Food and drug administration

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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.


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


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

ROBERT LANGER, Ph.D., Massachusetts Institute of


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

PRESENT (Continued):

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


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


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


MARK KRAMER, FDA Office of Combination Products








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


(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.


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.


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.


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.


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."


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?


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.


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."


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


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
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