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Us. Food and Drug Administration

Science Board

Meeting

.

May 19, 1998

9:50 a.m.

Doubletree Hotel

Plaza Room II

1750 Rockville Pike

Rockville, Maryland

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Members of the Board in attendance:

David M. Kipnis, M.D., Chair

Robert Langer, SC.D.

Leslie Z. Benet, Ph.D.

Charles Sanders, Ph.D.

Gilbert A. Leveille, Ph.D.

Richard B. Setlow, Ph.D.

Pedro Cuatrecasas, M.D.

Marion Nestle, Ph.D., M.P.H.

Invited Guest:

Bernard Liebler, M.S., HIMA

FDA participants:

Elkan R. Blout, Ph.D., Senior Advisor for

Science, FDA

Michael A. Friedman, M.D. , Lead Deputy

Commissioner, FDA

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

Chief Scientist, FDA

Susan K. Meadows, M.S., Executive

Secretary, FDA Science Board

Elizabeth D. Jacobson, Ph.D., Deputy

Director for Science, CDRH

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Donald E. Marlowe, Director, Office of

Science and Technology, CDRH

Kathryn C. Zoon, Ph.D., Director, CBER

Neil D. Goldman, Ph.D., Associate Director

for Research, CBER

Susan Homire, D.V.M., Office of Science.

Neil Wilcox, D.V.M., M.P.H., Office of

Science

Donna Mentch, Office of Science

Brenda Gomez, Office of Science

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Agenda

Introductions

Elkan R. Blout, Ph.D. 5

Opening Remarks

David M. Kipnis, M.D. , Chair 5

Status Reports:

Subcommittee on Toxicology

Richard B. Setlow, Ph.D. 11

Biomaterials Forum

Bernard Liebler, M.S. 29

Public Awareness of FDA Science

Michael A. Friedman, M.D. 35

Elkan R. Blout, Ph.D.

Subcommittee for CBER Review

Leslie Z. Benet, Ph.D. 68

Peer Review Process

Leslie Z. Benet, Ph.D. 115

Bernard A. Schwetz, D.V.M., ph.D.

Science at the FDA

Bernard A. Schwetz, D.V.M., Ph.D. 124

Public Comment 165

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1 PRO CE E D I NG S

2 DR . KIPNIS: Elkan. Dr. Blout, would

3 you care to make the introductions?

4 DR . BLOUT : We have a new member -- at

5 least we did have. Oh, she’s getting coffee.

6 I’m very pleased to welcome Dr. Marion

7 Nestle as the newest appointment to the Science

8 Board. As most of you know, she’s an

9 outstanding worker in the field of nutrition.

10 She’s now Professor and Chair of the Department

11 of Nutrition at NYU, and she comes to NYU from

12 the other side of the country, where she took

13 her degrees at Berkeley.

14 We’re very happy to have her here.

15 She’ll provide scientific expertise and

16 guidance for us in issues regarding nutrition

17 and also in part represent consumer interests

18 on these issues.

19 I could tell you all her

20 accomplishments . I won’t do that, but she’s a

21 potentially very good member of this Board, and

22 we welcome her.

23 DR . KIPNIS: Thank you very much, Dr.
6
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1 Blout.

2 We have, as I indicated, a fairly busy

3 schedule today. I’d like to welcome all of the

4 members who are here, many of the FDA

5 personnel, and those of the public. The public

6 will have an opportunity to comment in this

7 afternoon’s session.

8 Several of the reports are status

9 r e p o r t s to the committee, of committees/

10 subcommittees we either formed or we requested

11 attention to a specific topic. There is, of

12 considerable interest to many of the Science

13 committee, a presentation this morning on

14 “Public Awareness of FDA Science” . Dr.

15 Michael Friedman, the lead Deputy Commissioner,

16 will be here at 10:15 to participate in that

17 presentation.

18 Most members of the Board and its

19 subcommittees are seriously concerned about the

20 fiscal constraints, both by budgetary decisions

21 in Congress as well as from other sources that

22 have restrained or restricted the development
..— ..
23 of science within the FDA, a development which
7
—.
1 most of us consider essential for it to in

2 essence perform its regulatory function in an

3 appropriate manner.

4 I think the members of the Board who

5 are here are Dr. Benet, Dr. Setlow, Dr.

6 Leveille, Dr. Marion Nestle who has just been

7 introduced, Dr. Pedro Cuatrecasas, Dr. Bob

8 Langer. I don’t know if Dr. Sanders is here

9 yet this morning. Was he scheduled to attend?

10 VOICE: Yes.

11 DR . KIPNIS: I wonder if the other

12 members of the FDA would care to introduce

13 themselves? .

14 DR . BLOUT : Maybe David, we should

15 mention that a Board member, Bob Langer, has

16 just received an outstanding award, the

17 Lemuelson prize. It’s only been awarded three

18 or four tipes, and we are pleased that you

19 received this award, and we hope it will allow

20 you to continue to serve on the Science Board.

21 (Laughter)

22 DR . KIPNIS: Congratulations.

23 DR. LANGER : Thank you very much.
8
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1 DR . KIPNIS: Bern, do you want to

2 introduce yourself, then we’ll just go around.

3 DR . SCHWETZ: I’m Bernard Schwetz, the

4 Interim Chief Scientist of the FDA, working in

5 the Office of Science, and also the Director of

6 the National Center for Toxicological Research.

7 MS . MEADOWS: I’m Susan Meadows, I’m

8 the Executive Secretary to the Science Board.

9 DR . WILCOX : Neil Wilcox, Office of

10 Science.

11 MR . LIEBLER: Bernie Liebler from the

12 Health Industry Manufacturers Association, here

13 to report on the Biomaterials Forum.

14 DR . JACOBSON: I’m Liz Jacobson, from

15 the Center for Devices and Radiological Health.

16 DR. MARLOWE: I’m Don Marlowe, Center

17 for Devices and Radiological Health.

18 DR . KIPNIS: Thank you. There will be

19 various other members of the FDA sitting at the

20 table, depending upon the presentations to be

21 made .

22 Susan, do YOU have some housekeeping
—_
23 remarks to make for us?
9

1 MS . MEADOWS: We have just a few

2 things. One is, I would remind all of you,

3 particularly the audience, to please use the

4 microphones when speaking so that we can get

5 you into the official record.

6 Please note that there’s no break

7 listed this morning, nor a break listed this

8 afternoon. Please help yourselves, board

9 members, to the refreshments as you need them,

10 and take breaks as you need them.

11 We are going to move through the

12 schedule fairly quickly. A couple items for

13 the Science Board members. You have a mailing

14 package inserted into your notebook. Should

15 you want us to mail your materials to you,

16 please insert them into the mailer, and we will

17 take care of that for you. Just leave them at

18 the table after you’re finished.

19 We have had a change in the way that

20 we reimburse our expenses, and I would plea to

21 you, we would like to reimburse you for your

22 expenses . It will be done with the new system,
.-.
23 and we unfortunately have to have you do direct
10

1 deposit forms. So please send those in as soon

2 as possible so that we can take care of this

3 for you.

4 DR . BLOUT : I will tell you, I’ve had

5 experience the last month, and it works.

6 Things have arrived.

7 DR . KIPNIS: We’ll start this

8 mornings’ s proceedings with the Status Reports.

9 One was the Subcommittee on

10 Toxicology, which was chaired by Dr. Richard

11 Setlow, a Member of the Board. The committee
_—_
12 was formed because very early in its

13 deliberations, it recognized the increasing

14 importance of toxicology and the advent of

15 newer elements of science, which broadened the

16 horizons of toxicology and how best to in

17 essence accommodate those rapid changes in the

18 FDA.

19 Dr. Setlow.

20 Subsequent to Dr. Setlow’s

21 presentation, Dr. Wilcox, from the Office of

22 Science, will also make some comments.
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23
11
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1 DR . SET LOW : The Science Board,

2 Subcommittee on Toxicology met actually last

3 September. We had a long meeting. We got

4 together with a facilitator, and over the next

5 few months arrived at a vision and a mission.

6 Neil Wilcox, of the Office of Science,

7 boiled the five general things down into three,

8 and I’ 11 present them, at the moment. You’ll

9 find copies of these in your black notebooks,

10 for those that don’t wish to remember or to

11 copy .
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12 In any event, the vision is we’re

13 committed of course to protecting public health

14 through improved toxicological testing methods,

15 and our mission is to coordinate a

16 collaborative effort between public and private

17 sectors to develop better methods for doing

18 toxicological testing.

19 I could spend a lot of time on these,

20 but I can give handouts if anyone really needs

21 them.

22 There were three goals that were
_—
23 summarized for me by Neil Wilcox with approval
12
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1 by me . The first is to identify areas of

2 toxicity testing, and there are four

3 objectives:

4 Develop a comprehensive list of testing

5 areas, prioritize areas of toxicity testing for

6 the purpose of continued study by the Science

7 subcommittee;

8 Select specific standardized testing

9 methods within priority areas; and from these

10 methods in Objective 3,

11 Conduct a retrospective review to compare
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12 preclinical and clinical regulatory data to

13 determine the extent to which safety and

14 efficacy were adequately protected and

15 predicted.

16 So that’s Goal A. Under each of these

17 objectives there’s an action plan; but those of

18 you sitting in the rear couldn’t read the fine

19 print in the action plan if I really showed it,

20 but it exists, and 1’11 just give you an

21 e x a m p l e at the end.

22 so each of these goals has objectives,
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23 each objective has action plans. So that’s
13

1 Goal A. There are only going to be three

2 goals, so bear with me.

3 Goal B is to foster and facilitate the

4 development of more predictive toxicological

5 models through a coordinated effort that

6 targets high priority endpoints. And the

7 objectives, 1, 2, 3, 4/ 5 are really to

8 identify testing areas, identifying new and

9 emerging alternative testing methods, establish

10 criteria -- it doesn’t do any good to identify

11 unless you have some way of measuring what YOU

12 wish to measure. Identify potential

13 contributions from basic science, suggesting

14 paradigm shifts, and identify programs where

15 mechanism-based research, et cetera, are

16 developed.

17 So these all have objectives. And the

18 last goal with its objectives, is to encourage

19 acceptance and integration of new testing

20 methods into regulatory and industry decision-

21 making . Obviously if we have great new things,

22 they’re not going to be of any use unless
-—
23 they’re going to be used, which means unless

14

1 they’re going to be accepted by both sides of

2 the problem.

3 so these objectives are to support the

4 acceptance and integration. We have to develop

5 a process that encourages industry to submit

6 data for new, more predictive tests. They have

7 to be validated and they have to be accepted

8 internationally, not just nationally, not just

9 in Washington, D.C. or in Rockville. We have

10 to promote the development of new methods,

11 facilitate continuing education, encourage

12 international harmonization, and then regularly

13 review product safety evaluation for the

14 purpose of identifying and prioritizing

15 effective approaches.

16 [Overhead]

17 So that was Goal C, and I’m going to
-
end by just flashing UP -- You can’t read ‘t ‘

19 under each Goal, for example, in Goal B, there

20 are a number of action plans. A whole set.

21 And we have copies if anyone wishes, but these

22 are how we’re going to approach these goals.

23 I will end with just one example from
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s— —.

1 the literature of what’s going on.

2 [Overhead]

3 Again, you can’ t read it except for

4 the headline. The National Toxicology Program

5 is really pushing transgenic animals. This

6 isn’t only in the National Toxicology Program,

7 but it has to do with the FDA.

8 So in the Office of Testing and

9 Research, they’re trying to stimulate people to

10 develop and invest in some new approaches and

11 supply new insight into risk assessment, and
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12 that’s Joe Contrera. Just as an example of all

13 sides of the system trying to develop quicker,

14 better, easier predictive methods.

15 So this is where we are. If we’re to

16 go further, we have to have obviously more

17 meetings. We’ve had a lot of input from

18 committee members by Email, but in order to

19 synthesize that into something, we really have

20 to sit around the table and decide how we’re

21 going to do that; and I know, speakin9 for Neil

22 Wilcox, he would say “naturally, we need more

23 resources to accomplish that final goal. “
16
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1 We’re halfway there, but we need something

2 else.

3 Thanks .

4 DR . KIPNIS: Thank you, Dr. Setlow.

5 Dr. Wilcox, did you have any

6 additional comments that you wanted to make?

7 DR . WILCOX: No prepared documents,

8 Dr. Kipnis, but we would ask the Science Board

9 if you have any questions or comments on the

10 objectives that Dr. Setlow has just presented.

11 DR . KIPNIS: Are their comments by the
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12 Board?

13 Dr. Leveille.

14 DR . LEVEILLE: Not a comment, a

15 question. What’s the next step with these in

16 terms of implementation?

17 DR . WILCOX: The next step is a

18 difficult one. As Dr. Setlow alluded to, we’ll

19 convene the committee, probably late summer,

20 early fall, and explore options for how do we

21 move forward in what is clearly a long range

22 plan that is resource–intens ive, quite frankly.
_—_
23 The genesis for this endeavor really
_—_
17

1 started a couple years ago with the

2 recommendations from this Board for the agency

3 to review its approach to toxicology. And in

4 doing so, that in and of itself has many

5 dimensions, and it requires looking at what

6 types of data currently exist that we can mine,

7 if you will, to see how well we’ve done in our

8 preclinical studies compared to our clinical

9 studies; where have we done well and where are

10 there data gaps where we need better methods to

11 generate data on endpoints that are more

12 specific for what we’re looking for.

13 So this then will lead to recommending

14 research -- or, what I like to refer to as

15 directed research to develop methods that

16 target specific endpoints that we don’t

17 currently target.

18 So this really involves looking at

19 what we currently do and then -- an eye toward

20 the future in trying to stimulate research in

21 the private sector to come up with a better

22 method. So in an environment when we are
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23 trying to live day-to-day and put out fires,
18
_—_

1 it’s hard to come up with such a comprehensive

2 program for the future, but that’s indeed what

3 we want to do. And hopefully the Subcommittee

4 on Toxicology will act as a consortium to bring

5 resources together.

6 DR . KIPNIS: Dr. Setlow?

7 DR . SETLOW : I should say that the

8 industrial members of this subcommittee are

9 also working hard, and they’re trying to

10 establish a toxicological database of results

11 from the industry point of view that would be

12 available.

13 DR . KIPNIS: I recall that there had

14 been previous discussions about that, and the

15 concerns of confidentiality were also raised at

16 that point. Have they been addressed in some

17 of your d e l i b e r a t i o n s ?

18 DR . SETLOW : We have not yet as a

19 committee, but I know that the industrial

20 members are concerned with this and are trying

21 to devise a way of doing this.

22 DR . WILCOX: There is, if I may add --

23 there’s an international effort going on that’s
19

1 been organized by Dr. Kathy Stitzel from

2 Procter & Gamble. And in a meeting last fall,

3 which was a very promising meeting,

4 representatives from industry and academia and

5 various government agencies from around the

6 world gathered, and there was a great deal of

7 enthusiasm and optimism about being able to go

8 into industry and actually use their data

9 without giving away confidential, proprietary

10 information.

11 There is at least one model that we’re
.—_
12 currently looking at in Europe; it’s called the

13 Lhasa model, not to be confused with a lhasa

14 apso -- but this model, where they actually go

15 in and they use the data to develop a

16 predictive modeling system without really

17 knowing what the total chemical moiety from

18 which it came, so it doesn’t give away trade

19 secrets.

20 So it’s doable, and there’s interest

21 if we can get by the attorneys.

22 DR . KIPNIS: Dr. Schwetz, did you have

23 some comments?
20
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1 DR . SCHWETZ: Thank you, Dr. Kipnis.

2 There is a point that I wanted to raise that is

3 relevant to the recommendations that the

4 Science Board made that led to this discussion

5 and review within the agency of these new

6 toxicology approaches.

7 Those of us within the field of

8 toxicology have been saying -- a lot of us have

9 been saying for years that we should replace

10 some of the empirical tests that we use with

11 mechanism-based tests. That was before the
.~.
12 mechanism-based tests were close by, and there

13 was support and enthusiasm for that idea.

14 Now the transgenic models represent

15 mechanism-based test models that are here, and

16 in the evaluation and validation stage, and I

17 see something going on between government,

18 industry and academia, the people who are all

19 interested in the development and use of these

20 methods that is contrary to what you

21 recommended. And now that the methods are

22 here, there’s a building resistance to use

23 them.
21

1 Dr. Setlow mentioned the NTP review.

2 I was on the Board of Scientific Counselors for

3 that specific review of the transgenic program

4 that NIEHS and the NTP has; and within that

5 Board of Scientific Counselors review there was

6 a pretty strong sentiment to just throw all

7 this out because it isn’t going to work, in

8 reference to transgenic animal models for

9 predicting carcinogenesis.

10 There are a number of reasons why I

11 think there is reluctance to change now in all

12 of these sectors, to use transgenic models in

13 lieu of the two-year bioassay for detecting

14 carcinogenic activity; but it kind of stands in

15 the way of what you were recommending earlier,

16 that the FDA use the best scientific methods

17 that we can. Because now there is a tendency

18 to be reluctant to do that.

19 DR . KIPNIS: May I ask, is the

20 reluctance to the science, or is it to

21 scientific considerations or other elements

22 involved in this?

23 DR. SCHWETZ: I think to some extent
22
_—_

1 it’s just the reluctance of change, and also

2 that the test methods are not fully validated

3 yet. There’s a fear that we don’t know how to

4 use these new methods; and it’s either going to

5 prolong the length of time it takes to make a

6 decision, or we’re going to use transgenic

7 models and then turn around and say “Well,

8 we’re not sure how to interpret the data, so

9 you have to do two year studies anyhow. “

10 DR. KIPNIS: Dr. Leveille.

11 DR . LEVEILLE: Well, that really gets

12 to the point of my original question; the, in

13 food area as contrasted to the drug area, the

14 issue becomes even more complex when you think

15 about international harmonization of

16 regulations and so on.

17 The constraint against using new

18 technology is really a regulatory one; the

19 model we’ve evolved in this country is the

20 establishment of a template against which

21 everything has to match exactly. So a new

22 method coming along requires a change in a

23 template which doesn’t occur readily; and
23
.....

1 that’s really the dilemma.

2 So what the committee is I think

3 working on is to get increased flexibility into

4 the system, and at the same time find a way to

5 quickly get international harmonization and

6 acceptance of new approaches. And that’s

7 critical, but the ability to change the system

8 is a crucial factor, and that’s why I ask how

9 quickly we’re going to move to implementation,

10 because currently the system does not allow

11 that flexibility.
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12 DR . KIPNIS: Dr. Cuatrecasas?

13 DR . CUATRECASAS : I would think, at

14 least in my experience, that the reluctance to

15 move forward more rapidly with transgenic

16 animals in toxicology is based on the science.

17 There’s certainly no reluctance to proceed with

18 respect to biological activity, with respect to

19 using these as models of disease, novel models

20 which previously didn’t exist.

21 There are so many uncertainties

22 related to, and so much ambiguity as to what
..—%.
23 value a transgenic may have in a toxicological
24

1 study that people are reluctant to use these,

2 and I think correctly, quite yet. I think we

3 have to be more patient.

4 I am much more encouraged in what I

5 have heard, and I want to congratulate and

6 support the committee in what it’s doing. As I

7 look at what’s happening in companies and at

8 the FDA with respect to toxicological testing,

9 I see tremendous progress over the last ten,

10 even five years. There’s no comparison.

11 The discussion and the level of

12 involvement of mechanistic toxicology is

13 incomparably further along than it was before.

14 There are many, many approaches to mechanistic

15 other than using transgenic animals, as we

16 know; in cellular biology, molecular biology,

17 and in so many other approaches I see that the

18 industrial toxicologist is being encouraged and

19 have found a receptive audience.

20 I’ve experienced some really very

21 exciting discussions, and resolutions of

22 problems based on scientific concepts and

23 methodologies which I think are fairly modern.
25

1 So I’m not sure the subcommittee’s

2 efforts are responsible; but I think that in

3 part certainly symbolically that we should give

4 encouragement, and in that indirect and

5 intangible way I think that you might have an

6 effect.

7 DR . WILCOX: Thank you, Dr.

8 Cuatrecasas . What you just stated so

9 eloquently is a very important factor in this

10 international attempt to look at the new

11 technology and what we’re doing, and the mere

12 fact that we have this committee, and that we

13 are willing to look forward and bring people

14 together from all the different stakeholders,

15 that in and of itself has been a tremendous

16 impetus and note of encouragement to the

17 international scientific community.

18 And there are efforts going on

19 internationally in a tremendous display of

20 cooperation and eagerness to work together

21 toward the many dimensions in this area of

22 toxicological testing and new methods.

23 So it’s been exciting, and the message
26

1 that we sent has been very positively received.

2 DR . KIPNIS: I noted the term,

3 ‘international activities. ‘ I think that’s to

4 be encouraged. The customer base which the

5 FDA deals with is increasingly

6 internationalized . And indeed, you don’t know

7 who’s what and what’ s who anymore in terms of

8 interactions; so it’s critically important that

9 international actions are encouraged. And

10 there’s no one monopoly on scientific knowledge

11 or creativity, and we ought to take advantage

12 of it all.

13 But the other is another point; and

14 that is, anytime any new methodology is

15 introduced, validation is an important element

16 to it. One of the concerns I have is, who is

17 going to do the validation, because that does

18 take time and it does take money, and it takes

19 effort. And things have to be validated.

20 Is that potentially a cooperative

21 venture in which there will be multi-

22 institutional -- when I say institution now,

23 I’m talking about government, industry and
27
_=——..
1 academia involved in certain validation

2 efforts. If there is no validation, we may be

3 back to the same questions a year or two years

4 from now.

5 DR . SETLOW : Well, the committee

6 consists of academia, industry, and government;

7 and I think they’re working together. And

8 that’s the only way that we’ re going to get an

9 answer. Each of these members has input via

10 Email to a big circle of collaborators, and

11 they all have suggestions coming in. So I

12 think this is going to be the direction, to

13 validate.

14 DR . WILCOX : As a matter of fact,

15 there is a new entity that has been formed as a

16 standing committee; and the impetus for it was

17 a mandate that came out of the 1993 NIH

18 revitalization act; and it’s called the

19 Interagency Coordinating Committee for the

20 Validation of Alternative Methods. It has now

21 become a standing committee, and has created a

22 center that is run by an external contracted

23 group that is housed within the National
28

1 Institute for Environmental Health Sciences and

2 the National Toxicology Program jointly.

3 The purpose of this group, called

4 ICCVAM, is to review and assist in the

5 validation of new methods. And ultimately,

6 once it has determined that a method is

7 validated for its intended purpose, to then

8 bring it to the regulatory agencies and suggest

9 that this method exists, to demonstrate what it

10 has been validated for, and then it would be up

11 to the individual agencies to incorporate these

12 new methods into the regulatory paradigm.

As a matter of fact, this afternoon

14 1’11 be speaking at a congressional briefing

15 where there has been a consortium of industry

16 members that have come together; Proctor &

17 Gamble , Colgate and three or four others, where

18 they are sponsoring a bill to help fund this

19 new ICCVAM committee that is made up of 15

20 different federal agencies.

21 So there is a tremendous amount going

22 on in the arena of validation.

23 DR . KIPNIS: Why don’t we go on, in
29

1 order to stay close to our schedule, to the

2 next report, by Mr. Bernard Liebler, who is the

3 Director of Technology and Regulatory Affairs

4 of the Health Industry Manufacturers

5 Association, for an update on the Biomaterials

6 Forum.

7 MR . LIEBLER: Thank you. In your

8 package is a one-sheet report entitled:

9 Biomaterials Forum, Progress Report and

10 Recommendation.

11 The recommendation is very short. It

12 says : We recommend that we place the project

13 to develop a Biomaterials Forum indefinitely on

14 hold.

15 The original intent of the forum was

16 to develop a means for improved communication,

17 particularly for the FDA, to deal with their

18 customers, the device companies in our case.

19 And also academia and anyone else that had an

20 interest in the biomaterials area. It was

21 mostly spurred by the biomaterials shortage

22 that occurred I guess about five years ago now,
-——_—.
23 and in many ways still continues.
30

1 What’s happened in the interim is, FDA

2 -- particularly CDRH, has undergone a

3 reengineering program, and revived the product

4 development protocol, which was in the original

5 device amendments, which allows for increased

6 communication with the agency on exactly how a

7 product will be developed and tested from the

8 very beginning.

9 Also, the new Modernization Act allows

10 for, and requires meetings on clinical studies

11 and again on the data that will be required

12 very early in the approval process. And the

13 feedback I’ve been getting from other people; I

14 was talking to one member or I got an Email

15 from one member of our subcommittee, Peter

16 Johnson who runs the Tissue Initiative out at

17 University of Pittsburgh, who was saying that

18 he was at a meeting last week that again

19 demonstrated the improved communication.

20 We think that the attention that was

21 brought by the forum work plus all these other

22 activities has led to the kind of communication

23 we wanted to see. So that pursuing the forum
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31

1 in a formal manner which would be developing a

2 web site and probably expending a good deal of

3 time and money is probably not useful at this

4 point. It’s an idea that still remains viable

5 if it’s needed in the future, and the Science

6 Board can always revive it.

7 1’11 be glad to answer any questions.

8 DR . KIPNIS: Are there any other

9 comments?

10 DR . BLOUT : Bernie, what do you see

11 about -- what new materials, improved materials

12 are being developed?

13 MR . LIEBLER: That’s a hard one to

14 even begin to address. Traditionally,

15 materials for devices have not been developed

16 for devices. And considering the market sizes,

17 it’s hard to believe that traditional materials

18 are going to be developed, traditional type

19 materials.

20 I think that you really need to talk

21 to someone like Peter Johnson, who really has a

22 good understanding of tissue engineer. Because
_—-—-—_
23 I think tissue engineering and that kind of
32
_-———__

1 bioengineered hybrid material is where things

2 are going to have to go. A better stainless

3 steel is certainly not going to be developed,

4 just as an example, for a medical device.

5 It may be for an automobile. Those

6 people buy it by the carload and ton; we buy it

7 by the cup full and the gram. It’s not worth

8 anybody’s money.

9 DR . M A R L O W E: Mr. Chairman, I think

10 you have one of the world experts sitting at

11 this table on your panel that can speak to the

12 evolution of materials. And I think Bob Langer

13 would agree with me that the evolution is going

14 to be away from traditional materials, as the

15 Science Advisor just asked, and towards

16 materials that are more actively engaged in the

17 process of body rebuilding or organ

18 replacement. We’re going to see a paradigm

19 shift over the next ten years in materials;

20 materials ten years hence won’t look anything

21 like the materials that we’re using today.

22 DR . LANGER : I agree with what both of
———
23 you are saying. I think from a scientific
_—_ 33

1 standpoint there’s no question that what you’re

2 saying is right. I think the impediment to

3 creating new materials is often legal issues in

4 terms of lawsuits. That’s been the biggest

5 single problem discouraging innovation.

6 I think when I lectured here a couple

7 of years ago at one of the meetings, one of the

8 points -- and I think Bernie could probably

9 give statistics on this -- is that what you’ve

10 seen is a number of these small medical device

11 companies who are very innovative, you see the

12 percentages decreasing in the U.S. and

13 increasing other places.

14 I think one of the -- and you also see

15 a decrease in innovation, and in large

16 companies like Dupont, the classic example is,

17 Dupont spent more money defending themselves on

18 lawsuits that they never lost than they ever

19 made on selling one of their materials to a

20 company that was making an artificial jaw.

21 So I think it’s more the laws that are

22 creating the impediment. Medically I think

23 what you’ re saying is exactly right, because
34
—-_
1 the bulk -- the tissue engineering in many

2 other areas, the need to create materials that

3 can be tailor made to improve and save human

4 lives is absolutely there. But I think what we

5 also see, a legal problem in this country, and

6 I think that makes it hard.

7 DR . KIPNIS: By the way, there are two

8 other individuals from the FDA here; Dr.

9 Elizabeth Jacobson, who is the Deputy Director

10 for Science, and Mr. Don Marlowe, Director of

11 Office of Science and Technology. Any

12 comments?

13 DR . JACOBSON: I just wanted to add

14 one comment, and that that has to do with sort

15 of another shift in the regulatory handling of

16 materials that’s been allowed by the new law.

17 And that is that as a result of the new law,

18 we’re allowed to recognize consensus standards

19 in the premarket review process. And I think

20 that’s going to have another helpful push to

21 increase communications, and will allow easier

22 harmonization.
.—.
23 The emphasis on the use of standards
35
-=

1 is going to do things like encourage the MOU

2 that we already have with NIST and NIH to

3 develop standard reference materials. And that

4 ought to help, maybe it will even help with the

5 legal arena where everyone in the world is

6 agreeing on standards related to biomaterials.

7 DR . KIPNIS: Any other comments?

8 If not, thank you for all the

9 participants, and we’ll go on to the next item

10 on our agenda, which is: Public Awareness of

11 FDA Science. Two of the individuals who will

12 comment about that are Dr. Michael Friedman,

13 who is the Lead Deputy Commissioner of the FDA,

14 and Dr. Elkan Blout, who is the senior Science

15 Adviser at the FDA.

16 Dr. Friedman?

17 DR . FRIEDMAN: Thank you. I’d like to

18 spend a couple of minutes talking about a

19 variety of issues. The title of this is not

20 complete or completely accurate, but it does

21 convey at least some of the thoughts that I

22 wanted to share with you.

23 There are really three or four issues
36
————_
1 that I wanted to touch on; and I’ll ask Elkan

2 to please interpolate as I deal with each one

3 of these. The first is that this Board has

4 been very consistent in its urging us to

5 consider in its support of the recruitment and

6 appointment of the Chief Scientist; and we are

7 all very committed to doing that.

8 The announcement for the availability

9 of such a position is going out. You have been

10 asked in the past, and you will continue to be

11 asked for your suggestions about who such an

12 individual would be. We very much would

13 appreciate that.

14 Elkan I think has some remarks about

15 how he sees this process developing; but this

16 is not a mere figurehead; this is an important

17 representation of agency commitment and a much

18 more precise focus in terms of both internally

19 and externally leveraging what’s the very

20 skeleton and framework of our agency in that

21 science.

22 Elkan, what would you add?
.—.
23 DR . BLOUT : I consider this one of the
37

1 most important positions the FDA has created.

2 We would like your suggestions of people who

3 could be candidates for this position. David

4 Kipnis is going to chair the search committee;

5 the search committee is being formed now. And

6 we’re beginning to find -- we have found a few

7 people who would be appropriate.

8 My thought is, the chief scientist

9 must be an internationally-recogni zed

10 scientist, and we start from there. He could

11 come from academia, from industry or from

12 government , but he must be internationally

13 recognized as a symbol of science.

14 Secondly, Dr. Friedman is modest. He

15 has made available funds through the budgeting

16 process to make this position attractive to the

17 person who is chosen. And we hope this will be

18 a really outstanding position.

19 DR . FRIEDMAN: I should clarify that

20 those funds are for discretionary use and not

21 salary funds, because we can’t make it as

22 attractive as we would like.

23 But Elkan is quite right; the sort of
38
—..
1 candidate that we’re looking for, he or she

2 must be a very distinguished scientist, must be

3 capable, must be articulate, must want to

4 create and share a vision of clinical and

5 laboratory science at the Food and Drug

6 Administration, and that’s a very important

7 responsibility, and we’re going to do

8 everything we can to move that search along.

9 That’ s number one. Number two is, a

10 very satisfactory exercise that scientists

11 within the agency have been working on, which

12 both laboratory and clinical scientists from

13 all divisions within the agency have been

14 meeting under the leadership of Bern, to answer

15 a number of questions that I’ve posed to them.

16 I have been proceeding on a couple of

17 hypotheses, but realized that I hadn’t had

18 those hypotheses formally vetted. One

19 hypothesis was that everybody would agree that

20 science is critical to the agency and it should

21 be no surprise to YOU that these scientists

22 reaffirmed that and said yes, that was their

23 understanding as well, and their vision as
39
-
1 well.

2 The second was that the needs for good

3 scientific input broadly ranged across the

4 entire agency, that there was no one component

5 of the agency that needed science more or less

6 than other components within the agency. And

7 that can be challenged. That was my thinking,

8 but I asked them to please challenge that and

9 tell me if they agreed.

10 And again perhaps not surprisingly but

11 in a very satisfying way, the scientists all

12 agreed that all components, all the divisions

13 within the agency required -- not deserved,

14 that’s the wrong word -- required good science

15 in order to do their job. That was very

16 helpful to me.

17 Because I told them that if they had

18 come back to me and said that there is one area

19 that needs this acutely now, that we would all

20 work together to try and address it. They

21 could not identify that but did say that

22 broadly and in a number of areas across the
——
23 agency, there were important needs that should
40
—__

1 be addressed. And I very much appreciated

2 their input.

3 What they also did was to begin to

4 craft a priority list of agenda items,

5 scientific issues that they thought were most

6 important to the agency. Not just for today,

7 but where we want to be in two, three and five

8 years. And I appreciated that very much.

9 That’s a process that’s ongoing but it

10 represents the sort of forward planning that I

11 think is exactly appropriate and essential for

12 us to complete.

13 Let me link that with the third point

14 -. and 1’11 just ask whether you want to add

15 anything to that at this time?

16 DR . BLOUT: No, not at this time.

17 DR . FRIEDMAN: Okay. It was a very

18 helpful exercise; it shows how unselfish and

19 collegial the scientists can be in caring about

20 the interests of science broadly across the

21 agency. These were not parochial interests,

22 these were very broad public health interests.
_—_
23 The third thing really is how those
41

1 interests can be integrated into a larger

2 package. And this is the point where I am

3 making a pitch to this group, to everyone who’s

4 listening, as I have been to virtually every

5 constituency with which we deal.

6 One of the segments of the FDA

7 Modernization Act of last year, in Section 406,

8 and I am told it is Section 406(b) although for

9 all the world, it looks like 406(f) ; but none

10 the less, the agency is instructed to do the

11 following: To consult with appropriate

12 scientific and academic experts, health care

13 professionals, representatives of patient and

14 consumer advocacy groups in the regulated

15 industry to develop and publish in the Federal

16 Register a plan bringing the Secretary into

17 compliance with each of the obligations of the

18 Secretary under this Act, and “this act” refers

19 to the Food, Drug and Cosmetic Act -- it is a

20 modification of the Food, Drug and Cosmetic

21 Act.

22 This exercise to me is an extremely
.-—.= 23 important exercise, because what it does is it
42

1 means that we are instructed to go to each of

2 our constituencies and to say to them: What

3 gaps currently exist between what is called for

4 and what we are doing? Please help us

5 prioritize that, please help us identify ways

6 to address that, and in order for us to then

7 propose to the administration, to the Secretary

8 and to our congressional committees ways in

9 which we wish to deal with those things, to be

10 part of that process.

11 Now the reason I think that’s such an

12 important activity is that it mirrors exactly

13 some of the things that many of you have told

14 me privately, and that you’ve said publicly,

15 about the needs to address scientific

16 activities within the agency. Since I see

17 science not as a separate line item, not as

18 something that sits, in sort of splendid

19 isolation, but as really being integral to

20 everything that we do, I think this group, this

21 committee and others can help have input to

22 those considerations.
.—
23 This first report, which must be a
43

1 yearly annual report, will be published by

2 November 21st of 1998, in the Federal Register.

3 We’re instructed to do that and we take this,

4 as we take all of our FDA modernization

5 responsibilities very, very seriously. That

6 leaves us relatively little time for this first

7 iteration.

8 There are three broad areas that we

9 have identified as being important. We are

10 going to all of our constituencies, all the

11 stakeholders who have a vested interest, and

asking them to please comment on but also to

13 add and to re-prioritize interests; SO b y

14 saying to you three things that we are focusing

15 on today that’ s not to suggest at all that

16 that’s the limit or that’s even the order of

17 the ones that will be picked. But it is to say

18 that we have to do part of this, which is to

19 begin to create this formal agenda.

20 We’ve tried to pick things where we

21 see important gaps that exist between statutory

requirements in our performance and things

which will have important public health
44

1 benefit, and those two things must go hand in

2 hand.

3 The three areas that we’ve identified

4 so far as being very important are: Adverse

5 event recognition reporting, modification,

6 management . I don’t think anybody could argue

7 that that’s an important area. It is broadly

8 true for the entire agency. I’m not talking

9 about drugs, I’m talking about requirements for

10 devices, but also for foods, for cosmetics, for

11 a number of other areas.

12 We’re not only talking about a better

13 system for evaluation and management; this is I

14 think a perfect example where science and

15 research skills are incredibly necessary. Here

16 we’re talking about epidemiologic and

17 statistical, but also clinical skills.

18 So I think this should be a topic of

19 interest.

20 The second is the broad area of how we

21 assure the quality and safety of products,

22 inspection and compliance activities, where

23 there are important gaps that exist between our
45
_fT.
1 statutory requirements and our ability to

2 perform; and we are talking again to a wide

3 variety of organizations.

4 I should just reiterate here, we have

5 not reached out to all the organizations; but

6 I’m doing this -- as meetings come along, I and

7 other people are making this case to the

8 public, and we will be doing so in a more

9 formal way. This is sort of a welcoming of

10 people to please come to us, even on bid, and

11 say we’d like to offer you our proposals, we’d

12 like to share with you our division of what

13 this should be.

14 That second area is an important one.

15 The third is in the general area of premarket

16 review activities. As you all recognize, for

17 human drugs and biologics, the Prescription

18 Drug User Fee program has been spectacularly

19 successful, but there are other important

20 product areas where the agency is not meeting

21 its statutory deadlines. We’re doing

22 beautifully with human drugs and biological;
–~.
23 we do not have such a good record in some other
46

1 areas, and I fear our performance in those

2 areas will actually get worse as budgetary

3 constraints weigh heavily upon us.

4 There are important benefits for the

5 public that will be delayed if we can’t move as

6 quickly and with as much care as we would like.

7 Again, it should be obvious to you that there

8 are opportunities for science; laboratory

9 investigation and non-laboratory investigation,

10 that are relevant to these areas.

11 I don’t mean this to be a

12 comprehensive list; I’m giving you just a

13 shorthand version of three areas that we think,

14 we believe are important that we believe

15 broadly, the community, the lay community,

16 industry, governmental organizations, that

17 others will also feel are very important. But

18 the list is much longer than this, and our

19 concerns are to prioritize those things that we

20 think are most critical or most accessible

21 during this next fiscal year to begins to craft

22 ways in which we address those issues.

23 And let me just restate: I’m not
47
__—__

1 suggesting that we simply throw money at

2 things, although resources will be an important

3 part of this. What we’re asking for also is

4 ideas of ways in which we can discharge these

5 responsibilities in innovative, novel ways that

6 may save resources or may do a better job.

7 So this is not a commitment to do

8 things in the same old way; it is a commitment

9 to meet what the public expectations are, and

10 that’s our ongoing goal.

11 How can you all be helpful in this?

12 Well, I think you can imagine a number of ways

13 in which you could be helpful. As these

14 discussions go further, as we’re able to flesh

15 out better what we are, what we are see are our

16 most near term goals. You all can have input

17 to that, you can help change that agenda, you

18 can suggest resources or ways to address what

19 will be necessary; you can give us ideas of how

20 to do our job better.

21 I think this provides a public means

22 for discussion, and that’ s very important.
_-.—.=
23 This is a public discussion which is called for
48
.———.–.
s——

1 by the Act, and we want to conform fully to

2 what the Act requires.

3 Let me stop there and answer any

4 questions, if I may.

5 DR . KIPNIS: Any comments by members

6 of the Board?

7 DR . CUATRECASAS : Could you elaborate

8 a little more on the second issue that you

9 discussed?

10 DR . FRIEDMAN: You mean inspections?

11 DR . CUATRECASAS : Yes.

12 DR . FRIEDMAN: There are a variety of

13 industries where we have -- where there are

14 statutory guidelines for how often a facility

15 will be inspected and we’re not in full

16 compliance with that? And I think that we

17 want to figure out how to address that.

18 1’11 give you some other examples.

19 We’ve entered into a number of mutual

20 recognition activities with foreign governments

21 for facilities that are there. Living up to

22 those obligations will be difficult in real
-——–.
23 time. We think that international activities
49
——–
1 are very important, but we’re trying to say,

2 rather than taking a decade to meet certain

3 expectations, can we bring that down to a more

4 reasonable time frame and are there other

5 countries that we aren’t even able to engage in

6 activities with now who we could think about?

7 Again, it’s not just a matter of drugs

8 and biologics; it’s generic drugs, it’s

9 devices, it’s all sorts of things -- animal

10 products. It’s very broad ranging, and I think

11 that what we want to do is look at what are

12 those statutory expectations that have the most

13 public health benefit? Those are the ones we

14 want to focus on first.

15 The background of this is that I think

16 that the agency has demonstrated that when we

17 get the resources and when we have clear goals,

18 we do a great job. When we don’t have the

19 resources or the goals, the expectations are

20 not so clearly articulated, we do a less good

21 job. And we want to try and fix both of those

22 things.

23 The agency’s budget has roughly
50
_—_
1 doubled between the beginning of the decade and

2 the end of the decade. And our workload has

3 probably gone up five or six or eightfold,

4 depending upon how you look at it; so that even

5 with much greater efficiency, which I give the

6 centers and the management of the agency

7 tremendous credit for increased efficiencies,

8 even with that we’re still struggling to meet

9 our obligations; and we just need to recognize

10 that and to engage with the public and with the

11 public’s representatives in Congress; what do

12 we want as citizens, how do we want it, and

13 what are we prepared to provide in order to get

14 that?

15 It’s just a very serious,

16 nonemotional, a n a l y t i c discussion.

17 DR . CUATRECASAS : Thank you.

18 DR . FRIEDMAN: Like all of our

19 discussions.

20 (Laughter)

21 DR . BLOUT : Thank you, Mike, for that

22 last few words.

23 I just have two points I’d like to
—=
51

1 make to the Science Board. One, this search

2 for a chief scientist is really starting now,

3 and many of us here would like to see it

4 completed within about six months. We want to

5 get somebody on board, the right person. So

6 please send in suggestions as soon as possible,

7 and they can go either to Dr. K i p n i s or to me.

8 Secondly, I want to say a few words

9 about my personal experience. During the

10 slightly more than six years I’ve served in

11 this position, I’ve had many positive
_———__
12 experiences at FDA. But it would only be fair

13 to say, I’ve had many frustrations. And the

14 frustrations generally encompass the feeling

15 that people outside the agency don’t understand

16 what the agency is trying to do or how they’re

17 trying to do it.

18 I think the awareness of the agency’s

19 scientific work within, both in terms of

20 laboratory work in the various centers and its

21 use of science is not appreciated widely in our

22 society. And I would urge us to think how we
_——_
23 can convey to the people who make decisions
52

1 about the agency, the importance of science.

2 We should stop talking to o u r s e l v e s

3 exclusively. We’ve got to talk to o u r s e l v e s

4 often. But we should try and talk to other

5 people, to the staffs of congressional

6 committees, to the important people relating to

7 appropriations .

8 So anybody who has ideas or is willing

9 to participate in this activity, let’s go.

10 DR. FRIEDMAN: Let me give the usual

11 bureaucratic clarification. What Elkan is not
-
12 suggesting, of course, is lobbying activities

13 that we’re asking for from the agency. We’re

14 talking about educational activities -- I think

15 he’s talking about educational activities, and

16 I want to be very clear about that.

17 The points to remember are the vast

18 investment that’s being made by the

19 pharmaceutical industry by device

20 manufacturers, by food companies, cosmetics,

21 the whole -- veterinary products. We’re

22 talking of something getting close to $40
—_
-.
23 billion a year just in R&D in the United
_—_
53

1 States, including NIH.

2 It is inconceivable that that amount

3 of investment won’t result in important

4 products in the near and more products in the

5 long-term future. And what we’re talking about

6 is having an agency that is prepared to deal

7 scientifically with the breadth and the depth

8 of those products.

9 And unless we want to go back to a

10 time when things are slowly evaluated, I don’t

11 think anybody does, then we must have a system

12 in place that is suitably vigorous and

13 efficient to deal with this vast number of new

14 products that we’re going to be facing.

15 So how do we best do that; and I think

16 science is an important component. Simply

17 educating people about that, simply asking

18 people, what are your expectations for the

19 future, I think is a useful sort of discussion.

20 DR . KIPNIS: Dr. Leveille?

21 DR . LEVEILLE: That’s certainly true,

22 as you well know, Dr. Friedman, in the food

23 area, in spades. Good or bad, the focus has
54

1 really changed by the food safety concerns that

2 have emanated over the past few years. The

3 unfortunate thing is that CFSAN in FDA has had

4 to divert increasingly limited resources to

5 activities other than premarket evaluation; and

6 that has been very seriously damaged. They

7 have not been able to deal with any citizens

8 petitions that have come before them; they have

9 not been able to deal with other premarket

10 submissions that have come before them, in an

11 efficient way. Very different from the drug

12 side, as you well know, and I would hope that

13 would be one of the areas that would get early

14 attention.

15 DR . FRIEDMAN: I think that’s well

16 said; I think there are a variety of nonuser

17 fee areas where those same concerns are true.

18 I recognize and agree with what you’re saying,

19 and I think there are important benefits for

20 the public. It’s not just the law, we’re

21 supposed to be doing things in certain

22 statutory frameworks, time frames; it best

23 serves the public’s interest.
55

1 We’re not satisfied with that; we want

2 to try and address that, too. And we think

3 that, looking at our processes, looking at our

4 resources, these are the things that we want to

5 broadly engage everybody in.

6 DR . KIPNIS: I’d like to make a few

7 comments relevant to some of the issues that

8 have been raised repetitively by Dr. Friedman

9 as well as Dr. Blout and others, and that is:

10 Consistency of recognition even within the

11 agency that it is science-based. For the four

12 years I’ve participated in this committee,

13 every single official, well before your

14 administration, has always introduced the

15 comment that it’s science-based. Indeed, even

16 the legal personnel have used those terms.

17 The problem is there’s a distinction

18 between hyperbole and substance. And if they

19 really mean what they say their actions ought

20 to be based on.

21 I would present two things that are

22 argumentative, but nevertheless strike me. One

23 is that science has been used as the base for
56

1 the FDA being involved in the critical issue of

2 tobacco. The issue of nicotine addiction is a

3 scientific-based phenomena. Indeed, it was

4 known, but much of that information never

5 released to the public even by industry in this

6 essence.

7 Also, the epidemiologic data relating

8 smoking with malignancy is well known. So

9 there are scientific bases that legitimize the

10 approach . On the other hand, a major decision

11 was made on biomedical materials based on a

12 political decision without substantive science

13 behind it. The breast implant data is an

14 example of that.

15 So the consistency of the FDA from its

16 leadership to its most minor participant has to

17 be consistent that we are science-based. Now

18 I’ve heard that repeatedly said; but part of it

19 is a part of the, I would say celiac axis and

20 hypothalamus other than just the white cortex.

21 Until it is felt deep, it won’t be appreciated.

22 Now that is within the agency; but the
#-%.
23 other is the public, that expects a great deal
57

1 of the FDA, but doesn’t realize that its

2 decisions have to be based on the best

3 quantitative data you can secure with respect

4 to what science permits you to secure.

5 I think, therefore, the issue of

6 educating the public is critically important.

7 But the public also elects representatives; and

8 most of the representatives are public in this

9 sense, as well is their staff. And do they

10 feel that science is important?

11 1’11 give you an example of where I

12 think Congress and its representatives and its

13 staff recognize that scientific-based

14 information, given in a neutral manner without

15 political impact was important. And that did

16 with the sunshine laws, and the legal

17 interpretation constraining the National

18 Academy in terms of its capacity to respond as

19 a neutral source of scientific information.

20 Within one month, both houses of

21 Congress unanimously passed legislation and it

22 was signed, acknowledging history going back to

23 1860, where a neutral scientific factual body
58

1 should be free to present information but keep

2 the public informed; indeed, membership of the

3 societies informed, and reports.

4 So that it is an educational event;

5 but I would say even internally, by what I’ve

6 seen for four years, that has to be an espousal

7 at the highest levels including the legal

8 people who are involved to distinguish between

9 what is a political decision and what’s science

10 based.

11 The other deals with user feels. I

12 must admit, I’m confused as to why industry on

13 one hand expects high quality, rapid decision-

14 making, but in essence is unwilling to

15 acknowledge that user fees basically are

16 personnel sorts -- it’s people; it’s not the

17 computers that are doing the work. Once you

18 have them, it’s the cheapest element. But it’s

19 people.

20 And yet to acknowledge that user fees

21 are a legitimate basis for increasing the

22 quality of science so that you have better

23 people who make the decisions is something I
59
_-_—_ .
1 have a hard time to understand. It seems as if

2 one’s talking out of both sides of one’s mouth;

3 and I acknowledge that’ s a legal issue, that’s

4 a political issue; but purely from management,

5 how can you improve the quality of your

6 scientists if you can’t also put into it the

7 cost of making the decision. In order to make

8 that decision, you need the quality people as

9 well as the number of people needed to reach

10 those decisions. Those are comments; take them

11 or leave them.

12 DR . FRIEDMAN: Let me address briefly

13 both those areas. One is that we aspire to be

14 a science based agency, and sometimes as

15 science unfolds we’re proven to be correct or

16 we’re proven to have not had all the

17 information in making certain decisions.

18 I think that this body and the public

19 should hold us accountable in a very severe way

20 for how well we use scientific information; and

21 that we recognize that at any moment in time --

22 as scientists we recognize this -- we have
_—_
K-.

23 insufficient information to have a full view of
60
_-—.—_-..
1 things; and what we’re called upon to do is

2 make the best decisions given that moment.

3 Then to be charged with reevaluating that

4 decision forever, as new information comes in.

5 I hope that’s what we’ve done

6 successfully over the past couple of years,

7 anyway; because I think I’ve seen a lot of

8 serious commitment to that sort of activity,

9 even in the face of very controversial

10 decisions in virtually all of our product

11 areas; where some community has said we haven’t

12 gotten the science right, and other communities

13 have said that we have. And you can think

14 about that for foods, for devices, for drugs,

15 for virtually every area that we’ve been

16 involved in. And we’re prepared for that sort

17 of vigorous scientific discussion and even

18 controversy. That’ s number one.

19 Number two is, I actually think it’s

20 not as worthwhile to focus on where resources

21 will come from to do those activities that are

22 necessary for the agency as it is to decide
.—.
23 first what needs to be done and then at what
61
.s- -.

1 level and with what sort of resources; and then

2 to decide where those resources should come

3 from.

4 Leaving aside the validity of your

5 argument , David, about -- you know, for a

6 particular area. And that’s something that has

7 been discussed, it can be discussed more. I

8 honestly feel that’s not as important, because

9 there are a ton of other areas within the

10 agency that don’t have user fees and for whom

11 resources for scientific activities are

12 absolutely essential.

13 So leaving aside that question,

14 because I don’t quite agree with your synthesis

15 of it, but that’s not important; you’re making

16 the case that in order to do good reviews and

17 to manage portfolios properly, you need the

18 proper science. I certainly agree with that.

19 What I would like to do is not to get involved

20 right away and where the resources will come

21 from, because I think that’s going to be

22 actually diverting and confusing and
-- -.
23 contentious .

62

1 What I would like to do first is just

2 say: What do we want to do, What is it going to

3 take, and then we will decide how we will pay

4 for it. Otherwise we get short-circuited into

5 -- as you point out, these can be difficult,

6 contentious political and special interest

7 issues. We don’t need to go there right yet.

8 We will need to go there, and I’m not avoiding

9 that . I’m prepared to deal with the

10 difficulties of those discussions; that’s fine.

11 But let’s do that third. Let’s first decide

12 what do we want and what is it going to take.

13 Let me just close my section, if I

14 can, by apologizing; I’ve got to run to another

15 meeting, and I’m sorry that I won’t be able to

16 be here for a lot of the very important

17 presentations and discussions that will take

18 place later. But if people have comments

19 specifically for me, you know how to get ahold

20 of me. I’m not in the witness protection

21 program yet, so --

22 (Laughter)
————=_
23 -— please feel free to -- Bern or
63
-.
1 Elkan or others will convey things to me; you

2 can get to me directly. And I’m sorry, I wish

3 I could stay for the rest of the afternoon.

4 Thank you.

5 DR . KIPNIS: Thank you very much, Dr.

6 Friedman.

7 Why don’t we go on to the next

8 presentation, by Dr. Leslie Benet, the

9 Subcommittee for CBER Review.

10 DR . BENET: Let me say something before

11 Mike leaves, because I thought he was going to
—_
12 stay for this part; because we are going to

13 disagree with his premise in terms of what is

14 needed for the agency, and we are going to

15 state more of what our chairman had indicated

16 in terms of, that we are in a crisis situation

17 in CBER, and that the present approach that is

18 going on within the agency, which is reflective

19 of the government funding criteria, is
.
20 something that requires a committee such as

21 ours that are not employees of the federal

22 government , to make recommendations.
-—_— _—.
23 Specifically, the committee feels that
64

1 with Senate bill 1305 presented in October 22,

2 1997, the National Investment Act of 1998,

3 where the bill calls for increased U.S.

4 Government appropriations for basic scientific,

5 medical and preemptive engineering research in

6 federal government institutions, but that the

7 Food and Drug Administration is omitted from

8 this, is a grave error that can lead to a great

9 crisis in health of the population and of the

10 economy.

11 So this committee is going to make

12 recommendations that will reflect what we

13 believe needs to be there, Mike, but also are

14 going to vigorously make recommendations in

15 terms of funding of the agency relative to

16 this.

17 DR . FRIEDMAN: I appreciate that, and

18 welcome those comments. I don’t see that as

19 inconsistent with what I’ve said.

20 My understanding is that you all have

21 had a chance only to review the Center for

22 Biologics. And however passionately you make
.-— ..- —.
23 the case for them, and I think it’s deserved --
—_ 65

1 we have no disagreement about that.

2 I don’t think you can say, without

3 having reviewed the other areas, that the needs

4 in one area are more desperate than in others.

5 Make the case generally that -- if you can; I’m

6 not trying to put words in your mouth -- if you

7 make the ,case that these are urgent needs, and

8 I not only accept; I welcome those remarks,

9 that this is not at all inconsistent with what

10 I’m saying, but that these are agency-wide

11 issues.
—_
12 What I look to this Board to do is to

13 help provide the perspective agency-wide. Make

14 the best, most passionate, most convincing case

15 you can, center-by-center as you review it; but

16 recognize, I think, what our scientists have

17 told us internally and what I think is sort of

18 generally accepted folk wisdom; is that the

19 issues in CDRH or the issues in CFSAN or the

20 issues in CDER, CVM , are not fundamentally

21 different than the issues in biologics; and our

22 biologics laboratories are an important
———___
23 national resource. I think they’re very
_-—_
66

1 valuable to us. I think they’re essential to

2 our operating properly.

3 Make that case wherever you see it.

4 If you find that you don’t see it for one of

5 our centers, fine, make that case. I sort of

6 doubt that’s going to happen. But it might.

7 In the meantime, make your best case,

8 but realize that I’m going to act as a

9 spokesman for all the agency. Our scientists

10 have internally gone over this process, and

11 they’re continuing to do so. CBER has been

12 very clear about the needs that they have. I

13 find these legitimate needs, defensible needs,

14 supportable needs.

15 So I’m not sure that we’re saying

16 different things, except that you’ve looked at

17 the first center, you see this, you want to

18 make sure that we recognize this. I may be

19 putting words in your mouth and I don’t mean

20 to.

21 DR . BENET: Mike, you would never put

22 words in my mouth.

23 But let me say, that the report -- I
67
——_

1 don’t disagree with what your scientist said

2 and what your committee viewed. We all in this

3 committee here, the Science Board, very

4 strongly believes in the importance of science

5 within the agency. But our report will

6 differentiate the importance of laboratory

7 science within the agency, and we do believe

8 there are differences of centers in that

9 aspect.

10 No one believes that there are

11 differences in the need for science within the
_____
12 agency as a whole. But I do believe, and this

13 committee will make strong recommendations

14 relative to laboratory science.

15 DR . FRIEDMAN: Didn’t you also review

16 some of the clinical sciences? I thought YOU

17 also reviewed the statistical and epidemiology

18 component; I think he did.

19 DR. BENET: Yes.

20 DR. FRIEDMAN: And that’s very

21 valuable. I don’t want to preempt your report,

22 but my guess is you’re going to say that there

23 is some excellence there and the resources that
68

1 are needed there as well.

2 So with all due respect, it’s not just

3 the wet laboratory scientist. As good and

4 important as that is, and don’t let my remarks

5 be misunderstood -- 1 think those are terribly

6 important, but my guess is that what you’re

7 going to say is that wherever there is

8 essential quality programs, that those deserve

9 proper support. And I’m going to agree with

10 you if that’s what you say.

11 DR . BENET : Okay.

12 DR . KIPNIS: Thank you. We’ll go on.

13 Subcommittee for CBER Review

14 DR. BENET : Thank you, David.

15 [Overhead]

16 I had the pleasure, over the past five

17 months, of chairing a very prestigious group of

18 25 scientists and myself, who carried out a

19 very vigorous review of the Center for

20 Biologics; and the report is available to the

21 Science Board, and I will review the major

22 issues in the report for the committee at this

23 time.
69
F-

1 [Overhead]

2 1 thought it would be worthwhile

3 reviewing the process. CBER proposed the

4 appointment of an external peer review

5 committee to the Science Board as a

6 subcommittee on September 15, 1997; and in its

7 September 30 meeting, the Science Board

8 concurred. This committee was appointed in

9 December of 1997. In January of 1998 all

10 committee members received six huge notebooks

11 of documentation to review prior to a four day

12 site visit of CBER on the NIH campus, which was

13 held February 3-6, of 1998.

14 The committee reviewed one partial and

15 two complete drafts of the report, and has

16 unanimously reached consensus on this report

17 which we are presenting today to the Science

18 Board as indicated here.

19 [Overhead]

20 My slides are being shown by Dr.

21 William Fries, the acting Chief of Scientific

22 Advisers and Consultants at CBER. Bill served
-.
23 as the staff for the committee, and I greatly
70

1 appreciate all of the hard work that he and all

2 the members of his group in facilitating our

3 ability to put that report together.

4 The report consists of 12 pages of

5 public recommendations; a two-page

6 introduction, a one-page preamble, three-page

7 background and justification, three pages of

8 crosscutting issues and three pages of summary

9 assessments of the individual divisions within

10 CBER which we reviewed.

11 There are three appendices, a

12 committee roster, the letter of appointment,

13 and the full schedule of the site visit report

14 that are also included as Appendices A-C; and

15 there’s an Appendix D of nine pages which

16 includes written comments of review committee

17 members that were not included as text within

18 the report itself; and we’ll see as we go

19 through that these are related to some

20 particular overall issues, and give you an

21 understanding of different viewpoints on the

22 committee, but the strong sense of the
. -
23 committee members in this consensus
71

1 recommendation .

2 [Overhead]

3 There are also appendices E through N,

4 consisting of 41 pages which provide detailed

5 evaluations of each of the divisions. The

6 summary of the divisions indicator on pages lo-

7 12, the summary assessment.

8 We anticipate that the publicly-

9 distributed document will be these first 37

10 pages, and the 41 pages of the detailed

11 evaluations will not be publicly distributed,
~.
12 since the report contained evaluations of

13 individuals; it’s just as if a site visit was

14 carried out and each individual scientist in

15 m a n y cases, are reviewed.

16 I assume, though I don’t know it will

17 work, but I assume that this can be obtained

18 through Freedom of Information, but then there

19 will be deletion of individual names that will

20 be available. But the public document, Susan,

21 will be available at the conclusion of my

22 report to people in the room.

23 DR . KIPNIS: Outside the meeting room.
72

1 DR . BEN ET: Outside the room. It is

2 already available.

3 [Overhead]

4 Let me go to the next slide which is

5 from the introduction, paragraph 2, line 4, and

6 it is important because it reflects what I just

7 said to Dr. Friedman.

8 It also became apparent to the

9 committee, which, including outstanding

10 scientists from academia, major pharmaceutical

11 companies, the biotechnology industry, national
_—-_
12 health institutes; both representatives from

13 the U.S. and U.K., and research foundations.

14 It was necessary for the committee to go beyond

15 its specific charge and address the committee’s

16 unanimous concern that inadequate funding for

17 CBER, particularly the inadequate funding for

18 laboratory research within CBER, would risk

19 potential damage, not only to the health of the

20 p o p u l a t i o n of the United States, but also the

21 health of our economy by affecting an industry

22 that will rapidly expand in the 21st Century.

23 Thus in structuring its report, the
73

1 committee details within a preamble our great

2 concerns related to inadequate funding of CBER,

3 and recommendations attention to this issue not

4 only by CBER and FDA leadership; but also by

5 Congress, the administration, the Department of

6 Health and Human Services as well as the

7 pharmaceutical and biotechnology industries and

8 the public, whose health will be at risk.

9 [Overhead]

10 On the next slide I give you an

11 overall summary of the membership of the 26

12 members, and their listing is in Appendix A of

13 the report. The committee was composed of 16

14 academics, 3 representatives of what we would

15 call the major pharmaceutical industry, three

16 representatives of the biotech industry, 3

17 individuals from the national health

18 institutes, and 1 from a foundation. Of the 26

19 committee members, six of them were member of

20 the Institute of Medicine of the National

21 Academy of Sciences.

22 [Overhead]

23 When you look at the individual
74

1 division reports, you will see that this is not

2 a committee that uniformly liked what it saw at

3 CBER. There are very hard-hitting comments,

4 both in the summaries and in the individual

5 reports about negative aspects of what we

6 viewed within CBER and recommendations of

7 things that need to be changed.

8 I make that point because the

9 unanimous recommendations that we made reflect

10 individuals who have very strong opinions in

11 terms of the science itself but are unanimous

12 in their view of what’s important in terms of

13 funding laboratory research within this agency.

14 Within the introduction also, just in

15 a summary that appears on page 2 of the

16 introduction. Just finally, a brief assessment

17 of each of the individual divisions is

18 presented in pages 1o-I2. More detailed

19 evaluations of each division are presented in

20 the appendices. These contain internal program

21 reviews, and in many cases contain evaluation

22 of individual research scientists; therefore
_.-———-.
23 they will not be distributed outside the FDA as
75
—_—_
1 part of the committee’s report.

2 These appendices were prepared for FDA

3 CBER senior staff, and therefore as much

4 detailed information as the reviewers wished to

5 provide has been retained in the appendices

6 with only minimal editing. These appendices do

7 not follow a preset format, and reflect the

8 evaluation concerns of the individual committee

9 members; and these appendices are available to

10 members of the Science Board.

11 [Overhead]
_—_
12 The first paragraph of the preamble

13 indicates: It is the general consensus of the

14 review committee that the issues we are

15 evaluating here have major health implications

16 for the United States. Inadequate funding of

17 CBER can be predicted to lead to a crisis in

18 terms of health outcomes as well as a crisis of

19 confidence in the ability of our national

20 regulatory authorities to maintain health,

21 since the therapeutic, prophylactic and

22 diagnostic agents, about which CBER advises and
.—,
23 regulates affect all aspects of the well-being
76

1 of our population.

2 These areas of CBER concern include

3 vaccine in all age groups with particular

4 concern for children and the elderly. The

5 biologic diseases that are of great importance

6 to us as a population such as AIDS. The safety

7 of the blood supply in this country, and the

8 identification of infectious agents that could

9 contaminate various products that are

10 distributed to large portions of our

11 population.

12 We go on in the second half of this

13 first paragraph: In addition, the Center for

14 Biologics, Evaluation and Research at present

15 regulates the most rapidly expanding sector of

16 our drug industry; facilitating the United

17 States to be the leader in the development of

18 new technology and new products that relate to

19 biologics. This industry is an important

20 financial component of our economy. It is the

21 consensus of the review committee that for our

22 industry to receive prompt and appropriate

23 regulatory reviews, as well as for the ability
77

1 of our regulatory agency to respond to urgent

2 needs, it is of utmost importance that the

3 scientists in CBER have research capabilities

4 at the cutting edge that allows them not only

5 to understand rapidly expanding methodologies

6 to evaluate vaccines and biologics, but also so

7 that CBER’S scientist-reviewers can interact

8 with their colleagues in industry on a

9 knowledgeable, scientific and technicalogic

10 basis so that the appropriate recommendations

11 can be made.
F .,
12 It is the consensus of the committee

13 that CBER requires a strong laboratory research

14 focus and not a virtual science review process.

15 Otherwise, we risk the potential to damage not

16 only the health of the population of the United

17 States, but also the health of our economy in

18 terms of an industry that in the 21st Century

19 will expand by leaps and bounds.

20 Further on in the preamble, the

21 committee recommends to the Congress, to the

22 administration, to the HHS and to the Food and
g==.=
23 Drug Administration that it is greatest
78
-——

1 importance to provide the appropriate support

2 in expanding funding to CBER so that cutting-

3 edge research and cutting edge scientists

4 continue to be attracted to work in an agency

5 that is so central to both the health and

6 welfare of our economy.

7 We urge those reading this report to

8 recognize that the cost-effectiveness of the

9 products and functions regulated by CBER is

10 enormous . There is no doubt that the major

11 financial savings which we will make in health

12 economy are in the area of prevention. It is

13 CBER within the Food and Drug Administration

14 that regulates and approves vaccines which the

15 committee recognizes as the leading contributor

16 to preventive medicine.

17 [Overhead]

Continuing on in the preamble: The

19 review committee, in expressing its strong

20 support of the need for laboratory research in

21 CBER recognizes that this position is contrary

22 to the experience of the agency and the
——.
23 industry and the review and approval of drugs
79

1 by CDER, the Center for Drug Evaluation and

2 Research.

3 This position also differs from the

4 perception of Pharma, in the recent

5 renegotiation of PDUFA, the Prescription Drug

6 User Fee Act authorization, who felt that the

7 regulated industry should not pay for CBER

8 research. However, it is important to

9 recognize that b i o l o g i c a l are different from

10 drugs . Drugs tend to be low molecular weight

11 substances, capable of complete physical-

12 chemical characterization which defines product

13 quality and which provides a basis for

14 production of consistent, safe and effective

15 product.

16 In contrast, biological tend to be

17 high molecular weight substances which are less

18 capable of complete physical-chemical

19 characterization ; therefore, product quality
20 depends on in-process control and process

21 validation to a greater extend than for

22 chemical drugs.

23 Continuing on in this comparison
80
.——.

1 between drugs and biologics within the

2 preamble: Manufacturing methods for drugs can

3 generally employ non-physiological processing

4 conditions which provide an effective barrier

5 to product contamination by adventitious

6 contaminants .

7 For biological, the dependence of

8 biological function on delicate physical

9 structures usually prevents the use of harsh

10 processing conditions which are typically

11 employed with chemical drugs. Thus, some
_—_
12 biological have historically been associated

13 with adverse reactions and death related to

14 adventitious contaminants, particularly for

15 those products with little opportunity for

16 removal or inactivation of adventitious agents.

17 Again continuing in the preamble: The

18 committee believes that a credible emergency

19 response by CBER to adventitious agent problems

20 associated with marketed biological products,

21 including blood and blood products required

22 immediate availability of a laboratory-based
_——_
23 team of experts who understand both the
81

1 potential adventitious agents involved in the

2 scientific manufacturing control and clinical

3 aspects of the product.

4 I’m sorry; the last three came from

5 the background section which justifies -- that

6 comes from the background and justification for

7 the preamble. So these were why we made these

8 recommendations .

9 [Overhead]

10 We conclude this justification: In

11 summary, this review committee echoes the views

12 of our predecessor FDA Science Board

13 Subcommittee on FDA Research, that was convened

14 and chaired by Dr. David Kern, by affirming

15 that the FDA, through a vigorous, high-quality

16 intramural program of scientific research

17 provides the essential foundation of sound

18 regulatory policy and performance, and ensures

19 that the FDA is and will continue to be in the

20 best position to carry out its statutory

21 responsibilities to protect, promote, enhance

22 and affirm the health of the American people.
.- —-.
23 In light of the need for a vigorous
82
.m.
1 cutting-edge modern research program, the

2 decrease in the agencies “and particular CBER’S

3 budget in both dollars and full time equivalent

4 staff is a major concern. The review committee

5 believes strongly that depleting the agency’s

6 base of intramural scientific expertise must

7 inevitably compromise the quality of review and

8 regulatory activities as well as potentially

9 adversely affect the health of our population

10 and our economy.

11 Basically, the preamble and the

12 background justification are for this overall

13 view of funding of science within the agency

14 and our strong belief that the science,

15 laboratory science in CBER is different than in

16 many other areas and cannot be carried out

17 effectively with a virtual science program.

18 We then went on, in a series of

19 crosscutting issues, that the laboratory

20 science in CBER is different than in many other

21 areas, and cannot be carried out effectively

22 with a virtual science program.

23 We then went on, in a series of
83

1 crosscutting issues -- and I am not giving you

2 the entire report, I’m just giving you some

3 highlights from it -- in the crosscutting

4 issues, in recommending support for a strong

5 laboratory research focus in CBER, the

6 committee recognizes this research must be

7 mission-oriented and complementary to the

8 laboratory research programs of the regulated

9 industry, rather than duplicative of the

10 research ongoing within the industry.

11 Particularly, we indicated that there

12 was one area where we felt it was extremely

13 important for laboratory research to be within

14 CBER; that is in fact why you need this

15 research in CBER and it is not at all

16 duplicative of the industry, and that is in

17 this paragraph.

18 It was recognized by the committee

19 that a laboratory research function of CBER,

20 which is critical to the maintenance of

21 competence of agency scientists relates to

22 analysis. Through the agents that CBER

23 regulates and discovers in its own laboratory,
84
.4$--=

1 this agency has available a critical set of

2 macromolecules for analysis and

3 characterization .

4 Both the world and the agency are in

5 serious needs of methods for characterizing,

6 measuring and monitoring these agents. Efforts

7 to develop these methods are not what they

8 should be at CBER, probably for budgetary

9 reasons.

10 We believe that CBER needs to be among

11 the best regulatory agencies in the world, and

12 p r o a c t i v e in responding to the needs of society

13 and of manufacturers. The committee

14 recommends that CBER create a new measurement

15 science unit. That goes on in much greater

16 detail within the report.

17 [Overhead]

18 These are other areas, crosscutting

19 issues: The committee strongly recommends that

20 CBER institute an approach to quality assurance

21 of controlled testing, and that CBER create and

22 evaluate standards for measurements carried out
— _
23 within CBER research that are commensurate with
85

1 what CBER expects to see for data that are

2 submitted to the agency by the regulated

3 industry.

4 The committee also noted that the

5 statistical criteria which CBER scientists set

6 for themselves are far below the standards that

7 the agency requires for the regulated industry.

8 The committee believes it is important that

9 CBER use appropriate statistical criteria in

10 evaluation of their own research data, and note

11 a general lack of interaction of CBER

12 laboratory scientists with their statistician

13 colleagues.

14 In the design of studies to validate

15 a s s a y s and to analyze the results of the animal

16 model work, CBER scientists should have

17 statistical input prior to carrying out the

18 studies. The committee believes that a small

19 group of two or three statisticians should be

20 dedicated to supporting laboratory science

21 presently ongoing within CBER.

22 Further on in the crosscutting issues:

23 The committee recognized that there are
86

1 greater communication problems within CBER than

2 have been recognized by the senior

3 administration . One aspect of this

4 communication problem is the lack of

5 recognition of duplication of research in

6 different areas, or at least recognition that

7 different scientists, working on the same

8 project, are often not communicating. The

9 committee is also concerned about the esprit de

10 corps of the group itself, although the

11 committee recognized that some of this

12 dispiriting attitude relates to financial

13 cutbacks leading to FDA downsizing of science

14 at a time when the climate for strong support

15 of science at NIH is markedly improving.

16 Within the crosscutting issues, we

17 actually spoke directly toward the budget to

18 give you some awareness of what has happened in

19 the budget. The committee recommends that the

20 research budget be restored to at least 1994

21 levels. In that year the CBER research budget

22 was $18.4 million of a total CBER operating

23 budget of $44.5 million. This excludes
87

1 salaries for full time equivalent scientists.

2 The corresponding figures for fiscal

3 year 1998 are $6.9 million for research budget,

4 and $25.4 million of the total operating

5 budget . In addition, new money will be needed

6 for new initiatives such as the measurement

7 science unit recommended here and new

8 strategies that can enhance the program as well

9 as providing funds for special purposes.

10 Then at this time within the report

11 I’ve basically given you some of the text from

12 the introduction, the preamble, the background

and justification and crosscutting issues; I

14 will not give any of the details of the

15 individual division reports, but there are now

16 three pages summarizing each of the divisions

17 and our recommendation for those divisions.

18 [Overhead]

19 Following that is appendix D, which is

20 the last slide. In preparing the committee’s

21 report, a number of insightful comments

22 provided by committee members were not utilized

23 directly. Since these comments provide further
88

1 understanding of the committee’s views and

2 rationale for the committee’s recommendation

3 concerning the need for funding of laboratory

4 research at CBER, 16 of those comments are

5 appended here under three topics.

6 The first, research is a central part

7 of CBER’S regulatory role; two, the mission

8 relevance of research at CBER; and three,

9 research efforts at CBER and federal funding of

10 science.

11 So Mr. Chairman, I provide the entire

12 report to the Science Board. We enjoyed our

13 opportunity to review CBER. I think we have

14 made some tough recommendations , but I think

15 our report is in agreement with our previous

16 position of Dr. Kern’s committee in terms of

17 the need for vigorous science, and particularly

18 within CBER of laboratory science within the

19 FDA. Thank you.

20 DR. KIPNIS: There are two other

21 members of CBER here, Dr. Kathryn Zoon is

22 Director, and Dr. Neil Goldman, Associate

23 Director for CBER, who might wish to also make
89

1 some comments .

2 DR . ZOON : Thank you. One, I would

3 personally like to say thank you to this

4 committee and especially to Dr. Les Benet for

5 the tremendous effort that was involved in this

6 review. I’d also like to thank all the

7 committee members; in particular Dr. Tom

8 Waldman who cochaired with Les during the site

9 visit.

10 This is a very, very important review

11 for our Center. It has been enormously

12 important, not only for us in terms of helping

13 us to focus priorities at CBER at a time when

14 resources are becoming very limited, but it

15 also is very important because as this report

16 suggests, the importance of the work at the

17 Center for Biologics is incredibly important in

18 the public health realm.

19 This committee spent four what I

20 consider grueling days hearing many, many

21 presentations by a large number of our

22 investigators across all programs of the
_-—..
23 Center; and they included our laboratory-based
90

1 programs and as Dr. Friedman alluded to, a

2 number of our non-laboratory research programs.

3 The comments that we received during

4 the course of those discussions were on target,

5 very thoughtful and insightful. We got a lot

6 of good feedback during the course of those

7 discussions that I think have been helpful

8 already.

9 I’d like to say that I’m not going to

10 respond to the report now because I think such

11 a report needs to have a very thoughtful and

12 appropriate response. We will do that at the

13 Center; senior management will take this, look

14 at each of the issues, prepare an action plan

15 and a report which we will provide back to this

16 committee and present to this committee at the

17 time you believe is appropriate.

18 I just want to say that from the

19 Center for Biologics, we believe that this will

20 help guide us in our resource planning; and

21 two, we believe it’s very much on target with

22 our strategic plan. And we are very grateful

23 to all of you for this opportunity. Thank you.
91
_-a

1 Neil?

2 DR . GOLDMAN: Yes, I’d also like to

3 echo Dr. Zoon . I could not thank the committee

4 enough . This was a grueling experience, if

5 only at the beginning when we sent you those

6 six huge books of information to read; and then

7 to go on to those four complete days.

8 I think I’d like to add to what Dr.

9 Zoon said that this in fact has been enormously

10 valuable process, review process for us. We

11 are having to look in a very demanding way at

12 how we use our current resources, and your

13 advice is going to be critical to that use.

14 That in fact was part of our strategic

15 plan, to have a committee that actually

16 overviewed, at an upper level, the actual

17 research that went on. So the total research

18 program. And then to utilize that for doing

19 prioritization, this is very helpful to us.

20 I’d like to think that this process in

21 fact should not end; that this is similar to a

22 process that is actually ongoing at NIH where
_@===_
23 they are, they have their institutes reviewed
92
__——-
1 every ten years, in a similar manner at an

2 upper level. I would hope that that’s the case

3 here , that we maintain this oversight.

4 It’s critical to us, as Dr. Blout and

5 others had mentioned, in terms of getting the

6 message out that we do research in that it’s

7 important to the FDA; and that the FDA

8 understands its importance. I think it is

9 critical that we have an oversight committee

10 that reaffirms this.

11 I’d also hope that part of that
——.
12 committee may go on to be a more maintenance-

13 type committee that would provide counseling to

14 the Center on a more frequent basis, maybe

15 every six months or so. And I think Dr.

16 Schwetz will be talking about that when he

17 refers to peer review.

18 I guess ultimately I think that this

19 was valuable to us, and I agree with Dr.

20 Friedman that you didn’t have an opportunity to

21 see the others; and I would think that that’s

22 something of a challenge that he’s made to this
__—_
23 committee, and in fact you should be looking at
93
-—_.
1 all the other centers in the same light, with

2 the same amount of criticality.

3 So I hope that his concerns are taken

4 seriously. So again, I would like to thank the

5 committee for an outstanding job.

6 DR . KIPNIS : Thank you.

7 Dr. Blout, do you have any comments?

8 DR. BLOUT : Yes. I want to add my

9 word of thanks. You did an outstanding job,

10 and we’re all grateful for it. But it’s only

11 the beginning. And after lunch we should at

12 least think about where we go from here.

13 I don’t want to see this report

14 buried; and how do we get the word out in a way

15 that’s most useful to CBER and the agency?

16 DR . KIPNIS: I, too, I think I speak

17 on behalf of all the board members, this is an

18 extraordinary report and you and your

19 colleagues I think are to be congratulated.

20 What impressed me as I read through

21 the whole report, which is substantial, was the

22 willingness to make very candid comments but

23 not get lost in some of the details of
94

1 positivity and negativity in terms of the

2 overall conceptualization of science and CBER

3 and where it should be going and what resources

4 are needed, what organizational recommendations

5 should be given serious consideration. I

6 thought it was really extraordinary.

7 Also, the next issue relates very well

8 with what just has been done; namely, peer

9 review in the system so it allows a certain

10 continuation of the generalities of the report

11 to be considered; and I think also a break
_——_
12 would give other members an opportunity to

13 formulate some concrete questions that can be

14 raised before we bring recommendations to the

15 Board for acceptance.

16 Dr. Cuatrecasas.

17 DR. CUATRECASAS : I’ll make a few

18 comments that will throw a little bit of cold

19 water on some of the euphoria. The global

20 issues that Dr. Friedman spoke about

21 previously, and independently it really did

22 disturb me because I think overall it’s

23 possible this report could be counterproductive
95

1 to the overall process of what we’re trying to

2 achieve.

3 The specific charges given to the

4 committee are very clearly stated in Kathy’s

5 letter from December 22, and they don’t have to

6 do with justification or rationalization of the

7 research, or how critical the research or the

8 activities of the division are to public

9 health, to international health, or all of the

10 wonderful things we heard about.

11 They had to do with devaluation of the

12 current research programs; and specifically,

13 more specifically, they are all very clearly

14 spelled out. But the evaluation of the

15 research programs for their scientific quality,

16 mission relevance, and scientific management

17 and leadership. That’s it in a nutshell.

18 Now, that was done, and I think that

19 was done admirably well and is very valuable.

20 Those parts of the report I found extremely

21 useful and I would think that the agency would

22 find very -- the center would find very useful.

23 The problem I have is that the major
96
g--%,
1 thrust of the report is in the beginning, and

2 the parts that are highly editorialized in a

3 global sense; and I think these are in contrast

4 or in contradiction to David Kern’s committee,

5 to their recommendations.

6 The committee struggled for a year,

7 year and a half, with science at the FDA. Not

8 CBER but laboratory science was debated and

9 discussed. I was a member of that committee.

10 We struggled and we came to the very strong

11 conclusion that we had to strengthen the

12 scientific base across the board; the

13 technology, the science, and the laboratory

14 across the board.

15 Now this report seems to me to try to

16 distinguish CBER from the others. Certainly

17 there are differences -- I will not debate

18 that; there are differences. But in singling

19 out those differences and seeing how unique

20 they are, the implication is that the others

21 are not so important. And there are some

22 specific areas where there’s almost an

23 admission that the other centers do not need
97

1 laboratory science, and they don’t need the

2 same kind of scientific quality as CBER.

3 I think this has been based, not on an

4 incorrect assessment of what CBER is doing, but

5 in ignorance of what the other Centers are

6 doing.

7 There are a series of justifications

8 which I think are contrived. The notion that

9 this is the major area of health prevention

10 because of vaccines, that’s okay if you’re

11 thinking 50 years ago. But now, can we say

12 that the activities of CBER are more important

13 in prevention than food and nutrition, than

14 avoidance of carcinogens? Can we say it’s more

15 important than prevention of diabetes, early

16 detection, or tied to diabetes or Alzheimer’s

17 disease, prevention of cardiovascular disease?

18 We’re in an era where the tools that

19 CBER is using and the tools of biology, the

20 tools of genetics, are not being applied in a

21 preventive measure, in a preventive way across

22 the board. And also not only in human areas.

23 This is just one example; we can go
98

1 on . The other uniqueness that is claimed is a

2 molecular one. Now, I can’t accept that

3 laboratory science should be greater than CBER

4 simply because the molecules are big and the

5 other ones are small. I mean, it has to be

6 based on the biology, the medicine, and

7 something more fundamental.

8 The big molecules, the polymers, the

9 DNAs , the proteins, the -- within small

10 molecules, there are very many -- there are

11 molecules that may be genotoxic, molecules that

12 are small, that have uniqueness just as much,

13 because they can integrate into DNA or into

14 genetic material. It may have long term

15 consequences. Is that less important? Just

16 small molecules are steroidal molecules;

17 they’re also equally difficult. They are

18 molecules that are made by fermentation. They

19 are small molecules, they’re also very

20 difficult to produce, if we talk about

21 production.

22 Certainly you can’t deny that there
.~=
23 are unique aspects to producing and
99
___

1 characterizing proteins, but they’re equally

2 unique features about other kinds of molecules;

3 so please let’s not say that those things

4 justify vis-a-vis other centers and other

5 activities.

6 So I’m a little concerned that if we

7 do this for all the other centers, we’re going

8 to come up with a bunch of reports, each one

9 beating their drums, and we’re not going to get

10 anywhere .

11 I think as Michael said so eloquently,

12 We have to address the fundamental issues of

13 how do we elevate the quality of science for

14 the FDA. David Kern’s committee emphatically

15 said that to do that, we need active scientists

16 in the FDA, and we need them everywhere. Some

17 places will be more than others, of course; and

18 each center, each division, will have its own

19 character, its own differences, and I think

20 what we need to do is to respond to that.

21 But those are the aspects that concern

22 me . I present them dramatically --

23 DR . KIPNIS: No, no, Dr. Cuatrecasas;
100
.—-—=—=.
1 I think that the comments you made are very

2 valid. It is the inevitable problem when you

3 have one unit to review that the certain

4 element of focus evolves on that element when

5 other elements also have to be reviewed.

6 And I think what Dr. Blout has pointed

7 out is the critical need for the chief

8 scientist; because until you have an

9 organizational structure where there is a chief

10 scientist who then in essence, he or she,

11 imposes a demand on every element in there to
-_
12 contribute as a part of the whole instead of

13 conceiving themselves as the whole initially, I

14 think that that’s going to be a major role that

15 that chief scientist has to play, as an

16 advocate of the entire unit rather than

17 advocacy on an individual base.

18 On the other hand, it’s certainly

19 natural to anticipate that every director of

20 every Center is going to have a certain agenda

21 to impose the needs of that Center. So I think

22 that will be the evolution that would occur.
.—.
23 DR . CUATRECASAS : Absolutely.
101
- ———..-
1 DR . KIPNIS: But I do think that the

2 issues do have generic qualities; and I think

3 that it will be important for this committee to

4 acknowledge that this is a focal report that

5 raises the issues that have to be addressed on

6 a much more broader base. But there are

7 legitimate requirements for CBER itself that

8 have to be addressed at the same time.

9 I think it best if we break so we all

10 have time to think about some of the comments

11 we make, because they do lead into the peer
_——.—=_
12 review process, which has to be total

13 institution.

14 DR . BLOUT : What time do you want us

15 back?

16 DR . KIPNIS: Due back here at 12:30.

17 Try and make it even earlier if you can.

18 [Luncheon recess; 11:44 a.m.]

19

.-
102

1 A F T E RNO O N S ES S I ON

2 [12:45 p.m.]

3 DR . KIPNIS: I would like to call the

4 afternoon session to order to order, for the

5 Science Board. There were two things that the

6 Chair neglected to do that has been brought to

7 my attention.

8 One was to ask the committee whether

9 they accept the Toxicology subcommittee report

10 to proceed with the plan as presented.

11 Is there any discussion?
_— ——_
12 We need a motion.

13 [Motion.]

14 DR. KIPNIS: Is there a second?

15 [Second. ]

16 DR . KIPNIS: All in favor?

17 [Voice vote.] [Passed. ]

18 The next was, should the Science

19 Committee accept the recommendations of the

20 Biomaterials Forum not to proceed further

21 because of the discussion that ensued, with the

22 explanations being offered.

23 Is there such a motion?
103
.&==.
1 [Moved and seconded.]

2 DR . KIPNIS: All in favor?

3 [Voice vote.] [Apparently unanimous.]

4 DR . KIPNIS: I would like to add one

5 addendum, if it’s agreeable; and that is that

6 we ask the individuals involved, particularly

7 at the FDA, to give us a follow-up sometime

8 next year or the end of this year as to what is

9 happening in this arena so we keep informed.

10 Then we will continue with the CBER

11 review. Are any additional comments that the
. -
12 committee wishes to make vis-a-vis the CBER

13 review?

14 DR . CUATRECASAS : I just want to

15 perhaps clarify my comments, because it’s

16 possible again in the end that I was trying to

17 be fairly emphatic. And I didn’t want to

18 project as totally negative.

19 It’s a very valuable report, and I

20 think a few minor editorial changes, a few

21 minor editorial changes in the beginning,

22 particularly those that would imply that there
.~.
23 are other divisions, other centers of the FDA
104
.-7
1 that do not need perhaps similar kinds of

2 things .

3 So the uniqueness within this is such

4 that it needs research above any of the others,

5 I think to remove that kind of information.

6 Otherwise, I think the report is a model, and

7 the substance of it could be used, I think as a

8 model to show the integration of good science

9 with good regulation.

10 DR . KIPNIS: That’s the way I think

11 many of us -- 1 took your comments in that
.—~.-
12 context, that this is the format that can be

13 used for a more systematic review, and that it

14 could be very useful for the future chief

15 scientist to have this kind of database

16 available to whoever sits in that position to

17 adjudicate the kinds of natural competition for

18 resources that any institution would have.

19 I would like to make the suggestion

20 that now that the final report has been given

21 to us today -- by the way, your old reports, if

22 you brought them with you, can be left behind

23 in the box which will be shredded; but take the
105

1 reports with you. And I would like to have

2 each of the members of the committee then

3 submit to either Dr. Blout or myself whatever

4 additional editorial comments or modifications

5 you felt appropriate that we could then

6 incorporate and then check with all of you to

7 see if that’s acceptable before final action is

8 taken on the report.

9 DR . BLOUT : I wouldn’t think we’d have

10 to send you the whole report; we’d just send

11 you any modified pages, if that’s satisfactory.

12 And as I’ve said to Les, I’d like to see a

little more emphasis on what CBER has done

14 right out front so that we can use this in a

15 way that’s appropriate for the agency to use

16 it.

17 And I’m counting on Dr. Zoon and Dr.

18 Neil Goldman to give us that kind of material.

19 DR . KIPNIS: Is that agreeable with

20 the Science Board?

21 DR . BLOUT : It’s up to the Chairman.

22 Les, is that okay with you?

23 DR . BENET: Yes, that’s fine.
106

1 DR . KIPNIS: Then we’ll go ahead with

2 the program; Dr. Bern Schwetz is going to

3 present --

4 DR . BENET : I’m sorry; I would like to

5 make some comments in response to Pedro’s

6 comments --

7 DR. KIPNIS: Of course.

8 DR . BENET: -- and to everyone else,

9 and justify why certain things are in the

10 report and what’s the feeling, concerns of the

11 committee.

12 I think most of you are aware that I’m

13 not an expert in CBER. There were 25 experts

14 in CBER on this committee, and the report

15 reflects the strong feeling of the individuals

16 in the areas of biologics.

17 The report includes the wording that

18 includes, because this is the wording that the

19 committee wanted to have there. But I think it

20 is important to respond to Dr. Cuatrecasas’

21 comments and to at least give you the reasons

22 why some of these points were there that you

23 find objectionable at the present time, or of
107

1 concern at the present time.

2 There was a recognition within the

3 committee, and certainly from the industry

4 members on the committee, that maybe the

5 biologics community had not paid close enough

6 attention to what was happening in the PDUFA

7 reauthorization . Because one of the real

8 impetuses for Dr. Zoon asking for this report

9 is the necessity for cutting in essence her

10 science budget in half and her scientists

11 within CBER in half as a reflection of the

12 PDUFA reauthorization.

13 Committee members strongly felt that

14 there was a difference between biologics and

15 other issues that come before regulatory

16 agencies. And they wanted that information in

17 there. So they felt it was most appropriate

18 and necessary to contrast biologics with drugs,

19 for a very important reason; and that’s why

20 that information is there.

21 The PDUFA original five years and the

22 reauthorization recognizes the accomplishments

23 of the agency, particularly the Center for
108

1 Drugs, in rapidly approving and lowering the

2 waiting time and meeting the guidelines and

3 goals that were set for the agency in terms of

4 their review process with the idea that this

5 money would be utilized to increase the number

6 of reviewers within the agency and not be used

7 for other purposes.

8 So there is a record of great

9 accomplishment; and in my mind, that

10 accomplishment is primarily in the area of

11 drugs .

12 When the Science Board heard the

13 recommendation from the subcommittee that Dr.

14 Cuatrecasas was a member of, in terms of the

15 importance of science within the agency;

16 everyone believes that and thinks it is

17 correct, but there was basically no

18 justification in that report for why we needed

19 science in the agency.

20 And the members of this committee felt

21 strongly that they needed to say why we needed

22 science in CBER and laboratory science.

23 Because it was apparent that drugs succeeded
109

1 through the PDUFA in essence in a virtual

2 science environment . There is not large

3 amounts of funding for laboratory research, and

4 a virtual science environment concentrating on

5 biostatistics, on epidemiology, on clinical

6 aspects, seemed to have done very well.

7 Their concern is that a virtual

8 science environment in biologics will not work,

9 and that is why this report was written in this

10 way; and perhaps I did not do a good enough job

11 in pointing that out. They feel that the

12 science in biologics is moving so rapidly and

13 that the technology that is changing in terms

14 of the information that scientists within CBER

15 must have to do a good review is that if you

16 are not doing this science, virtual science

17 will not suffice.

18 And that is their position. They

19 pointed out that since virtual science has

20 succeeded in drugs, that although I can

21 understand the concerns of this Board, and this

22 Board is going to make its own recommendation ,

23 the members of the committee felt strongly that
110
_—_

1 they needed to differentiate what was the

2 issues in biologics versus the issues in drugs;

3 and that’s why that information is so hard-

4 hittingly put within the report.

5 So it is the committee’s belief that

6 this is something that has the potential to be

7 a crisis. And they do not want to have to face

8 reviewers within CBER who are not at the

9 cutting edge of the science. And their strong

10 feeling, not necessarily doing the same

11 science, but doing laboratory based science

12 that is concentrated on the measurement aspects

13 of what is being evaluated here is where the

14 emphasis was in this report.

15 So I can understand Dr. Cuatrecasas’

16 concern; I can understand the concerns of the

17 Science Board, but I wanted to reflect to you

18 that these were not issues that were not

19 considered. And it was strongly felt by this

20 committee that it necessitated a

21 differentiation between the types of science

22 that is done at least in drugs and in biologics
_———_
23 and by expansion from that, probably in other
111
.—=_
1 agencies, also.

2 I personally do not feel, my own

3 personal comment, that it’s going to be

4 possible for us to have an effective

5 recommendation if we suggest that science is

6 the same everyplace throughout the agency; I do

7 not believe that. And the group of people

8 that Dr. Friedman talked about in terms of

9 making these recommendations , that everybody

10 needs laboratory science; I agree everybody

11 needs laboratory science. But I think that
.——-..
12 there are big differences in the kinds of

13 science that you need and the expertise you

14 need in the different divisions, and that’s

15 reflected in this report.

16 DR . KIPNIS: Any comments, Pedro?

17 DR . CUATRECASAS : Well, my view is

18 that the activities and the value of CBER stand

19 on its own merits. Independent of what was

20 happening everywhere else within the agency.

21 Within CBER there are differences among the

22 divisions, and they do not all require the same
—————__
23 kinds of laboratory expertise that you’re
112

1 describing.

2 The kind of assessment and scrutiny

3 which has just occurred for CBER has not been

4 done with the other centers. So how can we

5 judge? We touched other areas which have

6 equally rapidly moving scientific

7 breakthroughs . A large number of the things

8 that are happening at CBER are going to quickly

9 be applicable to neuroscience, they’re going

10 to be applicable to bacterial diseases, they’re

11 going to be applicable to all kinds of things,
—-—_
12 and your divisions are going to be blurred.

13 so there’s no need, I think, to exalt

14 the scientific need of CBER as something unique

15 insofar as it reflects on other centers of the

16 FDA. So that would be my only point, is that

17 the uniqueness that you describe, yes; but

18 every other center is also unique.

19 DR. KIPNIS: I’ll just make one last

20 comment , if I may, and that is that the

21 organization of the FDA into centers implies

22 heterogeneity of needs. Otherwise, why have

23 different centers?
113

1 I was discussing with Dr. Blout, what

2 happens when potatoes are used as a source of

3 vaccines? It’s going to be the Department of

4 A g r i c u l t u r e and the FDA are going to be

5 involved in that. What happens when proteins

6 are isolated from tobacco leaves that are going

7 to be routinely used as drugs? Is that going

8 to be Agriculture or is that going to be the

9 FDA, and who in the FDA?

10 So that the issue of science per se is

11 critically important, and we all recognize that

12 science is not homogeneous and that -- well, it

13 is in a generic sense, but what does it mean to

14 you , scientific method? But the details of

15 science will reflect what is for that time the

16 major domain of one of the activities within.

17 But we also recognize, even in the report that

18 I think was well written by Dr. Benet, even

19 there the capacity of one division to talk to

20 another division and interact is critically

21 important because they’re sometimes

22 replications, some of which are good and others

23 of which would be less good than could be
114

1 existing elsewhere.

2 So I would think that the comments

3 made on the report will be more in the -- not

4 in the substance, but in the effort to get

5 across that here is something that should be

6 employed throughout the system in terms of peer

7 review, so that eventually a coalesced

8 presentation for the needs of science can be

9 made to the agencies that we’re going to be

10 dependent upon to support this, which is

11 primarily, it seems to me, Congress . But

12 Congress’ receptivity will certainly be

13 exacerbated and sensitized if the public also

14 accepts this, as does industry.

15 So I would think that the editorial

16 modifications would be more focused on -- this

17 is used as an example of what can be done

18 rather than as an endpoint in itself.

19 Does that reflect -- that’s I think a

20 critical point that should be made. If that’s

21 agreeable, we will now go on to the next

22 session in which Dr. Schwetz will present

23 Science at the FDA. Unfortunately I will be
115

1 leaving in about 25 minutes, and Dr. Elkan

2 Blout has with graciousness accepted the

3 responsibility of carrying on in my absence.

4 Peer Review Process

5 DR . SCHWETZ: Thank you, Dr. Kipnis.

6 Before I proceed on to the discussion of

7 science at the FDA, may I come back to one

8 other point of the peer review process, and ask

9 for some additional input?

10 The assumption is that we are going to

11 proceed through other centers with the peer

12 review process similar to what has been done

13 within CBER. But what I would ask of you is

14 whether or not you could provide us either from

15 within the committee itself or from the Center

16 or from the other Science Board members for any

17 additional input in how it should be done

18 differently in the other centers in the future.

19 There are a lot of dimensions of this

20 that we ought to examine one by one; the amount

21 of information you received, the number of days

22 it took, the level of detail into which the

23 reviewers went to get this picture of the
116
K-.

1 Center. How could we get a broader comparative

2 view of what’s going on within multiple

3 divisions within a Center as opposed to a

4 glimpse of 12 divisions fairly independent of

5 each other.

6 There are a number of things that I

7 think we need to consider as we design the

8 review process for the next one.

9 DR . KIPNIS: Bern, I would also make

10 the comment that I think the committee will

11 have the chance to review the issue of peer.

12 But I notice in the proposed peer review FDA

13 structure, several of us don’t believe that the

14 p o s i t i o n of the chief scientist is

15 appropriately recorded in the hierarchical

16 structure of what has been designed here.

17 Many of us thought that the chief

18 scientist should have direct access to the FDA

19 commissioner, and that the Deputy Commissioner

20 for Operations implements what the FDA

21 commissioner and chief scientist, and whatever

22 executive group that is decides should be
.-— -.
23 implemented; but not that the chief scientist
117
———..
1 is sort of a homunculus to decide between the

2 deputy commissioner.

3 I rely on others in this group to also

4 make their comments; and you can put them into

5 writing if you like, u s i n g capital letters.

6 DR . SCHWETZ: The chart that Dr.

7 Kipnis is referring to is one that’s in your

8 tab -- under the heading of Peer Review

9 Process. It’s the chart that looks like this.

10 DR . CUATRECASAS : It’s also, the

11 description of chief scientist, the
.-
12 announcement of this. And David, this also

strikes me, I don’t believe it was the

14 recommendation of the Kern committee; I think

15 the recommendation was --

16 DR . BLOUT : He would sit beside.

17 DR . CUATRECASAS : -- very strong that

18 the chief scientist should report directly to

19 the commissioner.

20 DR . KIPNIS: Thank you for pointing

21 that out. I agree with you wholeheartedly. So

22 we can voice our opinions to whatever is
.-.—..
23 ultimately decided.
_—_
118

1 But I agree; I think that as presently

2 constituted, that’s not what the Science

3 Committee had for the position of the chief

4 scientist.

5 DR . BLOUT : And that change could only

6 make the position more attractive.

7 DR . SCHWETZ: As we discussed this

8 internally, there are two things that I think

9 need to be accomplished, if you stand aside

10 from the question, for the minute of where that

11 line is.
_——._
12 First of all, the chief scientist must

13 sit with the deputy commissioners and the

14 commissioner in deciding the overall policies

15 within the agency. But the other part that has

16 to work is that the chief scientist also sits

17 with the center directors. Otherwise, the

18 operating space between the chief scientist and

19 the center directors will be such that there

20 won’t be any bridging.

21 so this was put together as a hybrid

22 to permit the chief scientist to work directly

23 with the commissioner on the FDA executive
119

1 committee, but to be sure that the chief

2 scientist met with the center directors on a

3 weekly basis on the business of the agency and

4 operations.

5 So your additional input would be very

6 welcome on this, but those are the two things

7 that we were trying to accomplish.

8 DR . LANGER : I guess the question is,

9 who does the chief scientist report to?

10 DR . SCHWETZ: For this chart, it’s a

11 direct line report to the deputy commissioner
_._=

12 for operations. And that’s what your question

13 is.

14 DR . LANGER : Yes. Because I don’t

15 think anybody would question the other issues

16 that you just raised. I think the question is,

17 what I just asked.

18 DR . SCHWETZ: Yes. We’d welcome your

19 further input.

20 DR. BLOUT : Who do the center

21 directors report to? Do they report to the

22 ~U pt2LlltiL L-11= G1lJ-e’L”DGlcI1 Lzsi–--cwerlsrls u.. Lb L -1. ~

23 with the commissioner on the FDA executive
120

1 DR . SCHWETZ: No. The center

2 directors and the director of the Office of

3 Regulatory Affairs report directly to the

4 deputy commissioner for operations.

5 DR . LANGER : Right . My question was,

6 who does the chief scientist report to?

7 DR . SCHWETZ: In this chart?

8 DR. LANGER : Right .

9 DR . SCHWETZ: And in the

10 advertisement, to the deputy commissioner for

11 operations.

12 DR . BENET : If I could just -- not on

13 this issue, but to come back to some of the

14 questions that Bern raised.

15 One of the real advantages of the

16 committee that I had was the dedication of

17 these outstanding scientists. And about 40

18 percent and maybe more -- Dr. Goldman and Dr.

19 Zoon can correct me -- were individual

20 scientists who had already participated in peer

21 review process at CBER.

22 so we were not a group of people that

23 were looking at science for the first time. We
121

1 had people with great experience who had come

2 two or three times. I think that is an

3 important part of this peer review process that

4 a good fraction of the committee be very

5 familiar with the science and be people who are

6 r e g u l a r reviewers.

7 Dr. Zoon or Dr. Goldman, am I correct

8 on my percentages about that stuff?

9 DR . ZOON : That’s right.

10 DR . BENET: So I think that’s

11 something that needs to be built into it, and

12 that is why in four days, which was a huge

13 task, but we were not operating with no

14 background about the scientists and about the

15 individual scientists.

16 In addition, one of the six volumes

17 that we received had all of those peer review

18 reports in it from the previous reviews of each

19 of the divisions. So we had the opportunity to

20 see previously what had been recommended within

21 the divisions.

22 So Dr. Schwetz, I think that’s a real

23 important component of how you do this; not
122
.&-%.
1 only expertise within the group but expertise,

2 continuing expertise to make such a report

3 possible.

4 DR . KIPNIS: I think those are very

5 good points you make.

6 Any other comments?

7 DR . CUATRECASAS : David, I think the

8 only -- again, when I think about the role of

9 the chief scientist and some of the things that

10 that person would do, what comes to mind is the

11 report we heard, the CBER report, was critical.

12 And I think you said earlier, before we broke

for lunch, what’s going to happen to this; we

14 don’t want this to sit on the shelf, we don’t

15 want to keep this —— missing forever. You

16 know, what would happen to it?

17 It could be used very effectively by a

person very high within the FDA; ideally, the

19 commissioner. Or possibly the chief scientific

20 officer could do that as well. But if the

21 chief scientific officer is working with the

22 commissioner hand-in-hand, then I think the

23 commissioner might be more effective, say if he
123
——–

1 were to place this before a congressional

2 subcommittee .

3 This is, also beginning to think about

4 how do you carry this report forward and try to

5 generalize it and try to catalyze more interest

6 in a broader sense. One wonders whether --

7 taking this a step further, even whether a new

8 commissioner should be exposed to this

9 beforehand, one at a time, and seek his or her

10 views on this report so that the concepts at

11 least are from the beginning understood and

12 also felt to be important in projecting them in

13 original hearings, and back in the beginning so

14 it doesn’t just take the secondary, tertiary

15 role.

16 DR . BLOUT : There’s one other issue

17 that hasn’t been verbalized today, but is on

18 the minds of some people. What is the

relationship of the agency to the department?

20 And to HHS and to the Department of

21 Agriculture? And are they consonant with the

22 view of the future of FDA?

23 DR . KIPNIS: I don’t know, Dr. Blout,
124
——-—=___
1 if those discussions have gone on.

2 DR . BLOUT : Well, they’re below the

3 surface most of the time, but they’re there.

4 DR . SCHWETZ: Elkan, all I would add

5 is that I think this series of reports, this

6 one and the ones that will follow, will provide

7 extremely important leverage for the

8 commissioner representing the FDA within the

9 discussions at the DHHS level to try to get

10 additional support through the Department level

11 for the FDA.

12 This is leverage that has to be

13 developed and used.

14 DR . KIPNIS: Okay.

15 Science at the FDA

16 DR . SCHWETZ: Under the heading of the

17 science at the FDA, there are several comments

18 that I would like to make specifically to the

19 issues that are laid out here; and then I’ve

20 got one transparency that I would work from

21 that relates to something that you have within

22 your packets.
.— -
23 The comments that were made in the
125
.-———..
1 review of CBER are interesting in the context

2 of the earlier discussions we’ve had about

3 developing virtual science capabilities within

4 the agency, because the sense up to this time

5 was that in order to change one of the

6 dimensions of the culture of science within the

7 FDA is that we have to reduce the barrier

8 between centers and have FDA scientists working

9 more closely together in the virtual sense;

10 that the scientists of the agency represent

11 capabilities of the agency to address

12 scientific questions.

13 And it’s interesting, Les, to hear the

14 strength with which your group reported that

15 the that may not be, if I understand correctly,

16 the way they would recommend that the science

17 of CBER be handled.

18 So I think we need to think further

19 what a virtual science center within the FDA

20 means. One of the things that I’ve been doing

21 in the past year is meeting with what I’ve

22 referred to as discipline groups; but they’re

23 g r o u p s of experts within a specific field.
.
126
.-—==
1 The statisticians, the people who are

2 working in immunology, the people who are the

3 neuroscience individuals and so on, through the

4 chemists, the mass spectrometrists. Groups of

5 this kind who represent areas of expertise that

6 go across the whole agency; one by one I’m

7 meeting with them to have them think as a team

8 independent of center barriers, center lines,

9 and to begin to think of themselves as an FDA

10 resource; so that at times when we need help

11 across center lines, we have people who are
—_
12 familiar with each other and know what the

13 capabilities are elsewhere throughout the

14 agency.

15 So to the extent that that gives us

16 more of a virtual capability to meet needs that

17 go across the agency, we are working on that;

18 and we need to think of that in the context of

19 this CBER report.

20 One of the efforts to make people

21 better known within the agency to each other

22 was the development of this expertise database,
_- —._
23 which we’ve summarized for you in the past .
127

1 We’re now someplace, something in the range of

2 25, 30 percent of the people whom we’d like to

3 have in this database are already in there.

4 That’s low and it’s not high enough to make

5 this an effective tool, but we have some

6 centers that are essentially 100 percent into

7 the database and others who are just starting.

8 So I have no thought whatsoever that

9 we’re going to peak out at 30 or 40 percent.

10 We have to get that up to 80 percent or more so

11 that this becomes an effective tool. All the
-
12 centers in ORA are committed to put their

13 people in here, who need to be in the expertise

14 database; so we’re continuing to populate that,

15 and I would hope that we would make

16 considerable progress toward that 80 percent

17 level by the end of the year.

18 In the area of research tracking, we

19 have now within the Office of Science collected

20 the definitions of all of the research projects

21 that are ongoing throughout the agency, and

22 that’s something between 700 and 800 individual
——
23 research projects for which there is a protocol
128

1 and a PI and a title of a study and so on.

2 This for the first time has permitted

3 us to analyze this database of some 700-plus

4 projects to identify what kinds of research the

5 agency is doing when you put all of the

6 projects from across the whole agency together

7 in one database and find out what percent of

8 this has to do with methods development, what

9 percent of it has to do with agent-driven

10 research, what has to do with clinical studies

11 versus nonclinical.

12 So we’re finally at a stage where by

13 default we can define what the FDA research

14 agenda must have been, assuming that that

15 relates to what we’re doing. Now with this

16 database in mind, I am scheduled in the near

17 future to bring an evaluation of this

18 collection of projects back to the center

19 directors and the deputy commissioners to

20 define for them what our research program looks

21 like and to be a little more proactive in

22 deciding that I would not have expected that 50
_——.
23 percent of our research projects have to do
129
—-
1 with methods development.

2 Do we want it to be 50 percent or

3 should it be more or less than that? So I see

4 it as an important step toward moving us

5 forward in developing an FDA research plan

6 instead of a collection of center research

7 plans that don’t reflect a lot of integration

8 with each other or a lot of conversation; not

9 as much as we need.

10 So I think we’re making progress on

11 this. All of the new projects that are

12 submitted for the next fiscal year, and that

13 will be developed over the summer, all of those

14 will be submitted in a format that we can build

15 a database that’s searchable and we can very

16 accurately describe what the research program

17 for the agency will be in 1999 based on these

18 submissions that come in at the end of this

19 year that represent next year’s research.

20 We’d be happy to share that kind of

21 analysis and information with the Science Board

22 at any time you would like it, either for

23 information or for discussion.
130
~———-.
1 DR. BLOUT : I think it would be

2 valuable, Bern, to share that because the

3 magnitude and the types of projects are not

4 known to the Science Board.

5 DR . SCHWETZ: Well, I would submit

6 they’re not widely known within the FDA.

7 (Laughter)

8 DR . BLOUT : And I’d agree.

9 DR. SCHWETZ: For example, for the

10 first time we will be able to see which

11 individuals are proposing work on Cyclospora,
.~.
12 and who are they and where are they coming

13 from, what’s the title, what’s the level of

14 commitment to this project? To this time, we

15 couldn’t have guaranteed that we knew which

16 projects were out there. You knew some of

17 them, but you didn’t know for sure if there was

an outlier someplace and somebody working on

19 it, and he wasn’t communicating with the rest

20 of them, you wouldn’ t have known it. Well, now

21 we will.

22 So we’d be happy to bring that, if

23 that’s desired by the Board.
131
-——–.
1 The other piece that I wanted to bring

2 forward is a proposal that has to do with

3 meeting some of the objectives that you’ve been

4 talking about here today. And one of those

5 pieces is to bring public input into the

6 evaluation and the review and the

7 identification of FDA priorities. So bringing

8 the public input into this priority setting

9 process.

10 The second objective, to receive input

11 more formally from a full range of FDA

12 scientists; and that would include laboratory

13 researchers, non-laboratory researchers and

14 reviewers; and the priorities for the research

15 and the scientific issue is related

16 specifically to the review responsibilities of

17 the agency. So a second one is input from FDA

18 scientists.

19 A third expectation for this proposal

20 had to do with leveraging. At a time when we

21 can’t deal with all of the issues that surround

22 the needs of the review process of the agency,
-~.
23 how can we leverage information, how can we
132

1 leverage resources to a better extent to reach

2 out to non-FDA scientists and resources to help

3 expand the size of our research program to a

4 larger extent.

5 A fourth objective of this proposal

6 is, how do we identify FDA research and science

7 priorities going beyond the individual center

8 priorities. How do we collectively identify

9 and define what the FDA research priorities are

10 rather than in a prospective or retrospective

11 manner as we’ve done it now?

12 Another objective then is, if we can

13 identify what those FDA priorities are, then

14 how can we reallocate resources to meet those

15 FDA-wide needs, and then this proposal also

16 shows you how the Office of Science fits in the

17 middle of all these objectives to accomplish

18 this. 1’11 work from a transparency.

19 [Overhead]

20 You have this table in your notebooks,

21 and I think it’s the last thing before -- .

22 If you can find this chart in your

23 notebook so that you can follow along and write
133

1 down whatever questions you have on it.

2 This chart focuses on generating

3 resources to be able to support the scientific

4 program of the agency, and then how these funds

5 might be used for support of this work. The

6 other important piece of this is the

7 identification of research and science

8 priorities that take into account the public,

9 the FDA scientists, research input from the

10 rest of the components of the agency, to help

11 develop that FDA research plan; and then the

12 role of the Office of Science kind of in the

13 middle of this, and then how this translates

14 into support of individual research projects.

15 Let me start up here on the upper left

16 talking about resource generators. This is one

17 place where I think the agency should have more

18 of an outreach program that formally brings in

19 input from industry and from academic centers

20 to review what there might be in terms of

21 resources to get the work done that’ the agency

22 needs to have done to be able to anticipate the

23 expertise needs that we’ll have in the future
134

1 to deal with the pipeline of new products

2 coming in in the future.

3 So when you talk to people on the

4 outside, there are all kinds of foundations,

5 there are research-supporting kinds of

6 organizations; there are sources of money that

7 the FDA has for a number of reasons not tapped

8 into, some of which are questions of legality,

9 of accepting money. But if we’re going to

10 reach out for opinions of what priorities are,

11 and how it is to fund them, this would be one

12 place where we could have some kind of a

13 resource leveraging committee within the agency

14 that would help bring to our attention what is

15 known more broadly beyond the agency of how

16 resources can be brought to bear to solve

17 research needs.

18 One of the things that we have started

19 in the last couple of years, more extensively

20 than we’ve had in the past, is memoranda of

21 understanding with other government agencies,

22 including Institutes of NIH. Liz, did you

23 mention the one that you have with the Dental
135

1 Institute earlier this morning? That’s being

2 increased widely, and we have a number of

3 interactions with other government agencies

4 where we agree to identify what the priorities

5 are, and to the extent that that results in

6 other means of support for FDA work, that’s

7 something that we need to recruit help from

8 other government agencies to meet our needs and

9 that’s one way to do it.

10 One of the things that’s been

11 discussed several times within the agency that

12 is being used with CDC and with NIH and with

13 other health research organizations is the

14 development of foundations, is what it’s been

15 referred to. Well, there’s a lot of baggage

16 that goes with foundations, and within the FDA

17 there has been a reluctance to develop a

18 foundation as a means of receiving resources

19 from the public to be used for purposes within

20 the agency.

21 so just to finesse the question of a

22 foundation or not, I’ve simply put the word
.—.
23 “alliance” that we would have some kind of a
136

mechanism whereby money could be received that

2 could for example be used for training of FDA

3 scientists regarding products of the future or

4 whatever it might be.

5 This might not be used directly to

6 support research, but it could be used for

7 other functions within the agency that would

8 permit our scientists to travel to the meetings

9 that they need to to get the information or to

10 afford other kinds of training; so this would

11 be a mechanism where you’d have a body of
-—–.
12 directors for this alliance that would receive

requests from the agency to support certain

14 kinds of activities; and the decision would be

15 made by them what things should be supported

16 and what shouldn’t.

17 DR. BLOUT : Bern, do you want

18 comment as you go along on these?

19 DR. SCHWETZ: Yes.

20 DR . NESTLE : Alliance with whom?

21 DR . SCHWETZ: Sorry; I didn’t hear

22 your question.
.-——.
23 DR. BLOUT : Alliance with whom.
137
——_
1 DR . NESTLE : I’m asking who you had in

2 mind as an alliance, and my question has to do

3 with maintaining the integrity of the

4 institution.

5 DR . SCHWETZ: The alliance itself

6 would be a Board of Directors who would be

7 responsible for this foundation or alliance,

8 whatever you want to call it; and that would be

9 the body that would officially receive resource

10 allocation.

11 DR . NESTLE : My question had to do
—-.
12 with, who are you expecting the resources to

13 come from.

14 DR . SCHWETZ: They would come from

15 philanthropic organizations, perhaps from

16 industry, perhaps -- from individual people who

17 wanted to supply money to some other research

18 function. There’s no limit there to where the

19 money could be received from.

20 DR . NESTLE : I would be very concerned

21 about the integrity of the agency in that

22 situation. Why would anybody give money to an
_—__
23 FDA alliance if they didn’t want to influence
_—--
138

1 what FDA was doing in some way?

2 DR . SCHWETZ: Well, that’s why it’s an

3 alliance and not money being given directly to

4 the FDA.

5 DR . NESTLE : I’m not sure laundering

6 solves the problem.

7 DR . SCHWETZ: That’s the problem with

8 foundations as they currently exist. And it’s

9 not clear that that laundering process is

10 effective in making this an easy transition.

11 Dr. Zoon?

12 DR . ZOON : I think there’s always a

13 sensitivity to the issue of, are you getting

14 something for something that perhaps might

15 influence a particular action, whatever.

16 I think what Bern is looking at is a

17 way to get resources that may have an

18 opportunity to support broad programmatic

19 areas; not an individual particular product.

20 It may be a specific scientific issue that

21 needs addressing that would cross-cut a variety

22 of programs .

23 In terms of other -- and those
.-—.—=.
139

1 resources could come from industrial groups,

2 they can come from private organizations, and

3 in fact we often have people actually asking

4 private individuals who’ve had some experience

5 that they just want to donate money to further

6 the action of the agency with no strings

7 attached.

8 And I think the sensitivity to make

9 sure that you protect from conflict of interest

10 is very important; but I think in the climate

11 of diminishing resources, we really need to

12 think appropriately on leveraging resources and

13 how to do that appropriately.

14 DR . SCHWETZ: There is another whole

15 philosophy that says that we shouldn’t go after

16 these small amounts of money in a tin cup. We

17 instead need to have appropriations to cover

18 what the agency needs to do, and that

19 appropriation needs to be large enough to

20 permit us to do the work that the agency should

21 be doing. As opposed to the signal that we’re

22 going to make up our budget deficit by virtue

23 of tin-cupping. So there are two sides to
.—.=
140

1 this.

2 DR. BLOUT: Dr. Sanders.

3 DR. SANDERS: But there are some

4 things that you might like to do which, even if

5 the government was of a mind to do so, they

6 just don’t have it in their brief to give you

7 money for a particular resource.

8 The parallels with the NIH, which has

9 created something called the National

10 Foundation for Biomedical Research to receive

11 funds in areas where the NIH funding itself
—-

12 cannot support particular programs, such as in

13 the clinical scholars program; such as perhaps

14 building a guest house for adults as they did

15 for the children; things that would be specific

16 to NIH programs but which the government won’t

17 pay for, Congress won’t appropriate money for.

18 To the extent that this alliance fits

19 into that particular model, I think it’s

20 appropriate; although I think Dr. Nestle’s

21 point is very important; that is, making sure

22 that there is a clear Chinese wall, if you
_—_
23 will, between the receipt of funds and the way
141

1 they’re used.

2 DR . NESTLE : With all due respect, I

3 would point out that this is a regulatory

4 agency, which puts it in a particularly

5 sensitive position. I don’t think you can be

6 too sensitive about this one.

7 DR. SCHWETZ: What you’re bringing up

8 is exactly the reason we don’t have a

9 foundation, up to this point. But what I’m

10 trying to point out with this collection is

11 that the agency has also not been very
——
12 aggressive in exploring other opportunities.

13 So we’ve brought this up for

14 discussion to be sure that there aren’t some

15 sources out there that would accomplish the

16 objective of reaching out to constituencies who

17 can help us not only identify good ideas of

18 where we should be going, but sources of

19 s u p p o r t as well.

20 And the support doesn’t have to be

21 just in money alone; it could be in information

22 or it could be in other forms of resources.

23 Dr. Sanders?
142
.— .
1 DR . SANDERS: I think Dr. Nestle’s

2 point is very well taken; that is that this is

3 a regulatory agency quite different from NIH as

4 such.

5 One way of handling this rather than

6 have FDA personnel man the alliance or whatever

7 is to have a group of volunteers who are in the

8 private sector handle it. So that they then

9 could -- they could have a separate foundation

10 outside of the internal workings of the FDA;

11 that would allow some independence and maintain

12 the security, if you will, of the FDA process

13 and administration. But you’ve got to be very

14 careful.

15 DR . SCHWETZ: Yes. To be sure, this

16 would not be in the Office of Science, or would

17 not be in one of the product centers. It would

18 have to be distant; and even then the extent to

19 which you could make it distant enough.

20 DR . SANDERS : But even the people who

21 worked there, which shouldn’t probably be paid

22 by the FDA.

23 DR . SCHWETZ: I agree. That’s for
143

1 sure.

2 DR . BLOUT : Bern, before we leave that

3 whole box, tell us a little of who you’d see on

4 the top line, the FDA resource leveraging

5 committee. How do you conceive that?

6 DR . SCHWETZ: Well, it could be that

7 this would be representatives from the major

8 trade associations whose products collectively

9 we regulate. So that would be one way to go,

10 out to trade associations. Another one would

11 be individual companies, if we chose to go that

12 way, and universities.

13 So I’ve not sorted that out further,

14 how we would reach out to the industry to be

15 sure that all of industry who wanted to

16 participate had an opportunity to do so; but

17 still to get some who represented major

18 portions of the industry. Some of you who know

19 the industry better than at least I do today

20 might well advise us on how we would reach out

21 to industry in a way that would provide us with

22 good input.

-.
23 DR . SANDERS: If I could just speak to
144

1 that, I think that’s even more delicate than

2 the foundation.

3 DR . NESTLE : Thank you.

4 DR . SCHWETZ: I would just be very

5 careful about that. I think that’s a potential

6 public relations nightmare. Maybe I state it

7 too strongly, but it’s just something that I

8 think you have to be extremely careful about.

9 Even the user fee question; you know,

10 we had to go through those. Since I’ve left

11 the industry, I assume that those are working

12 out reasonably well, but there were a lot of

13 questions raised about that and making sure

14 that the independence of the agency was being

15 protected at the time. I assume that that has

16 occurred.

17 But I think when you’re looking at

18 unencumbered funds that are being directly

19 solicited from those that are regulated, it

20 created some real problems for you.

21 DR . SCHWETZ: I would remind you again

22 that this is specific generation of resources,

23 not just money. And to the extent that this
145
.4-%
1 would develop better collaborations with

2 industry, to develop data jointly, and other

3 mechanisms for developing information not just

4 revenue to permit FDA scientists to cover the

5 laboratory work.

6 More traditional sources of funds for

7 the FDA to support this function are in the

8 lower left, up here; and that would be the

9 appropriations we get; interagency agreements,

10 and we have a fairly large number of agreements

11 with EPA and with institutes of NIH and with

12 other government agencies to support work;

13 cooperative research and development agreements

14 that we have, providing support for specific

15 research that’s funded by portions of the

16 industry, where it’s approved within the agency

17 that we can receive money for this particular

18 research project from industry, to be sure that

19 there’s not a conflict of interest here, but

20 within other product centers.

21 So we do have a fair number of these

22 CRADAS that are in operation.

23 The receipt of grants is one that
146

1 we’ve talked about with the Science Board

2 before, and I would remind you that within the

3 FDA, FDA scientists can not be the primary

4 investigator on a grant and receive money

5 through NIH-types of funding, for grants, but

6 we can be a coinvestigator and some other

7 institution can receive the grant money, and we

8 can work with that institution and receive

9 support for example in their institution.

10 But at this point in time we cannot

11 compete for grant money, but we can receive it

12 with another investigator.

13 DR. BLOUT : And what are you arguing,

14 that we should be able to receive grant money

15 directly, or the scientists should be able to

16 compete directly?

17 DR . SCHWETZ: The agreement that we’re

18 working under is an agreement within the Public

19 Health Service. So there isn’t a law someplace

20 that says that we cannot compete for this grant

21 money. This is an agreement within DHHS that

22 people from within the FDA will not compete for

23 this.
147

1 We’ve raised it for discussion in a

2 large number of audiences, and while there is

3 some agreement that FDA scientists for example

4 should be able to compete for NIH grant money,

5 it’s really a mixed response. And there’s

6 everything from “we don’t need more competition

7 for grant money” to the fact that you don’t

8 have to write grants and you should use the

9 appropriated money to support your research

10 work” to other arguments, that the scientists

11 within the agency feel that they can very

12 effectively compete with others who are

13 competing for grant money, and that they would

14 be willing to compete for it, and would be a

15 way of supplementing the resources, permit

16 research to be done.

17 DR . BLOUT : I’ve certainly heard the

18 argument that scientists within the agency can

19 compete for grant money, but they feel hobbled

20 by this Department rule.

21 Maybe somebody would like to speak to

22 that . From the audience.
-——_-
23 Dr. Zoon.
148

1 DR . ZOON : One of the areas that --

2 there’s a balance of different proposals on the

3 area of grants. And I think, I would say that

4 scientists would welcome grants, or the

5 opportunity at least to apply for grants.

6 The issue is, Bern, there are other

7 agencies or other organizations that FDA can

8 apply for for grants outside NIH and our

9 scientists do do them and they have been

10 successful.

11 There are some issues that I think are

12 of concern to the National Institutes of Health

13 with respect to giving grants within its own

14 sister agency; and in fact I think they would

15 prefer to work through the interagency

16 agreement mechanisms as an alternative. I

17 think the opportunities to look at this from a

broader, maybe department level might be

19 something they would want to reexamine.

20 DR . CUATRECASAS : Aren’t there grants

21 also from the IOM?

22 DR . BLOUT: Nothing significant.
————____
23 DR . BENET : Bern, I can understand
149
_-—-y

1 what the concern is in NIH and HHS, because for

2 example internal NIH laboratories cannot

3 compete for the external money, so there’s

4 something in the budget that says “this is what

5 we’re going to do for science internal, this is

6 what we’re going to do for the ROIS, this is

7 what we’re going to do for every area. “

8 What my committee was concerned about

9 is that there should be a line item for

10 research within the FDA, and that this should

11 be recognized as an important area, and that

12 it’s Congress that needs to recognize this; and

13 that’s what we pointed out.

14 It would be hard to imagine FDA

15 competing for an NIH grant when NIH people

16 can’t compete for an NIH grant. So I don’t see

17 how that’s going to work out unless it’s done

18 in some equitable manner throughout all of HHS.

19 DR . BLOUT : State your name and

20 affiliation, please.

21 MR . EAGAN : Bill Eagan from the Center

22 for Biologics. If I could just disagree with
..——..
23 my center director for the moment.
150

1 As Dr. Benet has pointed out, research

2 is intrinsic to the way we do business within

3 Biologics. It’s part and parcel of the

4 process, and it really should be funded as

5 such.

6 It should be funded as fully -- as,

7 you need this many people, this is the

8 salaries, this is what’s needed for business,

9 this is what ought to get funded.

10 I think many of these other mechanisms

11 which we’re exploring, we’re exploring I think

12 out of desperation, because the budget has been

13 cut so much. And there are conflicts in all of

14 these various mechanisms, including the C R A D A S;

15 they’re not without their problems, either.

16 That’s just my own view on this.

17 The NIH has a somewhat different

mission than we do; and unless we’re going to

19 refocus our mission to that of the NIH, there

20 are problems with getting funding there as

21 well. And I think you also have to wonder

22 about or consider the, Congress has given so
-——_-
23 much money to this agency for its mission, so
151
.- ...
1 much money to its agency for its mission, and

2 then have some kind of internal equalization

3 process, independent of what the Congress has

4 allocated.

5 I think these are large problems in

6 this area; and the simplest thing is to just

7 have Congress fund what’s necessary.

8 DR . BLOUT: Dr. Zoon again.

9 DR . ZOON : For the record, we don’t

10 disagree at all. My preference for any funding

11 for the FDA would be appropriated dollars. I
_—_
12 think we are in a time where we are trying to,

13 because of the cutbacks in the support for

14 research for FDA programs of trying to see how

15 we can survive; and I think that in the context

16 of this, we’re looking at alternative ways to

17 survive; and while these things are being

18 ironed out and really a clear discussion of how

19 this important work needs to be done can be

20 accomplished.

21 DR . SCHWETZ: Thanks, Kathy.

22 With that, let me move on to other

23 half of this, so that we have time to talk
——.
152

1 about this as well.

2 A very important part of where we

3 haven’t been in the past is to have a broader

4 input on identifying what the science research

5 needs and priorities are for the agency. So

6 this upper right-hand box is trying to pull

7 together where we are on that particular item.

8 In addition to input from the

9 commissioner and the Executive Committee of the

10 FDA about what the priorities and future

11 direction of the agency are, the input for

12 developing the research agenda and the

13 priorities should include the input from the

14 chief scientist and the center directors and

15 the associate commissioner for regulatory

16 affairs; the field organization of the agency.

17 So there would be inputs sought from

18 all of these, and there is now, but that could

19 be more formal. The rest of this is something

20 that is not quite as well developed. The

21 possibility that we would form a research

22 priorities committee, the Senior Science
.——_.
23 Council, is already in existence within the
_ —= 153

1 agency, and it represents many of the people

2 who were in the audience today that are the

3 senior scientists from the laboratory and the

4 review parts of the science of each one of the

5 agencies, who sit together in this Senior

6 Science Council on a monthly basis and discuss

7 what’s going on with the science and research

8 of the agency.

9 Then to more effectively bring in the

10 input from CAFDAS, the Committee for the

11 Advancement of FDA Science, the junior
—_

12 scientists of the agency, and bring the input

13 of the Senior Science Council and CAFDAS

14 together, and include a more formal mechanism

15 for bringing information in from the discipline

16 groups that I mentioned earlier.

17 If we ask all of the microbiologists,

18 what are the research priorities within the

19 area of microbiology within the whole agency,

20 and ask the statisticians and ask the

21 immunologists and all of the people who

22 represent cuts of a discipline of work

23 throughout the agency, we would like to receive
154
_ -_

1 input from these people who will see the

2 research needs of the agency a little bit

3 different than if you just asked them from

4 within one organization, within one particular

5 center.

6 To the extent that we would make that

7 a bit more formal so that people feel they have

8 input from throughout the agency into the

9 priority setting of the whole agency, I think

10 would be helpful.

11 To the extent that we had over here
-
12 that we would look to industry for advice on

13 how money and other resources could be pulled

14 together to support research, you would also

15 want to have some kind of a joint FDA-industry-

16 academic group who would advise on the research

17 priorities, independent of the funding process.

18 That we have a more extensive outreach to get

19 opinions from the groups whom we regulate and

20 the groups with whom we interact on a research

21 basis to get a more formal input into what the

22 future of research and the science issue should

23 be.
_ —_ 155

1 One of the things that has existed

2 within the agency on a spotty basis; at least

3 two centers have what they refer to as “science

4 colleges” for training people. In particular,

5 one of the things that we’ve been talking about

6 is the development of an FDA science college

7 that would be a voluntary organization of the

8 scientists of the agency who want to band

9 together to respond to FDA science issues. And

10 collectively they might define the training

11 mechanisms that could be used broadly

12 throughout the agency.

13 CDRH and CDER have -- Drugs and the

14 Center for Devices and Radiological Health have

15 these now within their two centers; but this

16 concept could be expanded so that there was a

17 broader involvement in the training activities

18 and a feeling of a broader availability of

19 these training possibilities to any of the

20 scientists within the agency, not just those

21 two centers.

22 This would also be another mechanism

.—
23 where, from the Office of Science, we could
156
_—__
1 take questions to this science college and ask

2 them to do homework for us to advise us on

3 specific questions within the agency that

4 relate to science and research.

5 Let me just talk a little bit about

6 where the Office of Science fits into this. To

7 the extent that we have memoranda or other

8 mechanisms whereby we’ re trying to generate

9 resources, the Office of Science can be

10 involved in that from a neutral standpoint as

11 opposed to a product orientation.

12 We in the Office of Science are in a

13 position to receive information from all of

14 these aspects that would be useful in

15 developing research and science priorities; and

16 to the extent that some of the money that is

17 appropriated to the FDA, beyond what would be

18 distributed to the centers for center-specific

19 research needs, to the extent that the Office

20 of Science would have a budget to support

21 agency-wide research.

22 That may not get supported through
.&
23 other mechanisms within the centers; it would
157

1 be helpful if the Office of Science would have

2 a small budget to support work also in the

3 centers; not to hold that money, but to receive

4 some and redistribute it to the centers to

5 support work that might have come through the

6 discipline teams or through other mechanisms of

7 identifying high priority agency-wide research

8 needs to supplement what will be supported

9 through the individual centers.

10 Then to the extent that in the future

11 we need to have research conducted, that the

12 agency scientists are not prepared to handle

themselves without major retooling, the

14 possibility would be that we would also have

15 extramural mechanisms whereby we could support

16 researchers on specific projects outside the

17 agency to develop the full complement of

18 research needs that we would have.

Now most of the money to support that

20 comes directly from these sources and is done

21 in the centers; but the Office of Science could

22 help redirect money to other high priorities

—.—
23 that wouldn’t be met otherwise.
158

1 DR . BLOUT : I’d like to ask the Board

2 to comment on this sort of large group of

3 subjects.

4 I know you’ve been thinking about it a

5 lot, Bern, but I’d like to hear the Science

6 Board comment if they feel it appropriate, on

7 these large ---

8 Who wants to start? Marion?

9 DR . NESTLE : Sure, why not.

10 This is the statement from the new

11 person in town. I’m impressed from reading the

12 CBER report and from hearing this that the FDA

13 has serious problems to deal with that include

14 funding, and that’s clearly a major one. But

15 also it has to do with presentation of the

16 agency in order to try to garner the funds that

17 it needs.

18 I’m kind of in shock that the kinds of

19 funding possibilities are being considered that

20 you laid out. I think anything that puts FDA

21 in an apparent conflict of interest is a

22 slippery slope that you just don’t want to get

23 on, because it will destroy the integrity of
159

1 the agency and its ability to function.

2 The organizational issues, it seems to

3 me , need to be addressed and need to be

4 addressed very, very rapidly. And I see it as,

5 from the standpoint of organizational

6 structure, that there has to be a level of

7 goal-setting and accountability that is readily

8 apparent so that anybody who is looking at the

9 agency can see instantly what the goals are and

10 how well the agency is meeting its goals, and

11 what it’s doing to meet its goals.

12 We heard some of that; I like the

13 goals, objectives, activities approach to it.

14 I think it’s a really good way of doing that.

15 I don’t know enough about it to know

16 how to go about starting on it, but 1’11 be

17 most interested in hearing what it is. But I

18 think this is a situation in which the agency

19 needs to hold firm in a number of areas, and

20 absolutely emphasize the importance of

21 maintaining the integrity of the review and

22 regulation process at every step of the way.
_——_
23 DR . BLOUT: Dr. Benet.
— 160

1 DR . BE NET : I’ll give a perspective of

2 something that I have raised at previous

3 meetings, and I think the best example of this

4 is in CDER. That is, the strong interactive

5 nature that the Center for Drugs has with

6 scientific societies in its discipline, and the

7 kinds of consensus-building issues that are

8 presented at such meetings.

9 And then working together, lead to new

10 regulation within CDER, and in fact some of the

11 new regulations that have come out have come
_-
12 directly from those meetings.

13 But it seems to me also that there are

14 research agendas that are beyond individual

15 companies, and also beyond the FDA. I think it

16 can serve as a focus -- it doesn’t necessarily

17 bring money directly into the agency, but it

18 does solve some of the problems in science

19 issues that the agency addresses.

20 I can see a particular scientific

21 society in conjunction with all of its

22 stakeholders including the FDA, suggest that
.
-.
23 this is a research project that we need to
161
_- —..
1 address in terms of something that is important

2 in the regulatory arena; and that that be the

3 focus of generating the money and addressing

4 the problem. It isn’t necessarily money that

5 comes in to FDA scientists because they’re

6 going to run that project, but they become part

7 of this project through the, sort of the

8 overall goal of this scientific society who

9 generates, raises the money and generates, and

10 in fact even controls the research, and the FDA

11 like they are now, are coinvestigators in these

12 projects.

13 But I think it allows us to get to

14 some of the problems that we feel that we don’t

15 know how to address. And I can think from a

16 CBER example, the ability to measure a certain

17 biological or an adventitious agent or

18 something like that, that says this is a

19 problem for everybody. And therefore we put

20 together an issue that the CBER scientists and

21 the FDA scientists as well as the academic

22 scientists and industry scientists under these
—.
23 -. the hierarchy of the scientific society
162
_——_

1 could have a potential of something we haven’t

2 done before; and yet works nicely as a model in

3 terms of conceptual ideas, and I think could be

4 addressed in terms of science ideas.

5 DR. BLOUT: Dr. Cuatrecasas.

6 DR. CUATRECASAS : I like those

7 comments, and would just like to add again more

8 broadly, that I think this is a good start,

9 it’s more than a start. I think this is the

10 kind of thing you need to do to come to grips

11 with the variety and complexity of problems
——_
12 that exist within the agency.

13 And it’s not only in the area of

14 funding, but there are issues, as you point out

15 here, that go far beyond funding. It’s not

/ 16 just finding more money. That’s necessary but

17 it’s not sufficient.

18 I see here an attempt in a disciplined

19 way to assess and to analyze and put on paper,

20 which is different, particularly one page,

21 something that begins to make some sense. It

22 doesn’t mean you’ve got all the solutions here,
.
23 but you’re beginning to really I think identify
163
.#-”%
1 some of the major issues, and you have to do

2 that before you can achieve innovative

I 3 solutions. So this is what’s necessary.

4 These are very difficult times. Very

5 difficult times, very complex times with

6 respect to funding and availability of

7 resources and the proliferation of scientific

8 disciplines, and I think we need imaginative

9 approaches .

10 So I would encourage you to continue

11 with things even which may be ultimately for
.—=
12 some reason unacceptable. Others may

13 ultimately not be unacceptable, because you’ 11

14 find that there’s a way to resolve that

15 problem.

16 So I applaud what you’re doing. It’s

17 not easy, and good luck.

18 DR . BLOUT: Dr. Langer?

19 DR . LANGER : I think what’s said has

20 been right; I think that what you’re proposing

21 is very, very important. The only issue is how

to get there, and I think there have been some

good suggestions.
164
.-+
1 DR. BLOUT : Any other comments?

2 Well, Bern, I know I speak for the

3 Board in thanking you for getting us started in

4 this way of thinking.

5 I’ve been told that -- it’s in your

6 book -- I’ve been told that I should announce

7 that the next dates, planned dates for the

8 Science Board meeting are October 21st and

9 22nd. I think it will only be a one day

10 meeting, one of those two days. But would yOU

11 hold the 21st and 22nd of October.

12 How does the Board feel about starting

13 later than we have in the past; namely, 9:45

14 versus 8:30 or 9 o’clock? Is it satisfactory?

15 It allows people on the East Coast to make it a

16 one day trip rather than ---

17 Let me just summarize, before we ask

18 for public comments, which are up next. Let me

19 just summarize what I think the Science Board

20 has done today; namely it has accepted --

21 first, it has accepted the report of the

22 Subcommittee on Toxicology, and we’ll look for

23 subsequent reports.
165
.n
1 Secondly, it has accepted the report

2 on the Biomaterials Forum, and we’ll put that

3 on hold.

4 Thirdly, it has accepted the report of

5 the Subcommittee for CBER review, subject to

6 specific changes from science -- suggestions

7 from Science Board members, and when those come

8 in, we’ll just send them out to everybody.

9 It’ll only be a few pages. We won’t send the

10 whole report, but we’ll send them out to

11 everybody before we take a final vote on
–—w
12 acceptance.

13 Is that satisfactory to you, Les?

14 All right; now it’s time for me to ask

15 for any public comments. Anybody in the

16 audience that wants to say something with

17 respect to this meeting of the Science Board,

18 please go to the microphone, identify yourself

19 and your organization.

20 PUBLIC COMMENTS

21 MR . GOLDHAMMER : Alan Goldhammer,

22 Executive Director, Technical Affairs, the

23 Biotechnology Industry Organization.
166

1 The report a very good one; we just

2 received it after the presentation. I would

3 like to clarify, on page 4 in the second

4 paragraph where you talk about the Pharma

5 perception on the negotiations during PDUFA.

6 This was jointly negotiated with both

7 of the industries; the biotech as well as the

8 mainstream pharmaceutical industry. I think

9 this is not quite fair to, even though we’re

10 not mentioned, but I would point out I don’t

11 think it’s quite fair to characterize it that

12 that was the tenor of the discussions.

13 Both organizations had a bottom line

14 from our Board of Directors in terms of how

15 much money we were prepared to contribute to

16 the renegotiated PDUFA. And there were a

17 variety of different program enhancements that

18 we wanted as part of that negotiation,

19 primarily oriented towards shortening drug

20 development, which was something that was left

21 out of the first round of discussions. We

22 looked at just raw approval times in getting

23 those down.
167
_——_
1 One of the things that came up

2 probably midway during the discussions was the

3 need for improvement of the computer system

4 which would lead ultimately to full electronic

5 submissions from IND all the way through to

6 adverse event reporting. We said “Okay, that

7 sounds good. We can see the benefits there.

8 We can quantify those. What is the price tag?”

9 That ended up being somewhere in the

10 neighborhood of $12-15 million added on top of

11 what we wanted for some of the other program
_——_
12 enhancements .

13 The bottom line, in keeping with the

14 price tag that the CEOS were willing to pay, we

15 had to look for some cost savings. I think the

16 reason that the CBER research unfortunately

17 suffered, and I’ll address that in just a

18 minute, was to try to bring this down to

19 something that we could sell both boards of

20 directors on; and hence the reason for this

21 phaseout over the five period of time.

22 Our experience in terms of what we
_–—_
23 have heard from some of our CEOS and regulatory
168

1 affairs people is the research has been very

2 beneficial in terms of dealing with clinical

3 holds, either preventing a clinical hold or

4 getting off of a clinical hold, addressing a

5 number of difficult safety issues, particularly

6 with regards to our membership we have

7 companies doing xenotransplant, cell and gene

8 therapy where there are real safety issues.

9 I think the agency is addressing

10 those; we would like to see that continue.

11 We’re struggling I think with some of the

12 proposals that you just saw with you as to how

13 to achieve that. We would love to see it done

14 out of appropriated funds, and we’re going to

15 work through the appropriations committee as we

16 have over the last seven years to ensure that

17 the agency is fully funded.

18 However, there are some political

19 realities that may or may not make that

20 difficult over the years to come, and we’ll

21 hope to try to work through some of those. We

22 do have a board level committee that’s going to
__——.
23 be looking very closely at this report; we hope
169

1 to supply Dr. Benet as well as the Science

2 Board with our input and take on it; but I

3 think the bottom line is that we I think are

4 all working to the common goal of increasing

5 the agency’s research resources, particularly

6 in the areas that affect these new and emerging

7 technologies.

8 DR . BENET : Thank you. I just want to

9 make sure I understand: So you think that what

10 I should have said was the perception of Pharma

11 and Bios in the recent negotiations. In other

12 words, I should have blamed both of you?

13 MR . GOLDHAMMER : Yes, you should have

14 blamed both of us, because I’m sure that the

15 Pharma people, when they see this, are going to

16 say “Well, how come you left out Bio?” So I’m

17 willing to be the scapegoat at least today, put

18 myself on that stand. But I just wanted to

19 also bring you up to what the realities we were

20 facing were.

21 We had a bottom line of somewhere,

22 about $115 million, I forget what it was, is
-——.
23 what we could negotiate on. And it was very
170
.- — ..
1 difficult to try to work within that framework.

2 DR . BENET: Well, we certainly were

3 aware -- I’m aware of it, and all we say there

4 is, it’s felt that the regulated industry not

5 pay for CBER research. So I don’t think that’s

6 incorrect. And we do address some of those

7 issues, certainly the xenotransplanation issue

8 the committee itself said “This is an area that

9 needs to be beefed up. “

10 I just wanted to make sure what you

11 thought I ought to correct.

12 MR . GOLDHAMMER : I think that’s good;

13 I think that the singlemost probably political

14 thing that one could do -- although that’s

15 probably impractical -- would be to get FDA

16 from out of the agricultural appropriations

17 subcommittee and over to the HHS committee.

18 We’re in a difficult position, because

19 our board has agreed to support the doubling of

20 NIH funds over the next kind of five or six

21 years, and yet we’re throwing -- throwing is

22 maybe the wrong word -- we’re putting this
_——.
23 money towards basic research, but if we’re
171
_——.
1 constricting the research effort at the agency,

2 which ultimately could adversely affect product

3 approvals , how can we derive the broader

4 benefits of all the biomedical research? And

5 that’s a tough one.

6 DR . BENET : I think the committee

7 certainly hopes that Bios and Pharma will

8 express their concern that in fact in the PDUFA

9 reauthorization and authorization, the idea was

10 that we would not decrease the budget that came

11 from the federal government for carrying out

12 aspects of research; and that this would be

13 additional money. And I think it’s very clear

14 that that has not happened.

15 MR . GOLDHAMMER : Yes.

16 DR . BENET : And I think again, when

17 you look at the budget for CBER and compare to

18 the years, it’s very obvious that that has not

19 happened.

20 MR . GOLDHAMMER : Well, there was also

21 a very heavy line item in there for money that

22 would come from the tobacco settlement which,
———..
23 as of this morning is still somewhere.
172
.#’-%
1 DR . BEN ET: Thank you.

2 DR . BLOUT : Mike, do I understand what

3 you’re saying is that there is a possibility of

4 increased PDUFA funding? Or you’re not saying

5 that.

6 MR . GOLDHAMMER: No. The PDUFA --

7 well, on a yearly basis the funding can

8 increase because there’s an inflation indexer

9 as well as a workload adjustor. In the budget

10 request that FDA submitted to Congress this

11 year, I believe they are asking for an increase

12 -- 230 I believe it is, FTEs from the PDUFA

13 program.

14 Primarily I think the baseline -- the

15 negotiated baseline in the absence of the

16 inflation and workload adjustor was $109

17 million for this fiscal year. Because of the

18 inflation in workload, I think the agency will

19 be collecting, I think it’s over $109 million.

20 For this fiscal year. Because of the inflation

21 in workload, I think the agency will be

22 collecting, I think it’s over $130 million.

23 So there are extra personnel that will
173

be hired within FDA as a result of the PDUFA

2 agreement, above what ought to have been

3 because of the increased workload.

4 DR . BLOUT : What is your feeling that

5 Pharma and Bios would be willing to support as

6 far as science in the agency?

7 MR . GOLDHAMMER : We have a conference

8 call on Thursday 1’11 have a better idea after

9 that .

10 DR . BLOUT : Thank you.

11 Any other comments? Anybody just want

12 to say something? Rosie.

MS . ELLISBERG: I’m Rosalie Ellisberg,

14 Center for Devices, cochair of the FDA-wide

15 junior science council, head of one of the

16 discipline groups in Genetic Tox. I’m also

17 President of the National Professional

18 Scientific Society in this field.

19 My lab budget is $4,000 per year;

20 that’s all I have. And we are indeed all

21 desperate in the fund raising area. I think,

though, to talk about all these alternative

sources of funding is really counterproductive .
174
_-#-%.
1 Anybody who writes for grants knows that it’s a

2 full time job. And I think any of these other

3 sources will divert us from our public health

4 mission and purpose.

5 We seem to need outside help, though,

6 to express to the world the fact that we don’t

7 have the critical funding that we need to

8 function. And as far as comparing CBER and

9 CDER goes, I think it’s great that you’ve

10 identified the really important public health

11 issues going on a CBER. But I think there are

12 similar but different issues in every center.

13 For instance, to say that the Center

14 for Drugs has functioned without basically any

15 research going on at all, very little, just

16 begs the question: That could happen in CBER

17 and maybe there would be contaminants in the

18 vaccines and you wouldn’t find out about it for

19 a year or a decade, two decades.

20 In the Center for Drugs, I’m not in

21 that Center, but I can think of a lot of issues

22 that are critically important, such as drug
.-~
.,
23 interactions when more than one drug is taken
175
.-=.
1 at a time. It’s in no pharmaceutical company’s

2 interest to study this. It’s in no

3 pharmaceutical company’s interest to really

4 develop drugs for individual people with

5 different genetic susceptibilities to drugs,

6 because it would end up that you would be

7 selling less of a given drug.

8 There are a lot of public health

9 issues like this that FDA could address. In

10 genetic toxicology, the test for cancer risk

11 assessment, the simple tests done first, we’re
.--=
12 using assays that are 20 and 25 years old. And

13 no one has the funding to develop new assays

14 and to look into these.

15 This is another thing that FDA could

16 do, it’s an FDA-wide issue and Dr. Schwetz has

17 tried very hard to institute FDA-wide issues.

We have no forum for this, and I do

19 think that everybody would be more cooperative

20 in FDA and among the Centers if we had

21 appropriate funding. But since we have such

22 little funding, we’re fighting over every last
.-—— —.
23 dime and nobody wants to give up anything for
176
-— —.
1 FDA-wide issues.

2 We’re losing the public health mission

3 here . I think the CDER report is a good step,

4 and I hope, as Dr. Benet said, the Kern report

5 didn’t seem to have any effect on the law in

6 Congress to beef up federal agency research

7 funding, because FDA wasn’t there. So somehow

8 we’re still not on their map. And I believe we

9 should focus our efforts to getting on the map

10 rather than talk about CRADAS and all t h e s e

11 other things that are simply diverting us from

12 the major purpose that we should have.

13 DR . BLOUT : Thank you, Rosie.

14 We happen to have two former drug

15 company executives sitting around this table.

16 Maybe one of them would like to comment.

17 (Laughter)

DR . SANDERS: 1’11 just respond in

19 part, respectfully that it is in the company’s

20 interest to determine whether or not there are

21 drug interactions, if there’s some reasonable

22 expectation that there might be. Not only from

23 the point of view of protecting the patients,
177
.-—.
-.
1 because it’s not good to have reactions to

2 one’s drugs, but also to seek competitive

3 advantage over other drugs that might be used

4 to treat the same conditions, to determine

5 whether or not the other -- you might have an

6 advantage in not having drug interactions.

7 It’s an area which is I think far from

8 zero or one; it depends on the circumstances

9 and you’ve got to keep an open mind about it.

10 But I don’t disagree with you that the

11 appropriate and most desirable way to solve the

12 problems that you’re facing funding research is

13 to have appropriations; and that of course is a

14 whole other subject of how you can get it at

15 the Congress and make sure that you can make a

16 case that says this is going to impact

17 favorably the way that we do our job at the

18 agency, and you know that lesson much better

19 than I.

20 DR . BLOUT: Dr. MacGregor.

21 DR. NESTLE : Could I comment on what

22 she just said before?
——-
c\
23 DR . BLOUT : Yes.
178

1 DR . NESTLE : I wanted to thank the

2 previous speaker for raising issues, and it

3 made me think that one thing that might be

4 helpful in making the CBER report respond to

5 Dr. Cuatrecasas’ comment about needing to

6 expand it a little bit wider would be to get

7 from each of the divisions maybe two or three

8 ideas of research projects that FDA could do

9 that nobody else was doing, just to have a

10 little catalog of the kinds of things that

11 would make the FDA’s research program much more

12 understandable to the public, perhaps.

13 DR . CUATRECASAS : That was actually

14 done with David Kern’s committee --

15 DR . NESTLE : Sorry.

16 DR . CUATRECASAS : I’m not sure it’s in

17 the summary.

18 DR . BLOUT: No, it isn’t.

19 DR . CUATRECASAS : Maybe you have to go

20 to the appendices, and there were a lot of

21 additional, supplemental things which in fact

22 did that. And we talked to every center

23 director, and they all made the case, they all
179
____—_-
1 made a case about what kinds of research they

2 were doing, what kind of research they could

3 do, internally or externally; because a lot of

4 it, a lot of the laboratory research that the

5 other centers wanted to do could be done on

6 contract; but they don’t have funds for that,

7 either.

8 So they made the case fairly strongly,

9 and that was the reason that I -- I made this

10 morning the comments that other centers have --

11 we just heard about that as well, and they

12 affect public health equally.

13 DR. BLOUT : We’ve heard a lot about

14 CDER and we happen to have somebody here who

15 can speak to the question.

16 DR . MacGREGOR : I’m Jim MacGregorJ I ’ m

17 with CDER, FDA, the Office of Testing and

18 Research. Actually, I wanted to comment on two

19 aspects of the discussion.

20 The first is the strong distinction

21 that was made in the committee report between

22 the need for research in CBER and CDER, and

23 it’s been said before by others; but I just
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1 want to say for the record that I consider it

2 to be an untenable argument that science is

3 less important for drug development than it is

4 for biological. I think we all recognize that

5 the advances in science have been enormous and

6 they cross-cut all aspects of our agency, and

7 it’s a necessary aspect of our function to

8 maintain knowledgeable scientific expertise

9 that understand those new systems in order to

10 do our job well.

11 The other thing I wanted to comment on

12 was the discussion on collaborations . I’d

13 actually like to raise a slightly different

14 focus on it than has really been the emphasis

15 of the discussion.

16 I personally believe that there are

17 many broad, crosscutting scientific issues that

18 need to be addressed that are equally important

19 to the public, the industry and the FDA. In

20 many of these cases the scope of resources

21 exceeds that of even industry, and there are a

22 number of examples of successful collaborations
—-—_
23 to identify these kinds of issues; and I think
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1 it’s more of an issue than just resources.

2 It’s also a matter of acceptance and the

3 motivation to bring new science into the

4 regulatory practice; because if industry and

5 government are completely separated, each

6 component has a very strong barrier against

7 innovating if they’re separated. And yet

8 science demands innovation and evolution to use

9 the new science for more efficient regulation.

10 And industry really cannot effectively

11 come forward with a novel approach that the

12 government doesn’t know about, because it

13 doesn’t make product development sense to risk

14 your product on something that you have no idea

15 how the government is going to approach it.

16 So therefore if you accept that idea,

17 the idea that you don’t need science in the

18 government and that you shouldn’t talk to

19 industry science I think is an untenable idea

20 and we shouldn’t lose sight of that fact.

21 In response to the concerns raised by

22 Dr. Nestle about the danger and the
_
23 impossibility of communicating with those that
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1 you regulate, I think there are many precedents

2 where that’s been done successfully and is

3 being done successfully, both in FDA and in

4 other regulatory agencies.

5 Just to take a number of different

6 kinds of examples, the Health Effects Institute

7 is one example where an entire institute is

8 built half by the EPA budget and half by the

9 regulated automotive industries budget. And

10 the entire purpose is to pool their resources

11 to look at crosscutting issues like new fuels

12 and particulate and ethanol additives to

13 gasoline and how to treat them and so on.

14 And have a long history of successful

15 approach to that sort of thing, and they’re

16 under exactly the same kinds of regulatory

17 constraints as the FDA.

18 Then there was reference to the fact

19 that you don’ t necessarily have to pass money

20 between the agencies to pool your resources.

21 And an example of that is the ongoing ILSI

22 consortium on new models for carcinogenesis .
_—_
23 There are about 40 laboratories working
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_- —.
1 together to look at these new transgenic models

2 for carcinogenesis, evaluate how they work; and

3 I would ask: Can the FDA afford not to be

4 involved in that kind of science? I think the

5 answer is no, that you cannot afford not to be

6 involved in developing those kind of models and

7 assessing their performance and so on. And yet

8 most of the resources coming from industry in

9 that case.

10 Yet it is our primary job to set the

11 regulations, to define what the regulatory

12 requirements are going to be. And 1’11 echo

13 what Rosie said there; I mean, clearly I think

14 we would all agree that it’s necessary to have

15 adequate appropriated funds to be able to

16 fulfill that.

17 The other thing that I should point

18 out that hasn’t been mentioned today is right

19 now there are some new collaborative efforts

20 underway that involve CDER and CBER. The

21 product quality research initiative and the

22 collaboration for drug development improvement,
—_ .—___
23 which are both programs that are involving
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1 industry, university, public and government

2 sources are very real; they’re public, they’re

3 ongoing, and I think they’re going to

4 contribute importantly to our mission.

5 DR. BLOUT : Thank you, Dr. MacGregor.

6 Does anybody want to respond?

7 DR . CUATRECASAS : Those were superb

8 comments .

9 DR . MacGREGOR : Thank you.

10 DR . BENET: Jim, when you make the

11 comments, there’s no one that disagrees with

12 science in the agency and its need in all

13 aspects; and that’s what you suggested maybe I

14 was saying or the committee was saying.

15 The committee’s point is the

16 difference between laboratory research and

17 virtual science. And as Bern gave in his talk,

18 the agency has been moving more toward virtual

19 science as opposed to laboratory science.

20 Now I know you meant to say this, but

21 I’m just saying, the next time you say it, say

22 it as laboratory science not just science,
__—
23 because --
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1 DR . MacGREGOR : Let me just add that I

2 just came to this agency to lead CDER’S

3 laboratory effort.

4 DR . BENET: I know that, and I’ve

5 known Jim for many years; I was on his wife’s

6 committee for her Ph.D. , so I knew him back

7 when he had brown hair, gray hair. And I think

8 it’s wonderful that you’re there. And I don’t

9 oppose it; I believe it’s important throughout

10 the agency. I reflected what my committee’s

11 task was in terms of that. And I think you,
-—_—_—.
12 Dr. Cuatrecasas and others, have pointed out

13 that we need to be broader in this, and I don’t

14 object to that.

15 DR . BLOUT : You’re saying there’s a

16 place for laboratory science in CDER as well as

17 CBER.

18 DR . MacGREGOR: I didn’t say there was

19 a place; I said I think it’s essential, just

20 like it is in———.

21 DR. BLOUT : Thank you.

22 Any other comments? Anybody else?

23 From inside or outside the agency.
186
.-,
1 Rosie, again?

2 MS . ELLISBERG: I think we’re

3 misinterpreting the virtual science center. I

4 don’t think it was juxtaposed against

5 laboratory science. It was an all-encompassing

6 term to link FDA science into one virtual

7 science center, so we could work together.

8 It’s not one or the other; it’s really -- we’ve

9 all been in favor of lab science, more lab

10 science. The virtual science center doesn’t

11 mean no lab science.

12 DR. BLOUT : Kathy? Dr. Zoon.

13 DR. ZOON : I just want to say, while I

14 support working in the virtual framework, I

15 think one can’t forget that there has to be a

16 direct interaction, either within a person or

17 with people who do the review work. To have

somebody off here asking questions and doing

19 something and having review over here, and not

20 having them interdigitate and supplement and

21 foster and create the kind of environment that

22 leads to the scientific knowledge base in

23 accepting and promoting the science in the
187

1 review work that we do would be missing the

2 point.

3 So I just want to make sure that while

4 we ‘ re all supporting this, and I think it’s

5 wonderful, the cross-fertilization, we cannot

6 forget the key importance of having that

7 science directly linked to the regulatory

8 process.

9 DR . BLOUT : Bern?

10 DR. SCHWETZ: I want to comment on the

11 virtual aspect as well, because there are some

12 places where it’ s more compelling than others.

13 For example, the recommendation to buy

14 a multi mass spectrometer means that there’s

15 going to be a lot of other stuff that can’t be

16 bought if you buy that piece of equipment. And

17 to the extent that we’ve got five or six of

18 those sitting around the agency all being used

19 part time, is not good management.

20 In that case, we’ve made an effort to

21 bring the mass spec people together and compare

22 notes on what capabilities do we have, where do

23 we have it, how much of it is being used in a
188

1 given site, and if anybody else needs it, we

2 ought to be using our mass spectrometers to the

3 full extent that we have before we go out and

4 buy additional ones.

5 So I think there are examples where

6 the virtual approach doesn’t make any

7 difference, in particular, but there are some

8 cases where it’s extremely compelling that we

9 look at the resources that we have before we

10 just go out and buy additional expensive pieces

11 of equipment making believe we have a lot of

12 money.

13 DR . BLOUT : I think we’re clarifying

14 this word ‘virtual’ .

15 Anybody else?

16 If not, 1’11 ask the Board if they

17 have any further comments, suggestions, before

18 1’11 ask for a motion to adjourn.

19 DR . CUATRECASAS : Elkan, just one

20 other -- this morning, Michael Friedman talked

21 about the issues and the topics which are being

22 examined and are going to be prioritized and a

23 part of the act; and I think he has to do this
189
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1 by November.

2 One thing that was not mentioned, he

3 only mentioned three areas, and he welcomed

4 more suggestions. One that I have not heard

5 and I think does need some attention is the

6 whole question of chemistry and manufacturing

7 standards. That’s something again I can

8 provide in a little bit more detail -- this

9 would be across-the-board -- but increasingly

10 complex and increasingly becoming rate-limiting

11 in drug development.
A-----
12 It is not the clinical data

13 development , nor usually the toxicology that is

14 rate limiting, generally, with few exceptions.

15 I’m seeing more and more the development

16 process, the discovery process being held up by

17 issues that relate to chemistry and

18 manufacturing. They definitely need to be

19 examined, and I don’t know how much of that is

20 happening.

21 DR . BLOUT : Less and less; and those

22 of us who have been involved product
~,---
23 development at one time in our lives realize
190
—_—+

1 the importance of that, and the very expensive

2 nature of that kind of activity.

3 Good point. Let’s put that in our

4 thinking.

5 Any other comments?

6 DR . MacGREGOR : Well, just with regard

7 to the last comment, I might point out that

8 this product quality research initiative that I

9 just referred to is directed specifically at

10 those kinds of issues; the quality issues, the

11 chemistry, quality manufacturing issues and the
_ ___
12 amount of regulations that are necessary during

13 scaleup process; all these sorts of issues.

14 So there is recognition of that, and

15 this is one of those things that we’re trying

16 to tackle through this joint industry-

17 government-public collaborative approach.

18 DR . CUATRECASAS : Thank you.

19 DR . BLOUT : Good point. Thank you,

20 Jim.

21 All right; anybody else?

22 If not, do I have a motion to adjourn?
.—
23 [Moved.]
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1 DR . BLOUT : So be it. We’ll see you

2 all in October if not before. Thank you.

3 [Whereupon at 2:29 p.m., the meeting

4 concluded. 1

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