U.S. FOOD AND DRUG ADMINISTRATION

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OFFICE OF THE COMMISSIONER

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SCIENCE BOARD

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MEETING

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FRIDAY,

NOVEMBER 5, 2004

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The meeting was held at 8:00 a.m. in Room

1066 of the Food and Drug Administration, 5630 Fishers

Lane, Rockville, Maryland, Dr. Kenneth I. Shine,

Chair, presiding.

PRESENT:

KENNETH I. SHINE, M.D., Chair

GAIL H. CASSELL, Ph.D., Member

JOSEPHINE GRIMA, Ph.D., Consumer

Representative

SUSAN KAY HARLANDER, Ph.D., Member

CATO T. LAURENCIN, M.D., Ph.D., Member

CECIL B. PICKETT, Ph.D., Member

F. XAVIER PI‑SUNYER, M.D., M.P.H., Member

JIM E. RIVIERE, D.V.M., Ph.D., Member

ALLEN D. ROSES, M.D., Member

KATHERINE M.J. SWANSON, Ph.D., Member

JOHN A. THOMAS, Ph.D., Member

LESTER M. CRAWFORD, D.V.M., Ph.D., Acting

Commissioner

NORRIS E. ALDERSON, Ph.D., Associate

Commissioner for Science

JAN N. JOHANNESSEN, Ph.D., Executive Secretary

ALSO PRESENT:

ROBERT BRACKETT, Ph.D., Director, CFSAN

KATHRYN M. CARBONE, MD., Associate Director

for Research, CBER

STEVEN GALSON, M.D., M.P.H., Acting Director,

CDER

AJAZ HUSSAIN, Ph.D., Deputy Director, Office

of Pharmaceutical Sciences, CDER

LARRY G. KESSLER, Sc.D., Director, Office of

Science and Engineering Laboratories, CDRH

JOHN R. MARZILLI, Deputy Associate

Commissioner for Regulatory Affairs

KARA MORGAN, Ph.D., Office of Planning, Office

of the Commissioner

LISA ROVIN, J.D., Director, Critical Path

Initiative

ALAN M. RULIS, Ph.D., Senior Advisor for

Special Projects, CFSAN

LEONARD SCHECHTMAN. Ph.D., Acting Deputy

Director, NCTR

DANIEL SCHULTZ, M.D., Director, CDRH

JOHN J. SPECCHIO, Ph.D., Montclair State

University

STEPHEN SUNDLOF, D.V.M., Ph.D, Director, CVM

DOUGLAS THROCKMORTON, M.D., Acting Deputy

Director, CDER

JANET WOODCOCK, M.D., Acting Deputy

Commissioner for Operations

I‑N‑D‑E‑X

AGENDA ITEM PAGE

Call to Order 5

Kenneth I. Shine, M.D., Chair, FDA Science

Board

Meeting Statement 5

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

Welcome and opening remarks 7

Lester M. Crawford, D.V.M., Ph.D., Acting

Commissioner of Food and Drugs

Update on the Critical Path Initiative 23

CDER Critical Path Activities 23

Douglas Throckmorton, M.D., Center for Drug

Evaluation and Research, FDA

CBER Critical Path Activities 44

Kathryn Carbone, M.D., M.P.H., Director, Center

for Biologics Evaluation and Research, FDA

CDRH Critical Path Activities 59

Daniel Schultz, M.D., Director, enter for

Devices and Radiological Health, FDA

Overview of Critical Path Docket Submissions 74

Lisa Rovin, J.D., Director, Critical Path

Initiative, Office of the Commissioner, FDA

Critical Path ‑ Current Activities and the 88

Path Forward

Janet Woodcock, M.D., Acting Deputy

Commissioner for Operations, FDA

Medical Technology Innovation Task Force 107

Larry G. Kessler, Sc.D., Director, Office of

Science and Engineering Laboratories

Foods Critical Path White Paper 118

Alan M. Rulis, Ph.D., Senior Advisor for

Special Projects, Center for Food Safety and

Applied Nutrition, FDA

Questions and Discussion with the 127

Board/Presenters

I‑N‑D‑E‑X (Continued)

AGENDA ITEM (Continued) PAGE

Open Public Hearing 173

Pharmaceutical cGMP Initiative 173

Janet Woodcock, M.D., Acting Deputy

Commissioner for Operations, FDA

Final Report on Process Analytical 204

Technology and Manufacturing Science

Ajaz Hussain, Ph.D., Deputy Director, Office

of Pharmaceutical Sciences, CDER, FDA

ORA Peer Review ‑ Overview of Report and Plan 245

for External Peer Review

John R. Marzilli, Deputy Associate Commissioner

for Regulatory Affairs, FDA

Questions and Discussion with Board ‑ 276

Recommendations

P‑R‑O‑C‑E‑E‑D‑I‑N‑G‑S

(8:00 a.m.)

CALL TO ORDER

CHAIRMAN SHINE: Good morning, ladies and

gentlemen. I\'m Ken Shine. I currently serve as Chair

of this advisory committee, and I would like to call

the meeting to order.

Our Executive Secretary, Jan Johannessen,

has a number of duties that he has to perform. So

I\'ll turn the microphone over to Jan.

EXECUTIVE SECRETARY JOHANNESSEN: Thank

you.

MEETING STATEMENT

EXECUTIVE SECRETARY JOHANNESSEN: I would

like to read the meeting statement. \"The following

announcement addresses conflict of interest with

respect to with this meeting and is made part of the

public record to preclude even the appearance of such

at the meeting.

\"The Food and Drug Administration has

prepared general matters waivers for Drs. Shine,

Pickett, Grima, Riviere, Laurencin, Swanson, Thomas,

Roses, Pis‑Sunyer, Cassell, and Harlander. A copy of

the waiver statements may be obtained by submitting a

written request to our Freedom of Information Office.

\"The waivers permit them to participate in

the Committee\'s discussion of the FDA\'s Critical Path

Initiative and related topics, cGMP reports, and the

peer review of the Office of Regulatory Affairs

Pesticide Program.

\"The topics of today\'s meeting are of

broad applicability. And unlike issues before a

committee in which a particular product is discussed,

issues of broader applicability involve many

industrial sponsors and academic institutions.

\"The participating Committee members have

been screened for their financial interests as they

may apply to these general topics at hand. Because

the general topics impact so many institutions, it is

not prudent to recite all potential conflicts of

interest as they apply to each participant.

\"The FDA acknowledges that there may be

potential conflicts of interest, but because of the

general nature of the discussion before the Committee,

these potential conflicts are mitigated.\"

We have an open public comment scheduled

for 1:00 p.m. I would just remind everyone to turn

your microphones on when you speak so that the

transcriber can pick everything up.

And I just wanted to make a note that Dr.

Throckmorton has to leave immediately after his

presentation to catch a plane.

Thank you.

CHAIRMAN SHINE: Thank you, Jan. That is

an even more important reason for us to start on time.

(Laughter.)

CHAIRMAN SHINE: We are pleased to have

the Acting Commissioner of Food and Drugs, Dr.

Crawford, to make some opening remarks. Lester?

DR. CRAWFORD: Thank you.

WELCOME AND OPENING REMARKS

DR. CRAWFORD: Well, first of all, let me

thank all of you for being here and giving of your

time for this all‑important undertaking. I will

discuss a little bit more about the elements of the

undertaking a little bit later.

First I have to say that Dr. Throckmorton

is not going to be catching a plane. He\'s going to

stay here. It\'s not approved. Any questions, Dr.

Throckmorton? Thank you.

(Laughter.)

DR. CRAWFORD: Now, the next thing is I

would like Dr. Pickett to step forward, please. Dr.

Pickett, as all of you know, has been both a faithful

and intellectually stimulating and hard‑working and

well‑prepared member of the Committee all of the time

that he has been on it. This happens to be what he

thinks will be his last meeting.

In recognition of the fact that he will

come back, just like MacArthur, we have a nice plaque

here, which says, \"In recognition of distinguished

service, the Science Board of the Food and Drug

Administration, Office of the Commissioner from August

2001 to December 2004.\"

And, Cecil, you will agree that those

three years seemed like the twinkling of an eye,

right?

MEMBER PICKETT: Absolutely. Thank you

very much.

(Applause.)

DR. CRAWFORD: It is usual and traditional

for the commissioner at this point to give an update

on what is happening in FDA. And, in addition to the

agenda, I want to talk about some regulatory

developments that we\'re going to be rolling out by the

end of this presidential term.

For some months, starting with a National

Press Club speech on August 2 of this year, we

indicated that we were going to wrap up all of the

different things that we had promised to do in terms

of regulatory changes that will improve FDA\'s ability

to advance public health and also to prevent unwanted

diseases and adverse reactions; in other words,

changing to the new FDA that was envisioned during the

time that Dr. McClellan and I were working together.

And, as he was leaving to go on to different pastures,

we indicated together that we would work hard to get

these things done and done by the end of this

presidential term.

I started at that point using the term

\"the end of this administration.\" I was admonished by

some people in the administration that that might not

be the best choice of words. So I modified. And now

we\'re using the term \"presidential term.\"

This particular week several things have

happened which are important. We have completed the

single‑use devices review. That\'s part of an overall

review of medical devices in terms of their reuse

capability and a determination of what would

constitute the criteria for single use.

The bioterrorism regulations, which, as

you may recall, were in four categories, have now been

completed. And we issued also this week Prior Notice

regulations. In other words, a provision of the law

of 2002 was that companies that were going to export

products to the United States had to give us the

privilege of knowing that they were coming.

The game of product roulette that had been

going on for decades was officially over when the

president signed the law in June of 2002. It awaited,

though, final clarification with the regulations. We

had some spirited review. And so we modified the

regulations and represented them. And now they\'re

gone forward.

The second one is registration. When

Secretary Thompson attempted to deal with, number one,

the 2001 9/11 disaster; and, number two, the anthrax

problem; and, number three, the possibility that the

next terrorist attack would be through the food

supply, he was chagrined and alarmed to know that he

did not have the capability of stopping products at

the border or requiring registration of firms that

manufactured in the United States or manufactured

elsewhere and exported to the U.S. So the passage of

the law was of great benefit to bioterrorism, as the

law implies.

Registration does require registration of

those facilities. And FDA will require that on an

annual basis. At this point, we have gotten

registration of approximately 300,000 firms. And we

expect that there may be 100,000 more that will come

in following this final regulation.

We also this week posted the Med Guide for

selective serotonin reuptake inhibitors. And that was

published on November 3. As you may also remember,

earlier this year perchlorate became sort of the next

toxicological concern.

As all of you know, perchlorate results

from the use of airline fuel, particularly in areas

where agriculture and airports and a large amount of

air traffic meet, there has been determined to be

contamination.

It first was detected in California. And

then a notable University of Arizona pilot study found

levels of perchlorate in a variety of foods as well as

other products.

We did a study starting with the

publication of the University of Arizona data. And it

is now on the web for consideration by the scientific

and medical communities and all other interested

people.

We find that the overall contamination is

not quite what we expected. It is a bit lower.

Nonetheless, contamination by products such as this ‑‑

I see Dr. Riviere paying close attention ‑‑ is a

matter of great concern. And so we will be monitoring

this very carefully and at some point actually asking

members of the Committee to be involved in our

evaluation.

A couple of other things have happened.

The so‑called solo‑shot syringe, which has been under

consideration for some time, was approved on November

3\. Essentially, this is a syringe that will save

doses of vaccine and is particularly useful during

this time of the flu shot, where we\'re trying to

conserve all the vaccine we have and also to find

other sources of vaccine.

The approval for this product by the

Center for Devices and Radiological Health indicates

that the saving in vaccine volume could be as much as

ten percent. So this would be a great thing to have

happen if you\'re dealing with 61 to 70 million doses

of vaccine when we were hoping for 75 million at the

least.

And then we also are issuing some changes

on Depo‑Provera that have been announced. These are

black box warnings. They\'re available also on our Web

site.

Yesterday we launched the dietary

supplement umbrella regulatory package, which gives a

structure to dietary supplement regulation. You

probably saw or heard it on the news yesterday.

For a long time since the passage of the

Dietary Supplement and Health Education Act in 1994,

FDA has attempted to deal with the articles and

particularities of that act. A couple of things were

sort of startling to FDA. One was that we needed to

get together good manufacturing practice regulations

for dietary supplements, a field that had never been

entered before by any country. And it has taken us,

frankly, ten years to get to the point that we are

now.

Later this month or no later than January,

we will have the dietary supplement GMPs out. And we

have also a research program for dietary supplements

that will involve the unit at NIH that deals with this

but also the University of Mississippi\'s Cochran

Center. They\'re trying to get a body of scientific

knowledge and a scientific literature base on dietary

supplements. There are about five other things in the

changes. But it finally gives us the structure to

regulate dietary supplements so both the industry and

the public and the regulators know what we\'re doing.

Drug safety announcements will come out

today, which characterizes to an extent what FDA

expects in terms of drug safety pronouncements and how

we will follow up on these particular issues.

We are also considering some changes to a

variety of other drugs that will be announced. There

are about five more that will be announced this

particular month. And we are looking at devices that

will help us to confront terrorism. These are devices

that can be added to the packaging for drugs that will

indicate whether or not the drug product is authentic

or whether or not it is counterfeited, whether or not

it may not be that drug at all.

Then later on we also will be issuing our

guidance on adventitious presence, which is a

particularly disturbing and complicating problem for

manufacturers, producers, and consumers of

bioengineered foods. This guidance will recognize

that some genetic material may stray, but within

certain limits or certain tolerances, we have

determined that public health significance is minimal.

The cloning risk assessment that has been

long been considered and also was the subject of a

National Academy of Sciences study will be released

sometime this month.

Good tissue practices, which also have

been the subject of a number of congressional hearings

‑‑ it seemed like one a month there for a while. But

now we have digested that material and information.

In mid to late November, we will be getting out this

particular package of guidances.

The food GMPs will be published in a

proposed form mid‑ to late November. I noticed on

these when it says \"mid‑ to late,\" it probably means

the next month. So let\'s say December because I know

a little bit about some of these.

Then food labeling rules, which were

promised with the Obesity Working Group, which was I

think premiered maybe even here, will be published,

again, probably in December. And essentially what

these particular two sets of rules will do will be to

try to give the public the information that they need

in order to control weight gain.

Currently, we have a very confusing

situation with serving sizes. This particular rule

will propose that companies that are manufacturing

processed foods and other foods will have the

requirement to publish both the serving size, caloric

content, and nutritional content on the nutritional

facts panel, but also they will have a dual label,

which will show what the total amount is.

When I was working with Commissioner Young

on the nutrition labeling for the Americas, both in

meat and poultry and other foods, in the early 1990s,

we were using routinely in the hearings that we held

12‑ounce cans of soft drinks that demonstrate our

point that consumers probably could take an 8‑ounce

serving size and translate that into a 12‑ounce total

can of soft drink. That seemed to work okay for a

year or two until the amount of fluid in the soft

drink cans or bottles increased to 16 and a half

ounces, to 24 and a half ounces, to 20 ounces. We

have found in focus groups consumers have surrendered

at this point. And they don\'t really care or know.

They just drink the whole thing. So we are now going

to make it possible for them to care, hopefully, and

to know surely.

Prominence of calories would be the second

aspect of these food labeling rules. There will be

more to come in the future. Although calories are the

first thing on the nutrition facts panel, it seems to

be the last thing that consumers look at. We don\'t

know whether we should make it like a computer blowup

model or sunburst or what, but we are going to propose

some changes in the listing of calories so hopefully

people will look at it.

The most significant thing in my mind to

that ‑‑ and I congratulate the Center for Foods people

on doing a great job of addressing a difficult issue

‑‑ the most prominent thing to me is that we will list

finally the daily value so that if you consume

something that has 1,000 calories in it, there will be

labeling which will show you or warn you or shock you

into knowing that you have just consumed 50 percent of

your daily caloric content. And although the

milkshake might have been great, it might have been

costly.

So that has never been on there before,

and we sort of exempted it because we weren\'t sure

about what the daily caloric intake should be. But

now that we have done this, I think we will be able to

forge together some changes in public thinking that

may actually help with the obesity epidemic.

As long as any commissioner stands here in

our lifetime, among the first things they are going to

talk about will be obesity because we have a problem.

And because the problem exists in other countries, as

some have claimed and certainly is the case, that

doesn\'t excuse FDA and the American people from trying

to deal with the problem.

We also are getting some changes in how we

label medical products. This will be called the

Physician Labeling Rule. Essentially it will address

a reordering of the information for physicians so that

they can make more intelligent decisions on behalf of

their patients and in consultation with their

patients.

There are a couple of other things here

that we are going to complete. Mark and I did not

want to go down as being referred to as the promissory

commissioners. We wanted to be the \"promises kept\"

commissioners. And so the carbohydrate rule that we

have talked about for a long, long time, even before

the Obesity Working Group, also is ready and should be

available before the end of this particular

presidential term.

Essentially what it seeks to do is to

demystify carbohydrates, on the one hand; and, on the

other hand, to give FDA a means for dealing with

mislabeled foods, some of which say there is no

carbohydrate. Others say there are special kinds of

carbohydrate, like celestial carbohydrates, for

example, I saw the other day in a food store. And

some of you, like Dr. Harlander and Dr. Swanson, may

know what a celestial carbohydrate is, but I don\'t

know.

This will say what should be on the label

and also will give our regulatory people the means to

control this, perhaps even on the Internet if we do it

right.

And on the obesity level, we have convened

and now funded a Keystone dialogue. The Keystone

Center has agreed to be a partner as we move forward

with a determination of what the public thinks should

be done, what affected industries and academic

disciplines think should be done in order to better

deal with the obesity epidemic.

The last time this was done with this

large a scope, as some of you remember, was on the

pesticide regulation issue, as we moved from improving

regulations, getting past the Delaney Clause. And

that resulted in the Food Quality and Protection Act.

This will probably result in something similar on the

nutrition side.

That dialogue took two years. Hopefully

this one won\'t take two years. It may take five

years. We only have one year worth of money, right?

That\'s good. Thank you, Dr. Alderson.

So, anyway, again, with the FQPA dialogue,

sometimes there were a couple of hundred people trying

to dialogue. It will be open to the public. And

hopefully people will get heavily involved in it, and

we have been promoting it in the industry and in

universities and the academic community in general.

And I believe that it will get done what we hope will

to done.

We\'re continuing to seek the proper amount

of funding and interest in the Critical Path. You

will hear a lot more about that as we go forward.

Needless to say, we believe that that is the calculus

by which FDA will move forward. And if, in fact,

there is a new FDA ‑‑ and I believe there is ‑‑ this

will be the means to accomplish that because there

will be a self‑renewing, not self‑fulfilling, but it

will be a self‑renewing, system for steady improvement

in this process at FDA across all the medical centers.

And now we\'re getting out a white paper on

a critical path for foods and veterinary products.

And I think it\'s ‑‑ I didn\'t have a lot to do with its

conception. Nobody is taking much credit for it now,

but once it becomes a success ‑‑ and I know it will ‑‑

it will have many progenitors, fathers and mothers.

And that\'s what we want.

So I think we have been open, and we have

also been attentive, and I congratulate Dr. Woodcock

once again for her leadership in this area.

And we will get it done because these

kinds of improvements have to continue from

administration to administration. It can\'t be

politicized, and it can\'t stop when you get a new

commissioner or an acting commissioner. They have to

keep going forward. This is the beauty of this

particular system.

And to all of you, particularly the

members of the committee that have commented on that,

we are grateful, and we appreciate it. There will be

much more commentary to make.

So, with that, I will close. And the next

time we will meet, those of you who were taking notes,

I expect some flagellation if none or all of these

come out. So please keep your notes, and we will meet

again.

Thank you.

(Applause.)

CHAIRMAN SHINE: Thank you, Commissioner.

We have about three minutes before the

next part of the program if any members of the

committee want to ask Dr. Crawford anything about his

presentation.

I would emphasize that since I have moved

to Texas, I have discovered that only Detroit exceeds

five Texas cities in the percentage of obesity. So we

are very much concerned about this. This is a public

health problem in a very large state.

Any other comments?

(No response.)

CHAIRMAN SHINE: And we will hear more

from the Commissioner at lunchtime with regard to a

couple of issues that he is going to brief us on.

Thank you very much. At this point I

think we\'ll move to the update on critical path

activities. I see Janet is here. Do you want to make

any comments before Dr. Throckmorton makes his

presentation?

DR. WOODCOCK: At the end, I\'ll be

explaining where we are on this and how we are going

to move forward, but what we\'re starting with is some

of the very specific projects that the centers are

undertaking or each medical product center way of

trying to get their arms around the Critical path

problems with their products.

So I think that is the purpose of the

initial briefings here, and that should set up your

understanding of where we\'re going to try to go with

this.

CHAIRMAN SHINE: Dr. Throckmorton, since

you\'re in flight.

DR. CRAWFORD: No, not anymore. He\'s got

plenty of time.

UPDATE ON THE CRITICAL PATH INITIATIVE

CDER CRITICAL PATH ACTIVITIES

DR. THROCKMORTON: Good morning. It\'s a

real pleasure to be here today. I\'m honored to have

an opportunity to talk about what the Center for Drugs

has been doing along the critical path.

I came to this current position relatively

recently, about six months ago. I was in the review

divisions previously and I would say had a less clear

idea of what the Critical Path was about, had read the

document but I would say had some questions. But in

the six months that I\'ve been there, I\'ve had the

opportunity to really understand where Dr. Woodcock

and Dr. Crawford are going with this. I think it\'s a

terribly important project, something that we really

need to succeed at.

What I\'d like to talk to you about in the

next few minutes is, first, where I think Critical

Path fits into the CDER overall goals and missions.

I believe it fits very easily within the larger

context of both CDER, FDA, and HHS goals and the

things that we are looking to accomplish.

I\'m then going to talk to you briefly

about several of the opportunities that Dr. Crawford,

Dr. Woodcock, and Dr. Galson have identified as

critical for the center to carry forward. I\'m going

to talk about them fairly briefly because there are a

number of them. And then I\'m going to end by

burrowing down on three specific projects that fall

into three different kinds of areas I\'ll go through in

a bit to give you a better flavor of the kinds of

things that people have been talking about doing and

conducting within the center.

So, as I said, I believe Critical Path

fits very easily within the CDER goals for 2005, as

articulated by Dr. Galson, the larger FDA strategic

goals, and the HHS, the Health and Human Services,

strategic goals. And if you look, you can see

Critical path. Well, maybe you can see Critical path.

That\'s all right. Maybe you can see Critical path at

the bottom of the thing there next to cGMPs, which is

something I think that you\'ll be hearing a great deal

more about today.

CGMPs in any ways is a critical path

function, a thing that, in fact, is looking to enhance

the efficiency of drug development as well. It\'s also

next to quality systems. It\'s next to follow‑on

biologics. It\'s next to things that sound very

similar to Critical Path that fit very clearly into

the larger mandate that the FDA has to develop both a

stronger FDA, a stronger, more consistent FDA as well

as enhancing risk management, patient safety, et

cetera, which, in turn, fits into the largest HHS

strategic goals, increasing the scientific enterprise,

achieving excellence in management, advancing health

care services. So I think this is pretty clearly a

thing that is consistent with the larger goals of the

agency.

So what has the Center for Drugs been

doing? What identified projects do we have as far as

the critical path? We received around 60 written

applications. Let\'s just say they had variable levels

of detail.\* RD stops \*

There were sort of two kinds of proposals

that we got. The first kind of proposal in the

largest sense dealt with things where we had data

in‑house, where the FDA had a large experience that

had either been submitted from sponsors or had been

accumulated from other ways that had not been looked

at systematically or maybe had not been looked at

systematically in this particular way, where looking

with a focused question, potentially with some

additional resources, would allow you to construct a

database, facilitate guidance, make a more efficient

drug development process.

The second bucket, if you will, the second

part of the kinds of projects were longer‑term or what

I\'m calling longer‑term projects. These are things

that deal with newer, more complex issues, where we

really didn\'t have particularly large amounts of

expertise or particularly large amounts of data

in‑house, where we would necessarily need to identify

external resources to look for both content and

expertise.

These things are terribly important,

however, but the idea was that maybe they would take

a bit more time, where we would need to identify these

sources and work towards guidance and

standard‑setting.

This slide is one that I am sure that all

of you have seen. It comes from Dr. Woodcock, from

the white paper that was published. I show it ‑‑ I

can\'t use the red dots ‑‑ mainly for the safety,

medical utility, industrialization words on the far

left of the slide. Those things are going to recur

because those are the three areas that the center used

to sort of think about the different proposals that

came in. I think at the end of the day, we got good

proposals in all three areas.

So what kinds of proposals did we see? I

am going to walk through several of them fairly

quickly. I hope Dr. Woodcock or Dr. Galson will be

able to give you some more details. If you have

specific questions, I would also obviously be happy to

talk with anyone later on to be able to give you more

details about them.

In the first area, these short‑term

projects you remember that I talked about, where the

notion would be that we have had data in‑house,

expertise in‑house, we would look at the materials,

come up with guidance, white paper, have external

conversations, and move towards standard‑setting, we

got a large number of projects. I would say the

largest single category of them was the development of

safety or efficacy biomarkers or surrogates. And this

slide lists three of them, three of the identified

issues that were submitted.

One issue that has been a particular

problem I will talk about a bit later on is how to

assess new drugs for their cardiac risk, whether or

not they are proarrhythmic in earlier models. And one

project that has been proposed is to look for

preclinical markers for that safety issue. So the

notion is, instead of conducting extensive clinical

studies, you could use preclinical models and

obviously make things a bit more efficient.

In a similar vein, there was a proposal to

warehouse ECGs to, again, make it possible to make the

development in this safety area a bit more efficient.

Another group proposed a database to

facilitate animal models to look at the standard

safety issues that confront all drug development:

carcinogenicity, genotoxicity, reproductive

toxicology, et cetera.

We also had a proposal, again, in the line

of reviewing our available data to look at the

controlled substances staff materials. We have

controlled substances decisions going back I guess

about 15 years now. And it\'s a science that I would

say would be useful to look back at and see if we can

identify a better way forward, maybe perhaps a more

efficient way forward to determine whether or not

novel compounds need to be scheduled in conjunction

with the DEA.

Another group proposed a centralized

approach to monitoring of exposures of novel drugs

during pregnancy, a thing that obviously has a huge

potential public interest.

With regard to efficacy and efficacy

biomarkers, you remember I told you those were a very

common thing. Here\'s a long list of them. I think

you have the slides in your packet. I won\'t go

through each of these individually.

I would say that in the main, they focused

on identification of either ways of conducting trials

more efficiently, making it easier to know when a

patient has a disease so that you\'re, in fact,

studying a person with a disease\'s response to a new

drug, instead of, in fact, testing it in an

undifferentiated population that might be less

efficient, or it\'s a way of looking at novel surrogate

developments, new, more efficient ways of conducting

trials in various therapeutic areas.

Also proposed, other examination looks at

the way we predict in drug manufacturing, ways that we

predict drug dissolution and bioavailability, moving

towards manufacturing. Is there a more efficient way

to replace the sort of paddle and wet chemistry

approach that has been used to assess post‑marketing

manufacturing and dissolution of drugs? Is there a

way that we can look at the available data on oral

contraceptives and systematically understand the best

trial designs there to understand the lowest amounts

of the various components that need to be used, again,

to both maximize efficacy and safety?

Then, finally, on this slide, to develop

a library of pharmacogenomic variations, this is one

that has had some interest, obviously, in the news of

late, to be able to characterize the children in

pediatric studies of depression so that, in fact, we

would understand better the nature of the disease that

is being studied in the various trials.

And then, finally, along the

industrialization path, it\'s been proposed that we

look at ways of understanding how changes to biologic

products affect the efficacy and safety of that

product. This is largely in post‑approval, but if I

change the conditions in the cell culture that has

been used to develop a biologic agent, when is it that

I need to conduct additional clinical studies? When

can I view that change as clinically not

consequential, perhaps not necessary to do additional

testing?

And there are two obvious places where you

might look. And obviously follow‑on biologics is a

place or whatever the words people call that these

days would be a place where that would be of interest.

Second largest group you remember was the

guidance and standard‑setting in new areas of drug

development, this place where we have relatively less

expertise, relatively less data.

CDER identified a group of areas. And,

again, I\'ll not read through these in the interest of

time, but they are all varied in the sense that some

are from manufacturing, developing a context, the

product development. Some are for efficacy

development, developing its novel statistical

guidances that are applicable to multiple therapeutic

areas. And you can see the list there.

The last, the bootstrapping methodology

was proposed to look at preclinical testing to make

potential use of fewer animal subjects to understand

the safe use in development of new drugs.

We had a proposal to look at

patient‑reported outcomes in phase III studies to make

that more efficient. We have been working on a

guidance, as you may well know about this, and hope to

be issuing that fairly soon.

Develop analytical methods for novel

dosage forms, novel ways of delivering product.

Liposomes and patches are two things that I have had

the good fortune of spending a lot of time discussing

with sponsors and things. They are terribly

complicated. And these are places were guidance from

the FDA I believe could make the process more

efficient.

Bioequivalence of locally acting drug

products. Again, this is a place where we have been

unable to use or we have not wanted to turn to the

standard bioequivalence testing of using serum levels,

et cetera. It would be nice to find alternatives.

So what three opportunities have we

identified that I would just like to share with you?

Again, largely in the interest of saying the

opportunities we have identified go across all three

areas. That is, they\'re related to both efficacy,

safety, and manufacturing. Many of them are

short‑term. And, again, there are some that are going

to take a bit longer to accomplish.

So the first one I mentioned briefly

before was the ECG research database and tool kit.

And I said drugs in development have needed to assess

their effects on cardiac arrhythmic risk. And we know

that there were several drugs withdrawn from the

market recently because they had an effect to cause

cardiac arrhythmias that had not been detected during

their drug development at a substantial cost to the

market and obviously of concern to everyone.

To prove that, the database proposal will

collect the electronic ECGs that sponsors currently

use to assess data, clinical data. These ECGs have

not been submitted to the FDA because there has been

no standard for submission.

We have had no data standard that allowed

sponsors to say, \"Here\'s an electronic ECG, and here

are its characteristics.\" By erecting that standard,

that standard in this case would be working through

the national standard‑setting groups.

It would enhance both efficiency of ECG

collection and submission to the agency. It would

also enable us to look at these ECGs in hope of making

drug development approval much more efficient.

I think there are a lot of questions

regarding cardiovascular safety that we simply don\'t

have any good idea about. Having this database

available in this case, it would be a database that

would be eternal. It would be held on a server and

available to academics, available to sponsors as well

as the FDA. And the ECGs are all anonymized. And so

you would have a much better way of assessing how best

to look at this.

The goals are to develop a standard, as I

said, to develop a research database and a Web‑based

tool and ultimately to support the develop of

standards in this area to test and guide development

of product safety. This would contribute to a more

efficient assessment of cardiac risk. It would

increase the ability of sponsors to predict successes

or failures early.

They could determine whether or not the

things that they\'re seeing in a preclinical model or

something, in fact, had some particular concern for

the clinic and potential identify novel ACG markers

that would make safety assessment more efficient.

Ultimately this would lower costs for new product

development and increase the ability of sponsors to

produce high‑quality products and applications.

The database is being worked on currently.

And I am optimistic that with some luck, it would be

possible that we would have this delivered within the

next year. Obviously I think that would be a useful

thing for drug development as a whole.

The second piece that I wanted to talk to

you about falls, I would say, more into the efficacy

realm. So we have talked about safety. Now let\'s

talk about efficacy or, in this case, what the

critical path document calls medical utility. We need

to understand very clearly how to look at drugs in the

pediatric realm.

We have a very large experience now from

the Best Pharmaceuticals for Children Act as

follow‑ons. We need to understand. And obviously the

SSRI issue has recently sort of reinforced this.

We need to understand the most efficient,

most effective way of assessing products in children.

We need to look back and understand quite clearly what

we have learned from these 150‑plus trials, something

like that, across many, many therapeutic areas.

We have all of those data in‑house. It

would be a goal of this particular project to develop

an analytic database of all of these trials since the

initiation of the BPCA and look at those trials for

appropriateness of extrapolation. Extrapolation is a

thing where you take what happened in adults and

conclude that it is very likely that that would happen

in children. That allows you to reduce the amount of

trials that you would need for children.

Is that appropriate under all

circumstances? Can we determine when that is and is

not appropriate, again to the extent of making more

efficient collection and trial conduct to determine

the best practices for children\'s trial designs and

promulgate guidance to guide future pediatric trials?

The interest in this is obviously high.

The potential gain I think for this is enormous.

Increased interest in feasibility of product

development in children I think no one would disagree

would be a terrifically good thing. It would also

enable sponsors to have more clarity about what would

be needed, what would be expected, what outcomes they

could expect from their trials, which I think would

stimulate additional research.

The time limits here are longer only

because, one, we have a very large database.

Therapeutic areas are very broad. And exactly how to

ask and frame those questions is going to take some

conversation in developing the analytic database may

take as much as two years. I guess, like Dr.

Crawford, I get to wave my hand.

I think this is a thing that is eminently

doable. These are data that have been tracked very

carefully in‑house. It\'s a thing that we could do

and, again, determining best practices and publishing

a guidance to guide development in this terribly

important area.

Then the final thing that I would like to

talk about falls into the realm of industrialization.

So this is manufacturing quality, chemistry, et

cetera. Here the need is to make it possible for

sponsors to use novel ways of assessing product

quality, both during manufacturing and

post‑manufacturing.

The during manufacturing piece you will be

hearing a great deal about from the cGMPs later on

today, I think. But one part of it is to say while

you are conducting your tests, it would be very useful

for you to use novel technologies to assess online

quality, quality as the product is being made, rather

than waiting until the product is final and then

taking a pill off the end of the line.

So the notion is that by R, you use

different mechanisms of understanding the distribution

of the product of the drug substance within a pill;

for instance, something like that. Rather than

destroying it at the end of the day, you understand it

through other more novel mechanisms. Well, novel

means there are no standards or at least potentially

means that you don\'t know what numbers to choose to

set your instrument to.

And so one particularly important part of

the cGMP initiative of a part of that called PAT

initiative is to expand our standard‑setting, make it

possible for sponsors to support the choice of

sponsors to use these particular novel technologies.

Facilitate more efficiently produced and consistently

formulated product is the need.

The goal would be to develop methods for

defining and validating these calibration standards,

to develop instrumentation standards after you decide

how best to go about doing that, and to publish

guidance describing those standards as well as

providing training to the CDER staff on these changes

because I will say cGMP and PAT is a thing that really

is a sea change in the way we have thought about

manufacturing, the thing that is requiring a change in

the way the review staff think about this. And it\'s

going to be important to make them aware of these

novel changes.

This will contribute to the FDA

utilization by quality, by design and risk‑based

assessment, which, again, you will hear more about.

It will reduce the likelihood of production of

low‑quality products, promoting consistency, et

cetera, and reduce the risk of defective or

contaminated products reaching market again, all very

important things.

The time lines for this are, again,

longer. This is a thing where we don\'t have extensive

expertise in‑house. This is a thing where we don\'t

have extensive databases to look to and analyze and

promulgate guidance from. It\'s going to be important

to partner with the outside, I think, and identify

places where we can locate resources to help in this

particular area.

There are going to be needs for specific

targeted studies by the FDA, I believe, in terms of

using the instrumentation, understanding its

characteristics well enough, again, to decide how to

set the standards, and then setting them, and then

ultimately to discuss and publish guidance with the

outside stakeholders.

So I am going to end by just saying that

I believe that having been in my current position that

the present state of health product development is not

sustainable, as Dr. Crawford said.

I think the FDA needs to lead to question

any assumption that limits or slows new product

development. We need to decide if those assumptions

are justified. We need to decide if there are more

efficient alternatives. And if so, we need to

understand why those alternatives are not being

utilized and work towards overcoming that resistance,

however we can.

I think the critical path is

well‑integrated into the CDER goals. And I think that

CDER has identified a preliminary list of critical

path opportunities that will have substantial public

health impact if funded appropriate.

Thank you.

CHAIRMAN SHINE: Thank you, Dr.

Throckmorton. Just clarify one thing for me I\'m not

clear on. You had indicated that there had been 60

proposals.

DR. THROCKMORTON: Yes.

CHAIRMAN SHINE: It\'s not clear to me.

Are these the three elements that you have selected

from among those proposals?

DR. THROCKMORTON: Yes. I know I ‑‑

CHAIRMAN SHINE: Are there going to be

additional proposal? I just want to understand what

the boundaries are.

DR. WOODCOCK: If I could clarify one

thing? We ran an internal process for our review

groups as well as the docket process we\'re going to

discuss later. What Doug is talking about is the

internal process within CDER, within its management

scope.

CHAIRMAN SHINE: And what\'s the outcome of

60 proposals?

DR. THROCKMORTON: The ones that you saw

were discussed with the agency group, Dr. Woodcock and

the group that has been meeting, as well as with Dr.

Galson. Dr. Galson and that group, the ones that I

have shown today have all been identified as

opportunities that CDER believes is ‑‑

CHAIRMAN SHINE: So those are your

priorities out of those?

DR. THROCKMORTON: Yes, that\'s correct.

The others, not to say they\'re unimportant, but that

these were the ones that, at least on surface, seemed

the most important to carry forward.

CHAIRMAN SHINE: The way the agenda is set

up, there is a discussion period from 11:00 to 12:00.

But while these presentations are fresh in your mind,

if you have a clarifying question or whatever, please

ask Cecil. Dr. Pickett?

MEMBER PICKETT: I have one questions

regarding the ECG research database and tool kit.

Well, first of all, I would like to just complement

the activity. I think it\'s a step forward as a whole

on some of the initiatives, certainly a step forward,

and important, really, for all stakeholders.

Specific comment about the ECG research

database and tool kit is that I would be concerned ‑‑

I think it\'s very important you check with sponsors ‑‑

that ECG collection is sufficiently robust early

enough in clinical studies that this database will

have any meaning, particularly if you\'re trying to

pick up things such as QTc prolongation.

DR. THROCKMORTON: Yes, terrific point.

There is a partner to this particular proposal that I

didn\'t talk about that, in fact, is collecting the

larger data of the preclinical data available on these

same studies, the changes in mean QT from the same

studies, and, in fact, asking that at that terribly

critical question. One, you know, are we detecting a

signal when we need to be detecting it? And, two, I

would say the preclinical is another part of that.

This one is particularly focused on how

best to look at the intervals, how best to measure

them, how best to bring them into the Food and Drug

Administration. What\'s the most efficient way of

doing the measurements?

There\'s another part to it about when

those measurements should most appropriately be done,

how best to understand those measurements, et cetera,

and that is an important part as well. Right.

CHAIRMAN SHINE: Well, thank you, Dr.

Throckmorton.

Let\'s move on. Is Jesse presenting or

Kathryn? Okay. Sorry about that. Kathryn Carbone is

going to report with regard to biologics.

DR. CARBONE: Thank you.

CBER CRITICAL PATH ACTIVITIES

DR. CARBONE: Welcome to the Board. And

thank you very much for being willing to help us in

our pursuit of this endeavor.

I want to start with a vision of CBER.

Upon his arrival, Dr. Goodman gathered the management

staff and revamped our mission statement and our

vision statement.

I would like to just start with our vision

statement that our goal is to protect and improve

public health and individual health in the United

States and, where feasible, globally. And I think the

recent events obviously with the flu vaccine have

shown that it is a global issue in public health,

facilitate the development, approval, and access to

safe and effective products and promising new

technologies and then to strengthen CBER as a

preeminent regulatory organization for biologics so

that we can serve as a resource to the United States

and the rest of the world.

Innovation is the science of biologics

product development. The innovations by definition

are required in effective biologics regulation. Our

goal to get more innovative biological products to

patients needs to be addressed from a scientific level

to feed into the regulatory decisions.

We want to achieve robust biological

product development to pathways that are efficient and

predictable. And this is difficult in some areas,

particularly in biologics, since there are no pathways

historically to simply follow. They need to be

created. And also with many problems comes a great

opportunity, which is to develop pathways that make

good scientific sense, good medical sense, and that

are based on modern technology.

So how can we do this? Well, as was

mentioned by Dr. Pickett, I think one of our most

important activities is to communicate more closely

with stakeholders from our sponsors to the public and

the patients and the consumers and the physicians.

We need to listen very carefully to see

what the needs are and where the priorities lie. Then

we need to work together to develop and evaluate the

scientific tool kits that are going to be able to

bring these scientific advances to actual medical

utility.

And so, in doing so, we have been taking

this opportunity through the docket of the whole FDA

effort, in addition to CBER effort with biologics,

biological products, stakeholders, to work with these

stakeholders to help us develop our pathways.

The CBER staff has a long history of

coordinating, collaborating with academia, industry,

scientists, et cetera, and those that are involved in

these areas, and work together to develop a common

understanding and to make pathways where none exist

and to improve pathways that do exist.

We have, at least in the research program,

every year a research program management report that

is submitted to me and analyzed. And every year we

end up in analyzing and leveraging and collaborations.

And we have collaborating activities with over 100

different institutions in the United States currently

and across the global scientific community.

We want to apply these new sciences to

chart the predictable and efficient pathways. And I

think what is very important when making a new

initiative and assessing where to go next is to take

these changes that we implement and approaches that we

implement and assess with periodicity how they\'re

functioning and make changes in our approaches, as

warranted by the outcomes.

Why CBER for biologics? What is the role

of the FDA, and CBER specifically, in the biologics

area that makes us have the hope that we can have

impact in these improvements? CBER guidances are

based on science.

Those based on science can foster

innovation and improve chances of success of entire

fields. We have the ability to look across an entire

field of product to see the common problems, the

common opportunities, and to advance the fields as a

whole.

Our CBER scientists who are in the

laboratories as well as our scientists who are not,

the biostatisticians, epidemiologists, et cetera, all

do review as part of their activities. They literally

open up applications and identify areas where the

information is simply not there, the scientific

knowledge or the scientific tools are not there to

move forward on the basis. And they identified

directly problems that need solution.

So, in addition to listening carefully to

the outside stakeholders, we also have internal

ability to add to that information and identify those

gaps.

And we believe CBER can play both a direct

role internally, gaining familiarity in expertise and

setting, turning some new pathways, but as

importantly, a role of convening, collaborating, or

simply stimulating an area to drive outside interests

in these areas for advancement.

So Dr. Goodman met with the scientific and

regulatory staff and came up with several areas that

we identified internally as important areas. Keeping

in mind that without clear pathways, there is likely

to be less innovation; new adjuvants, for example, for

vaccines. We have some classic adjuvants that have

been used for years, but there are obviously new

opportunities out there. However, it\'s difficult

without some sort of common knowledge and agreement

across the stakeholders for a single sponsor to invest

a tremendous amount of energy and economic effort into

developing a new adjuvant without knowing what the

FDA\'s thinking is, what kinds of issues are important.

By doing this ahead of time and working

together, we can actually identify areas, innovative

areas, and develop a common understanding of where

some promising pathways might be.

So to upgrade and advance the science of

vaccines is a very important area. To develop and

make available to cell banks in our discussions with

individual stakeholders as well as the meeting I will

tell you about in just a moment, we heard repeatedly

the issue of \"Wouldn\'t it be very nice to have

available a series of cell banks that have been

well‑characterized for safety, tumorigenicity,

adventitious agents that could be tapped to make

biological products that would be made publicly

available?\"

It\'s a difficult thing for a single

sponsor to take on. And if they took it on, it would

be their proprietary material. However, working

together in a community of stakeholders and CBER, we

could actually work to provide banks that would be

publicly available.

We have an area which has very little

regulatory historical pathways. We have several

areas, one being cell therapies, gene therapies. And

one of the opportunities in modern‑day science is to

be able to characterize these new therapies very

carefully and then link these outcomes, the

characterization information to clinical trials.

Now, biomarkers traditionally are to focus

on the human organism, but since so many biologicals

that we deal with are living organisms as well, there

may be an advantage in using a biomarker‑type approach

to characterize the product as well as the outcome.

Then, of course, there are many individual

methods that are currently of interest across multiple

areas, pathogen detection and biological products to

do this efficiently, to do it particularly in blood

supply, where volumes are important to keep to a

minimum volumes that are wasted or used in testing,

also the onset of pathogen inactivation and making

products safe once you identify a pathogen to be able

to inactivate and continue to use the pathogen and, of

course, from a public health standpoint improving

longevity in storage of blood and tissues; for

example, platelets having a fairly limited shelf life.

So as one of our first efforts in taking

some very good cues from the total FDA effort of

investing stakeholders in conversations, in early

October, we held a meeting with biologics and

stakeholders, including sponsors, patient advocacy

groups, industry, academic, other non‑FDA federal

scientists. And we formed panels to talk about

priorities and issues and to develop at least the

beginnings of a consensus. This is just the first

foray into this sort of discussion.

In the morning, we had presentations of

CBER offices about internal critical path plans and

activities and suggestions. And those presentations

actually are available on that link that\'s at the top

of the screen.

In the afternoon, we held breakouts for

different products, vaccine blood products, et cetera,

et cetera, and we collected that information. It\'s

been summarized. And we will be working with a

publishers to produce an article that summarizes the

field.

Now, this does not compromise our plans

for what CBER wants to do. This is to sort of hep

motivate the field, the whole field entirely.

So I\'m just going to very briefly finish

with some ideas that were brought up at the workshop,

many of which already resonated with us, but it\'s

partly an issue of prioritization.

We can all list 100 things we need to do.

We have to figure out which are the best things to

start with, as Douglas indicated. And I think these

discussions are very helpful in the prioritizing.

Obviously across the whole FDA ‑‑ and I

will mention this briefly because this is really an

across‑the‑FDA issue ‑‑ is study design and

statistical analysis for clinical trials. Then

specifically for biologics, the preclinical safety

assays, predicting cancer risk becomes very important

across all of our products, cell and gene therapies

obviously but also vaccines and cell substrate issues,

developing with our sponsors and stakeholders sort of

a uniform dialogue and approach to testing cell lines

used to manufacture biologics for tumorigenicity

potential, vectors, gene vectors, for tumorigenicity

potential

neurotoxicity so that we can do adequate risk analysis

and risk management for these products.

Animal models are critical because much of

what we do is safety and disease model‑oriented. In

vaccines, we have neurotoxicity, but there are other

very important types of preclinical studies that we

need to work on so that, as mentioned very eloquently

in the white paper, if a product is going to fail, let

it fail very early before a tremendous amount of

investment had happened. So preclinical studies for

safety and efficacy are very important.

Biomarkers and surrogate endpoints,

surrogate endpoints being a tremendous way to take a

vaccine trial from 40,000 down to 5,000 for the

efficacy portion. So these are ways certainly of

increasing the efficiencies of studying,

characterizing, and validating these products. And

there are many that currently need information that we

don\'t have validated endpoints, immune surrogates.

A classic example was the rotavirus

vaccine, for example. Despite decades of studies,

they were unable to really statistically associate an

immune surrogate. And so efficacy trials needed to be

done. So we need to pay more attention to those

areas, which will have large gains in efficiency.

Cell and gene therapies obviously in

collaboration with our colleagues at CDRH, for

example, the ability to use non‑invasive imaging to

verify that these cell and gene therapies\' work is

very, very important.

As I mentioned, the correlation of product

characteristics with clinical trial outcomes, we have

already made some in roads and some collaborative work

with NIH in stem cells and characterizing stem mast

genes in stem cell lines and then post‑marketing

surveillance, particularly important.

This was actually brought up by one of the

people attending our meetings. It was not an FDA

comment that when we use surrogate markers, surrogate

endpoints, biomarkers, that perhaps the importance of

post‑marketing surveillance only increases to make

sure that we have done a good job in identifying

correct markers.

Manufacturing is something that I think

needs to be highlighted in the critical path effort

tremendously since the FDA and industry and other

sponsors, in particular, are focused on that in ways

in which basic discovery science is not.

So the ability to qualify and study and

make sure that these products are safe and evaluable;

for example, the transmissible spongiform

encephalopathies is a huge issue. And the ability to

test materials, either used to manufacture biologics

or, for example, biological material, blood that will

be transmitted from one person to another, to be able

to test those in such a way that we know the TSE risk

would be a tremendous advance, potency assays to be

able to predictably measure what the product is in

that when somebody gets the product in January of \'05,

it\'s the same product that\'s January of \'06.

Stem cells therapies and cell tissue

therapies are particularly problematic because you

have cells that are inoculated in one form that

transfer in the body to another form. And how do we

connect the two reliably?

References standards, statistical

approaches to manufacturing are very important ways of

improving predictability, product quality, and trying

to streamline the process.

So, to finish up, basically our plans are

to continue open discussions of biological critical

path issues. We anticipate that this fall CBER

meeting will transform into product‑specific or

office‑specific meetings, where it will drill down

into more detail and to help set our priorities and to

develop some initiatives.

We will continue to seek this outside

input and hopefully where a plan is not only to work

internally to strengthen the science and to make sure

we are ready, set, go to evaluate anything that is

presented to us but also to sort of serve as a leader

and stimulate the field as a whole outside, outside

the FDA and CBER.

We want to keep the process as transparent

and as accountable as possible. The science

organization and priorities and outcomes for every

product office are going to be reviewed in 2005 in

open public meetings using our advisory committee

mechanisms, where we will seek input.

In addition, we will continue our regular

formal external reviews of the science program within

CBER at the individual science level to make sure that

their work, they efficiently use resources, that the

work is high‑quality and productive. And then we will

use these mechanisms to continually update our

priorities.

And then it is very important and I think

in any discussion of research and science in CBER and

in this critical path initiative at CBER that we be

very clear that the work is not done until there is

somebody there to hear the tree fall in the forest so

that the scientific advances that are made are clearly

communicated and guidance as policy, publications in

the scientific literature so that the field has

essentially been provided with the information, road

map to help move the fields along.

And I thank you for your attention.

CHAIRMAN SHINE: Thank you, Dr. Carbone.

Clarifying questions, Dr. Cassell?

MEMBER CASSELL: They\'re not clarifying

questions.

CHAIRMAN SHINE: Well, we have an hour

discussion. So in order to keep on schedule mostly

want to focus at this point on anything that was a

clarification.

I do think, Dr. Carbone, in the general

discussion, we are very much interested in hearing

from you and your colleagues about issues such as

incentives for some people to work on these

technologies when they are, in fact, intermediary

technologies and how the responsibility would be

shared between FDA and industry and so forth. But I

think that can be part of the general discussion.

I don\'t mean to inhibit your question.

MEMBER CASSELL: Don\'t worry.

CHAIRMAN SHINE: Okay. Very good. Well,

why don\'t we go ahead, then, and hear from Dan

Schultz? Okay. Very good.

DR. CRAWFORD: As Dr. Schultz is moving to

the microphone with stealthy strides, I would like to

introduce him to this group since I believe the last

time you convened, he was a glint in the eye as

someone who was called \"Acting.\" He is now permanent,

and it is my pleasure to introduce you to Dan Schultz.

He\'s a distinguished surgeon, had a great

career with the Indian Health Service, had that career

interrupted by the greater opportunity at the Food and

Drug Administration, and has exceeded in all things in

the Center for Devices and Radiological Health. He\'s

a joy to work with. I know you will profit from Dan

Schultz\'s leadership.

Dan?

CHAIRMAN SHINE: Dr. Schultz, I saw your

strides as being healthy, rather than stealthy.

DR. SCHULTZ: Thank you. Thank you. Yes.

I think a lot of that was exaggerated, but I

appreciate the words, nonetheless.

CDRH CRITICAL PATH ACTIVITIES

DR. SCHULTZ: How does critical path apply

to devices? That is really what I would like to talk

to you about. Before I can really talk about critical

path, I think it\'s important to understand that there

are some differences between devices, biologics, and

drugs.

So, rather than show you a lot of bullets,

I am going to show you some pictures because I think

pictures really tell the story of devices a lot better

than words do.

First of all, our goal remains the same.

We are here to make sure that devices that go to

market in the U.S. have a reasonable assurance of

safety and effectiveness. That has not changed. That

will not change. And all the things that we are going

to be talking about today are really efforts to

achieve that single goal.

This is a problem for us. We are talking

about a vast array of different kinds of products, all

of which fall under the umbrella of medical devices.

And to try to come up with a single pathway or a

single model that fits all of these different types of

products is, frankly, not doable.

So we in the device world have to be, I

think, in fact, even a little more creative in terms

of figuring out how the critical path will apply and

should apply to all of these different types of

products.

And just to give you a few examples of the

kinds of products that we have seen developed in the

last few years, we now have pills that you can swallow

that take pictures through the digestive tract. And

for those of you who are entering the age that I am,

this seems like a very attractive alternative to what

we are currently being subjected to. So we are very

hopeful that this kind of technology will move forward

and will move forward relatively quickly.

We see devices that are being developed

which allow people to use their senses in ways that

they have been unable to do that before. We have

devices that communicate, that do both diagnostic as

well as therapeutic functions, devices that can

actually start, are beginning to be able to talk to

each other and be able to communicate diagnostic

information directly to a therapeutic device and allow

people with chronic diseases to manage those diseases

a lot more effectively and allow them to carry out

their lives in a way that is not inhibited by their

disease.

Obviously things are getting a lot

smaller. We now have computer devices where as much

information is packed into a device the size of a

quarter that used to take up a whole room.

I don\'t think I have to tell you about the

advances that have been made in the area of stenting

over the last couple of years. The advent of

drug‑coated stents brings up a whole new era, I think,

of what we call combination products, where devices

are being combined not only with other devices but

with drugs and I suspect with biologics as well. This

creates a whole new challenge for us from a regulatory

standpoint and something I think that the critical

path will be important in trying to address.

So we have lots of new technologies. We

have important trends that are occurring in those new

technologies, miniaturization devices that are going

to the home, devices that are becoming more

intelligent. We have new materials. As I mentioned,

we have combination products. And we have disruptive

technologies, which are really changing the way

medicine is practiced.

This is sort of a picture of what we see

as the technology pipeline with respect to devices.

One of the great challenges that we have again that

makes us a little bit different is that once a device

comes to market, that same device does not stay on the

market for the next 20 years.

The device that comes to the market is

essentially being changed during the time that it is

being developed. And normally by the time the new

device gets to market, the next generations are

knocking at the door.

So this is something that makes us again

a little bit different and creates challenges for us,

both in terms of pre‑market evaluation, in terms of

post‑market evaluation, in terms of working with

sponsors to develop not only the innovative technology

but the next generations of that same technology.

Again, I mentioned there are some

differences. There are differences in what devices

contain. There are differences in terms of the

scientific questions that we have to ask. And there

are differences in the issues that we have to look at

with respect to medical devices.

So because devices are different, our

perspective of critical path, while no less important,

has to be different as well. We have different

regulatory provisions, including least burdensome,

quality systems, and design controls for

manufacturing.

We look at biocompatibility. We have, as

I mentioned, an iterative process where devices are

being changed and developed and where we have to be

working with sponsors not only in terms of the new

device but also in terms of the next generations.

We have a significant user learning curve.

It is a lot different using one of these complex

medical devices than it is taking a pill. So in terms

of how the device is used, the impact on its effect

and on its safety is dramatic. And this is something

that we have to pay a lot of attention to.

Performance and durability. Again, we

deal with a lot of things that remain in the body for

long periods of time. So it\'s not good enough to know

that something is manufactured and designed correctly

and that it will work the day that it is put in. It

is important for us to understand how it is going to

perform a year, five years, ten years down the road.

And we have a different industry. This is

something I think that I will be talking about further

during my talk, but it is important for us to

recognize that we deal with an industry that is made

up of some large companies that have extensive

resources, extensive regulatory groups, extensive

scientific components, and we also deal with some

parts of the industry that are companies that may have

less than five people, where there is basically

somebody who has got an idea.

We need to be prepared. And some of those

ideas are, in fact, the ones that are going to change

the way medicine is practiced in the next 20 years.

So we need to be prepared to deal both with the large

companies as well as with the smaller companies.

Devices are a growth industry. This is

data from Dun and Bradstreet showing the number of

device manufacturers and how it has increased over the

last few years.

If you look at that data in terms of

dollars, ‑‑ next, please ‑‑ you see the same thing.

The industry is growing. So our challenges from a

regulatory standpoint, from a scientific standpoint

are not diminishing. On the contrary, they grow every

day. And we need to be prepared to meet those

challenges.

I think this slide sort of speaks for

itself. But, again, in addition to the growth, one of

the things that I want to emphasize here is that the

device industry also has a lot of turnover.

So what we say to people one day needs to

be repeated and repeated and repeated because there

are constantly shifts in the industry, new players,

old players leaving, and we need to be able to

communicate effectively on an ongoing basis.

So how does science play into this? Well,

I think science is critical. Again, as I said, the

questions may be different. How we apply it may be a

little bit different. But the fact that we need to

apply good science in order to be able to solve

problems is something that applies as much to devices

as it does to any other component of medical products.

Some of the things that we have done in

the past that we think have been extremely important

and effective, we have formulated partnerships along

with NIH. And studies have been designed to look at

screening and digital mammography, which, if you

recall, about five or six years ago was one of our

regulatory issues, how to get digital mammography to

the market, what kind of data was required, and what

kind of follow‑up data would be done.

We ultimately were able to develop a

regulatory pathway. Those devices are on the market.

And more of them are coming to the market. And NIH is

conducting a study to look at some of the questions

that were not fully addressed during the pre‑market

period.

Use of objective performance criteria.

Rather than going back to the drawing board each time

with devices that are relatively mature and where we

have some understanding using objective performance

criteria as sort of controls for studies of those

types of sort of \"me, too\" devices, has proved to be

an extremely value tool for us to avoid some of the

large and expensive clinical trials necessary, again,

as I mentioned, for new generations of older types of

products.

Novel trial designs. Again, you have

heard that from my colleagues in drugs and biologics.

One of the most important things for us is trying to

figure out how to design trials that not only answer

the questions but can be done and can be done

relatively quickly and relatively efficiently.

Using different types of statistical

models, including Bayesian statistics, ROC analysis,

are things that we have used effectively in the past.

And I am sure that there are a lot more things that

can be done, both with these types of statistical

models as well as others in order for us to design

more efficient clinical trials.

Finally, guidance development. As I

mentioned, it is fine for us to have this knowledge,

but what is critical for us is to make sure that we

get this knowledge out to the industry and do it in as

clear, concise, and timely a manner as possible.

One of the constraints that we have is,

like everyone else, the same people that are supposed

to be writing guidance and doing this kind of work are

those people that are trying to do reviews. So it\'s

a constant struggle, but it\'s something that I think

is extremely important and is as critical a part of

our job as anything else.

Just to show you that I am not making that

up, we actually did a study that looked at for 510(k)

devices those with guidance and those without

guidance. As you can see, again, I\'m not a

mathematician, but it\'s not too hard to see that

review times for those products that were accompanied

by guidance were dramatically lower than those times

that did not have guidance.

So sharing information, making sure that

the industry understands what the requirements are,

what is necessary, making sure that we communicate

clearly is obviously something that is both good for

us, good for industry, and good for the public.

So now with the new User Fee Act, in

addition to our previous goals, we have goals that

require us to do even faster reviews. And we are

putting mechanisms in place in order to be able to do

that. We\'re looking at even faster time lines for

review of PMA devices and putting mechanisms in place

in order to be able to achieve those time lines.

Go ahead to the next one. Thank you. But

there is a lot more to the story of devices. I think

we all know and we have all seen over the last few

months ‑‑ next, please ‑‑ that even though

breakthrough technologies go out and do a lot of good,

there are problems. And those problems are amply

addressed in the medical journals, including The Miami

Herald and The Boston Globe and The Wall Street

Journal.

We have all seen the headlines. I think

that it\'s critical that we recognize that as these

breakthrough technologies go to market, not only might

there be problems, but there will be problems. We

need to anticipate those problems, and we need to be

prepared to deal with them.

Next, please. One of the things that

we\'re trying to do is make sure that our inspection

program is consistent with maximum use of resources

and making sure that the things that we\'re inspecting

are the areas where we can get the most bang for the

buck in terms of matching inspectional plan with risk.

Part of doing that ‑‑ and I think that

this is an area, again, that is ripe for critical path

research ‑‑ is trying to decide what the appropriate

questions are and how we can do a better job

identifying those areas where inspectional resources

can be better spent.

Next, please. As I mentioned, there are

a lot of questions that remain unanswered in the

post‑market: long‑term safety, performance in

communities, change in user setting, rare or

unexpected adverse events, rates of anticipated

adverse events, human factors issues related to use

and off‑label use. These are all things that we need

to be able to address on a long‑term basis, things

that cannot and will not be addressed by the time a

product goes to market.

So achieving proper pre/post‑market

balance is something that I think is an issue that we

have to deal with. I think it\'s something that we

have sort of danced around for a long time. And I

think it is something that needs to be addressed

directly and something that CDRH is going to be

focused on over the next couple of years.

Why? Because it will allow us to speed

new, innovative products to market. Because it offers

assurance that if we have a strong post‑market

component, it offers assurance to FDA and to our

advisory panels that products going to market will be

tracked and that problems will be identified and dealt

with efficiently and quickly in the post‑market. It

allows us to free up our post‑market staff to continue

to evaluate new technologies and make sure that those

are not held up while we are looking at all of these

other problems.

It generates data for the next generation

of devices, which, as I mentioned, is extremely

important, and generates data for enhanced labeling so

that when a device goes to market, if new information

is generated, that information should be passed along

to the public as quickly as possible.

So what is the current state of

post‑market studies? It\'s not very pretty. Many of

the studies that are currently being used I think it\'s

fair to say are ill‑conceived. A lot of them are not

even started. Many of them are not completed.

They\'re not well‑tracked. And our enforcement of

these studies has not been particularly stellar.

What would I like to see? I would like to

see better study designs. I would like to see a

standardized reporting system for post‑market studies.

I would like to see better tracking. And I would like

to make the status of those studies public so people

understand when companies agree to do and we agree

that post‑market studies are necessary, that they

actually get done and that the data is shared so

people will know what is going on.

Science is the underpinning to all of

these activities, whether they be pre‑market, whether

they be post‑market, whether they be compliance. I

put up a picture of our new laboratory. And this is

one example of how we are trying to make sure that our

science remains second to none.

I would look at science in its larger

sense, both in terms of bench science, in terms of

science that is done within the agency itself in terms

of science that is done in cooperation with academic

institutions in terms of clinical science, statistical

science, and regulatory science. Without good

science, the whole thing falls apart.

I am going to put up a couple of examples

of critical path opportunities that we have looked at

and think are worth pursuing. As has been previously

discussed, many examples have been submitted through

the docket. We have had discussions with a number of

different people, both within academia and industry.

And this list that I present to you today

is a preliminary list. It\'s some of the ideas that we

think can be pursued and can be addressed in the short

term but certainly by no means should be viewed as the

end of the line. In fact, I think it\'s very much the

beginning of the line with respect to what we

anticipate doing with critical path.

CHAIRMAN SHINE: Dan, we want to be sure

to have time for our conversation later.

DR. SCHULTZ: I apologize. Am I going ‑‑

CHAIRMAN SHINE: If you could just

summarize?

DR. SCHULTZ: Well, let me just have you

look at these, then, establishing a blood panel for

assessing sensitivity/specificity for hepatitis

assays, computer models for testing vascular stents

before they\'re implanted, a regulatory pathway for

looking at intrapartum fetal diagnostic devices.

Next. Sorry. I missed one. Anyway, you

got to read it.

So, in summary, I think we\'re making

steady progress towards meeting our review performance

goals and our total product life cycle strategic

goals. Success is achievable but highly

resource‑intensive.

CDRH continues to seek innovative methods,

partnerships for evaluating new technology based on

sound science, least burdensome manner. And critical

path will further our existing efforts to achieve the

right regulatory balance and ensure the safety and

effectiveness of medical devices.

Thank you.

CHAIRMAN SHINE: Thank you very much, Dan.

We want to come back to a number of

questions. Are there any kind of clarifying questions

that anyone needs to ask at this time?

(No response.)

CHAIRMAN SHINE: If not, then we\'ll hear

from Lisa Rovin before we take a break. Lisa?

OVERVIEW OF CRITICAL PATH DOCKET SUBMISSIONS

MS. ROVIN: Good morning. To those of you

who submitted information to the docket, we thank you

very much. We appreciate your efforts. And we\'re

paying very close attention to what you\'re telling us.

We got 120 comments. Actually, the

electronic docket may still be open. I\'m not sure

when they shut that down. Each of those comments

contains multiple, suggestions for scientific

hurdles that need to be addressed and opportunities

for us to improve the critical path.

Before getting into the scientific hurdles

and opportunities that you identified, I do want to

start with some of the broader themes that we\'re

seeing in the docket.

I think Dr. Woodcock has the best way of

describing the overall message, which is that the

critical path initiative has been met with \"violent

agreement.\" There is just overwhelming ‑‑ I hope you

don\'t mind if I quote you ‑‑ just overwhelming

concurrence, both with the diagnosis that this is a

problem of scientific infrastructure but also

concurrence with our proposed solution, the

prescription of looking at science, looking at

research, doing it collaboratively, and focusing on

science‑based standards. You have seen Dr. Schultz\'s

data on what a guidance can do. So that should come

as no surprise.

I am going to go very quickly. If I am

going too quickly, please stop me.

Another reason we call this \"violent

agreement\" is because we heard it from everyone, from

all sectors of industry, patient groups, academia. I

won\'t read you the quotations. They\'re in your

materials. But these are not things that we had to

thumb through the docket to find. These are all over

the docket, just a few examples.

These come from patients, to show you the

breadth of the recognition of the problem and also the

recognition of the important role that FDA has to play

in forming a focus for solving the problem.

FasterCures is a broad‑based patient

advocacy group looking at speeding medical innovation,

the prostate cancer people, AIDS Activist Coalition,

Osteoporosis Foundation. Also from industry: devices,

biologics, biotech drugs.

The AdvaMed comments were interesting. "We remark particularly on the
recognition that there is more to speeding up the overall process of
getting a product to market than simply revising the review

process." We see this also from Baxter, Bristol‑Myers, Johnson and
Johnson.

At the end of my slides, I am going to

tell you how to get into the docket and look and see

for yourself. I encourage you to do that. You don\'t

have to believe it because I am saying it.

The next thing we heard is a call for

action. People weren\'t just identifying hurdles.

They were making very good suggestions for things that the FDA can do.

So what are stakeholders asking us to do?

I will put some science in underneath this in a

second. But the other thing we were really gratified

to see is people aren\'t just telling us what to do.

They\'re offering to do it with us. We think that is

critical for this initiative. It\'s not just about the FDA.

In fact, there were so many calls for

action that the demand exceeds the supply. We have an embarrassment of
riches. And later this morning, actually, we\'re going to ask the Board
to help us suggest some principles that can guide our decision‑making in
how we decide to spend our resources.

A few very quick caveats and cautions.

This is not a comprehensive overview. Again, you will hear me over and
over telling you, \"Go on the Web.

See them for yourself.\" I\'m just going to tell you

the major themes, give you some flavor of the specific examples, lots
and lots of good ideas.

So what hurdles to efficient product

development were raised most often? Without even a

close second, we heard about clinical trial hurdles

and biomarkers.

I will tell you about more issues, but

first I want to spend a little bit of time here because we heard so much
about these two issues. No question this is where we have to do some
focusing.

Starting with clinical trials, the

concerns expressed about clinical trials addressed not just trial design
but also trial administration. So I will give you a sense of all of
that.

A wide array of themes within the overall

concern. Here are some of the ones expressed most

often. There was a lot of discussion about the need

for new statistical tools. You have heard about that

from all of the centers this morning. So it seems

like there should be no surprises here. Bayesian

methods and better use of historical data, methods for imputing missing
data were of particular concern.

People are also looking for help in

figuring out how to use adaptive designs, moving

forward on improving non‑inferiority trials,

proof‑of‑concept enrichment designs.

Modeling and simulation in the clinical

trial area, we got a lot of requests to do that and a

very strong recognition that we\'re really looking just for first steps
there. It\'s a long road, and we need to do some agenda setting.

The comments are not just about trial design, also trial administration.

The docket includes calls for standardization of data collection and
submission,

investigator contracts, lots of other calls for

standardization, of IRB issues, consent issues. And a number of these
comments do recognize the IT issues

that are embedded when you\'re talking about electronic

submissions. So we are looking at those.

In addition, the docket includes requests

for development of disease‑specific trial protocols. People wrote in on
specific diseases and asked for help on standardized protocols.

A fair number of concerns about patient

recruitment and enrollment and some suggestions about

education and IT solutions to those kinds of hurdles.

Calls for consortia and registries, either

disease‑specific or more broad; collaborations with

NIH and many others; and the harmonization of IRB and

consent requirements.

Sometimes when you go through a summary like this, you can get a sense
that the comments were very general. They weren\'t. They were very
specific. So I just want to give you a flavor of some of the specifics.

One comment asks for alternative

approaches to clinical trials for performance of

bacterial detection devices. Another suggested that

we create a clinical trial consortium to address

epilepsy.

One comment said that what we need is a

career model for clinical researchers. There are no

academic underpinnings for the people we need to do

some of the innovative trial designs. Another is

looking for the FDA to articulate its views on

situations where the control is a therapy we know to

be inadequate.

Biomarkers. Unlike the clinical trials comments the biomarker comments
sorted themselves out

into three pretty clear categories. One is people

really want the process for taking a biomarker and

knowing what kind of process and data we need to make

that a valid surrogate for efficacy.

And let me say I understand that the

distinction between a surrogate endpoint and a

biomarker is not optimal. My purpose here is just to

make it clear that there is a range of uses of

biomarkers that the comments were interested in.

The second is to clarify steps and

evidence using biomarkers for other purposes,

enrichment designs, all kinds of other purposes there; and, finally, a
lot of requests to the agency to work to establish biomarkers in
specific conditions.

The docket includes requests to publish

lists of biomarkers on all kinds of topics, ranging

from diagnostics for enrichment designs to valid

preclinical biomarkers from gene expression studies.

Some commenters are looking for guidance

on how we might look to post‑approval data to validate biomarkers. We
got a handful of

comments looking for standards and guidance on how

we might use imaging as a biomarker or a surrogate.

Numerous requests for the agency to work

with stakeholders to identify endpoints in specific

conditions ‑‑ here are just a few of them ‑‑ as well

as some commenters asking for better incorporation of

patient preferences into clinical trial endpoints.

Those were the two topics represented by

far the most, but there are several other topics in

the docket that were represented fairly well, and I

want to run through them quickly.

A lot of comments simply asked for

attention to particular diseases. We had a write‑in

campaign. People wrote in and asked us to make

epilepsy a focus for critical path activities.

I\'m not going to read all of the diseases. The take‑home message for us
is how important this is and what the potential public health benefits
are if all of us work together to solve the problem.

A lot of comments on different aspects of

cancer. The cancer comments really reflected the

other docket comments that I have told you about.

They are looking for new approaches to clinical trial

designs, looking for better approaches to biomarkers,

for more information about the process we expect on

biomarkers, and the need for public‑private

partnerships to boost trial participation. All of the things that you
have heard about, we also got a lot of comments specifically applying
them to cancer.

Again, because summaries can make you

think that the comments are general, here are some of the specific
comments on cancer: looking for validating PET for tumor progression,
ways to get some of these therapies tested earlier in disease
progression.

One comment asked us to prioritize

oncology drugs for study in children and at least one

‑‑ I think there were two that were looking for ways

to move away from survival as a primary endpoint.

Just to remind you, all of my general statements here, not just these,
reflect a rich set of specific

comments.

Here are some of the other topics that

were addressed in the docket. In vitro diagnostics

was a fairly important one numerically. The general

theme was to try to find some way to coordinate the

path of IVDs with their partner drugs, but there

were some also specific things.

One comment asked us to develop accelerated photostability models for
IVD reagents. A fair number of comments also on data mining, quite a
variety of those. A subset of those asked us to look at mining our own
data, the data that FDA holds.

These comments have 2 messages -- move forward, but be cautious.

One comment called this data a

national treasure, recognizing the wealth of data that we sit on \-- but
at the same time a lot of caution about how to move forward, recognition
that that data is proprietary. So we got both messages loud and clear.

Substantively those comments overwhelming

were looking at predictive toxicology, a few other

ideas, but that seems to be what everyone wants us to

look at with respect to the data that we hold. There

was also a very strong recognition in those comments

of the IT issues that are embedded and how we would

move forward on that.

The international harmonization comments

were also twofold. Most of the comments asked us to

do more and to harmonize better, recognizing the

importance of the multinational flavor of drug

approvals now, but there were also some comments who

identified specific standards that we were working on

and told us not to wait for the international

community, just go forward and get the standards out.

We got comments on modeling and simulation. I mentioned the ones earlier
about

clinical trials, but these were on other topics. And

these also focused primarily on toxicology issues and

a lot of preclinical modeling suggestions.

A set of comments asked us to clarify the

critical path for combination products, expressed some concern there.
Almost all of the comments we got on the industrialization piece of the
critical path focused on biologics and scientific hurdles for

manufacturing. Those are recently in the news.

We got some comments telling us we needed

to pay some attention to the scientific side of

developing medical countermeasures for bioterrorism.

Wrapping up quickly, we did get some

messages in the docket that although they\'re not,

strictly speaking, critical path, they weren\'t about

the scientific hurdles or opportunities for improving

product development, do contain some important

messages, and we want you to know we received them

loud and clear. So here is what they are. Critical

path must not substitute for improvements to the

review process. New critical path tools should not be add‑ons. They need
to substitute for the older, less effective tools. And we need to
clarify regulatory pathways for certain types of products, particularly
combination products and tissue‑engineered products.

A lot of people wrote us on that.

Guidances. Do more. Do them faster.

Keep them up to date. Keep them coming. And do them

collaboratively. If you go into the docket ‑‑ and I

hope you will ‑‑ just start picking random comments.

I would say at least half of the comments asked us for a guidance.

We got some messages on communicating

better, a lack of consistency, both within and across

divisions and over time, in our communication about

what is required for product development.

Another huge theme was asking us to create new venues for collaboration
on specific issues. Again, just start pulling up random comments, and
you will see this in I would say about 30 to 40 percent of the comments.
And more and earlier meetings with the agency.

A lot of messages on resource issues and concerns that we might be
diverting resources from

review to critical path. We are not.

Some concerns about adequate and

consistent staffing for product review and a lot of

questions about whether we have enough resources to do the critical path
initiative. And an implicit message that we get is that we need to
figure out a way to get continued input. The docket can\'t be the only
thing we do.

We got that message loud and clear, and we are talking about how to
continue to get input.

The last two slides just tell you how to

get more information. This is how you get into the

docket. Let me warn you since I am getting some phone calls. It is a
little bit cumbersome. There is nothing I can do about that. They are
apparently in there chronologically. You click on them day by day.

But it\'s worth doing.

And, finally, for more information about

what we are doing in the initiative, the general Web

site.

CHAIRMAN SHINE: Thank you very much,

Lisa.

We are a bit behind schedule. So let\'s

take a 15‑minute break.

Janet?

DR. WOODCOCK: I would just like to thank

Lisa. She has done a tremendous analytic job on this

docket as well as managing this initiative. We really couldn\'t be where
we are without her.

CHAIRMAN SHINE: Thanks, Janet. Let\'s

take a 15‑minute break. Let\'s convene promptly at

10:00, see if we can get back on schedule.

(Whereupon, the foregoing matter went off

the record at 9:43 a.m. and went back on

the record at 9:59 a.m.)

CHAIRMAN SHINE: As a number of the

speakers have commented, Janet Woodcock has been

spearheading this activity. And we are pleased to

have her give us an update on the current activities

and the \"path forward\" on the critical path. So lead

on.

DR. WOODCOCK: Thank you.

CRITICAL PATH ‑

CURRENT ACTIVITIES AND THE PATH FORWARD

DR. WOODCOCK: Good morning. You have

heard a lot of specifics of both comments from the

docket as well as what the various centers are doing.

Now I\'m going to talk about for the overall picture

where we are right now and where we expect to be

going.

Next one. First of all, I would like to

reiterate maybe not so much for the Science Board

because we have discussed this before but for the

audience that this initiative has public health

significance.

It\'s not just about speeding up products.

The overall goal is to improve health of the public by

increasing the efficiency, effectiveness, and the

informativeness of a medical product development

process. In other words, the new tools that we\'re

seeking to develop will actually give us more

information as we go about the process of studying

medical products preclinically and clinically and

getting them onto the market.

The problem we have identified is that

this development process, which is supposed to give us

this information, has been stagnating due to lack of

scientific attention to the process itself, to the

development process.

And our proposal at FDA is to modernize

this process by using the new scientific tools that

have been developed. Those range all the way, as you

heard, from modern statistics all down to process

control tools.

Next one. What we are foreseeing and the

reason we undertook this initiative is that we feel

there is going to be public health consequences if we

don\'t pay attention to this problem. We expect that

there might be fewer products directed at important

health needs, such as vaccines or antibiotics. And

having only a few or just having the current

armamentarium of these products is not satisfactory

and is going to become more critical in the future.

We feel that ‑‑ and we have objective

evidence from the developers ‑‑ there are now

disincentives to develop important public health

areas, such as targeted or individualized therapy or

preventive therapies. The reason for this is the high

barriers to entry.

We feel there are disincentives to develop

therapies or devices for less common diseases or

conditions, again because such a huge investment must

be put in that it\'s just not feasible to make that

investment when you are going to lose money.

We see increasingly diminished competition

in the medical products area. It was good to see

that, at least in the device area, the number of firms

is going up. That is very healthy.

We are concerned that we will get fewer

diagnostics in an era when the scientific

opportunities for diagnostics have made several logs

of improvement.

Next one. We are particularly concerned

about this, the slowness in the development of new

biomarkers. The reason for this is not just product

development, but today\'s biomarkers are tomorrow\'s

diagnostics. These are the ways.

This foundation of medicine is how we

determine who should be treated, how we subset people,

how we monitor the response to therapy, how we

evaluate whether they need additional therapy, how we

establish their prognosis. To improve health care, we

need to do all of these things better. And so we need

better diagnostics.

Particularly in the diagnostic area, it

appears that the incentives are really going the wrong

way. We have heard this from manufacturers.

For targeted therapies, the new

therapeutics, which are both biologicals or drugs that

are targeted towards specific pathways or hypotheses,

we often need a concurrent biomarker developed. It\'s

very much like HIV viral copy number that was used

with protease inhibitors to develop them, but we\'re

talking about the cancer drugs, many other conditions,

where we need to be able to subset people and identify

who would respond to a therapy.

So we need those biomarkers to be

developed along with the intervention. But the

current climate is definitely inhibitory. This is

FDA\'s observation.

So this is just the background under which

we undertook the critical path initiatives, the public

health reasons why an agency with FDA\'s mission would

be so focused on this particular scientific issue.

Next one. Now, what we have done to date,

we published the white paper in March. You have just

heard an analysis of what was submitted in the docket.

You have also heard that each of the medical product

centers and, actually, the agency as a whole has

undergone extensive discussion with the external

stakeholders and meetings.

We have had many, many requests for people

to come in based on the response to the document. And

we have had many discussions. We have also talked to

our reviewers in all the centers and the individuals

involved in scientific assessment and evaluation. And

you heard the results of some of those internal

discussions by the centers as far as the ideas coming

up from the troops, so to speak, the problems that

they see on the ground.

Next one. Of course, a tremendous number

of opportunities have been identified, as you already

heard, but there are common themes. And I think this

is helpful.

Number one, we need to focus on improving

the clinical phase of product development as a common

cross‑cutting theme. We heard that internally. We

have heard that externally. So obviously that is an

area of focus.

We need to accelerate the development and

regulatory acceptance of biomarkers and surrogate

endpoints. That is very clear. And we have heard a

message internally. And externally let\'s mine FDA\'s

databases, this national treasure, more than we have.

I was just talking to Joe Contrera. We

have done some of this, some predictive toxicology,

based on our databases. In the past, we have even

gotten tools out there in the public to use on

structure, activity relationships for carcinogenicity.

But we need to move this forward. That is a work

example that shows that is actually possible to do.

Next one. We were also asked to develop

additional science‑based FDA standards in a huge

number of areas, everything from computer modeling,

product testing, ‑‑ and you have heard a lot of

examples of that this morning ‑‑ statistical analysis,

and data collection and standards, data standards.

We have also been asked to develop

additional reagents, protocols, test protocols, and so

forth, in the industrialization area, particularly in

the area of biologics. And we have been asked to

perform all of these standards activities using a lot

of external collaboration with professional societies,

academia, industry, and FDA consortia, and so forth.

We have been exhorted to do that.

What we are going to do next, we want to

obtain your input on the priorities. We have some

questions that we are asking you. But before the end

of the year, we would like to publish our

opportunities list.

The form which that list will take has

partly to do with the input you will give us on how we

should prioritize or think about this. And we plan to

initiate ‑‑ and you heard a little bit about this this

morning ‑‑ a limited set of projects, you know, five.

And that would depend on the available resources,

which we\'re still evaluating, how many resources are

available. So I want to talk about that a little bit.

Next one. We will begin to at least scope

out and initiate improvement of clinical trials. This

is to streamline and make more efficient and more

informative the clinical phase of medical product

development.

One of the strong messages we got and

something we have been involved in for some time but

not in a very cohesive, systematic way is to

standardize data collection and handling, particularly

in a new electronic world.

You all heard, the Science Board heard,

from Rob Califf at the last meeting. And he believed

he could save 50 percent of the cost of trials from

this type of the standardization and streamlining

effort. We have heard even higher estimates from some

of our industry sources.

So it seems like this is somewhat

low‑hanging fruit. It\'s something we can do. There

are many stakeholders or parties who offered, in the

docket or elsewhere, to collaborate with us on this.

So we will begin undertaking this effort.

We have been doing some work with the

National Cancer Institute, for example, in partnering

with them because they are also very interested in

this as well as overall NIH.

The next other thing we will take on is

development of biomarker and surrogate endpoints. I

am going to talk about that a little bit more. So go

to the next one.

Now, in clinical development, you have

heard from Dan. They are particularly looking at

their themes in the medical device area on the

pre‑market/post‑market balance.

They are looking at bringing in ‑‑ I think

the Science Board has heard about this before ‑‑

additional expertise. An example of a product is

looking at surrogate endpoints for HIV‑induced

lipoatrophy treatments and actually developing a

pathway for that.

Next one. In drug development in the

clinical side, CDER has already begun and is

supporting an effort in quantitative disease modeling

and trial simulation.

This is paired with early meetings with

companies, whereby disease models are created,

quantitative disease models are created, on the

computer.

And then the known information about both

the diseases and the intervention, say it\'s

pharmacokinetics or what have you, are entered into

the model. And then simulation of various outcomes is

done. And the next steps forward in trial design are

model‑based, quantitative model‑based.

So we, the FDA, are working on this and

are initiating this right now. As I said, this

involves incorporation of early PK and PD data. And

this puts an onus on the companies to actually develop

this data early enough to have them be used.

We had a meeting, the FDA, that was

sponsored, cosponsored, by the DIA on dose response

trials and clinical development. This was to begin a

dialogue on how to improve early clinical trials using

modeling and simulation, using biomarkers and other

highly sort of technical issues.

This will also be linked with early

meetings with companies on this early trial

development because one of the hypotheses was really

put forward by the clinical pharmacologists, that

greater attention in this phase of clinical

development will yield better predictability, better

efficiency and informativeness in the later phases of

clinical trials.

That hypothesis is met with some question

by some, but what we need to do is try it and see, do

some work examples and see what it yields. So that

early drug development effort is ongoing. The pace

again will be determined by the available resources.

Next one. The streamlining for the data

collection analysis, what Lisa called the trial

administration piece, all the data standards, and so

forth, we have received many comments to the docket as

well as offers from potential collaborators. It\'s an

opportunity to save time and money for everyone. It

actually will save FDA resources, too, without

decreasing quality if we do it right. And we can

convene and lead an effort. We are in the early

stages. We will start that effort this year, this

fiscal year.

It is going to be complicated because

there are many parties, but there is a lot of

low‑hanging fruit here that we can probably execute

and complete this rather quickly and make some

incremental improvements that will save time and

money.

Next one. Now, another call, ‑‑ and you

heard from the various centers ‑‑ well, was to

accelerate development and regulatory acceptance of

novel trial designs. And that includes statistical

analysis.

A lot of designs have been widely

discussed. There have been many workshops on these

things but not necessarily accepted and used in

regulatory practice. That is due to concerns about

whether the regulators at the end of the day will

actually accept these.

We need either to do some concrete

demonstration projects with the industry or to do some

guidance or both to move the field along. And so we

plan again to initiate this in this year, perhaps not

complete it. Again, the pace of effort will depend on

available resources.

Next one. In particular, some of the

methodologic and analytic issues that really ought to

be addressed are how we are going to treat multiple

endpoints are going to become increasingly common.

We are very interested in multiple domains

of outcome. And the design and analysis of

non‑inferiority trials. Now that we have lots of

available treatments on the market, we are having many

more comparative trials. And we need to figure out

how we analyze those and settle on that more clearly

and then imputation or treatment of missing data.

Again, there is much more interest

nowadays in longer‑term trials. And in longer‑term

trials, you have more people drop out. So what do we

do about that? You can\'t just say, \"Well, we\'re not

going to do longer‑term trials.\" We have to figure

out a way that we can agree on how we\'re going to

treat and analyze those data. We will begin these

efforts this year.

Next one. For clinical trials, there is

a corresponding internal FDA assessment that has to be

made, which is our bioresearch monitoring and IRB

inspection effort, our oversight of clinical trials.

We have recently initiated that project.

That\'s in the formative stages. This is very similar

to the GMP initiative, where if we\'re making

scientific changes, we have to also correspondingly

change our regulatory structure to fit the scientific

changes that are being made. As Lisa said, there are

many calls for us to look at our side at least of the

IRB issues and requirements, make sure they fit into

the modern paradigm.

We are going to evaluate our programs and

their effectiveness. We will modify them as we move

forward in other parts of this initiative. And we

will make sure there aren\'t regulatory obstacles in

the clinical trial process and that we\'re meeting the

objectives of our oversight of clinical trials, which,

of course, is to make sure that the quality of

clinical trials meets acceptable levels and that

patients are protected in those trials.

Next one. Accelerate development in

regulatory acceptance of biomarkers and surrogate. I

should have had \"surrogate endpoints\" here.

Yesterday we had a meeting before the

Pharmaceutical Sciences Advisory Committee, the

Clinical Pharmacology Subcommittee of that committee,

where we began the public discussion of the framework

for work‑up and evaluation of biomarkers and surrogate

endpoints.

That is going to be a long process. It is

going to have to include all of the different product

areas. But at least we began a discussion. Our

discussion was with basically the clinical

pharmacology community, but there is obviously a very

wide community. That discussion has to be conducted

with we will also begin this effort this year.

We will have some public workshops and

perhaps put out a white paper on this or other

document to get this discussion moving. I think there

are tremendous opportunities to move this field along.

And this is a general issue of how do you do this,

rather than any disease‑specific or biomarker‑specific

area.

We hope to see further progress on

pharmacogenomics, which I have presented to this Board

early, as a worked example. We hope to get a final

guidance out on pharmacogenomics within the next

month.

That guidance had a process by which early

biomarkers, where you could come in and discuss those

with the agency without intersecting with the

regulatory process, if you recall, and having

regulatory consequences. That is working very well in

opening up the discussion about the use of biomarkers

and indirect development.

That particular field, the

pharmacogenomics field, is actually moving very

quickly. I think we will see approvals of drugs with

markers in the next several years. So we need to move

along on that. So we will undertake this process this

year as well.

Next one. Collaboration on specific

biomarker projects. We have initiated some research

already with industry on some safety biomarkers. I

think each center probably and perhaps the agency will

work on some specific projects. These will be smaller

projects on specific items.

We\'re also looking at data mining, as you

heard from, say, Doug Throckmorton, the issue of the

ECGs, for example. We\'re evaluating the use of

consortia to advance specific markers. And we have

had a lot of interest from academic, and we are

exploring that right now in setting up consortia that

will enable some of this.

Yesterday the pharmaceutical industry

raised this issue, that there are models, say, from

the semiconductor industry and others of

precompetitive research, where everyone can come

together in a consortium and pursue development of

this structure or underlying science in a

noncompetitive environment. And so we are exploring

that.

We also have been taking up imaging as a

biomarker, as a project. That is going fairly slowly

due to the number of resources we can put against it,

but it clearly is an extremely important and

burgeoning area that we are going to have to pay

attention to.

Next one. This is Gail\'s slide here.

Other important projects. We really are paying

attention in the antimicrobial, antiviral, and vaccine

development areas. We have not solidified what we are

going to do in that area, but we have been having

discussions with both the external folks and the

internal folks.

We have some good ideas about what needs

to be done. And we will move this along. You heard

from Kathy Carbone that, particularly in the area of

cell substrates, that is probably a critical need that

we have identified that we develop some qualified cell

substrates for production.

But we have some other ideas around

diagnostics and so forth that we think would really

help accelerate development in this field. And we

recognize from the HIV example that when you have

really good biomarkers, you can really spur

development rapidly.

Pediatric drug and device development.

You have already heard some of that. We are working

on that as well, including biomarkers and adolescent

depression. It\'s something that we\'re going to at

least explore this year, and there are many more.

Next one. In summary, we have identified

many important specific projects that could be

undertaken. We are going to undertake some. We are

going to undertake the overall clinical trials effort

as well as the biomarkers effort, but we need the

Science Board\'s advice on prioritization and general

advice because, as Lisa said, there was much more that

was suggested to us to do than we could possibly

undertake.

We will do a few projects, as I\'ve

mentioned, in \'05 where consensus and resources exist.

And we will seek collaborators. They are actually

sort of coming out of the woodwork, which is good, to

take on additional work.

How much work we can do we still have to

project manage and kind of lead these projects and

fully participate in them. So we do need to put

resources on them and make sure they are accomplished

correctly.

So I will close and allow for the

discussion. Thank you.

CHAIRMAN SHINE: Thank you very much.

Thank you very much, Janet.

We will want to spend a fair amount of

time responding to Janet\'s charge with regard to the

priority issues. Does anyone want to make a comment

at this point with regard to her presentation?

I guess, Janet, one of the things that in

the discussion would be very helpful to get a

perspective on is that if one is undertaking

initiatives, then clearly investments which have the

broadest possible applicability would make a certain

kind of sense.

So that, for example, you emphasized

biomarkers and surrogates as really a cross‑cutting

theme, which really emerges in all kinds of places.

And trial design has very much cross‑cutting kinds of

implications.

Maybe when we get to our discussion, you

might just comment on as you look at this very complex

set of opportunities, what do you think are the two or

three cross‑cutting themes that are likely to have the

greatest impact over time in this broad spectrum of

challenges? Maybe we can come back to that in the

conversation.

DR. WOODCOCK: Certainly.

CHAIRMAN SHINE: Thank you.

Why don\'t we move forward and hear from

Larry Kessler, who is going to report on behalf of the

Medical Technology Innovation Task Force? Larry?

DR. KESSLER: Thanks, Dr. Shine. And

thanks to the Science Board.

MEDICAL TECHNOLOGY INNOVATION TASK FORCE

DR. KESSLER: Around the Spring of 2004,

Secretary Thompson, likely largely as a result of

briefings on the FDA critical path, the NIH road map,

and similar initiatives throughout the department, put

together a task force to try and spur the innovation

of medical technology.

So his goal was to try to do something at

the department level. So when I talk about this

today, I am going to ask you to put on a little

different cap than you might usually wear in this

venue. And that is helping to think through what the

department at HHS can do that doesn\'t only belong to

the individual operating divisions, such as FDA or NIH

or Centers for Medicare and Medicaid Services.

So it\'s a different kind of role because,

as you may or may not know, the vast majority of the

budget and resources of the entire department, doesn\'t

rest at the head. It rests at the individual

operating divisions. So what the department can do is

kind of a challenge. And we will get to that.

So that was done in the spring. That is

when the Secretary put this together. Next slide,

please. And the two goals for the task force are to

weigh new ideas and promote new solutions to encourage

innovation in health care and to speed the development

of effective new medical technologies, such as drug

and biological products and medical devices.

Second, we have been asked to issue a

report this year on appropriate steps that can be

taken across the department to speed the development

and availability of new medical technologies.

The next slide shots the putative heads of

the task force or the members. Dr. Crawford is the

chair. Drs. Zerhouni, McClellan, Gerberding, and Von

Eschenbach are also members, but they have real day

jobs and they\'re kind of busy. So the next slide will

show you that there is a group of worker bees who have

taken this on as of this summer.

I have had terrific help from Nancy

Stanisik from FDA as well as from the Office of the

Secretary, Howard Zucker, who is one of the deputy

assistant secretaries for health. And then the other

characters are up there as well.

The task force was put together in the

spring. In the summer, an announcement was put out to

the public docket to ask for ideas, what the

department can do to spur innovative medical

technology.

Those results were in the end of the

summer, just at the time Dr. Crawford called me and

asked me to actually take charge and be the director

of the task force, which I have done for the past

couple of months. So we have taken two approaches

with the ideas from the docket and from the direction

we\'re taking in the task force.

Next slide, please. So the first thing we

try to do is find ways in which the HHS agencies can

better coordinate their efforts to speed technology

from discovery to delivery. And we should complement

the efforts in the FDA critical path or the road map

from NIH, et cetera, as well as other initiatives.

So here is the trick. The trick is to

find gaps between the agencies or ways we can shake

hands better. As you can imagine, comments from the

docket were replete with examples of things various

departments within HHS can do better.

Second, as we started to think through the

development of medical technology, we began to realize

that there was a large number of other non‑HHS

agencies that play a significant role in the

development of cutting‑edge medical technology. And

we thought that there might be a way to improve their

collaboration with the Department of Health and Human

Services. At the end of the talk, I will go through

a number of those and the kinds of things that they do

and how we might work together.

I am going to actually get you back on

schedule because I am going to be really brief. And

if you go to the next slide, this is an example of

some of the issues we have begun to raise from the

docket and try to think through what the department

can do in each of these areas. There are several

others that have emerged, but these are some of the

big ones. I will go over them very briefly once

again.

It should come as no surprise to see, the

same way Janet mentioned this and Lisa Rovin mentioned

this, that facilitating biomarker development turns

out to be at the top of everybody\'s process.

Now you have to think for a second. Well,

what can the department do that the FDA can\'t do or

vice versa? Well, the real trick is here to make sure

that if the FDA begins to develop surrogate endpoints

or biomarkers, that these are the items where NIH may

wish to put some resources into studying and doing

validation because you need validation trials, some of

which exceed the resources or inclinations of industry

or academic to do. You need some muscle behind it.

And in some of those cases, when you want

to tie the biomarker to a product, then you\'re talking

about reimbursement. And right now, the Center for

Medicare and Medicaid Services has no way to approve

a product for coverage using a biomarker. They

wouldn\'t quite know what to do with it.

So it would be great if we would do

something in the Center for Devices that says, \"Oh, we

can accept this as a market. CMS ain\'t going to pay

for it. It\'s not going to get delivered.\" End of

story.

So here is an opportunity for the

department as a group to get together and as the FDA

moves forward with biomarker development to make sure

that other partners in the department are sitting

around the table so that when something does move

forward, it can move forward in a coordinated way. So

that came up over and over and over.

One of the other interesting issues raised

from the department turned out to be what we have

called more informative development programs and data.

Now, the way this was actually expressed ‑‑ and this

came from major payers in the country outside of the

federal government. They actually wanted to see a

higher evidentiary threshold that would spur

innovative technologies.

That may seem somewhat paradoxical, but

the notion was clearly defined and well‑represented

evidentiary thresholds for products that could stream

through, both FDA and CMS at the same time could

promote people doing innovation.

If you know what the barriers are, you

know what the hurdles are, and you can meet them, even

if they\'re higher, at least you know what they are.

Right now the rules, certainly for innovative

technology, are unclear. So that was one of the

suggestions from the docket that I think may wind up

being controversial if it goes forward.

A third idea, not unrelated to the ones I

have just mentioned, is to streamline HHS involvement

in innovative technology. One of the models we are

using for this is something the FDA has been involved

in for the past few years chaired by the National

Cancer Institute and one of the members of our group,

Dan Sullivan, the Interagency Council on Biomedical

Imaging and Oncology.

This is a cross‑agency effort that has

full representation from the three big agencies I have

mentioned several times a swell as from industry. In

their participation in ICBIO, they have come back over

and over and over to say it is a successful way for

them to get product in early development in front of

the regulators, the researchers, and the reimbursers

to try and understand what they have to do to get

their products delivered.

It\'s been a very successful model. And

over and over we have heard from the individual

industry members as well as from the trade

associations that the ICBIO model would be great to

replicate.

There are areas where we are thinking

about ways in which we can replicate it. And as part

of our report, we will try to suggest some that may be

right candidates for developing such a model.

One of them might be interventional

radiology. It\'s an area where we think there is a lot

of movement in products. Things move very fast in

interventional radiology.

The Society for Interventional Radiology

has come and met with the FDA on a number of

occasions. And expanding that potentially to include

CMS, who it impacts tremendously, as well as NIH might

be an exciting way for them to vent their development

in a wider audience.

You have heard from Dr. Woodcock, Lisa

Rovin issues relates to facilitating in vitro

diagnostic development, antibiotic development. And

these are stalking horses for other kinds of specific

product areas and specific diseases that the docket

mentioned were things that the department if it took

a serious initiative in could really make a

difference. What the department can do is separate

from the agencies, again, something that is a

challenge for our group to try and figure out.

Finally, cross‑training technology

transfer in significant or senior project managers

across the agency is something that you will see us

likely adopt, not developing new material.

There is a lot of curricula available in

the way in which FDA, CMS, CDC does its business, but

it\'s clear from the comments in the docket there are

individuals who are key decision‑makers throughout the

department who don\'t know what the rest of the

department does. So it would be helpful to start

cross‑training people in the agency to understand if

they are looking at a regulatory submission how that

order would not affect the way in which CMS might make

a reimbursement or coverage decision.

Next slide. I promised you I would talk

about other organizations we have talked about for

collaboration. Interestingly enough, each of these

organizations that has come to the task force has been

eager, eager and willing to sign new memoranda of

understanding at the department level to improve their

collaboration with the variety of the agencies

represented around the table. And it\'s really been

interesting.

These are agencies that represent budgets

in medical technology development alone, anywhere from

100 million to 5 billion dollars. So these are

significant players in certain areas of medical

technology development. And they are eager to work

with us in a variety of areas.

This week Don Marlowe, who works in Norris

Alderson\' office, and I went to the National Institute

on Standards and Technology ‑‑ and they are

represented on our committee by Angie Hight‑Walker ‑‑

to talk with their senior management about ways in

which HHS can better coordinate some of our efforts

with NIST. Interestingly enough, they have a long and

distinguished track record in helping companies

throughout the world with manufacturing issues.

As you saw from the presentation on the

critical path, clearly an HHS‑NIST collaboration that

would work with industry to improve their

manufacturing processes may be the kind of project

that we could launch forward after this kind of

initiative.

We have also had outstanding presentations

from the Defense Science Office of the Defense

Advanced Research Projects Agency, DARPA; the

Telemedicine and Advanced Technology Research Center,

TATRC; ‑‑ they\'re part of the Army, and they\'re based

on Fort Dietrich in Maryland ‑‑ the National Science

Foundation; the National Institute on Disability and

Rehabilitation Research; ‑‑ and NIDRR looks a lot like

an NIH on rehabilitation research, but they are in the

Department of Education ‑‑ and the Veterans

Administration.

They are planning to come, actually, two

weeks from yesterday. We have not yet been working

with them, but they have been eager to talk with us

about the kind of studies they can do in the VA to

promote medical technology.

So we have got each of these agencies who

are thrilled and excited to try and find new ways to

collaborate with HHS. And they want things even as

simple as access to FDA reviewers who do drug,

biologic, and device review for their investigators to

understand what kind of hurdles they might face.

They\'re not looking for anything more than

simple advice. And we have to be careful how we do

that. We are a regulatory agency. And working with

other agencies, we have to be careful how we do this.

There is clearly an opportunity for us to help them in

their product development.

What are the next steps? Well, we have

been trying to start working on these ideas and

writing them up in succinct ways that promote action

items among the department. We\'ll develop the report

this month and deliver it to the Secretary and his

task force, Dr. Crawford and his esteemed colleagues,

by December 16th, at which point they will decide how

this goes forward as adopted and rolled out.

That is my presentation. Thank you for

your time.

CHAIRMAN SHINE: Thank you, Larry. That

is very inspiriting. I also want you to know that Dr.

Crawford is prepared to push back on whether he is a

worker bee or not. Why don\'t we go on and hear from

Alan Rulis?

And then we will have an opportunity for

some discussion. Alan?

FOODS CRITICAL PATH WHITE PAPER

DR. RULIS: Good morning, Dr. Shine and

members of the FDA Science Board. I am Alan Rulis.

I am Senior Adviser for Special Projects in the FDA\'s

Center for Food Safety and Applied Nutrition.

I am going to spend the next few moments

to provide you with a preliminary snapshot of a white

paper that we have in preparation at CFSAN in

collaboration with some of our colleagues at the

National Center for Toxicological Research in Arkansas

and also at the National Center for Food Safety and

Technology in Chicago that extends the critical path

concept into the area of food and nutrition.

Of course, you are aware of this critical

path document, March \'04, \"Challenge and Opportunity

on the Critical Path to New Medical Products.\" What

we are contemplating ‑‑ the next slide ‑‑ is a

somewhat complementary approach.

We have a document at the moment in draft

form, which we are calling \"Progress on the Pathway to

Healthier Consumers: Identifying and Filling Critical

Food and Nutrition Research, Technology, and

Information Gaps.\"

The premise of this document ‑‑ and the

next slide ‑‑ is that targeted research efforts in

specific areas of nutrition and food science have the

ability to accelerate progress in using nutrition to

achieve public health goals. This is really a

different flavor of critical path than what you have

heard so far this morning. It is quite a challenge,

but we think it has some important potential outcomes.

Whereas, in CFSAN we do have pre‑market

approval regimes for, let\'s say, new ingredient score

infant formulas, new ingredients in dietary

supplement, food and color additives, and we have a

regime in place for biotechnology‑derived new plant

products, food, as such, as we eat it, in the amounts

of two kilograms per day, each of us for a lifetime,

has enormous potential to affect our general health,

well‑being, and longevity.

And it\'s not regulated other than it

cannot be adulterated or misbranded, but food itself

that we buy in the grocery store is presumed safe.

And we have free access to it, and we make free

choices about it. Yet, those choices are extremely

important in determining long‑term health outcome of

our citizens. So this critical path approach is

intended to try to grapple with that important

reality.

Now, on the next slide, we found out, of

course, that the National Academy of Sciences had

already done this work ten years ago. They published

a nice paper ‑‑ and, Dr. Shine, you were President of

the IOM at the time ‑‑ a document that foresaw

potential advances in nutrition and food sciences as

among the most important determinants in advancing

public health and recommended five areas or themes in

which research should be focused.

Next slide. And you can see the title of

the document at the bottom of this slide. And the

five areas that were put forward in this NAS report

were the following: nutrients and biologically active

food constituents and development, cell

differentiation, growth, maturation, and aging; genes,

food and chronic diseases; determinants of food

intake; improved food and nutrition policies; and

enhancing the food supply.

Now, it\'s been ten years since that report

was published. And on the next slide, I would like to

say that not a lot has changed in terms of the

importance of nutrition. Nutrition is still a prime

determinant in public health. But there have been

some other kinds of changes, some of them good, some

of them not so good.

First of all, in the last ten years, the

Nutrition Labeling and Education Act was implemented

by the Food and Drug Administration in regulations.

We have had ten years of experience with the Nutrition

Facts Panel, the labeling of packaged foods.

Modern biotechnology has advanced

tremendously. Now we\'re talking about not only making

single gene transfers into plants for the purpose of

eliciting some specific effect, but we\'re looking at

total metabolic pathways in plants and making sure

that we can affect the profile of the fatty acids, for

example, in certain plant products.

Obesity has emerged as a major public

health threat in our country over the last year.

\"Omics\" technologies linking the genetics and

nutritional influences has emerged. And it is now at

our doorstep as something that is a practical tool

virtually.

Food technology advances are ongoing in

modified atmosphere packaging and all sorts of other

ways in which food is brought to us. And, of course,

if you opened The Washington Post this morning on page

2, you will see that dietary supplements continue to

be interesting and important foci for our work.

So on the next slide, then, the question

we are posing is, what is the approach for a foods

paper in this environment? We are making progress in

advancing nutrition knowledge that holds the premise

of improved health and longevity for millions of our

citizens. But along the pathway to reaching a

healthier society, one that lives longer, one that has

fewer chronic diseases are a number of research

questions and information gaps that still need to be

filled.

So on the next slide, our paper will try

to identify what we believe are critical food and

nutrition research technology and information gaps and

encouraged applied research and development of

evaluative tools in specific areas.

Underpinning these endeavors is the need

for FDA to be positioned with proper knowledge,

skills, and tools that will enable us to endorse and

promote the science behind these advances in

nutrition.

So we do have at the agency still

reviewers who are looking at many products that are

going to reach the marketplace. And we need to be

able to stand behind those products, say that we have

evaluated them effectively and critically and be able

to put the credibility of FDA behind many of these

products that are coming to the marketplace.

Let me give you on the next few slides a

couple of specific ideas of areas we think we are

going to talk about in our paper. General nutrition

research, of course, is a major area.

We want to look at what we know about

nutrition. Nutrition is a relatively young science.

For those in the know, it was only 1929 or so when

ascorbic acid was isolated as a pure compound.

So we are still learning a tremendous

amount about nutrition. And we are looking at it with

respect to adults and the elderly, for example, what

knowledge needs to be developed. Sometimes it

requires the use of animal models, not only rodents

but possibly non‑human primates.

Another area, infants, children, and

adolescents obviously, a major area for investigation

and developing further knowledge, filling some

research gaps.

We know, for example, that adolescents who

get on the wrong track in terms of their dietary

patterns can develop those patterns in ways that are

very difficult to reverse in adulthood.

Novel and new ingredients in infant

formula is a new area of extreme importance. The

National Academy just recently finished a report for

the Food and Drug Administration on how we should

approach evaluation of the safety of those kinds of

ingredients, but that is going to be an ongoing area

of great importance.

Next slide. Biotechnology, as I

mentioned, new techniques for evaluating biotechnology

to create foods that have enhanced levels of

nutrients; for example, fatty acid profiles in certain

plant products.

Omics research, as I said, is on our

doorstep as a useful tool. We think that there are

some ways in which the knowledge about the genetic

profile of an individual can be used to tailor the

dietary intake of that individual to better suit his

or her development throughout life.

Next slide. Research needs in the area of

food technology, as I mentioned, packaging,

preserving, and producing food. Behavioral research

is an extremely important area that is not receiving

enough attention.

The agency has thought long and hard about

how to develop messages to send to the public about

what foods to choose. As you know, the department is

now in the process of updating its dietary guidelines

for Americans in collaboration with the USDA. And the

Director of our Office of Nutritional Products

Labeling and Dietary Supplements, Barbara Schneeman,

is currently presiding over the policy group that is

developing those guidelines. But that information

doesn\'t really help much if people don\'t change their

behavior as a result of receiving that input, that

message. And we don\'t really know much about how to

get the public to make changes in lifestyle,

particularly food choices.

Of course, dietary supplements, as I

mentioned, an area where FDA is interested in ways to

evaluate the safety of new dietary ingredients and

make sure that the products that are on the market do

what they say they are going to do and do it safely.

Last slide. Next to last slide is a

little picture that basically is an attempt, our

little attempt, to try to say that there are gaps

between what we know from academic research about

nutrition to the healthier consumer.

That is a different kind of pathway that

we are looking at, but those gaps are real. They

require a focus. They require some concerted effort.

And it is our belief that if a critical number of

those gaps are addressed simultaneously, we can

accelerate, not just advance but accelerate, progress

along the pathway to healthier consumers in ways that

are way out of proportion to what can be done in other

areas of FDA\'s purview.

So, just to sum up on the last slide,

major focus of the initiative would be to enhance

long‑term health, well‑being of the American consumer,

looking for ways to fill those research gaps that we

think are standing in the way of that.

We think that there needs to be a holistic

approach to looking at the risks and benefits of foods

in the process and that when we do the research that

we are going to point to and we hope draw a strong

case for conducting, that we will, in fact, have taken

another step on the important pathway towards having

a healthier population in the U.S.

So those are my remarks. And I guess

we\'re ready for questions, then.

CHAIRMAN SHINE: Alan, thank you very

much. I wanted to thank Janet and Larry and Alan not

only for very good presentations but for getting us

back on schedule so we have some time for discussion.

QUESTIONS AND DISCUSSION WITH THE BOARD/PRESENTERS

CHAIRMAN SHINE: We have passed out to the

Committee a set of questions which Janet Woodcock was

referring to. The first has to do with critical path

issues and the principles to guide FDA

decision‑making.

It emphasizes five parameters: first, the

unique capacity of FDA to choose activities that

promote collaboration; secondly, the role of urgent

public health needs in at‑risk populations as a

principle for selecting activities; thirdly,

activities that can provide benefits across product

types, diseases, and industry sectors. Fourth,

hurdles that are causing product development

bottlenecks might be a high priority; and, finally,

those activities for which science‑based standards and

guidances can be provided.

There is a second question, which has to

do with the applying the critical path, including what

the various players from industry, patient groups, and

other stakeholders might do in terms of moving it

forward.

So I would like to now open the discussion

with the Committee with regard to any of the

presentations, any of the questions you may want to

raise about any of these.

Plus, in the course of your comments, if

you could give some indication as to how you think

about these principles, it would be very valuable, I

think. And you may have some additional ideas as

things go on.

Dr. Cassell?

MEMBER CASSELL: Yes. First of all, I

just would like to say I think that the progress that

has been made since March 18, when Dr. McClellan

announced the Critical Path is really unbelievable.

And I really applaud all of the efforts, but I know a

lot of different people.

In listening to everything that has been

said today and also realizing the funding constraints

for implementation of the Critical Path, it seems to

me that one of the highest priorities might be to

determine how better to establish these collaborations

and leverage your great resources and that of others,

so I like the idea of the interagency task force

looking at what the role of government should be in

medical innovation.

Kathy, you mentioned a number of times the

number of collaborations that CBER has. I think you

said there were over 100. I would like to know

exactly how those are structured. And if you compared

that to CDER and you compared it to Devices, I mean,

would you say that there are equal numbers of

collaboration? So that is one thing.

Along those same lines, I would just

emphasize that there are three great opportunities

that I see for collaborations that would bear on the

biomarker issue and the predictive tox issue and, in

particular, as it relates to some of your efforts in

CBER with regards to vaccine development biologics.

And that is an investment of \$25 million made by NIAID

about 3 years ago to establish a consortium between

Scripps, the Institute for Systems Biology in Seattle,

and the Rockefeller to characterize in a very

systematic way the inflammatory response and the

response to sepsis into well‑defined characterized

compounds and also molecules but also particularly

lipopolysaccharide, peptidoglycan, and other microbial

products.

So if there were some way to very closely

work with that collaboration that is already

established and be able to tap into the data  in

fact, one of the goals of that consortium was to

release the data so that it could be used by the

community.

Along those same lines, Heart, Lung and

Blood funded Vanderbilt University about three years

ago to functionate all of the proteins in the

inflammatory pathway in mice and using ‑‑ probably

Vanderbilt has one of the greatest vivariums for

approaching this that I know of.

So two opportunities to collaborate with

respect to biomarkers and predictive tox possibly,

particularly as it relates to the adjuvants and other

areas that you mentioned with regards to vaccines.

Lastly, you probably are aware that about

three weeks ago, I think it was, NIH released an RFA

for the establishment of translational research

centers. And I see that to be a great opportunity.

If there were some way to tag onto those

translational research centers, some active component

or interactive component, from FDA, a great chance to

get and accomplish a lot of some of the things that

you have been talking about.

Just one other last thing. Again, it

relates to collaboration, but this time amongst the

agencies. I was delighted to see NIST listed. And if

you are not focusing on the Advanced Technology

Program within NIST, I think it is one of the

well‑kept secrets as far as advancing some high‑risk

projects, products, and technology platforms but with

very large investments. And that could be a real

opportunity, especially if FDA could match them up,

say, with some of the people that come to you for

consultation when they\'re in the midst of development.

And then, lastly, I would just mention

that you did not mention the Department of Homeland

Security and HSARPA. Within that, you probably know

there is a huge investment in information technology

and data mining.

And I think it would be tools that could

very easily be applied to some of the efforts that you

would be undertaking as well as EPA and DHS when it

comes to detection of microbial products in very

large‑volume samples, such as air and water, that

could be applied to product safety but also hopefully

to diagnostics.

CHAIRMAN SHINE: Kathy, comments?

DR. CARBONE: I hope I hit all of the

areas of import. So let me know if I miss something.

Just to take the focused area of

collaborations, there are sort of, I would say, four

levels of collaborations. There are the people who

come to us because of our expertise and need help.

There are people we seek out because of our limited

resources and the need to incorporate and expand. And

obviously science is a brain trust issue. There is a

critical mass that you need.

In terms of collaborations, we have both

institutional level and sort of individual laboratory

research program level. I will give you some

examples.

At the institutional level, we do work

with NIAID, for example, on cell substrate issues.

That was a case where the meetings were held and we

were specifically sought out because we have expertise

in those sorts of issues.

I think what is important to think about

is in terms of translational research, where it stops

 and I will, of course, let Dr. Woodcock comment on

that as well, but I will take an example which is not

a pejorative one. It\'s a fact one. And that is \"HIV

vaccine will be ready in two years.\"

It has now been two decades. And probably

the limitations there are not the basic science in

understanding many of the limitations. So there are

some, the immunology, the effective protection from

HIV, et cetera, but a lot of the inhibitions to that,

a lot of the reason that is taking longer is because

of manufacturing issues and the demonstration issues

and the efficacy targets, et cetera, et cetera.

I think what we are talking about in terms

of the biologics end of critical path is that part of

the process where the attention has not necessarily

been focused in terms of scientific initiatives and

resourcing should have tremendous benefit. Discovery

is a tremendous thing, obviously, as you well know

from your situation.

So, in addition, we have formal

collaborations with NCI, the Interagency Oncology Task

Force, which is an FDA‑wide initiative, but we are

working carefully.

We have our first cancer prevention

fellow. Part of the issue there is in addition to

specific research. And their project is looking at

DNA and the risk of DNA inoculation, say, with a

vaccine in oncogenesis and developing ways to assay

for that.

But we are also training these people in

nonproprietary regulatory type training because FDA is

one of the few places one can get that type of

training. So that part of the program is to run these

fellows through and teach them something about the

regulatory process that clearly is distinct from the

proprietary end.

In addition to the individual

collaborations, basically it runs universities as well

a industry. We have collaborations with PATH and

global vaccine initiatives. One of our investigators

as part of his trying to characterize conjugated

glycoprotein vaccines actually developed a new method

for conjugating that has three times the efficiency,

is more uniform than the current methods. So that was

immediately picked up by WHO and PATH and is being

looked at in a global perspective.

We have many collaborations with

international regulatory agencies. Right now we have

a collaboration between Health Canada and NIBSC. PAHO

and WHO are also involved looking at small animal

modeling of vaccine neurotoxicity, trying to get away

from the primate models for a variety of reasons.

So we have multiple large sort of

institutional collaborations. Then we will have

individual collaborations where we need resources that

we simply don\'t have.

One of the areas that as research director

I have detected as a large gap I think in our ability

to perform or function is the characterization of

biological products, complicated novel techniques,

NMR, mass spec, et cetera. So we have collaboration

with NIH to provide resources and intellectual capital

that we don\'t currently have and we would like to

boost.

For example, Chip Petricoin is an

international authority on proteomics. And so he is

sought out. He does tremendous work, very practical

biomarker‑type work.

So we have multiple levels of

collaboration. Many people seek out Karen Elkins, who

is one of the world\'s authorities on tularemia. What

is very interesting I think about our program in many

ways is we have focused on expertise that is very hard

to acquire elsewhere.

There are many ways to make collaborative

efforts to work, and they should work. And we need to

incorporate these. But in some cases, simply the

mental resources are just not out there.

CHAIRMAN SHINE: Kathy, I don\'t mean to

interrupt, but one of the things I\'m really interested

in in this regard because of your work with the

workshops and so forth is that there are lots of

collaborations. You have got interested scientists

who want to work with a lot of interesting people, I

think.

Still in terms of the critical path, there

are certain places where, for the sake of arguing, you

want to see biomarkers developed.

DR. CARBONE: Right.

CHAIRMAN SHINE: How is that process

likely to go forward in terms of the responsibility to

do it given reasonably limited resources in FDA? What

is the kind of conversation that you can have with

collaborators which will result in a particular

outcome in terms of biomarkers that will move a

particular part of the agenda?

DR. CARBONE: Well, I think what is very

important is the process of continually evaluating,

re‑prioritizing, talking, and identifying the list of

the likely problems that are likely to be solved, both

the low‑hanging fruit and the tremendously critical in

terms of public health import, and the whole spectrum

in between. So we identify those sorts of issues.

And of the ways they are identified by

their reviewers and their staff who actually review

the problems and see the solutions, very practical,

smallpox, no high‑throughput quantitative way to

assess smallpox vaccine potency.

So in collaboration with NIH, this was

identified as a clear issue. In collaboration with

NIH, one of our researchers identified it.

CHAIRMAN SHINE: I can see the agency in

government. What about the private sector?

DR. CARBONE: Well, okay. We have this

mechanism. I want to finish the larger picture, but

let me just insert. There is a mechanism called a

CREDA, a cooperative research agreement. And we have

connections with industrial partners and sponsors

through those mechanisms, which, of course, are

carefully reviewed for ethical issues.

But basically the way that we do this at

CBER is there is the level of the scientist who needs

to deal with these high‑level technologies and deal

with the issues, which are not being resolved

externally. To maintain that expertise, we need to

support the infrastructure of the science at CBER.

There are connections that are made where

we can use that expertise to identify partners in

industry or academia where the expertise is shared and

we get the project done.

The third point is very important, which

is identifying for the larger world this concept of

critical path, where we may serve as the initiators,

coordinators, or simply the thought leaders in some

way and stimulate the outside world to take on

projects which they\'re currently not addressing.

CHAIRMAN SHINE: When you say, \"stimulate

the outside world to take on\" those projects, for a

number of these activities, the market is limited.

DR. WOODCOCK: What we were discussing

yesterday, specifically with regard to biomarkers, is

because this is to the extent any of these are

precompetitive.

In other words, they might be proprietary

knowledge, but they are not something that necessarily

could be marketed, the industry is willing to come

forward and put money down to work these up using a

consortium mechanism.

What we talked about was the mechanism use

in the semiconductor industry, the SEMATECH model that

we believe that we need to explore setting up such

collaborative models, probably using an academic

institution as the hub.

The FDA isn\'t going to be taking money

from industry. But it would allow money to be

contributed to specific projects with very specific

deliverables that could then be shared public

knowledge to advance the field.

DR. CARBONE: And I think another example

is the cell substrates.

DR. WOODCOCK: Yes. That\'s right.

DR. CARBONE: A single sponsor is not

going to develop a panel of cell substrate

opportunities and disseminate them free of charge. In

fact, it\'s an investment that probably would never

happen.

However, with the FDA coordinating funds

provided by the interested industry ‑‑ and we had many

conversations with multiple sponsors who said they

would support this as a collaborative effort ‑‑ those

could be provided through ATCC and without any

economic benefit but still of value.

CHAIRMAN SHINE: I interrupted your

response to Gail. I think this is a key area. And I

think whether you use the SEMATECH model or the cell

model or whatever, we need to create some models of

that kind because things are going to get tougher and

tougher and tougher in industry.

We are going to ask Cecil to give us his

prognosis for the financial future of the

pharmaceutical industry, for example. We have got to

figure out ways that we could pool resources and ‑‑

DR. CARBONE: And I guess what I am saying

is in some ways CBER is already doing that. It\'s not

institutionalized, formalized. It\'s well‑expressed by

Janet. But I think the seeds are there. I think it\'s

a matter of formalizing opportunities that have

already been initiated.

CHAIRMAN SHINE: I just want to give Kathy

a chance to respond to any of the other observations

that Gail made. I know she made some notes.

DR. CARBONE: I think one of the other

opportunities we have sort of as thought leaders is

that we have been approached by several NIH

institutes: NIBIB and DAIT through NIAID. Their

basic question to us is, we want to put out an RFA.

This is something that we would not be involved in.

We want to put out an RFA, but we need you to help us

identify critical areas.

I don\'t want to reveal any information if

they\'re not ready to put out these RFAs, but

basically, for example, a center of excellence. What

would they need? Some of our input was, how about a

way to provide regulatory training or training in the

manufacturing issues, which the average academic does

not understand? So those are also opportunities that

we take advantage of.

CHAIRMAN SHINE: Could I just add to the

point that Gail made that DHS, it seems to me, is

doing an increasing amount of work that bears on these

issues and I think should be very much in Larry\'s

target in terms of everything from the stuff that

they\'re doing in ports trying to look for contraband,

which ultimately has implications in terms of food

moving through ports and so forth.

I would also emphasize that DOD outside of

DARPA clearly has a number of programs that are of

great interest in this regard, including biologics in

the chem‑bio area.

MEMBER CASSELL: Small efforts,

comparatively speaking, but they are there.

CHAIRMAN SHINE: Yes, but some of that

technology is potentially transferrable. That\'s one

of the things that I like about the DHS piece.

There\'s a strong emphasis there on the tech transfer

piece. So that would ‑‑

DR. CARBONE: And one way of conceiving it

is that technology is developed and the FDA can help

with the application, validation, how it\'s used in

regulation. Those sorts of issues would be helpful.

CHAIRMAN SHINE: Yes. Is that happening?

DR. CARBONE: You know, I have to commend

Dr. Woodcock and Dr. Crawford into formalizing this,

making it cross‑center, stating the problem, the

issue, and devising the solutions as a conscious act.

I think we have been doing it for years, but this way

of formalizing it I think is going to advance it.

So I think yes, I could give you examples,

but I think this new initiative has been tremendously

helpful in advancing.

CHAIRMAN SHINE: Dr. Pickett?

MEMBER PICKETT: Just an impression from

the discussions. It seemed as if there were certainly

a couple of cross‑cutting themes that are important:

biomarkers, surrogate endpoints, new statistical

methods. But from the presentations, it seems as if

the individual centers are working as silos.

And it\'s not at all clear whether or not

there might be and there should be, it seems to me,

based on limited resources an opportunity to define

some critical path initiatives that can be trans‑FDA

to utilize precious resources in the organization.

I also think it\'s important to identify

two or three things that can be completed in one year

or two years, that there are some definitive time

limits, because I think if you don\'t do that, the

critical paths initiative will lose credibility with

your stakeholders. So I think that is absolutely

critical.

And then, finally, I think as you think

about developing new guidelines for the FDA, I think

it is also critical you reach out to other regulatory

agencies to harmonize, to do your best in terms of

harmonizing those guidelines because the industry\'s

response to different guidelines complicates clinical

trial designs.

DR. CARBONE: Right, right.

MEMBER PICKETT: So they will become more

expensive. And they will take longer.

CHAIRMAN SHINE: Thank you, Cecil. Let me

just reiterate the point that he made about the time

lines because I made the same observation. It seems

to me that one of the priorities ‑‑ and to a certain

extent, it comes out of number three here ‑‑ or

principles is to pick some activities that have

benefits across the whole system but which also have

a high probability of getting a result in a relatively

short period of time. I think that principle in my

view trumps a number of the others because of the

whole issue of demonstrating effectiveness.

This is exactly the point that Cecil was

making. I think it\'s a very important point to

maintain the momentum here in terms of proof of

concept.

Dr. Thomas?

DR. WOODCOCK: Could I just clarify

something?

CHAIRMAN SHINE: Sure.

MEMBER THOMAS: Yes. I have a couple of

comments. I happen to know that the EPA has a modest

initiative in biomarkers having just sat on a review

panel. So that\'s part of your group of collaborating

institutions as well as NIOSH for long‑term monitoring

of the various occupational diseases. So that might

be brought into the mix somewhere.

The other comment that I have is with

respect to disincentives. First of all, let me sort

of separate out biomarkers because sometimes it means

different things to different people.

Certainly some biomarkers are very generic

and it\'s very hard to find any private motive to

pursue any. On the other hand, some of them I think

are easily transmissible into some sort of diagnostic,

where there might be some incentive to put resources

in that from the industrial sector.

The other thing that I would comment on ‑‑

and I certainly haven\'t reviewed it for some period of

time ‑‑ is the orphan drug law and whether or not that

can undergo any sort of modifications that might, in

fact, provide some incentives for so‑called

biomarkers.

And perhaps finally ‑‑ and this is not

very profound, but as clinical trials are developed,

it seems to me that one of the things that the agency

should really stress and look at right up front is

quantifiable endpoints.

Now, again, as a scientist, I know that is

not always doable, but certainly it seems to me that

a lot of effort goes into designs. But if you had

poor endpoints, not very quantifiable, then you\'re

spending a lot of money. And you\'re really coming up

with trying to decipher at the end of the day what you

really have.

I think this is where we could put a

little more emphasis right up front as someone

reviewing the protocol. And it can go back as far as

the IRB, quite frankly. If the IRB is unsatisfied

with the endpoint, then you can be sure that down the

road somewhere, where you\'re looking for outcomes, it

is going to be very difficult to discern these,

whether they\'re toxicologic or efficacy‑related.

CHAIRMAN SHINE: Dr. Thomas, with regard

to the orphan drug law, are you citing that from the

point of view of the benefit to the manufacturer for

investing in this area?

MEMBER THOMAS: Yes, yes, purely from an

incentive standpoint, a monetary incentive. And it

wouldn\'t apply to all biomarkers, as I say. I think

you can sort of categorize it with something simply

too generic that you couldn\'t get any patent

protection. But if you have something that\'s unique,

it would seem to me that someone might want to look or

rethink the orphan drug law to see whether or not that

might be brought underneath the umbrella or somehow

modified to provide that incentive.

CHAIRMAN SHINE: Let\'s hear from Dr.

Laurencin. And then Janet I think has some points she

wants to make.

MEMBER LAURENCIN: Well, first I commend

the FDA for taking on the task. I know it is really

monumental. I think that there has been a lot of

progress since the announcement of it.

This may already be happening, but my

brief comments are I think that my impression is that

there may need to be more extensive discussions with

stakeholders involving the critical pathway.

I say this because I think that, for

instance, I am involved with the American Academy of

Orthopedic Surgeons. Certainly in terms of getting

their input of an exhibit at the academy, getting

involved with the instructional courses, getting

involved in terms of the mainstream projects that are

taking place in that organization, it is fairly easy

when there are very important issues that are timely

that come like this to get involved. I think it is

very, very important.

I think the Web site is important, but

that will get more of sort of a corporate view. I

think to get the view of all of the stakeholders in a

very intimate way, I think really active involvement

between FDA and the different organizations, member

organizations, is important.

Also, the second is in terms of industrial

affairs. And I think, again, methods to actively get

involved and tie in with the different stakeholders I

think is very important.

The second area is also in terms of

scientific priority meetings. Just as Dr. Carbone

alluded to, any time anyone is talking about

scientific priorities, the issues about the critical

pathway come into place because they actually will

determine what the priorities are in many cases. They

actually work with each other.

I am back here Tuesday for a meeting with

300 scientists. It\'s going to be a meeting chaired by

Dr. Zerhouni on one of our critical priorities between

the life sciences and engineering for the next ten

years in determining how we are going to fund it and

how we are going to proceed. Again, NIH, NSF, NASA

are going to be there, but FDA should be there, too,

as a part of that in terms of determining the future.

Two weeks from now I\'m at the National

Academy of Engineering meeting, where we\'re

determining what the priorities are, research

priorities are, for nanotechnology in medicine and

what the future in terms of that.

Again, that should be something where the

FDA should be at the center of that in terms of the

critical path because that is going to determine what

the future is in terms of being able to move these

things to market.

So I think that, again, through member

organizations is very important. Through any

organization where they say they are going to do

anything involving priorities, I think that this is

very timely for the FDA to be involved.

And the third is that the FDA may want to

have its own conference once it\'s gotten to the point

where it\'s got all of its comments together, it\'s

ready to unveil that it has one meeting where

stakeholders are brought together, actively brought

together, an FDA conference to say, \"This is what

we\'re going to be doing. This is the time to divide

into breakout focus groups and say, \'Is this going to

be constant with what our feelings are in terms of

where we\'re going to move forward and how do we also

make whatever decisions are made living in that we can

have active input over time?\'\"

CHAIRMAN SHINE: Dr. Woodcock?

DR. WOODCOCK: Well, I certainly endorse

those latest comments. You know, right now we are

very limited by resources. But if we can build this

program, we are going to have a very strong outreach

component because the multidisciplinary aspect of this

project is really incredible. And we need the

engineers and so forth at the table.

I just wanted to comment, Dr. Pickett. I

just wanted to clarify about the silos. We had to set

up the center presentations first because Doug had to

catch a plane, but we have been meeting very across

the agency, very routinely, on this and planning these

all together.

What we\'re doing is the initiatives I

talked about and clinical trials and biomarkers we

will do at the cross‑cutting agency level, but the

centers have very product‑specific areas that they are

going to lead. That is mainly what the centers talked

about.

So there are several pieces to this.

There is a cross‑cutting piece, which is a very major

piece, which would include a lot of the outreach input

efforts as well as some of the cross‑cutting projects.

And then there are very specific issues.

And there are issues that are between two centers.

And they are collaborating on projects that bridge

across two of the three centers.

CHAIRMAN SHINE: My comments were less

about silos than they were about ‑‑ I think principle

three trumps the principles at the moment. What I am

trying to get at is that while public health needs are

very important, I would argue that doing something,

let\'s say, in trial design that affects the whole

organization that can produce an impact relatively

quickly that can demonstrably move the process is an

extremely important first step. That\'s why I focused

on principle three in that regard.

Dr. Roses?

MEMBER ROSES: Yes. I get kind of lost in

initiatives and tend to think in experiments. When we

talk about biomarkers and I talk about incentives for

biomarkers, the incentive that a large pharmaceutical

company or a small pharmaceutical company would have

for a biomarker that would be in the public domain is

something that could shorten and provide a shorter

clinical trial with less people in it. In order for

it to be useful to us, it has to be in the public

domain, and it has to be validated. So the incentive

is there.

But then if you step back and you say,

\"Well, if I were going to develop a biomarker, is

during the clinical trial that I want to measure the

correct place to do it?\" The answer is no. By

necessity, even if you think about it, it will be

approvable, but then you will have to measure it in a

bunch of years.

So what would be the format for setting up

a prospective study for biomarkers? First of all, you

would need clinical granularity to a great degree

about the patients that you\'re calling, say COPD. You

would have to have a lot of information about

patients. You would have to follow them over time.

You would have to separate in your mind

what is a prognostic marker that has to do with the

severity of disease or progression of disease or

disease base versus a surrogate endpoint or a

surrogate marker that has to do with the therapeutic

agent that you\'re going to test. You probably would

want to design in the validation series being

collected simultaneously with the test series so you

could save time.

Now, how can the agencies agree how that

works? Well, I think it isn\'t agreeing about ideas

emanating from different sources. It\'s agreement

about an experimental design that will allow you to

get the answers that you want.

The SNP consortia was very, very simple.

You all remember that everybody and their brother were

patenting SNPs. For a SNP profile to be useful for a

pharmaceutical company to be used for efficacy or for

adverse events for a screening profile, it had to be

in the public domain.

That was an industry got together.

Industry said, \"We\'re going to do this. We\'re going

to put it in the public domain. And we\'re going to

pay for it because it is going to be a tool that we

would use and very effectively accomplish that.

I think in terms of biomarkers, the same

sort of collection of participants could be pulled

together as long as the experimental design allows us

to use omics techniques or whatever other techniques

are necessary to get the granularity we need.

In COPD, we don\'t need FEV1 as the only

thing we can measure a drug on. What about residual

gases? And what are the biochemical markers that

might reflect that? And what are the genomic markers

that might reflect that over time and if we\'re looking

at risk/benefit, a much better way of looking at what

actually happens during the course of disease so that

we could tell whether it\'s faster or slower with our

molecules or our biologics?

And so the point I guess I would like to

make is while this is a very, very exciting thing

about the critical path, I think the experiments that

we go forward with are probably more pivotal than the

way these things are bureaucratically arranged.

CHAIRMAN SHINE: Thank you.

Other comments from members of the

Committee? Yes, please, Dr. Harlander?

MEMBER HARLANDER: I would like to add one

principle I think to the list of five that you have.

It seems to me that FDA is in a really unique position

in terms of risk‑ranking. You see a diversity of

things coming in across biologics and drugs and

devices.

And in terms of setting up standards for

clinical trials or whatever, I think you are in a

position where you can say certain things maybe demand

a certain level of evaluation and others maybe less so

and making some decisions and guidance around that.

So I would like to see risk‑ranking added as one of

the principles.

The second thing, I didn\'t read all of the

comments in the docket, but I did go out. And I think

it\'s come up repeatedly that there are lots and lots

of priorities if funding is available.

So I think available resources are

something, and I don\'t know what the approach is for

getting that. I think consortia are really good, but

I think there was a pretty strong concern that

critical path is really important but everything else

that FDA is doing is important, too. And so we can\'t

divert too many resources away from drug review or

some of the other priorities. So I think that some

discussion around available resources and how that is

going to be managed is important.

My third comment relates to the critical

path for food. Alan, you\'re taking on a lot here, but

I think it is really important. And it is really

satisfying to at least two of us on the Committee that

actually were on the National Academy committee that

developed that report that someone is actually reading

it.

(Laughter.)

MEMBER HARLANDER: And, you know, the

priorities that we came up with and the

recommendations we made were pretty prophetic. So I

am pleased about that. It was a grueling process,

actually, if you recall, a couple of years of our

lives, but there were some very important things.

And food, when you think of the number of

people who are impacted by drugs, it\'s a significant

amount, but, you know, we all are impacted by the two

kilograms of food that we\'re eating every day. And so

I think that could have a really profound impact in

the long term.

And I was pleased to see biotechnology

included there because I think that there are lots of

advances happening there and concern that, is FDA

going to be ahead of that game when we start

nutritionally modifying food?

So I was pleased to see that there, and I

will look forward to seeing that white paper.

CHAIRMAN SHINE: Dr. Harlander, help me

with the risk‑ranking principle. It\'s not clear to me

what you are talking about. Are you emphasizing as a

principle things that have a very high risk or ‑‑

MEMBER HARLANDER: I think it is the whole

spectrum. Katie and I were talking just during the

break. Her company is involved in developing some

things like soaps that might be used or devices that

are used by physicians. Where do they rank relative

to someone who has pancreatic cancer who might be

willing to take some risks on some new drugs?

I think there is a whole spectrum there

where FDA is in a unique position to look at what

kinds of requirements do we have for all of these

different things that might be in the pipeline? And

how can we develop protocols that are ‑‑ what\'s the

word? ‑‑ consistent with the risk that might be

involved with those products?

DR. WOODCOCK: May I say something?

CHAIRMAN SHINE: Yes, please.

DR. WOODCOCK: Yes, we do that but

probably not in a formal way. We have had many

discussions about the need. This afternoon, we are

going to present our beginning efforts at developing

a scientific model for risk, for inspections, as part

of the GMP initiative.

We have done basic, the rigorous

scientific models that we could plug in data and

actually come up with numbers about what facilities we

feel are at higher risk.

We recognize we always make risk‑benefit

analysis. That is how we do our medical approvals,

but I don\'t know whether we have articulated that

publicly in a way that is transparent. Is that a fair

‑‑ and that probably reflects your comment, I think.

CHAIRMAN SHINE: In that regard, as long

as we are talking about additional principles, I would

like to have as one of your principles the

availability of clear benchmarks that could be used to

evaluate whatever you select.

I just think that we have got to ‑‑ if we

are going to go through all of this effort, we have

got to show that, in fact, it makes a difference.

And, therefore, identifying benchmarks it seems to me

would be very useful.

I think I saw another hand. Yes, Dr.

Swanson?

MEMBER SWANSON: Just building on the

point of risk ranking and, Ken, your point that number

three trumps everything, I think it is important when

you\'re looking at the models that you\'re going to be

starting out with that you do want something that is

going to be achievable, is going to be achievable in

a short term, but to the risk‑ranking perspective, you

look at the one that is going to provide the biggest

public health benefit overall as you go down the line.

That\'s one of the things that you can do

as you are sorting through which ones can we do

because resources are limited. That\'s one of the

things that you can put in.

CHAIRMAN SHINE: Yes. It\'s an interesting

point. I think the item 2 sort of emphasized the

public health needs of the at‑risk population. And

it\'s a very important principle. My argument would be

given that you\'re trying to prove that an approach on

the critical path would work, if you told me that

something was very high‑risk, very high‑payoff but the

probability that I could produce an intervention over

a couple of years to deal with that is going to be

very difficult, ‑‑ this is a personal view, not a

Committee view ‑‑ I would rather see the agency pick

something that they\'re likely to be able to implement,

see a difference, show that the process works in order

that that provides encouragement to continue to work

on that highest‑risk issue.

I\'m expressing a personal view about this,

but I think the issue of proof of concept, it goes to

a certain extent to Dr. Roses\' point, namely if you

can\'t do a good experiment in order to get the kind of

data that everybody will believe, then you are not

advancing the field particularly. You and I know that

some of the experiments are very hard to do in very

high‑risk situations.

I don\'t disagree with the importance of

risk. I was just making an argument for trying to

make sure that the system works.

Let me ask a couple of questions of some

of our presenters. The presentation, Dan, that you

gave on devices was very interesting. My question is,

do you think we have an adequate nosology for devices,

classification system for devices, such that people

really understand ‑‑ and my field is just cardiology,

for example ‑‑ what standards they will be held to for

a device which is a monitoring device versus a device

that is going to be used once to produce a shock to a

device that is going to be implanted and assessed over

time, such as a heart valve or a defibrillator or

whatever? And to what extent would a better

understanding of the criteria that would be used for

the evaluation of these devices, in fact, smooth the

critical path?

My sense is there is enormous variability,

that the guidance that the companies get is very

variable, that they often demonstrate certain levels

of efficacy in the course of their evaluations that

are different from one device to another. I\'m curious

as to how you see this area playing out.

DR. SCHULTZ: I guess the short answer to

your question is yes. You know, could we do a better

job in classifying different devices and providing

better information on what would be required? The

answer obviously is yes.

I guess I would go back to the fact that

not only do we have a lot of different kinds of

devices, but we have a lot of different intended uses

for those same devices. As the technology is

changing, so, too, are the indications, the claims,

the uses that those devices are being developed for,

which makes a classification system that was developed

in 1976, at the time that the medical devices

amendments were passed, continue to be outdated.

And it\'s something that requires, as I

mentioned, continuous updating in terms of the

classification, in terms of saying that a guidance

document that we may have written ten years ago is

still valid today. I mean, clearly it\'s not.

I think it\'s a fair comment. It\'s a fair

criticism. And it\'s something that, again, we just

need to continue to be doing and paying attention to.

CHAIRMAN SHINE: Yes. I would just

encourage you to do that.

DR. SCHULTZ: No argument.

CHAIRMAN SHINE: A second observation I

would make ‑‑ and this is a general observation. I

would be interested in Dr. Crawford\'s comment. It is

very striking in your data that from ‑‑ what was it?

‑‑ 1998 to 2003, expenditures in devices went from

about 120 billion to 320 billion. That\'s a doubling

roughly in every three to four years.

This year, the health care system is

probably spending 1.7 trillion, of which 200 billion

according to this chart is incremental device

expenditures, which raises the whole question of value

in the assessment of devices.

I understand the agency\'s not supposed to

look at cost as a consideration in terms of the

safety, efficacy issue, but I just wondered what your

thinking is when you look at these kinds of growths,

which are income to some people but are clearly

enormous costs to the health care system and whether

as, for example, Medicare, CMS is now looking

increasingly at quality of care as part of their

mandate. And they\'re beginning to talk about value.

Should we be thinking in terms of value?

DR. CRAWFORD: Well, the last time we got

into value was under the commissionership of Don

Kennedy when I came on board. That little meander

down the philosophical regions of the mind led to some

of the most memorable congressional hearings I can

ever recall.

I do not, speaking for myself, look

forward to any more of that. We can\'t really get into

that. I mean, we can opine here. And you know the

heart of most of the FDA people around the table is

very much in the direction that you mentioned.

Nonetheless, just speaking about devices

particularly from the standpoint, if you don\'t mind,

Dan, of when I came in, again, in February of 2002, I

found it somewhat to my surprise one of the most

exciting areas at FDA.

I had remembered it as being something

different from about 16 years earlier. At that point,

we decided we would go forward with the Medical Device

User Fee Act. As you know, it was passed.

And in the interactions with the public,

Congress, and the White House and everyone else, and

the industry, particularly, through its two major

trade associations, we found that although FDA

couldn\'t exercise value judgments and couldn\'t do much

in terms of presaging what CMS might wind up doing in

this particular area, it was a field that we had

better get on top of or, else, we were going to be

sort of in the same kind of situation we were in the

\'70s and early \'80s with the so‑called drug lag

because I believe it true ‑‑ I always get this wrong,

but Dan is very capable of correcting me ‑‑ about a

third of the products that were on the market when I

got here hadn\'t been on the market five years earlier,

something like that.

DR. SCHULTZ: I don\'t know the exact

number, but there\'s a ‑‑

DR. CRAWFORD: But it was rapidly

exploding.

DR. SCHULTZ: Exactly, yes.

DR. CRAWFORD: So we thought the user fee

system would help get resources and also focus it.

And it did, but we have had to continue to fine‑tune

both approaches and to stay in rather intimate contact

with the patient population and also with the industry

itself because it is going to be a logistical

challenge for FDA going forward.

And I have happily delegated all of those

worries to Daniel Schultz.

CHAIRMAN SHINE: Any other comments, Dan?

DR. SCHULTZ: I guess I don\'t know how

happy I am, but we\'ll do the best we can. Let me just

say I think that one example of exactly what you\'re

talking about was in the recent CRT studies and ICD

CRT studies, where we obviously looked at the safety

and effectiveness of the device and it was studied in

a large population and then CMS looked at that same

device and decided to pay for it in a smaller

population.

That is obviously something ‑‑ I see that

you\'re from the cardiology field ‑‑ that created a lot

of consternation and concern in the cardiology

community.

I had the opportunity to go to a number of

those meetings and hear exactly what the cardiologists

thought of us. Actually, the good news was that they

thought a lot more of us than they did of CMS.

(Laughter.)

DR. SCHULTZ: So that was actually sort of

a benefit of having them involved in that discussion.

But I think your point is very well‑taken.

And how we deal with it I think is something that we

haven\'t quite yet figured out yet, but it\'s something

that is going to become more and more of an issue.

CHAIRMAN SHINE: Speaking of cardiology,

I was interested in the ‑‑ and Dr. Throckmorton

couldn\'t stay. So we didn\'t have an opportunity to

talk to him about the ECG activity, but, as you

pointed out, technically that is not going to be easy.

DR. SCHULTZ: No, it isn\'t.

CHAIRMAN SHINE: I presume that there\'s a

good advisory group of electrophysiologists who are

helping him with regard to that activity.

DR. WOODCOCK: Yes. It\'s well underway,

actually. And our outside collaborators are, we might

say, among the best. So we don\'t have a concern about

the technical aspects of this, I don\'t think.

Also, we are establishing the standards

for the electronic transmission of the ECG data.

CHAIRMAN SHINE: Right.

DR. WOODCOCK: So that part is pretty much

settled. So this is more about what data are, how do

you fill in the fields and everything so that we have

the information that\'s germane to this. So I think

that that is underway.

CHAIRMAN SHINE: Good.

MEMBER PICKETT: Yes. You know, Janet, a

little bit of just a technical point. In my

experience, unless patients have been ultramonitored,

it\'s very difficult at times to pick up QTc

prolongation. So hopefully the data that is being

collected would be that type of data.

DR. WOODCOCK: Yes. I don\'t know. I

don\'t know the technical details.

CHAIRMAN SHINE: That\'s part of the reason

I\'m asking the question about making sure that they

are very experienced because everything from the

position that people are in when the data is obtained

and whether it\'s ultramonitored or whether it\'s others

all turn out to be very tricky kinds of issues.

We had a conversation at one of our

previous meetings about the genomics issue and the

question of how that was going to affect decisions on

the part of manufacturers to evaluate drugs, on the

one hand, the issue that they would ‑‑ and, as you are

well‑aware, there has been some recent very nice data

on ethnic and racial differences in terms of the

genetic receptivity or responsiveness to one drug

versus another.

But there was also the concern that

balancing the targeting of drugs with the marketing

capacity, that there might be a challenge in terms of

whether people would really want to segment the market

for identifying the most susceptibles versus others.

And I wondered if there had been any further progress

or insight with regard to that.

I know you made mention in your comments

about a paper that is going to come out, but I would

be very interested in terms of what we have been

talking about on the impact of genomics, whether there

is any additional insight about that problem.

DR. WOODCOCK: Well, since we published

the draft guidance on pharmacogenomics, which has a

process whereby ‑‑ and we discussed this with the

Science Board, if you recall, those of you who were

there. And there was endorsement of this.

There is a process by which manufacturers

can come in and discuss their genomic data outside of

the review process. That has been underway, and we

have had a number of meetings and exchanges of data

and submissions of data from the manufacturers, who

are doing various genomic tests in concert with

developing a drug.

We have heard from people. As soon as we

finalize this guidance, we will have more submissions

of that sort. And we expect to do that soon.

So that tension remains. I mean, that was

discussed yesterday in talking about biomarkers. The

tension remains between subsetting the market and

actually targeting the people who stand to benefit the

most, but I believe this will take care of itself in

some ways.

There may be smaller trial designs that

can be done, much faster development programs for

highly effective targeted therapy that may balance out

the problems of having a smaller market.

But manufacturers are going to have to

balance those two. What we don\'t want is

uninformative development because our people feel

inhibited by these commercial pressures.

CHAIRMAN SHINE: Dr. Roses?

MEMBER ROSES: Two points, one about the

balancing of the discovery in the pipeline. Actually,

one way of benefitting from being able to select out

patients who are going to have efficacy would be in

real time during a IIa or IIb study to identify a

population that has no efficacy.

We usually bring backup molecules along.

And drugs in a class frequently work on different

people. Therefore, there might be some sort of

sequential trial design.

I think the results of putting this is

working. So we recently published a IIa study that

basically said, \"Here are three undisclosed genes\"

that basically predicted who would not respond and who

would respond to this drug. That\'s in a IIa study.

We now will meet before the end of the IIb

study with the teams from the FDA to tell them that we

predict when these data come out that these data would

have allowed us to do a smaller, faster study.

Even when they do come out in IIb, we\'re

not going to change the III study. What we are going

to do is the same sort of reiterated analysis, so

basically at the end of the study said, \"This is what

we predicted. This is what we found. And it would

have cost us half as much in half the time.\" We do

enough of those, and I think you will actually see the

benefit.

The point of the benefit ‑‑ I think it is

an incredibly simply but important point ‑‑ is that

when you read the literature, you are reading about

efficacy of marketed drugs that have been looked at

retrospectively.

The only way it is really going to have an

effect on the economics of drug development is

prospectively.

CHAIRMAN SHINE: Good. Thank you.

Finally, Janet, I would ask you after your

talk whether you would comment on whether as you look

across this spectrum there are two or three areas that

you see as having this kind of very broad

applicability that might rise to the surface because

of the generalizability and because of the opportunity

that they might offer to produce changes fairly

quickly.

I am just curious as to if you want to

comment or you don\'t.

DR. WOODCOCK: Well, I think that there

are both long‑term effects but also low‑hanging fruit

and broad applicability are the areas of let\'s

streamline the clinical trials.

Let\'s get to the endpoint of writing down

some guidance on some of these new analytic

statistical methods. Let\'s get together. And we have

many collaborators who are willing to work with us on

the data standards. I think we can get that finished.

And people are going to step up to the plate and help

us finish that.

So that\'s one area, the whole area of the

conduct administration and design and analysis of

clinical trials I believe in the next two years, we

can make very significant progress on.

Biomarkers is another one. Some of them

are very ripe. And they just require somebody to kick

them over the goalposts by doing some additional

validation work in the clinic. Others are earlier.

So both the effort of writing down a

conceptual framework for developing biomarkers, the

types of things Allen was just talking about, people

don\'t know this. Okay? I know it. All right? You

know it. But people don\'t know actually what it would

take and how you would do such a thing within a

clinical development program.

To write that down and to make it

available to the world actually would be very

powerful, I believe, as well as for surrogate

endpoints. So that is another one.

The third area, which does not resemble

any of the parameters you have been talking about, but

I believe it is so important we have to do something

about it, is the diagnostic, whole diagnostic area.

Both in vitro diagnostics as well as other diagnostic

techniques, neuroimaging techniques, and so forth, we

simply have to do something about that that is more

challenging and probably longer‑term.

I think to your point, I agree and with

the Committee that we need demonstrable deliverables

that will come out within the next couple of years.

I believe we can do that because that will provide

that credibility and proof of concept that critical

path can work, but we also probably have to start work

on some of these more intractable problems because

they are going to take longer. And if we delay more

years, then it is going to take even longer.

Our real challenge is how to parse our

resources out amongst these short‑term and longer‑term

projects.

CHAIRMAN SHINE: Thank you, Janet.

Could I just get the sense of the

Committee? My sense, both from your comments and your

body language, is that the principles as articulated

by Janet and in the handout are very sensible. We

have suggested some slight nuances, and we have added

a couple of suggestions.

But is it the sense of the Committee that

you are comfortable with these as the guiding

principles in terms of this effort? Dr. Cassell?

MEMBER CASSELL: Absolutely. I would just

like to reemphasize, I think, that the possibility of

doing the cross‑training between the agencies that we

heard about should be a high priority.

I noticed that in some of the centers,

there are fellowships to try to bring in more of this

academic FDA collaboration. I wonder if you

proactively approach professional societies to ask if

they would be willing to set up a fellowship program

whereby they would fund these fellowships so that it

would allow some exchanges both ways?

I think you probably are aware that a

number of the professional societies each year fund

congressional fellowships through AAAS. We would

think that this would be equally important.

I don\'t believe the way the AAAS

fellowships are structured they would allow and don\'t

provide going into individual agencies. So it might

be something as you are interacting with the

professional societies to approach them about.

CHAIRMAN SHINE: I think it is a very good

suggestion, Gail. Have you had any of the DHHS

fellows? You have had DHHS fellows? Good. Oh,

you\'re considering it? That is another fellowship

pool that might be interesting to look at.

MEMBER CASSELL: And a big one at that.

CHAIRMAN SHINE: Yes. It\'s a one‑year

fellowship, but I wan to see them do some career

investigator work.

John?

MEMBER THOMAS: Yes. I was just going to

follow up on that. Yes. Certainly the medical

science programs, the combined M.D.‑Ph.D. programs,

particularly those that are on a clinical pharm track,

might be an appropriate place to entertain those types

of fellowships.

The other comment that was made by Ken

earlier was the time line. It may not apply to all of

your priorities, but where it could be incorporated,

I think some sort of Gant chart or whatever you could

call it, would be important as one goes forward and

sees what progress is being made.

CHAIRMAN SHINE: Any other comments? Dr.

Roses?

MEMBER ROSES: Just the one additional

comment. I think it\'s working fantastic because it

seems to be working, but one of the things if we could

influence, particularly in the other parts of the

agency, I think clinical research and the granularity

of patient description and the collection and putting

them together in terms of studies has been neglected,

terribly neglected.

I am a great spokesman for the genome, but

the genome is to look at people. And if we can\'t

select on characteristics of the people, this isn\'t

going to mean very much. And anything that we could

do, I think, to get that part of the balance elevated

I think would be of benefit.

CHAIRMAN SHINE: This is another area that

NIH is important in terms of their support of clinical

investigator and clinical investigator training.

A number of institutions in this area have

done a very nice job because of their interest in

technology transfer of connecting clinical research to

help with the IRB, with dealing with the regulatory

agencies, with trying to figure out ways to educate

young people as to how to do that. I think that we

really ought to encourage in terms of that

translation.

Gail? And then I think we will adjourn

for lunch.

MEMBER CASSELL: Thanks, Ken. You are

being very generous with me this morning.

Dr. Roses, I think you probably are aware

of this new initiative that the AAMC is starting in

clinical research. And it seems like what you have

just said would be a perfect thing for that group to

take up.

CHAIRMAN SHINE: Thank you, Gail.

Ladies and gentlemen, we are going to have

kind of a working lunch. That is, we are going to ask

you to have lunch and then ‑‑ Les, how should we do

it? Should we gather back?

DR. CRAWFORD: We have a room. We\'re just

going to stay in the room and do it.

CHAIRMAN SHINE: Okay. So we\'ll be

meeting upstairs with you briefly over lunch.

DR. CRAWFORD: Yes.

CHAIRMAN SHINE: And then we\'ll reconvene

here promptly at 1:00 o\'clock. We don\'t know if there

will be any open session.

EXECUTIVE SECRETARY JOHANNESSEN: I

haven\'t received any, but we\'ll ‑‑

CHAIRMAN SHINE: If there is not, we will

go directly to the 2:00 o\'clock agenda. We\'ll adjourn

for lunch.

(Whereupon, at 11:53 a.m., the foregoing

matter was recessed for lunch, to

reconvene at 1:00 p.m. the same day.)

A‑F‑T‑E‑R‑N‑O‑O‑N S‑E‑S‑S‑I‑O‑N

CHAIR SHINE: Could I ask whether there is

anyone who wants to make a statement as part of an

open public hearing? Could you indicate by just

showing your hand? I\'m trying to‑‑there is no one who

wishes to make a statement. I see no hand. So I\'ll

spare you the effect of reading the statement on

statements in open general sessions. We have one or

two other members who need to rejoin us, so we\'ll

reconvene in just a few minutes.

(Whereupon, the foregoing matter went off

the record at 1:07 p.m. and went back on the record at

1:08 p.m.)

CHAIR SHINE: The record will show that we

inquired as to whether anyone wished to make a

statement during the open public session, and no one

came forward for that purpose so we will proceed with

the agenda for the rest of the committee activity.

The first presentation will be with regard to good

manufacturing processes, or procedures. We\'ve heard

a bit about this issue in the past, and the Council on

Good Manufacturing Practices is moving forward, and

Janet Woodcock is going to give us an update on that

initiative. Janet?

DR. WOODCOCK: Thank you. Good afternoon.

This is a final report to the Science Board on this

initiative which is finished. We promised that we

would give you the conclusion on this and follow up.

I know some of the board members are new and don\'t

really know about this initiative, so I\'ll try to fill

you in a little bit as I go along. We\'re going to

have actually three presentations. I\'m just going to

give you the overview, and then we\'re going to have a

report on a risk‑based model, just the scientific

structure of that, and then Ajaz Hussain is going to

talk about the manufacturing science and how we\'re

moving ahead on that.

The initiative was announced in August of

2002, and was presented. We had two presentations to

the Science Board which are actually very pivotal

because this initiative was somewhat controversial in

the beginning. And the first presentation resulted in

all kinds of uproar on the outside, but the Science

Board was extremely supportive of us moving forward,

and really helped move this along. Our second

presentation endorsed some ideas around new methods of

process analytical technology, and looking at

individual samples. And that was also extremely

helpful in having us move forward.

We issued a progress report in August,

2003\. All the stuff is on the Web. And we just

issued our final report in September, 2004. Next one.

The major theme was trying to modernize

the actual practice and at the same time a regulation

of pharmaceutical manufacturing. Like many other

things that we\'re discussing today, as we move science

forward in one area you have to adjust your regulation

too, otherwise neither of them seem to move forward.

Our themes that we had under that were advancing the

science of manufacturing, number two, using a risk‑

based approach to regulating manufacturing of

pharmaceuticals. The Good Manufacturing Practices

Regulations, which were promulgated in 1978, looking

at them through the new lens of a quality system, and

as an example of a quality system, and then making

sure we were focusing on public benefits of doing all

this. And this was a joint initiative amongst the

field, the Office of Regulatory Affairs, Center for

Veterinary Medicine, Center for Drugs, and Center for

Biologics, all of which are involved in regulating the

manufacturing of pharmaceuticals of different kinds.

Next one.

Our initial findings were that

pharmaceutical manufacturing was really not fully

utilizing modern manufacturing technologies and

quality management approaches. And some of this was

presented by various outside parties at the first

Science Board meeting we had on this. We also found

that manufacturing expenses in the pharmaceutical area

exceeded the R&D investment made by at least the large

pharma industry for which we had numbers. It\'s

probably also true for biotech.

We discovered that there were many

perceived regulatory barriers to improving this

situation, incorporating the new science into

manufacturing, and there were additional reasons that

we were told for lack of investment. It is that the

companies kind of also focused on R&D and did not

invest in this particular area. Next one.

Our final announcement on September of

\'04. We had made many intermediate announcements. So

what we announced in September was we\'re going to

establish an FDA council on pharmaceutical quality.

It will include the same types of members,

representation from the various involved centers and

the field, and we will continue this momentum, but we

will sort of institutionalize this whole effort. At

the same time, starting with Center for Drugs as a

model, we are restructuring and refocusing the actual

pre‑market review process for the chemistry

manufacturing controls. And the reason was that in

doing this initiative we uncovered the fact that this

is really about pharmaceutical quality. And the way

we regulate pharmaceutical quality is really

structured and set by the way we do the pre‑market

review. And that then perpetuates itself into post‑

marketing area, and what\'s required under GMPs. And

this eventually, after much soul‑searching, led us to

conclude we\'re going to have to revise how we review,

and what we have submitted to us in the marketing

application for drugs.

We also devised a risk‑based inspectional

model that we released at that time. And you\'re going

to hear a little about that. We issued a bunch of

draft and final guidances. We\'ve been issuing

guidance all along in different areas. And we put

forth a model for quality system. We\'re using

basically the same generic internal model for quality

system for running quality systems inside the FDA, and

then we put forth a model for the outside world

whereby a manufacturer could have a complete modern

quality system and also be compliant with all the GMP

regulations at the same time. It\'s clear that maybe

sometime in the future we may need to revise all our

regulations to be consistent with this, and also

across devices and so forth, but that would be a very

long‑term project. We certainly have all talked about

this. And we did a very extensive analysis of all the

quality system requirements, both internationally and

within the FDA. So we have our arms around that.

Next one. Now, what did we achieve overall in this

initiative, and how does this relate to science?

Well, first of all one of the early things we did, and

we\'re still finishing this up, is the formation of the

pharmaceutical inspectorate within the field. This is

going to be a group of very highly trained inspectors

who will be the people who do the GMP inspections in

the facilities. They are completing their

certification. They had to go through a very lengthy

training and certification process to become

inspectors, and I think we all feel, John, we all feel

very positive about this overall. So that\'s moving

well. And the training there is co‑training. We\'re

training all the center people and the field people

together so that we\'re all being more consistent,

because one of the issues we got was scientific

inconsistency.

We issued a reform of Part 11 which was

the electronic records requirements. We\'re still

working on revising the actual regulation, and that\'s

moving forward. However, we issued guidance that I

hope brought a lot of clarity to this field. I see

some nods. And also we focused on manufacturing

science. And you\'re going to hear some of that from

Dr. Hussain in a minute. Process analytical

technology, we issued a white paper as part of our

final report on manufacturing science. And we\'ve set

up academic and industrial collaborations. And this

is to the point of what we talked about this morning.

We need to reach out to the outside world and bring in

a lot of this science to help us in different areas.

Next one.

We also developed a dispute resolution

process whereby if there is scientific dispute over a

finding on an inspection that there is a process

whereby the firm could ask for further adjudication of

that dispute. We\'ve only had one dispute asked to be

adjudicated. But what we have heard is this has

really changed the dynamic whereby this process is now

viewed as one that\'s an open scientific process that

is subject to questioning and scientific back and

forth. And we\'ve heard from our stakeholders and so

forth that this is really a good improvement.

We also improved the warning letter

process, and we\'re in the process right now of

implementing a quality system around our warning

letters. And that may seem not that important for the

uninitiated, but the reason that\'s important is a lot

of the detailed information is not released to the

public. But industry looks at these warning letters

and what\'s cited in there, and tries to decide that

that\'s the level of GMP requirements based on what

people were cited for. So we are going to put a

formal quality system into the warning letters to make

sure they\'re consistent, everyone buys off on what\'s

in there and so forth. And we think we\'ve improved

that process quite a bit now. But it has a way to go.

And then we clarified what we mean by

process validation. We\'re doing a whole effort on how

you actually qualify your manufacturing process. Next

one.

We issued a number of scientific

guidances, such as guidance on aseptic processing.

And we feel that one of the things that was lacking

before in the GMP regulation area was actual guidance,

written scientific policies and so forth. And so

companies were looking at these 483s and other

citations and everything to get guidance. And that\'s

really not the right way to do it. So we have a

program now that we will issue additional scientific

guidance in a variety of areas in the GMP realm. And

that\'ll come out from the three centers and the field

together. We also did the risk‑based inspectional

model that you\'re here about, and we did a lot of

analysis of the GMP regulations. Next one.

So we issued the model for the quality

system for pharmaceutical manufacturing. And we

issued about 18 documents in our final report. So

we\'re still waiting. People are still sorting those.

We\'re waiting for people to comment on them. We also

instituted a quick guidance process. And what that is

is when one of the centers makes a scientific or

policy cut on \`this process is adequate\' or \`this

equipment is adequate\' or \`here\'s how you interpret

this\' instead of just telling the firm what we do, we

send it around in this quick process, and then we

publish it as part of an ongoing guidance that we

have, so everybody is working from the same

information.

We are also in a number of international

discussions in ICH. We realize that pharmaceutical

manufacturing is a global effort, and much of it is

done, in fact, overseas. And therefore any agreements

that we make, we really don\'t make a lot of progress

unless we make it internationally. So ICH is the

International Conference on Harmonization of the

Technical Requirements for Pharmaceuticals. And

within that forum we are doing a variety of

harmonization efforts.

We have also approached an entity called

PIC/s which is a Pharmaceutical Inspectorate

Convention. That\'s an association of inspectorates

around the world. And that will be a venue to try and

harmonize inspectional processes, what the technical

approaches are. What we found when we did the

analysis of the regulations is they\'re very similar,

the quality system or GMP regs around the world, but

the implementation by the various inspectorates is

quite different, and the scientific interpretation of

what these very general regulations mean. So we

believe that through the PIC/s process we can improve

that. Next one.

So what are we going to do? We\'ve

completed, we think, what we set about to do, which is

to do an entire scientific assessment of the process,

and to develop a vision for the future. But we do

have things that remain to be done. We will run the

Council on Pharmaceutical Quality, and keep up the

momentum. We will keep ICH moving along. We are

implementing the quality system within FDA. It\'s

going to have to be implemented piecemeal due to

resource issues. However, we are implementing this in

a variety of areas that we have identified. And we\'ll

proceed through the Pharmaceutical Inspectorate

Convention. Next one.

The biggest scientific change that\'s going

to occur over the next year will be in the CMC review

process, refocusing and restructuring that. That\'s

requiring organizational restructuring and scientific

conceptual restructuring, if you will. But I think

this is very positive. And the goal at the end of the

day for those manufacturers who have good process and

product knowledge would be to decrease the number of

required manufacturing supplements that the FDA looks

at. And what that will do is allow continuous

improvement and innovation, and remove that barrier to

innovation in manufacturing. Next one.

So that means that we need to develop this

risk‑based approach to oversight. That\'s another

scientific activity that we have to do. We will look

at people who have good process and product knowledge,

and also have a robust quality system in place. And

we want a commensurate decrease in the submissions and

the inspection frequency so that we can shift our

resources to the higher risk areas. Implementation of

this is challenging because it requires using a

scientific model that models risk in various ways.

Next one.

As I said, we have to keep working on the

pharmaceutical inspectorate and get those inspectors

out in the field. But that\'s all worked out. It\'s

going through its ordinary process, so there\'s no

questions that this is going to happen and be

deployed. Next one.

What about the future though? Okay, we\'ve

done this evaluation. We can see where manufacturing

needs to go. And I haven\'t really given you that

vision, because I think Ajaz Hussain will do that.

But most of the change that\'s going to occur in

pharmaceutical manufacturing is incremental, just like

most change. But we need some leaders out there to

make what I call some quantum transitions, to make

some big leaps forward. We need to see some

continuous manufacturing models. We need to see some

innovation in this field, because that will then pull

the rest of the world along.

And then if we develop the kind of

statistical process control in this industry that we

see in other industries, then FDA can start thinking

about doing a virtual inspection via the quality

system controls, and the statistical knowledge of the

process, the trend analysis, rather than getting out

there and looking at all the documentation on paper

that exists about batch records and so forth. That\'s

where we all need to go. I see heads nodding so

people understand this. That\'s great. We understand

where we need to go, but everybody, the industry, the

FDA, everybody needs to move forward to get there.

Next one.

I think Ajaz will probably talk to you a

little bit about certain parts of the way we are

thinking about pharmaceutical quality. Right now it\'s

binary, a pass/fail type of thing. This really

constrains continuous improvement. We need to move

toward a more probabilistic definition. And we talked

about this a year ago at the Science Board and you all

endorsed that, and that\'s really helped us in moving

forward in this area. Next one.

How does this fit into Critical Path that

we talked about this morning? Obviously the

industrialization dimension of many products is an

important one, and I think you heard from Kathy

Carbone this morning how important it is, say, for the

biologicals. It may be one of the key barriers to

getting new biological products on the market. The

Critical Path Initiative intends to support robust

science at the FDA, the highest level of science, so

that we can evolve our regulatory standards to the

extent the science allows it, and the industry

practice allows it. And it also, the Critical Path

envisions collaborative research efforts to help

advance manufacturing science. So what I\'m saying is

if we can garner some resources for Critical Path

we\'ll be rolling in a lot of this manufacturing

science piece into the Critical Path Initiative in the

industrialization dimension as we move forward. Next

one.

So we\'ve had substantive accomplishments

within this initiative. We\'ve put out maybe 50

different guidances and documents and so forth. I

think you all don\'t need to be concerned if we pick up

another initiative that we will have milestones for

that initiative. But the next phase for this one is

basically consolidation and institutionalizing the

changes that we\'ve envisioned, and the progress that

we have made. Nevertheless, we really need, as I

said, some leadership out there to make some of these

big changes to model the path to the next level. And

as always, the science really can guide us in making

our way forward.

So what I\'m going to do now. Do you want

me to just announce? We\'ll have our next speaker now

on the risk model.

CHAIR SHINE: Dr. Kara Morgan of the

Office of Planning/Office of the Commissioner is going

to tell us a little bit about the planning model.

DR. MORGAN: Hello everyone. Janet asked

me to come here today just to give you a little

insight into this risk model that\'s a key part of the

GMP initiative. I worked on this model with CEDR.

Next slide.

I wanted to first place in context. We\'re

interested in the Office of Planning/Office of the

Commissioner in kind of upgrading risk management

tools across the board in FDA, and this fit well. It

really dovetailed with some of the strategic action

items and the strategic plan that had been developed.

We know that there\'s rigorous science‑based methods

available to do this type of improvement, so we\'re

interested in incorporating them, of course

incrementally. But this, I think, took us a big step

towards that. We had one of the action items was this

efficient risk management goal, but clearly it\'s

difficult to evaluate efficiency when you don\'t have

formal tools for making risk management decisions. So

that will help us in that area. Also, we\'re very

aware of OMB issues, including transparency,

consistency, and so on, and again, formalizing their

risk management tools will help us to accomplish that.

Of course, risk is a meaningful public

health metric to use. It\'s relevant across all the

centers, though each center has different definitions

of it. And I\'ll tell you about ‑‑ we spent some time

on this project, defining what it meant for this

particular project.

I did want to mention that though I\'m

talking about the CEDR model today, each of the

centers is implementing a type of prioritization along

the same lines. This is the most advanced technically

approach, but other centers are also trying to

accomplish this kind of task in terms of prioritizing

sites for inspection. And we also have in the

strategic plan plans to look at risk‑based methods for

improving compliance, and work planning as well. But

those are really just in the initial stages. Next

slide, please.

So, for this site selection model, I just

wanted to put in the context for where we had been.

Before this approach was implemented the process that

was used to prioritize sites was that CEDR used these

big bins of categories which are listed here, sterile

drugs, prescription drugs, new registrants who had not

previously been inspected, and explicitly excluding

medical gas. And these were identified as the high‑

risk sites. And within those categories the field

would choose where exactly they would go. The

problems with this was that we didn\'t have the

resources to inspect all of these high‑risk sites.

And CEDR felt that there was different information

that could also help. For example, some sterile sites

were more urgent needs for inspection than others. So

this wasn\'t really discriminating enough just to have

these categories, and there was additional information

that CEDR wanted to incorporate that the field might

not have available. So the solution was to develop

this formal model to rank the sites by risk for each

district.

And I did want to note here that before

this model was implemented for FY05, our decisions

were risk‑based in this area, but it wasn\'t formal.

And what would happen is the field would have this

information about kind of past history, indications of

risk, things that they knew, and they would

incorporate that information to decide where to

inspect. But the problem again was in terms of

evaluating the efficiency of it. We didn\'t have kind

of documentation of what the decisions were based on,

or how the history had developed. So this will help

us to maybe be able to go back and analyze the

decision‑making behind the inspections. Next slide.

So the process was kind of typical. There

was a working group developed, as Dr. Woodcock

mentioned. I was involved in this group. It involved

everyone who had input to this issue. We spent a long

time defining what risk meant for us in this context.

And we landed on risk is equal to the harm to the

patient from the low‑quality product. And clearly, as

you can see, there would be different definitions of

risk depending on what your goal is, and that\'s what

we\'re focused on.

Once we had that defined, we spent a lot

of time brainstorming factors that we thought would

contribute to a higher or lower likelihood of this

risk. And from this long list of factors, we

categorized them into three bins, basically product‑

related, facility‑related, and process‑related risk

factors. We then evaluated what information we had

available to assess these factors and develop the

weights. And I\'ll talk a little bit about each one of

these factors to give you a sense of the kind of

information that we used. I did want to note here

that some of the factors that we identified were ones

that there is not information on currently, or at

least information isn\'t in a form that we could link

it to sites to help us prioritize. So one of the

long‑term strategies is to help develop those

information sources so that we can really incorporate

all the factors that we\'re interested in.

So first, in product‑related factors we

did keep the sterile and prescription drug categories.

And the way to interpret that is if you had two sites

that were exactly the same on every other

characteristic, but one produced a sterile drug and

one produced a non‑sterile drug, we would be more

likely to inspect the sterile facility first. And

similarly for prescription drugs versus over‑the‑

counter drugs.

We also included another factor here on

recalls. We do have access to recall data, and the

team felt that this was an important indication,

something we want to take into account so that in the

big picture, if you develop a product that\'s in a

class that has a lot of recalls, that you would be

more likely to be inspected than if that\'s not the

case. And this also did include a measure of

severity. The recalls as they come are classified in

terms of levels of severity, in terms of potential

impact on public health. So that was also taken into

account in the model. Next slide, please.

The facility‑related factors are ones that

ORA probably already was incorporating even though

perhaps informally because they do have access to the

FACTS database that this information is contained in.

And the important pieces of information here are the

times since last inspection. Of course, any record of

violations, or other compliance information. We also

used an estimated production volume to get a sense of

exposure so that again, if you had two facilities that

were exactly the same in all their characteristics

except one produced millions of pieces of product and

the other one produced thousands, we would be more

likely to inspect the one that produces millions. And

establishment type, in terms of what the function of

the site is of course is relevant too. And all this

data was gained from FACTS, the ORA database.

And finally, these process‑related factors

were deemed as important. And the team felt that

there were inherent information about different kinds

of processes that would lead to more or less

likelihood of harm due to low product quality. And we

also wanted to take into account process controls and

risk mitigating components that may have been

incorporated. Unfortunately, there was no data

available that we could easily match up with our

facility level information. So what we did is we did

an expert elicitation within OPS and ORA and a couple

of other places to get people who had experience in

the manufacturing area to give us what their

assessment was in terms of relative risk of different

types of processing. And this was modeled on an

expert elicitation that had been done by the

International Society for Pharmaceutical Engineering.

And the idea was that people have, even though we

couldn\'t get our hands on this data, people have

information from their experience that can tell us

about the relative likelihood of something that would

cause a risk to product quality. So that was a big

undertaking, and we do plan to continue to develop

that as needed.

So we combined the factors in the final

model using weights for all these different pieces of

information, and had algorithms to combine the

weights. And what the outcome was for each site, each

active site in FACTS, they received a site risk

potential score with the indication that a higher

score is a place that we should inspect more than

something with a lower score. So basically each

district came out with a ranked list.

Just a plain language summary of the

influence of the factors. A site will be less

frequently selected for inspection if it\'s been

inspected recently, if it has few or no previous

violations of GMPs, and has a small volume of product.

This is in a facility weight. If it makes non‑sterile

over‑the‑counter drugs, and makes product types that

are not associated with a high frequency of recalls

with severe effects. And it makes products judged to

be relatively straightforward to manufacture, and not

vulnerable to contamination.

So what we did. In late September, each

district received a list of sites ranked by their site

potential risk score. And a description also, not

just of the total score, but of it broken down by

facility, process, and product, so that they could

really understand what was driving the risk. And

there was a lot of interaction with ORA. This is

clearly a process that we\'ll develop and fine‑tune

over time. We want to make sure that ORA had the

opportunity to incorporate information that we might

not have had access to. So the more information that

we gave them, the more information they could say, oh,

well, this says it wasn\'t inspected, but we know it

was just inspected last month, it just wasn\'t in the

database, and so on. So that we have that ability to

communicate about the details.

And I did want to note here that the field

was asked to use this list of ranked sites to

prioritize. The GMP inspections from what I

understand take up about half of the CEDR resources.

So this isn\'t directing all of their drug inspections,

just the GMP part, which is about half of their

inspections.

So the next steps. We of course are using

a model of continuous improvement. We want to provide

incentives for better data, both within the agency and

from the outside the agency. And as I mentioned

earlier, including the addition of factors that were

deemed to be important but we just simply didn\'t have

the information at this time to use. I mentioned

we\'re going to be interacting with ORA to get feedback

on the information we provided. You know, if we can

give them more information or less information, what

would be useful to them in terms of providing them the

best tool for doing their job. And we do plan to do

a sensitivity analysis of the weights and the factors

to really understand what\'s going on behind the model,

what\'s driving the scores, and how we might fine‑tune

things in the future.

There is an evaluation underway by the

Office of Planning of this particular model, as well

as the entire GMP initiative, which is going to be an

ongoing process. And I wanted to mention that CVM is

considering using this model for prioritization of

their animal drug inspections.

So the expected outcomes of this model in

the very big picture are the idea that we want to

provide better predictability for industry in terms of

the likelihood of inspection, and of course incentives

for them to reduce their potential for causing risk.

We\'re going to have some increased efficiency and

effectiveness and hope to be able to measure that so

that we can describe our improved efficiency in terms

of resource use. And of course, the lofty goals of

higher product quality and improved public health.

CHAIR SHINE: Thanks Kara. A question for

you and Janet. Will the kinds of metrics that you\'re

using here be part of the benchmarking that you do for

the overall initiative. That is, I could see ways in

which these measurements could show directional

changes depending on how the overall initiative goes.

And is it your intent at all to harmonize those as you

go forward, for the sake of argument saying as a

consequence of the work of the council there is less

problem with unsterile conditions, or better reduction

in recalls, or whatever, some of the things that are

working. So I\'m curious as to what the connection is

from that point of view.

And the second question is given the

references to sterility, I presume that this will have

a measure emphasis on vaccine production and

biologics. And my question is does the focus on

sterility overweight, or that\'s not quite the word I\'m

looking for, but does it tend to focus more on

vaccines and biologics than it does on drug

development. I\'m just curious in terms of the

probability that there would be difficulties.

DR. WOODCOCK: I\'ll defer to Kathy because

this ‑‑ the model was implemented for pharmaceuticals

not for vaccines right now, for the pharmaceuticals

regulated by CEDR and possibly then CVM.

DR. CARBONE: I\'d say the vast majority of

our products, especially the important ones, are in

the sterile category. So they almost by definition

fall into a higher concern category. Plus, I think

there\'s an element maybe a little different from

pharmaceutical that\'s hard to classify or characterize

products. And we\'ve been involved with clotting

factors, trying to get standards, some benchmark to

measure them against. And in these products, there

may be a higher issue in the risk because they\'re

difficult to characterize and make consistently.

CHAIR SHINE: I guess maybe I wasn\'t

entirely clear. Do you anticipate using the same kind

of risk approach to biologics and vaccines?

DR. CARBONE: Oh, we\'re part of the

initiative, yes. Absolutely.

CHAIR SHINE: Right. So you would be part

of this initiative.

DR. CARBONE: Yes.

CHAIR SHINE: So it\'s still not clear to

me, given that sterility is such an important issue,

whether that increases the probability that you\'ll be

looking at ‑‑

DR. CARBONE: You\'re comparing across

centers, for example.

CHAIR SHINE: Yes.

DR. CARBONE: Yes, I think as a center

we\'re going to fall into one of the higher risk.

CHAIR SHINE: And what about the issue of

metrics as far as the overall activity?

DR. WOODCOCK: Well, that\'s an interesting

suggestion. Actually, we regard the ‑‑ we discuss

some metrics, and we regard say seeing a lower number

of recalls, or whatever, they\'re less proximal

probably outcome. We want to look at probably some

more intermediate outcomes, like perhaps more online

testing, or innovation of technology put into the

plants as an intermediate. I think our long‑term

goals would be these goals, which would be fewer

recalls, fewer contaminations, and so forth and so on.

But we don\'t expect those to occur instantly.

CHAIR SHINE: But you\'re collecting that

data so that you would be able to follow those trends.

DR. WOODCOCK: That\'s exactly right.

CHAIR SHINE: I\'m just raising the

question of whether you use a similar kind of metric

for that as this, or whether there would be a

different metric.

DR. WOODCOCK: Well, one of the

disciplines we have under OMB is we have to construct

long‑term outcomes that we are aiming for, and then

work backwards from them and look at intermediate

markers or whatever, leading indicators, whatever you

want to call that might ‑‑ that would indicate that

we\'re moving along the correct pathway. So that is

the way we think about these things.

CHAIR SHINE: Good. Any other questions?

Yes, please. John?

DR. THOMAS: Go ahead.

DR. SWANSON: Okay. I really do applaud

a risk‑based approach in looking at things such as

this because it really does help you to allocate your

limited resources in the area that it\'s going to do

the most good. A lot of work is being done nationally

and internationally on risk management strategies.

And I like the comment that you had about defining

what risk is, and having brainstorming. One of the

things I would point out is it might be useful for

harmonization, especially in international circles, to

take a look at your definition. Because as I look at

this, this is more a definition of hazard. Because

risk to me always incorporates that element of

likelihood to occur, which you referred to over and

over again. So you might want to tweak the definition

so that everybody\'s talking in consistent words.

CHAIR SHINE: Thank you. John?

DR. THOMAS: Yes, I had a couple of

comments. Have you actually developed a syllabus for

your inspectorates yet? Or is that something in the

future? And are you going to share that with both

people in the FDA as well as some guidelines for

industry?

MR. MARZILLI: Yes, we have that training

developed. We developed it in concert with the Center

for Drugs. I\'m John Marzilli from the Office of

Regulatory Affairs. We developed it in concert with

the Center for Drugs, and we\'ve been offering it both

online and in face‑to‑face courses with both programs

represented, Center for Drugs, other centers, and the

Office of Regulatory Affairs at our ORAU campus. And

we have great oversight for the Center for Drugs

Office of Compliance as they occupy the top two floors

of that building. So they make sure that we keep it

straight as we\'re conducting this training.

DR. THOMAS: Another follow‑up on the

metrics that Dr. Shine asked initially, I think. Are

you going to sufficiently tailor these to the facility

so that you might in the future reduce the number of

actual site visits wherein you could have a self‑

report, or an interim self‑report? It would save you

a lot of resources, you know. Obviously if you\'ve got

a problem site that wouldn\'t necessarily apply. But

if these are routine, it seems to me that you could

use electronic self‑report as an interim type of

document.

DR. WOODCOCK: That\'s our hope. Right now

we don\'t get data, or we don\'t record data on the risk

mitigation strategies. And that\'s the piece we want

to incentivize, and that\'s the piece that would be

subtracting from the risk in these different terms.

And so we are going through like with our pre‑market

evaluation the changes we\'re doing there. Also

probably we\'ll have to do with the field, figure out

ways to incorporate those sort of bonus points, if you

would, where good risk mitigation in place, usually by

process controls or perhaps other means. And then

that will lower the rank on the model, which would

translate we hope eventually not only to fewer

inspections, but actually fewer submissions of

manufacturing supplements.

DR. THOMAS: And finally, what sort of GS

rating would these inspectorates have, for example?

Are you going to be competitive?

MR. MARZILLI: Well, we\'re competitive

within the government. The GS range for the

inspectorate is GS‑12 to 13 for those that specialize.

And then within FDA we also have an internal peer

review process by which people can go through

certification to be graded to a higher grade,

including 14 and in very rare cases the 15 level for

international experts.

DR. THOMAS: Thank you.

CHAIR SHINE: Dr. Pickett?

DR. PICKETT: Just a comment. First of

all, I would like just to, since I\'ve been here from

the start of this, like to compliment Dr. Woodcock and

her colleagues for really overseeing this initiative.

I think it\'s a major, major step forward. I think

it\'s obviously good for the FDA. I think it\'s good

for manufacturers because manufacturers can improve

their efficiency and can reduce costs. And that

reduction of cost I think will have important impact

on funding of R&D within organizations.

DR. WOODCOCK: Right.

DR. PICKETT: So I think that\'s a big

plus. And finally, I think it\'s obviously good for

patients, because patients are going to be the

ultimate beneficiary of making sure they get a

consistent product.

My only other comment has to do with the

risk‑based approach. And what I simply would request

is that that approach is simply transparent to the

industry. I think that that\'s extremely important.

And I notice Dr. Thomas brought up the same sort of

issue, but it wasn\'t completely addressed.

DR. WOODCOCK: Fair enough. And we are

contemplating ‑‑ I mean, we\'re not going to release

everybody\'s scores. But we need to get the parameters

out there so people know, and that gets the incentives

and so forth.

DR. PICKETT: Exactly.

CHAIR SHINE: Yes, Dr. Harlander.

DR. HARLANDER: But these scores will be

released to each individual facility ultimately. Or

are you just currently using this as an internal

management tool?

DR. WOODCOCK: That\'s correct.

CHAIR SHINE: Anything else? Thank you.

Why don\'t we go on to hear from Ajaz Hussain.

DR. HUSSAIN: Good afternoon. This is my

final report on Process Analytical Technology and

Manufacturing Science. I\'d like to share with you our

final report. The outline for my talk is to summarize

for you the previous discussions we had on these

topics at the Science Board. Started with the

emerging science issues in pharmaceutical

manufacturing, and identified opportunities for

improving pharmaceutical manufacturing, and then how

we have proceeded to make progress in this initiative.

How did we define the desired state, and what is the

desired state, and the progress made in the PAT and

the cGMP initiative. And how we plan to continue the

scientific and technological progress towards a

desired state to the Critical Path initiatives.

That\'s the summary of my talk. Next one.

The first FDA Science Board presentation

occurred on November 16 I believe, 2001. And we had

invited seven divisions from outside. One of them was

G.K. Raju from MIT, and he shared with us his analysis

of the current cycle time and efficiencies of

pharmaceutical manufacturing. And in summary, we

often spend time testing to document quality rather

than quality by design. And our testing times far

exceed or are equal to that of process times. Next

slide.

But that\'s not where the major problems

were. The major problems were the deviations, and our

specification results. Here is an example where you

see different batches of products being manufactured,

and on Y axis you have oral cycle time. G.K. Raju at

that time did not want to share the Y axis numbers.

The scale is 600 days. So it was taking 600 days to

manufacture and release many of these batches of

tablets. Conventional tablets, this is nothing

complicated. Because of exceptions, deviations, and

so forth, and the purple dots often, since root cause

is unknown, we throw away those batches. So that\'s

where the efficiency is built in. Next slide.

So if you look detailed analysis of some

of these examples. And these are products we have

approved recently, not older products. The average

cycle time to manufacture conventional tablet dosage

forms could be 95 days. But the process time actually

is about one shift. Standard deviation exceeds

average. So it\'s unpredictable. So in order to

maintain supply you have to have huge stocks. And

exceptions increase the variability. And capacity

utilization of the system was low, less than 10

percent in these cases. What that meant is less than

10 percent of the time manufacturing unit is actually

manufacturing something, resulting in the

investigating of specification results. Next slide.

Furthermore, Doug Dean from

PricewaterhouseCooper, now with IBM, came and shared

his analysis. The current utilization levels are 15

percent or less. Scrap and rework we plan for 5 to 10

percent accepted as necessary. Time to effectiveness

takes years. Costs of quality is in excess of 20

percent. Next slide.

From Pfizer, Norman Winskill, the Senior

Vice President for Manufacturing shared with us their

struggle. And they essentially said that Pfizer has

adopted a policy of don\'t use or don\'t tell. \"Don\'t

use\" simply means they will not use new technology

because of fear of regulatory concerns or uncertainty,

or they do need to use new technology, and they\'ll do

so, but not tell FDA, and still do the tests FDA

requires. And this we felt was clearly contradictory

to the public health objectives of FDA. Next slide.

At the second Science Board presentation,

we had a significant presentation by Ray Scerzher, who

is a Senior Vice President for Engineering at

GlaxoSmithKline. And his presentation title was

\"Quality by Design: A Challenge to Pharma Industry.\"

So he essentially challenged his own industry to say

think about the fundamental science, and think about

design, because this industry is high‑tech when it

comes to R&D, it is a low‑tech industry when it comes

to manufacturing. And it matters because the costs

far exceed that of R&D. Next slide.

He also went on to say how can we make a

difference. He identified the technology. Science is

probably not the right limiting step. We have

methodologies. Other industries have done this. For

example, online monitoring control going to

statistical process control and so forth. He also

emphasized that the financial drivers were very

strong. One percent yield improvement could be \$400

million saving. But the challenges were significant,

and these were cultural, organizational, and

historical. Next slide.

So our summary through the Science Board

discussion was that current state of pharmaceutical

manufacturing is a challenge, it is static. It is

based predominantly on empirical approaches. Industry

is reluctant to use new technology. And at some

level, fundamental science and engineering principles

are generally less developed compared to other

industry sectors. There\'s a high degree of

uncertainty that precludes risk‑based regulatory

decisions. If you are uncertain, you cannot make

risk‑based decisions. And manufacturing difficulties

can affect not only the cost, but the supply of drugs

to the American public. We have very low efficiency

and high cost, and clearly the current manufacturing

model may be inadequate to deliver quality products in

the future, especially as we go to complex drug

delivery systems, nanotechnology, and so forth, where

physical attributes get more important and we move

towards a genetically modified treatment that requires

flexible supply chain. Next slide.

We went on to hold several other meetings

under the Advisory Committee for Pharmaceutical

Science. We created a subcommittee called Process

Analytical Technology Subcommittee. And we heard the

message loud and clear: technology is there.

Technology may be rate limiting. Here is one example

of chemical imaging that can be brought to bear on

decision‑making, and identify causal links as well as

root cause analysis, where in this particular case

Steve Hammond from Pfizer shared what Pfizer is doing

with chemical imaging to understand dissolution of

tablets and how it relates to blending, for example.

Next slide.

Similarly, literature also shows that some

of these technologies already exist outside

pharmaceutical industry, and even pharmaceutical

literature is bringing some of this in. But industry

is reluctant to use this. Next slide.

Here is one other example from

GlaxoSmithKline where you are actually using new

technology to start predicting product performance.

On the first graph, you are actually predicting

moisture content, and replacing a Karl Fischer method

with online methodology. But on the other one I think

you\'re even getting the particle size and other

physical attributes. So the technology is bringing

physics and chemistry together, and that\'s one of the

key advantage opportunity we wanted to realize. Next

slide.

But it was not just physics and chemistry.

It was microbiology. Rapid microbial methods was a

topic of discussion at our third PAT subcommittee.

And in fact this was the first PAT submission approval

of introducing rapid microbial methods. And clearly,

rapid microbial methods are also available for quality

assurance. Next slide.

There was one other opportunity that we

identified and leveraged. That is, use of new

technology may support fundamental science itself

because of the ease by which you collect data, the

ease by which you characterize the kinetics of the

process, and so forth. So by virtue of having an

ability to do an experiment on a manufacturing process

and collect the information readily, you can actually

start modeling. You can actually get into simulation,

which we have never been able to do. So that was

another benefit that we wanted to leverage. Next

slide.

So the opportunity that we had, that we

realized, was over the last two decades we have

developed or utilized methods to solve complex multi‑

factorial problems, starting with simple design of

experiments. Multivariate empirical methods such as

Response Surface Methodology. Yet, none of that is in

our submissions. We see very few pharmaceutical

companies even doing that level, which is a 60‑year‑

old technology. New measurement, control and

information technologies have existed, but not in

pharmaceuticals, which provide improved ability to

predict and assure quality and assurance. Yet not

been utilized. Also, if FDA was asking the right

questions we could do significantly for the science

itself. The regulatory utility of fundamental science

and engineering principles is likely to accelerate the

development of these principles themselves, because we

have to keep that in mind. If we ask these questions,

industry will move in this direction. So that was

another opportunity we wanted to realize. Next slide.

But the challenges were great. Scientific

information related to product and process development

is often filtered out of our submissions because of

regulatory uncertainty, or fear of delayed approval.

And so we get bits and pieces of information, and we

have to make decisions on that. High degree of

uncertainty, again, precludes risk‑based decision. So

in absence of knowledge, we have the black box. Any

change is a risky venture, so we have to have a prior

approval supplement. So that\'s the dilemma we had to

break. Significant cultural and organizational

barriers within FDA also existed. Next slide.

So the way we moved forward was to come up

with an approach which says companies that acquire and

understand the manufacturing processes and products

should have a benefit from moving forward quickly. If

companies do understand and have this information, if

they share this with us, you have enhanced science and

risk‑based regulatory quality assessment possible at

FDA. That will involve how we set specification,

reduction in volume of data to be submitted. Just to

let you know, we get our submissions in a truck, that

is the volume it comes to. It\'s a lot of data, so

that makes our CMC review process as much an audit

function. So it has to be a scientific review

assessment. So you have to move towards knowledge‑

based review. It\'s only possible when they share

information. Flexible post approval change

management. Without that you don\'t have continuous

improvement. Next slide.

So the FDA Science Board discussions, the

advisory committee discussions, and our PAT

subcommittee discussions were essential to understand

and define the problem at hand. Then we went on to

show that current regulations and policies facilitate

innovation and continuous improvement. Dr. Woodcock

discussed some of that. We didn\'t see that as a

problem. And I\'ll come back to that later on. We had

to overcome cultural and organizational barriers. We

had tough issues. Our reviewers didn\'t want to talk

to inspectors. So we had to bridge that gap. We had

to develop new policies and procedures also, and

ensure that FDA staff are trained and work as a team

to address review and inspectional issues. So these

were the steps we took. And I\'ll share with you how,

and what other challenges were. Next slide.

The challenge that we face is great. In

our white paper we have argued that continuous

improvement and innovation actually is not possible in

the current model. And I\'ll share with you why we

feel that way. First of all, in absence of knowledge

conditions used, example mixing time for clinical

materials, become regulatory commitments. Process

control is predominantly based on documented evidence

of conformance to standard operating procedures.

Generally includes fixed process conditions and a lab‑

based testing of in‑process materials. And I

emphasize testing because testing is not controlled.

But the word \"testing\" in our vocabulary is controlled

today. Next slide.

Acceptable quality characteristics, or

specifications, are generally described in terms of

discrete or attribute data. By definition, continuous

improvement is aiming at a target, and reducing

variability around the target. Some of the

specifications we don\'t even have a target. It\'s a

range that we go anywhere acceptable. And when you

have a compendium type specification which were market

standard as release specification but no unit is

outside 75 to 125 for a sample of, say, N = 30 tablets

regardless how large your batch size is. What it does

is the standard deviation and conference intervals

that you have, you accept for example in USP 7.8

percent standard deviation is acceptable. And if it\'s

normally distributed, every batch is out of

specification then. And that\'s what Dr. Woodcock

presented to you at the second Science Board

presentation. So the rate of failure increases with

increasing sample size. This drives the industry to

minimalistic testing schemes, and discourages

collection of information. So we don\'t have a good

handle on variability to start with, plus it\'s an

ostrich mentality. Once the product is approved and

validated, we don\'t want to collect any more data. So

how do you improve? You do not improve. Next slide.

Material characteristics, especially

excipients, and their relationship to process‑ability

are not well understood. And I have been very blunt

on this in the first presentation itself. We don\'t

understand physics or physical attributes in this

industry. We have focused so much on chemistry, we

have done extremely well on purity and impurity

aspects. We have forgotten the physical

characteristics and how they relate to performance.

Variability, especially in physical material

characteristics, fixed process conditions (blend for

10 minutes), testing approaches that do not provide

robust estimates of variability, and complex standard

operating procedures can lead to frequent deviations

and out of specification observations. No wonder.

Next slide.

These investigations, our statistics show,

95 percent of the time root cause is unknown. The

rest of the time you blame the analyst, poor guy. So

how do you get out of this crisis of corrective

action? They take time resources. And since we don\'t

have a root cause investigation successful, we throw

away the batch. Low efficiency and costs associated

with manufacturing far exceeds those of R&D operations

in innovator companies. And this was something that

we did not understand till we had the first FDA

Science Board. And many at FDA still don\'t believe

this. Next slide.

Test‑to‑test comparison is the only

available option for validating new tools and

technology. To give you an example, if you have a

model sophisticated online sense that will contain

uniformity, we\'ll ask you today to go back and take

the sample using a key which we borrowed from the

grain industry which we never validated, but that\'s

the only option. So we had to move away from the

test‑to‑test comparison as the only option. The other

option is bring first principles, process

understanding, and validate it on that basis. We

often struggle today validating HPLC with potential

metric or TLC. That\'s a common debate today. New

control systems in the \"don\'t tell\" mode are

additional methods, and companies still have to

continue USP‑type testing, or regulatory‑type testing.

So what\'s the benefit of that? So we have to change

that too. Post approval changes generally require

regulatory notification, and in many cases prior

approval supplement. So you\'re looking at a 2‑year

process. Continuous improvement is not possible.

Next slide.

As we move towards that, the second step

was to examine our current regulations. We found that

our GMP regulations are actually very well written.

They\'re broad, and fairly applicable. In fact, the

practice of process validation, if you go back to the

definition is based on control. And if you think

about control from an engineering sense, our

regulations are far superior than our practices, with

the exception of Part 11, and I think Dr. Woodcock

addressed that. However, the current regulatory

practice and procedures reflect the current state of

information submissions. That had to change. Process

validation and inspection and CMC review, and Dr.

Woodcock covered some of that with you. Next slide.

However, overcoming the cultural challenge

was great. So what was the reason to change? The

answer was very clear to us. The current state is

untenable. Need to facilitate innovation and

continuous improvement in the interest of public

health was the common theme, and opportunities for

continuous learning and professional development was

great for us inside and for industry. Based on all

this analysis, we articulated what we call the desired

state for the 21st Century pharmaceutical

manufacturing, and actually presented that to you on

April 9, I believe, 2002. So this was ‑‑ we got your

input into that, and we took this to ICH. Next slide.

But before I share that with you, the key

was training and education. We formed a PAT team.

The PAT initiative was a collaboration between CEDR,

CVM, and ORA. So we focused on pharmaceuticals to a

large degree. We brought this thing together. We had

to bring a systems approach to regulatory assessment

of process analytical technology applications. So the

team consisted of reviewers, compliance officers, and

inspectors, all together working as a team. We

developed a comprehensive scientific training program.

Now, this is a different training program from the

pharmaceutical inspectors. This is a much higher

level of focus. And we actually developed this

curriculum through an advisory committee discussion.

We brought in three universities, and three scientific

disciplines to work with us. University of

Washington, which is a National Science Foundation

Center for Process Analytical Chemistry, Purdue

University which is the Center for Pharmaceutical

Process Research, and University of Tennessee which is

the Measurement Control Engineering Center. Because

we had to bring chemical engineering, pharmacy, and

chemistry to work together. Without these three

disciplines working together, this will not work. So

the training was conducted with hands‑on practicum

training at these sites. And as part of the training,

our teams actually did the manufacturing themselves

with various technologies, and some of them got

warning letters from FDA, so. But this was a very

successful team‑building and training procedure that

was absolutely necessary. Next slide.

So what was the desired state? The

desired state we presented to you, also we presented

that to ICH. And it was adopted, with slight

modifications. I\'ll give you the ICH version of our

desired state for manufacturing. That is product

quality and performance is achieved and assured by

design of effective and efficient manufacturing

process. So we focused on manufacturing first. To

achieve that, you need to have product specifications

based on mechanistic understanding of how formulation

and process factors impact product performance.

That\'s one way of bringing science to bear on, and not

be deterministic or attribute‑based in our

specification. The modification that ICH included was

the next sentence: an ability to effect continuous

improvement, and continuous \"real time\" assurance of

quality. So that\'s a harmonized desired state for

manufacturing under ICH right now. Next slide.

But from the regulatory perspective, Dr.

Woodcock has covered much of this, but I just want to

emphasize that our regulatory policies and procedures

will need to be tailored to recognize the level of

scientific knowledge supporting product application,

process validation, and process capability. So we

brought process capability as a risk mitigation

factor. Risk‑based regulatory scrutiny will relate to

the level of scientific understanding of how

formulation and manufacturing process factors affect

quality and performance, and the capability of process

control strategies to prevent or mitigate risk of

producing a poor quality product. So as the risk

model evolves, some of these principles will sort of

be built into that. Next slide.

The definition of PAT. We had to coin a

new term process analytical technology, which didn\'t

exist. We had to create a new terminology because the

vocabulary had to be created, because the vocabulary

that we had previously was all negative. So

manufacturing science and processing created a new

positive vocabulary for us to talk to each other

within the FDA, and to talk with the industry. So we

approached it as a system. PAT was designed as a

system for designing, analyzing, and controlling

manufacturing through timely measurement of critical

quality and performance attributes of raw and in‑

process materials, and processes with the goal of

ensuring product quality. The word \"analytical\" was

taken very broadly. It included mathematical

modeling, every aspect, not just analytical chemistry.

Next slide.

Removing the obstacles that we identified

through our discussions with you. We had a final

guidance on process analytical technology. It\'s

called A Framework for Innovative Pharmaceutical

Development, Manufacturing, and Quality Assurance,

which was finalized in September, 2004. I want to

emphasize this is a framework guidance, not a how‑to

guidance. Unfortunately when the draft came out many

companies said tell us how to do this. And our answer

was very simple. If industry is going to ask FDA how

to be innovative, they are barking up the wrong tree.

So this is a framework guidance. So if you don\'t

understand it, you\'re not ready for it. But it does

remove all the regulatory uncertainty. And we

supported the PAT guidance with a review and

inspection team which was there to ask the right

questions. We trained them, and that\'s the key

foundation. But also we created a committee under

ASTM International to provide the standards the

industry will need so the industry can step up to the

plate and develop these standards as needed. So that

FDA is not the bottleneck trying to create this

guidance. It\'s because we don\'t have the know‑how and

the technology, and it will take a long time for us to

get there. But working together, we can create the

standards under the ASTM. The other advantage of ASTM

was to bring the engineering focus. Because

petrochemical and other industries have thought of

this. You need to bring control theory rather than

testing theory to this. So ASTM became a very strong

conduit.

But I\'m very happy to also tell you that

there\'s a complete infrastructure emerging in

associations such as American Association of

Pharmaceutical Scientists, International

Pharmaceutical Engineering, and others, including

academia. There are six Ph.D. dissertations now with

FDA guidance. But most of them coming from Europe.

There are very few schools in the U.S. ready to reach

that. Harmonization has moved very quickly. The

European Union has a PAT team like ours, and other

groups have moved in this direction also. Next slide.

As we move towards the PAT process, we

will also bring the same concepts in ICH. ICH Q8 is

a guidance document which will focus on bringing

pharmaceutical development information in our

submissions. It is currently being developed. The

draft 3.1 is ready. Next week we hope to be in Japan

to bring it to Step 2. And this will be released.

And this really creates an opportunity for an

applicant to demonstrate an enhanced knowledge of

product performance over a wider range of material

attributes so that changes or movement within that is

not a change anymore. So that is essential for

continuous improvement. David is here. He\'s working

in ICH Q9, which is a risk management document. And

we hope to start a ICH Q10, which is quality system

for change control. Because this industry is not

ready for continuous improvement because even the

definition of continuous improvement is alien as

compared to, say, automobile industry. So I think it

will take some time to bring those things in place.

Next slide.

So summary. I think through the cGMP

initiative, the PAT initiative became a part of the

cGMP so there is one initiative now. What I would

like to propose is we understand and define the

problem, establish a sense of urgency, the quickness

by which we moved I think was itself an indicator of

a sense of urgency. We created a powerful guiding

coalition including this group, developed a vision,

the desired state, communicated and built consensus on

the desired state. You can see, except for one

sentence, that is a global desired state now. Removed

obstacles through our training and our framework

guidance, ASTM and other things. We also planned for

short‑term wins. We have several, at least five

companies which have moved very quickly in this

direction. And the quantum leap actually occurred

this week. We actually have a complete proposal on

continuous manufacturing of API. And what that does

is it miniaturizes that and brings that industry back

to U.S. So that is an advantage. I won\'t name the

company, but it is occurring.

I think we have also taken steps towards

anchoring the changes in our corporate culture and the

pharmaceutical community itself through the

infrastructure that has evolved. There\'s also a new

journal called Journal of Process Analytical

Technology now. Next slide.

Also, we\'ve created opportunities for

significant cost savings. Efficiency improvements

estimated to potentially save billions of dollars for

companies that move in this direction. One estimate

is by Professor Jackson Nickerson who has been doing

a benchmarking exercise and collaborating with us.

His conservative estimate, that\'s what he said to

emphasize, this is a conservative estimate, he says is

between, if companies move in this direction, \$15 to

\$50 billion will be saved every year because of FDA

initiative. There was a study published from the UK

which says based on one metric of performance, the

stop‑turn, if you move the stop‑turn of pharmaceutical

manufacturing to that of world class, let\'s say food

industry, you have an estimated cost saving of \$90

billion every year. That\'s 90 new drugs every year.

Next slide.

At the same time, I think the sense of

urgency we had was to prepare for the future, because

the future is upon us. In the future, pharmaceutical

manufacturing will need to employ innovation, cutting

edge scientific and engineering knowledge, and best

principles of quality management to respond to the

challenges of new discovery. Complex drug delivery

systems and nanotechnology. If you really look at

nanotechnology, what is different is the physical

characteristics, the physics which makes it different.

And we don\'t do that well in this industry right now.

Individualized therapies or genetically developed

treatment. What does that mean? You need a very

flexible supply chain. The current infrastructure and

the costs associated will not support that

manufacturing need. So we have to move quickly. Next

slide.

And the Critical Path Initiative becomes

a cornerstone for keeping our progress and moving in

the right direction. The industrialization dimension

is a key. Within our office, one of the weakest links

we have is the link between clinical and quality. ICH

Q8 opens a door to start making that link stronger.

And we are actually developing a model to establish

relevance of clinical to quality linkage so that our

specifications are more relevant, and our focus is

more relevant to what the intended use is. Cleary I

think sound scientific approaches for calibration and

validation of new technologies. And we have been

working in collaboration. For example, we have a

collaboration with Pfizer on learning about chemical

imaging and putting it online. And we have made

tremendous progress on learning about it, and how to

do it, what not to do, and so forth. Encourage

development of fundamental science and engineering

principles, especially material sciences, nano‑

materials, and processing. And the opportunity there

is American Chemical Society and American Institute of

Chemical Engineers have a Vision 2020 that allows us

to link directly to that which focuses on processing

and material guidance for nano‑materials. So that\'s

an opportunity.

But I would emphasize our educational and

research infrastructure in U.S. for pharmaceutical

manufacturing is lagging behind in very significant

ways. In fact, I would say we are 10 years behind

Europe right now in this sector. And if we don\'t

move, China will have a far better educated workforce

in this area than we will. And so support for U.S.

pharmaceutical academic program and pharmaceutical

education is an utmost need. And we don\'t get the

support because this area has been completely

neglected, and schools of pharmacy have moved away

from it because of the clinical focus. So

unfortunately, if we don\'t do something here, we have

lost the edge. I think that\'s my last slide. No,

next one.

I do wish to thank FDA Science Board,

because this is where some of the initial discussion

started, and without your support, and without your

blessing, I don\'t think we would have been able to

move as quickly as we did. Advisory Committee for

Pharmaceutical Sciences, the PAT subcommittee,

manufacturing subcommittee, allowed us to sort of

bring the stakeholders and discuss this very openly.

And others, clearly Dr. Woodcock and others who have

helped us lead in this direction has been tremendous.

Thank you.

CHAIR SHINE: Thank you, Dr. Hussain.

This presentation is open for comment. Yes, please.

DR. RIVIERE: I was here on the initial.

You made remarkable progress. It\'s really good to see

it moving forward, and all that I\'d like is that this

is what ‑‑ it\'s nice when you have a very focused, and

that was the point of this, set of goals, and an idea

how to implement it, and came right up front that the

regulatory hurdles were the problem. And people

could\'ve done this. I mean, I can remember I think it

was manufacturing M&M\'s was significantly more

advanced than any of our tablets. It\'s worked out

well.

CHAIR SHINE: Yes, Dr. Cassell.

DR. CASSELL: I hate to always raise some

of the same issues, but if I understood what you said

in terms of schools of pharmacy kind of moving away

for obvious reasons, and now other schools that would

be taking it up in terms of research that still has

yet to be done, the only place that I know of that you

could turn to for funding of that kind of work would

be the National Science Foundation that by comparison

also has a very small budget. And I wonder if you

know if the National Academy of Engineers are taking

this issue up, or if there are any reports within the

National Academy of Engineers that are really looking

at this problem.

DR. HUSSAIN: I think it has been a

difficult task to make a case for this. Our initial

discussions early on with NSF and so forth is

awareness of this problem was not there. And the

answer came back this is a rich industry, why do you

need this. This is no‑brainer sort of a thing. But

they haven\'t understood the complexity of when you

have processing. So this is an awareness issue, and

maybe I would request the Science Board to help bring

that awareness too at the same time. But we are

pushing in that direction.

DR. CASSELL: Well, I mean, as I think

about it too they have a big information technology

initiative. There\'s a nanotechnology initiative as

you know inter‑agency wide, and the timing might be

right to bring NSF along where they haven\'t been

before.

DR. HUSSAIN: Right.

CHAIR SHINE: Dr. Thomas?

DR. THOMAS: Physical pharmacy is probably

going the way of materia medica. There are fewer and

fewer institutions that are training these types of

people.

My question to you, and I wasn\'t here at

the beginning, and I was very impressed with the

progress you made. I was curious, you had recruited

someone along the way to do an efficiency study. Do

you have any inherent mileposts as you go along that

are going to help you judge the success of this

program?

DR. HUSSAIN: Well, I think as Dr.

Woodcock said, in a sense we have not defined that.

We are in the process of defining those. But one of

the metrics that we have used informally is how many

companies stop asking us to tell them how to innovate

is one metric, I think. But that\'s real, because I

think that\'s the challenge because unless they take on

this, FDA cannot do that for them. The other aspect

is the number of submissions, and number of requests

for meetings with proposals, I think is growing, and

we haven\'t formalized that as a metric, but that could

be one of the metrics. And as Dr. Woodcock said, in

a sense the implementation and how quickly we move to

a control mentality from testing mentality, and how

that might be linked to our risk model might be

another metric. But we haven\'t really formalized that

yet.

DR. THOMAS: Thank you.

CHAIR SHINE: Thank you. Dr. Hussain, a

couple of questions. One is this is, quote, your

final report.

DR. HUSSAIN: To you guys, yes.

CHAIR SHINE: To us.

DR. HUSSAIN: Yes.

CHAIR SHINE: This program is going to

continue? So you will continue working with industry.

Have you had an opportunity for example to meet with

the board at PhRMA, or some of the trade organizations

with regard to your studies and conclusions?

DR. HUSSAIN: Many times. Dr. Woodcock

met with them several times. So you want to say

something to that?

CHAIR SHINE: What is their response to

this sort of dire description? Are they going to all

move to China?

DR. WOODCOCK: You mean about the human

resources, the training issue?

CHAIR SHINE: No, about the issue of the

manufacturing processes in comparison to other

countries.

DR. WOODCOCK: Well, initially I would

say, and that\'s why the original Science Board

presentation was so important. Initially the reaction

was shock and denial, I think is the best way. That

couldn\'t possibly be true, you couldn\'t possibly be

spending this much money on manufacturing, that

manufacturing, quote, I was told, our manufacturing is

state of the art. We\'ve had all these people stand up

before you guys and present this.

So I think over the two years there\'s

really been sort of internal discussion within the

industry, and reflection, and really a turning around.

And I think there\'s tremendous support within the

industry to go here. There\'s still concern about

regulatory barriers, and there\'s concern about in this

particular time in the industry where there\'s other

issues around profitability and so forth, concern

about making the investment that\'s required. Because

although there\'s a tremendous payoff, there\'s also an

investment you have to make up front to get that

payoff. So there\'s a variety. We have early

adopters. Ajaz just said we have people who are

considering continuous manufacturing. That is a

quantum transition, because that\'s going from a huge

plant and multiple bins of product all over the place

and everything to a very parsimonious efficient

process. So we see a lot of movement.

Others are not going to move. And so our

model is going to have to be able to encompass the

people who are advanced, and then the people who are

going to stick with the current paradigm. And the

shortage of personnel qualified in this area will

retard progress in this country, and I think what Ajaz

is saying is maybe not in other countries to the same

extent. And to that extent it\'s a competitive issue

for the U.S.

CHAIR SHINE: Dr. Roses?

DR. ROSES: I wasn\'t here at the

beginning, so I have no idea why our manufacturing

people started to do this. But several years ago they

set up some processes to change the culture, which is

the single biggest part of this. And the milestones

that they essentially set up, I think the term is lean

sigma, that is you satisfy your previous customer.

And the customer then is the person ahead of you in

the chain. And so you actually start setting up

milestones that you can measure. But the biggest

milestone that comes out of this is I don\'t know about

the estimates in terms of \$90 billion, but I sure know

about estimates that are sizable that were measured

savings by doing this. And the trigger for this, as

I understand it, was a change in regulatory

perception, that you weren\'t going to have to just hit

these things forever and ever and ever, batch by

batch. And it works.

CHAIR SHINE: Good. In that regard, has

the same analysis been carried out in biologics and

vaccines as in drug development?

DR. HUSSAIN: I don\'t think so. I don\'t

have an answer for that.

DR. WOODCOCK: You can talk about

therapeutic proteins, right? You have some ideas

there.

DR. HUSSAIN: Yes, I think in some terms,

the situation is exactly similar. Probably a bit more

expensive on that side because the materials are far

more expensive, and losing one batch is quite

significant. We actually had an advisory committee

discussion on the biological Type A proteins, and then

the opportunities there. It\'s very, very similar.

Cost savings would be higher, probably, there.

CHAIR SHINE: Is there any interest on the

part of that part of the industry to move forward with

this approach?

DR. HUSSAIN: Yes. The final guidance

does bring our Office of Biotechnology as part of

that. And the second PAT training will bring the

biotechnology into this one.

CHAIR SHINE: And you made reference,

Janet, earlier to international harmonizations and so

forth. Clearly the Chiron experience has raised an

international problem. What are the lessons from that

that would be important in terms of moving forward

with this kind of initiative?

DR. WOODCOCK: I\'ll defer to Kathy on

that.

DR. CARBONE: Well, unfortunately, I think

we missed our opportunity, because Dr. Goodman was

here prepared to talk about that, but he had to leave.

So that\'s something that we\'ll have to raise in the

future. I don\'t want to speak. It\'s a complicated

regulatory issue with a lot of proprietary issues, and

I have not been heading that from my angle.

CHAIR SHINE: But I think in terms of the

ICH portion of this I would be very interested, since

that\'s ‑‑ we\'re now in a global process.

DR. WOODCOCK: Right. Well, certainly the

industry has told us from the get‑go on this it

doesn\'t help if just the U.S. moves.

CHAIR SHINE: Yes, you made that point.

DR. WOODCOCK: Yes. And we understand

that, and unfortunately there\'s two messages, as you

heard earlier. It\'s we need to move ahead as quickly

as possible with ours, but we also need to harmonize

as quickly as possible. And those two things are not

compatible conceptually with one another, given the

pace of international efforts. But we are trying.

We\'re very active in ICH. We\'re going to join the

PIC/s. And trying to advance the international

science base, and scientific consensus on these

manufacturing issues will also help, I think, from

kind of the ground up. So we are working on that.

Also, with regard to the Chiron issue,

what Ajaz talked about, and what we need to explore

more are modern ‑‑ the original PAT application that

came into us was a modern microbial ‑‑ rapid microbial

analysis method. It was applicable to multiple

products within that particular manufacturing train.

But that was an offline type of off‑fermenter type.

There are new things that need to be done. Basically,

we can all agree that the current manufacture of

influenza virus vaccine, and this is not proprietary,

is not new technology. It\'s exemplary of some of the

problems. It\'s 50 years old technology, and involves

eggs and so on. And so there are many things. We

talked about this morning industrialization as far as

new cell substrates, but also everything we\'ve talked

about here as far as process control is germane to

this.

DR. CRAWFORD: There was a congressional

hearing on the vaccine manufacturer subject in 2002

which dwelled on how much, as Dr. Woodcock said, the

ancient process and also the fragility of the

industry. And it charted the shrinkage of the number

of companies that manufactured vaccine for the U.S.

market and elsewhere. And actually in that testimony

I predicted that by this year we would have only one

supplier, rather than two. And we should make that

testimony available to the committee because it

probably in all of its aspects, I think there were

like three people giving testimony, it analyzed the

industry itself from the standpoint of good

manufacturing practices, and possibilities for relief

from the old egg‑based production techniques. So

we\'ll distribute that.

CHAIR SHINE: That would be useful. There

are a whole host of issues raised by vaccines,

obviously. This was just one aspect of it in terms of

manufacturing processes, but the intention of my

question was related specifically to that element.

Dr. Cassell?

DR. CASSELL: I think the problem with

vaccines is that we had report after report after

report telling us what the issues are, and everybody\'s

saying the same thing that we could\'ve anticipated

exactly what\'s just happened. But the problem is

inactivity, you know, once those reports are released.

And so it seems to me now it needs to be kicked up to

the highest level, and to really ‑‑ we have to change

the way we\'re doing business when it comes to vaccines

and possibly even antibiotics when we think of the

interagency committee and looking at vaccines and

antibiotics.

I just throw that out for what it\'s worth,

but along those lines, you know, one of the former big

producers of vaccines was Russia. And they currently

have a new mandate to bring manufacturers into GMP

compliance. And I was just sitting here wondering,

because they\'re so focused on emulating FDA, when you

change the processes here with respect to GMP, how do

you systematically tell other countries about what

you\'re doing, and do you do that at the very beginning

like when you started this process, or only now that

the report is released publicly?

DR. CRAWFORD: Yes. When we decided to

undertake the GMP initiative in 2002, we dispatched

teams of FDA\'ers to discuss this with other countries.

And I believe we touched 80 countries. And we used

embassies. We also went to the EU. And Dr. Woodcock

and her team put together a paper which was

distributed throughout the diplomatic community. I

did the trip to the EMEA, and they were very

interested as Janet knows, and Ajaz knows, and were

about to embark on the same kind of thing. So we\'re

extremely happy that we were. Dr. Lumpkin and his

group maintain very good communication.

With respect to the results of that 2002

hearing, three things were asked. One was a \$100

million research fund to enable grants, contracts, and

intramural research in improving the vaccine process,

going from egg‑based production to cell culture or

tissue culture. Congress funded half of that. And

now we are intensifying our efforts to get the other

half done so that we can serve as change agents for

the industry itself, because there\'s no question about

the fact that the bio‑burden that begins with the

inception of the vaccine production process and then

has to be progressively decontaminated is not what you

would design de novo if you were creating a vaccine

production process. So we have got to improve upon

that.

The second thing that was asked was an

analysis of the industry in terms of could there be

some sort of incentives, like tax incentives, or

financial incentives. We fell short of saying

nationalizing, or socializing, or anything like that,

as you might expect. However, we did go into a

considerable discussion of what might be done in terms

of incentivizing the industry. And the third thing is

we did link this to good manufacturing practices, and

we talked about what FDA was about to do in that

regard.

I think, well I know all three of those

have been acted upon. However, the incentivization

part is the one that basically was considered and not

much was done worldwide. And the reason for it was

not lassitude on the part of our Congress, or the

Administration, or FDA. It was because this is in

fact an international issue. It\'s not a U.S. issue.

And it cannot be solved except through international

organizations. We just had a conference call with

Klaus Stohr, who as you probably know is head of

influenza for the World Health Organization. And

there\'s going to be a hearing on ‑‑ the redux of that

hearing is taking place on November 16. And I\'m

happily ‑‑ two of us who are the lead witnesses are

going to have to appear again two years later, which

is always a disturbing thing, because you then ‑‑ it\'s

kind of like a baseball batter having to appear and

explain his batting average. We\'re not taking all

this on our shoulders, but we do want WHO to testify,

and also international economic organizations. They

had rejected coming here, and now I think we\'ve got

them talked into it because we have to recognize the

international aspects of this kind of production.

And also the fact that as has been said,

the ginning up of the industry in both Russia and

China in particular. They may have some techniques

and some plan modalities that we don\'t know anything

about. And so we may be able to learn from them and

work together. And if it is true that there will

still be only six manufacturing companies next year

worldwide that we have any access to, you know, we

have got to band together as both countries, an

international community, and companies.

CHAIR SHINE: Now, without reviewing all

the history, Gail is well aware that the Children\'s

Vaccine Initiative Report in 1993 laid out what was

going to happen, what had happened, what needed to

happen. And the only thing that didn\'t happen was

what needed to happen. We\'ve since had a whole bunch

of other reports that outline what was likely to

happen. The Institute of Medicine council issued a

white paper in November of 2002 making a number of

predictions and recommendations. And they were

strongly opposed by a number of our colleagues on the

industry side. But in fact the issue is going to have

to be rejoined.

But let me just say to the commissioner

and to Janet and all their colleagues that we\'ve just

had two reports on work that\'s been going on a number

of years. I think you sense that the committee is

really quite pleased with the initiatives that you\'ve

taken with regard to good manufacturing processes. I

think the creation of the council has been an

important activity. I think that the work that Dr.

Hussain and his colleagues has done has opened a lot

of eyes, and I think drawn a new perspective with

regard to these issues. We\'d like to see it

continued. It would be very helpful to us if we

periodically had a brief report. We don\'t need to

have a big, long complicated report, but I think we

would like to know what progress is being made, how

many companies get involved, what kinds of things

happen, so that we can be supportive of that activity,

and also so that we can engage as many in the

community as possible to try to participate in it. So

I think I speak for the committee that we\'re very

impressed by this effort and express our appreciation

and congratulations to you. Cato?

DR. LAURENCIN: Just to comment. I see

the last two slides are in terms of looking at the

future and the Critical Path talk about the issues of

nanotechnology and nanosystems. I think it\'s very

important because I think we\'re on the cusp of the

area in terms of nanotechnology manufacturing as a

commercial entity. And I just want to make sure that

the FDA is interfacing in that area. There\'s a new

National Nanotechnology Manufacturing Center that NSF

has just funded. And so again, that\'s an outlet

partner to move forward. And again, there are a

number of companies, smaller companies that are now

just starting to do nanotechnology manufacturing.

There\'s a couple of industrial fairs on nanotechnology

manufacturing that\'s actually taking place over the

next six months. And so this is an opportunity for

FDA to really start to get involved and interface on

what will be the next generation technologies that are

going to be there.

CHAIR SHINE: Any other comments from the

committee? We were scheduled to take a break, but we

are believe it or not actually ahead of schedule

because of the lack of public testimony. I would

suggest that if the committee\'s comfortable that we go

forward with the next presentation. And the effect of

that will be that a few people will make airplanes

they might otherwise not be able to make.

So let me just, before Dr. Marzilli makes

his presentation, remind everybody that one of the

responsibilities of this board is to periodically

undertake reviews of the science in various portions

of the agency. There have been activities in the past

involving CDRH and CBER and so forth. The current

activity is related to the oversight of pesticides in

industrial chemical program out of the Office of

Regulatory Affairs. We\'re going to hear from Dr.

Marzilli with regard to the assessment that he and his

colleagues and his advisory board have undertaken.

Following that activity, a panel

representing this group will conduct an additional

review. And I\'m very pleased that Dr. Thomas and Dr.

Swanson have agreed to act as co‑chairs of that

activity. In addition, Stephen Musser, Ph.D., of the

FDA Center for Food Safety and Applied Nutrition will

participate, as will William Cusick, who is the lab

director for the State of California Analytical

Center, and Pat Becket who is the chief of the Florida

Chemical Residues Laboratory. I think that this is a

group that will bring a considerable amount of

expertise to the review, and they will following this

meeting have an opportunity to consult with staff with

regard to the methodology they\'ll use. And I would

ask Dr. Thomas and Dr. Swanson to oversee that

activity on behalf of the committee and report back to

us in a timely way next year.

With that, Dr. Marzilli, we\'d like to hear

about the activity.

MR. MARZILLI: Thank you very much, Dr.

Shine and Dr. Crawford and members of the FDA Science

Board Advisory Committee. It\'s a pleasure to be here

with you today giving an overview of the Office of

Regulatory Affairs Internal Science Peer Review of our

Pesticide and Industrial Chemicals Program for the

agency.

We heard some incredible presentations

this morning from the agency on Critical Path. We

learned a little bit about the NIH Roadmap. Now, from

the Office of Regulatory Affairs we\'re going to talk

about our Mapquest in terms of our Pesticide and

Industrial Chemicals Program. And our Mapquest for

you is where are we, how did we get here, and for the

Science Board where do we go from here. So I want to

thank you.

My name is John Marzilli. I\'m the Deputy

Associate Commissioner for Regulatory Affairs. I\'ll

be giving you an overview of our science peer review

process that we undertook within the Office of

Regulatory Affairs. I\'ll also be presenting you with

our program management recommendations that we\'ve

presented to the Associate Commissioner for Regulatory

Affairs, my boss, Mr. John Taylor. And after I speak,

Dr. John Specchio, who\'s our Science Advisor for the

Office of Regulatory Affairs. He\'s a Professor of

Food Science at Montclair State University who will

talk to you about the science recommendations that the

ORA Internal Review Committee proposed. And these

again are being presented to Mr. Taylor for his

concurrence. And then I\'ll come back and wrap up with

the issues that we want to bring to the Science Board,

although we do invite your input on all the issues

that we have presented here today. And in your

packages in front of you you have the report that we

submitted to Dr. Alderson on October 12.

The ORA science peer review. Our

objectives were to take a look at the mission

relevance of our program, to review the quality of

science across the FDA organization in the area of

pesticides analysis and industrial chemicals analysis.

We took a look at program planning, inspectional work,

our investigations, laboratory analysis, regulatory

actions, and our quality management systems. We

investigated the adequacy of resources within the

field organization in particular which I represent

within the Office of Regulatory Affairs. We evaluated

the skills and expertise of our staffs, the

technologies employed by our laboratories in this

important program, and the organizational

infrastructure that we have within the Office of

Regulatory Affairs to support this program. And most

importantly, in all the work that we did, we focused

on the mission relevance of this program for the Food

and Drug Administration.

The peer review process that we undertook

consisted of a number of components. First of all,

the design and implementation of the data review. For

our process we went out to eight of our district

offices. We also visited six ORA laboratories, and we

corresponded with the other 12 FDA district offices

with a written questionnaire so that we could get

input from our entire field organization from the

investigations, and from those laboratories that are

responsible for the Pesticides and Industrial

Chemicals Program for FDA. Our onsite visits included

a review of the local SOPs for domestic and import

work in the pesticide program. We reviewed sample

collection reports, laboratory worksheets,

establishment inspection reports, compliance actions.

We reviewed all the data systems of which you heard

about one this morning, our Field Accomplishments and

Compliance Tracking System, the FACTS system, which is

the repository for our analytical and compliance work

at FDA. Our OASIS system, which is our import

operations system. We reviewed all the current

guidance for the pesticide program within the field

organization, and we undertook the examination of some

historical documents and some earlier studies that

were conducted in the area of pesticides work.

In order to do this work and to evolve

this database, our laboratory group in the Pacific

Region set up a database for us to use. This database

was used to validate all of our onsite interviews, our

interview teams that went around the country, reviewed

over 350 work products, the evaluation of these

reviews, and the interviews of over 150 individuals in

the field were all captured on the database, as well

as the additional comments that we received from

interested individuals which resulted in nearly 100

pages of documentation for the committee to review.

From this review, five key areas emerged:

program management, laboratory science, productivity,

resources, and compliance and regulatory policy.

Early on in our evaluation of the program management

we determined the appropriateness of redesigning the

work distribution for our domestic pesticide program.

And it\'s an ongoing effort within the Office of

Regulatory Affairs right now. It\'s an important

component of the work that we do in ORA, and for the

nation we are a part of that component, along with the

U.S. Department of Agriculture and our partners at the

state levels. And so it was good to see that we\'ll

also have state participation in the review from the

Science Board, because the work that our state

partners do and the processes that they use are

important to us, and I think it\'s going to be good as

we do the next step review of this process.

Some of the lab science issues that have

emerged and have been presented to the Associate

Commissioner for Regulatory Affairs to act upon, and

they\'re included in this report, is the establishment

of a national steering committee of field experts

within the Office of Regulatory Affairs for our

pesticide program, the establishment of a national

pesticide expert within the Office of Regulatory

Affairs, and to update our national laboratory

guidance that is utilized in our pesticide program.

One of the key areas that will be coming forward from

this would be looking to improve our productivity and

timeliness, especially for the Food and Drug

Administration in the area of imports. We\'re a part

of a global marketplace now, and as you look at the

report, you\'ll see that the mainstay and the bulk of

the work that we do at the FDA in the area of

pesticides and industrial chemicals today is in the

import arena. So productivity and timeliness is very

important. And you\'ll also see reports on us

regarding our resources, and some issues that were

uncovered regarding compliance programs and regulatory

policy, regulatory policy within the field

organization.

I\'m going to discuss our recommendations

for program management. These will be tasks that my

boss the associate commissioner will be tasking to me

as deputy to make sure that they\'re accomplished and

implemented, and we\'ve started working in some of

these areas already. One issue that came up early on

in our review here was that the compliance programs,

or as we refer to them the CPGs, for the pesticide

program were out of date. We found that our CPGs in

the area of our domestic program for pesticide

analysis were last issued in 1995 and are in need of

being updated and revised. The committee found the

field staff were often unaware of the contents of

these compliance programs because they were so far

outdated. So we first of all have to update and

reissue our compliance programs and our compliance

policy guides to our field staff. And right now will

be an important opportunity for us with our training

effort we have. As I mentioned earlier in our

discussion here, our mainstay for training efforts

within the Office of Regulatory Affairs is ORAU, ORA

University, which is located here in Rockville. And

an important function of that is our online training

that we have available to our field workforces across

the country so everyone can get the same message at

the same time. And we want to develop a training

module online for our employees through ORAU that will

explain the structure and function of these compliance

programs, and get people retuned and refocused in the

compliance programs, particularly in the area of

pesticides and industrial contaminants. Again, we

want to revise our domestic compliance program in

alter directions for sampling sites so that we are

providing the widest breadth of consumer protection in

the work that we do in the domestic area. As I said,

we\'re part of the analytical team in the domestic

area, along with our colleagues at USDA and folks at

the state level.

But the mainstay for the FDA pesticide

program within the Office of Regulatory Affairs is in

the area of imports. It accounts for nearly 80

percent of the work that we do in our pesticide

program, and it\'s important for all of us as consumers

in this country because so many of the products that

we consume, so much of the produce that\'s available in

this country is imported into the United States.

Nowadays you can virtually have any piece of produce

any time of the year available to you. And we all

know what the growing seasons are in this country, and

what the limitations were when we grew up as kids,

that certain products weren\'t available certain times

of the year because of growing seasons. Today, you

walk into a supermarket and 12 months of the year, 365

days of the year, you can get just about any type of

produce that you want. And we know that\'s

accomplished because these products are imported into

the United States. And the responsibility of assuring

the safety of these imported products, and assuring

that we don\'t have pesticide residues on these

imported products rests with the Food and Drug

Administration.

We have some tools that help us with this.

And we find that we have to make sure that all of the

data that we have, all of the guidance that we have is

up to date. We reviewed our import program and found

that the import program was due for revision in Fiscal

Year 02, and we\'ve been operating for the past two

years under a program that\'s outdated and in need of

being renewed. Again, for us at ORA this was an

internal review, and among family we\'re being honest

with the issues that were uncovered and the fact that

we\'re finding that we\'ve got some areas here that need

improvement, and some areas that need to be updated.

And in terms of our import compliance program, again,

we want to have that reissued and with the current

status of the marketplace.

We also want to make sure that our field

offices and our field laboratories have real‑time data

as we\'re getting information in the pesticide arena so

that they can retarget their efforts as they\'re moving

forward. So we want to make sure that data is entered

in a timely fashion, and people have access to that

data as they\'re planning their work and planning their

sample collections throughout the year. One thing

that we need to take a look was a policy that was

established back in 1997 referred to as our perishable

policy that set tight timeframes on our analytical

reporting on pesticide residues that were found in

perishable products, products that are refrigerated

and brought to the marketplace. It\'s time to take a

look at that and make sure that that guidance is

current, and make sure that we\'re giving the best

turnaround possible to the industry because today

there are so many products that are being imported

into the country so we want to make sure that we\'re

timely there.

Again in the area of imports, one area

that we would like to look at is the burden of proof,

is the burden of proof that we have in our regulatory

structure for our imported programs. Under 801 of

the Food, Drug, and Cosmetic Act, for imported

products we have a standard that\'s referred to as the

appearance of a violation. Hence we don\'t have to

require the extensive scrutiny and the extensive

reconfirming and retesting of products that the law

puts on us for domestic products. We could switch

that burden to the importing community by which they

would have the burden of proof put on them if we had

found problems with imported products. This is a

major philosophical change for FDA because

historically we\'ve treated imports and domestics

exactly the same in terms of analytical burden. And

for imports, and for the fact that imports are growing

so exponentially, we can reverse some of the burden

from our field offices to the importing community to

provide the data to show that these products don\'t

have residues.

Also we have tools available to us,

particularly in the area of import alerts. And this

is an area that we should further utilize in our

program management of the import program. And we need

to review the current policy and procedures for

placing imported produce that\'s found violative on

import alert so that we can issue these import alerts

in a timely fashion, which would again take the burden

off of our field offices in these areas with

collecting unnecessary additional samples of products

when the burden could be switched for us. An example

of this would be that say a particular country, or a

grower in a particular country were importing a

product, a produce product into the United States, and

we had found several consecutive shipments of their

product containing a violative fungicide. If we can

get that data into the import alert system in a timely

fashion, we can then have the product put on an import

alert, which would then put the burden on the

importing community to assure that their product was

free of a residue, thus freeing up inspectional and

analytical resources within our laboratories and our

inspection branches from collecting more and more

samples, and shifting the burden to the importer where

it more properly belongs. And this is going to

require some internal changes within the Office of

Regulatory Affairs to make sure that we issue import

alerts in a timely manner, to make sure that we get

the data into our Division of Imports Operations of

Policy so these import alerts can be issued, and that

we use ‑‑ we also want to review the pesticide‑

specific charge that\'s currently used in our import

alerts that wouldn\'t just limit the testing of that

imported product to the specific pesticide that we

found, but put the burden on the importers to say that

the product\'s been tested for Pesticide X and also

found to be free of a multitude of residues. Again,

it would shift the burden of the resources from the

government to the importer, and again it would be an

appropriate use of our resources so we could focus

ourselves on more products and assure broader

protection for the American consumers.

Another important recommendation regarding

program management are our pesticide coordination

teams. PCTs, or pesticide coordination teams, have

been around within our field offices, in our

laboratories for a number of years, but in some cases

the PCTs haven\'t been reactivated as people have moved

from one district to another. We\'ve found that only

one or two people were currently part of the pesticide

coordination team. Ideally, our pesticide

coordination teams consist of investigational staff,

laboratory staff, and compliance staff, dealing with

the local administration of the pesticide program. We

need to make sure that these teams are viable and

ongoing in each of our district offices, and as a

result of our laboratory consolidation that the

district offices are working closely with their

servicing laboratories. In the FDA that I started

with back in 1971 we had basically one laboratory per

district. Today we have 20 districts in the pesticide

program, we have five servicing laboratories to

service those districts. So making sure that these

teams are coordinated with their respective

laboratories is going to be an important program

management recommendation that will be coming forward

from this study.

Again, we want to make sure that the folks

are utilizing the data reporting systems that we have.

As I indicated, our system for tracking imports is our

OASIS system, and our system for tracking analytical

results and compliance tracking is our Field

Accomplishments Compliance Tracking System. I was

encouraged during the presentation today on GMPs to

see that the Center for Drugs was utilizing the FACTS

system to develop their strategic system for the risk‑

based inspectional approach. The FACTS system is

referred to as an ORA tracking system. It\'s an agency

tracking system. It tracks the work for the agency

that the field does. And it\'s important for us to

provide training for folks as we have with the Center

for Drugs under the new GMP initiative, but across the

various centers, and within specific programs in each

of the centers. Some of our pesticide programs are

spread among different offices in the Center for

Foods, and the Center for Veterinary Medicine. And

it\'s important to make sure that folks there are

trained in utilizing the FACTS system as a repository

for the data so that we\'re not having redundant

reporting systems as we currently have in the area of

pesticides and industrial contaminants. So that\'s

going to be an important training aspect for us to

work in collaboration with the centers.

It\'s important for our program management,

the annual reporting, particularly in the area of the

domestic work that we do. We need to make sure that

our reporting is timely. Also, our reporting of

analytical findings. We\'re not the sole repository of

analytical findings for pesticide work. We have state

counterparts that are probably doing 30,000 or 40,000

samples a year that are reported into state data

systems. We can utilize that data now as part of our

eLexnet system. Last week we worked with the Ag

Marketing Service so that their pesticide data program

data would be incorporated into FDA\'s eLexnet system.

Another tracking system, guys, but it\'s a tracking

system that\'s in conjunction with our state partners,

and we\'ve done this primarily through the Association

of Food and Drug Officials. It affords us a lot more

information beyond the information that we enter into

the FACTS system. And just as an add‑on, since I

mentioned eLexnet, the data that we enter into FACTS,

the analytical data that can be released to the public

goes into the eLexnet system so that our state

partners can track and trend FDA data that\'s been

screened properly so that they can do their work

planning as well. So it\'s going to be an important

aspect for us.

And the last two issues that I\'d like to

cover in the area of program management is the need to

designate a specific individual within the Office of

Regulatory Affairs as a clearinghouse for all policy

and regulatory issues concerning pesticides and

industrial contaminants program. It is a function

that many years ago did reside within the Office of

the Associate Commissioner of Regulatory Affairs.

That individual retired and we never really back‑

filled that job. And with the many changes and

challenges that we see in this area, it\'s important

for our field laboratories and our field offices to

have a single point of contact that they can reach

within the Office of Regulatory Affairs regarding

policy and regulatory issues in this important

program.

I\'d like to call on my colleague now Dr.

John Specchio to come forward and share with you some

of the science recommendations that the committee came

forward with.

DR. SPECCHIO: Thank you all. And I\'d

like to take over the baton here and continue on with

the science recommendations that the committee is

putting forth to the Associate Commissioner of

Regulatory Affairs. I realize it\'s three o\'clock on

a Friday so I\'ll be brief. My voice hopefully will

articulate enough to keep you awake. Being a

professor for 20 years, I realize that this is the

worst time to make a presentation, but we\'ll do the

best we can. Okay.

The science recommendations are very

clear‑cut, and again the committee put forth I think

a number of very, very positive and future

recommendations that will improve FDA\'s ability in the

pesticides and industrial chemicals area. Number one,

expertise on science expertise. The committee is

recommending the establishment of a pesticide steering

committee to address national program issues. Now,

this pesticide steering committee would consist

primarily of field technical experts with

representation also from CFSAN and the Division of

Field Science. The goal of this would be to fully

utilize the expertise of those experienced analysts

who are not only technically strong but who have

outstanding awareness of program issues.

Second science recommendation would be to

create a national pesticide expert position within

ORA. This, by the way, is in process already. PD has

been written, and it\'s starting to go through the

approval channels. The Pesticide Research Center no

longer exists as it once did, but the need still

exists for coordinated research in this area. This

person who fills this position must truly function on

a national scale issue. Hence the position would

really require the report to ORA headquarters, but

perform research and other activities in a field

laboratory.

In terms of science methods

recommendations, we\'re putting forth that we

incorporate state‑of‑the‑art pesticide methodology

into official regulatory procedures. Now the reason

for that is because rapid advances are being made in

pesticide methodologies. These methods are indeed

being incorporated into the local procedures of some

of our ORA labs, but they\'re not being uniformly

adopted, however. As well as being incorporated into

the Pesticide Analytical Manual, the PAM, these

methods should be incorporated into an ORA‑wide

national procedure.

Continuing on with science policy

recommendations, the committee is recommending that we

establish procedures for retention of analytical

records in the analyzing laboratories. Indeed, ISO

17025 requires that records be readily retrievable.

The committee found when attempting to retrieve

analytical packages that often major portions were

incomplete, or unfortunately sometimes missing all

together. Shipments of the records from analyzing

labs to compliance offices in a different location has

complicated the situation. The committee believes the

remedy is to retain the records in the analyzing

laboratory. The FACTS analytical screen would then be

the official regulatory analytical record.

Another policy recommendation in terms of

science was to review requirements for quantitation

and check analysis the samples containing quote

unquote \"no tolerance\" pesticides, as well as

pesticides with tolerances. And again, current

procedures are onerous, can lead to a tenfold increase

in analytical time. In this case, identity

confirmation is what is important. Quantitation is

not necessary for regulatory action on quote unquote

\"no tolerance\" pesticides.

Science recommendations in terms of the

domestic and import laboratory service. We\'re

recommending that we will consolidate all domestic

pesticide analysis within two labs. That would be the

Arkansas Regional Laboratory for Food and the Kansas

City Regional Laboratory for Animal Feed.

Concentration of domestic sample analysis will

facilitate higher throughput, and increase coverage of

the full range of pesticides that need to be covered.

We also want to consolidate all import pesticides

analysis in four of the ORA field laboratories. They

would be New York, Atlanta, Irvine, and Seattle. And

again, concentration of import sample analysis will

also facilitate higher throughput and quicker

processing of perishable samples.

Let\'s move on to scientific

instrumentation. This was an area that\'s close to my

heart and I think one that especially is important in

the field. The recommendation would be the pesticide

steering committee should determine configuration of

instruments to be used in all pesticide labs. Group

purchases whenever possible. Now, what we have is a

wide variety of instrument configurations currently

exist. In 2000, a new paradigm was established where

a single configuration of GC‑MSD instruments was

agreed upon and purchased by all of the labs. This

has proven to be extremely successful, so we need more

of this.

We also need to maximize automation

capabilities of the instrumentation. Right now, all

modern instruments have automation capability. This

is not fully utilized in the ORA labs. This should be

incorporated into national procedures as well.

And finally, we\'re looking at to negotiate

and fund service contracts for complex

instrumentation. The service and maintenance is

currently funded from lab operating budgets. So it\'s

very variable. Modern LCMS‑MS and GCMS‑MS equipment

is far more expensive to maintain than previous

generation of instruments, yet lab operating budgets

have remained fairly static.

Continuing on, we see that we do have an

issue with the science of the Pesticide Analytical

Manual, and the committee is recommending to initiate

a fast‑track process for updating the PAM‑1 with

methods and techniques currently used in ORA

laboratory. Laboratories are typically using methods

involving much more modern extraction and

determinative techniques than what are currently

included in the PAM‑1 which contains the multi‑residue

methods. Since PAM is referenced in the CFR as the

official source of regulatory methods, it does need to

be updated from time to time.

We also need to refocus PAM‑1 as a methods

manual, and eliminate textbook chapters on the general

technologies. The committee felt that general

chapters currently exist on such topics as gas

chromatography. There are other sources for this

information, and the committee felt it does not need

to be included in the PAM.

We also need to establish critical limits

for adjusting operating parameters when focusing on

individual pesticides. Currently PAM does not allow

for minor adjustments such as changes in temperature,

program, et cetera, to deal with individual situations

that may arise. This type of flexibility is

consistent with good science and regulatory analysis

in other areas.

And finally, we need to establish a

schedule for routine updates of both PAM volumes. And

this will allow, again, for PAM to remain current and

to remain usable in the field.

I\'d like to switch now to our science

dioxin analysis, and our committee recommendations.

The committee is recommending in the dioxin area to

establish a research effort for dioxin method

development in the Arkansas Regional Laboratory.

Dioxin is done at CFSAN presently. Methods are then

transferred to the Arkansas lab, and often require

extensive modification before use. A research

function should be established at the Arkansas

Regional Laboratory to compliment the work done and

collaborate with CFSAN.

Also, we need to reaffirm the need for a

second dioxin laboratory at Kansas City, equip the

laboratory appropriately with state‑of‑the‑art

instrumentation. Kansas was established as a backup

lab for dioxins. They were never provided the high

resolution mass spectrometer needed to become fully

operational.

Finally ‑‑ well, not finally but almost

finally, we have the Total Diet Study. The committee

is recommending that we implement the GC‑MSD method in

the Total Diet Study. GC‑MSD, which is mass selective

detector. These methods have been incorporated into

the general pesticide screen, but not yet into the

Total Diet Study program. This would allow expansion

of coverage to new classes of pesticides.

And finally, the committee felt very, very

strongly on Science Recommendation Number 19. And

I\'ve heard this several times before, and I was very

delighted to hear with other presentations that a

science dispute resolution option was being suggested.

And we are doing the same here. We are recommending

that we create and utilize a science dispute

resolution process based on the ad hoc procedures

described in the RPM Chapter 10. Again, you

justification for this is that currently no process

exists to resolve conflict on laboratory issues

between ORA and the centers. The process currently

established for resolving compliance issues should be

expanded to deal with laboratory issues as well.

And with that John, I\'m going to turn it

over back to you to look at the next steps in the

process.

MR. MARZILLI: Thanks John, and I know you

all have had a long day, so I won\'t keep you too long.

But to the Science Board today, particularly the 19

recommendations that Dr. Specchio made in the science

area, we\'d like some feedback from you as we move

forward regarding your concurrence with these

recommendations, and the program management

recommendations that I outlined earlier. We within

ORA and John Taylor has tasked me as his deputy are

implementing those as we speak, and we will be

discussing the program management recommendations with

our senior staff at our upcoming senior staff meeting

which we\'ll be having in two weeks with our regional

directors, district directors, and regional laboratory

directors. So we are well on the way to moving

forward with those.

Again, just to reiterate, the objectives

of our study here which were assess the quality of ORA

science in conducting our pesticides and industrial

chemicals program. We wanted to assess the adequacy

of resources within the Office of Regulatory Affairs

to efficiently conduct this program, and to once again

assess the mission relevance of this program to ORA.

Some questions, John and Katherine, that we\'ll be

posing to the Science Board as we move forward with

the external review for us to consider as we focus on

the peer review of our pesticide program concern

issues such as our sampling program, which we spelled

out in the report. Is our current sampling program a

risk‑based program? Is the sampling program that we

utilize at FDA statistically sound? Is there a

scientifically sound method in place to validate

sampling strategies, and make adjustments where data

has indicated? We have some related policy issues.

Is there a process in place to ensure that target

samples have in fact been collected? Does the

collected data represent the plans range of target

samples? How are our plans coordinated across

districts? That\'s an important aspect for us at ORA

today, because as we pointed out in our report, we\'re

now dealing with many districts that are collecting

samples and sending them to various laboratories

across the country, and we\'re talking about a

reconsolidation of our analytical efforts in terms of

having four laboratories geared toward the analysis of

imported products for pesticide residues, and having

the Arkansas Regional Laboratory and the Kansas City

Laboratory devoted to our domestic program, our Total

Diet Study, and our dioxin program. This is going to

be an additional change for us, so we want to make

sure that we have this coordinated across the country.

Importantly for the Science Board here

that we would like to have evaluated are the

analytical methods that we use. Are the methods being

used to analyze samples the most cost‑effective and

most efficient methods available? Whenever there are

newer methods of superior technology that become

available, do we have the proper processes for

validating and deploying these methods in our

laboratories? Does the validation process that we\'re

utilizing in our laboratories have the appropriate

vigor? Are there appropriate procedures for capturing

and sharing and auditing raw data that is useful to

our users? Are we utilizing proper quality assurance

in our data gathering? Some related science policy

issues: is the current requirement for using PAM

methods an impediment to integrating newer or superior

methods in pesticide analysis, and utilizing these

programs in our compliance program. Since we have the

PAM required under the Code of Federal Regulations,

are we properly utilizing the PAM? Do we have proper

procedures in place, or can we implement proper

procedures to assure that we have the most current

methodologies involved in our Pesticide Analytical

Manual.

Again, these are issues that don\'t just

face ORA. They\'re cross‑cutting, and that\'s why it

was important to have folks on the review committee

from our state counterparts, to have the Center for

Food Safety as part of the next review committee,

because these aren\'t answers that the Office of

Regulatory Affairs or the Science Board alone can

address, but we do need to address this on a cross‑

cutting area.

One of the issues that we pointed out is

the importance of having our compliance programs and

our compliance policy guides up to date. And the

reason for that is the Office of Regulatory Affairs,

our inspectional arm is spread out across 175 cities

across the country. We have to make sure that every

inspector and every investigator that\'s collecting a

sample, doing investigation, doing a trace‑back on the

misuse of a pesticide, are following current guidance,

and the guidance is up to date, and they have their

guidance available at their work station, online, and

it\'s real‑time, and it\'s accurate for the work that

they do. So that\'s, as we\'re revising some of our

programs and our compliance policy guides, as we\'re

revising our import alerts, we have to realize that

the audience that we reach to within the Office of

Regulatory Affairs as I said are in 175 cities across

the country. And God bless the Internet with all the

hits we get on it. There\'s a plethora of people

across the world that have access to that information

as well.

And as I pointed out, the work that we\'re

doing, we have a laboratory network of 13 laboratories

within the Office of Regulatory Affairs. The issues

that we covered in this program affect six of those

laboratories. We have our four multipurpose

laboratories in New York, Atlanta, Seattle, and

Irvine, California, and we propose that those

laboratories in this program serve as our import

analysis laboratories, providing rapid throughput,

high volume work so that we can better cover the

import programs that are coming into this country.

We\'d like to make sure that our domestic programs that

would be handled out of the ORA laboratory on the NCTR

campus as Jefferson, Arkansas, and our Total Diet

laboratory in Kansas City work collaboratively, that

we have redundant systems between them so they can

back one another up in the domestic area, so that they

can compliment one another in the area of dioxin

analysis as we\'ve talked about, and that they can work

collaboratively with our colleagues at CFSAN in

researching these methods and getting state‑of‑the‑art

methods with consistent equipment in these

laboratories to compliment the research done at the

Center for Food Safety. These are important tasks for

us.

Lastly I do want to thank my team members

that have been involved in this process over the past

two years. As I mentioned earlier I\'m John Marzilli.

I\'m the Deputy Associate Commissioner for Regulatory

Affairs. On the team we had Susan Setterberg, our

regional director from Philadelphia, Dr. John Specchio

co‑chaired the review team along with Pat Schafer

who\'s our compliance director from New Orleans

District. And I\'ll ask Pat to stand up because Pat

would you please be embarrassed. Pat Schafer came to

us from New Orleans District. She co‑chaired this.

And we didn\'t have her come all the way from the Big

Easy just to say hi. She\'s served for the past 30

days as our acting director in Division of Field

Office and I want to thank her for doing that. Tom

Gardine, our Philadelphia district director was on the

team. Sandra Whetstone, Sandra\'s here, Sandra say hi,

from our Division of Compliance Management and

Operations in our Office of Enforcement was an active

member of the team. Mike Ellison who\'s since retired,

our national food expert, from the Division of Field

Investigations. Frank Mazzoni, a supervisor from New

England District. I\'d like to thank Barbara George,

our program support specialist, for helping us out

here. Again, our co‑chair, Dr. John Specchio, who

spoke with you today. Tom Savage, our deputy director

in Division of Field Science was on the team as well

as others from Division of Field Science, including

Dr. Larry D\'Hoostelaere, Charles Parfitt who was our

senior scientific coordinator for pesticide programs,

has since retired. Tom Sidebottom, our assistant

regional director from the Pacific Region. Meredith

Grahn, our assistant regional director from Southwest

Region in Dallas who has since retired. And this

effort was spearheaded by Richard Baldwin, our senior

science advisor from the Office of Regulatory Affairs,

also retired. As you can see, Dr. Crawford, this task

knocked out a lot of people.

(Laughter)

DR. CRAWFORD: We\'re going to hire the

graduating class of the University of Georgia for food

sciences.

(Laughter)

MR. MARZILLI: Okay. Ken, I\'ll pose any

questions or any comments.

CHAIR SHINE: Thank you very much John and

John. How many inspectors do you have, order of

magnitude?

MR. MARZILLI: We have about 1,200

inspectors nationwide.

CHAIR SHINE: At 13 offices?

MR. MARZILLI: In 20 district offices.

CHAIR SHINE: Yes.

MR. MARZILLI: And 175 cities across the

country. We have what we call resident inspection

posts. They could have two to 20 inspectors working

in them.

DR. CRAWFORD: How many people in ORA,

though?

MR. MARZILLI: The Office of Regulatory

Affairs ‑‑ thank you Dr. Crawford ‑‑ the Office of

Regulatory Affairs now is about 3,800 employees. Is

that right Steve? 3,600. Woops, I lost 200 just

walking over here.

CHAIR SHINE: A lot of them retired.

Questions from the panel, keeping in mind that Katie

and John are going to be looking very closely at many

aspects of this, along with the ad hoc members of

their panel. As John pointed out, two of them are

based in states, which was something that we thought

would be very useful. John?

DR. THOMAS: I think Katie and I would

agree when we looked at one of your slides, 19

recommendations, do you concur. First question I

would have: would you prioritize that? And would you

tell us which are new, which are funded, which are

unfunded, provide some sort of matrix?

MR. MARZILLI: Yes sir, we will.

DR. THOMAS: So we can get our feet wet?

MR. MARZILLI: We will do that. Thank

you.

CHAIR SHINE: Other comments? Katie?

DR. SWANSON: Along those same lines, the

slide says 19 recommendations, the report had 21

science recommendations. So we have to sort out which

two dropped out.

DR. THOMAS: He\'s already squashed his

quad spec.

DR. SWANSON: Also, with the questions

related to the statistical sufficiency, we are going

to need access to a statistician now. And I don\'t

know that ‑‑ will FDA be providing a statistician?

MR. MARZILLI: I think, Bob, we can work

with the center? Any of the statistical work? Steve

Musser will help you from the center.

DR. SWANSON: Okay. Okay.

CHAIR SHINE: Other questions or comments?

DR. THOMAS: I have one question. What

does the EPA do in terms of dioxin? Do they have a

national lab for analytical work for dioxin?

MR. MARZILLI: I think the dioxin work is

all the work that we do. Norris?

DR. ALDERSON: I ‑‑ no. There\'s ‑‑ EPA is

heavily involved in dioxin as well. I don\'t know

which lab, Tom, they worked in but we can get that for

you. Oh, I\'m sorry. Obviously EPA has a big program

in dioxin, but which lab they have working in that

area I don\'t know.

DR. THOMAS: The other question relates to

collaboration, if you will. And that is how

effectively do you work with the USDA? I know you

have state departments of agriculture. How do they

interface, just in a general sort of way, with your

group?

MR. MARZILLI: We share work results with

the Ag Marketing Service at USDA. The USDA\'s Ag

Marketing Service in particular does a large

statistical sampling program for domestic products.

And what we try to do in working with them is first of

all our folks from the Center for Food Safety and our

pesticide expert who has since retired, although we

have a new one that\'s come on board just this week,

work closely with them on the methods that they will

be using for their sampling program for the year. And

their work is primarily conducted in state

laboratories that they contract with. So we work with

them on methods, and we try to keep in touch with them

regarding the samples that they\'re collecting so that

we don\'t have any needless duplication on the domestic

area. And keep in mind, if the states or the USDA

find violative residues, that then is turned over the

FDA for regulatory action, because we\'re the

regulatory body that takes care of that. So there is

a lot of close cooperation.

CHAIR SHINE: And I would think a

corollary to that is what\'s the nature of the

coordination when you look at products in areas where

inspection is carried out by multiple agencies.

MR. MARZILLI: And another thing is when

is the residue discovered, i.e., you discover the

residue upon harvest, and there\'s some time that goes

by. But when the result is found, say, by a state

laboratory, then reported to say the FDA that there

was a violative residue, now the product ends up in a

processed food, and there\'s the whole trace‑back that

we\'re involved with there. That\'s even in addition to

the analytical laboratory work.

CHAIR SHINE: Yes, but I\'m also thinking

about just coordinating all of the regulatory roles

since there are so many people involved at any given

time in certain kinds of products. Any other

comments? Questions? Thank you John.

MR. MARZILLI: Thanks, looking forward to

working with you. Thank you.

CHAIR SHINE: And I want to again thank

Katie and John for being willing to co‑chair this

effort. And they\'ll be reporting back to the

committee as a whole. Are there any other items or

issues that anyone would like to bring before the

committee before we adjourn? As we discussed, we will

be trying to get feedback from the members of the

committee about our agenda and various kinds of

activities that we want to look at over the next year

or two. Don\'t hesitate to send us an email in terms

of thoughts that you have, or areas of interest that

you think we ought to be thinking about. And we\'ll

work closely with the commissioner and his colleagues

in terms of how we do that.

I think Commissioner, it\'s been an

interesting day. I think you should be very pleased

with the progress that\'s been made in the Critical

Path. The devil\'s in the details. It\'s in the

experimental design of some of these activities, it\'s

in the follow‑up. We think that the initiative has

become and moved very nicely. I think we\'re very

pleased with the manufacturing processes development

and the technology assessment, and we look forward to

the review of pesticides and chemical contaminants, if

I get it right. If there\'s no other business, the

meeting is adjourned.

DR. CRAWFORD: Thank you. Your honoraria

will be in the mail.

(Laughter)

(Whereupon, the foregoing matter went off

the record at 3:33 p.m.)