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                DEPARTMENT OF HEALTH AND HUMAN SERVICES

 

                      FOOD AND DRUG ADMINISTRATION

 

                CENTER FOR DRUG EVALUATION AND RESEARCH

 

 

 

 

 

 

 

 

 

 

 

 

 

 

                  PEDIATRIC ADVISORY COMMITTEE MEETING

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

                     Wednesday, September 15, 2004

 

                               8:10 a.m.

 

 

 

                          ACS Conference Room

                               Room 1066

                           5630 Fishers Lane

                          Rockville, Maryland

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                        P A R T I C I P A N T S

 

      P. Joan Chesney, M.D. C.M., Chair

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

 

      Deborah L. Dokken, M.P.A.

      Steve Ebert, Pharm.D.

      Michael E. Fant, M.D., Ph.D.

      Samuel Maldonado, M.D.

      Robert M. Nelson, M.D., Ph.D.

      Thomas B. Newman, M.D., M.P.H.

      Judith R. O'Fallon, Ph.D.

 

      FDA Participants

 

      Solomon Iyasu, M.D.

      Dianne Murphy, M.D.

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                            C O N T E N T S

 

      AGENDA ITEM                                             PAGE

 

      Call to Order and Introductions - P. Joan Chesney,

      M.D., Chair, Pediatric Advisory Committee                  5

 

      Meeting Statement - Jan N. Johannessen, Ph.D.,

      Executive Secretary                                        5

 

      Statement of Dianne Murphy, M.D.                           8

 

      Subpart D Referral Process - Sara F. Goldkind,

      M.D., M.A., Bioethicist, Office of Pediatric

      Therapeutics                                              17

 

      Summary of Deliberations of Pediatric Ethics

      Subcommittee held on 9/10/04 - Robert M. Nelson,

      M.D., Ph.D., Chair of the Subcommittee                    26

 

      Overview of Adverse Event Reporting as Mandated by

      BPCA

       - Solomon Iyasu, M.D., Medical Epidemiologist

         Office of Pediatric Therapeutics                       70

 

      Adverse Event Reporting

       - Ocuflox (ofloxacin)                                   105

         Fosamax (alendronate)                                 110

         Hari Sachs, M.D., Medical Officer, Division of

         Pediatric Drug Development

 

       - Fludara (fludarabine)

         Susan McCune, M.D., Medical officer, Division of

         Pediatric Drug Development                            125

 

       - Clarinex (desloratadine)

         Jane Filie, M.D., Medical officer, Division of

         Pediatric Drug Development                            149

 

      Adverse Event Reporting for Drug Products

      Containing Budesonide or Fluticasone:  Pulmicort,

      Rhinocort, Flonase, Flovent, Advair, and Cutivate

 

       - Peter Starke, M.D., Medical Team Leader,

         Division of Pulmonary Drug Products                   172

                                                                 4

 

                      C O N T E N T S (Continued)

 

      AGENDA ITEM                                             PAGE

 

       - ShaAvhree Buckman, M.D., Ph.D., FAAP, Medical

         Officer, Division of Pediatric Drug Development       190

 

       - Joyce Weaver, Pharm.D., Safety Evaluator,

         Division of Drug Risk Evaluation                      199

 

       - Badrul A. Chowdhury, M.D., Ph.D., Director,

         Division of Pulmonary and Allergy Drug Products,

         CDER, FDA                                             211

 

      Open Public Hearing                                       --

 

      Final Comments and Adjourn - P. Joan Chesney, M.D.,

      Chair, Pediatric Advisory Committee                      239

 

                                                                 5

 

                         P R O C E E D I N G S

 

                DR. CHESNEY:  Good morning.  I think we're

 

      ready to begin today's deliberations, and I'd like

 

      to say that we're not going to introduce the

 

      committee members until Dr. Murphy has given us an

 

      overview of the previous and current committees.

 

      And so we really just, I think, need to start off

 

      the meeting by having Dr. Johannessen read the

 

      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 used for the treatment of ADHD and to the

 

      adverse event reporting session 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

 

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      appearance of a conflict of interest at this

 

      meeting, with the following exceptions:

 

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

 

      full waivers have been granted to the following

 

      participants:

 

                Dr. Patricia Joan Chesney for ownership of

 

      stock in a company with a product at issue valued

 

      at 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. Robert Nelson for an honorarium

 

      for speaking on an unrelated topic at a firm with a

 

      product at issue valued at less than $5,000.

 

                A copy of the waiver statements may be

 

      obtained by submitting a written request to the

 

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

 

      of the Parklawn Building.  In the event that the

 

      discussions involve any other firms or products 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

 

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      involvement, and their exclusion will be noted for

 

      the record.

 

                We would also like to note that Dr. Samuel

 

      Maldonado has been invited to participate as an

 

      industry representative acting on behalf of

 

      regulated industry.  Dr. Maldonado is employed by

 

      Johnson & Johnson.

 

                With respect to all other participants, we

 

      ask in the interest of fairness that they address

 

      any current or previous financial involvement in

 

      any firm whose product they may wish to comment

 

      upon.

 

                Thank you, and we'll now turn it over to

 

      Dr. Dianne Murphy.

 

                DR. MURPHY:  I wanted to just take a

 

      moment to welcome everybody and to also tell the

 

      committee that you may not have realized--or a

 

      number of people on this committee, that you have

 

      just made a transition.  That transition has been

 

      from a subcommittee, which was providing very

 

      important advice to us, but to now a full

 

      committee, which advises the Commissioner directly.

 

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      And you have certain responsibilities that are

 

      slightly different, and I'm going to go over those

 

      in a second.  And also to the fact that you are not

 

      only just a full committee advising the Commissioner, but

 

      that, as I said, you have certain

 

      responsibilities that you're going to hear some of

 

      them today that are clearly defined.

 

                You have moved from the Center for Drugs

 

      to the Office of the Commissioner, and the office

 

      has been--and this committee is now administered

 

      there the Office of Science.  And our new Exec.

 

      SEC. is Jan Johannessen, who has done an

 

      extraordinary making sure that everybody has been

 

      recruited and met all the criteria that we need to

 

      meet and getting you here and assembled and in

 

      helping us charter this new committee.

 

                It is really just a monumental feat

 

      because the agency basically was not allowed to

 

      have any new committees.  It actually took Congress

 

      to create you.  So I'm spending a little time on

 

      this so you'll understand how important your

 

      deliberations are to the agency.

 

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                One of the other activities that has

 

      occurred, as you know, is that there has been the

 

      creation of the Office of Pediatric Therapeutics,

 

      and that office is now responsible for all

 

      pediatric activities across the agency.  And,

 

      therefore, this committee may be hearing more--having been

 

      in the Center for Drugs previously, you

 

      may be hearing more about other products such as

 

      devices or formula.  So I wanted to make sure that

 

      you are also aware of that.

 

                And I know sometimes that's a bit

 

      overwhelming if you're a cardiologist or an ID doc

 

      or whatever your training.  The breadth of what

 

      we're asking you to deliberate upon is quite large.

 

      However, as those of you who have been on the

 

      previous subcommittee are aware, we always bring in

 

      additional experts, that you're here to bring

 

      particularly to those deliberations the pediatric

 

      perspective, because we have lots of technical

 

      committees that have lots of expertise, and we will

 

      always bring that additional expertise as needed to

 

      the deliberations.  But it's your particular

 

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      pediatric perspective and expertise that we depend

 

      upon at these meetings.

 

                I did want to spend a moment introducing,

 

      so that you can put some faces with names, the

 

      people who are now in the Office of Pediatric

 

      Therapeutics, which is Sara Goldkind, who will be

 

      speaking; Solomon Iyasu, whom you know, who has

 

      been on detail with us for a while; Ann Myers, if

 

      you'd put your hand up, Ann, who is our policy

 

      analyst, so you'll have a face there; and Jean

 

      Harkins, who is not here, but she is the person who

 

      actually runs the Office of Pediatric Therapeutics.

 

                I mention that because it is that office

 

      that is mandated to particularly focus on the

 

      ethical issues and the safety issues, and that this

 

      committee within the Office of the Commissioner has

 

      now also been identified to deal with those issues.

 

                I also wanted to comment on some other

 

      transitions for those of you who have been on the

 

      subcommittee.  I'm no longer with the Office of

 

      Counterterrorism, Pediatric Drug Development.

 

      Rosemary Roberts is the new office director, and so

 

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      she's still going to be very active in the

 

      pediatric issues, and the Division Director for

 

      Pediatrics, Shirley Murphy, is now the Deputy

 

      within that office. And we have a new Division

 

      Director, just so you'll know these names.  Lisa

 

      Mathis I do not believe is here.  She's dealing

 

      with other issues this morning.

 

                For the new members--and I apologize to

 

      the old members because I know you've heard this.

 

      I actually took it out of the slide on Monday

 

      because I didn't think that everybody really wanted

 

      to hear about all the accomplishments of the

 

      previous committee.  But I wanted the new members

 

      to hear a little bit about what the previous

 

      committee has actually--some of the issues they

 

      have dealt with.  And they have dealt with not only

 

      the ethical issues that have to do with normal

 

      volunteers, placebo-controlled trials, the

 

      vulnerable population within pediatrics.  They have

 

      dealt with an enormous array of scientific issues,

 

      from sleep disorders, hepatitis C, HIV, antiviral

 

      drug development in neonates, the current

 

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      epidemiology and therapeutics and development of

 

      therapies for hyperbilirubinemia, clinical risk

 

      management for HPA axis suppression in children

 

      with atopic dermatitis, tracking cancer risks among

 

      children with atopic dermatitis, and as you all are

 

      aware, last February a discussion of the FDA

 

      process and review of therapies for major

 

      depressive disorder.

 

                In addition, this committee has now

 

      reviewed--before today's additional eight products

 

      that you're going to be hearing about, has reviewed

 

      over 22 products that were granted exclusivity, and

 

      you have looked at the one-year post-adverse event

 

      reporting that has occurred for those products.  I

 

      can tell you that this is an important process that

 

      we are looking to evolve constantly.  It came up

 

      recently at a congressional hearing as to how were

 

      we doing this and what were we doing with it.  And

 

      I think it's important that this committee realize

 

      that it is important what you have to say to us

 

      about whether we should do anything else in trying

 

      to follow--gain a better understanding of what

 

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      happens to children after these products have been

 

      either approved--or approved and particularly after

 

      they have been studied, because as you heard

 

      yesterday, they don't always get an approval or a

 

      label change, but certainly they have been studied

 

      and they may be granted exclusivity.  And that in

 

      itself often results in additional information.

 

                As you go around this morning, it would be

 

      helpful if you would identify if you were on the

 

      previous subcommittee.  I'd appreciate that just so

 

      the new members will know.  And also, I wanted to

 

      particularly thank Sam--and is Steve here?  I don't

 

      see him.  Oh, there you are.  As Jan said, for

 

      doing double duty.  We are still in the process of

 

      identifying the industry and consumer

 

      representatives, a total different process, and

 

      they very kindly agreed to continue to assist us in

 

      these last rigorous days, the last few days.

 

                And, again, thank you for being here, for

 

      your participation, because I know it requires

 

      quite a commitment, and for your thoughtfulness as

 

      we move forward with this new committee.

 

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                DR. CHESNEY:  Thank you very much, Dianne.

 

                So I think we would like next to go around

 

      the room and have the new Pediatric Advisory

 

      Committee members introduce themselves, and I'd

 

      like to start with the members who are no longer on

 

      the committee, if they could--that was a joke.  So

 

      let's start with Dr. Maldonado.

 

                DR. MALDONADO:  Sam Maldonado.  I work in

 

      pediatric drug development at Johnson & Johnson,

 

      and as Dr. Murphy said, this is my last session

 

      with the committee.  There will be a new member

 

      from industry.

 

                DR. NEWMAN:  I'm Tom Newman.  I'm a

 

      professor of epidemiology and biostatistics in

 

      pediatrics at the University of California, San

 

      Francisco, and a general pediatrician, and I'm new

 

      to the committee.

 

                MS. DOKKEN:  I'm Deborah Dokken, and I am

 

      also new to the committee, and I am a patient-family

 

      representative and I really appreciate

 

      having that voice on the committee.

 

                DR. O'FALLON:  Judith O'Fallon.  I'm a

 

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      professor emeritus of statistics at Mayo Clinic.  I

 

      got called back half-time to cover a maternity

 

      leave, by the way, going back.  But I've been on

 

      the committee since its beginning.

 

                DR. FANT:  My name is Michael Fant.  I'm

 

      an associate professor of pediatrics at the

 

      University of Texas in Houston.  My expertise is in

 

      neonatology and in biochemistry.  And I'm new to

 

      the committee.

 

                DR. NELSON:  I'm Robert Nelson.  I'm

 

      associate professor of anesthesia and pediatrics at

 

      Children's Hospital of Philadelphia and University

 

      of Pennsylvania.  My clinical area is pediatric

 

      critical care, and I also work in the area of

 

      ethics, and I was on the previous subcommittee.

 

                DR. EBERT:  Hi, I'm Steve Ebert.  I'm an

 

      infectious diseases pharmacist at Meriter Hospital

 

      and professor of pharmacy at the University of

 

      Wisconsin, Madison.  I'm an outgoing member of the

 

      committee.

 

                DR. CHESNEY:  And my name is Joan Chesney.

 

      I'm a professor of pediatrics at the University of

 

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      Tennessee in Memphis, and my interest is infectious

 

      diseases, and I'm a former subcommittee member.

 

                DR. JOHANNESSEN:  My name is Jan

 

      Johannessen, and I'm the Executive Secretary to the

 

      Pediatric Advisory Committee.

 

                DR. MURPHY:  Dianne Murphy, Office

 

      Director, Office of Pediatric Therapeutics, FDA.

 

                DR. IYASU:  I'm Solomon Iyasu.  I'm

 

      medical team leader with the Division of Pediatric

 

      Drug Development and an epidemiologist with the

 

      Office of Pediatric Therapeutics.

 

                DR. CHESNEY:  Thank you and welcome to all

 

      the new committee members.  You're in for quite a

 

      ride, believe me.

 

                Our first speaker this morning--and,

 

      again, for the new committee members, what you're

 

      going to hear about next was really a historic

 

      process and a historic meeting on Friday.  And Dr.

 

      Sara Goldkind is going to introduce the topic for

 

      us.  She's a board-certified internist who did a

 

      clinical fellowship in medical ethics at the

 

      University of South Florida.  She also has a

 

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      master's degree in religious studies with a focus

 

      on comprehensive religious ethics--comparative

 

      religious ethics, excuse me, and she's been with

 

      the agency for almost a year, which she tells me

 

      seems like longer than that.

 

                Dr. Goldkind?

 

                DR. GOLDKIND:  It's my pleasure to be here

 

      today at the inaugural meeting of the Pediatric

 

      Advisory Committee and to tell you about the work

 

      of the Pediatric Ethics Subcommittee.

 

                As Dianne mentioned, this is really a

 

      landmark time in pediatric research.  That's the

 

      way we see it because we feel that this committee

 

      as well as the Pediatric Ethics Subcommittee can

 

      really make incredibly important decisions and

 

      consensus statements regarding pediatric research.

 

                So what I'd like to do now is talk a

 

      little bit about the role of the Pediatric Ethics

 

      Subcommittee.  It is going to be a subcommittee

 

      that addresses Subpart D referrals and also ethical

 

      issues that impact on research affecting the

 

      pediatric population.

 

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                Going back to the part on Subpart D,

 

      there's a mistake in the slide, and where it says

 

      "Joint 21 CFR 50.54 and 45 CFR 46.407 referrals,"

 

      those are referrals that will come to both OHRP and

 

      the FDA, and we actually had one of those to review

 

      on September 10th, which involved the effects of a

 

      single dose of dextroamphetamine in attention

 

      deficit hyperactivity disorder, a functional

 

      magnetic resonance study.  And Dr. Nelson, who is

 

      the Chair of the Pediatric Ethics Subcommittee, is

 

      going to give you a summary of the deliberations of

 

      the Pediatric Ethics Subcommittee in that regard.

 

                The subcommittee can also address

 

      referrals that come only to the FDA under 21 CFR

 

      50.54, and I'm going to talk about these

 

      regulations in a little bit more detail.  But if

 

      there are no referrals and there are burning

 

      ethical issues that we would like to address, we

 

      can also take those to the Pediatric Ethics

 

      Subcommittee for deliberation.

 

                So now to go into a little bit more detail

 

      about the regulations under which we can have these

 

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      referrals, Subpart D is entitled "Additional

 

      Safeguards for Children in Clinical Investigations

 

      and Research," and they are essentially identical

 

      for DHHS and FDA.  DHHS regs are Title 45, CFR 46,

 

      also known as "the common rule" because 17 federal

 

      agencies operate under those regulations.  And the

 

      FDA regulations are 21 CFR 50.

 

                There is a notable distinction between the

 

      two sets of regulations, and that is the issue of

 

      waiving parental permission can be done under Title

 

      45, CFR 46, but not under the FDA regulations.  But

 

      in terms of the Subpart D referral process and the

 

      general categories of pediatric research, those are

 

      identical between the two regulations.  And what

 

      I've done in these slides is include the citations

 

      for both regulations.

 

                So Subpart D has four different categories

 

      under which pediatric research can be conducted.

 

      The first category is 50.51/46.404, and that is a

 

      category which states that the research involves no

 

      more than minimal risk.  And it essentially does

 

      not discuss who benefits from the research, but

 

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      basically describes that there's a ceiling of

 

      minimal risk for exposure for the children.

 

                50.52/46.405 is research that involves

 

      greater than minimal risk but presents the prospect

 

      of direct benefit.

 

                And then 50.53/46.406 involves greater

 

      than minimal risk but presents a prospect of

 

      generalizable knowledge about the disorder or

 

      condition, but there's no prospect of direct

 

      benefit to the participants.

 

                So those are three categories under which

 

      an IRB can classify pediatric research.  If the IRB

 

      determines that it cannot classify the research

 

      under those first three categories, however, 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 FDA Commissioner or Secretary, after

 

      consultation with a panel of experts in pertinent

 

      disciplines, and following an opportunity for

 

      public review and comment determines the

 

                                                                21

 

      following...

 

                So, in other words, if the IRB feels that

 

      the research has merit for the general pediatric

 

      population but cannot be classified under one of

 

      the first three categories, it can make a referral

 

      to one of the federal agencies--and I'll discuss

 

      those details in a minute--to have the protocol

 

      reviewed by an expert panel.

 

                And so what must the research then

 

      satisfy, according to the expert panel?  The

 

      research, in fact, satisfies one of the first three

 

      categories, so the expert panel can make a

 

      determination that after it reviews the research,

 

      actually one of the first three categories does

 

      apply, or the following three conditions are met:

 

      the research presents a reasonable opportunity to

 

      further the understanding, prevention, or

 

      alleviation of a serious problem affecting the

 

      health or welfare of children; the research will be

 

      conducted in accordance with sound ethical

 

      principles; and adequate provisions are made for

 

      soliciting assent and parental permission.

 

                                                                22

 

                The composition of the Pediatric Ethics

 

      Subcommittee is the following:  Dr. Nelson is the

 

      Chair.  According to FACA, we also need to have two

 

      members of the Pediatric Advisory Committee

 

      represented on the Pediatric Ethics Subcommittee.

 

      And in addition to Dr. Nelson, we included Dr.

 

      Chesney and Dr. Gorman.  And we supplemented the

 

      Pediatric Ethics Subcommittee with an additional

 

      group of core ethicists:  Drs. Fost, Kodish and

 

      Marshall.

 

                The composition of the Pediatric Ethics

 

      Subcommittee under both DHHS regulations and FDA

 

      regulations states that the panel of experts in

 

      pertinent disciplines, for example, science,

 

      medicine, education, ethics, and law, and we

 

      selected from among those groups according to the

 

      protocol.  But most of those groups were

 

      represented on the Pediatric Ethics Subcommittee

 

      that took place on September 10th. In addition, we

 

      also had two patient advocates represent on that

 

      subcommittee.

 

                So once the IRB makes the determination

 

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      that it wants to refer to a federal agency, it

 

      refers to the FDA for regulated--if the products in

 

      the protocol are FDA-regulated, and it refers to

 

      OHRP if the research is federally funded or

 

      conducted.  And we have a very close working

 

      relationship with OHRP, and when a protocol comes

 

      to us, we also refer it to them for review, and

 

      they refer a protocol that comes to them to us.

 

      And in this case, the protocol was actually

 

      submitted to OHRP, but upon our review it was noted

 

      that two of the products in the protocol, both the

 

      MRI machine and the dextroamphetamine, were FDA-regulated

 

      and so we also had jurisdiction over that

 

      protocol.

 

                The review would then be conducted by the

 

      Pediatric Ethics Subcommittee expert panel, and as

 

      I said, each protocol--we will have a core group of

 

      ethicists, and it will be supplemented by

 

      appropriate expert panel members and patient

 

      representatives and/or community representatives.

 

                The Pediatric Ethics Subcommittee will

 

      bring its recommendations to the Pediatric Advisory

 

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      Committee for endorsement, as Dr. Nelson will do

 

      today, and then those recommendations will be

 

      submitted to the Commissioner of the FDA for final

 

      determination.  Once that determination is

 

      rendered, it will be forwarded to OHRP, and OHRP

 

      will send the Commissioner's memorandum on the

 

      Pediatric Ethics Subcommittee/Pediatric Advisory

 

      Committee's recommendations on to the Secretary,

 

      and the Secretary will have his final

 

      determination, particularly in regards to funding

 

      of the research.

 

                So our goals in this process, clearly the

 

      overarching goal is to advance an understanding of

 

      pediatric research, and we'd like to do that

 

      involving additional expert input and public input.

 

      We also want to have transparency in the process,

 

      and in that regard we had an open public comment

 

      period before the Pediatric Ethics Subcommittee.

 

      We also had an open hearing available at the

 

      Pediatric Ethics Subcommittee.  We also want to try

 

      and respond to these protocol referrals in a timely

 

      manner so that they will be helpful to the IRBs

 

                                                                25

 

      involved.  And we want to be able to handle these

 

      referrals in a consistent and clear manner so that

 

      they can advance the general understanding of

 

      pediatric research.  And we would like to do this

 

      and are doing this in harmony with OHRP so that we

 

      have a united federal agency response to pediatric

 

      research.

 

                Thank you.

 

                DR. CHESNEY:  Thank you very much.

 

                Maybe what we could do is introduce and

 

      hear our next speaker and then ask for questions

 

      from the panel.  Dr. Skip Nelson is the Chair of

 

      the Pediatric Ethics Subcommittee, and he will

 

      discuss with us the deliberations of the Pediatric

 

      Ethics Subcommittee with the invited folk that Dr.

 

      Goldkind just mentioned on last Friday.  And the

 

      issue here is that Dr. Nelson has prepared a

 

      summary of the committee's deliberations, which you

 

      have in front of you, and I'll let him highlight

 

      issues that he wants to bring to your attention.

 

      And what we're looking for here is an endorsement

 

      by the committee.  As we've mentioned, this took a

 

                                                                26

 

      whole day of fairly intense deliberations last

 

      Friday, and we don't anticipate that we will have

 

      to repeat that process here.  So we're just looking

 

      for the committee's endorsement and any questions

 

      that you may have, either for the process as Dr.

 

      Goldkind just outlined it or for the specific

 

      events of Friday as Dr. Nelson will present them.

 

                DR. NELSON:  Thanks.  You have the

 

      document before you.  Let me just note, as someone

 

      pointed out, I've got the wrong date in the

 

      heading.  That will be corrected before the final

 

      version goes up.  If you see any other typos, feel

 

      free to write them down and share them with us

 

      after our discussion.

 

                I'd like to walk you through the document.

 

      My intent here is not to read the document but to

 

      highlight what is in it, since you can probably

 

      read faster than I can talk.  The introduction

 

      simply restates the purpose of the meeting and then

 

      gives a brief summary of what's in the summary.

 

                But let me first start with what is the

 

      primary issue that would be raised by this

 

                                                                27

 

      protocol, which is the particular risk of the

 

      procedures that are contained within the protocol.

 

                Now, as a preface to this, one of the

 

      first things that an IRB must determine--and for

 

      this exercise, the Pediatric Ethics Subcommittee is

 

      effectively functioning like an IRB--that the

 

      research design is sound.  So after I talk about

 

      risk, I'll then run through a number of recommendations and

 

      stipulations that the committee made

 

      to assure itself that, in fact, the research was

 

      sound.  But assuming those are made, the

 

      subcommittee felt that the following risks would be

 

      appropriate:

 

                The first is the single dose of dextroamphetamine.

 

      Is that minimal risk?  The feeling

 

      was no.  We can a little bit later, if you'd like,

 

      about the definition of minimal risk, but, in fact,

 

      that was not minimal risk.  But the subcommittee

 

      felt that it was no more than what's called a minor

 

      increase over minimal risk, and it lists the

 

      reasons there, which I think I'll state in more

 

      detail for highlight.

 

                                                                28

 

                First of all, it has been used since 1937

 

      with a good safety record.  It is one of the only

 

      two stimulants that are approved down to age 3, and

 

      the children in this protocol are between 9 and 18.

 

      The greatest side effects are irritability,

 

      restlessness, agitation, and temper outbursts which

 

      generally last only 4 to 5 hours, are infrequent,

 

      and as you'll see later, one of our risk

 

      minimization strategies was to say they should do

 

      this in the morning so you don't have the kid up

 

      all night after you do this.  It's used universally

 

      in pediatric practice, and the more common risks

 

      are restlessness, anxiety, loss of appetite,

 

      insomnia--again, why we made that recommendation.

 

                There were two procedures we felt ought

 

      to--well, a second procedure that we felt ought to

 

      be drawn out and highlighted, and that's the

 

      withholding of medication for 36 hours from the

 

      kids with ADHD.  The feeling was that also could be

 

      characterized as a minor increase over minimal

 

      risk.  The reasoning here is that kids with ADHD

 

      often are not medicated over the weekend, often are

 

                                                                29

 

      not medicated when they're not going to school, and

 

      are often given holidays from the drug.  So it

 

      didn't feel that a 36-hour period of time was of

 

      any significant risk to those children.

 

                And then the remainder of the procedures,

 

      which are outlined further along, we all felt were

 

      appropriately considered minimal risk and,

 

      therefore, were appropriate for either group within

 

      the protocol.

 

                Now, the one design recommendation that we

 

      made was to consider narrowing the subject

 

      population that's part of this protocol.  There was

 

      some discussion about the variability in both

 

      neurodevelopmental stages and then response to this

 

      dose of the stimulant between the ages of 9 and 18

 

      years of age, with different points being raised as

 

      to the scientific advantages and disadvantages of

 

      either the younger age group or the older age

 

      group.  We didn't feel that we could make this a

 

      stipulation, but felt that the investigators should

 

      strongly consider narrowing that range within 9 to

 

      18 to get a more focused population.

 

                                                                30

 

                The other confounder that came up--and

 

      this is also in response to some points made in the

 

      public discussion--is that trying to tease apart

 

      the changes that might occur in response to the

 

      drug over time versus basic underlying differences

 

      in terms of, if you will, the neurological

 

      networks, that you need ideally to have treatment-naive

 

      subjects with ADHD, or at least less ideally,

 

      if that is a practical difficulty in doing in this

 

      particular age group, try and get a more uniform

 

      cohort of drug exposure, which is why we had the

 

      discussion of picking the lower-dose range.

 

                One reason for that was that the expert

 

      scientists felt that often the dose over time that

 

      you may need goes up, and if they unified the dose,

 

      then probably you would end up with a more uniform

 

      distribution of the length of exposure to

 

      treatment.  But we didn't feel that that reached

 

      the level of a stipulation, but certainly felt that

 

      that was a strong recommendation to consider

 

      improving the scientific value of the study.

 

                Now, there are a number of required

 

                                                                31

 

      modifications to the protocol.  Point A, which I'm

 

      not going to read, is basically my summary of all

 

      of the procedures in the protocol.  And one of the

 

      recommendations is--it was very hard to find all of

 

      these things, and it would be nice if they just put

 

      them in one place so no one had to go reading

 

      through it in all detail.  One, for example, that

 

      came up--and I'll just highlight this--is that

 

      every child will receive a diagnostic MRI scan,

 

      which is, in fact, part of NIH policy.  You could

 

      find that nowhere in any of the documentation, and

 

      that came out during discussion.  Things like that

 

      need to be in the protocol.

 

                I might add, what we will be doing is

 

      depending upon both the Office of Pediatric

 

      Therapeutics and the OHRP to make sure this

 

      happens, so it's not something that we need to then

 

      worry about.

 

                The second point, sequence of subject

 

      testing.  They're not planning to do the kids that

 

      are twins.  There are discordant twins, either both

 

      homozygous and dizygotic.  They're not going to do

 

                                                                32

 

      those twins unless they see differences between the

 

      kids with ADHD and the kids without ADHD.  That

 

      sequence of testing, which came out in testimony,

 

      was very hard to find anywhere in the protocol, and

 

      that needs to be included.  They won't do the twins

 

      if, in fact, they don't find a difference in the

 

      non-twins.

 

                It was very hard to find the right dose

 

      since there were these dosing discrepancies, and so

 

      that needs to be clarified.  But I've stated what

 

      the committee's understanding is, and, of course,

 

      if this is different--and this is based on the

 

      investigators' testimony--that will have to be

 

      dealt with.  And, again, I mentioned the morning.

 

                A functional MRI.  The protocol lacks a

 

      discussion of what came out in the testimony of the

 

      training that goes on to make sure these kids are

 

      comfortable inside the machine, make sure they can

 

      actually do the tasks that they're being requested

 

      to do, et cetera, exclude kids from claustrophobia.

 

      Not much in the protocol about that.  I already

 

      mentioned the diagnostic MRI scan, which needs to

 

                                                                33

 

      be in there.

 

                Pregnancy exclusion.  You only found that

 

      in the parent permission form.  The feeling was

 

      that that needs to be discussed in the protocol and

 

      the child assent documents, and in particular,

 

      mechanisms for protecting the confidentiality of

 

      the adolescent that she may or may not want to go

 

      into the protocol knowing that there's a pregnancy

 

      test depending upon activities.  That needs to be

 

      spelled out.  We weren't making a judgment about

 

      how that should be handled other than the

 

      importance of the confidentiality in soliciting

 

      that information.

 

                There was a significance discussion of

 

      neuropsychological--I would like to have questions

 

      at the end, because what will happen is I bet you

 

      some will be answered, but write them down.

 

      Neuropsychological testing.  There was a lot of

 

      discussion about this testing.  It's not being

 

      performed for diagnostic or treatment purposes, and

 

      we felt it would be a cleaner study if, in fact,

 

      this information was not provided back to the

 

                                                                34

 

      parents.  Part of that discussion was based on it

 

      not being done in that kind of a therapeutic

 

      context.

 

                And then genetic testing.  There is

 

      testing being done only for zygosity, and we felt

 

      since there was a whole slew of markers being done

 

      and no discussion about the risk of those markers

 

      relative to, say, late onset adult diseases, that

 

      the cleanest way to do that would be to destroy the

 

      data and the samples after you've determined the

 

      zygosity of the twins, maintaining only that piece

 

      of information.

 

                Modifications to the parent permission and

 

      child assent process in documents follow, of

 

      course, those that need to be included from the

 

      discussion of the procedures.  There were a couple

 

      of specific issues.  One is payment.  They were

 

      proposing a lot of money--I didn't put it in here,

 

      but a lot of money.  We felt it was too much and

 

      that basically the parents should get reimbursed

 

      for expenses, and that for young children, a token--although

 

      we didn't have a discussion of what that

 

                                                                35

 

      is, but allowing the IRB to have some discretion,

 

      and for older children who would be potentially

 

      capable of working at a wage position such as

 

      minimum wage, the wage model would be appropriate.

 

      And, of course, consistent with FDA policy, this

 

      would be, in fact, divided evenly over the protocol

 

      procedures so that a child who withdraws in the

 

      middle still gets part of the money.

 

                They needed to pay attention to the

 

      opportunity for dissent, particularly in the twin

 

      pairs.  We thought that the twin without ADHD could

 

      be under some pressure to be in the study, and they

 

      needed to provide that opportunity.  And then some

 

      clarification about the risks of the drug in the

 

      actual consent document, and in many ways we

 

      actually said you should overstate the risks in the

 

      consent document.  Although we do not feel that

 

      this drug presents any risk of addiction, the

 

      parents should know that, in fact, it's classified

 

      as a drug of abuse, with an important distinction

 

      being made by our experts between substance abuse

 

      and addiction.  It's one thing to say take

 

                                                                36

 

      dextroamphetamine to be able to stay up for your

 

      exams in college, but that doesn't lead to

 

      addiction because generally you don't then want to

 

      take it when you plan to fall asleep during

 

      vacation.  And, of course, both permissions.

 

                Now, there were some specific questions

 

      that we were asked to respond to, and I think for

 

      these questions, perhaps I'll just read our answers

 

      so that you get it clear.

 

                What are the benefits, if any, to the

 

      subjects and to children in general?  There is no

 

      direct health benefit to the children included in

 

      the research.  The protocol addresses the question

 

      of a unique central response to stimulants in ADHD,

 

      utilizing a better research design than previously

 

      published studies and controlling for performance

 

      differences.  As such, the protocol may be able to

 

      untangle clinical state and trait--meaning genetic

 

      relatedness--differences through the use of

 

      monozygotic and dizygotic twins who are discordant

 

      for ADHD.  Now, more speculatively--and this was

 

      part of the discussion--the results may improve our

 

                                                                37

 

      understanding of ADHD in order to enhance

 

      diagnostic precision and avoid misclassification

 

      and overtreatment.

 

                Now, the types and degrees of risk that

 

      this presents to subject, I've discussed a fair

 

      amount of that above, and, again, we thought that

 

      all of the procedures other than withholding of the

 

      medications and the blind administration of study

 

      drugs were minimal risk, and those two were a minor

 

      increase over minimal risk.

 

                In terms of whether the risks are

 

      reasonable in relation to anticipated benefits,

 

      this is a key point.  For all subjects enrolled in

 

      the research, the risks to subjects are reasonable

 

      in relationship to the importance of the knowledge--i.e.,

 

      the benefit to children in general--that may

 

      reasonably be expected to result.  However, it is

 

      only for the children with ADHD that the research

 

      is likely to yield generalizable knowledge which is

 

      of vital importance for the understanding of the

 

      subjects' disorder.

 

                For you regulatory junkies, you'll know

 

                                                                38

 

      that I'm reading language that is contained within

 

      the regulations as well, but the important thing is

 

      then that children without ADHD do not have a

 

      disorder or condition, which is why this then could

 

      not be approved by the local IRB, although the

 

      brain response of children without ADHD to a single

 

      dose of dextroamphetamine is an important part of

 

      the generalizable knowledge to be gained in this

 

      research based on the first step of the comparison.

 

                So we thought it did present a reasonable

 

      opportunity to further the understanding,

 

      prevention, or alleviation of a serious problem

 

      affecting the health or welfare of children.

 

                So, with that said, the determination of

 

      approval categories that the subcommittee felt was

 

      appropriate was that the interventions and

 

      procedures included in the research can be approved

 

      for the children with ADHD under 45 CFR 46.406 and

 

      21 CFR 50.53.  That's the category that says no

 

      more than a minor increase over minimal risk; that

 

      basically the experiences are reasonably

 

      commensurate with those inherent in their

 

                                                                39

 

      condition; the intervention is likely to yield

 

      generalizable knowledge about the subjects'

 

      disorder or condition, which is true for the ADHD;

 

      and then that there are adequate provisions for

 

      assent.

 

                Now, because of the lack of a condition in

 

      the kids without ADHD, we felt that it could not be

 

      approved under those three categories consistent

 

      with what the IRB found.  But we did feel that it

 

      presented a reasonable opportunity to further the

 

      understanding of a serious problem; that it would

 

      be conducted in accord with sound ethical

 

      principles; and that there are adequate provisions

 

      for soliciting assent and permission.  And as such,

 

      we recommend that the involvement in the research

 

      of children without ADHD is approvable, assuming

 

      all of the required modifications are made, under

 

      46.407 or 50.54.

 

                Then one final point.  It had been brought

 

      up in some of the public testimony, the applicability of a

 

      particular case known as Grimes v.

 

      Kennedy Krieger Institute.  Whereas, normally or

 

                                                                40

 

      often we might anticipate that the kinds of studies

 

      that come before us are going to be multi-institutional,

 

      multi-site, and multi-state and

 

      we're not going to want to get into the business of

 

      commenting on the legal interpretations of all of

 

      those different environments, we have the unique

 

      situation here where this is a single site located

 

      within Maryland, and this is a fairly high profile

 

      court decision.  So prior to the meeting, I had

 

      asked for clarification by both FDA and OHRP

 

      attorneys about the applicability, and the feeling,

 

      which I agree with and I think some other

 

      knowledgeable members of the subcommittee that I've

 

      talked with also agree with, is that the holding is

 

      not applicable for two reason:  One is NIH is a

 

      federal enclave and not subject to state law; and

 

      second is when this case was considered,

 

      reconsidered, the Maryland Court of Appeals stated

 

      that "the only conclusion that we reached as a

 

      matter of law was that, on the record currently

 

      before us, summary judgment was improperly

 

      granted."  So attorneys have a term called "dicta,"

 

                                                                41

 

      which means basically the judge expressed opinion

 

      on other matters, but, in fact, those other matters

 

      are not binding as law.  So for those two reasons,

 

      it was felt that we did not need to get into the

 

      issue of the applicability of this particular case

 

      as a subcommittee.

 

                So, with that summary, I guess how about

 

      questions about the document, the protocol and the

 

      like, and then after that, I certainly would be

 

      interested in any more general questions about the

 

      process, if that's a reasonable approach.

 

        T1B                 DR. CHESNEY:  We actually have a visitor

 

      this morning.  Dr. Bern Schwetz is the Director of

 

      the Office of Human Research Protections, and I

 

      wondered if we could call on him to come and make a

 

      few statements before we invite questions.

 

                DR. NELSON:  Sure.

 

                DR. SCHWETZ:  Thank you very much, Dr.

 

      Chesney.  I just wanted to express my thanks for

 

      FDA and this Advisory Committee creating the

 

      opportunity to do this joint review in one process

 

      rather than have the FDA and OHRP going in separate

 

                                                                42

 

      ways to review a protocol of this kind where

 

      there's joint jurisdiction.  So particular thanks

 

      to Dr. Nelson for chairing this review and this

 

      subcommittee.  In our opinion, the process went as

 

      we had hoped it would, with a very smooth review,

 

      but probably more importantly, a thorough review

 

      and a recommendation that we feel is a good

 

      recommendation coming to this Advisory Committee

 

      for your final review and hopefully approval.

 

                The review was done in a timely manner,

 

      and that was a challenge considering that this is a

 

      new committee, a new subcommittee, but it was done

 

      in a timely way.  And I think it was done with an

 

      appropriate cast of experts.  So we're very pleased

 

      with this process and, Dr. Chesney, with your

 

      permission, we're hoping that in those cases where

 

      we have joint jurisdiction over a protocol in the

 

      future that we'll be able to bring it back and

 

      handle it this way.

 

                So thank you very much.

 

                DR. CHESNEY:  Thank you for your comments,

 

      and maybe you could stay here just for a moment,

 

                                                                43

 

      and we'll ask now for any questions of the new

 

      committee members for either Dr. Goldkind, Dr.

 

      Nelson, or Dr. Schwetz.

 

                Dr. Maldonado?

 

                DR. MALDONADO:  I just have a quick

 

      question.  Dr Nelson, I see that on page 1 you made

 

      the statement--and I basically also agree that you

 

      did a great job with this review.  You listed the

 

      minor increase over minimal risk, which I agree are

 

      just a minor increase.  But then on page 2, you

 

      gave a--maybe I am just overreading this, but the

 

      subcommittee strongly encourages the investigators

 

      to narrow the age.  I know you focused on that, and

 

      I may have missed it.  My understanding is this is

 

      a single-dose study.  I don't know what the

 

      concerns will be with single-dose for neurodevelopmental

 

      stages with a single dose, low dose.

 

                DR. NELSON:  The issue is not the impact

 

      of that dose.  There might be a response difference

 

      that you could see, but the question is teasing

 

      apart--there is a debate on previous studies that

 

      have been done of structural MRI scans, and there

 

                                                                44

 

      are actually two previous studies of functional MRI

 

      scans where the question is whether or not some of

 

      the differences that may be seen are not related to

 

      any underlying biological differences, neurodevelopmental

 

      differences, but, in fact, the kids

 

      with ADHD had been chronically exposed to a

 

      medication which--I'm not a neuroscientist.  I

 

      guess I would characterize it as whether it's

 

      created some element of remodeling of those

 

      systems.  And so try and eliminate that confounder,

 

      the feeling was if they would narrow the age range

 

      and then try to either get treatment-naive, which

 

      may be difficult, or at least treatment-uniform at

 

      lower doses which would give you hopefully a lower

 

      duration of exposure, that you might be able to

 

      begin to tease apart those two issues.  That was

 

      the scientific discussion among the experts.

 

                DR. CHESNEY:  Yes, Dr. Fant?

 

                DR. FANT:  Yes, this question may be a bit

 

      naive, but it quickly comes to mind, especially

 

      from the standpoint of taking the kids off the meds

 

      for a couple of days and trying to ensure treatment

 

                                                                45

 

      naivete and the question that that may have on

 

      their response.

 

                And so the question is:  Are there any

 

      over-the-counter stimulants or food additives that

 

      could potentially interact with their response and

 

      somehow muddy the data?  And if so, is that being

 

      controlled for or addressed in the protocol?

 

                DR. NELSON:  The answer is yes.  I mean,

 

      one of the discussions, of course, by the IRB was

 

      whether caffeine and the element of caffeine

 

      consumption could be used as a judgment.  So there

 

      are some confounders and the need to collect that

 

      data, and it would be sort of self-defeating if

 

      over the weekend you take the kid off of his

 

      medication and then he drinks, you know, a couple

 

      of cases of Jolt Cola--which I don't even know if

 

      it's still made or not.  I have no stock in that

 

      company.  No conflict of interest on that

 

      recommendation.  Or Mountain Dew.  I think Mountain

 

      Dew has a lot of caffeine in it.  So, yes, they

 

      need to pay attention to that.

 

                DR. FANT:  And even with adolescents who

 

                                                                46

 

      may be concerned about weight and appearance and

 

      that sort of thing, some of the additives that are

 

      contained in supplements in GNC at the mall, you

 

      know.

 

                DR. NELSON:  Right.

 

                DR. MURPHY:  So, Dr. Fant, was that a

 

      question or just a recommendation, I guess is what

 

      I--

 

                DR. FANT:  Well, it's a concern because if

 

      we're talking about giving a drug to, quote, normal

 

      kids, you really want to ensure that the data is as

 

      clean, as interpretable as possible.  You wouldn't

 

      want to muddy the waters on something that could

 

      have easily been avoided.

 

                DR. MURPHY:  I think that, you know, if

 

      there are recommendations that this committee would

 

      like to make, that's appropriate.  And we wanted to

 

      make sure that that was--

 

                DR. NELSON:  I see that as just a

 

      refinement of the recommendation to make sure your

 

      subject populations are as uniform as possible.  So

 

      it's certainly consistent with our direction.

 

                                                                47

 

                DR. CHESNEY:  But we maybe should add a

 

      sentence or two, Skip, just to--I thought that was

 

      an excellent point if somebody does--I don't know

 

      how long those stay in the bloodstream, but if

 

      that's their breakfast and then they show up for

 

      the fMRI, there may be a confounding variable.

 

                Yes, Dr. O'Fallon?

 

                DR. O'FALLON:  Did you recommend that they

 

      collect that information?

 

                DR. NELSON:  No, but we can add a sentence

 

      to that.

 

                DR. O'FALLON:  Okay.  I think it would be

 

      helpful to make sure that they elicit that

 

      information.

 

                DR. CHESNEY:  Deborah, you were next.

 

                MS. DOKKEN:  I first want to compliment

 

      Dr. Nelson's subcommittee.  I mean, not only did

 

      you do a thorough job, but I could fully understand

 

      what you were talking about, and I was glad that

 

      you included the issue of compensation and the

 

      potential pressure on the twins in the assent

 

      process.

 

                                                                48

 

                I was also glad that at least in some way

 

      you directed attention to the permission and assent

 

      forms and talking about the chronology of the

 

      procedures.  But I had a further question about

 

      those forms, which, frankly, I don't know what

 

      their rating is in terms of reading level, et

 

      cetera.  But they certainly to me were not easy to

 

      read and, in fact, were mixed.  Sometimes they used

 

      almost simplistic language; then you know, the next

 

      sentence--did you talk at all about just the forms

 

      themselves and the language beyond the chronology

 

      issue?

 

                DR. NELSON:  Yes, we did.  But that's just

 

      captured on page 5 under age where we just say

 

      there's technical language would is not explained

 

      in lay terminology.

 

                I think two points on the process:  A,

 

      this still then needs to go back through the NIMH

 

      IRB, plus it has two offices, not just one now,

 

      that will recognize that for this to be finally

 

      approved would require that kind of changes in the

 

      documents.  And I'm absolutely confident that with

 

                                                                49

 

      OHRP and FDA's involvement in making sure that

 

      these requirements happen is that they will be in

 

      more understandable language.

 

                My own philosophy is there's no reason for

 

      us to sort of nickel-and-dime the actual text, but

 

      that was discussed.

 

                DR. CHESNEY:  Could I just add, there was

 

      a great deal of discussion about the protocol and

 

      about the consent form, and, in fact, one of the

 

      committee members asked if this was a draft of the

 

      consent form.  And the folk from the NIMH

 

      apologized and they said that they got so busy

 

      addressing the issue of whether this would have to

 

      come to a subcommittee that they hadn't really paid

 

      that much attention to the consent form, but that

 

      they would do that.

 

                Dr. Newman?

 

                DR. NEWMAN:  I also want to compliment the

 

      committee on a really very impressive, thorough

 

      review.  And I have three points.  One is just a

 

      clarification.

 

                Looking on page 7, comparing Parts a) and

 

                                                                50

 

      b), under--I'm just trying to figure out how--I

 

      have reservations about the value of the research

 

      to kids with ADHD.  I really--it's very hard for me

 

      to picture how this research will be useful, but

 

      maybe that's just due to my limited scientific

 

      knowledge.  It says under C, the procedure is

 

      likely to yield generalizable knowledge about the

 

      subjects' disorder or condition, which is vital

 

      importance for the understanding or amelioration.

 

      And I really couldn't go along with this being of

 

      vital importance.  But then under B it says it

 

      presents a reasonable opportunity to further the

 

      understanding, and I could go along with that.  So

 

      I'm not clear on which of these two is the standard

 

      that this research has to pass.

 

                DR. NELSON:  You point out an interesting

 

      ambiguity in the regulatory language for which

 

      there is no specific guidance about how one

 

      interprets "vital importance" or "reasonable

 

      opportunity."  My own view is that it needs to meet

 

      both, that you would not want reasonable

 

      opportunity to be a lower standard.  And the issue

 

                                                                51

 

      of vital importance is fundamentally subjective.

 

      And from that standpoint, there was a recognition--and

 

      that's why I put earlier on the notion that

 

      more speculatively.  I mean, this is what--I would

 

      characterize this as sort of a basic science

 

      question about the response and the neurodevelopmental sort

 

      of receptor physiology.

 

                If, in fact, there is no difference, it

 

      would have an impact significantly on the

 

      understanding of ADHD, and if there is a

 

      difference, it would impact significantly, and then

 

      might, not in this protocol but down the line,

 

      potentially drive diagnostic and therapeutic

 

      differences.  One thing I learned is there are

 

      individuals who are touting different structural

 

      scanning tools for diagnosis of kids with ADHD, et

 

      cetera, that many felt, in fact, were not evidence-based.

 

      And so after hearing that discussion, the

 

      subcommittee members felt that it did meet the

 

      regulatory standard both for vital importance and

 

      reasonable opportunity.

 

                There was no, if you will, easily defined

 

                                                                52

 

      paradigm for that.

 

                DR. NEWMAN:  Okay.  Well, that sort of

 

      leaves me uncertain.  Let me go to my next

 

      question, which was in the consent form they

 

      specifically addressed the issue of potential

 

      adverse effects of the MRI in terms of identifying

 

      some little something which then people go, oh, we

 

      wonder what this is, maybe you should go have that

 

      checked out, but that not being covered by the

 

      research study and the family may or may not have

 

      medical insurance to cover that.  And I believe

 

      that's more than minimal risk.  That's something

 

      well beyond the range of what people experience

 

      every day, the possibility of having some brain

 

      abnormality uncovered, which then you have to

 

      figure out how to deal with.  So I wonder why that

 

      wasn't considered, you know--

 

                DR. NELSON:  It was.  I didn't include it

 

      in here because the data actually is that out of

 

      3,000 scans, they've only found four abnormalities.

 

      And of those four, two were benign cysts and two

 

      were actually early diagnosis of tumors where the

 

                                                                53

 

      child benefited from that.  So there was a

 

      discussion in the subcommittee about the

 

      implications of using a screening test in a

 

      population that--you know, being a statistician,

 

      you can understand the sensitivity and specificity

 

      issues.  But after that discussion and the fact

 

      that it's being conducted--it's not a diagnostic

 

      reading of the functional MRI.  It's a separate

 

      diagnostic MRI scan that, after hearing the

 

      discussion, we felt that it was appropriate to

 

      consider that under that category.

 

                So they have enough data, I think, to sort

 

      of--at least reassure me that they're not going to

 

      be turning up a lot of things that end up with

 

      unnecessary testing.

 

                DR. NEWMAN:  If I were a parent trying to

 

      make an informed decision about participating in

 

      the study, those data would be very helpful to me

 

      to know what--to say this may happen, but they

 

      don't give any numbers on how likely it is to

 

      happen and what might be found.  And so, you know,

 

      I just think it's hard to ask someone to consent to

 

                                                                54

 

      something, you tell them that risk, but you don't

 

      tell them how big it is.  So I think that would be

 

      helpful for them.

 

                And my last question was just about the

 

      financial compensation.  For the controls, you

 

      know, it sounds like this may take several hours

 

      out of the parent's day, and so, you know, having

 

      tried to get people to enroll in studies before,

 

      you know, I don't know whether there have been

 

      pretests or what it would take.  But if you're

 

      going to ask someone to bring their normal child in

 

      and get a lot of stuff done, you know, to me I

 

      think maybe $100 or $110 split between parent and

 

      child might not be enough to get people to want to

 

      enroll.

 

                DR. NELSON:  No, it was not split between

 

      parent and child.  That would be wages for the

 

      child, and the investigator actually said--and this

 

      did influence the committee--that she did not

 

      anticipate any problem with enrollment even if the

 

      compensation and stipend was zero.  I'm just

 

      telling you, that's what she said.

 

                                                                55

 

                DR. CHESNEY:  Could I just also comment

 

      for Dr. Newman?  It was suggested that they publish

 

      the fact that they had only four abnormal MRIs out

 

      of 3,000, which is certainly not within the realm

 

      of most of our experience where MRIs show you all

 

      kinds of things that you don't want to know.  So

 

      that suggestion was made.

 

                We had a lot of discussion about the

 

      science because it's a very--to me it was a very

 

      complex study to understand, and a lot of it was

 

      based on the study by Viga (ph) et all that was

 

      published in '98 or '99.  And I thought--it wasn't

 

      until the very--long into the meeting that Dr.

 

      White, who's a child psychiatrist with a lot of

 

      familiarity with functional MRI scanning, pointed

 

      out the importance difference with respect to the

 

      performance task in this study as compared to the

 

      one published in '98 or '99, which had led to

 

      perhaps some erroneous conclusions.

 

                So I think that after a lot of discussion

 

      we finally became convinced that the science was

 

      important, if that's of any help.

 

                                                                56

 

                Any other questions or comments?  Dr.

 

      O'Fallon?

 

                DR. O'FALLON:  I was just wondering about

 

      the pregnancy exclusion.  I didn't look at the

 

      consent form closely enough to see.  Presumably

 

      they are excluding on the basis of pregnancy.  Is

 

      that it?

 

                DR. NELSON:  They are.  It wasn't very

 

      well described in the consent form, which was our

 

      point.

 

                DR. O'FALLON:  Okay.  Well, but that's the

 

      point.  So they have to--so they do have to take

 

      this--they have to have a pregnancy test.  Now, I'm

 

      just curious.  How do they think they're going to--I mean,

 

      how do they plan to deal with exclusion

 

      basically on pregnancy alone when they don't--they

 

      can't tell it to the parent?

 

                DR. NELSON:  They didn't outline that,

 

      but, I mean, I'm confident that they can come up

 

      with a procedure.  We're just asking them to do

 

      that, and I'm sure OHRP will make sure it's a good

 

      one.

 

                                                                57

 

                DR. O'FALLON:  Okay.  I wonder how they

 

      are going to do it.

 

                DR. CHESNEY:  Very important points.

 

                Any other--Dr. Newman?

 

                DR. NEWMAN:  Let me just explain what my

 

      reservations are about the value of the research,

 

      and maybe you can reassure me.  It seems to me that

 

      ADD is a clinical diagnosis, and in making the

 

      diagnosis, one of the main decisions that you're

 

      trying to guide is whether to begin stimulant

 

      medication.  And if you begin stimulant medication,

 

      you want to see whether it helps the child and

 

      monitor that and discontinue it if it's not working

 

      and continue it if it is.

 

                And I just cannot visualize how an MRI

 

      scan would ever sufficiently predict a child's

 

      response to medication to be clinically useful,

 

      because, I mean, they may well find some

 

      statistically significant differences where the

 

      something or other is, you know, a half a standard

 

      deviation different in one group than the other, or

 

      maybe they're quite different.  But the fact is

 

                                                                58

 

      whatever they find, the question is really whether

 

      this child would benefit from treatment or not.

 

      And, you know, the way you determine that is

 

      whether--either trying the treatment and seeing if

 

      it helps, or if you were going to do a study to see

 

      whether imaging helps, you would see whether

 

      imaging predicts response to treatment, not whether

 

      imaging predicts or is associated with someone

 

      having received this clinical diagnosis.

 

                So I am a little bit worried if it does

 

      show a difference that this will spawn a whole

 

      imaging industry of people wanting to get their

 

      children's heads scanned to see whether they really

 

      have it or not, which I think would just be going

 

      in the wrong direction.

 

                DR. NELSON:  I guess two comments.  This

 

      has nothing to do with the clinical response of the

 

      children.  There is no benefit.  It has nothing to

 

      do with that.  Whether or not it--if it does show a

 

      difference, appropriately designed, it would spawn

 

      a functional MRI industry I think is speculative

 

      and, in fact, is explicitly, if you at Subpart A,

 

                                                                59

 

      excluded from what an IRB ought to consider.  The

 

      long-term policy implications of research is not

 

      something that IRBs are supposed to consider, and I

 

      wouldn't necessarily import it under vital

 

      importance.

 

                The question is whether or not there are

 

      structural or functional differences, and

 

      presumably based on receptor density, et cetera--it's not my

 

      area so I'm just saying things that you

 

      could have read in the protocol and listening to

 

      the scientists.  And as a basic science question, I

 

      think that's an important one.  And how it might

 

      then impact down the road in terms of understanding

 

      whether there's a differential or similar response

 

      to stimulants, I mean, the literature is quite

 

      mixed in terms of reading some of the background

 

      material in the protocol.

 

                So there is no connection in doing this

 

      with determining why they might respond clinically.

 

      There is no--and, in fact, many of our recommendations were

 

      meant to prevent that confusion

 

      from being in the minds of the participants by

 

                                                                60

 

      removing any semblance of benefit from the sort of

 

      surrounding aspects of the science.  But, you know,

 

      I think ADHD is a controversial area, and it's

 

      partly why we felt this needed to be looked at

 

      carefully and then done well, because I think the

 

      positive or negative results could have an impact

 

      in different directions.

 

                DR. CHESNEY:  I think Skip expressed it

 

      very well.  The purpose of the study was not to

 

      have any clinical diagnostic value or clinical

 

      implications.  The purpose of the study is really

 

      to understand, as Skip said, the neurophysiology

 

      and neurochemistry--to try to understand the

 

      neurophysiology and neurochemistry of ADHD better,

 

      and because of the twin aspect, to see if there are

 

      any genetic aspects.

 

                Dr. Maldonado?

 

                DR. MALDONADO:  A quick question that goes

 

      beyond this study, but it's in the context of ADHD.

 

      One of the premises that I think a lot of

 

      researchers' work is under that if the studies can

 

      be done in adults, don't do it in children.  And

 

                                                                61

 

      now adults are being diagnosed with ADHD.  Has

 

      something similar been done in adults or can be

 

      done in adults, you know, consenting adults, so you

 

      don't use this area of consent of children?

 

                DR. NELSON:  Two points.  That specific

 

      question was raised by the subcommittee.  There

 

      have been similar but not identical studies, but

 

      it's clear that the adults are different in this

 

      regard and that the information that you would get

 

      would be of no use to this issue.  And that

 

      discussion actually is why you may even--in the

 

      discussion it was clear that the scientific

 

      arguments might push you in the direction of using

 

      actually the 9 to 12 age group as opposed to the

 

      older age group because there may even be those

 

      kinds of adult changes when you get into sort of

 

      late adolescence.  But we felt that that was not

 

      clear enough that we would make a stipulation as

 

      opposed to recommendation.

 

                So I think that is an important principle,

 

      and it was asked and answered in the negative, that

 

      adult information here would be of no use to

 

                                                                62

 

      answering this question.

 

                DR. CHESNEY:  Dr. Schwetz, did you have

 

      any additional comments about the questions from

 

      the committee?

 

                DR. SCHWETZ:  No, I don't have anything

 

      else to add.  Thank you.

 

                DR. CHESNEY:  Dr. O'Fallon, you look like

 

      you were--

 

                DR. O'FALLON:  I hesitated simply because--but I'm

 

      a mother and not an M.D.  I've had an MRI.

 

      I don't know what--for my neck.  I was wondering

 

      what a functional MRI for the brain involves for

 

      the child.

 

                DR. NELSON:  Nothing different than an MRI

 

      scan.

 

                DR. O'FALLON:  But the question is they

 

      are enclosed, so there is the issue of

 

      claustrophobia?

 

                DR. NELSON:  Correct, but they have

 

      screening procedures for that.  There's no issue in

 

      that.  The kids are actually less claustrophobic

 

      than the adults.

 

                                                                63

 

                DR. MURPHY:  Skip, why don't you describe

 

      the screening procedure--

 

                DR. NELSON:  They have a training MRI scan

 

      which is--and they make--you know, first they've

 

      got to make sure the kids can do these tasks, so

 

      they use the stop task and a training MRI scan.

 

      They have a whole sort of session.  I mean,

 

      everybody--if a kid doesn't want to do it, then

 

      that's the end of it.  You know, their procedures

 

      are excellent with respect to that.  The issue is

 

      not that they're not doing it.  The issue is they

 

      just didn't describe it in the protocol.  They

 

      described it quite completely in the discussion on

 

      Friday.

 

                DR. MURPHY:  I think as a risk what you're

 

      trying to get at is that those kids that are going

 

      to have that impact of anxiety, psychological fear,

 

      will be--will not be enrolled.  In other words,

 

      that's where the screening procedure would help

 

      select those children out.

 

                DR. O'FALLON:  Yes, but, of course, the

 

      screening itself could cause this--I mean, they

 

                                                                64

 

      could precipitate this anxiety.  I don't know what--at the

 

      time of my MRI, I was told that there's a

 

      fairly high percentage, like 25 percent of adults,

 

      anyway, that experience--well, that's what I was

 

      told, when I was told about it, that experience

 

      claustrophobia.

 

                DR. GOLDKIND:  Could I speak to that?

 

      They actually show the kids a video, and they have

 

      a very well organized approach, even before they do

 

      the screening program that was described to us on

 

      Friday.  Additionally, they said that because

 

      children are smaller than adults physically, they

 

      are not as confined.  They don't have the feeling

 

      of claustrophobia that adults do based on physical

 

      size and also based on psychological orientation.

 

      Generally speaking, children don't have as high a

 

      claustrophobia rate as adults do.

 

                So for all those reasons, the subcommittee

 

      felt that it was a minimal risk intervention.  And

 

      then as Dr. Murphy said, if a children demonstrates

 

      hesitation at any step along the way prior to

 

      getting to the actual enrollment, they're excluded.

 

                                                                65

 

                DR. NELSON:  Twenty-five percent sounds

 

      quite high to me, anyway, even for adults.

 

                DR. O'FALLON:  Maybe it's because of the

 

      practice of ours.  We have a whole lot.

 

                DR. CHESNEY:  Let me ask, not seeing any

 

      further hands being raised, does the committee feel

 

      that they are comfortable endorsing this summary of

 

      the events of Friday?  We're not required to take a

 

      vote on this.  Unless there is somebody who is not

 

      comfortable endorsing this, we would like to pass

 

      on to Dr. Murphy the committee's endorsement.

 

                [No response.]

 

                DR. CHESNEY:  Not seeing any hands being

 

      raised, I think that we can--yes, Dr. Nelson?

 

                DR. NELSON:  I just want to ask, you know,

 

      in terms of adding the issue of collecting data and

 

      trying to exclude caffeine and other stimulants

 

      under the design recommendation and the discussion

 

      of the communication of the risk of inadvertent

 

      findings on the diagnostic MRI scan, can that just

 

      be made by office staff?  Or do you want me to just

 

      do it myself and give it to you?

 

                                                                66

 

                DR. JOHANNESSEN:  We can do that.

 

                DR. NELSON:  Okay.

 

                DR. CHESNEY:  Thank you very much, Dr.

 

      Nelson, for chairing this--

 

                DR. MURPHY:  We have one more question

 

      over here.  Would you like to please identify

 

      yourself for the committee and ask them this

 

      question?

 

                DR. STITH-COLEMAN:  My name is Irene

 

      Stith-Coleman from OHRP.  What I would suggest is

 

      that if--in terms of the additional statement,

 

      could you clarify if you recommend that it be a

 

      recommendation or stipulation?  That would be of

 

      help to OHRP.

 

                DR. NELSON:  The first one about caffeine

 

      or other stimulations is going to go under the

 

      design recommendation, not stipulation.  And then

 

      the comment about communication of risk, one of our

 

      discussions at the meeting was whether they, you

 

      know, have all the data, but I think the

 

      recommendation that they communicate that

 

      information in a meaningful fashion to parents

 

                                                                67

 

      would go under the diagnostic MRI scan, which fits

 

      under a stipulation.  The only thing that's a

 

      recommendation to consider, which they could then

 

      come back with arguments for or against, is number

 

      3.  Everything else is stipulations.

 

                DR. MURPHY:  That was helpful.  Thank you.

 

      This is a new process.  As Dr. Schwetz said, we're

 

      very enthusiastic about the fact that we aren't

 

      setting up a process that would almost engender or

 

      increase the possibility of having differing

 

      recommendations if you empanel two different groups

 

      and have two different sets of experts.  There's

 

      always a probability that you going to get two

 

      different sets of answers.  So I think that--however, it's

 

      been very helpful to hear the

 

      comments from this group, and I think that at this

 

      point, Dr. Schwetz, what we need to make a cut on

 

      is where recommendations would just go straight up

 

      forward via both of these mechanisms versus if

 

      there were some major concerns, what we would do in

 

      that situation.  I think we're not at that level

 

      right now, but that is certainly something we would

 

                                                                68

 

      want to consider for the future.

 

                Skip?

 

                DR. NELSON:  Just one other point that I

 

      think, as word goes out, might be surprising to

 

      many IRBs, although I realize that it's, in fact,

 

      the correct interpretation of the regulations, many

 

      IRBs do not think simply because you're using an

 

      FDA-regulated product in a clinical investigation

 

      or in the research that it's an FDA--that the FDA

 

      has oversight.  You know, both of these products

 

      are being used in accord with clinical

 

      recommendations at doses that are being done

 

      clinically.  And I think that to many IRBs might be

 

      a surprise.  So just to alert you to that as this

 

      word might trickle out.  I do know that the FDA

 

      does have jurisdiction, even if it's an approved

 

      drug being used in a clinical investigation.  But

 

      many IRBs don't think that--or don't know that, I

 

      should say.

 

                DR. MURPHY:  And it's new for the agency,

 

      so actually it's something that we are making sure

 

      everyone within the FDA is aware of also.  So I'll

 

                                                                69

 

      just give you that sort of forewarning.

 

                DR. CHESNEY:  Thank you very, very much to

 

      everybody who prepared for Friday's presentations

 

      and for the process, Dr. Nelson for chairing it

 

      all, and Dr. Schwetz and the other members of the

 

      OHRP who were there, but who also took the time to

 

      come today.  We very much appreciate your time.

 

      And thank you to the committee for your questions.

 

      They were very, very perceptive given that you

 

      hadn't been at the meeting Friday.  You really

 

      raised some very important and additional issues.

 

                I think I will move on to--

 

                DR. MURPHY:  I just have one last person I

 

      wanted to thank, and that's Terry Crezenzi (ph) and

 

      Sara Goldkind, working with OHRP, spent many, many,

 

      many weeks and months putting this process

 

      together, and just because she made the terrible

 

      decision to leave us and go on detail elsewhere, I

 

      wanted to make sure we recognize the contributions

 

      that she has made to this process.

 

                Thank you.

 

                DR. CHESNEY:  Thank you.  We don't know

 

                                                                70

 

      about all the behind-the-scenes work, so thank you

 

      very much for clarifying that.

 

                All right.  Well, moving on to the next

 

      section of today's meeting, let me introduce Dr.

 

      Solomon Iyasu, who is a pediatrician and medical

 

      epidemiologist.  He was with the CDC for 13 years

 

      leading the Infant Health Program there.  And here

 

      at the FDA, he's a medical team leader in the

 

      Division of Pediatric Drug Development and a

 

      medical epidemiologist in the Office of Pediatric

 

      Therapeutics.  I don't know how you all keep track

 

      of who you are.

 

                Today's talk will provide an overview of

 

      the BPCA mandate for adverse event reporting, the

 

      review process, and FDA's adverse event reporting

 

      system.  Dr. Iyasu?

 

                DR. IYASU:  Good morning.  It's a pleasure

 

      to be here and present to you the adverse event

 

      report for several products that have been given

 

      pediatric exclusivity.

 

                The Best Pharmaceuticals Act for Children,

 

      which was enacted in 2002, does have a provision

 

                                                                71

 

      for mandatory reporting of adverse events for

 

      products that have been given exclusivity.  Under

 

      Section 17 of that act, FDA is required to review

 

      adverse event reports during the first one year

 

      after exclusivity is granted to a particular

 

      product.  And once that review is done, then the

 

      FDA will report a summary to the Advisory

 

      Subcommittee, which now is a full committee, for

 

      their review and recommendations.

 

                The review process that we have

 

      implemented at FDA for drug products includes a

 

      very close collaboration between the Office of Drug

 

      Safety, which does the primary review of the

 

      adverse events reported for the one-year period,

 

      and then also the Division of Pediatric Drug

 

      Development, who would be participating in this

 

      review, and then finally the Office of Pediatric

 

      Therapeutics, which is the new office which has

 

      overall responsibility over adverse event reporting

 

      for pediatric issues.

 

                Just to outline to you what we've been

 

      doing over the last two years in terms of the

 

                                                                72

 

      review process, we have implemented sort of a

 

      process which includes and defines responsibilities

 

      for each of the participating offices.  The Office

 

      of Drug Safety has responsibility for reviewing the

 

      adverse events reported during the one year and

 

      also has responsibility for immediately discussing

 

      any serious unexpected events including deaths with

 

      the Office of Pediatric Therapeutics and also the

 

      Office of Counterterrorism.  And, finally, it has a

 

      responsibility also for submitting the written

 

      safety review and sharing them with OCTAP, which is

 

      the pediatric group, and the Office of Pediatric

 

      Therapeutics, and, more importantly, with the

 

      review divisions that are responsible for these

 

      particular drug products.

 

                Then OCTAP, which is Office of

 

      Counterterrorism and Pediatric Drug Development,

 

      and OPT have joint responsibilities for also

 

      notifying the Office of Drug Safety once

 

      exclusivity determination is done for any products,

 

      so that the tracking could start then for a period

 

      of one year after that date of determination.

 

                                                                73

 

                The medical officers within these two

 

      office also have roles in reviewing the ODS reports

 

      that are submitted, and then also looking at the

 

      individual adverse event reports, the MedWatch

 

      reports, and also preparing summaries and

 

      presentations for this committee.

 

                We try as much as possible to focus the

 

      adverse event presentations on issues, safety

 

      issues that may have arisen during the review

 

      process so that the committee's time is better

 

      spent on important issues.

 

                We have also developed, in collaboration

 

      with the Office of Drug Safety, a template for

 

      summarizing the review, and the safety review

 

      includes an executive summary that sort of

 

      highlights what the issues are from the review.  We

 

      also include in that template a review of the

 

      adverse event reports for adults and pediatric

 

      patients from the original drug approval date up to

 

      the time that the drug has been reviewed for the

 

      exclusivity process.  So it's a longer view, but

 

      it's an overview, really, trying to see what the

 

                                                                74

 

      number of reports have been for adults and in

 

      pediatrics, and also trying to get a handle on

 

      whether--how many of them were actually U.S. origin

 

      and how many of them are actually foreign reports.

 

                Then for the more focused pediatric

 

      review, we have a detailed template which I'm

 

      highlighting here were the issues of the specific

 

      reviews that are done by the Office of Drug Safety.

 

      We expect counts and labeling studies of the top 20

 

      most frequently reported adverse events within the

 

      pediatric population as well as adults, but we

 

      focus more on the pediatric issues.  We also try to

 

      get from the MedWatch reports the summaries of the

 

      demographics, age, gender, distribution of the

 

      adverse event reports for the one-year period,

 

      including a description of the serious outcomes,

 

      indications, and doses that may have been

 

      associated with these adverse events.

 

                Then there is an evaluation of whether

 

      these adverse events reported during the one-year

 

      period are unexpected events or are they unique to

 

      pediatric patients and not reported in adults.  So

 

                                                                75

 

      there's an evaluation that's done sort of comparing

 

      adult and pediatric reports.

 

                Also, an evaluation of whether there is an

 

      increased frequency of non-pediatric adverse events

 

      in this population, but this is done for the one-year

 

      period.  And then, finally, sort of developing

 

      adverse event profile for that particular drug

 

      product, which will then sort of highlight what the

 

      issue is, if there is an issue that has developed

 

      during that review process.

 

                We also have for the denominator data,

 

      trying to understand what the exposure us in the

 

      pediatric population, we use various databases that

 

      are available to FDA, which I'll briefly describe

 

      later on, which estimate drug use in the outpatient

 

      setting for this drug product, as well as for the

 

      inpatient population.

 

                The role of the Pediatric Advisory

 

      Committee is really to assess and discuss the

 

      presented adverse events.  We've been doing this

 

      now for almost two years.  And if appropriate,

 

      recommend additional pediatric review and/or any

 

                                                                76

 

      regulatory action if deemed appropriate.

 

        T2A                 The role is evolving.  This is a new

 

      committee, and there may be other responsibilities

 

      or even roles that would be defined as we go into

 

      having more experience with this process.

 

                Now, I want to sort of give you a brief

 

      overview, top-line view of what the adverse event

 

      or the Postmarketing Drug Surveillance Program

 

      includes and the various components that may be

 

      tapped to assess drug safety.  The cornerstone

 

      about this is, of course, the passive surveillance

 

      system, which you've heard about so much in

 

      previous presentations, which is the Adverse Event

 

      Reporting System, which includes adverse event

 

      reports, spontaneous reports, and manufacturer

 

      reports that are sent to FDA.

 

                I also mentioned sort of the--on the

 

      denominator side sort of trying to assess exposure,

 

      the drug utilization databases that FDA has access

 

      to, which include outpatient, inpatient, and some

 

      longitudinal data.

 

                Other databases that may be tapped also

 

                                                                77

 

      for evaluation of adverse events, external health

 

      care databases which may includes claims databases

 

      from special populations or from the general

 

      population, and then there is also information sort

 

      of a repository of background incidence rates on

 

      different adverse events or conditions that may

 

      come from hospital discharge surveys or from the

 

      literature that we may actually tap in our

 

      evaluation.

 

                Then, finally, there are some active

 

      surveillance systems that look into possible drug-associated

 

      adverse events.  I'm not going to go

 

      into detail about this, but the DAWN is the Drug

 

      Abuse Warning Network, and then NEISS is the

 

      National Electronic Injury Surveillance System,

 

      which is run by CDC, and TESS is the Toxic Exposure

 

      Surveillance System, which is run out of the Poison

 

      Control Centers.

 

                Now, just to give you an overview of the

 

      most pertinent one, which is the AERS database, as

 

      some of you probably know.  It originated in 1969

 

      as the Safety Reporting System.  It currently

 

                                                                78

 

      contains more than two million adverse event

 

      reports in the database, contains drug and

 

      "therapeutic" biologic adverse event reports, with

 

      the exception of vaccines which has a separate

 

      reporting surveillance system.

 

                Just to give you some idea of what reports

 

      are, they are mostly voluntary/spontaneous reports

 

      that may come from health care professionals,

 

      consumers, patients, or others.  But also a large

 

      majority of them are actually mandatory reports

 

      that come from manufacturers required for

 

      postmarketing reporting purposes by law.  All

 

      adverse drug experience information obtained or

 

      otherwise received from any source, foreign or

 

      domestic, will be included in this.  And to give

 

      you more detail, there will be more detailed

 

      discussion later on about this.

 

                But in 1993, the whole Adverse Event

 

      Reporting System was redesigned and the MedWatch

 

      form was developed.  You probably can't see this

 

      slide, but in your handout you probably can

 

      identify some of the design aspects of the MedWatch

 

                                                                79

 

      system.  But, in short, this is the form that

 

      unifies in terms of reporting for drugs and also

 

      for biologic products and also for devices and

 

      dietary supplements.

 

                Now, by law there are definitions for

 

      different kinds of reports.  What manufacturers

 

      must report is defined under 21 CFR 314 that

 

      includes all adverse event reports from commercial

 

      marketing experience, postmarketing studies, and

 

      scientific literature.  And this may include all

 

      domestic spontaneous reports that must be reported

 

      to the FDA.  In terms of foreign or literature

 

      reports, all serious, unlabeled events are

 

      mandatory in terms of reporting.  And it may

 

      include also study reports which may be serious,

 

      unlabeled, or any adverse event with a reasonable

 

      possibility that the event may be related to a drug

 

      product.

 

                Adverse drug experience is also defined by

 

      the regs.  Any adverse event associated with the

 

      use of a drug, whether or not considered drug-related--this

 

      is an important point--has to be

 

                                                                80

 

      reported.  This may include accidental or

 

      intentional overdose or occurring from abuse or

 

      drug withdrawal or failure of expected

 

      pharmacological action.

 

                Now, I mentioned before the serious

 

      adverse events, and there is a regulatory

 

      definition as well for this:  any event occurring

 

      at any dose that results in any of the following

 

      outcomes.  And this has been mentioned several

 

      times in yesterday's presentation.  Some of you

 

      were not there, but this may include deaths or

 

      life-threatening adverse events or something that

 

      results in hospitalization or prolongation of

 

      hospitalization or persistent/significant

 

      disability or may result in a potential congenital

 

      anomaly or birth defect or requiring intervention

 

      because of an adverse event associated with a drug.

 

                Also, there's a definition also according

 

      to the regs for unexpected adverse drug events or

 

      experience:  any event not listed in the current

 

      labeling of the drug product, including events that

 

      may be symptomatically and pathophysiologically

 

                                                                81

 

      related to a labeled event, but differ because of

 

      greater severity or specificity.  So examples may

 

      be like hepatic necrosis versus hepatitis.  So

 

      there is a regulatory definition as well for those.

 

                Now, just to briefly go over the strengths

 

      of the AERS system, it includes all U.S.-marketed

 

      drug products.  It's simple because it's passive

 

      surveillance.  It's less expensive than having an

 

      active surveillance system, which may be very

 

      expensive.  It provides for early detection of

 

      safety signals, and especially good for rare

 

      adverse events.

 

                There are some very significant

 

      limitations of the AERS system.  Underreporting is

 

      a serious problem, but this varies from drug to

 

      drug and also over time.  Reporting may be more

 

      during the early phases of the marketing and may

 

      taper off later on.  If there is media attention or

 

      public attention on a particular safety issue,

 

      reports may go up.  Or it depends on what kind of

 

      drug it is, whether it's OTC or prescription drug.

 

      You may not get as many reports for OTCs and so on.

 

                                                                82

 

      So there is a problem with underreporting.

 

                Then there are also issues about quality

 

      and completeness of reports.  That also varies, it

 

      often may be poor.  You may not get information

 

      maybe that would help you assess temporality of the

 

      drug exposure with the event.  You may not get

 

      information on concomitant medications or may not

 

      get very good medical history of the patient from

 

      whom the adverse event is being reported.  So that

 

      is an issue which is sort of common to all passive

 

      surveillance programs.

 

                Another important aspect in terms of

 

      limitations, the limited ability of the system to

 

      really estimate, help estimate true adverse event

 

      risk rate because the numerator is uncertain

 

      because of underreporting, which I mentioned, and

 

      also the denominator must be estimated or it's

 

      projected from sort of drug use databases that we

 

      have, virtually--may be difficult for some

 

      inpatient or OTC drugs.

 

                I'll just briefly go over the outpatient

 

      drug use.  I'm doing this for the benefit of the

 

                                                                83

 

      new members to sort of give you what the sources

 

      are.  For outpatient drug use, we mainly tap into

 

      the IMS Health System.  One database is National

 

      Prescription AuditPlus, which provides an estimate

 

      of the number of prescriptions from retail

 

      pharmacies.  The point on this limitation is that

 

      it does not include information on gender or race

 

      or age.  So the information is limited, but it can

 

      give you an estimate of what the outpatient

 

      prescription volume is.

 

                The other database, which is also an IMS

 

      Health product, is the National Disease and

 

      Therapeutic Index, which is a survey of 2,000 to

 

      3,000 office-based physicians and really measures

 

      mentions of drugs during that encounter and

 

      includes a variety of specialties.  But one

 

      disadvantage is that the diagnosis cannot be linked

 

      to the drug use.  And the projections may be

 

      unstable, especially when use is very limited in

 

      some pediatric--for some drugs in the pediatric

 

      population.

 

                Another source for outpatient drug use is

 

                                                                84

 

      the National Sales Perspectives, which is also an

 

      IMS product.  This is really a measure of the

 

      volume of drugs that are sold from the

 

      manufacturers to various distribution channels.

 

      This may include retail outlets and non-retail

 

      outlets.  This is sort of a surrogate for use if

 

      you see that what is actually moving to the retail

 

      pharmacies or channels is really representing what

 

      is actually being used by patients.  But also an

 

      important limitation is that we don't have

 

      information on age and gender in this database, so

 

      we're not able to be more specific.

 

                For inpatient drug use, we have several

 

      databases.  One is AdvancePCS, which is based on a

 

      large prescription claims database of the insured

 

      population.  That includes about 75 million

 

      patients.  But we don't have a projection

 

      methodology to sort of estimate it on a national

 

      level.

 

                Premier is another database which comes

 

      from approximately 450 acute, short-stay, non-federal

 

      hospitals.  The projection methodology is

 

                                                                85

 

      available.  It may not be very good for some drugs,

 

      so it is selectively appropriate in terms of making

 

      national projections.  Again, the estimates cannot

 

      be linked to diagnosis or any procedure, and

 

      importantly, it misses the drugs that may be

 

      administered at the hospital outpatient clinics,

 

      especially come to mind oncologic drug products.

 

                The last database that we have utilized is

 

      Child Health Corporation of America, which includes

 

      really just pediatric hospitals, and the data come

 

      from about 29 free-standing children's hospitals

 

      distributed around the country.  An important

 

      limitation is that this is--we don't have a

 

      projection methodology to estimate at a national

 

      level, so whatever we get in terms of this

 

      database, although it may be specific to the

 

      pediatric population, is not representative of what

 

      the national experience may be.

 

                Now, having gone over this overview, I

 

      just wanted to touch upon the drug products that

 

      we've reported on under the mandated BPCA review

 

      process.  We started our first presentation in June

 

                                                                86

 

      2003, and we covered several products at that time.

 

      The second one was October, the third one was

 

      February, and then June.  So we've had four major

 

      adverse event reporting that we've done for over

 

      maybe 22 products, and today's presentations will

 

      be an extension of that.

 

                Just to give you examples of some of the

 

      outcomes of the prior Pediatric Advisory

 

      Subcommittee meetings, we've discussed very

 

      important issues including SSRIs and SNRIs in

 

      relation to suicidal behavior and then class

 

      labeling for neonatal withdrawal, again, with SSRI

 

      products.  That was actually a subject of

 

      discussion in the last AC meeting, subcommittee

 

      meeting.  And then we have also discussed the

 

      fentanyl transdermal products, which have been

 

      associated with inappropriate use that may have

 

      resulted in some pediatric deaths, and there were

 

      some specific recommendations that were provided by

 

      the subcommittee for FDA regarding these drug

 

      products.  So the mandated adverse event reporting

 

      has had important implications in terms of focusing

 

                                                                87

 

      our attention on some of the safety issues.

 

      Despite its limitation of being just for one year,

 

      it's really brought attention to looking at safety

 

      issues in the pediatric population.

 

                Now, just to give you an overview of what

 

      is going to happen today the way it's laid out, we

 

      are going to have presentations on several drug

 

      products, as you can see in the agenda.  Dr. Hari

 

      Sachs is going to be presenting the one-year

 

      adverse event reports for ofloxacin, and

 

      alendronate, and Dr. Susan McCune will be presented

 

      on adverse events regarding fludarabine, and Dr.

 

      Jane Filie will be presenting on desloratadine.

 

      And then we'll have a break, and in the next

 

      section we will have several presentations which I

 

      will introduce later in more detail, but we have

 

      adverse event reports for fluticasone- or

 

      budesonide-containing drug products.  And there

 

      will be a one-hour slot for this presentation.  In

 

      regard to the drug products containing fluticasone,

 

      we'll be addressing that.

 

                There is also a question that we have for

 

                                                                88

 

      you to consider, so I wanted you to think about

 

      this while the presentations are going on.  We'll

 

      ask you this question, and then we'll be very

 

      looking forward to your recommendations regarding

 

      these products.

 

                DR. CHESNEY:  Thank you very much.  That

 

      was extremely helpful to me, reviewing the

 

      databases.  You've probably done that many times

 

      before, and I didn't remember, but it's very, very

 

      helpful.

 

                Any questions from the committee?  Yes,

 

      Dr. Nelson?

 

                DR. NELSON:  I agree you've taken a system

 

      that doesn't provide a lot of data and tried to

 

      make it as best as possible.  I guess this is a

 

      comment that perhaps at some future meeting we may

 

      want to discuss what we could do in the future

 

      perhaps to try and get a better handle on safety.

 

      The reason I'm concerned is if you think about the

 

      expanse of the past two days, all of those drugs

 

      were labeled for suicide as an adverse event, and

 

      most individuals, apart from the signal that came

 

                                                                89

 

      out of the requested exclusivity trials, would

 

      think that, in fact, that's potentially unrelated

 

      to the drug and related to the disease.  And so

 

      none of that data emerged out of this.  What it

 

      emerged out of is a review of the exclusivity

 

      trials themselves.

 

                And at some point, I think it would be

 

      worth just discussing as a general topic, apart

 

      from the--you know, as we've done on individual

 

      agent can we do better than this system and what

 

      would that look like.  And I'm not sure what the

 

      answer would be in terms of that, but I'm struck--my

 

      impression is that we wouldn't have seen the

 

      signal that we saw that led to the past two-day

 

      meeting using this system.  And the only way that

 

      came up was with the request to exclusivity

 

      studies.

 

                DR. IYASU:  Yes, well, let me make a

 

      comment.  As you recall, since you've been involved

 

      in this committee a couple of years, we did a

 

      report on suicidal ideation and also suicidal

 

      behavior associated with drug products like

 

                                                                90

 

      Citalopram and Paxil in the past.  Now, we know the

 

      limitations of the system in terms of trying to get

 

      a handle on what the rates are or, you know, the

 

      estimates of the risk on this adverse event.

 

      Nevertheless, I think the AERS system, the best it

 

      can do is that it can sort of identify some adverse

 

      events that may not have been detected during the

 

      clinical trial, but sometimes it's also possible

 

      that if you see it in the clinical trial setting

 

      and you see it also in the one-year post-exclusivity period,

 

      then it sort of raises a

 

      question.

 

                So, actually, I want to go back to what

 

      happened early last year when we were talking about

 

      Paxil.  The discussion of the clinical trial data

 

      was done in conjunction with the adverse event

 

      report, so it was supportive in the sense of us--you know,

 

      mandating us to look more carefully at

 

      the clinical trial data because we were also seeing

 

      these reports in the Adverse Event Reporting

 

      System.

 

                So I would say that the AERS system cannot

 

                                                                91

 

      give you an estimate, but it can just focus you or

 

      even help you look more closely at clinical trial

 

      data if you do see these kind of events.

 

                DR. MURPHY:  Skip, I think what you're

 

      bringing up is a really important question, and

 

      actually, I was going to say this at the end of the

 

      meeting, but after we do maybe one more meeting

 

      with the new committee with this process, you will

 

      see we have already internally decided--and Dr.

 

      Lumpkin is now my new boss, and we want to

 

      internally review, including, you know, Office of

 

      Drug Safety, New Drugs, and other Centers, have an

 

      internal review of how to enhance the way we go

 

      about the safety reporting, because it's very clear

 

      to us that Congress wants us to be able to make

 

      valid reviews, if you will.  We're all telling you

 

      there are problems with this system and we all

 

      know, so how can we enhance it?  And I think the

 

      prior committee has seen that we've gone from just

 

      reporting AERS and what's in the label, to going

 

      back to the actual original clinical trials,

 

      looking at signals in those clinical trials and

 

                                                                92

 

      trying to tell you what was seen then, what's seen

 

      in AERS.  So we really do agree that we need to try

 

      to develop the most robust way of doing this.

 

                Now, having sort of laid bare the fact

 

      that we all think this is not the best system and

 

      we want to make this a useful process, I will tell

 

      you that just having the process has an impact that

 

      you don't see.  Okay?  You know, having been

 

      mandated and going to a division and saying this

 

      product is coming up for review and we need--it

 

      means the divisions, ODS, everybody has to go back

 

      and look at this material.  And as Dr. Iyasu was

 

      saying, Paxil was a--I think we mentioned to you,

 

      we delayed actually presenting that because of all

 

      of the activity that was going on.  And when we

 

      looked at the AERS system, we saw some actual

 

      concerning things.  Now, we couldn't make any

 

      attribution, but compared to the other products--and you

 

      have to do all those--you know, the other

 

      products weren't used as much, et cetera, there

 

      still were some things that were concerning.

 

                So I think we feel that the process, even

 

                                                                93

 

      as it is right now, has served some useful

 

      purposes, but that clearly we would like to enrich

 

      it and make it more robust and make it more

 

      scientifically useful for the committee to

 

      understand, because, otherwise, what we're always

 

      doing is putting pieces--you know, we're taking

 

      pieces of data and trying to make sense out of

 

      these pieces of data.

 

                So the intent is that we will be coming

 

      back to you, and as I said, we'll see, you know,

 

      how the next meeting or so goes, give the new

 

      committee an opportunity to see this and provide us

 

      additional--and probably come to you as a complete

 

      subject unto itself, a topic for the committee, how

 

      to better do this process.

 

                DR. NELSON:  And just to--my comments are

 

      meant to be critical in the positive sense.  The

 

      progress since when I remember first hearing some

 

      of this data two years ago has been phenomenal in

 

      terms of what's been able to be accomplished with

 

      all the warts and pimples of the existing data.  So

 

      just to say that.

 

                                                                94

 

                DR. IYASU:  Thank you.  I appreciate the

 

      comments, and we're always open to suggestions to

 

      make it even better and make it more useful.

 

                DR. CHESNEY:  I think Dr. O'Fallon and

 

      then Dr. Ebert.  No?  Dr. Ebert.

 

                DR. EBERT:  This is somewhat related, and

 

      I wonder whether the agency has considered this as

 

      well.  But a lot of what you've focused on have

 

      been, of course, adverse events that have happened.

 

      But I'm wondering whether there is also the

 

      opportunity to screen for medication errors that

 

      occur and whether that entire--it may be a slightly

 

      different database, whether that's through IMSP,

 

      for example, and whether there may be systematic

 

      errors that occur in treatment of pediatric

 

      patients as opposed to adult patients, whether it's

 

      product selection or selecting the wrong product

 

      because it looks similar to another substance, for

 

      example.

 

                But it seems that there's obviously been

 

      an increasing public outcry for making sure that

 

      our medical practices are also safe in addition to

 

                                                                95

 

      these adverse effects that occur.

 

                DR. IYASU:  I think that's an important

 

      point.  Again, AERS has limitations in that area,

 

      but, nevertheless, I recall in one of the

 

      presentations we had an issue with medication error

 

      involving two products, one was Zoloft and Zyrtec,

 

      and that came out loud and clear, I think, in the

 

      adverse event review, and there may be others also

 

      that may be picked up.  Yes, that's an important

 

      issue.

 

                DR. CHESNEY:  Dr. Maldonado?

 

                DR. MALDONADO:  Yes, I have a couple of

 

      questions of process or actually what you said that

 

      one of your list of five items there was unique and

 

      unexpected pediatric AEs, and I just kind of went

 

      through some of the presentations.  Is that data

 

      going to be presented in a way that we can actually

 

      see if there is excess pediatric risk in the use of

 

      these drugs, an excess compared to adults?

 

      Typically most of these drugs that are used in

 

      adults tend to advertise more than in children, so

 

      seeing a list of adverse events in children, maybe

 

                                                                96

 

      because I'm used to seeing it, without the context

 

      of knowing is this an excess risk?  Are children

 

      suffering an excess risk of X adverse event?  Or is

 

      this just the background that you see in the use of

 

      the drug?  That's one thing.  And I haven't seen

 

      that in previous presentations.

 

                And so I come out of the meetings, okay,

 

      yes, I saw several adverse events and some of them

 

      very horrible adverse events, but it doesn't give

 

      me a sense is this something that is a red flag in

 

      pediatrics that needs to be looked at more closely?

 

      That's probably why Dr. Santana asked for the adult

 

      data on SSRIs yesterday, and not so much to look at

 

      the adult data but is an excess risk there in

 

      children?

 

                And the other thing, in your last slide

 

      you said keep in mind the off-label use of

 

      fluticasone.  What exactly is it you want us to

 

      focus on when the presentations come so we're alert

 

      to that?

 

                DR. IYASU:  Are you talking about the

 

      question?

 

                                                                97

 

                DR. MALDONADO:  Pardon me?

 

                DR. IYASU:  Are you talking about the

 

      question?

 

                DR. MALDONADO:  Yes, the last slide.  I

 

      just don't know what you want us to focus on.

 

                DR. IYASU:  I think the focus would be for

 

      you to consider the presentations regarding these

 

      drug products, and there will be a series of them,

 

      and then to get your input as to whether there is

 

      any additional labeling concern or information that

 

      you would like to include in the label, concern

 

      about the drugs as--the use of the drugs as labeled

 

      currently.  So there is a concern about that.  Of

 

      course, you have the label that is included.  So

 

      it's as labeled now, they have been used in

 

      different ways, and is there any concern regarding

 

      that.

 

                DR. MURPHY:  Sam, they're going to present

 

      what they think the adverse event, if you will, is,

 

      what they've done to deal with it, what's in the

 

      label now, and does the committee think that's

 

      adequate.  So it's really--you're right.  You don't

 

                                                                98

 

      have any information to answer that question.

 

      They're just trying to show you where they're going

 

      with the information they're going to present.

 

                DR. IYASU:  The context for that question

 

      will be clearer, I guess, once the presentations

 

      are done.  But to go back to your first question

 

      about the unexpected--or regarding whether adverse

 

      events are occurring in excess in pediatrics as

 

      opposed to adults, I think that's an important

 

      question, and we haven't really done this for the

 

      products.  We do a top-line review for the one-year

 

      period, and then most of the review has focused on

 

      whether the same adverse events have also been

 

      reported in adults.  And we do sort of that kind of

 

      comparison based on how frequently the adverse

 

      event terms, as we call them, are reported.

 

                When there is an issue that may be

 

      considered to be critical, then we would like to do

 

      sort of additional cultivations trying to see what

 

      the background rates are, and then also look at

 

      what the reporting rates are.  We haven't done that

 

      except, I guess, for SSRIs.  But for other

 

                                                                99

 

      products, that's something that can be done, but,

 

      you know, you must know that there are a lot of

 

      caveats in trying to come up with a reporting rate

 

      or relative reporting rate for these drug products.

 

      But when there is a need to do that, we will

 

      actually do that.

 

                DR. CHESNEY:  Dr. Nelson has a question

 

      for you.

 

                DR. NELSON:  Actually, just a comment on

 

      that.  Knowing the deficiencies of the system for

 

      being able to get the denominator, it's not clear

 

      to me that we necessarily need to look at the ADER

 

      system in adults and compare them, and you're sort

 

      of comparing information where you don't know the

 

      denominator in either case.

 

                If you're comparing it to the data that

 

      obtain in clinical trials and look beyond just the

 

      pediatric data in clinical trials to the adult data

 

      in clinical trials and look at it in that context

 

      and see if there's anything, it's different as a

 

      signal for adults, probably that would be useful

 

      data because then you can actually establish

 

                                                               100

 

      frequency for adults because we have a hard time

 

      establishing frequency in pediatrics using this

 

      data, which is the main problem with it.

 

                So I wouldn't encourage you to try and do

 

      the thing that we can't do in kids in adults, too,

 

      but if the comparison is made with clinical trials

 

      where you can have that denominator, then that

 

      might--then I think that would probably be useful

 

      information.

 

                DR. MALDONADO:  I was referring actually--I've

 

      seen some drugs presented that I'm very

 

      familiar with, and what I've seen here presented,

 

      it's not very dissimilar to what I see outside this

 

      room, meaning that the same adverse events actually

 

      in absolute numbers, much larger in adults.  So my

 

      question when I see those presentations here, is

 

      this a signal in pediatrics?  Should it be worried

 

      to--and I'm not saying that we should look at the

 

      data.  I mean, I think they do a good, a much

 

      better job looking at the data.  That's what they

 

      do for life.  But it's to identify for us excess

 

      risks, because those are the ones that you really

 

                                                               101

 

      have--and I know it's difficult.  I know it's

 

      difficult.  But just looking at that list without

 

      the context, it leaves me like, yes, I'm not

 

      surprised that this is happening, this is happening

 

      in adults 10 times more or 20 times more.

 

                DR. IYASU:  I think you make an important

 

      point there, and we just have to live with the

 

      limitations of the data.  What we can do, when it's

 

      an important issue, serious adverse event, we can

 

      go out on a limb and go to other databases like

 

      Claims database, which has its own set of

 

      limitations and caveats.  So there are many avenues

 

      that you can go, but reporting rates or relative

 

      reporting rates are the best that we can do with

 

      this limited data set.  We have refrained from

 

      doing that because of the limitations in terms of

 

      defining the actual numerator that you use, and

 

      also the denominator, especially for pediatric.  So

 

      we may--we're concerned about sending the wrong

 

      signal as to the relative safety of certain drugs

 

      if we don't have--if we're dealing with uncertain

 

      denominators and uncertain numerators.  So that's

 

                                                               102

 

      where, I think, the problem is in trying to assess

 

      it.

 

                So what we've done is if there is really

 

      an issue, then our best resource is really the

 

      clinical trial data.  And what we've done is the

 

      initial sets of presentations that we've done for

 

      adverse events for these drugs did not include a

 

      review of what was actually in the clinical trials

 

      done for exclusivity.  Now all our reviews include

 

      summaries of the exclusivity trials and what kind

 

      of safety signal this might have resulted that may

 

      be similar or been supported by the adverse event

 

      reports.

 

                So we're trying to strike a balance here

 

      and trying to give you the best information that we

 

      have with all the limitations for interpretation.

 

      So I can't say anything more than that.  If there

 

      are other suggestions from the committee, we'll be

 

      very glad to consider them to improve the system.

 

                Thank you.

 

                DR. CHESNEY:  I think it also doesn't

 

      address the issue of the drugs that didn't go

 

                                                               103

 

      through exclusivity.  But I think in your spare

 

      time, if you could develop a national database that

 

      would capture this inform for us.

 

                [Laughter.]

 

                DR. CHESNEY:  Dr. O'Fallon?

 

                DR. O'FALLON:  This brings us back to the

 

      problem--clinical trials provides the very best

 

      data we have, no question about it.  You know, I'm

 

      a lover of clinical trials.  But there's all those

 

      comorbidities that are excluded that are

 

      encountered, and a good chunk of the patient

 

      population are excluded often from these clinical

 

      trials.  And so the question is:  If there are a

 

      lot of adverse events being encountered by kids

 

      being treated with these things but they're not in

 

      clinical trials because they keep getting ruled out

 

      due to the exclusion criteria, does the adverse

 

      events--the MedWatch, does that capture those?  If

 

      the parents are screaming, do those--like those

 

      people that were the public presenters on Monday,

 

      are their cases ending up in MedWatch?

 

                DR. IYASU:  Well, consumers also, you

 

                                                               104

 

      know, send their reports through the MedWatch

 

      program.  Health professionals do.  But as I said

 

      before, 80 percent--or more than 80 percent or 90

 

      percent of the reports are actually from

 

      manufacturers.  Some of them may actually have been

 

      reported directly to manufacturers from health

 

      professionals, and then they are transferred to us.

 

                The extent of the reports of adverse

 

      events or experiences of adverse events by patients

 

      directly is variable.  It's small, actually.

 

      Probably it's very underreported.

 

                DR. O'FALLON:  Yes.

 

                DR. IYASU:  So we really don't have a way

 

      of capturing that through a passive system such as

 

      AERS, unless you go and do an active surveillance

 

      system, which is a resource issue.

 

                DR. O'FALLON:  Yes.

 

                DR. CHESNEY:  I think unless there are any

 

      other pressing questions--we're about a half-hour

 

      behind, so maybe we need to move ahead.  Dr. Iyasu

 

      is going to introduce our next speaker.

 

                DR. IYASU:  Thank you.  Our first speaker

 

                                                               105

 

      for this section of adverse events is Dr. Hari

 

      Sachs.  Hari is a professor of pediatrics with over

 

      15 years of experience in private practice.  She

 

      also served on the FDA Non-Prescription Drug

 

      Advisory Committee and is one of the FDA liaisons

 

      to the American Academy of Pediatrics Committee on

 

      Drugs.  She will be presenting the adverse events

 

      for ofloxacin and alendronate.

 

                Dr. Sachs?

 

        x                   DR. SACHS:  Thanks again for that kind

 

      introduction.  Forgive me, I'm a little

 

      mechanically challenged, so if I screw up this

 

      presentation, at least the mechanics of it, bear

 

      with me.

 

                I'll be discussing the adverse events for

 

      ofloxacin, trade name Ocuflox, which is an

 

      ophthalmic anti-infective that was approved in July

 

      1993 for the treatment of conjunctivitis and

 

      corneal ulcers due to susceptible bacteria in both

 

      children and adults over one year of age.

 

      Depending on the condition, one to two drops of

 

      ofloxacin applied to the eye at frequent intervals.

 

                                                               106

 

      The exclusivity was granted in March 2003 based on

 

      studies of neonatal conjunctivitis, although

 

      ofloxacin is not approved for that purpose.

 

                As you can see from these statistics,

 

      millions of prescriptions for ofloxacin were

 

      written for both adults and children during the

 

      one-year exclusivity period.  Pediatric patients

 

      accounted for almost one-third of these

 

      prescriptions.  And, in fact, pediatricians

 

      prescribe almost as much ofloxacin as

 

      ophthalmologists, and not surprisingly, the most

 

      common indication is conjunctivitis.

 

                Now I'll look briefly at the studies

 

      performed for exclusivity, and as you can see, they

 

      are posted on the Web.

 

                The pivotal study was a one-week, active

 

      control trial which compared ofloxacin and

 

      trimethoprim sulfate treatment of conjunctivitis in

 

      infants less than one month of age.  The clinical

 

      cure was based both on resolution of discharge and

 

      erythema by  (?)  lamp exam and microbiology cure.

 

      The safety of ofloxacin is comparable to that which

 

                                                               107

 

      is seen in older patients in previous trials.  But

 

      although the clinical cure rate for ofloxacin

 

      exceeded the active control, neither of the two

 

      drugs exceeded the historical control, and,

 

      therefore, the study was--it was deemed that this

 

      was not an approvable indication.

 

                Note that the vehicle that's used that's

 

      the historical control does contain benzyl

 

      chromium, which has antibacterial properties.

 

                The submitted data from this trial doesn't

 

      really allow us to figure out why the cure rate was

 

      low, why this study didn't seem to work.  But

 

      potentially there are factors related to the design

 

      or conduct of the trial, the bacteriology of

 

      neonatal conjunctivitis, or perhaps the time course

 

      of it, or maybe a combination of all these factors.

 

                In discussing the relevant safety

 

      labeling, I'm going to highlight information that's

 

      either pertinent to pediatrics or the adverse

 

      events.  Ofloxacin is a Pregnancy Category C drug

 

      since there are no studies in pregnant women and

 

      there are some effects on animals.  It is

 

                                                               108

 

      potentially excreted in breast milk.  Under the

 

      Pediatric Use section in precautions, there's a

 

      statement that although the oral form of ofloxacin

 

      has been associated with arthropathy in juvenile

 

      animals, there is not an association for the

 

      topical form.

 

                There is a warning about allergic

 

      reactions, including anaphylaxis, which details a

 

      case report of Stevens-Johnson syndrome from the

 

      topical preparation.  Most adverse reactions to

 

      ofloxacin, however, are really mild and include

 

      ocular burning or discomfort and, very rarely,

 

      visual changes such as photophobia or blurriness or

 

      systemic symptoms may occur.

 

                Now that you're familiar with the label,

 

      let's look at the adverse events.  As you can see,

 

      there really are very few reported adverse events

 

      for ofloxacin in all ages.  And during the one-year

 

      post-exclusivity period, there were only three

 

      reports--or three events, actually, all unlabeled,

 

      two of which occurred in one adult and one that

 

      occurred in a pediatric patient.

 

                                                               109

 

                The pediatric event was a foreign report

 

      that is also found in the literature of corneal

 

      deposits in a 6-year-old who was receiving the

 

      ointment.  That's not available in the U.S.  And,

 

      in general, these types of corneal deposits

 

      actually resolved by themselves and are thought to

 

      be benign.  This patient was actually treated with

 

      scraping fairly early in the course.  The natural

 

      history actually is that it should have resolved.

 

                With such few events, we really can't draw

 

      a meaningful conclusion, and while this completes

 

      the one-year post-exclusivity adverse event

 

      monitoring, as mandated, we will continue our

 

      routine monitoring of adverse events for this drug.

 

                Are there any questions?

 

                DR. NELSON:  Just to repeat what I think

 

      I--you're unable to tell the ages of the pediatric

 

      use.  You can't tell how old the conjunctivitis

 

      prescriptions were?  In other words, is it being

 

      used on-label above one year of age, or is there

 

      any off-label use--

 

                DR. SACHS:  Most of the use was on-label. 

 

                                                               110

 

      There's one database that captured some of the use

 

      in kids under two, but it didn't separate out which

 

      were under one.  So it didn't help.  It is

 

      approximately 20 percent of the pediatric use for

 

      that, the lower age group.

 

                DR. CHESNEY:  Thank you very much.

 

        x                   DR. SACHS:  Switching gears from one

 

      system to another, I will now discuss the adverse

 

      events that occurred during the post exclusivity

 

      period for alendronate.

 

                Alendronate, or trade name Fosamax, is a

 

      biphosphonate which inhibits bone resorption by

 

      osteoclast, and it was originally approved in

 

      September 1995 for the treatment of osteoporosis in

 

      adult women.  Pediatric exclusivity was granted in

 

      April 2003 based on studies of children with

 

      osteogenesis imperfecta.

 

                Currently, alendronate is approved only in

 

      adults, and it's for the treatment of osteoporosis

 

      for both men and women, its prevention in women,

 

      and for Paget's disease.  The dosage varies from

 

      indication, and there are really no pediatric

 

                                                               111

 

      indications.

 

                As you can see from these numbers,

 

      although Fosamax is widely prescribed in the U.S.

 

      for adults, and the use is increasing, the use in

 

      pediatrics is really minimal.  There's like 10,000

 

      prescriptions in pediatrics compared to 22 million

 

      for adults.  Alendronate is primarily used in the

 

      outpatient setting with the lion's share of

 

      prescriptions from internists, OB-GYNs, and family

 

      practitioners.  Pediatricians write very few of

 

      these.

 

                Osteoporosis and osteopenia were the

 

      primary indications for therapy in adults, but in

 

      pediatrics alendronate is used off-label for

 

      treatment of osteoporosis and osteopenia either due

 

      to underlying disease, such as renal or connective

 

      tissue disease, or for its therapy, glucocorticoid

 

      therapy, for example,, fibrous dysplasia, and as

 

      you will see, osteogenesis imperfecta.

 

                I'll briefly discuss the results of the

 

      studies that were performed for exclusivity.

 

                Both pharmacokinetic and safety and

 

                                                               112

 

      efficacy and safety studies were performed to

 

      evaluate the treatment of severe osteogenesis

 

      imperfects, or OI, in pediatric patients ages 4 to

 

      18.  The PK studies found that the oral

 

      bioavailability of alendronate relative to the IV

 

      dose was really similar in both children and

 

      adults.  Exclusivity was granted based on

 

      submission of the 12-month analysis of this trial

 

      in pediatric patients with OI, and both doses that

 

      were used in the trial did significantly increase

 

      lumbar spine bone marrow density, which was the

 

      primary endpoint.  But, unfortunately, a key

 

      secondary endpoint was not reached, and that was

 

      actually the occurrence of fractures either by

 

      report or by x-ray.

 

                The adverse events in the one-year

 

      analysis appear comparable to those seen in adults,

 

      and it's hopeful that this trial--there's going to

 

      be more data coming in on a one-year extension of

 

      this trial.

 

                Once again, I'd like to highlight the

 

      relevant safety labeling for pediatric patients. 

 

                                                               113

 

      Alendronate is considered a Pregnancy Category C

 

      drug, with animal studies that have shown maternal

 

      hypocalcemia that sometimes leads to early

 

      delivery, and although there's no human data,

 

      theoretically there can be an effect on the fetal

 

      skeleton.

 

                Due to significant gastrointestinal

 

      irritation, alendronate is contraindicated in

 

      patients who have a risk of esophageal emptying--excuse me,

 

      have a delay in esophageal emptying or

 

      risk of aspiration or cannot stand upright.  And

 

      patients with hypocalcemia or allergy are told not

 

      to take the drug.  Esophageal perforation,

 

      including ulcerations or erosions, are also

 

      described in the warning section of the label.

 

                Precautions include the recommendation to

 

      monitor calcium and vitamin D status.  And

 

      gastrointestinal symptoms, such as abdominal pain

 

      or nausea, musculoskeletal pain, headache,

 

      dizziness, and taste perversion are the more common

 

      side effects that are seen.

 

                Now, since alendronate approval,

 

                                                               114

 

      paralleling the relatively small percent of

 

      pediatric use, pediatric adverse events really

 

      represent only a very small percent of adverse

 

      events.  There were 17 total reports for pediatrics

 

      out of 18,000 total reports.  And this is kind of

 

      indicated in the post exclusivity period as well,

 

      with only four pediatric case reports that were

 

      unduplicated.  And there were no deaths.

 

                The four reports include two cases of

 

      hepatocellular injury, one patient that suffered a

 

      drug-drug interaction potentially, and one infant

 

      that had hypocalcemia and prematurity.

 

                Hepatotoxicity was noted in two children

 

      that were treated for steroid-induced osteoporosis,

 

      and the details of their cases are reported on this

 

      slide.  But, briefly, liver dysfunction was

 

      temporarily associated with the onset of

 

      alendronate therapy and resolved after its

 

      discontinuation and treatment with pulse steroids

 

      in both patients.  One patient did have underlying

 

      liver dysfunction, and the other patient was on

 

      methotrexate.

 

                                                               115

 

                The drug interaction occurred in a 7-year-old with

 

      JRA who was taking cyclosporine, and after

 

      starting alendronate, the cyclosporine levels

 

      decreased, and his disease flared.  Once the

 

      alendronate was stopped, the cyclosporine levels

 

      returned to normal.  There was some fluctuation in

 

      baseline levels, so the exact interaction is

 

      unclear--I mean baseline levels of the

 

      cyclosporine, that is, before the alendronate was

 

      started.

 

                The last case was the prenatal exposure

 

      which describes hypocalcemia, hypocortisolism, and

 

      prematurity in a male infant that was born to a

 

      woman with multiple medical problems, including

 

      gestational diabetes, and who was on multiple

 

      medicines.  Hypocalcemia is known to occur in

 

      premature infants, infants of diabetic mothers, and

 

      several of these therapies, as well as potentially

 

      with alendronate.

 

                So, in conclusion, only a handful of

 

      adverse events were noted.  Most did have

 

      confounders or insufficient information to ascribe

 

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      causality.  We did look at a preliminary analysis

 

      of the adult hepatic events, and that does not seem

 

      to raise any concerns.  And this will complete the

 

      mandated reporting for alendronate from BPCA, but

 

      we will continue its routine monitoring.

 

                Are there any questions?

 

                DR. CHESNEY:  Dr. Maldonado, and then Dr.

 

      Nelson.

 

                DR. MALDONADO:  I observed that in the

 

      ofloxacin you had only one adverse event, and it

 

      was a different drug product, it was not the same

 

      drug product in the United States?

 

                DR. SACHS:  Right.  Well, it's the

 

      ointment form as opposed to we just have drops.

 

                DR. MALDONADO:  So it's a different drug

 

      product.

 

                DR. SACHS:  Correct.

 

                DR. MALDONADO:  And in Fosamax, also the

 

      four reports were ex-U.S.

 

                DR. SACHS:  That's correct.  They were

 

      foreign reports.

 

                DR. MALDONADO:  Do you know if it's the

 

                                                               117

 

      same drug product, or is there a possibility that

 

      it is a different drug product?

 

                DR. SACHS:  I believe that it's the same

 

      drug product.

 

                DR. MALDONADO:  And the reason I ask, for

 

      those who are not familiar, you see internationally

 

      the same names, and sometimes they are different

 

      products actually, because the FDA approves drug

 

      products, not drugs or--and sometimes there are

 

      different components in the drug product.  So when

 

      you include them, actually that's good that you

 

      highlighted that, because that may be relevant to

 

      the adverse events.

 

                DR. CHESNEY:  Dr. Nelson?

 

                DR. NELSON:  Just a question about

 

      labeling, but not in the safety and efficacy

 

      component.  I don't understand, if, in fact,

 

      there's been a pharmacokinetic study, why we would

 

      say that the pharmacokinetics have not been

 

      investigated in patients less than 18 years of age.

 

      I mean, that's what the label says.  Wouldn't we

 

      normally include some pharmacokinetic data even if

 

                                                               118

 

      we don't think safety and efficacy has been

 

      established?

 

                DR. MURPHY:  No.

 

                DR. NELSON:  Why?

 

                DR. MURPHY:  Because you're giving it an

 

      implied approval.  You're giving the dosing.  Now,

 

      if the--not always.

 

                DR. NELSON:  Well, we can--

 

                DR. MURPHY:  Let me--you know, that's a

 

      whole big discussion, and you heard we have this

 

      tension between trying to inform and not providing

 

      a marketing freebie at the same time.  So if that

 

      pharmacokinetic study was done and found that there

 

      was, you know, something very different going on or

 

      some concern, then we could say on a dosing--I'm

 

      talking about past.  I'm talking about prior

 

      practice, okay?  So whether that's all going to

 

      change--you know, it's good to provide you feedback

 

      on this.  I just wanted to say that in the past one

 

      of the concerns that has been expressed has been

 

      any information you put in the label about

 

      pediatrics--I'm just starting from the big global

 

                                                               119

 

      concern--depending on what it is, if it's not a

 

      safety, you know, warning, in essence provides a de

 

      facto approval and/or an ability of the company to

 

      market it.

 

                As an example, they could go out and say,

 

      well, look, FDA put this information in the label

 

      about how to use it in kids.  So there is that

 

      balance of trying to make sure that it's clear if

 

      we put information in, in what context that

 

      information is put in the label.

 

                Now, I mean, please proceed to say you

 

      think we should have put it in the label; we're

 

      interested in hearing that sort of stuff.  But I'm

 

      just trying to provide why we routinely wouldn't

 

      put information that we obtain into the label.

 

                DR. NELSON:  Just a quick response.  I was

 

      heartened to hear from Bob Temple yesterday that

 

      that position was being readdressed.  I previously,

 

      until your comment, wouldn't have applied it to

 

      just basically the pharmacokinetic information.

 

      But I'll also point out that most people, myself

 

      included, get my information from personal device-based

 

                                                               120

 

      systems, which do include dosing data.  And,

 

      in fact, one of those two systems I have on my Palm

 

      actually included depression as an indication for

 

      an unlabeled use.

 

                So I appreciate the concern about

 

      encouraging it, but I actually think adding more

 

      information might, in fact, discourage it if there

 

      was an emphasis of making sure that information

 

      was, in fact, accurate and then transmitted

 

      accurately to clinicians.  I know that's a whole

 

      broader discussion, but--

 

                DR. MURPHY:  I think we need to hear that.

 

      I mean, that's what this committee is here for.

 

      You're looking at the pediatric perspective on

 

      this, and there has always been this tension.  And

 

      I think I've told this committee before, there are

 

      those of us who think we are mandated in some ways

 

      to put some of this information in the label.

 

      There have been others in the agency who have been

 

      very concerned about doing that.

 

                I think what you heard yesterday was a

 

      very different approach that's being considered. 

 

                                                               121

 

      So we do want to hear these comments.

 

                DR. CHESNEY:  Dr. Maldonado, then Dr.

 

      Fant.

 

                DR. MALDONADO:  I'm just going to give you

 

      a perspective, and Dr. Murphy is right, people may

 

      misuse the information.  I'm not saying that that

 

      wouldn't happen.  But, for example, the drugs that

 

      are being used off-label--and we know--and I'll

 

      just give you the perspective of one that I'm

 

      working--it's a company, and we rarely have the PK

 

      data.  And we now found out, although we believe

 

      that the dose being used off-label was the correct

 

      dose, and that's the dose that we use in the PK, we

 

      found out that that's incorrect, that children are

 

      being underdosed.  This is an antimicrobial.

 

                The clinical studies are ongoing, and they

 

      may be ready in five years, by the way, because of

 

      the long-term follow-up that we need to do.  In the

 

      meantime, people are using off-label this drug

 

      incorrectly.  And you're in the bind that you

 

      cannot communicate that because it may be perceived

 

      as, you know, promotion.  But you want to

 

                                                               122

 

      communicate it.  It's difficult.  I know exactly

 

      the concern that the FDA has because it can be

 

      misused.  But at the same time, not conveying it,

 

      it allows people to continue using the drug

 

      incorrectly.

 

                DR. NELSON:  Can't your solution be--I

 

      assume there's some academic investigators

 

      potentially involved at study sites, letting them

 

      release at least the PK data in a publication?  Or

 

      does that also violate--I mean, here it sounds like

 

      you might even have a moral obligation to put out

 

      that data.

 

                DR. NELSON:  Yes, the data has actually

 

      been published in a poster format so people who are

 

      more sophisticated in the area of infectious

 

      diseases already know that that's incorrect.  And

 

      that's as far as we've gone.

 

                DR. MURPHY:  But I think that this is a

 

      perfect example of the quandary, because as all of

 

      you know--and you heard yesterday--we have a

 

      history of putting things in the label that nobody

 

      ever finds anything about the information.  I mean,

 

                                                               123

 

      that's just the way life is.  And with our health

 

      care system the way it is right now, it's actually

 

      getting worse, one could say, I think, as far as

 

      physicians having time to access some of this

 

      information in a timely manner.

 

                But I would say, you know, if I were in

 

      the Anti-Infectives Division and the company came

 

      to me and said, oh, we've got this information, we

 

      want you to put it in the label, but we're not

 

      ready to submit our application yet to show you

 

      whether it's safe or efficacious, you can see what

 

      the problem is.

 

                DR. CHESNEY:  Dr. Fant?

 

                DR. FANT:  One small point for completeness

 

      related to the case of neonatal hypocalcemia.

 

      You highlighted with an asterisk the drugs known to

 

      be associated with hypocalcemia, but it may be

 

      worth also putting an asterisk and highlighting the

 

      condition of diabetes itself in addition to the

 

      prematurity.

 

                DR. SACHS:  Yes, I mentioned that.

 

                DR. FANT:  Oh, okay.

 

                                                               124

 

                DR. SACHS:  I just put the medications,

 

      but yes, oh, yes.

 

                Behind these presentations, actually, are

 

      a group of folks at ODS and in the divisions that

 

      contributed to the report, and I just want to kind

 

      of publicly acknowledge them as well:  Jennie

 

      Change, Renan Bonnel, Mark Avigan, Wiley Chambers,

 

      Gianna Rigoni, Judy Shaffer, and Michael Evans.  So

 

      there's actually a lot of people that go into these

 

      presentations that you don't see.

 

                I would now like to introduce Dr. Susan

 

      McCune, who is a neonatologist, whose previous

 

      experience has included academic neonatal practice

 

      at Johns Hopkins and Children's National Medical

 

      Center.  She recently received her master's degree

 

      in education and has worked on computer-based

 

      educational models for pediatrics.  She will be

 

      presenting the adverse events for fludarabine.

 

                On a personal note, it's a pleasure for me

 

      to be working with her again because she was, I

 

      think, my chief resident when I was a resident at

 

      Children's.  Things go full circle.

 

                                                               125

 

        x                   DR. McCUNE:  Thank you, Hari.

 

                It was an honor to work with Hari as a

 

      resident, and it's an honor and a privilege 20

 

      years later to work with her again at the FDA.

 

                As Dr. Sachs said, I'm going to discuss

 

      the one-year post-exclusivity report for the

 

      adverse events for fludarabine.

 

                In terms of background information,

 

      fludarabine, or trade name Fludara, is a synthetic

 

      adenine nucleoside analog that primarily acts

 

      through inhibition of DNA synthesis.  It is

 

      produced by Berlex Laboratories.  Its indication in

 

      adults is for the treatment of adult patients with

 

      unresponsive B-cell chronic lymphocytic leukemia.

 

      Of note, there are no pediatric indications that

 

      are approved for this drug.  The original marketing

 

      approval date was April 18, 1991, and pediatric

 

      exclusivity was granted on April 3, 2003.

 

                I want to stop for a moment and talk to

 

      you a little bit about the background of oncology

 

      and pediatric drugs at the FDA, and I think this

 

      gets a little bit to some of the questions that

 

                                                               126

 

      you've been asking about because oncology drugs are

 

      a little bit different from some of the other

 

      drugs.

 

                There has been a special initiative at the

 

      FDA to increase pediatric drug labeling for

 

      oncology drugs and to prioritize the availability

 

      of new oncologic agents to pediatric patients.  To

 

      achieve this goal, three items that I'd like to

 

      point out for your attention:

 

                The first is the draft guidance for

 

      industry that's entitled "Pediatric Oncology

 

      Studies in Response to a Written Request" that was

 

      published in June of 2000.  The guidance is part of

 

      this initiative to generate new knowledge to assist

 

      practitioners and to provide early access to

 

      emerging new drugs.

 

                In addition, the Best Pharmaceuticals for

 

      Children Act that was signed into law on January 4,

 

      2002, established the Pediatric Subcommittee of the

 

      Oncologic Drugs Advisory Committee and prioritized

 

      new and emerging therapeutic alternatives that

 

      could be available to treat pediatric patients with

 

                                                               127

 

      cancer.

 

                Another report entitled "Patient Access to

 

      New Therapeutic Agents for Pediatric Cancer," which

 

      was published in December 2003 and was a report to

 

      Congress, was a report that identified areas in