The topic I have been asked to address, or the question to answer, looks to be far removed from the high-level scientific topics we have been addressing during the past two days. I hope you will find some connection with what has been said, because basically, especially in the field of vaccines, science and technology without policy and implementation is not helpful.
What I am going to do in the coming minutes is to understand whether what we call transfer of technology could be a solution to access to vaccines. But I have some preliminary comments on this.
(Click on image for a larger version)
First, what is at stake when we talk about access to vaccines? We are talking about access to vaccines for all, which means how to bridge the gap between the developed and the developing countries’ markets, and how the models we have been using – not only the ‘business’ models but also the ‘public health’ models which we will hear about later this afternoon – can close the gap beyond what has already been accomplished.
I have another concern as well, a question which was touched on a little bit yesterday. Are we talking about access to vaccines, or access to vaccination? In a rather provocative way I must say that vaccines do not prevent diseases. It is vaccination which prevents diseases. It is how we can use vaccines which will be effective.
Having this in mind, I will try to go a little bit further and review what has been done.
(Click on image for a larger version)
In 2008 we are going to celebrate the 30th anniversary of what has been called the Alma Ata Declaration, after the International Conference on Primary Health Care which was held in Alma Ata in 1978 and which called for ‘Health for All in 2000’. We are in 2008. Meanwhile, there have been a series of initiatives.
In the early ’80s, WHO developed its Expanded Programme on Immunization (EPI), which is aimed at reducing the incidence and mortality of six vaccine-preventable diseases – measles, diphtheria, tetanus, polio, pertussis and tuberculosis.
Then the next step, in the 1990s, was the creation of what has been called the Children’s Vaccine Initiative (CVI), in order to implement these policies. Whether it has been successful or not, it led to another initiative about which we will hear much more later this afternoon: the Global Alliance for Vaccine Immunisation (GAVI).
At the same time, the United Nations had been revisiting what it called its Millennium Development Goals (MDGs), which identifies all the actions needed to improve the welfare of those living in the poorest countries by 2015 – not too far from now. This includes the reduction of infant mortality through vaccination.
Two years ago, WHO enhanced again its approach through the Global Immunization Vision and Strategies (GIVS), which is expected to save 10 million lives, thanks to vaccination, once again between 2006 and 2015.
And in 2008, this year, WHO, along with the Program for Appropriate Technology in Health (PATH), is building a joint proposal to optimise immunisation systems and technologies for tomorrow.
So, as you have seen, during the past 30 years there have been a lot of initiatives.
(Click on image for a larger version)
Where are we now? Not very far, if we consider that in 2008, 2.5 billion people are living on less than US$2 a day, 30,000 children under five years of age die every day, mainly due to dehydration or undernourishment but also due to vaccine-preventable diseases, and one-third of the world’s population lacks adequate access to quality of health care, including vaccines.
This is not very positive. And this also applies to immunisation, with major gaps right now.
Despite the development of new vaccines, and their introduction in a number of developed countries – such as HPV, for instance – there are still nearly 30 million children born every year who are not fully immunised. The DTP vaccination rate in Africa has lowered by around 50 per cent for the past 15 years. New vaccines given in industrialised countries are under-used or not yet available in developing countries. And to some extent there is a lack of investment in vaccines against diseases which are prevalent in developing countries, what we call the ‘neglected diseases’.
(Click on image for a larger version)
Before addressing the technology transfer aspect, I would like to identify the three types of factors which can affect access to vaccines.
The first is the underlying general situation. Poverty is the main cause of poor health. Political stability is a critical issue, challenged by wars and conflicts. Political willingness is an important point, especially with regard to potential corruption. And there are still a lot of cultural – and sometimes religious – barriers to access to vaccines.
The second is programmatic, more technical. This includes a lack of health infrastructure, health care systems and logistics. If you want to use a vaccine, you need to have a proper cold chain system, you have to have delivery systems et cetera.
There is a lack of precise plans, in terms of policy and sustainability or long-term plans, which is an obstacle for sustained access to vaccines. There are, of course, financing aspects, with pricing, reimbursement and distribution costs. We often talk about the cost or the price of vaccines but we need to think about the cost of vaccination, which is often much higher than the price of the new vaccine, because it has to be administered through other channels.
There is a lack of capacity building in many different respects. And a point which is largely evolving now is the regulatory environment, which is all the quality levels to ensure access to vaccines: specific requirements or review timelines et cetera. These can result in a very long lag time for the introduction of new vaccines. For example, this has already been observed for hepatitis B, which took 15 years, and for Hib, which is not yet included in many developing countries.
(Click on image for a larger version)
The last, but not the least, aspect relates to the availability of appropriate vaccines. I will not go into detail, but there is more and more a gap between the type of vaccines being used in developed, industrialised countries, and those which are necessary in the developing world.
We need to have vaccines that are appropriate to the diseases which strike hardest in these countries. We need to have appropriate vaccines which are qualified, irrespective of their destination. They have to be adapted to the characteristics of delivery systems in developing countries. (There was recently the example of the new rotavirus vaccines, where the size of the packaging is simply so large that it cannot fit inside the usual fridge used in the bush). And they need to be available as quickly as possible to those who need them, regardless of where they live. For instance, Unicef has estimated that it takes an average of 45 days between the shipment of a vaccine to Unicef and its actual administration to a child, which is a big problem. Finally, vaccines should be appropriate not only for routine use but also for emergency needs.
So quite a lot of factors are influencing access to vaccines.
(Click on image for a larger version)
What can be done, in terms of solutions?
R&D is the first solution. That is why I believe that having this topic addressed in this type of forum is important, because one of the key factors in access is R&D: it is developing vaccines for neglected diseases, it is developing new health technology, but it is also partnering in R&D. I know there are good examples; we heard yesterday about the collaboration between Australia and Indonesia which is very important in this respect.
There are aspects relating to vaccine supply and procurement, which is a more technical layer. This includes a lot of technical assistance, which could be based on donation or at-cost sales, but also training, equipment and manpower. I mention here an evaluation made by the International Federation of Pharmaceutical Manufacturers and Associations, which has estimated that during the period from 2000 to 2006, 4.6 billion euros have been invested by the pharmaceutical industry in training, equipment and manpower in the developing world.
Differential pricing, or tiered pricing, is something which has been well known with vaccines for years and is now being used for medicines. And also there are not enough global financing mechanisms. Here again you see GAVI, and other acronyms like IFFIm, the international financing process for immunisation, or AMCs, advanced market commitments, or contractual agreements.
There are other types of partnership programs: for example, training and supply-chain management. Quoted here are statistics which show that currently there are more than 150 ongoing programs of partnership developed in the field of training, supply-chain management and so on.
And then there is technology transfer. I am sorry that it took so long to get to the point, but it was just to make you understand that this is not a magic bullet. Technology transfer has to be considered as part of a more global picture.
(Click on image for a larger version)
So what is technology transfer? Basically, establishing local vaccine production in developing countries has been suggested as a solution to increased access. This is also part of the TRIPs agreement, the Trade Related Aspects of Intellectual Property Rights, which was signed a couple of years ago. One of the paragraphs says, ‘Developed country Members shall provide incentives to enterprises and institutions in their territories for the purpose of promoting and encouraging technology transfer to least developed country Members.’ So this is part of a global commitment.
It may seem an attractive option, but I would like to explain now that many challenges must be overcome in order for it to be successful. The first one is to understand what we mean by technology transfer.
(Click on image for a larger version)
Technology transfer, in a very global definition, is a matter of flow of human knowledge. It is the transmission of human knowledge from one to another. This is not simply building a factory, for instance; it is much broader than this.
As you can see from the list shown here, there is a very wide range of health-related technologies which can be transferred to developing countries: R&D capacity, clinical trials, laboratory testing, quality assessment, supply chain management and logistical issues, training of personnel. As I said, transfer of technology is a matter of flow of knowledge from one human being to another, which means that human resources are crucial for technology transfer. It could be transfer of information technology, project management or human resources management. And then, there is local production.
It is important to see that many of these potential transfers of technology are not only in the remit of industry but under the responsibility of public health or national institutes, and governments.
The second point is that local production is just an example of technology transfer. We cannot summarise technology transfer as local production of vaccines.
(Click on image for a larger version)
If we are talking now about technology transfer for vaccines, there are some interesting points to be made.
The technology transfer for biologicals is different from technology transfer for pharmaceuticals. It has a much higher degree of technical difficulty and know-how. The duration of production of one batch of vaccine varies from six months to 22 months, which means that it is a very long process. And these long production timelines are extremely important to consider when we are thinking about transferring technology.
Technology transfer can only apply to mature technologies. What we have been hearing about during the past two days (research on new vaccines) has to go first to the industrial level and then to be standardised enough to be able to be transferred. This explains why local manufacturing in developing countries is currently essentially limited to some ‘basic’ vaccines.
We know, as vaccine producers, that transferring production to another building or to another site is a real challenge. What you have heard about shortage of vaccines or such big issues in the past years was linked sometimes to the difficulty of simply increasing capacity building within a given company.
The last point here is important as well. Quality control and compliance with regulations are by far the greatest tasks in manufacturing vaccines. Two-thirds of the time to produce a vaccine batch is dedicated to quality assurance and quality controls.
So there is a lot of specificity there which explains why there are rather few examples of truly successful technology transfer in the area of vaccine production.
(Click on image for a larger version)
So what are the key challenges?
The first one is: will technology transfer address the expectations placed on it, such as the expectation that it will speed up the availability of vaccines? Because of what I have just mentioned about compliance with GMPs (Good Manufacturing Practices) and regulatory validation, we are not sure that technology transfer is a way to speed up. (We will see an example later on.)
Will it make it possible to reduce the costs? Obviously, there is a potential for operating costs in developing countries to be lower, but we need to bear in mind that vaccine production is capital intensive, very time-consuming, complex and highly regulated. So an approach which just considers operating costs gives only part of the picture. It is always difficult to compare the price of a vaccine in a developing country with that in an industrialised country, because the content of the price is not the same. It is not simply production costs.
Will it be possible to sustain this for the long term? I think this is an important point in technology transfer for vaccines. It is not only an initial investment by the local producer; it is also a long-term commitment of finance, quality, expertise et cetera.
All of that means that, to be a bit cautious, transfer of technology is not always viable.
(Click on image for a larger version)
What is required to be successful?
First of all the requirement is for a strong rationale for the parties involved, a strong rationale about the industrial or economic values for both parties (whether it is for the self-sufficiency of a given country, or to extend production to other countries), and then again a strong rationale based on the level of expertise at the local production level.
To be viable, it must make sense. That is, it cannot simply be a political decision. It must make sense through achievable objectives and a business case.
Finally, and I will illustrate this, it is only case by case analysis which can assess feasibility and chance of success. It is not a philosophy; it is a case by case approach.
(Click on image for a larger version)
Let me summarise the conditions for a successful transfer.
The first is the existence of scientific capacity, infrastructure and collaboration; it is the existence of local technical infrastructure, of experienced and trained staff, and, last but not least, of competent national control authorities. Without national regulatory authorities it is not possible to conduct a technology transfer.
It has to get a strong rationale for partnership. You have to make sure that the vaccine produced locally will have the same quality as the one which is produced elsewhere. And you need some guarantees of respect of, as I mentioned, the TRIPs agreement and the World Trade Organisation agreements.
(Click on image for a larger version)
So, practically, technology transfer in vaccines has to be considered as a stepwise approach, which is first to secure the downstream processes and then to go to production capacity. That is illustrated in this slide.
The first phase, which I call the downstream process, is the packaging and distribution of the finished product, also called fill and finish, or finishing and packaging. This step is an important one because it allows you to develop the basic quality control aspects, the labelling techniques, the cold chain control and the distribution system, but also adverse event reporting systems et cetera. So it is usually the first phase to do with a tech transfer.
Then we can go to the second phase. This is to manipulate the product itself through the filling of the bulk itself, which needs to have sterile filling units, sterility assurance, quality control expertise, validated suppliers and quality assurance.
Then we can move to the third step, which is the production of the active principle itself. This needs the implementation of higher technology engineering, bulk production expertise, sustainability and so on.
This is the only way we can really proceed.
(Click on image for a larger version)
To conclude, let me give the example of what my company sanofi pasteur is going to do – as announced last year – for the creation of an influenza vaccine production facility in China. I have been analysing what have been the elements for this.
The first one was the background: first sanofi pasteur is the largest flu vaccine manufacturer, so it has some expertise there; second there is a growing demand for flu vaccines, especially in the context of pandemic flu; and third there is good experience in China in the process of developing and producing flu vaccines.
So how to do this? Sanofi pasteur has some experience of long-term collaboration in other countries. For instance, mentioned here is Hib, with Brazil. There are also other approaches in Mexico. And the company has a local partner in Shenzhen, China, called Kangtai, with a joint venture which was established 10 years ago. So there was a good basis for a partnership.
The objective then was defined as building a manufacturing facility in order to supply the Chinese market by 2012 – this was announced in 2007, so this is a five-year perspective – and would also enable a switch from seasonal flu to pandemic flu vaccine production when needed, using the current technology, which is a mature technology.
(Click on image for a larger version)
How does it work? This is a very simple summary of the timelines.
In 2007 the site was selected, with acquisition of the land and all the administrative procedures to start building the plant itself.
In 2008 we arranged the construction licence, the selection of an egg supplier, the buildings – so this is the visible part of the plant.
And then there is almost three years forwards to develop the pharmaceutical qualification of the building, to develop all the validation process for developing consistency batches and to get the regulatory submission, in order to be ready, hopefully, by 2011 or 2012 to start industrial production.
So, as you can see, it is a long process. But what we expect from this is that it could be successful, firstly because there will be sustainable involvement of highly skilled technical talents, with exchange between the countries, and the appropriate supply (eg, using quality standards, multiple suppliers, transportation). Also one of the key success factors, when we are talking about flu vaccines, is that there will be a seasonal flu vaccine market in China, which is definitely linked to vaccination policies developed by the Ministry of Health in China.
(Click on image for a larger version)
The first thing I would like to say is that I hope you have not got the message that technology transfer is not feasible or is not possible, or that industry is opposed to it. I just want to say that there are minimum conditions that should be met if we want to talk about technology transfer. These are technical feasibility, economical viability and political willingness. Without these, it is not possible.
To guarantee success, it must proceed in phases, in a step by step manner.
It can only be a case by case approach between manufacturers and the interested party or parties, whether they are public or private parties.
We must also bear in mind that there is, especially for new vaccines, a relatively low probability that technology transfer will result in less expensive or more innovative products.
(Click on image for a larger version)
Nevertheless, to be more positive at this level, industry is always seeking innovative ways of ensuring adequate supply to meet the world’s needs.
There has been significant progress. I should have put up a couple of additional slides on that, but significant progress has been achieved, and technology transfer in the field of vaccines is extending more and more – extending essentially for three reasons. It is extending because, more and more, the technology is broadly available. It is extending also because there is a trend to harmonise regulations across the world, which helps in extending technology. And, thirdly, it is because now there is a movement from a self-sufficiency approach to a more global market, which means that technology transfer can be more viable.
The last point is that if technology transfer’s purpose is to facilitate access, we need to consider that there are other initiatives that should be explored. It is not the only approach, and there are probably many other initiatives that could leverage the industry’s commitment to supply vaccines at affordable prices to international organisations.
(Click on image for a larger version)
I started with preliminary comments. I will end with a final one, which is that access to vaccines and vaccination for all ultimately relies on a series of elements: vision and long-term commitment, some passion, sharing of expertise, innovation, partnership and, last but not least, transparency.
Discussion
Question: Going to the first part of your talk, before you got to the tech transfer part you painted a fairly bleak picture of the current situation with respect to access to vaccination, rather than vaccines. (I take your point on that.) But I had thought that over the last five to eight years – I don’t know what the most recent data is – we were on a pretty good, very positive upward trajectory with respect to coverage of childhood vaccination. That is not the message I got from your first five minutes. Have I got it wrong up until now?
Luc Hessel: No, you’ve got it right. And I am sorry to have been a bit pessimistic in the initial part of my presentation, but this is the current situation. I think we are always praising the fact that there has been a lot of progress et cetera, but there is still a lot to do. There is still a gap. I could have presented the situation as, yes, millions of lives have now been saved – say, three million lives every year have been saved – but it was just to illustrate that there is a gap. As I was going to address access, I wanted to identify the half-empty glass and not the half-full one.
Question: I would like to ask about a unique problem I will return to in Taiwan. (I have never dealt with vaccines before.) The Taiwan politicians are very concerned about pandemic influenza, H5N1, and so the government wants the research institutions as well as the manufacturing companies in Taiwan to be self-sufficient. So they have charged the people working on vaccine research as well as production with a great deal of responsibility, based on what you were saying, in which we went through all the processes of quality control. Actually, our institution has a pilot plant which has started to make H5N1 and then it has to go through the trials.
My question is about the accessibility of flu vaccine – it may not be H5N1. Since the pandemic is so hard to predict for a country like Taiwan, which may not have access to any of the product from your company or many other companies, what should they do about this?
Luc Hessel: This is a very accurate situation, and has been an ongoing question for many countries. There are two aspects.
It is legitimate to be concerned about being self-sufficient in pandemic vaccine production, but the first thing is that there is no way you can develop a pandemic vaccine production facility if it is to be used only in the pandemic situation, because you cannot predict when it is coming. So, one of the prerequisites for developing an approach for pandemic vaccine production is to develop a seasonal flu vaccine production facility. It has to be put into the perspective of a seasonal flu production facility being upgraded to this.
On the second aspect, the technology, I think that as soon as a country has the existing technology for producing vaccines, there is basically no real barrier to development –except through the planning, the money, and the investment. I think that in respect of the capability, especially with Taiwan’s regulatory environment, this is definitely feasible. I don’t see major obstacles in terms of technology.
On the third one, the point seems to be the access to those strains. Is that what you were mentioning?
Question (cont.): Yes. If Taiwan cannot be self-sufficient, for example when a pandemic comes, what should we do about this? Do they need a prior affiliation with some kind of production company? Really, I am not speaking now for myself; I am speaking for the politicians in Taiwan who are so preoccupied with this particular issue.
Luc Hessel: What I said in some slides is that there is a need for partnership. So you need to identify what type of partnership you need. Either you are viable to fully self-sufficient, and you do your own job, or you say, ‘Okay, there are gaps.’ And then it is the gap analysis which will help in identifying who could be the best partner, whether it is a public health institute, an international organisation or a private company. I think a lot of actions are going through international organisations or public health institutes for technology transfer.
So I think it is a matter of gap analysis: what are the needs?Visit these websites
The Sir Mark Oliphant Conference Series is supported by the Australian Government under the International Science Linkages Program.
© 2008 Sir Mark Oliphant Conferences.
Website design acidgreen
