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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