43rd Meeting National Bioethics Advisory Commission September 13, 2000

43rd Meeting
National Bioethics Advisory Commission
September 13, 2000
8:00 a.m.
U.S. Chamber of Commerce
Anheuser-Busch Briefing Center
1615 H Street, NW
Washington, DC 20062
EBERLIN REPORTING SERVICE
14208 Piccadilly Road
Silver Spring, Maryland 20906
(301) 460-8369
2
C O N T E N T S
Page
Opening Remarks-Dr. Shapiro------------------------------3
Ethical and Policy Issues in the Oversight of
Human Subjects Research
Discussion of Chapter 1-Dr. Speers-------------------4
Discussion of Chapter 5 Recommendations-Dr. Meslin-------16
Ethical and Policy Issues in the Oversight of
Human Subjects Research (continued)
Panel II: Privacy/Confidentiality
Dr. Sieber-------------------------------------52
Prof. Goldman----------------------------------64
Discussion with Commissioners------------------75
Panel III: Quality Control: assurances, site
inspections, accreditation, certification, and
licensure
Dr. Koski--------------------------------------97
Dr. Lepay-------------------------------------103
Mr. Hamm--------------------------------------117
Discussion with Commissioners-----------------127
3
1
P R O C E E D I N G S
2
OPENING REMARKS
3
BY HAROLD SHAPIRO, Ph.D.
4
DR. SHAPIRO:
Colleagues, those members who are
5 here, I would like to assemble and get our meeting
6 started this morning.
We are a little short of time.
I
7 want to make the best use we can of it.
8
Let me tell you what I propose to do this
9 morning.
I want to spend about a half hour right now on
10 a very brief review and reaction to Chapter 1 of the
11 Oversight Project which you have all received.
12 turn to Marjorie in a moment to do that.
I will
But I would
13 also like to ask Marjorie to indicate from her
14 perspective what kind of feedback that she needs in order
15 to continue to make forward progress here.
16
We have really quite an accelerated schedule in
17 front of us in the Oversight Project.
Our hope is that
18 we will have four chapters available for the Salt Lake
19 City meeting roughly six weeks from now.
20 certainly have three.
We will
And so, we are going to make rapid
4
1 progress here, and it is going to be dependent on
2 thoughtful feedback from the Commission to Marjorie.
We
3 will not have time for all that today, obviously, in half
4 an hour.
5
But I do want to save a half hour before we go
6 to the panels that are coming this morning to revisit a
7 couple of issues in the International Report, so we can
8 also move that forward.
And in particular, with some
9 recommendations in Chapter 5 we never got to discuss, I
10 want to go to those.
We really have a lot of information
11 and feedback on the others which will be restructured
12 along the lines of our discussion yesterday, because my
13 intention is still to try to get a full set of
14 recommendations out for public comment within the next
15 couple of weeks.
And so, we will certainly produce new
16 drafts almost immediately after this meeting, and look
17 forward to some feedback from you so we can then have-18 these go out for public comment.
19
As I mentioned yesterday, the public comment
20 session will take us beyond the Salt Lake City meeting,
21 so that report will probably not be in front of us at the
22 Salt Lake City meeting; we will spend it exclusively on
23 the Oversight Project, and as you know, we have two other
24 panels coming this morning on that.
25
So, in view of our tough time constraints, I
5
1 want to turn directly to Marjorie, and have her say a few
2 words about Chapter 1, and then get some feedback from
3 the Commission.
Marjorie?
4
ETHICAL AND POLICY ISSUES IN THE OVERSIGHT
5
OF HUMAN SUBJECTS RESEARCH
6
DISCUSSION OF CHAPTER 1
7
PRESENTATION BY MARJORIE A. SPEERS, Ph.D.
8
DR. SPEERS:
Thank you.
Just to remind you of
9 what we are trying to do in this chapter, we are trying
10 to lay out the rationale and justification for the
11 Oversight Report.
In particular, we are trying to very
12 clearly state what the problem is, and what it is the
13 Commission will be addressing in subsequent chapters.
14
In part, this chapter is before you now in
15 response to a request that you made at the June meeting
16 in San Francisco that we very clearly state what the
17 problem is.
So, what I would like to get from you today
18 is, is the problem clearly stated here?
19 problem that you think it is?
Is it the
And when I say problem, I
20 recognize that it is a multifactorial problem.
So, have
21 we emphasized the right aspects of the problem, or the
22 ones that you want us to address?
23
Before we do that, I wanted to just spend a
24 couple of minutes telling you about the next three
25 chapters that you will be getting.
Again, what we are
6
1 trying to do in this chapter is very clearly state what
2 the problem is, so that then, the next three chapters
3 will address recommendations related to the problem, and
4 we have conceptualized those three chapters in the
5 following way.
One of the chapters will deal
6 with the oversight system at the national level, or at a
7 macro level.
It will be a chapter that provides a very
8 broad perspective, and recommendations related to an
9 entire oversight system.
10 Another chapter will deal with selected ethical issues,
11 and how those ethical issues, then, are applied, or
12 carried out through regulation and guidance.
And then,
13 the third chapter will address issues related to the
14 local oversight system.
15
So, we are envision taking this problem and then
16 addressing the solutions for it, and the recommendations
17 that you will make, by categorizing them into those three
18 areas, the national level, ethical issues, and then the
19 local level.
It is very likely that then there would be
20 another chapter that puts it all together and summarizes
21 it.
22
We are working on Chapter 2 now, and have a
23 fairly good draft of Chapter 2.
It was very clear in
24 writing that chapter that everything is connected to
25 everything in this system, and it really becomes very
7
1 difficult in some ways to write the chapters with the
2 recommendations, because it assumes--and even to deal
3 with the system on a national level, it assumes that you
4 already know what we are going to say about the local
5 level, or what we are going to say about some of the
6 substantive ethical issues.
7
For that reason, it is likely that you will get
8 the next three chapters as a package.
And I know that
9 that is a burden for you to have three chapters at once
10 to read, or even two chapters, if we do the next two for
11 sure.
But I think the more that you have in front of you
12 when you are looking at any one chapter, so that you have
13 as much of the entire system before you, it will be more
14 helpful to you in reading it.
So, anticipate that that
15 is what we are planning to do.
16
And as Harold said, it is our intention and goal
17 to try to have those three chapters, plus this Chapter 1,
18 so four chapters, before you at the October meeting.
If
19 we don't achieve that goal, then our second goal is to
20 have three chapters before you, the next two plus this
21 Chapter 1 as it is revised.
22
We will send out an e-mail to you asking you to
23 provide your comments, particularly the ones that we
24 can't go over today, over the next week to ten days so we
25 can continue to work on Chapter 1.
8
1
So, what I would like to hear in terms of
2 discussion and what would be helpful to us again, is to
3 hear whether you feel that we have accurately described
4 the problem, whether you feel that the balance and tone
5 in this chapter is appropriate, and if there is anything
6 that we have missed.
7
DR. SHAPIRO:
Thank you very much.
8 the comments of Commissioners.
9
10 praise.
PROF. CHARO:
Let's go to
Alta, Bernie, then Carol.
First, let me start the chorus of
It is really good.
It does a wonderful job, and
11 it covers a lot of material, and it was a pleasure to see
12 it, and get a sense of where the report is going to go.
13 So, first, thank you very, very much.
14
My comments are three items that I think we
15 might add, or emphasis somewhat differently.
The first
16 is very small, and it is on page ten, where you talk
17 about NBAC's unique interest.
I think there was an
18 inadvertent oversight because in your list of reports
19 there is one other official action.
Our very first was a
20 formal resolution about extending human subject
21 protections beyond federally funded and FDA regulated,
22 and I thought we should add that.
23
The second had to do with the phenomenon of
24 state, that is, not federal or governmental in general,
25 but actually state-level government, or county-level
9
1 government funded research.
I know I have got it marked
2 here, but there is a page where there is an
3 acknowledgement that some research is done by state
4 governments and less frequently counties, but from now on
5 we will call it private sector research.
6
I understood that, you know, from a syntactical
7 point of view, but actually, it allows us to slide over
8 what is an interesting area that dovetails with one of
9 our reports which is research with people with mental
10 illnesses or other decisional impairments, a lot of which
11 goes on in state hospitals, and is beyond the pale of the
12 current federal regulations under many circumstances, and
13 I think raises, (and this now dovetails into the third
14 point), raises the very special issues of trust which is
15 discussed here in other places.
16
But as has been mentioned in other meetings, one
17 of the distinguishing factors of the research
18 relationship in the biomedical context, is the subtle
19 change of a relationship in which there is a great deal
20 of trust on the part of the patient toward the
21 professional into one that does not deserve exactly the
22 same kind of trust.
You might still have trust in the
23 research enterprise, but it is not the same as the trust
24 in your personal physician.
25
And I think that that issue of trust is also
10
1 profoundly altered when we are talking about governmental
2 sponsorship, funding, and conduct of research, because I
3 think that our historical experience has been that, when
4 it is the government that actually seems to be in charge
5 of the research and something goes wrong, it seems to be
6 doubly shocking to the conscience.
And I would hate to
7 lose that, either the relational aspects of research in
8 general as one of the reasons why we regulate research,
9 and then, very specifically, try to find a way to pull
10 out the role of state governments and county governments
11 in that area.
12
DR. SHAPIRO:
Thank you.
13 commissioners want to speak.
Quite a few
Let's try to be as brief as
14 possible since we have very limited time on this one.
15 Bernie.
16
DR. LO:
Marjorie, I also want to add my thanks
17 and praise for your efforts on a very complicated topic.
18
My main concern is a matter of emphasis or
19 balance.
As I read this, I tried to take the perspective
20 of a citizen who is not an aficionado of government
21 regulations, and what I didn't find here, and what I
22 would like to see, is a sense of what are the current
23 problems from a human perspective or from a patient
24 research perspective.
We don't really make any mention
25 of the current things driving the discussion, for
11
1 example, the Jesse Gelsinger case or some of the things
2 we have considered in previous reports.
So, I would like
3 to see a sense of what are the actual--scandals is too
4 strong a word, but the cases that made people stop and
5 say "Whoa!
If that is what is going on, there is a
6 serious problem."
7
I think a lot of the first chapter really has to
8 do with regulation issues and composition of IRB issues,
9 that really I don't think grab the public attention.
I
10 don't want us to fall into the trap that, for instance,
11 many scientists say that it is just a matter of complying
12 with regulations instead of real substance.
13
And my second point is that I would like to, if
14 possible, and of course, this may be asking you to
15 predict the future, to tie the introduction into the
16 conclusions.
To the extent to which we can anticipate in
17 the introduction some of the big recommendations we are
18 going to make, we need to set the stage here.
So, let me
19 just take a crack at throwing out some issues I think we
20 are going to want to make some recommendations on.
21
One is more attention to the consent process, as
22 opposed to an emphasis on consent forms, and you know, to
23 use some examples here where people just didn't
24 understand what they were getting into, even though the
25 consent form said it in fine print.
The issue that Greg
12
1 Koski raised about the current oversight is totally
2 driven to front-end IRB approval, and no concern about
3 how the research is actually carried out, and how, in
4 particular, researchers deal with unexpected issues that
5 emerge in the course of doing research.
And I think, you
6 know, to me, that is one of the real tragedies of the
7 Jesse Gelsinger case.
8
A third issue, I think, is a sense that there is
9 too much regulation of relatively low-risk research, and
10 not enough attention, or at least cases where dramatic
11 research was carried out under IRB approval, that in
12 retrospect, people said how could that happen.
So, you
13 know, to take an example from the recent past, the
14 approval by the IRB, post-hoc though it was, of the
15 blastomere separation experiment.
You know, it was
16 approved; it was approved after the experiment was done.
17
But they clearly didn't (inaudible) the issues, and we
18 need to sort of address that, I think.
19
And finally, I think we need to address the
20 issue of whether we really know what IRBs are doing.
21 There is so much emphasis on, you know, that they didn't
22 keep minutes right or they didn't have the quorum right
23 or the composition wasn't right.
But what we really
24 don't have, and this goes to some issues we are going to
25 talk about later, in terms of what is their actual
13
1 performance, and on things we really care about in terms
2 of protecting human subjects, whatever those variables
3 are, do we really know what they are doing?
And I think
4 to the extent we are going to talk about certification
5 and training, I think we have to try and anticipate the
6 substantive issues.
7
So, if we could highlight those things, I think
8 the report will find a wider audience than its current
9 emphasis might give it.
10
DR. SHAPIRO:
Thank you, Bernie.
11 really very extremely helpful comments.
12
DR. GREIDER:
13 a question.
They were
Carol?
I have just one comment, and then
And the comment is to add my voice to the
14 others who have said that this is really terrific.
I
15 think that there is so much here in Chapter 1, and I like
16 the completeness of it.
That said, there are just a few
17 places which I can give written editorial comments, where
18 I think that maybe there is a little bit too much detail,
19 and those might be put into later chapters.
20
But the question is, as you laid out the other
21 chapters, national issues, ethical, and local, in the
22 past we have tried to ground a lot of our conclusions on
23 substantive, ethical issues, and norms, and so I am
24 wondering why we would start with national oversight,
25 rather than the ethical.
Why put the ethical issues
14
1 second?
2
DR. SPEERS:
In part, it seemed to me, in
3 working with this report that in needing to start
4 somewhere we, in part, have to do some very basic things,
5 like define what an oversight system is, define what the
6 components of it are, define who the players are, and
7 what the functions are.
So, it seemed to me that that
8 would come first, and then after we discuss some of the
9 ethical issues.
10
We actually toyed with the idea of doing it the
11 other way, but I think that given that we have to jump in
12 somewhere, we should jump in with defining what the
13 oversight system is.
14 it.
So, that was the reason for doing
I think that again, when you see the chapters, if
15 you feel they should be re-ordered, that can clearly be
16 done.
17
DR. GREIDER:
It just might go to addressing
18 some of the things that Bernie was saying, to have some
19 of the actual cases as it relates to people.
It might
20 help in that, but I am willing to wait and see.
21
DR. SHAPIRO:
Thank you.
I do want to make a
22 comment.
David is next on my list here.
But we really
23 do want any detailed comments you have made and marked up
24 copies. They are extremely helpful to Marjorie and anyone
25 else involved in actually doing the text.
So please,
15
1 either leave them with us or send them to us, any way you
2 want.
3
We surely want to get those comments.
DR. COX:
This will be fast.
David?
It is great.
4 Going a little bit along Bernie's lines, a feeling that
5 is missing is that people are in control of their own
6 protection, because there are lots of players.
The
7 system is paternalistic, and it doesn't allow the people,
8 who are being protected, enough say in their own
9 protection.
And that came out in the testimony
10 yesterday, and I think that it is not much of the system
11 right now, but to make sure that those people who we are
12 trying to protect, are seen as some of the players in the
13 mix.
14
So, I don't have specific places to do that,
15 Marjorie, but I think you understand what I mean.
16 Because the way it was historically, and you lay out very
17 nicely, is that it was a very protectionist,
18 paternalistic approach, and that is really changing.
In
19 fact, it is one of the reasons that has necessitated
20 rethinking a major overhaul.
So, it was just a feeling I
21 didn't get very much in terms of the text right now.
22
DR. SHAPIRO:
Thank you very much.
Are there
23 other comments people would like to make with respect to
24 the draft of 1?
Understand, we are not having a full
25 discussion now; we are limited in time.
But other
16
1 comments that you think might be helpful, suggestions,
2 questions, et cetera, to those who are going to be
3 producing the next draft of this chapter and subsequent
4 chapters?
5
All right, that is fine.
But let me again
6 repeat what I said just a moment ago.
I have a very
7 heavily marked up copy, and I am sure that many of you
8 do, too, and they are invaluable if they are legible.
I
9 have decided I have to go back to my word processor since
10 mine look illegible to me, but I will send them in to
11 Marjorie, and I hope you all do the same.
12
Okay.
Thank you very much.
As I mentioned
13 earlier on, our panels start approximately at 9:10 or
14 9:15, I have forgotten what the time schedule is, and
15 since we have visitors coming for that, I don't like to
16 delay that if we can avoid it.
But we do need to spend a
17 little bit of time, perhaps we have three-quarters of an
18 hour, to pursue some further issues on the International
19 Report.
In particular, there were some recommendations,
20 many recommendations that you saw yesterday, that are
21 going to have to be redrafted along the lines of our
22 discussion, and we don't have time to go back to that
23 today.
But you will certainly hear very quickly about
24 this with some new proposals very shortly.
But I do want
25 to ask Eric to just go over a few of the recommendations
17
1 that we didn't get a chance to discuss yesterday, just to
2 get a sense of where the Commission is, so as we redraft
3 this, we can restructure these recommendations in ways
4 that seem sensible to the Commission.
5 Eric.
So, let me turn to
Eric?
6
DISCUSSION OF CHAPTER 5 RECOMMENDATIONS
7
PRESENTATION BY ERIC A. MESLIN, Ph.D.
8
DR. MESLIN:
I won't repeat the things that we
9 have already discussed.
The recommendations that we have
10 not discussed directly in Chapter 5 are recommendations
11 5.4 to 5.9 inclusive.
I am going to suggest if you still
12 have the handout version of the recommendations that I
13 provided to you that there are some in that list which
14 are, if I can predict what you might think, are not
15 terribly controversial.
I may be wrong, but that is my
16 sense.
17
The two that come immediately to mind are
18 Recommendations 5.6:
“The relevant U.S. research
19 regulations at 45 CFR 46, Sub-part A should be amended to
20 include a section that addresses international
21 collaborative research conducted or sponsored by the
22 United States.”
When I say non-controversial, that was
23 put in as a kind of cumulative recommendation that you
24 may wish to add at the end of Chapter 5, or at the
25 beginning, and simply repeat or cross-reference with
18
1 those other recommendations that do have a need for
2 regulatory change.
That may or may not stay depending on
3 whether you think it is a good idea to have such a
4 cumulative recommendation.
5
Diane?
6
DR. SCOTT-JONES:
Would that recommendation
7 perhaps be better coming before Recommendation 5.3?
8 Because 5.3 and 5.4 talk about issues that are addressed
9 in that regulation.
10
DR. MESLIN:
Right.
That is one of the reasons
11 that I suggested it may not be a controversial
12 recommendation as much as where it needs to be placed
13 after you have agreed on the other substantive ones.
14
Alex, did you want to--?
15
PROF. CAPRON:
Well, I, frankly, did not
16 understand what 5.6 was trying to achieve in the context
17 of these other recommendations.
Is there a way of
18 summarizing that quickly?
19
DR. MESLIN:
Only what I had said before.
It
20 was put in there as a way for you to decide, if you felt
21 that a cumulative recommendation that summarized those
22 other relevant recommendations, which in this case would
23 probably be, depending on how 5.3 and 4 are written,
24 should be mentioned.
25 recommendation.
It is, by no means, a required
19
1
PROF. CAPRON:
So this is a statement of
2 something that is implicit otherwise.
3
DR. MESLIN:
4
PROF. CAPRON:
Yes.
Oh, okay.
Because I thought
5 somehow it was suggesting-6
DR. MESLIN:
7
PROF. CAPRON:
No.
--that there was going to be an
8 additional category.
9
10
DR. MESLIN:
PROF. CAPRON:
Originally, in the form-Instead of saying "that
11 addresses", why don't we say "to include the substantive
12 changes relating to international collaborative research
13 contained in the recommendations of this report".
I
14 mean, that is the thrust of what we are trying to say.
15 Otherwise, I had a sense that the implication is,somehow
16 the present regulations don't address international
17 collaborative research, which made no sense to me.
18
DR. SHAPIRO:
19
DR. MESLIN:
Good point.
Right.
Thank you. We can make
20 that-21
PROF. CAPRON:
This would be, if anything, the
22 very last recommendation of the entire report, and we are
23 in effect saying bite the bullet, and amend 45 CFR.
24
DR. SHAPIRO:
To accommodate these
25 recommendations, exactly as you said.
That is a good way
20
1 to put it.
2
PROF. CAPRON:
3
DR. SHAPIRO:
4
DR. MESLIN:
That is not the way it reads.
Right.
The other, and I said I was taking
5 these slightly out of order, thinking that they were non6 controversial, was Recommendation 5.9: “NIH, CDC, and
7 other agencies that sponsor international research should
8 permit researchers to request financial support for the
9 cost of compliance with ethical requirements at the
10 institutions with which they collaborate, et cetera.”
11
PROF. CAPRON:
12 are now prohibited?
Is that the present understanding?
13
DR. MESLIN:
14
PROF. CAPRON:
15
DR. MESLIN:
16
17
Sorry.
Is there any indication that they
Prohibited from requesting?
Yes.
No, they are not prohibited from--
Are they prohibited from-PROF. CHARO:
This came up at the San Francisco
18 meeting, as you may recall, and I think Rachel was
19 helpful on some of the details here and came up with some
20 suggested language, because there were different kinds of
21 restrictions depending on which agency it is that was
22 funding the research.
23
DR. MESLIN:
This is the language that emerged
24 to some extent from that meeting in San Francisco.
25 was general rather than--
It
A former recommendation had
21
1 indirect cost rates, and a number of those sorts of
2 things, and this was made more generic.
3
PROF. CAPRON:
Could we replace the word "IRB"
4 in the last line with the word "review"?
Because IRB is
5 a generic--I mean, it is a specific U.S. parochial term.
6
DR. MESLIN:
7
DR. GREIDER:
Right.
Carol?
It stood out to me that in this
8 recommendation NIH and CDC are singled out, whereas in
9 the other recommendations it just said "U.S agencies that
10 sponsor".
I wasn't clear as to why that needed to be
11 different.
12
DR. MESLIN:
No, it was an artifact of former
13 drafting.
14
Other thoughts about those?
Those were the two
15 out of the six that were remaining that I thought were
16 non-controversial, and we might want to go on to others.
17
PROF. CAPRON:
And in light of Alta's comment,
18 the word "request" is going to be replaced with the word
19 "receive"?
20
PROF. CHARO:
I don't think anybody is really
21 confused by it.
22
MS. LEVINSON:
I will work with Eric on this one
23 to tweak that because, of course, they can request it,
24 but Alta is right.
There are caps on administrative
25 costs that make it difficult to receive them, so we will
22
1 work on finessing.
2
DR. MESLIN:
Okay.
3 hope will be discussion.
Now we are left with what I
I am not sure, Alex, whether
4 you had done any nighttime work.
5
PROF. CAPRON:
6
DR. MESLIN:
7 for--
(Inaudible.)
Okay. Do you also have it, at least
Which one were you working on, so we won't go to
8 that one?
9
10
PROF. CAPRON:
DR. MESLIN:
Oh, 5.3, 5.4.
Okay.
11 would like to suggest--
That leaves 5.5 and 5.7.
And 5.8.
I
I would like to
12 suggest, Harold, unless there is any objection, that 3,
13 4, and 5 actually are seen as a cluster, depending on how
14 the determinations of equivalent protection are made, and
15 by whom, and with what degree of authority a central body
16 has.
It may be that 5.5. which for those who, perhaps,
17 don't have it in front of them, "Where national laws,
18 regulations, or guidelines have not been adopted by the
19 host country, U.S. sponsoring agencies should recognize
20 the host country's authority to adhere to accepted
21 international guidelines."
22
The basic message behind Recommendations 5.3,
23 5.4, and 5.5. is how does the U.S. government, and
24 through what mechanism, grant or determine that another
25 country can use guidelines that are equivalent or
23
1 provide equivalent protection to those of the United
2 States.
Whether those are national guidelines of the
3 country, or whether they are international guidelines
4 that the country uses in lieu of national guidelines may
5 be irrelevant once issues around who determines
6 equivalent protection are settled.
Maybe we should wait
7 there for Alex's text to be circulated, to have that
8 discussion.
9
The issues in 5.7 should be familiar to the
10 Commission.
This is brand new. It is on page 27 of the
11 longer text, or just the bottom of page 2 of the handout.
12
Formerly, there was a recommendation that encouraged the
13 old OPRR to use other mechanisms in addition to the SPA
14 process.
Because we are aware that the assurance process
15 is under revision, and there are new proposals for how
16 the assurance process will work, both simplifying and
17 shortening, et cetera, it made sense to us that NBAC
18 would be wise to make this type of recommendation, rather
19 than to just simply encourage them to do something else.
20
Let's see how well the whatever else they are working on
21 is doing.
So there is no editorial pride in the
22 language.
The essence was that this process should be
23 evaluated after a period of time.
24
Bernie?
25
DR. LO:
Eric, to pick up on a point you just
24
1 made, I am wondering if somewhere there should be a
2 recommendation that we support and encourage the
3 simplification and, you know, lessening of the burdens of
4 obtaining these assurances.
I mean, many of our
5 recommendations, it seems to me, are secondary to the
6 primary recommendation that things have got to be simpler
7 and, therefore, better.
So, not just the 3, 4, and 5
8 that go into who gets to determine what is equivalent
9 and, therefore, simplify, but also, this recommendation
10 which has to do with seeing whether those goals are
11 achieved.
We need, I think, to declare our support for
12 those goals somewhere as a recommendation.
13
DR. MESLIN:
Bernie, were you suggesting that
14 that would be part of what is now 7, or a separate--?
15
DR. LO:
No, I would like to see that as a high-
16 up recommendation, that we want the simplification
17 process simplified and made easier, while still assuring
18 adequate protection.
19
DR. SHAPIRO:
20 important point.
I think that is, actually, an
I haven't thought through exactly where
21 it should come, but I think we often overlook that issue
22 in some of the things that we discuss, and that is one of
23 the criticisms of all this, that things are unnecessarily
24 complicated.
Some things need to be complicated, but
25 some things are unnecessarily complicated, and prevent,
25
1 you know, ethically quite appropriate research from going
2 forward, just because the bureaucracy gets in the way.
3 And that is a point we need to make, and it is a high-up
4 point, as you point out.
5
DR. LO:
But also, it is an assumption that
6 underlies a lot of our other recommendations.
I just
7 think we need to make it more explicit.
8
DR. SHAPIRO:
9
PROF. CAPRON:
Right.
Alex?
Well, you know, the urge to say
10 we should back off of all of this, I sympathize with.
It
11 is, however, true that on the domestic side, while this
12 is a time when, I think, Dr. Koski and others have an
13 opportunity to rethink the entire mechanism, (and I take
14 from his testimony yesterday that he plans to do that),
15 at the moment, any thought that there should be less
16 oversight of, less encouragement to good practices in,
17 and so forth, IRBs either domestically or
18 internationally, strikes me as, perhaps, getting the cart
19 before the horse.
20
I mean, we do not now have a system which has
21 been able to uniformly provide, even at very good
22 institutions, a commendable implementation of the
23 expectations for ethical human subjects research.
And
24 while I do think that, if there are countries which have
25 systems in place, that there is a certain, to use the
26
1 word Alta used yesterday, need for comity in treating
2 their systems, the notion that what we really want to do
3 is get all the regulations out of the way, and make this
4 just as simple as possible, I don't have the sense that
5 around the world, anymore than around the United States,
6 we would be happy with the results that would flow from
7 simply stepping back.
8
Now, maybe I have misunderstood your urge--
9
DR. LO:
No, I think that is a good point,
10 because I didn't state what I wanted to say clearly.
I
11 think what we want to simplify is the assurance process,
12 not back off on sort of oversight.
I think, you know,
13 you are right, that we need to be very careful about the
14 language we use, but I am talking about what now is,
15 generally, I think conceded to be a very cumbersome
16 special assurance process that is very burdensome, but
17 doesn't necessarily provide substantive protection.
18
PROF. CAPRON:
May I, Mr. Chairman, respond to
19 that?
20
DR. SHAPIRO:
21
PROF. CAPRON:
Yes.
In that line, I would agree, but
22 it would seem to me that the major thrust of what we are
23 talking about is something that will come up, really, in
24 the report domestically, because most of the research
25 that we are still talking about occurs domestically, and
27
1 a change in the assurance process domestically ought to
2 lead to simplification and have better mechanisms for
3 encouraging the right outcomes, and so forth.
4
I would, therefore, think that we should refer
5 readers, as it were, to our forthcoming report.
In other
6 words, here, rather than having a major recommendation,
7 it would be a matter of saying we note the plans for
8 revisions that are underway; we encourage and applaud
9 efforts to simplify the assurance process; certainly,
10 that should have an impact internationally as well as
11 domestically, particularly making the assurance process
12 more relevant to international standards, rather than
13 solely the language and procedural expectations of the
14 domestic system which we know is a stumbling block for
15 getting those assurances.
And the notion that that whole
16 mechanism, including its international side, ought to be
17 evaluated after several years.
18
But I would not be comfortable going much beyond
19 that, because we really haven't explored what it would
20 mean to have something in place of the present assurance
21 system.
We just had hints from Dr. Koski yesterday about
22 what he was thinking of.
23
DR. SHAPIRO:
24 want to--?
25
Other comments?
Alta, did you
David?
PROF. CHARO:
David was ahead of me.
28
1
DR. COX:
So, I am sort of in between on this,
2 and let me just tell you the feeling that I get from
3 reading these recommendations is that I don't want to be
4 there, because it sounds like government, you know,
5 bureaucracy.
That is what I see Bernie responding to.
6 On the other hand, I agree with what Alex says.
7
So, what one can put in the recommendations that
8 is not there at all is some clue to the process of how we
9 are going to do this, and the way we are going to do it
10 is that there are going to be some overriding principles
11 on which one makes these kinds of determinations.
Now, I
12 know that that is obvious to us around the table, but it
13 is not obvious to a reader that reads these
14 recommendations, because we just say do it, but we don't
15 give any clue to a structure behind how it is going to
16 happen.
17
So, how does one figure out what an equivalent
18 protection is?
Well, it is because we have certain
19 principles that we hold fundamental, some so fundamental
20 that we won't even let research be done in a place, you
21 know, if those principles are violated.
So, that tone
22 doesn't come through these recommendations at all.
23
Now, I realize this isn't very helpful in terms
24 of the specific, you know, word-smithing of them, but I
25 think it is that lack of that feeling that is causing
29
1 this, I believe, discussion between Bernie and Alex.
2
DR. SHAPIRO:
3 appropriate--
Well, look, if we can find
I don't want to take any longer on this
4 particular issue because we have to get on, but as I
5 tried to say carefully before, if there are things we can
6 see that are unnecessarily complicated, not because we
7 want to relieve people of burdens they need to carry; we
8 want to relieve people of burdens they needn't carry.
9 Then, we ought to be sensitive to that.
What we will
10 find, I don't know.
11
So, let's go on, because we just have not got
12 very much longer.
13
DR. MESLIN:
Do you want to go to Alex's?
14 Because he has done some work on 5.3 and 5.4.
15
16 that?
DR. SHAPIRO:
Okay.
People all got a copy?
17 you don't have a copy.
Has everybody got a copy of
Just raise your hand if
Thank you.
18
Alex, why don't you--?
19
PROF. CAPRON:
20 intention.
Well, let me just tell you the
The intention was to summarize in one
21 sentence, the first sentence of 5.3, the notion of the
22 process, led by OHRP, and involving the other agencies
23 that would lead to the policy guidance, and move forward
24 the process of equivalent protection.
By the way, I make
25 no promises about that being the right section.
It is
30
1 what I got out of reading the report, and I may have
2 misread it.
So, please, someone--
I didn't have the
3 regulations at hand.
4
The second sentence is intended simply, really
5 almost descriptively, about the effect of a determination
6 under that policy guidance, and it is there-7 the passive voice.
It is in
The intent is to say once such a
8 determination has been made, then the federal agencies
9 treat the IRB, or the review body (I tried to avoid the
10 word "IRB") as equivalent.
11
Then, in 5.4., I took the next step to try to
12 say what is going to happen if there is a problem with
13 this implementation process, and OHRP becomes explicitly
14 the lead agency on this.
Now, that we had talked about,
15 but I don't know that I summarized everybody's view on
16 that.
I thought we needed something to shoot at.
So,
17 that is what 5.4 tries to do.
18
Two steps then, policy and implementation.
19
DR. SHAPIRO:
20 discuss this.
21
22 5.3.
Thank you very much.
Let's just
Carol, and then Bernie.
DR. GREIDER:
I just have one question about
It doesn't seem to me that it says who is making
23 the determination.
The first sentence just talks about
24 setting forth criteria and a process, and the second
25 sentence says "once a determination has been made", and I
31
1 ask, "Made by whom?"
2
PROF. CAPRON:
3 right now.
This is what I tried to address
This is, in effect, a description of the
4 effect of such a determination.
The "made by whom" is
5 5.4, and the reason for doing that--
The second sentence
6 could become commentary, if you are more comfortable with
7 that, and probably as commentary it could be massaged
8 even into several sentences.
9 a thing?
I mean, why do we need such
Because if we have it, then once an agency has
10 made a determination--
Now, we could just say that "once
11 an agency has made a determination", if that language
12 would make you more comfortable.
13
DR. GREIDER:
Could you put the second sentence
14 of 3 below 4?
15
PROF. CAPRON:
16 policy guidance do?
Well, the idea was what does this
Policy guidance means that if
17 implemented, there is an equivalency of the review bodies
18 that have been found by that country to meet its system
19 with our own MPA-qualified IRBs.
And as I say, it may
20 just be that that sentence really should just be
21 descriptive commentary, because it is--
Or maybe not.
22 Or, to follow my general sense, and the point you are
23 making, maybe I should have written it in the active
24 voice, and say, "Once a federal agency has determined--"
25
Would that make you--?
I mean, I could certainly say--
32
1
DR. SHAPIRO:
Let's--
We certainly have some
2 options there, but let's try to focus in our discussion
3 here on the substance, the principles behind this which I
4 think are really quite clear the way Alex has written it
5 although, you know, perhaps it could be improved.
6
I have a number of people who want to speak.
7 Bernie, Steve, Alta, and Larry.
8
DR. LO:
9 and I like them.
I think these revisions are very clear,
Again, I am concerned about trying to
10 step back a step, and it seems to me that a basic problem
11 is that the current existing authority to declare that
12 another country has equivalent protections has not been
13 acted upon.
And I think what we want to say is, alot of
14 countries out there may well have policies in place that
15 are equivalent, and we haven't declared that, and as a
16 result, they have to go through--you know, people doing
17 research in those countries have to go through an
18 incredibly cumbersome process, and that whoever has the
19 authority to do that ought to get on the ball and look at
20 these things, and say these countries have equivalent
21 protections, and make it easier to do research, because
22 we think subjects are being protected.
It seems to me
23 that is the preconception to which Alex's two revisions
24 give a very clear laying out of how to do that.
25
DR. SHAPIRO:
That is very helpful.
Part of
33
1 that, but not all of it, is in the text, and I think that
2 will help us think-3
(Simultaneous discussion.)
4
DR. LO:
And I tried to--
Did I give you
5 something on-6
(Simultaneous discussion.)
7
DR. SHAPIRO:
8
DR. LO:
9
DR. SHAPIRO:
10
Okay.
MR. HOLTZMAN:
Yes, I have that right here.
That tries to-And that will be helpful.
Yes.
Steve?
I would like to second
11 Bernie's motion there, that the focus should be on the
12 substantive end that we are trying to achieve which is,
13 effectively, a certification process of other nations,
14 right?
Because the rest of this is just because of the
15 way we currently have a system with different agencies.
16
Alex's draft of this that OHRP coordinates--
17 And we could go stronger, and say it is important to get
18 to the substantive, and OHRP take the lead, and we
19 recommend other agencies follow their lead.
We could go
20 that way.
21
DR. SHAPIRO:
Alta?
22
PROF. CHARO:
I think that what has been drafted
23 here works very well, but it is necessarily tied to the
24 current system, and as it has been mentioned, that may be
25 in flux.
So, it is possible that this would be helped by
34
1 having a recommendation next to it that anticipates its
2 goals, but doesn't specify the mechanisms so precisely.
3
It is, I think, a little bit of what Bernie was
4 saying, if I may, something that goes something like "The
5 federal government should encourage and facilitate
6 international research to that end.
It should help U.S.
7 researchers to identify sites and collaborators where
8 research can be conducted in a manner that satisfies the
9 following core ethical and procedural values".
And then
10 begins to pull out a list, so that we get to this
11 question of what constitutes substantial equivalence
12 without using that language, and without tying it to
13 current regs.
And on the list is things like independent
14 prior review, minimization of risk, favorable
15 risk/benefit balance, ideally, adequate compensation for
16 injury, individualized informed consent from all
17 competent adults if the research is more than minimal
18 risk, things like that.
19 stage.
And in that sense, set the
And then, with some text saying if we were to do
20 it under current rules, we would recommend that this be
21 the way you do it, and I think, then, Alex's language
22 gets very nicely to how we go about it.
But it sets out
23 the over-arching goals should those current rules change,
24 and if the system moves toward registration instead of
25 assurances, et cetera.
35
1
DR. SHAPIRO:
Okay.
Helpful comment.
I hope
2 you will give us the--so we can at least review it
3 carefully.
4
PROF. CAPRON:
Can I just suggest--?
I think
5 that is a very helpful comment, and in a way, it is a
6 framing comment for the whole report, and I would put it
7 right up at page 3 of the first chapter.
I mean, it is
8 at that point that we recite those three basic
9 principles, and an over-arching recommendation that
10 recognizes that the system is in flux, and this report
11 contains a number of specific recommendations framed
12 within the present system, but the goal is to--
And just
13 take the transcript and take Alta's paragraph and plug it
14 right in there, and make that a recommendation right at
15 the first chapter.
And that is, as you say, an
16 orienting, or framing-17
PROF. CHARO:
We would need collectively to make
18 sure that we are comfortable with the particular list of
19 things we have now identified and announced as core.
20
DR. SHAPIRO:
That is always a problem whenever
21 you construct a list like that, but we can find ways to
22 deal with that that don't focus on, you know, whether we
23 left out one, or forgot one, or something, and so on. So,
24 let's have the text, Alta.
25
Larry?
36
1
DR. MIIKE:
Wait long enough in this group, and
2 you don't have an original thought.
3
DR. SHAPIRO:
4
(Laughter.)
5
DR. MIIKE:
That is my strategy.
I was going to comment basically
6 what Alta said, because if you look at the chapter, and
7 not the list of recommendations, these are obviously tied
8 together, and it needed some--
Since many people are
9 just going to look at the recommendations, they needed
10 something, and a statement such as what Alta said needs
11 to be done.
12
On Alex's two clarifying changes, I agree.
But
13 Alex, why did you put the weasel word "endeavor" in
14 there?
15
DR. SHAPIRO:
16
DR. MIIKE:
That is an editorial comment.
You sort of let the agencies out by
17 saying they should endeavor, rather than they should do
18 it, uniformly.
19
MR. HOLTZMAN:
It is a recognition of human
20 imperfection, Larry.
21
(Laughter.)
22
DR. SHAPIRO:
23
Okay.
24
DR. MURRAY:
25 that colloquy.
Including our own.
Tom?
It is going to be hard to follow
This has been a very good discussion.
37
1 Thanks to Alex for drafting, and Alta for her useful
2 additions.
I am now getting a little less clear what the
3 status of Recommendation 5.3 would be.
Would it--?
If
4 we are going to keep it as a recommendation, I would
5 still revise it in the sense that I would put-6 have two sentences, I believe?
We now
I would start with a
7 sentence that frames the broad principle that we want to,
8 you know, respect other nations who are, with integrity,
9 attempting to protect their own subjects.
10 do something that frames it broadly.
So, we want to
And then, probably
11 use a version of the current first sentence which says
12 under the current system, this is how we would do it.
13
The third one reads like a legal contract, and I
14 think it would be at most--could be broken up and just
15 added as commentary later on.
16
17 to--
DR. SHAPIRO:
Okay, thank you.
And I do want
It is helpful that when these things are inserted
18 in text, it is hard to know whether you want that
19 introductory language in the text or in here, but that is
20 something we need to work on.
But I think that is
21 helpful.
22
DR. MURRAY:
I think in the recommendation the
23 first sentence ought to be an enunciation of the general
24 principle.
25
DR. SHAPIRO:
No, I understand.
38
1
DR. MURRAY:
Not introductory text, but actually
2 the language of the recommendation.
3
DR. SHAPIRO:
Okay, last comment on these,
4 because then we just have to go on.
5
PROF. CAPRON:
Stimulated by Carol's good
6 remark, let me suggest to you that if we have anything
7 like this, the second sentence of 5.3 might read as
8 follows: "Once a federal agency that sponsors
9 international research has determined, pursuant to this
10 policy guidance, that a nation's human research
11 guidelines and procedures provide quote 'equivalent
12 protection', review bodies established or accepted by the
13 appropriate authorities in that nation may be treated by
14 the agency as equivalent to a domestic IRB possessing a
15 valid federal MPA."
16
DR. SHAPIRO:
Okay.
If you would just give us
17 the language, we will continue to work on the language,
18 and I think we understand the general point.
19
I would like to spend--
20 language from Alex.)
(So, you will get that
I would like now to move on to the
21 other recommendations we haven't even touched on, there
22 are only one or two, and just get some initial responses.
23
I mean, we can't resolve all of this today, given our
24 time, but just get some initial responses to it.
25
DR. MESLIN:
Believe it or not, we have
Eric?
39
1 discussed all but one remaining of the recommendations,
2 and that remaining recommendation is 5.8: "Independent
3 review of proposed research must be conducted by an
4 unbiased, competent body in the country where U.S.5 sponsored research takes place.
In addition, independent
6 review must also occur by the sponsor.
In the case of
7 U.S. sponsors, this review should be conducted in
8 accordance with U.S. research regulations, or those
9 deemed to provide equivalent protection to participants."
10
And then, we reference other recommendations.
11 "Researchers should include in the research protocol
12 plans for facilitating communication between or among
13 IRBs in the United States and collaborating countries."
14
The principle that this recommendation is
15 supposed to illuminate is how many IRBs does it take-16
DR. SHAPIRO:
17
(Laughter.)
18
DR. MESLIN:
To change a light bulb.
--to allow research to go forward,
19 and which IRBs should they be.
The first part of the
20 recommendation says the host country's IRB has to review
21 this.
How many others, and which others, have to review
22 it is the question that this recommendation is supposed
23 to answer.
The last sentence just makes sure that
24 everybody is talking to each other.
25
Now, just--
Go ahead.
40
1
PROF. CAPRON:
It seemed to me that the phrase
2 "U.S.-sponsored" in the second line is too narrow.
I
3 would suggest that after the word "research" in the first
4 line, we add "subject to U.S. regulations."
5
DR. MESLIN:
Right.
6
PROF. CAPRON:
That is--
Yes.
And then, drop the words "U.S.-
7 sponsored" and just replace it by "the".
At the end of
8 the last full line, add "review bodies in".
So, it says
9 "between or among IRBs in the United States and review
10 bodies in collaborating countries."
Again, not assuming
11 that IRB is the right way to describe them.
12
DR. SHAPIRO:
As Eric has said, the issue here
13 is what do we feel are the minimal requirements.
14 Obviously, people will have their own view as to whether
15 they want to involve their IRB in a lead or subsidiary.
16 I mean, there are all kinds of views individual countries
17 might have, but the question is, what do we feel is the
18 minimal requirements to assure the ethical conduct of the
19 trial.
20
One recommendation here is it has got to take
21 place at least in the host country.
That seems pretty
22 straightforward, and I don't think any of us would
23 disagree with that.
The question is what else we want to
24 put in as minimal requirements.
25
Steve, then Alta.
41
1
MR. HOLTZMAN:
Question of clarification.
I
2 think the paradigm in mind here involves a U.S.-based
3 investigator with a foreign collaborator.
Are there
4 cases where, first off, there could be direct federal
5 funding of investigators none of whom are in the United
6 States, all right?
In which case, who is the relevant
7 internal review body in the U.S.that we are referencing?
8
And second, to the extent that we want this to reference
9 outside of federal funding, and as a suggestion, for
10 example, to the private sector, or (inaudible) FDA11 mandated again, is there necessarily a domestic nexus for
12 this in the U.S.?
13
DR. SHAPIRO:
Alta?
14
PROF. CHARO:
I am going to take the case of the
15 publicly funded research first, because it is a little
16 bit easier.
I would say that the answer to how many IRBs
17 it takes to change a light bulb is two: one in the
18 country where the research will take place, and one here
19 in the United States, so that we have both local
20 conditions, and interpretation of U.S. regulations
21 adequately covered by respective bodies.
22
With the private sector--
23
MR. HOLTZMAN:
24
DR. SHAPIRO:
25
MR. HOLTZMAN:
(Inaudible.)
Touch your button, Steve.
--stay on the feds.
So, is a
42
1 direct funding where it is the investigators, there is no
2 local investigator, no U.S.-based investigator.
3
PROF. CHARO:
So what you are contemplating then
4 is that having determined that there is a collaborative
5 site in Rwanda that we have come to know is reliable and
6 well-staffed, and has all the capacity necessary, we
7 would fund researchers at the University of Rwanda
8 through a federal grant, and have only the Rwandan
9 university's own local review board go through it, just
10 as if you were funding research at the University of
11 Wisconsin.
12
13 research.
PROF. CAPRON:
That is not collaborative
There is no collaborator from this country,
14 just money from this country.
15
(Simultaneous discussion.)
16
MR. HOLTZMAN:
17 moment.
Assume I am really dumb for a
I am asking a question of whether there are any
18 cases where the United States funds research, human
19 subjects research, where there is no U.S.-based
20 investigator involved.
21
DR. SHAPIRO:
22
MR. HOLTZMAN:
The answer to that is yes.
So therefore, who is the relevant
23 IRB, who is the U.S. IRB, that is involved?
That is my
24 question.
25
PROF. CAPRON:
What would be the U.S. IRB?
If
43
1 there is no U.S. collaborator, if it is just U.S.
2 dollars, then it would--
But the same is true today.
3 mean, if CDC--
If the Cancer Institute gives
Not CDC.
I
4 money to the University of Wisconsin for research, the
5 Cancer Institute doesn't run an IRB on it, they expect
6 Wisconsin to do it, and if it is the University of
7 Abadan, and they are not sending U.S. investigators from
8 Wisconsin over there, there is no reason for the
9 Wisconsin IRB to be involved.
10
DR. SHAPIRO:
I think there is some--
11
(Simultaneous discussion.)
12
PROF. CAPRON:
--someone who qualifies for
13 Cancer Center money, but they happened to be based in
14 Africa.
15
DR. SHAPIRO:
I think if I could just ask Steve
16 if I get the point he is making.
The second sentence
17 here is what Steve is focusing on, I believe, and
18 correctly so.
That is, the way this is written, it
19 assumes that there is a collaboration, and Steve is
20 correctly pointing out that that is not necessarily the
21 case. My understanding of the way things currently stand
22 is in the case that you pose, that takes place in the IRB
23 in the country where this is taking place.
And so, you
24 are quite right to point to that, that we have to
25 accommodate that.
44
1
MR. HOLTZMAN:
Right.
And so then, what Alta
2 gave was an in-principle argument about why there had to
3 be domestic review in the U.S.-4
PROF. CHARO:
It was assuming a former
5 collaboration that was not present-6
(Simultaneous discussion.)
7
DR. SHAPIRO:
8 point here.
9
I agree.
You have made a good
I agree.
Tom?
Excuse me, Alta is next.
You are on my
10 list then, Tom.
11
Did you make your point already?
I can't
12 remember?
13
PROF. CHARO:
Who knows?
14
DR. SHAPIRO:
Tom, let's go.
15
(Simultaneous discussion.)
16
DR. MURRAY:
You can follow on whatever I am
17 going to say, Alta.
18
Imagine the headline:
"American--
U.S.
19 Company, Pharmaceutical X, Pays for Research for Its New,
20 Dangerous Drug in Country Y Somewhere in the Developing
21 World". Company X's spokesperson says, "We didn't have an
22 American investigator.
We relied on local people for the
23 work, and so therefore, all of the review and other
24 requirements of this commission report are irrelevant to
25 us."
45
1
PROF. CAPRON:
No, they are not.
They would
2 have to be relevant.
3
DR. MURRAY:
4 spokesperson will say.
I am just telling you what the
I am not saying that it is all
5 correct.
6
PROF. CAPRON:
7
(Simultaneous discussion.)
8
DR. MURRAY:
9 review.
But the FDA--
But there would be no U.S. IRB
Would the FDA require a U.S. IRB review?
I
10 don't think so.
11
PROF. CHARO:
12 IRB review.
The FDA wouldn't require a U.S.
It would require that whatever review
13 process was used was one that met the FDA's standards
14 which we, in an ideal world, know would incorporate all
15 of the brilliant recommendations that we have made here.
16
DR. SHAPIRO:
And maybe some of the ones that
17 aren't so brilliant.
18
19 them.
DR. MURRAY:
So, that is how we would catch
If they wanted to market it back in the U.S.?
20
DR. SHAPIRO:
21
DR. MURRAY:
That is right.
If they want to market it back in
22 the U.S., then we wouldn't have that-23
(Simultaneous discussion.)
24
PROF. CAPRON:
25
DR. SHAPIRO:
That is true today.
True today.
Still true.
46
1
Okay, any other comments?
I still want to focus
2 on-3
Sure, Tom?
4
DR. MURRAY:
I was just struck by the phrase
5 which would have--in the second line of the
6 recommendation, that the review "must be conducted by an
7 unbiased, competent body in the country", and who could
8 disagree with those words, that the review body should be
9 unbiased and competent?
A cynical person in another
10 country could say, well, you know, U.S. committees are
11 generally the creation of the institutions who are
12 getting the money to do the research.
13
Are they unbiased?
So, it could be turned back against us.
And
14 secondly, I think if we were going to say this, we need
15 to somewhere in the report elaborate what we mean by
16 unbiased and competent, or else it will be taken as a
17 kind of arrogant claim by a country that may not be so
18 clean on its own regard.
19
DR. SHAPIRO:
20
DR. COX:
21 did you want-22
I am sorry.
David?
This is on a different question, so
Go ahead and make your point.
DR. SHAPIRO:
23 Commission has--
I guess--
Okay.
I am wondering if the
There is a kind of multi-center trial
24 analogy in international collaborative research to the
25 multi-center trial issues that we have in this country
47
1 regarding whether or not there should be lead IRBs, or
2 how many IRBs you need; does everyone have to have their
3 IRBs, and so on.
4 here.
5
That whole issue just plays out again
It is really in principle the same issue.
Do any commissioners feel that issue itself, in
6 the context of international collaborative research, that
7 we need, or should, say something about that?
8 anything to say about it?
Do we have
Is that something we should
9 try to work on?
10
David?
11
DR. COX:
So, this had to do with my point.
12 answer to that question is yes.
My
And the part of this
13 recommendation that says "researchers--", and I have made
14 this point in previous meetings of the Commission,
15 "researchers should include in the protocol plans for
16 facilitating communication amongst IRBs".
17
18
How?
You know, I mean, I have been in that situation.
It is almost impossible to do.
So, that is putting--you
19 know, requesting researchers to do something without
20 giving a plan of how they are going to accomplish it.
21 So, it falls into exactly what you are saying, Harold,
22 which is that you want to facilitate all these different
23 things, but that it is not clear the process by which you
24 are going to do it at all.
25
DR. SHAPIRO:
To me, at least.
Larry?
48
1
DR. MIIKE:
Well, the last comment that Tom made
2 raises some issues for me on this recommendation, because
3 if we look at it in light of the discussion we had on 3,
4 4, 5, and 6, I believe, 3, 4, 5, and 6 look toward
5 assuring that the IRBs in the foreign country, the host
6 country, does meet this criteria of an unbiased,
7 competent body, yet I assume that we still conduct
8 research in countries where they may not have that, and
9 that there is a body there that reviews it, and there is
10 a body in the United States if it is a sponsor that does
11 it.
This recommendation puts us in a dilemma then,
12 because how are we going to proceed with research in
13 those countries which have not met the test of our prior
14 recommendations, and still come out with ethical
15 research?
16
DR. SHAPIRO:
I presume we do it, the last
17 couple of years, through the Single Project Assurance
18 mechanism, which I believe could allow that to go ahead
19 if a particular location can convince us that they-20
DR. MIIKE:
All I am saying is that the way it
21 is currently written, following those other
22 recommendations-23
DR. SHAPIRO:
24
DR. MIIKE:
I understand.
--would naturally follow that they
25 have met these, and so we are going to--
49
1
(Simultaneous discussion.)
2
DR. SHAPIRO:
3
Bernie?
4
DR. LO:
I understand.
I think the issue we are running up
5 against is the different levels of review we want to see
6 in place.
On the one hand, we are saying countries
7 should have policies that are equivalent to the U.S.
8 policies, or adopt international standards, and that, I
9 take, is what 3,4, and 5 are about, certifying the
10 country's sort of ethical principles, so to speak.
There
11 is a whole other issue of what is the IRB going to do in
12 a country that has good principles.
Is the IRB going to
13 apply them with wisdom and discretion the way we would
14 hope an IRB in this country would?
And here, I think we
15 have to say there is a real issue, that we may think the
16 principles are good, but we have no evidence as to
17 whether IRBs any place in the world, even in this
18 country, are really doing a good job working at those
19 principles.
20
And so, you know, we are talking about
21 certifying IRBs in this country somehow; we don't know
22 how we are going to do it yet.
Given that skepticism
23 about how our own U.S. IRBs work, it seems to me one
24 could have similar skepticism about IRBs in other
25 countries.
And see, that, to me, is where the rub is.
50
1 Even if you know that the country's principles are good,
2 you have just certified the country.
You haven't
3 certified the IRB in any way, and that is where, I think,
4 Tom's headline will cause troubles, because there are
5 going to be allegations raised that the IRB was pretty
6 naive, and inexperienced, and not very good at doing its
7 job protecting subjects.
8
Because of that concern, do you want to put on
9 an extra sort of over-the-shoulder second opinion look in
10 a foreign country, where you wouldn't necessarily do it
11 in this country unless there was sort of cause directed
12 at the institution?
13
14 to
15
DR. SHAPIRO:
Alta?
Then we are going to have
close this discussion.
PROF. CHARO:
Bernie, I think the difficulty you
16 raise is extremely important.
I think it also dovetails
17 with yesterday's conversation about what recognition of a
18 foreign country's policies really means, because the
19 notion of comity is that, once you have recognized that
20 government's authority, you have recognized their
21 authority not only with respect to their principles, but
22 with their ability to implement those principles.
23
Now, in the United States, we put down certain
24 kinds of procedural requirements with regard to the IRB
25 operation so that there is that second level of
51
1 protection, and those procedural rules include things
2 like adverse event reporting, and continuing review, and
3 then all the paper work requirements that annoy people so
4 much, the minutes, and the quorum votes, and all that
5 stuff.
And we can certainly list those things that we
6 think are essential procedural safeguards that help to
7 ensure that policies are implemented most of the time in
8 a way that is acceptable, but I don't think that we want
9 to be in the business of not only having to recognize a
10 foreign government's approach to human subjects
11 protection, but also in individually certifying each
12 individual researcher, because like I said, it is like
13 recognizing New York State's ability to marry people, and
14 then having to individually interview all their judges.
15 I mean, you will never simplify and streamline the system
16 if you are going to go that route.
There has to be some
17 degree of trust in the other government, and that is what
18 the capacity-building recommendations are all about.
19
DR. SHAPIRO:
It really is an issue, and I don't
20 know that we will resolve that issue, but it is an
21 important issue.
We have to find some way of
22 highlighting it, focusing on it, not letting it pass us
23 by, even though we may not be able to fully resolve it.
24
Okay, we are going to have to end our discussion
25 on this particular topic now.
Why don't we take a five
52
1 or seven minute break before the panel-2
DR. MESLIN:
Yes, Eric?
Since this is the last time at this
3 meeting we are going to talk about the International
4 Report, I just wanted to give you the timetable and
5 homework assignments, lest we forget them.
If you have
6 marked up, edited copies of the chapters, please hand
7 them to Alice or me or the staff before you leave today.
8
9
If you have them elsewhere, send them immediately.
Secondly, we will be sending around the proposed
10 edits to the recommendations for 4 and 5 that we have
11 been discussing the last couple of days.
We will try and
12 do that within the next 24 hours to you, and please let
13 us know if they meet your approval.
And then, you will
14 see revisions to the text of 4 and 5, hopefully, within a
15 week or so, with the goal of getting these five chapters
16 and recommendations into the public comment process
17 within, as Harold said, 10 days plus or minus a few days.
18
19
I can't give the public who is here the exact
20 date that the public comment period will start.
It will,
21 hopefully, start, you know, on or about the 20, 21st,
22 22nd of September, which is 10 days from now, but
23 understand that it may take another couple of days, but
24 our process will kick in 45 days of public comment as
25 soon as we are done.
53
1
And that is all.
2
DR. SHAPIRO:
3
(Whereupon a brief recess was taken.)
4
DR. SHAPIRO:
Okay.
Let's reassemble at 9:15.
As soon as everyone is stoked up
5 with an adequate amount of caffeine, we will get
6 underway.
7
PROF. CHARO:
No such thing.
8
DR. SHAPIRO:
It is probably not strong enough
9 for you, Alta, right?
10
We have two panels that we are going to hear
11 from this morning which are dealing with subjects which
12 are directly relevant to our Oversight Project, one
13 dealing with privacy/confidentiality, and the other
14 dealing with quality control, and with respect to the
15 first panel which we are going to turn to right now, you
16 have also seen papers which have been presented to us,
17 and we want to welcome back Professor Sieber who has been
18 before this commission before.
19 you here again.
It is marvelous to have
Thank you very much.
20 course, Janlori Goldman, welcome.
And also, of
It is a great pleasure
21 to have you here this morning.
22
So, let's just launch directly into the panel.
23 We have scheduled--
Again, we would like to keep this to
24 about an hour, so I will ask you to keep your
25 presentations in that context, since we do want to leave
54
1 plenty of time for commissioner's questions that they may
2 have.
And I think the way we will proceed is that we
3 will start with Professor Sieber, and then I would like
4 to go directly to Professor Goldman, and then we will go
5 from there, because I don't want to use up all our time
6 on one of these things, which can happen.
7
8
So, Professor Sieber, please.
Oh, you want also the overheads.
Press the button.
They have to be
9 reloaded, I am afraid, or something has to happen.
10 turn my glasses backwards.
I can
Maybe that will--
11
(Simultaneous discussion.)
12
PROF. SIEBER:
They need to go in upside down
13 and backwards.
14
DR. SHAPIRO:
My students once pointed out to me
15 that I could only misplace these slides so many different
16 ways, and I said that is true, providing I don't repeat
17 the same mistake an infinite number of times.
18
PANEL II: PRIVACY/CONFIDENTIALITY
19
PRESENTATION BY JOAN E. SIEBER, Ph.D.
20
PROF. SIEBER:
Okay, well, let me begin, and
21 presumably my slides will catch up with me quickly.
22
Good morning, and thank you very much for
23 inviting me.
It may please you to know that I am not
24 going to summarize the whole paper.
Rather, I am going
25 to summarize the main problems and the recommended
55
1 solutions, and then, within the solutions which I won't
2 go into in detail are really all of the elements of the
3 paper.
4
As you know, my emphasis is on the need for
5 clarity and for education.
I have tried my
6 recommendations out on many IRB members, and all agree
7 that researchers and IRBs need more education, not more
8 regulations.
And I would like to add that they have all
9 told me that they are so concerned that they feel
10 micromanaged, that common sense has gone out the window,
11 because so frequently regulations do not really fit the
12 specific circumstance.
13
(Slide.)
14
The Common Rule does not define--
Ah, good!
15 Progress!
16
DR. SHAPIRO:
17
PROF. SIEBER:
Caught up.
The Common Rule does not define
18 privacy, although it has a section called "Definitions".
19
The IRB Guidebook, in Chapter 3, page 27, does a halfway
20 good job.
It defines privacy as having control over the
21 extent, timing, and circumstances of sharing oneself
22 physically, behaviorally, or intellectually.
23
24
But it is naive and ethnocentric in instructing.
"Decide whether there is an invasion of privacy by
25 basing your decision on your own sense of propriety, and
56
1 the circumstances of the study."
This advice is
2 sometimes okay, but it is pretty amateurish.
3 more sophistication than the IRB may have.
4 understandable.
It presumes
But this is
Before Web-based education, the task of
5 communicating in detail with researchers and IRBs about
6 judging privacy interests of others would have been
7 really daunting.
8
(Slide.)
9
Presumably, everyone knows what privacy is.
10 is a word we toss around a great deal.
It
The existing regs
11 and guidebook offer no suggestions for helping a
12 researcher who seems insensitive to the particular
13 research populations' sense of privacy.
There are tools
14 for learning what is private to others who are situated
15 differently from oneself.
If a researcher's seat-of-the-
16 pants judgment about invasion of privacy fails, the IRB
17 needs to require the use of relevant tools.
If the IRB
18 and the researcher lack such tools, both subjects and the
19 research may be at risk.
Even the researcher may be at
20 risk.
21
(Slide.)
22
When a subject responds to something that he
23 perceives as an invasion of privacy, there are various
24 things that he might do.
25 our privacy.
We all have ways of protecting
He could decline to answer, which we have
57
1 told him he can do.
More likely, though, if he wants to
2 appear polite, he will lie, which provides great data, of
3 course.
He may be evasive; he may quit the session; or
4 he may reveal more than intended and then worry about it
5 a great deal.
6
The researcher would do well to respect personal
7 privacy.
8
(Slide.)
9
But that is not easy.
10 sensitivities.
Let's look at our own
What is private to you here today at the
11 Commission differs from what is private to you elsewhere
12 at another time.
It depends on where we are on an issue,
13 on our mood, on our recent past experience, and so forth.
14
15
These unpredictable and sometimes ephemeral
16 individual differences are handled through informed
17 consent.
Where privacy is an issue, relevant attention
18 should be given to the way informed consent is worded,
19 and more importantly, how it is delivered.
We all keep
20 saying informed consent is not a consent form, and you
21 bet it isn't.
It needs to be delivered with a real
22 understanding that you may be dealing with very personal
23 sensitivities, and there is nothing in the regs that
24 talks about your body language, comprehension, and so
25 forth.
58
1
(Slide.)
2
Apart from our own individual idiosyncratic
3 senses of privacy, there are major differences between
4 populations in what they consider private.
And as it
5 says on the slide there, gender, ethnicity, age,
6 socioeconomic status, education, ability level, social
7 and verbal skill, health status, legal status,
8 nationality, intelligence, many things relate to what we
9 consider to be our privacy interests.
10
There are many tools for finding out what these
11 interests are, but those tools are rarely used.
12
(Slide.)
13
Thus, researchers and IRBs often rely on their
14 own sense of propriety.
And I really want to emphasize,
15 this sets an ethnocentric, capricious, and inconsistent
16 standard for respecting privacy.
17
(Slide.)
18
A useful definition of privacy in the regs is
19 one that is really quite general and simple.
20 be--
It might
This would be in the definition part of the regs.
21 "Privacy refers to persons, and to their interest in
22 controlling the access of others to themselves.
23 example, via informed consent."
For
This definition suggests
24 the dynamic and subjective nature of privacy interests.
25 The regs should refer readers to other sources for
59
1 further elaboration on how subjects and researchers
2 regulate access.
3
(Slide.)
4
People regulate the access of others to
5 themselves irrespective of whether a researcher is
6 sensitive to their privacy, but they don't always do it
7 in a way that protects themselves, or that fosters valid
8 research.
So, the researcher has a very important role
9 to play in providing and communicating the appropriate
10 respect and appropriate protections.
11
(Slide.)
12
As detailed in the paper, there are many ways to
13 learn about and respect the privacy of subjects, and I
14 won't go into detail here.
But they include, of course,
15 informed consent, knowledge of the subject's culture,
16 rapport, and sensitivity to the individual, having
17 research associates from the culture that you are
18 studying who can be really good informants on cultural
19 determiners of a sense of privacy, and extensive
20 consultation with appropriate professionals and peers of
21 the subjects.
22
(Slide.)
23
Now, here is the real clincher.
Most research
24 methods courses do not teach this material.
A critical
25 problem is that most research methods courses and
60
1 textbooks don't teach you how to understand privacy, or
2 to assure confidentiality.
Many scientists still take
3 the "get data" approach that ignores the subjective
4 sensitivities of subjects, and so, of course, then, the
5 data they get isn't very good.
6 on what professors want.
Textbook publishers focus
The relevant literature that
7 researchers need in order to know how to protect privacy
8 and confidentiality happens to exist in rather out-of9 the-way applied research journals, and a few really
10 excellent books, the very best of which currently is out
11 of print, and that is Boruch(?) and Cecil Assuring the
12 Confidentiality of Social Research Data.
13
(Slide.)
14
In short, the regs are no help, the IRB
15 Guidebook is naive, and research training is inadequate.
16
(Slide.)
17
But there are solutions in sight.
18
The Common Rule also does not define
19 confidentiality.
I will be briefer here.
The problems
20 are much the same as for privacy.
21
(Slide.)
22
The Guidebook assumes, or hopes, that there is
23 IRB expertise concerning mechanisms of assuring
24 confidentiality.
I have given a lot of IRB workshops,
61
1 and I have never quite found that member who knows a
2 great deal about this.
3
(Slide.)
4
The Guidebook does not even hint at the
5 multitude of techniques for protecting confidentiality,
6 at their advantages and limitations, how they are
7 applied, or how some of the more sophisticated methods
8 which are fairly arcane, just might come in very handy.
9 One is left thinking that there is just a handful of
10 common sense techniques when there is so much more.
11
(Slide.)
12
The literature on these techniques is scattered
13 in applied research and applied statistics literature, so
14 the poor IRB chair, or staffer, who seeks to find these
15 literatures, interpret them, and make them available to
16 the IRB and to researchers, just can't do it.
They need
17 a lot of help.
18
(Slide.)
19
There are other complications.
20 continual changes in issues.
21
There are
Let me just mention three.
Electronic media rapidly change and challenge
22 confidentiality.
Keeping pace with this is a big job,
23 and this isn't the kind of literature that the average
24 researcher or the average IRB member readily reads or
25 understands.
62
1
Relevant state and local laws are rarely tracked
2 or interpreted by most IRBs.
3
Also, increasingly, data sharing is being urged,
4 and data audits are occurring.
These need to be planned
5 for in special ways, and each researcher shouldn't have
6 to reinvent procedures of planning for these.
7
(Slide.)
8
Let me give you a suggested definition of
9 confidentiality.
"Confidentiality is an extension of the
10 concept of privacy.
It refers to data, (that is,
11 identifiable data about a person), and to agreements
12 about how data are to be handled in keeping with
13 subjects' interest in controlling the access of others to
14 information about themselves."
15
As you will see, this definition is further
16 enhanced when we get to the informed consent requirement
17 that I am going to recommend.
18
(Slide.)
19
The proposed definitions of privacy and
20 confidentiality bring with them a need for changes in
21 informed consent requirements, and also, a need for
22 educational resources that would be available in a user23 friendly form on the Internet, kept up to date, and
24 tailored to each institution by its IRB.
25
(Slide.)
63
1
Informed consent is integral to privacy.
Hence,
2 regarding privacy, the informed consent element
3 concerning risks would be modified as follows. In CFR
4 46.116 (2) in parentheses, "A description of any
5 reasonably foreseeable risks or discomforts to the
6 subject--", then we would add "including possibly
7 unwelcome seeking or presenting of information or
8 experiences; that is, possible invasions of privacy."
9
10
(Slide.)
Regarding confidentiality, the consent statement
11 would be changed to--just entirely changed.
12 direct the researcher more exactly.
It should
Since anonymity is
13 highly desirable where possible, it needs to be
14 specifically mentioned.
15 would read:
The recommended new element
"A statement of whether and how data will be
16 rendered anonymous, or a statement describing the
17 conditions of confidentiality of identifiable data, who
18 will have access to such information, what safeguards
19 will prevent or reduce the likelihood of unauthorized
20 access, and what unavoidable risks of disclosure may
21 exist."
22
That definition doesn't let the person think
23 that confidentiality is just promising you won't tell
24 other people.
25
It implies the more sophisticated issues.
(Slide.)
64
1
2
The educational resources would be on Web pages.
They would be formatted with the help menu, much like
3 the help menu on your word processor, so that information
4 would be found via a table of contents, and an index.
5
There is a big Web site and a little one.
The
6 big page would be a user-friendly resource for everyone,
7 researchers, IRBs, and teachers of research methods who
8 wanted to turn it into curriculum for their courses. It
9 would be user-friendly, and also, I really want to
10 emphasize my recommendation that it be non-regulatory,
11 though the IRB could treat parts of it as requirements at
12 their discretion.
The rationale for this is that
13 institutions are irrationally--(well, not irrationally
14 given the penalties), are very fearful that they will
15 inadvertently do something that will get their research
16 closed down by OHRP.
They are motivated more by fear of
17 violating a regulation than by a sense of ethics and
18 intelligent interpretation.
They have a sense of ethics;
19 they are not allowed to use it.
This must be avoided.
20
(Slide.)
21
The initial contents of the big Web page would
22 be all the topics included in my paper, perhaps, would be
23 how to handle informed consent with links to relevant
24 topics, how to develop a protocol with links to relevant
25 topics, and any other topics deemed appropriate.
65
1
(Slide.)
2
Just to give you some sense of what some of the
3 contents might look like, there would be guidelines for
4 "ethical proofreading" of case study material to prevent
5 harm, assuming that your cover is blown, that all of your
6 efforts to mask identity get seen through.
7 limit any harm?
How do you
Something like how to obtain a
8 certificate of confidentiality, and what that covers and
9 doesn't cover.
Federal laws governing school research;
10 tips on respecting privacy and ensuring confidentiality
11 in Internet research; uses and methods of inter-file
12 linkage; tips on handling mandated reporting issues.
13 Just as examples of some topics.
14
(Slide.)
15
Very briefly, the developers of this document
16 would be experts, researchers from various disciplines,
17 and experienced IRB folks, with input from this
18 commission, and OHRP.
The work would be commissioned,
19 overseen, and edited by a standing committee of
20 specialists and representatives of this commission and
21 OHRP.
There would be a Web master appointed to create
22 and maintain the Web.
As it approaches completion, it
23 would be reviewed by IRBs and researchers who volunteer
24 to be involved.
25
This would be an iterative process.
Issues
66
1 change, technology changes, and improvements would be
2 suggested.
The Web would always be a work in progress,
3 an evolving document.
4
The little IRB Web page would instruct each IRB
5 how to tailor the big educational resource to their
6 institution by putting local information on their own Web
7 page, and linking it to the big Web.
8 mandatory.
This would be
While the big page would not be considered
9 regulatory, I would propose that IRBs be required to use
10 the big page, and to tailor it as suggested on the little
11 page.
12
(Slide.)
13
(Slide.)
14
The little Web page would provide guidelines on
15 how the IRB might appraise its need for local expertise,
16 develop workshops and materials for its clientele, select
17 and develop new resources for its clientele, organize and
18 format the local Web, and communicate with their
19 institution's Web master, and update the local Web.
20
(Slide.)
21
The overall goal here is to provide the
22 resources, guidelines, and context for IRBs, researchers,
23 and students to engage in rational, sophisticated
24 approaches to respecting privacy, and assuring
25 confidentiality.
67
1
(Slide.)
2
And as befits professionals, without fear of
3 violating, or seeming to violate, federal regulations.
4
(Slide.)
5
Thank you.
6
DR. SHAPIRO:
Thank you very, very much.
We
7 will come back in a few moments with questions.
8
I would like now to turn directly to Ms. Janlori
9 Goldman.
Once again, welcome.
We look forward to your
10 remarks.
11
12
PRESENTATION BY JANLORI GOLDMAN, J.D.
MS. GOLDMAN:
Thank you.
Thank you very much
13 for inviting me to be here this morning, and I want to
14 also thank the commission for commissioning a paper from
15 us.
It forced us to sit down and do a rigorous study
16 which we had meant to do for a while, and there is
17 nothing like having a deadline to get you to do that.
18
I want to acknowledge Angela Choy who is sitting
19 here to my right, who works at the Health Privacy
20 Project, and who is the co-author on the paper, and who
21 serves many different functions in our organization since
22 we are only about four folks, as a senior researcher, and
23 Web master, and field director.
And when we have a
24 chance for some give and take, she may be able to answer
25 your questions better than I can.
68
1
Before I get into talking a little bit about
2 what we did in our paper, I wanted to just talk a little
3 bit about the Health Privacy Project which I direct, and
4 which I created a number of years ago, and which is
5 housed at Georgetown University.
The project is
6 essentially focused on trying to ensure that privacy is
7 protected in order to improve the quality of care, and
8 access to care, and we have been involved in a number of
9 studies that look at exactly what Dr. Sieber was talking
10 about, which is the impact of not protecting privacy in
11 the health care environment, what are the consequences.
12
And so, we have seen that there is a direct
13 impact in terms of people being afraid to share openly
14 with their health care providers, that people are giving
15 inaccurate information in order to shield themselves.
In
16 some instances, they are obviously paying out-of-pocket
17 to avoid having a claim submitted, and in the worst case
18 scenarios, they are avoiding care altogether.
I am sure
19 that many of you are already aware of this in terms of
20 anecdotal, but what we have tried to do is to create an
21 empirical basis for understanding this so that we can
22 then use that in making some policy decisions down the
23 road.
24
In our paper, we essentially surveyed the law
25 related to research and confidentiality.
We looked at
69
1 policy and ethics, and we made a number of
2 recommendations.
I think that a number of things
3 that have already been said this morning are important
4 here, but I want to just elaborate that when we are
5 talking about confidentiality in research, there is very
6 little guidance in the Common Rule itself, and some
7 guidance in the OPRR Guidebook.
But essentially, the
8 Common Rule was not written with an eye toward addressing
9 confidentiality and privacy concerns.
So, whatever is in
10 there, I think we are trying to read between the lines,
11 we are trying to pull something out of it that doesn't
12 currently exist.
13
So, we not only have a lack of guidance in the
14 regulations, we also have a lack of expertise and
15 resources at the IRB level, and at the association level,
16 because there has been no incentive to develop it.
So,
17 it is not necessarily that people are insensitive, or
18 that they are intending to do harm, or that there have
19 been mistakes that are being pushed aside.
It is that
20 there is no legal incentive even if there is an ethical
21 incentive to address confidentiality.
22
Now, in a clinical context we have seen that it
23 is addressed probably to a greater extent, to a more
24 thorough extent.
But in just participating in an
25 Institution of Medicine study that was chaired by Bernie
70
1 Lo, in looking at confidentiality in health services
2 research where you don't necessarily and don't usually
3 have direct contact with individuals, and the use of the
4 information for research is secondary, confidentiality is
5 not addressed.
It is not addressed by institutional
6 review boards; it is not addressed by researchers in any
7 kind of a comprehensive way.
And it is certainly not
8 addressed, I think, sufficiently by those that are giving
9 the information out for health services research.
10
So, I would argue that we do need regulations in
11 this area, not because I am necessarily a proponent of
12 the heavy hand of government coming in and telling
13 researchers and institutional review boards what they
14 should do, but because that is the necessary trigger to
15 begin to develop the resources, the guides, the rules,
16 the training that has to happen in order to begin to
17 address confidentiality.
18
Now, because the Common Rule had not been
19 written, obviously, with an eye towards confidentiality,
20 and this has been an emerging issue in the last few
21 years, the Congress and the Secretary of HHS is
22 attempting to craft a set of rules that will change the
23 way that institutional review boards address
24 confidentiality, and we do go into this in our paper, but
25 I want to spend just a few moments on it.
71
1
In about three or four weeks, maybe five weeks,
2 depending on who you talk to, the administration will be
3 issuing a set of health privacy regulations.
They will
4 be the first ever nearly comprehensive privacy
5 regulations to be issued at the national level.
And
6 while they do many things, they essentially will cover
7 health plans and health care providers as they use
8 identifiable information.
And they will affect directly
9 researchers that are getting access to identifiable
10 information from those providers, and from those plans.
11 Researchers that are acting independently, and gathering
12 information in an independent context, in other words,
13 not with a dual role as a health care provider, or not as
14 receiving the information from what is being considered a
15 covered entity, would not be covered.
But let's put that
16 aside for a moment, and just talk about what changes may
17 occur, because I think they may--
My hope is, anyway,
18 that they will have a ripple effect in the research
19 community.
20
What the administration is proposing in its
21 draft regulations is to do two things: one, to expand the
22 scope of coverage of the Common Rule; that it will no
23 longer only apply to federally funded research, but will
24 apply to all research, regardless of the source of
25 funding.
And the second major change is to add four
72
1 additional criteria to the Common Rule to specifically
2 address confidentiality.
And while you could argue that
3 the existing criteria that are there that need to be
4 applied by the institutional review boards in the event
5 that informed consent is waived, and the four criteria
6 there are what need to be waived in order to justify
7 waiving informed consent, the additional four criteria
8 are meant to address confidentiality specifically.
9
And I just want to quickly go over them, because
10 I think that they are important in trying to understand
11 what it is that the administration is trying to do here.
12
Now again, these are draft proposals, and we don't know
13 what the final wording will be.
But to add to the
14 existing four criteria the four new criteria, the
15 proposal is that the IRB would look at: whether or not
16 the research could not practicably be conducted (and
17 again, that word "practicably" is consistent with it
18 being used earlier in the Common Rule) without access to
19 and use of the protected health information (the IRB
20 would have to assess that); the research is of sufficient
21 importance so as to outweigh the intrusion of the privacy
22 of the individual whose information is subject to the
23 disclosure; there is an adequate plan to protect the
24 identifiers from improper use and disclosure; and there
25 is an adequate plan to destroy the identifiers at the
73
1 earliest opportunity consistent with the conduct of the
2 research, unless there is a health or research
3 justification for retaining the identifiers.
4
Now, I do not expect that if that is finalized,
5 that IRBs and IRB members will look at those new criteria
6 and say "Ah!
Here are some new criteria. Let's go
7 through and check them off."
There is going to have to
8 be, I would say, very substantial training, resources
9 developed.
I am hoping that OPRR would take the lead in
10 that, but that the associations that work with
11 researchers, and work with IRBs, will be very involved in
12 developing a set of consistent resources and guidance in
13 terms of how to apply the new criteria.
14
One of the other things that is interesting
15 about what the administration is proposing is to allow,
16 particularly for non-federally funded research, to allow
17 something called a "privacy board" to essentially mirror
18 or replicate the institutional review board.
There has
19 been some resistance, as you might imagine, on the part
20 of the private sector to always having to go through the
21 formal IRB process, and so, there is something called a
22 "privacy board" which would be allowed to be developed by
23 that private sector research institution to review the
24 confidentiality concerns.
25
I think that there is a weakness there in that
74
1 that entity would only be constructed to assess privacy
2 and confidentiality, and so, the other ethical issues,
3 and the other issues of protecting human subjects, would
4 not be addressed by that privacy board, and would fall by
5 the wayside.
So, it would essentially create two
6 different systems of review.
But that may be where we
7 are going here.
8
The recommendations that we make in our paper in
9 terms of how privacy and confidentiality can be better
10 addressed hit a number of points that have already been
11 made by other committees, commissions, by the
12 administration.
Some of them are already embodied in the
13 IOM report that was just released on health services
14 research and confidentiality, and by a report that we did
15 last year on best principles for health privacy.
Thanks
16 to Bernie who chaired that, we were actually able to find
17 some common ground among some pretty diverse groups on
18 where to go in the confidentiality area as it relates to
19 research.
20
But essentially, our recommendations are focused
21 on having privacy and confidentiality be considered a
22 central element in the designing of a research protocol,
23 and in the initial review by an IRB, as well as the
24 ongoing review; that the issue should be front and
25 central along with a number of other ethical issues that
75
1 are already being addressed, and it should be built in to
2 the proposal, and built in to the review.
3
We, obviously, and I have said this a couple of
4 times, but I think it is critical to the success of
5 having confidentiality handled in the research context,
6 we need resources for training, for support for technical
7 assistance.
I am hoping that this would come, again,
8 from OPRR, that NIH would be directly involved, that the
9 associations would do this.
10
But I would recommend something a little bit
11 different than what you heard earlier.
I think that the
12 guidance in this area, and the technical assistance,
13 needs to be uniform; it needs to be consistent.
I think
14 that one of the problems that we could run into is
15 allowing institutions to develop their own unique type of
16 guidance, and type of regulations in this area.
We
17 really need some consistency and uniformity, and we need
18 to encourage individual members to develop expertise in
19 these issues so that it is not just are you keeping the
20 records in a locked filing cabinet, but that someone has
21 some expertise in talking about removing identifiers.
22 What does it mean to create non-identifiable information?
23
That is not a simple issue.
It is not easy to develop
24 expertise in that area, but there are resources available
25 that could guide someone in that process.
76
1
I think the greatest benefit to having this
2 front and center is that the question will need to be
3 asked by researchers, by IRBs, by individuals looking to
4 participate in a research project:
5 identifiable data?
Do you need
We don't ask that question now.
6 There is no legal incentive (and again, I focus on that
7 because that is often the incentive that works) to ask do
8 we need identifiers for this particular project.
And if
9 we don't, let's have them removed before the information
10 is received.
Or if the resources aren't available on the
11 part of the disclosing entity, then once the information
12 is received, let's remove the identifiers that are not
13 needed for the project.
You minimize risk in that kind
14 of a situation, and you don't then have to worry about
15 how the information might be used later, once it is out
16 of your hands if, in fact, it is ever out of your hands.
17
18
One of the things that I think has been very
19 troubling for the public, and has certainly been
20 troubling for us in looking at this is that we don't
21 question the intentions of researchers or institutional
22 review boards that are assessing confidentiality.
I
23 believe that people want to do the right thing in this
24 context, and that everybody has altruistic motives.
But
25 what we have seen is that once information is gathered,
77
1 and it is available in an easy to use form, and
2 electronic form, that it is organized, that the
3 researcher has done this stellar job in making the
4 information usable across the database, or across the
5 file, it becomes extremely tempting to use it in another
6 context.
And we have seen that with the
7 Framingham study, that those individuals that gave their
8 consent to participate in an ongoing research project are
9 now being subjected, and may be subjected, to having
10 their information used in a different context.
And it is
11 an afterthought to suggest that we are going to go back
12 and get consent, and that we are going to try to remove
13 identifiers, but we are not really sure what that means,
14 and that these issues have to be addressed at the outset,
15 and not after the fact once we have decided that this is
16 in some ways an irresistible temptation, and we want to
17 be able to use the information for another purpose.
18
And so, that is really, I think, the larger
19 piece that is missing from this debate, is that we
20 haven't yet institutionalized a way of addressing privacy
21 and confidentiality up front.
I am hopeful that once we
22 do have a set of enforceable rules, and that they are
23 applied across the board, and individuals don't worry is
24 this a privately funded project? is this a federally25 funded project? do the rules apply? do they not?, that
78
1 they will have some assurance the information is going to
2 be held in a confidential way across the board, and they
3 won't have to worry about whether to be honest, they
4 won't have to worry about whether to share information
5 fully, or that it might be used to deny them insurance,
6 or employment, somewhere down the road, that it might
7 become an irresistible temptation, and that we can then
8 have better confidence in the integrity of the data.
9
Right now, where people are leaving information
10 out, where they are failing to participate, where they
11 are providing inaccurate information to researchers, we
12 don't know where that information is unreliable.
We have
13 no way of measuring where people at the outset, either
14 with their doctor, or with their health plan, or with the
15 researcher, where people are afraid, and where they have
16 skewed data, or where they have just left something out.
17
This way, we can encourage people to much more fully
18 participate in their own care, to get better care at the
19 outset, and also, to provide better information down the
20 line for research and for public health.
21
22
23
Thank you.
DISCUSSION WITH COMMISSIONERS
DR. SHAPIRO:
24 both very much.
Thank you very much.
Thank you
I am sure there are a number of
25 questions from the Commissioners.
I have some questions,
79
1 but let's go to commissioners first.
2
Alta?
3
PROF. CHARO:
Some fine points, if I may.
Ms.
4 Goldman, both you and Dr. Sieber have frequently used the
5 words "identifiable" or "anonymous".
Now, in the context
6 of our report on research with human biological
7 materials, we struggled to come to an agreement about how
8 to use those terms, and we settled on an interpretation
9 which is the same as the interpretation that NIH's former
10 OPRR had recommended be used.
And that was that
11 identifiable information is not only information that is
12 tagged with a name and an address that is obvious the
13 person using it.
It could be tagged with any number of
14 obscuring identifier links, such as codes and such.
15
So, first, how are you using the word
16 "identifiable", so that we can then continue the
17 conversation all talking about the same thing?
18
MS. GOLDMAN:
It is an excellent question, and I
19 have struggled with it as well.
Let me tell you where I
20 am at on it.
21
We look at information on a continuum.
You are
22 not talking about information which is either
23 identifiable, or non-identifiable, or anonymous.
24 Information is very identifiable.
Maybe it has been a
25 little identifiable as you remove certain pieces of
80
1 information, and on the far side of the spectrum, on the
2 far side of the continuum, you have anonymous
3 information, which is there is no way to then re4 identify.
Anonymous information for the most part, I
5 think would be extremely difficult to achieve, and maybe
6 not as useful, whereas identifiable information,
7 obviously, is the richest, most layered data.
8
The proposed health privacy regulations actually
9 create a definition of identifiability, and say that any
10 information which is identifiable comes under the scope
11 of the regulations, and the way you determine if it is
12 identifiable is whether or not 19 different data elements
13 are included.
If any of those elements are included in
14 the record, the information is then considered
15 identifiable.
And that includes both name and address,
16 as well as, you know, Social Security number, zip code,
17 birth date, phone number, certain demographics data,
18 race, age-19
20 then.
PROF. CHARO:
So--
Let me give you a little quiz
No, so, I mean, I just really want to
21 understand how it interacts with our report, if I may,
22 with your permission.
23
In our report we said, okay, imagine a
24 researcher has a piece of tissue that has nothing but a
25 code.
It is just a series of random numbers that have
81
1 been assigned.
2 code-breaker.
But far away, in a locked safe, exists a
The researcher may not even know the name
3 of the person who is the code-breaker; there may be three
4 intermediaries.
But there is a code-breaker, and so, in
5 theory, with enough collaboration, the code could be
6 broken so that the tissue could be matched to a specific
7 individual.
Would that be considered identifiable or not
8 under the proposed privacy rules?
9
MS. GOLDMAN:
I would say that it would be
10 considered non-identifiable under the proposed rules,
11 because if the information as it sits in front of the
12 researcher is non-identifiable, the prospect that
13 somewhere it could be re-identified is not enough (this
14 is, again, my opinion; it may not be the opinion of the
15 administration) is not enough to render it identifiable.
16
However, if the information is then re-identified, it
17 then triggers the regulations.
If at some point,
18 somebody does match it with information from another
19 place, and it is then re-identified, it then triggers the
20 laws.
21
PROF. CHARO:
So, it is non-identifiable so long
22 as it is not being used in certain ways, but--
So, the
23 information collected from me will be considered non24 identifiable because it is being collected with all these
25 coding routines, and then, 20 years from now when
82
1 somebody comes back and says, you know, we chose to re2 link everything because we decided there was a reason for
3 re-linking, it now has been transformed into identifiable
4 information.
From my perspective as the source of
5 information, the status of that information changes over
6 time.
7
MS. GOLDMAN:
That is right.
And there may be
8 prohibitions, there should be prohibitions, on re9 linking.
It is not just that there is the possibility of
10 doing it, and maybe it will happen.
The idea of having a
11 federal scheme in place is to give guidance that this is
12 not appropriate, that the re-linking is not appropriate
13 by the researcher.
It may be appropriate in some
14 treatment context, just as an example.
But this is an
15 issue that has to be determined early on, that we are not
16 saying it is non-identifiable today, but 20 years from
17 now maybe we will decide to re-link, that we need to make
18 these decisions early on, and to create some prohibitions
19 and limits.
20
PROF. CHARO:
Last question.
At the time we did
21 the HBM report, it was my impression that not only OPRR
22 but NIH as a whole had endorsed the version of
23 identifiable which we used in our report, which is
24 somewhat more solicitous of individual privacy.
Has NIH
25 changed its position, or was its position overruled by
83
1 the Department?
2
DR. MESLIN:
I wonder if we could go and maybe
3 ask Julie Kaneshiro, who I believe is here from NIH.
4 Julie, are you prepared to respond to that question from
5 Alta, and maybe just give an update on what the status
6 is?
Just come on up to the table, and take a seat at the
7 microphone, and push your red button.
8
MS. KANESHIRO:
Hi.
Thank you.
I would just say that the
9 NIH is currently considering the NBAC's report on human
10 biological materials through a working group that is run
11 at the Department level, so we are considering it in
12 collaboration with the multiple agencies within the
13 Department, and are coming up with a formal response. So,
14 I would say that the activities of developing a final
15 rule on privacy, and also considering the Commission's
16 report on biological materials is happening concurrently.
17
So, at this point, I would say that we have not reached
18 a conclusion about the issue of identifiability.
19
PROF. CHARO:
But there was a prior position?
20 Or was I misinformed?
21
MS. KANESHIRO:
There were comments that we
22 submitted to you in response to your draft report which
23 did indeed, you are right, support the Commission's
24 interpretation.
25
PROF. CHARO:
Thanks.
I just wanted to kind of
84
1 get everything straight.
2
DR. SHAPIRO:
Okay, thank you.
Thank you very
3 much.
4
Tom?
5
DR. MURRAY:
This is also for Janlori Goldman,
6 and hello also to Joan.
Janlori, first of all, let me
7 commend you on trying to make an active and widely
8 understood principle that when there must be identifiable
9 data in research, that it should be only as much as is
10 necessary, and only for as long as is necessary.
11 are very important principles.
Those
Some of us have tried to
12 honor them, but they really need to be made an active
13 part of the consciousness of researchers and IRBs.
14
But then, let me ask about the Framingham study,
15 because I started scratching my head and wondering just
16 what you were asking us to do.
As I understand the
17 Framingham database, and other large, longitudinal
18 databases, the whole point of creating them is that we do
19 not know when we begin just what questions we will want
20 to put to the data in the future.
And one of the glories
21 of those databases is that they allow us to later on
22 frame questions that we didn't even imagine we would be
23 interested in asking.
24
So, what would you have us do then with the
25 people who contribute to those databases in terms of
85
1 protecting their privacy adequately?
2
MS. GOLDMAN:
Well, I hope I am not going out on
3 a limb to suggest that my unease with what has happened
4 with the Framingham study is that it is going to be in
5 the hands of the private sector, and that it is going to
6 be--that we will not necessarily have the same-7 really know what the future is of it.
I don't
But let me say
8 that it puts it into question, and I think that it raises
9 ethical issues, it raises some legal issues, and I think
10 that it creates unease on the part of those initial
11 participants.
Because while, yes, it is a rich database
12 that you want to be used over time, so that as you ask
13 and answer certain questions it opens other doors and
14 makes that information available for other purposes,
15 there is a sense of trust that it will never be used in a
16 way that could harm individuals, or that could be used to
17 deny them certain benefits, or to expose them in any
18 unwanted way.
But that has always been in some ways a
19 matter of delicate trust, and not necessarily one of
20 legality.
And so, as we are seeing more and more the
21 information being sold, or made available for other
22 purposes, it raises this issue of initial control.
And
23 it is the second, and third, and fourth uses of the
24 information that were gathered for an initial purpose
25 that raises concerns on my part.
86
1
DR. MURRAY:
Just a brief follow-up.
I think I
2 hear two different threads of potential objection here,
3 maybe three different threads.
One is the privacy
4 issues, which is what we are putatively talking about
5 this morning, and I have never heard people--I have never
6 heard sustained complaints about privacy concerns for
7 the, you know, follow-up uses of the databases, even
8 though they may have been uses not contemplated before.
9 So, I am not sure that that is the central issue.
It
10 seems to me the two other issues are, number one,
11 privatization of the database, marketing of the database,
12 that that is something people--
And related to that, the
13 understanding that people at least implicitly may have
14 had when they agreed to participate in the study decades
15 ago, that it would be used for certain kinds of purposes
16 and not others.
And the issue here is not personal
17 privacy, but sort of respect for the subjects' wishes in
18 terms of what uses might be made of the database, even if
19 privacy were totally protected.
20 the table right now.
21
23 a moment.
I just want to make that clear.
DR. SHAPIRO:
22 commissioners who--
I think those are all on
Okay, I have quite a few
I will recognize Professor Sieber in
So, I would ask commissioners and respondents
24 to choose their most important question, and also, make
25 it brief.
87
1
Professor Sieber.
2
PROF. SIEBER:
I think it is important that we
3 also, however, figure out ways of honoring commitment to
4 data sharing.
I think that most subjects are willing to
5 be subjects because they want to help science, not a
6 particular scientist.
And I think also that the cost of
7 research, and the uses of research, is really helped
8 greatly by figuring out the best ways to organize data
9 sharing.
10
If we are concerned about privatization, we
11 might then be concerned about some of the organizations
12 such as
13 Sociometrics that gets very worthwhile social and
14 behavioral databases, cleans it, documents it, and then
15 sells it to institutions for educational purposes.
I
16 think we have to be very careful to protect those
17 interests.
18
DR. SHAPIRO:
19
Alex?
20
PROF. CAPRON:
Thank you.
I would like to thank both of you
21 for one of the most informative and concise presentations
22 of a difficult issue we have had in our work as
23 commissioners.
I would like just to get your
24 help, Professor Sieber, on the definitions that you put
25 forward, because I think it is helpful to us to think
88
1 about them as contributions that we could make in gaps in
2 the present federal regulations.
And I just wanted, if
3 you could, to explain, on page 90, where you give a
4 definition of privacy, why you state that privacy refers
5 to, and here you underline it, "persons and to their
6 interests", rather than saying "privacy refers to
7 persons' interest in controlling access".
And on page
8 91, if in your description of the addition to risks and
9 discomforts, it would be adequate to say "including
10 possibly unwelcome attempts to obtain private
11 information".
12 suggestions.
13
Just those two questions to you about your
Use your microphone, please.
PROF. SIEBER:
Thank you.
My underlining of
14 "persons" is to indicate that this is not about data.
15 is about people.
It
And I think that to say that one has an
16 interest implies something cognitive and active, and I
17 might not think about my interest in something, but I may
18 come from a subculture in which, after I reveal some
19 information, others of my kind would say, well, that was
20 really dangerous, or stupid, or you are very naive.
And
21 so, I want to take it out of the exclusively cognitive
22 realm when we talk about an interest.
I don't think it
23 is strictly an active thing.
24
Now, Alex, your second question was about--?
25
PROF. CAPRON:
The second question--
You used
89
1 the phrase "including possibly unwelcome seeking or
2 presenting of information or experiences, i.e., possible
3 invasions of privacy", and you seemed to use the word
4 "invasion" of privacy in a situation in which you would
5 include authorized access to that information, whereas I
6 think in ordinary language, the word "invasion" suggests
7 some unwanted intrusion.
And so, I was wondering whether
8 the idea would be conveyed by simplifying it, and simply
9 saying, as I think your point is, that you can feel
10 stressed or discomforted by a possibly unwelcome attempt
11 to obtain private information.
12
PROF. SIEBER:
I like that.
13
PROF. CAPRON:
Okay.
14
DR. SHAPIRO:
15
Steve?
16
MR. HOLTZMAN:
17 Tom to Ms. Goldman.
Okay.
Thank you.
Thank you.
This is a follow-up to Alta and
First off, a quick clarification.
18 thought I heard you say that identifiable in the new
19 proposed regs, that there are a specification of 19
20 different criteria, the presence of which, any one of
21 which, would constitute identifiable.
22 zip codes.
One of those was
So that is this record said the following
23 information about me, all this generic information, but
24 said 02139, that would make it identifiable?
25
MS. GOLDMAN:
Well, the way--
I
90
1
MR. HOLTZMAN:
I think that is what I heard you
2 say, but is that--?
3
MS. GOLDMAN:
The way the regulation is written,
4 and I know that sounds--the way that you have posed it
5 makes it sound very far-fetched, but what has happened is
6 that the way that they have tried to write it, and again,
7 it has come under quite a bit of criticism, is to suggest
8 that if zip code is attached, and then you have a
9 diagnosis, and you have a diagnosis and maybe an age, or
10 a diagnosis and maybe an employer, there are
11 opportunities in certain areas to identify individuals.
12 And so, they are trying not to make a hard and fast rule,
13 but to suggest that the presence of certain identifiers-14
MR. HOLTZMAN:
15
MS. GOLDMAN:
Okay.
It is just the way census data--
16 It is a very similar way that census data is handled.
17
MR. HOLTZMAN:
So, but very specifically, I
18 thought I heard you say that any one was sufficient, but
19 what I am hearing you saying is the reg is basically
20 saying look at these, and make a judgment, or--?
21
MS. GOLDMAN:
The way it is written as a
22 proposal, and I think we will see some changes, is that
23 the presence of any one of those is sufficient to make it
24 identifiable, which means that it is covered, which means
25 that you then have to follow a set of rules in handling
91
1 it.
2
PROF. CHARO:
I am sorry, but I find this so
3 odd, because if there was a code that could actually be
4 broken and lead you to the name and address of the
5 person, that is not identifiable because that is a
6 prospective use, but if there is a zip code that somebody
7 might possibly in the future try to correlate with
8 something else in order to be able to figure out the name
9 and address of the person, that is identifiable, even
10 though it is not a current use.
I am just very puzzled
11 about the hierarchy of concern.
12
MS. GOLDMAN:
Well, and I think many people were
13 exercised about it, and so it probably will change.
14
DR. SHAPIRO:
The analysis of these proposed
15 drafts we ought to stick away from.
You can ask specific
16 questions, but we will wait and see what these things
17 look like, and worry about it at that time.
18
Steve, you had another follow-up question?
19
MR. HOLTZMAN:
Yes, I just want to make clear if
20 you think about something like Framingham and the whole-21
I think there is a red herring introduced when there is
22 private sector involvement.
One of the things we are
23 concerned of in the private sector is for the majority of
24 our research, we don't want to know the individual.
25 are very, very happy to go through coded information.
We
92
1 What we do want to have is follow-up information with
2 respect to the condition that is being studied.
3 Commission--
This
That requires at least a one-way code.
4 There has to be a logical connection, even if in our
5 hands we don't know, and couldn't possibly but for
6 breaking a code, access the individual.
This
7 Commission took the position that that should have, as it
8 were, the ontological and moral status of identifiable
9 information with everything that goes along with that in
10 terms of consents, et cetera.
My understanding of where
11 the proposed regs were going were saying something
12 different, that that would not be considered
13 identifiable, and hence, a lot of the apparatus about
14 respect for autonomy would not go into place.
Is that a
15 fair interpretation?
16
MS. GOLDMAN:
My understanding of what the
17 proposal seeks to do is to say if a code exists somewhere
18 else, if it is not within the control of the entity that
19 has the data, that that suggests that the entity that is
20 holding the data is not holding identifiable information,
21 that it may be re-linkable if they then hook up with the
22 disclosing entity, for instance, or the trusted third
23 party that is holding the code, which is, I think, where
24 we are going to end up going in this area, because you
25 do, for certain purposes, want to be able to re-link, and
93
1 the suggestion here is not that you should never be able
2 to do it, but there are certain kinds of information that
3 would be outside the scope of the regulation, and certain
4 that would be within.
And being within doesn't mean you
5 are prohibited from using it.
It means that you have to
6 follow certain ethical and procedural rules.
7
So, the idea that who is controlling the ability
8 to re-link, that is an important question.
And at the
9 point at which information would be re-linked, it would
10 then trigger a review and examination, the application of
11 the rules.
12
DR. SHAPIRO:
Okay.
I have a number of
13 Commissioners on my list, and if anyone asks questions
14 that are too long, I will hold you responsible for having
15 other commissioners left off completely when we adjourn
16 this session.
So, Diane, you are next, and then David,
17 then Larry.
18
DR. SCOTT-JONES:
I am sure Harold didn't mean
19 to make that comment just before I started talking.
20
(Laughter.)
21
DR. SHAPIRO:
22
DR. SCOTT-JONES:
You are right about that.
Okay.
I have a question for
23 Joan.
24
Joan, you have been very helpful in helping us
25 think about how the social and behavioral sciences need
94
1 to be included as well as biomedical research, and my
2 question has to do with that, and it is also related to
3 what Alex asked earlier about your definitions of
4 privacy.
You made the point in your paper for us that it
5 is important to focus on education, and not just more
6 regulation, and you pointed out how the Common Rule
7 defines private information, but not privacy itself, and
8 that it doesn't really define confidentiality, but merely
9 interchanges that with privacy.
I would like you to
10 say a little bit more about how we in our report might
11 attend to the social and behavioral sciences, so that
12 whatever we recommend is appropriate broadly for
13 research, and not remaining focused on biomedical
14 research only.
What are some specific steps that we
15 might take as we work on the report?
16
PROF. SIEBER:
Well, one of the things that
17 comes to mind immediately is that the issue of personal
18 privacy having to do with emotional and social features
19 of one's life is so central to social and behavioral
20 science, and I think, incidentally, most of what I have
21 said is relevant to a lot of practice of biomedical
22 science, and certainly epidemiology, which fits between
23 the two categories.
24
I would like to take your question under greater
25 consideration and get back to you.
I don't think I can
95
1 give you a good capsule answer that I would be happy with
2 tomorrow.
3
DR. SHAPIRO:
With apologies for imposing upon
4 you, that would be extremely helpful to us as something
5 we are struggling with, and you have a lot of experience
6 in this area and have thought about it carefully, so that
7 would be very, very helpful to us.
I would appreciate it
8 if you could possibly take the time.
9
PROF. SIEBER:
Maybe we could take a little time
10 after this session and discuss the points that you have
11 in mind.
You have criteria that I might not think of.
12 Thank you.
13
DR. SHAPIRO:
14
David?
15
DR. COX:
Thank you.
So, I have a question for Ms. Goldman,
16 and a straightforward one.
As you might have gotten the
17 drift, a number of Commissioners may have a different
18 view of what identifiable is than what you are
19 presenting.
So, in the spirit of not killing the
20 messenger, but finding out who they are actually
21 delivering the message from, could you clarify precisely
22 the body, and even the person who is making this-23
(Laughter.)
24
DR. SHAPIRO:
25 mind, David?
What could you possibly have in
96
1
DR. COX:
--making this particular suggestion--
2
(Simultaneous discussion.)
3
PROF. CAPRON:
Who may then become a body if we
4 get our hands on him.
5
DR. COX:
--so that NBAC would be in a position
6 to maybe make a comment to that body or individual?
7
MR. HOLTZMAN:
You can use one of 19 different
8 identifiers here.
9
10
(Laughter.)
MS. GOLDMAN:
I am going to give you a serious
11 answer, but you won't like it, so you will continue my
12 role as the messenger that is getting shot.
13
When the administration proposed the health
14 privacy regulations in November of '99, they opened up a
15 public comment period, obviously, and my understanding is
16 that NIH and a number of others were involved, and that
17 we, obviously, submitted comments.
There were about
18 55,000 comments that were received; about half of them
19 did come from consumer groups.
And one of the issues
20 that was highly contentious was this issue of when is
21 information identifiable.
It took a lot of heat.
The
22 public comment period closed on February 17th, so there
23 is no one that you can call or talk to who is going to
24 listen to you in any official capacity.
25
However, I think there are people who are
97
1 continuing to struggle with this issue, and continuing to
2 try to write something that is both privacy-protective,
3 and workable.
I think that is the goal, to say in their
4 defense, that is the goal, and hopefully, they will
5 achieve it.
6 flux.
So, I think that it is a proposal that is in
I can't speak to, you know, it any more than that,
7 because I don't know.
I am like you are, on the outside
8 looking in, wondering what they are going to do.
9
Does that help?
10
(Laughter.)
11
DR. SHAPIRO:
12
DR. MIIKE:
Sort of?
Not really.
Larry?
I am sorry to end this on a more
13 sobering note, but Dr. Sieber, you mentioned something
14 that is really not important in the greater scheme of
15 things, but it pushed a very hot button on me, and that
16 is about talking about ethnic differences in the sense of
17 privacy, and you used an example, ethnic Japanese who
18 don't want to look you in the eye, and then you say,
19 "especially in Hawaii", as a treatment of disrespect, but
20 you give no references, and I would say that if
21 researchers came to Hawaii from California with that in
22 mind, a whole bunch of their research subjects like me
23 would say, "Those are really weird researchers.
24 of them would look me in the eye.
25 out of this project!"
Not one
I am getting the hell
98
1
(Laughter.)
2
DR. MIIKE:
So, I guess from my side, you
3 inadvertently made your point, but not in the way that
4 you intended.
5
PROF. SIEBER:
Well, I think it is true.
In
6 giving IRB workshops in Hawaii, I have often been told
7 that.
However, it is a very good example of how
8 generalizations never work, and I think that for the
9 purposes of the paper-10
DR. MIIKE:
Give me the names of the people in
11 Hawaii-12
(Laughter.)
13
PROF. SIEBER:
This is some group here!
I
14 thought you were kind of mild-mannered, intellectual
15 academics.
16
Everyone is taking names!
PROF. CAPRON:
We are known as the Bioethics
17 Enforcers.
18
DR. SHAPIRO:
19
DR. MIIKE:
20
DR. SHAPIRO:
Larry, I think we will-Zip codes won't work.
That is right.
And you don't want
21 just a number, right?
22
Thank you very much.
23
I just want to--
We have to bring this session
24 to an end because we have another panel about to start.
25
First of all, I want to thank you both for very
99
1 helpful papers especially, and for your presentation, and
2 also your presence here today.
3 you.
We are very grateful to
I want to pose a question.
I don't want to
4 get a response now because we just simply don't have
5 time, but one industry that has collected very personal
6 and private information for a very long time is the
7 insurance industry.
And they have very sophisticated
8 ways of sharing that data amongst each other, and they
9 have a whole organization which, as far as I know, has
10 done its best to protect the privacy of this information,
11 but I don't have any direct knowledge, but that is my
12 understanding.
It seems to me to be a very good case to
13 look at, and if on reflection either of you have any
14 observations, or any place you might send me to look and
15 read about that, I would appreciate it, because a lot of
16 the health data we are considering now is really for the
17 first time being collected and used and so on.
So, I
18 would appreciate that, any reference you might send me
19 to, or any body you might send me to, that would be very
20 helpful.
21
PROF. CAPRON:
Mr. Chairman, I don't think we
22 should end this discussion without noting for David Cox
23 and other members of the Commission, that we did respond
24 during the public comment period.
25
DR. SHAPIRO:
Yes, we did.
100
1
PROF. CAPRON:
All right.
Because it sounded as
2 though you thought-3
DR. COX:
4
PROF. CAPRON:
5
DR. SHAPIRO:
6 much.
No, no.
All right.
So, once again, thank you very
If the commission is agreeable, I would
7 like to go just directly into the next panel.
So, thank
8 you very much for being here today, and I will try to get
9 our next panel to join us immediately.
10
We are running a few minutes early right now, so
11 let's take a bit of a break, because some of the panel
12 members are not yet here.
Let's just take a five or ten
13 minute break.
14
(Whereupon a brief recess was taken.)
15
DR. SHAPIRO:
Thank you very much.
Our final
16 panel today, as you know, deals with quality control,
17 assurances, site inspection, accreditation,
18 certification, licensure.
I mean, those are all items
19 that are up there in the air being talked about, and
20 which we are going to have to be considering in one form
21 or another.
22
And first of all, I want to welcome back Dr.
23 Koski who was just here yesterday.
Thank you again.
I
24 think we have used up 39 percent of your total time on
25 the job in the first few days, and it will not continue
101
1 in this manner is the only thing I can assure you.
But
2 thank you very much for taking time again to be here
3 today.
4
We also have Dr. Lepay is with us here, and of
5 course, Michael Hamm, and you have seen some of the
6 materials that he has provided us with before our meeting
7 today.
8
So, I will turn directly to the panel, and start
9 with Dr.--
I will just go across this way, and start
10 with Dr. Koski.
11 PANEL III: QUALITY CONTROL: ASSURANCES, SITE INSPECTIONS,
12
ACCREDITATION, CERTIFICATION, AND LICENSURE
13
PRESENTATION BY GREG KOSKI, M.D., Ph.D.
14
DR. KOSKI:
Thank you very much, Dr. Shapiro.
15 Thank you, Commissioners.
16
Nice to be back.
Trying to catch my breath.
17 minute late.
I am sorry to be a
I got off at the wrong Metro stop.
18 still learning Washington.
I am
And I am sure that is not the
19 only lesson that I will have to learn.
20
Let me just, before I begin remarks let me
21 acknowledge my colleague, David Lepay, in his new role
22 seated here to my right, because David and I are going to
23 be working very closely together on a lot of things, and
24 I am sure he is going to be a good partner, and he is
25 going to be playing a very important role in the things
102
1 that we all have to do.
2 work with you.
3
So, David, it will be nice to
Thank you.
I guess with respect to the question before us
4 on this broad topic of quality assurance, quality
5 improvement, licensure, certification, accreditation, and
6 so on, it may be useful to at least give a few kind of
7 broad comments that sort of focus on my own perspective
8 on this.
9
I think that if we simply look at the activities
10 that go on in the world around us in almost any
11 specialized field of endeavor, no matter what it is,
12 there is generally an expectation that the practitioners
13 of that particular endeavor will meet a certain standard
14 for performance, and that they will have a certain
15 fundamental knowledge base, tool set, if you will, for
16 performing those activities.
And we see that in every
17 facet of our lives, whether it is in our schools, in our
18 drivers, as well as in our professions.
So, it is
19 certainly an important part of the way we operate.
And
20 in general, many of those licensing or certification
21 activities result from the fact that there is a certain
22 expectation from society that people will be performing
23 at a certain level of proficiency.
24
Now, we see this particularly in the
25 professions, whether it is in the medical profession, or
103
1 law, or other professions.
Certainly in medicine, since
2 the time of the Flexner Report, we have seen a radical
3 change where medicine has changed from what was an
4 apprentice system to one that used rigorous curriculum
5 for education of the practitioners, as well as
6 certification, licensing, examinations.
I think that it
7 is fair to say that probably none of us would knowingly,
8 willingly, send our children to an unlicensed medical
9 practitioner, because we know that if they are licensed,
10 at least there is a higher probability that they will be
11 performing to the standard that is expected.
12
My own feeling is that clinical research,
13 particularly all research involving human subjects, has
14 reached the point where it needs to undergo a similar
15 transformation in that the apprentice system that has
16 generally been the operating model for much of the
17 clinical research that has been done is probably no
18 longer up to meeting the challenges before us, and that
19 it is time to recognize that we should have appropriate
20 standards, requirements, for education and training, as
21 well as performance.
And that includes, I believe, not
22 only individual practitioners, but also the various
23 entities that are involved in one way or another, be they
24 IRB committees, or data safety monitoring boards, or
25 institutions, corporate sponsors.
104
1
As I mentioned in the model that I proposed in
2 my comments yesterday, this subject-focused collaborative
3 model, each and every one of the parties engaged must
4 know what their responsibilities are, they must be
5 properly trained to execute those responsibilities, and
6 there needs to be some, I believe, objective means to
7 assess and document that, in fact, they are prepared to
8 do that.
So, I think that sort of covers the sort of
9 basic layout.
10
To go into a bit more specific detail, it would
11 make sense to me to have a uniform set of educational
12 requirements, or expectations, standards, again, for all
13 of the individuals participating in clinical research.
14 Although there are, as we mentioned yesterday, separate
15 regulatory authorities for the various agencies within
16 the federal government which to a very large extent
17 either fund or regulate most of the research that is done
18 with human subjects in this country, it seems to me that
19 it should be possible through the acceptance of standards
20 at a high level by all of those agencies for there to be
21 independent application of those within their own
22 regulatory framework, at least as a starting point,
23 recognizing that it may be necessary to move further
24 toward rules and regulations in the future, in order to
25 ensure that all of the agencies are able to meet their
105
1 specific regulatory requirements.
2
So, I believe that starting with individuals,
3 laying out clear and uniform standards for the training
4 and education is an important start.
I see absolutely no
5 reason why an individual who is doing research under
6 corporate sponsorship that is regulated by the FDA should
7 have any less training, or any more training, than anyone
8 who is doing research for another federally-funded
9 project.
A clinical investigator who is working with
10 human subjects, in my mind, is pretty much the same
11 across the board, and those requirements should be
12 uniform.
13
I believe that OHRP in its new configuration is
14 well-suited to helping lead the effort to establish those
15 uniform requirements, and we look forward to working with
16 the other federal agencies, both within HHS and outside
17 of it in order to do that.
18
With respect to the entities, I believe that,
19 again, institutional review boards and data safety
20 monitoring boards should have specific standards that
21 they should work to.
There already, as you are well
22 aware, is an effort ongoing with strong support from AAU,
23 AAMC, PRIM&R, and other organizations to begin to
24 establish standards for IRBS.
25
In the current world, it is entirely possible
106
1 for a small start-up company to find a group of five
2 qualified individuals and establish it as an IRB as long
3 as they meet the requirements within federal regulations.
4
That may not be the standard that we want to apply.
It
5 seems to me that an IRB that is constituted for a short
6 period of time in order to approve a couple of studies
7 and then abandoned is not the way to go, so that having
8 standards that will apply, again, for all institutional
9 review boards is, I believe, a critical step forward.
10 Those standards would need to be established and
11 recognized by the entire country, and hopefully, we would
12 be able to even achieve international standards for
13 institutional review boards, since as was discussed
14 yesterday, there is an increasing amount of research that
15 is done in the international domain.
Applying those
16 standards through a publicly accountable accreditation
17 process is an important step toward bringing all of the
18 IRBs up to a level of function that we can be proud of
19 and comfortable with.
Clearly, we need to do that in
20 order to establish the trust that is so important for the
21 biomedical research endeavor.
22
Finally, I believe that, you know, just as
23 industries currently will proudly display their ISO 9002
24 certification on the side of their buildings, it is
25 important to recognize that there is a powerful motivator
107
1 here for all industries and all institutions to adopt
2 these standards in all of the research that are performed
3 at their institutions, or supported by their
4 institutions.
It will actually facilitate the conduct of
5 research on all fronts by letting everyone know that it
6 is being done at the highest possible standard.
And so,
7 there is value to, you know, industry as well as the
8 academic institutions to making appropriate assurances
9 that they are going to use accredited institutional
10 review boards, and have work performed by certified
11 members of the research team.
12
There is a long way to go to bring all of this
13 about, but you have to start somewhere, and I think that
14 this is probably a good time and place to start.
15
DR. SHAPIRO:
Thank you very much.
16 to follow the practice we have set.
I would like
We would like to
17 hear from each of the speakers before we go to questions.
18
19
So, Dr. Lepay, thank you very much for coming.
20 I think, in addition to many other distinguished aspects
21 of your career, your title is one of the longest we have
22 had to type down here, to my recollection.
23 welcome-24
DR. LEPAY:
Thank you very much.
25
(Simultaneous discussion.)
But anyhow,
108
1
2
DR. SHAPIRO:
--in the FDA.
Yes.
PRESENTATION BY DAVID A. LEPAY, M.D., Ph.D.
3
DR. LEPAY:
I want to thank Greg Koski, also,
4 for the introduction this morning.
We certainly do look
5 forward to working together very closely, particularly
6 over the next several months where there is a lot to be
7 done.
8
(Slide.)
9
I am going to be very concrete today, because
10 the charge that was given to me by the Commission was to,
11 in fact, address FDA's inspection program for IRBs as it
12 exists.
This sounds like a fairly straightforward task,
13 even given the time constraint of about 10 minutes to do
14 it, but in fact, it is not all that simple a task,
15 especially when one of the goals, I would imagine, of the
16 Commission is to compare and contrast systems, and to
17 develop some recommendations from the results of their
18 analysis.
19
And I think what makes it difficult, in fact, is
20 that the clinical trial process is a very complex one
21 with a large number of players, a large number of shared
22 responsibilities between these players, and a very large
23 number of interactions that go on in implementing these
24 responsibilities.
And in fact, I think the best analogy
25 may be one of neuroanatomy, and that is the one I will
109
1 propose here, namely, that you have to initially get some
2 kind of handle on each of the individual components.
You
3 have to learn each of the individual pathways, but it is
4 not, in fact, until you are at least familiar at some
5 level with all of the pathways that you can begin to make
6 some sense of the specifics of any one given pathway.
7 And in fact, from that standpoint, I will say that the
8 whole may be greater than the sum of its parts.
9
So, in fact, and in dealing with a few opening
10 perspectives here that we are going to project, I think
11 there are a couple of points that need to be raised right
12 from the start about FDA's--or about any oversight
13 system, but FDA's in particular.
First of all, we have
14 to avoid taking up IRBs as independent of the other
15 parties that are involved in the clinical trial process.
16
Fundamental.
We have to avoid from FDA's standpoint,
17 the possibility of taking up on-site inspections
18 independent of FDA's in-house review process.
This is a
19 process that, in fact, is going on in real-time, involves
20 several thousand people in Rockville looking at
21 protocols, receiving and analyzing safety reports, and
22 following trials through all phases of drug development.
23
A third point that I think is important to
24 address is we have to avoid taking up FDA inspections
25 independent of discussing a sponsor's responsibility in
110
1 the FDA system for real-time monitoring and auditing.
It
2 is often very simple to say FDA is not out there
3 everywhere in real-time, but in fact, we have a system of
4 shared responsibilities in place that put some of that
5 burden on sponsors to be out there in real-time.
6
We have to also avoid taking up U.S. GCP
7 standards and implementation without considering the
8 interrelationship of U.S. and international GCP standard9 setting, the various international regulatory cooperative
10 activities that have been going on for the past decade,
11 and the fact, indeed, that harmonization is leading to
12 improvements in the clinical trial process globally.
13
And I think the fifth point I want to take just
14 as an opening perspective is that we have to avoid
15 looking at data quality and integrity as separate or
16 isolated from human subject protection.
17 very important point.
And this is a
We have to look at data from the
18 standpoint of what it is.
Data that is generated from a
19 previous study is going to be used as the basis for
20 decision-making about whether a new study should proceed,
21 whether indeed, data has to be taken into account in the
22 process of initial review.
Data that is generated during
23 the course of a study is going to be important to analyze
24 in continuing review.
25 public protection.
So indeed, that is part of a
111
1
And finally, data that is submitted at the
2 conclusion of a study that is submitted for marketing
3 purposes is going to form the basis for labeling of that
4 product, the way it is going to be used in promoting the
5 public health as well as a public protective measure in
6 conveying risk.
It is going to be used in the scientific
7 literature as a basis of influencing medical decision8 making, and ultimately that data from any particular
9 product is going to be used as the basis for decision10 making on the next set of clinical trials when you have
11 to decide what control arm you are going to use, and how
12 you are going to appropriately use it.
13
So, I think it is very important to keep all of
14 these points in mind, and not simply focus on one
15 particular element out of context.
And that is where I
16 am really going in these opening perspectives.
Very
17 quickly, as we say here, the point being that good
18 clinical practice, that which we are trying to achieve in
19 FDA, is a system of shared responsibilities in which
20 there are defined responsibilities for each of the
21 participants.
22
(Slide.)
23
Additional points that I, hopefully, have made
24 is that each party involved in clinical research has
25 responsibility for human subject protection under FDA
112
1 regulations.
Human subject protection is not solely the
2 IRB's responsibility; it is the responsibility of all
3 four parties, and this is written into our regulations.
4
Human subject protection is also, as I
5 mentioned, a component not just of on-site inspecting,
6 and we don't want to restrict ourselves to say FDA
7 oversight is only what we do on-site, or at an IRB.
In
8 fact, the in-house review component is very critical to
9 human subject protection at FDA.
And the integration of
10 review with inspection is also a fundamental tenet of how
11 we operate.
12
(Slide.)
13
Each party involved in FDA-regulated research is
14 subject to inspection.
It is not just the IRB.
There
15 are programs for all of these parties, and human subject
16 protection is addressed in inspection of each of the
17 involved parties.
18
(Slide.)
19
So, very quickly, I am going to go through in a
20 very few minutes what the nuts and bolts of our
21 inspection process is.
Our inspections are, in fact,
22 conducted according to protocol; SOPs are compliance
23 programs.
They are available publicly.
24 widely through industry, among IRBs.
They are known
They know what we
25 are going to look at, what we are focusing on.
Our
113
1 inspections are typically pre-announced, but we do have
2 the authority to go in if conditions should warrant in
3 unannounced inspections.
And the way inspections are
4 developed, they are assigned by offices in Rockville at
5 headquarters in conjunction with our review division, and
6 are conducted by field investigators located in locations
7 across the United States close to the site of inspection.
8
(Slide.)
9
Our inventory.
We have about--
At the moment,
10 the way we develop our inventory of IRBs is based on
11 investigator statements.
It is a requirement of
12 investigators, at least in drugs and biologics, to sign
13 an FDA form 1572 which includes basic information as well
14 as commitments as to what that investigator is agreeing
15 to in taking on the responsibility for an FDA-regulated
16 study, and one of the pieces of information that is
17 required of investigators is identification of their IRB.
18
And from that information, we within drugs and biologics
19 have a database that currently contains 1573 IRBs that we
20 know are doing FDA-regulated work.
21
When we choose among these to inspect, obviously
22 we have limited resources, and we have to be able to
23 prioritize.
And our priorities as we have set them up in
24 our stratified schema is to look at the three areas that
25 are indicated here, first and foremost, that is, new
114
1 IRBs, IRBs for which we may have information of problems,
2 either through our review division or outside complaints
3 that we have received, as well as if we have inspected
4 previously, we have cited deficiencies, we need to go
5 back sooner, of course, to confirm that these
6 deficiencies were corrected.
7
(Slide.)
8
The inspections take typically two to five days,
9 conducted by a single individual, in work hours about 58.
10
And indeed, right from the start, the focus of our
11 inspection program as it is stated in our compliance
12 program for IRBs is that the inspection is there to
13 provide on-site information and guidance to IRBs.
14 Obviously, there is a compliance process associated with
15 this.
If we do see serious problems, we have the ability
16 to impose administrative sanctions.
But our inspection
17 program for IRBs is designed with the concept that IRBs
18 are allies in the process of assuring human subject
19 protection, and we are out there to be on-site to provide
20 information and guidance.
21
(Slide.)
22
It is a process-oriented inspection, and this
23 has been discussed, I think, at various levels both here
24 and within the Inspector General's office.
But of
25 course, in designing an inspection program, we have to be
115
1 guided by our regulations.
We are a regulatory unit, so
2 therefore, of course, we have to build into our
3 inspections what we are supposed to do, and look at by
4 regulation.
5
And indeed, this is how we have developed.
We do, in fact, choose current as well as recent
6 representative studies when we go on-site to IRBs.
It is
7 not necessarily or, hopefully, not frequently done where
8 you are just going after a study that is three years
9 completed.
The idea is to identify with the IRB the
10 current inventory, and to follow through, to track
11 through how an IRB has handled the oversight of this
12 particular study, as well as the paperwork that is
13 associated with it.
The inspection does include
14 interviews as well as examination of procedures and
15 records.
16
(Slide.)
17
So this is what is in the compliance program.
18 This is what is examined.
Basically, very quickly,
19 looking at IRB membership, looking at the written
20 procedures that are out there, following through with
21 current protocols, initial and continuing review from the
22 standpoint of authority, process, frequency of continuing
23 review.
24
(Slide.)
25
Our regulations require documentation.
That is
116
1 a regulatory authority.
So, certainly, we have to be out
2 there looking at documentation and record-keeping.
3 is a focus.
This
We are looking at a systems approach here.
4 We are looking at how IRBs interact with the clinical
5 investigators, and with the institution.
We also are out
6 there looking to see if they are properly using expedited
7 review, if they are properly using emergency review, and
8 that can be review for emergency use, or under waivers of
9 informed consent for emergency research.
And we are out
10 there also acquiring representative informed consent
11 forms, looking, indeed, whether the informed consent
12 forms meet the basic elements of the regulation, and
13 also, enquiring about the process by which consent is
14 being obtained.
And that is an important component of
15 what we do on interviews during inspections.
16
(Slide.)
17
The follow-up to an inspection.
18 the
At the end of
inspection, there is an exit interview, and at that
19 time, if there were any inspectional observations, and
20 observations have to large--at least what is printed,
21 what we write, has to be built on regulatory
22 requirements.
We may discuss practices, we may discuss
23 what we have seen that may be different from guidance and
24 so forth, but ultimately, we have to focus in on what we
25 have regulatory authority over.
And from that exit
117
1 interview, from any observations that are taken, those
2 are the observations of the investigator on-site.
3
He or she will develop these into a report
4 including exhibits, documentation of what was observed.
5 These will then be forwarded back to the assigning office
6 at headquarters where they will again be reevaluated.
7 There will be a final classification, and a close-out
8 letter, as well as if there are any needs for initiation
9 of compliance actions, that is when it will be taken.
10
(Slide.)
11
I think we have gone through these at times
12 before, but it is useful to remind.
What are our
13 authorities as far as compliance actions against IRBs?
14 With IRBs, we are not necessarily--or we are not talking
15 about rejection of data.
Most of our inspections are, in
16 fact, voluntary action inspections, and the corrections
17 are typically achieved quickly.
The official actions
18 that we can take, however, include warning letters,
19 include the withholding of approval of new studies,
20 include the withholding of enrollment of new subjects.
21 We can terminate ongoing studies, and we have the
22 authority, at least, to take both administrative
23 procedures toward disqualifying an IRB, as well as
24 criminal procedures where that might be necessary,
25 including injunction and prosecution.
118
1
(Slide.)
2
It is a due process system.
3 respond, as can any inspected party.
The IRB can
They can respond to
4 FDA at any point during, after the inspection, and
5 indeed, those responses will be reviewed when they come
6 back to us. If we have them at the time that we are
7 making our assessment, all of that is taken into account
8 in developing our regulatory communication, and in
9 developing regulatory action.
10
We also do exchange information, and certainly,
11 that flow has improved greatly in the recent past between
12 ourselves and OPRR, now OHRP, in the exchange of
13 regulatory communication, our close-out letters, and we
14 receive copies of OHRP's regulatory communication.
15
(Slide.)
16
So, what are some of the limitations?
We said
17 that we have an inventory of about 1573 IRBs out there.
18 We have the resources, what we are given the resources to
19 do is about 250 to 300 IRB inspections per year.
Of
20 these, from FDA's perspective, about four to five percent
21 of these result in official action.
The official action
22 is most typically a warning letter with corrections very
23 quickly put into place by the IRB.
They respond very
24 fast to warning letters in just about every case.
In
25 three cases in the past fiscal year, we had to impose
119
1 sanctions, and those sanctions were limiting new studies,
2 and limiting enrollment into new studies.
3
(Slide.)
4
The problems that we see when we have to take
5 actions, they are not isolated, single problems with,
6 indeed, a piece of paper that wasn't flowing.
If you
7 look at these, of the 15 warning letters that were issued
8 between January of '99 and March of 2000, you will see
9 there is tremendous overlap in problems.
Fourteen of the
10 15 have problems with procedures; 13 of the 15 also had
11 problems with documenting activities; 10 of the 15 had
12 problems with continuing review; nine of the 15, problems
13 with expedited review; seven of 15 with problems in
14 informed consent and meeting the requirements of informed
15 consent.
16
We don't take official action lightly.
17 looking, in fact--
We are
We are trying to approach this from
18 an education and corrective stand.
However, when you see
19 multiple problems as you do in these 15 cases, that is
20 where we go in with action, and that has typically been
21 our approach.
22
If I can have the next slide--
23
(Slide.)
24
It is not to say there are not a number of
25 areas, in fact, that do evoke voluntary action, and where
120
1 we have to work to identify and educate correctable
2 process deficiencies.
And many of these, again, deal
3 with documentation, but they are fundamental.
Eight
4 percent dealing with problems, even the performance of
5 continuing review.
6
So, where does that take us?
If I can go to our
7 last slide.
8
(Slide.)
9
Obviously, this is a dynamic process.
I think
10 it is a mistake to look at any inspection program as
11 simply a static process that goes unchanged, that does
12 not take into account emerging problems in clinical
13 research or emerging technologies, and certainly, we have
14 to take those into account ourselves.
And over the past
15 four years, in my work in DSI, certainly we have tried to
16 look at ways that we can improve the process within the
17 framework of our regulations.
18
And for us, where we are going right now,
19 certainly we are focusing much more on the informed
20 consent process versus the form.
We are very interested,
21 again, within the capacity that we can define it within
22 our regulations, into enquiring about the qualifications
23 of those administering informed consent.
And
24 particularly, if those are not the physicians who are the
25 clinical investigators themselves.
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1
We are looking at subject recruitment, and
2 subject recruitment in our eyes, in our regulation, is
3 the beginning of the informed consent process, and this
4 is, of course, an area that we need to reaffirm with
5 IRBs, and we need to move forward and put attention to.
6
As we look to how we can improve IRB
7 performance, one of the key issues in IRB performance is
8 access to information for subjects, and this is something
9 we are looking to increasingly enquire about.
10 numbers that are given real?
Are those
If somebody dials a number,
11 a contact number, are they getting the contact they wish?
12
Are they getting the information out of it that they
13 wish?
These are things we can approach, and we are
14 moving toward.
15
About four weeks ago, of course, the Department
16 sponsored a workshop on conflict of interest.
This is
17 still a very active comment period extending until the
18 end of September.
We expect that as those comments come
19 in, as we have dialogue across the Department, that will
20 be a direction as well that we will be pursuing.
21
And finally, responsiveness to complaints.
And
22 when I say that, I am speaking of both responsiveness to
23 complaints by IRBs, as well as by each of the processes
24 in regulated research, including ourselves.
This is
25 something we have to build into the system.
We talk
122
1 about real-time, we talk about real-time protection.
One
2 of the best ways of assuring real-time protection is to
3 be responsive quickly to problems as they occur, and that
4 is certainly a focus right now of FDA's inspection
5 program.
6
I thank you very much for the time.
7
DR. SHAPIRO:
Thank you.
Thank you very much
8 for those very helpful remarks.
9
Let me now turn to Mr. Hamm for his remarks, and
10 then we will go to questions.
11
12
PRESENTATION BY MR. MICHAEL S. HAMM
MR. HAMM:
Okay.
Thank you for inviting me to
13 address the Commission.
14
I am a consultant for certification and
15 accreditation organizations, and organizations interested
16 in developing these programs, so I am approaching this as
17 a lay person from your point of view, but I can address
18 questions regarding these organizations and what they do,
19 how they operate.
20
I thought I would just give you a little
21 overview of the accreditation/certification world.
The
22 first thing I always address with crowds that are
23 somewhat new to this are some definitions, because the
24 terminology has been somewhat of a problem.
25
Generally, I refer to accreditation as a process
123
1 to evaluate an organization or a system, whereas
2 certification is a process to evaluate the knowledge,
3 skills, or abilities of individuals, and unfortunately,
4 for various reasons, some organizations prefer to use one
5 of the terms just because they think it sounds better,
6 and there is a fair amount of confusion there, but that
7 is always an issue.
I have to ask when someone says "We
8 accredit or certify", you always have to ask exactly what
9 they mean, because the terminology is used in various
10 settings in different fashions.
11
I guess the issue of why it is important to
12 government, when I hear of government approaches,
13 regulatory approaches, I think of this as the club or
14 stick.
Voluntary certification/accreditation are more
15 the carrot side, although having said that, there is
16 shades of gray.
I guess I would have to say as
17 accreditation/certification programs evolve, in terms of
18 their relationships with government and other
19 stakeholders, they also have a little stick, too, and
20 sometimes that stick is growing.
So, there is a lot of
21 overlap, and in fact, some attorneys have even described
22 some of the more powerful accreditation programs in the
23 country, such as the Joint Commission for the
24 Accreditation of Health Care Organizations, as quasi25 regulatory bodies.
And it is an interesting
124
1 concept, because even though it is voluntary, frankly,
2 from the point of view--
I come out of a hospital
3 background, and the reality of it is, in 2000, if you are
4 a tertiary care center involved in research and teaching,
5 accreditation is not voluntary; it is mandatory.
So, I
6 mean, that is some of the dynamic that we are dealing
7 with.
8
But in terms of the things accreditation can do,
9 and I will start out with what I think is the most
10 powerful impact, both accreditation and certification
11 have the power to improve the performance of individuals
12 and organizations, and that is the bottom line.
That is
13 why I deal with organizations, sometimes looking at their
14 strategy or mission.
15 of it.
I mean, that is really the essence
And they can achieve this in kind of an
16 interesting fashion, not by forcing something, but by
17 letting the peer pressure, and building this philosophy
18 of self-improvement, and that is really powerful.
To me,
19 I like this much better than regulatory approaches
20 because I have seen the whole change that can take place
21 in an industry when there is this philosophy of self22 improvement, like we would rather do it ourselves, set
23 the standards, and try to live with them, than have
24 someone else impose things.
25
I realize, of course, in every field there have
125
1 to be requirements, too, but certification and
2 accreditation can complement regulation.
In
3 accreditation in the field you are dealing with, federal
4 regulations have to be a major component of it.
So, I
5 think the two fields are complementary, but the important
6 thing is the voluntary, private accreditation efforts
7 actually have that potential to sort of improve through
8 changing the whole mind-set about improvement as a
9 responsibility coming initially from the organization.
10
The other thing I would say is from a government
11 point of view, this saves money.
12 effective.
These are very cost-
To have another organization take on the role
13 of developing the standards, building support for them,
14 measuring compliance with them.
If a federal agency were
15 to fulfill that requirement, it would be a whole new
16 regulatory initiative.
So, many agencies look at this as
17 a way of, basically, extending the impact of the
18 government through a private sector initiative.
19
And also, the standards, as I mentioned, there
20 is interchange.
The accrediting bodies can use
21 government standards; government agencies will be looking
22 at the accreditation standards, and certification
23 standards.
So, there is an exchange of the information,
24 although this is a little bit dangerous at times.
25 guess one of the fears, occasionally sometimes a
I
126
1 government agency will use an accreditation standard for
2 a purpose it wasn't intended for.
I will give you one
3 example.
4
In another life, I was working with an
5 organization, the Accrediting Commission for Graduate
6 Medical Education, ACGME.
At one point, one of the
7 federal agencies decided that maybe they could use
8 accreditation systems to rank residency programs, and
9 decide who should be funded.
Well, there is an example
10 of something that may have looked very nice in terms of a
11 way to have somebody get some information that could help
12 achieve another agenda, but I can tell you from the point
13 of view of an accrediting body, that was a kiss of death.
14
And of course, they backed off from that.
That is the
15 danger, though, of misrepresenting sometimes what is the
16 purpose, or the results.
17
And both certification and accrediting bodies
18 have to be very careful about how they represent what
19 their achievements mean, and how they are used.
20 Sometimes, for instance, a danger in certification is
21 people equate certification with competence, an overall
22 definition of competence, and I am always warning people,
23 it is just one part of it.
Competence is more than
24 passing an exam showing a minimal level of knowledge,
25 skill, or ability.
There is a lot more to it.
You have
127
1 to be very careful, because sometimes employers or other
2 stakeholders assume, well, if
someone is certified or
3 licensed, they have been blessed.
4 that you can expect.
5
There is nothing more
And that is wrong.
And again, it goes back to that question of
6 asking the questions of the quality of the certification
7 program, or accreditation program.
There are very good
8 programs, and there are some very bad ones.
Fortunately,
9 by and large, in certification and accreditation, most of
10 the organizations, because of the very nature of this
11 business, are interested in doing a good job.
This is
12 not a field where a half-baked effort has any benefit.
13 Most of the organizations, before they get into these
14 fields, realize they are making a commitment to quality,
15 and they are coming up with, basically, the best programs
16 they can.
But it is not easy.
Certification and
17 accreditation are expensive activities.
They take a lot
18 of time.
And they are very controversial, too.
19
One of the interesting things is that the
20 sponsors of most certification and accreditation
21 organizations in the United States are non-profit
22 associations, professional associations, 501(c)3 and (c)6
23 organizations.
One thing that comes as a little surprise
24 to these organizations when they get in the accreditation
25 business, all of a sudden they are in the discrimination
128
1 business, and this comes as a little shock.
Whereas,
2 normally an association can be helping its members by
3 educating and training them, giving them all sorts of
4 benefits, now, all of a sudden, you are saying, "You are
5 in, and you are not in".
And that results in lawsuits,
6 legal challenges, ill-will.
7
So, as a result, many of the certification and
8 accreditation bodies look toward an administratively
9 independent structure, sometimes separate from the
10 organization, and that is another sort of a good practice
11 in both certification and accreditation.
But the dilemma
12 of that is that it costs extra money, it is harder to put
13 together, so many of the organizations have to start out
14 within an association very close to it, but hopefully,
15 moving toward an independent structure which is
16 frequently more acceptable by other stakeholder groups
17 such as government, the public, et cetera.
18
Just a couple of trends in
19 accreditation/certification you might be interested in.
20 The number of certification bodies is growing fairly
21 rapidly.
I wrote an introduction to a directory about
22 five years ago that listed 1600 certification and
23 accreditation bodies.
24 growing.
It is well over 2000 now, and
Far more certification than accreditation,
25 although there is growth in accreditation, too.
129
1
The quality of certification and accreditation
2 bodies is improving.
The staff, the structure, the
3 funding, I see definite improvements, although there are
4 not any national or international bodies that set a
5 minimum standard to be an accrediting or certification
6 body.
So, literally, any organization can put together a
7 certification or accreditation program, and sort of it is
8 let the buyer beware.
So, there is questions you always
9 have to ask as a third party, sort of looking at how
10 valid and reliable the process is.
11
Other trends.
12 interested in both.
Government is increasingly
I see sometimes certification used
13 in bid specifications in the health care field.
Health
14 care has embraced both the certification and
15 accreditation.
As I mentioned, Joint Commission for
16 Accreditation of Health Care has a major role in
17 establishing quality standards, not just for hospitals
18 now, but for a variety of health care organizations.
19 They even have the concept of deemed status which is
20 interesting, saying that if you meet the private,
21 voluntary accreditation standards, you are deemed in
22 compliance with Medicare conditions of participation.
23 So, this is a strong link between government and a
24 private standard-setting initiative.
25
Another example where you have this link is in
130
1 education.
The U.S. Department of Education, the
2 Secretary of Education sets standards for academic and
3 educational accrediting bodies, and in fact, the reality
4 of it is, those standards are so powerful now, they drive
5 a lot of the practices in academic accreditation.
It is
6 not an option, frankly, if you are accrediting
7 institutions.
8
So, there is a lot of interest, and in fact,
9 there is even a national commission looking into
10 standards for certification to be used in bid
11 specifications.
I think it is primarily of interest to
12 the Department of Defense, but I think that will also
13 probably affect other government agencies.
14
So, those are some of the things that are
15 happening, and I think should be of interest.
16
Some of the concepts that I think are important
17 to keep in mind, accrediting bodies are given a fair
18 amount of leeway by the courts.
19 legal trouble.
They still can get in
The greatest danger for accrediting
20 bodies is anti-trust, or restraint of trade issues.
They
21 have to be very careful to make sure the standards really
22 don't have the impact of discriminating against a certain
23 class of provider, and frequently the challenge is in
24 size.
25
The smaller organizations are challenged.
When I worked for the American Hospital
131
1 Association, sometimes I used to deal with the Joint
2 Commission for the Accreditation of Health Care
3 Organizations, and my test was, if that nine-bed hospital
4 in Jackman, Maine, can do it, I will feel comfortable
5 with it.
6 do.
And that is a challenge.
That is not easy to
And I will have to tell you, when you look at that
7 book of requirements for accrediting health care
8 organizations, that is a constant source of tension.
9 it is one of the biggest challenges.
But
And you can always
10 go to court if you feel the impact of the standards is
11 some form of discrimination.
12
The other thing is marketing challenges, and
13 this is somewhat of a dirty word in the standard-setting,
14 but the reality of it is new certification and
15 accreditation efforts have to sell themselves, especially
16 if they are not mandated, and that is not easy, when you
17 think about it.
18 being tested?
19 tests.
Who gets excited about taking a test, or
You remember the reactions you had about
It is not something that people have a warm,
20 fuzzy feeling in their heart about.
It is generally
21 something you do because you feel it is important to your
22 career, your profession, an employer encourages you.
But
23 it is not easy to sell these things.
24
The same thing with accreditation.
25 accreditation is an expensive process.
Applying for
It is a major
132
1 decision for an organization.
2 pros and cons.
3
They have to weigh the
So, marketing is a major issue.
Some of the ways that--
I don't have much time
4 left here, but I will just give you a few of the
5 benchmarks I use to evaluate certification/accreditation
6 programs.
Probably the most important is the standards
7 themselves.
Are the standards valid and reliable?
Valid
8 meaning, do they measure what they are supposed to
9 measure?
Reliable meaning, can they do it consistently,
10 looking at different applicants and organizations?
11 those are sort of the gold standards.
So,
And those things
12 are not easy to measure, but any organization looking at
13 an accreditation or certification process needs to ask
14 that question.
15
The other thing, a trend in both, primarily
16 accreditation, but certification, too, is getting away
17 from looking at the structure and process, and more the
18 outcomes.
Outcomes is sort of the major movement in the
19 accreditation world.
This is hard to do, but it is
20 something most accrediting bodies are looking at, and the
21 issue being is somebody may have all the pieces in place,
22 have nice sets of minutes, comply with all the
23 regulations, but if the outcome isn't what you want, they
24 really haven't achieved the goal of the process.
25
For instance, in educational accreditation, (I
133
1 have served on an educational accrediting body), when all
2 is said and done, you go out and talk to the students.
3 You know, you can look at papers, minutes, accounting
4 records until they are coming out your ears, but what is
5 it all about?
You have got to go out there and just
6 measure exactly what did it achieve.
And sometimes it is
7 actually talking to the students, talking with the
8 patients, things like that.
And putting the burden on
9 the organization to say what was your objective, and how
10 did you meet it?
Because sometimes the accrediting body
11 really can't decide that.
It is going to differ from one
12 setting to another.
13
14 things.
But at any rate, those are a couple of the key
I think I will cut it off here.
It is bad to be
15 competing with lunch, too, I guess.
16
17
DISCUSSION WITH COMMISSIONERS
DR. SHAPIRO:
Well, thank you very much, and
18 thank all of you for keeping your remarks exceptionally
19 coherent, but also, within our time frame.
20
21 second.
Let me just begin by turning to Marjorie for a
She wanted to ask a specific question of Dr.
22 Koski, and then we will go to members of the Commission.
23
DR. SPEERS:
Dr. Koski, my question for you is,
24 could you, in just a few minutes, tell us what is the
25 status of your office's revision of the current assurance
134
1 process?
We have heard that that process is being
2 revised, so we would like to know the status of it, and
3 it would be helpful for us if you could address it, both
4 in terms of domestic assurances, and international
5 assurances.
6
DR. KOSKI:
Thank you, Marjorie.
The assurance
7 process has had an enormous amount of effort put into it,
8 headed up primarily by Tom Puglisi and Cliff Scharke, and
9 basically, they are pretty much on the launching pad with
10 the simplified assurance process that was recommended,
11 and our hope is--
I mean, the original target was to be
12 able to roll it out yesterday.
We missed yesterday, but
13 the pressure is on to continue to get that, you know,
14 completed as soon as possible, and right now I think the
15 target for that would probably be October 1.
16
So, that process is one that accepts the
17 recommendations that have been made to simply have a
18 single standard assurance.
There are some challenges
19 with respect to implementing that for the single sites we
20 have called Single Project Assurances, but again, we will
21 continue to work on that.
But basically, that part is
22 ready to go.
23
24 also.
And there is a Single International Assurance
I have spoken with the team about actually rolling
25 those two together into a single process.
We think that
135
1 this may not be the time to do that quite yet, but
2 indeed, I think that yesterday there were citations of
3 some of the international standards that have already
4 been established with the CIOMS, or the ICH GCP
5 guidelines, as well as others that are there.
There is
6 even a set of international operational procedures and
7 guidelines for institutional review boards that I believe
8 were--
I saw the book waved around at the front table
9 yesterday.
So that simply, again, by recognizing those,
10 having a standardized international assurance should also
11 be possible, and that will be rolled out concurrently
12 with the other.
But for now, we will keep the--
Because
13 there are some subtle differences between the
14 international guidelines and those that we use in this
15 country, we will probably keep the two separate for now.
16
I hope I answered your question.
17
DR. SHAPIRO:
Okay.
Thank you very much.
18 go to questions from commissioners.
19
DR. LO:
Let's
Bernie, then Larry.
I first want to thank all three of you
20 for very useful and concise, lucid comments.
21
I want to try and take some points that Michael
22 Hamm raised, and ask Dr. Koski and Dr. Lepay how that
23 might play out.
I mean, it seems to me in any
24 accreditation or certification process, the choice of
25 standards, or variables to look at, is key.
And Mr. Hamm
136
1 correctly pointed out that ultimately we are interested
2 in outcomes, rather than structure or process.
And as we
3 all know from clinical quality improvement initiatives,
4 it is much, much easier to look at structure and process,
5 and in many ways, that is the bedrock.
If you don't have
6 a quorum, you know, how can you do anything?
7
But as I think about the kinds of issues that
8 have raised the substantive concerns, the consent
9 process.
Dr. Lepay mentioned that.
But it is not just
10 the qualifications of the people getting consent, it is-11
You know, the form was right, but what was said
12 contradicted the form, or gave the wrong impression, or
13 somehow at the end of it, when you talked to the
14 patients, studies show over and over again they don't
15 understand what they just consented to.
16
And as I think about medicine, we have been
17 lucky that for many things we care about, there are
18 measures that are easy to collect, that everyone agrees
19 are important.
You know, post-op complications and
20 morbidity, you know, we want to reduce those.
21
Where do we get standards that are valid,
22 reliable, ethically meaningful, and easy to collect, so
23 we are not sort of imposing a whole new set of data24 gathering activities that sort of aren't worth the cost
25 of collection?
It seems to me, those are challenges, and
137
1 if you folks could give us your thoughts on that, it
2 would be helpful.
3
DR. KOSKI:
Well, I will just jump in.
I will
4 tell you that we are currently engaged, and have been
5 engaged in a process to deal specifically with the
6 challenge that you mention.
7
Establishment of standards, as Mr. Hamm pointed
8 out, is something that must be done with sufficient input
9 from sort of all of the stakeholders in the process, as
10 well as the experts, that what comes out of that process
11 is something that is going to be universally recognized
12 as being both valid and reliable, so that they can be
13 applied, essentially, by any, you know, body that chooses
14 to get into the accreditation process.
And we are
15 currently working on doing that, and I think that what we
16 are trying to do is to capture the value of the work that
17 has already been done to try and leap-frog this process,
18 and move it forward as quickly as possible.
19
Actually, I will be announcing specific details
20 of this soon, but I am not at liberty to do that right
21 now.
But clearly, this is a very, very high priority,
22 and I think I wish that I had said everything that Mr.
23 Hamm said, because it clearly, I think, lays out very
24 clearly what the challenges there need to be.
25
With respect to the quality issue, that is, you
138
1 know, the Holy Grail.
How do we really get there?
2 we sure that we are doing what we want to do?
3 are no easy answers to that.
Are
And there
Again, as you pointed out,
4 sometimes you have to go to the people who, you know, if
5 the goal is to protect human subjects, then you may have
6 to go to the human subjects and find out, okay, what is
7 the incidence of their actually understanding what they
8 got into.
What is the incidence of people actually being
9 harmed in research?
10
I actually met last week with John Eisenberg
11 from AHRQ.
They are trying to develop appropriate
12 methods to validate quality of care, and so on.
John
13 seemed very enthusiastic about bringing the intellectual
14 resources of his organization to bear on this process as
15 well, to try and define the, you know, what quality would
16 be.
17
The process that we are moving forward with is
18 one that incorporates into it not only the establishment
19 of standards that could be used for accreditation of
20 institutional review boards, but also, as a second part
21 of that effort, a definition, an analysis and definition,
22 of what appropriate outcome on quality measures would be,
23 so that when we look at what we have done two years from
24 now, we will be able to make an objective assessment as
25 to whether or not we have accomplished our goals.
139
1
DR. SHAPIRO:
Thank you very much.
Larry?
Oh,
2 sorry-3
DR. LEPAY:
Again, this is an area of certainly
4 very active conversation in Dr. Koski's three official
5 days on the job, my 13 in trying to coordinate some of
6 these efforts across FDA.
We have had now two
7 conversations that have dealt very much with this
8 particular subject, and clearly, it is very clear as we
9 discussed it internally within FDA, that we have to find
10 a way to engage stakeholders in this discussion.
And we
11 have to make sure that all stakeholders are, indeed,
12 represented.
We can't simply just go to the IRBs, or to
13 their administration.
We have to make sure, in fact,
14 that the academic medical centers and their
15 administration is tied in, as well as a recognition that
16 more than half of FDA-regulated research is now performed
17 outside of the academic medical centers.
18
So, it is really getting this dialogue going,
19 and then trying to, in fact, systematically sort through
20 the recommendations that are given to us, and we are
21 certainly looking at ways of soliciting those
22 recommendations.
23
DR. SHAPIRO:
As I looked at some of the
24 overheads that you projected of what you did in
25 inspections, and people you spoke to, I understand it was
140
1 a summary; it wasn't meant to be fully detailed, and so I
2 just want to ask a question.
Would any of those
3 inspections ever speak to human subjects, people who are
4 actually participating?
5
6 effort.
DR. LEPAY:
Is that ever part of the effort?
It is not a routine part of the
I mean, typically, we have gone to speak with
7 subjects when, in fact, the subjects themselves have come
8 to us with complaints.
We have gone in cases where we
9 have seen particular issues that, in fact, require our
10 resolution with individual subjects.
I think, as was
11 discussed yesterday, in fact, when we are talking about
12 IRBs, most IRBs themselves do not have contact with
13 subjects.
So consequently, going to an IRB, we do sit in
14 on meeting on occasion, but going to an IRB is not going
15 to be a source of contact with subjects, and being able
16 to pursue from that end.
17
DR. SHAPIRO:
18
DR. KOSKI:
19
DR. SHAPIRO:
20
DR. KOSKI:
Thank you.
Larry?
If I may just add one quick comment.
Yes?
It may well be that establishing
21 simple mechanisms for the public, for the subjects, to
22 actually get in touch with those people who are
23 responsible for the oversight, where we could even, for
24 instance, track the number of, you know, calls of
25 concern, or complaints, or whatever, over a period of
141
1 time--
And one of the measures of effectiveness that you
2 could imagine was to see a decrease in the numbers of
3 problems that are reported.
You could even count news
4 stories in the media for that matter.
But I
5 think looking at various indices that provide some real
6 evidence that at the point where protections are supposed
7 to be having their benefits are actually working, will
8 serve us well.
9
10
DR. SHAPIRO:
DR. MIIKE:
Larry.
Sorry.
Listening to the discussion on
11 accreditation and certification, it seems to me that (and
12 I know we can't get into it over here) is that it is not
13 just an add-on.
It is going to change your whole way
14 about how research is done, who is eligible.
And say,
15 for example, you are certainly not going to be able to
16 come out with a Single Project Assurance accreditation,
17 and things like that.
So, it is going to change the
18 whole way in which the research is going on, especially
19 as it seems to be decentralizing more and more.
20
But my specific question is for Dr. Lepay.
You
21 mentioned that in your oversight of the research that is
22 undertaken, you look at the researchers, you look at the
23 sponsors, you look at the contracting research
24 organizations, you look at the IRBs, and the human
25 subjects, however adequately or inadequately, is
142
1 addressed in all those issues.
2
Now, what we hear over and over again is that
3 the kind of routine examination of IRBs you do is exactly
4 like what OHRP does in the process side.
Have you folks
5 ever examined the information that you get across the
6 project in these different areas?
Or alternatively, is
7 that information available and subject to analysis so
8 that you can give us a more systematic overview about
9 here is the IRB, here is--well, actually what you find
10 out in these other areas?
11 there?
12
Where is the disjoint in
And where is the information that supports it?
It seems to me that your information is
13 something that can start to help address that question
14 without having to undertake a whole, brand-new approach
15 to that.
And I know there would be issues of
16 confidentiality, et cetera, but you can certainly do an
17 across the board group analysis of that, and it probably
18 would be helpful to Dr. Koski's organization.
19 you done that?
But have
Any of those kinds of things, and try to
20 improve your examination of the IRB process in the FDA
21 oversight?
22
DR. LEPAY:
Well, I think this is something we
23 are talking about, certainly as we look into more
24 scientific approaches to be able to get information from
25 our inspections.
And indeed, you know, it has only been
143
1 the past few years where we have really started--two,
2 three years, because that was an interest of mine, into
3 even developing some basic metrics.
I think now we are
4 at a point where we need to refine what those metrics
5 might be, and how we can use them.
I mean, we have tried
6 to develop them from a standpoint of sponsors, what they
7 do in monitoring, get some basic information.
8 certainly, these are areas we need to--
But
We need to look
9 at how the data that we have in-house can be better
10 utilized to, indeed, look at trends.
11
And in some cases, I need to also mention, when
12 we give figures here, we are talking about metrics, and
13 not statistics, if you will.
And I think one of the
14 approaches we need to look at as well, and maybe we need
15 to target from year to year in different areas, if you
16 will, looking at what the status of that particular
17 entity, or what that particular area happens to be at
18 that time, do some more focused statistical sampling at
19 that point, and be able to use that data in a more
20 meaningful way.
21
DR. MIIKE:
But let me--
Don't you now--
It
22 seems to me that you would, logically, instead of doing
23 these site visits, and taking them as individual site
24 visits, and continuing to do what you do all the time,
25 that you would look at what you have collected to change
144
1 the focus when you go on into future site visits directly
2 inspecting--
You know, you shouldn't be looking,
3 concentrating, so much in this area now.
So, if you have
4 done that, then you have already got the basis for
5 starting to take a look at the relationship between what
6 the IRB knows in an institution, and what has been going
7 on.
8
DR. LEPAY:
I think I would have to say we have
9 done that in areas broadly across the program.
We saw
10 problems over the past several years, going back when I
11 first started looking at metrics, in the informed consent
12 itself, in the informed consent process at the clinical
13 investigator's site, and we have directed a lot of our
14 attention, as we train our own investigators, into
15 putting more focus in this particular area, and we have
16 actually seen, again, not metrics but statistics.
We
17 have seen some improvements there.
18
Right now, we are having some issues that are
19 coming up about adverse event reporting, and meeting
20 FDA's requirements as far as safety reporting is going.
21 We are getting that out at clinical investigator sites.
22 We are putting more emphasis in the training of our
23 inspectors in what we are requesting individually of our
24 inspectors to look at based on those particular metrics.
25
But again, you know, these are just loose trends
145
1 that we use as a basis to be able to guide where we are
2 next going.
We also have started placing more emphasis,
3 if you will, on what is happening in CROs, what is
4 happening in monitoring programs, because indeed, that
5 was not a focus of FDA's inspectional attention back
6 three, four years ago, and as we started looking at it,
7 approaching it first from the clinical investigator site,
8 we developed certain concerns, and there was a lot of
9 public attention at that time to what some of these
10 concerns might be.
And as a result, we have refocused
11 our program in that direction.
12 more of that.
13
We need to be able to do
And some of that can come--
You know, again, we have to see ways of
14 leveraging our resources to be able to pull more
15 information in, so we can use our resources more
16 appropriately, to direct them to what really needs to be
17 handled, and what needs to be improved.
18
DR. SHAPIRO:
19
DR. KOSKI:
Thank you.
May I comment?
Yes, Dr. Koski?
Obviously, one of
20 the problems with any statistical approach, while it
21 helps to target areas of concern and all, is the fact
22 that in order to get the statistics, things have to
23 already have happened. And so, one of our challenges is
24 to find out, you know, how to get closer to where things
25 are really happening.
146
1
And I want to emphasize something that David
2 said, that the FDA has been very good at this, and
3 working with industry.
There is a requirement for
4 ongoing monitoring by study monitors who come in and look
5 at studies while they are going on.
And by and large,
6 that has focused on sort of the, again, the integrity of
7 the process.
But there is a real opportunity for us to
8 work to incorporate more protections for human subjects
9 in that part of it as well, so that if deficiencies are
10 noted in the first monitoring visit, and there may be
11 multiple visits during a trial, we should be able to
12 utilize that information in a real-time feedback process,
13 to apply it to protection of human subjects, rather than
14 waiting until the study is done.
And that is not
15 currently something that has happened.
16
Even at institutions where, you know, they know
17 that there is monitoring going on, there is no
18 requirement that information from those monitoring visits
19 go back to the IRBs.
And indeed, it should.
In fact,
20 the Association for Clinical Research Professionals,
21 ACRP, has implemented a certification program for
22 research coordinators, and they are building into that
23 process, you know, increasing amounts of information
24 about the protection for human subjects, so that, indeed,
25 people like the research coordinators at a site could
147
1 play an effective role in protection of human subjects,
2 again, in real-time, as could data safety monitoring
3 boards.
And linking the adverse event reporting process
4 into all of this gets to new ways to take what we are
5 already doing, and applying it in a manner that is going
6 to improve protections for human subjects.
7
This is one of the great opportunities that we
8 have, synergizing, using those things that we already
9 know are in place and working, and taking advantage of
10 them in new ways to make the process better, and I think
11 we will see some progress in that area.
12
DR. SHAPIRO:
13
PROF. CAPRON:
Thank you.
Alex?
This is an enormously exciting
14 time for the field of the protection of human
15 participants in research, and I think that, you know, it
16 is no secret that those on the Commission, as well as off
17 the Commission, have been somewhat frustrated with the
18 speed with which we have addressed one of our central
19 mandates, which is this question of the oversight
20 provided by the federal government for research.
But I
21 think as it is turning out, Mr. Chairman, we have the
22 opportunity to come at this critical juncture, and I am
23 enormously impressed and pleased to hear, both from Dr.
24 Koski and Dr. Lepay, the sense that the process is being
25 fundamentally re-examined.
148
1
I would urge staff to come back to us as soon as
2 possible with a set of preliminary recommendations that
3 we could, given the time it takes us to get through
4 recommendations and refine them, that would address this
5 issue of accreditation.
I think there is, from what I
6 have heard in the several years that we have been
7 thinking about this, and talking about it, widespread
8 support on the Commission.
There is agreement, I think,
9 on the objectives of an accreditation process for the
10 review procedures that are used, IRBs or otherwise,
11 looking first at risk reduction.
That is the safety
12 issue, the protection of human subjects, both from
13 physical and non-physical risks.
14 assurance and quality improvement.
15 provides predictability.
Second, quality
Third, a system that
That is, after all, the very
16 idea of the assurance system itself, assurance that you
17 will follow federal regulations.
Fourth, consistency.
18 That is to say, reliability across organizations.
And
19 fifth, independence, the sense, as we were talking today
20 in our International Report, that there is a reason that
21 these determinations have credibility.
22
I want to raise three problems with the whole
23 panel, and ask how you think we can address them.
The
24 first is, achieving standards and processes that
25 appropriately combine substantive knowledge about the
149
1 field, (that is to say, the field of human subjects
2 research), and expertise in assessing the structures and
3 processes, and measuring outcomes.
4 separate things.
Those are two
And my sense is, from what I have seen
5 happening, partly in response to, I think, a call from
6 the VA, is that some groups that have some knowledge
7 about accounting, and measuring, and so forth, that is on
8 the measurement and the process and outcome side, may be
9 weighing in, and other groups that have knowledge about
10 human subjects regulation are weighing in, and do you
11 think it is going to be possible to marry those two?
12
The second problem, or question, is how do we
13 satisfy stakeholders with potentially conflicting, or at
14 the very least, different interests.
15 need public accountability.
On the one hand, we
But we also need, as several
16 of you have said, acceptance by the field, which by
17 itself is made up of researchers, the reviewers, the IRB
18 members, institutions, and sponsors of research.
And
19 they may all have different interests.
20
Within the Joint Commission, it has seemed to me
21 that, putting aside those of us who are public
22 commissioners there, that even within the organization,
23 there is a good tension, because on the one hand you have
24 the doctors who want standards to be high because they
25 want to do the right thing for their patients, and on the
150
1 other hand, you have the institutions who, of course,
2 want good reputations, but have to worry about how do we
3 pay for all this?
4 feasible?
How do we organize it in a way that is
And so, there is a natural tension, and the
5 joint aspect of the commission represents that.
6
How do we achieve a similar balance here?
How
7 do we have the public's interest in high standards
8 matched with something that will have appeal to the
9 people who will really be paying the price, the customers
10 as it were, who will have to pay for a process if it is a
11 process of private accountability?
12
And third, what about the problem that Dr. Lepay
13 just addressed, which is the growing use of non14 institutional settings to conduct research?
And again,
15 some of this is research which may already be reached by
16 the FDA, but our Commission early on reached the
17 conclusion that we favored a system of federal oversight
18 that would reach non-federally-funded, and non-FDA19 reviewed instances in which human subjects are used.
And
20 how do you adopt an accreditation system that can reach
21 those non-institutional settings?
Because as Mr. Hamm
22 said, when we speak about accreditation, we usually are
23 thinking of institutions, as opposed to a certification
24 of individual investigators.
25
Those are three problems that I hope we will
151
1 address, and I would like any help we can get from the
2 panel.
Specifically, I would also love to know from Dr.
3 Lepay, since we heard a little bit more enthusiasm from
4 Dr. Koski, whether you think there is any possibility
5 that given the relatively small resources you have, (from
6 what you said, the ability to look at an institution
7 probably once every six years, roughly, given the numbers
8 you gave us), about using this kind of public/private
9 mixture that accreditation is, do you think there is any
10 possibility that part of your process would be a deemed
11 status relationship with accredited IRBs?
Is that in the
12 cards, do you think, for the FDA?
13
But I would like response on the three problems
14 and the objectives from any of you, but that is a
15 specific question for Dr. Lepay.
16
DR. LEPAY:
Yes, let me start with the specific
17 question, because I am not sure I have good answers for
18 the first three.
19
I think very much we are looking for ways, as
20 any inspectional system would, or any regulatory agency
21 would, to be able to leverage resources.
And ultimately,
22 the way we have to do that is to look at approaches, to
23 ask the question is inspection the only way out there
24 that we can, in fact, achieve what we need to in this
25 process.
And we already recognize that the answer to
152
1 that is no.
We recognize it even internally within FDA
2 in the way we collaborate between our review process and
3 our inspectional process.
We recognize it in the
4 collaborations as they have come increasingly to exist
5 between ourself and other federal agencies in sharing
6 information.
In fact, from our standpoint, we have
7 different leveraging points in the clinical trial process
8 than perhaps OPRR formerly had.
We are not directed--
9 We are directed toward IRBs, but we are not specifically
10 directed toward institutions.
11
Our basic leverage point, or our most
12 fundamental leverage point outside of the clinical
13 investigator, is the sponsor themselves.
The sponsor is
14 not--is typically a leveraging point for federally-funded
15 research.
So, in fact, there are ways in which we
16 already recognize that there is the ability to complement
17 the kind of information we have, and we have to be able
18 to find ways of being able to share that information, and
19 to be able to leverage.
20
I think when we start talking about
21 accreditation, I think that this is something that can
22 move forward within the FDA framework.
That is not to
23 say that we have any anticipation that FDA would run an
24 accreditation program.
25 contrary.
In fact, I think quite to the
I think it is the way that we have worked with
153
1 other certification programs.
We have worked with a
2 number of organizations that were mentioned out here
3 today, and we have worked with them, so far, in an
4 educational setting.
And that is not to say we cannot
5 work with them in other capacities as well, recognizing
6 at the moment at least, we don't want to endorse any
7 particular certification program.
But again, as we start
8 to talk about more widely accepted standards, that may
9 become less of an issue as time goes by.
10
And I think that comes back to your first three
11 questions, how do you achieve that kind of
12 standardization, and how do you get that kind of
13 agreement, and how do you identify the stakeholders, and
14 getting them all to participate.
15 it is an area--
And as I say, I think
Of course, we are going to you as well
16 to try to provide us with some guidance in that regard.
17 And we are discussing within and among ourselves.
I
18 can't say that I have any immediate silver bullet at this
19 point, but it is something we are talking about very
20 actively.
And hopefully, it is something that we can
21 talk about quickly.
22
DR. SHAPIRO:
23
MR. HAMM:
24 several of those.
Mr. Hamm?
Just if I could comment quickly on
There is not any short, quick answer,
25 but if I could go through each of them.
154
1
On the standards.
Good accreditation programs
2 use consensus standards with input from basically all the
3 stakeholders, and that is not saying that one stakeholder
4 group is going to prevail, because it is a balance.
5 Obviously, if it was just the federal standards, it turns
6 into a regulatory process.
7
So, you have to balance.
But the good accreditation programs, they are
8 consensus standards, and the standards, before they are
9 finalized, are passed around to every group, literally,
10 that has an interest in them.
11 is dynamic.
And they are ongoing; it
They are never carved in stone.
12 other thing that is a key.
That is the
So, I mean, the potential is
13 there, but it takes a lot of time, a lot of effort.
It
14 is not easy building good standards, but that should be
15 the goal, is to come up with a standard that will address
16 the perspective of the multiple stakeholders.
17
Also, stakeholder representation.
Good
18 accreditation programs are not going to be governed by
19 just IRB members, or one segment.
It should have
20 representation from the different parties that have an
21 interest.
22 act.
Again, with balance, an incredible balancing
If you have got 12 seats on the board, you have got
23 to make sure that no one group has the power to dominate
24 it.
25
In terms of looking at entities other than
155
1 institutions, here again, the accreditation world has a
2 tremendous opportunity, because sometimes the private
3 sector is most interested in having this recognition.
4 helps sell the effort with their stakeholders.
It
So,
5 accreditation is definitely flexible enough to look at
6 various settings, including the private sector.
And
7 just--I thought of an example of the FDA process of
8 perhaps a look every six years.
An accreditation program
9 in this field could set any time period they want, three
10 years, five years.
11
The other thing accreditation programs do
12 generally is have an annual report.
Even though you may
13 be accredited for a three to five year period, and
14 usually that annual report is hunting for the incidents,
15 or anything that requires some immediate attention.
So,
16 I think it would be very complementary to the regulatory
17 process by having another peer group have a mechanism in
18 place where they can go in if there is evidence that
19 something is out of line, and take action.
20
So, the accreditation process is flexible enough
21 to, I think, address your needs, but it takes time to
22 develop them.
The standards are, as when groups start
23 out, I hear people say, well, can we have a set of
24 standards in a year?
25 depends.
And the answer has to be, well, it
If you have been working on it for maybe a
156
1 decade, and you have already got a lot of interest, you
2 can do it.
But generally, to start out building these
3 from scratch takes quite a bit of time, and especially
4 the outcomes.
This is the hardest thing in most fields.
5
6
And sometimes, one strategy that I encourage in
7 outcomes is to put a little bit of burden on the
8 applicant organization.
9 model.
For instance, I use the academic
Some universities, their strategy may be
10 targeting people in certain fields, and in a geographic
11 area.
If that is one of their outcomes, they should
12 declare that, and they should be measured by that.
And
13 some of the process may be educating the human research
14 protection programs to set some of their own outcomes,
15 and be held accountable for them.
That may be one of the
16 most important impacts of the accreditation process.
17
DR. SHAPIRO:
Dr. Koski, you will have the last
18 remark, because we are going to have to-19
DR. KOSKI:
Yes, I know that our time is up, but
20 I want to thank again Mr. Hamm for making his comments.
21
I will say, although I am just new on the job, I
22 have actually been working as a consultant with OHRP
23 since its inception back in June, and almost all of my
24 efforts during that time, and apart from doing the
25 necessary hand-holding or shaking, has been to work on
157
1 this issue of coming up with accreditation standards.
I
2 can tell you that we have been actively involved in
3 discussions, okay, with you know, an organization that
4 would be recognized as being impartial and of sufficient
5 stature to bring this process together.
And I think,
6 clearly, all of the stars are aligned right now, okay?
7 This is probably the one opportunity that we are likely
8 to have, and we must take advantage of it.
9
But yesterday, after my comments, I was
10 approached by representatives from the biotechnology
11 industry, from the pharmaceutical industry, as well as
12 from the patient protection advocacy groups, all of them
13 saying sort of "Let's go".
And I think that represents
14 the enormous energy that is really behind this right now.
15
There is work that has been done for more than
16 almost two years now already out there that can help to
17 leap-frog this effort toward accreditation standards for
18 institutional review boards.
19 playing field.
There must be a level
There must be buy-in, and I think by
20 simply having the different parties engage in the
21 process, as Mr. Hamm pointed out, is certainly the way to
22 get there.
23
So, this is a high priority, fast-track
24 initiative that we must move on, and I think that this
25 has been an extremely valuable discussion for helping us
158
1 get there.
2
DR. SHAPIRO:
Well, let me thank all three of
3 you for being here today.
We very much appreciate your
4 presence, and your contributions to us.
5 to adjourn.
So, thank you very much.
Sadly, we have
Thank you,
6 Commissioners.
7
8 leave.
DR. MESLIN:
One brief announcement before we
Just for the public who is aware, the Commission
9 next meets in Salt Lake City in October.
10
And I wouldn't want commissioners to leave
11 without being made aware that today is the last
12 Commission meeting of one of our most cherished staff.
13 Stu Kim is going to be moving on to a position in the
14 private sector at a law firm, and I know the
15 Commissioners, and certainly all the staff, have been
16 very grateful for Stu's contribution.
He leaves on the
17 6th of October, but I wanted to let Commissioners and the
18 public know how much we appreciated his work.
19
(Applause.)
20
DR. SHAPIRO:
21
(Whereupon, at 12:07 p.m., the meeting was
22 adjourned.)
Thank you.
Good.