were greater than or less than the standard\--sorry\--the reference,
> but I don\'t know how to interpret that. So we end up with the study
> group having a mean weight at six months, which is the 55th percentile
> of those standard.
>
> The conclusion of that is I don\'t know how you get beyond that, and
> so my view is that if it\'s felt that it\'s important to evaluate
> normal physical growth, it should be done in the context of concurrent
> randomized controls.
>
> DR. GARZA: Dr. Clemens?
>
> DR. CLEMENS: Clemens. I trust that we don\'t make a decision
> recommendation this evening on this, Bert. Tomorrow, we have some
> public comment available and also the three medical directors for the
> manufacturer was making comment on this question, and other related
> questions, which we have not addressed tonight. So, again, I trust
> that we don\'t make a recommendation to the FDA this evening.
>
> DR. GARZA: We can hold off on that until tomorrow.
>
> DR. CLEMENS: I would trust that\--discussion is good, but no
> recommendation at this time, please.
>
> DR. THUREEN: Thureen. I\'d like to note that Dr. Anderson\'s comments
> closely reflect Dr. Frongillo\'s report of earlier today, where he
> really elegantly laid out the advantages and disadvantages of
> concurrent reference and historical reference data or controls, and I
> was already convinced this morning, after his talk, and I\'m now more
> convinced after hearing your opinion.
>
> DR. GARZA: One of the things that I\'m reading into what you said, Dr.
> Anderson, is that the absence of standards really limits us in terms
> of making those comparisons, so that having a concurrent randomized
> control group makes a lot of sense; is that one of the major factors
> in your conclusion?
>
> DR. ANDERSON: Yes, you said that very well. I think that if there were
> data which were generally agreed reflected in an agreed upon standard,
> and I have not heard that today, then the discussion could be
> broadened because then it would be possible, for instance, to say that
> any outcome which led to results which were within .2 standard
> deviations of the standard would be considered acceptable evidence of
> normal physical growth, in the absence of a standard, and with the
> presence of what I gather are generally agreed upon as references,
> that kind of argument is not permitted.
>
> DR. GARZA: Dr. Baker?
>
> DR. BAKER: I\'d just like to put in my two cents here. I think that we
> all agree that the gold standard, the thing we all like to see, is a
> concurrent randomized control group.
>
> DR. GARZA: Is the mike on? I can\'t tell.
>
> DR. BAKER: What we\'d like to see is a randomized control group, and
> so that we put as number one, and then I would put a longitudinal
> reference group as kind of the second choice, and then a
> cross-sectional reference group as a third choice, and most often, the
> historical control is way down there.
>
> On the other hand, I would have to say that there might be some
> circumstances where the historic control group might be reasonable,
> and that would be in a situation where you were doing rapid sequence
> studies with very similar formulas and just changing one thing. So
> you\'d use, for those series of studies, you might use one historic
> control group, but\--
>
> DR. GARZA: You may want to hold the mike closer to you.
>
> DR. BAKER: \--but to think about using a control group from 10 years
> ago, seems to me, unreasonable.
>
> DR. GARZA: Thank you.
>
> Dr. Heubi?
>
> DR. HEUBI: Heubi. I would agree with Rob. I think that historical
> controls are probably only acceptable if they\'re fairly recent, and
> whatever fairly recent means, I don\'t know, within a year, two, three
> years, but not ten years. But the ordering, I think I would agree with
> him totally, concurrent controls should be the gold standard, and a
> longitudinal reference group, like Fels-Iowa, would be a second, and
> then a cross-sectional and then finally historical controls.
>
> DR. GARZA: Dr. Stallings?
>
> DR. STALLINGS: I think the concurrent control group is essential. I
> think often when the rest of us are doing things that are research, we
> wouldn\'t be able to do research without an adequate control group,
> and we\'re not setting policy or regulating anything or making
> products that, you know, millions of infants will be exposed to. So I
> really do feel strongly about that, and I concede that there may be a
> time, if you really are designing things, that the concurrent control
> group might be able to serve for a series off studies.
>
> I feel like the historical, as defined when we started this, the
> historical group, which might be proprietary and might be specific to
> a single formulation, a small population, less-well described, I
> really don\'t think that\'s adequate sort of for the modern times,
> partly because I think it\'s not in the public domain.
>
> And if we\'re saying you don\'t have to do the study, which might
> remain proprietary, that somebody really needs to agree that, other
> than the regulatory group, agree that it was a good choice.
>
> So I think it does come down to the control groups, if we reach the
> level where a growth study is required, then it should be an optimal
> growth study.
>
> The issue of the reference data, I really learned a lot over the last
> couple of days reading about this and listening to the comments. I
> think I have come to believe that because the reference data represent
> so many years, and we really don\'t know what\'s optimal, and that\'s,
> you know, we need many more days conference on that, that I\'m less
> inclined to use reference data. I would have it available for
> descriptors because what you would want to know, if there is some
> complete quirk, and now the control group and the study group happen
> to all be at the one standard deviation of everything, you would want
> to know that, that that\'s the data you would be looking at, but I
> don\'t think it would be\--and I would worry about how we got into
> that fix\--but that would be a bit different.
>
> So I\'m really voting for the contemporary control groups.
>
> DR. DOWNER: Downer. I, too, agree that the historical control would
> not have much implications for the growth study at this time and that
> the gold choice, of course, the concurrent randomized trials, would be
> the one to select. The longitudinal reference and cross-sectional
> reference, too, would not be of great importance here, but it would be
> good to look at over the long haul just to see what has happened and
> to make comparisons over time.
>
> DR. SIGMAN-GRANT: This is Sigman-Grant. I, too, agree that the
> concurrent controls would be the most ideal.
>
> I\'m sitting here reflecting. It\'s interesting because when I work
> prenatally, there\'s the issue of what happens prenatally determines
> potentially what might happen postnatally, the so-called metabolic
> imprinting in Barker, and yet we seem to think that, okay, we\'re just
> looking from birth on, and so without a concurrent group and using
> previous information makes me question if, indeed, metabolic
> imprinting, as a hypothesis, is explored and expanded.
>
> There\'s a lot of difference, maternal differences, between, say, the
> \'50s, \'60s and \'70s and what\'s now recommended\--weight gain,
> smoking, alcohol use. If that, indeed, affects infant growth,
> postnatally, which it probably does, it might, then if we use data
> that was presented for those years, are the infants truly
> representative of the cohort from today?
>
> DR. GARZA: Are there any other comments that anyone would like to add?
> And we\'ll come back to this issue tomorrow after the public comment
> period. Any other\--I\'m sorry, go ahead. I didn\'t see you.
>
> DR. MOYER-MILEUR: That\'s okay. Moyer-Mileur. I would just like to say
> I assume we\'re all talking from the term baby point of view at the
> moment, but for preterm babies, there is no reference. So I think for
> preterm studies they always have to have a concurrent control because
> medical care in the NICUs is changing constantly, and you can\'t
> really use a historical control from even a year in the past.
>
> DR. GARZA: That\'s a good point.
>
> Any other comments? Your free to speak today. We\'re going to just
> come back to it tomorrow. I want to make sure that we\'ve got the
> time. So you can speak today or tomorrow.
>
> DR. KUZMINSKI: Just a comment. I concur with the comments made by the
> rest of the committee on concurrent controls, as the gold standard,
> but I feel that there is place for historical controls. To me, it
> depends upon how, an agreement with another comment that\'s been made,
> how long back in time that history is, in terms of that data. I think
> a driving point also is how relevant was that study population to the
> current study population that is being proposed in the current study?
>
> It gets back to my question, I guess, I posed to two of the speakers,
> Dr. Denton and Dr. Bier today, what is that gray area that we use
> experience to make a judgment not to use, not to do a clinical growth
> study, and do we just automatically default to doing a study? I think
> that\'s a very difficult question to answer.
>
> This hits on it, also, on historical controls, and the reference data,
> I agree with the others as the third most\--
>
> DR. DENNE: Denne. I guess I don\'t have much to add. I would agree
> with the previous comments about the value of concurrent controls and
> the significant lower value of any other approach.
>
> DR. THUREEN: Thureen. I agree.
>
> DR. BRILEY: Briley. I would like to make a statement in regard to what
> our current consumer is, in terms of it\'s different than what we\'ve
> had in previous years, like Maureen had said, and so I feel like the
> gold standard is the concurrent controls. I think it has to be there
> because society has changed, and the young mothers today have a
> different role to play than what they did 10 years ago, and 10 years
> is too long.
>
> DR. GARZA: Would any of you have any questions to any of the
> presenters that might have addressed this topic earlier today?
>
> \[No response.\]
>
> DR. GARZA: Then, we pretty much have dealt with, A, for term infants,
> we had Dr. Moyer-Mileur addressed the preterm as being a special case
> where, in fact, that\'s even truer in terms of reliance on a
> concurrent control.
>
> Does anyone want to speak to preterms or would the discussion that
> we\'ve had, in your view, pretty much reflect your sense of preterms
> as well?
>
> \[No response.\]
>
> DR. GARZA: People are pretty tired, Dr. Sigman-Grant is telling me.
>
> DR. STALLINGS: Dr. Stallings.
>
> Just to clarify, though, I think what Laurie was addressing, we had
> some diversity about whether concurrent controls were almost the only
> thing or they are second and third rank. I think you were suggesting,
> and correct me, that in preterm you really have to have concurrent
> controls all the time because of the changes in care practices and how
> rapidly things can happen and because we simply don\'t know enough
> about those babies, for all of the practice environment of a preterm
> environment.
>
> So if that\'s what you were saying, I would agree with that, that it
> isn\'t a one, two, three; it\'s really sort of a one.
>
> DR. GARZA: I\'ll ask the group, as we conclude today, to please think
> about, B, because we pretty much addressed A. To a certain degree,
> we\'ve addressed B, but I\'d like to come back to that tomorrow after
> the public comment period, and then, depending on what we do with B,
> more explicitly, perhaps even returning to C, but maybe that won\'t be
> necessary, and then we\'ll pick up 5, and 6, and 7 at the remaining
> time.
>
> I want to thank the group because, Dr. Sigman-Grant is absolutely
> correct, you guys have worked hard today, and you have one more chore
> before tomorrow morning and that is thinking about Question 7. You may
> want to do that after dinner, rather than before.
>
> I want to thank our presenters, because they\'ve obviously made this
> discussion much, much easier than it otherwise may have been, and
> staff for getting this organized as well as it has been. So to each of
> the players, thank you, and we\'ll be back tomorrow at 8
> o\'clock\--8:15. I\'ve been corrected.
>
> \[Whereupon, at 5:51 p.m., the proceedings were adjourned, to
> reconvene at 8:15 a.m., the next day, Tuesday, November 19, 2002.\]