UNITED STATES OF AMERICA

FOOD AND DRUG ADMINISTRATION

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WORKSHOP ON

INNOVATIVE SYSTEMS FOR DELIVERY OF DRUGS AND BIOLOGICS:

SCIENTIFIC, CLINICAL, AND REGULATORY CHALLENGES

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TUESDAY, JULY 8, 2003

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The workshop was held in the Grand Ballroom of the Bethesda Marriott,
5151 Pooks Hill Road, Bethesda, Maryland, at 8:00 a.m.

[PRESENT]{.underline}:

DAVID FEIGAL, JR., M.D., M.P.H., Center Director,

CDRH

MARK McCLELLAN, M.D., Ph.D., Commissioner, FDA

ROBERT LANGER, Ph.D., Massachusetts Institute of

Technology

DAVID C. KLONOFF, M.D., U.C. San Francisco

[PRESENT (Continued)]{.underline}:

JONATHAN B. KRUSKAL, M.D., Ph.D., Harvard Medical

School

RICHARD E. KUNTZ, M.D., M.Sc., Harvard Medical

School

AJAZ HUSSAIN, Ph.D., Nektar Therapeutics

CHET LEACH, Ph.D., Nektar Therapeutics

BILL VAN ANTWERP, Ph.D., Medtronic MiniMed

KEVIN C. SKINNER, V.M.D., Genzyme Corporation

JONATHAN S. KAHAN, ESQ., Hogan and Hartson, L.L.P.

KEITH SMITH, Becton, Dickinson, and Company

CHRISTINE ALLISON, M.S., RAC, Eli Lilly and Company

JOHN JENKINS, CDER

MARK KRAMER, FDA Office of Combination Products

ASHLEY B. BOAM, MSBE, CDRH

RICHARD P. FELTEN, CDRH

DAN SHAMES, M.D., CDER

JESSE GOODMAN, M.D., FDA

NANCY ISAAC, Aerogen

C-O-N-T-E-N-T-S

PAGE

Welcome, David Feigal, Jr., M.D., M.P.H. 6

Presentation of Mark McClellan, M.D., Ph.D. 9

Presentation of Robert Langer, Ph.D. 26

Presentation of David C. Klonoff, M.D. 71

Presentation of Jonathan B. Kruskal, M.D., Ph.D. 119

Presentation of Richard E. Kuntz, M.D., M.Sc. 155

Presentation of Chet Leach, Ph.D. 188

Presentation of Bill Van Antwerp, Ph.D. 210

Presentation of Kevin C. Skinner, V.M.D. 224

Presentation of Ajaz Hussain, Ph.D. 235

Public Comment, Dr. Paul Goldfarb 254

Presentation of Jonathan S. Kahan, Esq. 271

Presentation of Keith Smith 297

Presentation of Christine Allison, M.S., RAC 322

Presentation of Mark Kramer 339

Presentation of Ashley B. Boam 359

P-R-O-C-E-E-D-I-N-G-S

(8:14 a.m..)

DR. PROVOST: Good morning. We\'re going to go ahead and get started.

My name is Mariam Provost. I work for the FDA and the Center for Devices
and Radiological Health.

And I just want to make a few announcements before we introduce the
first speaker. I also want to say welcome to the people across the hall
on watching us on the TV and also people who are phoning in. We also are
providing this conference through an audio hookup. So welcome to
everybody.

And I also want to say thank you to all of the speakers who have agreed
to come today. I think we have a very interesting program. It\'s a very
full program. So there\'s just a couple of things that I want to
mention.

In order so that we can stay on time as best we can, we have structured
the morning session so that there\'s a question and answer period. So we
would ask that if you do have questions, if you could wait until the
question and answer period to ask them, I think that will help us to
keep on time.

I also do want to mention there is going to be a panel discussion at the
end of the day. So if you don\'t get a chance to ask some burning
questions because of the limited time, you can save your questions for
the end of the day, and we do have 45 minutes set aside for panel
discussion.

We are, as I mentioned, audio broadcasting this conference. It\'s also
being transcribed. So if you do have a question, we ask that you
identify yourself and also please speak into the microphone so that
everybody can hear.

And, finally, very important, lunch. We\'re a pretty big group here
today. So that everybody can get lunch and get lunch on time, we\'ve
arranged with the hotel to provide a box lunch, and there is an
attendant from the hotel who is here out in the hallway, and they ask
that you order the lunch by 9:30 this morning.

So if you want to get a lunch, please, I urge you to order your lunch
now so that it will be here when you need it.

And that\'s all for the announcements of that type. I would just like to
introduce Dr. David Feigal, who is the Director of the Center for
Devices and Radiological Health, who is going to give us some welcoming
remarks.

(Applause.)

DR. FEIGAL: Well, thanks.

One of the most important things that I could do this morning is to
thank Mariam Provost and Vickie Babb, who arranged this meeting on
relatively short notice as far as meetings go, and the challenge of
finding a room like this that\'s ideally configured for talks and
speeches. The only one that actually was more interesting was one once
where we had a lot of press with lights, and it had mirrored columns all
around the room.

(Laughter.)

DR. FEIGAL: So every time they would turn it was like begin inside a
prism. It was very interesting.

One of the real challenges in medical product development is to bring
the first of a kind to the market. As we\'ve looked back at what kinds
of applications are approved rapidly and which applications take longer,
it\'s quite clear that the first of a kind products are often difficult.

It\'s also very clear that if we can sit down and have a discussion of
what is needed to establish the kinds of information that you need to
bring a product to market, that you can facilitate this process. And
there are times when this is done quite formally in the shape of
developing guidances.

There are other times when it seems to evolve product by product.

Now, it\'s challenging to bring one new product to market. It\'s even
more challenging when you have a combination of products. When you have
two products, one of which may be novel, both of which may be novel, you
have particular challenges to know exactly what is the regulatory path
going to be.

It\'s also a challenge when you yoke together a pharmaceutical, which
often comes from a very large and well resourced company, with the
device industry where many of the innovators are small companies work on
closer margins, on more rapid cycles.

There\'s a difference in the way that the intellectual property of
devices is protected than drugs. So there are many, many challenges, and
as we looked for topics that we could address and begin to develop, the
whole concept of combination products and particularly products where
there was a novel mechanism of delivering a drug or a biological
therapeutic seem to be particularly timely.

So my task this morning is to moderate the session, introduce our
speakers, and this afternoon we\'ll come back and have time to actually
more explicitly talk about some of the regulatory challenges.

As you are aware, if you followed some of the developments in the center
in the last four or five years, we view the regulatory process as an
intensely scientific one. This isn\'t a type of a decision-making that
can be done simply by developing checklists and looking for completeness
or other types of processes.

So it\'s appropriate that we begin this morning with an intense look at
some of the science and some of the exciting science in some of the
important disease areas, and that we begin the morning with some remarks
from Dr. Mark McClellan, who is Commissioner of the FDA and who is
responsible for this meeting, which will probably just be the start of a
series of workshop-styled meetings on product development.

So with that, let me turn the mic over to Mark and let\'s get started.

DR. McCLELLAN: Thank you, David.

It\'s a pleasure to be here with you all this morning at this new
workshop on innovative systems for the delivery of drugs and biologics.
This is a particularly important pleasure for me because of all of the
people here with our devices center and with the biologics center and
our drugs center who have contributed to this effort.

As David mentioned, this is an early effort in what I think will be a
series of programs designed to focus on the important questions of
emerging technologies and our effective approaches to regulating them,
to demonstrating that they\'re safe and effective in getting better
treatments to patients as quickly as possible.

I also want to spend a minute thanking Dr. Robert Langer for his work
and his contribution to FDA, in general, and to this meeting, in
particular. Dr. Langer just finished as Chair of our Science Board for
several years, and that was only one of many efforts in improving
biomedical technology.

Dr. Langer is a professor at MIT who has made many contributions in
chemical and biological engineering, ranging from insights in basic
science and improvements in biomedical technology to actually bringing
those products to market through patents and through the development
process.

And I think Dr. Langer\'s efforts exemplify the kind of work that we
want to highlight here and the kind of perspectives that we want to
bring to the FDA\'s efforts in these development workshops.

One of his recent articles, which is in the packet included for this
meeting, is on how to get drugs where they need to go, and I think this
conference and the efforts that will follow from it are an effort to
build on that by figuring out how to get drugs where they need to go
quicker and more effectively and more safely. That\'s the goal that we
are attempting to fill with this workshop effort.

As Dr. Feigal mentioned, this is the first in a number of workshop that
have developed from a strategic planning process that we\'ve undertaken
at the FDA over the last six months or so. This is an effort to develop
clear guidance, clear regulatory pathways for product developers in a
range of innovative areas. It includes not only novel systems for
delivering drugs and biologics where they need to go, but also such
areas as pharmacogenomics and cell and gene therapy, as well as many
priority areas for product development, such as cancer treatments,
obesity treatments, and treatments for diabetes.

In our strategic planning process, these were areas where our staff felt
that there were opportunities if not to actually identify more clear and
effective regulatory pathways, at least a need to take stock of recent
developments in the sciences as applied to product development.

And so that\'s why we\'re having these activities where we can get
people together and figure out if there are clear ways in which we could
improve regulatory pathways. This is more important today than ever
because of the tremendous potential out there for improvements in
medical technology.

You all are quite familiar with what innovations in health care have
brought to patients in recent decades. For example, treatment of heart
attack, which used to involve largely supportive care as recently as a
few decades ago, has transformed as a result of innovations in drugs,
biologics, devices, and combination products, has transformed heart
attack care into a condition that most people now should expect to
survive.

This is a big change in recent decades. Diabetes is also an area where
tremendous changes have occurred, and some of the greatest improvements
in the treatment of these conditions have come from combination
products, devices and drugs, devices and biologics working together.
These involve treatments that may permit the delivery of medications
more accurately and effectively, as is the case in a product that we
approved yesterday that combined a blood sugar monitoring system with a
continuous insulin delivery pump to permit more accurate and at least
the promise of more accurate and timely delivery of insulin on an
ongoing basis.

It includes treatments that permit drugs to get to the right place in
the body more accurately, as in some of the liposomal delivery systems
that have been developed recently. It includes ways of targeting
particular cells more effectively, for example, through new
nanotechnologies.

So there are many applications of new technology in the area of
combination products, and the potential for these technologies to have
an impact on improving patient care in the years ahead, I think, is even
greater. But it\'s not something that\'s going to happen automatically.

And one of the things that has concerned me since coming to FDA is all
that I\'ve been able to learn about some of the challenges facing
product development today. If you look at just plain, old drugs, small
molecule drugs which in many ways are not the only kind of innovative
treatment coming along now, the development process has gotten
considerably longer and more expensive, and this is not something I
think is the fault of regulation primarily or maybe even at all, but it
is a fact.

It now costs, according to some estimates, over \$800 million to develop
a new drug, and while that number is somewhat controversial, there\'s no
arguing with the fact that it has gotten a lot more expensive than it
used to be because of a more extensive preclinical development and
testing process.

It has also gotten more uncertain than it used to be with only a small
fraction of the drugs that enter clinical development actually resulting
in applications to the FDA and only less than one in two that make it
even to the advanced phases of clinical testing, the so-called Phase III
trials, resulting in applications to FDA.

And in the past few years, we\'ve seen a downturn in the number of new
product applications coming into the agency, and so that\'s an area of
concern where, on the one hand, the amount of investment in new research
and development both in the private sector and in the government through
increases in the NIH budget have reached an all time high, but on the
other hand, we\'re not yet seeing that translate into a significant
upturn in the number of valuable new products reaching patients.

And this may be something that is just going to take a matter of time to
resolve. I\'ve got a lot of long term confidence in the biomedical
industry to improve care, but this delay is something that adds to
health care costs because of the cost that goes along with developing
new products and has an impact on quality of care because it results in
longer times before patients can get access to safe and effective new
treatments.

So this is a real challenge as products become more complex, and in
meeting this challenge FDA can and will maintain its gold standard for
the world for product approvals. That means we will continue to make
sure that products are safe and effective before we approve them.

At the same time, with all of these insights coming in the form of new
products, I think there are opportunities to find way to make that
development process work more efficiently. Again, this is not something
that the agency can solve by itself through just reducing review times
and the like. It\'s something that will require some creative thinking
and efforts to make sure we are applying the best and latest
translational science to our regulatory processes, to make sure that we
are using the most effective mechanisms for designing studies, for
developing endpoints, for doing follow-up studies after approval and the
like, to get to our determinations of safety and effectiveness as
efficiently as possible.

So as part of this effort, which is a key element in FDA\'s strategic
plan, we announced a new FDA initiative on improving medical innovation
earlier this year. The goal of this set of efforts is to bring more
clarity and consistency to the review process for new and emerging
medical technologies, and we\'re aiming to do that in several ways.

First, as Dr. Feigal mentioned, we\'re conducting an internal review, a
root cause analysis of cases where new products took more than one cycle
to reach a determination of safety and effectiveness.

In our preliminary results, it looks like in a lot of cases the multiple
cycles were unavoidable. New things were discovered in development
process late, clinical results that were unanticipated, that required
some further evaluation and the like.

But in some cases, it appeared that earlier and clearer communication
with product developers about the standards for approval and about what
exactly was required for approval would have helped, would have helped
them get it right the first time on their product applications.

So a couple of the other major components of this initiative are
designed to try to address that issue.

We are also doing a number of guidance development programs like this
meeting here today. This discussion is intended to lead to written
guidance that can help in the development of products in the area of
novel delivery systems for drugs and biologics, and I mentioned some
other areas of emerging technology where we are conducting similar kinds
of activities.

In addition, we are in the process of implementing some quality systems
for product reviews. We have a lot of expertise in the agency on the
best ways to approve and review new products, and we want to make sure
that the best practices in various parts of our agency are shared
throughout the agency and are used to implement more efficient
regulatory processes.

And this is something that we are undertaking, in part, in conjunction
with outside consultants in developing better performance measures, in
part through internal work to identify best practices, develop
performance measures related to them, and implement them more widely
throughout the agency.

So these are all major elements of our effort to improve the innovation
process, but I wanted to ask you to take a step back and think more
broadly about this. Most of the time and product development obviously
doesn\'t occur in the review times at the FDA. Most of the time in
product development occurs between the time someone has a good idea in
the basic biomedical sciences of a proof of concept and then starts
moving that idea into preclinical and then clinical testing.

That\'s a process that can take many years and, as I mentioned earlier,
can be very costly and have many uncertainties along the way. Anything
that we can do through clarifying what our regulatory standards are to
make that part of the process work more efficiently as well will only
add to these potential savings and reductions in uncertainty in the
process of product development.

So it\'s not just about our review time. It\'s about clarity in what is
needed for determining that a product is safe and effective, and so
that\'s why it\'s very important to have many of you here today who are
involved in product development, who have terrific experience in the
regulatory process and who can give us hopefully some insights that can
serve as a basis for our written guidance to make this whole process
work more efficiently in such emerging areas of technology as novel
systems for delivering drugs and biologics.

This is an area where these combination product areas have not gone as
smoothly as they might in the past, and we are already taking some steps
to try to address that. One of the first things that I did as
Commissioner was set up a new Office of Combination Products, headed by
the very capable Mark Kramer, in the Office of the Commissioner to
provide better oversight and to help develop clear guidance about
jurisdictional issues and other issues that are unique to combination
products.

One of the other things that I\'m working hard on now with Dr. Feigal
and the rest of CDRH and our Office of Combination Products is the
effective implementation of the new Medical Device User Fee and
Modernization Act. This is a very important piece of legislation that
will give us additional resources not only to turn around reviews more
quickly, but hopefully to spend some more time and effort on identifying
more efficient regulatory practices, to have those kinds of early
conversations with product developers that help us by making sure we
understand some of the latest technologies that are coming along and how
to best evaluate them, and to help product developers by giving them
some of our insights in terms of what it actually takes to demonstrate
that a product is safe and effective and meets FDA\'s regulatory
standards.

We are fully committed to the goals of the Medical Device Users Fee
Modernization Act, and we will implement this program successfully.
We\'re working closely with OMB and others on Capitol Hill to make sure
that the adequate funding will be there to meet those program goals, and
we\'re going to succeed.

So this is a very important time in product development for combination
products and novel drug and biologic delivery systems for a number of
reasons. We\'ve got new resources. We have new programs in place
already, and we have a strong commitment from the people at CDRH, CBER,
and CDER to find more effective ways to implement, to determine that
these new technologies coming along are safe and effective, and it
couldn\'t happen at a more critical time with the investment in
biomedical R&D in these combination product areas at the highest levels
ever and the potential for important new technologies reaching patients.

If we can demonstrate they\'re safe and effective, the potential is
greater than ever. So this is a critical time for health policy. We
think that at FDA we\'re in a great position to help with this
innovation process, and we\'ve got more experience and data on the
factors that influence success or failure of new treatments than anyone
else, and we want to find ways to bring that knowledge to bear and bring
some of the new insights in biomedical research to bear in these areas
as effectively as possible.

So I am looking forward to hearing from all of you here today and
hearing about the results of this conference. It sounds like a great set
of sessions this morning on reviewing some promising clinical
applications in the areas of novel delivery systems and some of the
preclinical challenges, this afternoon moving on to perspectives from
product developers and the FDA on challenges for product development,
all with the goal of finding a clear basis for the regulatory processes
that we require for demonstrating the products are safe and effective,
and getting safe and effective products to market as inexpensively and
with as little uncertainty as possible.

Thank you all for participating in this effort. As I said, this is, I
hope, going to be an early step in an ongoing effort to make sure that
our regulatory processes are up to date and are helping patients get
access to safe and effective treatments as quickly as possible and at
the lowest possible cost.

And we definitely need this to be a collaborative effort. We\'ve got a
lot of good ideas internally. We need to bounce them off people outside
the agency, and there are also a lot of good ideas outside, given all of
the progress that has occurred recently in such areas as novel delivery
systems.

So this seems like the right time and the right topic for a kickoff
conference on improving innovation process, and I want to thank you all
again for coming here today and also for listening to me this morning.

Thanks very much.

(Applause.)

DR. FEIGAL: Well, it\'s my pleasure this morning to introduce our
keynote speaker, Professor Robert Langer. Again, thanks are in order for
the service that he provided by chairing the Science Board, and part of
that time period was when the center itself actually went through an
external review of our science program. So we appreciated his efforts in
that very much.

Dr. Langer is the Kenneth J. Germeshausen, Professor of Chemical and
Biomedical Engineering at MIT and is a member of the National Academy of
Engineering, National Academy of Sciences, and the Institute of
Medicine, one of the few people to hold memberships in all three of
those academies.

The kinds and nature of the contributions that Professor Langer have
made are particularly relevant to our program here today, and without
any further ado, let me ask Dr. Langer to come and begin.

(Applause.)

DR. LANGER: David and Mark, thank you very much. It\'s an honor for me
to be able to speak to you all today, and it was certainly an honor for
me to work with the FDA as well.

I\'ve had the fortune over the years of giving a lot of talks. Usually I
end up giving them at universities, though I\'ve given them at
companies, too. And usually what I talk about are drug delivery systems.

A few years ago, though, I was giving a talk at the University of
California at Berkeley. So it was the other side of the country, and I
got in very late at night, and I was trying to think how to introduce my
talk. And I thought for a second and I said, \"Well, probably everyone
here has taken drugs.\"

(Laughter.)

DR. LANGER: That\'s what they did, too. They laughed, but of course,
what I meant were drugs like all the ones that are regulated by FDA, and
that is what I want to talk about today.

In particular, what I will try to do this morning is to give you an
overview, and obviously it can\'t be complete, but what I\'ll try to do
is go over a little bit about why drug delivery is important, where it
is in terms of some of the products, and where it\'s going.

Let me start with a slide. I just want to make sure. Do I do something
to get this on? I\'ll try to tell some more jokes in the meantime.

(Pause in proceedings.)

DR. LANGER: So anyhow, I think I can do this almost without slides, but
at least the first couple of ones.

Thank you very much, Mary.

So what I was going to say, and people obviously have probably seen
things like this before, but if you take a drug, really any drug and
really by almost any means, mouth, skin, whatever, the drug level starts
out very low, reaches a peak, and then goes down, and that peak and
valley level, the problem is those peaks can cause huge safety problems,
sometimes death, and the valleys, the drugs, are not effective.

One example I sometimes use in class are, you know, sleeping pills. If
you take too much you could die. If you take too little, you don\'t go
to sleep. I mean, there\'s various ones you could think about.

So that provides the motivation for could you come up with a way \-- and
this is not always what you want to do, but for a lot of cases what
you\'d like to be able to do is take a drug and have it go to the
desired range and stay there for as long as possible.

Let me just give you a striking example of that that ALZA did working
with Pfizer. So they had a drug that was called Nifedipine, which also
is known as Procardia, a calcium channel blocker, and all throughout the
1980s it was taken by a soft gelatin capsule, so sort of immediate
release. It was quite a successful product. It sold about \$300 million
a year.

It was always, though, if you took it and got the soft gelatin capsule,
peaks and valleys just like you saw.

ALZA, using an osmotic pump system, and I\'ll mention that a little bit
more later, figured out a way to get it at pretty constant release. That
product actually became very successful. Not only was it used for
angina. It also got a new approval for congestive heart failure.

What happened if you looked at the side effects are huge. Here you can
just look at the comparison of the two, and if you compare things like
headaches or flushing or dizziness or palpitations, there\'s a huge
difference.

Taking the controlled release form you get many, many fewer side effects
than the soft gelatin capsule form, and from a cost standpoint, from the
company\'s standpoint, it became a \$1.5 billion a year product rather
quickly.

Let me mention a few products to just give you an idea, though I imagine
people are aware of this, of the range of things that are already being
used in this actually very young field. I think if you look at this,
almost all controlled release systems at least that I\'ll be talking
about, will be approved in the last 20 years or the last 21 years. This
was about one of the earliest ones.

It\'s the nitroglycerine patch, one of a number of transdermal systems
that can deliver drugs just passively in this case through the skin.
Here it does it for a 24-hour period. Over 500 million of these were
used last year.

This is the longest. Sometimes people ask me how long can a controlled
drug delivery system go. Well, this is the longest one that I know of.
This is the Norplant. These are little silicone capsules that you can
place underneath the skin for contraception. They\'re approved in over
50 countries.

And what you can see here is these capsules, which are simply the size
of match sticks, are able to release the drug for over 2,000 days or
five years from these tiny little implants.

This is the very first controlled release system for a protein. For many
years people didn\'t think you could ever deliver proteins. Alcames,
which is a company I\'ve been associated with for a number of years,
developed along with Genentec tiny little microcapsules that you could
put human growth hormone in.

Normally a patient with pituitary dwarfism would take the shots once a
day. Now with this you could take them once a month.

And another one, the last that I\'ll mention at least right now is
really a very innovative thing that ALZA did for Ritalin. If any of you
have children that have attention hyper deficit disorder, they may take
this.

Normally what people had to do was take Ritalin, you know, several times
a day, and if you\'re a small child that means you might have to go to
the nurse. It might be embarrassing, and maybe it doesn\'t even work as
well in the regular forms.

ALZA discovered that actually you don\'t only want to get steady
release. You actually want to have a time where the release is
increasing, and because they were able to design a special version of an
osmotic pump shown here where they\'ve got an overcoat, they\'re
actually able to do this.

So they developed a system called Concerta based on an osmotic pill that
you could take, a child could take generally once a day to treat ADHD.

Let me just give you some statistics, again, for part of this overview
that adverse drug effects where people take drugs kind of the way
they\'re supposed to, they can cause up to 15 percent of hospital
admissions. This was in JAMA a few years ago. One hundred thousand
deaths; that\'s more than four times the number of deaths caused by AIDS
in this country, \$136 billion in health care costs.

Patient compliance, that can cause up to ten percent of hospital
admissions, particularly in the elderly that forget to take drugs.

And of course, one of the things that motivates a lot of companies,
which it should, is can you make a profit in this area. And if you look
at this, as I mentioned, controlled drug delivery systems in the 1980s,
the sales were about zero. In 2001, they\'re about \$20 billion, and my
expectation is that number will go up rapidly for a single reason that
I\'ll mention later and will be talked about later today.

Just look at drug eluting stents, totally based on controlled release
technology. Sales are projected to be five to seven billion dollars
rather quickly. So there\'s enormous opportunity in this area, as well.

The advantages of controlled drug delivery are reduction of adverse side
effects, which I\'ve mentioned. You can keep drug levels in the
desirable range, and much less drug is desired.

You get improved patient compliance, and as we will go over all day, new
therapies are possible.

People \-- I just want to grab myself some water \-- people, you know,
you can approach drug delivery from a number of standpoints. One
standpoint is pretty much every part of the body \-- this may be a
little hard to see in the back \-- but I think that sometimes people ask
me, \"Will there ever be an ideal delivery system that you could just
take by one way?\" And I think the answer is no.

People have been successful at delivering drugs orally, nasally,
transdermally, through the lung, transmucosally, like vaginal, buccal,
in the eye, by liposomes, by injection. All of these, almost all of them
are multi-billion dollar markets in and of themselves.

So there have been successful products in almost all of these areas, and
I expect that that will continue because there\'s enormous opportunity
in each of these areas. There\'s specific diseases in some of those
areas, and many of these areas can be a portal to the rest of the body
for delivering drugs.

I thought I would try to focus in the interest of some of the goals of
this meeting on four areas: the need for new materials;
nanotechnologies; noninvasive delivery; and high throughput approaches.

So I\'ll focus on each of these just in context to illustrate what I see
as some of the ongoing work and some of the challenges ahead.

First, let me go over new materials. You know, this is something that I
got involved in personally in the 1970s. I was actually very surprised
to see this. My own background is a chemical engineer, but when I got
done with my degree I worked at Boston Children\'s Hospital, and being a
chemical engineer, I guess I just thought naively that the people who
were driving the work for bringing new materials into medicine would
have been older chemical engineers or chemists or material scientists.

But when I looked into this, I found that it was rarely the case. Almost
always the driving force for bringing materials into medicine were
clinicians, and they wanted to solve a problem and solve it as quickly
as they could, which is good.

But what they would do is generally they would take a material that was
usually in their house and that kind of resembled the organ or tissue
they wanted to fix, and they\'d use it in the human body. And that led
to some progress, but also to some problems.

And just to give you some examples, this may be cut off a little bit,
but it\'s an artificial heart. But you probably figured that out.
Anyhow, let me just tell you a story or two, and these are all true.

In 1967, clinicians at the NIH wanted to come with an artificial heart,
and they wanted something with a good flex life, you know, for a heart.
And they said, \"What object has a good flex life?\"

And they said a lady\'s girdle material. What\'s that made out of? It\'s
made out of polyetherurethane. So that\'s what they began to make the
artificial heart out of. That was 1967.

Now we\'re in 2003. It\'s still made of that, and you can imagine from a
regulatory standpoint once you start going down that path it\'s not so
easy to stop. And that happens in many different areas. Dialysis tubing
was originally sausage casing. Vascular graft, that\'s an artificial
blood vessel. It was a surgeon in Texas going to clothes store, and
breast implants. One of those was a lubricant \-- oh, thank you \-- one
was a lubricant. The other was a mattress stuffing. Probably you figured
out the logic.

But these are all true, and that\'s often how materials have come into
medicine, and I started thinking in the \'70s, well, you know, maybe you
could take a different approach, and I believe we\'re going to start to
see more and more of that today.

And that is rather than take these materials that might exist in your
house, could you actually ask the question what do you really want in a
biomedical material or drug delivery system from a chemistry standpoint,
biology standpoint and engineering standpoint, and could you synthesize
it from first principles.

I thought I\'d give you an example.

At any rate, let me give you that example. When we started in the 1970s,
there was only one material approved by the FDA that was synthetic
degradable material, suture materials like polyesters, and they
displayed bulk erosion kind of like this. So it would start out \-- now
this isn\'t working either. That\'s okay. I\'ll go over here. I\'ll get
some exercise this morning. Oh, but I think \-- is that going to be a
problem?

(Laughter.)

DR. LANGER: Maybe we had better get one that works. Anyhow, so it might
be good if we got one that works. At any rate, I\'ll try to do this with
my pointing. It might be harder on some of the slides.

Thank you very, very much. Will you remind me to give it back up? Okay.
I got it. Thank you very much.

Okay. So bulk erosion, usually you put the drug uniformly throughout. It
starts out getting spongy, and then it could fall apart. That, by the
way, is fine for a lot of drugs, but if you had a really toxic drug
like, say, insulin or a cancer drug, it might not be so good because you
could get bursts of the drug coming out.

So we said from an engineering standpoint what you\'d really like is
this: surface erosion, kind of like the way a bar of soap dissolves. So
the challenge is how could you do it.

So I won\'t go through all of the chemistry, but basically what we did
is we took this from an engineering design standpoint. We said, well,
what are the right bonds. We thought anhydride bonds. We thought what
are the right monomers, and we came up with a couple of monomers, very
hydrophobic ones that could keep water out. This is extremely
hydrophobic CPPP, and sebacic acid is a little less so.

What was interesting is that by simply adjusting the ratio of those two
not only could you get surface erosion, but you could get these to
dissolve at almost any rate you want, from zero percent sebacic acid. So
about eight percent is gone in 14 weeks. It will take three or four
years for one of these to dissolve fully.

But if you add a little bit more sebacic acid, it dissolves faster-
that\'s 15 percent, 55 percent, it dissolves faster, 79 percent it\'s
all gone in two weeks.

So you could simply dial in your monomer ratio and make these last for
whatever length of time you want.

So with that, you could think about using it for all kinds of
applications. One of the early applications that came up was Henry
Brown, a young neurosurgeon \-- he\'s now head of neurosurgery, chief of
neurosurgery at Johns Hopkins \-- came to see me in the 1980s,
mid-1980s, and he said, \"Could we change the way people do chemotherapy
with this kind of approach? Could we do local chemotherapy?\"

So here was the idea. He would normally go in, operate on patients, take
as much of the tumor out as he could in the brain. He would always do
this, as would everybody else. But he said is after that, you know, they
have to give this drug, BCNU, intravenously. Could we do local
chemotherapy? This drug is enormously toxic.

So the idea was could you take polymers like this, allow him as a
neurosurgeon to put the drug in in little wafers that would locally
deliver it to any remaining tumor he couldn\'t get. The idea is that
could tremendously spare the body the side effects of this terribly
toxic drug, but give high concentrations right to the brain tumor where
you want it to be.

So let me just show you that. If anybody is squeamish and doesn\'t like
to look at blood \-- and I\'m serious about this \-- don\'t look, but
here is what it looks like, a little wafer the size of a dime going in.
Usually you put seven or eight and then close it up.

I always show those slides rather quickly. You know, it\'s very hard to
get good advice when you give a talk, but a few years ago my wife Laura
came to one of my talks. She\'s a neuroscientist, and I asked her at the
end. I actually was showing those slides.

I said, \"What did you think of the talk?\"

And she said, \"Well, Bob, the talk was okay.\" That\'s actually very
high praise.

(Laughter.)

DR. LANGER: But she said, \"You know, there was this 12-minute period of
that talk where you had those two bloody slides on and you explained
every detail of it to the audience.\" This was all chemical engineers I
was speaking to, and she said, \"I don\'t know if you were looking, but
they were all turning green and looking at the floor.\"

So ever after that I\'ve done just what I did today, showed them real
quickly and I warn people. But I do want to tell you a sequel to that. I
give talks to lots of different groups, and I happened to be giving a
dinner speech to a group of neurosurgeons and neurologists, all M.D.s,
and I did the same thing, and at the end of the talk a number of the
neurosurgeons came up to me and they said, \"You know those two bloody
slides you showed?\"

I said, \"Yes.\"

They said, \"Those were fine. No problem,\" but they said, \"Those
chemical formulas.\"

(Laughter.)

DR. LANGER: You know, right after dinner. So you have to be very careful
who you speak to.

(Laughter.)

DR. LANGER: At any rate, there are a lot of challenges \-- I\'m just
going to go back a slide \-- that we had to overcome, which are typical
I think in any of these areas, and I\'ll just go over those briefly.
These were all actually things at the National Institutes of Health
Study Sections, other professors told us why we couldn\'t get it to
work, but basically it\'s just a synthesis, reactivity, strength of the
material, toxicity, diffusion of the drug, manufacturing, and so forth.

All of these were challenges that had to be overcome. Actually they made
for a lot of good theses in our lab. Later on we licensed to do a
company, Guilford Pharmaceutical, and actually the FDA did approve this
originally in 1996. It was the first time that a local chemotherapy
system got approved. That was approved in 1996 for recurrent
glioblastoma. It was extended this year for primary glioblastoma, but
it\'s an example which I wanted to pick of how you could use new
materials to create new therapies in drug delivery.

Also, it illustrates a very early example of local chemotherapy, which I
think is very powerful, and of course, I think the most powerful example
of that which you\'ll hear more about later today is applying this idea
to coated stents where basically you put stents in to keep blood vessels
open, but the problem is, as people will hear about, that for a fairly
high percentage of the time those vessels will close due to restenosis,
smooth muscle proliferation, and so forth.

But you can take some pretty toxic drugs like Taxol and repromicin or
others, put them on a tiny polymer film, locally deliver them, and the
results have been very, very dramatic by many companies in terms of
keeping these blood vessels open.

That\'s the first topic that I wanted to mention, is this idea then of
new materials and local delivery.

The second is nanotechnology. Nanotechnology is something I\'m sure
everybody reads about in the newspapers. Probably everybody wonders what
it really is. Even I wonder what it is sometimes because it has so many
definitions.

But I think there\'s several ways nanotechnology can make a huge impact,
and I thought I\'d give you a couple of examples.

The first actually is work that was done originally by John Santini when
he was my graduate student at MIT and now president of MicroCHIPS, which
is a company I\'m also affiliated with. I had this idea about ten years
ago. I was watching this TV show on how microchips are made in the
computer industry, like Intel, and I thought, gee, this would be a very
interesting way of doing drug delivery.

So along with Michael Sema and John, we came up with originally a very
early design, which I\'m showing here, and the idea is rather than take
a chip for your television set or your computer, what you could do is
build little nanowells \-- I\'ll show you these in a minute \-- into
little chips. Originally they were made of silicon and covered with
gold.

They can, by the way \-- some of our more recent students have made them
out of polymers. They can be made out of almost anything, but basically
you can build little wells into them. This is a cut-away. So on one side
there\'s an impermeable epoxy, and here we\'re using gold as sort of the
cover. They\'re hermetically sealed. You can actually keep them on the
shelf or in the body for a couple of years. Nothing will happen.

But if you apply selectively one volt to any of these welds, they\'re
all individually addressable. What will happen is the gold will come
off, and the drug will come right out. And you can program these to get
almost any delivery pattern you want because if you want to get
instantaneous release, well, then you just have the gold come off.

But let\'s say you wanted the release to be more slow. You could put a
polymer or a gel right underneath it. Also, you could deliver one drug
multiple times. I\'ll show you an example of that in a Pulsatile
fashion, but if you wanted to actually delivery many drugs, like say
we\'ve often considered this like a pharmacy on a chip, you could do
that. If the drugs are potent enough, you could put all of the drugs you
want on such a chip.

And you can make them very tiny like nano, which is what I\'m talking
about, but you could make them bigger, too, if you had drugs that were
less potent.

Let me actually show you what they look like in a picture. This is from
MicroCHIPS, and this is a real good example of nanotechnology. These are
pencils, and here\'s the chip. Here\'s one side and here\'s the other.
There\'s hundreds of wells. Each of these contains a different drug or
the same drug at a different dose.

And then what\'s done to use these, they\'re battery powered, and you
could control them by telemetry. In other words, the same way you might
open up a garage door, you could open any of these wells. You could
envision a day when you might have a wristwatch or some unit like that
that you could just do remote control, and you could open up any
individual well whenever you want. And then it\'s like encased in
something like a little pacemaker.

Also what I believe we\'ll see in the further future is even very smart
systems where you could put biocensors \-- I think Dr. Klonoff may talk
about this more \-- where you could put biocensors on these chips along
with a microprocessor and a power source, and you could get direct
control.

Let me actually show you how this works. What I\'m going to show you is
a quick video. You have to look quickly, but I\'m going to just show you
a single well where you\'re going to be looking at the top of the well,
and then we\'re just going to apply this one volt selectively, and what
you\'re going to see is the top dissolve, and then you\'ll see a little
conical bottom, and so let\'s take a look at that.

Here\'s the video. This is the top. Immediately the gold came right off.
As soon as it does, the drug can come out. So basically it\'s just that
quick. It can be made instantaneous.

Here\'s an [in vivo]{.underline}. This is done in animals, and this just
shows you you can get very reproducible Pulsatile release of the single
drug, and you could do this with multiple drugs if you wanted to.

So this is, I think, one example of nanotechnology where you have little
nanowells, and also a good example of another thing that people
sometimes hear, MEMS devices, micro electrical mechanical system.

The second example of nanotechnology that I wanted to do is at a more
molecular level. There are a whole range of different polymer
therapeutics that you might think about as nanosized medicines. Some of
these are things like polymer drugs. You could actually take a drug, and
I\'ll give you examples in a minute, but I just wanted to show you the
range and also the sizes so that you could have polymers combined to
drugs which could change the drug\'s properties.

You can have polymer protein conjugates. A very good example of this
which we hear a lot about are PEGylated, and I\'ll mention this more.
You could take a protein, which might normally have a short half life or
might be immunogenic, and yet you can conjugate polyethylene glycol to
it, and change both of those.

Another example are polymers for DNA delivery, and I\'ll talk about this
more, but it\'s a huge area because if you wanted to deliver DNA, right
now the only way to do it is with viral vectors, and I think everybody
here at the FDA and elsewhere have made it pretty clear there are some
huge safety issues with it.

Could you make nanosized polymers \-- and I\'ll mention a method later
\-- where you might be able to make a polymer behave like a virus, but
without the safety problems associated with it?

Polymer drug conjugates where you could actually target the drug to a
particular place in the body, like, say, a tumor.

And finally, micelles.

So all of these things are being studied. I\'ll just go over one or two
a little bit, but some of them are already approved. The first one is
the drug attached to a polymer that\'s been approved for liver cancer in
Japan, and then there are a variety of pegylated molecules like
asparaginase, interferon on CGSF, which have been approved by the FDA
for different diseases.

Now, these have made a very substantial impact on medicine already, but
there\'s more coming, and some of the things that are coming are to
really engineer drugs with polymers to get very desired properties. So
maybe you could put in a targeting residue so that it would target to a
receptor. Maybe you would have a biodegradable linker, and people are
already studying these for cancer.

Apart of the basis for treating cancer is that a tumor has very leaky
blood vessels. So you might imagine a polymer, since it\'s big. Well, if
the blood vessel is not leaky, it\'s not going to get out.

But when it gets in the leaky region of the polymer, it will get out,
and that\'s called the EPR effect. And there are a variety of these
systems in various stages of clinical trials for delivering drugs like
Taxol or camptothecin, and some of them even have targeting moieties on
them, like lactosamine.

So many, many that probably will keep the FDA busy over the next number
of years.

The third thing that I wanted to go over is the idea of noninvasive
delivery of complex molecules. Can you do it orally? This would be like
a protein or DNA.

Can you do it transdermally? And I\'ll talk a little bit about both of
these.

Pulmonary, actually somebody from Nektar is going to be speaking. So I
thought I\'d let them do that, and there\'s also various other routes
that we might consider, but I\'m going to just focus a little bit on
these two today where there has been probably a lot of work done, as has
there been there.

So first, oral. There has been at least four strategies that have been
used: carriers, and I\'ll give an example of those; nanoparticles that
might be able to be taken up by M cells, for example in the Pyrus patch
(phonetic); targeting to various receptors in the gut or Pyrus patches.

And even bioadhesive approaches are being worked on by a variety of
groups. I was just going to mention one briefly, which is the carrier
approach, which is probably furthest along, and David Klonoff may talk
about this more, too, but there\'s a company, Emispheres, which has
synthesized some molecules which they call eligens, and their idea is to
complex them to drugs, to deliver them transcellularly without
compromising cell integrity.

And you see an example of this top panel here where insulin is being
delivered to a cell monolayer at different concentrations, and you see
it getting through, and yet the lower panel seems to show that it
doesn\'t affect the tight junctions and so forth.

They\'ve used this to deliver insulin in patients. This is oral insulin,
and they have also used it to deliver human growth hormone.

Probably the big issue that will come up here for oral delivery with any
of these things are two or three things. One is bioavailability. Do you
get enough in? And two is safety, or do other things also get
transported? And these will be some of the key issues to look at.

Nonetheless, I think it\'s very exciting that we\'re already seeing a
delivery of large molecules in people.

The second area that I want to talk about is the skin, and the skin has
been a normally incredibly impenetrable barrier though right now there
are ten transdermal products on the market, all by passive delivery, a
\$3 billion market, and some of them are huge, like Fentanyl patches,
which are for pain management. People, I\'m sure, are familiar with
smoking cessation, and so forth.

Well, why is it so hard to get drugs through the skin? Well, first, I
think we should all be very glad that it\'s hard because otherwise we\'d
get infected.

But what makes it hard is all of the resistance to the skin is the
outermost part of it, the stratum corneum. It\'s only 15 cells layers
thick, and it looks like a brick wall if you looked at it under the
microscope. You have deal cells, keratinocytes, and lipid bilayers here.
So it\'s like bricks and mortar, and it provides a terrifically tight
barrier to get through.

That being said, a variety of groups are trying to do this. Vyteris is a
company, a spinoff of Becton-Dickinson, and they\'ve developed an
approach using iontophoresis. This is using an electric field basically
to transport drugs across the skin. This is their system, and they\'ve
actually developed pretty advanced approaches. They are actually
delivering in this case calcitonin in people this way.

ALZA, which has certainly been a leader in transdermal drug delivery,
has developed what we call the E-TRANS system, and here they\'re putting
Fentanyl, the drug I mentioned, which they\'ve worked on with Johnson &
Johnson, which has been very, very successful, and here they\'re putting
it on the skin, and it slowly delivers it, but as I\'ll show you, by
applying the electric field, and this is sort of what it looks like;
they\'ve got an on demand button, a red light diode. This is kind of the
structure of it.

But what you can do is if you want to get a pulse of Fentanyl, feel more
pain, you can just do this rather quickly. So this can actually provide
Pulsatile Fentanyl delivery using, again, iontophoresis.

And here we\'re looking at them delivering another peptide. This is
luteinizing hormone releasing hormone in a Pulsatile fashion. This is a
drug that people might use for fertility control. It has also been used
for other treatments as well.

ALZA has also developed a kind of micro needle approach. As I mentioned,
really if you want to deliver a drug through the skin, if you could get
through relatively painlessly that thin stratum corneum, you could
deliver a drug. So they\'ve developed what\'s called the macroflux
transdermal patch, which has these little protrusions. You can put it in
the skin, and here they\'ve done like an example of delivering what are
called anti-sensal nucleotides (phonetic). These are about 7,000
molecular weight through the skin this way. So that\'s another approach.

And the final transdermal approach that I wanted to mention is one that
I\'ve been involved in. You\'ll see Coats in our laboratory and then
Santra Company that we\'ve been involved in that has developed what\'s
called the SonoPrep system, and the idea is you can take ultrasound, and
this probably gets an order of magnitude more increase in flux than you
get with iontophoresis, but it\'s at an earlier stage.

But the idea is that you can apply the ultrasound maybe for about 15
seconds, and that will permeabilize the skin. You could then put a patch
on, and that patch, for example, could deliver insulin. Here\'s an
example. You could actually lower blood sugar. It\'s being tested on
man. You could deliver pain medications, and also I think what\'s
particularly exciting is you could do noninvasive extraction.

Both Signas, a company in California, and Santra have been developing
noninvasive ways. Say if you open up the barrier for delivery, you could
also open it up for getting interstitial fluid out, and so you might be
able to, for example, which is in clinical trials now, detect glucose or
many, many other different substances.

And again, I think we will see all examples of this someday

So the final thing that I wanted to go over today before summarizing is
could we look at high throughput approaches, and I thought I\'d give you
two examples of that.

First, what I mean by high throughput approaches. If I looked at the
pharmaceutical industry and I don\'t mean to be insulting by this, but
from the formulation standpoint, it\'s sometimes a little bit slow. I
mean, basically people make the drug, and then you have a formulation
pharmaceutical R&D department, and they have to formulate it.

It\'s a huge, huge challenge as everybody knows, and I thought I\'d just
pick a couple of examples where you could maybe use high throughput
approaches to make these faster. One of them is gene therapy. As I\'ve
already mentioned, gene therapy is an area which I think is badly in
need of better delivery systems.

In fact, it\'s interesting. If you talk to the gene therapy experts,
like Endar Verma (phonetic), for example, I remember he was quoted a few
years ago. Somebody asked him what are the three biggest problems in
gene therapy. In other words, why is gene therapy not being used in
patients today.

And he said, \"Well, there are three big problems,\" he said,
\"delivery, delivery, and delivery.\"

And that I think is true. It has been a huge, huge problem, and it is
unsolved. Richard Mulligan, whom I work closely with, another gene
therapy expert, the same thing. How could se solve that?

Well, one strategy might be to come up with better viral vectors that
would be safer. That\'s a strategy. Another might be nonviral vectors.
Could you make polymers that could behave like a virus, but without the
safety problems of a virus?

And I won\'t go through that much of the science. I just want to
illustrate the high throughput idea, but David Lynn, one of the graduate
students in my lab \-- he\'s now a professor at Wisconsin \-- came up
with the idea of synthesizing certain polymers that would, in fact, have
many properties of like a virus. They would be taken up by cells and so
forth.

But what was particularly interesting is he came up with a synthesis
approach where he could make what are called polybeta amino esters,
where he would simply take amines like this and conjugate them to
diacrolates (phonetic) like this, and the idea is that with this
particular set of chemical structures, he could take a whole range of
commercially available starting materials. He could polymerize them in a
single step. Many polymerizations, by the way, are done in many, many
steps, but the particular beauty of this is there\'s no byproduct. So no
purification and no protection and de-production steps.

So you could actually set this up for high throughput. So Dan Anderson,
another postdoc of mine \-- this slide is a little busy, but it will get
across the point \-- basically what he did is he took 909 amino
monomers. Those are shown here. Twenty-five diacrolate (phonetic)
monomers, and he used a robot and developed high throughput synthesis
methods and then also high throughput screening methods using cells, and
what he was able to do in really a couple of weeks is make over 2,000
structurally diverse polymers, like a whole polymer library.

And here\'s the robot, and he could take these polymers, semi-automate
it, cell based, and screen up all of these polymers, 1,000 in a day, and
he found 46 new polymers. This is just coming out in publication very
soon. Forty-six new polymers that could at least themselves deliver DNA
as good or better as polyethylene amine, which is one of the standard
polymer vectors.

Again, it\'s just an illustration, I mean, of where high throughput
could make an impact, but I think there will be many other examples as
people think about this.

And the final example that I wanted to pick is a company that I\'ve been
associated with called Transform Pharmaceuticals, and here the idea is
could you apply high throughput approaches and robotics and
bioinformatics to pharmaceutical formulations.

And Colin Gardner, who used to be VP of R&D at Merck, Sharpe & Dome, and
now is chief scientific officer at Transform, has done this, but
basically if you look at what we\'ll call form, which might be crystal
structure, which is a real big deal in drug delivery and formulation.
Traditionally, you might take a month or two and there\'s almost no
informatics or data mining done. This is classical.

What Transform has done, and they\'re working with Johnson & Johnson,
Eli Lilly, many other pharmaceutical companies, but basically they\'re
able to because of the use of robotics approaches, and I\'ll show you
this in a minute or two, are able to do 200 to 20,000 experiments in two
to four weeks, and every time they do an experiment, they use all of
this informatics to tell them how to do the next set of experiments. So
you can be faster and faster and smarter and smarter, and I think this
is going to be the kind of way that will make sense more and more.

And let me illustrate that a little bit, and what I\'ll also do is show
you a video to just give you a little feel for the high throughput idea
that they\'re doing.

And in particular, what I want to show you is how they\'re analyzed. In
other words, they\'re using robotics to make these things, but you also
have to do analysis. Let\'s say you want to make a new crystal
structure. How do you know that it\'s a new crystal structure or an old
crystal structure?

So what they\'ve done is they\'ve used Raman Microscopy to analyze
these, and I just thought I\'d show you this video rather quickly.

So the idea \-- if I can do this \-- so here you\'re looking at the
robot. It just takes the vial after all of these thousands and thousands
of things, puts it into \-- it\'s all done robotically, no people \--
puts it in here, puts it under the microscope. Here\'s the crystal.

Now this is real time, looking at Raman spectrographs. Then it takes all
of the data like this, mines them, and you see three crystal structures.
So all done real time, and this, I expect, is going to be more and more
what you could see in the future.

Well, does it make a difference? Let me just show you a couple of key
publications that Transform has just done. They took acetaminophen. I
think people are familiar with that. That\'s Tylenol, and they, by using
this approach because you could do it so much faster, so much better,
came out with the new crystal structure for Tylenol.

They did 10,000 experiments in three iterations in six weeks, published
in JACS last year. So that\'s one example.

An even more striking example is this one, which certainly the FDA
probably would be familiar with, Ritonavir. This was an Abbott drug.
Here\'s what happened in initially. Abbott launched this drug for AIDS.
It was originally in crystal form I, but 1.5 years after the launch, it
converted it into an unanticipated crystal form. Sometimes this happens.
Form II, but that form was 50 percent less soluble.

So Abbott obviously was compelled to recall and reformulate it. It cost
them hundreds of millions of dollars and so forth.

Using the high throughput approach, what did Transform do in just a few
weeks? Well, even though Abbott could never get Form I back, Transform,
since they were able to do tens of thousands of these, got Form I back,
got Form II obviously, also found three new forms that were never found
before. So characterized them, you know, and made them.

This was just published in PNAS just a couple of months ago. Again, an
illustration of what high throughput might be able to do for you.

So let me end the talk by telling you some even further future
challenges about what I expect, and I\'ve been trying to keep on time.
So I think some of the challenges which I\'ve begun to touch on,
they\'ll increase. One of the tremendously exciting things in the times
we live in are all of the new pharmaceuticals that are being made.

Certainly we\'ve had protein therapeutics for years, and yet there are
still very serious delivery challenges. Today there\'s still only, you
know, a few examples of the pegylated one and the neutropin depo where
you can deliver proteins, and I think that the opportunity for
delivering proteins is just huge, whether you could do it by controlled
release to make it last longer or noninvasively. That will be very big.

DNA, obviously we\'ve talked about that. Delivery is probably the
central problem, and so there needs to be a lot of \-- that\'s a big
challenge.

And there\'s even newer things that are coming out. People may be
familiar with RNA interference. These are really incredibly exciting
molecules. Our [Science]{.underline} magazine called them the molecule
of the year last year. These are very powerful, very specific units,
about 20 base pairs of RNA that can interfere with cell function.

Another big area, and this was mentioned actually in Mark McClellan\'s
introduction, is the delivery of cells. Could you deliver cells to the
human body to create new tissues, a field we call tissue engineering?

And finally, I think there is going to be deliveries to new locales. In
particular, one of the big areas I expect will be delivery to the back
of the eye, just picking this as an example, which is clearly going to
be critical because right now there are many new drugs that people are
developing for treating diseases like macular degeneration or diabetic
retinopathy, but the target is the retina, and these drugs, it\'s going
to be very hard to get the drugs back there.

So there\'s a number of companies developing approaches to deliver the
drug to the back of the eye.

I think there\'s also enormous opportunities in other areas of the body,
like could you deliver a drug to the nerves, for example to great herpes
or other diseases, and I\'m just really giving you \-- and probably
many, many others, delivery to the ears, i.e., you know, for children.
You could go on and on, but I think there\'s many great opportunities
and yet many challenges where drug delivery can make a huge difference.

That\'s largely what I\'d like to say to you today, but what I want to
end with is one of the things that has been a personal pleasure for me
is to be having been involved in the drug delivery field for now about
30 years. It has been wonderful to see the enormous progress that has
been made by so many scientists and so many people throughout the world
to the point where we see all of these kinds of therapies and many more
that you\'ll hear about today that are really relieving suffering and
prolonging life and obviously will do so more and more in the years to
come.

Thank you so very much.

(Applause.)

DR. FEIGAL: You did get us almost back on schedule, and we have time for
some questions.

DR. LANGER: Maybe it was very clear and people want to leave very much.

DR. FEIGAL: Yes.

PARTICIPANT: (Inaudible.)

DR. LANGER: So the question is what are my thoughts on personalized
medicine and individual therapy. Well, I think that that will come to
pass. I think that in the genomic era we will see examples, you know,
where we\'re learning more and more about individual people.

I think something like that microchip that I mentioned is a very
interesting example of where you could some day, you know, create like
this pharmacy in a chip for individuals. You know, maybe that would be a
pill or a patch in some form, but I think that that drug delivery can
make a huge impact in that area at some point.

Yes.

PARTICIPANT: (Inaudible.)

DR. LANGER: Would I like to speculate in the regulatory process?
Actually, you know, let me make two points on that. The answer is no,
but one thing I should \--

(Laughter.)

DR. LANGER: \-- but one thing I probably should have mentioned that I
think also could be interesting by these techniques is actually record
keeping. You know, I also think that when you do things by these kinds
of smart medical things that, let\'s say, it was a chip or something
else, that whenever somebody takes a medicine that you could actually
get a permanent record of whatever drug somebody gets and, you know,
have that transported to your computer so that that would probably be
useful information for the FDA as well as the patients and doctors and
medical companies to have.

It\'s hard to say. You know, when we deal with things like personalized
medicine, it\'s, at this point, easy to say things will happen. I think
you have to break it down into individual cases to say exactly what the
regulatory process would look like or should look like. I think it\'s
too diffuse at this point really for me or probably anybody to comment
on, other than to know that many years from now we\'ll probably see
something like that.

DR. FEIGAL: Well, let me thank you very much for coming and joining us
this morning.

DR. LANGER: It\'s a pleasure to see you.

DR. FEIGAL: Thank you.

DR. LANGER: Thank you.

(Applause.)

DR. FEIGAL: Well, continuing with our program and actually even with the
novelty of being a little bit ahead of schedule, our next speaker this
morning is David Klonoff, who is here from the Mills Peninsula Diabetes
Research Institute in San Francisco, talking about how these
technologies will have an impact on diabetes.

DR. KLONOFF: Good morning. I\'d like to thank Dr. Provost and the people
at the FDA for inviting me to come out from California to talk about
diabetes.

I\'m an endocrinologist. My topic today is novel technologies for
treatment of diabetes. I\'ll be discussing metabolic monitoring, the
artificial pancreas, and alternate routes for administering insulin.

This is where I\'m from, and this is the hospital that I work at in San
Mateo, California. I\'m editor of [Diabetes Technology and
Therapeutics]{.underline}, which is a journal that covers an area I\'m
very passionate about, which is new technology to help people with
diabetes, and through the journal we also organize an annual diabetes
technology meeting, and some of you in the room have attended that
meeting.

When I was asked to discuss new technologies for delivery of insulin, I
thought first that I would approach it from the standpoint of asking
three questions. First, with respect to insulin, why develop this type
of new technology?

What is the new technology?

And how good is the new technology?

So the first question I\'m going to address is why develop the new
technology. I think everybody knows that giving insulin through shots
hurts. It\'s even in the latest issue of [Popular
Mechanics]{.underline}. Certainly all of my patients know insulin hurts,
and basically that means that there are barriers to the use of insulin.

When I tell patients that they need to use insulin, they usually don\'t
want to go onto insulin, and I think that if we can discover some new
routes of insulin delivery, we can help overcome barriers to the use of
insulin for patients who really need this drug.

And some of these barriers now include the pain and trauma from being
pricked by an insulin injection needle, the inconvenience of carrying
needles, and also the risk of hypoglycemia from an inadvertent excessive
dose of insulin or hypoglycemia from rapid absorption of insulin.

So there\'s clearly room for new routes of insulin delivery. So the
second question is: what is the new technology? How can insulin be
delivered?

Well, I\'m going to be covering metabolic monitoring, as well as the
other topics. So first, metabolic monitoring.

This is the current status of metabolic monitoring in diabetes. First,
in terms of performance, the blood glucose monitors that are now
available require less blood than ever, less times than ever to get the
reading, and they provide more data management, better performance.

Second, they\'re greater options in terms of body fluids that are
tested. It\'s not just blood anymore. In terms of sites, it\'s not just
the fingertip anymore. And in terms of how automatic the readings are,
it\'s not just whenever the patient remembers to check themself anymore.

Finally, we\'re starting to see a trend in integration. There are two
themes in diabetes technology now. One is better blood glucose
monitoring. One is better insulin delivery. They\'re starting to come
together within products, within the same product.

And so what we see is that these blood glucose monitors are now being
linked to insulin delivery systems. So, again, the current status of
metabolic monitoring is greater performance, greater options, greater
integration.

I\'m going to discuss the performance. The current level of performance
of blood glucose monitors is that the blood volume that\'s required is
now as little as 0.3 microliters, which is about one tenth of the volume
that was required ten years ago. So we\'ve come an order of magnitude in
ten years.

Second, the measurement time. We can now get a reading in as little as
five seconds, which is also one tenth of the time that was required ten
years ago. This is quite a dramatic improvement in just ten years.

Finally, a typical blood glucose monitor can store up to 3,000 results.
This goes along with the issue Dr. Langer raised about storing data, and
this means that you can provide with this information mean blood glucose
levels over the previous one week, two weeks or four weeks, and this
type of data can now be downloaded into a computer or to personal
digital assistant.

That\'s performance. Next, as far as metabolic monitoring is the
options. What we\'re seeing now is that we have options that are
available on current blood glucose monitors, but we\'re seeing some new
options that are emerging that are starting to become available and will
become available in future blood glucose monitoring. These involve the
body fluid sampled, the sites that are sampled, and what I call the
automaticity, how often and how it\'s tested.

So where currently you\'ve all seen a blood glucose monitor, it\'s
invasive. It\'s jabbing the fingertip to get a sample of blood, and that
hurts also. People don\'t like that.

What we\'d like to see is more noninvasive or minimally invasive
technology, and it\'s coming. It doesn\'t have to be the fingertip where
all of the nerve endings are. People can now check blood glucose at
alternate sites, such as the forearm or the thigh. Fewer nerve endings;
patients are more likely to want to test themselves.

Finally, the glucose testing is not just intermittent, but it can be
done continuously, which means it does not require patient effort to
remember to check themselves. So I\'m going to cover each of these
options.

First, the non \-- minimally invasive, then the alternate site, and then
the continuous. So regarding noninvasive and minimally invasive
monitoring, first, I\'m going to define noninvasive blood glucose
monitoring. This is an area that all of my patients ask about: when is
it going to be here?

A noninvasive blood glucose monitor generates and processes optical
signals. It does not harvest body fluids, and it measures three
compartments when optical energy is put into the body. It measures
blood, interstitial fluid, and skin cells as a blended reading, and most
of the noninvasive monitors that are being developed are using optical
energy applied to the skin. There are a few that are applied to the eye
and instead could measure aqueous humor.

So what you see is you\'re applying an energy source, and it goes to
these three body compartments, the blood, the interstitial fluid, and
the intercellular fluid. They all reflect in some way, depending on the
property of optical energy that\'s being used, the radiation into a
detector, and you get a blended reading. And it\'s up to the engineers
to sort this out and figure out how much glucose is in each compartment
and whether there\'s any type of a lag between the reading that comes
back out of interstitial fluid or intercellular fluid relative to blood.

Now, when you apply optical energy, there are various measurable effects
of this light that can be measured, and it turns out that there\'s a
scientist or company somewhere that\'s using every one of these
principles of light to measure glucose, and part of the issue is finding
the right wave length and the right type of energy.

But I\'ve made a list of the measurable effects on light that glucose
can have. You can measure absorption of light or scattering, refraction,
Raman scattering, rotation, fluorescence, impedance, photoacoustic
heating, and there is at least one company working in each of these
areas.

This is a picture from my hospital of a patient who has given permission
to show his picture, having a noninvasive blood glucose test done. This
is a glucose clamp study where we keep the blood sugar constant by
infusing high doses of glucose and high doses of insulin, and then we
can keep the glucose level constant for a long period and make multiple
measurements. His right arm has three IVs in it. His left arm is on the
noninvasive monitor which is purposely not being shown in this picture,
but he\'s going to be here 12 hours for this study.

Now I\'m going to discuss minimally invasive blood glucose monitoring. A
minimal invasive blood glucose monitor means that the skin barrier is
disrupted, but not a blood vessel. So you\'re digging, but not all the
way into a blood vessel. So what you\'re measuring is either
interstitial fluid or some other extravascular fluid that\'s harvested
from skin.

It turns out you can measure some type of a diluted interstitial fluid
or real interstitial fluid. You can make a reading either
intermittently, if you sort of drill intermittently, or you can leave
the sensor under the skin, and then you can read a continuous reading.
You can either pull the interstitial fluid out so that it will harvest
it, so to speak, and measure it after it is out of the body, measure
continuously, or you can leave a sensor under the skin and measure it
continuously in the body.

There are a number of ways of pulling interstitial fluid out of the
body, different types of ways of disrupting the skin so that you can
measure the glucose concentration of the interstitial fluid, and it
turns out in most cases that the interstitial fluid glucose
concentration and the blood glucose concentration are very similar. Now,
they\'re not always the same, and that\'s a subject of research in
itself, but they\'re often about the same, and that\'s just the first
approximation.

So these are some methods that are being used now to pull out
interstitial fluid. You can apply current, and that method is known as
reverse iontophoresis. You can apply laser to drill a hole, in effect.
That\'s called microporation. You can use ultrasound, such as what
Santra Medical is using. We saw a picture of that. That\'s referred to
as cavitation, creating a space between cells and the interstitial fluid
sort of comes up to the surface.

You can puncture the skin with a very fine needle. You can abrade the
skin surface with powder. You can dissolve the lipid barrier of the skin
on the surface with chemicals. You can apply very strong suction or you
can penetrate the skin with a fiber optic filament. And these methods
are all ways of disrupting the skin, but not going so deep as to draw
blood.

This is the last method that I mention. This is a technology that we\'re
about to be testing at Mills Peninsula Health Services in which you have
a fiber optic filament that\'s inserted to measure epidermal
interstitial fluid glucose, and this method just stays in the epidermis
and through an optical fluorescent reaction on the surface. You actually
send light down the needle it fluoresces according to how much glucose
there is, and you\'re measuring the fluorescence within the needle.

Okay. I\'ve talked about one type of emerging option, which is
noninvasive and minimally invasive monitoring. Another option that\'s
available for patients now is alternate site blood glucose testing.

This is one of my patients about to do violence to herself, and imagine
if you had diabetes and you had to check yourself four times a day, or
maybe even seven times a day. This would really be a drag.

Imagine if you could check a blood sugar, but you didn\'t have to use
your fingertip, if you could go to a place where it just doesn\'t hurt
as much. That\'s known as alternate site blood glucose testing.

The status is now that five of the six major manufacturers have products
approved for alternate site by the FDA, and I know that the sixth
company is working on it, and we\'ll probably hear something from them
any time. So basically I expect that at least five, probably six of the
six will have products approved by the FDA.

Clearly there\'s less pain than a fingertip site. As far as when is it
okay to check an alternate site, there\'s a question of the lag for two
hours after meals and during hypoglycemia, which means that as the blood
sugar is rising and you know it\'s rising if you do fingertip blood
glucose levels, it doesn\'t rise as quickly from the alternate site.

So if you check the blood sugar at the route of the alternate sites,
using the forearm or thigh, within the first two hours you might think
it\'s not as high as it really is because of this lag. So most of the
products that are approved for alternate site recommend that you just
not test the alternate site within two hours of a meal.

Most people with diabetes aren\'t checking themselves within two hours
after a meal. So it doesn\'t affect their lifestyle, but they might. A
pregnant woman would frequently check during this time frame, and she
should not use the alternate site if she\'s testing within two hours and
if the product says not to test during that time period.

There\'s some thought that agitation \-- I actually went to college at
Berkeley. We know a lot about agitation there. Does agitation correct
the problem?

Well, they don\'t mean here protest marches, but actually rubbing really
hard so that the skin actually becomes warm and red. There\'s some
question that this may improve the blood flow in the forearm so much
that that could eliminate the lag. So this is being studied, and it
could be that the lag will be less of a problem.

This is one of the first people in the world to have an alternate site.
He\'s one of the first 50 people. He\'s one of my patients who also gave
me permission to show his picture here today, and as you can see, he\'s
not really sure if this is going to work out, but he\'s being tested on
the forearm.

This product is so historic in the field of alternate site testing it
has actually already been on the market and gone off the market, but
this is the first alternate site blood glucose monitor. It was called
the Atlast by Amira Medical, and Amira Medical was later purchased by
Roche Diagnostics, and one of the things Roche did was take this product
off the market.

But this is the beginning of an era of alternate site testing.

Now, the next option that has become available for patients is
continuous blood glucose monitoring. There are four products that one
can use in the world for continuous blood glucose monitoring or
continuous glucose monitoring. Two of them are available in the United
States and Europe, and the other two are available only in Europe and
are not FDA approved for use in the U.S.

These are the products, and I\'m going to say something about each of
them. Starting with the continuous glucose monitoring system and the
Glucowatch, the Glucoday and the Pendra.

So first, the continuous glucose monitoring system which has recently
been upgraded to a second generation product. Now it\'s known as
continuous glucose monitoring system gold And this is manufactured by
Medtronic MiniMed in Northridge, California, and it consists of three
parts.

First is a sensor that goes under the skin, and it can sit there for 72
hours in the subcutaneous tissue. There\'s a little wire from it, and
this wire is connected to a monitor that stays out of the body. It looks
like a pager, about the size of a pager, and that stores the data. It
stores the data but does not project the data in real time, just like a
24-hour Holter monitor stores the heartbeat data but does not tell the
patient what the heartbeats are at that time. And it could be, in future
generations we could see real time data, but what\'s on the market at
this time is more like a Holter monitor.

And then you can take this monitor and put it into a docking station,
and then link it to your PC to download the data, and what you get is a
picture that looks somewhat like this, which each color throughout the
day is a blood glucose level, and what you look for is certain times of
the day when there\'s a pattern when things look really high, like maybe
at this time of day here, or maybe when they look really low, like
around this time of day here.

And thanks to some technology that has to do with smoothing, Medtronic
MiniMed has recently found a way to connect the lines at midnight so
that there\'s less of a disparity.

Next I\'m going to talk about the Glucowatch G-2 biographer. Glucowatch
is well known among diabetes circles. We\'re on our second generation
device now. This is what it looks like.

It could be useful for a person at night because it has an alarm to wake
them during hypoglycemia. This is manufactured in the county I live in,
San Mateo County, by Cygnus in Redwood City.

So what you see here are three types of input. This device tells you the
time, which is in green. It tells you the blood sugar level, and
there\'s a trend arrow, and this trend arrow to me is a nice idea. It\'s
really easy to make, but what you see is if your blood sugar is sort of
borderline, and it\'s on the way down, it\'s really important. Now
you\'ve got to eat or take some action, or conceivably if your blood
sugar is high and it\'s on the way up, it\'s time for some extra
insulin.

I should point out that under the terms of this product being cleared,
it\'s not cleared for use such that you can take the blood sugar reading
and act upon it. For example, if you see a 110 and your doctor has said
when the blood sugar is under 120 you\'ve got to eat and you\'re seeing
110, does that mean now you should eat because the doctor said under 120
you should eat?

No, because the terms of the clearance, what\'s said, is that this
information, if you\'re going take some action based on the reading, you
have to go check yourself with the traditional blood glucose monitor and
use that information to decide what to do.

So it tells you, in effect, if the number looks alarming that it\'s time
to check yourself with the traditional blood glucose monitor. I think
this was possibly a step to give a patient an extra measure of safety
because this is an early device that measures glucose in a
nontraditional way, and by putting in this extra step, if for some
reason the device was not giving you an accurate reading, you\'re still
protected because you\'re going to go out and do a traditional blood
glucose reading.

Here\'s how it works. This is a cut-away. On the face you have a display
unit in purple. Now we go to the bottom, and what\'s happening is that
the electrodes in yellow create an electrical current. The current pulls
salt from the skin toward the surface. The salt carries water that\'s
dissolved, and water carries glucose that\'s dissolved within the water.

So what you\'re pulling up, in effect, is a diluted form of interstitial
fluid. The glucose is trapped in these glucopads, also known as
autosensors, and a chemical reaction occurs with the biosensor, and you
get a glucose reading.

The way this device operates is there\'s a two-hour warm-up. You put it
on and it gives you no readings. Then after the two hours you still need
to do a single calibration every 13 hours, which is how long it lasts.
That is, you get readings for 13 hours. It will deliver six glucose
measurements per hour that you can read. So every ten minutes it gives
you a reading. It has a programmable alarm for panic values, such as
that woman who was sleeping. If the blood sugar gets below a certain
level, it will make a noise and wake her up.

Excessive sweat cuts off the measurements, and it uses a triple A
battery every 13 hours. This is a product that\'s approved in Italy.
It\'s a continuous glucose monitor known as Glucoday. It uses a
principle called microdialysis in which interstitial fluid is sort of
rinsed, and the fluid that comes out contains glucose and using a
proprietary formula, the concentration of glucose in this rinsed fluid
is supposed to be proportionate to glucose in the interstitial fluid,
which is supposed to be proportionate to blood glucose.

Another product which recently received clearance in Europe is the
Pendra. This is an interesting device by Pendragon Medical in
Switzerland. This is actually a noninvasive monitor. So there\'s no
fluid. The skin doesn\'t become wet underneath, and it uses a method
known as radio frequency impedance, and it sends a radio wave to the
blood.

And it turns out that, according to the Pendra, that if the blood
glucose level changes, that changes the shape of red cells, and that
changes the dialectric properties of red cells and changes the
impedance. So they\'re measuring glucose indirectly by this method.

I made a list of some other promising technologies for implanted, either
minimally invasive or invasive, monitors that will be used as continuous
sensors in the future. I think any one of these on the list could be the
next continuous sensor that we\'re going to see.

And the type of signal that they read generally is either an
electrochemical signal, such as an enzyme sensor under the skin, or it
measures optical energy.

So when we go through these, I see first you can have a microdialysis
catheter subcutaneously. That\'s what the Glucoday uses, and recently
Roche Diagnostics has announced that they\'re very interested in this
type of technology as well, microdialysis.

Viscometry is a method in which you\'re rinsing interstitial fluid out
as you would with microdialysis, but there\'s sort of a catch to it, is
that you\'re using a solution that contains dextran and Concanavalin A,
and in effect, the higher the glucose concentration, the more glucose
will be pulled off the dextran onto the Con A, and the viscosity is
less, vice versa.

So, in effect, high glucose is low viscosity. Low glucose is high
viscosity, and that\'s a viscometry method. This method has been
developed by Disetronic in Switzerland, and Roche Diagnostics recently
acquired Disetronic, and we\'ll see what happens to viscometry.

Another method could be to implant a Fluorophore, an agent that
fluoresces under the skin or put a tatoo under the skin and then you
interrogate this agent with light. That could be a continuous monitor.

And there\'s a company near here in Germantown, Maryland, called Centers
for Medicine and Science, that\'s working on this technology.

You could use an enzyme tipped catheter implant, which is essentially
what the continuous glucose monitoring system gold uses, and there can
always be a new generation by Medtronic MiniMed or some other company,
and this could either e a subcutaneous device or an intravenous sensor,
and here again Medtronic MiniMed is working on one and so is Animas in
Pennsylvania.

And Animas\' method is using a near infrared spectrophotometer
intravenously, which is pretty interesting. The idea is that you\'ve got
a noninvasive type method, which is shining light, but they actually
have the light and the receptor so small and so close to each other that
they could implant that as a unit into a blood vessel.

Okay. The last area where there are more options in terms of metabolic
monitoring are integration. I can tell you at the American Diabetes
Association meeting, which was in New Orleans last month, for the first
time I was struck by a trend which is integration between blood glucose
monitors and insulin delivery systems.

People are talking about it, but it was everywhere you looked at the ADA
meeting.

Now, there\'s two kinds of integration. There\'s the mechanical
integration where two different systems are located next to each other,
but they don\'t necessarily work together, but even more important is
functional integration where they actually function together.

Now, the first mechanically integrated system was known as the InDuo,
and when it came out, the manufacturers, Novo Nordisk, which is an
insulin company and Live Scan, which is primarily a blood glucose
monitoring company, asked the question, \"How did you manage before
InDuo?\"

And they showed this mess of stuff that you have to deal with because
now they came out with the first ever \-- I insert the word
\"mechanically\" \-- integrated blood glucose monitor plus insulin
delivery system, but there\'s no sharing of data. This looks like a
blood glucose monitor on the outside, but it\'s a shell. When you lift
it up, it contains an insulin delivery system, which is basically a
fancy pen system for delivering insulin.

So it contains both, but there\'s still just two things that are linked
together. They don\'t necessarily work together.

The second mechanically integrated blood glucose monitoring plus insulin
delivery system was created by BD. They call this the Latitude diabetes
management system, and this system contains various features that a
person with diabetes would need, a glucose monitor; this is in
millimoles per liter, not milligrams per deciliter, and it contains a
lancet, and it contains an area where you can put a pen.

So here, again, these are mechanically integrated, but not functionally
integrated. Now we\'re getting into functional integration, and these
are four recent alliances that I\'ve become aware of \-- just some of
them recently, some of them still not very long ago. I\'ve listed them
from top to bottom according to the size of the insulin pump company.

Medtronic MiniMed is the largest insulin pump company, and they\'ve
recently formed an alliance with BD, which is a blood glucose monitoring
company.

The second largest is Disetronic out of Switzerland. They\'ve recently
not just formed an alliance, but been acquired by Roche diagnostics.
That\'s definitely an alliance.

The third largest, Animas from Pennsylvania. They formed an alliance
with Lifescan.

And then the fourth largest, which is pretty new on the market in
insulin pumps is Deltec in Minnesota, and they formed an alliance with
TheraSense.

I\'ll say a little bit more about what each of these alliances consist
of. This slide was stamped on the upper right corner \"FDA Clearance
July 7th, 2003.\" So as Dr. McClellan stated, we now see that here we
have FDA clearance for a combination product which is a blood glucose
monitor developed by BD and MiniMed called the Paradigm Link Monitor.
Here\'s the person sort of on the run holding their blood glucose
monitor, and by radio it sends a message to the insulin pump that the
person is wearing, the Medtronic MiniMed Paradigm 512 pump.

So now for the first time you have an FDA approved combination product
which is functionally integrated. The glucose level is projected into
the pump.

Medtronic MiniMed then took it even one step further in terms of
integration, and they created a type of software which they say does \--
they call it diabetes math. It tells you based on \-- you know what\'s
your blood sugar now, and it tells you there. You know what you want
your blood sugar to be. You program that in. You know what you\'re about
to eat. The device is pre-programmed with how sensitive you are to
insulin and how sensitive you are to calories.

And with that information, as well as one other factor which is how
recently did you take some insulin, it will tell you what type of a
bolus of insulin you need to get your blood sugar down to this target
level.

And they actually did a study which they published in [Diabetes
Technology and Therapeutics]{.underline} in June where they took some
experienced people with diabetes and said, \"Okay. You must know how
much regular insulin to give yourself at a meal, and so half of them,
use how much you think you should use. The other half, don\'t use what
you think you should use. Use what our diabetes math formula tells
you.\"

And it turns out that the control was exactly the same, but from the
standpoint of the manufacturer, that was a good thing because there are
a lot of people with diabetes who aren\'t so experienced and have a lot
of trouble figuring it out, and the machine \--the software\-- did as
well as what an experienced person could do. So that\'s a promising sign
as far as integration goes.

Now, Disetronic and Roche, what do they have planned? This is a part of
a press release on May 2nd, after we see the Roche acquire Disetronic.
By combining the two businesses, Roche will be able to offer
comprehensive diabetes management solutions from blood glucose meters
for self-monitoring to sophisticated, programmable insulin pumps that
allow patients to continually administer insulin doses according to
their individual needs.

So to me this sounds like they are getting ready to integrate their
pumps and their glucose measurement systems.

Now, Animas and Lifescan. I\'m not sure exactly what they\'re doing
together, but I can tell you that each company has a link to the other
on their Web site and to no other diabetes company. So that tells me
something is going on.

Finally, Deltec and TheraSense have created a product which is not FDA
approved, but people form both companies are optimistic, and what you
have here is an insulin pump made by Deltec and then clipped over it,
this basically just looks like a little holster or clip. It\'s actually
a TheraSense Freestyle blood glucose monitor.

So we look at this from the front and from the back. So one thing that
TheraSense is good at doing is creating blood glucose monitors in
different shapes, and they have created a monitor that basically looks
like a clip, and you stick the strip in the bottom of it, and you get a
reading here.

So I\'d say from a design standpoint this is a nice integration of a
glucose monitor and a pump. It looks and feels as if it\'s one unit.

Okay. The next topic I\'m going to talk about is the artificial
pancreas. Now, we don\'t have an artificial pancreas on the market yet,
but I\'m going to tell you what the artificial pancreas will look like
in a broad sense when it is available.

First, it will contain a continuous sensor. It will contain an insulin
delivery system, which you can think of as a pump. There will be a
controlled processor which receives a glucose signal and then uses an
algorithm to drive the pump. That links the glucose measurement with the
insulin delivery, and then there will be a radio that will first link
the sensor with the insulin delivery system so that it knows how much
insulin to give and with an external monitor so that the patient will
know what their blood glucose level is at all times.

This is a potential candidate to become an artificial pancreas. They
still have a lot of work to do, but this is the Medtronic MiniMed
long-term implanted sensor pump or sensor and pump system. This round
system is an insulin pump. It\'s implanted in the abdomen, and you see
the different parts of it.

At the tip of it is an insulin delivery catheter, which would be way out
here. It\'s a little bit cut off, and then it\'s also connected to an
intervascular glucose sensor here. So this device is put in the abdomen.
The tip of the sensor goes into the peritoneum, and the peritoneal
delivery of insulin has some advantages because it goes right to the
liver, and the other end of it is an intravascular glucose sensor
that\'s intended to stay in the superior vena cava for a year. So
that\'s one way, but there\'s other ways.

An artificial pancreas could contain an external insulin pump. The
insulin could be delivered subcutaneously, and so there\'s different
combinations, but there are some problems that have to be solved in
order to have a successful artificial pancreas, and each component has
problems. The continuous sensor, for example, will have calibration
drift. There has to be some way of recalibrating regularly. When you put
a sensor in, you can\'t just leave it.

You can have a lag between dynamic changes in blood glucose and
interstitial fluid glucose if the sensor tip is not in a blood vessel,
but in the skin, and the majority of artificial pancreas systems that
are being developed have the sensor in the skin.

There can be lag. There can be fouling of the sensor. There can be
immune rejection or fibrosis of the sensor so that the body forms a
capsule around it, and then it\'s not reading true interstitial fluid
but just some kind of altered fluid that\'s within the cap. And there\'s
local complications.

Insulin delivery in an artificial pancreas could have some problems,
namely, nonphysiologic response to elevated blood sugar. There are some
other stimuli that affect insulin beside glucose, and the current
artificial pancreases are not really taking that into account.

Insulin can be denatured if it stays in the body, which is nice and
warm, for three months at a time. There\'s systemic complications, and
there\'s anesthesia and surgical risks of putting it in and taking it
out.

And then additional problems with the artificial pancreas is that you
just can\'t have hypoglycemia. You\'re the manufacturer. Your algorithm
must protect against severe hypoglycemia or the patient is going to get
sick and sue. There could be product recalls. A lot of bad things could
happen.

So you have to run the sugar a little higher than you need it, and yet
the whole idea of an artificial pancreas is to keep it normal.

Currently the artificial pancreas is being developed to treat low blood
sugar because it\'s so important to avoid low blood sugar means that in
effect you\'re going to have more high blood sugar than you want, and
then finally there\'s the economic impact of improving control from
current levels to better levels with the artificial pancreas is unknown.
This can be very expensive. It\'s not clear who\'s going to pay for this
technology.

Another device that\'s being developed is a bioartificial pancreas, and
this is a device that would substitute for an endocrine pancreas, but
instead of being purely bioengineered, it contains synthetic materials
and functional islet cells that are encapsulated within a semi-permeable
membrane to protect them from immune rejection.

So within the membrane, glucose comes in. The eyelet cells see it. They
figure out how much insulin to make. The insulin goes out, and this
membrane protects the eyelet cells from being destroyed by antibodies or
lymphocytes. The results look good in rodents, but we don\'t have good
results in larger animals or in humans.

We need better immunoisolation to protect these cells. Every year I go
one year further out. So you come back next year and it will say 2009
maybe, and it\'s certainly going to be expensive, about \$20,000 a year.
I\'ll show you a picture of an artificial pancreas.

This is produced by a company in San Francisco called Islet Sheets
Medical. We\'ll look at a liver, a dog liver, and on it is this sheet,
and within the sheet there\'s a little cuff that\'s dark, and then this
sort of milky white square. This milky white square are islet cells, and
this sheet was sutured to the liver in a pancreatectomized dog in the
hope that these eyelet cells would protect it from hyperglycemia.

Unfortunately in this particular experiment the sheet fell off. The
sutures broke, and they don\'t know why this tends to happen. So that\'s
a problem they\'re working on.

The last area I want to discuss is alternate routes for administering
insulin. Dr. Langer covered some alternate routes for drugs in general.
Insulin has some areas that I think are, I think, interesting.

Some promising technologies include inhaled, oral, buccal, nasal,
transdermal, all of these ways of getting insulin into a person other
than with a needle.

Now, here\'s why inhaled insulin looks promising. If you give a person,
say, in the hospital intravenous insulin, which is red here, what
happens is it gets in very quickly. You want rapid action.

If you give the person subcutaneous insulin, which is yellow, it lasts
for a long time. So that can be good in some situations.

If you give inhaled insulin, what tends to happen is you get rapid
absorption of insulin so that what you\'re seeing is similar to IVs. So
it gets in quickly the way IV insulin gets in, and it lasts for a long
time the way subcutaneous insulin lasts. So in theory inhaled insulin
would be very useful for people, especially at mealtime.

Now, I\'m going to show you what the system looks like from what used to
be called Inhaled Therapeutics, now known as Nektar. I was an
investigator with three of their trials that they did with Pfizer.

This is the lady taking out the device. It looks like an asthma spray
device, but it\'s a little bigger. She\'s putting in an insulin-like
little sheet. This is powdered insulin, and there\'s a bubble that\'s
going to go inside the device. So she\'s putting that in.

Now she\'s sort of getting the trigger pulled back, and when she pressed
the button it\'s going to fire. She\'s turning the mouthpiece. It\'s
going to be facing her, and now she\'s firing the trigger, and what\'s
happening now is that the blister of insulin is ripped. Air comes in,
and suddenly disburses the insulin into a cloud, and now you see a cloud
of insulin. This is correct. It\'s white. They call this a standing
cloud. It\'s inhaled insulin, and she\'s inhaling, and in just a moment
it has gone clear. I\'ll show you that again.

Here it is, a cloud of insulin. It\'s clear. Where did that go? It went
into her lungs. So that\'s inhaling dry powdered insulin.

Now she\'s finished. She puts the two cylinders one on top of the other
and puts it away. So that\'s one way of delivering inhaled insulin.
She\'s all finished.

Another way is being developed with liquid insulin. This is by a company
\-- I should say Inhaled Therapeutics, Inc. is in San Carlos,
California. This is being developed by Aradigm, which is in Hayward,
California. This is a first generation device. This is a second
generation device with liquid insulin.

They\'re putting a blister in here. The insulin blister strip is
inserted. Now you rotate this mouthpiece, and a pin punches the blister
strip, and when the person inhales, they\'re getting an aerosol of
liquid insulin.

This is a third generation device by Aradigm. They call it the AERx
pulmonary drug delivery system. In that you\'re going to have buttons
and a mouthpiece and a screen.

But an interesting feature here is this green light. This is the breath
control guidance light. Here\'s why this is important. In order to make
inhaled insulin work, to get it into the alveoli where you want it and
not have it land in your mouth or in the trachea, you have to breathe at
the right speed and without turbulence. It has to be even and at the
right speed. If you breathe fast and jerk, it\'s going to go too fast
and it won\'t get into the alveoli.

So people are trained to breathe properly, and the idea of this device
is as the manufacturer claims, that only if you\'re breathing the right
way will it fire and deliver the insulin, and if you\'re the patient,
you don\'t know whether it fired or not. You can\'t even taste it. So if
you see a green light, you know you got your insulin. If you see a red
light, you have to take another dose until it gives you a green light.

This is a method known as PDC Technospheres. This company has been known
as PDC, Pharmaceutical Discovery Corporation. Recently it has been
acquired by Mannkind. Now these are Mannkind technospheres. We\'re about
to do a Phase II trial at Mills Peninsula on these spheres.

This is an interesting technology. You take fumaric acid. You polymerize
it, and you form a shell around powdered insulin. You get an insulin
loaded Technosphere, and the fumaric acid was selected because at the pH
of alveolar air it melts, turns into liquid, and now the insulin is in
the alveoli. It gets absorbed. Fumaric acid is absorbed.

And according to what the company has told me, that the fumaric acid is
not toxic, and so they found another way of delivering powdered insulin
to the alveoli. This is what their inhaled device looks like.

Another method that actually Dr. Lander is associated with, I\'ll just
say a word about it, is Alkermes\' air particle. This is an interesting
particle. You want an aerodynamic diameter of one to five microns if you
want this powder to be absorbed. This particle has a larger geometric
diameter, five to 30 microns, but it\'s very fluffy. It\'s looks like a
flower, and it functions as if it has the small aerodynamic diameter,
and this device uses an inhaler air dispersion chamber which delivers
porous powders.

And they\'re working with Eli Lilly, and one of the scientists form
Lilly showed me this device at the American Diabetes Association meeting
a couple of weeks ago, and he put in like an empty capsule into the cap
and he started breathing, and it sounded as if there was something wrong
with his hygiene.

But as it turned out it wasn\'t his hygiene. It\'s this capsule is
designed to rotate around. The cup that it\'s in is slightly eccentric
and as it rotates, it spins off the insulin. So it\'s designed that way,
and they seem to be making good progress with this technology.

This is the last company I\'m going to mention, Aerogen in Sunnydale,
California. The Air Alkermes is in Massachusetts. They were in the air
inhaled insulin business. We did a user study for them, but they
recently announced in December that they\'re going out of the inhaled
insulin business. They\'re just going to work on inhaled drugs other
than insulin but use a Piazo electric effect that, in effect, shakes
insulin, and it sprays out.

Okay. Now, oral insulin. Oral insulin would be very attractive. No
needles. People are used to pills. Why can\'t insulin be needles or why
can\'t insulin be pills?

Well, if you can have an oral insulin, you would need to avoid the
acidic degradation of the stomach, the enzymatic degradation of the
intestines, but preserve the potency of the insulin molecule. That\'s
the challenge.

So three different solutions have been proposed. One is to conjugate a
low molecular weight polymer to the insulin to preserve adequate
activity and resist digestion. That\'s what Nobex Corporation is doing.

Or you can have a delivery agent that carries intact insulin into
intestinal cells as Dr. Langer showed. That\'s what Amesphere is doing,
or you can PEGylate \-- that means conjugate with polyethylene gylcol
\-- the molecule and then create a micelle with Casein, and this will
increase transport to the gut epithelium.

This is an example of the polymer where you\'ve put a polymer onto
insulin. This is an example of how you have a delivery agent mixed with
insulin. You\'ve just got a plain, old pill, and this is an example of a
calcium phosphate insulin that has been pegylated and you\'ve formed a
micelle, and basically because you have a casing coating around these
little blue insulin balls, this means that you can pass through the
stomach of the intestine, and it sort of falls apart. It stays intact in
the stomach, but it falls apart in the intestine, and then because it
has been pegylated, it can get into the small intestine.

Here\'s buccal insulin delivery. It looks like you\'re spraying it into
the \-- as if you\'re inhaling it, but actually you\'re not. You\'re
aiming at the buccal mucosa here. It contains permeability-enhancing
agent. It gets absorbed very rapidly just like we know nitroglycerine
from buccal mucosa gets absorbed rapidly.

Nasal insulin requires dissolving insulin with some type of calcium
carbonate, and there\'s different forms of calcium carbonate.

Finally, there\'s transdermal routes of injection, that is, getting
insulin to the skin without a needle. You could use a jet injector or a
patch or an implanted chip, which you\'ve seen, or micro needle.

This is the Med Ejector Vision. We\'ve done a study on this one at Mills
Peninsula Health Service. The ideas are injecting the insulin not as a
puddle, but as a spray, and that perhaps the insulin can get absorbed
more quickly than if it was injected by a needle. That\'s being studied.

This is using encapsulation systems with an ultrasound to break the skin
cell barrier. This is similar to what Santra Medical is doing. This is a
company called Encapsulation Systems, Inc., in Pennsylvania.

This is using the MicroCHIPS technology, which Dr. Langer discussed and
showing how this could be applied to insulin. Each of these pyramids
here, which are sort of small, here you see blown up in this case
contains insulin, and when you put the right charge on it, the gold cap
in the presence of a high concentration of electricity just blows off,
and now the contents, which are here, this spray, the insulin, are
strayed into the body.

So a person could program how much insulin they need with a wristwatch
or you could use different kinds of microneedles. This is a human hair
to show that micro needles are not much different in size than a hair.
This is a 25 gauge needle, which you think of as small, but it\'s
massive compared to these microneedles.

And this is one other type of device which uses a microneedle, and it\'s
so small you can\'t even touch the needle. So you program it with a
wrist watch.

Okay. the last question I want to ask now that I\'ve shown you all of
the different toys that we endocrinologists have to work with is, how
good is the new technology, and there are three types of questions that
I think should be answered with new technology.

Is the patient receiving the desired dose? Is the innovatively delivered
insulin safe? And is the innovatively delivered insulin effective?

So regarding the dose, if you have a blood glucose meter determining the
insulin dose, is that really the amount that\'s needed by the patient?
We need to be sure.

Also, is this innovatively delivered dose predictable and consistent?
People want the same amount every time. Is this innovatively delivered
insulin lost to the environment? And if so, how much is lost?

And is absorption of the alternately administered insulin predictable
and sufficient?

These alternate routes tend to not have as good bioavailability as
injection. It all gets in. If you give it by mouth or by nose or by
inhaled, only a small percentage gets into the body.

Safety. Is there local toxicity of the innovative insulin delivery
system? Is that system itself irritating to the body? Are there immune
problems? Is the insulin itself causing local toxicity? Could it even be
causing cancer because it\'s a growth factor?

And finally, effectiveness. Is the bioavailability of this alternatively
administered insulin, is it adequate and consistent? Is the availability
affected by common environmental factors, such as perhaps inhaled
insulin? Could it be affected by a person with asthma or smoking?

Do the pharmacodynamics and pharmacokinetics resemble subcutaneous
insulin, and are both types of doses, bolus, which is short acting, and
basal, which is continuous dosing options, available for the patient?

So I raise some questions. I\'m going to show you how one man\'s
approach to this, and this is Dilbert. This next to the last slide shows
innovative technology according to Dilbert, and here Dilbert is getting
a report.

The new product brochures have already won design awards. Dilbert is
going, \"That\'s great, but our product won\'t do any of the things you
claim here.\" I wonder who says that all the time.

\"Well, who should we believe, the award-winning designer or the guy who
can\'t stop complaining?\"

(Laughter.)

DR. KLONOFF: So in conclusion, regarding new technologies for innovative
insulin delivery, improved metabolic monitoring now allows improved
bolus dosing. Continuous monitoring will allow improved basal dose
adjustments. Closed loop artificial and bi-artificial pancreas systems
are coming, and new routes of administration will remove barriers to use
of insulin.

And if we do these things and have better methods for delivering
insulin, then all of our patients will have better glucose.

Thank you very much.

(Applause.)

DR. FEIGAL: Well, thank you.

Our next speaker, changing topics, is going to take a look at the
emerging techniques and technologies for treatment of solid tumors. Dr.
Jonathan Kruskal from Harvard University.

DR. KRUSKAL: Dr. Feigal, colleagues, I, too, would like to thank the
organizers for inviting me to participate in today\'s seminar.

One hat I wear is that of an interventional radiologist performing
minimally invasive tumor oblations in solid human organs, and I\'d like
to share with you this morning in the time remaining some of the
exciting emerging new techniques and new technologies that we are using
both in the laboratory and already in the clinical setting.

Some of the challenges that we face in a daily basis for treating solid
tumors include, first of all, vector engineering. How do we optimally
take drugs or genes to get these to a site in the body for optimal
efficacy?

Secondly, how do we deliver these? What are the options available to us
as interventional radiologists that allow us to deliver drugs or genes
into solid tumors in pretty deep cavities of the body?

What you\'ve heard so far this morning are the transdermal, the
inhalational. They\'re pretty superficial ways of delivering drugs in
genes, but in the real world setting with solid tumors, you really need
to get deeper, and image guidance provides us with opportunities to get
needles pretty deep into the body and to deliver locally.

And finally, how can we inhibit efflux? It\'s all very well dropping the
payload into a tumor. It\'s all very well trying to enhance uptake of
that payload into a tumor, but if we just leave it, it\'s simply going
to be washed out or metabolized, and we need to see what options are
available to us now in terms of inhibiting efflux of drugs out of solid
tumors.

What I teach our fellows in residence in terms of drug delivery into
tumors is ways of an approach to enhancing the payload efficacy, and the
way we would like to look at it is simply how do we deliver drugs. How
do we deposit these into tumors? How do we get these to be detained
within the tumors? And how can we ultimately destroy these tumor?

Some of the innovative techniques that we\'re now using for treating
solid tumors can be categorized either into the intervascular area,
interstitial treatments and efflux inhibition, and I\'ll go through all
of these in the remaining time and show you what we are already doing
and how some of these can be approached.

Well, let\'s start off with payload with efficacy. How can we look at
the new strategies available to us in terms of delivering drugs with
genes into tumors?

These tumors on the left, you can see this is a typical conventional
delivery of drugs into liver tumors. This is a catheter inserted by the
groin all the way up the aorta into the hepatic artery supplying the
liver, and you then deliver \-- you can see these lines over here of the
pacified arteries going into the tumor. You can deliver drug into these
large round liver tumors. This is drug that we on a daily basis deliver
in a poppy seed oil extract called ethiodol, which is a depo delivery
system for enhancing retention of drug in these tumors.

We can image this. We can see exactly where the drug is going. We can
look at the efficacy of the drug in terms of serial CTOMR to know if a
tumor is being made any smaller.

But what we don\'t know at this point is, in fact, is the drug getting
to where we want it, and on this complementary electromicrograph, you
can see this small lipid particle, this liposomal aggregate which has
got into the tumor cell and is actually adjacent to the cell nucleus.

So what are the ways that we can do right now to enhance delivery both
from delivering it in an endovascular route all the way into the nucleus
of the cell to effectively get the treatment we want?

Well, let\'s look at some of these ways. Catheter design. There are some
remarkable new advances in terms of catheter design for delivering
drugs. We will be hearing a little bit later on today about some of the
drug-eluting stents. These right now are primarily for cardiovascular or
angiogenic type treatments, drug eluting stents or other deliver
chemotherapeutic agents, those that will prevent stenosis. We are
putting stents into livers to, in fact, prevent portal hypertension in
patients with cirrhosis.

But what\'s equally important is to deliver drugs into the wall of these
stents that will prevent these from occluding and allow these patients
to continue living good quality existence.

We are currently seeking further oncologic applications. These are
minimal right now, and I\'m sure there\'s a huge amount of opportunity
for oncologic applications of these drug-eluting stents.

Intervascular circled [in vivo]{.underline} bioengineering, which is
where genes are delivered into endothelial cells via catheters. The
catheters are inserted into specific vessels in the body. You can then
implode. You can drive these genes into the cells lining the vessels,
endothelial cells, effectively to create, for instance, a situation
where these blood vessels will not be blocked off.

And, once again, we have not taken adequate advantage of the entire
field of angiogenesis. Right now in tumors a lot of the theory behind
tumor treatment right now is unblocking the blood vessels, destroying
the blood vessels to the tumor.

But a lot of the patients we see, again, on a daily basis, the minute
the blood vessels have been knocked out supplying the tumor, it
effectively takes away a lot of the options we have for treating these
tumors. Since we are delivering a lot of drugs via the vessels by
blocking these major vessels going to the tumors, we\'ve effectively
taken away several major options for our patients, which is not an
optimal situation.

So there are ways of taking advantage of angiogenesis to find a nice
match between the two.

This is two examples I\'ve taken from an article of John Thomas in
radiographics in 1998, and these are types of catheters which are being
developed now for drug or gene delivery. You can see over here this is
simulated vessels. Two balloons are blown up in this catheter, and you
can then perfuse a drug or gene mixture in the vessel to allow it to
deliver into the endothelial cells.

More exciting is this type of catheter, this patch type catheter where
the wire is inserted into a vessel, it\'s blown up, and you can see this
loop which develops, it does not block the vessel. It allows the blood
to continuously pass through the vessel without causing any ischemia or
occlusion, and you can then profuse your drug or gene in this helical
tube, and it then leaks out. It\'s a very permeable membrane, and it
leaks out into this little cavity over here, and it will then allow it
to basically be taken up by the endothelial cells.

These are the types of systems that are now being delivered and explored
for local delivery of drugs or gene product and peptides into the
endothelial cells lining vessels.

What about some of the therapeutic vectors, the therapeutic ways in
which we delivery payload into tumors?

And the four categories I will be talking about will be radio
immunotherapy, vector engineering and design, some of the new cell
delivery techniques, and some of the new gene delivery enhancement
techniques.

Selective internal radiation therapy, I\'m sure many of you have heard
about this. As an example I\'ve just selected the Yttrium microspheres.
These are very small, 32 approximately micron resin microspheres onto
which is bound some radiation, Yttrium 90.

This is then delivered. We put a catheter all the way up, again, up the
aorta. We target this catheter with guide wires into the tumor, and then
you can deliver these small, little microspheres directly into the
tumor. There\'s preferential deposition in very vascular angiogenic
tissue, and we can deliver, therefore, therapeutic dose of radiation to
the tumor and not to the entire organ.

The liver, as an example, is a very sensitive organ. If you expose the
liver to conventional doses or radiation treatment, you\'re going to
wipe out the liver function, and the patient might succumb. However, if
you can deliver this local radiation treatment to solid vascular tumors,
it allows you to then subject this to a much higher radiation exposure
than conventional radiation treatment.

However, this technology certainly needs to be optimized. There are lots
of companies out there which are exploring it. We need to see some good
comparative prospective studies. We need to see the technology optimized
before I would certainly be happy about administering this to any of our
patients.

Immunocongugates monoclonal antibody therapy also is being used right
now, not with too much success in our experience, and as an example, if
you take colon cancer, which expresses what\'s called a carcinoembryonic
antigen on its cell surface, you combine radiation Iodine 131 to these
monoclonal antibodies. You can deliver these intravenously, and these
will then bind onto the cell surface of any tumor cell which is
expressing this antigen.

The problem, of course, is that many other normal cells in the body
might express it, such as the colon, and so we need to basically improve
ways of targeting the immunoconjugates. It\'s not sensitive enough at
this time. The monoclonal antibodies need to be worked on. It\'s not
enough to simply use a rather specific monoclonal-type antibody. You
need to use antibody fragments and small, little peptide fragments,
cyclic peptides as well, and this might improve the localization.

The other area which is explored in many laboratories is once you\'ve
actually delivered these onto the surface of the tumor cell, how do you
get these inside. How can you internalize either this radiation or, in
fact, whatever you might put on it. This might be drugs. This might be
other types of therapeutic agents. How do you get these in?

And the areas which are being looked at now with some, in fact, quite
optimistic early results include radio frequency or heat, sonoporation
using focused ultrasound, and UV light. All of these techniques are
being explored in the laboratory setting for enhancing uptake and
internalization of delivered immunoconjugates.

Vector engineering is another area which is receiving a lot of interest
in the laboratory setting. I\'ll give an example of what we refer to as
immunoliposomes. Some of the very good work has come out of David
Cheresh\'s group in La Jola, and what they\'ve done is they\'ve taken
advantage of tumor angiogenesis. The integren off of E-beta-3 is
expressed on very early angiogenic vessels.

What they\'ve done is they\'ve bound a monoclonal antibody to this
integren, to a small, little liposome which contains gadolinium. We can
see gadolinium with MRI, and therefore, if you give the small
immunoliposome into an animal at this stage, it will actually localize
in areas where there are integrens being expressed in very early
angiogenic territories, and you can see it because of the gadolinium.

In further studies, what they\'ve done is they\'ve also then bound
doxorubicin, the chemotherapeutic agent doxorubicin, to this same agent,
and this, again, will then target the doxorubicin to the integren which
is being expressed.

Phage display technology is a very exciting, I\'d like to say, new
technique. In fact, it has been around for a while, which really allows
us to target far more specifically than monoclonal antibodies would, and
in using phased( )display technology, that group and others have
certainly been able to identify small what they call cyclic peptides,
and these will target not only small integrens, but as more work is
done, in fact, they\'re finding that these probes target multiple
different receptors.

They\'re able to target angiogenesis. They\'re able to target receptors
on tumor cells. They\'re able to target other enzymes which might be
expressed prior to angiogenesis, such as the so-called
metalloproteinases.

So, in fact, a more and more basic science is being performed, they\'re
identifying more and more applications for each of these probes.

Similarly, tumor receptor is another big, exciting area. A lot of work
has been done on tumor proteases. Ralph Weissleder and his lab in Boston
has developed a lot of imaging probes to the cathepsins and other
proteases. Metrics metalloproteinase is one of our own optical imaging
probes actually showing a circular room of matrix metalloproteinases
being expressed around the periphery of a colon cancer metastasis in
this video micrograph of a colon metastasis in a mouse liver.

And there are also a variety of growth factor receptors which are now
being targeted, and remember we can use these not only for diagnostic
purposes, but also for therapeutic purposes. So we can try and look at
developing probes which show us on an imaging basis where these
receptors are, confirm that they\'re being expressed, and then block
them with a lot of these very exciting, new factors which are being
engineered.

VEGF, the vascular endothelial growth factor, also very exciting. VEGF
is being used. You\'ll hear in subsequent talks this morning about the
way in which it\'s being used in Hans angiogenesis.

VEGF can also be targeted for gene therapy. We use VEGF; in fact, we
drop it onto tumors with needles, and it enhances the permeability of
the leakiness of tumors, and we can then pulse this with drugs off to
its enhanced delivery of drugs into tumors.

So whereas VEGF might not be the ideal agent being expressed by tumor
cells because it enhances angiogenesis in growth, we\'re also
administering it to enhance delivery of drugs into these tumors.

Targeting tumor-associated cells, this is something that we hit on
inadvertently a couple of year ago through our radio frequency ablation
program. It\'s well know that many solid tumors, breast, for instance,
will recruit systemic macrophages. Systemic macrophages are recruited
into the center of solid tumors, and these then might play either a pro
or an anti-tumor effect depending on which specific population of
macrophages these are.

However, we have now found, in fact, that when you ablate a tumor with
radio frequency ablation, you can actually recruit specific types of
macrophages that would have an anti-tumoral effect on the tumor.

And we have taken advantage of this. This is a small colon cancer
metastasis. This is a video micrograph of an exteriorized mouse liver
with colon cancer, and by sticking a needle in and ablating this for
about 30 seconds and waiting for a few days, we\'ve recruited these very
Agard phagocytic macrophages into the cell. These black cells infect all
systemic macrophages which have taken up these small carbon micro
particles, and this is a different population of macrophages to which
reside in the typical growing antiogenic tumor cell.

So therapeutic macrophage recruitment is interesting not only because of
its anti-tumoral effects, but because these avidly phagocytic cells, to
me, seem to represent a wonderful delivery site for drugs or for genes.

Taking advantage of tumor permeability, you have already heard in the
previous two talks about pegylated liposomes. We have certainly played
around with these a lot. This is just an image. You can see this is a
diagrammatic illustration of a liposome. These yellow bands along the
periphery are the polyethylene glycol.

And what this does is they provide stearic hindrance. What this means is
that if you just inject these into the blood stream, they will
circulate. They will have a prolonged intravascular residence, and these
thin strands of polyethylene glycol will prevent these from being taken
up by macrophages throughout the body. They, therefore, would stay in
the blood stream for up to two days.

The illustration on the right, again, is one of our small \-- this is
about a two millimeter colon cancer tumor growing in a mouse liver. You
can see PV is the portal vein, is the blood vessel supplying the tumor,
labeled as T, and what we have done is we have simply given these
animals an injection of a small amount of these pegylated liposomes
containing doxorubicin, and these will simply leak out because of the
leaky vessels within the tumor.

And more interesting, in fact, is that the doxorubicin will only
fluoresce once liberated from the actual liposome, and all of this
bright white area is the liberated doxorubicin which we can see in real
time.

So taking advantage of tumor permeability is another broad area that to
me seems quite optimistic and hopeful.

So we\'ve looked at the vector engineering. We looked at the catheters.
Now let\'s look at cell transplantation. Cell transplantation certainly
we\'ve heard in this previous talk. There\'s a lot of opportunities for
diabetes.

We are injecting islet cells into patients in our institution, but
what\'s sort of strange and bizarre to me as a radiologist is that
clinicians come to us; they give us a little vial; they provide the
patient\' and they say, \"Please inject this into the spleen.\"

And we inject these eyelet cells into the spleen, and we have no idea
where these cells are going, and this, of course, I think is one of the
big challenges we\'re dealing with in liver cells as well. We\'re
injecting hepatocytes into the spleen, and there\'s a lot of work that
needs to be done in the laboratory to know exactly where these cells are
going. They seem to be working in some patients, not working in others.

And interestingly, we\'re finding with our liver cells, which we\'re
giving to patients to tide them over prior to transplantation, that they
seem to reside within the spleen and do quite well and actually work.

So that opens up another whole possibility. You can have ectopic
location of normal functioning cells. They don\'t need to be in the
organ where they normally function.

In our oncology patients, we\'re injecting the fibroblasts and the
dendritic cells into the peritoneal cavity. We do this under image or
ultrasound or CT guidance, and again, these are cells which have been
transduced to produce things like human growth factor, some of the
clotting factors in our hemophiliac patients, and this again provides a
wonderful opportunity.

However, as has been said before, we certainly await new techniques for
improved targeting of these cells, and I think this is another big area
that a lot of work needs to be done.

So recruitment I\'ve mentioned here. Some cells can be recruited.
Certainly image-guided MCF delivery; what I mean by MCF is the
macrophage chemotactic factors. You can literally pick up the sigma
biochemicals catalogue and purchase overnight a whole variety of
different chemotactic peptides, and a lot of these now that we inject in
an image guidance into a solid organ in the body will then recruit
macrophages, which might have an anti- or pro- tumoral effect. And we
need to explore this area further. There\'s a lot of opportunity here.

Radio frequency tumor ablation we\'ve shown. Our own institution
recruits macrophages, and this, again, was data that was sitting in
front of our eyes for years and years, since every time we did this to
an animal or patient we would get histology that would show a lot of
macrophages, and the assumption that we made, that this was simply the
RF-induced inflammatory response.

So certainly there\'s a lot of data out there that we just need to look
at again and take advantage of.

And these cells, again, are a wonderful depo for drug and gene delivery.
These are two micrographs, again, in our little mice in the lab. This is
an exteriorized mouse liver. You can see the vessels draining out. This
is the portal vein coming into the liver. These are the individual liver
cells, and these small white dots, in fact, are the liver macrophages,
also known as the Kupfer cells, and we\'ve delivered a fluorescent
peptide to these, and you can see the broad delivery of these.

Whereas once we let a tumor grow inside, we ablate this tumor with RF.
You can see a different population of macrophages which takes up a
different dye, which has been localized around these tumor cells.

So depos for drug and gene delivery, I think, are another bit area that
deserves some further work, and this is, again, one of our images. This
is radio frequency recruited into two macrophages, and what these have
now done is they\'ve taken up liposomal doxorubicin, and it is being
released in these macrophages.

So this is a one millimeter tumor. These are macrophages which are being
recruited often within the center of the tumor for about two to three
days after RF ablation, and these are not there before, and you can then
deliver drugs to these.

And these are also a rich population for delivery of gene products.

Adoptive immunotherapy, I don\'t want to get into this in too much
detail, but it is certainly being performed in patients in our
institution. What we mean by this is one of several things.

First of all, you can take natural killer cells from the patient or
others. You could activate these with lymphokines, reinject these into
the patient, and then hope that these will somehow attack the tumor for
some therapeutic purpose.

The trouble is the nonspecificity of these cells, and again, to improve
targeting of these natural killer cells.

And then lastly, in this category, the so-called TIL, the tumor
infiltrating lymphocytes. What we have in our institution is one of the
basic science researchers takes lymphocytes. He transfixed them with a
cDNA of carcinary rheonic antigen, and then what they do is they
actually ultimately start making an antibody for the carcinary embryonic
antigen, and we then reinject these back into the patients, and they
will then home in on our patients with colorectal cancer metastases in
the liver.

And we are just sharing these, and this, again, is one of our
micrographs of a small mouse liver. This is looking directly into a live
tumor in the liver through a microscope, and these small, little cells
here are the lymphocytes which, in fact, fluoresce under the appropriate
conditions, and we can target these to the tumor.

However, clinically is it successful? I\'m not convinced. It seems to
target other parts of the body, such as the colon, and it\'s an area
richly in need of good research and optimizing this technology.

Gene-based therapies. We hear earlier that gene therapy has not been
performed that much in humans. Certainly in our institution it appears
to be. We\'ve seen some major hurdles over the last couple of years, but
with a lot of trepidation and being extremely gentle with the patients,
we certainly are delivering genes to patients.

Two of the major innovations that I think we\'re going to hear about for
treating solid tumors are the use of tissue specific promoters and the
use of inducible enhancers. And what I mean by this is the ways in which
genes are being synthesized now are to allow specific factors on them to
promote gene expression, and one which is being used is VEGF, the
vascular endothelial growth factor.

And what this means is that in an animal model you could introduce genes
into solid tumors, wait for these to become angiogenic, become invasive,
and the minute VEGF starts being expressed, it turns on therapeutic
anti-tumoral genes.

And then what we\'ll also look at is how we can actually enhance
delivery of genes, and the areas which are being looked at with most
interest are heat, hypoxia, and ultrasound.

The inducible enhancers of gene expression, a little gene fragment, a
little cDNA fragment consists of an enhancer subunit, promoter subunit,
and the actual gene.

And what you can do is, if you can basically subject this enhancer
subunit to one of many ways of activation, it will, in turn, activate
the promoter subunit, will activate expression of the gene product,
which will then be released and go off and have the therapeutic effect.

How can we take advantage of this? Well, certainly with hypoxia. Hypoxia
inducible factors can be inserted on the enhancer unit, and then in the
presence of hypoxia, these will then be activated to express genes, such
as the gene for VEGF of a variety of other genes.

Believe it or not, in the year 2003, we are delivering chemotherapy to
patients with solid tumors. We\'re then blocking the vessels in the hope
that this will occlude the blood supply and kill the tumor.

But as I\'ve just shown you, in fact, to make a tumor hypoxic, it, in
fact, stimulates VEGF expression and should, in reality, induce further
growth of the tumor. And this really is sort of the take-home point I\'d
like to leave us all with, is that a lot of things that we are doing to
patients right now, they seem to have a wonderful, positive effect on a
lot of patients, and in theory some of these might not work that well.

Ultrasound is something that Bob Langer mentioned, and certainly he
deserves even more credit than we can give him for what he has done in
this field, but heat shock protein is another protein which has recently
been identified as a protein which can be up-regulated by the presence
of the heat delivered by ultrasound. If you can make a gene that has
heat shock protein inserted into it, you can then target ultrasound
directly to this gene and it will inactivate this and induce gene
expression.

The trouble is that this has not been done with too much efficacy at
this point, and we need to look at all of the entire spectrum of other
available heat opportunities for this.

So we\'ve not delivered vectors. We\'ve delivered genes. We\'ve
delivered drugs into the tumor. How come we enhance the delivery here?

First of all, drugs, which can enhance permeability and, secondly,
mechanical; there\'s a variety of different pre-targeting drugs that we
can look at. VEGF again, as I said, we drop it onto tumors to increase
endothelial pores. We can actually deliver via catheters transient
permeability enhancers. You can see all of these that I\'ve mentioned
over here on this slide: platelet activating factors, bradykinin, all of
these will, in fact, enhance permeability.

Mannitol is used by neurosurgeons to a large extent to disrupt the
endothelium, and then mechanical enhancement. It\'s well known that RF
ablation as well as electrophoresis or antiphoresis, all of these will
enhance permeability to allow drugs to be delivered.

This is one of our tumors we have subjected to 30 seconds of RF ablation
and changed this with small fluorescent microbeads, and all that you can
see the track of the needle inside the solid tumor, and you can see how
the microbeads, they leak out around the tumor. So certainly RF can
enhance permeability.

Something I suspect we might be hearing a little bit more about later
on, these so-called magnetic targeted carrier particles. These are
small, little magnetized particles onto which different chemotherapeutic
drugs can be bound. This is then delivered via catheter into a
patient\'s blood system, and then these magnetic particles can
effectively be sucked out by a magnetic field placed onto the patient\'s
surface.

Here\'s an example of this, a catheter that has been delivered into an
artery supply in these liver tumors. These magnetic targeted carriers
are delivered into the liver tumors. Magnetic field is placed over there
that would suck these out, and then these are delivered into the tumor.

And you can use MRI to actually see this small, little magnetic
particles in the tumor. What needs to be looked at, in fact, not only is
the system being fully optimized, but once you\'ve got small magnetic
ion particles in the liver, what effect would this have on other
therapies?

For instance, if you use ion and RF ablation, what effect would ion and
RF ablation? Would this be synergistic? Would this be antagonistic?

There\'s a lot of additional exciting work that can be done here to
further optimize this, and this sort of falls into the category of what
I call cooperative therapies, something that hasn\'t received much
attention, but for an example, RF can be used to recruit targetable
macrophages.

We already are injecting the genes for P53 into solid tumors, and what
these do is they then allow the tumors to, in theory, re-get into the
normal way of dying, but P53 also allows us to subject these tumors to a
lower level of radiation.

Radiation-inducible promoters are another entire area.
Thermally-activated vectors, vectors which can be delivered in the blood
system, into solid tumors and then shattered by subjecting these to
different heat techniques.

[In vivo]{.underline} electroporation, sticking a needle into a solid
tumor, delivering drugs systemically, and then by subjecting this to a
local electric field, allow these drugs, just as we do in the
laboratory, to be taken up into the tumor cells.

And then, of course, a nice combination that we have done and published
last week, in fact, is a combination of radio frequency and liposomal
doxorubicin, and our theory here was that once you have a tumor in the
liver, you can give the patient liposomal doxorubicin or, in fact, any
liposomal agent. It will then surround the periphery of the tumor.

We then, using image guidance, stick a needle into this tumor. We turn
on the RF ablation. You can see the red heat, and then what this does is
it actually extends all the way out to ablate the entire tumor.

And I was also actually very excited. We\'ve done this in quite a few
patients. The regulatory issues in and of themselves are very
interesting because RF ablation is approved. Liposomal doxorubicin is
approved. So we\'ve taken two approved technologies, and what we\'re
getting over here, this is one of our patients, and it\'s showing us
some very surprising results.

This is a tumor which has been ablated. This is the liver. This is a CAT
scan through the patient\'s upper abdomen. This big, black area is the
dead tumor, but you can still see a few blood vessels within it.

And about two weeks later these blood vessels have disappeared
completely, and the types of results we\'re seeing, in fact, is that
whereas a couple of months ago we could only ablate tumors up to four
centimeters in size, we\'re now getting up to eight centimeters in size.
So a 100 percent increase in tumor size.

We\'ve even showing in our animal studies that the survival of the
animals has increased. We\'re also getting slowed growth not only when
the entire tumor is ablated, but when parts of the tumor are ablated,
and we\'re also knocking out blood vessels which may be residual.

So the combination of interstitial treatment, such a microwave or radio
frequency ablation and drug therapy, certainly is being used at this
point in patients and deserves further investigation.

In such activation of expression of drugs or genes, you can certainly
induce local liberation of contents of drugs with photoactivation,
radiation of sound radio frequency, heat sensitive liposomes, a lot of
great work being done by Needham\'s group down in the Duke hypothermia
project, and here they are using special liposomes which are activated
or shattered apart by heat.

And of course, sonoporation of using ultrasound to shatter liposomes,
and this is an example. Some of the ultrasound contrast agents are being
designed to have a biomaterial on the outside, which are antibodies
which can target these to specific surfaces of tumor cells.

They have a polymer inside which is specifically designed to be
shattered by using conventional ultrasound waves, and then inside they
could have a drug or a gene.

And then what you do is you subject this to ultrasound waves. This will
then break it apart, release the small, little peptides, and allow local
release of gene or drug inside a tumor.

And we, in fact, are doing this in the laboratory. This is the liver
ultrasound delivered doxorubicin. This is a small liver in a rat, and
there\'s no ultrasounds being given when you subject this to
conventional ultrasound, and by conventional, exactly the same
ultrasound that many in this room may have gone to have your fetus, your
embryo imaged. It\'s not using any higher frequency ultrasound
whatsoever, and you can show the marked increase in the fluorescence of
this doxorubicin when this is subjected to approximately 30 seconds of
conventional ultrasound.

What we have shown that\'s even more interesting, in fact, is that in
the presence of a tumor, you can get even further delivery. So this
really opens up a whole new ball game where we can use conventional
ultrasound, and already we\'re exploring this.

The patient comes in. We can image the tumor in the liver. We can then
give a drug and actually use that exact same ultrasound while we\'re
imaging it, target the beam, and try to deliver this, get local delivery
and implosion of the ultrasound contrast agent.

Detention of the payload. We\'re almost done. There\'s certainly a lot
of pharmacologic inhibitors. These are efflux inhibitors. Once you\'ve
got the drugs into the set tumor cells, we could take advantage of the
ATP dependent pumps, P-glycoprotein multi-drug resistance pump is
something that a lot of drugs being used for other purposes will block,
and there are a variety of these multi-drug resistance-associated
proteins.

Any of these infective, once the drug is inside the tumor by giving
these to the patient or to the animal, it will inhibit efflux of these
drugs out, and of course, the mechanical inhibitors.

And there\'s some very good work that has come out of the laboratories
of Genzyme in Boston showing that gene delivery intravenously in animals
by inhibiting flow out of the liver, by occluding the hepatic veins,
will cause significant increase in the uptake of genes into these cells.

So, of course, using catheters and other engineering techniques to cause
local increase in interstitial pressures certainly may have a positive
effect on gene and drug delivery, and this is, again, one of our small
colon cancer cells, and what we\'ve done is we\'ve given verapamil and
Cyclosporin A, and this has inhibited efflux of doxorubicin out of this
tumor cell.

So these are types f therapies, types of approaches that need to be
looked at once you have delivered the payload, once you\'ve deposited in
the cell. You need to prevent it from being released.

So in summary, this was a very brief overview. For the treatment of
solid tumors there really are a variety of emerging techniques and new
technologies. There are a huge amount of opportunities for optimization
of these techniques, especially these combination therapies. However,
someone who is doing these on a daily basis \-- and I think this is
where the challenge really is \-- we still do await some good quality,
peer reviewed, published science showing which techniques are the best.
We need to compare the techniques, and we would really as clinicians
love to get involved in some good, prospective, randomized studies to
see which are really going to be best for our patients.

Thank you very much.

(Applause.)

DR. FEIGAL: Thank you.

Our final speaker before the break is Richard Kuntz, who will be talking
about the novel technologies for the treatment of cardiovascular
disease.

DR. KUNTZ: Good morning. I\'d like to thank Dr. Feigal and Dr. Provost
for inviting me to this wonderful session.

And I\'d like to talk in the next few minutes about the clinical impact
of some of the technologies that you heard about this morning, mainly
focusing on the drug eluting stent experience.

We all know that coronary stents use funny, little metal cages that have
been around for about 15 years, made of about three different types of
materials, mainly stainless steel 316L or Nitinol or recently cobalt
chromium. These materials are now referred to as bare metal stents
because of the drug-eluting stent environment, have basically
revolutionized the treatment of coronary disease throughout the world.

That is, these cages basically open lumens that are blocked in the
coronary arteries and maintain, because of their physical properties and
mechanical properties of plastic deformation, can maintain an opening in
the artery despite injury sustained by the stent, and overcoming the
reaction of vascular injury.

Now, one of the problems is that when you start to expand any new
therapy, you start to see a problem associated with expansion of the
clinical outcomes. We initially evaluated stents in basically simple
patients, and they could be defined by patients with large vessels and
generally non-diabetics. They had rates of failure that were very, very
good and basically were associated with pretty much a breakthrough
therapy in coronary disease. That is, only about ten to 20 percent of
the patients who were treated with coronary stents in the simplest
lesions would ever fail over the course of the restenosis period, which
is about six months.

But as expansion included diabetics and longer lesions and vessels that
are smaller, we started seeing that these parameters are actually quite
influential on the geometry of renarrowing. So that when you have
patients who are diabetics with long vessels and small lesions, failure
rates approach 50 percent.

So this is, I think, a pretty typical cycle of any new technology, that
when it is initially introduced it is with really fantastic results.
Clinicians figure out a way to expand it to patient populations where it
fails again.

(Laughter.)

DR. KUNTZ: And then it\'s time for us to now engender a new need for a
new breakthrough therapy.

So the drug-eluting stent process started out, and it wasn\'t
necessarily that it was a drug-eluting approach. Early on we know the
biology of thrombus and neoplasia, which is the renarrowing process of
restenosis, is guided by four different types of pathological processes.

One is that when you put a stent or injure any artery, you get initially
thrombus that forms on the artery. This engenders an inflammatory
process at the site with recriminative white cells and macrophages. This
leads to stimulation of the deeper tissue in the vasculature of
proliferation, both of in situ perivascular cells and also media which
transform to macrophages in the fibroblast and recruit more cells and
they basically heap up the scar that if you\'re in a vascular bed,
generally it causes a reduction in the lumen size.

And then finally, arteries that don\'t get stented actually can contract
around the inflammation itself so that there are these four process that
we have known for years cause a problem.

The problem has been that almost every drug available in the last 15 to
20 years has been tested in over 40 or 50 multi-center randomized
trials, and all have failed. So the notion in the mid-\'90s was that
maybe we should reevaluate some of these drugs with the emerging
technology of local drug delivery.

That was always in the back of the mind of many of the scientists that
not enough drug was getting to the tissue site because it had to be
given systemically. So the notion of local delivery really has been
manifested as a success and the poster child for drug delivery at this
point is the drug-eluting stent.

Now, in conjunction with this concept that local delivery was important
was even more science that was added by Nurse, Hartwell, and Hunt, who
ultimately ended up winning the Nobel Prize in 1991 for their similar
work on understanding the importance of specific key proteins
orchestrating cell division. These include Cyclin CDK, CDK1, and a
variety of P proteins.

Simplistically one can look at a variety of compounds that have been
around for a while and look at their impact using this model on the cell
cycle and, in general, knowing that the implementation of a stent would
cause activation of inflammation followed by cell division, and trying
to process some of the data from those Nobel Prize winning science, we
could see that potentially these drugs that have been used in other
areas, including immunosuppression and chemotherapy, might be valuable
loading a stent to stop a cell from getting into mitosis.

Now, early on we know the radiation therapy is extremely effective in
that, and there was a heads-up with respect to that working because
radiation therapy is extremely effective in the prevention of in stent
restenosis, that is restenosis happening a second time.

So we do know that we can inhibit mitosis, and radiation therapy is kind
of a no brainer approach, but we can reduce this problem of repeat
failure after stenting.

A variety of different drugs that are mentioned here include Sirolimus,
which is the brand name for rapamycin; paclitaxel and actinomycin D.

Now, if we look specifically at the first compound extensively studied,
which is rapamycin, Sirolimus, we know that processing some of this data
that a variety of cell receptors, both stimulated by white cells and by
platelets lead to activation of some of these key proteins that are
synthesized at some unknown protein enzyme, and this has been referred
to as the target of rapamycin because it is felt that rapamycin works
after combining with a KPB12 to inhibit the function of TOR in leading
to the synthesis of these key proteins, which lead to cell division.

So one had to utilize this science with the emerging technology, as was
pointed out by previous speakers, of polymers that can hold and deliver
the drug.

So the concept of drug-eluting stent was started, pioneered throughout
several centers throughout the world, including MIT, with some of Dr.
Langer\'s students, including Elazar Edelman at the Biotechnology
Center.

And these agents were felt to be part of a three-part process of
combination, including the initial stent itself, which was generally
just a stainless steel stent on the market; a pharmacologic agent which
was going to work and have some theoretical advantage to prevent
mitosis, and, of course, the most critical thing was the drug vehicle.

And if you follow the coronary field in polymer science in the last 15
years, we actually didn\'t get off to a good start initially. Polymers
were probably the harder nut to crack rather than the drug itself
because the initial polymers were so toxic that they in themselves would
cause dramatic vascular responses.

Well, after a lot of work, and this is almost ten years of work at
Cordis in conjunction with Wyeth-AIRS, there had been multiple efforts
to try to develop the ultimate polymer-holding drug with a top coat that
would allow for delivery to stent without rubbing off the drug, and
ultimately release of drug over the course of 30 days that would, in
fact, interfere with the process of thrombus and inflammation, which was
the kind of ring leader of the restenosis process that occurred
subsequently for six months.

The notion was, in fact, if you could stop the upstream processes of
cell division, you wouldn\'t get the manifestation of heaped up
neomyplasia after six months. So the notion was to develop a rapidly
releasing polymer that would get drug into the vasculature within the
first seven days and possibly as late as 30 days.

Now, I\'ll jump right to the clinical trials because we could spend a
lot of time on the polymer science here, and there are better speakers
than me to talk about that, but with respect to how this has manifested
itself out, early on there were some studies done in South America, as
are a lot of kind of under the radar screen studies that are done
outside the United States, and one of the initial studies with this drug
showed up as a winner.

The first in-man analysis demonstrated that after treatment of 40
patients there was absolutely no latent loss that would be expected to
be seen at six months, and this triggered initially Cordis to start two
prospective studies.

Now, the prospective studies were first a study called RAVEL done in
Europe, and then the FDA regulated study in America called SIRIUS, which
was more of a pivotal trial study.

The RAVEL study was actually designed to demonstrate reduction in a
surrogate of restenosis, which is angiographic narrowing. A 200-patient
study generally wouldn\'t show reductions in clinical outcomes, and it
was substantially and markedly positive. That is, if we look at the
classical measures of narrowing, which is the crossing of the 50 percent
narrowing diameter stenosis at angiograph at follow-up, it rate was 26
and 27 percent, as we would expect, in the control arm, and in the
active arm it was zero.

Now, there are a variety of ways of measuring narrowing within the stent
and outside the stent, but regardless of how we measured it, it was
quite fantastic, and this study was performed by Dr. Serois in Rotterdam
using his European colleagues, and it was probably the most substantial
breakthrough in the field of interventional cardiology in the last 30
years.

Now, this was in tandem and slightly frame shifted behind, performed
with a study called SIRIUS, which was the American study. Again, this
study is a lot larger because it\'s powered to demonstrate reductions in
the clinical restenosis rates, which are lower and less powerful
endpoints than that established from angiographic measures, and we see
that the restenosis rates angiographically were also substantially
reduced. You can see the reductions here, almost 90 percent, depending
on how we measure restenosis.

This, again, is unprecedented not only in coronary cardiology, but in
medicine in general.

If we look at other measures of what the target was, which is this
amount of neomyplasia best measured by three dimensional intervascular
ultrasound reconstruction, you can see that when the patients were
exposed to normal stenting, they had 34 cubic millimeters on average of
neomyplasia compared to 2.6 from the other group, again showing
substantial reductions.

And then if we go to the robust clinical measures, that is, does the
patient have to be revascularized, what about if they had a heart attack
and other kinds of very robust measures?

This is the major clinical outcome called target lesion revectorization,
and that was reduced almost fourfold, from 16 to four. And if we look at
that event plus anything else that can happen to the patient, including
small heart attacks, it was still substantially reduced.

Now, it was interesting because we have a paper pending in the [New
England Journal of Medicine]{.underline} that should be out next month,
and in the initial review the editors asked us to remove the words
\"marked\" and \"substantial\" that we were using in the manuscript
because they said it sounded like a marketing brochure rather than a
scientific paper.

And we tried to figure out a way to describe the 91 percent treatment
effect without using the word \"substantial\" or \"marked.\" It was
pretty hard.

(Laughter.)

DR. KUNTZ: So you\'ll see sentences like, \"A treatment one effect was
found, 91 percent.\"

What\'s interesting is that this is almost a dream come true from an
initial perspective, and that is the field of DES, I think, is more so
than just SIRIUS itself, Sirolimus. These drugs in their initial
incarnation so far appear to work without any increase in adverse
events, and stent thrombosis was something of great concern because we
were putting a polymer on top of the surface of the stent, and that
might be a problem.

And in a variety of different studies from Europe and Canada, America,
and others, the pooled analysis shows the same thrombosis rate or even
lower from what we would expect at least on the patients we\'ve studied
so far.

So in general, the inclusion criteria for this trial, which included
relatively sick patients, had fantastic results from a stent thrombosis
perspective.

What also is interesting was that if we looked back at those predictors
clinically of increased restenosis, which is the length of the lesion,
the size of the vessel of the person with diabetes, there was a really
uniform treatment effect \-- this is looking at clinical restenosis \--
across the board.

That is, if we looked at linear, nonlinear modeling, if we looked at
actual results and we tried to smooth them in a variety of statistical
ways, we would find this consistent effect.

So this, again, is a little bit unusual to see in medicine where almost
all subgroups benefit to some degree.

Another way to look at that is just to break them down by the observed
outcomes, and this is the classical odds ratios analysis, and, again,
this is a familiar graph that one takes a positive study like this with
its odds ratio reduction from the active arm and its confidence
intervals, and then measures it against the unity line, and then looks
at a variety of subsets.

And it\'s very hard to come up with any other study in medicine I know
of that has all of these subsets located so far to the left. So it was
very hard for us to find any subsets that didn\'t have substantial
advantage in this group overall.

What\'s more interesting mechanically is that we\'ve always known that
with the advent of stenting and its ability to prevent abrupt closure
and other acute complications, many interventional cardiologists use a
lot of stents because they could really get themselves out of problems.

But there\'s a price that you pay, that is, the increase in stent length
was associated with substantial increase in restenosis, and this is
mainly a probabilistic reason statistically.

Well, this was almost negated by our experience so far with the
Sirolimus stent, suggesting that now the interventional cardiologists
can have their cake and eat it, too, that they can put the long stents
in, the so-called full metal jackets, and not pay the price they have
before with substantial increases in restenosis per se.

Now, we don\'t want these interventional cardiologists to go hog wild
and start putting a lot of stents in. Surgeons certainly don\'t want
that, but at least when one is concerning themselves about an acute
complication, like an edge dissection, and you\'re always debating as to
whether you should put that extra stent in, we feel that the patient can
actually benefit from having a safe approach by putting the extra stent
length in because the price we see so far of restenosis is very minimal
for extra stent length.

We followed this for now a year, and what we see is that even from the
initial nine month outcomes which were reported to the Food and Drug
Administration and led to approval of the one-year data, still is
maintained, and if anything, we still see a slight reduction in freedom
from restenosis in the control arm by the main endpoints, and it is
still maintained, I assume, more robustly in the active arm.

So our treatment effects actually have lightened, interestingly enough,
even from nine months to 12 months, to suggest that there is no evident
catch-up phenomenon.

If we look at the RAVEL study, the one that was started slightly before,
the two-year data suggests that we have still maintenance of good
clinical outcomes, and there\'s clearly in all of the angiographic
analyses no evidence that this process of delay or narrowing that occurs
in six months is delayed any more than what we normally see in six
months.

Now, European studies have just been reported a few months ago. Again, a
new data set; again, phenomenal results overall, and I think overall the
results of rapamycin with three randomized trials now suggest that this
is a good drug.

Well, what about other drugs? Does it work? Is the answer local drug
delivery or is the answer Sirolimus?

Well, paclitaxel is another important therapy, and its first study was a
500-patient study done in Europe, and it also showed marked reductions
in restenosis. The FDA study called TAXUS-4 in America, which has,
again, over 1,000 patients will be presented relatively soon, whose
results, I think, are being filed if not now, to the Food and Drug
Administration, and I think they\'ll be presented some time in August or
September.

But if it does follow this initial European experience overall, we\'re
looking at probably another 50 to 60 percent reduction in restenosis.
We\'re the second drug now attached by polymer to a stent.

Does that mean that every drug-stent combination now works? The answer
is no. Actually it doesn\'t. The same drug, paclitaxel, was shown not to
have substantial reduction in restenosis, 13 versus ten, when directly
applied to the stent surface. Okay? Paclitaxel is a sticky molecule, and
if you spray it on and then put it in the body, it actually doesn\'t
seem to prevent restenosis to the same degree that we certain saw with
rapamycin or the other formulation of Boston Scientific TAXUS stent.

So I think the polymer technology is critical, at least from my limited
perspective, so far. It looks like that is an important component rather
than just drug and stent alone.

There are lots of other polymers out there. I just want to give you a
little sampling now of what they look like. Abbott, in collaboration
with Biocompatibles in the U.K., has access to phosphatidylcholine,
which this agent is like a sponge. It essentially is easy to apply. It
holds molecules up to 2,000 Daltons. It is a natural reservoir and can
be easily manipulated to change its kinetics of release.

Abbott, in conjunction with Medtronic, are looking at a variety of
different compounds, including a rapamycin analogue called Rapalog, or
ABT 578, and both of them have licensed this compound, and there are two
studies that are ongoing right now in Europe.

Interestingly enough, there is some interesting data from basic old
drugs that are off patent and have been studied before and were
negative, and when combined with a polymer looks initially like it might
have good results as well, and they include dexamethasone estradiol.

And of course, Guidat has another rapamycin analogue in a polymer called
everolamus, and this in a study called FUTURE in Germany has
demonstrated fantastic results so far.

If we look at the overall experience so far, we can start to classify
them, and this is from Peter Fitzgerald, who is virtually the
intervascular ultrasound core laboratory in Stanford for almost all of
these studies, and what he\'s seeing is that he\'s got a marked
reduction in neomyplasia using either paclitaxel or the limus family.

Now, I don\'t know that there\'s a difference between these two. These
are very small sample sizes overall. I\'m a little skeptical about that.
I think when we find the actual results from the TAXUS-4 study we\'ll be
able to tell whether, in fact, they\'re all in the same class or not. My
guess is they probably are.

In any event, they\'re substantially lower than that seen in the bare
metal stent. Again, polymer is the key for a variety of these drugs that
work.

Now, I just want to point out one other stent just to show how the
technology can go further. This is just an interesting company that has
a stent in which the struts now have little holes in them, and what
these holes are are little wells that can contain drug.

And there is a manufacturing process that can precisely place in these
tiny holes levels of drugs with different levels of polymer and
different elution characteristics so that one could stack a variety of
different drugs with different release kinetics so that if you want to
have a drug for the first three days, it would be released, a drug for
the next week would be released below that, and so on and differential
release both to abluminal and vessel size.

This is a very interesting type of new technology, and I think we\'ll
see more and more of this. Trying to design a trial, I think, to deal
with all of these permutations may be difficult, but in general if one
comes up with a theoretical nice combination of drugs, such approach
might be something interesting and may stimulate other people to think
about likewise approaches.

Now, one of the important things is how does drug-eluting stents, even
as in its infancy right now, how does that impact on how we take care of
patients with coronary disease per se. Well, as an interventional
cardiologist, we\'re constantly measuring ourselves against the
surgeons, and early on we felt that we owned a single vessel disease
problem. That is, the heart usually has three vessels, and if one is
blocked, you generally don\'t want to send someone to surgery for that.

Well, there have been a variety of studies done on patients with
multi-vessel disease and comparisons with surgery, and in general,
there\'s not much of a difference except for maybe a subset of diabetics
with severe vessel disease. There\'s not much difference between
mortality or other major adverse events between the two therapies.

That is, angioplasty or bypass surgery tend to be extremely effective
with respect to the ability to revascularize and also has about the same
major adverse event outcomes.

But the main problem with angioplasty has been that the restenosis
process requires that it be reintervened on, and that gap was 32 percent
when balloon angioplasty was initially out there.

This slide, by the way, I borrowed from Dr. Serois in Rotterdam who made
this up. Now, Dr. Serois is also the PI of the ARTS study, which is the
first stent study versus bypass surgery, and that gap for
revascularization repeat in intervention has narrowed to 14 percent.

Even with conservative predictions of what the drug with the stent world
can look like, it now appears that even under multi-vessel angioplasty
and stenting we not only will be as safe as surgery for many
multi-vessel diseases, but possibly even have fewer revascularization
failures than surgery alone, and this is going to have a tremendous
impact, I think, in how patients with multi-vessel disease are going to
be treated, and slowly we\'ll have to do clinical trials to prove that
one can shift into the coronary surgical arena.

And, in general, I think that this is very good for patients because the
noninvasive approaches or less invasive approaches, I think, are going
to take over in a big way from the more invasive surgical procedures.

Now, if you\'re a stent company with a new drug-eluting stent, the
question is how are you going to do your study, and if you are around a
year or two ago, you could do this study, which is like TAXUS or SIRIUS,
and do a 1,200 patient study compared to bare metal stent.

But now that the first drug-eluting stent is out of the bag and CMS is
paying for it, it\'s hard to do a study against bare metal stent because
everybody is going to get a drug-eluting stent in America. It seems that
way, at least.

So we have to consider looking at equivalency studies overall, but if
you look at trying to be equivalent to something that only has a five or
six percent rate of failure clinically, you need to do a big study, four
or 5,000 patients, or if you try to beat the five percent, you know,
failure rate, which would be very hard to do, that still requires four
to 5,000 patients overall.

Well, I think what you\'re also going to see if you\'re interested in
the clinical field here is that I think in collaboration with the FDA
there are going to be several clinical investigators and others working
with a large group at the FDA interested in surrogate outcomes, and
we\'ll try to make a case for angiography and also intervascular
ultrasound as very powerful measures of looking at how these stents work
and prevent people from having failures, and they include measures of
narrowing of the artery.

And we do have a long history of well designed studies with good
follow-up that demonstrates angiographic outcomes actually very good,
and when we employ these kinds of outcomes, we can reduce the sample
size substantially and I think still do something there, but we have to
go through the classical analysis that will support surrogacy for these
endpoints overall.

Right now, what some companies are doing is, they are trying to either
go through a U.S. dominant approach, which would be to try to do a large
scale equivalency trial at the FDA or go to Europe where the bare metal
stent is not being paid for by any third party payers, and you can still
do a bare metal stent study.

So the drug eluting stent still can be randomized against a bare metal
stent, and there\'s a lot of kinks in these approaches, and they\'re all
trying to work out both in collaboration with notified bodies in Europe
as well as the FDA, but I think that this is kind of the current status
right now, and I think we\'ll work ourselves out a little bit better.

I just want to spend the last few minutes on potentially other
applications overall, and this is very speculative. So I don\'t want to
say that this is proven at all, but I think that with the advent of
drug-eluting stents we can actually get into completely new uses of
these little vehicles.

To me, and I think to others, now that we\'ve essentially solved
restenosis to some degree, and I think we have largely, maybe we can
start to do things that make sense. As interventional cardiologists, we
have never really helped extend anybody\'s lives. We basically make them
feel better when they play the 18th hole, or maybe they can walk, you
know, 18 without using a cart. We make their quality of life better, and
that\'s really what angioplasty does.

But still, almost a million people a year die of heart attacks, and
heart attacks occur because of plaque ruptures, not at the sites where
blockages occur. Usually they don\'t rupture, but at sites that we
don\'t treat, the ones that don\'t cause obstructions.

Well, we analyzed a variety of different locations for these MIs, and
this is my fellow John Wang who had done this, and we found that the
distribution of MIs is mainly in the LAD and RCA if we look at a
consecutive series of a couple of hundred patients at the Brigham, for
example.

And interestingly enough, there seems to be some clustering. That is, we
can see if you look at the LAD most of the MIs occur in the first couple
ten, 20, 30 millimeters of the artery itself, and that\'s been kind of
observed by a lot of people for a while.

If we apply a continuous frequency distribution curve to the location in
the LAD, for example, of where these occur, we can see that about 80
percent of the MIs occur in the first 30 millimeters of the vessel
itself.

So the notion might be that we actually have vulnerable hot spots in the
artery. Not actually vulnerable hot lesions, and that we don\'t have to
really try to search out to find the plaque that\'s going to rupture
tonight. Just use some basic shoe leather epidemiology and say that this
is where the heart attacks occur.

And if you are to look at the other notion that once you put a stent in
the artery, the neomyplasia that occurs there or the scar that happens
makes it impossible for atherosclerosis to grow anymore. I mean, you
have basically ruined the fertile ground of atherosclerosis, and we have
good evidence for this.

We can actually take arteries and remove their ability to have plaque
rupture by just putting a stent there, and hopefully if we have a stent
that reduces restenosis, we can have a nice, thin layer of neomyplasia
and basically prevent that segment from ever having an MI.

So you know where I\'m going on this one. If we are to actually look at
the instantaneous probabilities of restenosis overall and apply a
variety of different simulated models, this is a model for an eight
millimeter single stent. We have them up to three or four stents now.

We can see that the placement of a stent, and it\'s eight millimeters
subsequent, can actually reduce \-- we can actually optimize and find
where to place the stent.

Well, to make a long story short, our initial analysis has suggested
that with the use of two stents, a 28 and 23 millimeter stent, we can
reduce someone\'s MI risk by almost 50 percent, just placing them in the
proximal LAD and in the proximal right coronary artery.

Now, if you\'re a diabetic with three vessels, it\'s easier. MI risk is
something like \-- it was in the Berry study \-- which was 70 percent of
five years or your fatality risk is close to 30 percent of five years if
you\'re diabetic. A 50 percent reduction in MI could be a substantial
thing.

So I think that what you\'re going to see is a wide expansion of these
new stents with anti-restenosis therapies to potentially prevent heart
attacks in the future, and how we get to those patients I think will be
the \$64,000 question, and how we utilize other diagnostic approaches
such as imaging techniques I think will be quite interesting.

So let me just conclude with our experience so far with drug-eluting
stents. Drug-eluting stents can definitely reduce restenosis, and right
now the Level I evidence is for the CYPHER stent or rapamycin, and
there\'s Level II evidence and hopefully Level I pretty soon for
paclitaxel.

The long-term effects at this point appear not to be problematic, that
is, we do have data out to three years for the first in man, two years
for this RAVEL study done in Europe, and one year for the SIRIUS study,
and we see no catch-up phenomenon. We see no later aneurism formation,
and we see no late thrombosis problems. So far it is almost a dream come
true.

Other drugs are certainly going to work. There\'s no question that with
the wide formulation of the polymer, which I think is the key component
here, drugs that we always thought should have worked that didn\'t in
the past are now going to be given a second chance, and they include
paclitaxel, rapamycin, and possibly even other basic and inexpensive
therapies, such as steroids.

Finally, cost effectiveness, which I didn\'t review here, actually looks
quite good, and that\'s because restenosis is a costly event, and even
at the prices that are being charged now for the Cypher stent, they\'re
still cost effective, and hopefully with more approvals of proven
therapies the prices will come down, which is what\'s important for most
patients overall.

And I think ultimately drug-eluting stents will be used for other
functions and indications in the future, including potentially to take a
bite out of MIs in the future.

And I\'ll stop there. Thank you.

(Applause.)

DR. FEIGAL: Well, I think you\'ll agree with me this morning has really
been a tour de force. I think almost every type of therapeutic product
has been mentioned in one respect or another.

We\'ve run a little bit over time. So if you have questions, seek out
the speakers during the break. We will reconvene at 11:30.

(Whereupon, the foregoing matter went off the record at 11:15 a.m. and
went back on the record at 11:33 a.m.)

DR. HUSSAIN: Good morning. We are ready to start the second session on
preclinical challenges. Please take your seats.

We had planned for four presentations on different issues with respect
to preclinical challenges, and these presentations are roughly about 20
minutes. So if we get started on time, we\'ll have lunch on time. And I
was told that if we don\'t start on time, lunch is on yourself.

(Laughter.)

DR. HUSSAIN: My name is Ajaz Hussain. I\'m with the Office of
Pharmaceutical Science at Center for Drugs, and I\'d like to welcome our
first speaker, Dr. Leach. He will be speaking on preclinical development
and considerations for preliminary delivery of drugs approved for other
routes of administration.

Dr. Leach.

DR. LEACH: Thank you very much. And thanks to Dr. Provost and the other
organizers for inviting me to speak.

It\'s been an interesting morning.

I\'ll go pretty quickly here because I doubt that a lot of people are
interested in the nitty-gritty details of preclinical sciences. So I\'ll
try and give you an overview of some programs that have been
successfully done, as well as some ones that are in the development
process, as well as some that are in the early research stage, and you
get to choose which is which.

Okay. So to begin with the obvious, maybe it\'s a good time to always
state the obvious. A lot of thought really needs to go into any of these
program a priori.

The first thing you need to know is has the drug been to the site
before. Particularly with the lung, a lot of people have nebulized
things before and have gotten some amount of drug to some areas of the
lung, and that information may be very valuable.

Is the local concentration at the new site higher than before? Well,
almost always yes. We\'re trying to get more drug into the lung for
targeted lung disease, as well as new systemic applications of drugs,
existing drugs delivered by the lung.

The next thing is are the metabolic pathways present in the new site.
There are usually less metabolic pathways present, for example, in the
lung than there are in other tissues, like the liver or the kidney or
serum enzymes, that sort of thing. But you have to make sure. Maybe your
drug is a PRO drug by the IV route. You have to make sure you have the
enzymes to metabolize it to the active form.

Are there new susceptible cell types? We heard before that insulin is a
growth factor, and is a growth factor given in concentration of the lung
which has never been there before an issue?

Will new or existing excipients cause problems? This is a huge area. For
example, some excipients which are normally benign cause bronchospasm in
asthmatics or even normal individuals.

And, of course, our favorite, membrane disruptors. Those are usually a
no-no in lungs. You can get away with them in other areas, but membrane
disruptors in a lung, which may be part of a normal formulation is a
major issue.

And of course, my personal favorite, which is antibodies to proteins and
peptides. Will antibodies form? Will they be neutralizing or
anaphylactic? If they\'re anaphylactic, of course, you\'re out of
business, and if they\'re neutralizing, to a large extent, then with
repeated exposure your dose must go up and, therefore, it might be
impractical.

Okay. So let\'s start out with a couple of simple examples and work our
way towards the more complex. First would be approve drug, Proventil
HFA. It\'s called Air Amair (phonetic) in Europe, versus the existing
albuterol CFC products. It was the same drug. It was in a different
propellant. It was the same amount of drug delivered, same particle size
distribution, but it did have some improved dosing characteristics.
Okay?

So if you look at Ventolin on the bottom versus Proventil HFA, you can
see there\'s a clear difference there in what we call the plume, and in
fact, there\'s only about half the propellant in the Proventil HFA as
there is in Ventolin, and this resulted in a warmer spray and with less
force behind it.

The thought here was that there\'s a cold freon effect that causes some
asthmatics to have a cough or mild bronchospasm, and then if you reduce
that, then you could get more drug in more consistently. Pretty simple.

So to support that, we embarked \-- this is a 3M pharmaceuticals
product, and we embarked on a program and again went to the regulatory
authorities, and this is the first time there had been a switch from
CFCs to HFAs, and essentially they said, \"Gee, we have no idea what to
do. Go and do something and come back to us and we\'ll tell you if it\'s
okay or not.\"

Hopefully from the talk we heard this morning we won\'t be doing that
anymore and we\'ll have a lot better communication on new things in the
future.

So we designed our own program, and it basically was this. It entailed,
fundamentally, what you would do with an NCE at the very beginning
stages, say, through Phase I, maybe early Phase II.

And the studies we designed were actually fairly complicated in the
sense that we included safety pharmacology in them, as well as recovery
periods, and tried to design very well targeted studies to answer
specific questions that we thought of beforehand.

There was an inhalation teratology study in rats done, which of course
was negative for albuterol, and by and large unnecessary in our minds.
But at that time reproductive studies were in vogue in the \'90s, and
everybody wanted a reproductive study on everything regardless of
whether there was an indication or not.

Okay. Just to pick out one clinical study to prove the point that this
was, indeed, the same product as the old product, this clinical study
was a 12-week clinical study where half of the patients were exposed to
the HFA product and the other half the old CFC product, and this is a
durational effect in terms of FEV, and I\'ve actually shown you the back
half of this.

The first half was when the yellow ones are the HFA. They had no
difference in duration of effect through the 12 weeks, but then we did a
split-off study where we took those patients who were the CFC patients
at the end of this 12 weeks and then split them in half, continued one
half on the CFC and put the other half on HFA, and again, we see no
difference here in duration of effect.

And of course, there were many parameters involved in the study. This is
just one of them.

So for this particular study compound, then we had no preclinical
surprises. We knew exactly what the old CFC version produced in animals,
and we had no surprises in the animal studies that we did conduct.

We had no PK/ADME clinical surprises, and we had no efficacy surprises.
So no further preclinical studies were necessary, as deemed by the
developers, us and the regulatory authorities around the world.

Pretty simple, right? Well, three and a half years after we started
this, we made a submission, and about one and a half years later it was
approved. So this was a five-year program, and I think one of the
simplest that\'s ever been done.

If we go on to the next most complicated one, this is QVAR. It\'s also
approved in about 40 countries now, versus the old CFC product. Here we
have the same drug, different propellant, a different amount of drug,
different particle size distribution. Therefore, it went to different
places in the lung, as I\'ll show you in a minute, as well as some
improved dosing characteristics, which I won\'t go into.

Okay. So here we\'re going to see a very large difference then. If you
look at the old CFC products, they were about three and a half microns,
which is actually fairly large for pulmonary delivery. Greater than 90
percent of it actually went into the mouth, and less than ten percent
went into the lungs.

Not only that, but you can see a big difference here. That doesn\'t even
cover the large airways which actually extend to the periphery in two
dimensions of the lungs as opposed to the QVAR product, which is 1.1
microns, a very small amount relatively speaking, only 30 percent in the
mouth and 60 percent in the lungs.

And you can see that the lungs were covered very well. Well, this was
terrific, except it did raise some preclinical safety issues. This drug
is going to all the airways, as well as the alveoli, and what are the
safety consequences of that?

It should be great efficacy-wise, but this did raise a lot of questions.
So we performed the following preclinical program, which was, again,
sort of a modification of what you would do for any NCE, range finding
studies, 14-day studies, and then a 12-month inhalation study.

And the rationale behind the 12-month study was that this could cause
some endocrine disruption in young animals, and there needed to be some
long-term exposure. There was no scientific rationale to speak of behind
this, but nonetheless, there were people who thought this was important.

The other maybe more applicable explanation for requiring such a long,
hard study was that it might have an effect on the developing one on
branching. Again, there wasn\'t any real precedence for this, but some
people felt like it was important, and of course, again, in the middle
\'90s, being we conducted an inhalation teratology study in rats, again,
reproductive studies being in vogue then.

In fact, it was negative in that teratology study, but because the class
of steroids is labeled as having reproductive effects, this ended up
with a label anyway. So I\'m not sure why we did the study.

Okay. Well, let\'s take that product then. We did a preclinical program.
We showed that it really wasn\'t any different once you understood the
dosing between the CFC and the HFA product. What happens when you go to
Phase I?

And I don\'t really separate preclinical from clinical very well. They
should fuse right into each other and sometimes feed back. So, in other
words, if you set up your preclinical program and you find clinical
results in your early phases, they should go back to the preclinical,
explore those differences and then come back to clinical, and so forth,
and have an exchange that way.

So this is a prediction then of what would happen. If you give the
beclomethasone to the lungs, it\'s 100 percent bioavailable. It is about
20 percent bioavailable by the oral route. So if you come up with these,
you can do a projection here and say if you believe the dosing, if you
believe the deposition studies, then when you do your Phase I TK study,
if you give the same amount of Beclovent 100, which is the old CFC
product, versus the HFA product, you should get about 2.6 times as much
in the serum with the QVAR product.

So we tested this hypothesis, and we actually gave 400 microgram of the
BDP, old BDP against 200 and looked at the pharmacokinetics, and you can
see that, indeed, when you adjust for double the dose here, it was about
two and a half to one ratio with the BDP-HFA being the yellow line here.

Now, there\'s a couple of things you might notice. First of all, the
Tmax happens quicker with this than it does with the CFC, and that\'s
because of the oral contribution. So this actually did confirm not only
by the AUC two and a half difference, but also by looking at the
Cmax/Tmax values and showing that our hypothesis did appear to be
correct.

Okay. So then we\'re ready to go into the clinic, and so we did a dose
response relationship between the QVAR and the old product, got these
lines, drew the equivalence there and saw that it was as efficacious at
about 2.6 times less dose.

So, again, this is fitting with our preclinical, with our Phase I, and
so forth. And in fact, when you go on to long term clinical studies, you
can see breakthrough of asthma here, and you can see the yellow line
being the QVAR. You can see that at a two to one switch here there was
actually less breakthrough of asthma than there was with the old
product.

So the safety parameter. We looked at many, but of course, urinary free
cortisol is one of the major ones, and so you worry about that kind of
dose being given, and is it different?

When we looked at the urinary free cortisone, this is the placebo, and
these are the different doses, and in fact, we found that the \-- boy, I
switched colors here, yellow and red, just to see if you\'re awake.

In this case the yellow \-- oh, the yellow is the HFA. Sorry. The CFC is
the red, and you can see that there was no additional safety concern
matching doses of 800 versus 800, even though clinically 400 was
equivalent to 800.

Okay. So once again, we had no preclinical surprises in the two species.
We were able to predict the PK and the ADME clinical results, and there
were no efficacy surprises. So there was no further preclinical studies
required.

Now, this program, again, took about five and a half years to complete
and another almost two years to get registered once it was submitted.

So even these simple cases have not turned out to be so simple or cheap.

So now let\'s move into some of the things that are being worked on.
You\'ve heard a lot about proteins and peptides and insulin. Everybody
is very, very excited, as are we because there are just so many proteins
and peptides that are being explored now with so many exciting results,
but they have very serious delivery problems. They need to inject. No
one wants that.

The time of action is too short. Native structures are just too
susceptible to the peptidases, and all of those severely limit the
application.

Normally we\'re not allowed to show animals in distress, but you know,
this is not too distressful. This would be the same thing that you would
see in a human being. You\'ve probably heard that the average diabetic
may inject themselves 40 or 50,000 times during a lifetime. No one likes
that.

One of the things you probably don\'t hear enough about is the fact that
there are so many borderline diabetics or diabetics who just plain
refuse treatment because they don\'t want needles, period.

And that actually is a very important segment of population, in my
opinion.

Well, why don\'t you just swallow it? Well, with the bioavailability
orally of growth hormone, you\'d need about \$120,000 a day and quite a
bit of eating. That\'s not very practical.

So why not inhale? People say it\'s too hard. It takes too much
education, whatever. The fact of it is an 18 month old can use an
inhaler, sometimes even by themselves.

Just to back up a little bit, too, on what is the lung, the lung has 23
generations of airways, and those airways\' surface area would be the
equivalent of that towel thrown on the tennis court, and the tennis
court would be the equivalent of your lung surface area, and if you talk
about the volume of lung surfactant, it\'s about 30 mils.

So when people say they\'re worried about high doses to the lung, if you
have a very dispersable, well aerosolized product, that whole product
can actually use that whole lung, and you can imagine that a milligram
or three milligrams \-- whoa, five minutes? He\'s vicious. Okay. I\'m
going to have to skip some. I think the introduction went into my time.

(Laughter.)

DR. LEACH: So you can see that even though you\'re talking about a lot
of surface area, and sometimes you\'re talking about three milligrams,
four milligrams of drug, when you imagine those little particles spread
over that tennis court, it\'s really not a high concentration.

In fact, the concentration you\'re given by IV or Sub-Q is much greater
than this.

Okay. I\'m going to have to skip some here.

The rule of thumb though is that for about two to five percent of the IV
dose actually reaches a lung. That\'s not very efficient, not very
attractive.

Five minutes. So I\'m going to have to skip some of this.

Let me give you a couple of examples here. Leuprolide, which you\'ve
already heard about, is very, very limited by its side effects. We
wanted to see if we could get inhalation bioavailability to match an IV
dose in this, and in fact, this is a human clinical study, and I\'m
sorry it didn\'t show up that well. But we showed that we could do a
dose by IV injection and match that dose by inhalation very well.

As you know, the side effects can be severe, headaches, and especially
with these implantable devices. Once you get them implanted, you\'re
going to live with the side effects for a very long time, as opposed to
inhalation product where you can titrate yourself down or even stop
temporarily.

PulmoSpheres are our version of what you\'ve heard about this morning.
They\'re wonderful materials. They\'re hollow. They\'re porous. They\'re
ultra low density. They\'re able to get to the deep lungs so that you
can take advantage of that huge surface area.

They are actually made of lung surfactant themselves. DSPC and DPPC are
natural components of the lung excipient.

And so what are the preclinical issues here? Well, again, there\'s
larger lung concentrations that are going to be seen from leuprolide.
Lung doesn\'t normally see leuprolide, but again, you get big doses
spread over that tennis court, gives you reassurance that it\'s not
going to be too bad. One must certainly do the work anyway.

There\'s the antibody question, and then there\'s the excipient question
here. That\'s why people choose excipients that are very compatible,
biocompatible.

Okay. One of my personal favorites I want to spend a minute on is
antibiotics for lung disease. It\'s so unattractive to give an
antibiotic either orally or IV for a lung disease that I\'m surprised
that we haven\'t gone a lot further with inhalation antibiotics than we
actually have.

Here\'s an example of one that\'s actually on the market. If you look at
the blue lines here, they\'re what normally happens when you inject it
by IV. You can see that you get a nice, good curve here.

But when you go up and look at the lung, the lung values here \-- I\'m
not sure it\'s showing up. My angle is not good here \-- it\'s about 20
micrograms per gram of tissue. Okay? This actually is not too much
approaching the MIC.

Now, if you look at the lung lavage, you can see they\'re almost not
detectable. Well, you can take that same dose and give it by the lung
and you get none in the plasma. You get a fairly significant amount in
the lung lavage, which means that it\'s on the mucosal side where the
actual bug is, and a huge number in the lung.

In fact, there is a line broken here, and this number is 1,500 versus
about 20 on this line. So you can see that if you just have a good
powder, and I emphasize you just can\'t put these things in nebulizers
and expect to get these kinds of results because they\'re notoriously
inefficient. They don\'t get to the deep lung, et cetera.

If we go on to a more sophisticated study in dogs, this is an actual
tox. study, PK study and whatever kind of name we could put on it to get
to our endpoints. We see the same thing. We could get a nice, good dose
response relationship. We get plasma half-lives at 28 hours, and we get
lung tissue half-lives of 19 days.

And I think the important point here is we can get four orders of
magnitude difference between lung and plasma. So the hypothesis here is
that if we want two to three times the MIC, the plasma levels are likely
to be undetectable, and the plasma levels, again, are the limiting side
effect of this particular drug, and so those have the potential of going
completely away.

Skipping some of the good stuff, I added this in because of the mention
of PEG. PEG insulin is a very important thing right now. If you have a
long acting PEG, then you can provide basal levels to diabetics, and I
think most of Type Is and about 20 percent of Type IIs actually require
some basal injection.

And even when the inhaled product comes out, they\'re still going to
require that unless we come up with a longer acting. We think PEG is one
of the ways we can do this. PEG is a really interesting. They\'re very,
very safe. They\'ve been in many approved products, and the PEG is
actually a long chain here, and this would be the drug.

And not shown here is the hydrodynamic diameter. There\'s actually about
five to ten times the molecular weight of water that actually surrounds
this. So it protects it from the immune system. It also protects it from
degradation in the lungs, et cetera.

And I\'ll just show you one piece of data on that, and that is glucose
suppression. Again, I don\'t have time to go into a lot of details. For
those of you who know about insulin and know about glucose suppression,
if we give normal insulin, we normally can suppress glucose that would
go down to these sorts of levels, and it lasts about two hours and then
comes back up. You saw a similar graph earlier today.

If we use PEG insulin here, then we can go down, suppress it, and stay
out here. And we\'ve gone out to eight to ten hours, and we presented
this at the ADA meeting about a month ago. So we\'re very hopeful that
we can come up with a pegylated insulin that might last as much as ten
hours and get people through the night.

Okay. In summary, a route changed inhalation can offer fast onset. I
didn\'t get a chance to really talk about that, but, for example,
nicotine by inhalation only takes six heartbeats to reach the brain. So
things like fentanyl might be very interest for instant relief.

Higher bioavailability than some other routes. Freedom from ejection,
less side effects. The preclinical requirements should be unique to each
new change in route. I don\'t believe there\'s ever going to be a cookie
cutter approach to these issues. It needs very close work with the
regulatory authorities.

Preclinical programs should stress the exploration of known differences,
not unsubstantiated speculation or not what\'s particularly in vogue.
These things add up to a fear of the unknown and unreasonable
preclinical and clinical requirements that keeps many new drugs from
really happening, especially for the non-blockbuster category drugs.

I can\'t tell you how many conversations we\'ve had with drugs that we
know we can make significantly better or we can give by the pulmonary
route and really improve and meet an unmet clinical need, but if
they\'re in the 50 to \$100 million range, nobody wants to touch them.
There are many, many, many like that, and it\'s really heartbreaking to
know that we could do such a better job than what\'s out there, but the
economics are driving it.

And the fear of the unknown, which is my last slide.

(Laughter.)

DR. LEACH: Thank you.

(Applause.)

DR. HUSSAIN: Thank you for the excellent presentation. I\'m sorry I had
to show you the five minute page.

The next presentation is entitled \"Protein Delivery from Implantable
Devices: Challenges and Opportunities,\" to be presented by Bill Van
Antwerp, Vice President and Chief Scientific Officer of Medtronic
MiniMed.

DR. VAN ANTWERP: Well, thank you. I\'d like to thank Miriam and the FDA
for inviting us here to tell you a little bit about our view on protein
drug delivery.

You\'ve heard a lot this morning about things that might happen in the
future. Bob Langer, in particular, gave us a vision that\'s incredibly
long seeing.

I\'m going to tell you a little bit more about the grunt work that you
have to do in the lab to make some of these products possible.

Okay. So why protein drugs and why protein drugs and devices? Proteins
are becoming increasingly important for a variety of disease states:
diabetes, which is near and dear to our heart and everyone else\'s;
cancer; cardiovascular treatments; inflammation; HIV/AIDS; Hepatitis C,
for example.

Those are drugs that are now coming or now approved. There\'s a variety
of drugs from a variety of companies also coming on line that are
proteins. Proteins need delivery, as we have all heard. They need
delivery. They\'re not very bioavailable. They get denatured. They get
hydrolyzed. They get degraded by enzymes, and if those escape some of
those routes, they\'re not absorbed very well either due to their size
or due to their polar or charged distribution.

There\'s a variety of companies developing novel technologies. We just
heard about pulmonary delivery. There\'s a variety of depo injection and
other technologies. We\'re going to talk about the old fashioned way,
which is basically delivering through the skin through a subcutaneous or
interperitoneal infusion using mechanical devices, pumps.

Bob Langer showed you something like this slide earlier. This is a
classic case where we have a drug that has about a six-hour half-life,
and if I deliver it via injection and then I have in blue here a
therapeutic range, I need to give another injection 12 hours later when
I\'m just at the nadir of activity. Well, I have to deliver 14 times as
much drug.

More importantly, the side effects are often due to the peak
concentrations. Enzyme activation is incredibly important. In fact, in
Colin Denney\'s group at M.D. Anderson he\'s shown that high
concentrations of drug actually deactivate enzyme or activate enzymes
that deactivate the drug, and I can deliver via mechanical devices drugs
with a perfect matching of the drug to the therapeutic range.

Today parenteral delivery of drugs are done via two old routes, IV
administration, subcutaneous injection. Two routes that have had some
success, continuous subcutaneous infusion via mechanical pumps and
continuous interperitoneal infusion, both of these mostly for insulin,
but they\'ve been used for a number of other compounds as well.

And we\'ve heard a lot about subcutaneous depos, PLGA microspheres, PEG
attached peptides, micro emulsions, pulmonary delivery, and also
there\'s some new routes, intrathecal and intraparenchymal delivery.

Medtronic has a significant business in intrathecal delivery of small
molecules, morphine and baclofen, although just recently we\'re starting
to look at those routes to get drugs into the brain, cross the
blood-brain barrier using proteins.

Well, what are the challenges? Well, Bill Clinton said it about the
economy. Here I would tell all of you involved in drug device
combinations that it\'s the formulation. Formulation, formulation,
formulation.

Old challenges, formulation stability, chemical stability, clearance
issues in the body once you inject it, but when you start to give drugs
by mechanical devices, you run into two new problems.

One is physical stability. If you pull a syringe full of insulin out of
a bottle and I inject it Sub-Q, I don\'t have to worry too much about
the physical stability of that insulin.

If I put it in a mechanical device, I have to worry a lot. I also have
to worry about some PKPD issues because now I\'m giving it continuously
in a trial that we just finished, the Phase I trial. We had a dose
escalation study planned. It turned out to be a dose de-escalation study
because when I gave the drug continuously, it was much more effective
than we had thought by continuous or by multiple injections.

We found that patients had to down-dose rather than up-dose, and we have
to think a little bit about toxicity in a different way. This is not
systemic toxicity, but if your formulation isn\'t right, we need to
worry about localized site reactions. If I have got an injection
catheter that\'s in the subcutaneous tissue and it\'s supposed to be
there for three days, I have to make sure that the formulation of the
drug is suitable for those three days of delivery.

Regulatory hurdles, let\'s not reinvent the wheel. We build devices. The
device physics are what they are. If we build a pump, it turns out every
time we want to put a new drug in the pump we have to prove that the
pump pumps again, even though we\'ve shown in the laboratory that it
pumps with a wide range of viscosities. It\'s always an indication that
we have to prove that the pump pumps again.

The same thing is happening with drug chemistry. We\'re developing a
prefilled insulin cartridge. The insulin degradation chemistry has been
well known since the late 1920s. Yet we have to show that the impurities
in our insulin are exactly the same as the impurities in all the other
insulin formulations that have ever been developed.

The same with drug packaging. We try to use for pumps the kind of
packaging materials that people have been using for the drugs for a long
time, but again, we need to show stability.

There are, however, two areas where we need to pay much more attention.
One is pump-drug interactions and drug physical stability. What we like
to say in our laboratory is that when God invented insulin, She didn\'t
design it to be stable for 90 days at body temperature sloshing around
in a metal can.

These are the kind of things that traditional drug systems don\'t need
to think about. We need to think about physical stability.

Stability in pumps has two components: chemical stability, which in our
hands looks very much like stability in primary packaging. We don\'t see
chemical changes in formulations that we don\'t see at the same
temperature in primary packaging.

Physical stability is important. Why is it important? I\'ll show you in
a minute some results from some studies, but physical stability
generally leads to things like soluble aggregates, Soluble aggregates
are well known to lead to antibody issues that you don\'t see, for
example, with noncontinuous infusion.

There have been a wide variety of measurements of physical stability in
the protein business. Every protein company has five or six in their
labs. None of them seem to give you exactly the same results, at least
in our hands, and I want to propose some testing that I think makes
sense in a lot of situations.

People have looked at turbidity, concentration changes, fluorescent
spectroscopy, microcalorimetry, and a whole variety of other things.

As I said before, chemical stability determined by the molecule, by the
formulation. One important point to note, that relatively
straightforward formulation changes can affect stability, and what we
have seen in devices ranging over a wide range of molecular types,
interferons, insulin, interleukins, and a variety of peptides, large and
small, is that the stability in the device is pretty much the stability
in the primary packaging.

Physical stability, however, isn\'t. It depends on a number of things.
Probably most important: the physics of the device, whether they\'re
sheer or compliance in the system; what the materials of contact are,
Teflon, titanium, polyolefins, silicone oil. All of these are common in
medical devices.

Agitation is incredibly important, as is body temperature storage.

We believe that in physical interactions there are a couple of steps
that are important. The first is absorption. The next is denaturation,
typically on the surface, and we believe that a lot of the story in
terms of physical stability of proteins and devices can be told by
looking at partially unfolded intermediates.

Tony Fink\'s group up at U.C.-Santa Cruz has been a leader in this idea,
and we concur with some of what he has done. Once we get these partially
unfolded intermediates they lead to aggregation on the surface, which
then leads to aggregation in solution.

We have a model here. Part of this model was originally proposed by Bob
Langer many years ago now, but we have a protein. It sticks to the
surface, then unfolds, falls back into solution, forms aggregates, and
the model is autocatalytic.

And we test this in the laboratory now. Five years ago it took six
months to a year to understand all of the physical stability of a
protein in a pump. We can now test it in a few hours or a few days.

And basically this is the autocatalytic curve. We put the protein in a
96 well plate with some Thioflavin T. Thioflavin T is a fluorescent
molecule that only fluoresces when it\'s bound to aggregated proteins.

We look at the fluorescence as a function of time, and we curve fit this
to the autocatalytic curve model. You see that the correlation
coefficient is .99, which is quite nice.

What\'s the point of all this testing? Well, the point of all this
testing, one point here is to look at the physical stability in contact
with a number of materials so that when you\'re designing devices you
always have to design with materials that are available. You know, FDA
doesn\'t like to see new chemical entities particularly that might end
up in your drugs.

So here we\'ve taken a formulation of insulin and compared it in the
same experiment with Teflon, polyethylene, glass and titanium, and what
you see is that the Teflon is by far the most susceptible to
aggregation, whereas glass and titanium are quite nice.

And this difference here, this difference between 50 hours and 150
hours, we have good correlation to stability in clinical testing in
pumps.

Similarly, and this is the formulation issue with a different compound,
different formulation, we have two drug substances, a new one and an old
one, and we formulated them two different ways. In one case we simply
dissolved the protein at high pH and then pH\'ed it down to pH 7.4, and
then the one we call low pH, we took the drug substance, dissolved it in
acid and then took it up through the PI to the appropriate pH.

And you see that even though the end formulation is exactly the same by
any chemical tests that we can do, the physical stability when I start
out at low pH versus when I start out at high ph, this is a factor of
four or five more stable, which has significant implications in the
clinic.

Okay. So where does that leave us? Formulation, formulation,
formulation. We\'re a device company. We\'re not a drug company. All of
the products that we put in our devices come from biotech companies,
typically not big PhRMA, although insulin is obviously not the case.

If you want to talk to someone about devices, if you\'re a PhRMA company
or if you\'re a device company wanting to talk to PhRMA, start with the
formulation. There are multiple interactions that you need to study.
Control of the material interface is the most important thing, and
what\'s very important from the regulatory standpoint, device design and
formulation need to work together and be regulated together.

We always talk about our devices breaking proteins. This is a picture of
a protein that actually broke the device. This is a seal. This is a
titanium seal, and you can see the titanium here. This is a deposit of
insulin crystals that formed on this seal, and this was ten years ago
now, on an implantable pump, and you see that this seal worked perfectly
fine, except where this crack was.

This crack allowed actually insulin to flow out. The seal no longer
worked. This caused us a lot of headaches. It turns out that it was a
materials and formulation issue which has now been solved thankfully.

So in conclusion, interactions need to be managed. They need to be
understood. Pump design and formulation need to work together.
Combination product components can be evaluated separately using
historical data. We have pumps. We know how they work.

However, we need to pay appropriate attention to the drug-device
interactions. Those are the things that are critical.

And when I talk about \"we,\" I really mean \"they.\" This is the
Protein Formulation and Stability Group at Medtronic MiniMed. They only
let me in the lab now to get coffee for my coffee machine.

(Laughter and applause.)

DR. HUSSAIN: Our next topic is developing a local drug delivery
combination product for postoperative atrial fibrillation, preclinical
challenges, by Dr. Kevin Skinner.

DR. SKINNER: Thank you very much, and, Miriam, thank you for organizing
this conference.

We\'ve been working on this project for two years. So I\'m going to
discuss the development process, and at this point in time we\'ve gone
from concept to a bench research level, and we\'re at a preclinical
research level.

And the concept actually came from clinicians and marketers, and they
brought that idea to us. We started evaluating this concept of marrying
biomaterials with an old drug entity called amiodarone, and then we took
it into preclinical research to get a proof of concept.

In the near future we\'ll take it into a preclinical development phase,
which will enter into a history design, and then move it into the
clinic.

So postoperative atrial fibrillation, it\'s a kind of tachycardia that
you see in patients following CABG and bowel surgery. It happens around
20 to 30 percent of the time, and usually happens within three to five
days, but it can happen up to two weeks following surgery. It increases
the length of stay for the hospital or for the patient up to 1.5 days,
and people have assessed or have followed this from an economic
standpoint, and it can cost the patient about 8,000 more dollars.

You get a decrease in cardiac output. You get an increase in stroke due
to stasis in the atria, and there have been prophylactic treatments, but
they\'re not widely accepted. Amiodarone is a drug of choice for
treating postoperative atrial fibrillation, but it requires at least for
oral dosing seven days prior to surgery, and if you use the IV
formulation, you have some severe side effects.

So amiodarone is probably the most widely used antiarrhythmic for
clinical use. Its label indication is for ventricular tachycardia and
for ventricular fibrillation and super ventricular tachycardia. However,
it is used off label for atrial fibrillation. In fact, it\'s the most
common use of or amiodarone is the most common use for AF.

It\'s a Class III drug, which means that it increases the action
potential, and increases the effective refractory period.

But, as I said, one of the drawbacks with the drug is it has high
toxicity for pulmonary, and it also causes bradyarrhythmias following
loading doses. The systemic doses you actually have to load up to gram
quantities within the first week, and then it tapers down to between 800
and 400 milligrams.

So the thought was: could we deliver that drug locally? And there was
some basic research done by Ayers and Zipes, where they locally
delivered the drug into the pericardial sac. However, they had to load
it for three hours, and they looked at several doses. They looked at the
EP parameters following the administration of amiodarone locally, and
they measured myocardial drug levels.

So what we have here is we have both the atrial refractory period and
also the dose level, and so what you see is increasing from the control
up to the five milligram dose you get an increase in atrial refractory
period and also an increase in tissue levels.

And the effective doses or therapeutic levels that they saw in the
tissue was between 20 and 120 micrograms per gram of tissue, and this is
the data that you see in humans, patients that have died, and they have
posted their tissues and have posted the level of amiodarone. So, you
know, that\'s the therapeutic level of drug.

And in these animals they only had a small amount of trace drug that was
found following the dosing for three hours. So the thought was could we
find a biomaterial that we could put amiodarone into it.

Genzyme had a collaborative research with a company called Focal and
subsequently acquired the company, and the technology is a
bioreabsorbable PEG based hydrogel. It\'s actually approved in the
United States and in Europe for lung sealants for pulmonary leaks, and
in Europe it\'s approved for dural sealants. It\'s tissue adherent.
It\'s compatible with drugs and biologics. You spray it on or you can
drop it on as a liquid and you photopolymerize it with light. The
product can be tailored to whatever application you\'d like to use it
for.

So the questions we wanted to answer were could amiodarone be delivered
via this tissue adherent hydrogel and could we get effective doses, and
can we reduce the amount of drug levels, and would it not be
systemically found?

And can these drug levels cause an EP effect that would prevent AF?

So the product characteristics were could it adhere to cardiac tissue.
We have a pumping structure. So that was a challenge for us. Could we
deliver the drug locally? Were we able to reduce the level of drug? And
could we deliver it up to 14 days? And was it compatible with cardiac
tissue?

So before we even went into doing animal studies, we wanted to make sure
that there wasn\'t a drug-device interference or a device-drug
interference. So we wanted to make sure that the hydrogel did not affect
the amiodarone. So we did HPLC mass spec analysis and demonstrated that
the drug was not affected by the hydrogel or its individual components.

We also made sure that the amiodarone didn\'t affect the in situ
polymerization of the hydrogel or other properties of that hydrogel, and
we could load up to five percent of amiodarone into the gel without
affecting those properties, and then we demonstrated [in
vitro]{.underline} release that we could get up to two to three weeks of
drug being delivered out of that hydrogel, up to one percent of the
amiodarone being loaded into the hydrogel.

So in the first study that we did preclinically, we implanted the
hydrogel amiodarone at a half a percent and one percent onto the canine
heart. We came back seven days later, looked for levels of amiodarone in
the cardiac tissue and also its active metabolite desethyl-amiodarone,
and we also looked at other tissues in the body, lung, kidney, and
liver, and also urine and blood, and then we observed for any adverse
events in animals.

So after seven days at the half percent we got around 64 micrograms per
gram of tissue in the half percent loaded gel, and the one percent gel
gave us around 230 micrograms per gram of tissue.

The gel itself had only eluted only 30 percent of the drug at day seven,
and we found four to six percent of the metabolite desethyl-amiodarone
in the treated tissue, and there were no measurable drug levels in the
lung, liver or kidneys. We did see some in the cardiac pad around the
pericardium, but it\'s known that amiodarone, because it\'s fat soluble,
will reside there. And there were no adverse events seen in any of the
dogs.

So our next study was, you know, we can deliver the drug, and the amount
of drug that we can deliver, would it have an EP effect on that?

So we looked at four groups: just the hydrogel itself, the hydrogel
loaded at half a percent and one percent, and then we did a surgical
control group.

And we measured EP parameters preoperatively, postoperatively, three to
five days, ten to 14 days, three to six weeks, and collected the tissues
for drug level.

So what I have here is a chart that shows pre-op. Basically there\'s no
difference between any of those groups.

Immediately after implanting the hydrogel or the hydrogel and drug, you
see an elevation in EP, but the sham group also shows an elevation. So
just the act of surgery increased the atrial refractory period, but by
day three and five we see a significant increase in the treated group of
almost a 50 percent increase in the EP in the treated group, and by day
14 you see the elevation of the EP relative to the control group, and we
also see the effect out to three weeks.

And then when we harvested tissue at three weeks, we had therapeutic
levels of the drug within that tissue.

So what we had shown in the preclinical research aspect of this project
is that we\'re able to deliver amiodarone to the cardiac tissue at
therapeutic levels, which is significantly lower than IV and PO routes.
As I said previously, you have to deliver gram quantities of amiodarone
orally or milligram quantities IV. But for us, we were delivering
milligrams, 16 milligrams, 32 milligrams, and we were delivering it once
over a three-week period.

And all of those studies that we have done so far have shown no systemic
levels of the drug other than where we placed the material.

And the product has been well tolerated in all of the animal studies,
and we demonstrated that we were able to elevate the effective
refractory period, which is indicative of the proof of concept to reduce
the incidence of AFIB.

So where are we today? We\'re getting ready to plan the preclinical
development strategy, and one is to leverage the existing data from
FocalSeal. It has been approved in the United States and also in Europe,
and the amiodarone has been approved for IV and oral formulation, and
there\'s a generic form out there already.

So what we\'d like to do is bridge those existing data that\'s out there
and just do studies that are necessary to really evaluate it for the
specific use we\'re using.

In this chart, you know, when we were coming up with a strategy, we were
trying to figure out, you know, was this going to be ruled a device or
is it going to be ruled a drug, and somebody in our regulatory
department came up with this cartoon.

And so if you look, what you have is the drug, the potential drug, and
the way of delivery, and what you\'re looking at is a generic drug which
is amiodarone or a new indication or a new drug entity, and if you, you
know, look at how it would be delivered, whether it be chemically
modified or would it be a depo effect or does it also have a device
action.

So when we talked about drug eluting stents today, you either can look
at it as a dip coated stent where it was a generic drug and it had a
device action and it was ruled by CDER or whether it\'s a drug coated
stent with a polymer that\'s being ruled by CDER or, in our particular
situation, we have a generic drug, and it has a depo effect. So it\'s
being ruled by CDER.

So, you know, what are the bridging studies that we think we need to do?
One is to look at the long-term degradation of this product on the
cardiac tissue, and what are the acute toxicity issues of placing a
biomaterial on the heart with the drug being delivered to the specific
part of the heart?

And then what are the temporal drug deliveries? We\'ve only looked at
very short-term delivery of that drug, and we need to look at long term.

And then we would do confirmatory EP studies once we finalize the
formulation.

So in summary, post AFIB is a serious unmet medical need which may
benefit from the advances in therapeutics that are delivered at the time
of surgery. The combination product of amiodarone and a synthetic
adherent PEG based hydrogel shows promise for safety and efficacy in
preclinical models.

We\'d like to leverage prior studies and perform appropriate bridging
studies that should provide facilitated regulatory approval of this
drug-hydrogel combination.

And this combination product is a good example of a device/drug
combination with a primary pharmacologic mode of action.

Thank you very much.

(Applause.)

DR. HUSSAIN: Well, I was conflicted. I wanted to keep everybody else\'s
time on the thing so I could use all of the time.

(Laughter.)

DR. HUSSAIN: No, what I\'d like to do is sort of in some ways connect
the various presentations that occurred this morning and also hopefully
help set the tone for the afternoon discussion on regulatory.

Although I\'m from FDA, I\'m not actually taking a regulatory
perspective, but more of a scientific, broad, almost an academic
perspective. So the title of my talk that I\'ve selected is different
from what\'s in the brochure. I essentially would like to sort of take a
step back and summarize for you some of the discussions this morning and
present to you the concept of quality by design, which I think is a
preclinical opportunity to address many of the challenges.

In this session we had three wonderful presentations before mine, and we
looked a preclinical challenges with respect to pharm tox and the need
for doing additional pharm tox studies when there is a route of
administration change or when there is a potential for change in
exposure, and the exposures may lead to or trigger some safety concerns.
And I think if there is a better way of addressing that, that would be a
step forward.

And the second presentation was, I think, very important from my
perspective to sort of highlight the importance of physical stability
and in some ways I have sort of built some information on that from my
perspective also. And I think physical stability is a gap in terms of
our ability to analyze, do testing, which is proper and relevant, and I
think there\'s a significant opportunity for collaboration there.

And then finally we had a presentation on local drug delivery and how
does one sort of not only start with [in vitro]{.underline} methods that
start screening interactions as well as moving towards a methodology
that sort of demonstrates the local effect, and local effectiveness is
also a significant challenge for us as we move forward.

So to sort of summarize some of the discussion and looking at quality by
design concepts, what I thought I\'d do is share with you the current
FDA initiatives. This workshop is focused on the initiative as Dr.
McClellan talked about, improving innovation in medical technology. This
is the workshop sort of starting this initiative, but there are two
other initiatives, and there are synergistic interactions between these
initiatives, and I think hopefully you\'ll see a linkage between these
two.

I would like to sort of put on my academic hat and use a very old slide
that I used to use when I used to teach, and this was sort of an
evolutionary step in pharmaceutical products and process development,
and I want to sort of use that as a framework for defining quality by
design.

Pharmaceutical manufacturing, as opposed to, say, device manufacturing
and so forth, essentially originated in the other pharmacy compounding,
and it has moved over the last 30 years to more science and engineering
based.

So now you can start talking about pharmaceutical engineering, and I
think there is a big advantage of thinking of developing products from
an engineering perspective.

In that vein, I think we have moved from dosage forms to now what we
call drug delivery systems in the late \'80s. And now we\'re moving
towards innovative or more intelligent drug delivery systems, and I
think that\'s the drug delivery systems and intelligent drug delivery
systems which is essentially the focus of this initiative and workshop.

But in terms of, I think, quality by design, we have to take a step back
and see how we are developing these products and what impact does that
have on efficiency of development and time to market.

Traditionally pharmaceutical development started with trial and error
type of experimentations where it\'s often difficult to manage the
multi-variables and the interactions between those variables. We moved
to a more of design of experiments, more empirical statistical designs
in the mid-\'70s, but yet we have not moved to computer aided design,
and I think we have an opportunity to start thinking in those terms, and
it can have a very significant impact on not only the development time,
but I believe on the regulatory assessment itself.

If we\'re able to move in this direction, I think we will have our
resources focused on testing more creative options, and that\'s what I
want to sort of convey with this slide at this point. The other aspects,
I think, end product testing, a focus on testing to document quality as
opposed to real time quality assurance also has some bearing and is part
of the other initiatives I talked to you about, but I will not get into
that in detail here.

If you look at the traditional approach to formulation development,
Professor Langer had a slide in his second to last slide, I believe,
where he had a black box, and through strategic experimentation and so
forth, if you notice the black box became transparent, then you could
see inside the black box, and I think if we are focused on trial and
error and being part of the art of product development, then I think we
have a black box to deal with, and that poses significant regulatory
assessment challenges and leads to questions which may not really be in
the best interest of the development program.

So if you look at traditional dosage forms, a typical pharmaceutical
focus would be making sure it\'s stable and then it\'s bioavailable, and
we approach that formation development looking at drug and excipients,
the physical and chemical properties to develop a formulation and then
try to understand the [in vivo]{.underline} and [in vitro]{.underline}
attributes of those products that we develop and screen, and how are
they absorbed and are they bioavailable or not?

So there are many aspects that sort of bring in the physics and the
chemistry as well as the test methodologies or also the physiology that
comes into consideration to develop a formulation which is bioavailable
and stable.

But this is relatively simple when it comes to drug delivery systems. I
think the challenges get confounded and have significantly much more
than that, and typically I think the CMC and GMP considerations that I
think we struggle with is to insure consistent quality and performance
is the objective. How we design and how we develop specification for a
given product, how do we manufacture and how do we establish
manufacturing processes and their controls, test methods and shelf life
are key challenges.

And then once we have an approval, you know, process validation,
manufacturing under GMPs and making sure that the manufacturing remains
consistent are significant challenges, too.

Studies during development can have a significant impact on development
time. Many speakers before me have touched upon that, but I think I\'m
talking about bridging studies with respect to bioavailability
characterization from a chemistry perspective. So you have to address
some of those, and in absence of good analytical methods that relate to
[in vivo]{.underline} of performance or to shelf life, it becomes very
difficult to manage changes that are necessary during the development
program, and the bridging studies can become very elaborate and can
often be clinical studies themselves.

So unless I think we think of new methods, I think these are potential
bottlenecks in the development program that I think we will face.

Post approval changes often is not on the minds of people who are
focused on developing formulations and doing the clinical studies. But I
think thinking about post approval changes is important. Change is part
of life, and changes lead to improvement at the same time, but if
you\'re not able to change and justify those changes, that can lead to
significant problems, too.

And I think that\'s the point I was trying to make with continuous
improvement, is if the regulatory process is tedious, the methodologies
that we use to define comparability or establish comparabilities are
difficult. Then the technology, the innovation is hindered, and I think
we have to start thinking more proactively in terms of how we move
forward here.

And this is the point I want to make, is when you start bringing drug
and drug delivery systems, you have not only a large number of factors
to understand and optimize, but you have an even larger number of
interaction terms, and these include, I think, considerations from
anatomy, physiology and pathology, pharmacology of the drug,
pharmamechanics of the drug, biopharaceutics, physical and chemical
attributes of the drug, the polymer, and your device.

And in fact, the drug delivery system itself is quite complicated, and
if we remain in sort of a black box mode, bridging studies, post
approval changes, even establishing specifications can be very
challenging.

So I think we have to start thinking of more of an engineering approach
to designing these systems, and that\'s the phrase I have used, is
quality by design. We all know Quality 101. You cannot test quality in
the product. I mean, that\'s well established. You have a design for
quality.

And I think I have defined quality by design as achievement of product
and process performance characteristics that are adequate for the
intended use through scientific understanding and management of sources
of variation and other risk factors due to manufacture.

Most of this process gets started in the development itself, and based
on my experience at FDA, much of this information is not either shared
with FDA or there\'s a strong hesitation to share this. So the
regulatory assessment without some of this information can sometimes
become quite challenging.

So I was recently looking at Los Alamos Laboratory presentations on
designing missile systems and so forth, and I stole the plane from that
slide, and I think the key here is what are the design objectives, the
target to reach our target goal, and in the case of drug delivery
systems, they have very exciting design objectives, and I think the
hypotheses out there are mind boggling, and I think the innovation that
will occur in the next ten years is going to be amazingly productive and
useful for public health.

But I think we have to be very diligent in moving towards this in a
structured, scientific way to make sure the innovation is not hindered
because of regulatory concerns or, as one of the speakers used, fear of
the unknown.

If I take a look at drug delivery systems now, past and present, our
focus has been on changes in route of administration and bringing drug
delivery systems through different routes. Clearly the deployment, how
we administer this has been relatively simple.

For example, if you have a transdermal drug delivery system, some of the
key features that are important for deployment is the adhesive
performance, but the deployment can get more complicated, say, if you
think about a drug eluting stent. It\'s a procedure that require
additional deployment attributes to be considered.

Drug delivery in the current situation is primarily based on PK and PD,
and the intention or the design objectivity of the drug delivery system
is between proof compliance, patient compliant, and also to improve
safety and efficacy. Many have used examples of the peak concentration
and potentially that relating to safety, and I think more controlled
release allows you in many ways to improve safety.

But the future, I think I see the deployment attributes could get more
complicated because now you\'re looking at more sophisticated devices
either implanted or otherwise, and you may have to have considerations
for what are the right deployment attributes and how does a drug coating
or a drug combination alter that or how do we manage that from a
chemical stability, shelf life perspective also?

And clearly I think the desire is to move towards more target oriented
drug delivery system. The challenges and the opportunities associated
with those challenges are currently in the pharmaceutical development
quality and performance consistency has been based on traditional
chemistry testing. I feel, and I think the previous presentation made a
good point for that, that there are gaps in physical test. We have a
difficult time addressing physical changes which are important and
establishing shelf life based on physical changes are still more
complicated.

The way forward in my opinion is we have to be proactive and look for
these challenges and start working on those now. If we don\'t then we
create bottlenecks and its difficult to get over those bottlenecks.

Clearly, if I just use a quick example of drug coated stent, but
starting with stents themselves, I think if you look at what are the
design considerations here, intracoronary stents are deployed to form a
scaffolding for the coronary artery vessel wall during coronary
angioplasty. So I think the applied and the procedure leads to a number
of issues that I think we have to think about.

How does the drug coating affect this process? Or is this process
affecting the drug coating itself, and so forth? That sort of comes
through that in the design consideration.

I\'m going to skip this slide.

So as we start thinking about how do we identify and optimize critical
factors, trial and error experimentation under all selected conditions
is one way, but I don\'t think it\'s practical. There are significant
opportunities where I think quality by design brings in an engineering
approach where computer analysis employs numerical techniques of finite
elements coupled with completion of fluid dynamics can help us
understand our systems better and actually help us control or design
systems that will address the sources of variation quickly and up front
and also have this information available to at least discuss with the
agency.

One of the issues, i think, which is quite important, is the release
rate. Many speakers have essentially argued the importance of the
release rate from either drug eluting stent or any other delivery
system. But what are the design objectives? What is optimal [in
vivo]{.underline} release profile? What is the mechanism and rate and
duration of this release? How do we establish specifications?

These are important questions, and unless we think of different ways,
the way today is to establish these specifications based on a limited
amount of information. The opportunity is there to actually get to the
mechanisms of these release profiles and actually start building back
into the decision making criteria both in the companies and FDA.

So how do we establish controls and tests? Factors that influence
release profile [in vivo]{.underline} as well as design feature itself
and manufacturing factors, [in vitro]{.underline} test methods, quality
assurance, and [in vivo]{.underline} relevance I think are important
questions.

And with a focus on testing to document quality, these would be quite
challenging, but with a move towards quality by design through
scientific understanding, I think we can find a better way of moving
forward.

For example, I think with drug eluting stents what is an appropriate [in
vitro]{.underline} method? I think that is a significant discussion
point and a debating point of how does one start addressing that
question.

Is that the right way of dealing with the quality issues or even
establishing [in vivo]{.underline}, [in vitro]{.underline}, and real
correlation? I think these are topics that I think we need further
discussion.

The only point I want to make here is if we assume traditional drug
release profiles and use, for example, bulk elution models, this is a
publication from MIT-Harvard. Professor Hwang is one of the authors of
this, and this was published in [Circulation]{.underline}, essentially
identifying some of the challenges in terms of drug release.

If you use traditional approaches, we get a flat concentration profile,
but if we examine the coronary artery after application of a stent,
there\'s a potential for localize effect, which may be very different
from and is not picked up by the traditional pharmacokinetics modeling.

So if we establish an [in vitro]{.underline} release profile or an [in
vivo]{.underline} release relevant to a traditional [in
vitro]{.underline}/[in vivo]{.underline} correlation, is that the right
question? Is that the right thing or are we even asking the right
question?

So these issues come up. So I think there is a wonderful connection
between the new initiative and the initiative on drug quality system,
and I want to sort of end my presentation \--I\'m on time \-- end my
presentation with a couple of slides sort of explaining the other
initiative and so that you can see the connection between the two.

In the direct quality system for the 21st Century, I think what we have
articulated here is a vision. Pharmaceutical manufacturing is evolving
from an art form to one that is now science and engineering based.
Effectively using this knowledge in regulatory decisions as we establish
specifications and evaluating manufacturing processes which can
substantially improve the efficiency of both manufacturing and I would
argue development manufacturing and the regulatory process.

This initiative is designed to do just that through an integrated
systems of product quality regulation founded on sound science and
engineering principles for assessing and mitigating risk of poor product
and process quality in the context of intended user of pharmaceutical
products

So the desired state essentially as we have defined here is product
quality and performance achieved and assured by design of effective and
efficient manufacturing processes, and this is the point I was making.
Product specification based on mechanistic understanding of how
formulation process factors impact product performance, guarantees real
time assurance of quality, but in order to get there, I think the
regulatory system that has to evolve, our regulatory policy should be
tailored to recognize the level of scientific knowledge, supporting
product applications, process validation, and process capability.

Risk based regulatory scrutiny then relates to level of scientific
understanding of how formulation and manufacturing process factors
affect product quality and performance, and the capability of process
control strategy is to prevent or mitigate risk of producing a poor
quality product.

With that I\'ll stop. I know we\'re running late. If you have any
questions, I think why don\'t we have you sort of contact the speakers
directly?

So we will hold the questions to individual questions if you can catch
us. If not, then have a great lunch. Thank you.

(Whereupon, at 12:49 p.m., the meeting was recessed for lunch, to
reconvene at 2:00 p.m., the same day.)

A-F-T-E-R-N-O-O-N S-E-S-S-I-O-N

(1:47 p.m.)

DR. PROVOST: We did offer the public the opportunity to comment, and we
did have one request to speak, and that is Dr. Paul Goldfarb. He\'s with
Oncology Associates and is a clinical professor of medicine at U.C.-San
Diego, and Dr. Goldfarb will make his presentation now.

DR. GOLDFARB: Thank you.

My name is Paul Goldfarb. I\'m a surgeon actually, and I do cancer
surgery. I trained at Memorial Sloan-Kettering, and so I guess in the
context of today\'s meeting I\'m a maximally invasive radiologist.

(Laughter.)

DR. GOLDFARB: I have had the opportunity to work with two different
companies that deal with ablation of tumors using drugs. I find it
intriguing because in doing surgical oncology we\'re always looking,
despite what most other physicians think, we\'re actually looking for
new ways of achieving the same goals using less invasive technologies
and trying to find new ways of dealing with it.

I\'ve been to the agency several times with Genetronics, and I\'ve
certainly been aware of the work at FeRx and have helped them do one of
their trials that we\'ll discuss today as well, and the reason that
I\'ve come again is because I think these are critically important
issues to us who do clinical medicine and surgery that need to be
addressed.

Today I\'m using a computer generated presentation. The last time I came
in November I did it with overheads. So even I have moved forward with
the technology.

I think there\'s a pressing clinical need to develop new technologies to
control localized disease. I think more and more we\'re finding other
needs to control local manifestations of disease, either primary or
recurrent.

We\'re looking for less invasive ways of doing it, and we want to find
ways that are more protective of normal tissues. The rapid adoption of
thermal ablation targeted radionucleotides, hypothermia, embolic agents,
and cryosurgery reflects the fact that all of us are looking for these
noninterventional ways of approaching these kinds of tumors.

The drug-device combinations as novel drug delivery systems provide the
potential to enhance the effectiveness and reduce the adverse events of
intertumoral delivery. Right now we have tumor ablation systems that
combine drug delivery systems in multiple parts of the body, and as you
can see from the slide, those are all of the organs, all of the solid
organs that we\'re now looking at using drug delivery systems to try to
treat with local therapy.

Now, we are able to achieve high local drug concentrations. There\'s low
systemic exposure, and we have equivalent response in the tumors to
other ablative forms of therapy, including surgery, the advantage being
that we\'re able to preserve adjacent normal tissue.

This is one of the ways I actually got into doing radio frequency, was
that it seemed like such an obvious move that if I could use an ablative
technology that would preserve the half of the liver that the tumor was
sitting in, that I\'d be able to manage the patient much better than
doing right hepatic lobectomies, even though it pays less.

The two companies that we want to talk about are FeRx. FeRx you\'ve
already heard described briefly this morning in the discussion by the
radiologists. It\'s an intertumoral drug delivery system which takes
doxorubicin and uses small magnetic pellets to put the drug directly
into the tumor.

And as you saw this morning, it\'s easy to target the tumor using the
technology, using a simple external magnet.

Genetronics is a company that uses electroporation as its way of
enhancing the delivery of drug. Electroporation is the technique where
you create an electric field within the tumor by using a series of
needles. You inject the bleomycin into the tumor initially, and then by
creating the field you allow the drug to enter the cell, and you
essentially get ablation of the malignant tissue with protection of the
normal healthy tissue around it.

In both of these systems \-- and that\'s why I came back, because now we
really have two different products that address things the same way.
Utilizing well characterized drugs with known safety profiles, we
deliver the drug to a localized area with minimal systemic exposure.

What we\'re really doing is utilizing novel devices to deliver this well
established drug. In both systems we have an ablative effect that\'s
confined to the area of the drug delivery and affects malignant tissues
independent of histology and demonstrates a clinical benefit analogous
to that of thermal ablation or surgical resection.

The issues that I want to talk to you about for a few minutes are the
regulatory pathways and the standards that we\'re using for these sorts
of products I believe are inappropriate for the perceived clinical
benefit; that in both cases CDER is the lead review agency for both of
these combination products, and I understand why CDER is the review
agency, and my education in this that has gone on for the last five
years has taught me that the issue is really not which agency reviews it
or which division reviews it, but how it\'s reviewed, and so I don\'t
think that\'s an issue.

There are no other products that have localized ablative effects at
disease sites that have been required to do such extensive testing and
have such extensive review.

The drug components of these combination products in both cases that
have been approved and used clinically for decades, they have safety
profiles that are well characterized. They have extensive scientific and
medical therapy supporting multiple therapeutic applications, and the
technologies in these two cases are being developed by using reduced
therapeutic doses of drugs.

So really the dose of Adriamycin or bleomycin used in these technologies
is essentially homeopathic, and that they have minimal systemic exposure
to the drug. Both of these products which have a local effect are
currently held to the same evidentiary standards and regulatory burdens
of new drugs having untested and potentially significant systemic
effects.

FeRx is in the process of conducting a Phase III study of over 200
patients with hepatocellular carcinoma, comparing their local therapy to
a systemic chemotherapy in patients with end stage disease, and the
study is using the survival endpoint.

The Phase I and II studies have already been done, demonstrated
efficient tumor targeting using their product with Adriamycin; showed
durable local disease control; and showed that the dosing paradigm was
really based on the size of the tumor and not on the patient weight.

The new paradigm that we\'re looking at is to use ablation therapies
regardless of what they are in terms of hepatocellular cancer because we
now use it as a bridge to liver transplant. Liver transplant is
perceived as the gold standard for the treatment for liver cancer. The
role of ablation technologies has really become one to stabilize the
patient until the liver is available.

And so in a sense, that\'s the clinical arm. That\'s where we would be
using it clinically. We\'d be much less likely to use this local
ablation therapy in people with far advanced disease.

And as I say, stabilization of the disease then becomes a viable
surrogate clinical endpoint because that\'s what we would be doing in a
clinical environment.

Here\'s an example of how the FeRx product works. Here\'s a tumor. You
see the blood supply on the left.

Since I took my pointer back, I\'ll have to use \-- there\'s the tumor,
and you\'re able to actually put the drug just where the tumor is and
have the clinical effect of ablating that tumor.

What\'s been interesting and what I\'ve worked with FeRx on is using the
same technology in a group of patients who have metastatic cancer. So
these are people who have non-hepatomas, and the question would be: can
this drug Adriamycin, which we normally would not use in these other
settings, be of value?

And, two, the thought had always been that the blood supply to
metastatic tumors was such that it didn\'t allow for easy interarterial
therapy. In fact, what we demonstrate, and these are studies using PET
scans, and so what you\'re really saying is that this is the tumor
before treatment, and the patient after treatment. At least
physiologically you can say that the tumor is not viable.

These are early studies, but we certainly plan on following up on this,
and I think this is the future for this kind of therapy. I use it to
highlight the issue that the therapy works independent of histology just
as radio frequency works independent of histology.

This was the second patient where, again, there\'s the tumor and there
was the effect on PET scan.

Genetronics is a company that has a local therapy, and they embarked
upon treating head and neck cancer as the model that they wanted to test
in, and we were initially involved in a classic Phase III randomized
trial in which we were going to take people with far advanced head and
neck cancer. Half would get this local therapy. All would get systemic
chemotherapy, and we would try to demonstrate a survival advantage.

I must say as a surgical oncologist I thought that the study was
inappropriate in the sense that that\'s not where I would use a local
ablation therapy, and I thought the chance of meeting that goal was
unlikely to occur.

And so I called Mark Kramer about a week after he got his new job and
said, \"You\'re in Combination Products. I\'ve got a combination
product. We need to figure out where do we go from here.\"

And so with Mark\'s help and in renegotiating with CDER, we have now
evolved a study which I think is more clinically relevant in which we
take people with early recurrence or second primaries, and we\'re
looking at comparing the role of this ablation technology to surgery
because that\'s really the standard.

I would not expect that the ablation to do better. So as we saw this
morning when they were talking about stents, we\'re sort of trapped
because we have this positive gold standard comparator rather than
comparing it to nothing.

But I think what we could show is that the control rate of these tumors
will be no worse than it is with surgery, and arguably since we\'re able
to do a much smaller, less invasive procedure than what I would normally
do as a surgical oncologist, we should show functional improvement, and
we should show pharmacoeconomic advantages that it should be cheaper and
easier to achieve the same goals.

Now, the ongoing challenge is this is a stretch for the people at CDER
just as it\'s a stretch for all of us, and so it has required ongoing
negotiations about what really is a functional benefit and how do we
measure this and how will we really know what\'s going to happen.

What we had shown originally with electroporation is \-- I\'ll go over
it. At the agency\'s behest, we took a bunch of people and injected
bleomycin into the tumor with no electroporation, and we got essentially
no result.

We then took people with far advanced cancer and injected bleomycin,
electroporated them, and essentially we got a 50 percent objective
response rate.

But we also had a group of people in Europe who had primary head and
neck cancer, and these people were treated in a way that\'s very similar
to what\'s been done with ablation. They had their tumors
electroporated, which consists of injecting drug, putting the needles
in, treating the whole tumor. They were electroporated, and then several
weeks later the tumors were cut out. So we basically had a treat and
resect model, which is the classic ablation technology.

In those now 20 patients there\'s nobody who has had a local recurrence
out to two years. There were three who had microscopic cells in the
resected specimen.

I argue that if I was coming with a new form of ablation technology that
used luke warm temperature instead of hot or cold and I said we have 20
people where we treated and resected, we\'d have a discussion about
whether this is approvable instead of embarking upon a 400-patient
study.

I realize the challenge that I\'m presenting, but I think that these are
issues that need to be raised, and since the afternoon is set aside for
discussion of regulatory issues, I hope this is a good lead-in to that
discussion.

Now, my suggestions are both of these products are subject to review
standards typically applied to novel drugs with unknown risk and safety
profiles, with large numbers of patients, and a survival endpoint. The
device products that have been approved for local ablation type effects
have been subjected to much less extensive clinical data requirements.

Given that the safety profiles of both drugs are well characterized,
there\'s minimal systemic exposure. The requirements for approval should
be comparable to devices that have an ablation effect.

When I came in November, my approach was basically at that meeting that
we should look at all of the \-- everything we\'re dealing with either
has a local effect, a regional effect, or a systemic effect, and so it
doesn\'t matter, I would argue whether it\'s a drug, a device or a
biologic. We look at the effect on the patient, and that sort of defines
how we should look at it in terms of regulation, and that might make it
easier.

Both products are innovative device-drug combinations that utilize a new
route of administration for old drugs, drugs that have been formerly
administered intravenously and should have reduced time in clinical
development and reduced evidentiary requirements.

Recommendations. New therapies need to be compared to other therapies
that have a similar effect on the patient. Therapies which are local,
regional and systemic in their effect should be compared to therapies
with a like effect regardless of which division is assigned as the lead,
Device Drugs or Biologics.

To expedite the review and approval of innovative devices for the
delivery of known drugs, the evidentiary standards must be appropriate
to the potential risk-benefit in cancer patients. And I speak basically
as a surgical oncologist.

We need to implement new regulatory pathways and least burdensome
principles for innovative technologies that allow for rapid market entry
and for patient benefit.

I\'ve been working with these products for over five years. It seems to
me that after five years and several hundred patients were treated it
would be nice if we could find a way to move this forward in a more
expeditious manner.

I understand what the barriers are, and certainly we\'re living within
those guidelines and moving forward, but I think as a surgical
oncologist, first because of my surgical personality, and then, two,
because of my ongoing clinical needs, I come to say to you we need to
find a better way to do it.

I\'d close by saying it reminds me of what Yogi Berra said. Yogi Berra
said that in baseball 50 percent of baseball is 90 percent mental.

(Laughter.)

DR. GOLDFARB: And so I think regulatory approval is the same in a sense
in that regulatory approval, 50 percent of regulatory approval is 90
percent negotiation, and so I hope that this opens the door so that we
can continue that process.

Thank you very much for allowing me the time.

(Applause.)

DR. PROVOST: Thank you.

And now I\'d like to introduce the moderator for the first session of
this afternoon on regulatory issues, the industry perspective, and
we\'re very pleased to have Dr. Liz Jacobsen here. Liz is a former
FDAer, was at FDA for a long time, and is now at AdvaMed as the
Executive Vice President for Technology and Regulatory Affairs.

DR. JACOBSEN: Well, thank you very much, and it always bothers me a
little when they say \"a long time.\"

(Laughter.)

DR. JACOBSEN: Welcome to the industry perspective session. It\'s my
pleasure to be the moderator for this segment and also for the final
session, which is going to be the FDA-industry kind of Q&A session.

And we\'re hoping to get some good discussion going at the end of the
day, and first we\'re going to have remarks from sort of a legal
perspective from the device and drug industries and from FDA.

So we are going to ask you if you would hold your questions for those
sessions, either hold them in your head so you can go up to the
microphone at the last session of the day or write them down and you can
give them to Miriam at the break or whenever you see her, and she\'ll
make sure that they get up here, and we\'re hoping that that will work
because obviously we would like to have some good Q&A.

Okay. Well, first up in this session, the industry perspective, is
Jonathan Kahan, partner at Hogan & Hartson, and he\'ll be talking about
regulatory and legal challenges for the developers of drug delivery
systems.

MR. KAHAN: Thank you very much.

Good afternoon. I want to thank Dr. Feigal and Dr. Provost for inviting
me to speak this afternoon. I promise to be on my best behavior.

And there is good news and bad news, I think, in my presentation. I
think the good news is I will have no slides of blood fields or tumors,
and the bad news is I\'m going to try to walk you through some fairly
dry legal and regulatory issues, although I\'m also going to try to give
you, I think, the perspective, at least my perspective, on some of the
significant issues that industry has faced over the years in this area.

I\'m going to start out by talking very briefly about the legal
framework. I\'m then going to talk about the historical approach that
FDA has taken to the regulation of combination products and drug
delivery devices over the years.

And then I\'m going to talk about the obstacles and challenges that
we\'re all facing in this area and try to talk about some new policies
and procedures which may be appropriate in this area to try to change
around what I think a lot of us, including many at FDA feel is not an
optimal area right now. There are many, many delays and inefficiencies
in the process, and I think we\'re going to have a good discussion about
that this afternoon.

Just for those of you who are interested in definitions, a lot of what
we\'re going to be talking about this afternoon has to do with the
definitions of drugs, devices, and biologics. And without going into too
much detail and putting everybody to sleep, basically drugs are articles
intended to prevent, cure, and treat disease, intended to affect the
structure and function of the human body. It\'s basically the same
definitions for devices, except the devices do not typically achieve
their primary purposes through chemical or metabolic action.

I\'d say the rule of thumb is if it\'s more mechanical, it\'s a device.
If it\'s more metabolic and chemical, it\'s a drug, although they, as
we\'ll talk about probably in depth this afternoon, they very often tend
to merge, and it becomes a very metaphysical discussion as to whether
the action of the product is chemical, metabolic, or physical. In many
cases, as we\'ll discuss, it\'s all three.

Biologics, I have no clue as to what a biologic is.

(Laughter.)

MR. KAHAN: This is the definition of biologic. It\'s sort of like
pornography. You know it when you see it, but it\'s hard to define, and
biologics are basically derived \-- there are definitions under the
Public Health Services Act and we\'ll talk about in a minute that are
actually products that are combinations of drugs, devices, and
biologics, all in one specific product.

Just historically, just to give you the perspective of what we\'ve all
been facing for years and years, back before 1990, we sort of addressed
all combination products, including drug delivery devices on sort of a
case-by-case basis, and you\'ve heard that very often it was a question
of negotiation, and that\'s absolutely true.

In many of these cases, there was negotiation not only between the
companies and FDA as to how the product was going to be regulated, but
there were also negotiations within FDA as to how the product was going
to be regulated.

I\'ll give you just one example. I\'m going to try to keep the war
stories to a bare minimum, but biliary lithotripters is just a good
example to start out on and combination products generally because with
respect to that product you had a lithotripter that could fragment
gallstones, but it needed to be used with a litholitic agent, which at
that time was ursodiol or Actigol, the product that was on the market at
that time.

And the companies came to FDA and said, \"We want PMAs for our
lithotripters. Clear these devices.\"

And FDA said, \"No, this is a combination product, and it needs to be
used with the drug,\" and they said, \"But the drug has already been
approved for the dissolution of the stones.\"

And Steven Fred then in [Gastro]{.underline} at CDR came back and said,
\"Wait a minute. It was cleared for nonfragmented gallstones. We need an
NDA supplement for fragmented stones.\"

That was basically the end of the process. The drug company was not
willing to work with the device companies, and 12 years later, probably
13 years later, the drug company finally decided to allow access to its
NDA files, and that product was approved.

But that roadblock, which I\'ll talk about again in a minute between
access to drug files and master files and IND files is one of the key
factors that has led to many, many problems over the years in the drug
delivery area and in combination products generally.

How did we seek to resolve this issue? I believe that the disaster we
face on biliary lithotripters was one of the reasons that Congress
decided to address the law in the Safe Medical Devices Act of 1990,
which added the combination product regulations.

As a matter of fact, the person who actually drafted the first
combination product statutory division was Pat Schraeder, who\'s not
here today, when she was working with Senator Kennedy\'s committee on
that, and at that time, the first draft of this regulation and statute
was essentially designed to allow one filing. There was not going to be
an NDA and a PMA for one product.

Congress backed down on that probably through the second or third draft
of the law, but essentially what came out of the law was we need some
structure to combination products, and the way we\'re going to add
structure is we\'re going to work with FDA and we\'re going to say that
the primary mode of action is going to be the key standard for
determining whether a product is going to be regulated by the device
center, by the drug center, or the biologics center and under which
statutory authorities is that product going to be regulated.

The problem is that Congress never defined primary mode of action, and
to this day it has never been defined, and FDA, as I understand it and
will talk about this this afternoon probably during Mark Kramer\'s
presentation, FDA, I believe, is now starting down the road of seeking
to actually define primary mode of action, and I think we all welcome
that.

Mark is also going to talk about the definition of combination products.
So I\'m not going to get into it very much, but simply to say that the
technologies that are coming along right now are mind boggling. You\'ve
only heard of some of them, and I never cease to be amazed by the
combinations of drugs, devices and biologics that are presently on the
drawing board and which FDA is going to be facing very shortly.

And one of the things that we\'re going to talk about today is whether
the 20th Century standards and regulations that FDA now has in place are
going to be adequate to handle the 21st Century technologies that are
presently coming down the pike. It\'s no longer going to be are we
looking at prefilled syringes, but are we going to be looking at
products, for example, a dopaminergic cell that\'s encapsulated in a
semi-permeable polymer that elutes dopamine. So you have a drug,
dopamine. You have a dopaminergic cell, which is a biologic, and you
have a semi-permeable polymer, which is a device. And there are many,
many products that are presently coming down the road that are going to
be combinations of many different kinds of tissues, drugs, deices, and
biologics.

So I\'m going to let Mark handle the rest of that one.

(Laughter.)

MR. KAHAN: With respect to exactly the regulatory structure, again,
others are going to be better able to deal with this. I\'m just going to
very quickly talk about sort of what really happens when a company has a
combination product.

Over the years, we basically have dealt initially with the product
jurisdiction officers. That would be Warren Rumble right now in drugs,
Gene Burke over in Devices, and Cheryl Lord Weiford over in Biologics,
and often we simply seek to get an indication or a feeling from them
when we initially have a product.

What do you guys think, based upon your institutional memories? Do we
need to file a request for designation?

And under the Safe Medical Devices Act of 1990, Congress said, \"Wait a
minute,\" and FDA implemented regulations under Part 3 that said, okay,
if you\'re not sure, you can file an RFD, a request for designation, and
we will tell you within 60 days how we\'re going to regulate your
product, what\'s the primary mode of action, and in some cases in those
letters, they actually tell you whether it\'s going to be a PMA, a
510(k), and what the NDA process may look like.

And we often start out with discussing these issues with the product
jurisdiction officers. We find that helpful. We then move on to the
request for designation, and the next stage is, once you\'ve gotten the
designation, we then go to a pre-IDE or a pre-IND meeting to actually
flesh out exactly what the data requirements are going to be.

Now, if you\'re a smart company, you start thinking about the data
requirements at the early developmental stages of your product, not when
you\'re sitting down with FDA and talking to them in a pre-IDE or a
pre-IND meeting.

And, therefore, I think the most important thing I can probably say
today is start early and communicate very well with both your
clinicians, your engineers, your regulatory affairs people, and try to
prophesy early on what you might need for that pre-IDE, pre-IND meeting
later on.

And then you\'re going to later have to face, if it is a combination
product, coordination between CDRH, CBER and CDER. Mark will talk
probably more about exactly what they call their consultative meetings
and their collaborative reviews and consultative reviews.

But the bottom line is if it\'s going to be one center with primary
jurisdiction, they will consult with another center, and if it is a
collaborative review with two primary reviewers, you\'re going to have
input from two centers at once, and that\'s often not the best way to do
it.

So I think most of us would try to seek to have one center with primary
jurisdiction and the other center consulting so that you\'re not
whipsawed between two centers during the process.

Just to again give you the historical picture here, over the years FDA
has sort of developed their own gestalt internally, some of which is
reflected in the inter-center agreements, which I would urge all of you
to read, although I\'m about to tell you I think they are out of date,
outmoded and need to be revised.

But they give you a picture of what FDA\'s thinking actually is, and if
you look at the inter-center agreements, you\'ll see that things like
prefilled syringes and infusion pumps and transdermal patches, those
kinds of things have all been pretty much defined as to how FDA is going
to look at them. That\'s what I call the early generation products,
although ionaphoresis devices have given FDA heartburn for quite some
time, and I won\'t go into how FDA has regulated ionaphoresis devices
over the years, but it\'s not a pretty picture.

And with the new products coming down the road with regard to
ionaphoresis devices, hopefully meetings like this can help develop new
paradigms for how to regulate products like that.

Simply another very quick example on metered dose inhalers, if those of
you who remember those products were originally all regulated in the
device center through the 510(k) process, there were then I wouldn\'t
say it was a fight. It was a very cordial discussion between the device
center and the drug center about whether the droplets and the size of
the droplets and the efficacy of the drug that is taken in through the
metered dose inhaler requires the inhaler to be regulated in the drug
process with the approval of the drug, like albuterol sulfate, for
example.

And that\'s what happened. All got shifted over to the drug center based
upon the safety and efficacy issues that CDER thought were raised as
part of the drug delivery process of the drug.

The second generation products, most of you didn\'t realize that your
cigarette was a drug delivery device. Neither did the Supreme Court,
and \--

(Laughter.)

MR. KAHAN: \-- therefore, that issue is no longer on the table, but
there are many other products during the second round, which I believe
FDA has been thinking quite a bit about. The drug-coated catheters and
stents have primarily been regulated through the device center where the
drug coating on a catheter, for example, if you had an antimicrobial
catheter, if it\'s an approved antimicrobial the device center has
pretty much kept jurisdiction.

On the drug-coated stent, you\'ve heard a lot about that. We\'re going
to talk a lot more about it later. The bottom line is there that I
believe that what FDA did there they should be congratulated on. It was
a very well thought out, a very common-sensical approach. The studies
and the way FDA is handling that I think is optimal, and I hope that
that kind of paradigm can be used further in the future.

I did sit in in one meeting where Dr. Lipicky, the head of
Cardiovascular Drugs, indicated that he wanted a 10,000 patient study,
and I think the device company fell out of their chair at that point,
but what we ended up with was studies that started out initially with
1,000 patients, with post-market requirements up to a couple of thousand
more patients.

And while it is true that a two to 3,000 patient study cannot meet the
ICH guidelines for a one in 10,000 adverse event rate, identification
rate, I believe that the approach that\'s been taken here with the
coordination between the drug center and the device center and the
working groups that have been set up is absolutely a paradigm that can
be applied to other drug delivery devices in the future.

I\'ll just mention a couple of others. There are drug delivery
lollipops. In working on that one, FDA\'s primary concern was that
Grandpa would leave his fentanyl lollipop on the stand and his grandson
would get a nice dose of a controlled substance, but chewing gums and
lollipops and other drug delivery devices through the oral mucosa is
another way that we\'re going to see in the second generation those are
already now on the market and in use.

Now, this third generation of products is one that I think is going to
cause FDA a lot of trouble, and it\'s going to cause the companies a lot
of trouble, and it\'s going to require a lot of creative thinking, and
we\'re going to talk about this in a second, but one of the major issues
that we\'re going to be facing now is that some of these drug delivery
devices are going to be delivering multiple drugs at one time.

And let\'s say that you had \-- I think Dr. Langer talked about the
microchips device which could have 100 wells, and let\'s say you\'re
going to have 20 different drugs in those 100 wells. Do we need to get
an NDA supplement or an NDA for each drug that\'s going to be in that
little pacemaker?

I think those are the kinds of issues that we\'re going to be facing in
the very immediate future.

I\'m now going to talk about the challenges that we\'re facing with
these products, and I\'ll try to be quick because I don\'t want to take
too much more time.

Drug delivery devices are often developed initially by the drug
companies for uses with approved drugs or biologics, and that usually is
the easiest paradigm to deal with. If it\'s an approved drug, usually
CDER and CDRH are pretty comfortable with it, and that\'s why you will
see some of the silver-coated wound dressings or antimicrobial bone
cements. There\'s not too much heartburn at FDA about that, and the
agency has been able to regulate those products fairly well.

However, when you switch to new or different indications for the drug or
you have a different mode of delivery or a different drug or dosage
schedule, all hell breaks loose, and then you have to really start in
what is essentially a scientific regulatory negotiating process with the
agency.

And the question then is when you modify the drug formulation to
optimize delivery with the device, are you now having, as a couple of
people have said, are you now about to reinvent the wheel and have to
start over with, let\'s say you can skip Phase I of the drug process and
go to a Phase II/Phase III drug trial, at the same time that you\'re
demonstrating the safety and efficacy of your device.

That is not something that most device companies want to do. They do not
want to reinvent the drug wheel. And so the question is: is a new NDA
required for the drug if you have a different delivery mechanism than
the mechanism that was described in the NDA-approved label?

In other words, the NDA was approved for IV use or subcutaneous
injection and now you want to deliver it in that little pacemaker
that\'s implanted. Does that require you to have to go through an
entirely new NDA process?

Let\'s say that you change nothing with respect to the drug that\'s
being delivered, although there may be stability issues and a tiny bit
of a reformulation. Are you going to have to start the NDA process over
again?

I\'m going to raise a lot of questions. I\'m not even going to pretend I
have the answers to all of these questions. I tell my kids I have all
the answers. They don\'t believe me either, but I\'m not going to try to
answer all of these. Maybe this afternoon with people smarter than I
we\'ll be able to try to answer some of these questions.

All I can say is that it is not optimal to start over when you have a
new drug delivery device, to start over in the entire new NDA process,
and I\'ll talk about a couple of alternatives in a second.

So the question is, when you have this sort of combination of a drug
delivery device and either a new drug or a drug which has been modified,
which predominates in the review process? Is it the PMA for that new
novel MicroCHIPS pacemaker type device or is the NDA process going to
predominate?

And does the device labeling have to conform, mutually conform to the
drug labeling? This is an issue which Mark has on his plate right now
for several different companies and the inter-center agreements say that
the drug labeling and the device labeling have to mutually conform.

So you couldn\'t clear a device, theoretically, unless the device\'s
labeling was in conformance with the drug labeling, and the inter-center
agreement primarily talks about conforming in terms of formulations,
dosage and schedule, but it doesn\'t necessarily address all of the
issues.

For example, if you have a device that\'s now being delivered
subcutaneously and you now want to have it implanted in a pacemaker to
deliver the drug over time, does that now mean that you have to have an
NDA supplement or change the drug labeling?

And if you\'re not the drug company, what do you do? You can\'t change
that drug company\'s labeling if you\'re a device manufacturer. So what
do we do?

Here\'s the challenge. The challenge is that if the pharmaceutical
manufacturer authorizes access to their master files, their DMFs or they
authorize access to their NDAs and their INDs, all of the world would be
a lot easier, and it is not very often that you have the drug and the
device company in the same shop. I mean, there are companies like
Johnson & Johnson and others that are lucky enough to have both drugs
and devices in the same company, but very often the device company
doesn\'t have access to the drug company\'s files.

So especially if the device allows a broadened use of the drug the
pharmaceutical company would probably likely agree. That\'s more drug
sales and, therefore, they\'re more likely to grant access or authorize
access to their master files or their NDAs.

But in some cases drug delivery devices allow a more optimal and
efficient delivery of the drug, and therefore, less drug is going to be
sold if that drug delivery device is approved by FDA, and that\'s a
disincentive for PhRMA to cooperate with the device industry.

So what are the regulatory implications here? Without PhRMA cooperation
the device companies have a very difficult time obtaining NDA approval,
as we saw with the example I used earlier with respect to Actigol and
the biliary lipotripsy paradigm.

The applicability of Section 505(b)(2) is an issue presently on the
table. 505(b)(2), it\'s not really a paper NDA, but it\'s like a paper
NDA where you rely upon literature and existing data to avoid having to
file a 505(b)(1) brand new and spanking new NDA.

And query whether a device company using the 505(b)(2) process can with
a different, let\'s say, route of administration and a clear drug
product, can they then rely on 505(b)(2) without a drug manufacturer
even on the horizon to get their product through?

A real tough issue. I don\'t have the answer. It is something that a lot
of companies are looking at, and it is one way for the companies to
proceed.

The regulatory pathway conundrum: should a 510(k) or PMA be required
with an NDA for each new drug delivery device? In the QLT example with
photodynamic therapy we had sort of a pullout PMA for the lasers and the
fiber optics that went in at the same time as the drug NDA, and believe
it or not, it was a miracle. The three PMAs and the NDA were all
approved on the same day.

That example worked out well there. There have been other examples.
There was actually a 510(k) with a pullout NDA for these H. pylori
breath detection devices where you had C-13 labeled \"urea\" having to
be approved by the device center. That pullout didn\'t work real well.

So I think what I\'m pushing for is more along the lines of what the FDA
has done with drug eluting stents. If you look at the Cypher labeling,
it looks like drug labeling through a lot of the package insert, and I
believe that with these combination products, you can mix drug labeling
with device labeling to appropriately reflect the intended use of the
device with the appropriate precautions and warnings such that the user
of the product will have information that\'s appropriate for both the
drug and the device side.

The lead center conundrum, I\'m going to let Mark address this since
I\'m just about out of time, but let me just say that we need a new
definition of primary mode of action. Primary mode of action is one of
those areas where we need guidance from FDA.

There is a very, very extensive database of primary mode of action
decisions under the RFD process that have never been made public, and in
fact, I don\'t think FDA ever put them in one spot. I think Mark is now
gathering the historical precedents in this area, but I think we would
all feel very much more comfortable if we entered into the process
knowing more about what primary mode of action means.

Finally, just to sort of sum up here, I believe that there should always
be a preference for one submission. The idea that you have to go through
the NDA process and the PMA process or 510(k) process at the same time
to me is not optimal.

And the idea that we had back in 1990 for a unitary approval mechanism,
I don\'t know whether you want to call it a CPA or a combination product
approval, but maybe we need new legislation that would allow us to look
at whether we still want to keep primary mode of action as the standard.

Do we want to have a new statutory provision that would replace primary
mode of action and go to a uniform, a unitary combination product
approval to avoid what was just stated in the last presentation, where
you end up with a disconnect between the way the drug center would treat
the product and the way the device center would treat the product?

And I believe that many in industry believe that there is a different
approach to product approvals within the device center and the drug
center.

Conclusions. Dual approvals, not optimal. I think most people would
agree with that. Primary mode of action, standard. We need a new
guidance. We think it\'s outdated.

I believe that guidance documents with respect to specific classes of
drug delivery devices would be very, very helpful.

How about guidances with respect to drug eluting stents? What do you
expect on the drug side? What do you expect on the device side?

Nasal inhalation devices, what do you expect on the drug side? What do
you expect on the device side?

A lot of work. It\'s going to require a lot of coordination between the
centers, but specific product area guidances would be very, very helpful
to the companies going through the process.

A uniform, unitary drug delivery device mechanism, such as a combination
product approval, that would be great. More involvement by the Office of
Combination Products. I\'m not trying to get more staff for Mark, but I
believe that it would be extremely helpful for the really novel drug
delivery devices and combination products for somebody in the Office of
Combination Products to have liaison responsibility with the centers,
not that they need adult supervision. It\'s just it would be helpful to
have some liaison and someone that\'s involved in the process from the
very beginning to help negotiate and have a liaison between the centers.

Thank you very much.

(Applause.)

DR. JACOBSEN: Thank you very much, Jonathan.

Jon mentioned in his talk about Pat Schraeder being an early player in
combination products, and Pat sends her apologies to everyone. She
intended to be here to represent AdvaMed and to give the device
industry\'s perspective, but she had to cancel at the last minute, and
we\'re very fortunate to have her colleague, Keith Smith, who is
Director of Regulatory Affairs from BD who has graciously agreed to
present this perspective in Pat\'s place.

And then Nancy Isaac, Vice President for Regulatory Affairs and Quality
at Aerogen, is going to take her place later today on the FDA industry
panel.

So with that, we\'ll turn it over to Keith.

MR. SMITH: Thanks.

Good afternoon. I\'m sure most of you know Pat. So I certainly don\'t
look like Pat or talk like Pat, but I\'m going to do my best.

Okay. My name is Keith Smith. I\'m Director, Regulatory Affairs at Beck
and Dickinson, but I am here today as a member spokesman on behalf of
AdvaMed or Advanced Medical Technological Association.

AdvaMed is the largest medical technology association in the world,
representing more than 1,100 innovators and manufacturers of medical
devices.

One of AdvaMed\'s principal roles is to support laws and policies that
foster innovation and bring safe and effective technologies, including
novel delivery systems, expeditiously to the market.

In January, the FDA announced a new initiative to help make certain
innovative medical technologies available sooner and to reduce the cost
of developing safe and effective medical products. While still
maintaining FDA\'s traditional high standards of consumer protection, we
applaud the agency for identifying as one of the core areas of attention
of this initiative novel drug delivery systems.

Novel delivery systems are an important subset of combination
technologies ranging from implantable infusion pumps to magnetically
based delivery devices, to systems that automatically deliver anesthesia
drugs in response to a patient\'s vital signs.

The new technology intended to improve targeting of chemotherapeutics by
blocking blood flow, novel delivery systems were identified as a
priority area for FDA\'s initiative because they represent an exciting
area of technology development with potential to significantly improve
patient therapy and public health yet are often slow to reach market due
to complexities and uncertainties in the pre-market review process.

Our discussion today focuses on these pre-market complexities and
uncertainties and how we might improve our regulatory processes so as to
further the Commissioner\'s goals of encouraging delivery system
innovation.

The comments we provide summarize the principal concerns and
recommendations received from AdvaMed member companies on the three
questions identified in the June 5th [Federal Register]{.underline}
notice.

The first and most general and overarching of the agency\'s questions
asked that we identify current critical challenges in developing and
bringing to the market novel delivery devices.

As an initial comment, we are gratified that some of the historical
challenges relating to regulatory processes are beginning to be
addressed. As you know, AdvaMed, working closely with FDA and Congress,
helped implement Section 204 of MDUFMA which, among other things,
created for the first time in the Office of Combination Products having
as one of its key functions to serve as an advocate for combination
technology, including novel delivery systems.

MDUFMA also provided a statutory directive for the office to help ensure
timely and efficient premarket process and to establish dispute
resolution mechanisms should impediments arise during those processes.

With this new law, we have an important first step to refining and
improving premarket systems in this area.

Challenges, however, remain; four in particular, all relating to the
fundamental framework of premarket review, still requiring further
consideration, clarification, and consensus if we are to preserve the
progress we have made thus far in combination technology and achieve
further improvements.

First, we have conveyed previously we must reaffirm the agency\'s past
interpretation of primary mode of action, which has allowed so many
innovative and important combinations to reach market using device
jurisdictional standards.

Second, we must refine and preserve the agency\'s historic inter-center
practice of applying flexible approaches to cross-labeling, an issue
that arises not just at the end of a premarket review, but also early on
in setting jurisdiction and defining pathways for many novel delivery
systems.

Third, we need to create new guidances that allow for more creative and
flexible approaches to data development for this class of products, with
the device authorities clearly and consistently applied for the device
and/or the device component parts of these reviews.

And finally, we need better understanding and clarification of those
circumstances where parallel path review may or may not be appropriate.

These four framework issues are, of course, not the only instances that
require continued collaboration attention. For example, enhanced
communication and transparency, greater predictability of data
requirements, and further efforts to reduce the number of review cycles
are all important areas for ongoing improvement.

However, our focus today is on a broader framework of challenges, using
the premise that if the framework itself is first optimized to foster
innovation and to reduce needless data burdens and avoidable delays,
secondary product improvements more easily fall into place.

First and foremost among industry challenges in the jurisdictional
standard of primary mode of action and reaching consensus with the
agency on the appropriate interpretation of this term.

Before discussing this issue, however, a brief comment on the agency\'s
reference to novel drug delivery systems in this context. The term
suggests devices serving to deliver a drug which may inadvertently
misdirect primary mode of action analysis and thus inadvertently
misdirect jurisdiction.

For example, some of the devices listed in the [Federal
Register]{.underline} and agency press releases and Web announcements
leading up to this meeting, including orthopedic products containing
biomaterials, hyperthermia/drug combinations, and drug eluting stents.

In each of these cases, the device component has been determined to
provide the primary mode of action with the drug facilitating the
device\'s performance. These are not drug delivery systems for purpose
of jurisdictional determinations. For this reason, we suggest not using
the term \"delivery systems\" unless the primary intended use of the
device is, in fact, to deliver a drug.

Without this subtle but important clarification, there may be undue and
potentially misleading emphasis on the jurisdictional role of the drug
component.

In interpreting primary mode of action, and as we have conveyed on a
number of prior occasions, AdvaMed\'s member companies have come to rely
and build their combination business around two fundamental
interpretation standards that have now been replaced for more than a
decade.

First, the combined product, that is, the product as a whole is analyzed
for purposes of determining the primary mode of action.

And second, mode of action is determined based on the primary intended
function of the combined product.

The principal theme of the CDRH-CDER inter-center agreement, as you
know, provides that products which are primarily structure, physical
repair or reconstruction purpose should be regulated as devices.

For the inter-center agreements from our RFD decisions and from informal
center assignments over the years, there has emerged a long and varied
list of combination products granted primary device status based on the
intended function of the composite product. Among them, human fibroblast
derived skin substitutes, bone cements containing antimicrobial agents,
spinal fusion products containing biomaterials, dental devices with
fluoride, and condoms with contraceptive agents. All of these examples
may deliver a drug or a biologic, but that function was not deemed the
primary intended function of the combined product for jurisdictional
purposes.

FDA\'s historic interpretations of primary mode of action have served
both the agency and industry well. They have fostered innovation, on one
hand, and protected and preserved public health on the other, the
precise two goals of the Commissioner\'s new initiative

Innovation has been fostered because of the legal and policy initiatives
that are uniquely available under our device premarket review structure,
including early collaboration meetings, 100-day meetings, modular
reviews, least burdensome review principles, and humanitarian device
exemption initiatives.

From the public health perspective, we have had over a decade of
combination assignments to CDRH, and to our knowledge, not a single
post-market safety issue has arisen as a result of these assignments.

For these reasons, maximum use of device jurisdiction authority should
be encouraged. If Commissioner McClellan is to truly accomplish his
initiative in making innovative medical technology sooner and reducing
the cost of developing safe and effective medical products while
maintaining standards of consumer production since CDRH jurisdiction
over a combination has a demonstrated effective review history in these
instances where primary mode of action is otherwise unclear.

And companies believe that a device assignment would serve to foster and
advance their technologies. Strong deference should be given to this
principle.

For the subset of combination products that, in fact, serve to deliver a
drug, for example, new aerosolized insulin systems and lasers to deliver
topical anesthetics, there are other jurisdictional principles that have
been placed over the years which like the agency\'s primary mode of
action, interpretation will be important to preserve.

For example, the inter-center agreement provides that for drug delivery
devices intended for use with marketed drugs and used together as a
system, CDRH will have jurisdiction if the device technology
predominates. From this jurisdictional interpretation, whole industries
and, indeed, whole new standards of care have been born.

Elastomeric infusion pumps, for example, are delivered systems that
historically have been granted device review. CDRH jurisdiction and
related innovations under our device authorities have allowed this
delivery system technology to progress and evolve quickly from hospital
to home-based patient use, bringing improved standards of patient care
and significant cost savings to our health economy.

The challenge of cross-labeling. A second and particularly significant
challenge for novel drug delivery systems is cross-labeling. Since 1991,
when the agency first articulated its framework for combination
products, including how labeling must conform for these products, market
introduction of novel delivery systems have been aided tremendously by
FDA\'s flexible approach to cross-labeling issues.

For the last decade, cross-labeling/mutual conformance have been defined
through the inter-center agreement. From this inter-center agreement
important guidance has been provided both to FDA and industry on the
issue of cross-labeling, used not simply for final labeling discussions,
but also early on and concerning framework/jurisdictional issues for
novel devices intended primarily to deliver drugs.

The inter-center cross-labeling standards are fourfold. First, the
inter-center standard states there are three essential aspects of drug
labeling requiring mutual conformance: indications, general mode of
delivery, drug doses/schedule equivalence.

If device labeling is generally consistent with these key parameters of
drug labeling, the essential elements of mutual conformance will be
assumed. When there is general mutual conformance, the agreement states
that the FDA should do two things. It should grant CDRH jurisdiction for
the product, and it generally should waive additional clinical showing
of drug effectiveness.

A second standard. The agency has recognized that as delivery system
technology evolves, models of delivery and dose schedules for drugs may
inevitably be refined. To accommodate these refinements, two of the
three key drug parameters in the standard are described with some
flexibility.

Specifically, the mode of delivery need only been the same general mode
of delivery, and the doses/schedule need only be equivalent.

Also, the term conformance. Using the standard does not convey verbatim
replication of or precise equivalence to drug labeling. Device labeling
need only be generally consistent with the labeling of the drug intended
to be delivered.

Examples of the precedents that have relied on the flexibility of this
labeling standards include continuous delivery devices for insulin and
fibron sealant mixing and delivery systems.

As a third inter-center cross-labeling principle, even if there are
changes to these three critical drug parameters described in the
cross-labeling standard, the standard nevertheless affords CDRH further
flexibility to consult with CDER and to resolve those issues through
device labeling.

And finally, the inter-center agreement on cross-labeling does not
purport to address any other secondary aspects of the drug labeling
beyond the three stated parameters of indications, mode of
administration and dosage. Under this interpretation second drug
labeling issues have been available to be addressed through device
labeling and review.

In keeping with the Commissioner\'s goal of encouraging innovation in
this area, we ask that these four historic cross-labeling standards,
reaffirmed through agency device reviews over the years, continue as
policy practice in this area. Without these flexible policy approaches,
significant new challenges will be added to pathway development for this
category of products.

A third challenge for novel delivery system relates to data burdens and
the need for new guidance that permit more flexible, more predictable,
and more consistent approaches to data development. In the novel
delivery system context, data challenges can sometimes be very different
depending on whether CDRH or another center has received primary
jurisdiction for the composite product.

Compounding these challenges is the reality that, in contrast to certain
other forms of combination products, delivery system technology often
involves two severable components, and review standards for those
components are not always clear or even applied.

If CDRH jurisdiction has been granted for delivery systems, historically
it has been because the drug is marketed, has been generally approved,
and the device issues thus predominate. In this context two data
challenges have emerged.

First, our members believe that there needs to be stronger emphasis on
the principle first articulated in our inter-center agreement that
whenever possible, delivery systems need not reprove the fundamental
efficacy of a drug already approved for the same general mode of
administration, dosage, and indication.

In reaffirming this historic standard, our members ask that the agency
provide concrete and specific guidance through examples as to how this
principle can be more effectively and consistently applied.

As a second challenge our members also feel strongly that any CDER
consult process, while important to resolving unsettled drug issues, not
be permitted, directly or indirectly, to set the review standards for
the composite product. CDRH product jurisdiction, if it is to be
meaningful, necessarily must involve device authorities.

Defining the combined product. In this context we need to make certain
that the tried and true drug standards are not applied to combination
technologies. These technologies represent breakthrough thinking and
application of established drug standards may not in most instances be
an appropriate standard for review.

CDRH has a long history of establishing flexible standards because of
the nature of the products they regulate. This history gives CDRH a
unique experience based on the development of review criteria for those
novel products.

In instances where CBER and CDER have granted jurisdiction of novel
delivery systems, it is generally the case that both aspects of the
product, both the device and the drug that are biologically being
delivered, have been deemed investigational.

In this context, industry data challenges are somewhat different. First,
for the device combination of delivery system combination, the agency
needs to be clear that device authorities, including least burdensome
principles, frame the review for the aspect of the product. This
component part of the evaluation could occur through separate review
and/or consultation process at the sponsor\'s discretion, but it is
important that it be undertaken effectively.

Too many of our members have expressed concern with the agency\'s
internal assessment, published last October, which acknowledged that
some reviewers in CDER and CBER lacked fundamental understanding or
appreciation of advice premarket review authorities.

The ability to ensure proper device review becomes more important the
more complicated the device design, and complexities are increasing
reality for delivery system as many new technologies involve software
electronics, electromagnetic principles, ultrasound energy, and other
sophisticated forms of device engineering.

As a second more general challenge, our members convey that when CDER
and CBER jurisdiction is granted, there is little, if any, incentive at
the moment for reviewers in those centers for seeking mechanisms or
employing standards and encouraging the development of novel drug
delivery systems.

If we are to achieve meaningful premarket improvements in this area, it
will be important to develop new guidance specifically addressing
delivery system combinations and acknowledging the sentiments expressed
at the agency\'s January 31st press release which launched this
initiative.

At the risk of repeating ourselves in that release, the Commissioner
described the agency\'s desire to help make innovative delivery systems
available sooner and to reduce needless costs and burdens while ensuring
safe and effective medical products.

We believe this initiative represents a form of least burdensome
philosophy now sanctioned expressly under our device laws. New guidance
for novel delivery systems should attempt to reflect this standard as
appropriate and consistent with the current law.

We believe that separate guidance specifically encouraging and promoting
novel delivery system development will give CDER and CBER reviewers one
more reason to think creatively and flexibly about data issues and to
avoid any temptation for more doctrinnaire data demands.

A fourth and final issue that challenges the framework for premarket
review of novel delivery systems is the subject of separate parallel
past submissions, and better understanding those circumstances where
parallel review may or may not be appropriate.

In the November hearing on combination products, we let the agency know
that our member companies see the advantages and disadvantages of
separate applications in different ways at different times, depending
upon the specific regulatory, factual, and business circumstances
presented by the particular combination.

We believe, however, that these differing views may be fully reconciled
by distinguishing required separate filings that may be an option of the
sponsor. Several specific recommendations highlight and explain how this
distinction would be implemented.

First, in order to avoid redundant reviews and excessive regulation,
only one filing should be required in the majority of the cases. Indeed,
we believe that as the consultative process continues to be regulated
and improved and held accountable, there should be fewer and fewer
mandated separate applications.

There are certain selected circumstances, particularly for novel
delivery systems, where a company at its option might see a separate
filing as useful for regulatory business/marketing reasons. Factors
include:

One, where two different companies, for example, a drug company and a
device company, are involved in the manufacturer of a combination drug
delivery system.

Two, where delivery system components are expected to have separate
distribution and use/reuse patterns.

And, three, where primary jurisdiction for the combination delivery
system has been given to the center other than CDRH and the delivery
device component is capable of being separately defined and reviewed.

Examples include novel ultrasound infusing catheters, nebulizers, jet
injectors, insulin pens, and drug delivery systems that monitor a
patient\'s vital signs. In these circumstances AdvaMed believes that the
separate filings are appropriate.

The key to this recommendation, however, is that the option of the dual
filings is left up to the sponsor. We believe this theme of flexibility
and sponsor discretion is important if we are to encourage the
development of novel drug delivery systems in an industry with such a
wide array of corporate and technological interests.

Your next two questions inquire about areas where guidance would be
helpful on how the agency can best collaborate with industry and other
institutions in the development and encouragement of novel delivery
system technology.

Given the commonality of themes presented by these two questions, we
have consolidated a response and have several recommendations to
provide. We believe the four framework issues just discussed should be
reaffirmed in separate or consolidated guidance documents, and those
documents should be developed following notice and comment processes
required by good guidance practices.

Further agency collaboration with industry on development of these
documents also would be beneficial. We also agree with the agency that a
drafting process which is as interactive as possible, for example,
through stakeholder meetings, would allow for further debate and
reiterative refinement of FDA and public views on those important
issues.

As part of the guidance process we also recommend that the agency\'s
initiative and intent to encourage novel delivery systems be fairly
stated and specifically supported. In particular, industry would
appreciate receiving concrete examples of how the agency process to
reduce needless delays and avoidable product developments cost in the
premarket process.

We believe suggestions that the agency already has made concerning
improvement and review in communications and proceduralizing combination
reviews will facilitate the agency\'s goals, but we request that
additional mechanisms for more efficient review processes and further
encouragement of flexible review standards be considered as well.

Implementation of this initiative will work best if all aspects of the
agency\'s review chain are trained well on the principles adopted. If
the agency is to have all reviewers consistently thinking creatively and
flexibly in this area, there must be regular, internal reminders of this
goal to all three centers involved.

Industry would also appreciate ongoing efforts to make combination
product include a novel delivery system database as transparent and as
informative as possible, consistent with FDA\'s nondisclosure
obligations and the proprietary interests of sponsoring companies.

Data on approved products should convey primary jurisdiction, time frame
for reviews, available information on consultative or collaborative
processes invoked, the number of review cycles involved, and public
summaries for review.

This database should be separate and apart from other databases for
approved products to facilitate industry\'s efficient review of
combination precedents.

With those recommendations, AdvaMed thanks the agency for its
consideration of our comments. Our members strongly support the
agency\'s ongoing efforts in this area, and we look forward to working
closely with you to further reduce regulatory challenges and to improve
premarket processes so as to foster and facilitate innovation of
delivery systems and other forms of combination technology.

Thank you.

(Applause.)

DR. JACOBSEN: Thank you, Keith.

And finally, Christine Allison from the Global Regulatory Affairs Group
at Eli Lilly is going to discuss the drug industry\'s perspective on
combination products.

MS. ALLISON: Thank you.

First, I\'d like to thank FDA for sponsoring this very important
workshop. For those of us that have been working on this type of
combination products for years, this is exactly what we have been
looking for, an opportunity to have an open dialogue with the agency and
to discuss about some of the issues and challenges we have been dealing
with and struggling with on a daily basis.

I\'m also very honored to be invited as a speaker today.

My presentation goals today is first to give you a brief introduction of
the type of products that my company has been working with, and also
hopefully walk you through some of the regulatory challenges that we
have experienced during development and market applications and
post-approval, and then touch a little bit on the challenges that we
have experienced working with partners, and some global challenges, and
then I\'ll summarize some key points and conclude it with our
recommendations to the agency.

Lilly\'s experience on the combination product is mainly on the
drug-device combination. We are currently working on several innovative
products, for example, pulmonary inhalation system for systemic delivery
of drugs and also other, you know, interesting, innovative products, and
those are all at the development stage.

We also have many years of experience working on the pen injectors,
which is already in the market, and for those products we have post
development and post approval experience. Although I don\'t consider pen
injectors as an innovative product, however, I believe that some of the
post approval experience that we have will be good examples for us to
look forward once the innovative product has been approved in the
market.

My presentation will also be focused on the CMC issues.

For innovative products, a lot of time the questions surface very early
in the development stage, even before we are ready to request for lead
center designation. A lot of time we will have a lot of questions,
sometimes drug questions or device questions, and we often struggle
which center we should go to to ask those type of questions.

So it would be very nice if we have a single focal point so we can just
channel those questions to. So we recommend that the Office of
Combination Products be the coordinator and facilitator for identifying
the appropriate centers for technical consultation prior to lead center
designation.

Some of the challenges we have experienced is also the consistency in
lead center designation. We understand that the statutory history does
not mandate that the sponsor has to go to the Office of Combination
Products to request for designation of lead center.

So sometimes the sponsor can choose to go to individual center instead
of go to the Office of Combination Products. So this could result in
some similar products, combination products that result in different
lead center assignments. It depends on which center the sponsor goes to
first.

And often the consultation centers are not defined at the time of lead
center assignments. So we suggest that internal procedure be developed
to guide each center for routing those requests to the Office of
Combination Products for review to ensure the consistency of lead center
designation.

And also we recommend that Office of Combination Products also identify
those consulting centers at the time of lead center assignments.

Some of the major CMC challenges that we have experienced for innovative
drug delivery systems, because this type of product is very new and is
kind of unique, and because a lot of times the agency has no experience
with dealing with this type of product, a lot of time the agency will
request a commercial system to be used for pivotal studies.

And this creates a lot of technical challenges for us. It means that we
have to lock in the CMC development process in a very early stage of
development, and this also prevents us to continue to improve the
process during the clinical phase and feed it back to our design.

In addition, early resource commitment is required. Sometimes we have to
purchase commercial equipment or even build manufacturing sites in the
very early stage of development, sometimes even as early as Phase II or
III. It depends on what kind of clinical plan that we have.

And so this is a very typical approach. It compares to the normal
product development process, and if we have a change that is not
avoidable, then we have to make those changes.

The difficulty is to establish successful, satisfactory comparability
protocol between pre-commercial and commercial systems to satisfy
agency\'s expectation. So we encourage the agency to consider the role
of reaching strategies to allow product process improvements during the
development through commercialization, and also clear and documented
expectations from the agencies are needed.

And this is not an easy task. We realize this is not an easy task.
Therefore, I think frequent dialogue with the agency regarding specific
issues is very critical throughout the entire development process.

The traditional pre-IND meetings, or end of Phase II meetings, it is
just not sufficient for us. Therefore, we encourage that the agency to
be flexible in granting the request for meetings and consultations when
dealing with this type of product.

Another major CMC challenge for us in dealing with this type of
innovative drug delivery system is that the drug and device is an
integrated system. This is an integrated system. It\'s got drug
components in there and the device components in there, and both
components have to work together as a system.

And, therefore, it requires a lot of time, with frequent consultation
with multiple FDA centers and sometimes multiple divisions within the
same center.

Currently, based on our experience, alignments and communication with
multiple centers and divisions has been a challenge, and therefore, we
believe that it would be very beneficial if agency\'s review team can
include members from all relevant centers and divisions from the very
first sponsor meeting.

Another major challenge that we face is quality systems. The question is
which regulations you apply for the drug-device combination. Is it drug
cGMP or should we apply the device QSR or both? And which compliance
guidance will be used during the preapproval inspection?

It is our opinion that the drug regulations should apply to the drug
portions of the products, and the device regulations should apply to the
device portions.

And we also believe that clear policy is needed with regard to the FDA
inspections for preapproval inspection of the combination products.

And also, we encourage that the investigators to be trained and to
perform combination product inspections using the appropriate regulation
for each component of the combination.

Another challenge is during the development, is the regulatory
reporting. It\'s unclear what are the requirements for AE and device
reporting during the clinical study. Should we follow the 21 CFR 312 or
21 CFR 812?

Especially when it comes to the device expedited reporting requirements
for the device portion submitted under the IND in terms of the device
malfunction and the inclusion of the device investigation results.

It is our opinion that in principle, reporting requirements for both
drugs and devices should be applied as appropriate. We believe that if
device malfunction is reportable under the device regulation, it should
be also reportable even if submitted under the IND.

We also believe that device investigation results should be included in
the report, and this report should be directed to the lead center doing
the review.

As far as the reporting time, we have no preference one way or the other
as long as it is clear to us what kind of reporting time we need to
follow.

Moving on to the challenges during the market applications, the question
is always is it a single or dual submission, and if it\'s dual
submission, would dual user fees apply?

And also, what is the format we should use to include those device
information in a CTD submission? And what kind of device information
needs to be included in drug submissions?

We support the concept of a single premarket review mechanism leading to
a single approval of combination products. We understand that there will
be exceptions when the DOS submissions may be more appropriate.

In terms of the formats, submission formats, we recommend that
standardized formats and also provide guidance for us to include the
data, the data requirements for the device information to be included in
the CTD submission.

In addition, the phase-appropriate data requirements for the device to
be included in the INDs. From our experience, a lot of times we find out
it\'s very beneficial if we prepare the device information in a format
that is familiar with the CDRH reviewer. So if we prepare that
information, for example, in a 510(k) format, it will be much easier for
a CDER reviewer to hand it over to the CDRH reviewer for consultation.

Moving on to some of the post approval challenges, the difficulties we
have encountered the most is when we have to deal with device changes,
when this device information is part of the NDA submission, and
currently because there is no clear guidance on how to handle this,
it\'s been a challenge for us.

We recommend the use of the CDRH 510(k) decision tree as a guidance. If
we go through the 510(k) decision tree and the conclusion is we don\'t
need to have a 510(k), we suggest this type of change will be
communicated to the CDER reviewer through the annual report.

And if we go through the 510(k) decision trees and the 510(k) is
required,, then we suggest that this type of change will be communicated
to the CDER reviewer through the NDA Supplement B or C.

Again, talk about the post-approval regulatory reporting requirements.
There\'s currently no clear guidance on how to conduct those AE
reporting and device reporting for drug-device combination products.
Which regulation should we apply? Is it 21 CFR 314 or 21 CFR 803?

The same challenges when we talk about doing the IND stage is for those
expedited reporting, device reporting, do we include the device
investigation result in the report?

It is our opinion that, in principle, reporting requirements for both
drugs and devices should be applied as appropriate. We believe that if a
device malfunction is reportable under the device regulation, it should
be reportable as well when it is submitted through the NDA, and we also
believe that the device investigation results should be included in the
report.

And those reports should be directed to the lead center that has
reviewed the submission and approved the products. Again, for the
reporting time, we have no preference one way or the other as long as
it\'s one clear reporting time that we have to follow.

Another challenge we have experienced for the post-approval is the
cross-labeling of products intended to be used together. An example of
some cases is that some of the 510(k) devices approved in the market,
cleared in the market can be used for multiple products. When the drug
company wants to include those devices into the drug label, there\'s no
clear guidance how to do this, to reach conforming labeling.

And since there is not a user fee associated with this type of labeling
change, therefore, there\'s no set reviewing times, and in some cases it
takes a long time to have this labeling change accomplished. Sometimes
when we are waiting for the approval the device that we try to include
in there, the model already is obsolete. We know it is very dynamic in
the device work. So that means that we have to then restart it again for
this whole entire reviewing process to include the new versions of the
model.

And sometimes the reviewer may repeatedly review the data set that has
already been reviewed by the other center, and in some occasions the
reviewer may request additional data beyond what was required by the
other centers.

Therefore, we believe that clear guidance is needed on how to obtain
mutually conforming labeling. And we suggest that allowing the
510(k)-cleared device to be included in the drug label is appropriate,
and communication of this type of labeling change be made in the annual
report.

To touch a little bit on the challenges we have experienced working with
partners, very often a device company may work with multiple drug
companies with the same device platform. So those device information
will be considered proprietary, and when we have to submit an NDA to
include this device information, we will not be able to describe those
information in detail without reference to a DMF.

And the regulatory challenges come into play when the reviewer wanted to
discussion or has questions regarding to those informations. It would be
very difficult for the FDA reviewer to discuss those issues with the
sponsor due to the confidentialities. And this is the same challenge
once the product is in the market and we have changes made in the device
portion.

And sometimes the device company may have a different approach,
regulatory approach or interpretation than the drug company, especially
in a controversial area, such as we mentioned earlier, some of the GNP
requirements or regulatory reporting requirements.

And I believe that those differences can be minimized once the agency
has a clear guidance on how to deal with those issues.

Some of the global challenges that we have experienced. A drug device
combination product approved under the CDER NDA may require a market
authorization for the drugs and a CD marking for the device in EU, and
this reports a lot of challenges in terms of submission document
preparations, quality system requirements, post-approval changes,
regulatory reporting, labeling, and compliance inspections.

And, therefore, it would be very nice if the agency, when dealing with
certain policies and guidance, if you can work with your counterparts in
the other parts of the world and work toward a direction of having a
global harmonization. That would be very nice.

Therefore, in summary, we have identified many challenges throughout the
entire product life cycle for innovative device products. We also
identify many areas that we need guidance, such as quality system
requirements, post approval changes, regulatory reportings, and
cross-labeling.

And we believe continued dialogue between sponsors and the agency is
critical to ensure successful development and timely review of market
applications.

And in conclusion, we would like to recommend that the agency when
setting policy and guidance, please consider using Office of Combination
Products as a single focal point to handle the issues regarding the
combination products, and keep it simple. If we can do it with one
process let\'s not use two processes.

Reduce redundancy, especially in the reviewing process. If one center
already reviewed the data, the other center does not need to review it
again.

And also when setting guidance and policy, not only market applications,
please consider also post approval requirements and think through the
entire product life cycle.

And the last if not the least, please consider global harmonization
needs.

Thank you.

(Applause.)

DR. JACOBSEN: Okay. Thank you very much.

That\'s the end of this session, and I think we\'re scheduled to have a
break now. So if you could all be back at 3:30, we\'ll get started again
with the FDA session.

Thanks.

(Whereupon, the foregoing matter went off the record at 3:17 p.m. and
went back on the record at 3:33 p.m.)

DR. JENKINS: We will begin the FDA session. I\'m John Jenkins. I\'m the
Director of the Office of New Drugs in the Center for Drugs. I\'m here
substituting for Dr. Woodcock, the Center Director, who was not able to
be here because of a conflicting schedule on her calendar.

It\'s a pleasure to be here, and I think from what I\'ve been hearing in
the hallway, this is the session you\'ve been waiting for, which is FDA
perspective on all of these issues.

So I\'m going to serve as a moderator, and let me introduce our first
speaker. Mark Kramer I think you all know. He\'s the Director of FDA\'s
new Office of Combination Products.

Mark.

(Applause.)

DR. KRAMER: Thank you, John, and I\'d like to thank Dr. Feigal and Dr.
Provost for inviting me to be with you here today and talk about what
we\'re doing.

The first thing I have to do is start out by saying that I\'ve been
asked to focus on the role of the Office of Combination Products and the
kinds of things we\'re doing. What I wished we had, and this is what
I\'m going to cover today, is just to give an overview of what is and
what is not a combination product; give an overview of how we regulate
combination products at FDA; talk about the role of our office and also
some of the current initiatives that we have gotten underway.

I really wish I had a fifth bullet here, which are the answers, the
answers to all of the questions that people have been raising today, but
as I think you\'ll hear, we are beginning to work on these issues, and
clearly these kinds of sessions really help give us the kind of input
that we need in order to anticipate the products that are coming down
the line, and there\'s clearly a lot of new things that I\'ve heard
today in terms of products that we have to anticipate.

So the first thing I wanted to do is start out with a question. Are
novel drug and biologic delivery systems combination products?

And I think the answer is it depends, and as I\'m going to lay out the
definition of a combination product, I think we use the term loosely,
but really many of the products that we talk about as being combinations
might not meet the regulatory definition of a combination product.
However, they may still raise complicated regulatory issues and,
therefore, we sort of, you know, are trying to address these types of
products at the same time.

This is a regulatory definition of a combination product, and the
regulation provides \-- this is in 21 CFR Part 3, 3.2 \-- there are
really four different types of combination products, and the third and
the fourth bullets are tied together.

But sort of the quintessential combination product is a product where
the product itself comprises two or more regulated components that are
physically, chemically, or otherwise combined or mixed as a single
entity, and a good example there would be the drug eluting stent that
has been discussed much today.

But it has its forbears, things like antimicrobial coated catheters,
heparin coated catheters, condoms with spermicide that have been around
really for a long time, and those are combination products, too, and we
have been effectively regulating those for quite a long time.

The second type of combination is where we have a kit or a co-package
that in itself is comprised of separate products, drugs and devices,
devices and biologics, or drugs and biologics. Together they create one
product which is a combination product because it contains different
types of regulated articles.

And the third category is really one of the most complicated for us, and
this is where you have separate products, often provided by or
manufactured by separate companies that their use together constitutes a
combination product. Both products are required to achieve the intended
use, indication, or effect, and where upon approval of the proposed
product, the labeling of the approved product would need to be changed.
And this is the so-called cross-labeling issue that\'s been raised by a
couple of the speakers earlier this afternoon.

In the interest of time I\'m going to run through these examples pretty
quickly, but they are in your notebook, devices coated, impregnated or
otherwise physically combined with a drug or biologic. I gave some
examples of the drug-device combinations. There are also drug-device
biologic examples, such as skin substitutes with cellular components,
orthopedic implant with growth factors, and there was one of those that
was recently approved in the least year.

Prefilled drug or biologic delivery devices are also combination
products. Some of the simplest ones that we have are just prefilled
syringes, a syringe that is filled with a drug or biologic is a
combination product because the syringe is a device and the drug or
biologic obviously is regulated separately.

But we also have insulin, epinephrine, interferon injector pens, metered
dose inhaler, transdermal patches, again, all examples of combinations.

Drug or biologics that are provided with an applicator or delivery
device; drug-biologic combinations. We haven\'t spoken about that too
much today, but radiopharmaceuticals combined with a biologic or
monoclonal antibodies combined with a chemotherapeutic drug,
interferon-ribavirin combination for Hepatitis C. These are
drug-biologic combinations.

And then again in that last category of combinations, separate products
that may constitute a combination: a hyperthermia device used with a
chemotherapeutic drug; photodynamic therapy drug and laser light source,
and you\'ll be hearing from Richard Felten about that soon after my
talk.

Diagnostic devices that require the administration of a particular drug
or biologic, or a drug requiring a specific diagnostic device. These are
examples of separate products that used together might constitute a
combination.

What are not combination products? Well, combinations of two drugs, two
devices, or two biologics. They may raise some of these types of
regulatory issues as well, but in order to be a combination product by
the regulation, you have to comprise different types of regulated
articles: a drug and a device; a drug and a biologic; or a device and a
biologic.

Most concomitant use of drugs, devices and biologics is not a
combination product, and also general drug or biologic delivery devices,
such as an infusion pump that\'s not intended for use with an
individually specified drug or biologic product, they don\'t meet the
definition of a combination product.

And I think those are some of the types of things we\'re discussing here
today that may actually fall in that last bullet and not technically
meet the definition of a combination, but may pose some of the very same
issues that combination products raise.

These are the various regulatory approaches we have in our
armamentarium. Devices generally get approved under the PMA or 510(k)
process and are investigated under IDE. Drugs approved via NDA, studied
under IND, and biologics under BLA and studied under an IND.

And what somebody once told me at the last talk I gave where I had this
same slide was it\'s like worlds colliding. If anybody remembers
Seinfeld, there was an episode where George felt his worlds were
colliding. His girlfriend was getting to know his friends and his work
people, and he didn\'t like that.

And somebody told me once that\'s what happens with combination
products.

(Laughter.)

MR. KRAMER: But when we look at the intersection here, I think it\'s
what makes combinations unique because we have the regulatory
flexibility to apply the most appropriate regulation to a combination
product by tailoring the approach to taking pieces of drug regulation,
pieces of device regulation or biologics as appropriate.

But what we haven\'t had in the past was a very consistent way of doing
that, and that\'s what we\'re in the process of doing.

Some of the things that are unique about the way we regulate combination
products, first, as you heard earlier, they\'re assigned to a lead
center based on the s-called primary mode of action. As Jonathan pointed
out, not defined in the law, not defined in our regulations, although we
are in the process of formulating a regulatory definition for primary
mode of action that will be made available for public review and
comment, and we feel that\'s a very important first step in the process
of ensuring that these products are appropriately regulated and that we
have a good way for determining which center will have lead review
responsibility.

Another one of the hallmarks of combination product regulation is that
we often, but not always, have consultation or collaboration between the
centers. That is a way of applying the best mixture of expertise to
insure that one center can supplement its expertise in order to best
understand and tackle the review issues associated with that product.

Jonathan asked me to touch on the difference between consultation and
collaboration, and I\'ll try to do it in ten seconds, but consultation
is what we generally have. In most of the cases this is where the lead
center is ultimately responsible for all decision-making on an
application.

But we also have an approach of collaboration that allows basically the
two centers to have equal votes at the table, and both centers would
need to reach agreement on the outcome of a submission in order to
approve or disapprove the product.

I mentioned earlier that we do have the flexibility to tailor the
premarket regulatory authorities, and we have the same flexibility to
tailor the post-market regulatory authorities. So we may have a product
that might be subject, for example, to elements of the quality system
regulation and to elements of CGMPs.

And we have done that, in fact, with drug eluting stents where the drug
substance needs to conform to drug GMPs up until the time that it\'s
coated on the stent, and once it\'s a combination product, then the
combination is subject to the quality system regulation.

The other thing is one application versus two, and this is an important
issue not only because it affects, you know, really the whole regulatory
landscape of how these products are regulated, but some companies, as
AdvaMed pointed out, prefer one application and some prefer two. And
sometimes there are business reasons that affect what a company\'s
preference is.

And we\'re trying to look at tailoring our approach in terms of making
it as \-- our ultimate goal is to try to have one application whenever
we can, but we recognize that there will be instances where two will be
most appropriate in order to regulate a product, and there are cases
where a company may actually prefer to have two even if we feel they
only need one.

There are user fee issues associated with that. I think Christine
mentioned that in her presentation, and therefore, there are important
ramifications to a decision as to whether to require one or two
applications.

The Office of Combination Products was established in December of this
year. We have six main roles that are outlined in the statute, and this
was all part of the Medical Device User Fee and Modernization Act.

We have responsibility for assigning combination products based on the
primary mode of action to ensure the timely and effective premarket
review of combinations, to ensure the consistent and appropriate post
market regulation of combination products.

We also have a role with respect to dispute resolution, review and
update of guidance agreements and practices relative to the assignment
of combination products, and we have to report to Congress on an annual
basis on the activities and impact of the Office and provide some
prescribed data.

In terms of the assignment of combination products, the statute tells us
that we have to promptly assign an agency center with responsibility for
jurisdiction of a combination products, and our goals there is to have
as efficient an RFD process \-- that\'s the request for designation
process \-- as possible and to make it as consistent, transparent and
predictable as possible.

Some of the things we\'re doing I already mentioned. We are developing a
definition of primary mode of action, which we think is probably one of
the most important steps of this process, but we\'re also working on
guidance on the selection of premarket authorities so that our reviewers
understand what tools are available to them in order to regulate a
combination, but that we have a framework in order to do it in a
consistent and transparent and more predictable way so sponsors will
have a better understanding of how their product will be regulated.

Similarly working on guidance for the one application versus two, we\'re
in the process of continuing to make the RFD process as efficient as
possible. We just modified 21 CFR Part 3 for some administrative changes
to implement MDUFMA and recognize the Office\'s role here, and we are
documenting the various precedents \-- I think Jonathan mentioned this
earlier \-- to make them much more searchable and readily available. So
we were able to have a much better assessment of what we\'ve done in the
past with similar products and can help ensure better consistency.

In terms of review of combination products, again, here what does the
statute tell us? Ensure the timely and effective premarket review by
overseeing the timeliness of and coordinating reviews involving more
than one center, and these are the kinds of things that we\'re doing in
that regard.

We do have an SOP on the inter-center consultative collaborative review
process, and on my next slide I\'ll just give a few quick bullets about
that.

We\'re also in the process now since February 14th actually when we
modified our SOP in order to allow us to do this, is to monitor the
consultative process between the centers, and what we\'re doing is when
the centers initiate a consult request to another center, they copy us
on that request. We sort of have a low-tech way that we\'re doing this
right now, but we\'re in the process of developing a data base,
basically an automated way of doing this so that we\'ll know in the
background every time one of these consults is going on.

And what we do is we take a pretty active approach when they come in to
make sure that the request is clear, that the second center, that is,
the center that is being asked to help understands what\'s expected of
them, what the time frames are, and then we monitor that process to make
sure that the originating center actually got the input that it was
expecting and on time.

We also have an effort underway where we\'re reporting and tracking
other combination products, that is, combinations that don\'t require
consultation, but are combinations nevertheless, and these include
things like prefilled syringes and transdermal patches which are
typically not consulted out to another center, but there\'s also a lot
more sophisticated combinations as well, where the lead center has
developed an expertise over the years and doesn\'t require consultation.

Well, what we have underway now is a process where every major type of
premarket submission in all three centers as of May 1st is categorized
as to whether it concerns a combination product or not and if so, what
type, and we actually have eight different types of combination products
that we\'re categorizing, and our first annual report to Congress is due
on October 26th, and we\'ll be providing that data.

This first year we won\'t have very much to report just because of the
time we\'ve started. There won\'t be a lot of combinations that are
actually approved by then, just given the statutory time frames, but the
data are being collected and we will really have for the first time
knowledge of how many combination products we get each year, how many we
approve, what types they are, which centers are doing them, and all of
that. And up until now we really haven\'t had that kind of data.

We\'re also available as a resource to sponsors and review staff for
combination products, issues and questions. We\'re in the process of
developing reviewer tools and training.

For example, on the consultation process, by actively monitoring the
consults, we\'re seeing first-hand a lot of the issues that are
presented by consulting reviews, and we have some lessons learned beyond
what we thought we had already addressed in the SOP, but real-life
practical issues that when somebody is actually looking and seeing every
one of these, some of the common denominators of problems, and we\'re
going to be disseminating those to review folks.

The SOP, in two words about the consultation process, says that consults
count. Consulting reviews need to be given due priority, and it\'s all
part of the agency\'s work. So if one center asks another for help, the
second center needs to do its part in order to make sure that the lead
center is able to meet its review goals.

And the consulted centers are expected to be consulted with respect to
the time lines for the consulting review, and in turn, held accountable
for the timeliness and the quality of their consulting review.

Very quickly on post-market regulation, the law tells us to ensure the
consistency and appropriateness here. What we\'ve begun doing where
possible is in our RFD letters providing preliminary determinations of
what GNPs and adverse event reporting requirements a combination product
will be subject to.

We have two active working groups in this area, one on GNPs, one on
adverse event reporting, to be able to provide some of the guidance that
Christine Allison from Lilly said was badly needed in this area.

Some general considerations. Really my point here is that one size
doesn\'t fit all. I think that point was made this morning. There is no
cookie cutter approach. These products, you know, I think we heard this
morning that they really run the scope of a wide variety of different
products in the kinds of issues that they raise, and therefore, there is
not a one size fits all approach.

We\'ve had combinations approved under HDE with as few as 30 or 40
patients, and then we\'ve had combinations reviewed with much larger
randomized controlled trials.

So I think consultation with FDA is very important. I think some of the
technologies that were described this morning I personally hadn\'t heard
about before, and I think it\'s very important, not that that means
much, but I think it\'s important that these dialogues, you know, the
dialogue with FDA begin as early as possible so that we can help work
with you on what regulatory pathway will be followed.

Just very briefly, collaboration between the device and drug or biologic
sponsors I think is very important. That was mentioned earlier, and I
have seen first hand that when the collaboration or cooperation exists,
the process does work much better.

It is very difficult, as Jonathan pointed out, for a device company
without any drug company or biologic company partnership to be able to
independently work on changing the label of an approved drug.

And this is going back to the question in the beginning. If my product
is not a combination product, will these initiatives still help?

And I hope the answer is yes. It\'s our intent that they will. I think
they present some of the same issues even though a product may not
technically be a combination, and I\'d encourage you to contact our
office. We do have the liaison role that I think that Jonathan mentioned
earlier in working with the centers, and I\'m hopeful that we\'ll be
there to help make a difference and make the development program easier
for your product.

So I think there will probably be a lot of issues that come up in the
Q&A section, and you know, if you have issues you\'d like me to address
afterwards, I\'ll be happy to stay after the conference and address them
at that time, too.

Thanks.

(Applause.)

MR. JENKINS: Thanks, Mark, for that overview of the Combination Products
Office.

I think you\'re doing a great job there, and we\'re all very fortunate
to have you there.

We\'re going to enter into a series now of some vignettes about the
current approach to review of some of the combination products, and
we\'ll start off with one that has been very hot in the news recently,
and it sounds like it has been the topic of much discussion already here
today, and that\'s the drug eluting stents.

We\'re fortunate to have Ashley Boam, who is the Chief of the
Interventional Cardiology Branch in CDRH to give us that overview.

Thank you.

DR. BOAM: Thanks, Dr. Jenkins.

I thank Dr. Provost and Dr. Feigal for setting up this workshop today,
and I appreciate being asked to speak on this very hot topic, drug
eluting stents.

We\'ve heard a lot about it today, and we have a few more little items
on this today.

This is kind of a redundant slide at this point. I should have realized
talking at four o\'clock you would have known the answer to this
question by now, but for those of you who maybe stepped out this
morning, this is an example of a drug eluting stent.

This is a diagram of the Cordis\' CYPHER Sirolimus-eluting stent which
was approved just this last April. As you can see, the stent consists of
a bare metal stent platform with a polymeric carrier in which the drug
is loaded, and the drug elutes from the polymeric carrier on the surface
of the stent.

One of the things we found to be very important when looking at
applications for drug eluting stents is that this really is a three
component system. There is the stent platform and delivery system which
has traditionally fallen to CDRH for review. There is the polymeric
carrier in which the drug is loaded. That has also kind of fallen to
CDRH review. And then there is the drug substance which has fallen under
CDER review.

So today I wanted to talk about some of the review challenges for drug
eluting stents kind of as a real life example that we\'ve been through
in the last couple of years. Some of those topics include regulatory
jurisdiction, inspectional authority and site readiness, disparity in
statutory and regulatory requirements between the two centers involved,
then appropriate leveraging of information from other sources,
appropriate preclinical and clinical trial design issues, and then a
little bit on post market studies and surveillance.

First, as Mark just ably described, combination products fall under Part
3 of 21 CFR. Request for jurisdiction was made for these products pretty
early on, and jurisdiction was granted to CDRH as lead center with
Center for Drugs\' consultation.

But as you can see, there are quite a number of divisions in both
centers that are involved in the review of these devices ranging from
the Division of Cardiovascular Devices and the Division of Mechanics and
Materials Science within CDRH to the Cardiorenal Drug Products Group,
the New Drug Chemistry Group, and Pharmaceutical Evaluation folks from
CDER.

Since CDRH does have the lead jurisdiction for these products, the
appropriate marketing submission is a PMA, and the appropriate
application to investigate these devices is under IDE.

Just to give you a hint as to some of the complexities of these devices,
there are quite a number of areas that require expertise from mechanical
performance and testing to drug substance and polymeric carrier
chemistry, to animal studies, to PK/PD clinical trial design, and not
the least of which, manufacturing.

I guess all of this is to really say that it has really been a
successful collaboration between the two centers that has really led to
the success that we\'ve had in the review of these applications thus
far.

One question that has come up earlier today, Christine mentioned this in
her talk, was the question of inspectional authority, and for drug
eluting stents, as I believe Mark mentioned, the inspections are
conducted by CDRH\'s lead center, but have involved participation from
reviewers from CDER\'s Office of New Drug Chemistry.

It\'s important to note that for these devices, as Mark mentioned, the
drug regulations have been applied to the drug substance, and then the
device QSR regulations to the finished product.

It\'s also important for companies who are making these devices to have
their validations complete prior to inspection. We have worked very
interactively with the two centers and with companies to try to get
inspections done as quickly as possible, but it\'s very important to
have all of those validations done.

We understand these are very complex products, but if there are
subsequent changes and subsequent validations, we may have to go out for
a second time, and it\'s the best use of all of our resources if we go
out once and get you taken care of.

There are a number of differences between the different centers, CDRH,
CDER and CBER, when it comes to marketing applications and the statutory
authorities. As you can see, for CDRH an IDE is what\'s filed to start
an investigation, whereas in CDER and CBER you have an IND.

And then for a marketing application for these devices it would be a PMA
as opposed to an NDA in CDER or a BLA in CBER.

There are also a number of differences in development. I think this has
been pointed out today as well. The rate of technology change for
devices is much faster than that for drugs. I believe there was an
example earlier that devices can become obsolete within six to 12
months, whereas a drug might be on the market for ten, 15, or even 20
years.

There are a number of other differences that are very important in our
consideration of these devices, and that relates to the influence of
physician technique on the results, on the number of full scale studies
that are usually required, and how we regulate products in CDRH
according to risk, in which there are three classes versus one class for
new molecular entities in Center for Drugs.

Companies that are investigating these new products often want to know,
well, what kind of information do I need and where can I get it. How do
I not have to reinvent the wheel?

And whether you have to reinvent the wheel or not really depends on a
couple of items here, and it\'s really in this table. It depends on
whether your stent platform is approved or not approved, and it depends
on whether your drug substance is approved or, as we say, unstudied.

The easiest scenario in terms of being able to leverage information from
other applications is the box marked one where both your stent platform
and your drug substance are approved.

The most difficult situation is where both the stent platform and the
drug substance are unapproved or unstudied, and that\'s the box marked
four.

As you can see, there are guidance documents for both centers that can
help you to put together the right information to get started with the
study for these devices.

So if I have an unstudied or unapproved drug, what type of information
do I need that I may not be able to get from somewhere else? For all of
these drug eluting stents, we\'re requiring that sponsors provide the
equivalent information that would be required in a Phase I IND for CDER.

It\'s also important to understand that an analogue of an approved drug
is considered to be a new molecular entity by both CDER and CDRH for
these products. So Phase I IND information for an analogue to an
approved drug would also be required.

There are several categories of safety information that fall under the
Phase I IND requirements. That includes chemistry manufacturing
controls, otherwise known as CMC. Both preclinical pharm-tox and
systemic clinical exposure in normals are required prior to doing human
investigations of the finished product as a device.

It\'s also important to note that if your drug substances has not been
studied before, this Phase I IND safety information could very well
inform on the clinical trial design that would be necessary for the
finished product. If there are toxicity issues or potential drug-drug
interactions, that are identified during the Phase I safety information
gathering. It may be necessary to alter your clinical study to look for
those when evaluating the drug eluting stent.

In terms of preclinical testing, I think one of the most important
messages we try to get out is that characterization of the finished
sterilized product as it is to be studied is really essential. We
realize that a lot of changes and design improvements go on during the
design and development, product development process, but by the time
you\'re ready to do a clinical trial we really need you to characterize
the actual device you want to study so that we know when you get
clinical trial results what they really represent.

And a couple of those areas include characterization of the coating and
the drug substance, [in vitro]{.underline} and [in vivo]{.underline}
elution characteristics with release rate of the drug, and also methods
and some initial specifications for stability of both the drug substance
and the polymeric carrier, if applicable.

Also, adequate animal studies are really needed to assess safety prior
to going into human clinical trials for these devices.

A few more specifics here in the preclinical area. Some of the common
deficiencies that we see are inadequate stent platform testing in terms
of looking at fatigue and corrosion testing. This is not testing that
can be leveraged simply from the bare stent platform. With the addition
of a coating, it becomes important to look for fatigue and the effects
of corrosion through potential cracks in the coating.

We also see inadequate analysis of any surface modifications made to the
device, either through application of the coating with the drug
substance in it, and so this relates to coating integrity, durability
testing, and also characterization of both drug content and its
uniformity along the length of the stent.

We also see incomplete [in vitro]{.underline} pharmacokinetics both in
terms of methodology, and we strongly recommend that sponsors attempt to
develop an [in vitro]{.underline}/[in vivo]{.underline} correlation if
at all possible.

This becomes very important in terms of scale up from a clinical trial
batch or precommercialization to commercialization manufacturing. It
also becomes very important if there are changes or improvements that
you want to make in the device because the better you can characterize
the device you study, the better you can evaluate what those changes
might look like in terms of clinical sequelae.

And also CMC issues not being adequately addressed, stability and shelf
life are very important. I think device companies are very much used to
a device paradigm where accelerated aging with real time aging to
confirm those results have been accepted.

We typically review protocols, and when we\'re very comfortable with
device materials and device packaging materials, they\'re pretty
straightforward protocols, but when you introduce the drug substance and
a polymeric substance, there are a lot of new issues that need to be
looked at in terms of stability, and we recommend that sponsors follow
the ICH guidelines for evaluation of stability especially of the drug
substance.

In terms of animal studies that we receive, we often receive inadequate
reports to allow us to make an assessment of safety, to know whether
it\'s appropriate to start a clinical trial, and that involves lack of
an evaluation of the doses that are intended for use in the clinical
study, and we also require doses higher than this. We require overdosage
to make sure that we understand what the toxicity limits are in an
animal model.

We look for serial sections of myocardium, arterial histopath, and
necropsy reports for any deaths that might have occurred during the
study.

As we move to the clinical evaluation of drug eluting stents, first and
foremost, we\'re looking for a reasonable assurance of safety and
effectiveness, and it\'s important to remember that your clinical trial
design should look to meet both of these objectives.

The usual standard of evidence for these products at this point is the
randomized controlled clinical trial, and in terms of study endpoints
for coronary drug eluting stents, we\'re looking for primary endpoint or
endpoints that include at least a clinically meaningful endpoint.

We\'re also evaluating the use of surrogate or co-primary endpoints at
this point. As I believe Dr. Kuntz mentioned this morning, now that we
have an approved drug eluting stent on the market, there are a lot of
questions about how do you design a study to be performed in the U.S. if
I don\'t feel I can do a placebo trial because the penetrance has been
so remarkable.

And these are some of the areas that we\'re looking at in working with
sponsors as well as our statistics group to come up with reasonable
clinical trial designs that will still give us evidence of both
effectiveness, but also, and most importantly, of safety.

We also recommend the use of independent core labs, clinical event
committees, and an on-line, very active data safety monitoring board.

I wanted to mention that TPLC is really critical for drug eluting
stents. The first drug eluting stent is estimated to have been implanted
in over 50,000 patients since it was approved in late April, which is a
pretty remarkable roll-out for a new product.

And compare that 50,000 number to the 1,100 patients that we saw in the
U.S. clinical trial. There\'s a lot of information you can get from
1,100, but it\'s never going to tell you everything about what happens
when it gets to 50,000 or 100,000 patients.

And so we feel that information gathered in the post market is very
important for these products. We are requiring five-year follow-up for
all of the cohorts that have been enrolled in support of an application.

We\'re also requiring additional data collection in the post market
period to get a further understanding of what happens when real docs put
these in real patients because we know that sometimes there are
differences between what happens in a clinical trial and what happens in
the real world.

It\'s important to note though that in the post market as folks are
looking at new indications and new patient populations for these
products, those indications and those patient populations should be
studied under the IDE process.

There was a question about adverse events earlier, and for these
particular products, in collaboration with our folks in the Office of
Surveillance and Biometrics and the people in the Office of Drug Safety
over in CDER, we have made a determination that for coronary drug
eluting stents reports will come to CDRH through the MDR process, but we
have made arrangements for data to be shared with CDER, both preapproval
and post approval, as information is gained on both sides about drug
substances.

And so in closing, if you have questions, certainly we encourage very
early meetings with us. We\'re happy to meet with you. We\'re happy to
talk with you very early in your process and then as needed again as you
get further through your product development.

I\'m the Branch Chief that handles the coronary drug eluting stent
program. Lisa Harvey is handling the peripheral drug eluting stent
program, which I didn\'t really speak about today, but it has its own
set of challenges as you get great big stents with lots more drug and an
area where bare stenting doesn\'t have approved products. So a lot of
their own challenges in that group.

But I encourage you to contact the folks on this slide if you have
questions, and we look forward to continuing our collaboration with CDER
and with the Office of Combination Products to make efficient and
effective review of these applications.

Thank you.

(Applause.)

MR. JENKINS: Thanks, Ashley.

We\'re going to move along quickly. We\'re running a little long on
time. I recognize that, but I see a lot of attention in the audience. So
I think that\'s okay.

Next we\'re going to talk about photodynamic therapy systems. We have
Richard Felten from the General Surgery Devices Branch of CDRH.

Richard.

MR. FELTEN: I\'ll just actually go to the next slide very quickly.

This I think, hopefully, is a success story, but it also gives a good
idea of how we got where we are in this particular area. If you\'ll
notice from the slide, there is a pre-1984 date. The drug that initiated
photodynamic therapy and the combination product review that we used to
get this finally to market was originally submitted as an IND in 1978.

We became involved from the standpoint of devices with this product in
early 1980, \'81, by being asked by the Center for Drugs to look at the
light source that was being used to activate that drug.

We formalized that arrangement in 1985, where I was actually designated
as the lead reviewer from the Center for Devices to look at these
products at the time.

In 1989, we developed a collaborative process for review with the Center
for Drugs following lots of conversations between Center for Drugs,
Center for Devices, and the company on how best to proceed with these
products, and as formalized through the interagency agreement in 1981.

The reason we did this is \-- and you\'ve already seen this slide sort
of \-- Center for Devices has a very involved process in getting things
to market. You have premarket notification, PMAs, the premarket
notification that\'s in our 510(k), the premarket approval which is
PMAs, and some other sources, where essentially drugs has NDA. The
generic drug approval process is not even close to something we do.

The problem, therefore, was how to take these products and have them
reviewed efficiently and at the same time make sure that both the device
and the drug were being addressed in the appropriate ways.

The important thing to remember in this area is all of these drugs are
brand new drugs. These are not already marketed products. These do not
have a history. These are brand new drugs.

In some cases they are derivatives of biological products like human
blood. Other times they are simply chemistries that somebody has
developed on a lab bench that has a photosensitive property. So that
alone is what led us to decide that Center for Drugs would have lead in
all of these products with Center for Devices acting as the consultant.

The way this worked was we encouraged the companies through
conversations to have these meetings with us. Center for Devices took
lead. We consulted the Center for Devices on the device section. All
official correspondence during the initial IND stage was sent through
Center for Drugs to the drug company. The device companies were involved
peripherally through the drug company to submit their device section as
part of the IND. We reviewed the device section, sent our comments to
Center for Drugs, who reported back to the drug company, who talked to
the device company.

As Jonathan has mentioned, although nobody believed it was going to
work, it apparently worked very well and very efficiently. We did have
an oral arrangement with Center for Drugs that allowed me to talk
directly to device companies if I needed to, but official correspondence
was always through Center for Drugs.

Once the clinical trials were completed, the issue came up then how do
we submit this application and what do we do with it. One of the
interesting parts of this particular initial application which was for a
drug eventually called Photofrin was that the drug company very clearly
told the agency, \"We do not want to be a device company. We want to
have nothing to do with the devices once you approve this.\"

And the reason for that was that in the initial first one of these
drugs, which was Photofrin, the light source were commercially available
surgical lasers. Surgical lasers, as laser products, have regulatory
responsibilities under the Center for Devices\' performance standard for
light emitting products. The drug company didn\'t want to be a device
manufacturer because they didn\'t want to be responsible for all of the
reporting requirements lasers have once you market them and post market.

In those conversations with the drug company, who very clearly said,
\"We don\'t want to be a device manufacturer,\" between Center for Drugs
and Center for Devices there was an agreement reached that what would
happen would be that a single application would be submitted as an NDA.

We, the Center for Devices would take the device section out of the NDA
and convert those into PMAs. We made three PMAs out of the device
section, two laser PMAs and a fiber optic PMA.

Now, the reason we did that was, of course, to make this work more
efficiently for the drug company after the approval process because once
they sold off the device sections, we needed a way to be able to track
those post marketly in case there was design changes to the lasers, if
there was design changes to the fiber optics, if there are new
indications for use to come along with a different drug. We needed a way
to be able to at least track the devices.

For the drug company, of course, they wanted to not have anything to do
with the devices after the fact. Historically actually what has happened
since then is we have had two new indications for use added to the
devices since the original approval, and the fiber optic systems have
had three PMA supplements for design changes in the fiber optics.

This has made it much easier for them to make these changes to the
devices because they could come directly to a device document that
existed, and it makes it easier for the Center for Devices to track
these changes, and this is why we\'ve done it.

That process has continued for subsequent drugs. Presently we have three
approved photodynamic therapy device-drug combinations. The original
one, which was by QLT, was for palliative treatment of esophageal
carcinoma. The second one is for a topical drug for treatment of actinic
keratosis, where we\'ve done the same process where the NDA was
submitted. We pulled out the device section, created a PMA for the light
system, and we have continued to follow that device separately, and we
have some suggestions again that the company has come in subsequently to
the original approval and made a device modification to that device
under the PMA as a PMA supplement, which again allowed that to work very
smoothly for us.

And then the most recent approval, which I cannot remember now, is like
three or four years ago. It was again from QLT for the treatment of age
related macular degeneration, again using a laser light source with a
drug, which again we created the PMA process.

We\'ve found that to work very well because in most cases so far, lasers
have been the light source of preference because most of these systems
so far require the ability to transmit light down fiber optics, and
lasers give you that very nice ability to do that.

It has also allowed these companies to sell off the laser part of their
approvals so that they don\'t have to be laser manufacturers.

Whether or not that\'s the future to where we will continue I have no
way of knowing because the laser is a very unique part of this system
and has unique responsibilities with the CDRH requirements under the
light performance standard, but this history for the photodynamic
therapy is how we got to where we are today with what we\'re doing. It
is mainly because this was the first one of these to come into the
system in 1978 actually, and when we first started this process, we had
no previous histories.

And it did require a lot of collaboration between the Center for Drugs
and the Center for Devices, and I will repeat what everybody else is
telling you. With these kinds of products you have to get involved with
the centers early on in discussions to find out not only where you\'re
going to be placed as far as jurisdiction, but to find out from the
reviewing centers what are going to be your responsibilities.

And I thank you for your attention.

(Applause.)

MR. JENKINS: Thank you, Richard.

Our last speaker is Dan Shames, who is the Director of the Division of
Reproductive and Urologic Drug Products in CDER, who is going to talk to
us about his experience with contraceptive delivery systems.

Dan.

DR. SHAMES: Thank you.

I just noticed that the title of this conference is \"Innovative Systems
for Drug Delivery.\" I\'m the only person from CDER talking about the
drug portion of the review, and I\'m the last speaker. So I guess this
is what everybody is waiting for right here.

I want to thank the device folks for asking us to give our perspective
on the review of drug device combinations. I\'m going to discuss the
particular experiences of our division in this area. I think our group
has a particular interest and perhaps expertise since the gynecologists
and urologists in our division have significant clinical experience with
devices and drug-device combinations.

I was asked to evaluate our review process regarding contraceptive
implants, and actually let me go back. I was asked to review
contraceptive implants, but what I did was I expanded this to
contraceptive drug-device combinations and other devices that we\'ve had
experience with in our division.

I\'m going to take the experience that we\'ve had over the last five or
six years and give you what lessons we\'ve learned regarding these
combination products.

I\'m first going to describe five contraceptive systems that involve
cooperative review of device and drug components. The approval year is
in parentheses. The first are a group of device drug combinations that
are all variations of subdermal progestin releasing implants for
contraception. They deliver the drugs systemically. These are rods that
are made up of a co-polymer core surrounded by thin walled elastic
tubing.

I think that the lesson I got from this group was my personal education
regarding the chemistry and the sort of engineering and pharmacokinetic
experience related to quantifying manufacturing processes. So I
personally learned a lot, and our division learned a lot by reviewing
these materials.

Now, all of these and all of the products I\'m talking about went
through the same type of clinical trial experiences that oral
contraceptives would go through. So the review standard was the same for
these products as they would be for any other kind of contraceptive
device.

Next is Lunelle, which is a monthly injectable that delivers a
combination of estrogen and progestin for contraception. The take-away
message here is that although this was a prefilled syringe and should
have been fairly straightforward, there were issues related to
manufacturing the syringe and the vial, et cetera, which did make the
review challenging.

The other thing that should be a lesson here is that there were two
drugs involved, and we had to deal with the combination rule regarding
drugs in themselves. So we not only dealt with the device issue. We
dealt with the fact that we have to show that each individual drug adds
to the safety and efficacy of the product.

Mirena, which is the next one, is an intrauterine system which delivers
levonorgestoral both locally and systemically. I think the important
take-home message for this one is that although there have been IUDs
around for some time, there was a challenge here to show that the
addition of the drug added to the effectiveness and safety of the
product itself, which is something that products have to do, combination
products have to do in general.

This next one is an intravaginal ring, which delivers estrogen and
progestin systemically. This was relatively recently approved. It can be
inserted by the individual themselves. Vaginal contraceptive rings have
been studied for decades, but it took some innovation on the part of the
developer to get it quite right regarding both placing the estrogen and
the progestin, and the right combination of materials to make this work
properly.

I think this is our last example. This is a transdermal system which
delivers estrogen and progestin, and although you might think at first
glance, well, this, you know, should be fairly easy, we have a lot of
transdermal systems. We\'ve had transdermal systems for menopausal
symptoms for many years, but as you may or may not realize, it requires
more drug delivery for contraception than for menopausal symptoms, and
it took some significant innovation for the developer to create a system
which is only about the size of a match box and deliver the appropriate
amount of estrogen and progestin.

So I was asked to look at all of this and look at our experience and ask
myself what did we learn from this. Well, the good news is that as far
as CDER, we can work with device technical experts in a productive and
efficient manner to review innovative drug delivery systems, and we have
done it, and we continue to do it, and most of the time it goes fairly
well.

In this case, with contraception, it was relatively easy because we used
the same standards for review, the same clinical trial standards, and
that was not terribly burdensome on the device systems.

And also, as many people have said, it goes much better when we discuss
these issues a priori, before we start.

The other news, the good news and then the other news, when it doesn\'t
go well. It doesn\'t go well, I find, when things are a little out of
the box, which, of course, is happening more and more. I find that at
least with our division the problem is not necessarily the scientific
challenges. It\'s how to fit the scientific issues into the regulatory
constraints that we all seem to have, and I think that\'s improving.

Then, of course, we have the issue about who\'s in charge, which we\'ve
talked about, CDER or CDRH. I\'ve never seen a turf battle, but I guess
that could possibly happen.

We also have what I call culture clashes, and I didn\'t see Mark\'s
slides. He calls it war of the worlds or colliding of the worlds.
Sometimes critics of CDER might characterize our reviewers as what I
have here, the pointy headed bureaucrats whose main goal is to keep
things off the market because they have no regard for the
entrepreneurial spirit and good old American ingenuity. We\'re just
obstructionists, et cetera, et cetera, you know, versus the critics of
CDRH who think the reviewers are those people who will approve anything
that doesn\'t blow up when they plug it in regardless of consequences to
patient safety.

Of course, none of that is true, but there is a bit of a culture clash,
and you know, I try to think what is the origin of this culture clash.
Well, maybe it\'s engineers and doctors, you know. There\'s a lot of
doctors in CDER. There\'s a lot of engineers in CDRH, and I really
don\'t think that\'s the basic \-- I think it\'s a matter of working
together more because the doctors in CDER seem to get along well with
the chemists, which we deal with. We\'ve had a long history with, and I
just think we should be able to get along with the engineers also.

Perhaps another issue that may be more important has to do with this
reasonable versus substantial evidence, which is in our regulations.
I\'m not sure that\'s supposed to be an issue. I\'ve had sponsors and
lawyers for sponsors tell me, well, that\'s only in the eye of the
reviewer, you know. You determine what\'s reasonable and substantial.

And then there\'s the issue of the big PhRMA versus small firms, and it
is true that we deal with larger companies in general, but we do deal
with smaller companies, and I think that\'s something maybe we all have
to learn how to deal with better.

However, the future looks good in my estimation. I think Mark\'s group
has actually improved things. We\'ve had a very difficult issue that had
been essentially in regulatory and scientific limbo for years, and Mark
was able to get us to move forward on this issue, find a way to move
forward, and I think the regulatory hang-ups can often be the most
difficult hang-ups.

I think we are improving in terms of the culture gaps or culture
differences between the two areas, and I think getting the message out
that we have to be talking about development very early on with
companies is important.

However, I think most staff at CDER and CDRH enjoy working on innovative
products and are well motivated to assist the sponsors and improve our
internal processes.

Thank you.

(Applause.)

MR. JENKINS: All right. Thanks, Dan.

I guess we\'re done with this section, and we\'ll move on to the panel
discussion.

DR. JACOBSEN: While she\'s collecting the questions, let me just welcome
everybody back to this final session where we have both FDA and industry
on the panel up here. We have tried to put FDA and industry folks on
both sides of the table so that we\'re coming across with a message that
this is not an us against them. This is an exciting new area or an
exciting old area really if you listened to Richard Felten, and just
listening to the talks this morning, it was, I think extremely exciting
to see all of the things coming down the road.

Clearly, we\'re going to have lots and lots of issues to work through
together, and I think together ought to be the underlying take-home
message from today.

I have one. Do you have more written questions?

I think the appropriate thing to do is this is your part of the meeting,
to let people ask questions, and as I said before, you can either walk
up to the mic and ask it out loud or you can send your question up on
paper and we\'ll try to, you know, get them answered.

I mean, I can do a kick-off question from the paper if that makes
everybody more comfortable. I have one.

Miriam, do you have something?

Stuart, go ahead.

DR. PORTNOY: Hi. My name is Stuart Portnoy, and until a year ago I
worked at CDRH for eight years, most recently as a Branch Chief of
International Cardiology Devices.

While I was at the FDA and in the past year since I joined PharmaNet as
a medical device consultant, I have closely monitored the regulatory and
scientific requirements for drug-device combination products, especially
drug eluting stents.

And it has been my observation that while CDRH has been designated as
both the lead review center and the regulatory authority for drug
eluting stents, the agency has clearly and consistently raised the bar
so that these products are actually regulated more like drugs than
devices.

I\'m concerned that if this trend were to continue, that some new and
potentially breakthrough combination technologies may face significant
delays in making it to the marketplace and putting it to clinical use
because of unrealistic agency expectations and requirements.

And specifically, I\'ve noticed a trend of what I consider to be overly
burdensome requirements for things like kinetic drug release testing,
stability and lot release testing, and other traditional drug testing
requirements.

Now, while I agree with the FDA that such testing is absolutely
necessary and fundamental to demonstrating acceptable product
performance, I still believe that the agency is already going too far in
their requirements that the drug-device combination products are held to
the same standards and level of quality control as pharmaceuticals.

And let me emphasize that this is for drug agents that have previously
been demonstrated to be safe in an NDA.

So to address this concern, I hope and recommend that the agency and
specifically the Office of Combination Products considers a reasonable
and feasible approach to regulating combination products that lies
somewhere between the current requirements for traditional
pharmaceuticals and perhaps the less burdensome standards for medical
devices, and I invite panel discussion of this important issue.

DR. JACOBSEN: Just let me add that we are joined at the panel \-- I
should have done this before \-- we have two center Directors joining
the panelists who have already spoken here today: David Feigal, the CDRH
Director, and Jesse Goodman, the CBER Director. Obviously they really
need no introduction, but I figured I\'d better do it anyway.

Anybody want to start off with that?

DR. FEIGAL: Well, let me make a comment. I don\'t think the standards
are the same. If the standards were, then some of the things you have
asked for would not get alternatives. If you didn\'t understand the
release kinetics and couldn\'t do bridging between release kinetics of
two formulations, the only thing you could do if you changed
manufacturing would be to repeat the clinical trials.

And so I think there is a real vested interest for us to make this as
scientifically based a process as possible because we have not taken
that stance, nor have we taken some of the other types of traditional
pharmaceutical approaches of requiring the manufacture of three complete
commercial batches prior to NDA approval. We haven\'t required only
testing, only doing clinicals on products manufactured in the final
formulation.

So I think there still is a fair amount of flexibility there. The one
sort of wish that we often hear is to say we\'d like to have a
breakthrough product and we\'d like to not have to submit any evidence
for it.

(Laughter.)

DR. FEIGAL: And to me it has always struck me as sort of strange when
someone says we have enough evidence to show that it\'s safe, but this
is a breakthrough product and we haven\'t seen the evidence of
effectiveness yet.

It would strike me that if you\'ve got enough evidence for safety so
that you\'ve begun to see what the side effects are and so that you\'re
seeing side effects but you haven\'t seen any benefits yet, you must not
have a positive risk-benefit ratio.

So I think that all of the centers, when you have a product that\'s
dramatically different than the existing therapies, treat those products
differently. The evidence requirements are generally less, and I think
it would have been a mistake to have simply stopped with the European
experience. The limitations there weren\'t so much the small numbers,
but the very careful limitation of the types of patients studied and
have led the public to believe that that\'s the expectation of what to
expect from the product.

There\'s a need to characterize how these products basically work. In
other words, I think, you know, we can join the advertising promotion
staff of the companies, as many of our former employees do.

(Laughter.)

MR. HUNTER: Richard Hunter, and I\'m not a former employee.

(Laughter.)

MR. HUNTER: I have been in the business for 35 years in industry to get
products on the market, but just to ask my question, can you use your
imaginations here to determine how a company like mine, Altea
Therapeutics, that has a technology for delivering drugs and other
products through the skin, can avoid double jeopardy, triple jeopardy,
whatever, every time we go to a different division, a different center,
which we will and have to some degree already?

In terms of some of the major questions, I know that there will be
tailored questions per patient group and per drug, but the major
questions, the blockbusters that would put us back to square one in that
particular area. Can you imagine a better world, is what I\'m asking.

MR. KRAMER: I think we can imagine that world. If I understand the
question correctly, I guess what you were indicating was that when you
have a new indication for an existing product, that that indication is
going to different divisions within a center, and therefore, new
questions are generated each time.

I think the intent would be not to have to, you know, reinvent the
wheel. We\'ve heard that before. If that\'s a problem that you\'re
encountering, then you should definitely bring that to the agency\'s
attention so that we can look into that.

I mean, clearly indication-specific questions will arise, but if
fundamental questions, as you say, have been answered, then I don\'t
think the intent would be to have to review those all over again.

DR. JACOBSEN: Okay.

DR. GOODMAN: I\'d just make one addition, which is certainly in our
world you can refer to master files and data generated in other settings
to support an application involving portions of the same product. So to
the extent that the developers of these products are the same or are
cooperating, you know, we\'re very open to looking at data broadly, but
as Mark said, there are going to be some kinds of data that are distinct
for a new combination.

DR. VAN ANTWERP: We\'ve talked a lot about today \--

DR. JACOBSEN: Could you identify yourself?

DR. VAN ANTWERP: Oh, I\'m Bill Van Antwerp from MiniMed, Medtronic
MiniMed.

We\'ve talked a lot today about drug delivery systems, but we all, or at
least those of us in the diabetes world, believe what David showed us
this morning, that devices delivering drugs or biologics controlled by
diagnostics are going to be the future of diabetes therapy, at least,
and perhaps in a whole bunch of hopefully other therapeutic regimes.

So how does the addition of a diagnostic tool change what we\'ve talked
a little bit about here today? So I have a drug that\'s made by one
company, Christine\'s perhaps, and then we have a device, a pump, and
then we have now a diagnostic device. Does that change anything in your
thinking, your fundamental thinking about how these systems get
approved?

And where I\'m going is is the ultimate endgame therapy, delivery? Is
there going to be the possibility of approval for a therapy that
includes some of these kinds of systems?

DR. FEIGAL: I can give you an example of one that\'s already on the
market that has got a diagnostic, and that\'s the variations of
different pacemakers that sense rhythms, sometimes deliver intermittent
shocking therapies, decide whether or not to pace the heart, and it does
introduce a whole additional number of issues in terms of the way the
software is written. There\'s an amazing number of lines of code
imbedded in the people\'s chest as they walk around, and you need to
make sure that the software behaves properly in addition to the sensors
behaving properly, in addition to the whole logic.

And then you have to prove that the whole strategy has a net benefit,
and that I think has been one of the successful areas where the devices
are actually starting to look better than the drugs that used to be used
for arrhythmia.

So I think that\'s possible. I think that some of the challenges laid
out this morning specifically for diabetes identifies, you know, that
not all side effects are created equally; that hypoglycemia is
potentially fatal and much more devastating than loose control. And so
how do you back into this and how do you do this in ways? And it
probably isn\'t even so much a matter of whether it\'s an implantable,
tiny device, which we\'d eventually like to see, or initially if it\'s
something that\'s done in a more controlled environment.

But I think that\'s where some of the paradigms are. I think what\'s
interesting is you watch and you see these things being developed
incrementally and you see changes, and this is different than drug
development. You\'ll see a change in pacemaker features from the same
manufacturer every six to nine months, and you\'ll see new strategies
that are unproven being planned to be imbedded in the future models to
treat different types of things. I imagine there will be that sort of
incremental benefits in developing software for diabetes management. You
may not try to do anything very complicated at first and deal with the
safer sort of things that you can treat and then gradually work into the
other things as you develop the safety track record for that.

What often you don\'t have is a sense yet of sort of what will the
clinical and the patient population and the public bear in terms of
complications. There are some products \-- Jesse has unfortunately a
couple of them \-- where it\'s national news if there\'s a single
product failure. You know, one patient gets an HIV transfusion, and
it\'s news.

And there\'s other products that are over the counter drugs that we
tolerate a certain serious complication rate and even death rate, you
know, a death rate from, and so how the technology is developed and the
comfort that people have with the technology so that we don\'t make our
patients into Luddites who think, \"Oh, it must be the technology that
is going to be bad.\"

How we build that trust as we build that to say that the products are
safe and effective is very important, and it\'s a complex process. It
even involves things like handling recalls responsibly and safety alerts
responsibly.

There have been a lot of pacemaker safety alerts, recalls over the years
that haven\'t undermined the confidence in the products because they\'ve
been viewed largely as proactive measures to deal with problems as
they\'re discovered, as opposed to manufacturing problems that weren\'t
anticipated and other kinds of problems.

MR. KAHAN: Can I add just one regulatory point to that? What you\'re
talking about in a regulatory sense is a closed-loop system where the
actual control of the release of the drug is by a diagnostic feedback,
and our discussions with FDA over the years on closed loop systems is
that they certainly can be cleared through the agency. However, the
approval process will be one that will be extremely rigorous because the
potential for underdosing or overdosing if somehow there\'s a gap or a
data glitch in the loop through a software or other problem has raised
the agency\'s hurdles here.

And I think we\'ve been talking about these products for at least ten to
15 years, and now they\'re about to come to be very, very quickly, and
so can we think out of the box? I think the good news is that you\'re
going to be, especially with insulin, you\'re going to be delivering a
drug that has a well-known character and a well known profile.

On the other hand, the closed-loop side of this is going to lead to
possibly FDA scrutinizing the product more than they would scrutinize a
pacemaker or an automatic implantable defibrillator because you\'re
relying totally on the software and the feedback.

DR. JACOBSEN: Let\'s take this question, and then I have a written one
that I want to ask.

MS. ITANI: Temima Itani with Ethicon Endo-Surgery.

I was struck this morning by the complexity of the programs that were
presented, and I believe that they will undoubtedly present a big
challenge to the regulatory system. I\'m interested in hearing from the
various center Directors here what are their thoughts on where FDA needs
to go to meet these challenges.

What are the changes that need to be made, the competencies, et cetera?

DR. FEIGAL: Jon\'s taking the easy way out. We\'ll make you Deputy
Center Director for the hour.

(Laughter.)

DR. FEIGAL: So that you can answer the question, Jon.

But I think the hardest thing for CDRH, one of the things, we were
talking about the culture differences. It isn\'t just the fact there\'s
different application processes and things. The thing that is different
and was alluded to a little bit in Ashley\'s slides is our
responsibility to make risk-based determinations in an application.

And so even within an application not every question has to be settled
with clinical data. So one of the hardest things is to decide which kind
of things are actually better determined with performance
specifications, engineering specifications.

And sometimes it\'s thought of as a lesser standard, but you know, I
would argue there are some things like radiation therapy equipment where
you\'d rather have a physicist measure the beam than try and figure out
how sharp the beam is by

testing it on patients. You\'re better off with performance standards in
that kind of setting once you\'ve established that a beam has some
therapeutic uses.

So I think a lot of the strategies that were presented this morning,
which included drugs which were activated by the use of energy, by the
use of light, that included many new sort of novel fabrication
technologies to make needles that were smaller than were possible
before.

A lot of that, I think, comes down to really identifying what are the
different characteristics of those products that are really going to be
essential to their performance and that will make them safe and
effective, and to figure out which of the things, even though they\'re
new, are probably better determined by looking closely at the
engineering than at the clinical data.

So I think that\'s probably going to be one of the challenges, is making
that sort of risk based assessment. I think the fortunate thing for
devices is that they are built incrementally and iteratively, change by
change, and that gives us the ability to creep up on some of those
technologies, but some of them seem awfully slow in the development.

Was that in the 1840s that those laser \-- that those light activated
drugs started? That was a long time ago.

John, do you have any comments on new technology and how CDER can learn
about it?

MR. JENKINS: Now that I\'ve been promoted to head pointy head
bureaucrat, I guess.

(Laughter.)

MR. JENKINS: I took offense to that remark.

I think the biggest challenge that we face in CDER is becoming more
familiar and aware of the CDRH regulations and statutory provisions.
Most of our reviewers really have very little knowledge about the CDRH
process. So when they get asked to do a consult or a collaborative
review for a drug device combination may be where CDRH is the lead
center, it\'s really a whole new world for them.

I\'ve watched the collaboration that\'s been going on for the last six
or 12 months between Ashley Boam\'s group in CDRH and the Cardiorenal
Drugs Division in CDER, and I think they\'ve developed a really good
working relationship, a good understanding of the procedures, the
regulatory hurdles, and the pathways, and I think that\'s worked very
well.

So at some point you develop a critical mass of relationships and
understanding that make it go well. All too often most of our divisions
see one of these, you know, every year or once every two or three years.
So you don\'t really develop that critical mass of knowledge.

One of the other things that struck me as I was thinking of answering
this question is it may not be apparent to most of the people in the
audience, but most of the people at CDER don\'t even know people at
CDRH. We\'re not in the same physical location. We rarely run into each
other in the cafeteria or whatever. In fact most of us don\'t even know
where CDRH is located.

(Laughter.)

MR. JENKINS: So it would be, I think, really nice if, down the road, the
White Oak campus does actually bring us all together on the same campus
where there can be shared training opportunities, where you can kind of
walk across the courtyard and go to a device meeting rather than now
trying to figure out how to get your way up 270 to go to a device
meeting.

So I think training, opportunity to interact and experience go a long
way to making these collaborations work well.

DR. GOODMAN: Well, you know, I think CBER has some unique perspectives
on this that I think are relevant to this in terms of constantly dealing
with a lot of new technologies and cutting edge technologies where risk
is often uncertain, and where as David said, a risk based approach and
an iterative approach is important.

I think these are big challenges for the agency. I think everything the
agency does is a big challenge for it, but I think new technologies are
particularly big challenges, and then new technologies that cross
regulatory lines are even more difficult ones.

To me some of the things we need to strive for in FDA and you outside
need to help us with are our expertise, you know, and when you\'re
dealing with new technology, with new material science, with new
biologics and cells or drugs, you really need people who are cutting
edge and have stayed current.

So we need to invest in our own people in terms of being scientifically
up to date, and I include there not just the technology, but in being in
touch as much as possible with clinical reality, clinical trials, et
cetera.

And I think most people at FDA would like to see that, but when people
are working very hard and don\'t have a lot of time, that\'s one of the
things that tends to suffer. It also suffers from the resource point of
view, but I know all of the people sitting up here from the agency are
very conscious of trying to support our people to be as expert as
possible.

Anther part of that, I think, is collaboration and consultation both
within the agency and then outside, and how can we find nonconflicted
ways, for instance, to collaborate more and get more outside the agency,
and to me for CBER that\'s a real priority.

And finally, as I think both previous people said, I think, you know,
this is sort of \"Brave New World\" technology that many of you have
talked about earlier today, and it really has to be, as David said, in
devices you see this all the time, but in the other areas we don\'t see
it as much; that there needs to be this iterative approach to how we
evaluate products and react to new information and a degree of
flexibility that one needs to strive for.

But I think all of those things to do them, you know, have required
expertise and good communication, all very resource-intensive stuff, but
I think it\'s stuff ideally we want to work with you to do.

DR. JACOBSEN: I\'m not a center Director. In fact, I don\'t even work
for FDA anymore, but can I make a comment on this question anyway?

DR. GOODMAN: Sure.

DR. JACOBSEN: Even though it was asked for the center Directors.

Mark said earlier that he had really liked the talks this morning and
this early afternoon, that he hadn\'t heard of a lot of the
technologies, and that he thought that his take-away message as a result
of seeing all of those exciting technologies was that companies need to
dialogue with FDA. I think he said begin early, and I agree with that.

But I also would add that it seems to me that this kind of open meeting
really helps that dialogue start to happen and maybe we should do more
meetings with industry and FDA staff like this one where you really get
a chance to hear the talks on new technologies like we heard this
morning, maybe even have the products, you know, area specific.

I don\'t know, but sort of talking together about the technologies that
are leading to these new and interesting combination products. I mean,
the platform presentations were really terrific, but the hallway
conversations were just as terrific.

So that would be my suggestion, but I don\'t know how you all feel about
that.

DR. GOODMAN: Yeah, we think it\'s great, and you know, the other thing
some people have done is just come in and talk to us about their future
plans and portfolios, and it\'s a little bit of, you know, meet and
greet kind of thing.

On the other hand, we find it very informative to be aware of not just
what\'s there, but what\'s coming to be sure we have the right kind of
expertise.

DR. JACOBSEN: I have a couple of other written. I don\'t see anybody
else at the mic.

The question is insulin is currently not FDA approved for IV route of
administration. IV is an off label use. The insulin manufacturers don\'t
seem interested in filing with FDA to do the studies for IV insulin to
be approved, yet it\'s widely used.

If IV insulin was approved, then that would open the door for novel IV
insulin devices to be developed for hospital patients. Can IV insulin be
cleared without much initiative from insulin manufacturers?

IV insulin devices are not approvable now with IV insulin being used off
label.

MR. JENKINS: Sounds like a drug question.

(Laughter.)

DR. GOODMAN: We would be very open to having sponsors of the insulins
come forward to develop, you know, approved indications for use of
insulin IV. I think we already have the dosage forms. I think the forms
that are available may be appropriate, although I\'m not sure of that.
There may be some modifications that need to be made in the
preservatives or whatever.

Sometimes the agency finds itself in the situation where sponsors don\'t
come forward, and sometimes we find that we have to develop the data
ourselves. It may be possible that there\'s adequate data in published
literature that someone could put together and come forward and submit a
supplemental application to get that approved.

Sometimes it comes down to we have to do it ourselves, which is
obviously a very resource- intensive process to go through reviewing the
literature and developing an understanding of whether the product is
felt to be safe and effective, and then we can put out calls for
applications.

So that\'s a question we could take back to our Metabolic and Endocrine
Division, but I think we also have a representative from one of the
major insulin manufacturers on the panel. So she might want to address
coming to us for an indication.

MS. ALLISON: I think I\'m probably not the proper person to answer that
question, but it would still be welcome if anybody wants to discuss
about this approach to our company, and we can talk about that.

DR. KLONOFF: David Klonoff from Mills Peninsula.

That was actually my question, and I just wanted to have a follow-up to
that, which is: do you think that if a device company came forward
because they have a method of delivering insulin by an alternate route,
namely, intravenously for hospital patients, that this would be
sufficient for you to look into the IV insulin indication or would you
still say that this device company must bring on board an insulin
manufacturer?

MR. JENKINS: Well, I think there are different ways that you can
approach it. Clearly the most straightforward way is as the question was
written, is if the insulin manufacturers would get approval for an IV
indication that would help, obviously, the device manufacturers.

The other approach would be for you to come in in partnership with an
insulin manufacturer or maybe not even in partnership; just, you know,
some of the pumps are not in partnership with the insulin manufacturers.

You yourself could be the one who could summarize the literature and try
to present the evidence to support approval that, you know, IV insulin
for whatever indication you\'re seeking is safe and effective, and there
maybe adequate data in the literature to help support much, if not all
of that indication.

So I would encourage you to, you know, consider talking to the Metabolic
and Endocrine Division about what they might need to feel comfortable
for that indication.

DR. KLONOFF: Okay. Thank you.

DR. FEIGAL: There is one historical example. The very first H. pylori
approvals were done based on literature reviewed by an FDA reviewer. It
didn\'t occur to me at the time, but that might have had some user fee
implications \--

(Laughter.)

DR. FEIGAL: \-- because if you were to come in with an efficacy
supplement for insulin, wouldn\'t he need a drug user fee for that?

MR. JENKINS: Probably if you\'re submitting the simple clinical
literature to try to support an indication. That would probably meet the
definition of clinical data for review, but there obviously are also
provisions for waivers of fees in some cases.

We have taken the approach occasionally of, you know, developing the
data ourselves. We did that with levothyroxine. We published a [Federal
Register]{.underline} notice saying that we, you know, based on the
accumulated scientific evidence found levothyroxine to be safe and
effective, and what we needed were manufacturers to submit NDAs to show
that they could manufacture a quality product that was stable over time.

We did that recently with Prussian Blue for the indication for
elimination of radiation from the body after accidental exposure. So we
published a [Federal Register]{.underline} notice saying that we had
reviewed the scientific literature and concluded that Prussian Blue was
safe and effective for that use, and now we\'re looking for
manufacturers to come in and basically do the manufacturing package, the
CMC package.

DR. JACOBSEN: Okay. I think we have time for one more question.

(Participant speaking from an unmiked location.)

DR. GOODMAN: Well, you know, I think the question, because that mic
doesn\'t seem to be working, was about vaccine delivery devices, and
we\'ve actually talked recently about potentially having a public
workshop about this. I think it\'s a very rich area.

I think there are several different technologies out there that are
quite exciting that offer promise of more rapid or less complicated
vaccine delivery.

I think with vaccines the general point of view has been that each
vaccine is a new product, but I think just like a syringe is a vaccine
delivery device, some of these formats readily lend themselves to
multiple vaccines.

So we do want to both hear more broadly about some of the technologies
that are out there being developed as was suggested and then discussion
some of the regulatory implications.

But as I said, it is very exciting. When you think of, for instance,
we\'ve had discussion about this, you know, there are issues in the
Third World about reduction of needle transmission of infections, and
potentially some of these devices if they were not too costly could have
tremendous promise in alleviating global health problems.

There are some suggestions that some of these devices may be able to
deliver equivalent immunogenicity at lower antigen levels. That\'s a
hope. So I think it\'s a very exciting area, and as I said, we may be
able within the next year or so to be thinking about a workshop just on
that subject.

DR. JACOBSEN: Well, it\'s five o\'clock, and the agenda promised that
you would be out by five.

I\'d like to thank all of the panelists, and also I\'m sure that if you
have individual questions, they probably would be willing to hang around
for a few minutes if you want to grab them before they can get out the
door.

I don\'t know if there are any other wrap-up comments. Are there any
other wrap-up comments?

(No response.)

DR. JACOBSEN: Okay, and I\'d like to say again thanks to Mariam and to
Vickie for putting on such a good workshop in such a short time.

(Applause.)

(Whereupon, at 5:05 p.m., the meeting in the above-entitled matter was
concluded.)