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FOR FURTHER INFORMATION: Helen K. Chang, 650-723-3358, Fax: 650-725-6750
Remarks by the 2005 International Development Conference Panel on Medical Innovations
February 26, 2005
Moderator Panelists Douglas Holtzman George Rutherford Katherine Woo Nzeera Ketter |
Vera Kallmeyer: I got appointed to this yesterday night so bear with me when I use just my historic passion for infectious diseases. Now I really think infectious diseases are very important and not only for us. I worked in a flu company and when they argue whether flu is a neglected disease or not and whether there are better ways to treat it, as we can see in this flu season. But before I go on, I would like to have the panel introduce themselves, both who they are and what their organizations are. And after that we will have a series of prepared questions and of course this is interactive, so if any of you have any questions, please don't hesitate to interrupt us.
Douglas Holtzman: I'm Doug Holtzman, I'm a senior program officer at the Bill and Melinda Gates Foundation in the infectious disease group. First I'd like to thank Dr. Okiasu and the organizers for inviting me to participate on the panel. It's really a great honor to be able to come here to represent the Bill and Melinda Gates Foundation. I'm a relatively new employee, I've been there for less than one year. And one of the most exciting things about my position is that I can interact with people like yourselves that are dealing with big issues in development. For a research scientist who has spent six years studying one molecule, it's kind of nice to speak to and learn from people who take a macro-view. It's really very, very informative.
And so looking over the assignment that was given the panel I kind of slump my shoulders a bit because there's really no way for me to describe in 5 minutes what the specific activities of the foundations involved in the global health space. I don't think I could do it in 50 minutes and if I tried I would suck all the oxygen out of the room, I'd be speaking so fast. So rather than go through a laundry list of grants and projects, I thought that the informative thing that I could do would be to share with you some of the underlying philosophy that drives all of the activities at the foundation and to touch on a few examples of some of the partnerships we're involved with as illustrations.
Across the entire foundation, and that includes the Global Health Program as well as the Education Program, the Library Program and the Pacific Northwest Program that are not relevant to today's conference but are all extraordinary programs in their own right, the driving force is the benefactors' desire to reduce societal inequities. And for the Global Health Program, that translates to the simple but I think profoundly inspiring vision which is to ensure that a child born in the developing world has the same chance for good health as a child born in the developed world.
One of the key goals, which as I understand in the field of health development may be a little more controversial, is to build on advances in science and technology to save lives, improve health and reduce disease in the developing world. And I say that it might be somewhat controversial because I understand that there is a school of thought in the development camp that sort of rejects the techno-medical approach and perhaps we'll return to that issue later on in the question and answer. The reality is that we have living benefactors and this is their vision that we are executing on and there's no guesswork involved. We really know exactly what they want and it's terrific because they are there and very present if not on a day-to-day basis, they're presence is felt.
So rather than starting with what we do, I thought it might be instructive to describe what we don't do. So first of all on the most basic level, we don't actually do the work ourselves. Everything that we do is in partnership with implementers and some of them are sitting here at this table. We're fundamentally a granting agency although I would argue that we have some very important differences with other agencies that you may be familiar with like the World Bank and USAID. In addition, much to the consternation of some of my friends in the life sciences, we don't fund basic curiosity driven research. And we're not looking to compete with the NIH and we recognize these activities are essential for innovation but it is not in our mandate as defined by the benefactors. We also don't build hospitals and deliver health care and do a lot of the capacity building which are issues that have been raised at the table. And even though we agree completely that this is essential, we feel this is really the job of governments to help provide for the basic needs of their citizenry. And we think that our foundation has an important but a limited role in the health sector and that it's going to take the combined action of all the players in the space to have a true deep and sustained impact of infectious diseases to improve international health.
Before I move on I want to contradict myself just a little bit here and I want to say that some of you are probably very aware that we're heavily invested in the discovery, development and delivery of vaccines because the benefactors feel that this is an incredibly cost effective way to achieve incredible impact in global health. In fact our largest grant, mentioned earlier today by Vidya in the first panel, and it's GAVI, the Global Alliance for Vaccine and Immunization. And some of you may be aware that at the end of January an announcement was made that the foundation give another $750 million to recapitalize the GAVI fund. So at the simplest level, their goal is to reduce vaccine-preventable deaths by delivery of new and sometimes not so new vaccines to those societies that can presently no afford them. This may sound like a distinction without a difference but there's an important point that I want to make and it's that we believe that the role of government is to help provide the infrastructure to support basic health care delivery. At the same time we understand that we live in an imperfect world so some of what we're trying to do is to deliver the tools and evidence-base to have others understand what can be gained by taking certain actions.
There was an excellent article in the Economist a few weeks ago that describes the foundation. I highly recommend it. I think that he got it exactly right and that if in 15 years the foundation is still playing a lead role in financing vaccine delivery, that will really be a bad thing and it will be a failure in terms of the sustainability factors that are critical to the whole discussion. And I don't think that this is going to be the case, and there's been discussions recently that have been catalyzed by Gordon Brown, some of you may be aware of, in the U.K. about the international finance facility for immunization, which is really a very exciting development in this area. So to narrow the lens a bit on medical innovation—which is really the sum and substance of this panel and my own work at the foundation—I'm going to steal a line that we used to use when I was a Dead-head, and it's with respect to product development for neglected diseases, the Bill and Melinda Gates Foundation isn't the best at what we do, we're really the only ones that do what we do. I want to hasten to add that I mean no disrespect by that. I know there have been other efforts over many years in this area by a large number of groups including TDR at the WHO, including the pharma industry, including other foundations and research institutes.
However, having said that, the sheer magnitude of risk capital that the benefactors have been willing to place in this sector, without any expectation of financial return, is unprecedented. I mean, it's just mind boggling and it really takes my breath away every time I think the foundation and what's going on. From $50 to $100 million for the malaria vaccine initiative, major investments in TB drug and vaccine development, $350 million to support the HIV vaccine enterprise and $450 million to support the grand challenges in global health. It's absolutely stunning and it's an excellent and exciting time to be involved in global health. So to close I want to come back to one point which is the importance we place on partnerships and respect and that includes to our grantees, to other institutions that are in the health sector, and I think most importantly, to the individuals in the developing countries whose health we are committed to improving.
Katherine Woo: I am director of scientific affairs at Institute for One World Health. We were founded in 2000 and we're based in San Francisco. We're the first non-profit pharmaceutical company in the U.S. and we are a public charity which, at our founding, was really an oxy-moron. When we said we're a non-profit pharmaceutical company, people would always stop and ask, what do you mean? Throughout the years we have tried to educate the public about what we really do and I think that these days people are beginning to understand that term.
So let me just backtrack. We were founded in 2000 by Dr. Victoria Hale who is pharmaceutical scientist who worked in the FDA and in the biotech industry. She founded the company because she has a vision that there are drug candidates in the for-profit sector which are not being developed but can be used in the developing world or to treat diseases that are neglected. So the mission of One World Health is to develop effective, affordable, new therapies for diseases that afflict predominately citizens of the developing world.
We are a group of pharmaceutical scientists who are trying to adopt the for-profit corporate model into this social enterprise and apply this in global health. We focus on a number of diseases including parasitic such as schistosomiasis and chagus disease. We're now entering a new phase where we are beginning two large programs, one group of diseases in malaria and also diarrhea diseases. And in malaria in particular, we have a program to produce low-cost, microbial artemisinin and we also have a small program in vaccine. Much as what Doug eluded to, we are one of the grantees of the Gates Foundation as well as a number of other foundations by individuals. Our main role is really to produce tools that implementers can use in global health setting and our core competency, if you look at the spectrum of product development, is in the development area. And we partner both with discovery scientists to bring leads into our company to develop and after the drugs are approved, we partner with NGOs on the ground for the delivery and implementation, very much like the group we heard earlier. So I think that's all I have.
George Rutherford: I'm a professor of epidemiology and pediatrics and UC San Francisco and the director of the Institute for Global Health which is a combined research unit from the medical school at UCSF and the public health school and Berkeley. And I have to say, it's a pleasure to be back at Stanford. The last time I was in this room was at summer school 1974 watching an all-night long Buzby Berkeley revival and I noticed they still don't have a central aisle in this auditorium.
I guess I'm sort of the unlikely role of representing academia on this panel. So I don't know if everybody knows what UCSF but the University of California San Francisco, I'll give you the UC speech, is one of 10 campuses of the University of California, second oldest campus in the UC system. There are four professional schools, UCSF is all a graduate school. There are four professional schools, medicine, nursing, pharmacy and dentistry. Every time I do that I almost always forget one.
Female Voice: Physical therapy?
George Rutherford: No, that's not a school. There's a large graduate division and a massive basic science enterprise, sort of on the level with Stanford's basic science enterprise. The public health school with which I do a lot of my work is actually physically at the Berkeley campus, although there's some odd strings attached from UCSF that have some historical interest only. Our group, the Institute for Global Health, was founded in 1999 by Richard Feachem who's now the executive director of the Global Fund for AIDS, TB and malaria and on leave from UCSF, along with a few other people. And we have a group of 12 full time, geographically-based faculty members at the Institute for Global Health.
There's a larger group of about 80 other faculty members from UCSF, Berkeley, UCLA, Lawrence Livermore, Lawrence Berkeley labs who are also part of the sort of grander scheme of things. We concentrate primarily on translational research and there's a sort of tension that's true between the last panel and this panel that we feel in our group as well, which is sort of the rising tide raises all boats school of global health, which is if you improve economics, if you can improve basic biology, if you can improve agronomy, if you can improve the transportation systems, all health will follow. And then there's the public health side which this panel represents because we're all in infectious diseases and train in infectious diseases and we're going to, oh, I want to take care of that disease right there. And if I make that go away, like HIV, Zambia's life expectancy will double overnight.
And so we try and work in both areas and do both general health policy research but then also work very specifically in sort of translational research. We have four major trials in the field right now, just to give you a little flavor of what we do. One is a randomized control trial of different ways to monitor antiretrovirals therapy in rural Uganda. The base case for this trial is that people have antiretrovirals drugs delivered in these seven day packs, you know like your grandparents have, once a week by guys on motorcycles that go all over this rural district in Uganda. There's one road, at least I've only ever seen one road there. And we're looking at whether you can monitor people clinically, whether you need to do CD4 counts, so it's clinical versus clinical plus CD4 versus clinical plus CD4 plus [plasma-viralose], [plasma-viralode] technology, has not had tons of investment made in trying to move it towards this reagent-less, electricity-less platform. If you could get away with just clinical monitoring, that would be great. If you could get away with clinical plus CD4, that would be not as great but better than if you had to use plasma-viralode as well. So we're working on that.
We also have another trial that's just been moved from Cambodia to Thailand which is looking at a new, second generation antiretroviral drug called tenofovir which has a long half life and using it for pre-exposure prophylaxis in women in the sex industry who basically in Cambodia kind of come down from the hills, work for a couple of years, then go home with some money and get married. Pre-exposure prophylaxis is like when you guys go out and take malaria pills, it's to keep you from getting the disease so you don't have resistance issues unless you get infected. And there are four of these trials going on, they're very controversial, and ours actually just got moved from Cambodia to Thailand. Almost all of them are going on in women in the sex industry because it's a real high incidence population.
We also have a very interesting evaluation of a sort of experiment of nature with permethrin impregnated bed nets for prevention of malaria in a nation called Vanuatu which nobody used to know of before Survivor had an episode. Vanuatu is, if you draw a line north from New Caledonia and east from New Guinea, that's where Vanuatu is. There are two major islands. Rotary of New Zealand. Rotary is a wonderful organization for public health and has funded most of the polio eradication efforts around the world. They did a big fundraiser to get permethrin—treated impregnated bed nets to Vanuatu, but sort of ran out of money half way through, so these bed nets are essentially distributed randomly through the islands. You can go back down, try and figure out malaria rates, and it's a true evaluation trial.
And then finally we work on a disease called [cocsidio-edomycosis], which unless you're from Bakersfield, you've never heard of it. It's also called San Joaquin Valley fever. It's a big history at Stanford at the Medical School, but I'm sure it's lost in the mists of history. It's a disease that's endemic to the desert southwest of the U.S. and desert northwest of Mexico and also central Argentina. It causes a disease much like tuberculosis. It's badly neglected even though it occurs in the United States and there are probably thousands of cases a year in the Unites States. There are 4,000 reported and that's probably just people who are hospitalized. It's an interesting crossover about fundraising because when we're out trying to shake the trees for essentially very early vaccine development effort, we go to foundations, but because all the desert warfare training for the United States goes on in exactly these endemic areas, we also sort of also play it out of the other side of our mouth that this is a national defense thing, that the Department of Defense should contribute, that we should do all the trials in the Marine Corps doing desert warfare training in 29 Palms. It's sort of the mix between the bio-terrorism world which some of us have to live in being in infectious diseases, and the global health world. So, that's the fourth little project we have going on. But it's a pleasure to be here.
Nzeera Ketter: I'm the director of efficacy trials at the International AIDS Vaccine Initiative. Our goal is to develop a safe, efficacious and available and accessible vaccine for the developing world. And I come from an infectious disease background, pharmaceutical industry and now a not-for-profit, so I've had a taste of all three.
The International AIDS Vaccine initiative was constructed really to accelerate the development of an AIDS vaccine to prevent HIV and AIDS. And in terms of innovation, it really it is a trickle-up development program in that unlike previous vaccines where you start in the developed world and you find the molecule, you do your phase one trials and then you go into larger and larger trials till you became FDA approved, and then you think about the developing world. The time to actually getting a product to the developing world is 10-15 years. It could be more, could be never depending on whether people see this as an income-generating project. We, on the other hand, have decided to do trickle-up development which is start with the developing world and work in parallel with developing countries so that they're both doing things at the same time, shortening the development time. In fact, we are now working in several countries in Africa: Uganda, Kenya, Rwanda, Zambia, and South Africa. We're also working in India. And using in the vaccines that we're working with the very strains that are present in Africa, rather than the B strain from Europe and North America. Combination products in the end will be the way to go, we think, but we're starting there rather than ending there. I think what's innovative about IRV is that they've really taken the energy from public-private partnerships and our very sort of enlightened funders, the original funders, the Gates Foundation being one of them, Rockerfeller (Foundation), governments of very small countries like Ireland and Holland and the European Union, and putting that energy into creating a very different atmosphere for developing new products.
We are very focused on one goal which is an AIDS preventive vaccine. However, how we implement it is innovative. We are thinking about how to integrate communities with governments and people eventually release the product and allow it to be uptaken by the community as the driving force to develop these products. So, my job is varies from designing the study in human beings and creating an environment for doing large scale efficacy trials in 10-50,000 volunteers to actually trying to figure out how to do that in these countries. So we develop these partnerships with groups that are actually working in those countries. They may be very small to start with and then expanded from this center of excellence that grows into a more and more diffuse, community oriented clinical trials network so that where the rubber hits the road, it is more visible and believable for the community at large.
I've been seen to go in Landrovers to visit chiefs of villages who are wearing a bra with a bone in their nose and talking to me about AIDS vaccines. I remember going to a place and being told there's a lot of stigma, you have to be really careful about talking about HIV. People will shun you if they think you are working in HIV vaccine research or even working in HIV. And with that sort of nervousness, I went with the malaria team. Malaria is sort of well known, they've been there for 36 years, they see this as the magic pill, the impregnated bed nets, it's working, although, newer and newer drugs are needed. So when the chief asked me: "And what are you doing here?" I was very nervous and I started to hedge a bit and I said "AIDS" and "a vaccine" at the tail of sentence. And he said, "When are you going to do this?" And I said, "Well, we're trying to organize and beating about the bush." And he said, "Well hurry up because my people are dying."
I think that was the signal that I needed which is everyone who tells you there are all these problems out there and you can't start or you can't go there because there are these hot-button issues are often not listening to the people. The main thing I would like to tell you is, when you go out in the field and you want to start something or develop something, listen and look and watch because while you're doing that, you can figure out what is needed and you can glue it together. And you can make readjustments as well.
So what do I do? I design these studies and then I start to prepare communities and environments for clinical trials. Clinical trials require a huge array of things to be in place all at the same time to make it possible and the quality has to be so high that you can actually get it approved and get it eventually manufactured and delivered. Because it doesn't matter how good you think it is, if it isn't good enough to be approved then you've wasted your time and many years and many lives. We have to start with governments of countries, getting all their appropriate permissions, getting all the regulatory permissions, finding people to work with that are scientists, physicians, nurses, community workers, and then finding a community that is beginning to be receptive. They're not always receptive at the beginning but you can start a sort of expanding, energetic approach to how you do things. And then figuring out how do I make this community get mobilized and how do I then support the system to allow us to do high class, good quality, HIV vaccine prevention trials?
You often need a lot of epidemiologic data before you can even start a study. For instance, what is the incidence or the number of new cases per year because if you're designing a big study, you need to compare the number of new cases in a placebo arm versus a vaccine arm before you can actually get a statistical analysis of whether this vaccine in quotes, works, or prevents against HIV infection. In many places there's no such data. You actually have to generate the data and create studies that allow not only the accumulation of this data but the development of the infrastructure, the capacity to do this kind of research and develop it to the point where in a couple of years you can actually really do such a trial if there is a vaccine available. In the mean time, the R&D folks are developing with private industry these new molecules, these new vaccines and we are preparing the field in parallel. We are not doing it sequentially, we are doing everything in parallel to shorten the time.
I think that one of the things I'd like to emphasize is that there are some very basic things that are necessary when you start such a study. For instance, volunteering, counseling and testing is the common final pathway into vaccine trials. You take people who are HIV negative and enroll them in a study and then vaccinate them, etc., etc. But in the process you identify all these HIV infected people who didn't know they were infected so they need referral networks to go to for care. You identify pregnant women who have never had prenatal care so you've got to have those referral networks in place. You might find people who are pregnant and HIV infected who need prevention of mother-to-child transmission. You will diagnose sexually transmitted diseases, and need that infrastructure to take care of them. You will find that they have TB and malaria and diarrheal disease and all those other things.
We cannot work in a vacuum, that is for certain. We really have to have a comprehensive approach. What we are trying to do at IAB—and we are actually new at this, we've only been at this a year and a half—but what we are trying to do is build a program for high class clinical research and the use our equipment and our space and our expertise to provide the excess capacity to other groups who are actually working in the same community.
As an example, our clinic rooms in the afternoon are used by the HIV treatment people to do operational research. The treatment people also use our CD4 counter. When we're doing research studies we do 100, 200 a month whereas the capacity is several thousand. So we donate that excess capacity to the treatment folks. In the meantime, the treatment guys take care of our people who become infected or who have been identified as being infected. In the same building, we have donated three spaces for tuberculosis, sexually transmitted disease care, and prenatal care and family planning. Those things are intimately integrated into everything we do because if we don't take care of those diseases within that community, we are doing something that's considered icing on the cake, not the cake per se. We like to think more innovatively about the community and what they need and then put what we are trying to do with them on top of that. In the process, educating community about research in general, about vaccines in general, about treatment in general has actually provided the environment for childhood vaccination update to be better for volunteer counseling and testing to be better in the whole community, not just the people who will participate in clinical trials. We're trying to think of it comprehensively, trying to partner with other groups such as Global Fund, CDC and people who deliver care, but also with universities who provide additional capacity and training.
I just want to end with what I really do. I spend half of my time setting up these research programs and actually conducting the research, but I spend another third of my time building buildings, putting in electricity, putting in wells and power and ensuring that there is safety, things that a physician is not trained to do generally. And one realizes that you have to rise to the occasion and really tackled much more than you would have otherwise. Making videos to explain research but also HIV and what this disease is all about to people who don't read and write. So now I'm a film maker and an electrician and a few other things.
The thing that is most frustrating, and I should probably end with this, and that is we received funds from many places and some of these funds are unrestricted which allows some flexibility. So it allows us to react to our own experience. We are always collecting data and re-evaluating how we're doing things so that we can make adjustments quickly. If the funds are too restricted, then you can't make these adjustments easily and they stick you in a very rigid box. There is a lot of money for many things and everyone has jumped on this bandwagon of training. Training is the be-all and the end-all of it. There's plenty of money for training but there's no place to train somebody and there's no buildings to actually manage patients so that people can actually train in a real environment as an apprentice rather than from a book and from a screen. So I think we need to think about physical plant, this is a hole, this is a real gap in funding where outreach clinics.
Vera Kallmeyer: I think in fact it's quite fascinating to hear how diverse these organizations are because you know from my perspective with neglected diseases, I think there are various definitions. The first definition, I think, which is the most widely accepted is neglected disease are primarily tropical diseases. In fact there are all kind of statistics out there that over the last 25 years there have been about 1,400 drugs approved but only 16 for these neglected diseases which count tropical diseases plus some tuberculosis. In fact there are other statistics that say because the pharmaceutical industry is so profit oriented, a compound will have a 13 times higher chance of approval if it's cancer or cardiovascular related because the profits are so high than if it's infectious disease related.
Looking at these at the various ranges of activities of these organizations targeting neglected diseases, what do you consider a neglected disease? Is it a tropical disease like sleeping disease, etc.? Is it really targeted maybe for the clinical need? And then the question is what do you count with that? Would it include bird flu in Asia, or HIV? I ask myself, is HIV really a neglected disease or is it really targeting poor populations that just can't afford drugs that are available. And so back to the panel, with the HIV vaccine effective, it is pretty clear that the top priority is HIV one, two and three? But with all the other groups, what would be your definition of a neglected disease plus your one, two and three targets that you think are the most neglected and ought to have the most attention?
Douglas Holtzman: That's an easy one, it depends on where you're sitting. The malaria guys look up at the HIV guys and they say, man they've got it made. They've got more money than they could possibly use. The worm guys look up at malaria guys and they say, if we only had it as good as malaria. So we consider them, and by the worm infections I mean onchocerciasis, I mean lymphatic filariasis, I mean loa loa, I mean helmenthic intestinal infections, things that don't get almost any attention. And so at least at the foundation, there are the big three, HIV, TB and malaria. Frankly to some degree, when I talk about it, at least in my own role as a program officer in the infectious disease group, we talk about neglected diseases or diseases of neglected populations, I'm actually referring to that other set of diseases that gets almost no attention, like trypanosomiasis for example.
Katherine Woo: Yeah, I completely agree. And we are focusing on anti-parasitic disease such as kala-azar. I mean a lot of people would look at the malaria folks as well and say, you guys are really well funded now. There are a number of criteria that go into selecting a drug to develop and that's sort of tied to the disease. Obviously where you are effects what your choices are but from our perspective we first ask whether there's really a need for a new therapy. Now a number of diseases that are neglected by definition also could be ones that have no effective treatment currently or there are treatments that are ineffective or have toxic side effects.
So that's one criteria. Once we identify the disease that we want to look into and identify the drug that we want to make, then we ask the question: Can we find a candidate that could provide increase efficacy or can we make a safer version of what's out there? Can we make something cheaper and also can we make something that would encourage people to use it more, to be more compliant? And it's really a mixture of factors that go into deciding what disease to go into and that kind of drive our decision process.
Vera Kallmeyer: So how exactly do you prioritize? Is it clinical needs, is it the impact of how many millions of people are infected?
Katherine Woo: Not necessarily.
Vera Kallmeyer: Or is it the availability of targets?
Katherine Woo: Absolutely.
Vera Kallmeyer: I mean, the return of investment essentially.
Katherine Woo: Well it's not a return in investment in a sense that can we identify candidates that can be taken to the people in the shortest path. In some diseases there are off-patent drugs that could be used in another indication. The drug that we're taking forward for visceral leishmaniasisor in India is off-patent, broad spectrum antibiotics called paromomycin that has been used in over the world for the last 30 years. But it's an o-drug, it's an off-patent drug. But it has effects on neglected diseases like kala-azar. So in that sense, we canvass the world for direct targets and then find the ones that could be applied more efficaciously. And then match it with a disease that has a need.
George Rutherford: Well, I guess I'm going to commit heresy here. Basically, we look at these from a public health standpoint trying to match the burden of disease with the kind of availability of treatment. And there's a so-called 90-10 gap where 90 percent of the resources go into the diseases of 10 percent of the population. I think that there are a couple of things we haven't talked about here. One is non-communicable diseases which cause a huge burden of disease in the developing world. And, I was thinking about making some totally toxic statement like, well [Beatrin]'s the most important drug in the world today for smoking cessation. There's massive epidemics of smoking in eastern Europe and China and India, there are huge amounts of alcoholism in large parts of the world. You think of Russia but it occurs in other places.
There are lots of obstetrical problems, maternal deaths remain very high in many parts of the world, which really probably isn't that amenable to drug therapy short of magnesium sulfate, but is more of an infrastructural kind of issue. And injuries, primarily road traffic accidents cause a significant amount of deaths in the developing world. And my most unpopular question I ask when we're out doing this study in rural Uganda was whether the guys on motorcycles had helmets. I don't think anyone had every asked that question before in Uganda. But they did, I was pleased to see.
Coming back to infectious diseases and biology, we concentrate on human disease but diseases of livestock and veterinary indication for antibiotics are very, very, very important in the developing world. And agricultural uses—diseases of plants—are similarly very important. It's a sort of thing that we don't cross over with very much. We do a little bit with veterinary applications, but it's something that I think it's worthwhile to keep if you're thinking of these sort of perfect drugs, especially the wonderful stuff like One World Health does. Some of that stuff comes out of veterinary applications and some of things they find have veterinary applications. If you could something about hoof and mouth disease, you know, you'd be hero. They'd name the U.S. Department of Agriculture after you.
Katherine Woo: The example that was given in a previous panel, Merck donated ivermectin, and ivermectin's actually an approved veterinary drug.
George Rutherford: Yeah, I'm talking about the other way around though. Human drugs for veterinary applications.
Katherine Woo: Okay, sure, absolutely.
George Rutherford: The original mumps vaccine was canine distemper vaccine, just to let you know that this stuff has happened before.
Katherine Woo: I think it's another example you're showing, you mentioned animal diseases cross over. Well there are treatments for animal diseases that could be used to treat other neglected diseases that you might not think about.
Douglas Holtzman: Can I pitch in just 30 seconds more? From the foundation's perspective, we tend to do things that others are not doing, and by others I mean specifically the pharmaceutical sectors. So for example, when SARS came out everything ground to a halt and there was a lot of fear and activity in that sector. And frankly we're quite confident that the pharmaceutical sector will handle that because it effects the bottom line western population.
Female Voice: The 10 percent, right? Who get all the resources?
Douglas Holtzman: But no, I mean even in China. But I mean it had a very significant economic impact that drew a lot of attention to it. So the foundation is less worried about things where the markets are working and we tend to place more emphasis and more dollars, although HIV is perhaps a counter-example of that. But even there, most of our funding is going to HIV vaccines rather than HIV drugs. So again, we tend to prioritize both at the level of disease burden but also at the level of attention.
Vera Kallmeyer: In the neglected diseases, I think. 1. Resources are so limited. And 2. there's a limited number of compounds. Because nobody does research anymore one question would be where do you derive the compounds? The other shortcomings are the difficulty in distribution, especially in the vaccines. I think there are a lot of available drugs, you just don't get them to the people. And so the question is how do you prioritize where do you allocate your dollars to get really ultimately the best return on investments. And I think the Gates foundation is very famous for putting the money into vaccines. But is it distributing the vaccines? Because I think a lot of vaccines could for example reach more people in the southern hemisphere if there were alternative routes—if they were intra-nasal and didn't have to be injected or if they were temperature stable and wouldn't need to have refrigeration. How do you look at these issues and is that sort of a short term goal that you think you can accomplish? Five years from now, what do you try to accomplish with your organizations in your work today, and how did you decide on those goals, and how achievable are they? May we start over there on the HIV?
Nzeera Ketter: Yes. I think that we all thought that prevention and treatment should really go hand in hand and one cannot be separated from the other in communities when multiple people are affected by many things. I think this is a tough goal. I think it's going to take many years. But I think the risk is of not doing it.
Vera Kallmeyer: What is your five year goal for your organization? What do you think you'll have done at that time?
Nzeera Ketter: I think we will probably have screened at least 10 to 15 vaccines in pre-clinical testing, at least 10 or so in animals, at least 6 or 7 in humans. And hopefully we'll have started at least one efficacy trial. And that just shows that the pipeline shrinks as you go down. The last efficacy trial was done nearly eight years ago and we're still waiting for the next best vaccine to start a new efficacy trial.
George Rutherford: Actually, what we're trying to do in academics, this is completely off the point, we're hope to have a doctoral program established in global health sciences at UCSF. We would give jointly with probably four or five developing world institutions where it would be—to use a baseball analogy—kind of a home and away deal where people would come to UCSF for basic sciences and then go out to say the University in Dar es Salaam, Tanzania for a research year, and then come back to write dissertations. Or if they're from Tanzania to start with, to stay there to write their doctoral dissertation and to have joint faculty and stuff. While I agree training is an issue, there is no shortage of training around the world. But being in the education business, I guess we have to sort of say that education's good. And that's kind of one of the things we're trying to do to really create some structures that move technology and academic expertise into the developing world a little more than it has been before but in a way that doesn't create brain drain, which is a huge issue over on our side of the street.
Vera Kallmeyer: One World Health. Five years from now?
Katherine Woo: Well there are a number of things we hope to be able to accomplish in five years. We just completed our re-clinical trial for treating kala-azar in Bahar, India for a drug called paromomycin and we are hoping that that would be register for use next year and distributed to the hands of the patients next year. So at the end of five years, I'm hoping that we'll be making impact in this disease in at least the Indian subcontinent. Another thing that we hope to be able to accomplish in five years is we just began a new program in producing microbial artemisinin in collaboration with UC Berkeley and a biotech company. And the goal of this project is to produce a stable source, scalable source of artemisinin derivatives that can be used in artemisinin combination therapy. And as some of you might know, that's the therapy that's been recommended by WHO as well as the Institute of Medicine. You get artemisinin these days from worm wood plant, you extract it with a very organic process that has really low yield and it has a lot of impurities in it. And because of the world wide demand for malaria treatment, there's actually a critical shortage of artemisinin being available to be put in a medicine. In fact, I remember an article in the Economist that said half of the needs this year have not been met. Farmers in countries that grow wormwood are jacking up their prices and increasing the cost of these drugs that are being recommended to be used. So there are countries that normally would be able to afford Artemisinin combination therapy are not able to do so because there's really not enough supply out there.
Our goal in this program is to be able to find a way to stabilize the supply. And also by substituting a synthetic process to create Artemisinin rather than extracting from natural resources, we're hoping to be able to meet global demand as well as drive down the prices so that the combination therapy will be much more affordable to everybody. And that's just two programs that we have and we're also hoping to embark on a number of clinical trials to look at treatment for pediatric diarrheal diseases.
Douglas Holtzman: Again, it's really not us, it's really sort of the work we're supporting around the globe. I'd say one of the most important things that I would really hope to that would happen in the next five years would polio eradication. Many of you know about the situation in Africa, how there were cultural clashes and a resistance to some vaccination programs and that it sort of fanned back out. The WHO group is really charging on that hard.
To speak to new technologies, one of the grants that I was involved in sort of writing up the support for, that's what I do as far as my role is to sort of analyze technologies and review the grants that come our proposal and things like that and make recommendations to those who make the decisions. But we supported a grant for the development of a mono-valent polio vaccine. So despite sort of best efforts, they've been unable to break the transmission chains and some high, intense transmission area including India and Egypt in particular. So we're supporting a program to sort of go back. Instead of having a tri-valent vaccine which works well when you're healthy, but not so well if you've got diarrhea, etc., etc., to use a mono-valent vaccine to break the transmission chains. It's a little bit technical but I thought I would throw that out as a sort of medical innovation because that's the focus here.
We are the program in nasal administration of measles. Measles is like the classic case. In some ways it's sort of the canary in the global health mine. This is a 20 cent vaccine that's very effective and 500,00 kids die a year in Africa of measles. This is just unacceptable. There are these delivery issues and again, we're technological folks, so while we support other types of approaches, one of the grants we have is to develop a measles vaccine. Some of you may have heard about the grand challenges in global health. If you haven't, I encourage you to go to the foundation website. Really fantastically interesting set of activities where again, we're not trying to control the agenda, we're really just trying to sort of stimulate and catalyze the agenda. A group of big heads decided these are the kinds of things that would make a huge difference in global health and came up with 14 ideas. Proposals came in, there was a final sort of winnowing down, and there some that I know that address the issue of sort of thermal stable vaccines and what that would do to eliminate some of the cold chain limitations that we find with some vaccines. In a very concrete way the area that infectious disease takes care of, some combination therapies for malaria. MMV, The World Health Organization's Medicine for Malaria Ventures and a grantee of ours, is much like Malaria Vaccine Initiative. They've been very successful in moving products through sort of a real corporate type portfolio. We expect them to have some things out to the market and I am the malaria vaccine initiative program officer. I think that five years would be great, but there's a lot of work going on with collaboration with a GlaxoSmithKline (GSK) product and it may be, cross our fingers, in the next five to seven years you would see the first licensed malaria vaccine with at least limited but convincing efficacy.
I think in five years time, we as a community in global health should think about re-engaging for a for-profit pharmaceutical company to come back into looking at some of these neglected diseases. And how do we do that? That, I think, is an area where some of you in the audience could try to innovate partnership structure, innovate organization and maybe pathways to enable companies to participate in the trickle method that was discussed earlier so that medical innovation when it's developed can be applied in parallel both to developing world and developed world.
Vera Kallmeyer: I think it's an important point you make and I think Doug said to me earlier: Ultimately the resources are so limited that even the Gates Foundation can't really do enough. You have to have to invest and shame others into doing the same. And it's true. Ultimately the money has to come from the for-profit world. You mentioned GSK. I think they made a very interesting proposal to say in exchange for us developing drugs for neglected diseases, please extend our patent life for the diseases where we sell the drugs to western world so we can essentially share the cost burden of disease. We basically develop drugs that we won't make any money off but instead of having 13 or 17 years of patent protection, give us 25 years of patent protection on something that we can really earn money on. And I think they're considering that which may be one way to look at this—that everybody pitches in. I don't know whether any other initiatives are underway but that's one in the U.K. that I heard of.
Douglas Holtzman: It's already true that many of you out there in the audience are subsidising the pharmaceutical activities for the rest of the world. That is to say that the patent system, the way it's structured is a very, very complicated discussion to get into here. But I worry a little bit about that because I worry you already hear about grandmas up in Vermont who are driving over the Canadian border to get drugs. I don't know how receptive the U.S. public is going to be to extending patent life on certain drugs. The pharmaceutical industry has undergone a tremendous change and today are sort of all wearing a black hat. They're almost view as the tobacco industry right now.
I spent the last 10 years of my life in start up bio-tech companies, so my passion is for global health but at the same time I appreciate how difficult it is to develop products. I mean this is a very, very, very hard thing to do and it's not to say that the pharma guys don't play around at the edges in terms of the patent system and all that. In my own experience and in the training, I think there's not always been an appreciation for the fact that these guys did not cause HIV and that there's a need for all players. There's a need to create the proper incentive structures. And that's again what we try. We try and sort of lower the hurdle so that maybe they wouldn't spend the time to set up an insectary and find the right antigen but if we can help them through collaboration with academics to identify the antigens well maybe they would then go ahead and use their know-how and their skills to develop the vaccines. I'll just to sort of throw that out there as something to think about.
Vera Kallmeyer: Well, I think we see a lot of that in HIV because that's a disease that's not only affecting the people in the developed world. And I think that sort of leaps to the last question: How do you solve the ethical issue? For example, to test drugs in the poor communities in a very cost effective way then they should work and be safe and be efficacious, and of course we sell them here at a profit. But how do you solve the ethical issues of drug testing in Cambodia, Thailand, or wherever without having parallel trials in the U.S.? Maybe that's a question to you.
Nzeera Ketter: Yes actually, I think International AIDS Vaccine Initiative (IAVI) was founded with the understanding that anything that's tested in a given country will also be accessible to it at the end of the game. The relationships and the public-private partnerships that we make put that piece into the agreements at the front end. What industry is very good at doing is manufacturing and what we as NGOs are not very good at doing is that one thing. So we could take it to the go-line and then have them manufacture at a much lower cost than we could possibly do because the basic infrastructure is already there. The factories are there quite often and all we need is slots. But the arrangement has to be that where you test them, you have to make sure that there is forethought into access at the end of the road. And access is part of the first line of IAVI's mission.
Vera Kallmeyer: So it's access after the trial but what about during the trial? I mean, you have a drug that may not be safe that may never make it to market but a lot of people die from it. And it hasn't been tested in any rich nation.
Nzeera Ketter: You're talking about safety issues particularly. I think you should run trials like you would run them in the U.S. and you have to be very vigilant about safety issues.
George Rutherford: One of the basic principles of medical ethics is that you share the benefits of a potential therapy across everybody at risk and everybody who has the disease and you also share the risks of potential preventive therapies or prophylactic therapies like vaccines. I can tell you for this tenofovir pre-exposure prophylaxis trial there's a U.S. study that's happening in the Castro district of San Francisco and also in Atlanta. For our cocci vaccine trial, when those go on, we will probably test those just in the United States rather than in Mexico. We might have a Mexican arm, we might not. If the disease is here in the U.S., standard of practice is that it will be tested here in the U.S. as well as in other places which may have incidence. You may get to the end points faster. but nonetheless, the standard is that you test them here as well. Where the diseases don't occur in the United States, like malaria, then obviously there are some issues of efficiency.
You can't put all 300 million people in the world with malaria in a box and sample 1,000 of them randomly. You have to do it in a handful of places and you try and do it as efficiently as possible. To run an inefficient trial where you waste time and you waste money I think is equally unethical. Running trials in populations that have very low incidence just to sort of make it convenient for you, while there's a population in some other country where you could reach the endpoints of the vaccine trials much more rapidly or whatever trials much more rapidly. I think that's a real basic ethical issue as well.
Vera Kallmeyer: I agree. Any questions from the audience?
Q: Yeah, I apologize for the specificity of this question but I really was interested about a point that Mr. Holtzman brought up. One of the things that you're funding is the global HIV/AIDS vaccine enterprise. I was wondering if you could speak about that and also if Dr. Rutherford and especially and Dr. Ketter could speak about how that's going to work out. I know it's a pretty big system that's going to change things as far as vaccines and such goes for AIDS.
George Rutherford: It's going to work out just great. So first of all, I'm not in the HIV group but I think I can at least speak to your question. The vaccine enterprise, the concept there is we're trying to transform the way things operate sort of at the academic and industrial interface. So normally what happens is there's a lot of: We've seen the enemy and it is us. I mean people, because of very legitimate reasons of self-interest, work on their own project—they have their data and they need to publish it if they want to be a professor at Stanford, etc., etc. But that means that a lot of failed experiments don't get shared. It means that for a lot of successful experiments, it takes another year or two for them to get published so someone can try and build on them. There's a lot of implications for that so what we're trying to do, I guess we heard about carrots and sticks and all that. We're trying to lay out some very juicy carrots I think to get people to cooperate and to try and tackle what is one of the most important issues of our time in the most effective way possible.
So there are a couple of things that have been put out there in terms of these requests for proposal that just got announced two weeks ago that I mentioned briefly. $350 million has been pledged by the foundation to support collaborative research efforts that will involve cross-group activities in order accelerate HIV vaccine research.
Nzeera Ketter: I am actually on the committee for the enterprise and the way the enterprise was set up was by taking people who are interested all across the globe and actually putting them into the same room and letting them find these synergies. And there are lots of large cooperative efforts that have come out of this relationship and having the funds in one place to actually build this collaborative environment will accelerate things for sure. Now, for instance, a clinical trial site, I have six. But the NIH has another 10 you could do the trial in one year or two years instead of 15 years if you did it by yourself. That hugely accelerate everything. So if we could share, do one vaccine in all the clinical trial sites and use the same system to collect the data and analyze it, we can all benefit by the acceleration of time and time to approval.
Nzeera Ketter: Terrific. There was another question over there.
Male Voice: I wanted to follow up on what Dr. Rutherford was saying about chronic diseases because that has been really ignored here today. And I want to begin by trying to correct a misconception that you might have if you read the description on this medical innovations panel which says that infectious diseases account for only 1 out of 10 deaths in the world's richest countries, yet among the poorest people, developing countries presumably, 6 in 10 still die of infectious diseases according the WHO. The implication there is that infectious diseases is really the major problem and these chronic diseases are not really that serious yet in these developing countries. And that's an incorrect perception. Dr. Rutherford referred to traffic accidents. That's a huge problem. I was in India last year, 100,000 people die from road accidents in India. That's more than die from infectious diseases.
Now I'm not saying criticizing the Bill and Melinda Gates Foundation for spending huge amounts of money developing vaccines, but I'm saying where's the money? If I ask you for $50,000 to develop a road safety program for India or a heart disease prevention program that will save a million lives, your response would be: There's no vaccine so we're not going to fund that. And again, I'm not criticizing that, that's terrific. These vaccines are important but where is the resources to deal with really what are going to be the more important health issues in the world—that is heart disease and cancer and diabetes which are already the major killers in countries like India and China. Where's that money?
Douglas Holtzman: I'll take that as a critique then, not a criticism and I'll just say again—I went to Harvard School of Public Health, there's a huge, huge program on traffic prevention and so I'm very familiar with the stats there. I think that we're really looking to target the most vulnerable populations and we're doing it on the basis of the vision of our benefactor. I can tell you frankly, my uncle was pitching the issue of water bags three weeks ago. Water is a huge problem. Clean water, access to clean water, this a big deal. But it's just not in our mandate right now and I really want to emphasize that we do what we do and we're not trying to say that what we do is the only thing that's important. I can't over-emphasize that enough because obviously where the money is, that's where the attention goes and it's not meant to be that way. It's not meant to exclude other activities. If you want to consider motorcycles helmets as a medical innovation, you know let's go, let's get it out there. There's no problem. But this is what we're focused on.
George Rutherford: I think the other thing to think about is that a lot of these infectious diseases are diseases of young children and infants and as Dr. Ketter whispered in my ear, we kind of have to get them out of childhood before they can die of cardiovascular disease. I'm a pediatrician so I think this is as good a place to start as any. A lot of the stuff that I was talking about in terms of chronic diseases is infrastructural things like better obstetrical care and transport services. The way you do secondary prevention for road traffic accidents is to have somebody swoop them up, pick them up in an ambulance and bring them to the hospital within the golden hour. And that stuff's just not there in most countries.
My wife's the chief of ER at Oakland Children's. We were 20 miles outside of Capetown, the heart of developed South Africa, the most developed part of the continent without a doubt. There was a traffic accident in front of us, a guy dislocated his shoulder and somebody else had a tib-fib fracture. It took an hour for an ambulance to come. Absolute heart of South Africa and I became really convinced about road traffic accidents and then a subsequent trip to Ho Chi Minh City with the motorcycles 20 abreast lined up at the red light without a single helmet in sight sort of tipped me over the edge. They are important things but some of it involves health care delivery like the obstetrical stuff and trauma care. That takes a massive investment and even in the Latin American countries that are really quite developed, that investment is still lagging. The engineering things and the legislative things that go with the profession of road traffic accidents, that's another completely separate investment. And the economy has to catch up with those kinds of programs. It just doesn't have that magic bullet.
Vera Kallmeyer: Sorry to say but I think we're at the end of the very interesting session. Thank you everyone and I think it should be inspiring to everybody that there's of places for innovations.
Closing Remarks
Peter DeYoung: I'm Peter DeYoung, I'm a student at the graduate school of business and I was given the dubious honor of trying to summarize five hours of great discussion in one minute. So I guess I wanted to first thank the excellent speakers we had here and all of you for participating. I think this was a really great discussion. And then I wanted to draw on the three inspirations behind why we held this. We wanted to try and bring a realistic picture for all of you as to what's actually happening in the world right now in terms of bringing access to global health. The second thing we were looking at was based around hope and that we wanted to try and look at what are the new innovations in medicine and delivering and funding that can change where we are today to where we want to be in the future. And finally there is action. How can we translate this hope in terms of these new innovations to changing it so that the reality that we're at now is not where we're going to be at 5or 10 years later.
More personally, how can you improve health through what you do. How can you think about doing a student project. How can you think about doing an internship or trying to integrate global health into some aspect of your career either in the immediate future or in the long term future. So along those lines we have some student panels organized, some in this room. I think there are three if you go out here to the right. And in the descriptions of who's in what panel was in your program, so you can look that up. But also of course a shameless plug we have, a brief description from Mindy about SAID and what they're doing on campus.
Mindy Doe: My name's Mindy Doe and I am one of the co-presidents of the San Fran Association for International Development. I also want to thank all of our speakers and thank all of you for coming to our conference today. I want to echo Pete's comments on becoming involved in those development issues that you have been inspired by. I'm sure as we've listened today to all the speakers we've begun to think about our own future careers in development but I'd like to remind you that you can start becoming involved right here on campus. And I'd like to make a shameless plug for SAID. Lauren Rodriguez and I will be available after the conference to talk about your interest in becoming involved or taking a leadership role in SAID next year. I guess on that note I'd like to ask everyone to join me in thanking our speakers again for coming out today.
Related Links
2005 International Development Conference
Remarks by the Conference Panel on Delivery Innovations