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                DEPARTMENT OF HEALTH AND HUMAN SERVICES

 

                      FOOD AND DRUG ADMINISTRATION

 

                CENTER FOR DRUG EVALUATION AND RESEARCH

 

 

 

 

 

 

 

 

 

 

 

 

 

 

                  PEDIATRIC ETHICS SUBCOMMITTEE OF THE

 

                      PEDIATRIC ADVISORY COMMITTEE

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

                       Friday, September 10, 2004

 

                               8:35 a.m.

 

 

 

 

 

 

 

                           Double Tree Hotel

                              Regency Room

                          1750 Rockville Pike

                          Rockville, Maryland

                                                                 2

 

                              PARTICIPANTS

 

      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.

 

      FDA

 

      Julia Gorey, J.D.

      Dianne Murphy, M.D.

      Sara Goldkind, M.D., M.A.

      Bernard Schwetz, D.V.M., Ph.D.

                                                                 3

 

                            C O N T E N T S

 

                                                              PAGE

 

      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

                                                                 4

 

                         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

 

      introductions?

 

                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

 

      Therapeutics.

 

                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

                                                                 5

 

      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

 

      Philadelphia.

 

                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

                                                                 6

 

      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

 

      Statement.

 

                           Meeting Statement

 

                DR. JOHANNESSEN:  Thank you and good

 

      morning.

 

                The following announcement addresses the

 

      issue of conflict of interest with regard to the

 

      study drug dextroamphetamine and competing products

                                                                 7

 

      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

                                                                 8

 

      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

                                                                 9

 

                       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.

 

                [Slide.]

 

                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

 

      week.

 

                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.

 

                [Slide.]

 

                The FDA involvement with Subpart D

 

      regulations began in the 1990s when the Advisory

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      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.

 

                [Slide.]

 

                The Children's Health Act of 2000 mandated

 

      that HHS funded, supported, or regulated research

 

      comply with these additional protections for

 

      children.

 

                [Slide.]

 

                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.

 

                [Slide.]

 

                The Pediatric Advisory Committee is

 

      endorsed by the Best Pharmaceuticals for Children

 

      Act in 2001 and the Pediatric Research Equity Act

 

      in 2003.

 

                [Slide.]

 

                Now, I am going to talk about Subpart D

 

      referrals specifically, and those come to us under

                                                                11

 

      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

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      understanding, prevention, or alleviation of a

 

      serious problem affecting the health or welfare of

 

      children.

 

                2.  The clinical investigation will be

 

      conducted in accordance with sound ethical

 

      principles.

 

                3.  Adequate provisions are made for

 

      soliciting assent and parental permission.

 

                [Slide.]

 

                So, the possible recommendations open to

 

      the Pediatric Ethics Subcommittee that it can make

 

      to the Pediatric Advisory Committee are the

 

      following:

 

                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

                                                                13

 

      proceed because it satisfies the three conditions

 

      that I just previously outlines under 46.407 or

 

      50.54.

 

                Or it can recommend that the protocol not

 

      be allowed to proceed, providing specific reasons

 

      for its rejection.

 

                [Slide.]

 

                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

 

      manner.

 

                Now, I will turn the podium over to Dr.

 

      Schwetz.

 

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

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                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

                                                                15

 

      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

 

      review.

 

                [Slide.]

 

                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.

 

                [Slide.]

 

                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

                                                                16

 

      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

                                                                17

 

      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

 

      funded.

 

                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

                                                                18

 

      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,

                                                                19

 

      depending on your age and refraction of your

 

      glasses.

 

                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.

 

                [Slide.]

 

                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.

                                                                20

 

                [Slide.]

 

                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.

 

                [Slide.]

 

                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

 

      result.

 

                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

                                                                21

 

      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.

 

                [Slide.]

 

                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.

 

                [Slide.]

                                                                22

 

                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

 

      discussion.

 

                After you have made that determination to

 

      sort of move down in this algorithm, once you

                                                                23

 

      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

 

      directions.

 

                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.

 

                [Slide.]

 

                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

                                                                24

 

      two different questions with respect to that.

 

                [Slide.]

 

                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

                                                                25

 

      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.

 

                [Slide.]

 

                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.

 

                [Slide.]

 

                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

                                                                26

 

      the language that there need to be adequate

 

      provisions for child assent and parental

 

      permission.

 

                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.

 

                [Slide.]

 

                In terms of child assent, this again is

 

      the regulatory language.  Adequate provisions for

                                                                27

 

      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.

 

                [Slide.]

 

                Again, some of the general criteria of

                                                                28

 

      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.

 

                [Slide.]

 

                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

                                                                29

 

      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

                                                                30

 

      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

 

      guardians.

 

                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

                                                                31

 

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

 

                Norm.

 

                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

 

      office.

 

                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

 

      visit.

                                                                32

 

                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

                                                                33

 

      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

 

      reports.

 

                Dr. Rapoport.  Just to give us an

                                                                34

 

      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.

 

                [Slide.]

 

                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

                                                                35

 

      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.

 

                [Slide.]

 

                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

                                                                36

 

      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.

 

                [Slide.]

 

                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.

 

                [Slide.]

 

                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

                                                                37

 

      opinion.

 

                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.

 

                [Slide.]

 

                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.

                                                                38

 

                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.

 

                [Slide.]

 

                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

                                                                39

 

      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

                                                                40

 

      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.

 

                [Slide.]

 

                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

                                                                41

 

      the differences are related to just the state of

 

      having the disorder or represent an underlying

 

      trait.

 

                [Slide.]

 

                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.

 

                [Slide.]

 

                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.

                                                                42

 

                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.

 

                [Slide.]

 

                I think this has already been covered.

 

                [Slide.]

 

                I think this has also already been

 

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

 

                [Slide.]

 

                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,

                                                                43

 

      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

 

      question.

 

                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,

                                                                44

 

      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

                                                                45

 

      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.

 

                [Slide.]

 

                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

 

      population.

 

                So, I interpret the long-term data as

                                                                46

 

      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

 

      process.

 

                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.

                                                                47

 

                DR. NELSON:  Okay.  Norm and then Rick.

 

                DR. FOST:  Dr. Rapoport, I have three

 

      questions.

 

                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

 

      determined?

 

                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

                                                                48

 

      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

 

      it.

 

                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

                                                                49

 

      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

 

      whatsoever.

 

                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

                                                                50

 

      of--well, I will just leave it an

 

      inconvenience--that payment has now become the

 

      norm.

 

                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

                                                                51

 

      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

 

      afterwards?

 

                DR. RAPOPORT:  It is extremely low, but

                                                                52

 

      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

 

      that.

 

                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

                                                                53

 

      detail.

 

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

 

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

 

      reactions?

 

                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

                                                                54

 

      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

 

      performance.

 

                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

                                                                55

 

      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.

                                                                56

 

                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

 

      this.

 

                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

                                                                57

 

      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

                                                                58

 

      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,

                                                                59

 

      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

                                                                60

 

      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

 

      place?

 

                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,

                                                                61

 

      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

 

      pass.

 

                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

                                                                62

 

      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?

                                                                63

 

                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

                                                                64

 

      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.

                                                                65

 

                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

                                                                66

 

      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

 

      issue.

 

                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

                                                                67

 

      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

                                                                68

 

      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

                                                                69

 

      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

                                                                70

 

      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

                                                                71

 

      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

                                                                72

 

      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

 

      study.

 

                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

                                                                73

 

      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

                                                                74

 

      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

                                                                75

 

      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,

                                                                76

 

      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

 

      trial.

 

                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

                                                                77

 

      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

                                                                78

 

      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

 

      child.

 

                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

                                                                79

 

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

 

      published this month in the American Journal of

 

      Psychiatry.

 

                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

                                                                80

 

      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

 

      protocol?

 

                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

                                                                81

 

      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

 

      units.

 

                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

                                                                82

 

      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

                                                                83

 

      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

                                                                84

 

      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.

                                                                85

 

                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

                                                                86

 

      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

 

      this.

 

                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

                                                                87

 

      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

                                                                88

 

      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.

 

      Jacobs.

                                                                89

 

                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

 

      Administration.

 

                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

                                                                90

 

      some of the fears that they might have about these

 

      medications addressed explicitly in the consent

 

      form.

 

                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

 

      medicine.

 

                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

                                                                91

 

      related.

 

                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

 

      mass.

 

                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

                                                                92

 

      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.

                                                                93

 

                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

 

      group.

                                                                94

 

                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.

                                                                95

 

                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

                                                                96

 

      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

                                                                97

 

      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

 

      study.

 

                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

 

      minutes.

 

                DR. FOST:  It opens a whole can of worms

 

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

                                                                98

 

      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

 

      finding.

 

                DR. RAPOPORT:  They are less considered

                                                                99

 

      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

 

      form.

 

                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

                                                               100

 

      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

 

      answered.

 

                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

                                                               101

 

      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.

                                                               102

 

                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,

 

      formication.

 

                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

 

      NIH?

 

                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

 

      list.

 

                When there are no data relevant to the

 

      side effects for a single dose, it makes it more

                                                               103

 

      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

                                                               104

 

      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

                                                               105

 

      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

 

      test.

 

                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

                                                               106

 

      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

                                                               107

 

      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

 

      responses?

 

                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

                                                               108

 

      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

                                                               109

 

      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

 

      child.

 

                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

                                                               110

 

      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

                                                               111

 

      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

 

      concerns.

 

                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?

                                                               112

 

                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

 

      adults.

 

                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

 

      effects.

 

                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

                                                               113

 

      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

 

      to.

 

                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

                                                               114

 

      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

                                                               115

 

      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

                                                               116

 

      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

                                                               117

 

      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

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      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.

                                                               119

 

                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

 

      summarize.

 

                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

 

      issues.

 

                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

                                                               120

 

      institution.

 

                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

 

      expertise.

 

                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

                                                               121

 

      and guardian may discontinue participation at

 

      anytime.

 

                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

                                                               122

 

      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

 

      forms.

 

                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

 

      fashion.

 

                The lay person felt, you know, maximum 570

 

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

                                                               123

 

      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

 

      gained.

 

                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

                                                               124

 

      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

 

      break.

                                                               125

 

                [Break.]

 

                          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.

                                                               126

 

                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

 

      speaking.

 

                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

 

      position.

 

                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

                                                               127

 

      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

 

      argument.

 

                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

 

      related?

 

                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?

                                                               128

 

                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

 

      addiction.

 

                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

                                                               129

 

      are.

 

                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

                                                               130

 

      pig?  But then whose children are we considering

 

      here?

 

                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