FOOD AND DRUG ADMINISTRATION



































                     Wednesday, September 15, 2004


                               8:10 a.m.




                          ACS Conference Room

                               Room 1066

                           5630 Fishers Lane

                          Rockville, Maryland



                        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.



                            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


       - 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



                      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




                         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




      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




                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




      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




                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.




      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.




                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




      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




      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




      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




      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.




                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




      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




                DR. CHESNEY:  And my name is Joan Chesney.


      I'm a professor of pediatrics at the University of




      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




      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.




                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




      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




      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






                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.




                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




                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




                So once the IRB makes the determination




      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




                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




      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




      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




                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




      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




      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




                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.




                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




      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.




                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




      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




      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




                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




      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




      parents.  Part of that discussion was based on it


      not being done in that kind of a therapeutic




                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




      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




      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




      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




      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




      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




                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




      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,"




      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




      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,




      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




      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




      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




      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




                DR. NELSON:  Right.


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


      question or just a recommendation, I guess is what




                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.




                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




                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






                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




                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




      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




                Looking on page 7, comparing Parts a) and




      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




      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




      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




      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




      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




                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.




                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.




                Any other questions or comments?  Dr.




                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




                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






                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




      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,




      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




                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




      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




      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




      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




                DR. O'FALLON:  But the question is they


      are enclosed, so there is the issue of




                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.




                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




                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




      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




                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.




                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?




                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




                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




      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




      want to consider for the future.




                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




      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




      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




      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




      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.




                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




      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




      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




      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




      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




                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




      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




      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




                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




      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




      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.




      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




      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




                Another source for outpatient drug use is




      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




                Premier is another database which comes


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


      hospitals.  The projection methodology is




      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




      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




      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




      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




                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




      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




                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




      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




                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




                So I would say that the AERS system cannot




      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




      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




      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.




                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




                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




      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




                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




      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




                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






                DR. MALDONADO:  Pardon me?


                DR. IYASU:  Are you talking about the




                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




                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




      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




      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




      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




                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




      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




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




                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




                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




      through exclusivity.  But I think in your spare


      time, if you could develop a national database that


      would capture this inform for us.




                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




      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




      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.




      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




      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




      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.




                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. 




      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






                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




                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




      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. 




      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




                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,




      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






                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




                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




      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.




                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




                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




      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




      we don't think safety and efficacy has been




                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




      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




      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. 




      So we do want to hear these comments.


                DR. CHESNEY:  Dr. Maldonado, then Dr.




                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




      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




                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,




      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




                DR. SACHS:  Yes, I mentioned that.


                DR. FANT:  Oh, okay.




                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.




        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




      you've been asking about because oncology drugs are


      a little bit different from some of the other




                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






                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