1


                 DEPARTMENT OF HEALTH AND HUMAN SERVICES

                    SECRETARY'S ADVISORY COMMITTEE ON
                       HUMAN RESEARCH PROTECTIONS


                                 MEETING

                                 MONDAY
                            JANUARY 31, 2005

                      The Advisory Committee met in the
          Jefferson Ballroom in the Radisson Hotel Old Town

          Alexandria, 901 North Fairfax Street, Alexandria,
          Virginia, at 8:30 a.m., Ernest Prentice, Ph.D.,
          Chairman, presiding.

          PRESENT:

          ERNEST D. PRENTICE, Ph.D.         Chair

          BERNARD A. SCHWETZ, D.V.M.,Ph.D.  Executive Secretary
          CATHERINE SLATINSHEK, M.A.        Executive Director
          MARK BARNES, J.D., L.L.M.         Member
          CELIA B. FISHER, Ph.D.            Member
          ROBERT G. HAUSER, M.D.,F.A.C.C.   Member
          NANCY L. JONES, Ph.D.             Member
          FELIX A. KHIN-MUANG-GYI,Pharm.D.  Member
          SUSAN KORNETSKY, M.P.H.           Member

          MARY L. POLAN,M.D.,Ph.D.,M.P.H.   Member
          ADA SUE SELWITZ, M.A.             Member
          SUSAN L. WEINER, Ph.D.            Member

          Ex Officio Members
          PEG BARRATT, Ph.D.                National Science
                                            Foundation

          HOWARD L. BRADLEY                 Social Security
                                            Administration
          SARAH CARR (for Amy Patterson)    National Institutes 
                                            of Health
          KATHRYN LYNN CATES, M.D.          U.S. Department of
                                            Veterans Affairs
          ROGER CORTESI                     U.S. Environmental

                                            Protection Agency






                                                                          2


          Ex Officio Members (continued)
          PATTY DECOT                       U.S. Department of
                                            Defense
          HELENE DERAMOND                   U.S. Department of
                                            Education

          SALLY FLANZER, Ph.D.              Agency for
                                            Healthcare Research
                                            and Quality
          SUZANNE GAYNOR, DrPH,RN,MBA       U.S. Department of
                                            Housing and Urban
                                            Development



          ALSO PRESENT
          KELLEY BOOHER, Office of Human Research Protections
          MICHAEL CAROME, Office of Human Research Protections
          JULIE KANESHIRO, Office of Human Research Protections
          LAURA ODWAZNY, Office of General Counsel
          IVOR PRITCHARD, Office of Human Research Protections

          IRENE STITH-COLEMAN, Office of Human Research
                Protections






                                                                          3


                                I N D E X

                                                          Page

          Welcome, Opening Remarks                           4

          Ernest Prentice, Ph.D., Chairman

          Report of Issues                                   5
          Bernard Schwetz, D.V.M.,Ph.D. Director, OHRP

          Overview of Charges to Subcommittees              12
          Approval of Minutes

          Ernest Prentice, Ph.D., Chairman

          Public Comment                                    16

          Report of Subcommittee on Research Involving      17
          Children
          Celia Fisher, Ph.D., Co-Chair

          Susan Kornetsky, M.P.H., Co-Chair

          Public Comment                                   156

          Report of Subpart C Subcommittee on Research     162
          Involving Prisoners
          Mark Barnes, J.D., LL.M., Co-Chair
          Nancy Dubler, LL.B., Co-Chair


          Public Comment                                   307

          Report on Subpart C Subcommittee on Research     317
          Involving Prisoners (continued)

          Discussion of committee business/adjourn         355






                                                                          4


                          P R O C E E D I N G S
              1

                                              Time:  8:36 a.m.
              2

                      CHAIRMAN PRENTICE:  Good morning,
              3


          everybody.  Let's get started.  We are running a
              4

          little bit late.  I would like to welcome you all to
              5

          the January 2005 SACHRP meeting.  My name is Ernie
              6


          Prentice.  I am Chair of SACHRP.  
              7

                      I am going to go through the normal agenda
              8

          by reminding everyone of our charter.  This is the
              9

          charter of SACHRP set forth by former Secretary of
             10


          HHS, Tommy Thompson and, as you can see, we have
             11

          focused our efforts on protection of vulnerable
             12

          subject populations, and indeed, as we progress
             13

          through the day, you will see that that is what we
             14


          have been doing primarily during the last year and a
             15

          half.
             16

                      These are the members of SACHRP, and I
             17


          would like to welcome our newest member, Ada Sue
             18

          Selwitz.  Welcome, Ada Sue, the young lady there in
             19

          the red from Kentucky, and you will have no doubt
             20

          where she comes from when she talks.  
             21


                      I also want to recognize the efforts of
             22






                                                                          5


          Cathy Slatinshek, the Executive Director of SACHRP,
              1

          and Kelley Booher, the Program Analyst.  They make
              2

          everything run smoothly.  They take care of all of
              3


          your travel, all of your reimbursement, setting up the
              4

          meeting.  So we really owe them a debt of gratitude,
              5

          because they make life so easy for all of us.  so
              6


          thanks very much, Cathy and Kelley.
              7

                      I also want to remind everybody about the
              8

          working relationship that we have with Dr. Schwetz and
              9

          the OHRP staff.  SACHRP works very closely with OHRP
             10


          staff.  As a matter of fact, all of our subcommittees
             11

          have designated OHRP staff assigned as liaisons to
             12

          provide expert advice.  So that is a very, very
             13

          constructive working relationship.
             14


                      I want to thank the participation of ex
             15

          officio members of SACHRP.  This is the list of all of
             16

          the individuals who are designated as ex officio
             17


          members.  Thanks for all of their efforts.
             18

                      Next I would like to ask Dr. Schwetz to
             19

          give us a report on issues and, Bern, I assume you
             20

          will do it form there.
             21


                      DR. SCHWETZ:  Yes, I will, if that's okay,
             22






                                                                          6


          Ernie.  Thank you, and good morning to all of you.
              1

                      I have a list of things that are
              2

          unrelated.  So don't expect a theme here.  It's just
              3


          a series of things not even in order of priority
              4

          necessarily.
              5

                      As of January 19, OMB approved the revised
              6


          FWA forms.  After a long incubation period to get to
              7

          that stage, it is now approved.  That will result in
              8

          substantive revisions to the forms, and there will be
              9

          instructions coming out for guidance to all of you on
             10


          the fact that this is now somewhat changed.
             11

                      All of the revised documents and the other
             12

          information will be posted on our website by the end
             13

          of this week.  So you can certainly ask questions of
             14


          us, but you can go to our website for additional
             15

          information as well.
             16

                      What it means is that OHRP will only
             17


          approve Federal-wide assurances in the future, not the
             18

          other forms of assurances that have been approved in
             19

          the past.  So single project assurances will remain in
             20

          effect to the end of the project for which they apply. 
             21


          So we are not asking people to change mid-stream. 
             22






                                                                          7


          Cooperative project assurances and multiple project
              1

          assurances must be replaced by an FWA by December 31,
              2

          '05.  So by the end of this year, you have to get
              3


          those changed.
              4

                      So the assurance options have been reduced
              5

          to three different agreements:  The FWA, the IRB
              6


          Independent Ethics Committee agreement, and the
              7

          Individual Investigator agreement.  I am not going to
              8

          go into more detail.  We have people here who, I am
              9

          sure, will be helpful to answer whatever questions you
             10


          might have.
             11

                      Parallel to that, the OHRP web-based
             12

          electronic system for FWAs and for IRB registration
             13

          has been enhanced, so that all of the FWA holders and
             14


          registered IRBs can submit updates and renewals
             15

          online.  So it makes it easier for us to access the
             16

          information, and it makes it a lot easier for you to
             17


          submit information as it relates to your FWA and your
             18

          IRB registration.
             19

                      In an earlier meeting, SACHRP recommended
             20

          that there would be an IRB workshop that OHRP and
             21


          others would be working on developing.  Just to update
             22






                                                                          8


          you, we have had input not only from the agencies that
              1

          were charged with coming up with this workshop but
              2

          significant help and input from SACHRP.
              3


                      We are in the process of putting together
              4

          the program for that workshop that is really going to
              5

          focus on why central IRBs are not being used to the
              6


          extent that we thought they could be, and I think in
              7

          a different way of putting it, to explore alternatives
              8

          to local IRBs and to not create this as it's either a
              9

          central IRB or a local, but to explore how we can use
             10


          alternatives to local IRBs more effectively.
             11

                      So we are in the process of looking for
             12

          outside partners to help put on such a workshop.
             13

                      The IOM Committee that has to do with
             14


          ethics research in prisoners:  They continue to make
             15

          progress.  We have talked to them.  They consulted
             16

          with us about people who might be on this committee. 
             17


          Obviously, it is their decision, not ours, and the 
             18

          IOM has now posted the proposed list of committee
             19

          members on their website.  That just happened at the
             20

          end of last week.
             21


                      They are looking for input in this 20-day
             22






                                                                          9


          period.  So if you want to find out who has been
              1

          proposed as members and chairs, I encourage you to go
              2

          to that website.
              3


                      A significant event that happened late
              4

          last year that -- It happened early in the year, but
              5

          it became real later in the year.  By virtue of
              6


          statute, the Department of Homeland Security now comes
              7

          under 45 CFR 46, and that is something that some of us
              8

          have been working on for the last couple of years to
              9

          figure out why that didn't happen.  Well, now it has.
             10


                      So that means they will have
             11

          representation in various committees that we meet with
             12

          to talk between government agencies.  Now I would
             13

          assume in time there will also be a place for an ex
             14


          officio spot here in these meetings where someone from
             15

          Homeland Security will be attending.
             16

                      Just to update you on where the two
             17


          letters are that have gone from SACHRP to the Office
             18

          of the Secretary.  They have now gone out of the
             19

          Office of the Secretary.  One went to the Office of
             20

          Civil Rights, and the other one came to us in OHRP and
             21


          FDA to deal with all of your recommendations, and
             22






                                                                         10


          progress is being made as we work on those.
              1

                      I would also come back to the issue of
              2

          international research.  You touched on it once, made
              3


          some observations.  Well, the Interagency Working
              4

          Group that is the Human Subjects Research Subcommittee
              5

          -- another group, not ex officios, but it includes
              6


          some of them -- We meet on a monthly basis to discuss
              7

          issues of common interest among the agencies.
              8

                      That group has now formed a working group
              9

          on the international research issues, to start out, as
             10


          it pertains to the Federal agencies:  How consistent
             11

          are we in how we manage our research that we support
             12

          that is conducted outside the U.S.?  What issues do we
             13

          have?  How do we solve them?  What problems do we
             14


          have?  So this working group, hopefully, will bring a
             15

          better understanding among the common rule agencies in
             16

          how we are managing the issues that surround
             17


          international research.
             18

                      Also, since we met last time, the
             19

          celebration that we held at the great hall downtown
             20

          here to celebrate the 25th anniversary of the Belmont
             21


          Report not only happened, but it happened, I think,
             22






                                                                         11


          with some considerable success.  We got a lot of
              1

          positive comments on that, not only from the people
              2

          who were up on the stage but from a lot of the people
              3


          who attended.  So thank all of you who helped to make
              4

          that a good celebration.
              5

                      The outreach pamphlet that we have created
              6


          to communicate with the public about what it means to
              7

          be a subject in research -- that has begun
              8

          distribution.  We have copies -- will have copies here
              9

          that you can pick up and use as you want to.  We
             10


          welcome input.
             11

                      We are at a stage now where now we are
             12

          pushing the subset of this that has to do with
             13

          reaching out to minorities.  So we are modifying this
             14


          first pamphlet that we have to be sensitive to not
             15

          only the language but other issues that have to do
             16

          with the populations that we are trying to reach with
             17


          this pamphlet to try to rebuild some trust among the
             18

          public and, in particular, to rebuild some trust among
             19

          minority groups to consider being participants in
             20

          research.
             21


                      The last thing I would have is that
             22






                                                                         12


          Secretary Thompson has left his office as Secretary of
              1

          DHHS.  Secretary Levitt is now in the office. 
              2

          Secretary Levitt, in preparation for his hearings, was
              3


          briefed on human subject protection issues and SACHRP
              4

          and the other components under the Common Rule.
              5

                      I am assuming that at some point in time,
              6


          and I hope it isn't because we have an emergency in
              7

          this field, that we will have the opportunity to
              8

          communicate with him more and brief him more about
              9

          human subject issues, rather than have an emergency
             10


          where we have to go in and brief him so he knows what
             11

          is going to be in the newspapers.
             12

                      So that's it for me, Ernie.  Thank you.
             13

                      CHAIRMAN PRENTICE:  Thank you, Bern.  I
             14


          want to provide an overview of the charges to the now
             15

          three SACHRP subcommittees, first the Subcommittee on
             16

          Research Involving Children.
             17


                      You already know, for those of you who
             18

          have attended previous SACHRP meetings, that we have
             19

          provided recommendations on the 407 review process to
             20

          the Secretary.  Those have been accepted by the
             21


          Secretary, and OHRP is in the process of implementing
             22






                                                                         13


          those recommendations.
              1

                      Now the Subcommittee on Research Involving
              2

          Children is concentrating on other aspects of Subpart
              3


          B, and you will find out more about that today, but
              4

          specifically the 406 category and the 405 category,
              5

          and this committee is under the co-chairmanship of
              6


          Celia Fisher and Susan Kornetsky.
              7

                      I really want to take this opportunity to
              8

          compliment the work of all of our subcommittees.  I
              9

          attend most of the meetings, and what you see is the
             10


          by-product of an awful lot of work on behalf of SACHRP
             11

          by these subcommittees.  So thanks very much for all
             12

          of your efforts.  
             13

                      The Subpart C Subcommittee is dealing with
             14


          additional protections for prisoners who are involved
             15

          in research, and they are under the Co-chairs Mark
             16

          Barnes and Nancy Dubler, and we are going to hear a
             17


          report from the Subpart C Subcommittee.
             18

                      Then our newest subcommittee is the
             19

          Subpart A Subcommittee which was designated by SACHRP
             20

          at the last meeting, and the charge of this particular
             21


          subcommittee is to review and assess virtually all
             22






                                                                         14


          provisions of the basic protections of human subjects
              1

          in 45 CFR 46, i.e., Subpart A, as well as any relevant
              2

          OHRP guidance, and then to provide recommendations for
              3


          consideration by SACHRP in order to achieve the goals
              4

          of enhancing protection of human subjects and reducing
              5

          regulatory burdens that do not contribute to the
              6


          protection of human subjects.
              7

                      OHRP is very concerned about regulatory
              8

          burdens, and we have seen a slow creep, I think, in
              9

          the IRB world of this excessive regulatory burdens
             10


          driven by a variety of different factors.  So we want
             11

          this subcommittee to take a look at all aspects of
             12

          Subpart A.
             13

                      The Co-Chairs are Felix Gyi and Dan
             14


          Nelson, and they will be giving us a report, not of
             15

          their activities but a report of planned activities
             16

          later on today, or maybe it is tomorrow.  Yes.
             17


                      Now this is the overview of the meeting
             18

          agenda.  We have already gone through the opening
             19

          remarks.  Dr. Schwetz has reported on the issues.  I
             20

          have given you the charges to the subcommittees.  
             21


                      I would like to now ask for a motion to
             22






                                                                         15


          approve the minutes from the October 4-5 meeting.
              1

                      MR. BARNES:  So move.
              2

                      CHAIRMAN PRENTICE:  Mark.  Second?
              3


                      DR. GYI:  Second.
              4

                      CHAIRMAN PRENTICE:  All right.  Multiple
              5

          seconds.  Any further discussion?  All those in favor? 
              6


          Any opposed?  Any abstentions?  Motion carries.  Thank
              7

          you very much.
              8

                      I am going to go through the next part of
              9

          the agenda before I come back to the public comment
             10


          section.  
             11

                      At roughly 9:30 or before, we will have
             12

          our report of the Subcommittee on Research Involving
             13

          Children delivered by Celia Fisher and Susan
             14


          Kornetsky.  We will then take a short break.  We will
             15

          come back for the report of the Subcommittee on
             16

          Research Involving Children again.  It will just
             17


          continue after the break.
             18

                      We will have a lunch between 12:00 and
             19

          1:00.  Then between 1:00 and 3:00, we will have the
             20

          report of the Subpart C Subcommittee delivered by Mark
             21


          Barnes.  Nancy Dubler, unfortunately, could not be
             22






                                                                         16


          here.  
              1

                      Now sometime in this period between 1:00
              2

          and 3:00, more than likely around 1:30, Dr. Christina
              3


          Beato, who is the Assistant Secretary of HHS, will be
              4

          coming to say a few remarks to you and perhaps stay
              5

          for about an hour.  So if you don't mind, Mark, your
              6


          presentation will be interrupted just for a little
              7

          while.  
              8

                      We will take a break between 3:00 and
              9

          3:15.  Then, Mark, you have an opportunity to continue
             10


          your report.  We will have another public comment
             11

          section, discussion of committee business, and then
             12

          right around five o'clock we are going to adjourn.
             13

                      Any questions about our agenda?  Okay.
             14


                      Now, we think it is very important to
             15

          provide an opportunity for the public to address
             16

          SACHRP.  Cathy, did we have anybody who actually
             17


          signed up to address the public?
             18

                      MS. SLATINSHEK:  No, not at this time.
             19

                      CHAIRMAN PRENTICE:  Okay.  Is there anyone
             20

          here who would like to address SACHRP?  All right. 
             21


          You will have another opportunity later on today. 
             22






                                                                         17


          Hearing none, we are running early.  That's good. 
              1

          That gives both of you more time, if you need it.
              2

                      So, Celia, I am going to ask you and Susan
              3


          to take over.
              4

                      DR. FISHER:  Okay.  So you can all hear
              5

          me?  All right.  Well, this is our fifth report, and
              6


          what we are going to do first -- I wanted to thank all
              7

          our fabulous members who worked very hard, along with
              8

          the SACHRP staff, OHRP, and others who come.  It's a
              9

          wonderful group.
             10


                      What we are going to do today is to remind
             11

          you that our meeting goals have been from the
             12

          beginning to work on the interpretation of Subpart D. 
             13

          At our last meeting we focused on 406, minor increase
             14


          over minimal risk, and then we moved on to 405, not
             15

          that we are finished, but we began to move on.
             16

                      So what I wanted to do was to remind you
             17


          of what we did last time and what we had done before,
             18

          and the way the subcommittee is viewing our work on
             19

          Subpart D is continuity between the 404 up through the
             20

          407, and that is one of the reasons I am reminding
             21


          you.
             22






                                                                         18


                      So just to remember that SACHRP made its
              1

          recommendations.  Our Chair sent them off to HHS with
              2

          respect to the 407 review, which is for research
              3


          otherwise not approvable by an IRB.  You will see that
              4

          that is always important in terms of the
              5

          subcommittee's consideration, that there is an
              6


          opportunity to approve research that is not under 404,
              7

          405, 406, in another type of venue.
              8

                      Then last time Susan and I presented the
              9

          recommendations on 404, which is minimal risk
             10


          research.  That is the result of around three meetings
             11

          that we worked on and had feedback from you, and I am
             12

          going to go through very quickly the 10 proposals that
             13

          SACHRP conditionally approved.
             14


                      We conditionally approved them -- SACHRP -
             15

          - because we realized that there is this ongoing
             16

          interplay between what happens in recommendations for
             17


          405 and 406.  
             18

                      So just to remind you of the minimal risk
             19

          definition:  Research not involving greater than
             20

          minimal risk.  The problem with minimal risk was what
             21


          is it?  How do you interpret?  There was a lot of
             22






                                                                         19


          different interpretations.
              1

                      The first proposal that we made after a
              2

          lot of dialogue among ourselves and among SACHRP, and
              3


          along the lines of NHRPAC's and IOM's recommendation
              4

          was to adopt a uniform standard for the definition of
              5

          minimal risk.
              6


                      What is important is that you will see
              7

          that for 406, which is a minor increase over minimal
              8

          risk, we are also going to recommend a uniform
              9

          standard.  So we are trying to look at that in terms
             10


          of the continuity of ethical justification and
             11

          rationale that has gone into this.
             12

                      The second proposal that was conditionally
             13

          adopted was, if you are saying there is a uniform
             14


          definition, what is the reference point?  The
             15

          reference point was normal average healthy children
             16

          living in safe environments.
             17


                      So for daily life and for routine medical
             18

          treatment and assessment, it was the healthy child. 
             19

          The reason here -- and as you will see, there is a
             20

          follow-through in our rationale for 406 -- the reason
             21


          being that children with disorders or conditions or
             22






                                                                         20


          who are vulnerable should not be exposed to greater
              1

          risk then by a researcher for a non-beneficial study
              2

          than other children.
              3


                      Proposal three was that minimal risk
              4

          should be age indexed, because obviously the lives of
              5

          normal healthy average children, the risks they
              6


          encounter are different, depending upon their age.
              7

                      We also underscored that this proposal
              8

          about minimal risk is the upper limit.  It does not
              9

          prevent IRBs from looking at a particular group of
             10


          children and saying that the type of conditions that
             11

          would be minimal risk for the average healthy child
             12

          is, in fact, of greater than minimal risk for the
             13

          particular sample population.
             14


                      We also recommended that, when we are
             15

          talking about the average healthy child living in safe
             16

          environments, their daily experiences, we are not
             17


          talking about the exact experience, but we are talking
             18

          about whatever experimental procedure is being used,
             19

          that it should be equivalent in terms of the magnitude
             20

          and probability of risk.  It doesn't have to be an
             21


          exact activity that children have engaged in in the
             22






                                                                         21


          past or are expected to.
              1

                      The equivalence criteria would be that, in
              2

          terms of evaluating whether or not the magnitude and
              3


          probability of risk is equivalent, the IRB would look
              4

          at the duration, the cumulative characteristics of the
              5

          procedure, and the reversibility of harm.
              6


                      In addition, we attempted to look at what
              7

          might be guidance with respect to what is a routine
              8

          medical examination or test.  There didn't seem to be
              9

          a routine out there.  However, we thought that one
             10


          reasonable basis was the well child visit, and we went
             11

          on to list the kind of activities that are typically
             12

          conducted during a well child visit as guides for IRB. 
             13

          Obviously, these would be age indexed.
             14


                      Then finally, the last proposal that was
             15

          conditionally approved was that the uniform standard
             16

          must apply internationally.  The rationale for that
             17


          was that, if there is an ethical justification based
             18

          on justice for not subjecting children who are more
             19

          vulnerable to greater risk, then that should apply
             20

          internationally.
             21


                      So that's our recommendations that have
             22






                                                                         22


          been conditionally approved in the past, and we
              1

          started our work on 406.  I believe we talked a little
              2

          bit about 406 last time, but at this point I can't
              3


          even remember anymore.
              4

                      So just to remind you, 406 is also
              5

          research with no direct benefit, and the regulation is
              6


          DHHS will conduct or fund research in which the IRB
              7

          finds that more than minimal risk to children is
              8

          presented by an intervention or procedure that does
              9

          not hold out the prospect of direct benefit for the
             10


          individual subject or by monitoring procedures which
             11

          is not likely to contribute to the wellbeing for the
             12

          subject only if the IRB finds that...
             13

                      I put in red all the terms that the
             14


          subcommittee attempted to address in the criteria that
             15

          are in Federal regulations, and so we will go through
             16

          them in a systematic order.
             17


                      So the first one that we are going to go
             18

          through -- First, we wanted to say is there a
             19

          justification -- or we wanted to explore, is there a
             20

          justification for exposing children to an increase
             21


          over minimal risk for a research that will not have
             22






                                                                         23


          any possibility of benefitting them directly, and we
              1

          looked both at the National Commission as well as had
              2

          discussion, and we propose that --
              3


                      First of all, the National Commission said
              4

          that foreseeable benefits in an identifiable class of
              5

          children may justify a minor increase of risk to
              6


          research subjects.  The committee also came to the
              7

          conclusion that there is research that is vital to the
              8

          welfare of children that can't be conducted unless
              9

          children participate in it.
             10


                      So there is an ethical justification for
             11

          exposing children to a minor increase over minimal
             12

          risk for nonbeneficial research.
             13

                      So then, if you are trying to define what
             14


          minor is, a committee in SACHRP is going to have to
             15

          grapple with kind of the two ends of a continuum.  One
             16

          is:  Do we want to give IRBs greater discretion to
             17


          approve greater than minimal risk research without
             18

          direct benefit?  That would be to have a broader scope
             19

          of what minor is.    
             20

                      Then on the other side of the continuum
             21


          is:  Or do we want to limit that kind of a discretion
             22






                                                                         24


          and place a greater percentage of decisions in the 407
              1

          process, which is a national perspective?
              2

                      So here are some additional cautions of
              3


          defining minor increase.  If it is too broad, then we
              4

          may be exposing children to unacceptable research risk
              5

          and permitting a certain amount of exploitation of
              6


          child populations.  However, if the definition of the
              7

          minor increment is too narrow, then we will deprive
              8

          children of research necessary to their health and
              9

          welfare.  
             10


                      What we heard was that investigators
             11

          sometimes move into trying to stretch the fact that
             12

          there is some benefit, so that they can call it a 405. 
             13

          On the other hand, we don't want protocols to be
             14


          submitted to 407s which really are not 407s, because
             15

          the IRB just throws up its hands and can't decide what 
             16

          to do with the protocol.
             17


                      A reminder is -- and this was always very
             18

          important to us, because some people want the minor
             19

          increase to be broader, because you've got to do the
             20

          research, which we agree.  The research is important. 
             21


          At the same time, it is important to know that
             22






                                                                         25


          research that is not approvable under 406 can be
              1

          approved under 407.  
              2

                      So if we are looking at research that has
              3


          a minor increment over minimal risk with children who
              4

          do not have a condition, and we are going to look at
              5

          what the condition is defined, this still could be
              6


          approved under a 407.
              7

                      Okay.  So now we get to minor increase,
              8

          and we are trying to address it in the same way that
              9

          we did the minimal risk.  So first we tried to grapple
             10


          with the notion of should it be a uniform or relative
             11

          standard.
             12

                      Now a uniform standard would say that the
             13

          degree of risk defined as minor should be the same for
             14


          all children.  The ethical justification there is
             15

          that, when research offers no probability of direct
             16

          benefit, children should not be subjected to greater
             17


          research risk simply because their daily lives are
             18

          filled with greater risk than healthy children or
             19

          those living in safe environments.
             20

                      So that the increment over minimal, which
             21


          was uniform, the argument is that increase should also
             22






                                                                         26


          be uniform.
              1

                      The relative standard argues that the
              2

          degree of risk defined as minor should be relative to
              3


          the experiences of children with specific disorders or
              4

          conditions.  The rationale for that argument is the
              5

          greater needs of children in the general population
              6


          who share the subject's disorder or condition
              7

          justifies exposure to increasing levels of risk.
              8

                      The other rationale is that children who
              9

          undergo minor increase in minimal risk procedures as
             10


          part of their regular care will experience less harm
             11

          from procedures when used for experimentation than
             12

          other children.
             13

                      Our committee did not agree with that
             14


          latter point, and I think we heard many stories of
             15

          children with diabetes don't necessarily like, you
             16

          know, venipunctures or blood testing.  They have to do
             17


          it.  They are used to it, but one more is not
             18

          necessarily something that they enjoy more than a
             19

          child who doesn't typically get them.
             20

                      For the rationale that the greater needs
             21


          of children with the child's disorder would obligate
             22






                                                                         27


          children with a disorder or condition to be burdened
              1

          with increased risk, we couldn't look at a
              2

          justification for that.  We understand it is
              3


          utilitarian, but we didn't think that, just because
              4

          you have a vulnerability, you have a greater
              5

          obligation to serve others than a child who doesn't
              6


          have that obligation.  
              7

                      So I am sure there are arguments in the
              8

          other direction, but we had a very difficult time with
              9

          any other justification.
             10


                      So for that reason, we propose a uniform
             11

          standard for a minor increase over minimal risk, and
             12

          the rationale was that, when research offers no
             13

          probability of direct benefit, children should not be
             14


          subjected to greater research risk simply because
             15

          their lives are filled with greater risk.
             16

                      We also noted that research not approved
             17


          under 406, if it is legitimate research and judged to
             18

          be important and ethical by the IRB, can be submitted
             19

          to a 407 and approved under that, if appropriate, and
             20

          that a uniform standard is consistent with what has
             21


          been conditionally approved for minimal risk.
             22






                                                                         28


                      Then we had to try to figure out, as we
              1

          talked about last time, what is minor.  I think, as we
              2

          mentioned last time, the problem with minor is, you
              3


          know, some of the other -- The preamble to the final
              4

          rule -- I think we mentioned this last time -- left
              5

          the determination of minor increase over minimal risk
              6


          to the IRBs and, as I said last time, we could
              7

          understand why.  It's so difficult.
              8

                      Then but definitions from NHRPAC, from
              9

          IOM, we believed, was not satisfactory, because they
             10


          just replaced the term minor with just a bit or a
             11

          little bit more than minimal or a slight increase.
             12

                      So also a problem with defining minor is
             13

          that the procedures are all so different that you
             14


          really can't have a uniform quantitative variable. 
             15

          You can't say liters or weights or pain threshold,
             16

          because the risks in procedures are all different.
             17


                      So we propose to apply a uniform standard
             18

          for assessing whether research presents a minor
             19

          increase over minimal risk, but that it requires a
             20

          process of deliberation based upon ten different
             21


          criteria.
             22






                                                                         29


                      I would like to -- Bob Hauser was very
              1

          helpful to us last meeting.  Susan and I were sitting
              2

          there trying to figure out some of the feedback, and
              3


          he was talking about some other medical judgments that
              4

          are based upon these steps in criteria.  Although we
              5

          couldn't use any of the specific ones, it did serve as
              6


          a model for trying to come up with what might be
              7

          really helpful in terms of minor.
              8

                      So now I am going to go over the 10
              9

          criteria that an IRB would use in order to evaluate
             10


          whether or not a procedure subjected the child to a
             11

          minor increase or a greater than minor increase or
             12

          less than a minor increase.
             13

                      Okay.  So first of all, appears quite
             14


          obvious, but this reminds me what we did for 407. 
             15

          Remember, from 407 we are requiring the IRB to provide
             16

          a rationale for why it is not a 404 or why it is not
             17


          a 405, why it is not a 406.  So the first requirement
             18

          is to look at this and say it is not minimal risk.  So
             19

          it is not a minimal risk study.
             20

                      The second requirement is that, if an
             21


          investigator is arguing that the risk is minor, then
             22






                                                                         30


          it should be based on scientific evidence.  So there
              1

          should be peer reviewed scientific evidence of the
              2

          range of risks associated with the population -- I
              3


          mean with the procedure for the subject population or
              4

          the procedure is sufficiently similar to other
              5

          interventions with well characterized risks that
              6


          prudent, informed judgments about risks can be made.
              7

                      One of the kind of framing concepts that
              8

          began to guide our deliberations was a term we decided
              9

          to call evidentiary protection, that as the risk is
             10


          increased over minor that evidence to support
             11

          decisions to subject children to greater than minor
             12

          increase -- a minor increase over minimal risk --
             13

          should be based upon evidence.
             14


                      Now here the second point in proposal 2 is
             15

          also recognizing, as we will get to and as you will
             16

          remember with minimal risk, is that we are talking
             17


          about equivalent procedures.  Actually, I think there
             18

          are examples in the PowerPoint as well.  
             19

                      Do you have copies of the PowerPoint? 
             20

          Okay, great.
             21


                      Okay, number three, certainty of evidence: 
             22






                                                                         31


          So the extent and quality of the evidence is such that
              1

          there is little uncertainty about the risks involved,
              2

          and that a lack of sufficient data for a risk profile
              3


          would create a higher level of uncertainty supporting
              4

          a more conservative approach.
              5

                      So that we are trying to assist the IRB in
              6


          -- and I think this is similar to what SACHRP
              7

          recommended for 407, and that is that the onus and
              8

          direction and guidance is placed on both the
              9

          investigator -- on the investigator to present to the
             10


          IRB evidence and sufficient rationale for why this is
             11

          minor, and it gives the IRB guidance as to what to be
             12

          asking the investigator for.
             13

                      The fourth factor to consider are the
             14


          documented harms.  There has to be some documentation
             15

          that the harms are not serious for the subject
             16

          population that is in the research.  That is that the
             17


          data indicates no or an extremely small probability of
             18

          risk of major complication.  I think Ernie just
             19

          pointed out before that major complication is too
             20

          severe and, if anybody can come up with a different
             21


          example or different term for major, that would be
             22






                                                                         32


          helpful.
              1

                      Harms associated with the procedure do not
              2

          require in-patient monitoring or follow-up evaluation. 
              3


          so we are trying to define for the IRB what we mean by
              4

          harm that would be greater than a minor increase, and
              5

          the harms, if they occur, are transient and
              6


          reversible.
              7

                      By transient and reversible, we mean
              8

          restricted to time of procedure or a short
              9

          experimental period; because, remember, these are
             10


          studies that are not under monitoring once the child
             11

          leaves, typically.  It is not a treatment study per
             12

          se.13

                      Then reversible means that the procedure
             14


          to reverse the effect requires no more than a short
             15

          term simple clinical intervention.  So we are defining
             16

          within the minor increase category what we mean by
             17


          reversibility.
             18

                      The procedures are equivalent.  Just like
             19

          in minor increase, the procedures are equivalent in
             20

          risk to documented risk profiles in terms of duration
             21


          of harm or discomfort and the cumulative effect of
             22






                                                                         33


          procedures on the probability and magnitude of harm.
              1

                      Remember, we talked about similar with
              2

          respect to minimal risk.  That is that it is not just
              3


          one minor increase.  If, in fact, something that is
              4

          considered a minor increase is done 10 times when the
              5

          equivalent procedure that it is being related to is
              6


          only done once, then you have to take that into
              7

          consideration, that that may be cumulative harm that
              8

          is greater than minor.
              9

                      Whenever possible, to try to get some
             10


          impression about how participants react to these
             11

          procedures or equivalent procedures.
             12

                      To think about mitigating factors:  The
             13

          procedure as to -- When you are deciding whether or
             14


          not it is a minor increment, the procedure reflects
             15

          consideration of documented mitigating factors known
             16

          to minimize or exacerbate the risk.  That is, you
             17


          know, is there a way that the procedure has to be
             18

          conducted that it's minor?  Is there a particular
             19

          competence that is necessary?  Is there a particular
             20

          subject population to which it might be more than
             21


          minor?  So those are examples of mitigating factors.
             22






                                                                         34


                      Inclusion/Exclusion criteria:  The
              1

          investigator needs to demonstrate that they have taken
              2

          into account the subject characteristics of the
              3


          particular population that may influence -- I used
              4

          moderate, but I used that in a statistical sense, and
              5

          I shouldn't have put that word in.  But it really
              6


          means to influence the probability and magnitude of
              7

          harm of the procedure, more or less.
              8

                      That there should be an adequate
              9

          monitoring process, if this is a minor increase.  Now
             10


          once again, we are not saying what that monitoring
             11

          process should be, because every study is so
             12

          different, but some type of monitoring process in
             13

          terms of the reversibility and the duration should be
             14


          put into effect.
             15

                      That is quite new, because in some sense
             16

          safety data monitoring is not typically applied to
             17


          non-treatment research.
             18

                      The procedure will be performed in a safe
             19

          and competent way.  That is that the investigators or
             20

          whatever staff is going to be conducting the research
             21


          is competent and that it is done in an environment,
             22






                                                                         35


          because the Subcommittee was talking a lot about how
              1

          there are procedures that can be done very safely by
              2

          a competent person, but if the person hasn't been
              3


          trained in those techniques, it can be quite
              4

          dangerous.  So we tried to take that into account.
              5

                      What I am going to do, unless there are a
              6


          lot of questions -- I don't think any of this makes
              7

          sense without going down the line and defining
              8

          everything else and with the examples, as Felix
              9

          mentioned.  So I am going to go through it, and then
             10


          we will come back in detail, because I think it is the
             11

          only way to begin to grapple with some of the
             12

          complexities.  So these are the 10 criteria that we
             13

          can come back to.
             14


                      The next part of the definition or the
             15

          guidance for what is a -- when you can do minor
             16

          increase over minimal risk is that it has to be of
             17


          vital importance.  It's very hard, because vital
             18

          importance and condition go together, because it's got
             19

          to be of vital importance for the understanding and
             20

          amelioration of the subject's disorder or condition.
             21


                      So the fact that we are presenting vital
             22






                                                                         36


          first or condition first is really -- I thought this
              1

          might be clearer, but the committee kept talking about
              2

          both.  We realized how interlinked they were.
              3


                      So our proposal for vital importance is
              4

          that, in order to be considered "vitally" important,
              5

          knowledge gained as a result of the research must have
              6


          clear implications for:  Understanding the etiology,
              7

          prevention, diagnosis, pathophysiology, or
              8

          amelioration of the condition; for developing
              9

          treatment for the condition; or determining future
             10


          directions for research on the condition.  I know
             11

          Ernie had a point about this, but now I forgot it.  So
             12

          I'm sure he will bring it up later.
             13

                      The issue -- The reason we wanted to
             14


          define it in this way is because, as people on the
             15

          subcommittee mentioned, every investigator thinks that
             16

          what they are doing is of vital importance, but when
             17


          you are increasing the risk over minimal, there has to
             18

          be a little more in there that justifies why children
             19

          should have this burden.
             20

                      Now here I wanted to justify why we used
             21


          the different language.  "Clear and significant
             22






                                                                         37


          scientific implications for yielding generalizable
              1

          knowledge" -- What is generalizable?  What about clear
              2

          and significant?  
              3


                      The rationale was to ensure that child
              4

          protections for greater than minimal risk research
              5

          with no prospect of direct benefit -- that
              6


          determination is vital must be granted in scientific
              7

          validity of the claim.  This is not novel.  It is
              8

          certainly consistent with Subpart A 46.111.
              9

                      The other rationale was for the language
             10


          "understanding the etiology, prevention, diagnosis,
             11

          pathophysiology, amelioration or treatment of the
             12

          condition or disorder."  As we were talking about it,
             13

          we realized it is not just vital interest but vital
             14


          interest to a condition or disorder that that
             15

          particular child has, because that is what the
             16

          language says.
             17


                      So the rationale is that for greater than
             18

          minimal risk research that doesn't have direct
             19

          benefit, children should not be used as a sample of
             20

          convenience or means to an end.  For example,
             21


          toxicology or pharmacokinetic test of a potential drug
             22






                                                                         38


          for treating a disorder the child does not and is not
              1

          expected to have.  That child should not be subjected
              2

          to the minor increase.
              3


                Number 2, the research must be designed to ask
              4

          a question that is vital to understanding or
              5

          ameliorating the subject's disorder or condition.  So
              6


          you can see why this is to interlinked with what is a
              7

          condition or a disorder.
              8

                      So that brought us to "condition."  You
              9

          may recall -- First of all, we didn't grapple with
             10


          disorder, although we will later.  We will talk about
             11

          it a little bit, because disorder can be defined by
             12

          diagnoses, by different protocols and templates that
             13

          are already out there.  But the question is what is a
             14


          condition.
             15

                      NHRPAC has dealt with this, and IOM dealt
             16

          with this.  So here are the cautions of defining a
             17


          condition.  The cautions are to be overly broad, and
             18

          so simply children as a -- having the status of being
             19

          a child could be included, and I think that was the
             20

          concern that NHRPAC and IOM brought to the table.
             21


                      On the other hand, if it is overly narrow
             22






                                                                         39


          and it only includes children of a very, very severe
              1

          disorder or a diagnosed disease, then we are
              2

          eliminating research that may be vital to healthy
              3


          children.  So that is what you begin to grapple with.
              4

                      Justice was once again something paramount
              5

          in our minds.  How should "condition" be defined to
              6


          address the paramount ethical issue of justice in
              7

          balancing risks and benefits for children as a class,
              8

          for children with a disorder, for children at risk for
              9

          a disorder, and for healthy children?
             10


                      In research with no prospect of direct
             11

          benefit, having a health risk or a negative condition
             12

          or disorder -- this is what I mentioned before -- does
             13

          not confer greater obligation on someone to be
             14


          involved in research for the benefit of others.
             15

                      Children with negative conditions or
             16

          disorders should not bear disproportionate risk for
             17


          research with no prospect of direct benefit simply
             18

          because of their health vulnerability.
             19

                      So that leads to the question -- We are
             20

          not saying that minor increase should not be dependent
             21


          upon a condition or a disorder that the child has. 
             22






                                                                         40


          The question we are really asking is:  Should healthy
              1

          children be exposed to a minor increase over minimal
              2

          risk?  Can they ever have a condition without being so
              3


          broad that they are exploited or 406 is basically
              4

          meaningless?
              5

                      So we concluded that there may be
              6


          pediatric research designs with no prospect of direct
              7

          benefit that can answer a question of vital importance
              8

          to understanding or ameliorating a condition of
              9

          healthy children that can only be answered if healthy
             10


          children are involved in the research.
             11

                      Here are some examples:  Knowledge that
             12

          would significantly advance understanding of
             13

          susceptibility to childhood diseases such as colds or
             14


          ear infections; or knowledge that would advance
             15

          understanding of nutritional, physiological or genetic
             16

          factors contributing to the timing or delay of
             17


          puberty.
             18

                      So proposal 4 is, in fact, condition and
             19

          vital must be linked.  The determination of
             20

          "condition" and "disorder" should depend upon whether: 
             21


          The research question is vital to the wellbeing of the
             22






                                                                         41


          subject population; and it can only be answered by the
              1

          subject populations' involvement in the study.
              2

                      Now this gets really interesting, because
              3


          it also means that "disorder" -- you just can't expose
              4

          any kid that has a disorder to research because you
              5

          are interested in doing that.  So -- and I think I am
              6


          going to get to it, but obviously not in this slide,
              7

          quite.
              8

                      The next thing we did was go to approval
              9

          of the health comparison group.  When a healthy -- You
             10


          know, let's say that you are doing a study in which a
             11

          child has a disorder or condition, but in order to
             12

          understand that disorder or condition in a non-
             13

          treatment study, you need to have some data on healthy
             14


          children.  Otherwise, the research is not meaningful.
             15

                      When a healthy comparison group is
             16

          included in a study that presents a minor increase
             17


          over minimal risk, the research may be approved under
             18

          406 if the research is also designed to collect data
             19

          that is vital to understanding the healthy child's
             20

          condition.
             21


                      An example is factors contributing to
             22






                                                                         42


          neonates' natural immune response against maternal
              1

          HIV, because there may be no understanding of why
              2

          children are -- some children are immune to the HIV
              3


          virus in their mother, and so, therefore, studying
              4

          them is providing information on that in that it is
              5

          equally as important as understanding the immunology
              6


          of the children who contract HIV.
              7

                      Health comparison groups that are not
              8

          approvable under 406 might be:  Research designed to
              9

          only answer a question of vital importance to a
             10


          population with a disorder that requires a healthy
             11

          comparison.  The example there is a study comparing
             12

          brain activity responses to  Ritalin in children with
             13

          and without ADDH, because one couldn't think of why it
             14


          would be important to study healthy children.  They
             15

          might be interesting scientifically, but not vital to
             16

          the healthy child's life.
             17


                      So proposal 6 is that you define condition
             18

          as follows:  A specific or a set of specific physical,
             19

          psychological, neurodevelopmental or social
             20

          characteristics that an established body of scientific
             21


          or clinical evidence has shown to be -- and once again
             22






                                                                         43


          you see there is an evidentiary protection -- a
              1

          characteristic that is unique to the subject
              2

          population and essential to empirically answer a
              3


          question.
              4

                      Now unique here is that -- What we mean by
              5

          unique is not necessarily that the population is
              6


          unique, but they have a characteristic that is
              7

          essential that only they have, or within the context
              8

          to answer the question, and of vital importance to
              9

          understanding that particular condition or disorder.
             10


                      Rationale:  Interpretation protects
             11

          against over or under-inclusion, because it is tied to
             12

          the research question, whether involvement of the
             13

          specific child population is essential to answering
             14


          the research question; whether the research question
             15

          will address an issue of vital importance; and whether
             16

          the study is designed to address a question of vital
             17


          importance to the prospective subject population.
             18

                      Example 1:  Healthy preschool children
             19

          might have a "condition" for a pharmacokinetic study
             20

          designed to test immunogenicity of a potential vaccine
             21


          for a serious common childhood disease, but not have
             22






                                                                         44


          a "condition" for the same type of study if it is for
              1

          a potential for treating childhood Leukemia.
              2

                      So I think -- I hope that is clear, and we
              3


          go over it.
              4

                      Example 2:  Children with diabetes as a
              5

          class might have a "disorder or "condition" for a
              6


          study designed to test pharmacokinetics of a new form
              7

          of insulin, but not have a "disorder" or "condition"
              8

          for the same type of study for a potential treatment
              9

          for iron deficiency.
             10


                      So you couldn't -- So once again, you
             11

          can't use kids with a disorder as a sample of
             12

          convenience to study anything just because they have
             13

          a disorder.
             14


                      Then we get to the word commensurate. 
             15

          Remember, this is just the regulations.  The
             16

          intervention or procedure presents experiences to
             17


          subjects that are reasonably commensurate with those
             18

          inherent in their actual or expected medical, dental,
             19

          psychological, social or educational situations.
             20

                      I am going to point out, and the committee
             21


          wanted me to point out, that "expected" gets really
             22






                                                                         45


          difficult here, in that in some sense it -- You know,
              1

          depending on how you define actual, if there is a
              2

          rationale for actual and then you throw in expected,
              3


          it gets very difficult, and you will see that as we
              4

          move on.
              5

                      Commensurate -- Now the question was, and
              6


          I think we raised this last time:  Is commensurate
              7

          supposed to be a way of helping the IRB evaluate the
              8

          risk level or was it meant to say that, in addition to
              9

          the protection of minor increase and vital and
             10


          condition, that there is also an additional
             11

          conservative approach that the parent and/or the child
             12

          has to be able to judge to understand the informed
             13

          consent, and the way you protect that is that they
             14


          have had some kind of experience that is commensurate
             15

          with what the researcher is describing in the informed
             16

          consent.
             17


                      We rejected the use of commensurate as a
             18

          definition of the level of risk, for several reasons,
             19

          one being that that would create a relative standard
             20

          again, that if a child was exposed to greater risk,
             21


          you could increase what would be a minor increase for
             22






                                                                         46


          them.
              1

                      In addition, we went back to the National
              2

          Commission and read what they had said, and they said: 
              3


          "The requirement of commensurability of experience
              4

          should assist children who can assent to make a
              5

          knowledgeable decision about their participation in
              6


          research based on some familiarity with the
              7

          intervention or procedure and effect."
              8

                      Then they also said:  "The use of
              9

          procedures that are familiar or similar to those used
             10


          in treatment of the subjects should not, however, be
             11

          used as a major justification for their participation
             12

          in research, but rather as one of several criteria."
             13

                      So I think they were, in some sense -- We
             14


          thought, at least, that they were arguing against
             15

          using it as a way to define risk.  My understanding is
             16

          that IRBs are very confused about this.  So any kind
             17


          of guidance that SACHRP can give, I think, and OHRP
             18

          can give will be helpful.
             19

                      So defining commensurate, our proposal is
             20

          that commensurate applies to the parents' or child's
             21


          understanding of the experimental procedures, that it
             22






                                                                         47


          is an assent consent guidance, during parental
              1

          permission and asset.  
              2

                      So what that means is that minor increase,
              3


          vital and condition apply to the risk-benefit
              4

          calculus, but the word commensurate only applies to an
              5

          understanding of the research procedures.
              6


                      Now this is very hard, because people on
              7

          the committee were raising:  Just because a child
              8

          hasn't been through a procedure, you don't want to
              9

          rule out any type of research, because it really is
             10


          very conservative.  So once again, as we did with
             11

          minimal risk, the procedures don't have to be
             12

          something they have actually experienced, but are
             13

          equivalent to something that they have experienced or
             14


          would be expected.
             15

                      Once again, expected -- It's really hard
             16

          to understand how expected really fits in here.  It is
             17


          just a problematic word, because if it is supposed to
             18

          improve assent or consent, I don't understand how
             19

          expected does that.
             20

                      The only thing that -- I was speaking to
             21


          somebody who had been involved in the discussions, and
             22






                                                                         48


          they said that in the 1970s, given it was a very, you
              1

          know, biomedical approach, that their model was that
              2

          kids were sitting in a waiting room with other kids
              3


          with a disorder waiting to have a treatment so that
              4

          they were in some sense expected meant in the next
              5

          hour they were going to get it.  So something like
              6


          that, but you know, whether that's true or not, I
              7

          don't know, but I do think it is very difficult for
              8

          today's application.  Not just me, but the committee
              9

          does.
             10


                      So the term commensurate should be
             11

          interpreted as requiring that children and/or the
             12

          guardians are familiar with procedures that are
             13

          reasonably similar in nature and risk proportionality
             14


          to those that the child has or is expected to
             15

          experience.
             16

                      The rationale:  The research activity must
             17


          be commensurate with, or reasonably similar to,
             18

          procedures that the prospective subjects and others
             19

          with the specific disorder or condition ordinarily
             20

          experience, by virtue of having or being treated for
             21


          that disorder or condition.
             22






                                                                         49


                      Now that is very interesting, the "by
              1

          virtue," because that gets us -- Well, just remember
              2

          it.  When we are talking about equivalence criteria,
              3


          we are once again saying that the IRBs should use, is
              4

          it similar to the nature of the procedure, the
              5

          magnitude of discomfort, the duration and cumulative
              6


          effect of procedures that they have been familiar with
              7

          or are expected to be?
              8

                      So, for example, under some condition --
              9

          Let's say a child never got an intravenous.  A
             10


          venipuncture might be considered a commensurate
             11

          experience that you could describe how the
             12

          venipuncture would feel in terms of -- I'm sorry.  You
             13

          could describe how the intravenous would feel in terms
             14


          of the child's experience with venipuncture.
             15

                      So, remember, it is assent.  That is not
             16

          the definition of the risk level.  It is whether they
             17


          could understand it.
             18

                      So then you had to ask:  Are we talking
             19

          about commensurate with experiences of the subject him
             20

          or herself or to the subject's population?  Are we
             21


          going to be requiring investigators to ask every
             22






                                                                         50


          single subject whether or not they ever had this kind
              1

          of procedure?
              2

                      We thought, well, maybe that's what they
              3


          meant by "expected," but IRBs should evaluate the
              4

          commensurability of a research procedure with respect
              5

          to the experiences that most children within the
              6


          population of interest have or are expected to
              7

          experience.
              8

                      So the research activity -- and here we
              9

          took from the National Commission.  The research
             10


          activity must be commensurate with (i.e. "reasonably
             11

          similar to") procedures that the prospective subjects
             12

          and others with the specific disorder or condition
             13

          ordinarily experience by virtue of having or being
             14


          treated for that disorder or condition.
             15

                      The committee wanted us to note that we do
             16

          not think in any way that simply this notion of
             17


          commensurate is sufficient in terms of issues that
             18

          have to do with parental permission and child assent,
             19

          and we assume, as the Chair has told us, that that is
             20

          something that the Subcommittee and SACHRP will be
             21


          pursuing.
             22






                                                                         51


                      So for example, commensurate for children
              1

          and parents may be very different in terms of their
              2

          perceptions and motivation.  So there's a lot of other
              3


          issues that need to be addressed in terms of child
              4

          assent and parental permission in the future.
              5

                      Okay, here is a summary of the proposals. 
              6


          So I am going to stop there.  I don't know if it is
              7

          going to be most helpful -- Susan, maybe we should
              8

          both be up here, whatever, because I don't know -- or
              9

          if somebody wants to manipulate.  Susan and I could
             10


          both be over there, if somebody wants to manipulate. 
             11

          Maybe that's better.
             12

                      CHAIRMAN PRENTICE:  Okay, thank you very
             13

          much, Celia and Susan.  Yes?
             14


                      MS. KORNETSKY:  I just want to say that,
             15

          from everyone's faces, it's a lot and it is
             16

          overwhelming.  But I do think, if we go back and break
             17


          it into pieces now and discuss it, it will become
             18

          clearer.  It is even difficult being in an IRB dealing
             19

          with children's issues 100 percent of my time thinking
             20

          about all these things.  But I think that when the
             21


          Subcommittee did this, you really just have to now go
             22






                                                                         52


          back and ask specific questions and break it apart,
              1

          and that's what Celia and I can do and provide some of
              2

          the rationale, maybe some of the reasons why we threw
              3


          some things out, why we have put things certain ways.
              4

                      So we do expect that you will have lots of
              5

          questions and issues to bring up.
              6


                      CHAIRMAN PRENTICE:  Thanks.  I want to --
              7

                      DR. FISHER:  Do you want Kelley --
              8

                      CHAIRMAN PRENTICE:  Yes, I will let -- Not
              9

          necessarily.  Well, let me think.  I want to make a
             10


          couple of preliminary comments first.
             11

                      First of all, I am really impressed with
             12

          the work that your Subcommittee has done.  I've had a
             13

          long time interest in Subpart D.  I don't know how
             14


          many talks I have given on Subpart D.  I've spent a
             15

          lot of time thinking about how to interpret it
             16

          appropriately, and this is really a nice piece of
             17


          work.  And I agree, it is very complicated.
             18

                      As a matter of fact, I have read it
             19

          several times and, as you presented it, it still
             20

          raised more questions I hadn't thought about before.
             21


                      There are a couple of ways we can approach
             22






                                                                         53


          this.  One, we can just start asking questions or,
              1

          two, we can just start going through your sequence of
              2

          slides.  How would the committee like to proceed?  I
              3


          have about eight or nine slides that I have questions
              4

          about.  
              5

                      MS. KORNETSKY:  If I could suggest -- Just
              6


          to make sure that everyone understands, I would like
              7

          to suggest that maybe -- You know, there are sort of
              8

          four major sort of points here, as far as, you know,
              9

          first the minor increase, then the "vital" and
             10


          "condition," and then the commensurability. 
             11

                      It might be helpful just to sort of
             12

          organize at least the feedback for Celia and I to sort
             13

          of go through those.  We can come back to bringing
             14


          them together and sort of address them sort of the
             15

          different issues is what I would suggest as opposed to
             16

          just opening it up to all the different issues.
             17


                      CHAIRMAN PRENTICE:  Okay.  Fair enough. 
             18

          Well, we have already basically approved the
             19

          definition of minimal risk, utilizing a uniform
             20

          standard.  I would assume that there are no questions
             21


          or concerns.
             22






                                                                         54


                      MR. BARNES:  No.  I think there are some
              1

          questions or concerns, because the definition of the
              2

          uniform standard that we have talked about before has
              3


          not been in this context, and we raised the issue in
              4

          the last context, which was in 404, about how, even if
              5

          one adopts a uniform standard for minimal risk under
              6


          404, it is still arguable that there may not be a
              7

          uniform standard under 406 because of the presence of
              8

          that criterion regarding commensurate.
              9

                      You know, I have to tell you, kind of the
             10


          more I think about it, the more I'm not even sure that
             11

          I agree with the uniform standard for 404, and I don't
             12

          know what I think about it.  But I think that it -- I
             13

          don't think that uniform standard has been decided by
             14


          SACHRP yet in regard to 406, and I guess what I'm
             15

          saying is I am not even sure that I agree with myself
             16

          from the last meeting about 404.
             17


                      CHAIRMAN PRENTICE:  Okay.  Let me respond
             18

          to that comment, Mark.  I understood the uniform
             19

          standard of minimal risk as applying to the 404, which
             20

          provides the baseline, and it also applies to 405 when
             21


          you are talking about greater than minimal risk, and
             22






                                                                         55


          when you get into 406, it is also the baseline.  Then
              1

          you take that standard, that uniform standard of
              2

          minimal risk, and then you talk about a minor increase
              3


          over minimal risk.
              4

                      You've got to have one threshold level of
              5

          minimal risk, and I don't see commensurability
              6


          altering the interpretation of minimal risk.  
              7

                      MR. BARNES:  Maybe you are right about
              8

          that.  I mean, I think that, certainly, though, the
              9

          question is whether -- The question then would be
             10


          whether minor increase -- whether the standard of
             11

          minor increase over minimal risk is itself either a
             12

          sliding scale or an objective standard.  So I think
             13

          that is what is called into question directly by the
             14


          use of the term commensurate.
             15

                      CHAIRMAN PRENTICE:  Okay.  Well, let's get
             16

          into minor increase a little bit later.  Nancy?
             17


                      DR. JONES:  I do have some questions, too,
             18

          about the relative standard versus the uniform.  I
             19

          would say, on your slide on page 12 on the relative
             20

          standard, that there is one other justification for a
             21


          relative standard.  
             22






                                                                         56


                      Even while there is no direct benefit, the
              1

          generalizable knowledge that you are investigating,
              2

          the research question that is linked to the condition
              3


          that the individual has, has the potential for benefit
              4

          for that class but not for another class -- like all
              5

          the different examples that you gave.
              6


                      So there is one other justification.  It
              7

          goes back to the point that Mark made with
              8

          commensurate where there is a link back to that
              9

          particular condition that you are testing, the
             10


          experimental question, why you were put in the
             11

          research in the first place.
             12

                      So there does seem to be always this link
             13

          toward you are in this research protocol because you
             14


          are a member of a particular class that you are
             15

          testing the research question for.  So then there is
             16

          that potential that ultimately you could benefit or
             17


          your class could benefit from the knowledge that is
             18

          gained.
             19

                      So there is another justification for
             20

          that.
             21


                      DR. FISHER:  I think there may be
             22






                                                                         57


          confusion.  I get confused myself.
              1

                      The issue -- You are absolutely right that
              2

          the way the regulations are written, it is relative to
              3


          vital and condition.  But what we are arguing should
              4

          not be relative is the ceiling for minor.  But a
              5

          particular child who is healthy may not be justifiably
              6


          exposed to that minor increment if they don't have a
              7

          condition and the research isn't addressed to
              8

          something that is vital to them.
              9

                      So in that sense, that part is relative,
             10


          but when we say relative uniform, we are addressing
             11

          the increase in risk; and we said that we couldn't --
             12

          and what is also relevant -- and this is what makes it
             13

          all so hard -- is that we came up with 10 different
             14


          variables that have to be considered, obviously,
             15

          because it is contextual.  But contextual doesn't
             16

          necessarily -- It means in relation to, but it doesn't
             17


          mean that the standard is lower, that you could have
             18

          a lower threshold or whatever it is --- a lower
             19

          threshold for children who have a vulnerability in
             20

          terms of what you do to figure out whether or not that
             21


          increase is minor.
             22






                                                                         58


                      So I think that is where the confusion
              1

          lies.  So remember that we are only arguing that the
              2

          uniform is to what is considered minor.
              3


                      DR. JONES:  I went back and forth with
              4

          that in my mind, but I think that is the hard point to
              5

          communicate effectively without getting into all the
              6


          other considerations.  I think that type of
              7

          justification where you are putting the ceiling on the
              8

          level of risk -- I don't think that comes out clear as
              9

          you work through it yet.
             10


                      So I mean, I could agree to that, but I
             11

          think you still revolve around when you are designing
             12

          the research protocol if it fits into this category
             13

          based on whether or not -- what condition the
             14


          individual has.
             15

                      DR. FISHER:  Absolutely.
             16

                      CHAIRMAN PRENTICE:  You know, I see where
             17


          you are going.  I think that there is a uniform
             18

          standard of minimal risk.  I also think that there is
             19

          a uniform standard of a minor increase over minimal
             20

          risk.  Where the variability comes in is how you
             21


          define a disorder or a condition, how you approach
             22






                                                                         59


          commensurability, how you define vital importance.
              1

                      That is what determines whether or not --
              2

          all of those factors -- whether or not a protocol
              3


          qualifies under 406.  I do not see commensurability,
              4

          condition, or vital importance elevating the risk
              5

          level that would be a minor increase over minimal
              6


          risk.  So it is not really, in my mind, a relative
              7

          standard.
              8

                      I got to tell you that prior to working
              9

          with this particular subcommittee, I advocated a
             10


          relative standard for a minor increase over minimal
             11

          risk, and I still have some feelings about that.  But
             12

          the subcommittee has been pretty adamant that they
             13

          need to have an absolute ceiling, and the only way you
             14


          could do that is to have a uniform standard.
             15

                      DR. KORNETSKY:  Let me just give you an
             16

          example perhaps, maybe to talk -- to give you.  If you
             17


          had a child with a certain type of condition that,
             18

          during the normal course of their care, required a lot
             19

          of biopsies -- and so the type of biopsy, let's say,
             20

          is you would not consider a minimal risk; it is more
             21


          than a minor, in the next category-- you wouldn't want
             22






                                                                         60


          to use the justification just because these children
              1

          have had it that you would make the risk relative to
              2

          that.
              3


                      That's where we come back to the uniform. 
              4

          And I am taking out of the equation the issue that it
              5

          would help their care or whatever.  If it was just,
              6


          you know, to get extra tissue, and you figure those
              7

          kids have had it, that's the problem you run into when
              8

          you start taking for a minor increase and trying to
              9

          make it sort of relative; and that's where IRB's can
             10


          go with that very easily.
             11

                      DR. FISHER:  One of the things we did, we
             12

          started off the session last time when we had our
             13

          subcommittee meeting with what is the ethical issue
             14


          underlying this.  The ethical issue really is justice,
             15

          and the question is whether or not, for research that
             16

          has no possibility of direct benefit, it is just to
             17


          obligate children who are vulnerable, who have
             18

          experienced greater degree of risk, to a higher degree
             19

          of risk in research that will not benefit them.
             20

                      We could not think about -- and it is a
             21


          utilitarian concept -- right? -- in terms of where --
             22






                                                                         61


          I mean, that's what our risk-benefit judgments are. 
              1

          They are utilitarian.  They are asking to make an
              2

          assessment of risk to an individual versus benefit to
              3


          science or society or others, and we couldn't think of
              4

          any reason why a healthy child shouldn't be as
              5

          obligated as a non-healthy child, if in fact the
              6


          research is addressing an issue that is important for
              7

          a class of children that are similar.
              8

                      So we could not find a rationale for --
              9

          Now it may be that children with disorders are more
             10


          likely to be in 406 research, because research that is
             11

          of vital importance -- there may be more of that kind
             12

          of research when you are talking about kids with a
             13

          disorder, but a priori it should not be assumed that
             14


          they should be exposed to more risk -- Well, it's not
             15

          the exposure.  It's that they have a higher obligation
             16

          than other children to be exposed to this risk.
             17


                      So I hope that frames where we went with
             18

          the uniform.
             19

                      CHAIRMAN PRENTICE:  Felix?
             20

                      DR. GYI:  I am having a hard time just
             21


          wrapping my arms around a lot of this, much like
             22






                                                                         62


          everybody else, and I wonder if I might take this back
              1

          up to the 50,000 foot level for just a moment.
              2

                      What I heard was that the term
              3


          commensurability should be applied toward
              4

          determination of informed consent related issues,
              5

          assent, parental consent.  That makes sense on a very
              6


          high level, but then when we try and apply it, it
              7

          seems to intersect with the risk-benefit analysis
              8

          discussions that we have.  
              9

                      So I don't know how to separate that out,
             10


          and I wondered if we might spend some time with that,
             11

          because we get back down to this issue of how do we
             12

          make that determination.
             13

                      The other thing that I am having a hard
             14


          time with is a statement that you just made about the
             15

          application of the justice principle.  But when I put
             16

          on the IRB hat and have to drill down from the top
             17


          level of principles, it really does impact on how we
             18

          make the determination of risk-benefit analysis.
             19

                      So again, I am having a hard time with
             20

          that as well.  Because I don't live in this world like
             21


          you do, Susan, I wonder if you might agree to a couple
             22






                                                                         63


          of different things.
              1

                      If we say that commensurability is simply
              2

          going to be linked to the informed consent issues, I
              3


          wonder if we might put that as a category and take
              4

          that off the table, and say we won't come back to it
              5

          until we have to.  But, you know, I don't know how we
              6


          do that, again, without intersecting with the other
              7

          issues.
              8

                      So I'm not sure that I am giving any
              9

          direction, but rather just stating some level of
             10


          confusion that I have that needs some direction.
             11

                      DR. FISHER:  Do you want to answer it?
             12

                      CHAIRMAN PRENTICE:  Let me try.  I'm not
             13

          so sure that there is quite the intersection between
             14


          the risk-benefit relationship with research and
             15

          commensurability that you are concerned about.  If we
             16

          look at the risk-benefit relationship of the research,
             17


          as you know, the risks have to be balanced by the
             18

          potential benefits to the subject and/or to society,
             19

          depending upon what category we are talking about
             20

          under Subpart D.  That is a separate issue.
             21


                      Then you get into commensurability under
             22






                                                                         64


          406.  As the National Commission indicated, and it is
              1

          also indicated in the recommendations from the
              2

          subcommittee, that it is tied to the parent and/or the
              3


          child's understanding of a procedure and, if they have
              4

          not had that procedure, then it is their understanding
              5

          of a procedure that might be expected, that they might
              6


          undergo at sometime in the future.
              7

                      Now if you are talking about a very young
              8

          child, obviously, they have no concept of expectation
              9

          of a particular procedure.  They can't assent.  The
             10


          parents, on the other hand, can perhaps understand a
             11

          particular procedure that the child is likely to have
             12

          in the future to treat their particular disorder or
             13

          condition, or that they have already had.
             14


                      So I don't really see the relationship
             15

          that you are concerned about in terms of risk-benefit
             16

          and commensurability.  
             17


                      DR. JONES:  I guess I do see it.
             18

                      CHAIRMAN PRENTICE:  You see it?
             19

                      DR. JONES:  Reading the other part of it,
             20

          it's not the major justification, but one of several. 
             21


          I think, in terms of commensurability, the way that I
             22






                                                                         65


          would interpret what is written here, not seeing the
              1

          whole passage or in context, is that you're there. 
              2

          You have more familiarity with the whole ball of wax
              3


          so that you can judge better whether or not you want
              4

          to put your child at risk.
              5

                      CHAIRMAN PRENTICE:  Yes, but that --
              6


                      DR. JONES:  But it's not -- But I think it
              7

          is both.  I think it also involves in whether or not
              8

          you say this is risky enough toward no direct
              9

          possibility.
             10


                      CHAIRMAN PRENTICE:  Agreed, but it cannot
             11

          elevate the level of risk --
             12

                      DR. JONES:  Sure.  It cannot elevate it,
             13

          but it is one of the factors.
             14


                      CHAIRMAN PRENTICE:  Yes, but nor can it
             15

          change the risk-benefit relationship of the research. 
             16

          Because you have commensurability, you don't say,
             17


          well, now we have commensurability, therefore that
             18

          makes the risk-benefit relationship of the research
             19

          acceptable.  You can't do it.
             20

                      DR. KORNETSKY:  Those four conditions have
             21


          to be independently satisfied.  So you have to sort of
             22






                                                                         66


          look at them independently.  When you get to that
              1

          part, when you've thought about the risk level, then
              2

          when you get to that part, that's yet another thing
              3


          that has to be satisfied.
              4

                      You can get to the risk level, and there
              5

          is no commensurability.
              6


                      CHAIRMAN PRENTICE:  Then you would not be
              7

          able to do it.
              8

                      DR. KORNETSKY:  Then you wouldn't be able
              9

          to do it.  So those can be separated.
             10


                      CHAIRMAN PRENTICE:  Mark?
             11

                      MR. BARNES:  This is -- I still agree with
             12

          Nancy.  I mean, I think the fact that it is one of the
             13

          four criteria, and because others might trump it,
             14


          still does not mean that commensurability must itself
             15

          be only tied to increasing the accuracy of the
             16

          perceptions of children and their families.
             17


                      If you even look at the quotations that
             18

          Celia used -- it's on page 30 of our handouts -- it
             19

          doesn't say that, you guys.  I mean, I haven't read it
             20

          in context, but what it says is "The requirement of
             21


          commensurability should assist children and their
             22






                                                                         67


          parents to understand."  It doesn't say that that's
              1

          the only purpose of it.  It says that it should
              2

          assist, that that is one purpose of it.
              3


                      Then if you look at the second quotation,
              4

          "the use of procedures that are familiar or similar to
              5

          those used in treatment should not, however, be used
              6


          as a major justification."  It doesn't say it can't be
              7

          used as a justification.  It says it can't be used as
              8

          a major justification, but rather as one of several
              9

          criteria regarding the acceptability.
             10


                      I mean, that's just on that particular
             11

          point about whether it means only perception or
             12

          whether it means something else.  But let me get back
             13

          to kind of first principles, which is that -- and I'm
             14


          talking against some of the same logic that we used in
             15

          the Subpart C report about uniform standard of minimal
             16

          risk versus relative standard.
             17


                      I think that, you know, we all kind of
             18

          instinctively go toward a uniform standard, because
             19

          we've been burned by the use of relative standards or
             20

          we have seen subjects endangered perhaps by the use of
             21


          relative standards.  But when you think about like
             22






                                                                         68


          actual cases -- and I think here, you know, just in
              1

          terms of what I've done recently in terms of the
              2

          international research context, and I am not just
              3


          talking about 406 here; I'm talking about 404 also.
              4

                      I can understand the instinct, because I
              5

          share it, to use a -- to adopt a uniform standard, for
              6


          example, in the context of international clinical
              7

          trials, because we don't want to take children, for
              8

          example, in Nigeria or Uganda and subject them and
              9

          their mothers to risks that we would never find
             10


          acceptable subjecting American children and American
             11

          mothers do.  I understand that.
             12

                      On the other hand, if you -- But that is
             13

          not the only case that you can have.  One can have a
             14


          situation in which there is an American researcher
             15

          doing international research regarding HIV
             16

          transmission -- regarding these days HIV transmission
             17


          and preventing HIV transmission from mother to child
             18

          in utero in which, in fact, there is almost no HIV
             19

          pediatric problem in the U.S. anymore in terms of new
             20

          cases, the new accrual of cases.  They almost don't
             21


          exist.
             22






                                                                         69


                      So if one is, therefore, as an
              1

          international researcher, for example, at Cornell is
              2

          trying to do a clinical trial of a new antiretroviral
              3


          agent used to try to prevent transmission of HIV from
              4

          mother to child in utero, and one is doing it in
              5

          Uganda, then the purpose of why one is doing it is to
              6


          help the children in Uganda.  It has nothing to do
              7

          with helping children in America.
              8

                      The benefit that the children in Uganda
              9

          could derive from this -- perhaps not themselves
             10


          directly, but of direct benefit to the class of
             11

          children in Uganda who are at risk for HIV infection
             12

          could be so great that it would seem to me that an IRB
             13

          could make a rational and moral decision to tolerate
             14


          a higher level of risk than would be tolerated for an
             15

          American child in similar circumstances.
             16

                      In other words, what I'm saying is that --
             17


          I mean, it's very -- It is more complicated than just
             18

          saying -- To me, it just seems that -- and I haven't
             19

          thought this out fully.  I think it deserves a longer
             20

          discussion than we can give it today.  But it seems to
             21


          me that there is, when it comes to the question of
             22






                                                                         70


          uniform risk, whether it is in this Subpart or whether
              1

          it is in Subpart C, you know, I guess I just think the
              2

          world is more complicated than just thinking that a
              3


          uniform standard is the way that -- is the only way
              4

          that an appropriate and moral risk-benefit calculus
              5

          can be made.
              6


                      CHAIRMAN PRENTICE:  I need to respond just
              7

          a second, and I'll ask you to respond as well.
              8

                      Are you saying, Mark -- and we go back to
              9

          the uniform definition of minimal risk, and I refer
             10


          specifically to healthy children living in safe
             11

          environments.  Are you suggesting that our
             12

          interpretation of safe environment should be in a
             13

          cultural context, so that, you know, a safe
             14


          environment in Uganda for Uganda kids may not be the
             15

          same thing as a safe environment in some rich suburb
             16

          of Chicago.  Is that where you are going with that?
             17


                      MR. BARNES:  Well, yes.  That is -- I
             18

          don't know what I believe.  I'm saying that I think it
             19

          is more complicated than just saying that we must
             20

          always say that the standard to apply here for all
             21


          IRBs across the country under this subpart must only
             22






                                                                         71


          be the definition that we would adopt in Scarsdale,
              1

          New York, for a child -- a healthy child in a safe
              2

          environment.
              3


                      CHAIRMAN PRENTICE:  Okay.  Mary?
              4

                      DR. POLAN:  I guess I would like to second
              5

          what Mark said.  As you describe that example, I'm
              6


          thinking of rotavirus, which causes -- I don't know --
              7

          4-5 million deaths a year in the developing world, but
              8

          it isn't a problem in this country.
              9

                      So the amount of benefit a child in Uganda
             10


          or someplace in sub-Saharan Africa could derive from
             11

          a new vaccine would be enormous, and you might not --
             12

          in that it is not a disease that is a problem in this
             13

          country.  So how do you -- If you would limit it to
             14


          the United States, I can understand that you have a
             15

          uniform definition, but if you are going to talk about
             16

          international research, given that the conditions are
             17


          so very different and the disease possibilities are so
             18

          very different, I find it equally hard to think about
             19

          a uniform standard.
             20

                      DR. KORNETSKY:  The examples that you are
             21


          both referring to and are talking about things,
             22






                                                                         72


          interventions or research where there is probably
              1

          going to be a benefit side to it, which is not what's
              2

          on the table here.  If you are talking about testing
              3


          an investigational vaccine for rotavirus in a country,
              4

          I don't think, most of those, there would be a
              5

          potential for direct benefit.  So it's not something
              6


          without a potential for direct benefit.
              7

                      The example I would like to give, though,
              8

          is going back to sort of a biopsy type of thing. 
              9

          Would you be more likely to just go and do a biopsy on
             10


          a kid with no potential for direct benefit from
             11

          another country versus here?
             12

                      Maybe you folks can come up with some
             13

          examples, but you were talking about a treatment, and
             14


          you are talking about a vaccine.  Those are things
             15

          with benefit.
             16

                      DR. FISHER:  I also think there is a
             17


          little confusion here.  It sounds like there is the
             18

          notion that we are ruling out the research.  That's
             19

          not the case.  Something that -- Just because a study
             20

          is going to be done like Mark -- let's say there is no
             21


          direct benefit; it's not a treatment study -- and it
             22






                                                                         73


          is greater -- It's the kind of risk that children in
              1

          Uganda are always exposed to, but it is not the kind
              2

          of risk that children in this country, the healthy
              3


          average child, is exposed to.
              4

                      We could still as an American IRB approve
              5

          that under 406, for example, because the child might
              6


          have a condition.  That is where condition permits. 
              7

          That is vital to that child.  But what people seem to
              8

          be forgetting is that everything can be approved if it
              9

          is a really good study under 407.  
             10


                      Nothing is preventing research that is
             11

          ethical and important from occurring.  What we are
             12

          talking about is how an IRB decides the extent to
             13

          which the harm that the child is going to be exposed
             14


          to, number one, should be categorized under the -- and
             15

          whether or not it's justifiable.
             16

                      The uniform only says that the degree of
             17


          risk that is approvable under a specific category has
             18

          a ceiling for children as a class.  It does not say
             19

          that research cannot be approved, because we have the
             20

          407.  
             21


                      So what you have to step back and think 
             22






                                                                         74


          about is -- and I understand the commensurate.  Now
              1

          commensurate has been -- If commensurate ends up to be
              2

          used as a relative standard for level of risk, it
              3


          wipes out all the others.  It is really irrelevant to
              4

          whether it is -- You know, everything becomes
              5

          relative.  
              6


                      So the question is -- Another way to look
              7

          at commensurate, even if it has to do with risk, is
              8

          that it places a final ceiling on how much risk is
              9

          there; because if -- Even if something is important to
             10


          a child's disorder or condition, if it is not an
             11

          experience that they are familiar with, you can't do
             12

          it.13

                      So don't think that commensurate allows
             14


          more risk.  It can also be looked at as placing a
             15

          ceiling.  But I think what you all have to get back to
             16

          is, one, nobody is saying the research can't be done. 
             17


          It's saying that it may have to go to a 407 or, if it
             18

          is a 404 here, it might have to go to a 406 for
             19

          another country or another environment.  So it is not
             20

          saying the research can't be done.
             21


                      The second question is do you think
             22






                                                                         75


          children who are more vulnerable are obligated to be
              1

          exposed to a higher level of risk for others, and a
              2

          different set of criteria put on them; or is it that
              3


          it is always a utilitarian framework that is utilized,
              4

          and the risk is always defined in terms of how
              5

          important the research is to children who are similar
              6


          to the child that is being asked to participate, and
              7

          what the evidentiary information is to support the
              8

          fact that the risk will only be minor.  But it's very
              9

          hard.
             10


                      MR. BARNES:  I agree with Celia that one
             11

          can always say that none of this research is precluded
             12

          by the decisions that we make under 404, 405 and 406
             13

          standards.  So that's true.  But one can always resort
             14


          to the 407 kind of special case scenario, but that
             15

          still doesn't really answer the question; because the
             16

          question is, if you put up so many hurdles to research
             17


          -- In other words, this is a triage mechanism, the way
             18

          that it is set up, because the less risky the IRB can
             19

          just pass on.  The most risky goes to the Secretary of
             20

          HHS.
             21


                      If one puts up so many -- But procedure is
             22






                                                                         76


          not without cost.  If one puts up too many procedures,
              1

          then what happens is that research studies are either
              2

          delayed, deferred or investigators simply decide that
              3


          there is so much delay in a 407 process that they just
              4

          won't do it.  They will move on to the next study.
              5