FOOD AND DRUG ADMINISTRATION



































                       Friday, September 10, 2004


                               8:35 a.m.








                           Double Tree Hotel

                              Regency Room

                          1750 Rockville Pike

                          Rockville, Maryland





      Robert M. Nelson, M.D., Ph.D., Chair

      Jan N. Johannessen, Ph.D., Executive Secretary


      P. Joan Chesney, M.D.

      Norman Fost, M.D., M.P.H.

      Richard L. Gorman, M.D.

      Laurence L. Greenhill, M.D.

      Ruth Hughes, Ph.D., CPRP

      Janis E. Jacobs, Ph.D.

      Eric Kodish, M.D.

      Mary Faith Marshall, Ph.D.

      Diane Treat, Patient-Family Representative

      Tonya Jo Hanson White, M.D.




      Julia Gorey, J.D.

      Dianne Murphy, M.D.

      Sara Goldkind, M.D., M.A.

      Bernard Schwetz, D.V.M., Ph.D.



                            C O N T E N T S




      Call to Order, Introductions

        Robert M. Nelson, M.D., Ph.D.                            4


      Meeting Statement:

        Jan N. Johannessen, Ph.D.                                6


      Subpart D Expert Panel Process

        Sara Goldkind, M.D., M.A.                                9

        Bernard Schwetz, D.V.M., Ph.D.                          13


      Overview, Charge to Panel and Final Outcome

        Robert M. Nelson, M.D., Ph.D.                           18


      Background on ADHD/Protocol Overview

        Judith L. Rapoport, M.D.                                34


      Questions and Panel Discussion                            46


      Summary of Submitted Public Comments

        Robert M. Nelson, M.D., Ph.D.                          119


      Open Public Hearing

        Vera Sharav                                            126

        Alan Milstein                                          131


      Questions and Panel Discussion                           139



                         P R O C E E D I N G S


                      Call to Order, Introductions


                DR. NELSON:  Good morning.  We still have


      a couple of people that we waiting for, but I


      thought we could start with our introductions and


      get the meeting going.


                Bern, do you want to start with the




                DR. SCHWETZ:  I will start and introduce


      myself. Thank you, Skip.


                Good morning to all of you.  I am Bernard


      Schwetz, the Director of the Office for Human


      Research Protections in HHS.


                DR. GOLDKIND:  I am Sara Goldkind, the


      bioethicist at the FDA in the Office of Pediatric




                DR. MURPHY:  I am Dianne Murphy.  I am the


      Director for the Office of Pediatric Therapeutics,


      and I wanted to tell you how delighted I am that we


      are having this combined meeting and look forward


      very much to your deliberations.


                MS. GOREY:  Julia Gorey, Office for Human



      Research Protections.


                DR. JOHANNESSEN:  Jan Johannessen.  I am


      the Executive Secretary for this meeting.


                DR. NELSON:  Robert Nelson.  I am chairing


      the meeting, and I am from Children's Hospital of




                DR. CHESNEY:  My name is Joan Chesney.  I


      am in Infectious Disease, and I am a Professor


      Pediatrics at the University of Tennessee in


      Memphis and also direct the Academic Programs


      Office at St. Jude Children's Research Hospital.


                DR. MARSHALL:  I am Mary Faith Marshall.


      I am a bioethicist at the University of Kansas


      Medical Center.


                DR. FOST:  Norm Fost, pediatrician at the


      University of Wisconsin, Director of the Bioethics


      Program and Chair of the IRB.


                DR. GORMAN:  Rich Gorman, pediatrician in


      private practice in Ellicott City, Maryland, and


      Chair of the Committee on Drugs for the American


      Academy of Pediatrics.


                DR. KODISH:  My name is Rick Kodish.  I am



      a Professor of Pediatrics and Bioethics at Case


      Western Reserve University in Cleveland, Ohio.


                DR. JACOBS:  I am Jan Jacobs.  I am a


      developmental psychologist and professor at Penn


      State University.


                DR. GREENHILL:  Larry Greenhill.  I am


      child psychiatrist and professor at New York State


      Psychiatric Institute, Columbia University.


                DR. WHITE:  Tonya White.  I am a child and


      adolescent psychiatrist and a pediatrician at the


      University of Minnesota.


                MS. TREAT:  I am Diane Treat.  I am a


      Patient and Family Representative.


                DR. NELSON:  Thank you.


                We will have a reading of the Meeting




                           Meeting Statement


                DR. JOHANNESSEN:  Thank you and good




                The following announcement addresses the


      issue of conflict of interest with regard to the


      study drug dextroamphetamine and competing products



      used for the treatment of ADHD, and is made part of


      the record to preclude even the appearance of such


      at this meeting.


                Based on the submitted agenda for the


      meeting and all financial interests reported by the


      committee participants, it has been determined that


      all interests in firms regulated by the Food and


      Drug Administration present no potential for an


      appearance of conflict of interest at this meeting


      with the following exceptions:


                In according with 18 U.S.C. 208(b)(3),


      full waivers have been granted to the following


      participants:  Dr. Patrician Joan Chesney for


      ownership of stock in a company with a product at


      issue valued between $25,001 and $50,000 and for


      her spouse's honoraria for speaking on unrelated


      topics at a firm with a product at issue valued at


      less than $5,000, and Dr. Laurence Greenhill for


      his consulting with companies with products at


      issue between $10,001 an $50,000.


                A copy of the waiver statements may be


      obtained by submitting a written request to the



      Agency's Freedom of Information Office, Room 12A-30


      of the Parklawn Building.


                In the event that the discussions involve


      any other products or firms not already on the


      agenda for which an FDA participant has a financial


      interest, the participants are aware of the need to


      exclude themselves from such involvement and their


      exclusion will be noted for the record.


                We would also like to note that Dr.


      Richard Gorman is participating as a Pediatric


      Health Organization Representative acting on behalf


      of the American Academy of Pediatrics.


                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 whose product they may wish to comment on.


                Thank you.


                DR. NELSON:  Thank you.  Let me introduce


      our first speaker, Sara Goldkind, who is a


      bioethicist with the Office of Pediatric


      Therapeutics at the FDA.


                     Subpart D Expert Panel Process



                       Sara Goldkind, M.D., M.A.


                DR. GOLDKIND:  As. Dr. Murphy said, we are


      extremely excited to be a part of this landmark


      time in pediatric research and look forward to the


      deliberations of this committee.




                As you all know, this is the inaugural


      meeting of the Pediatric Ethics Subcommittee, which


      is a subcommittee of the Pediatric Advisory


      Committee, which will meet for the first time next




                The Pediatric Ethics Subcommittee is going


      to address, as it will do today, the Subpart D


      referrals and also, in the future, we look forward


      to it addressing ethical issues that impact on


      research affecting the pediatric population.


                Today is the first open meeting with OHRP


      regarding a joint referral under 45 CFR 46 and 21


      CFR 50.54.




                The FDA involvement with Subpart D


      regulations began in the 1990s when the Advisory



      Committee at that time made a recommendation on


      November 15, 1999, that Subpart D be adopted.


                The recommendation was endorsed by the


      American Academy of Pediatrics and by PhARMA.




                The Children's Health Act of 2000 mandated


      that HHS funded, supported, or regulated research


      comply with these additional protections for






                Finally, in April of 2001, the FDA adopted


      Subpart D regulations which are identical to the


      Subpart D regulations found in 45 CFR 46, which is


      considered the common rule for HHS.




                The Pediatric Advisory Committee is


      endorsed by the Best Pharmaceuticals for Children


      Act in 2001 and the Pediatric Research Equity Act


      in 2003.




                Now, I am going to talk about Subpart D


      referrals specifically, and those come to us under



      45 CFR 46.407 and 21 CFR 50.54.  That Subpart D


      regulation is entitled, "The Additional Safeguards


      for Children in Pediatric Research," and it states


      that if an IRB does not believe it can approve the


      research under one of the first three categories of


      Subpart D, the clinical investigational research


      may proceed on if:  "The IRB finds that the


      research presents a reasonable opportunity to


      further the understanding, prevention, or


      alleviation of a serious problem affecting the


      health or welfare of children," and "The Secretary


      and/or Commissioner of the FDA, and the Secretary


      of DHHS, after consultation with a panel of


      experts, such as yourselves, in pertinent


      disciplines, science, medicine, education, ethics,


      and law, and following an opportunity for public


      review and comment determines either that the


      clinical investment in fact satisfies one of the


      first three categories of Subpart D, or the


      following three conditions are met:


                1.  The clinical investigation research


      presents a reasonable opportunity to further the



      understanding, prevention, or alleviation of a


      serious problem affecting the health or welfare of




                2.  The clinical investigation will be


      conducted in accordance with sound ethical




                3.  Adequate provisions are made for


      soliciting assent and parental permission.




                So, the possible recommendations open to


      the Pediatric Ethics Subcommittee that it can make


      to the Pediatric Advisory Committee are the




                It can recommend allowing the protocol to


      proceed because it satisfies on of the first three


      categories of Subpart D.


                It can recommend allowing the protocol to


      proceed, with modifications, because those


      modifications would then allow the protocol to be


      approved under one of the first three categories of


      Subpart D.


                It can recommend allowing the protocol to



      proceed because it satisfies the three conditions


      that I just previously outlines under 46.407 or




                Or it can recommend that the protocol not


      be allowed to proceed, providing specific reasons


      for its rejection.




                The goals under Subpart D that we feel


      that this process is trying to meet are:


      transparency, opportunity for public input,


      opportunity to make the determinations and


      recommendations in an efficient and timely manner,


      with clarify and consistency, the opportunity for


      expert input, and additionally, harmonization with


      OHRP, so that we have a unified, comprehensive,


      federal process.


                Of course the overarching goal of this is


      to advance pediatric research in an ethically sound




                Now, I will turn the podium over to Dr.




                     Bernard Schwetz, D.V.M., Ph.D.



                DR. SCHWETZ:  Thank you, Sara.


                I just wanted to take a couple of minutes


      to comment again about the joint nature of this


      review, because normally, there would be a


      subcommittee that would be reviewing a question


      that dealt with the FDA, and the outcome of that


      deliberation by the expert panel would go to the


      Commissioner of the FDA, or there would be a panel


      of experts addressing a question about a protocol


      because it was HHS funded or conducted, and it was


      at the 407 level of discussion, and the question


      doesn't involve an FDA-regulated product, but it


      does involve an HHS-funded study, then, that panel


      would make a recommendation that OHRP would carry


      to the Commissioner.


                When there is a situation where it is an


      FDA-regulated product, and it is an HHS-funded


      study, then, we end up in the situation where we


      have a joint review, and we did not want to create


      a situation where we had two separate expert panels


      review of the protocol, not only because of the


      redundancy involved, but the possibility that two



      different groups of people would see the protocol


      differently, and we would have conflicting reviews


      of one protocol.  So, that is why we have the joint






                I just want to assure you that the HHS and


      the FDA regulations regarding the protocol reviewed


      through .51, 2, and 3, and 404, 5, and 6 are


      comparable, so that you needn't worry today about


      whether or not the discussion takes into account


      one set of regulations for the FDA versus a problem


      with the HHS regulations.  They are comparable.


                The difference comes after the Advisory


      Committee makes its decision, and what I want to


      lay out for you next is what happens in the case of


      the outcome of a joint review as opposed as what I


      have already described for the review of either an


      HHS protocol or an FDA protocol.




                So, after today's meeting, Dr. Nelson will


      make a presentation to the meeting of the full


      Advisory Committee on September 15th, and in that



      meeting, he will summarize the discussion today,


      and he will summarize your recommendations, because


      as a subcommittee, you can't bring this to


      completion yourself.


                As an Advisory Committee, they have the


      responsibility for making the final decision, so


      your outcome will be recommended to the full


      Advisory Committee, and presumably, they will


      either accept your recommendation or come back to


      you with some questions or some recommendations for


      you to consider.  It is unlikely they would reject


      your recommendation, but they could come back and


      ask for further clarification of something.  But


      that would be up to Dr. Nelson to handle, but


      whatever that recommendation is, then, the


      recommendation of the full Advisory Committee will


      go to the Commissioner of the FDA, and assuming


      that the Commissioner of the FDA then recommends to


      go forward with this protocol, with this study,


      then, the process is half done.


                At that point, we would take the message,


      or OHRP would take the message to the Secretary's



      Office that we have had the expert panel review, we


      have had public input, the FDA Commissioner has


      made the determination, whatever it is, to go


      forward or to not go forward, so then we would


      carry that message to the Secretary's Office for


      final decision on funding of the study.


                So, if, in fact, at that point, the


      process has included a recommendation for some


      revision to the protocol, we would also negotiate


      that revision to the protocol with the PI and with


      the sponsor, but when that would be taken care of,


      then, the decision of the Secretary's Office would


      be either to fund the study or not.


                So, if, in fact, the decision from the FDA


      Commissioner is to not allow this study, to not


      support this study, then, we would simply carry


      that message to the Secretary, but it would not be


      revisited of whether or not the study would be




                The Secretary's decision would carry the


      day, but if, in fact, the Commissioner says to do


      the study, then, the Secretary's Office does have



      the opportunity to take into account all the


      considerations and decide whether or not this study


      should be funded.


                So, then, that would be the end of the


      line when the Secretary advises NIH that the study


      should be funded or not.


                That is the process, Skip.  I will turn it


      back to you.


                DR. NELSON:  Thank you, Sara, and thank


      you, Bern.


              Overview, Charge to Panel, and Final Outcome


                DR. NELSON:  On the assumption that we


      were not going to assume that everyone in the


      audience, although I hope everyone on the panel,


      but not everyone in the audience is familiar with


      Subpart D, and that we would run through a little


      bit of what an analysis of a research protocol


      involving children would look like, and I will


      basically be following the algorithms that you


      should have in the handout of this particular


      presentation, and you can either look at the small


      print, page 1, or the large print to page 1,



      depending on your age and refraction of your




                In effect, this is an unusual occurrence


      although depending on your state and whether your


      have sunshine laws, we are pretty much carrying out


      an IRB meeting in public, which is an auspicious


      event, and here is a copy of the overall protocol,


      at least in terms of Section 1 and Section 3, and


      what we will basically be starting with is looking


      at the fact that you need to place pediatric


      research in the context of Subpart A, which is the


      common rule to start with, so I will give some


      initial orienting remarks about that.




                Then, we will look at Subpart D


      specifically and the specific protections there,


      and then return back to Subpart A and look at


      issues surrounding assent and permission, and just


      take you through the algorithm.


                As you will see, the questions the


      committee will need to address reflect the issues


      that those regulatory criteria bring.





                So, the general criteria of Subpart A, in


      other words, the common rule, basically say that


      risks to subjects are minimized by using procedures


      which are consistent with sound research design, do


      not expose subjects to unnecessary risk, are


      performed for diagnostic or treatment purposes, and


      then selection of subjects is equitable, and then


      there is an evaluation of risks and benefits with


      respect to the research.




                Now, what makes pediatrics a little bit


      different is in Subpart A, the common rule, in


      terms of all subjects, you will notice that the


      risks are reasonable in relationship to anticipated


      benefits, if any, to subjects and the importance of


      the knowledge that may reasonably be expected to




                Now, logically, if you look at that, you


      can have risk balanced by knowledge, whereas, in


      pediatrics, there is a limit to the risks that we


      can expose children to for the purpose of



      generating knowledge, and that is where we end up


      with the specific additional safeguards for


      children that fall into two main categories.


                The first is the restrictions on allowable


      risk exposure for research not offering the


      prospect of direct benefit, which are found in


      either minimal risk or minor increase, and we will


      go into that, but the second is the notion that the


      justification for risk exposure, if there is


      benefit, would be constrained, as well, by the


      language in Subpart D.


                So, I am going to run through briefly how


      that would look with this particular algorithm.




                The first step, assessing the level of


      risk presented by each research intervention or


      procedure, and deciding whether it is either


      minimal risk, and then approving it, disapproving


      it, or considering it under 406, 407, or 50.54,


      which is this panel, or that it is more than


      minimal risk.





                Now, the definition of minimal risk has


      been a point of discussion in the ethics


      literature.  The current definition of minimal risk


      is it means the probability and magnitude of harm


      or discomfort anticipate in the research are not


      greater in and of themselves than those ordinarily


      encountered in daily life or during the performance


      of routine physical or psychological examinations


      or tests.  I would anticipate that we would have


      some discussion around this particular definition.


                What I have added is something that is not


      in the regulations, which has been recommended by a


      number of different commissions and reports, is


      that minimum risk should be understood in terms of


      the normal, average, healthy children living in


      safe environments.  That language happens to be


      taken in the Institute of Medicine report on


      research involving children that came out in March


      of this year.  So, that may be a point of




                After you have made that determination to


      sort of move down in this algorithm, once you



      determine that it is more than minimal risk, you


      then have to evaluate whether or not there is


      direct benefit from that particular intervention or


      procedure, and that would move you in two different




                If you did feel that there was a prospect


      of direct benefit, you then have to ask about the


      justification for that risk exposure.  The risk


      should be justified by anticipated benefit and the


      relationship of anticipated benefit to risk needs


      to be favorable as available alternatives.  We are


      likely not going to engage in this particular


      conversation today given the nature of the


      protocol, but this would be the one route that you


      would move down, and then if you decide there is no


      prospect of direct benefit, you would then move


      further down the algorithm to then evaluate the


      level of risk.




                You end up then deciding is it a minor


      increase over minimal risk or is it more than a


      minor increase over minimal risk, and then asking



      two different questions with respect to that.




                Now, here is the minor increase over


      minimal risk. The series of questions that need to


      be examined is, first, are the experiences


      reasonably commensurate, Yes or No.


                If the answer is No, you either disapprove


      it or it may fall into 407 or 50.54 review.


                Does it provide an opportunity to


      understand or ameliorate the child's disorder or


      condition?  Again, Yes or No takes you in a


      particular direction.  If the answer is Yes, then,


      you have to ask the question will there be, in


      fact, generalizable knowledge of vital importance


      achieved through that.


                If at the end of the day, you think it


      falls through here, you can end up approving it or


      disapproving it.


                One of the reasons this says disapprove


      here instead of possibly going to 407 or 50.54, is


      as Sara and I were talking, the language is


      different, but it is hard to understand how we



      might interpret reasonable opportunity under 407 or


      50.54, if, in fact, is it not of vital importance.


      The language is different, but that is an editorial


      interpretation. If anyone wants to discuss that


      interpretation, we certainly could in the course of


      our discussion.




                But then you get back to the 407 or 50.54,


      which basically then says if there is greater than


      a minor increase over minimum risk, we need to


      understand that it is a reasonable opportunity to


      understand, prevent, or alleviate a serious problem


      affecting children's health or welfare, and then


      conduct it in accord with sound ethical principles.


      Based on the judgment there, you can either then


      consider it for possible approval under 407 or


      50.54, or, in fact, if it doesn't meet those


      criteria, recommend it for disapproval.




                Now, once you have done that, we should


      then turn back to the issue of parental permission


      and child assent. All four categories simply have



      the language that there need to be adequate


      provisions for child assent and parental




                It doesn't provide any particular advice


      about what that adequate provision might be, but


      that is something that we would need to discuss.


                Now, permission of one parent is


      sufficient, if consistent with State law, for


      research under 404 or 50.51, 405 or 50.52.


                For research approved under either the


      minor increase over minimal risk, which is 50.53 or


      46.406, the permission of both parents is necessary


      unless, of course, one parent is deceased, unknown,


      incompetent, or not reasonably available, or when


      only one parent, in fact, has legal responsibility


      for the child, again consistent with State law.


                So, that would be true of both the 406


      category and the 407 category of 50.54.  So, then,


      that needs to be considered by the IRB.




                In terms of child assent, this again is


      the regulatory language.  Adequate provisions for



      soliciting assent when, in the judgment of the IRB,


      children are capable of providing assent, and the


      advice about that capability to the IRB is that


      they need to account for the age, maturity, and


      psychological state of either some or all of the


      children.  So, an IRB could make a determination


      for all of the children in that particular project


      or they can basically make a sort of case-by-case


      or sort of classy-by-class depending upon the range


      of ages.


                Now, assent is not a necessary condition


      for proceeding with the research if the IRB


      determines that the capability of some or all of


      the children is so limited that they cannot


      reasonably be consulted, or if the intervention or


      procedure involved in the research holds out a


      prospect of direct benefit important to that child


      where we would, in fact, think it is appropriate


      for a parent's permission alone to suffice for


      enrolling that child in the research.




                Again, some of the general criteria of



      Subpart A that need to be satisfied, adequate


      provisions for monitoring the data collected to


      ensure the safety of the subjects, and then, where


      appropriate, adequate provisions to protect subject


      privacy and to maintain data confidentiality.




                So, that basically takes us through sort


      of an analysis of a protocol, and what I am going


      to recommend to the panel is that we consider, as


      we go through this, to make sure that we have


      touched on all of those particular issues, and if


      we have, I would hope that we have covered pretty


      much everything that is important in the discussion


      of this particular protocol, and perhaps some other


      things, as well, but we should at least make sure


      we cover all of those basis, because otherwise we


      are not being I think true to what the regulations


      would require us to do.


                But the overall charge is to provide


      advice and recommendations to the Pediatric


      Advisory Committee on FDA's and certain HHS


      regulatory issues.  As Bern went through, as a



      subcommittee, we actually don't have the regulatory


      authority to advise the Commissioner and the


      Secretary, but we will then, through the Pediatric


      Advisory Committee, have that recommendation.


                I certainly hope our discussion here is


      sufficient and exhaustive enough and clear enough


      that it will be readily apparent to the Advisory


      Committee that they should agree with what we


      decide, but they certainly have the authority to


      think differently about that.


                Now, the outcome is we should develop


      recommendations whether the protocol should proceed


      and specifically address whether and how, so there


      may be things that we would recommend need to be


      adjusted for the research to it either does satisfy


      us as currently written, or, in fact, could satisfy


      if we had some additional conditions, either the


      categories that are approvable by local IRB under


      minimal risk, minor increase over minimal risk, or


      prospect of direct benefit.


                If not, however, we could then look to


      whether or not the research could or does meet the



      following conditions: that it is a reasonable


      opportunity to understand, prevent, or alleviate a


      serious problem affecting the health or welfare of


      children; that it can be conducted in accord with


      sound ethical principles, and I think one challenge


      for us will be to try to articulate what we believe


      those sound ethical principles are that would, in


      fact, justify it if we come to the conclusion that


      it should go forward under that category; and then


      adequate provisions for soliciting the assent of


      children and permission of their parents and




                So, at the end of the day, I hope we have


      a very clear set of recommendations, concrete,


      straightforward. There shouldn't be any


      interpretation on my part about what that is.  You


      should leave this room feeling that, in fact, what


      I am going to say Wednesday morning reflects


      exactly what you want me to say.  So, that will be


      the goal.


                With that, I think we are actually moving


      along quite expeditiously, and we can move on to



      Dr. Rapoport if there is no questions by the panel.




                DR. FOST:  I just wanted to make a


      comment.  That suggested modification of the


      definition of minimal risk, I think is welcome and


      desirable, but there is another element of the


      definition that is widely disputed, that I think we


      might want to get to today, and those of you who


      are involved in advising, you might want to think


      to think about.


                That is, the phrase "routine physical


      examination or test," there is wide variability in


      IRBs in whether they interpret that as a routine


      visit to a general pediatrician for a health


      supervision visit or to a nephrologist who routine


      does kidney biopsies in people who come into his




                In fact, IRBs have approved


      non-therapeutic kidney biopsies, small bowel


      biopsies on the grounds that the nephrologist


      investigator says this is what happens on a routine





                I was at the meetings of the National


      Commission when this was discussed, and there was


      no question that what was intended was a routine


      visit to a pediatrician for a health supervision


      visit, but in a drafting error, as commonly occurs,


      that didn't get in there.


                I think that is what was intended.  I


      think it would be helpful if there is agreement on


      that, for that to be incorporated in the


      definition, and if it comes up today, it would be


      helpful if we agreed on that.


                DR. NELSON:  Okay.  Mary Faith.


                DR. MARSHALL:  I just want to ask you to


      clarify our understanding of the criteria under 407


      and 50.54, a serious problem affecting the health


      or welfare of children, that we would interpret


      that to mean all children.


                DR. NELSON:  I guess I am a little


      reluctant to provide my interpretation of language


      that has no interpretation or guidance provided on


      how to interpret it.


                DR. MARSHALL:  That may come up in the



      discussion today.


                DR. NELSON:  As it comes up through the


      discussion, I think we should talk about how that


      impacts on our decisionmaking, if it does, and if


      it does, I mean I think cases are the best way to


      try and specify principles. I really don't have any


      sage advice on how to interpret that.


                In terms of Norm's comment, I think he is


      right on target, but another interesting question


      is how to interpret this notion of daily life, so


      that other half of the equation has also been


      subject to a fair amount of discussion, and I think


      may impact on our assessment.


                DR. FOST:  But doesn't your added phrase


      take care of that?  I mean it clarifies it by


      referring to some normal environments.


                DR. NELSON:  It helps clarify that, in


      fact, that phrase, but at this point, you know,


      that has not been formally adopted in any kind of


      official guidance other than commissions and




                Dr. Rapoport.  Just to give us an



      approach, I mean we will start off with the


      investigator, then, have some comments.  I don't


      know if Don has organized remarks or is available


      for questions.  Dr. Rapoport says she can be here


      for a while with us, but won't be here the whole


      day, so I am hoping the panel can be able to get


      whatever questions they feel are important to ask


      kind of out of the table at the start of the day.


                Thank you.


                  Background on ADHD/Protocol Overview


                        Judith L. Rapoport, M.D.


                DR. RAPOPORT:  Thank you, Dr. Nelson, and


      members of the committee.  I appreciate the chance


      to present this. As far as slides go, I think they


      reflect both slides that were prepared by Dr.


      Rosenstein, as well as myself, so I think the


      slides, as you will see, will reflect both IRB and


      my own statements, and I will add some background.




                My own work has involved several different


      disorders with children, but I have been at NIH for


      more than 20 years, and a large part of our work



      has had to do with the effect of stimulants, not


      just stimulants used therapeutically in ADHD, but


      the effect of dietary substances that are


      substances, particularly caffeine on behavior.


                Children at least in the Washington area


      drink a lot of Cokes, as well as an amazing amount


      of iced tea, and as a result, we do have extensive


      notion of what an ordinary child would experience


      by way of exposure to 50 to 100 milligrams of


      caffeine in terms of what you would expect in an


      ordinary day.




                This was a protocol to study a single dose


      of dextroamphetamine in ADHD.  ADHD is a very


      controversial, but extremely widespread condition.


      It is probably the single most common disorder in


      child psychiatry clinics today.


                It remains very much a bone of contention.


      Like many psychiatric disorders, there is very


      little by way of laboratory definition, that this


      diagnosis is made by interview and various


      checklist ratings and duration criteria, disruption



      to life, et cetera, but there is certainly no


      laboratory experience, and the advent of


      functionality MRI has been, for pediatrics, quite


      remarkable particularly for child psychiatry as a


      possible window into understanding the physiology


      of this disorder.




                I don't think for this group I need to go


      into details about the symptoms, but it is a


      question of degree, and part of the controversy


      comes because what is seen by people who are


      skeptical as being very arbitrary.  As a cutoff, it


      is really a degree and duration and interference


      with life decision since all of the behaviors are


      things that children very commonly and often


      exhibit in certain situations.




                Stimulants remain the treatment of choice.


      Unfortunately, other nondrug-related treatments,


      while being somewhat helpful, really are of a


      different order of magnitude in their effect, and


      the treatment decisions again based on clinical





                There is increasing public health concern


      on high rate of stimulant use, and there is


      considered a great deal of neuroscience-based


      diagnostic treatment and outcome measures.




                So, one of the questions, and let me say


      that this is a really old question that goes back


      to perhaps an unfortunate statement in the 1930s


      when children on stimulants were seen to calm down


      when they were first used actually to help them


      calm during a procedure, a radiographic procedure,


      that was they were sort of almost accidentally


      found to be useful, and there was an unfortunate


      statement made that this was a paradoxical effect


      with paradoxical calming.


                That led to the very unfortunate use of an


      observation that children would calm on stimulants


      for many pediatricians for a generation to tell


      parents that their children must have "minimal


      brain dysfunction" because they actually did calm


      down on the stimulants.



                I mention this just because I want to


      point out that there was considerable indirect


      benefit to older observations than studies we did


      in the early '80s, that, in fact, all children calm


      down, and that, in fact, is not a diagnostic


      response to the stimulants and had very great


      benefit on practice, immediately became a board


      question both for child psychiatry and pediatrics,


      because they thought the point was so important to


      get home.




                Our question was do children with ADHD


      have a different brain response to stimulants, and


      this was provoked by a very small study that had


      been approved at Stanford earlier, but let me just


      say that we thought it was very important to see


      whether this is an opportunity to see, with the


      functional MRI, whether there could be actual


      difference in brain response in spite of an


      exhaustive earlier study that showed that by almost


      any measure, whether it's motor activity, verbal


      fluency, ability to retain material, but by every



      measure that the children's behavior was the same,


      and we thought we had actually laid this to rest


      that a stimulant had no difference in effect


      between ADHD and healthy children except, as I say,


      a couple of studies came along, which are reviewed


      in detail in the protocol, which raised the


      possibility that, in fact, there might be a


      "paradoxical response."


                There were major problems with these


      studies, not just their small size, but the nature


      of the tasks, the lack of data in one case, and the


      choice of task in the other, where you couldn't


      unconfound task performance with central nervous


      system response.


                These studies, however, because of the


      importance, because the conservative definitions


      place ADHD at perhaps 3 to 4 percent of the


      population, and because of the continuing debate, I


      think it's notable how important and the great


      interest in the study, that even that small study


      of Vaidya's, which was approved I think without


      much comment at the Stanford Review Board, but that



      was published in PNAS, and I think that attests


      more to the considered importance and interest in


      the issue than that particular study, as our


      excellent colleague would be the first to say


      herself, I think.


                At any rate, we felt this could provide


      some fundamental information about the


      pathophysiology of ADHD and effects of treatment.




                So, the proposed study was 14 children


      with ADHD, and 14 healthy controls.  I am


      deliberately reading out of order because only if


      there was a difference between.  If there was no


      difference between their response in the fMRI,


      between the controls and ADHD, we were not then


      going to go on and do the twin part of the study.


                But it then involved recruiting.  I say


      "recruiting" because we have some twin studies


      ongoing, but over time some children, of course, go


      out of the age range, so you need to recruit more


      mono and dizygotic twins, concordant and discordant


      for ADHD as an approach for understanding whether



      the differences are related to just the state of


      having the disorder or represent an underlying






                There is history and physical examination,


      blood work, neuropsychological testing, single


      functional MRI session, but there was also


      several--in fact, I am sorry, I believe that is an


      error--I think it involves two MRI sessions, and


      subjects to be paid what is an amount which we


      calculate just by how many hours.  This is a


      payment that is arrived at simply by going through


      a checklist of procedures and can be modified one


      way or the other by IRB.




                The IRB concerns, and as I say, these are


      slides because when these were prepared, it wasn't


      clear that Dr. Rosenstein was going to be


      presenting, but the primary IRB concern was about


      the risk level of the study for healthy children


      and whether the administration of a stimulant was


      approvable under federal regulations.



                Questions were raised about the value of


      the study in the IRB, although the three outside


      scientific reviews were the strongest reviews that


      I have ever gotten for outside reviews of many


      protocols.  They were concerned about the level of


      payment, and I think wanted to adjust that downward


      if the study were approved.




                I think this has already been covered.




                I think this has also already been


      covered, and so I don't think I will go into this.




                What I would like to say is that in terms


      of the risks, we have had years of research with a


      single dose of stimulants in hyperactive children,


      as well as a very well known study that I alluded


      to, in the '80s, with healthy children, and the


      single dose was likely to cause, if administered in


      the morning, some loss of appetite at lunchtime,


      possibly someone might feel a little bit nervous or


      have some trouble sleeping at night, but, for many,



      because of the duration of effect, if given early


      in the morning, even these would not occur.


                The IRB request to this committee was for


      waiver of more than minimal risk.  That will have


      to be represented by Dr. Rosenstein, because my own


      feeling was that this represented minimal risk, so


      therefore, I am not a good advocate for that




                A bit of history might be of interest.  As


      always, we always with all of our pediatric


      studies, consult both formally and informally with


      the hospital ethicists.


                A very excellent ethicist was present when


      I did the study in the 1980s, John Fletcher, and I


      asked John, as I always did with all my studies,


      did he have any special recommendations, and he had


      two recommendations, one which would be illegal


      now, but made intuitive sense to me at the time,


      was that if one or two of the investigators had


      children in the right age, it would make sense if


      their own children took part.


                At the moment, this would not be legal,



      both because you are not allowed to use your own


      family members, and because NIH employees and their


      families are not supposed to take part, and so on,


      but I must confess that when I review and I am on


      panels, such as this, which I have been regularly,


      in my own heart I often ask myself would I allow a


      child of mine to be in the study.  So, both with


      his recommendation at the time, we not only would,


      but a couple of us did.


                He made another recommendation, which was


      that we should pay a lot of attention in this


      protocol to informed consent, and suggested that


      both parents consent and that they both be highly


      educated.  So, this is the only study I have ever


      done in which all of the parents of all of the


      children had graduate degrees.


                That was an interesting process because


      the parents were all extremely interested.  We were


      not concerned that the children particularly liked


      the experience, although they did enjoy getting out


      of school for a couple of mornings, but the


      parents' interest in the child's improvement on



      test performance was considerable.


                I think the major thing that I was left


      with from that experience, I knew many of these


      children, and so I knew a lot of formal and


      informal follow-up over years, and they considered


      it an interesting experience, but otherwise totally


      benign, and what most of them remembered later was


      just that they did something different that week


      rather than the usual routine.




                There have been studies that showed that


      even with long-term use of stimulants, three or


      four showed no long-term use of subsequent


      substance abuse.  There is certainly no data


      relevant to a single dose, and even the one study


      that suggested that children, after years of


      stimulant, who had ADHD, might have a slight


      increase in risk.  Those were children that


      included some conduct disorder children who would


      be at predicted higher risk relative to the general




                So, I interpret the long-term data as



      being negative, and these are for ADHD children


      with multiple problems who have had stimulant drugs


      for years, and it is on that basis that I don't


      consider a single dose as a risk in healthy


      children in this regard.


                I think that is all, and I stayed well


      within the timeline.  I would be happy to answer to


      any questions.


                DR. NELSON:  Before we get to questions,


      Don, do you have prepared remarks or not?


                DR. ROSENSTEIN:  I do not.  I was asked to


      come just to answer questions about the IRB




                DR. NELSON:  Why don't we then go to


      questions, but if there is a question asked that


      you want to defer to the IRB Chair, feel free.


                     Questions and Panel Discussion


                DR. RAPOPORT:  Right.  I should also


      mention that Dr. Daniel Pine is sitting here, and


      if there are very specific questions about the


      cognitive neuroscience part, I rely on him for some


      of that.



                DR. NELSON:  Okay.  Norm and then Rick.


                DR. FOST:  Dr. Rapoport, I have three




                First, dose.  It is stated in three


      different ways in the protocol that we got.  In


      some cases, it is per kilo, some as a single flat


      dose for everybody.


                Could you clarify how the dose is




                DR. RAPOPORT:  Yes.  That reflects that in


      addition to whatever personal inconsistencies, the


      differences occurred because we had used a fixed


      per kilogram dose earlier.


                The general thinking about


      psychopharmacologists with a wide range of ages was


      that it made better sense to give a low, fixed


      dose.  I consulted with several experts in the


      field.  However, the way it should have read is


      that we would give 10 milligrams per kilogram,


      10-milligram dose, period.


                In any cases where it would end up being


      more than a per-kilogram dose, we would adjust it



      downward, would not include that subject.


                DR. FOST:  So, 10 is the most that anybody


      would get?


                DR. RAPOPORT:  That's right.


                DR. FOST:  Second, on the compensation or


      the payment, you said you something about toning


      that down, and I had a couple of questions about




                The total in the protocol we got was it


      might go as high as $570.  Number one, was that


      intended to go to the parents or the children, or


      divided in some way?


                Number two, there is three reasons for


      giving money.  One is to compensate people for


      expenses, which should be the parents, not the


      children.  Two, as an honorarium to thank them.


      Three, as an inducement because of the feeling that


      you would have trouble recruiting if you didn't.


                Could you clarify which of those you had


      in mind with this money, and if it's the last, if


      it's an inducement, do you think it is necessary,


      or whatever your current thinking is about



      modifying it?


                DR. RAPOPORT:  Right.  I might add that in


      the 1980 study, nobody was paid anything because


      that was the policy at the time.  I think I would


      rather defer the question to Dr. Rosenstein on


      this.  Frankly, from an investigator's point of


      view, you see what everyone else is doing, and you


      look it up in a list, so he is the one who can give


      the informed answer.


                DR. ROSENSTEIN:  It is a tough question,


      because it gets at the motivation, and I am not


      sure.  I think what you just heard from Dr.


      Rapoport was that there wasn't any specific


      decision that we wouldn't be able to do the study


      unless we paid this amount of money for an


      inducement.  I mean there was no evidence of that




                This is a moving target, as you know, and


      I think that at the NIH, what we have seen over the


      last several years is that for studies that did not


      offer a prospect of direct medical benefit, that


      involved time, inconvenience, and a variety



      of--well, I will just leave it an


      inconvenience--that payment has now become the




                How much to pay is a complicated question


      that I don't anybody has got the answer to, but I


      think the notion is that payment should be for some


      combination of the time lost and the inconvenience


      to the subjects.


                I also don't think that there is agreement


      upon whether all the money should go to the parents


      or the money should go to the children in the form


      of a gift certificate to a book store or somewhere


      else and how you work that out.


                So, quite frankly, we didn't get that far


      because at the IRB, where we got, we decided it


      wasn't approvable at our level.


                DR. FOST:  So, if understand you, and I


      just want to make sure Dr. Rapoport agrees, you


      don't think it is necessary to recruit to this


      study?  That is, if you had no compensation, you


      think you could still get sufficient enrollment.


                DR. RAPOPORT:  I don't know the answer to



      that.  I just don't know.  It is much more


      complicated now.  Everybody's parent works, has to


      take off time, et cetera, so things have change a


      lot in terms of these are children, they need a


      family member to be there for the whole time, and


      things have changed a lot.


                Certainly, it wasn't necessary when we did


      the study the first time, and that had no part of


      it.  I can't tell you the answer to that.


                DR. FOST:  The third question is a


      question about risk and assent, not about the


      possible medical risk, but the anxiety of being in


      a scanner.


                There is some comment in the protocol


      about your previous experience with functionality


      MRIs and MRIs, and it sort of implies that there


      has been almost no adverse reactions.  Is that


      case?  What is the incidence of children in your


      setting who had sufficient anxiety in the scanner


      that they want to come out or that they report




                DR. RAPOPORT:  It is extremely low, but



      you understand that we have a very different


      process from the medical world in which this is not


      the case, where children typically have MRIs when


      there is other stressful circumstances.  They are


      not interviewed ahead of time to be in the study


      based on their sense of whether they would mind.


                We have the luxury of having a whole


      practice session and pretend MRI, a mock MRI.


      Children also have less claustrophobia because just


      literally, they are physically much less closed in


      than adults are, so they are much less bothered by




                As a result, because we prescreen children


      for all of our children, describing the MRI, et


      cetera, et cetera, it is almost zero, but I don't


      think that our experience would generalize to the


      real world, of course.


                DR. FOST:  Right, and you say almost zero


      in the practice MRI session?


                DR. RAPOPORT:  Even that, because we tell


      the child about it, I mean as part of even the


      informed consent process, we go into this in





                DR. FOST:  So, by the time you get to the


      "real one," have you had any experiences of bad




                DR. RAPOPORT:  Not with any volunteer


      subjects, of which we have now more than 3,000 MRI


      scans, but with patients occasionally.


                DR. NELSON:  Rick Kodish.


                DR. KODISH:  Thank you for clarifying


      which Rick.


                Two questions.  The first has to do with


      age and assent or consent.  I was struck by the


      fairly broad age range in the protocol, I think 9


      to 18.  There was some text that suggested that


      there was a significant brain change in adolescents


      that makes the investigators think differently


      about post-adolescent subjects.


                I am wondering if it is the case that from


      an ethics perspective, an age range of 14 to 18


      might be preferable for better assent, close to


      true consent, but from a scientific perspective,


      and this is not my area, that, in fact, the 9 to



      12, 9 to 14 age.


                Is that accurate, and is there a


      scientific preference?


                DR. RAPOPORT:  Right.  You are asking a


      very good question.  We would prefer to have


      children that are between the ages of 8 and 12.


      Eight is the lower level age largely because of the


      nature of the tests and the ability for




                We had very clear reasons why we didn't


      feel a study would be useful in adults, which I


      think are described in the protocol.


                Do you want to comment on that?  I think I


      would like to ask them because this had to do with


      the neuroscience issue.


                DR. PINE:  I would just like to add to Dr.


      Fost's comment, that we also routinely do many


      studies in children who have very high levels of


      anxiety disorders, and really would just second the


      comments that Dr. Rapoport made, that any child who


      is going to have a significant problem with an MRI


      scan, really never gets very far along in the



      process of doing the study, because it becomes


      pretty obvious both to parents and to clinicians,


      as well as the child, that this isn't for them.


      So, that's the first thing.


                The second thing is I think some of the


      major questions at a neuroscientific, neurochemical


      basis, related to stimulants, relate to changes in


      the dopamine system in the brain, and some of the


      most pressing questions focus on the precise age


      range that Dr. Rapoport was just discussing, the 8


      to 12 range.


                Many neuroscientists feel that after even


      early adolescence, the changes in the dopamine


      system are so profound that even among 15- or


      16-year-olds the relevance of the data that you


      would acquire for younger children, who are


      definitely prepubertal or perhaps even in the early


      stages of puberty would not be comparable and would


      not really be sufficiently compelling.


                DR. NELSON:  Would you mind on tape just


      introducing yourself for the purpose of our


      documentation, please.



                DR. PINE:  Sure. I am Dr. Daniel Pine.  I


      am a child psychiatrist in the NIMH Intramural


      Research Program.


                DR. KODISH:  So, to follow up, the


      eligibility criteria for the study strike me as


      ambiguous.  I mean one can say clearly that it is 9


      to 18, but am I hearing correctly that from a


      scientific perspective, you would prefer 9 to 14, 9


      to 12--


                DR. PINE:  Yes.


                DR. KODISH:  --and in some sense, the


      upward expansion of that is to make it ethically


      more reasonable.  I mean certainly from the ethics


      perspective, my thinking is that older kids would


      be more able to participate in a decision to do




                I do have one more pharmacology question.


                DR. ROSENSTEIN:  Let me just add one


      comment about that, and this was not a position


      that the entire IRB shared, but there were some


      people on the IRB who also thought it would make


      more sense to study younger children because those



      people who were worried about the potential message


      of it being okay to take a single close of a


      medication might be more of an issue for older


      children than for younger children.  So, the ethics


      argument cuts both ways with respect to the age


      range.  Again, that wasn't an unanimous opinion,


      but that was one that was articulated at the IRB.


                DR. RAPOPORT:  I certainly think that from


      the point of view of both things, that is more


      compelling to use it in younger children, both


      because of the science of it and that those people


      who were "ADHD," older, may not be representative,


      in fact, of the child population.


                But I think from a mood response, the


      younger children are very unlikely to get any


      positive mood response to it.


                DR. KODISH:  And then the last one, which


      will be shorter, has to do with this particular


      drug.  I was struck by your introductory comments


      about the incidence of caffeine use in children,


      and I am wondering if there is, the way that one


      has narcotic pharmacoequivalency, is there data you



      can give us about 10 milligrams of amphetamine, how


      much caffeine?


                DR. RAPOPORT:  Our own data is the most


      extensive on that.  We had several schools that


      participated in this, so we knew about children's


      habitual diet, their habitual behaviors, and then


      they took part in various low and high does


      caffeine versus placebo, and these were actually


      more extensive than single dose studies.  These


      were for two weeks at a time.


                The lower dose, which was about 50


      milligrams, 75 milligrams, as I recall, of


      caffeine, seemed to be about equivalent to what a


      single dose of ADHD, there wasn't a sense of any


      change in appetite or problem sleeping.


                DR. KODISH:  So, what is normal?


                DR. RAPOPORT:  The trick was we did a


      survey of households at several parochial and


      public schools, and so on, and households seemed to


      be quite dichotomous.  About half of the school


      children had very generous exposure to both


      caffeinated soft drinks, as well as iced tea,



      sometimes, to me, astonishing amounts, that the


      kids would have several hundred milligrams a day,


      because iced tea is always "okay."


                DR. KODISH:  But several hundred


      milligrams exceeds the equivalent of 10 milligrams


      of amphetamine?


                DR. RAPOPORT:  By far, by far.  On the


      other hand, you know, there were plenty of


      households that didn't, too.


                DR. KODISH:  Thanks.


                DR. NELSON:  Dr. Gorman.


                DR. GORMAN:  I have a couple of questions


      related to the actual protocol.  You have already,


      in response to Dr. Fost's question, mentioned that


      there are several discrepancies in the protocol in


      terms of dosing.


                Could you walk us through, as a committee,


      how NIH deals with revising protocols, so these


      discrepancies are eliminated in what I assume would


      be a final protocol, which we are not reviewing?


                DR. RAPOPORT:  Right.  I think I can only


      apologize, and I will take whatever responsibility



      for inaccuracies or inconsistencies, but there is


      multiple review, typically with protocols, it is


      read at several levels by the IRB, and usually


      meticulously, and at the meeting, not only are the


      broader issues described, but we are presented with


      very detailed list of typos, inconsistencies, and


      so on, and I would say most of the time, the review


      proceeding is extremely detailed and careful.


                DR. GORMAN:  I appreciate that.  I am more


      concerned or more interested actually in what


      happens in the future.  In the protocol, there is a


      typo about the dose, which would need to be


      corrected, so that you wouldn't be in protocol


      violation every time you dosed a child.


                DR. RAPOPORT:  Right.


                DR. GORMAN:  How does that procedure take




                DR. RAPOPORT:  I think I would have to ask


      Don to speak to that.


                DR. ROSENSTEIN:  This is a human process.


      We do the best we can.  It is reviewed by outside


      scientific reviewers, inside scientific reviewers,



      a pre-review before the IRB.  There are 14 members


      of the IRB that all review it.  At the time of the


      continuing review, hopefully, that would be, you


      know, an error like that would be picked up.


                So, the answer is the process is people


      read the protocol as carefully as possible.  If


      there are discrepancies that are missed, they are


      missed, and hopefully, we pick them up at the next




                DR. GORMAN:  In the IRB world that I live


      in, which I deal mostly with industry-sponsored


      surveys, this would require a protocol amendment


      that would clarify the errors, and that would be


      incorporated into the protocol.


                DR. ROSENSTEIN:  Of course, once it's


      identified. I thought you were asking how were we


      going to identify--


                DR. GORMAN:  No, how are you going to


      correct it, so that when we--


                DR. ROSENSTEIN:  With an amendment to the


      protocol, sure.


                DR. GORMAN:  There will be an amendment to



      the protocol that will deal with the dosing issues?


                DR. ROSENSTEIN:  It will clarify whatever


      the error was.


                DR. GORMAN:  Okay.


                DR. RAPOPORT:  Absolutely.


                DR. GORMAN:  The second question comes to


      deal with the MRI itself.  In the protocol, it


      describes that this is a 3-Tesla coil.  Is the


      3-Tesla coil experimental or in common clinical use


      at this point?


                DR. PINE:  I think it is fairly well


      articulated in terms of the view of 3-Tesla magnet,


      but it is used regularly for clinical studies


      including at the NIH.


                DR. GORMAN:  I am sorry, not for clinical


      studies. Is it a clinically approved device?


                DR. PINE:  Yes, it is a clinically


      approved device.


                DR. GORMAN:  Thank you.


                Do you plan on getting two parental


      signatures on this informed consent if this study


      is found to be approvable?



                DR. RAPOPORT:  I hadn't been, but I


      believe I have learned this morning that I should.


                DR. GORMAN:  Thank you.


                DR. NELSON:  Dr. Chesney.


                DR. CHESNEY:  I have questions about the


      need for using stimulant in normal children at this


      point in time, and I have read the protocol, I have


      gone back and looked at a number of the original


      articles, and as a neophyte, tried to understand


      the neuroscience, but I obviously have many holes.


                Since fMRI is so new, I wonder if we


      should or potentially should focus efforts on


      learning more about the fMRI findings in normal


      children without stimulant, and in newly diagnosed


      ADHD children, and in ADHD children on chronic


      medications before we need to look at the issue of


      stimulant use in children.


                Again, in looking at what has been


      published, which looks to me fairly minimal in


      terms of fMRI findings, I, in looking at dopamine


      receptors and transporters, and so on, and trying


      to understand all of that, and I may not be



      understanding it, but it seemed to me like we still


      have a lot to learn just by looking at normal


      children again without stimulant, and newly


      diagnosed, and chronically treated ADHD children


      before we may need to look at the issue of giving


      stimulant to children, which would make the issue


      temporarily a little more straightforward.


                So, I wondered if you could comment on


      that concept of whether we really need to learn


      more about what the activation in normal children


      is.  Thank you.


                DR. RAPOPORT:  Well, I think Dr. Pine will


      also like to comment, but I would like to say that


      at the NIH, there is always a tension between the


      very strong interest in the basic kinds of


      observations that you describe and when you apply


      them as a clinical problem.


                But at least at the NIH, there has been a


      great deal of very active work already in children,


      in healthy children with some of these tests, and,


      in fact, Dr. Pine's collaboration and co-PI on this


      protocol reflects that.



                So, there is a great deal more, the change


      from PET scan to a test that doesn't involve


      exposure to ionizing radiation really


      revolutionized pediatric studies, so in a limited


      field of research where there isn't much research


      all together, relatively speaking, there has been


      quite a considerable amount already, several from


      people who trained at the NIH and have gone out to


      other leading centers.


                So, I don't think it is quite so minimal


      given that pediatric research is minimal in its own


      way anyway.


                I think this a problem, though, that


      remains very important, that there really are


      people that are using all sorts of tests and


      selling them as diagnostic processes to the general


      public.  I think you could make an argument that


      this is a compelling question.


                DR. PINE:  I actually, first of all, want


      to thank you for your question because I think it


      does point out almost a procedural element of the


      document that you have, so there are three specific



      comments I would like to make.


                One is that both Dr. Rapoport and myself


      are--I don't know if beat is the right word--but


      really taught and forced to write an extremely


      focused document that very tersely and very


      narrowly identifies a key question, so that people


      reviewing the protocol can look at that specific




                As Dr. Rapoport mentioned, there is


      actually an incredibly exciting, burgeoning


      literature and a number of studies supported by


      DHHS-funded studies that are answering just the


      kind of questions that you raise, and the


      technology that we are going to use, if we are


      allowed to do this study, takes advantage of some


      of the things that people have learned by doing


      just the kind of studies that you have mentioned,


      doing large-scale fMRI studies looking at these


      types of functions in healthy kids, in kids with


      ADHD, in fact, even today, there is a paper that


      came out in the American Journal of Psychiatry that


      uses a very similar technique that compares brain



      functioning in children with ADHD and healthy


      children, that is consistent with the work that we


      are proposing, so that is the first thing.


                The second thing is, you know, it is also


      very exciting to think about things like dopamine


      receptors and wanting to do more basic work using


      those types of methods.


                The thing that many people don't


      appreciate is that virtually all of the other


      methods for looking at neurochemistry could not be


      approvable because the potential risks for children


      would be higher than the risks that are in this


      protocol as they are described, second of all.


                Third of all, one of the things that


      really captured my attention when Dr. Rapoport


      first approached me about this protocol is I


      remembered very vividly where I was when the study


      from Dr. Vaidya was first published, and I remember


      if for a couple of reasons.


                One reason was it gathered a huge amount


      of media attention, and I think one of the reasons


      it did was it brought to the fore this idea about



      is there a fundamental distinction in the way in


      which the brain of a child with ADHD works relative


      to the brain of a child who does not have ADHD.


                That has been a question that we have been


      grappling with for 30 years, as Dr. Rapoport has


      mentioned. There has been virtually no way to get


      at that.  The finding, as it was reflected in that


      1998 paper, by far and away provides the most


      compelling hint that that is true, that there is a


      fundamental distinction between in which the brains


      of healthy children and the way in which the brains


      of children with ADHD functions.


                If that is, in fact, correct, it could


      have monumental impact in terms of how we think


      about this condition, and there is just no other


      way with the current technology that we have to get


      at that question.


                DR. RAPOPORT:  I totally agree with you,


      and I think that is very exciting.  I mean this is


      a huge problem in pediatrics, but I wonder if it


      wouldn't be helpful to focus initially on fMRI as a


      diagnostic tool.  I mean that is the most exciting



      thing to me, that you could actually distinguish


      those who truly have ADHD, not that whole


      population that is being treated that probably


      doesn't need to be treated versus the controls


      before we need to get into the stimulant medication


      for control issues.


                Do you understand?


                DR. PINE:  That has already been done, and


      when that has been done, what we tend to see in


      regular fMRI studies is a pattern of findings that


      is very similar to many other findings on ADHD in


      general, meaning that there are relatively subtle


      differences in terms of how the brains of healthy


      children relative to children with ADHD work when


      they are studied with current fMRI technologies,


      but they suggest, much like, you know, a lot of the


      literature that has led to the current controversy


      that there is not a quantum categorical difference


      in terms of the functioning of the healthy child's


      brain and the brain of the child with ADHD, and


      there is considerable overlap in terms of how that


      bring appears in a healthy child versus the child



      with ADHD.


                Given that problem, the likelihood that


      that technology, as it currently exists, is going


      to be used as a diagnostic tool is very limited.


                DR. RAPOPORT:  Well, this gets to the core


      of what has been of interest to me.  If there is


      that much variability, how will you be sure that


      you can interpret the results with the stimulant in


      a meaningful way?


                DR. PINE:  There is variability in the


      studies that use current fMRI technology without


      the stimulant challenge.  When you look at the


      results in that one paper that was published in


      1998, you see a completely different pattern of


      results, to the point where there is virtually no


      overlap between the two groups, and that is what


      really generated the enthusiasm both in the


      scientific community, but also in the lay public


      that this was the type of test where theoretically,


      potentially, there was not that degree of


      variability, but one could only see that difference


      if one looked at scans acquired both during a



      placebo condition and under methylphenidate.


                The variability was diminished when you


      looked at the change in brain functioning when a


      child was taking stimulants, and that is why it is


      so important to pursue this particular issue of


      what happens to the brain of the child when they


      are taking psychostimulants.


                Let me rephrase it, that most biological


      measures that we have, we see this pattern of


      overlapping distributions for virtually every test


      that we do and virtually every psychiatric


      disorder.  Once in a while we come upon real


      categorical distinctions where we get two


      distributions that are just not overlapping.


                Whenever we get those, they are incredibly


      important to pursue.  In the field of ADHD


      research, the one area in the last decade where we


      have had this is when we look at this study that


      was published in 1998 where there were


      fundamentally categorical distinct responses in


      these two groups.


                Was it a fluke?  Maybe, but if it is not a



      fluke, it fundamentally changes the way we look at


      the disorder. That is why it is so important to


      pursue.  It has not been pursued for the exact


      reasons that you guys are assembled here today to


      discuss.  It has not been pursued because it can


      only be pursued by examining the response of a


      healthy child's brain to psychostimulants, and that


      just has not been done since 1998 in that type of a




                DR. NELSON:  Mary Faith Marshall.


                DR. MARSHALL:  I am going to focus on


      something that is a little different than the


      previous question.


                I would like to ask, during the consent


      process, how you would go about explaining the


      testing for the exclusion criteria in a pregnancy,


      so the pregnancy testing, how that would work out


      in terms of the informed consent process.


                DR. RAPOPORT:  Right.  That is difficult.


      There is an absolute requirement that any women,


      girls who might be sexually active absolutely have


      to have a-- it is not a popular requirement with



      the investigators, and we don't feel any credible


      evidence that there is a good reason for it.


                We would explain to them that there is


      this requirement and explain this as part of going


      through a urine test would be necessary, just to be


      in the study, explained that way.


                DR. MARSHALL:  Is it done in the presence


      of their parents?  What I am getting at is what


      privacy protections do you have during the process,


      and also I would ask, there are several consent


      documents or versions of consent documents in our


      folder.  I think three of them are versions of a


      parental permission document, and then the child


      assent document, and I don't see anywhere in the


      child assent document mention of pregnancy testing.


                DR. RAPOPORT:  Right.  I am going to ask


      Dr. Pine who has had more experience with that.  I


      think not having it mentioned is probably an


      oversight, that's for sure.


                DR. PINE:  I guess I would say two


      comments related to the questions about the IRB


      process, having put a number of the protocols



      through the IRB.  The first thing to realize is


      that the discussion of this protocol was tabled


      very early in the process, so I think the IRB got


      to a really core question that if they couldn't


      answer it, you know, they were not going to move on


      to the discussions of these other details, and I


      think that the key issue was whether or not one


      could give a psychostimulant to a healthy child,


      and once they decided that they were not going to


      approve that, they did not discuss some of these


      other issues.


                I will tell you that this issue, as well


      as some of the other issues in our other fMRI


      studies, has been a bit of an evolving process, and


      what we do now, having learned from experience, is


      in the consent form of the parent and the assent


      form of the child, it says to both a pregnancy test


      will be done, your mother or your father will be


      told if your test comes back positive.


                We have kind of learned the hard way in


      terms of clinically and ethically, that that is the


      most justifiable thing to do in discussions with



      the IRB, and this way, when people come into the


      study and assent for it and consent for it, both


      the child and the parent know that if their child


      comes back with a positive pregnancy test, which


      unfortunately happens more likely than we would


      want, everybody knows that going in.


                DR. MARSHALL:  I guess I would just make


      the observation then, that as common as this is, I


      would, if I were sitting on your IRB, expect to


      see, within the protocol itself, a discussion of


      the process and the privacy and confidentiality


      protections that are there, and that that should be


      upfront in any protocol, and wouldn't have to wait


      for IRB review.


                DR. NELSON:  Let me follow up, I think


      Joan's line of questioning, and ask a question


      about sort of data analysis.  One way to approach


      the issue of the inclusion of the normal controls,


      and particularly the intervention group, normal


      controls is to ask whether the data analysis truly


      needs to be blinded and whether there can be a


      sequential process by which, at the end of the day,



      you can demonstrate that you actually need the


      controlled intervention data as opposed to the


      controlled placebo data to interpret what you have


      then seen in the ADH control and intervention data.


                So, I mean this is not a drug trial in a


      sense where you need to have, you know, if you take


      a look at, you pay a penalty in your statistical


      significance, so I am just curious, could you do


      some sort of sequential design or at least the


      burden of proof that you need the control drug data


      as sort of elevated beyond what might be in a sort


      of standard prospective randomized, controlled




                DR. RAPOPORT:  Well, in order to get good


      data because of differences across individuals, of


      levels, and so on, you would need any subject to


      have both a non-drug and a drug condition, so since


      they have to agree to come twice, blinding and


      having one placebo, so that the subject is blinded,


      you don't really lose anything.


                I think more to the point of answering


      your question, since the point of the study is the



      change between off-drug and on-drug condition, that


      is what the study is doing, what I think we would


      probably do would be, with a smaller number than,


      say, 14, take a look at the data and say if one


      had, say, 8 subjects, did one need 14 and had a


      very clear answer, and that says test fewer


      patients, healthy subjects, if we needed fewer.


                Am I answering your question with that?  I


      thought that is what the implication of your


      question was.


                DR. NELSON:  I guess the way I would


      rephrase that, is there any problem if one delayed.


      It needs to be blinded to the individual in the


      scanner, I assume, and blinded to the interpreter


      of the FMRI, but is there any way that you could


      design it in a way that you would gather all of


      your ADHD data and then have the control data


      blinded in a way that at least you then have


      demonstrated the need for the control drug data to


      make that interpretation.


                DR. RAPOPORT:  I think we wouldn't be able


      to, because each study, each test situation is



      different enough that I think you would, in order


      to know whether they were different from the


      control or not, you would simply have to design


      standardized tests and standardized applications,


      that in any given experimental situation, I don't


      think you would know enough conceivably from just


      ADHD alone to be able to know whether they are


      behaving the same or differently from a healthy




                DR. NELSON:  One of the other key things


      is an order effect.  You know, that there is a fair


      amount of concern in order effects.  So, if you


      were to do a study where everybody gets placebo


      first, including the kids, the healthy kids and the


      kids with ADHD, and then they get stimulant second,


      you couldn't tease apart the specific effect of the


      medication, on the one hand, versus the fact that


      the medication scan always comes second.


                You know, half the kids are going to have


      to get the medication first, the other half are


      going to get placebo first, otherwise, the study is


      not interpretable, or it basically becomes the same



      type of study that has already been done, that's


      published this month in the American Journal of




                You are looking at the change, but if you


      always do the placebo first, you can never


      interpret the change as due to the medication.  It


      might be due to the medication or it might be due


      to the order effect.


                DR. RAPOPORT:  We always, though, try to


      minimize the number of subjects and the exposure.


      If we had clear results with 8 subjects instead of


      14, we would stop there. If there were no


      differences between the ADHD delta and the control


      delta, we would not go on and do the twin studies.


                DR. NELSON:  Dr. Greenhill.


                DR. GREENHILL:  Just in response to your


      question, and I apologize if I missed this point


      that was in the protocol, another aspect of what


      you are talking about, the blinding relates to


      possible or potential benefit to the individual


      subject.  If the family might get the results of


      the study after all the participants have gone



      through, in other words, they would learn if there


      were differences in the performance of the


      subjects, that particular individual subject, when


      he or she took the test, is that something that is


      built into the protocol at this point, because I


      know in our IRB, we insist in industry protocols


      that the blind be broken, so that subjects can get


      results of their experience in the particular




                DR. ROSENSTEIN:  I think that question may


      have more relevance for the children with the ADHD


      than the children without, because from our


      perspective, from the IRB's perspective, there is


      no prospect of benefit for those children who don't


      have ADHD, that they be interested in finding out


      the results of the study, and I think every


      investigator handles that differently depending on


      when the overall blind of the study is broken and


      what kind of information can be communicated in


      real time.


                But looking at how that information was


      exchange to the families of the children who don't



      have ADHD was never a consideration with respect to


      prospect of benefit.


                DR. GREENHILL:  I was just talking about


      the subjects who had diagnosed ADHD.


                DR. ROSENSTEIN:  I understand, but again,


      I think the reason that this protocol is before you


      is principally for the children who don't, and I


      just wanted to emphasize that.


                DR. NELSON:  Mary Faith Marshall has


      another couple of questions for Don, and then we


      are scheduled for a break at that point.


                DR. MARSHALL:  One is just a clarification


      question, Don, and that is relative to the IUs that


      were used to derive the compensation scheme for


      this study, whether that stands for inconvenience




                DR. ROSENSTEIN:  Inconvenience unit.


                DR. MARSHALL:  Are those standard


      throughout the NIH?


                DR. ROSENSTEIN:  Yes, they are guidelines,


      but there is also, as Dr. Rapoport suggested


      earlier, there is room for variability in how you



      apply those, so that there are certain procedures


      that are thought to carry with them greater levels


      of inconvenience than others, even if they take the


      same amount of time.  So, there is some


      interpretation in that, but there are some basic


      guidelines that we could make available to this


      committee, if you would like, from the NIH.


                At the end of the day, the IRB has to look


      at the bottom line and whether that is consonant


      with the study.


                DR. MARSHALL:  Thank you.  The second


      question relates to the discussion that the IRB had


      in executive session about the protocol on October


      28th, I guess sort of the final ones perhaps, the


      final discussion.


                I want to commend you on the minutes that


      are taken of your meetings.  They are excellent,


      they really are, very thorough.


                This may just be a reflection of how the


      minutes themselves were written, but under


      Discussion in Executive Session, the minutes say,


      "Discussions supporting designating the study as



      minimal risk, focused on the compelling scientific


      justification for the study and the opinion that


      the risk of exposure to this drug In a supervised


      setting does not exceed the risk children are


      typically exposed to."


                I was wondering if you could maybe just,


      if you remember, can describe for us the component


      of the IRB discussion of discussion that supported


      designating the study as minimal risk relative to


      the compelling scientific justification for the


      study.  Is that a fair question?


                DR. ROSENSTEIN:  I understand your


      question because they are apples and oranges, but


      they go into the same equation.  There were some


      people on the IRB who felt like this clearly fell


      within minimal risk, and other people who felt like


      it was a stretch and that it would have to be


      called a minor increment over minimal risk.


                The reason again that this is here is


      because the IRB, in its final deliberations, felt


      like this was an important study to do, but there


      wasn't a majority that felt that they could call it



      minimal risk, so we are not forwarding it to you to


      kind of do our work for us, but because we thought


      that it was a study that should be approved.


                In the discussion of whether it's minimal


      risk or not, some people raised questions about how


      important is it really, so if it's minimal risk,


      you know, there may not be the same burden, you


      know, on the science in a sense, and other people


      felt like, well, yeah, it's an interesting question


      and this is clearly the next logical step, but how


      important is it to demonstrate that the brains of


      children with ADHD are different.


                That was a minority opinion in the IRB,


      but it was expressed, and so I think that is what


      the minutes reflect there, that the IRB was


      struggling with a risk level that was right on the


      border and how compelling the science was to


      justify it, you know, whether it was just below


      that level or just above that level, if that makes


      any sense at all.


                DR. MARSHALL:  It does, thank you.


                DR. NELSON:  Ms. Treat.



                MS. TREAT:  I just had a couple of


      questions.  I bring to the table the perceptions of


      the general community and families.


                There is the perception in the general


      community among both ADHD kids and the parents, and


      healthy kids, too, that the stimulants that you are


      using, especially the one that you are using, is


      highly habit-forming and can cause various other


      side effects.


                I was wondering, since there is so little


      research on healthy children, if the stimulant


      might--I recognize that you might believe that a


      single dosage carries very low risk based on your


      studies of ADHD subjects--but there is a concern


      among some of the people I serve that even a single


      dose might cause or might aggravate predispositions


      in healthy children, such things as eating


      disorders or later abuse, that kind of thing.


                In that regard, I also noted that the


      dosage that you are using, the 10-milligram dosage,


      is higher than the recommended starting dosage of 5


      milligrams for the stimulant you are using.  I was



      wondering if you could address that.


                DR. ROSENSTEIN:  That last question, I


      will defer to Dr. Rapoport and Dr. Pine.  With


      respect to the first comment, this is the challenge


      that all IRBs have in interpreting the regulations


      when you have an absence of data.  No one can


      answer the question of what risk there might or


      might not be with a single dose of a medicine like




                The data that Dr. Rapoport summarized


      earlier suggested even when you are using


      stimulants chronically, there is not an increased


      risk of substance abuse, but perhaps a decrease in


      risk.  Whether that applies at all to healthy


      children who get one dose, we, quite frankly, don't


      know.  So, I think other people around our table


      were wondering about that as a contributor to


      whether this ought to be considered slightly more


      than minimal risk or not, but we just simply don't


      know, to answer that question about the dose.


                DR. RAPOPORT:  Yes, we were torn.  People


      with hyperactive children often do start with a



      single 5-milligram dose, that is absolutely true.


      Our own experience with numerous behavioral


      measures is that that so often doesn't give a


      recognizable signal.  We certainly didn't want to


      go through all of this and not have anybody


      including the hyperactive children have any change.


                It was the smallest dose to get any


      reliable change, and even though any good


      pediatrician or doctor would always try to start


      conservatively when people are going to start off


      and taking something, you know, every day for


      weeks, we thought this was the lowest dose that


      would be worth doing, because too many children in


      our experience don't change in a measurable way in


      a single dose of 5, but I am not criticizing the


      pediatric approach.  Just for a single-dose study,


      it didn't make sense to us.


                MS. TREAT:  I did have one other question,


      and that concerned the IQ parameter that you have.


      In the protocol, it says that your only parameter


      is the low one, the low IQ being 80.  When I and


      some of my friends had taken their kids to take the



      test, the go/no-go test and the stop test, I was


      told by the doctor that IQ did have a bearing on


      responses to those tests, the higher the IQ, the


      less likely or the more likely the subject was to


      be able to perhaps even beat the test.


                I was wondering if maybe a smaller


      parameter for you would--


                DR. RAPOPORT:  You mean to have a higher


      cutoff, as well as the lower cutoff?


                MS. TREAT:  Yes.


                DR. RAPOPORT:  I think I will ask Dan.


                DR. PINE:  In general, it is true that


      there are some associations between IQ and


      performance on these types of tests.  There is wide


      variability across the different kinds of tests, in


      the strength of that association, and when we use


      these tests behaviorally, meaning just having kids


      do the exact same paradigms that Dr. Rapoport is


      going to use, we find extremely small, if any,


      correlations between IQ and these specific tests.


                DR. NELSON:  Dr. Greenhill and then Dr.





                DR. GREENHILL:  Since we are discussing


      the consent and assent forms, there are a couple of


      questions or suggestions that came to mind.


                The perception of families about these


      medications relates to the fact that


      dextroamphetamine is a schedule drug, which means


      that it is classified as a drug of abuse by the


      Drug Enforcement Administration.


                Pharmacists often remind families of that


      when they get a prescription of the drug, and in


      some states, those drugs are delivered on different


      prescriptions, and they are tracked and monitored,


      and physicians' prescribing rates are tracked.


                So, it is important in all our consent


      forms that involve schedule drugs, to tell parents


      that this is a schedule drug, and considered to be


      a drug of abuse by the Drug Enforcement




                The other thing is that we tend to be more


      explicit about adverse events that are connected to


      stimulant medication, and even if they play a small


      role, it is important for parents to at least have



      some of the fears that they might have about these


      medications addressed explicitly in the consent




                A number of families confused


      dextroamphetamine with methamphetamine, and it is


      helpful in some of our consent forms to make it


      clear that although this is a related product, it


      is not speed.


                In terms of adverse events, there are


      infrequent adverse events, but the ones that we see


      that occur, such as stomachaches, headaches, and


      particularly involuntary motor movements are a big


      concern of families, and they occur in these


      patients.  It is not clear whether they are


      triggered by the medications, but should they


      appear, the first response on the part of almost


      every family I have worked with is get them of the




                So, they might have some concerns if their


      child took one dose of stimulants and began to


      sniff or have a blink, and they might associate it


      with taking that medication ever if it weren't





                Finally, there is a section in the assent


      form that says, "Occasionally, the MRI examination


      will detect something unexpected, in the child's


      brain is a mass or any kind of abnormality."


                This has been a big issue at the


      institution where I work because that might lead to


      every scan requiring a licensed or a


      board-certified radiologist looking at them to make


      sure there is no evidence of an abnormality or a




                This is just a question I would have for


      Dr. Pine. We have been told on the IRB that the


      protocol for the MRI scans are not designed to


      optimally look for masses or other clinical


      abnormalities, but to focus on functional, bold


      kind of results for registration, and a clinical


      wouldn't turn to that protocol if he were


      clinically evaluating a symptom complex in


      patients, looking for a brain tumor.


                It may be misleading to tell parents that


      this test will give you a bill of health, and I am



      not clear it does, so I need to ask Dr. Pine.


                DR. PINE:  It is funny that Dr. Greenhill


      says this, because I began my MRI studies at Dr.


      Greenhill's institution and was taught to think


      about MRI studies the exact same way, and I was


      shocked when I came to the NIMH four years ago to


      learn that we take an additional 20 minutes to put


      every child through a far more rigorous


      comprehensive clinical assessment of brain anatomy,


      both normal and pathological, and that is a rule of


      the NIH Clinical Center, that every single child


      who will go into the MRI scanner once a year will


      have a comprehensive bona-fide clinical assessment


      that will be read by a trained neuroradiologist, so


      that we can say exactly what is written in the


      consent form, and it is very different relative to


      any other MR center that I have ever seen.


                DR. GREENHILL:  That is a benefit.


                DR. PINE:  It is a benefit.


                DR. RAPOPORT:  It is not a choice for us,


      it's an absolute clinical center rule.


                DR. NELSON:  Dr. Jacobs.



                DR. JACOBS:  I would like to return to the


      age question that we were talking about a little


      earlier.  I am a developmental psychologist, so in


      all the research that I look at and do, age is very


      big issue.


                It seems to me that what we are doing here


      is weighing the science and the value it will have


      for future treatment an future diagnoses against


      the risk to some individual children.


                So, the science matters a lot, and it


      seems to me that the range that you have proposed,


      from 9 to 18, is really too broad, and we have


      already talked about that.  It appears to me that


      particularly the upper ranges, you may have brains


      that have changed, and it will be difficult for you


      to actually lump that data in with the data from


      the younger children, and you don't have that many


      subjects, so it will be difficult to really tease


      it out in a different way.


                So, I wonder if you have considered really


      narrowing the range especially to the younger





                DR. RAPOPORT:  Yes.  I think that it would


      make a good deal of sense to narrow it from 8 to


      13, for example.


                DR. JACOBS:  Thank you.


                DR. NELSON:  I know there is other


      questions, but before doing that, let me just ask.


      I know, Dr. Rapoport, you said that you have some


      commitments, you may need to leave.  My question is


      whether we should--I mean we do have plenty of time


      for discussion--whether people want to continue


      this conversation or have a break and then continue


      the conversation.


                I see panelists nodding continue, which is


      fine. If anyone needs some natural stimulant, get


      it on your own.


                Mary Faith had her hand up, then Norm, and


      then Dr. Greenhill.  So, Mary Faith.


                DR. MARSHALL:  Mine was really a follow-on


      to the informed consent document itself, and these


      are just observations, not questions really, and


      they may be more appropriately directed at the


      Chair of the IRB.



                One is in the consent documents, the word


      "placebo" is used early on, and I don't see it sort


      of spelled out for those who may not understand it,


      and that is an obvious thing.  It is just an


      observation, I am not asking for any defense.


                The second one is the use of the word


      "treatment." I understand that the substance that


      is under investigation is approved in certain uses,


      but this is research, and others may not agree with


      me, but I have a big allergy to the use of the word


      "treatment" rather than study drug or something


      along those lines.


                To me, treatment implies something that


      has been empirically derived and is standard


      practice.  Again, I sit on several DS&Bs for the


      NIH, and I bring it up every single time, so I just


      have to do it and go on record as saying that.


                I do want to reiterate to both of you, I


      would see a young girl who tests positive for the


      pregnancy test, and it's a surprise for everyone,


      and us knowing some of the sequela that could come


      about because of that, as potentially being greater



      than any of the other risks we are talking about


      here today.


                One thing that I see that is common among


      protocols and IRB review of protocols is what I


      would consider to be a really cavalier approach to


      that whole issue and the whole process of consent


      and privacy and confidentiality.


                So, I really just would like to say that


      again, and again I am not asking for any sort of


      defense or whatever.  I just want to get it out


      there on the table.


                DR. ROSENSTEIN:  Can I respond just to


      that one?  We do take it very seriously, and we


      have modified our approach over the years at the


      IRB.  I think that whether you agree with this


      approach or not, where we are at right now is that


      we don't test anyone unless they know they are


      going to be tested obviously.


                The investigators have a great deal of


      sensitivity to asking in private are you sexually


      active, is there any chance that this might be


      positive.  I mean all of that isn't necessarily



      laid out in this consent form in front of you, but


      we take it seriously, and the other part of it is


      that if the terms of the study are unacceptable,


      either to the child or to the parent because of


      that eventuality, they don't have to be in the




                DR. MARSHALL:  Right, and I appreciate the


      fact that they do it seriously, but as a reviewer,


      I don't see a reflection of that here, and thus, I


      have no way of knowing that that is the case.


                DR. ROSENSTEIN:  Fair enough.


                DR. NELSON:  Norm.


                DR. FOST:  I just wanted to make sure I


      understood the previous exchange about MRIs.  Did I


      understand you to say that every child, not just in


      this study, but at NIH in general, will get a


      standard clinical MRI also?


                DR. PINE:  Every child and every adult,


      every person gets a standard, and it takes 20




                DR. FOST:  It opens a whole can of worms


      that we probably don't have time to discuss at this



      minute, but I will have to discuss later, so I just


      want to identify it before you leave, so you can


      comment on it.


                There is a possible benefit, but it is


      much more likely to be a risk than a benefit.  That


      is, when you do screening procedures in a healthy


      population, a population that is not expected to


      have brain pathology, you are much more likely to


      pick up false positives, adventitious findings,


      then, someone has to explain to the parent there is


      a little something in your child's brain, we don't


      know what it means, but he ought to be followed or


      it ought to be repeated.


                I am astonished that you (a) would do


      that, and I am confused as to why you would do it.


      Why being in a study should lead you to have a


      clinical MRI.  Of course, the whole same set of


      questions are raised by the fMRI, which can raise


      adventitious findings.


                DR. PINE:  I would disagree with the fMRI




                DR. RAPOPORT:  They are less considered



      diagnostic.  We have the largest series of normal


      child, healthy child MRIs, I think in the world,


      and I can echo though while, of course, it almost


      never happens, we have had 4 instances out of 3,000


      MRI on about 500 children, who come back every few


      years, and 2 of them were benign cysts that the


      parents got further consultation and did nothing


      about, but in 2 cases they turned out to be brain


      tumors that were operated on and had a good outcome


      before we found it, so we are 50-50 in our


      experience out of these 3,000.


                DR. FOST:  That is interesting.  I hope


      you publish that or plan to.


                Again, I didn't see anything.  This is the


      first I learned of it from this interchange.  I


      didn't see anything in the protocol or the consent




                DR. PINE:  I can also tell you, much like


      the issue of pregnancy, that working with IRB, we


      have adapted the language in the consent form, and


      the process for discussing that for the very reason


      that you mentioned.  I am sure, as Dr. Rosenstein



      would say, the final consent form, should it be


      approved, would reflect the current language, which


      goes into far more detail about what it means to


      have a clinical MRI, what are the range of findings


      that we can get, what you will be told, and when


      you will be told.


                DR. FOST:  Like Mary Faith, I am confused


      as to what this consent form is.  Is this just sort


      of a draft consent form?  Why is not all this in


      the--especially when it gets to this level, I would


      think you would want--


                DR. ROSENSTEIN:  It is not a draft.  I


      will try to answer this the best way I can.  This


      protocol has been through many, many, many


      iterations, and at some point, the fundamental


      question about whether it's permissible to


      administer a single dose of a stimulant to


      children, to anyone under 18 has to be asked and




                You have got competing demands of kind of


      getting some read on that versus having a document.


      I am more than happy--Dr. Rapoport said she would



      take responsibility--I will be responsible for any


      typos, any omissions, any misleading statement in


      the consent form.


                We are more than happy--if you want to


      send it back to us with an answer, we will kind of


      work on that.


                DR. NELSON:  If I may, we will stipulate


      that the IRB recognizes their process was


      short-circuited by the question of whether they


      could do this from a regulatory perspective.  I


      think it needs clean-up.


                DR. ROSENSTEIN:  Thank you, Dr. Nelson.


                DR. NELSON:  I think we have beaten them


      up enough on that point.


                Dr. Greenhill.


                DR. GREENHILL:  I just have a question for


      the head of the IRB.  Where do you draw the line


      for listing adverse events of a particular


      intervention?  Our IRB tends to go down the list,


      knowing that some families will go the Physicians


      Desk Reference and find disturbing adverse events,


      and not realize they are under the rare section.



                So, for example, we would put in the


      frequent adverse events, headaches, stomachaches,


      decreased appetite and decreased weight.  We would


      put in the infrequent adverse events, such as tics,


      and then the rare, such as hallucinosis,




                And then we would address one that is of


      great concern to the public, which is growth


      slowdown and delay, and to try to put it in the


      context this is a single dose.


                That is one of the questions I have.  Do


      you have kind of a guideline that you use at the




                DR. ROSENSTEIN:  We follow a very similar


      approach, and whenever there are numbers available,


      we include those numbers to try to make it more


      understandable. Again, I think everyone here who


      has served on an IRB knows that it is as much art


      as science about exactly how many things that you




                When there are no data relevant to the


      side effects for a single dose, it makes it more



      difficult to know how much information is then


      misleading, you know, to report the side effects


      that are associated with higher doses for chronic


      duration may not be doing anyone a service.  It's a


      tough question.  We try to be as thoughtful about


      it as we can.


                DR. GREENHILL:  The other question I have


      is whether the consent form has to be quite so


      conservative in terms of the benefits.  Now,


      clearly, there is no medical benefit, but there is


      a benefit from coming to the NIH and having an


      evaluation by an expert team, and there is the


      potential benefit of taking the results of the


      tests and preparing some kind of report.


                I want to just expand this a little bit.


      If you don't indicate, if you give a WISC, and then


      the child six months later goes to school and has


      to get a test in order to enter a special program,


      for example, get special education, which a lot of


      children with ADHD do, they can't be tested at that


      point because there is as practice effect.


                So, we generally put in our consent forms



      something to let the parents know that by taking


      the WISC, they will not be eligible to take the


      test again for a year to have it interpretable.


                For that reason, we try to give the


      parents some kind of a form and a report.  Now,


      initially, when we did a big outpatient study with


      the NIMH, called the MTA study, we had a licensed


      psychologist sign off on it, so that that piece of


      paper that came from the evaluation served as an


      official statement of the results of the WISC,


      which can play a big role in special ed.,


      accommodations of getting special provisions and


      getting classification.


                Is that something that you might consider?


                DR. ROSENSTEIN:  Sure, and I think that


      over the years, some investigators have shared the


      results of some neuropsychological testing, but not


      all of the neuropsychological tests are


      administered in the same way that they would be in


      a clinical setting.


                It is analogous to the discussion we were


      just having about the MRI.  On one level you would



      think of this as a benefit, on another level you


      could think of it as a risk.  There are some


      parents who bring their children into a study as a


      child without any problems, but because they have


      got suspicions that there may be some difficulties,


      and then sure enough, in the course of the


      evaluation, some psychiatric problems are


      identified.  Is that a risk or a benefit?


                In the past, we have left the sharing of


      information about the evaluation, what is


      clinically relevant and what is not, up to the


      discretion of the investigator.


                DR. GREENHILL:  I just want to indicate


      that this is a unique situation because getting an


      MRI at the NIH doesn't preclude you getting one


      next week, but it does preclude you getting an IQ




                DR. ROSENSTEIN:  I understand that, and I


      wasn't aware.


                DR. GREENHILL:  The last thing I wanted to


      mention is there are a number of issues that I


      think have been addressed, and I am trying not to



      beat a dead horse with this issue of the age, but


      the older an individual is who has ADHD, the more


      likely he has had chronic exposure to stimulants.


                Is there any way--I don't think there is


      any answer I can come up with off the top of my


      head--but some investigators have required them to


      be stimulant-free before coming in and getting an


      evaluation.  That really impacts the feasibility of


      a study because if you are looking even at a


      13-year-old who had ADHD, they are very likely in


      this country to have been exposed.


                Is there any way you can factor in the


      exposure, prior exposure in terms of interpreting


      the results of the functional MRI, or do you think


      that is a problem?


                DR. RAPOPORT:  I think ideally, one might


      be having ADHD children who had never had


      stimulants before, but that is not likely to be


      true.  Our own experience of over 20 years of doing


      these studies, where we did have many children that


      we were taking total care of, was that the 100th


      response to a dose of stimulant tended to be



      identical with the first, so for this study, I am


      not really concerned.


                DR. NELSON:  Dr. Gorman.


                DR. GORMAN:  I am not through beating up


      the age question.  Has this question been answered


      in adults?  Have adults with ADHD been tested with


      single doses, and have normal adults taken single


      doses of stimulants to look at their brain




                I ask that question because I have three


      children in college, and I can tell you that their


      friends' most common request of me is can I write


      them a short prescription for a stimulant medicine


      during exam period. So, I suspect there is a lot of


      people undergoing this clinical experiment on a


      regular basis.


                DR. RAPOPORT:  The problem is that as Dr.


      Pine and other people have shown that different


      parts of the brain change, that are active, in


      response to these drugs with age.  Furthermore,


      when you look at who are adults, you need to test


      adult ADHD with adults, they turn out to be a



      puzzlingly very different population, the


      attributes of adults who identify themselves as


      ADHD, there are more females than males, there is


      very heavy comorbidity with alcoholism.  They don't


      resemble the long-term follow-up prospectively of


      children with ADHD, who, when you follow to that


      age, they don't seem to have the same profile.


                So, we don't believe that we would


      necessarily be studying the same disorder in the


      adult patient controlled, so to speak, as well as


      the same brain regions.


                DR. GORMAN:  Leaving out the different


      adult population, you seen to be in a unique


      position with your 20 years of experience following


      these children, that you would be able to find a


      more select population as young adults that have


      been diagnosed as ADHD as children.


                Is that not true?


                DR. PINE:  You are still not going to


      know, if you were to do that study, and you were to


      find a difference, you are still not going to know


      if that is a sequelae of having a disease for 20



      years with all the concomitant things that can go


      on in the brain as opposed to what that means for a


      child who presents to your office as a 10-year-old,


      and you are trying to make the decision about, you


      know, does this child have a normal or abnormal


      functioning brain.


                Data in an adult, even an adult who you


      know what has happened to them definitively, over


      40 years, you can never answer the question about


      is the brain function that you are seeing in that


      adult really just a downstream reflection of what


      has gone on in the past 20 years, and what we


      really need is date that speaks to the 10-year-old




                DR. RAPOPORT:  Moreover, we are looking


      for long-term follow-ups with continued subjects


      right now, and they are a very small fraction, I


      mean vanishingly small, that we couldn't do this


      study.  We are trying to follow up from 15 to 20


      years, the 300 patients we have characterized, and


      no, we are not able to find a sufficient number


      that don't have other major disorders that still



      would meet criteria above the age of 18.  I have


      that data.


                DR. GORMAN:  The paradigm that the


      American Academy of Pediatrics recommends is that


      if you believe the pathophysiology is the same, is


      to test, before you test in children, to test in


      adults, and that is why I am asking that question.


                So, I will ask once again very simply.


      Has this experiment been done in adults, and does


      it show that normals and adult-diagnosed patients


      with ADHD have different responses?


                DR. PINE:  There has not been an exact


      replication of the Vaidya study that was published


      in 1998, doing the exact same study in adults with


      and without ADHD, on the one hand.  On the other


      hand, there has been an extensive series of fMRI


      studies in healthy adults and adults with other


      forms of psychopathology looking at the fMRI


      response to psychostimulants.


                The feeling is that due to some of the


      questions that Dr. Rapoport had raised, about how


      do you make the diagnosis of ADHD in adulthood and



      how does it relate that many people have been very


      hesitant about embarking on everything that would


      be involved in doing that type of a study in


      adults.  I would add that we share those scientific




                I think for that reason, the study has not


      been done because no matter what you found, many


      would question the implications of the findings.


                DR. RAPOPORT:  There has been one study by


      Dr. Volkow, which used PET, which is using a


      technique not accessible to children, that did


      suggest there might be some difference with respect


      to dopamine receptors, but that wouldn't be


      appropriate, and again, she had all the


      peculiarities of her adult sample that I mentioned.


                DR. NELSON:  Dr. White.


                DR. WHITE:  I had a question regarding


      since fMRI measures, change in hemodynamic


      response, and dopamine is involved in the


      hemodynamic response, does your design take that


      into account, and also, is that a rationale for


      using controls?



                DR. PINE:  One of the unique things about


      the study is that a particularly sophisticated


      group of fMRI methodologists have been assembled at


      the National Institute of Mental Health, and, in


      particular, Peter Bandatini, who heads the


      Methodology Group there, and in his earlier work at


      the University of Wisconsin, he actually looked in


      adults, the effects of various agents including


      psychostimulants on bold perfusion effects in




                So, Peter is a collaborator on the


      protocol and ensures Dr. Rapoport and myself that


      we will be able to disambiguate hemodynamic effects


      due to vascular effects versus neurocognitive




                DR. NELSON:  Dr. Chesney.


                DR. CHESNEY:  I don't mean this to be


      simplistic, but I guess where will the results of


      the study take you?  I didn't really see any


      hypotheses, I sort of wrote out three or four on my


      own, but other than simply learning more about,


      which is absolutely important in and of itself, and



      I know research doesn't necessarily have a


      pragmatic outcome, but you mentioned that clinical


      severity would be taken into consideration


      depending on where the results came from and went




                But I guess in the bigger picture and in


      terms of helping us assess the importance of the


      stimulant in normal children, what are your


      hypotheses, where do you think will take you and


      what will be the next step?


                That would certainly help me sort out the


      overall importance other than just saying what


      activates and what doesn't activate, which is very


      interesting of itself.


                DR. RAPOPORT:  One, on a scientific level,


      it would provide the strongest evidence to date


      that there is something different in the way the


      brains of ADHD children functioned, which would be


      a more abstract scientific level.


                i think our hypothesis at the moment would


      be that with the appropriate tests where you


      disengage performance from brain activity and



      response to the drug, my hypothesis is that there


      would not be a difference, and this would help and


      counteract a great deal of fraudulent behavior on a


      clinical level that is going on, because there are


      a great many people out there selling diagnostic


      tests that people pay for in spite of the fact that


      they have no legitimacy.


                I think there is another answer here also.


                DR. PINE:  I will say again two things.  I


      think this is a great question that cuts to the


      core really of the protocol, and hopefully, it is


      reflected in the IRB minute notes, but the IRB


      really held both Dr. Rapoport and myself, and the


      entire team, to a very precise answer to that


      question, and constantly asked us to reframe that.


                I would say that Dr. Rapoport and myself,


      while we agree on the importance of the question,


      and it really is fundamental, on the one hand, and


      on the other hand, maybe we have slightly different


      visions about where it might go.


                Where I really come from is this idea that


      I think has been implicit in many of the questions



      that people have asked about how do you tell the


      difference between a child who really had ADHD and


      a child who doesn't.


                As reflected in Dr. Rapoport's answer, I


      am not sure that we would totally agree on how


      close we are to doing that.  If this study were to


      find similar results that Dr. Vaidya's study found,


      that would tell us that we are getting reasonably


      close to doing that, and that would tell us that in


      the not so distant future, when a parent comes to


      see us with a child who is basically high


      functioning, who is having mild problems in school


      that are very common, and the parent says to us


      isn't there a test that you could do that would


      tell me definitively whether or not my child really


      has ADHD or not, this study would be a very


      important first step towards developing that type


      of technology and developing that type of finding.


                On the other hand, if the results of the


      study were negative, it would say that this


      approach is not a good way to go, and that this way


      of trying to develop the test as specified in that



      protocol might not be the best way or perhaps we


      might be a long way away from developing that kind


      of test.


                But that is really the importance of the


      work.  It is trying to develop a better


      physiological based measure that can tell us, yes


      or no, does this child have a problem in the way in


      which their brain is functioning or not.


                MS. TREAT:  You know, it seems that there


      are a lot of diagnoses of children, young children,


      with ADHD.  I believe Dr. Jacobs' comments sort of


      support this.  As they get older, their brains


      change, and many of the people that I know of who


      are diagnosed with ADHD as children, got to a point


      as they grew older, in the later teen years, where


      they no longer needed to be on the medications,


      they were better able to concentrate, and that kind


      of thing.


                I am not a professional, so I am not sure,


      but it seems that it would indicate that they may


      have been misdiagnosed when they were younger.


                In that regard, to me, it seems to make



      more sense to restrict--is you were going to


      restrict your age range, to restrict it to the


      upper age range rather than the lower.


                You had mentioned that you would restrict


      it to the lower age range, 8 to 13.


                DR. RAPOPORT:  Yes, for several reasons.


      The natural history of ADHD is that as children get


      older, they tend to, particularly in adolescence,


      many of them no longer meet criteria.  It is a


      disorder that for many children, when they get


      older, they no longer have the problems, and when


      they do, it is expressed somewhat differently,


      often with more inattention and less motor


      restlessness, for example


                I think, in general, that there is a wide


      degree of misdiagnosis of ADHD, but I think that


      when it is done carefully, and when you require


      that you have a sustained period of more than six


      months, starting before the age of 7, and going on


      with the considerable interference with functioning


      in at least two settings, not just the home or not


      just the classroom, that, in fact, the misdiagnosis



      at a certain level of severity, of the sort that we


      do in our studies, I think the prediction from year


      to year of continuation up until adolescence is


      very high.


                The natural history of the disorder,


      though, is different, and I think the points that


      were made by several committee members is that I


      think it does get more complicated in the older age


      range, and that anything we found out earlier would


      be much more generalizable to the vast majority,


      the great majority of ADHD children and the ones


      for whom these questions were initially addressed.


                DR. NELSON:  Thank you.  I think at this


      point, I would like to transition to some material


      we need to get on the table before we do our public


      discussion period at 11:00 and then perhaps give


      people a chance to stretch their legs before that.


                I would like to thank Dr. Rapoport for her


      patience and clarity in answering our questions,


      and Don, as well, and your colleague.


                DR. RAPOPORT:  Thank you.  Dr. Pine had to


      make a plane, and that is why he left early.



                DR. NELSON:  Thank you.


                At 11:00, we will be having a time of open


      public hearing, but before that, there were some


      comments that were submitted in response to the


      request for public comments that I was going to




                Basically, we can then take a short break


      before we have the open public hearing at 11:00.


                  Summary of Submitted Public Comments


                     Robert N. Nelson, M.D., Ph.D.


                DR. NELSON:  The full text of the public


      comments should be in the packets that people have


      for this meeting.  I have summarized them by


      basically dividing them into issues, so we can see


      what each person said or didn't say about given




                The backgrounds of the three responses


      that we received, one was the parent of a child


      with ADHD, also who had chaired an IRB in the past.


      One was a health professional, and the other was a


      lay person who also happens to be a grants and


      contracts administrator at a university level





                In terms of scientific merit, parent of


      the child with ADHD, and these are quotes taken


      from those comments, thought that there was a


      possibility of great scientific benefit with


      respect to the causes, diagnosis, and treatment of


      ADHD, which poses significant challenges to many


      children and their families, and may also help


      distinguish between appropriate medical uses of


      dextroamphetamine and more questionable uses.


                The health professional simply commented


      that the studies needed to generate important


      information, and the lay person felt that being


      able to comment on the scientific validity or


      utility of doing the study, particularly in normal


      children, was beyond, in this case, her particular




                In terms of risks to subjects, two


      commented on this.  The parent of the child with


      ADHD felt that a single dose of dextroamphetamine


      is unlikely to be harmful, further, there are


      safeguards in place, and the child and/or parent



      and guardian may discontinue participation at




                The lay person expressed concerns regard


      the drug abuse potential that might be suggested by


      having one dose, which might lead to curiosity


      about additional doses.


                In terms of parental permission, the


      parent of the child with ADHD thought the consent


      documents are clear.  The health professional


      thought they were clear.  The lay person had a lot


      to say about the consent forms, and I have not


      quoted it all, I have simply summarized her points.


                I didn't feel that the documents fully


      explained the procedures involved in the study, and


      particularly she mentioned the screening, physical


      exam, the teacher contact for rating scales,


      genetic testing for twins, the decision to test


      twins with respect to zygotic status could have


      emotional implications for parent and twins, the


      MRI in terms of full description, and she felt that


      the technical language, it was a bit too technical


      as opposed to lay terms, and that they didn't



      really provide much discussion to the alternative


      to participation.


                In terms of child assent, the health


      professional said that the assent documents need to


      be written at age appropriate reading level, but


      did not say, although you could infer, that they


      didn't feel that this was the case with these




                The lay person felt the inclusion criteria


      in the protocol states that it should have consent,


      but she pointed out they should have talked about


      assent, and also commented on the fact that the


      pregnancy testing was not mentioned in the assent


      form, nor whether the results will be shared with


      the parent.


                In terms of financial incentives, the


      parent of the child with ADHD felt that the


      payments were not too high, but did feel that the


      payments ought to be directed to the child in some




                The lay person felt, you know, maximum 570


      being paid, but it doesn't describe who will be



      compensated.  To this person, it seemed like a


      large amount for the child, and it seems


      inappropriate to compensate the parent.  "It


      appears coercive" is a direct quote.  With no


      direct benefit to the child, it appears that the


      parent is benefiting financially while putting the


      child at some risk and certainly an inconvenience.


      The benefit section refers to the compensation as a


      benefit.  Again, this becomes coercive.


                Assessment of risk category.  This was the


      parent of the child with ADHD who you may recall


      also chaired an IRB.  For children with ADHD, I


      would consider the study a minor increase over


      minimal risk within the range usually borne by


      children with the disease with an offsetting


      societal benefit that could not otherwise be




                For the normal controls, the risk is


      greater than minimal in that they would not receive


      the medication or the functional MRI in normal


      life, however, it is unlikely that a single dose of


      dextroamphetamine would cause harm, and again



      safeguards are in place.


                The bottom line.  The parent of the child


      with ADHD felt that I would encourage approval of


      this study, and the lay person said I do not feel


      comfortable about approving this study in its


      current form.


                So, that is a summary of the three


      responses that we received as a request for the


      public comment period, and you have the full text


      of those comments that are being handed out now,


      and I think were available to people that are here


      for the public session.


                In order to give us at least a little bit


      of a transition between our discussion and the


      public comment period, I would suggest we take a


      break, which by my watch will be about 12 minutes.


                We will take a short break.  Thank you.


                For the panel members, I was asked to read


      this before the break.  The discussion of the


      protocol is a public one, therefore, we should not


      discuss the protocol amongst ourselves during the







                          Open Public Hearing


                DR. NELSON:  We will now be moving into


      our open public hearing.  Before introducing the


      people who have requested time to speak, I have a


      statement to read.


                Both the Food and Drug Administration and


      the public believe in a transparent process for


      information gathering and decisionmaking.  To


      ensure such transparency at the open public hearing


      session of the Advisory Committee meeting, FDA


      believes that it is important to understand the


      context of an individual's presentation.


                For this reason, FDA encourages you, the


      open public hearing speaker, at the beginning of


      your written or oral statement to advise the


      committee of any financial relationship that you


      may have with a sponsor, its product, or, if known,


      its direct competitors.  For example, this


      financial information may include the sponsor's


      payment of your travel, lodging, or other expenses


      in connection with your attendance at the meeting.



                Likewise, FDA encourages you at the


      beginning of your statement to advise the committee


      if you do not have any such financial


      relationships.  If you choose not to address this


      issue of financial relationships at the beginning


      of your statement, it will not preclude you from




                At this point, there are two individuals


      that have requested time to speak, and since Vera


      Sharav had requested it officially prior to the


      meeting, I think we will allow her the first




                You can speak from the podium, so you can


      see us, and we can see you.


                              Vera Sharav


                MS. SHARAV:  I am Vera Sharav and I am


      President of the Alliance for Human Research


      Protection, an organization that focuses precisely


      on ethical research issues and recently, in


      particular, on ethics of using children in


      non-therapeutic experiments.


                Having listened to some of the



      presentations as far as the scientific issues, I


      think part of what I was going to comment is right


      flat-out there.


                There is a fundamental flaw with these


      neuroimaging experiments including this one, and


      that is, that the children diagnosed with ADHD for


      the most part have already been exposed to drug.


      Those drugs, dextroamphetamine, Ritalin, whichever


      one they use, does, in fact, alter the brain, and


      there is no quarrel with that, there is no




                How can you then do a scientifically valid


      experiment in which you are comparing the brains of


      children who have never been exposed to drug and


      those who have and then claim to find some


      differences that you could be sure of are not drug




                I think the fact that this hasn't been


      done, or if it has been done, it hasn't been


      published, we ask why.  Wouldn't it be simple to,


      first of all, establish, in fact, what the brains


      of normal children are like and do the ADHD differ?



                Now, as far as this experiment, this


      experiment would expose healthy, primarily


      disadvantaged children, let's face it, with the


      amount of payment, to a brain-altering substance


      for no benefit to that child.


                Now, this is a clear-cut affront to the


      moral standards of the Nuremberg Code, the


      Declaration of Helsinki, and the 1983 Federal


      Protections that were established precisely to


      protect children from experiments such as this.


                Dextroamphetamine, I want to remind you,


      is a DEA Schedule II drug.  It is a controlled


      substance, which means it is addictive.  Now, Dean


      Nadler of UCLA has done extensive work to show


      that, indeed, Ritalin is addictive and leads to




                The proposed experiment fails to meet the


      fundamental principles of the Belmont Report -


      respect for persons, beneficence, and justice,


      which are the very basis for 45 CFR 46.


                Why are we even considering using children


      as human guinea pigs in such an experiment?  But we





                The Advisory Panel would be derelict in


      its responsibility if it did not study carefully


      the landmark 2001 Maryland Court of Appeals


      Decision, Higgins v. Kennedy Kreiger, which


      resolutely affirmed the Nuremberg Code and


      prohibited using children in non-therapeutic


      experiments if there is any but a minimal risk.


                The Court stated:  "It is not in the best


      interest of any healthy child to be placed in a


      non-therapeutic research environment which might


      possibly be, or which proves to be, hazardous to


      the health of the child in order to test methods


      that may ultimately benefit all children."


                The proposed experiment is a giant step


      backward. It was immoral when Dr. Rapoport


      conducted it in 1978, and it is immoral today.


      Changing the scanning equipment does not change the


      immorality of the experiment.


                By what ethical standard is it acceptable


      for anyone to entice a child and parents with a


      $570 stipend to become an experimental human guinea



      pig?  But then whose children are we considering




                If this experiment goes forth, the lessons


      to disadvantaged children will be to earn money,


      sign up for drug experiments, amphetamine today,


      cocaine tomorrow, Ecstasy next month.  There are


      always researchers looking for subjects in


      experiments, such as this.


                Should children be the first on whom this


      is done? Again, I refer to the Maryland Court,


      which is the highest court in Maryland.  It


      declared:  "To turn over human and legal ethical


      concerns solely to the scientific community is to


      risk embarking on slippery slopes that all too


      often in the past, here and elsewhere, have