Potential Stakeholder Roles And Incentives for Participation

Very good morning to you all and welcome to the third and final day. This particular session is going to be on the potential stakeholder roles and incentives for participation. I’d like to call on our first speaker that is Dr. Maria Elena Bottazzi, who’s the Associate Professor and Vice Chair of the Department of Microbiology, Immunology and Tropical Medicine at the George Washington University. Thank you Dr. Bottazzi. Hi good morning everyone. Thanks so much for the invitation, the organizers, Dr. Puren. I have to apologize Dr. Peter Hotez was not able to attend, so he sends me in representation. After talking to him, we’ve been trying to look to see how we could provide some insight of what could be potential stakeholder roles and incentives for participation specifically for vaccine production, for flu. So the way we actually looked at this is that there are certainly some clear incentives for participation and certainly we can go over the roles that we think are important. I’m going to start by showing you this slide that actually shows you that in the recent years if you look at a landscape of where the funding for R&D and specifically for development of biologics, primarily the total R&D funding that it comes from is divided into let say three major funders: Governments, of course, with primary public big OECD governments, but also innovative developing countries have been starting to provide funds for developments of new biologics. Certainly non-profit organizations; we have the representation of the Bill and Melinda Gates Foundation amongst them, where there’s been a big influx of funding. Certainly private: Big Pharma and Small Pharma. But what I think is important to see is that the way that they’ve been funneling the funds is using very specific mechanisms which are to go through what we call the “Product Development Public Private Partnerships”. That’s what I’m pretty much going to focus on, to use the model of PDPPPs as potential stakeholders and what will be the roles that we could play. I’m going focus primarily on the Human Hookworm Vaccine Initiative, which is one of these PDPPPs and how we have built our capacity and how we now can leverage and certainly sustain it by providing our participation in other development of vaccines such as flu vaccines. This is another slide from the Moran paper. Again, it’s just to summarize that the public-private-philanthropic sectors fund through PDPPPs and this is just an example. There’s an array of PDPPPs as well as the Tropical Disease Research, WHO, PATH, etc. But if we go in to more detail, I wanted to focus in those that are vaccine public-private partnerships. You can see some examples of some of the major PDPPPs for vaccine development. It’s clear that in the recent year we have seen clear value that comes out of developing biologics, especially vaccines using this modal. Primarily, as the slide summarizes, PDPPPs tend to integrate and coordinate the different partners, whether its industry, academic, public contractors, and they create this collaboration. I think this is very important. It of course uses business like practices, which for some of us, for instance, we’re in the academic sector, its novel and it’s actually applying how private institutions apply business models and we look to see how we can do those when we work in academic environments. We have certainly continued to apply basic science approaches and now we have moved more forward toward translational type of development by doing more technology exchanges. Certainly PDPPPs also provide a mode of portfolio management, where in fact where they can dictate where funds really go to based on where the program is at a certain point; whether it should go more towards R&D or more to process development, scale up and then eventually clinical testing. So they manage based primarily on relative merits of where is it that the funds should go. Of course they champion also the role of advocacy and also provide where the progress is, certainly also indentify gaps. So I’m going to now try to focus on giving you an example. I’m going to use the Human Hookworm Vaccine Initiative Partnerships. We are a comprehensive program which primarily focuses on recombinant types of vaccines. Of course we not only focus on hookworm now but also an array of tropical diseases which I’ll show you later. We use a network of global partners. We certainly use a model of product development, tech transfer and clinical development. If we look who are our partnerships, of course I represent the George Washington University, which we do a lot of the product development activities, which I’ll show you our capacity. But we work under a big umbrella of sponsoring institution which is really what holds our PDPPP, which is the Sabin Vaccine Institute. They provide regulatory sponsorship and also quality assurance. We also collaborate with institutions such as Queensland Institute of Medical Research, London School, and the Institute of Parasitic Diseases in China. For our clinical testing as well as for our manufacturing we work in Brazil primarily, both with the ministry of health and well as Instituto Butantan. The way that we have established our program is really trying to establish solid partnerships and enhance collaborations with other PDPPPs to eventually provide a clear impact on how to develop recombinant protein vaccines. Of course because we’re trying to develop vaccines for the poor primarily, we’ve certainly have tried to apply local approaches and we use a model for vaccine development that we call “Fast transition to Phase 1”, which is the first in-human model. But to summarize, and I’ll go into more detail in the next couple of slides, we have attempted to do it in different stages. We first had to build the expertise, build the technology, build the lab in field infrastructure, and then we expanded it and tried to leverage it now. Of course eventually we will need to sustain it, to try to diversify our portfolio both financially and also by objectives and certainly start thinking how we will make an impact through our global access plan. So to summarize again, the HSVI has decided to primarily apply the first in-human model for vaccine development. The premise is that we look to accelerate candidate advancement, to go very quickly into Phase 1 clinical trials. We do that by really putting a slightly smaller upfront investment for the actual product development and process development and we focus to very rapidly go into safety testing to try to then down-select those that are safe versus non-safe. Certainly we understand that it is a high risk approach and that eventually those that pass the first stage will have to involve longer development time and have to go back and develop better processes for development of the vaccine for Phase 2 and Phase 3. But it has worked well for us. We have already had one molecule that has been accelerated and we’re almost ready to transition a second molecule into Phase 1. Now even though we’ve used that model, we certainly do not go different from any other vaccine development program. We started at product development we still use the same concepts, we have a target product profile. We create product development strategies and those are what we really focus on at the George Washington University. We of course have done all ready all that discovery but we focus on feasibility, small scale expression, formulation, some quality control, and then ideally, the tech transfer into the manufacturing and then provide clinical development. So very briefly I’m going to go over some of the capabilities that we have established at GW. We’re proud of the fact that we have set up a set of technical units that dedicate specifically for advancing the product development, starting from molecular biology units that focus on early feasibility and expression of our different molecules. Primarily we use both bacterial as well as yeast expression systems, then of course we transition into scale up. Mid-scale we have capacity up to the 10 liter scale fermentation as well as purification. With Purification we have the capacity of doing up to 60 liter scale purification processes. Of course we have Formulation units. Then we have a very strong quality control which includes animal development, animal testing and a pre-clinical and clinical immunology unit. After we have set up the processes up to the 10 liter scale, we certainly have worked with several organizations including Butantan in Brazil, the AERAS TB Foundation and Walter Reed to tech transfer and scale up for manufacturing up to the 60 liter. With Brazil we primarily have helped them suit up a pilot plan that they have up for 60 liter scale. So we’ve been very successful with that in that front. More specifically for the clinical development it’s been a very interesting collaboration with the Ministry of Health in Brazil. We work primarily in the state of Minas Gerais. We picked that region because of the types of the diseases that we work on. We, along with them, developed a clinical field base unit where we prepare and design clinical protocols. We of course go through the regulatory experience both in the U.S. as well as Brazil. We have built a clinic with them. We have prepared the community and we pretty much have the capacity of doing first in-human trials there. So everything that I’ve said, it’s been certainly an endeavor that we’ve been doing for the last nine years. You see where we are right now. So to summarize in the first years and certainly through solid funding that have been receiving and through the Saban Vaccine Institute and organizations such as the Bill and Melinda Gates Foundation, we have been able to really create strategic and strong partnerships. We certainly have developed in house technical expertise for fermentation, formulation and purification technologies as well as quality assurance and quality control systems. We have established good training programs, field site selection and preparation. We have clinical laboratories and certainly we have good program and regulatory management. We now are in what we call the leverage and expansion mode where we continue to strengthen our expertise. We certainly work based on milestones and we always acknowledge dissemination through publications and right now we’re entering a phase where we’re certainly are looking to be potential new stakeholders for example to diversify our portfolio, to provide to others developing biologics our capacity. Currently we have programs to develop hookworm vaccine, the Schistosomiasis vaccine. We have a small program to advance a molecule. We just got an NIH grant in collaboration with New York Blood Center to down select and pick some potential vaccine candidates. We recently received a feasibility of expression project from PATH/NVI to develop malaria transmission blocking vaccine. We’re working with some small pharma to attempt to leverage and use our clinical trial sites. We’re trying to diversify our funding. In summary, major milestones that could be applied to other PDPPPs is to establish vaccine R&D and process development. We have done it in house at GW. We certainly have established processes of successful technology transfer, working with some of the developing countries’ vaccine manufacturers such as Butantan as well as here in the U.S. We have established good infrastructure for our clinical testing and certainly we go through the same processes for regulatory. We recently are trying to expand into adjuvant evaluation programs. We recently acquired a license for using GPG for NTD vaccines. We certainly continue to publish and disseminate our findings. I think that’s all I have to share with you and I’m looking forward to more discussions. Thank you. Thank you. Thanks very much Dr. Botazzi. I’d like to call on Dr. Norbert Hehme. He is the chair of the IFPMA, Influenza Vaccine Supply International Task Force. Dr. Hehme. Thanks very much. Good morning everyone. I would just like to thank the organizers for inviting IFPMA to provide some considerations from the industry side. Flu vaccines, IFPMA stands for the International Federation of Pharmaceutical Manufacturers Associations being headquartered in Geneva and the Influenza Vaccine Supply International Task Force is representing one of the dedicated working groups on the roof of IFPMA. It has been established a couple of years ago, and it is representing now sixteen research based vaccine companies which are engaged in the development and manufacturing of seasonal and pandemic vaccines. Currently I’m the chair of the IBS Task Force. Our work is structured into two working groups. One working group is dealing with science production and regulatory issues and it’s chaired by Tony Colgate who is also attending that workshop and might support me during the upcoming discussion later on. A second working group is dedicated to practices, policies and communication aspects in regard to flu vaccination. If we talk about the production influenza vaccines in developing countries we need to understand first some specific elements because there is no doubt that many vaccines are manufactured in large volumes and will be used around the world, including developing countries. This is not widely the case for flu vaccines due to the low demand for seasonal vaccines in any of these countries. There are very few chances to predict in advance the period the occurrence of concrete pandemic event. That’s why the establishment of local vaccine manufacturing capacities, which has been proposed as a possible solution to increased local supply capacities for vaccines requires to understand intrinsic links between the demand and supply of influenza vaccines, because without having a clear demand for seasonal vaccines in place we are not seriously in a position to develop a model rich guarantee a long term sustainable approach in that field. Generally speaking of course there are some challenges and limitations which require short, medium and long-term approaches. If we try to investigate, there are a couple of factors affecting the access to vaccines. There is of course the need to have a basic infrastructure in place and that implies in particular to culture requirements. We should also be able to rely upon long term forecasting models. We have to deal with financial and logistical models. Capacity building for sure, it’s the main element in these kinds of programs but we also widely discussed very much in detail-and I was especially pleased about that part of the program yesterday. Last but not least we need to rely on the political willingness of stakeholders. That’s raising the question at the end: what could be the role of technology transfer in these matters? We used to talk about the needs and views of pandemic strains. There are a couple of elements which applies the same way to seasonal flu vaccines. What manufacturers have to do in collaboration with other stakeholders is to adopt vaccines frequently-to the changes in the global epidemiology. It’s a seasonal product and we have needs to replace strains, sometimes one strain, sometimes two strains year by year. We are facing a very limited production period of just between six and seven months to make the vaccine available in time to the different marketplaces. If we are not able to do so from a pharmaceutical industry’s point of view we will just accumulate waste of material because vaccine cannot be stockpiled for later use and we have to avoid such financial consequences. We have heard a lot in these two days about the development of normal vaccines and technologies. We should take into account that for the time being most of the influenza vaccines which are produced globally are still active vaccines. The final element is that it’s also quite important to understand that the technology is specific for each inactivated and life attenuated vaccine. There are a lot of similarities in terms of upstream processes but we see plenty of specifics in the design of technologies for unstrained processes. That’s just summarizing the annual cycle for seasonal vaccine manufacturing and I’m coming back to the point I made already about the time limitations we are facing because the prerequisite is of course to know in advance what to produce, and so far the WHO Strain Recommendation Pro Task is representing one of the key elements in terms of flu vaccine manufacturing. We have two meetings a year; a meeting in mid-February to issue a strain recommendation for the upcoming season in the Northern Hemisphere. We are also doing the same in favor of the Southern Hemisphere situation in the second part of September. Assuming that usually at least one strain needs to be replaced; it will take some time to make first seed virus materials available. Typically we are not getting access to these seed virus candidates before April and as discussed yesterday a second very important element is the availability of strains in order to determine the potency of the vaccine. The technical independencies are complimented by a couple of regulatory needs. The elements I have highlighted. They refer in particular to the European regulatory situation. The existing basic files need to be updated year by year in terms of providing a technical file update, a strain file update. Don’t forget they need to run annually licensing trials in Europe and that’s why at the end, a clinical file is completing these efforts. Considering the technology transfer ideas and principles, there are a wide range of technologies which can be transferred at that was discussed also yesterday already because we have to take into perspective that we are not just talking about establishing manufacturing capacities, we have to think about the needs behind the training of personal clinical development programs, establishing lab testing capacities, having appropriate quality management systems in place, being able to manage supply chain needs, and logistical specifics. We need to rely on support provided by Key Systems. They are a project in HR management requirements. We are facing main elements of production. So far it is a local production, meaning to think about specifically manufacturing thoughts and the capacities for it. It’s just one type of the technology transfer requirements. A similar picture has been presented yesterday already it’s just to illustrate the collaborating efforts in producing flu vaccines and applies the same way finally for seasonal as well as pandemic vaccines, because it’s not an exclusive scope of activities, which is under the control of the vaccine industry only. We can only do our job in a very strong and effective collaboration with other stakeholders like WHO. WHO collaborations are essential as are regulatory agencies. It keeps included specific elements-the election of appropriate virus samples in order to prepare seed virus candidates. The evaluation of seed virus materials is a timely production of reagents. In addition to actual collaboration we have in place we also put some efforts behind in order to fund these activities financially. We have signed with the New York Medical College and one of the WHO Essential Regulatory Labs meetings-NIBSC for the development of reassortants, the extended isolation of seasonal influenza viruses in eggs, which means to support the activities at CDC in Atlanta, the WHO collaborating center in the National Institute of Medical Research in London. The total financial support amounts to approximately 2 million annually. There are also a couple of generic elements if you think about the technology transfer for vaccines and biologics, because these approaches in the case of biologics present a high level of technical difficulty. We still believe that basically a tech transfer approach should be based on mature technologies and licensed products. Even for an experienced vaccine producer transferring production to another building or site is a real challenge and quality control and compliance with regulations are by far the greatest tasks in manufacturing vaccines and require constant management. I want to show you the timeline of these investment projects. If we take into consideration all the elements-the preparation steps, by defining user requirements, developing design phases, then moving into the construction activities, and ending up finally with the qualification and validation needs. We’re talking in total about the time frame between 4 and 5 years. IFPMA IVS members are willing to discuss various approaches to local production in developing countries including secondary manufacturing approaches, but we suggest considering these kind of projects on a case by case approach, following a step wise effort and framework of a long term co-operation and partnership wherein adequate and effective application of intellectual property rules supports the continued development of vaccines. Successful partnership results from: A strong economic / strategic value for both parties, an appropriate level of expertise at the local level; a set of realistic and achievable objectives, the ability to achieve consistent quality conditions to meet quality standards for the vaccine, having a competent national control authority to provide rigorous regulatory and quality oversight. Last but least, local production of influenza vaccines must be coupled with an implementation of a seasonal influenza vaccination programs taking into consideration the interdependencies between seasonal and pandemic seasonal flu vaccine manufacturing in order to keep these manufacturing efforts, in particular for pandemic scenarios sustainable in the long run. That’s the end. I would just like to present an overview about a couple of concrete transfer projects that have been put in place already. Nobilon has granted to WHO for egg-based seasonal and pandemic live-attenuated influenza vaccine technology allowing WHO to sub-license to developing country public sector vaccine manufacturers. Thailand is the 1st country to request a sub-license. Last year, Sanofi Pasteur signed an agreement with Birmex, a Mexican federal vaccine manufacturer, to build a facility to manufacture seasonal and pandemic influenza vaccines. GSKBiological went into a joint venture agreement with Shenzhen Neptunus Interlong in China to develop and manufacture seasonal influenza vaccines and pandemic influenza vaccines. A similar agreement in China was signed one year before between Sanofi Pastuer and the local producer. Biken from Japan has signed an agreement with Bio Farma in Indonesia to build a facility to manufacture seasonal influenza vaccines. We had the very first huge project initiated by Sanofi Pastuer in collaboration with Butantan in Saulo Paulo to build a facility to manufacture seasonal influenza vaccines. Thanks very much. Thanks Dr. Hehme. I’d like to thank both of our speakers for the comprehensive outlines; I’d like to open the discussion to the floor. If you have any questions and discussion points, please feel free to raise them. Dr. Hehme I think we agree on most of the points you have made about the need for a seasonal vaccine market. Just two points I’d like to make is that: if the idea of the notion behind setting up a local production of influenza vaccine is for pandemic preparedness, I would like to bring attention to the fact that going only for secondary manufacturing will not work because, for example, there are secondary manufacturers of influenza vaccines in Europe also and during the pandemic they could not produce any vaccines because they have been incapable of securing access to bulk. This approach would work with seasonal but unlikely to work with pandemic preparedness. The other point that I would like to make is that indeed all these projects in technology transfer should take into consideration the respect of intelligent property rights provision in the various countries. For most of the technology that’s for making influenza vaccines, there are currently no IP barriers, so this is a hurdle which is very current for certain new vaccines, but very much less so for influenza vaccines. Thanks. Thanks for your comments. I entirely agree with the points you made. Though in the long run it’s definitely needed-how we could establish secondary activities at the local level. Usually, and that leads back to the point I made about following step-wise approaches, it might accelerate the process and get a more reliable approach having these kind of activities established first, and then moving into next phases in a prudent approach. As you see from the examples I have summarized on the last slide, this is the case for each single project. What we are going to do with GSKBiological in China is exactly to take into perspective those elements: secondary manufacturing to get the project started-and at the end to end up really in a collaborative effort for both the development and manufacturing of the seasonal and pandemic vaccines. Things are running in a similar way for these other projects, which have been summarized. As far as intellectual property aspects are concerned, basically you are right. There is not so much an IP dimension behind these technologies which are firmly established for a while already, but it can look different already if we take into perspective vaccines which have been developed more recently. I’m talking about, for example, adjuvant vaccines. Normally adjuvants are patent protected. This is actually a question-I don’t know whether it’s a comment or a question-but you can interpet it however you like. For both speakers, we talked yesterday about the need for successful business models that could enable the increased manufacturing capacity in developing countries. I’m just wondering if either speaker could, from the academic side in terms of the know-how transfer and the partnering, the first part of the question is: What are the critical enablers that predict a successful partnership with either academic institutions or companies or either partners in developing countries, that we can learn about, and are there particular business models that have been more successful in promoting these kinds of partnerships that we could be looking to in terms of lessons learned and applying to other situations? I can share with you some of the experiences that we’ve had. Certainly as far as what has been critical for us to be successful when we as an academic institution enter into the collaborations, is certainly transparency; which means that you have to have the ability of really showing all the information and all the data with whoever you want to partner and they should also be able to show their capacity as well as what their information is. The way that we have approached it, and I can use an example with Instituto Butantan for instance, is that we set up teleconferences and site visits one or twice a year and they come up and visit us once or twice a year. That allows us to really see how their processes are and as well as the needs that we have when we attempt the technology transfer and have them manufacture what we need for our vaccines. As far as the business model that we have been using, it’s really a combination-being an academic environment we work a lot under material transfer agreements as well as research agreements. I think also, even as simple as a memorandum of understanding where it clearly states what are the responsibilities and the expectations of each of us-like if we’re going to enter into a solid collaboration as simple as who is doing what and what resources each would be willing to provide whether it’s a financial resource, or just a personnel or technology capacity-that’s what we’ve basically been using. So I think that primarily, we have learned that you should definitely be engaged and physically work together. We sit with them and go over the processes step by step because there are things that we use in our labs here that that they don’t apply; for example, the types of gels that we use for testing. They have different types of systems that they use down there and we have to adjust to those systems. I don’t have much to add. Basically it’s the same way in regards to the industry’s experience. The big pharmaceutical manufacturers, in particular, rely on a widespread collaboration in regard to development projects. There are many stakeholders in biotech and academia, as just maybe one additional element, in particular, with regard to such tech transfer projects for supporting expanded manufacturing capacity. We have to take into perspective of course a couple of commercial elements: market access, reflections, and this is typically creating a win-win situation for both sides because there is no doubt that there are restrictive regulations in place blocking or even making it for companies quite difficult to get market access-that’s why collaborating with a local company, with a local partner, is an appropriate way to overcome this type of hurdle and creating a beneficial situation from a commercial point of view from both sides. I just wanted to congratulate the speakers, I thought, Norbert, your presentation was excellent. I think we kind of need to distinguish between business processes and business models. I think everything you said was really focused on the mechanisms of collaborating and interacting, and I think the business model is a little bit more towards yesterday’s question of sustainability and how you are going to engage that. I agree that when we think about short, medium and long term approaches that your concept of starting with finding partners and using that to sort of drive, as you said, engagement in a seasonal flu distribution programs within countries-that seems to me to be a sensible first step to try and find the committed partners even as countries grapple with the less concrete concerns about when will the next pandemic be. This is a question for Dr. Hehme. I would like to discuss a little about the benefits of transfer technology in case of secondary manufacturing. We know that manufacturers will have as a main priority to supply the demand of their own country. We know that in this case the receptor country of secondary technology will receive the benefit of the product until their country and the manufacturer’s country will have a supply. I think the secondary manufacturer will benefit the country only if it has the intention to have the complete technology transfer to the receptive country. Thanks for your comment. I think it leads to the point Marie Paule Kieny made by basically agreeing with this kind of considerations. As I tried to explain before, starting the secondary activities might represent an appropriate step to get such a collaboration started in the short term. But you are right, it’s a long run, it should keep at full scope of manufacturing activities because otherwise we are missing a lot of efficiency potential, in particular in case of a pandemic spread. All these transportation needs behind in case of a more serious pandemic are not representing an easy task because we could easily experience a more sophisticated system next time, in term of closing borders and things like that-having a huge burden in transportation and logistical systems, which might create a lot of very sophisticated problems; in order to keep such a collaboration alive, if you still have to rely on a transfer of huge volumes of materials into a receptive country. Question to Norbert. You very nicely highlighted that in tech transfer projects, it’s not just the actual production know-how it’s a whole range of other elements that need to be transferred. So in the experience that’s being gained within the pharmaceutical industry in these tech transfers are there any particular elements that are more difficult or more complicated to do than others? Do we need to pay particular attention in the tech transfer process to particular elements? David, I’m afraid it’s quite difficult to provide a generic answer on that question because it will look quite different project to project. One of the major aspects behind is really a level of expertise and know-how. You can rely to getting started these kind of projects and based on the experience we have a couple of sophisticated elements which represent intrinsic orders in the regulatory field in the field of having appropriate level of expertise in regards to quality management requirements, training of people and stuff like that. It’s purely daydreaming if somebody would believe you could get these kind of projects started with inexperienced people and that why I can only echo the comment Marie Paule provided yesterday, that WHO is requesting for all these tech transfer projects that it’s not exclusively relying on a project for flu vaccine manufacturing, there should be some expertise in place, having at least one additional vaccine production established already. I have a comment for Dr. Hehme. From our own experiences in the business relations between Japanese countries and their partners in some Asian countries, we also agree that the incremental step by step and case by case approach seems to be appropriate in technology transfer. We actually have done the combination between incremental approach and also public-private partnerships. At the very beginning of the pilot phase, the Japanese government has sent the experts on their own budget as part of its official development assistance project to those companies in those Asian countries. These experts are actually retired or incumbent experts working in the Japanese pharmaceutical companies. Once the mutual trust is developed, through the pilot phase, then the private-public partnership will be developed. After that they would go on to expand the technology transfer or other kind of Business Corporation. So that’s what we have been doing. Thank you. I fully agree with the points you’re making and it’s representing a very generic experience among industry partners. What you have tried to highlight is representing a very crucial element because we need to able to rely on efficient interaction between humans. That requires to initiate in very early stages an exchange of people; bringing in people from the partner companies to get first insights into the established operations at a level in certain countries, these companies who would act as a donor company. It requires the same way to bring in people from the donor company in the early stages to the receiving country in order to get started in very effective collaboration between the people who have to manage these kinds of projects and creating in very early stages a reliable understanding about the challenges those partners are doing to face the foundations which are in place already or need to be developed in the short to mid-term and therefore thanks for your comment, it’s an overview representing a very important element. Dr. Botazzi, do you have any comments? Yes and I think the bottom line is what you had mentioned, it’s commitment that you want from the partners. If you go into technology transfer, if you transfer some expertise, you know whoever is accepting that expertise, it provides additional commitment that will lead into potential sustainability of the program because it’s not fair just to go in, do a project and then not leave anything or leave any capacity-but not only leaving the capacity, but insuring that theres’ going to be commitment to internally continuing the project. So I think it all comes down to commitment on both sides. I’ll add just one additional aspect. It’s an intrinsic element of these kinds of projects, in particular if you have a phase that concrete activities are going to start already, it’s suitable to establish mixed teams-keeping partners from both sides. That’s the only way these kind of projects will fly in the end. You have to define also in early stages some timelines which need to be respected which meaning how long delegated people need to stay in such a partnering company, and so far, cutting a long story short, it’s requiring a very collaborative effort of people working together on the same goal and objectives. I was thinking of something additional which is referring to the fact of how do you then establish the sustainability and I think at some point it was touched on the political willingness also and for instance I think one of the challenges we’re going to face is, for instance, when we’re working in Brazil, we can do really short term projects that’s at the pilot level. But when we’re starting to think of what’s going to happen when we have to look for Instituto Butantan to go into Phase 3 or eventually licensure and the limitations they have because they’re still linked to the fact that they need political willingness because the funding that they get is not their own, it’s the government’s funding. So ideally it’s not only to work with the partner in the short term but also engage whoever the political influences that ensure that there will be sustainability and that there’s not going to be any issues in the long term to have them continue the projects and to getting the projects into licensure. At least that’s our case, maybe for flu it’s more advanced, but in our case we’re starting with very small scale productions but eventually somebody has to make the hookworm vaccine that we will have to license and I think right now we need to ensure that Butantan-if it’s the partner we will be doing vaccines for, let’s say Latin America-who will be supporting that political willingness of having them take charge of those kinds of activities. So it has to be looked at more outside of the box and more long term. That comment sort of goes into my question for you Dr. Botazzi. Dr. Hehme mentioned that one of the obstacles for getting more people interested in flu vaccines is the appreciation for the need of the vaccine. In the Hookworm Project you mentioned a very robust and interesting program of making the vaccine and developing it and testing it. You didn’t mention as much about the activities surrounding creating and communicating the appreciation and the need for the vaccine. Is that part of your program? Do you have activities and surveillance disease burden estimation communication? Yes that’s correct. I alluded that we do have a program where we focus on what we call a “Global Access Plan”. That involves certainly understanding the burden of the diseases that we work on, especially hookworm and where we actually do those studies. For instance in Brazil the way we originally started with our field sites-it was primarily to establish studies and that lead into determining which of those sites would be selected for eventual use in clinical testing sites. So we have been involved, and of course Peter is big into neglected tropical disease advocacy and policy to try to make these diseases more into the awareness of not only scientists but also the political. So we have been working very strongly with the governments in Brazil and even other governments to make sure that they understand that there will be a need and that these diseases and these types of control programs will certainly compliment other control programs. For instance we believe that it has to be very much in sync with the current drug, chemotherapy and de-worming programs. So it has to go hand in hand with even other things like child immunization-there’s a lot of things that we have to consider because it’s a vaccine that may not be as clearly perceived that it will be needed. Just to compliment the comment that you made. Brazil is one of the countries that is an important manufacturer in the region. In fact they already have a plan for influenza vaccine. This is a plan for capacity of 60 million doses per year. They already have the plan and the equipment installed, but they have so many other projects and I think that this is a problem. They have to define what exactly are going to be the priorities of the country-if it’s one country and one manufacturer it has the probability to have a lot of success in Butantan. We’re also certainly working with other partners as well. Like you said, they have very many different projects at all levels. Of course we are at very early stages-you have programs such as the Influenza Program, but we are going to competing with much more, maybe, important programs than maybe hookworm is perceived currently, so we really need to try to advocate and look for alternatives, even internally in Brazil, so it’s going to be important. Thank both of you for the brilliant presentations; it’s certainly been an eye opener for me. What I’m though is something that I think is somewhat of a conundrum. So if I could pass a direct question, perhaps uncomfortably: If you have two companies, one in a middle income country, one in a low income country, both have the same longevity, both have been around for 15 years, both have more than one product line, so they’re not dependant on seasonal influenza, and both have business plans and have face to face meetings and demonstrated commitment; One exists in a climate of political stability, the other, in the low income area, in a politically uncertain environment to say the least. Which one, and you can only make the choice of one or the other, which one are you likely to choose and if you say you are going to choose the middle income country, is the standard business model sufficiently robust to overcome the inherent environmental inertia that holds many of these countries back because these are the kinds of countries in which we are trying to increase capacity as well as demand. So I wonder if this is an appropriate model to address that challenge that faces this particular conference. I think you have highlighted a very important aspect. But I’m afraid it’s not easy to give a single answer which would cover these kinds of aspects because-one thing is for sure, this type of political stability aspects are representing a key element in the selection process for these kinds of partnerships and you cannot ignore these uncertainties if you tried to create a sustainable project in particular in the long run. On the other side I think, it would not be appropriate to say it’s black or white, but it’s for sure representing one of the key aspects in evaluating potential partnering approaches. I may have a slightly different answer. In the context of what we are trying to attempt because when we look also for the hookworm vaccine program, even though we are strongly focusing on Brazil right now we of course have to look for what going to happen down the road when we actually have to address the needs in the rest of the world. So we could actually see the scenario maybe this way: where if we decide to select the IDC country manufacturer or developer, maybe they can also take a lead in transitioning and tech transferring and capacity building with low income or other countries that need more capacity building and a typical example is I know Brazil is interested now in doing south-south collaborations with Africa, especially with Portuguese speaking African countries. So you could see a scenario where you can start with an IDC and then the IDC with the developed country will take the lead in going into the more unstable or less built countries or manufacturers. So maybe that could be an approach that could be considered. I have a multi-staged question as usual. In terms of where the business plans are and business models are frequently related not only to market and pricing and market share, but also related to intellectual property-I don’t want to divert into an intellectual property discussion-many of you are aware of ongoing controversies and quagmires that we find ourselves related to influenza and intellectual property. A relatively recent new model as you even indicated on your slide is the Nobilon model. Do you have any sense in terms of granting sub licenses to international organizations such as WHO? Do you have any sense within your own federation as to-I don’t want to get into proprietary or discussions that you’re uncomfortable with in a public arena, but is that a model that is generating any interest or what might be some of the concerns that have come up in the federation discussions in terms of that approach. I think-I’m trying to give you an answer-because starting in 2006 or 2007 if my recollection is correct, we moved into a so called intergovernmental pro-task and it is was initiated at that point in time by Indonesia, requiring virus samples-the H5N1 subtype-that scope of activities has proven significant over time and the process is still not completed. So far the point you have raised represent intrinsic elements of discussion in regards to that inter-governmental pro-task. Your question about the appropriateness of a deal which was authored by Nobilon to WHO, if this could represent the kind of standard approach for vaccine industry at all, I cannot say yes or no because it needs to be investigated and decided company by company and an industry association like IFPMA is not in a position to take a generic position on these kinds of activities and projects. I think I was trying to take a step wise approach in my question in terms of has it generated-I know being intimately engaged in those 3 years of negotiations, well aware of the sensitivities on having an opinion one model or another, but I was wondering if this was an active agenda item of discussion within the federation; as a step wise in terms of understanding what options might be. As I tried to explain these kinds of considerations belong to a bigger scope of sorts because we have to deal first with the ideas with the requirements we are facing in that intergovernmental pro-task coming from countries, coming from the public sector, on the other side we have still not completed the process of how to react in a conciliated way from the industry side-it’s still under discussion and we will face the next serious round of discussion with regard to the upcoming executive board meetings this year. Thank you, I hear the telegraphed message thank you. In terms of a follow up question: to anybody in the audience; one is we heard a lot in the last two days about the hope of the new technologies. In term of meeting-there are opportunities perhaps to get around and beyond some of the inherent limitations of egg based technologies as well as some of the inherent challenges of the influenza virus itself. Being that there are many optimists in the audience, if I could ask the panelists if the academic sector and the private sector in general shares that optimism and if they share the optimism then what are some of the enablers that could accelerate that movement towards the new technologies. Two easy answers: of course we are optimistic, and what would be an enabler, money. Of course the academic environment is where a lot of the novel technologies, ideas and research are attempted to be discovered or answered. So I believe through certainly the NIH and government funding sources, private funding, that really what enables universities to advance new discoveries and then confirm that those are good discoveries and advance them to the next stage so I think now that academics are trying to attempt to go further than just discovery and actually try to confirm that technology can be translatable. We are certainly very optimistic. I think from the private sector side we have a more balanced view. Because there is no doubt that we are talking about very promising development projects. But we shouldn’t ignore the timelines behind in order to get licensed products. A second point is sometimes there are unrealistic expectations which are still firmly established in different audiences, and I can refer in particular to the expectations about advantages in tri-culture technologies. What I am talking about is the theoretical opportunities to upscale immediately I case of a pandemic spread-for example, existing manufacturing capacities and I’m afraid it’s a bit far from reality, because once a company has to decide to invest in a technology, it doesn’t make so much difference if it is an egg based technology or tri-culture technology. In case of an egg technology, you will invest preferably in egg incubation capacities and the complimentary treatment. In case of tri-culture technology, you will establish a certain fermentation capacity; once you have done it, it’s a given and you cannot increase these fermentation capacities in the short term. The second aspect is, quite often the comment will be made “ok, at least Big Pharma should have additional capacities which could be used in a specific situation in favor of producing flu vaccines which are usually dedicated to producing other vaccines.” Even if this would be feasible in regard to the upstream activities, we will face easily serious hurdles in terms of downstream needs; because in order to purify, to concentrate, to isolate the biologically active intrigants, we are talking about very antigen specific technology. Once you have, for example, established a facility which is used for the production of Hepititus A vaccine you cannot use the same downstream technologies for purifying influenza viruses and antigens. A final aspect is recently highlighted during a conference in November also being held here in Washington, if you take into perspective the very recent experience in terms of timely availability of vaccines, during that H1N1 event, it’s not really supporting all these claims about an earlier availability of tri-culture derived vaccines because it’s not exactly a repository. I’m not at all averse to putting people in uncomfortable positions in terms of questions and I’m going to put everybody in the audience a little bit here. So we helped with WHO and Oliver Wyman to develop a report around the H5 stockpile, that’s publicly available. If we reflect on what we’re trying to accomplish here and some of the comments including from PAHO. You know, I think of course everybody would like to have their own manufacturing capacity and full control of their destiny. But I do think despite the fact that I’m an optimist, we have to separate science from science fiction and I think what I’d ask to anybody who would like to comment on, in that report about deployment of the stockpile, you could look at two opposite poles. You could look at a single site that held all the H5 vaccine and then try to distribute it out to every single country or you could have individual country stockpiles and again just like the manufacturing issues, there are logistics issues that come with this kind of distributed approach, so to me the key question that needs to get grappled with is: how do we integrate this sort of, the economics and the politics and the technology and logistics issues and what data is missing right now to take a look at that whole picture because in the end, preparing for a pandemic is little bit like an insurance policy. I mean it’s not, I don’t think it’s realistic to think that we’re going to be using 6 Billion doses of seasonal flu on an annual basis anytime-you know, in my lifetime right now. It’s not the way it’s looking. So you know there is a technology component, but how much are governments willing to pay, how much institutions are willing to pay for that insurance policy and what’s the right balance between the sustainability and that broader need. I don’t know how to sort of bring those analytics together but I think it’s going to take a lot of work from where we are today and I think that we need to consider that question. I entirely agree. It’s fully highlighting reflections and yet over time with regard to this kind of activities and I would like to underline in particular the point you made about science and science-fiction. What I strongly believe is it might be premature for the time being but quite soon we will be in the position to take some lessons learned from concrete activities put in place in fighting against pandemic spread and that keeps included the very important stockpiling approaches from WHO’s site, supported by some of the donor companies. We should really evaluate how the working models be put in place how to deploy it. These stocks work in reality because from my personal point of view I’m very much more in favor of thinking about a regional approach instead of a nation-based approach and that refers in particular to the scope of complexities from a logistical perspective. The point you made at the very end is also a very important one because that’s really representing science fiction if you would finally believe in the reliability of plans, producing on a regular base one seasonal flu vaccination program- six million doses per year, because it would fully ignore the reality we have in place. Because we are still facing a lack of understanding of the epidemiology in many parts of-especially is the situation in Africa, that’s the situation in major parts of Southeast Asia, it’s still the situation in some parts of Northern Asia, and so far as discussed yesterday, a lot needs to be done to improve the global surveillance, in order to understand the medical needs. And the second point is we have also taken into perspective some experience from the more reliable situation we have already in the developed countries, because it’s a matter of fact that many of these industrial countries are still far away from the WHO targets in terms of Vaccination coverage. Dr. Botazzi do you have any closing comments? Thank you. I think this is certainly for me been very interesting considering I’m not in the field of flu vaccine development. But, when certainly I was asked to come and represent Peter and provide some potential roles of new stakeholders and even what would be incentives, I think that, you know, what I can provide, or what I’ve heard also is provide the models or the examples or the lessons learned that play a game into developing control tools for specific different diseases. You know the model of partnerships and product development, partnerships like the doctor was mentioning about the different lessons learned with different technology transfers, working with different partners, whether it’s in an IDC country or whether it’s a developing country or developed country, I think those are all thoughts that you all can take and learn from and attempt to see what would apply and what wouldn’t apply to developing certainly vaccines for flu and all their inherent issues with regards to the fact that is probably more complicated than other vaccines. As far as the incentives I think that more than anything it’s always going to be driven certainly by the global health needs and by the fact that we’re all here to try to insure that we have better health in the world and by developing products that attempt to especially alleviate the needs in populations that are more unfortunate than we are. So the incentives, I think, should be driven mostly for there but of course you have to have all the other resources: funding, technology, and capacity, available for being able to use those technologies. Thank you. Dr. Norbert. Two to three very short points from my side as far as the discussion is concerned, we are just going to complete, I think it’s highlighting that in regard to a lot of different aspects and elements, there is wide consensus. Second I was very pleased with the outcome of the workshop taking into perspective in particular the experience of the last two days, because we gained a much better understanding of the complexity behind these plans and ideas and I’m referring back again to the very constructive and important discussion we had yesterday about the regulatory dimension behind. My final point, referring back to the question which was raised by Dr. Miller and also saying it’s made most probably not the objective for that meeting about the affordability of vaccines in the least developed countries, it’s for sure not a huge specific issue. It would apply the same way for other types of vaccines and products and I think we all can all agree that we need to explore creative models in order to overcome these kinds of hurdles we have still in place. Thank you. Well I’d like to thank both of our speakers for the excellent and stimulating talks they have given and to stimulating your thoughts and I appreciate your contributions. Thanks everyone.