U.S. FOOD AND DRUG ADMINISTRATION
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OFFICE OF THE COMMISSIONER
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NOVEMBER 5, 2004
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The meeting was held at 8:00 a.m. in Room
1066 of the Food and Drug Administration, 5630 Fishers
Lane, Rockville, Maryland, Dr. Kenneth I. Shine,
KENNETH I. SHINE, M.D., Chair
GAIL H. CASSELL, Ph.D., Member
JOSEPHINE GRIMA, Ph.D., Consumer
SUSAN KAY HARLANDER, Ph.D., Member
CATO T. LAURENCIN, M.D., Ph.D., Member
CECIL B. PICKETT, Ph.D., Member
F. XAVIER PI‑SUNYER, M.D., M.P.H., Member
JIM E. RIVIERE, D.V.M., Ph.D., Member
ALLEN D. ROSES, M.D., Member
KATHERINE M.J. SWANSON, Ph.D., Member
JOHN A. THOMAS, Ph.D., Member
LESTER M. CRAWFORD, D.V.M., Ph.D., Acting
NORRIS E. ALDERSON, Ph.D., Associate
Commissioner for Science
JAN N. JOHANNESSEN, Ph.D., Executive Secretary
ROBERT BRACKETT, Ph.D., Director, CFSAN
KATHRYN M. CARBONE, MD., Associate Director
for Research, CBER
STEVEN GALSON, M.D., M.P.H., Acting Director,
AJAZ HUSSAIN, Ph.D., Deputy Director, Office
of Pharmaceutical Sciences, CDER
LARRY G. KESSLER, Sc.D., Director, Office of
Science and Engineering Laboratories, CDRH
JOHN R. MARZILLI, Deputy Associate
Commissioner for Regulatory Affairs
KARA MORGAN, Ph.D., Office of Planning, Office
of the Commissioner
LISA ROVIN, J.D., Director, Critical Path
ALAN M. RULIS, Ph.D., Senior Advisor for
Special Projects, CFSAN
LEONARD SCHECHTMAN. Ph.D., Acting Deputy
DANIEL SCHULTZ, M.D., Director, CDRH
JOHN J. SPECCHIO, Ph.D., Montclair State
STEPHEN SUNDLOF, D.V.M., Ph.D, Director, CVM
DOUGLAS THROCKMORTON, M.D., Acting Deputy
JANET WOODCOCK, M.D., Acting Deputy
Commissioner for Operations
AGENDA ITEM PAGE
Call to Order 5
Kenneth I. Shine, M.D., Chair, FDA Science
Meeting Statement 5
Jan N. Johannessen, Ph.D., Executive Secretary
Welcome and opening remarks 7
Lester M. Crawford, D.V.M., Ph.D., Acting
Commissioner of Food and Drugs
Update on the Critical Path Initiative 23
CDER Critical Path Activities 23
Douglas Throckmorton, M.D., Center for Drug
Evaluation and Research, FDA
CBER Critical Path Activities 44
Kathryn Carbone, M.D., M.P.H., Director, Center
for Biologics Evaluation and Research, FDA
CDRH Critical Path Activities 59
Daniel Schultz, M.D., Director, enter for
Devices and Radiological Health, FDA
Overview of Critical Path Docket Submissions 74
Lisa Rovin, J.D., Director, Critical Path
Initiative, Office of the Commissioner, FDA
Critical Path ‑ Current Activities and the 88
Janet Woodcock, M.D., Acting Deputy
Commissioner for Operations, FDA
Medical Technology Innovation Task Force 107
Larry G. Kessler, Sc.D., Director, Office of
Science and Engineering Laboratories
Foods Critical Path White Paper 118
Alan M. Rulis, Ph.D., Senior Advisor for
Special Projects, Center for Food Safety and
Applied Nutrition, FDA
Questions and Discussion with the 127
AGENDA ITEM (Continued) PAGE
Open Public Hearing 173
Pharmaceutical cGMP Initiative 173
Janet Woodcock, M.D., Acting Deputy
Commissioner for Operations, FDA
Final Report on Process Analytical 204
Technology and Manufacturing Science
Ajaz Hussain, Ph.D., Deputy Director, Office
of Pharmaceutical Sciences, CDER, FDA
ORA Peer Review ‑ Overview of Report and Plan 245
for External Peer Review
John R. Marzilli, Deputy Associate Commissioner
for Regulatory Affairs, FDA
Questions and Discussion with Board ‑ 276
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
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
"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.
CHAIRMAN SHINE: Thank you, Jan. That is
an even more important reason for us to start on time.
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.
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,
MEMBER PICKETT: Absolutely. Thank you
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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?
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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.
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
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
CHAIRMAN SHINE: And what's the outcome of
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.
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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.
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?
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
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
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
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
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
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
CHAIRMAN SHINE: Thank you very much,
We are a bit behind schedule. So let's
take a 15‑minute break.
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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.
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
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
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
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
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
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
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
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
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
For example, Chip Petricoin is an
international authority on proteomics. And so he is
sought out. He does tremendous work, very practical
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
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
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
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
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
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
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
DR. WOODCOCK: Could I just clarify
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