Transcript
P R O C E E D I N G S
Opening Addresses
MS. WOOLLEY: Our program is Transforming Health, Fulfilling the Promise of Research. I am Mary Woolley, president and CEO of Research!America, and along with the Honorable Billy Tauzin, president and CEO of the Pharmaceutical Research and Manufacturers of America, we thank you for joining us today.
We are particularly pleased to have Dr. Elias Zerhouni with us as our keynote. Thank you for being with us, Dr. Zerhouni.
We have a very distinguished group of panelists and moderators whom you will hear from shortly.
PhRMA and Research!America are pleased to present today's conference because both our organizations are absolutely committed to the goal of fulfilling a promise of research. Progress toward that goal means progress towards transforming health for the better.
During our program today, you will hear a number of viewpoints as to what the future may hold, as well as suggestions on how we can overcome barriers in order to properly foster research and make our vision a reality.
One of the keys to overcoming current barriers is collaboration, collaboration between the government, academia, and industry. It is central to fulfilling the promise of research, and another key is earning and maintaining the public's confidence, trust, and support, and it is that topic that we are going to begin with.
Research!America and PhRMA have commissioned a public opinion study to find out what Americans are thinking these days about medical and health research, to take a look at expectations, perceptions, concerns, and priorities. The bottom line is this. The American public wants research to succeed, and the sooner, the better.
There is a rich pool of data in this new poll, data that has, in fact, a great deal in common with scientific data. It reveals both the expected and the unexpected, and points us to topics that need further exploration, but public opinion poll data is unlike other scientific data in that public policy‑makers are more often going to pay attention to it, public opinion poll data, and that is another reason that we commission public opinion polls, to share our findings with the people whom we elect to help provide the environment and the resources we need to fulfill the promise of research to transform health.
Our survey methodology is the standard public opinion poll, survey methodology, and we can provide additional details for anyone who is interested. There is a quote here from President Lincoln who surely understood the value of public sentiment and public opinion, as do we.
Now, research for health takes place, of course, in the broader context of health, and it is a frame for what should be our most effective messages. So it is important to keep the public's view of current health issues very much in mind when we talk about the importance of a more robust environment for research. We need to connect the dots for people about how research is going to help them not only in curing cancers and other diseases, but how research can help us drive down health care costs and help us find effective ways to assure that more people realize the benefits of research through accessible evidence‑based health care.
One of the ways we, all of us in the research community, can better connect our enterprise to top‑of‑mind public concerns is by talking more about prevention, and I know we are going to be hearing more about that today.
I said earlier that the American public wants research to succeed. There is absolutely no question about that. We have been seeing evidence of this in our polling for many years. The public has very high expectations for research. This level of confidence is, in fact, more broadly shared in the general populous than we sometimes hear in this city, at least judging from the current funding and policy environment that we are all faced with.
Now, here we have asked an open‑ended question about what people feel are the most important health benefits of medical research, and you can see the way they talk, of course, about new cures and preventions, and that is pretty much what we would expect, but, again, this gives us clues in the words people use that we ought to be using in making our case.
Given what respondents said about the benefits of research, we actually found it surprising that only 57 percent said that research has helped them or someone close to them. This is an indication that we are not connecting the dots as well as we might when it comes to making it clear that everything in health care started out as a research question. We have to talk about it over and over and over again, reinforcing that point.
Now, in stark juxtaposition to that last slide, here we see that the overwhelming majority of Americans say they have benefitted from medical research over the last past year, they are just not seeing it that way. We should consider the fact that we have a work assignment here. If 90 percent of people say they purchase prescription drugs, they have benefitted from medical research, but they haven't made that connection. We need to help.
This is an interesting finding indicating that 57 percent of the public believe we are not making enough progress in medical research. It is consistent with the high hopes and expectations we saw earlier, but it also raises a question as to what people think is standing in the way of more progress. So we asked that question.
Here is a list of five possible barriers to research, ranked according to whether or not people felt each of those barriers was, in fact, getting in the way of progress. We have seen this ranking hold up quite consistently over time, and it gives us confidence that the public will resonate with calls for removing regulatory barriers, sustaining the R&D tax break, and spending more money for research.
For the first time in this series, we asked about low participation of volunteers in clinical trials, and you can see that people aren't as convinced that this is a problem, but there is some concern. The higher percentage of "don't knows" in that category, I think might actually be an under‑representation, since other work has demonstrated that most people do not, in fact, know much of anything about clinical research.
One reason people don't know about clinical research is that their doctors are not talking to them about it, as is shown on this slide. This only refers to participation in trials, of course, this particular question. So it probably understates the percentage who have heard something about clinical trials, but even if we double the 7 percent figure, we can see that we have a long way to go in working with the medical practitioner community, as well as the public, in highlighting the importance to the future of health of more people being willing and interested to participate in research.
Indeed, everyone has a stake in research, a health stake and also a financial stake. The responses to this question show us that one way or often in more than one way, we all pay for research. We pay for research as consumers of health care, including consumers of prescription medications, and we pay for research via our tax and philanthropic dollars, and you can see on this presentation that some of these overlap and can be combined. The point is everybody pays. Support for research comes across the full gamut of the public and their activities and their government.
We also asked a question in the environment that we hear within the research community about clashes, potential conflict of interest and other issues, whether Americans think that the different kinds of institution that perform research should be working together, and overwhelmingly, that is exactly what people say. They want all elements of the research community to work together because the simple equation there is if everybody who is smart and committed is working together, we will get the answer faster.
I think that the public believes that the red flags that are sometimes raised within the community are the community's responsibility to resolve, kind of inside baseball issues. The public just wants us to get the job done.
One of the reasons we want to be assured of the public's continuing support of research is that we want their support to help grow investment in research. You see here in this investment study how industry leads the way in its amount of funding for medical research with the Federal Government and other sources behind, but significant. We are talking about a lot of money here, but it is plateauing out, and that has ramifications for the public's health, as well as for the health of the research enterprise.
I believe that the findings in our poll today as well as the findings of our work over the past many years on these issues reveal that the public is actually ahead of our decision‑makers in wishing to make research for health a much higher national priority.
For the most part, the public doesn't know about the problems caused on both a short and long‑term basis due to the current low‑priority status of research. All of us in this room and our colleagues across the country have an obligation to speak out about this.
One way we can all do that is to participate in getting the nation's leadership back on track in making research for health a priority and encourage candidates running for the Presidency to declare what they will do as President to assure a vibrant research enterprise in this nation.
PhRMA is one of Research!America's partners in a new initiative to make the views of the Presidential candidates known to stakeholders and to the general population via this website. You can help us, you can help the research enterprise, by contacting candidates and urging them to participate. Please check it out.
That concludes my remarks, and I am delighted to be able to turn over the platform to the Honorable Billy Tauzin, the president and CEO of PhRMA.
[Applause.]
MR. TAUZIN: Thank you, Mary, and thank for all of you joining Research!America and PhRMA today in this very important question to focus on, indeed as this poll has shown, the importance of research to patients not only here in this country, but increasingly around the world.
Secondly, let me really thank Dr. Elias Zerhouni for being with us today. We are old friends, and we worked together for many years, me in my congressional role, he in his amazing scientific role on behalf of the patients of our country, and the work you do at NIH, Elias, it will live long after both you and I are gone for many, many years. I want to thank you for all you do and thank you for being a part of this discussion today. We look forward to it.
Mary asked a question, talked about a question in the poll, about whether Americans felt a connection to research and whether they felt benefitted by the research that occurs in the health care communities of our country, and surprisingly, so few do. Sometimes disease has to strike very close to you and very severely in your family before you begin to focus on that issue. There are other things that, obviously, take your attention away, until that awful diagnosis.
I went through that. I got that terrible diagnosis. I got that call from the doctors in Bethesda that, in the middle of a wonderful career in Congress, I had cancer. The advice was to drop everything I was doing and go fight the battle for my life because I was given about a 5‑percent chance.
Somewhere in that course of surgery and chemotherapy and radiation, they took the 5 percent away and basically said I was going to die. I remember that extraordinary moment when Cecile, my care‑giver, my wife, an amazing moment, and I sat with the Dr. Wolf at M.D. Anderson and got that death sentence. I remember looking at him and said, "I'm going to die, but not today, not now. We're going to find something, aren't we?" He said, "Yeah."
So I was lucky. I was very, very lucky because just two years earlier, Genentech had won approval for a drug called Avastin, and it wasn't approved for my cancer. It had nothing to do with my cancer. It was a colorectal drug, but Dr. Wolf and I and my wife, living in this country where we could make decisions like that, made a decision to take advantage of that amazing research and to try it.
I remember he told me, "This drug may kill you because it may interrupt all of the surgical healing. It is going to interrupt the formation of capillaries, the structures the doctors created to put your gastric system together, but it just might save you, too. It might starve the tumor of its capillaries, and we might get that thing, and I will show you a non‑identifiable screen of a liver cancer where we did it off label, and it worked. So maybe it will work for you, because we got nothing else for you. We can give you standard cancer therapy," and they did. They gave me some great drugs from Sanofi, Oxaliplatin, and Xeloda from Hoffman‑La Roche, and I took all of that, obviously, but it was the Avastin I think that made the difference. It really was.
As a result, seven or eight months later, the cancer was gone. I remember going to radiation, I said to the doctor, "Now, don't do anything we can't correct with surgery because we got to go back in. Don't burn me so bad, we can't go back in." He said, "Billy, if we sent a surgeon in right now, we couldn't find the thing." It was gone.
So was I lucky? Yeah. Was I extraordinarily lucky? Yeah. But was it luck that brought Avastin to the marketplace? Was it luck that brought Avastin to the attention of Dr. Wolf? Was it luck that brought Avastin to me? No.
I had traveled to California. I met the team that worked for 14 years on Avastin. I went to Nutley, New Jersey, and I met the 14‑year team that worked with the team in Genentech. I heard their story about how they almost gave up two or three times on the drug because of how difficult it was to take it through that very extraordinary clinical process model we have constructed sometime in the last century here in America and how they persevered, and the stuck to it, and they eventually brought this amazing drug out. It is being tested now in all sorts of cancers, as you know.
I remember thanking them. I remember they were crying. I was crying. We were crying there together, and one of them said, "Billy, nobody comes back and says thank you." I said, "Yeah, but where I'm working now, I know where you live. Most people don't know where you live, or they'd be here to say thank you, too, if they knew where you lived."
So, Mary, I think the poll is right. I don't think Americans yet understand how critical that 14‑year process was, but for all of us who benefitted from it, we not only understand it, we deeply appreciate it. We deeply understand the message of what research can mean to families and lives and loved ones.
Now, not only am I alive today and having a second chance at life, I remember John Breaux said, "Billy, when you were dying, did you see that white light?" I said, "No. I felt a little heat around my ankles. I figured I'd better come back and do something good." Not only am I alive, but I got to see my two grandchildren born that I wouldn't have seen, and they got to see their grandfather. We are going to have a good life together. I got to walk my daughter down the aisle that I never thought I would get a chance to do.
There are all kinds of amazing things that happen because research presents us with those opportunities that otherwise would have been lost, and the last 10, 20 years were being lost to so many people who now have the opportunity to see grandchildren and walk daughters and see their sons get married. Those are the connection points that make the real understanding of how critical research is to Americans, and we need to make those stories real and make people understand how much we depend upon the researchers at NIH and all the 3,000 hospitals and institutions that receive the 50,000 grants a year that literally award 300,000 researchers in America with the tools and the assets they need to conduct basic research in this country on disease and on potential treatments.
It is the connection between what we do at PhRMA, where we spent $55 billion last year in this country, out of $80 billion spent worldwide, $55 billion spent in this country, the only grant that has gone up. That is why we do this in this country because at least here in America, we still have that connection. We still understand it, not enough yet, Mary, but we still understand it, and it is still rewarded and supported.
The question that Dr. Zerhouni needs to get an answer to is will we continue to support it. I was in Congress when we fought to double the NIH budget. We accomplished that. The NIH budget with inflation factored in is going down again. Thankfully, I saw the latest appropriation granted some increases, but we have got to be concerned that not only is the NIH budget relatively flat, but that it could continue to go down, and that is a dangerous signal for every patient who patiently waits for the next great discovery, and are they coming?
Well, here is some good news. Here is some really good news. In our pipeline today, 650 new drugs being tested today for cancer, 140 for heart disease and stroke, 77 for HIV/AIDS, 185 being tested today for infectious diseases, 197 for mental illness, over 300 for rare diseases, and that is pretty new, by the way. There is more and more research being done on the 6,000 diseases that affect 25 million Americans that don't ordinarily get a lot of attention, and PhRMA is proud to work with other organizations, NIH and their department, to, in fact, intensify efforts on those rare diseases. There is a lot of great work going on.
We are going to hear today from a care‑giver who has spent 11 years caring for a husband who suffers from Alzheimer's. We are going to hear what that is like. It is an amazing story. Meryl Comer is going to give you a personal insight of what it is to witness that disease every day in your life.
But here are the danger signals I see. One, we are increasing life expectancy in America with all this great research, with all these new technologies, and we are bumping up to 78, 79, and pretty soon, we will top 80. Most Americans believe they are going to live way past 74. The sad truth is that if we as a couple live into our eighties, one of us will probably have Alzheimer's, unless we somehow find some solution to it.
So, in the silly season of politics, when everybody is running for President, and Congress and the President are dueling it out over there on appropriations measures, let's think about that. We are a country that is about to see an obesity explosion. We are a country that is going to see a diabetic explosion, an explosion of asthma, an explosion of all sorts of diseases. We are going to see it in our children right now because of the way in which we literally have allowed lifestyles to change in this country, and we haven't focused on prevention. We haven't focused on early intervention. We haven't focused on early disease management.
We spend 85 cents out of every dollar today on treating the damage done by disease untreated, uncared for, undetected, when it should have been detected a long time ago and we should have dealt with it earlier. That is why we helped with Dr. Ken Thorpe to put the partnership together on chronic disease and why we are trying to make that a center of this debate in the silly season, how we might reform health care in this country by focusing on that little simple tenet, that if you really focus on early intervention, prevention, and detection, you can save incredible dollars and untold suffering and amazing dollars to the U.S. economy in terms of productivity. We can be a healthier and wealthier people if we have a good debate on how to change health care.
But at the heart of it, we also have to think about will our health care system, will our government structure that is admired around the world, where we fund with government taxpayer dollars this amazing basic research through NIH and all of its affiliates and all the institutions that receive grants and the tools they need to conduct some of this research, and where our companies more and more do the research on applied sciences and really are taking those products to the point of approval and marketing, that combination is the envy of the world. Will we see it sustained in this country? Will we see those pipelines that I described to you begin to fail? How do we make a connection that American really feel before they have to feel it, as I felt it and so many other patients feel it, on a personal level when someone they love or themselves are stricken with awful disease? How do we get that message across?
We at PhRMA have been thinking about that for the last three years, too, and we are working on several ideas. One thing came to mind to me when I was thinking about all of this earlier. As a kid growing up in rural Louisiana, if anybody came to me and said, "We want to build a new electric powerplant, and we want you to support it, but the wires are not going to reach your house," I would say, "Go away. Leave me alone. I've got no interest in your powerplant. I've got no interest in your research on new efficient ways to deliver energy to people if you are not going to connect your pipeline to me and my family." That simple thought helped us to put together the PPA program because you can't have people in America who don't have insurance and can't access medicines supporting research if you don't somehow make those medicines available to them, too, and the same thought has occurred to us internationally.
You can't have people around the world supporting intellectual property and the development of new products and new discoveries in a system that rewards that research, you can't have them supporting that legal system of patents and intellectual property protections that reward the research that occurs if you don't somehow connect them to the medicines that that research products.
So, today, we are working in Geneva with many other partners on new systems by which we can better serve people around the world who can't afford our medicines, particularly in those neglected diseases, how we might do research on diseases that nobody has paid attention to, collectively, and how we might create more accessible structures for people to get those medicines. So there are some lessons there. I think it is one of the things we have to focus on in this country is how we can make everybody understand that research is important to them; first, make sure they get the medicines they need; second, make sure they get the best health care they can. That means you can't have anybody in this country without insurance, as simple as that.
It is crazy, this insane subsidy system we have built in America where the people we are subsidizing to provide insurance to their employees are paying more to subsidize other people who don't have insurance. That is what our system does. Doctors provide $25 billion worth of free medicine in America. Hospitals provide $25 billion of hospital care. We at PhRMA provide something like 7 or 8 ‑‑ I'm not sure. I can't, under antitrust laws find out, but it is something like 7‑, 8‑, $9 billion worth of free medicines through our discount programs and our free programs. We are all doing that. Who ends up paying for that? It is the other people who buy insurance. So we are discouraging them from having insurance because we subsidize those that don't have insurance through insurance costs that we are trying to subsidize insurance for. Isn't that pretty crazy?
If we want a good health care debate in America, a good policy debate, it ought to focus on how we can connect everyone in a system where they get the advantage of the best medicine available in this country through a good insurance program, that gives them a chance to get early interventions, preventive care, and care that literally gives them a chance to manage their disease before it damages and wrecks their body totally. Those are the kind of things I think we ought to be doing, and then we ought to do something else. We really have to somehow defend the system that continues to reward research and development in this country. That is the reason so much occurs here. It is the reason why research and development has left other countries. It is the reason why Japanese pharmaceutical firms do their research in America and why more European firms do their research in America. It is because in those countries, they are not awarded to do research. They are rewarded to build generic products, but not to do basic research anymore.
How do we maintain that system when Americans are increasingly upset because they seem to be the only ones paying for this research? Tough questions.
And the most important one, how do we continue the enormous amount of money we spend in research and development when pipelines are beginning to fail, when this process that now takes about 14 years, much too long, and spends about a billion dollars per drug, knowing that 7 out of 10 won't capture that cost in the marketplace once they get approved, and after they approve more and more, obligations are placed upon them because of safety concerns? How do we maintain that structure when we will be dealing with personalized medicines in a world where science teaches us that we can build medicines for smaller and smaller patient populations?
Think of what I just said. The current model focuses on broad clinical trials and is designed for us to spend a billion dollars over 14 years to produce a new medicine for the broad population, and we try to know everything we can about it in 14 years. Hopefully, we won't be surprised. Three percent of the time, we are.
The new science tells us that very soon, we will be able to identify smaller and smaller patient classes for whom a medicine is specifically designed.
Now, we know in rare diseases, it is hard to put a billion dollars worth of research and development behind a disease with only a thousand patients. How are we going to have research and discovery conducted in this country at a billion dollars a clip for smaller and smaller patient populations, and is 14 years, is 14 years satisfactory to anybody? Is 14 years satisfactory to anybody who is waiting for that new medicine who might not be as lucky as I was because it didn't quite come out in time for them to save their mother, their father, their daughter, their son?
We got some huge challenges. So, while we are thinking in this silly political season about who's got the best health care plan and who knows what is best politically to gather enough votes to be elected President or Senator or Congressman or whatever they are running for, why don't the rest of us be thinking those deep thoughts. How can we build new models that are much more efficient than the current model? How can we convince Americans, more and more Americans, Mary, on how important research and development is before they get that ugly diagnostic call? How can we make sure that no one in our country is left out of this process, so that they all support it, and how can we make sure that in the ugly contest for scarce taxpayer dollars that we never, ever forget how important it is to continue to fund National Institutes of Health, and how we keep that extraordinary cooperative spirit going between the private and the public structures that do research in America?
Now, I was one of the lucky ones. The Cancer Society tells us that there are more and more lucky ones like me. Cancer deaths are finally going down in this country, successively for several years, at an accelerating rate, but there are tens and tens of thousands of new diagnostic cases every day, and what we see in the future is an ugly, ugly situation where America gets sicker and poorer unless we answer some of these deep questions I have asked you to think about today.
So today is a good day to begin thinking and talking about them, and today we have assembled in this room some pretty good people who can help us think it through, starting with Dr. Zerhouni.
Before I bring him up, Mary and I would love to answer any questions we can right now, if you want to take a moment or two to ask us a couple of questions, and then I will bring up the real story, and we will hear from the guy at the point, as the Marines call it, in this effort to battle disease at every element.
Any questions, anyone? Yes, sir.
ATTENDEE: You had talked about personalized medicine and how that is going to transform the way we think about that. So, from the organization that you represent, do all of the members of your organization embrace personalized medicine and all of the implications that are associated with it in terms of the cost and how they would be able to change the patterns of health care that we provide to all of our citizens?
MR. TAUZIN: Absolutely. The one thought in their mind, however, is will they do that here in America, or will some other country come up with some models that work much better.
For the first time this year, more than 50 percent of the market for America's pharmaceutical companies will be outside of the United States. The markets are growing abroad as more and more people can afford and take advantage of newer medicines as they come out.
The real question is whether some country, rich with oil revenue, loving to do a great economic incentive program, might invite all our countries to go over there and do the research there because they are going to set up models that work in a personalized medicine world.
I did something this year that didn't get a lot of attention, but let me tell you about it. I got associated with a group called the X PRIZE Foundation. You may remember them from Space Launch. They are interesting people. Their theory is the theory that brought Lindbergh to Paris. He didn't go to Paris to see the girls, although that would have been okay. He went to Paris to win a prize, and that is when he flew across the Atlantic. It made history.
The X PRIZE Foundation is built around that notion. If you create prizes, you can incentivize people to do some interesting things. So they offered a $10‑million prize for the first people that could launch a commercial space vehicle, and the Mojave group did it. They spent about $150 million to win a $10‑million prize. It's the glory of it, the excitement of it. Now their commercial development is around it.
They came to me and said, "Billy, you served as chairman of the Commerce Committee, Telecommunications, Health, Energy. Give us some ideas." So I gave them a bunch, and one of them we came up with was we really needed a genetic prize. If you did a personal genetic screen, it would take a long, long time and cost about $2 million when we started this. It is coming down rapidly now. If you did 100 of them, it would take 12 years. That is coming down, too. We said how can we really drive it down, how can we drive it down to where a personal genetic screen, a total screen, could cost less than $1,000. So we offered $10 million. We found a diamond mine operator in Canada who had a lot of money to give away, and we got $15 million from him. We offered a $10‑million prize to the first team that could put together a system that would do 100 personal genetic screens in 10 days, that will drive it down to under $1,000 cost, and they have to do it twice. They have to do it on their first team and then on a team of so‑called personalities. I am one of those. I am a personality.
[Laughter.]
MR. TAUZIN: Hawkins is another one who volunteered. Larry King, "Larry King Live," is another volunteer. A hundred of us volunteered to be the second guinea pigs, and that is a little interesting because there is on protection for us. There is no privacy protections or anything right now, but we are going to do it. We think it is worthwhile.
But what happens when we get to that point? Do you see where I'm going? When we really get to the point where we can do individual personal genetic screens and we understand a great deal more about the way in which those genes work together and pathways to either create or defend against disease, we are going to be down to that question. Do we have a model that allows us to do research in that world? We don't. We do not. The current model will break. It will shatter. New discoveries will be thwarted, and I suspect some country is going to be looking to pick up the pieces if we don't pick them up ourselves. All of our companies are thinking about that.
Anyone else? Yes, sir.
ATTENDEE: You see now most of us who advocate for research are essentially licking our wounds this morning from the House failing to override the President's veto of the Labor‑HHS bill.
Having served in Congress ‑‑ and you have sort of alluded to this ‑‑ how do legislators square the fact that many of them stand up and give very moving, passionate speeches, as you have done, for medical research, but when push comes to shove during the votes, they just don't support the bill that will carry that research?
MR. TAUZIN: Don't misinterpret that. The people that voted against it, this is a political fight going on. It is not about the dollars or what is in the bill so much as a political fight or the priorities in the bill.
I can tell you that 99 percent of them, if you give them a choice among things to support, they will want to fix the roads in their district. They want to do what they call "earmarks," all those things that make a difference for their constituencies, and then they want to do some nice broad things and help the country. Most of them are good people.
I have been Democrat. I have been a Republican. John Breaux called me a "Transvesticrat."
[Laughter.]
MR. TAUZIN: I have been one of each. Winston Churchill switched parties three times. They asked him about it. He said, "To rat is difficult. To re‑rat is very difficult." I haven't re‑ratted.
But the bottom line is they are both good people. They are going through political warfare right now. They are not interested in accomplishing a lot, so much as they are trying to affect the results of the next election round. That is sad, but that is true.
Inside that, however, is a lot of support for NIH and for medical research. We have just got to somehow get them past the nasty politics they are caught up in, and it is nasty. I miss Congress a lot. I don't miss that part. I really don't.
So don't misinterpret that. You will have a lot of those "no" votes who really support NIH. They are just playing politics right now.
Yes, sir.
ATTENDEE: I am trying to develop a new message campaign to drive NIH funding. I am curious if you would comment briefly on the viewpoint that says that grass‑roots campaigns are difficult and unnecessary, that you just need to get to the subcommittee chairman and then you are done. Could you comment on that?
MR. TAUZIN: Well, I think that might have been true at some point. I don't think that is true today. I think more and more, you have to have a combination of both grass‑roots messaging and organizations and work done with key players in the bodies.
The contest for funding is huge. There is never enough money, no mater how much taxes you collect, to do everything everybody wants to do. There never will be. That is why, if I can put a plug in, these government‑run systems in Europe make bad decisions about new medicines because there just isn't money to fund them. So they leave them out of the formulation.
The truth is you have got to have both. Members have to feel that they are hearing something from their constituents. Whatever you think about Members ‑‑ and Congress' reputation is pretty low right now ‑‑ whatever you think about them, most of them have pretty good standing in their own constituencies, in their own districts. Everybody hates the other congressman, but they pretty well get along with their own.
For the most part, most of them pay a lot of attention to what they are hearing from home folks. I remember my rule was when anybody showed up at my office, even Dr. Zerhouni, if there was somebody from my district in the outer office, they came to see me first. You take care of your local constituents first. So you can't miss that, but you can select what districts you are working in. Obviously, if you are trying to influence the decision of some key players, work in their districts. That is where your grass‑roots campaigns ought to go.
While we are at it, don't forget the FDA. Funding NIH is critically important, but FDA is woefully underfunded. PhRMA is putting up 70 percent of their budget today. That is too high. Realistically, that ought to be under 50 percent. I would feel much better ‑‑ we all would ‑‑ if we saw more congressional funding of the FDA as well.
So those are messages that resonate with Members when they hear from people at home, "Hey, don't forget to fund these agencies. They are critical to food safety. They are critical to research and my health and my family's health." When they hear that, then when you go in their office, it resonates better when they talk. Don't forget grass roots, very critical.
I want to bring Dr. Zerhouni up. So I will take one more. Go ahead.
ATTENDEE: I am John Reichard with Congressional Quarterly.
I just want to take another crack at that question that was asked earlier. You emphasized the importance of funding NIH. Was it a mistake for the President to veto the Labor‑H bill?
MR. TAUZIN: I don't know all the reasons why he vetoed it. He may have vetoed it for other reasons. I don't think he vetoed it because of the level of NIH funding. I would be surprised if that was his reason. I suspect there are other reasons why, including some political reasons, but I know him and I know his administration well enough to know that they value medical research, and Dr. Zerhouni will verify that, that they support very heavily.
In Texas, for example, where the President comes from, the people of Texas just approved a $3‑billion bond issue to study cancer and to research cures from a State government level. So I know the President comes from a State where there is a strong emphasis.
We just did a fund‑raiser for NIH last night in this city with Tom Hanks who is playing the role of Charlie Wilson in the new movie. Go see it. It will be fun.
So my guess is that it wasn't NIH funding that was in his mind when he vetoed the bill, but in the end, obviously, the Congress and the President are going to have to come to some agreement on the total funding in the bill and a place where the President can sign it because it is a critical bill. It has to get signed.
I am going to take one more, and then we will finish. Go ahead.
ATTENDEE: [Inaudible.]
MR. TAUZIN: Well, a couple thoughts. Let me tell you. Just recently, I think it was Bob Eisner who was talking about the concern that he had that FDA was turning down new drugs because there were other drugs that were nearly as effective or as effective in a disease class.
That is a bad decision. Let me tell you why. One, it enforces monopoly. One of the good things we have is that we have got a lot of companies competing in the same disease class, trying to find a lot of drugs that serve patients in that area, and the idea that they are all competing and that they are offering drugs in the same disease class from whom doctors and patients can choose, that is good for patients. It is bad for patients when you only got one drug in a disease class. That is a monopoly, and that is not going to lead to the kind of marketplace competition that leads to hopefully lower prices and more affordability in drugs.
Secondly, I don't have to preach this to people in this room ‑‑ I think you well know it ‑‑ that all drugs operate very differently in the human body, and they all have different side effects for the human body. You may have two or three drugs that are in a disease class that are very useful for some patients, that are very unuseful for another.
I was surprised to learn more about that when I went through cancer treatments, how when they read me the list of all the side effects, I said, "My God, I don't want to do this." Listen to some of the ads on television that recite all the side effects. Why would I take that drug? They don't all happen. They happen for some. Some happen for others. Most of the patients who took the drugs I took lost hair. I grew hair. I am trying to figure that out. Maybe it is in my Cajun heritage or something. I don't know. But the bottom line is you can't make a judgment that you ever have enough drugs in a class until you got 100 percent of the patients in that class getting the best treatment from those drugs.
What traditionally happens is an evolution in discovery. We discover a drug that is good for 10, 20, 30 percent of the patients in a class. Then another company comes out with a slightly different version of the drug, but it takes care of another 10 or 20 percent that were not serviced by the first drug or couldn't take it because of the side effects, and then we come up with another one in the class that takes care of the next 20 or 30 percent. Eventually, you get to 80, 90 percent of the patients who have a drug that works for them, that they can tolerate, and then the next effort in evolution is to find out how to take that drug in a pill instead of an infusion, how to take it once a month instead of once every three hours. You get user friendliness innovations in drugs, and to forget those things is really to harm patients.
I will be very specific to you. When you build a drug that, for example, an alcoholic has to take every day, you are probably not going to help that fellow that way. They are going to forget to take it, and then they are going to take a drink instead. But if you build a drug that they can take every week and tolerate or every month and tolerate, you can really go after alcoholism in that patient, and that is repeated across the spectrum of diseases.
So keep that in kind when you talk about that. Do you ever have enough choices when it comes to getting the right medicine for the right patient? Of course, you reach a point at some point. When you got 100 percent covered, it should be there, but should you stop when you are just taking care of 50 percent of the patients of a class and say we have got enough generic drugs available, we don't need a new drug? Ask the other 50 percent.
I will give you another great example. Xigris is a drug made by Lilly for sepsis. It will take care of a third of the patients with sepsis. It doesn't work for the other two‑thirds. We don't know why. One day, we will find out, but in the meantime, if somebody comes up with a drug that works for another third or another third, God bless them. It will save some lives. Is it satisfactory that Xigris is around? No. We still need to take care of the other two‑thirds.
Thank you very much.
Ladies and gentlemen, let me bring in the star performer here. I want to hear from him.
MR. TAUZIN: He has really brought the institution into the modern age.
He has obviously got a huge background himself in radiology and medicine. He spent his career in clinical and scientific administrative leadership. He was at Johns Hopkins I know where I got my surgery, that doctor and where the brilliant work they did. He is credited with developing the imaging methods used for diagnosing cancer and cardiovascular disease. He is one of the world's premier experts in magnetic resonance, the MRIs. He has extended the role of the MRI in taking snapshots of gross anatomy, visualizing how the body works at the molecular level, not just the gross level, and he has pioneered magnetic tagging which is a non‑invasive method of watching the heart in action, which is pretty cool, and he is renown for refining an imagine technique called ‑‑ and this is a tough one ‑‑ computer tomographic densitometry ‑‑ is that pretty close? ‑‑ which really helps designate or discriminate between non‑cancerous and cancerous nodules in the lung. How cool is that, that you can tell that just by imaging.
He has done some amazing work. So he is a visionary. His role is seeing things more clearly and allowing science to see things more clearly. Isn't that a beautiful metaphor for what NIH does and for what Dr. Zerhouni does? His work, his background is in helping us see through science what disease looks like and how we can find an answer to it. He is a champion, a pioneer, a warrior in the fight against disease, running the institution that helps us all find those answers.
Please welcome Dr. Zerhouni.
[Applause.]
Keynote Address
DR. ZERHOUNI: Well, thank you, Billy, and thank you, Mary, for having me today. I always marvel, really marvel about the ability of Billy to weave together in the same speech the most humane consideration about patients and himself and the human dimension of what we do with the highest strategic insights and how to really crystallize together the hope of research and the delivery of the research results to the people.
I really cherish the moments we worked together. You were a great champion of the doubling of the NIH when I became director. You remember the 2001, 2002, 2003 were the last three years, and there were lost of questions then because the Federal budget had gone into deficit.
I remember in 2002 when I became director, something unique in the history of the budget committees of Congress. I was called to come back and testify, basically after the fiscal year was already ongoing, and in a testimony that I had to give about why should we not slow down the doubling of the NIH budget, and in 2002 ‑‑ this is a little secret history ‑‑ there was a proposal to slow it down to about 5 or 6 percent a year. I would say that at that time, his committee and many Members of Congress came forward and said, "No. We committed," and the President himself said, "We committed to finishing the doubling," and they finished the doubling. It was a 16.5‑percent year, the last good year of my tenure.
[Laughter.]
MS. WOOLLEY: So far.
DR. ZERHOUNI: So far.
But it has been an exciting, exciting time, and I think I could not really agree more with what Billy said, and that is, never underestimate the power of innovation and imagination because if you do you are going to miss what I think we are all about. We are not the National Institutes of Health. We are the National Institutes of Hope to millions of patients who are really counting on that, and at the end of the day, after five and a half years in this job where I have had pretty much a unique perspective about what is really being done both here in the United States and worldwide in medical research and knowing the state of the research, I come with the absolute conclusion that unless we speed up our understanding of biological systems and unless we do that and succeed at it, the risk is that 25 years from now, we will practice medicine in the same context, with the same concepts that we do today, and that will be an unmitigated disaster for mankind, not just for the United States.
There is no doubt that life sciences and the breakthroughs that we want and we need in life sciences are going to be a determinate for the history of modern civilization, just like physical sciences in the 20th century. Make no mistake about it. It is the absolute frontier of knowledge that will determine whether or not we are successful in health, but also whether or not we are successful in environmental remediation, environmental strategies, and creating alternative sources of energy.
The evolution of 4 billion years has developed systems which we do not yet understand, and yet, they contain the solution to many of the ills that we as a civilization are confronted with.
So what I would like to do is share with you some of the strategic visions. I am going to try to emulate Billy here and try to really give you the major forces that are driving both our thinking at NIH and where I think we fit in the total picture because it is a total picture. You cannot succeed from any one component of the system ‑‑ innovation, pharmaceutical, biotech, government, academic ‑‑ without understanding the total system.
So let me just start by saying that transforming health and fulfilling the promise of research is going to require new thoughts, new concepts, new methods. What we have today is just not efficient enough, and I think you heard it from my friend.
The question there is how, how do you go forward, what is the shape of things to come, and how do you then strategize the total investment of the NIH budget to advance that.
First, I think we have to look at the track record and where we have been, and there is no doubt that the investment in biomedical research has paid off enormously. I think you just heard the statistics about cancer death in the United States. This was starting in 1991, '92. There was a trend in the rate, but people said, "That is just a fluke, that is just people stopping smoking which is a major reason for that, but in absolute numbers, cancer deaths are not going do." Well, for the past three years, they have. Not only they have, but they have gone down in an accelerating rate, and there are many reasons for it. Much of it is due to our early screening and prevention strategies, but a lot of it is also due to advances in our understanding of the disease process.
What is the investment in this war on cancer that we have conducted now for about 30 years as the Cancer Act, 1971? About $9 per American per year.
If you look at heart disease, we have had a 60‑percent drop in mortality. In fact, if we had not had the advances we have witnessed over the past 30 years, there would be 1.3 million people dying abruptly today, instead of today we have 500,000, 500,000 too much, but think about the economic impact of saving the lives of so many young people who then remain productive.
Economists have shown that this value per year is anywhere between 1.5‑ and $2.5 trillion; investment, $4 per American per year. So the investment you as an individual have made in the past 30 years from your own pocket to not have the risk of acute heart failure and heart disease, coronary heart disease, has been about that much.
There is no doubt that return is there. If you look at disability, it is obvious that we are aging, but also, we are living longer younger because the disability rates have been dropping for the past 20 years to about 30 percent for Americans over the age of 65. What that means is that we have made advances that are able to maintain the quality of life for much longer with a life expectancy that has gone up by one year every five years. The total NIH investment over the past 30 years averaged, per American for all of this, $44 per American per year.
So it is not like we are talking about breaking the bank here. We are really talking about probably the best ratio between investment and return that I can think of in terms of government activities.
So let me just say that the track record of biomedical research and research in general has always been at the core of the advances of this country and in maintaining its preeminence, and I think the public knows that through Mary's pose. There is a sense that unless you advance in your knowledge of the physical world, it is very hard for you to implement policies that will be of service to the entire nation, but also to the world.
And it is what I said about, for example, the telephone. If you had frozen telephone innovation 50 years after the beginning of the research on the telephone, remember that when Alexander Graham Bell proposed the telephone, he was turned down. Western Union turned him down. They thought the telegraph was going to be the answer to that. Everybody predicted that it would be eight people who could afford that telephone. Fifty years later, this is 50 years later now. This is about the same amount of length that I am describing here, 50 years of molecular research that we have done at the NIH, 50 years hence is about 1925, 1930. Imagine that some smart person said, "You know, it is too expensive, this telephone." At that time, you had the connectors, and it cost you about $75 in 1930 dollars to make a one‑minute phone call to Europe. $75 then is about $1,000 a minute today. Suppose we had come in and said, "You know, this is going to break the bank. This telephone is crazy. Why do we need to talk to each other? Let's stop this innovation. Let's not have it." That is exactly the conversation we are having here. Let's not make a mistake. This is fundamentally what is being discussed, the freezing of innovation for years and years to come, and I think it is clear that if we don't respond to this in a very clear way, the picture of having computers and then better communications and then cell phones that everyone can get in the middle of India ‑‑ I was just in India ‑‑ in the middle of India where there is absolutely nothing, everybody has a cell phone. So Graham Bell was absolutely a visionary, but more importantly, we did not stop the innovation. That is the key to this message.
So we have made advances. There is no question that we have funded scientists across the U.S. If you look at the productivity of this, there has been between 1998 and 2004, 3,114 new technologies that have been brought to market. What that means is that they have been marketed, licensed. Somebody has said these are valuable enough to spend dollars on. This had a huge impact on biotechnology with the whole biotechnology industry created.
Now, having said that, let's just look at the other side which is the challenge. I don't believe that we are making the progress and the speed and effectiveness and productivity that I would hope to see, clearly.
So, having said that, everybody can say that, public polls included, and say we are not making progress fast enough, and it's like, "Okay. So what do you propose? Do you have a better idea?"
I had a talk one time with some advocates who are famous, who have developed computer systems and understand a lot about engineering, computer systems, and software and so on, and one of them was telling me how they felt absolutely outraged that NIH had not yet developed an HIV vaccine, and that every time we try, it fails, and we go on for 20 years and it didn't work. It worked for drugs, and yet in 1985, everybody predicted that a vaccine would work and drugs would not, and the opposite has happened.
I was flabbergasted that someone so experienced, so successful in life would tell me that, and I turned back, and I said, "You know, when I use your computers, I have viruses and bugs in my software that you have not been able to eliminate. I am so worried about the viruses that come from the system that you designed. I have to figure out the virus from the system that was designed by God knows how and when and has evolved for 4 billion years." So the difficulty should not be underestimated.
There is a tendency to underestimate the difficulty of biomedical research and poopoo it and say, "If we just had better this or better that, the disease processes would not impact us as much as they are," and there is a good reason to be prodded to make progress, but I think there is also a good reason to look analytically about where the challenges are and what we need to do about it.
No doubt, biomedical health expenditures are going to be the dragon or is going to drive public policy, the growth of Medicare much higher than the GDP growth, and we are going to face a real challenge. Biomedical research must be part of the answer. We must help somehow find a way to deliver more effectively than we have.
The cost of health care is going to reach $4.1 trillion. It will double in 10 years. No one can really sustain and afford that in any form, even if we improve the delivery system, and God knows how much we know that our delivery system is not as efficient as it could be. Even if you did that, you still would have a problem.
So some real breakthroughs, innovative breakthroughs are going to be needed, and that really needs to be understood in the concept of what are the real challenges we are facing. The first and foremost is chronic diseases. We have had a shift from acute to chronic diseases. Eighty percent of our expenditures are in chronic diseases. Of those, five conditions make up 80 percent of those expenses, and you know which they are. Often today, the same patient may have multiple diseases at once. So that even the concept of diseases and institutes that study this and not that starts to meld together at a time when there is scientific convergence as well between diseases and our understanding of the different diseases.
Aging of the population, health disparities remain a problem both within countries and between countries. I think emerging and reemerging infectious diseases are going to be a huge challenge. They are reemerging for good reasons, because there is an unsettled situation worldwide in terms of human population and its relationship to its environment, and obviously, we are seeing also emerging noncommunicable diseases, obesity being the primary example, but we are seeing a rise in mental health conditions, for example, that will reduce, in fact, the quality of life in one of the most important populations, 25 to 44, worldwide. This is actually one of the fastest rising cause of disability worldwide, as identified by the WHO.
So obesity clearly is the shape of things to come. We do not wish to see this happen. It is obvious that we have to respond to these rising threats.
So these major factors will force a transformation, whether we like it or not, and I always remind myself of Billy when he was in Congress always tried to build bridges, I would say, and maybe a transvesticrat is what you need to do that, but he did it.
The thing that was interesting to me is that these factors were there. They are there today. They are going to be there, the Medicare cost, the entitlement cost, the pressure on discretionary budgets, the choices you have to make. Clearly, everybody knows that whether we like it or not, whether it be a revolution or a good evolution, something has to change, not just something, but a lot of things have to change, and I think when you look at that, you need to have some sort of driving strategy.
The driving strategy that I have tried to come to is this one, and that is that we need to change the paradigm of health care. You have heard it, and people say it in different ways, but I have been talking about this since 2003 where, in fact, a very simple econometric analysis will tell you that today, as we know it, there are very few diseases that occur overnight that you could not predict were there before. Infectious diseases, you catch a bug, that is not predictable, but most of the other diseases, we find markers, biological markers, years before the disease strikes, so that you can see that there is a preclinical phase, the phase that is existing in our population that we do not detect, and the disease becomes obvious. You have high blood pressure or high cholesterol, and we start to take care of that, but more often than not, the patients come at the last stage.
Then if you look at the cost curve, in our system, there is an exponential growth as you wait in terms of intervention. So, if you can catch hypertension early at age 30, it is basically a dollar a day, go to exercise and diet and you will fix it. If you don't catch it, it is $10,000. If the patient has a real infarction and you need to treat that, it is $100,000 for a bypass, and if that fails, you need to go to a transplant, a million dollars. So it is 1, 10, 100, 1,000. You see the growth is really fast.
So there is no doubt that if you look at the strategy that we have been following because of our lack of knowledge primarily, it is the curative treatment. It is the worst part of the curve to intervene.
Over the past 30 years, the progress that I have described to you has been primarily related to our ability to do symptom management, understanding that a symptom drives a particular disease process like high cholesterol or smoking or high blood pressure, and then we treat that symptom. So we manage the symptom down, and sure enough, there is a result that you see in the fact that by moving the curve back, you are able to achieve some cost savings, both in terms of disability, quality of life, and cost, real dollars, but at the end of the day, you realize that if this is the model, that there is a long preclinical phase, that you don't develop Alzheimer's disease overnight, that you do it 25 years before diabetes or Parkinson's disease, then you need to put your research at the very early stages of that disease, and that is what we call "molecular preemption."
In other words, you need to understand the molecular pathways that are really determinant in this disease in that individual and intervene at that point. Well, let me tell you, the bad news is we don't have that knowledge. The good news is we have tools that are emerging that tell me that we have never had better opportunities to have that knowledge than we do today.
So it is the simple, straightforward approach to go from a curative paradigm to a preemptive paradigm. It will require quite a bit of research, quite a bit of development, and I show you this in a real disease process.
This is rheumatoid arthritis. When you look at this hand, you can see what, in fact, has happened. We did not know the immunoresponses that were involved and the damage to joints in rheumatoid arthritis. So we had symptomatic treatments that just took care of the pain, but the hands would end up being deformed, as you see on the right‑hand side.
With the new class of antirheumatic drugs, the TNF‑alpha inhibitors and specific agents that were active, the progression has been dramatically slowed and in some cases actually reversed. It is unbelievable. This had never happened in a disease process, but in the past two years, we have discovered three genes, and I can tell you all the efforts we are making right now are focused on these three genes. It is almost like you have lamp posts that are lighting up, and all your researchers are going there and looking at that, and the hope is that you will be able to intervene, no longer after joint damage has started, but before joint damage started.
That is the picture of the future. This is what we call P4 medicine or Four P's of medicine. First and foremost, you need to be more predictive. If you have no knowledge of the behavior of a biological system, all of the talk we have about side effects or personalized medicine, when we say is that going to destroy the business model of PhRMA, maybe yes, maybe not. Why not? Because you could have personalized approaches that affect different populations. One molecule could be at play with different disease processes.
The example is Avastin being used not in colon cancer, but in your particular condition, or Avastin being used by a thermologist for macular degeneration today, same molecule, three different diseases, and it is something that may happen, but it will not happen unless we have an understanding, predictive understanding of what is going on.
This means also personalized preemption. What is the difference between prevention and personalized preemption? The difference is that if I today give statin drugs to 100 million people, I know statistically that only 10‑ to 15 million of those will eventually develop a heart attack. I am using statins in 85 percent of that population with not a real shred of strong evidence that that patient in that disease will suffer.
On the other hand, if I knew the 15 percent that did, I would go after those, and then instead of treating 100 million because they have insurance, I will treat 15 million times 100 worldwide because I know those are the ones at risk. That is the difference between general prevention and personalized preemption, much more cost effective and at the same time much more productive in terms of being able to have the health impact that you need.
Then you need to develop preemption. A cancer vaccine this past year on cervical cancer is a good example of that, and the fourth P is that you will not be able to deliver that medicine if it succeeds in any way, shape or form without a complete reform of the health care delivery system because patients will not be as sick or will not be sick at all. They will not be patients. They will be normal, and because of that, you will have to redeploy the way we pay for and we encourage people to and how we train our health care professionals to deliver this care.
Having said that, let me tell you it sounds like a great idea, but what is the scientific challenge? I am going to try to crystallize it because, at the end of the day, we can make very long speeches about what is happening in different diseases and different approaches to disease, but at the end of the day, I have come to the conclusion that there is one fundamental challenge, and the challenge is as follows.
If you look on the left‑hand side of the slide, what you are seeing there is just one little part of a response pattern for a cell that has been damaged, either by x‑rays or ultraviolet light or an infection, whatever it is. It seems like the cell responded in a very prototypical way, except that in this case, you find over 150 molecules that seem to be involved and interrelated in how the cell responds. That is 150.
Now, when I was Dean of Research at Johns Hopkins, we were expecting that there would be about 140,000 genes in the Human Genome, and then it was 60,000 and then 40,000 and now 25,000. We know there are 25,000 genes. We also know that there is about 300,000 proteins that are coded by this genome, and the forms of these proteins are about three times greater, to about a million. So what I am showing you here is 150 of a million different kinds of proteins interacting or molecules interacting. That is the challenge.
The challenge, we didn't know that in 1971. In 1971, there was a sense that cancer was one disease that you could find the magic bullet, that perhaps Alzheimer's is one disease that you will find a magic bullet. This concept is just what is misleading. I don't think the reality is that simple. It is more complex, and we need to realize it, and we need to admit with humility that we may not know 90 percent of what we need to know. We may know 10 percent of what we need to know when you look at the complexity that has been unraveled over the past 20 years in terms of the advances we have made, but that doesn't mean we will not be able to overcome that. How do we overcome that?
So, on the right‑hand side of the slide I am showing you, a chip, and I betray my scientific background in physics and engineering and mathematics. That is pretty much where I come from. I am a systems person. When you look at that chip, let me just get you into a thought experiment for a second.
Let's suppose you are a martian. You are coming from Mars, and you are a scientist. You have never been on earth before, and one of your researchers brings you this chip out of the computer that we are using today and says, "You know, this civilization, they were using that chip. I don't know what that is. I don't know what it does." Well, you look at it and you say, "Well, let's study it." How would you study it?
First, you would study the components of the chip, the transistor, and the resistance and whatever else there is, and the wires, but at some point, even if you had that knowledge, you wouldn't know that that chip was used to make a PowerPoint presentation by the director of NIH. You don't know that by looking at that. You would need another class of research strategies to be able to do this, and this is what I mean.
I said over the past 50 years, science has been involved in looking at the components of biological system,s just like you would look at the components of a newly discovered integrated circuit, but we do not understand who they are all interrelated and how they interact in health or disease. That is, in one word, what I consider the core challenge, the central challenge of life sciences in this century.
So we need to move from the hardware of life, which has been the sort of historical period we have gone through over the past 50, 60 years. We are still in there. We are still going to do that. We don't understand all of the components in cell biology, but we are getting there, to the software of life component where we need to understand molecular pathways in the regulation, their interaction in health and disease.
Is there hope to do that? Yes. I think one of the first things that I was convinced of was we could not advance scientifically unless we had a different roadmap, a different conceptual understanding of what needed to be done to advance the science, and we did and came up with these three‑legged roadmap for medical research at the NIH.
One is what we call New Pathways to Discovery, which means what are the tools, what are the resources, how do we implement the breakthroughs to understand this complexity.
The second is Research Teams of the Future. Research is no longer something you can do in a small lab with two people and three pipettes. You really need very powerful resources. A $1,000 genome capability will be a huge breakthrough for us, proteinomics capabilities, analytical capabilities, computers. You need people to come together in ways they have not come together before.
So my role at NIH has been to break those barriers between disciplinary fields, so that they can collaborate together. We have created a new grant mechanism, so that scientists from physical sciences can work with biological scientists and researchers in cancer, if need be. That is the key to it.
In a period of rapid innovation, the most important thing you need to do as a leader is remove the barriers to interactions, whether it be regulatory barriers or be because we grant things in a certain bureaucratic way or because we have no vision of where it needs to be, and to me, that is the second leg of this roadmap. It forces the agency to try new things that would not have been tried otherwise.
The third one is something that is right in line with the surveys, and that is that people do not participate in medical research to the extent that we need them to, and that means we have to change the way academic institutions interact with industry, interact with government, to be able to make sure that patients do get asked to participate.
We were always criticized at one point and said, "Well, you don't have enough participation," except for the cancer patients who participated at a high rate. Parkinson's disease patients don't participate. Why? Because they are not asked. When you do the surveys, you find that the great majority do not get asked to participate. That means we need a reengineering of our clinical research engine. We cannot keep doing what we have been doing at the cost we have been doing it and ultimately end up with the rate of failure that we are ending up with. So that is the third leg of the vision, if you will.
So let me just give you one example of how this vision, if you will, is playing out in real terms. When I became director, we knew the Human Genome was going to be completed, but it was very important not to stop, even though the budgets were flattening, not to stop the exploitation of that. It is not enough to have one sequence. You really need to have the sequence of many, many different people, and so even though it was very expensive, we went ahead and created the HapMap with collaborations around the world with the leadership of Francis Collins.
What was very interesting is that that advance was very controversial. A lot of people criticized us for it. They said, "That is not part of what you should do, and you should let people come up with their own small grants and ideas," but unless you have that tool, your own researchers get stymied. They would not develop insights because they would know that they could not really test them.
So this has made it possible, and I am just going to show you why I believe that we have never seen as many opportunities in science as we have in this decade.
In 2000, there was one gene that I knew about that had something to do with diabetes, PPAR gama. It is an enzyme. I was waiting for the discoveries. In 2001, there were two discoveries that were made that related to Crohn's disease, inflammatory bowel disease, two genes.
When I became NIH director, I kept asking. I said, "Please tell me what is happening that will tell us that we are delivering on our doubling." The legislators were every day asking me, "We have doubled your budget. What have we gotten for it?" So I really was around the NIH asking them to show me what the breakthroughs were.
2002, none. 2003, one major one, which was the discovery of a master gene in diabetes. 2004, nothing. It is hard to be NIH director and report nothing, and then 2005, age‑related macular degeneration, all of a sudden, there was a spat of discovery in April of 2005. Remember that month because it came within two weeks of each other, and they discovered basically two genes and then a third one that showed that macular degeneration was actually an inflammatory disease and not a degenerative disease, as we called it, so, again, a complete rethinking of the disease process.
2006, it gets better, five. Prostate cancer, all of a sudden, there is a possible discovery about why African Americans have a high rate of cancer.
2007, the first six months of 2007, an enormous influx of new discoveries. The second six months, look at the diseases where we have made what I call lighting up lamp posts where we didn't know there was any discovery to be made before, not that those discoveries are going to be the key, but I have to tell you between 2001 and 2002 where I can count on the fingers on my hand, the discoveries that relate to common diseases now. I am not talking about rare diseases, and then you have this, and actually, it continued.
This is 2007. This is the sort of harvest of what we have been saying all along, that investment at the basic level is key to making this progress.
So, for example, multiple sclerosis, there has not been a factor discovered in multiple sclerosis for 30 years. Until the HLA discovery of the '70s, nothing had been discovered, and all of a sudden, two, then childhood and adult obesity and then host control of HIV‑1, we are finding why some people are resistant to HIV, and then Type 1 diabetes and on and on. This is obviously an enormous harvest, but an enormous harvest also posted some logistical problems, how are you going to study all of this, because remember an association is not a causation. We need to really prove this.
So we are really coming to a point where I as a director find that we have enormous opportunities, but enormous needs at the same time to really make that progress. So it is a long and treacherous road. It is not going to be overnight, but ultimately, what we are doing will allow us to develop the tools to understand that chip that I was telling you about at the software level, not at the component level, and that is where we are reengineering in the clinical research.
We have basically phased out the 55‑year‑old clinical research system of the United States, which was based on general clinical research centers, and phased in a new, completely different system called the Clinical and Translational Science Awards, and it has been received with a lot of enthusiasm. Why? Because for the first time, it allows you to train a next generation with completely novel methodologies, completely different ways of looking at a human population or human samples. This is something that to me is what the agency should do.
It was difficult. It was a lot of political pushback because you are changing something that has been three for 60 years, but ultimately, 24 institutions bought into it, the best institutions, but they agreed to work in a different way. They will collaborate in an open environment with all of the partners that we need to have, and this is really my message here.
There is an ecosystem of science and biotechnology. You cannot look at any one actor and think that that actor will make it happen. Public organizations, patient organizations, universities, Congress, FDA, all of this is an ecosystem that is envied in the rest of the world. Everywhere I go, I get asked about this system.
So preserving this and the energy of that will require proactive steps and a balanced national portfolio of research, and what I mean by that is if you look at what NIH spends, it is like a pyramid. We spend 55 to 60 percent of our research on basic research, and the reason for that is because no one can sustain 30 years of basic research in something that may or may not work, except the government, and 40 percent is in translational clinical research, especially rare diseases or diseases where there hasn't been really fundamental progress.
Industry spends more than we do, $59 billion. You are double our size. In fact, when we doubled, industry almost quadrupled since 1991, and that may be a reflection of the productivity issue, that $1 billion per drug, but it also shows that we do most of the R and industry does most of the D, and the two together is the balanced portfolio that I talk about. So you never can look at one at the exclusion of the other, and that is why we believe that there is a strategy we need to follow, and that is a strategy of defining what I call a precompetitive world where industry, academia, government need to build databases of knowledge that are available, openly available, that we don't just restrain in terms of access to it.
For biomarkers, for example, biomarkers will be key to progress, and I think you are going to hear more during this program. Having databases where the scientific information is not hidden, but made open to the public, so that when we do a gene sequence ‑‑ and we are going to do more and more and more ‑‑ that it is available to companies, to scientific institutions, academia, all of it, because it is not competitive.
The complexity of what we are dealing with is such that I don't believe that it is going to be one magic bullet for one disease at a time. It is going to be a network of different approaches that will be balanced according to individual variability. You cannot approach that unless you build an infrastructure of information that allows exchanges, very quick exchanges, so you don't spend your time duplicating something, as someone else has already done and already wasted millions of dollars on and knows it is not working.
So NIH wants to be that glue of information and the broker, if you will, and last but not least, despite all of my entreaties, if you will, despite the sense that I have that we are at the edge of a real revolution, that we have made progress, that only research can really bring the breakthroughs, what is also important is I don't think that we can just rest on our laurels and things are going to happen just by itself. We need to encourage new pioneers, new investigators, new scientists thinking differently, because we are just blocked and stuck in the way of thinking which I think can only be broken by pioneering young scientists encouraged to come into the system. Right now, we are discouraging them. If they think that this is not a career choice for them, the 300,000 scientists that we have, the average age has increased by 10 years.
If you look at the curves, we will have more scientists funded that are older than 65 than scientists that are younger than 35 in 10 to 15 years time. This is not sustainable.
So one of my passions is to take money from existing programs and putting it into what I call "new innovators," "new pioneer programs," "new pathways to independence," because trust me, new ideas come from people who have not been indoctrinated in old ideas.
So the Pioneer Award Program is something that works. I will give you one example which I like to cite. This is Karl Deisseroth, who is an M.D., Ph.D. from Stanford, applied three times to NIH in the regular process and couldn't get funded. Why? Because he had this crazy idea of taking the human neuron, a neuron in the brain, and going to a discovery that was made in Germany in an algae. This is a plant that had a receptor that changed colors when there was a certain wavelength of light, and he said, "You know, I am going to take that algae receptor. I am going to mix it with a human ‑‑ mice neuron at the time, but my goal is to do it in human neurons by having sort of a genetic engineering technique, and I am going to be able to activate the neuron just with light. So think of it, a series of brains, and you would create essentially a light‑activated brain. How is that for an interesting idea?" Well, turned down, turned down, turned down.
So he came to this process, the Pioneer Award Program, which is a bold program, sort of a very, very far out idea, and he proposed this idea. He said, "If I succeed, I will then use a jellyfish molecule that has been shown to turn off neurons." Well, two years later, he is on the cover of Nature. He is one of the most successful scientists. He has been able to devise a system whereby through genetic engineering, you can make neurons anywhere in the brain on demand, to be activated or deactivated, and he sent me a movie of a worm, a C. elegans worm, which is sort of an experimental animal. He said, "Doctor, let me show you the worm is going to go from right to left," and he flashed the lights, red‑blue, red‑blue, red‑blue, and the worm went right to left, and then he said, "I am going to make him reverse," and then he went blue‑red, blue‑red, blue‑red, and the worm reversed. That is the only way you are going to be able to study the complexity of the brain, but you cannot think of studying that complexity unless you make breakthroughs like this.
So the last message I have is the greatest risk for innovation is to stop taking risks, and this is my message. We are at the edge of exciting times. I cannot tell you how exciting they are, but we will have the duty of implementing and encouraging breakthroughs that you can I cannot describe today.
Thank you very much.
[Applause.]
DR. ZERHOUNI: I will be happy to take a few questions if you have time.
MR. TAUZIN: Doctor, what is the political implication of a worm that turns right or left, depending upon red or blue?
[Laughter.]
DR. ZERHOUNI: I think it is a transvesticrat on demand.
[Laughter.]
DR. ZERHOUNI: I would be happy to answer a few questions. Yes, sir.
ATTENDEE: You have alluded to the health care system, as did Mr. Tauzin when he spoke, and I wanted to address that in terms of prevention and ask this question.
We have an employer‑based private sector health care system in this country, and I have often asked myself this question as an economist. What incentive does the employer have to offer preventive benefits when we have such a high turnover rate and mobility rate of the work force, when that person will benefit maybe 10 or 15 years in the future, when the average time with a firm is less than four years in this country? So the small coffee shop on the corner, should they offer preventive benefits? That person is going to be gone in three years working for a competitor who will reap those benefits.
You did allude to the health care system, and so did Mr. Tauzin. I ask you, perhaps we ought to examine our employer‑based and maybe do something with it. It is a little bit out of your scientific area perhaps, but I know you think often of these issues as well.
DR. ZERHOUNI: Well, fundamentally, the question you are posing is to the extent that we know what to do that we didn't know in 1965 or before, how adaptable is our system to knowledge and that is developing.
I mean, frankly, an employer didn't know 30 years ago that if you control hypertension and cholesterol, you are going to have a healthier patient, or diet. That was not in the cards.
On the other hand, I think this idea of life cycle management ‑‑ because when I talked about the fact that today, a disease should not be looked at as the last event, but as a process that takes 25 to 30 years, and you have to manage or recycle, I can see a world ‑‑ because remember we have aging of the population. We have a 17 million qualified job deficit coming in front of us, nurses, doctors, software engineers, you name it. There is not going to be a problem to employ and find qualified employees and employers are going to compete on the availability of employees, but you would want them to be healthy and not disabled and so on.
First of all, you are posting a right problem, we are not managing the life cycle of the disease. Our system is not designed for that. It has never been designed for that. There is a lot of gridlocking going on and a one‑size‑fits‑all approach. I don't think that is the way the American system works. It is usually you let the genius of the best practices sort of be tried, and it is very hard to do in our system, but at the end of the day, that issue of taking into account the total cycle of the disease is the only solution.
Yes, sir.
ATTENDEE: [Inaudible.]
DR. ZERHOUNI: Yes. It is actually interesting because prioritization is always multifactorial. So we started, first and foremost, with the 10 most common diseases ‑‑ it makes sense, right? ‑‑ than the ones that have the largest impact, and then we said where are we in many, many other diseases in terms of having the populations that are already studied.
Remember that the fundamental strategy is if you have a genome, that is not enough. You need to understand the environment of that individual. Right? So, over time, you really need to study patient cohorts that have a particular disease over years and years and years, and we have 119 of those at the NIH. The most famous one is the Framingham Study since the '50s. So, by having these cohorts already available, we knew 5, 10 years ago that it would be really important to look at the DNA. So we preserved the DNA.
So a lot of these studies are done on populations that were already studied by our researchers before. So the priority is done on, A, the target of opportunity. You have the patients. You have the ability to take a thousand patients, a thousand controls, collaborations with other countries. In the diabetes research, we found 12 genes. Do you remember I started with one in 2002? We have 12 today. It is all because of collaboration between the Welcome Trust, the NIH, and Finland because they have a high incidence of this. So it is target of opportunity towards understanding population cohorts in the most common diseases that we can study practically in a context of having the material, having the ability to do those studies.
MS. WOOLLEY: Can you take one more?
DR. ZERHOUNI: Okay.
ATTENDEE: Without minimizing the challenges, the scientific challenges that you talked a bit about here, can you talk a little bit more about the cultural and institutional barriers to kind of speeding things up, building the kind of collaboration that you clearly see as necessary in breaking down these barriers, and what the NIH's role in doing that sort of thing is?
DR. ZERHOUNI: So you are pointing your finger on the most important thing. Academia is portrayed as being very resistant to change, and I happen to disagree and agree at the same time.
Let me give you an example of why. If you look at the 100 top governments in the world in 1900 and if I asked you the question how many of them have survived intact in 2007, the answer is two, Britain and the U.S. Every other government has gone through revolutions, destruction, rebirth.
If you look at academic institutions and I ask you the same question, the top 100 universities in the year 1500 ‑‑ not 1900, but 1500 ‑‑ and I ask you the question of those, how many are currently active and viable, do you know what the number is? 75. So there is the ability to adapt. They don't adapt fast, but they do adapt. It has arrived. That survivability is the proof of adaptation.
So what I think we need to do is a little bit of what I try to accomplish with this roadmap. It is to sort of show where there is a consensus and there is a need, and then create the programs that incentivize that behavior, and it is happening. I can tell you it is happening.
There is a new department at Harvard that was created four years ago called the Department of Systems Biology. Now, creating a new department at Harvard is harder than solving the Middle East crisis.
[Laughter.]
DR. ZERHOUNI: So trust me, it is a revolutionary change. I am seeing that happening around the country because we are encouraging also interdisciplinary research funding. So, in these grants that we have generated, there is one reform that we have implemented, which is sort of under the radar. People don't appreciate that, but we work with the Office of Science and Technology. We had a lot of support from the White House.
The President, with all the criticism that people get when they are in political life, has come five times to the NIH. This is the President that has visited the most, and he helped us in changing the Federal rules that says that for any grant, there should be only one principal scientist investigator. So we have changed the rules in the Federal Government to allow what we call multi‑principal investigators from different institutions being able to work on the same problem. Before, it was impossible. You had to give it to somebody at Harvard or Hopkins or in physics or in biology, but not all four. Today, we can do that, and it is changing the behavior of institutions, but again, you are absolutely correct. When you observe it, you feel like it is unchanging, but it does change. It takes a generation almost, but it will happen. It is happening.
ATTENDEE: [Inaudible.]
DR. ZERHOUNI: And the other thing that is driving it, too, it is like what we say in terms of institutions. People in the field, scientists in the field, are noticing that science is converging, that to solve a problem today, you cannot just stick to your discipline. You really have to use different approaches, different tools, different methods, and because science is converging, departmental structures are going to blow up, and they are going to be different than what they are today, and already, you are seeing that. So there is a fundamental movement because of the problem being redefined and the approach being different.
Thank you very much.
MS. WOOLLEY: Are you willing to do one more? We had a lady who was overlooked.
DR. ZERHOUNI: I'm sorry.
MS. WOOLLEY: In the light, it is hard to see.
ATTENDEE: My question to you is regarding emerging and reemerging infections. What do you think the NIH wants to see come out of that area? What kind of research questions, I think it is better asked, that you would want to see derived out of that area?
DR. ZERHOUNI: Well, first of all, we need to have a global view of this issue, and let's face it, it is going to be probably the number‑one cause of public health risk worldwide and probably the number‑one cause of public instability worldwide, and we need to make investments at the global level.
Actually, NIH has been probably one of the most proactive in this domain. We quadrupled our investment globally, and we are now present in 110 countries. You need scientific capacity in those countries who are collaborating with scientists across the world.
In fact, the scientist that discovered SARS was an NIH‑funded scientists in Hong Kong, and we need to keep that going and collaborate with WHO and create a capacity for analysis and research in the fields where this whole issue can come up.
By the way, it is not just in Africa that it happens. It happens right here. So the multidrug‑resistant Staph. aureus problem is not a problem of someone else's. It is our problem, too. It is happening right here. So capacity‑building is one.
The second is to build a complete understanding of the microbial world. So the two major programs launched this year through the NIH roadmap, one is the Epigenome which is an understanding of regulations of the genome, and the other is the Microbiome, and the Microbiome is going to give us probably the best ID card for every organism that exists, both in ourselves and interacts with ourselves worldwide. So you need to have the tools developed, and you need to really be strategic about that.
The third is remember that we have an issue in terms of developing vaccines, antibiotics and so on, an issue that is economic for vaccines, and antibiotics is also becoming an economic issue, and we need to really be proactive in that. So we are going to develop the capacity of understanding in a different way the immune response and the ability to interact with that.
That is a comprehensive plan. It is not one thing, but it is clearly something that is reemerging as a major issue, not just because of diseases of poor, but also because of resistance in our own environment, drug resistance.
MS. WOOLLEY: Thank you.
[Applause.]
MS. WOOLLEY: Thank you so much, Elias. Aren't we privileged to have you as the director of the National Institutes of Health, what extraordinary leadership, and your remarks about risk‑taking is something that we did a little of here this morning. We took the risk of getting behind schedule just a few minutes in order that we all could benefit from this extraordinarily rich set of remarks and challenges that Dr. Zerhouni has provided. So thank you for that, Elias. Thank you for all you do.
We are going to take a brief break and ask that you come right back here in 10 minutes, which would be five minutes to 11:00 on my watch.
[Break.]
Panel 1
Transforming Health: How Will Research Shape the Future?
MS. COMER: We are short‑circuiting introductions. I was in television for 30 years, and that means it puts me somewhere between virginity and death. So that is all you need to know about me.
I would suggest to you that any session on the future is akin to the new release, How to Talk About Books We Haven't Read, quoting The Wall Street Journal review, "Just because one hasn't read a book doesn't mean that one cannot talk about it with the same confidence as someone who has, and perhaps with greater acumen not having to be bogged down in the messy details." So I would suggest that that happens most often in conversations about the future.
For the next 90 minutes, we are going to rid ourselves momentarily from the drag of reality, from the fact that today the House was unsuccessful in overriding a Presidential veto of a $60‑million health and education bill, $30 billion of that was targeted for NIH funding, and the other that forecasted that Medicare is about to implode.
We are going to fast‑forward. We have a very distinguished panel, and detailed bios of the panelists are in the program, but I have been struck over the years that titles really don't give us any insight into one's life work or passion. So I will ask each of our panelists to tell us what it is they do and what drives them.
Leading off to help set the vision is Dr. Garry Neil. He is group president, Johnson & Johnson, pharmaceutical research and development.
DR. NEIL: Thank you very much, Meryl.
My responsibilities now at J&J are to head the Corporate Office of Science and Technology, and that means that we are involved in just about everything that the corporation does, since we are broadly based in health care. I have spent most of my career in pharmaceutical research, but I have become very, very interested and quite passionate, as I will say something about in a minute, about using the convergence of medical devices, diagnostics, and pharmaceuticals in a better way, to deliver better solutions for patients.
We heard an awful lot in the previous sessions, excellent talks really, about why we have become so interested in changing the paradigm of health care, and from the pharmaceutical business point of view, obviously we realize that we are facing big challenges, but these are the challenges that are driving us more than the financial and business ones. It is the enormous burden of chronic illness which is producing literally a crisis in our health care system, but I am actually very excited about that because form crisis comes opportunity, and in addressing this crisis, we are more likely to find the types of solutions that we are going to need.
So the opportunity ‑‑ and we talked a lot about this, this morning ‑‑ so far is clear, moving more towards health than the old paradigm of disease treatment, and the scientific advances that we have already seen in personalized medicine, even though we are just on the cusp of that now, theranostics which is a combining of therapeutics and diagnostics to get better outcomes, advances in surgery, and miniaturization of electronics, as well as the market pressures we have already talked about, including tougher regulatory scrutiny, more demand for safety, but also increasing consumer demand for better therapies, more accessible therapies.
Personalized medicine, this is something that we embrace in the industry, certainly at Johnson & Johnson. What does it mean? Is it reality? Is it here today, or is it hype? Well, it depends what you talk about because the idea of personalized medicine is by no means new. It actually goes back to ancient times, and even in surgery anatomy, we are very well aware of the fact that everybody is different. So tailoring therapies for people is a very obvious thing to do. The question is how do you do that.
We do know that the problem with drug therapy is that it doesn't work, at least not all the time, and sometimes it is toxic. So many have hit upon the idea of using pharmacogenomics or the genomic profile of individuals who are going to receive a treatment to see whether or not it would be suitable for them.
However, again, we are just on the threshold of this. There is more than a million snips that have been identified, and we don't have all of the relevant clinical information to make sense of that, but there is something that we can do today, and that is to really work harder than we have perhaps in the past to nail down diagnoses of the illnesses we are trying to treat, so better screening, diagnosing, and monitoring disease to be able to intervene earlier and to make better decisions for patients, and also the theranostic approach, which is using the diagnostic tests in real time to determine whether or not the patient is responding to the therapies they are being given and also to determine whether or not they are getting the right dose.
Now, there are a few examples of this, and I don't want to labor this. We at J&J and our colleagues in industry are investing a lot in all of these approaches to personalize care and to make it more effective, both on the drug biologic side and others, but just as an example, an advanced diagnostic test that we have developed called CellSearch with our Veridex company that allows us to detect small numbers of circulating cancer cells and to be able to link those to patient outcomes, and technology convergence, again, surgical technology, advances in biopharma, information technology to help us to identify the right patients at risk, and then nanotechnology to apply this.
Just a couple of examples that we have used, the CYPHER stent, which everyone knows about, drug‑coated stents to reduce complications and inclusion of stenting post surgery; Ionsys which is a patient self‑administered fetanyl patch, allows patients to control their own post‑operative pain safely in a needle‑free system, and to maintain their own comfort after surgery in a hospital setting, but we have not gone beyond that to develop systems that allow patients to control their own anesthesia in outpatient procedures. So they can use this device which monitors their physiologic state, their heart rate, their respirations, and so on while they are having the initial application with colonoscopy. We think it can go beyond that and to control the amount of comfort that they want to receive during the procedure.
Hemostasis, again, in surgery, the ability to use fibrin sealants and apply that to patches that surgeons can use in the operative setting to be able to control bleeding, which is a very difficult thing sometimes without having to open the patient in laparoscopic surgical applications, and cartilage injuries, a major unmet need that we have seen and driving a large business in artificial joints, but why not use the patient's own cartilage to repair defects in joints and make them more mobile? We have developed a system for being able to harvest in real time, a cartilage from healthy parts of the joint and to use that to be able to repair cartilage in diseased joints.
And lastly our effort in retinitis, but pigmentosa, our stem cell project, you can see patients are only 75,000 Americans that have this rare condition, inherited condition, but it ultimately destroys their quality of life by degeneration of the retina, and we are now working with a number of J&J companies to produce a stem cell solution. We are now starting clinical trials which we hope is going to be able to restore the sight in some of these patients, even a small number of patients in perhaps a subpopulation that couldn't have been addressed in any other way.
So these are the types of approaches that we and many other companies are taking to personalize medicine using convergent technology, and again, I think biomedical research, as we have heard, is a great investment. It can positively impact health, prolong life, reduce suffering, and reduce health care costs, increase productivity, and overall increase the prosperity of the country.
Thank you.
[Applause.]
MS. COMER: How much do we really want to know? Let me give you an example. On June 1st, the New York Times reported that the complete DNA sequence of Nobel Laureate James Watson of DNA double helix fame had been sequenced and handed over to him on two DVDs. I think the price tag was a million dollars.
Now, Watson says he will make his entire genome, warts and all, available to researchers to study, with one exception. He doesn't want to know which isoform of the APOE gene he has inherited because it can predispose him to Alzheimer's disease. That is his limit.
June 3rd, New York Times again, story claiming thousands of people may be able to have their genome done, and the price, as Billy Tauzin was talking about, will go down and down, maybe a thousand dollars for each of us, and then it paraphrased our bad boy of science, Craig Venter, the president of Celera Corporation, as saying he has already sequenced his own genome, and he consults his data daily every time a new announcement of a gene discovery comes out. So what we are seeing is very smart men, one interested in knowing so much and then not any more, and the other saying, "Bring it on. I'll take it. I'll take it."
So the whole issue is what do we do to dare to know our genes, and joining us now is Dr. Raju Kucherlapati, the scientific director of the Harvard Partners Center for Genetics and Genomes.
Dr. Kucherlapati?
DR. KUCHERLAPATI: Thank you very much.
So you asked the question, what drives each of us. I was trained as a geneticist and practices genetics throughout my career, and I had the privilege of being a part of a Human Genome effort, trying to develop the technologies and using the technologies to sequence the Human Genome, and one of the group of people that were most excited when the Human Genome was coming about were the physicians, and the reason why they were excited about the Human Genome sequence is for the first time, they were able to see that all of the patients that they take care of, day in and day out, can benefit from this genetic knowledge in prediction, diagnosis, prognosis, and treatment of the disease, and I have decided that I want to devote the rest of my career in trying to bring genetics to the clinic.
So why genetics? When I talk about genetics, three revolutions have occurred during the last 40, 50 years. The first of these revolutions that occurred during the last part of the last century is the recognition that virtually all aspects of human health and disease has a genetic basis.
The second revolution is that if, indeed, genes play a very important role in every aspect of health and disease, wouldn't it be great if it would be possible for us to identify these genes very rapidly and try to understand how those genes, our genetic changes, cause disease? It is with this view that the Human Genome Project was started in 1990, and the culmination of that project was in 2003, the completion of the Human Genome sequence, just in time to celebrate the 50th anniversary of the discovery of the structure of DNA.
The third revolution that is currently underway is the utilization of this information for patient care, and I just want to talk about the role that research is playing in this particular case.
The first of these is that once we discovered the Human Genome, then everybody was curious about trying to figure out what is it that makes us different from each other. So, when we actually begin to look at individual differences between each of us, each of us carries nearly 3 billion nucleotides of DNA sequence, of which there is only a million of those nucleotides that are different between any two individuals. That means 99.9 percent of our genomes of any two individuals in this room are identical and only these tiny amounts of differences.
So these tiny differences that we have between the genomes, in one way, to be able to say that we are all part of one human entity, we are not so different from each other. Yet, you look at the other ways, that people are different from each other. People are different from each other in trivial ways.
Me, I am short. I am bald. I am jealous of the people who are tall and have lots of hair on their head, but maybe that is a trivial difference, but there are other types of profound differences that we have between us, the way that we are susceptible to disease, the way that we are resistant to disease, the probability that we will live to be 100 years old, the way that we will be able to respond to drugs. All of these types of differences reside in that 1‑percent difference that we have between individuals. So there is a tremendous amount of effort that is currently underway to define what those differences are and how those differences make us unique. So that is a great area of research.
As a result of that, you have heard from Dr. Zerhouni, how the ability to be able to look at those differences is enabling us to identify genes that are important in the diseases that effect us day in and day out, and the rate at which these discoveries are happening and the technologies that are enabling us to do that are accelerating at a very rapid rate.
So, once we have this information, how do you use that to manage health? I want to say manage health, and something else we want to think about is the kinds of way we should be thinking about it. When everybody thinks about health care, everybody thinks about health care cost. I want for us to think about it and change our way of thinking about it and not in terms of health care cost, but health care investment. How do we make the population better, more healthier, at a lower cost? Genetics, I think can do that.
So how can you do that? The first thing that you could do that really doesn't cost a lot of money right now is to try to identify people who have predispositions to particular types of disease and manage them based upon those predispositions. Those predispositions could be cancer. Those predispositions could be diabetes. Those predispositions could be hypertension. Those predispositions could be immunological disorders. Those predispositions could be psychiatric disorders, whatever the case may be. Do you know what is the most important risk factor for all of them? It is family history.
It is relatively easy to try to get family history, and if you can get family history, it is possible to just add that simple thing today, and in the future, we would be able to add genetic information to that, that is going to be able to profoundly change the way that we would be able to think about managing disease.
So we are also beginning to understand the tremendous amount of examples of how this information is going to help the development of pharmaceutical companies. Just yesterday, I have heard in the last five years, the so‑called drugs which are targeted against particular genetic changes, that are known to be involved in the predisposition or onset of disease, has increased by a factor of 10. So every pharmaceutical company is thinking about these targeted types of drugs and therapies that are going to be effective, and I think it is a wonderful development.
Garry might be able to comment more about this particular feature.
Once you identify these types of genes, it is also incumbent upon us to show that using genetic information in making clinical decisions would result in better outcomes for patients, and it is also important at the same time to show from a pharmacoeconomic point of view that using such genetic information has societally an important pharmacoeconomic benefit to be able to do that.
So, one of the things, we should be thinking, and we have started at Harvard a number of these clinical trials to show that genetic information is going to make an important difference in the outcomes for patients.
Finally, I want to make the comment that the amount of information that we are getting from, the genetic and genomic information that we are obtaining from individuals is expanding at a very, very rapid rate, and we need to be able to have the appropriate types of methodologies to try to identify the ability to acquire this information, store this information, retrieve this information, analyze this information, and make decisions using that information. This is an IT challenge, and therefore, there has got to be a relationship between medical industry and IT industry to be able to come together. We are working with Hewlett‑Packard to try to set up examples of how a medical center and an IT company would be able to do that.
Finally, it is also important when all this information is available, the person that has to take care of the patients is the primary care physician. That is who we see most of the time, and so we need to provide the tools for the primary care physician to be able to use this information. So we are trying to develop clinical decision support tools within the electronic medical records that would enable the physician to be able to say when a patient comes in, this patient needs to get this particular diagnostic test, and when the information comes back and says this patient is going to respond to this particular drug or treatment and at this particular dose, to be able to provide that kind of information.
So many people think that this is something way in the future, but it is not way in the future. It is happening today, and I think all of us here are excited to be a part of this revolution in medicine.
Thank you.
[Applause.]
MS. COMER: Thank you, Raju.
Please correct me if I am wrong, but it was the genetic study of Down's syndrome that really led them to the first gene discovery on Alzheimer's because they found that children who now live to their forties, thanks to advances in technology and medicine, all of them get Alzheimer's, a double jeopardy for families who have spent their life with children who have been ill.
Targeted treatment versus the blockbuster. Well, the development of patient databases and biobanks is leading to accelerated understanding of new biomarkers, but which disease areas are considered most promising for biomarker development, and how will they change treatments for patients in the future?
Joining us now, please welcome Dr. Anthony Altar, director of The Biomarkers Consortium. Dr. Alter?
[Applause.]
DR. ALTAR: Thank you very much for that kind introduction.
I think to answer the question of the hour, what are our drivers in our lives, for me, my main driver ‑‑ and this might be like the Tony Altar mission statement, but I think it is being part of innovative approaches to science discovery to improve human health. It has always been for me an exciting aspect to be at that very earliest phase of science discovery and seeing its fruition to where people actually benefit.
One of the stories I can relay actually builds on what Billy Tauzin told us about, the really miracle drug, Avastin, and the 14‑year effort that was involved in its discovery, and it makes me think back to my days at Genentech in the late 1980's. It was my fortune to actually share a laboratory with Napoleone Ferrara who was busily slaving over an HPLC column trying to find an extract from tissue that would stimulate the growth of these vascular endothelial cells. It was only FGF that was known at that time.
Napoleone and I had a little bit of a competition. I was working on nerve growth factor and trying to figure out how we could treat diabetic neuropathy with NGF, and our competition was pretty simple. It was who could leave the lab last.
So the evenings got later and later, and invariably, it seemed like it was me who would leave first. Then I remember one day, very clearly, getting back to the lab in the morning, and there was Napoleone working over his HPLC as always, and I said, "Napoleone, it looks like you are starting even earlier now," and he said, "No. I just never left." I think it is that kind of doggedness at the individual level that can make some really great discoveries.
Some of those discoveries, even veg factor, may be the basis of biomarkers for improving human health. There is some evidence, for example, that urinary veg factor may be a correlate of tumors, and that is a very interesting kind of finding. Veg factor seems to play a big role in a lot of what we are doing.
So I would like to tell you now a little bit about biomarkers, how they represent one of the most exciting and promising areas for transforming biomedical research in the coming decades, and today, I would like to tell you what The Biomarkers Consortium specifically is doing to help make that a reality.
I think as we have heard already, it is clear that biomarkers are nothing really new in medical science. They go all the way from recording a patient's pulse, pretty simple, to imaging the very complex interactions of a test drug with the brain receptor and using that to gage drug dosing and potentially predict efficacy, and both of those things have proven to work.
Biomarkers provide the clinician with information critical to a patient's diagnosis, treatment, and response. The fact that there are hundreds of biomarkers already in standard medical practice clearly attest to the fact that they are indispensable to human health.
What is new are the many new technologies that have now been brought to bear on discovery of biomarkers. We have heard about some of them already today. Those techniques include, for example, the sequencing of the Human Genome, and I think an analogy to Lindbergh's flight to Paris and how that ushered in an era of unexpected value in modern aviation, I think the Human Genome discovery will do an even far greater thing, as we have seen from Dr. Zerhouni's slide, very recently now an exponential growth in the number of genes that are positively linked to important medical diseases. So I think by comparison, I think the aviation industry will be smaller, after all is said and done for the Human Genome discoveries.
Other discoveries that are critical to this process are being able to measure tumor growth and decreases in brain metabolism using in vivo brain imaging, and for the first time, we can peer inside the human and actually see these processes not only at one point in time, but spatially throughout the individual, quantitatively, and as they change over time, and that is a real revolution.
We can also collect tissues and cells from individual patients and profile them, those cells in vitro as a measure of diagnosing disease and measuring therapeutic response.
Now, exciting new technologies like these provide an unprecedented opportunity to realize the promise of personalized medicine, particularly when the biomarkers measured over time during a patient's lifetime, as well as throughout the course of their illness. I think this is a key goal for biomarkers because it is much harder to make a prediction on a single patient basis than on a group population basis, and for that reason, the individual approach is very important. It is a Gold Standard test of our precision in what that biomarker can tell us, and because once a biomarker is clearly identified as being useful for an individual, it become relatively easy to use that in population or group studies where we have the power, and really and most importantly, I think consensus between people who are involved in this effort through coordination of diverse biomedical research sectors.
In response to these challenges, The Biomarkers Consortium was established in October of last year as a large public scale, public‑private partnership. It is uniquely dedicated to discovery and development of biomarkers. We are managed by the Foundation for the National Institute of Health, or FNIH, and it was founded by FNIH and colleagues at NIH, FDA, and PhRMA.
A lot of work went in that first initial period, and there was the strategic guidance from an executive committee composed of volunteer representatives, including Dr. Ellen Sigal who is here today, Garry Neil here to my right, Mary Woolley of Research!America, and also the biotechnology trade organization, BIO, and CMS. These individuals have been the strategic guiding force for The Biomarker Consortium.
So, during our first year, the consortium is established, the governance organizational principles and infrastructure, and has launched two projects in cancer imaging. We have recruited the volunteer efforts of seasonal professionals from NIH, industry, academia, and FDA to serve on four steering committees, and those committees now are in the areas of cancer, metabolic disorders, inflammation and immunity, and psychiatric and neurological diseases.
These committees which have roughly 30 members on each from all of these same sectors are seasoned experts in their field. They help solicit, prioritize, evaluate, and select the projects that we get from all sectors. Anybody can submit a project concept to The Biomarkers Consortium as the submitter.
Approved concepts are developed into a research plan by a team of experts that is selected by that steering committee, and they work closely with the FNIH project manager and the concept submitters.
So let me give the status report for where we are now and where we would like to head in the future. To date, we have received over 40 project proposals from which we hope to fund and implement at least six more by the end of 2008.
I would like to tell you a little bit about the most promising of those, including the FDG‑PET Lung and Lymphoma Projects. These studies use the metabolic imaging agent radiolabeled 2D‑oxyglucose to assess the size, progression, and response to standard treatment of lung carcinoma and lymphoma.
This work is supported by $6 million that has been raised by the consortium from nine corporate sponsors, and nearly $4 million provided by the National Cancer Institute. So funding comes from a variety of sources, and that is one of our goals is to not only get scientific input at a variety of levels, but to get support, either in kind as well as cash support for these studies.
Cancer research has also shown that circulating tumor cells contain genetic duplications and other anomalies that can identify the presence and origin of cancer. Our cancer steering committee is also now considering developing a project to characterize circulating tumor cells, using similar methods that Garry just described in existing clinical trials, these data made through prognostic or diagnostic tests for breast, prostate, lung, and colorectal tumors and link drugs to particular outcomes.
Another area of health concern is diabetes, and we have heard a lot about the evolving shape of diabetes not only in the United States, but worldwide. This is a growing epidemic. Interestingly, there is another protein marker that may be very useful in clinical trials. It is called Adiponectin, and it is a fat‑derived molecule which represents another project area that we are pursuing, and I think this project, which is relatively mature now, is exciting because it involves four pharmaceutical companies who, in a relatively rare occurrence, are combining their data from various clinical trials looking at PPAR agonists, and they are looking whether that aggregate data provides even greater support for Adiponectin's role. I think this data is very promising.
Metabolic disease is also a project area within that committee to look at MRI methods that can measure corroded artery plaques and their individual composition and also importantly demonstrate their response to therapy.
Interestingly, a project that has come from a totally different side of the consortium, from the imaging project team, has identified research at NIH that is using a novel PET radioligand, which also recognizes macrophages that constitute the vulnerable component of atherosclerotic plaques, and it will be very interesting to see if these two projects can both mature, so that we have complimentary ways of looking at the same disease.
Interestingly, this same PET radioligand that is being considered for atherosclerosis is also able to look at the inflammation in various neurological conditions, such as Alzheimer's disease, stroke, Huntington's disease, and multiple sclerosis. Each of these diseases have a very profound neuroinflammatory component, and so it is reasonable that this kind of ligand may be able to work, so that we could peer inside the brain of patients with these diseases and tell how fast their disease is progressing, but potentially, also, how well they are responding to therapies that can be directed.
It is interesting that in Alzheimer's, for example, there was a very large European study on antiinflammatory drugs which actually succeeded. Then subsequently studies failed to show an effect in Alzheimer's disease. Wouldn't it be interesting if one could sub‑select those patients who had a very strong inflammatory component at AD? Maybe that would reinvigorate trials in this area.
I think that same kind of concept of stratifying patients ahead of the clinical trial bodes well for stroke, for example. Another project that we are looking at very carefully is proposing to use MRI to identify areas in patients who have had stroke, those areas that are now still vulnerable to dying, and separate out those patients for whom there is no hope for any more tissue to survive after treatment is started.
It is interesting that in the 1990s, there was a huge effort in anti‑stroke medications which uniformly, except for tissue plasminogen activator, these studies failed. Wouldn't it again be important to consider reinvigorating this area to identify those patients who are greatly at risk?
Finally, in the area of Alzheimer's disease, we are considering looking at protein markers and cerebral spinal fluid in blood that may be predictive for not only people who progress from mild cognitive impairment to Alzheimer's, but who develop mild cognitive impairment from having normal cognition, because there is already data from two protein markers, amyloid and tau, that has shown that you can do just that.
So the portfolio projects planned for The Biomarkers Consortium are exciting. We do have issues to contend with. Briefly, those are that we need to select the projects that best satisfy the broad group of stakeholders that we represent. So we have a large group of parties who are interested, but that is a wide swath of medical import that we have to deal with. We need to provide a timely return on investment, and we also need to better engage the diagnostic industry.
Our realistic expectations and goals for the future are to increase the number of qualified biomarkers, to standardize methods that are used to assess them in the context of drug dosing and efficacy, to identify aggregates of biomarkers, to improve sensitivity, and precision of identifying patients. So that maybe not just one marker is used for prostate cancer, like prostate‑specific antigen velocity, but if we could add three or four more to that, we can better subdivide patients and better identify them, and finally, to support personalized medicine with markers that have impact for an individual, over that person's life, and as a result of their illness.
So, in summary, I would like to say that biomarkers are one of the most promising and exciting areas that we are considering now to transform biomedical research. The consortium, which is unprecedented in its breadth of the founding membership, is working to infuse that promise with a means for its realization at a time when that promise has never been greater.
Thank you very much.
[Applause.]
MS. COMER: What is clearly evident is that everyone on the dias really deserves about an hour for their own time, but we are working against a clock. All experts are compromised when you say do it in 10 minutes. It just doesn't seem to work.
There was an illusion to the computer industry, and my favorite line by Alan Kay is: "The best way to predict the future is to invent it." Well, that is easy for computer scientists to say, but drugs are not like computers.
So joining us now is Dr. John Leonard. He is vice president of Global Pharmaceutical Research and Development at Abbott Laboratories.
John?
DR. LEONARD: Thank you, Meryl. I will try to get us back within that time, a 10‑minute window.
You asked what drives us and a little bit about us. My own experience in the industry has been very much influenced by HIV research. We ran our HIV program in the early '90s when there was really very limited therapeutic options, and we led the introduction of HIV protease inhibitors, some of the very first cocktails, and have really had an opportunity to see what can happen when you find the right molecules and put them together at the right place. So my own career has been about just that, finding those molecules and hopefully putting them in patients.
So what I would like to do in just a couple of minutes is supplement sort of what we have heard so far. We have heard about drugs and devices. We have heard about genetics. We have heard about hopefully predictive markers. I just don't want to lose track of the molecules themselves because they have got to come from somewhere.
Everything we do in the industry and with patients is hopefully find those molecules and put them into people, and the way we think about this begins with the discovery of natural products, some 50‑plus years ago, which has led to a way of thinking, and that the idea is that there is a drug that will interact in a very specific way with some part of our body, and that has driven sort of a reductionist approach that we have taken which is all about the targets that we have been hearing about. So, if you can find a target, link it somehow to a patient population, have epidemiological verification for that or animal model validation, you are off to the races.
Now, it is a very different test from what was done with penicillin and other drugs through time, and sometimes I wonder if that reductionist philosophy may be leading us a little bit astray. Nonetheless, it guides us today.
So how do we deal with the other side of the equation in actually finding those molecules? Well, there was a time when we literally looked under rocks. People went off and screened for mold and fungi, et cetera, and what we have tried to do is industrialize that approach and accumulate libraries of these molecules and subject ever increasingly the sophisticated targets to larger and larger libraries.
So we have industrialized that. We have identified high throughput screening sorts of processes where now companies literally have accumulated a million, sometimes 2 million, in one or two instances, 3 million unique chemicals in their libraries that they subject these, hopefully, validated targets to, but where do we go from here? It is not just ever‑increasing libraries. It is more and more sophisticated ways of teasing out the subtleties that may exist. So there is a lot of technological work to find ways of probing for these interactions. If you can take the target, crystallize it, and dip it into soups of molecules and find interactions that may not have been there or would not have been found through high throughput screening, that is something that can inform us.
If you can take whole molecules and chop them up into fragments and use NMR‑based technologies to find binding services where we may not have been able to find them before and then stitch them back together for very avid binding in ways that we can now interfere with protein/protein‑based iterations, that is a major advance, or pathway‑based screening where you can take a cell apart and look at all of the different genetic relationships that have been led up as a result of exposing it.
So we do that with small molecules, which is the origin of our pharmaceutic approach, but we have also moved into protein‑based therapies. It is no longer just the replacement of proteins that the body is missing, insulin, for example, in diabetes, or growth hormone, but we have moved into very directed‑based therapies which are increasingly antibody‑based.
The first ones were mouse antibodies, then they became chimeric, and now they are typically human‑based, and a lot of the technology we are working on is how can you manipulate those antibodies, so they bind in ways that they wouldn't have been binding before, or you can turn on or off the cells that are typical affecters, how can you stack up binding domains, so that you can have them bind not just the original ligand, but multiple different ligands for a different therapeutic effect, and importantly, because biologic‑based therapy is so expensive, as Dr. Zerhouni said, how do you bring the innovation to the larger patient population. There is a lot of work going on to find ways to produce them more cheaply, not with large capital‑based expenses, but maybe in some cases, down the road, will be in plastic bags and bring them to patients who would never have hoped to have seen that with a current set of circumstances.
Finally, new therapeutic modalities in terms of where do the molecules go, we are moving into the era of nucleic acid‑based therapies, and one of the, I think, very exciting frontiers is RNA‑based therapy or siRNA where here one can have incredible specificity, unique affinities, if we can solve some very basic problems, like how do you get what is inherently an unstable molecule into the body, through the bloodstream, to the cell, and then ultimately to the gene that it is targeted against.
So, if you can take the totality of the small molecules, biologic‑based, protein‑based therapies, and nucleic acids, the tools that we now have and the technology that we are bringing to bear, coupled with the targets and some of the predictive tools that we may have, I think it will lead to just some incredibly exciting therapeutic outcomes.
So thank you.
[Applause.]
MS. COMER: I would actually like to lead off and ask Garry, how do drug companies view pending diagnostic for their drugs, and what is sufficient validation in your mind for a biomarker?
DR. NEIL: First of all, it is going to depend, in every case, what the disease is, what the risk and benefit of a specific therapy might be, how toxic it might be. You would take a different approach to cancer and AIDS than you would to perhaps strep throat or another more benign type of infection. So I think you have to individualize that for every case and individualize it for every patient.
We have a perfectly good biomarker, let's say, for diabetes we think, blood sugar or hemoglobin A1c, but depending on what the therapy is ‑‑ I used to think that diabetes was a medical disease. I am not so convinced anymore that at least for a lot of patients, it is not a surgical disease. So how do you put all of that together to be able to come up with the right benefit risk and degree of certainty and degree of invasiveness that you want for an individual situation? So it is a hard question to answer.
MS. COMER: Anyone else would like to comment on the panel?
DR. LEONARD: I would throw something in there. The way I think about it from a diagnostic point of view, in personalized medicine, you are really trying to accomplish one or two things. Number one, because most therapies are population‑based, how do you reduce the variability? It makes sense to do that when you have chronic therapeutics, typically very expensive. Short‑based acute therapy, I think biomarkers in most cases are not going to be identified and utilized by pharmaceutical companies or by other health care practitioners.
The other big determinant is economics. If you are going to embark on a very expensive course of therapy, you want to know who to exclude to avoid the cost and not have the lost resources that go with it. So those are the two dimensions to it.
MS. COMER: Do you have a question?
ATTENDEE: This is for the entire panel. The panel discussed on the one hand how the regulatory apparatus is adapting or how well it is adapting to the emerging science of personalized medicine, some of the discoveries you are making, and could you speculate a little bit, if you have time, on how the payment structures for payers would adapt to the new sciences as well?
MS. COMER: Before we start, let's throw in the whole issue of intellectual property.
Raju?
DR. KUCHERLAPATI: I think you will probably hear more about what the regulatory agencies are doing, but certainly, the Food and Drug Administration has taken an important lead.
One of the examples is the recent label change this summer for an anticoagulant drug, Warfarin. In that particular case, during the last couple of years, there is evidence to suggest that simple genetic tests will enable us to figure out which patient would receive what does of Warfarin as an anticoagulant drug, and the FDA used that information to get to their advisory committee, and it got approval to change the label. They negotiated a pharmaceutical company to change the label, and now the label has changed.
Actually, as a result of that, I think the payers might be skeptical about the usefulness of such tests and how useful they are in trying to predict the right treatment on thinking about that, and some of the people have already made the decisions that they were, indeed, reimbursed for the tests because the FDA has made a recommendation. So that is just one example.
There are many other examples that other people can talk about as to many pharmaceutical companies are beginning to file for approval of their drugs with companion diagnostics, and that is also going to have a huge impact.
DR. NEIL: The most famous example probably is Herceptin, which was approved with a diagnostic biomarker at the same time in 1998, and FDA is very interested in doing that, as are the other regulatory agencies around the world, but the concern that continues to come up is, "Well, okay, we know you have studied it for this particular population. You have this marker that identifies it," but as in Billy's case with Avastin, now somebody is going to use it outside of that indication, and what evidence do you have that the drug might be safe in that situation or might be effective? So payers can use that information to deny payment sometimes, even if there is some evidence, but sometimes the FDA has to make a tough call. If you have a drug which could ultimately have a very wide use, but it hasn't yet been proven to be effective and safe in that population, do they release it into society for a more narrow indication, or do they wait?
DR. LEONARD: That is sort of it. Do you start by having a very narrow population because you have some hypothesis of how your drug works and then expand out of it, or do you start by studying a large population and tyr to find out who responded in that population and condense it out? They both have their limitations. They both have different regulatory requirements. They both have this seductive statistical margin of correlation as opposed to causation, and so a question is how much data do you really need to know that these things are informing us properly. There are some wonderful examples, and I think the consensus is they are confusing.
DR. ALTAR: I think some of the best data comes from the initial clinical trials that help support the approval process of the drug. Right now, if we are looking at a large population that is mixed with responders and nonresponders, a biomarker can be used to identify those who are likely to respond. That does a number of things. First, if it is really the mechanism of the drug's action that the biomarker refers to, like inflammation, for example, then we have confirmed to some degree our mechanism of action. So that proof of concept is very important.
It also would help decrease the variability in that selected population. So the clinical trials are more likely to be a success. I think that is a big win.
A lot of the costs that Dr. Zerhouni talked about, the pyramid for pharma is just opposite of what it is for NIH, all the costs seem to be in development. So, if we can diminish those development costs by making those trials more efficient, I think we will be able to focus back on the basic research.
I think in terms of the question about payment, I think that would apply there, too, because a lot of the costs of medical practice are finding the right drug for that patient. The patients go on one drug and then the next and the next, and these all require physician visits. These are very costly. If we can identify that right drug for each patient early on, I think that would lower the overall cost long term.
DR. LEONARD: We just have to be clear that we know what we are taking about when we say biomarker. If it is consistent with a biochemical hypothesis that we have for novel pharmacology, we haven't validated that that biomarker correlates with clinical outcomes, we may be mislead, which is not a reason not to study them, but we have to be cognizant that sometimes the state of knowledge is such that there is a hypothesis that we are testing. If we build our entire development program around it, that may kill decisions on that, we could be misled, which is different from instances where we know that the biomarker does correlate with clinical outcomes, but they fall into those two categories.
DR. NEIL: But it is a very good question because oftentimes the regulatory and reimbursement models are really lagging behind the technology that we have, and that was alluded to several times this morning, how do we change and turbocharge the way that we collect evidence to make it usable, and how do we then talk about the reimbursement for those procedures based on an outcome or are we still just selling stuff. In turn, it is circular because changing the reimbursement model drives a lot of things, as John and Tony pointed out. If you have a really expensive therapy and it is not going to work for somebody, you want to avoid that if, for no other reason, than economic ones.
DR. ALTAR: John raised a really important point about whether one goes broadly for the large population to see who really benefits versus the very targeted approach, and I think one of the ways the FDA is considering accommodating those two diverse approaches is looking at a clinical trial initially that you have a biomarker component to it, see if the population as a whole benefits, and if they do, there can be a biomarker independent approval process, which doesn't require any particular labeling, but then if there is not an efficacy in the population as a whole, the biomarker can be used to subpopulate postdoc. It was not really a postdoc analysis, but it is a more qualified analysis of who those patients respond as they were defined by that biomarker, and then that would require some additional labeling, but at least it gives the company a second shot on goal for improvement. I think that is probably the best strategy.
MS. COMER: We have another question.
ATTENDEE: I think this discussion really links very well to what I would like to hear your comments on, which is sort of three additional challenges to fulfilling the promise.
If we move to a prevention and much earlier treatment paradigm, my questions would be related to the regulatory paradigm, how do you get that approved if you are treating basically healthy subjects, intervening at a stage where the ultimate clinical advance may be 10 or 15 years later, and linked to that are what would be the safety requirements to demonstrate suitability for that sort of long‑term treatment, and then the third question would be related to question compliance, without symptomatic benefit to encourage patients to actually be maintained on the treatment.
I think if we look at either drug or lifestyle changes for blood pressure or statins, the challenge of maintaining patients is there. So how do we manage that in this paradigm?
MS. COMER: We need to take all three of them on in six minutes.
DR. KUCHERLAPATI: This notion that prevention is something novel is not true. We practice it today. In the case of if we go to the doctor and we find high cholesterol, you change lifestyles or you begin to get treated with statins, for example. That is true. If you find out that you have a family history or a woman has a family history of breast cancer, ovarian cancer, be able to have more frequent monitoring of that, or people who are susceptible to get colon cancer, that get more frequent colonoscopies, or if some of the kinds of things that Tony is talking about, that we would be able to have biomarkers, that we would be able to identify them much more easily, and you would be able to do that.
So prevention strategies have a tremendous potential. There is a beautiful study that has been done with diabetes which has shown that if you can identify pre‑diabetic patients ‑‑ and it is possible to do so ‑‑ then you would be able to reduce the incidence of diabetes in that population by 70 percent.
So I don't think it is necessary that you need to have a drug intervention. Simple types of lifestyle changes can also have a very profound effect on how you would be able to manage them, and that would not involve regulatory aspects and so on.
DR. NEIL: But there are some things that we do know, but there is probably a lot more that we don't know, and the problem with prevention studies is that nothing happens and if you are really preventing things. It can take a long time to show that nothing happened, and if we have to do with low incidence types of outcomes, if you have to gain that evidence through controlled clinical trials looking for the actual outcome ‑‑ like let's say it is esophageal cancer and somebody with Barrett's esophageus. Those trials would be enormous. They would take forever, and it would be extremely expensive.
So we do need a whole new set of tools and approaches to this, and one of the goals of the Reagan‑Udall Foundation, which FDA is working on, will be to try to develop additional tools using epidemiology and other population‑based methods to try to get at this, but I think it is going to be challenging for some of those types of interventions.
DR. LEONARD: I will toss in a sentence or two, and I am thinking about from a pharmaceutical perspective, which fully acknowledges the behavioral and all the other stuff that should precede that.
If it starts with why would a company go do this, the longer it is and the hardest to finding the outcome, the less likely that anybody will ever embark on this. It is just an unfortunate reality.
The less that happens, the more the benefit risk test gets tipped to less and less risk that is acceptable, which is extremely difficult to do with drugs.
So just to be a little provocative, if we are going to have our standard intellectual property system where you file a patent and it expires within 20 years, people aren't going to do that. So we need a different kind of system that says if you generate the data, even though the patent may have been long expired, there is some kind of protected time after that to recoup the investment.
DR. ALTAR: I think the IP issues are a real issue. There is going to have to be some change in provisions for those kinds of drugs that are prodromally prescribed for 10 or 20 years before those are a proof of principle. I think that is a good point.
I think where this will first start to happen are those diseases where there is an absolute death sentence. Like for Huntington's disease, if someone has the Huntington gene and it is a long CAG repeat, they know they are going to get the disease. The only problem now is there is nothing to treat them. I think those kinds of diseases are the ones where we will start to see long‑term prodromal therapies because that patient will get the disease, and they are probably going to be the ones that will step forward.
MS. COMER: On that very point, Raju, do you see that patients see the convergence of all of this targeted information as the loss of privacy? I mean, could there be a backlash against all of this excitement about the future?
DR. KUCHERLAPATI: That is a really very important question, and I think that is the reason why it is very important for us to support the bill that is currently in Congress to prevent discrimination based on genetic information. That bill has been passed by the House and is waiting Senate action, and I think that we need to have a national law to do that, and I think that is something that could be done. That would change the landscape very significantly.
MS. COMER: Unfortunately, we are almost out of time, but I am going to do what I used to do in my talk shows and give them 10 seconds each.
My problem with futurists is you can fast‑forward, and they are never held accountable for what they say. It is the media labs. Everyone projects out of the future.
So I am going to ask you to project out, give me five years out on a projection you can live with attached to this conversation.
John?
DR. LEONARD: I will be retired.
[Laughter.]
MS. COMER: All right.
DR. ALTAR: I will be supporting my second child going through college.
[Laughter.]
MS. COMER: Raju:
DR. KUCHERLAPATI: I think there will be a very significant amount of genetic information that will be available for each of us, and we will be utilizing that information to make healthier decisions.
MS. COMER: Garry?
DR. NEIL: I agree with that.
I do think that in the shorter term, though, we can start to apply what we know in a very personalized way, looking at outcomes, and we have to be a little bit less siloed in our thinking. So it will be the combination of drugs, devices, body computing, diagnostics, everything that we can do to be able to impact health.
MS. COMER: Let's do an anecdotal survey. How many of you, if the price tag on your genome went down to $1,000, would participate? Raise your hands.
[Show of hands.]
MS. COMER: Now you have a sampling if human nature.
Thank you so much. We are going to recess for lunch. You will have an opportunity to talk to our panelists. Let's thank our panel again.
[Applause.]
MS. COMER: Lunch is going to be ‑‑ if you walk out the doors, it will be in the other room. Thank you.
[Luncheon break.]
Luncheon Keynote Address
MS. WOOLLEY: The lights went down. The conversation level went down a little bit. I hope you have had an opportunity to learn more from one another and meet new people over lunch. If you have just joined us, welcome. I am Mary Woolley, president and CEO of Research!America, and along with PhRMA, we are delighted to be presenting a really content‑rich program today, one in which we hope to engage all of you, both formally and informally, in talking about how we transform research and deliver on its promise of transforming health.
We are going to have a special speaker at lunch who knows a lot about what it is like to live with challenges to health, but the truth is all of us live with challenges to health, to our own and to our family's health, every day, every month, every year.
We don't always talk about it publicly, sometimes because it is too hard, but I know that the driver for myself and many of my colleagues in doing the work that we do, it is because we want research to succeed for health. We have been there, individually and collectively, watching what happens when we don't have the research answers, and some of us are fortunate enough to have had research work for us in extraordinary ways transforming our lives.
So I think this, though a serious topic, is exactly the kind of grounding topic that we all need to reflect on from time to time, and to help us do that, we have Meryl Comer, who asked me not to give a long introduction, and those of you who saw her this morning and heard her know of her many, many skills, but she brings together actions and beliefs from the heart that have stood the test of time and made her successful in every endeavor and, in fact, makes her an award winner on every level.
Meryl?
[Applause.]
MS. COMER: Thank you. A woman in pain, I have been served up as Exhibit A, but never with lunch. So I ask you to bear with me a bit.
Here are the stats worth knowing. Every 72 seconds, someone develops Alzheimer's disease. It is the seventh‑leading cause of death and fifth among people over the age or 65.
Alzheimer's disease is not ‑‑ let me repeat ‑‑ is not a normal part of aging. It is a progressive degenerative and fatal and neurological disease, and the most common form of dementia. When you talk to families, it doesn't matter what the dementia is. The management of a loved one is about the same.
I thought I would begin, again, because we are at lunch, with a short video of what we call "Lost Faces." We often show it at Alzheimer's galas. They are famous people who have disappeared behind the veil of Alzheimer's over recent decades. Now, the obits usually read pneumonia, which suggests the stigma attached to this disease. The reality is that they are forgotten and disappear long before they pass away.
Let's take a look. Those of us over 50 who know those people and have watched those people, it is very striking.
I was struck by two findings released by Research!America this morning in response to the question, what one thing you would like to see medical research accomplish in the next 10 years. Fifty‑one percent of those interviewed said a cure for cancer. Well, I don't blame them. I think cancer, too. Only 3 percent said a cure for Alzheimer's, and I am here to argue, not if you have seen it up close. Make no mistake, Alzheimer's is the ultimate in identity theft, and you never recovery from it.
When asked if you can guess how long you think you will live, I found this fascinating. Thirty‑three percent said, "Oh, from 75 to 84." Another 33 percent said, "From 85 to 94." All right. We have an assumption of longevity, and we are about to ignore a pending epidemic that is not theoretical. Unlike the Avian flu, the devastating from Alzheimer's will be a guaranteed pandemic, and we are talking globally now because of the aging populations across western Europe, Japan, China. This is a huge global issue.
You put the findings together, and I call it denial, an attitude that will, after all the exciting conversation we had this morning, deal with the future when it gets here, and a lack of understanding what it takes, for example, in research to get to the future.
How many in this audience qualify as baby‑boomers? Now, you have to have been born between '46 and '64. I cheat a little. Raise your hand. I really want company in this, please.
[Show of hands.]
MS. COMER: Thank you. All right. I am here to tell you, maintain your brain all you want. The longer you live, the greater the odds you will get Alzheimer's, if you are genetically predisposed. It is not unlike HIV/AIDS where it lays dormant in your forties and fifties and then becomes full blown a decade later. There is also a great deal of comorbidity with Alzheimer's attached with other diseases like Parkinson's, vascular disease, diabetes, depression. We are learning more and more all the time that at the end stages of many diseases, whether it is addiction, there is a dementia component.
So, if 60 is the new 40, how many of us buy into that? I do.
[Laughter.]
MS. COMER: Be forewarned that there is no cosmetic fix for an intellect robbed or a mind unraveled. If you make it to age 65, your chances of succumbing to Alzheimer's are 1 in 8. At 85, the odds are 1 in 2. So, if I split this room down the center, half of you are going to get it, and half of you won't.
For women, this is exceptionally poignant. You will live to forget the name of your ex‑husband. You will definitely make it past that issue. Okay?
[Laughter.]
MS. COMER: The bottom line is for most of us, even if you are younger, even if you are in your thirties and forties, we are all ticking time bombs, and we just don't know it.
While you are in the laboratories and clinics ‑‑ and I would like to ask how many are researchers and involved with research in this audience today ‑‑ I have been at the beside. I have been slow‑dancing with a stranger ever since my physician husband, Dr. Harvey Gralnick, was diagnosed 14 years ago at the age of 58. He was a hematologist/oncologist at NIH. He was chief of the department. He devoted his wife's work to unveiling rare blood disorders like von Willebrand's disease, unknowingly fated by a genetic predisposition to another incurable disease.
Five million‑plus Americans and 20 million globally share his fate. The cost to Medicare, now at $140 billion annually, will hit $180 billion by 2010 when we are going to have 13.9 million Americans with Alzheimer's that are going to need specialized care, and I say there is a great difference between custodial and specialized care. Unlike children, if there is an issue, you simply pick them up and move them. With someone with dementias, you negotiate their reality, not reality as we know it.
The average life span from diagnosis to death is eight years. The range is three to 20. Typically, unfortunately, the diagnosis for Alzheimer's comes two years after the symptoms first appear, and that is because both of denial and misdiagnosis. It is a heartbreak because the four drugs that have been approved for use, they are best used with an early intervention, and unfortunately, you have lost two years. What we are looking about is trying to buy five years of quality of life.
Doctors are the worst patients, gentlemen. I will tell you that. My husband was in denial. A lawyer helped me get him to a doctor, a neurologist, but he confounded them. They suggested that it was Type A stress. He was a Type A personality, depression, a brain lesion. Because he had just come back from London from a medical symposium, they thought it might be mad cow's disease, but the Scarlet Letter A for Alzheimer's was not on the radar screen, too young at 58, too fit, too productive, 200 published papers in his field, three languages, a long distance runner. Guess what? It didn't matter.
Smart people have a reserve capacity, and they haven't figured out quite why yet, to hide out in the illness for a very long time because social skills go last, and let's be very honest. For those of us in Washington, I could bathe my husband and dress him, and if I kept moving at a cocktail party, no one would notice. We are so self‑absorbed and so busy, as long as you keep moving, nobody pays attention.
We have the reserve capacity. Everyone who has had the disease knows what happens, and everyone has an inkling that something is wrong. My husband took himself off clinical work at the NIH hematology. He took care of all the patients in Building 10. He knew that enough, but his passion was research. Think about weaning away a man who loved his research. Think about taking a Porsche away from a 58‑year‑old man. His independence ended when I thought he endangered himself or someone else.
I slipped out at night, pulled the spark plugs, didn't know what I was doing, locked the garage door, and for five years, I told him that his car was in the shop. Every day, he asked for it for five years. I said, "You had to get one of those damn foreign cars," until he stopped caring about the conversation.
Every care‑giver's story, I don't care what the disease is unique, but it is always somewhat the same. But when the onset is early and what makes me so passionate is that it is like being a witness to the future, and I am really terrified for us all. All the approved protocols with antipsychotics made him more aggressive. He never sat down. He paced the hospital ward. We fed him walking, and all personal care was a confrontation. It took four male nurses to restrain him for a blood draw. That is how aggressive he was.
After a two‑and‑a‑half‑month stay at Johns Hopkins, the doctor's final report read early onset Alzheimer's with a behavior disorder, "Your husband is too dangerous to come home." They sent him back to me. The medications, Aricept, 16 Depakote ‑‑ it is an antiseizure medication ‑‑ and four Ativan a day.
Now, no institution wanted us. They don't have to take you, by the way. This is private pay. This is not reimbursable. So I brought him home. Today, 14 years later, he has late‑stage dementia, 24/7 care, and still at home.
I really apologize for this at lunch. I just got off the night shift when I came here this morning, but PBS, I invited them into the house, and as a journalist, I had asked people to open their lives about other diseases because it is very important to get a view into what people really live with as a way to say we need better research. So I invited PBS in on the conditions that they would respect his dignity. This is what came out of it.
Two years later, it is still very painful for me to watch that, but if watching that persuades any of you to push barriers in research, support faster cures, it is worth the pain of being sort of displayed open publicly. That was two years ago.
Just a footnote. My husband is still at home. I did the night shift last night, and now I have two. My 86‑year‑old mother was formally diagnosed after about five years, where we tried to create an infrastructure because she was an independent proud woman, and she now lives with us because I cannot afford round‑the‑clock care, 24/7, for two people. I will be bankrupt if my husband lives another five years. If he lives another five years, the house goes, simple as that.
And we were two upper middle class, worked hard. Gone. That is the financial penalty of this disease, huge economic consequences. $24 billion is spent annually by Medicaid for those who go bankrupt trying to take care of their loved ones. Seventy percent of families try. There is always an episode, whether it is endangerment of some kind or the care‑giver wears out or they are elderly and they just can't do it anymore.
Thirty years ago, there was no hope. Today, there is hope, and I am counting on it, and it is about the future. We hope that in the future that AD will be managed the way cardiovascular disease is handled now.
Just last week, perhaps prematurely, although probably Dr. Altar would not say so, scientists at Stanford reported progress for the development of a blood test that is 90‑percent accurate in diagnosing Alzheimer's disease, years before the debilitating memory loss sets in. The question is whether they can replicate the findings that they have had, but then who wants to know if there is no cure or at least a disease‑modifying drug?
Intensive studies underway on multiple fronts, we need a complete rethinking by the FDA of the timelines needed to develop and approve new drugs for Alzheimer's disease and other chronic drugs. No new rules need to be written for our call for subparting. We are only asking for the same priority treatment that has been given to cancer and HIV.
If society ‑‑ and it was alluded to earlier today ‑‑ adopts the mind‑set that no medicine is acceptable unless it is 100‑percent safe, with 100‑percent of the population, we will have no innovation and no new drugs at all, and then we really have to ask ourselves what are the risks to society of being so risk averse.
I am a care‑giver, not a criminal, and I do believe in the regulatory process designed to protect patient safety. Yet, in desperation to manage my husband's behaviors, I researched a drug ‑‑ remember, I was married to a doc ‑‑ that had been used in Europe for 10 years, minimal side effects. The drug was Memantine. And I couldn't wait on the FDA to approve it. I went to Europe, bought it over the counter in Paris, $200 a pill. I then went on to England. I was stockpiling. Here I am. I went on the Internet. Desperate populations do whatever they have to do, simple as that.
Six months later, it passed the FDA. When you live in the margins, I don't care what disease it is, every day counts. Every day matters. My act of desperation made it possible for me to keep my husband at home. The alternative was to put him in an institution, have him restrained because of his behaviors, and overmedicated. That is the only way they would have kept him in an institution.
Guess what, folks? I have no regrets for what I did, and if you asked any other family member attached to any other disease, my guess is they would say the same thing.
As families, we desperately need access to therapies. We will manage the side effects and consequences. That is what we do all day. The brain is the last black box of science, as far as I am concerned, and all protocols, in my opinion, are trial and error.
Think of the challenges for researchers are unraveling the Da Vinci Code to the mind. If advances in genetics and imaging give scientists the tools they need to find risk factors, what are we waiting for?
As our scientists more precisely define cause and cure, we have to start to get ahead of the future, and we have some other questions to ask. How will we pay for the treatment of Alzheimer's on the massive scale that the aging baby‑boom generation will require? This is our choice. Will we pay to prevent the disease, rather than pay to treat those who have become demented?
Just recently, the results of a study suggested that one specific type of statin reduces the risk of developing Alzheimer's disease. Now let me give you a little insight. I haven't met a resident at a hospital who was not taking Lipitor prophylactically. Would this unanticipated value be reflected in the kind of cost‑effective analysis that is going on both in Australia and Great Britain where now you cannot get Aricept for this disease?
If we impose blunt controls like comparative or cost‑effectiveness requirements before giving patients access to new medicines, we are going to take away the incentive to discovery new cures.
Wyeth alone reported committed over $450 million into researching a cure for Alzheimer's, 23 different projects from small molecular to vaccines and biotechnology, and quoting incoming president, Bernard Poussot, "Who else can devote these kinds of resources? What other industry takes this kind of enormous fundamental risk on what is, after all, only a hypothesis?"
Already ‑‑ and trust me, already it is happening ‑‑ under challenge is reimbursement for presymptomatic diagnostics like MRIs and PET scans for Alzheimer's disease. What you are hearing are my personal Cliff Notes on a disease, but I hope they trigger some alarm.
The century of Alzheimer's that we have to worry about is not the one passed. It is the one ahead. That being said, it is imperative ‑‑ and I ask all of you, attached to whatever disease it is ‑‑ to settle the issue of value before it causes a split‑second delay in getting a single transformational therapy to any patient. The bottom line is we have all come too far and lost too much, only to find that we can't afford to pay for it, for the answer, when we finally have it.
Thank you very much.
[Applause.]
MS. WOOLLEY: Meryl, that was extraordinary. It was clearly from the heart and moving in so many ways.
I hope that this provided for all of you, as it did for me, a renewal of motivation to leave no stone unturned, to get right back to work, to do our part to delivering on the promise of research.
We are going to talk in a few minutes at our next panel with some how to's and stimulate more conversation, but in the meantime, let's thank Meryl once again for sharing.
[Applause.]
MS. WOOLLEY: We are going back into the main meeting room, and we will get started there in five minutes. Thanks.
[Break.]
Panel 2
Pathways for Innovation: How Do We Foster Research?
MR. LEINWEBER: For the sake of time, we are going to go ahead and get started. We are running a tad behind schedule, and everybody is busy. We appreciate you reconvening after lunch. I am sure you were as moved as I was by Meryl Comer's very poignant story and, as Mary Woolley pointed out, motivated as well to get back to work.
We have a very distinguished panel this afternoon that is with us to really expand on the conversation that we began this morning around the theme of our program today, Transforming Health: Fulfilling the Promise of Research.
Our panel this afternoon is going to speak to a variety of elements that serve to foster advancement in research, and you are going to hear a range of topics and issues that will address keeping in mind that research is done within a public context, within a policy context, and not in a vacuum, and some of what the individuals with us this afternoon are going to share are their insights on how policy impacts advancements in research and what we can do in our individual roles as scientists, as patients, and as advocates to advance research.
One of the findings for the poll that was released this morning by Research!America and PhRMA ‑‑ and I know you all have a report in your packet ‑‑ indicates with very strong majority support that Americans very much want our nation to sustain its world leadership in medical and health research. To do that requires a strong cooperation from the public sector and the private sector, and there is a strong policy context for that, that we are going to address this afternoon.
I am not going to spend a lot of time reading the entire bios of each of the panelists. You have those, but starting us off with some remarks this afternoon will be Dr. Scott Gottlieb. Scott is a Resident Fellow of the American Enterprise Institute for Public Policy Research and former FDA Deputy Commissioner for Medical and Scientific Affairs.
I know many of you have seen articles that Scott has had published in various publications. Scott continues to practice medicine in Connecticut, and we appreciate him being with us today.
Scott?
DR. GOTTLIEB: Thanks a lot, and thanks for the opportunity to be here.
There has been a lot of angst in public sector about what people perceive as a lack of productivity in terms of new drugs, new medical devices, for all the investments that we are making in health care research, and certainly, given the enormous increases in the amount of money we are spending both in the public sector in terms of NIH's budget and other public sector sources and in particular the private sector in terms of the R&D spending of drug companies, there is an expectation that we ought to be seeing more innovation coming out of both the public and private sectors.
I think a lot of this is probably a supply‑driven demand. Our expectations have certainly increased over time, given all the enormous benefits that we have seen for medical progress, but I am, in fact, extremely encouraged by what we are seeing, and I think that we often tend to understate the amount and level of the case of innovation that is happening because of the parameters that we look at.
Jack talked about this. Jack Calfee is going to speak next. He talked about this in a great article in the American Enterprise, the magazine of our thinktank, that a lot of the innovations taking place after drugs make it to the market in terms of doctors and companies finding new uses for those products, and we often tend to look at static metrics, like the number of new molecular entities approved as a metric somehow for the amount of innovation that is happening in health care, and I think it dramatically understates what is going on inside medical practice, inside hospitals, even inside my own clinical practice.
I took a year off from clinical practice when I first joined the FDA, and in literally the eight or nine months that I was away from clinical practice, the approach to certain kinds of patients completely changed. One of the startling places where it changed was the approach to heart failure patients with the introduction of a new test to better determine which patients in the emergency room getting admitted to the hospital were coming in with heart failure. Oftentimes, we had had trouble distinguishing heart failure form pneumonia or other clinical entities, and suddenly, we had a test to detect that very early, and also the treatments, the approach to treatments literally changed in a year, so a dramatic amount of innovation just over a very short period of time.
The other thing that is extremely encouraging is that the translation from a fundamental discovery, a fundamental basic science discovery, to a practical useful item that can affect patient care is becoming more and more compressed. So, if we think about it, over time we have had fundamental discoveries of basic science, of health care, the early discoveries about the role of hygiene in promoting health care and promoting public health. Other things over time, other sort of basic fundamental discoveries about health and the propagation of disease, it took a very long time for those to get translated into practical things that patients can use. That is not the case anymore.
So, if you go back just 20 years, we made some fundamental discoveries about the basis for immunity and how the immune system works, and probably more fundamental discoveries just recently, and you are already seeing that new scientific understanding translated into new kinds of drugs, whether it is the monoclone antibodies that can replicate immune functions or drugs like Tasabri that intervene in the immune system in very unique ways, same thing with protein synthesis, so a fundamental discovery about how to create new molecules pioneered probably about 20, 25 years ago by a handful of biotech companies, now resulting in not a few, but literally dozens of products.
So the basic scientific discoveries are being translated much more quickly, and if you look, as I did when I was at FDA at the early pipeline, the INDs coming into the agency, you see many, many drugs derived almost entirely from science that as basically engineered, pioneered just a short time ago, whether it is genomics or proteomics, structure‑based drug design, computational approaches to designing drugs, other kinds of science.
So I am extremely optimistic about what we are seeing, and I think the metrics that we have used over time are the wrong metrics because they don't really get at what is happening in clinical practice and how much medicine is, in fact, changing over very short bursts of time. So we really need to look beyond that.
That said, there are reasons to be cautious and I think things that we need to be conscientious of as we continue to try to push out the boundaries of medical science, and I think one of them ‑‑ and it was talked about over lunch, and I am going to talk about it a little bit differently ‑‑ is our tolerance for risk and our tolerance for uncertainty, not just from a regulatory standpoint, but from a marketplace standpoint, and even from a clinical practice standpoint.
I heard a comment the other night from one person involved in drug development, that the more people who need to agree that something is innovative, the less likely it is to be innovative, and that can certainly be an epitaph maybe for the development approaches of some companies that have systemically de-risked themselves over recent years, and it maybe even could be a way to describe our regulatory process and our approaches to looking at products as they come onto the market.
So I want to talk about this phenomenon, our tolerance for risk and the impact that I think it could potentially have on our willingness to innovate, our ability to innovate and change medical practice, and what we could do it about it from a policy standpoint.
From a marketplace standpoint, since I have left the agency, I have had the opportunity not just to speak with people involved in the early financing of medical products, but also work with some of these companies, whether it is venture capitalists or other kinds of entrepreneurs, and I can tell you that they pay an awful lot of attention to regulatory uncertainty, more so than I ever could have imagined when I was at FDA.
Investors, even very early stage investors, focus on trying to model risk, and they have all kinds of ways to model marketplace risk. They do all kinds of sophisticated analyses to try to model what the potential market is for a product, what uncertainties could come along the way, what competition could happen. The one risk that they can't model and they can't get any appreciation for is regulatory risk. To them, it is a very binary risk, it is a very black box risk, and there is no computational model they can build and no way they can really get a handle around it. They can consult all the experts in the world, but to them, it still remains something that is very uncertain.
So, in areas of regulatory risk, I do see investors expressing increasing trepidation, and I have to believe the same thing is going on inside drug companies, which I have less insight into, and I think this is something we should be concerned about, that areas of great risk also will tend to be areas where people don't invest and don't try to innovate, and oftentimes, those areas of the highest risk are also the areas where you have the greatest ability to impact medical practice. It is often from the boldest ideas or the boldest attempts to try to change our approaches to managing certain kinds of diseases that we really have pushed out the boundaries of medical practice over time.
So the other place I think that this is an issue, obviously, is at the Food and Drug Administration, and I know Doug is going to talk about some of the things that FDA is doing to address these kinds of regulatory uncertainties, but one of the things that I found at the agency ‑‑ and I don't think this is necessarily a fault of the agency, it is sort of a structural issue, it is a resource issue, it is a cultural issue ‑‑ is that there is not a lot of tolerance for dramatic change in medical practice.
So, when you look at things like cancer and a new drug comes along for cancer, oftentimes it is added to existing therapy. If you look in the antiviral area, antibiotic space, it is often very hard to dramatically change medical practice with the introduction of a new drug. So it is often the case that drugs are introduced initially in the places where they have the least ability to really impact care.
So, in cancer, when you look at cancer, oftentimes the drugs are approved for a third or fourth line treatment of cancer, and it takes many, many years to determine that they could be much more effective when used earlier in front line treatment, and I think that this was because there is an approach to drug regulation and an approach to drug development, even inside the companies, that is more iterative, and it doesn't allow for really paradigmatic change, and it is often with paradigmatic change that you really get the dramatic improvements in medical practice, and that sort of paradigmatic change, if you will, often happens after the fact. It happens after regulatory approval, in the post market, by clinicians trying out new things with patients, with doctors, with hospitals who have more of a tolerance for risk than the system that we have created here does, and that is really where you see a lot of this pioneering work going on, and that is where you see I think so much innovation.
In Jack's article for the American Enterprise, he talked about all of that follow‑on innovation that is happening, that that is really where we start to see dramatic improvements in public health from the follow‑on uses of many of these products after they come to the market.
So what is a solution to these challenges? I think in part ‑‑ and I come from a regulatory orientation ‑‑ it is a regulatory challenge. It is a much broader challenge than that, but I think in large measure, it is a regulatory challenge.
Certainly, it is a resource challenge for the agency. In an ideal world, you would want the agency able to work to help define pathways for drug development for the kinds of paradigmatic change before the fact. Rather than being a reactive agency, you would want them to be proactive and help to outline some of these pathways, whether it is a pathway for developing drugs that can help prevent the onset of diabetes, as they recently laid out in a guidance document, or other kinds of pathways of how to really change clinical practice. That is a resource challenge for the agency, being able to fund and do that kind of scientific work.
It is a cultural issue. I don't think historically it is something that the agency has been engaged in. I think it is partly the temperament and the way the agency is structured that it is easier to react to proposals coming in rather than to come out and practically try to delineate what a pathway would be, and very often, the drug companies themselves don't want the agency doing that. They would rather take their shots with a proposal of their own and think about how to do something and have the agency react rather than ask the agency to outline a pathway forward, for fear that the pathway that might be outlined would be more stringent and a higher hurdle than what they might be able to negotiate if they had gone in on their own.
But I think it is going to be extremely important in the areas of health care that we care about, that we care about trying to incentivize new product development, to try to invest in doing more work up front, to delineate what it would look like to try to do a prevention study in cancer, to try to do front line trials in certain cancers where sponsors repeatedly go and try to get approval for third and fourth indications, try to do a prevention study in Alzheimer's, as we heard over lunch, because not only is it becoming an impediment I think for the drug companies, but more importantly and what I worry about most of all is it is becoming a disincentive for the investors and all the people who take the risks very early on to try to put these things into development.
When they see an area of a high regulatory uncertainty where the path hasn't been chartered before, I think too often, increasingly ‑‑ and I worry about this all the time ‑‑ people just choose to stay away and say no and put their money and their capital and their time in areas that have been chartered before, and it is very often not those areas that really end up changing medical practice in ways that we care about.
Thanks a lot.
[Applause.]
MR. LEINWEBER: Thanks, Scott. A very helpful insight and a good lead into some remarks by Dr. Doug Throckmorton who is with us today as really the face and the voice of the FDA, the agency whose name has been on the tongues of a lot of folks today as both the solution and the problem to what we are looking to move forward with in terms of transforming health and transforming medicine.
Dr. Throckmorton is the Deputy Director, Center for Drug Evaluation and Research at the U.S. Food and Drug Administration, and we look forward to your remarks.
DR. THROCKMORTON: Thank you very much.
First, I appreciate the opportunity to speak about fostering innovation. Perhaps there was a time when we would be brought on as the foil to fostering innovation, but I do think, in fact ‑‑ and in my remarks, I will sort of try to make the case that I think we do have a role in there, a role that the FDA leadership understands fairly clearly.
Scott, I am not going to talk to the cultural comments that you made or the resource comments. It is not because I disagree with them. I think they are good points. They are very large conversations, and I think today, I would like to focus on that notion of the reactive forces in product innovation and things like that.
I think the FDA regulators in general have had historic roles in fostering innovation, if you will, and we need to keep those in mind, but there has also been a more recent I would say innovative, I would say proactive role that we have that we have now understood. I think that it is better understood within the culture of the agency, one that I think we can use and should talk about today.
So our historic role ‑‑ and this has been something that people have written about for a very long time ‑‑ has been to provide that clarity and that surety in product development. Obviously, in my world, it is drug product development, telling people clearly what the rules are, what rules are in operation, and how they will be interpreted through guidance, rules, hopefully to reduce regulatory risk, as Scott suggested, ensuring a level playing field, so that one person coming to the agency doesn't get a different answer than another person bringing a similar set of facts to the agency. That is process transparency. That is equity. That is timeliness, whenever possible. It is what Peter Barton Hutt called "consistent and dependable rules that are equally applicable to everyone," and I think that was very well said. He wrote that in the mid '70s. So this is not something new as far as what people have been thinking about.
I believe that application and the way he talks about it, done well, done with a process that is appropriate, encourages and does not stifle innovation. I think that requires careful thought, and, Scott, having come from the agency, you know that there are always ways for those kinds of processes to go awry and, in fact, to slow things down, but those processes are necessarily as a sort of foundation to start with, I believe. That is a task that we have often understood, I think. We have worked through outside standard‑setting organizations. We have worked through harmonization, through the International Conference on Harmonization and in GTFA, other places, to make sure that the rules are transparent, applied equitably and equally, and are reasonably understood by everyone, to reduce some of that risk.
I also agree with you that that is not enough, and I think this is where the agency came to a few years ago, particularly under Janet Woodcock, enforcing those rules, making sure that those processes in place were not sufficient for the place we find ourself today, and so she came up with the notion of the critical path, the idea that we needed to focus particular attention on the space between the identification of a potential therapeutic and its marketing, that bridge between discovery and delivery to the health care system.
Her idea was that that was as place we had not paid sufficient attention, and that by doing that, we could reinvigorate, make medical product development more efficient. The fundamental that that starts with is that the current paradigm is not adequate, and this is something I think everyone within the leadership of the FDA believes. The present paradigm will not suffice to develop the medical products that we need to have in the next decade and the decades beyond, and that if we don't make fundamental shift ‑‑ "paradigmatic," did you call it, Scott? ‑‑ paradigmatic shift in the way that we thought about new medical product development, we would not succeed as an agency, sponsors would not succeed, the health care system as a whole would not succeed in delivering the therapeutics that we really needed.
We also believe within the FDA that we are in the nexus, at a place where we can help that change occur thoughtfully. We see opportunities and wasted opportunities. We see the science and the challenges that, with some particular attention, could make that process more efficient, and what Janet said is we need to engage in that process. We need to not wait for ideas to come to us. In fact, we need to find a thoughtful, careful way to engage in outside collaboration to make sure that we move those ideas forward, so that we make the changes we need to, to enable changes to be made in the sponsor culture, to enable changes to be made in health care delivery, to really reinvigorate product development. That is a dialogue.
I believe it is consistent with the FDA's mission to protect and promote, promoting in this case the health of the American public at large that is a proactive as opposed to reactive stance, and I think it is something that we absolutely need to engage.
So what does this mean? In other places, I have described the critical path as basically being willing to question your assumptions, and I ask sponsors that I interact to be prepared to do that and then for all of us to be prepared to change our behaviors based on that questioning of those assumptions.
So, if a particular trial design has been used for a couple of decades because it is safe, because it has some clarity in terms of the rules that are necessary and things like that, but it will not provide us the kinds of information we need, for instance, about personalized response or something like that, we need to be open to new challenges and new ways of looking at business. That is a thoughtful collaboration. That is a discussion within a context of law, but that is absolutely a thing we have to be prepared to do.
We need to enable standards that make that easier. We need to set up tool kits to make that more available, more accessible to the public. Disease models are something that I will talk about in a bit, but I see that as a hugely powerful tool to sort of move some of these places like Alzheimer's, other diseases like that forward.
What specifics am I talking about? I will just choose a couple off the shelf. We have set up a program where genomic databases come into the agency in a nonregulatory fashion. Sponsors and people that have those data come in to us, ask a question, can ask any question that they want. Those data are then discussed with the content experts within the agency, the content experts within academia, the content experts that the sponsors bring to the table. No question is off the table because the discussion itself is not a regulatory one. It is not a question of am I going to get my drug approved depending on the outcome of this discussion or not. It is a scientific exchange, a collaboration, a sharing of ideas that helps us be better regulators, and I think moves the field of genomics and the development of medical products forward.
Another example are the disease models that I mentioned before. Disease models hopefully allow a sponsor to put the data that they have for a promising molecule into a model and understand better where to expect the benefits and what potential outcomes are going to be negative that they are going to need to monitor for.
So, for instance, we, as an agency working with some of the data we have available, working with sponsors we are interested, have erected disease models for Parkinson's disease and non‑small cell lung cancer. Those disease models are available publicly. Sponsors can use them to plan their next trials, to decide their next doses. As they gain information, they can iterate that model and change how it works.
Yesterday, Janet Woodcock signed ACRATA to erect a disease model for Alzheimer's disease with the American Academy of Pharmaceutical Sciences. Again, to go back to Meryl's comments over lunch, those kinds of things are essential to change how we develop products in that therapeutic area in the same way it is for any therapeutic area that desperately needs new information, new therapies. Using the data we have available to do a better job of developing the new drug seems to me absolutely the right way forward, and those are examples of places that we have done that. I am hoping that that continues to be a success.
I won't talk about the sentinel network except to say that IT is going to play a huge part on any of these solutions. We have a lot of interest in post‑marketing safety that we are going to need to address as an agency. It is clear to us that the path of surveillance systems are an important part of what we are going to end up using in the future years, but they are not all we have to work with, and we need to know more about the use of linked databases, the better use of those kinds of data to make better decisions in post marketing.
The common thread to all of this is collaboration. As Scott said, the agency lacks resources. In some sense, this lacks the culture, although I think the culture is changing to be more open to these sorts of things. My people all have day jobs that do not include, for the large part, thinking creatively about new ways to do these things. They are very open to them. I will say that I think our culture has changed. People now see the advantages to these more innovative things. They are very open to them in many parts of the center, and we are working on the parts that potentially may have a few questions remaining. That collaboration is a requirement, and I don't think it can happen waiting for the FDA to come up with something and put it out in a guidance. That is a reactive stance I think that we need to try to get away from.
I think in future, we have some opportunities. In the last couple of months, we have had some things happen to the agency that some people have wondered would make these things slower, will FDAAA, will the new focus on safety slow these things or reverse some of the activities that Dr. Woodcock has going on under critical path.
I believe the answer to that is resoundingly no. I think, one, FDAAA does place a lot of new obligations on the agency. It also does have the promise. We don't have our budget yet. So it is a hope for some additional resources that will allow us to focus on areas like the critical path do better in some of these areas that Dr. Woodcock and others view as really high‑value targets for moving medical product efficiency better.
I think drug safety is something we are going to have to respond to. To pretend that that wouldn't affect in some way how the agency reacts to the public, I think would be disingenuous. On the other hand, we are a rules‑based agency. We respond to the rule of law of what Congress tells us to do. I do not see a change within the agency to wake up and get out of bed in the morning and all of a sudden decide to up the ante on the amount of data that are required for medical approval. We respond to the data and the rules as we see them, as we understand them. We should have that opportunity to talk with the stakeholders for every one of those as they come along, but I don't think that is going to slow down what we are doing around the critical path, slow down what we are trying to do to reinvigorate medical product development.
I think it will be a challenge that we will confront. We are trying to confront with some communications things that we are doing, trying to confront it with some new science that we are applying, but at the end of the day, I think both FDAAA and the new interest, continued interest in safety are going to be new facets to, I hope, a reinvigorated proactive collaboration, to try to really do better than we have in the past because I think we owe it to everyone. We owe it to ourselves. We are all patients and care‑givers, and we really need to do better than we have been able to in the past.
So thank you very much.
[Applause.]
MR. LEINWEBER: Our next panelist and speaker is Dr. John, or Jack, Calfee, Resident Scholar of the American Enterprise Institute for Public Policy Research, and he will be speaking on some policy issues with a focus on intellectual property.
DR. CALFEE: Thank you, Bill. It is nice to be here with such distinguished cospeakers.
As Bill said, I will talk a little bit about IP. My view is that pharma R&D rests upon a three‑legged stool, one of which is the science itself which is where FDA tends to get involved the most. Another is on pricing, profits, et cetera, because, for better or for worse, most new drugs are the result of some private firm trying to make money by developing and testing a drug, and then finally, IP, which means mainly patents. Almost every economist who has looked carefully patenting over the years has concluded that there is something about pharmaceuticals and biotechnology, and essentially, what is special is there is no other industry in which so much has to be invested after an invention or discovery has been filed and usually revealed to the public, but before there is any kind of revenue stream that can provide a payoff from that research. So it really is true I think that when it comes to patents, the pharma industry is a special case.
The patent system has been under stress. I don't think that is any secret to people who have been looking at this. The last 10, 15, 20 years have been very difficult years for the PTO, the Patents and Trademark Office. There has been an onslaught of new technology which arguably involves its own sub‑onslaught of arguably patentable devices, technologies, research results, et cetera, and it isn't just the sheer volume of these discoveries and inventions that is a problem, but also the fact that they tend to raise very tricky, intellectually challenging questions about how to interpret the standard criteria, the law‑based criteria for when patents are awarded and how that is done, and then on top of all that, the PTO has faced genuine constraints in its budgets, personnel, et cetera, a user fee system that has not worked very well at all, and one of the results ‑‑ there's two basic results. One is, as I mentioned, some very tricky questions about how these standards work, and the other is that the PTO at least for a while had real serious problems in keeping up with the volume of their work.
This is a graph that I and my colleague, Claude Barfield, pulled off of a source. I have forgotten now where it is. It is not the kind of a graph that economists like because the left‑hand scale doesn't go all the way down to zero. It starts at 100. Nonetheless, it is perfectly clear when you look at this that sometime in the late 1990s, the volume of filing for patents increased very, very dramatically. The PTO responded, more or less, as well as it could, while also mulling over exactly what is patentable and what isn't, and particularly, in the late 1990s, the number of patents awarded almost skyrocketed, and then it basically leveled off, and it leveled off partly because the backlog was increasing faster than the number of patents issued and partly because there was some rethinking about what is patentable, what the standards are, and that kind of thing.
I should mention that my colleague, Claude Barfield, and I recently published a book at AEI that is essentially an overview of the patent system and patent reform and that kind of thing, and our take, after looking at the literature pretty carefully, is that despite the very serious problems in the patent system, that the system has been recovering remarkably well, more or less through innate self‑correcting forces, including the Federal courts, as well as the PTO itself.
We are certainly now out of the woods, however, at this point. I think there are some serious things to worry about, and some of the most serious things are ones that pertain particularly to the pharmaceutical industry.
So let me mention a few of those. In the first item, it isn't really an issue for the PTO at all. It is the fact that every once in a while, people do seriously propose a policy system for pharmaceuticals. At least one Presidential candidate has announced his own intention, his own desire to do that. You don't usually get that kind of talk in the U.S. or in the European Union or in other advanced nations, but it does come up occasionally. Needless to say, I am not a big fan of that idea.
I think we already know what the alternatives are to the patent system because we already have experience in areas where there is no intellectual property where patents are essentially impossible to obtain, and what we observe in areas like tuberculosis, malaria, you could even look at the history of research in aspirin and heart disease, and what we have observed is that if you don't have a patent, you don't see much clinical research being done. You don't see the long‑term extremely expensive clinical trials that are necessary to find out what works and what doesn't.
So I am reasonably satisfied at this point that the alternative to the patent system is almost certainly a vast slowdown in drug development.
Another issue which may be unfamiliar to a lot of people in this room, but certainly not to the lawyers, if there are any, is concerns, KSR vs. Teleflex. This is a case that went through the Federal courts, was appealed to the Supreme Court. Back in April, the Supreme Court reached a verdict in this particular case. It had to do with a new way to devise a brake pedal in an automobile, which doesn't sound like it has a lot to do with developing drugs for cancer and Alzheimer's, but the issue was whether or not this particular invention was novel or original enough to be patentable.
In the case of reviewing this particular patent, which was overturned by the Supreme Court, the Court essentially laid out new criteria for when a discovery or an invention is sufficiently non‑obvious to be patentable, and in going through that discussion, when you are reading the Court's opinion, it looks as if there could be a lot of work that is now done or has been done in the pharmaceutical industry that might raise new questions about what is and what is not patentable because, essentially, the Court said even if your device has never been seen before, you were the first one to find it, to discover it, if, nonetheless, people who are practitioners in this particular art, et cetera, et cetera, et cetera, if it is very likely that someone else would have discovered it anyway, but just by doing the things that were sort of, more or less, obvious to do, then your patent is too obvious to be patentable, and this could raise very serious issues in the pharmaceutical business.
I think it was last week, certainly very recently, the PTO issued its Federal Register Notice about its take on this particular decision. When you go through that Federal Register Notice, it has lots of examples. Quite a few of those examples involve biotechnology and pharmaceuticals. Quite a few of those examples involve situations in which the PTO says, "We do not think this particular situation, this particular invention would be patentable under the new criteria," and sometimes these involve the kinds of products that are worth developing.
The tension here, the basic problem is that the patent system was devised to reward finding things, inventing things, discovering things. It wasn't really devised to reward research and development after something has been discovered or invented, but in this business, the business we are talking about, most of the money is spent not on finding the molecule or something else, but in research it and running through the clinical trials.
No one knows at this point what are likely to be the practical consequences of the KSR decision, but I think it is something to keep an eye on. There are reasons to be concerned about how this can play out. We will see whether the fears are genuine.
PTO also announced at least in the past few months or so a new policy regarding what are called "patent continuations." I am not a lawyer. My understanding of it is basically a biotech firm comes into the PTO seeking a patent on a particular. It might be a gene snippet, it might be a protein, something like that. I am portraying my ignorance, obviously. I am an economist. And they provide certain information to justify that patent, but what often happens is that what they are working with is so complicated, the science is so complicated, the patent itself is so complicated, that as time proceeds, as they continue to research that particular invention, they learn much more about it, and they learn much more about why it is patentable in the first place and exactly what it is that should constitute a patent, and this is for future reference as a researcher product possibly put on the market and possibly facing patent challenges and so on.
The practice, the tool for dealing with the fact that you learn more about the intrinsic nature of an invention well after it is actually filed, the practical tool has been that companies have filed continuations of that patent to flesh out the details of it. Thousands of these continuations arrive at the front door of the PTO every year. PTO, as I mentioned, is under stress for lack of resources, and so what they have decided is a way to cut down on their own workload. They are severely limiting the number of these continuations.
It is another one of those things that we don't know exactly how it is going to play out, and we do know that one pharmaceutical firm, GlaxoSmithKline, went to court and persuaded the court to issue an injunction to halt the PTO for the time being from enforcing this new rule. So that is now being litigated, but this is the kind of thing that could make a difference, and it also raises a question of what else the PTO might do in order to control its own workload in the future that might involve something that could seriously abrogate the patenting process itself in a way that would disadvantage or inhibit the development and the research of new inventions in this particular area.
It is another one of those things where we don't know how this is going to play out, but we have to keep an eye on it. Now, if Congress is able to do something useful regarding the resources available to the PTO, then this policy might change, and the problems might go away.
One of the things that came up in this morning's session in the discussion about individualized medicines and biomarkers, et cetera, towards the end during the Q&A part, there was a brief discussion about the role of intellectual property which is something I was going to say something briefly about this afternoon. I think I will mainly just refer you back to that discussion this morning, but the essence of this is that as scientists go into this rather adventurous new territory, figuring out the genetic foundations of patient's susceptibility to both the risks and the benefits of drugs, there is a lot of research that will be very expensive, it will be very time consuming, and there will be serious questions as to exactly when IP is available and when patents are available and when they are not.
That dividing line, the relative availability of IP can make a big difference as to whether private firms have an incentive to get out, get in there, discover biomarkers, discover other gene markers related to drug safety and drug efficacy, and to research those possibilities as opposed to leaving it all to the public sector. It is another one of those areas where we don't know how this is going to play out, but I think it is worth paying attention to.
Specifically, the question is will there be serious IP impediments to the exploitation of the new knowledge that is arriving so rapidly about the genetic foundations of individual patient response to drug therapy.
I just have one last item I will do briefly, and then I think I will get close to my 10‑minute limit. I am told by the lawyers in the area that when you patent a biologic, especially one involving biotechnology methods, that the patents can be quite complicated and look very different from the traditional patent for a traditional small molecule.
So far, this has not made a big difference because, as a general rule, biologics are patented, researched, finally obtain FDA approval, and then are placed on the market and achieve some revenues and maybe some profits, not always. That hasn't been a big problem because there is no regulatory pathway for generic versions of these biologics, which means that the actual patent life is not nearly as important as it is for, say, Zocor or Lipitor or Prozac or other small molecules.
As the prospect emerges of the FDA approving bio‑similar, so‑called generic biologics, so‑called follow‑on biologics, then the pure IP component of these products becomes much more important, and one of the issues here is that there are some uncertainties about just how solid the entire patent paraphernalia is for at least some of these biologics because, as I mentioned before, the very standards for what is patentable is sometimes up in the air, is sometimes confusing, and what every biotech manufacturer fears, their worst nightmare is you patent something, it goes through the patent process, you research it, you spend five years researching it, and you spend a great deal of money, you get the product approved by the FDA, it gets out there, and then as soon as it is approved by the FDA, the other firms start attacking your patent base. If they can erode that patent base, you could have a serious problem.
In the European Union where they move much more rapidly towards follow‑on biologics and bio‑similars, they have given a lot of attention to the idea of data exclusivity. That is, if you can prove that your product works in a unique way, provides unique benefits, et cetera, then no one else can piggy‑back on the data that you used in order to prove that, which means all of your clinical data, and that you have a certain period of time on the order of roughly 10 years or so in which you have exclusive rights to use that, to market that product, regardless of the patent status.
I think it is pretty clear we need something like that in the U.S. if we move rapidly towards bio‑similars, et cetera. There has been a lot of talk about this in Congress. It is part of the bio‑similars legislation in Congress that has yet to pass. Some of the talk is about zero years of data exclusivity. Sometimes it is five years. I am one of those people who thinks 10 to 12, 15 years makes a lot more sense if we are going to have a viable substitute for a traditional, more or less, unshakable patent apparatus for newly developed drugs.
Those are my remarks.
[Applause.]
MR. LEINWEBER: Thank you.
Our final panelist and speaker this afternoon is Ellen Sigal, Dr. Ellen Sigal, the founder of the Friends of Cancer Research, a very effective and powerful advocacy organization here in Washington, and many of you are familiar with Friends of Cancer Research and Ellen. We appreciate you being here today to talk about the role of advocates and advancing research. Thank you, and you are set here.
DR. SIGAL: Good afternoon. I was asked to speak about advocacy research and public policy. That may be easy after talking about patents, but it is actually just as complex.
We all know about advocacy, and we understand it, and clearly, in the world that we live in, it goes on every single day. However, it is becoming extremely complex because we have disease du jour, organ site du jour, different messages. In cancer, we have probably a thousand groups that have "Cancer Research" in their name. We all don't want the same thing. It is good because we have advocacy, but it is also very complex today to get the messages across and to be effective.
We all know successful advocacy. My sister was treated and died for breast cancer 22 years ago, 23 years ago. At that time, the only advocacy that existed was AIDS, and they did an extraordinary job. Now these are just a few notable campaigns, but every single day, we have something. So the good thing is that our community is energized. We are educated, and we care, and it makes a difference, and groups like Research!America who brings us all together can really bring us under one umbrella because we should not be fighting one another. So we have made a huge difference, and I think we can complement one another.
However, we have responsibilities in advocacy. It is not just being there whining for more money, asking for more and more and more, because as we go to the media, as we go to the public, as we go on the Hill, just as soon as we walk in, someone has walked out, and as soon as we walked out, someone is walking in. So we really need to know what we are talking about. We need to be informed. We need to have data that is meaningful. We should not be fighting the disease wars.
The worst thing in the world we can do is start to fight cancer doesn't get enough, Alzheimer's gets too much, breast cancer gets more than prostate cancer. It is a terrible mistake. I think that message has become very clear in the public. We can care about the diseases that we care about, but we should understand that basic research, immunology, all the things that we talk about in basic science will benefit all diseases, and it is very dangerous if we start to fight one another. I think we have gotten better, and frankly, thankfully to Research!America who has really guided us there, and I think we would not have gotten to the doubling of the NIH if we didn't go hand in hand.
But our messages have to be compelling. They have to be factual, and we have to understand that just going in once to have an op‑ed or going into a Member of Congress' office or to even do a town hall that our job is done. It is every single day.
We started in Friends 11 years ago doing town halls all over the country, and we were very proud of that model because we bring a Member of Congress, a Cancer Center director, researchers, patients, and it was terrific, but the next day, it was over. So being in touch with that office and continually keeping in the public, keeping our agenda on and being on message and understanding that there are so many other compelling needs is extremely important. So I think we are trying to get better, but we have to understand our work isn't over with one visit, one letter, one op‑ed. It is constant, and we have to be data‑driven.
The challenges are clear. We have stagnant research budgets. On the Hill, a few years ago, there was the issue of accountability, "We have doubled your budget. What did we get for it? We didn't cure cancer. Stop complaining. You're a bunch of needy people in white coats." That was the message. I think it is getting a little bit better. The political climate is toxic right now. Health care costs are going out of whack, and somehow we have not been able to make the effective argument about the investment in research and health care.
Last year, we were completely consumed with drug safety. What does that mean? Everyone wants drug safety, but does that mean no pipeline, no innovation? Disease is not healthy. So there was that kind of rhetoric, and that took away the message from research and innovation and other things that we should be talking about.
Now we have the new message for 2008, comparative effectiveness. Well, that is important. We need to know if we are getting value, but the only value we are going to get is through innovation. So we can spend billions and billions of dollars deciding whether one drug is more effective or cost effective. What is the criteria we are using? Is it going to be cost? Is it going to be side effects? Is it going to be duration? In diseases like cancer, that is going to be very complicated. So we have to really keep our eye on the message, and that is really research and innovation.
We have enormously heard a lot today about science and research. Today, we know if we can treat early, if we can research early, if we can get the markers, we are going to make a huge difference. That seems easy, but it is very complicated, and it is complicated because of the regulatory environment. It is complicated because of science. It is complicated because of lots of limiting power issues. It is extremely important, but we have to figure out how to get there, and I will tell you we are not going to get there if we fight one another.
So the science, we all know about. I don't think I am going to spend a huge amount of time on the science because probably everyone here knows more about the science than I do, but it is an enormous time of great opportunity, and we should be doing things together, and I think if we can really harness the power and the science and really think about what needs to be done and really have a strategic plan for it, I think we will have much better, more effective drugs and intervention and frankly knowledge. We can't have innovation without knowledge, and if we don't keep research going and if we don't fund the FDA and if we don't fund the agencies that are responsible for it, if we don't fund young scientists, we will not have knowledge. So we have to remember that.
It is a collaboration. The NIH is a major portion of it. The academic environment, the industry, patient groups have to work together. There is some very interesting models out there, and I think we have to create more models because that is really where we need to go.
So we have become a little bit better, a little bit more educated in advocacy. So we really now have to have better messages. It is just not that we are entitled or that this disease burden is terrible. It is really we have to talk about the economic impact, the patient benefit. We have to talk about the health care burden. If it is what is going on in Singapore or in Europe, we have to get that argument. We have to know who we are speaking to, and the dividends that this will pay not only in human toll, but in financial models, those are very important things for us to discuss and to understand, but it is always human, and at the end, it is always about the patient.
Nobody could be as effective as a Meryl Comer, someone who is really dealing with that disease, because it is about the patient. It is about their burden. It is about that burden on society and all of us. It is personal, and we can't forget about it.
We have heard from Tony Altar about the Foundation for the NIH. They are doing extraordinarily important innovative partnerships. Public‑private partnerships are happening all over the country. It is very important. I am sure you have heard a lot about what we are doing there. The Reagan‑Udall will be an opportunity for regulatory partnerships to work together on science. It is extremely important that science get integrated into the regulatory environment. It is an enormous opportunity.
There are State initiatives in Texas that was just a huge ballot on Proposition 15 which will be put billions of dollars into the health care system. I think that is something to look at. We know about the stem cell initiative. There are other models for a partnership as well. The Gates Foundation, you know about. Entertainment Industry Foundation is doing things. There are funds in California. So I think we need to really harness together and look at that, and we should never expect that all of this money is going to come from government, but it is about the patient.
I am going to show you a video that many of you who have heard me speak before probably have seen, but it is really important. This was a patient that we had asked to speak during the LiveStrong debates, and it is a young woman who is 41 years old.
I think you all are going to put the video on.
[Video presentation.]
DR. SIGAL: The reason I play this is, first of all, it is real. Second of all, we all know that prevention is where we need to be, but you know, there are people that have this disease. There are people that six months a year, two years, any quality of life would make a difference.
It obscures the real goal, which is science and innovation and patient care, and we get really obsessed with arguments on safety and get obsessed on billions of dollars on comparative effectiveness, and no one is suggesting that we shouldn't be responsible. It really takes away the message which is really we have to do better. We need knowledge. We need science. We need innovation, and we need rational public policy, and we have to cut through the clutter and the politics, and we have to do better on this.
These are things that we have all talked about, and now this is the last slide which I played before. We need innovation.
So thank you.
[Applause.]
MR. LEINWEBER: Thank you, Ellen. That was very thoughtful.
We are going to open things up for questions here for a few minutes. Are there questions that individuals have for any of the panelists from anybody in the audience?
I will get us started. Scott, when you spoke, you talked about the difficulty of modeling regulatory risk and the impact that has in terms of investment, particularly from the private sector.
I am wondering, since you were at the FDA, if you had a magic wand and you could change or modify any one or two things, what would those be in terms of providing an environment that would be more inviting to investors and mitigating some of what they receive and believe to be regulatory risk that is just not at all able to be predicted?
DR. GOTTLIEB: Well, I am not sure I talked about in terms of creating an environment at FDA that would be more hospitable to investors. Certainly, if I were to talk like that when I was at the agency, it would probably be before certain committees.
[Laughter.]
DR. GOTTLIEB: I agree with Doug that the environment at the agency has changed a lot, just in a short period of time, and there is much more of an openness to try to think about how to push out the boundaries of the science that the agencies have to grapple with on a daily basis.
Mind you, this is an agency where the resources are barely enough to keep up with the day job of handling the In Box, and it is an agency where I think the structure of the agency doesn't reward people for working on scientific endeavors to try to change the regulatory architecture around the paradigms in which they work. So people do this. A lot of times, people do this on their free time and as an adjunct to their normal work.
I think having been in the agency, out of the agency, in the agency, out of the agency, and having worked now with the investment community, both before I went into FDA and now after, from an investment standpoint, if you do believe that a lot of the really breakthrough, blockbuster, paradigmatic ideas are coming out of smaller companies that are willing to take more risk, coming out of very expensive venture capital, rather than less expensive capital that the pharmaceutical companies play with, then the idea that the agency signals an openness to new areas of drug development has an awful lot of impact on shifting around those resources.
So let's say we care about diabetes, the prevention of diabetes. Diabetes is often thought about as a disease you treat. You treat glucose levels in diabetics. Well, now we are learning a lot about science that says that you potentially could prevent the onset of diabetes is you could identify patients are risk.
I think that the agency's willingness to even talk about that concept in a recent guidance document had an awful lot of impact on the investment community and the early research community in terms of saying, "Okay. The agency is thinking about this. There is a pathway. They are thinking of developing a pathway. Let's invest in this because five or six years when this product matures, by that time they will have done even more thought."
But when there is absolutely no pathway that has been adjudicated before and no pronouncement from the agency of a willingness to even think about it, being open to it, it is not necessarily that people think the agency would close to it. It is people think it can't be traversed.
So, if there are areas that we do care about ‑‑ and Janet talked about this in the Critical Path Initiative where she outlined a few areas of critical public health need, I think it is incumbent upon us to give the agency the resources to work on the scientific pathways that could at least lay the foundation of a way forward for drug development.
MR. LEINWEBER: That is very helpful.
Garry?
DR. NEIL: Could I comment on your answers from a pharmaceutical industry perspective, looking at the venture community? What I have noticed, at least in health care, is that the venture community is probably a lot more risk averse than the pharmaceutical industry has been with respect to what they are willing to invest in, and the drivers for that may be the fact that three‑quarters of venture firms don't make it. They don't survive to get another round of funding. Whereas, at least until recent times, it has been a little bit more stable in the pharmaceutical industry. So we have been willing to take greater risk, and that includes looking at what you would call regulatory risk where if there isn't a straightforward pathway to approval, you have to think about how you can potentially engage with the agencies that we work with to try to define what that pathway is going to be at the time, but it can be rewarding in setting a paradigm.
So I don't know whether you share any of that.
DR. GOTTLIEB: Obviously, my experience is anecdotal, but having seen the inside of some big pharma companies and seeing the inside of some small biotech companies, I think a lot of the risk‑taking is in the smaller stage companies that are willing to really take significant risks, largely because they are dependent upon a single product, and pharmaceutical companies tend to de-risk as they get into later stages of development.
Your company is unique in some respects. It has a collection of some biotech companies, in many respects, but I think that the pharmaceutical industry over time has successively de-risked itself, and so you see a lot of the risk‑taking on the smaller side of the market now.
MR. LEINWEBER: A couple of folks have mentioned, both in responses and their remarks, the Critical Path Initiative.
Doug, going to you, coming from the FDA, and sharing with us some of the vision for the Critical Path and Dr. Woodcock's vision and the implementation and execution of the Critical Path, I am wondering, because I am in a lot of meetings, like I am sure folks here are, where the Critical Path is discussed, and there is a lot of head‑nodding, but I am wondering if you can give us some of what you would identify. If you had a mirror, looking at 5, 10 years down the road, and the Critical Path Initiative continues to unfold with success and with the resources necessary, what is going to be different at the FDA, 10 years from now, if indeed that happens, than it is today as we sit here? What would you identify as some key differences?
DR. THROCKMORTON: I will answer personally, just sort of the trends that I have seen in Critical Path, sort of seen so far, which is when Janet first stood this up. I think there was initially ‑‑ I don't want to call it disbelief. Let's just say it was another thing, and as Scott said, we are under tremendous resource constraints. People looked at this and said, "You know, I am not sure if this is going to survive or not, honestly." I think there was some skepticism, let's say. I think that has gone away. So people now understand this is really fundamentally part of the FDA culture. It is something that is going to survive this champion. It is here for good.
The second trend I think I would say is those first years were occupied with process. Again, coming from a regulator, I guess that is probably not too surprising to anyone.
We had to work out how to do these collaborations, first and foremost, legally, but second, successfully to sort of identify the partners that are going to be able to do this without getting criticism and being able to do this productively. That has taken some time. It took a few lawyer hours and those sorts of things. That is now accomplished. I think we now have models in place where we have reformed, productive collaborations. Biomarkers Consortium is here. I know we have had a tremendous interaction with them. Places like that, we have worked out how to work with.
I think the next few years are going to be occupied with sitting back and looking at really what are the best targets for us to do. Again, depending on the kinds of resources we have available to us, we have to have a really hard conversation, and Janet and I have talked about this. We have to be able to say that is a terrific idea, but it is one of a large number of ideas, and we need to find a way to meaningfully decide which ones to engage in to make them work.
We haven't done that up until now because we really wanted to foster that collaborative spirit, talk with a lot of different people, let a thousand flowers bloom or whatever, and it has been a lot of fun, but if our resources are not up to where they need to be, we are going to have to make a process again in place to make those kinds of decisions equitably, openly, transparently, so everybody understands the tradeoffs that we are having to do.
Then I guess the last thing that I think we really need to work on as a group ‑‑ not just us, because I will return to say I think sponsor culture, I think the cultural change here is not simply within the agency, but there is a regulator's value, knowing a pathway, being able to describe it to a sponsor is rewarded. It is should be rewarded. It is a scale that is a good thing to have. You like it when people move beyond that and start asking questions about are there other ways to do it. Cultural changes is a whole other challenge, and I said I wasn't going to talk about it, but it is I think the thing that is going to be required for us to really make this a sustainable thing.
MR. LEINWEBER: Helpful. I saw some other hands.
ATTENDEE: Hi. This question might be best directed to Dr. Calfee.
You presented some interesting new decision on the KSR vs. Teleflex in April of 2007 about diminishing the ability to get patents or things that were considered more obvious and might have been expected from the original patent.
Can you give us any feeling for how that might impact on the patenting of small molecules? There are examples of molecules like Lanzapine which are 3 atoms different from others that have been around for many years before that which were, nonetheless, granted, a patent. Would that change under this new thought?
DR. CALFEE: It might. I will refer you to the delightful drudgery, the Federal Register Notice which is dated October 10th out of the PTO, and it goes through a number of examples, including one that involves Neurovasc, a fairly small prominent molecule.
In some cases, they are talking about a salt of a molecule, and more or less, they are saying, "Gee, wasn't it kind of obvious that you test all these different salts?" or there is another case. In this case, it is someone trying to devise a sustained release formulation of a drug. My impression, that has always been somewhat squirrely for patenting purposes, but it goes through several examples.
I don't want to take the time now to go back through this, but one that I recall is essentially what the PTO said was there are only 50 or 60 different possibilities here, maybe 50 or 60 molecules or salts or something like that, and there's plenty of incentive for firms to investigate all of those. Consequently, it was bound to happen, which means that the results would not meet the new non‑obviousness test.
I don't know how much there is like that. I will say that the first person to call this case to my attention was a well‑known, well‑established lawyer here in Washington who does a lot of FDA work, and he called me within a week or two and said, "Let's get together for lunch," and all we talked about was this thing. His basic point was the one that I tried to make in my talk, which is the patent system is devised to reward coming up with something. It is not devised to reward the research after you come up with it. This is an industry where mostly research is afterwards, and we could have a real problem if we move further towards a system that is concerned exclusively with the effort required to discover something as opposed to the effort required to find out whether that discovery is useful.
ATTENDEE: John, in those situations, if you are able to demonstrate that that salt which might have been an obvious thing to look for was based on unexpected benefit to ‑‑
DR. CALFEE: If it is sufficiently unexpected, yes. Right.
ATTENDEE: And that would be something that would ordinarily be clinically relevant. Otherwise, what difference does it make anyway?
DR. CALFEE: It could be. My reading of this language is that the predictability of the benefit is right now a term of art that has not really been interpreted, and I just think there is a lot to be explored here that we don't know, but at some point, my fear is we are going to arrive at the basic problem which I think of as the aspirin in coronary heart disease problem.
Everyone knows the substance is out there. Everyone knows there is a pretty good chance it has a real benefit. No one has an incentive to research it with the idea of making money out of it. Consequently, it might take aspirin, as we lost 10 or 20 years in which only cardiologists were taking aspirin every day.
MR. LEINWEBER: Good point. Other questions?
ATTENDEE: Bill, just a quick follow‑on to that actually, and this is somewhat for everyone up there.
Patent reform legislation, some people have been pushing it for a few years now, and it is sitting in the Senate Judiciary Committee right now, and the House has passed it, but there are aspects of that, because it was driven by a certain industry which was the IT industry, that may cause problems for what you would consider a longer term type industry like life sciences. So can you speak to that?
DR. CALFEE: Well, they have almost perfectly opposing interests because the high‑tech industry, they manufacture or generate patents at an incredible rate. The half life of a new patent there isn't very long. You have a really neat idea, you get a patent on it, and you go out there and you use it. Within a year or two, someone has invented around it, but in the meantime, you have gotten some use out of that thing, but you start getting revenue from your patent, more or less, immediately. It is incorporated in a product. You are selling a product. It has a feature that someone else doesn't have, and you can get something out of that.
So they really don't have an interest in the system that keeps these patents in force for a real, real long time that emphasizes the uniqueness of a particular patent. This plays out in all sorts of places, including how you calculate damages and other issues, when you can get a preliminary injunction and those sorts of things. In each of those cases, the interest of the so‑called high‑tech industry, which I think is computer hardware and software, et cetera, as opposed to the biotech and pharma industries, their interests are really quite opposed to each other.
Now, where we came out, Barfield and I in our book, was we are probably better off letting the courts sort this out. The courts are quite capable of saying that if a generic manufacturer is going to market without having broken a particular patent, but they think they are going to break a patent, then the owner of that patent should be able to get a preliminary injunction to stop that because, after all, if the generic manufacturer does go to market, he is not going to make nearly as much money as the patent owner will lose in the meantime. So the generic manufacturer, if they eventually lose in court, would not even be able to repay the lost profits.
But in other cases, a preliminary injunction is almost certainly not appropriate, like in the BlackBerry case where I think that was a mistake.
We think we are better off letting the courts sort out how you calculate damages, whether you only look at the damages for infringement, that are associated with a marginal value provided by a patent, or whether you can look at the value of the entire product containing that patent. Let the courts sort it out rather than let Congress set hard and fast rules because our fear is that if Congress sets hard and fast rules, someone's lobbying will prevail, and we are going to end up with something that works well some of the time and works very badly the rest of the time.
MR. LEINWEBER: Thank you.
Questions? Any questions or comments? Ellen?
DR. SIGAL: I want to kind of respond to Doug, and please, I think you are extraordinary. I think FDA does a really good job, generally, but I do want to talk about the reality of what is out there and the reality of what this environment that we live in really happens. It is somewhat anecdotal, but it is real, the issue of the culture of safety. So now we have legislation, but there is absolutely no incentive for anybody in a regulatory environment in this day of The Washington Post or the L.A. Times or the New York Times taking any risk, any risk at all, because there is no reward, and in fact, the pipeline and the decisions that have to be made require more and more and more and more data.
I know that the leadership and I know that many people are scientifically driven and really say that, but the reality of it is they will tell you quietly, when nobody else is there, "Well, you know, I can't do anything because people want more and more and more data. It is not perfect, and this is a very difficult situation," and it is happening. It is reality, and I don't know how to do anything about it.
Then the other issue is this issue of disease models which I know people are struggling with, too. That may be good, but it is almost antithetical to science, where science is going. It is so interesting to figure out how we can solve these issues through being driven by the science and not Congress or not The Washington Post or not five different patients' view of what safety happens, but the reality of it is I think people in the agency are not rewarded for risk, particularly in this environment that we live in, and they say, as an example, in cancer, it is different, but it is not.
Again, please understand I am not attacking you. I think you are terrific, and I think that you and many, many, many others are doing everything they can to ask people to be data‑driven, but it is really a reality of the culture that we live in.
MR. LEINWEBER: Any response?
DR. THROCKMORTON: Well, except to say that we do talk about it. In some sense, you are right, I guess. It is hard to prove the negative in this sense, and other people have written eloquently about the risks to a regulator of approving something too soon versus approving something too late, something where the risk is always in the former. It is the hypothesis that people say. It is if I let something go and I shouldn't have, that is when I am going to get criticized, not if I say no, even though it really did meet the standard.
I guess I go back to process. I go back to being sure that the agency, the leadership, the people in the places that are making those decisions are talking about the standards and talking about what it really means to have sufficient safety. Safety standards do change over time in therapeutic areas, and that makes it harder.
I came from a cardiovascular world where the first approvals were on 2‑ or 300 patients, tops. Mostly, I think they were sort of anecdotal, open‑label kinds of things. The drugs that we approved for hypertension in the early 1960s are authentically scary if you go back and read the labeling now. You had to be hospitalized because about half the time, you would pass out the first few times you got the drug. I mean really scary stuff, but the disease was so prevalent and the outcome so horrible, we sort of accepted that, and then as we got safer drugs, drugs with fewer side effects, we started tolerating those side effects less. As we came with more efficacy, we were able to sort of move away from those products to an area where hypertension is now quite risk averse. We really have a very safe set of compounds. A new drug with safety trouble, it really is going to have to have some unique advantage.
That makes it harder to have this conversation because that occurs in a lot of areas. The HIV world is a place where we grew from a paradigm where efficacy was necessarily the only thing to really be concerned about. I remember the first time the Act Up stood up and said, "Don't approve this drug. It is too unsafe. It might work, but it is not safe enough." That is a paradigm shift that we have to respond to. You listen to that, and we have to bring that into our own calculus, too, but we are driven by the 63 standards, and we really need to be grounded in that through the process I think, where I am saying the same stuff that I am talking to the office directors, and the office directors are talking to their staff.
John Jacobs who heads that office is really very aware of this, is really very aware of the need to have that conversation and is having it. I mean, it is something that he tries to talk to people about. So I think it is an important issue.
MR. LEINWEBER: Thank you.
One last question back here?
ATTENDEE: Does this risk averse paradigm shift that you are referring to have implications for off‑label use, and if so, what do you think they are? Anyone.
DR. THROCKMORTON: Off‑label use, we don't regulate. So absent an observed safety finding that we feel necessary to communicate to someone, because in that population it is demonstrably less safe for something like that or a new finding in terms of efficacy or whatever, that particular part of drug use we really stay away from.
DR. GOTTLIEB: I think it is probably the case that considerations about how a drug might be used off label factor more and more into regulatory decisions made inside the agency insofar if they believe a drug is going to be used predominantly in an off‑label way once it is on the market, they want to understand the safety profile of the drug in that, even if it is not what the sponsor is seeking approval for. I have to believe that that is factoring in more and more, even though it is not within the very clear regulatory architecture, the traditional regulatory architecture, and I also think that the agency is going to be called upon more and more in the future to promulgate risk management plans to try to mitigate some of the off‑label use, where the risk benefit profile might not align as neatly or as favorably in the political calculus of Washington.
I think now that the risk management architecture is part of the law, I think there is going to be political pressure to use it. I am still waiting for the first congressional hearing when someone from FDA gets hauled up and there is a certain drug side effect and Congress says, "We gave you the authority. Why didn't you use it?" I am still waiting for the first hearing when someone gets hauled up and they say, "Well, you put the risk management plan in place, but did you audit to make sure the company was actually making sure doctors were complying with it?" All that stuff is going to happen. So I do think this is going to be an issue.
DR. SIGAL: Let me add to that. I agree with Scott fully.
The other issue is with off label. We are kind of evolving, but in cancer, most of our drugs are off label, and you see this now as in the payer, the Medicare and reimbursement side of it. So there is dramatic impact on that right now, and it will get worse.
Closing Remarks
MR. LEINWEBER: I will let that be the last word.
I want to thank all of our panelists. Please join me in thanking them.
I also want to thank you for joining us on behalf of Research!America and PhRMA. We really appreciate your participation today.
Dr. Zerhouni this morning shared a quote with us, "The greatest risk in science is to stop taking risks." I think we have heard a lot this morning and this afternoon about why it is so critical that we are in an environment that allows us to move forward and take risks to advance health and transform medicine.
So thank you again.
[Applause.]
‑ ‑ ‑