Chief Executive Officer (ad interim), Idorsia
Recherche académique et industrie biotechnologique - Jean-Paul Clozel
Colloque de rentrée 2010 : La mondialisation de la recherche
Conférence du jeudi 14 octobre 2010 : Recherche académique et industrie biotechnologique
Intervenant(s) : Jean-Paul Clozel, Président d'Actelion Pharmaceuticals Ltd
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About Jean-paul Clozel
Jean-Paul Clozel, CEO ad interim of Idorsia, has spoken extensively about the role of university-industry partnerships in drug discovery. In lectures at the Collège de France, he described the interaction between academic research and biotechnology companies as fundamental at every stage of drug development, from initial ideas to clinical testing. He stated that "without fundamental research, no discovery can be made" and that the origin of innovation "practically always comes from the university." He also cautioned that the precautionary principle used by many countries tends to favor the absence of risk, adding that "there is no medicine without risk." Clozel has discussed the creation and culture of biotechnology companies. He said that a biotech company can only be created from a scientific idea or vision, and that someone starting a company with a commercial idea or to make money has "no chance" of succeeding. He noted that most early failures in biotech are due to rivalries between people. After selling Actelion to Johnson & Johnson, Clozel co-founded Idorsia, which he described as a continuation of the same scientific projects. He stated that "previous success can be a very big handicap" and warned against overconfidence and arrogance. He advised young entrepreneurs not to underestimate the amount of work and problems they will face, adding that "if your motivation is to be rich quickly, don't do it."
Transcript (8 segments)
J
Jean-Paul Clozel0:33
Thank you very much and hello. I simply wanted to begin by introducing myself: I am a doctor and cardiologist. After a period of academic research and also within a pharmaceutical company, Roche, with three friends we created a company called Actelion, which was founded twelve years ago and is now the largest biotechnology company in Europe, employing 2,500 people including 1,000 researchers. Today I wanted to thank you for this invitation. I wanted to talk about the fundamental relationships between a biotechnology company, the pharmaceutical industry, and academic research. What you must understand above all before we begin is the problem of the pharmaceutical industry. We are an industry that lives off patents, and every 15 years these patents expire. It is as if we asked an industry like Renault every 15 years to throw away all its models, all its car models, all its factories, and start over from scratch. They would have to create new models, build new factories to produce these models, and start over with new car concepts, new engines, new gearboxes, starting from zero. That is what happens in this industry: every 15 years patents expire and we must find new drugs. This explains the importance of research in this industry. When I was asked to think about its relationships with academia or university research, I thought of five main points which obviously do not cover all the problems but are very interesting to discuss and also highlight the problems and opportunities of this industry. The five points I would like to consider are: first, explaining the importance of fundamental research; the importance of intellectual property; the investments which are increasingly important; innovation and the importance of innovation in this industry; and finally, to conclude, I would like to talk about neglected diseases and the thinking that must be done on these diseases.
My first point, and it is absolutely essential for me, is the importance of fundamental research. You need to know that there has been no innovation, no new drug discovered in recent years that was not discovered as a result of a discovery in the fundamental domain. People always talk about the biotechnology industry as applied research, which is obviously the case since we discover and develop drugs for patients. But you must know that without fundamental research, no discovery can be made. This obviously highlights the importance of the role of fundamental research and the role of the university. If we look at the distribution of biotechnology industries in the world, we see that these industries are located near the best universities. The majority of biotechnology industries in the United States are close to Stanford, the University of California in Silicon Valley, and they are close to Harvard and near Boston. In Switzerland they are close to the Swiss Federal Institute of Technology in Zurich or Lausanne. So all these industries are close to discoveries because in fact they use these discoveries for their applications for the patients. I was also very interested this morning by the notion that obviously this is a very competitive industry and that only the elite of research can be useful for this industry. A patent is only given to the person who discovers, to the person who is first in a field. The second has no right to a patent. If a discovery is made two hours or a day after another laboratory, there will be no patent for the second. This therefore reinforces that the university, university research, we need for the biotechnology industry not just any university research but elite research that is concentrated in laboratories that can make the difference. Also very important, and I find fundamental in this university research, is the notion of large projects. Today a project, as you saw with this demonstration of the importance of computing for example in discovery or in research in biology, requires multidisciplinary university research. We need to bring together disciplines, whether bioinformatics, physics, electronics, all these subjects must be brought together in order to make these discoveries. And large projects, and I take the example of the Alzheimer plan, have for me an obvious advantage: they force different disciplines to join forces for a single goal, namely improving treatment but also the follow-up and quality of life of patients. When we see that this plan ranges from basic research understanding the disease, it also includes understanding the fundamental bases of this disease, and this plan goes all the way to treatment, meaning that every day the nurse treats the patient who unfortunately has this terrible disease. We see that through a plan, a project such as this one, we can improve not only research but also we can learn how to discover new drugs, how to test them, and afterwards we can see the impact these drugs have on these patients.
What I wanted to say is that competition is obviously growing. We have seen that countries like China and India are launching into pharmaceutical research. At the beginning they started by making copies: at first China and India focused on generics, but now much basic research is taking place in these countries. It is therefore important for countries like France or Western countries to remain very competitive if they want to have a chance of persisting in this industry. So as I said, without a patent there would be no biotechnology industry today. The cost of manufacturing a drug is a small percentage of the selling price. What a company sells is knowledge: the knowledge it has created by conducting clinical studies to determine the dose, efficacy, and side effects of any drug. It is somewhat comparable to when you buy a disc with a computer program. Obviously it is not the cost of the disc that you pay but the cost of programming and the cost of the programmers who made this program. It is the same thing when you buy a box of tablets: what you pay for is the information work that was required to be able to register and have the right to sell this drug. What is interesting and important to know is that patents are short-lived. A patent in the pharmaceutical industry lasts at most 18 years. And 18 years seems long, but when you know that a minimum of 10 years is needed to develop a pharmaceutical product, out of those 18 years, 10 years are already spent developing without having the right to sell the product. So today at most we have 7 to 8 years to use this new invention. You should know that these costs, the cost of patents, is increasing because today all countries in the world are capable of manufacturing or innovating in the pharmaceutical domain. So it is essential to patent every new invention not only in the country of discovery but everywhere in the world, which increases costs. And we therefore come to this problem: a patent is the reason for having invented the patent system, which is a very old system, obviously to stimulate research. Researchers or industrialists are stimulated to do research because they know that their discovery will be protected and their work will be protected and can therefore be used. But it is obvious that today, all universities, all academic institutes that do research also want to use their inventions and want them as a source of income to be able to do research. This is completely understandable. But at this point, the problem is simple: every new researcher in an institute has a goal, which is to publish, obviously to have his information about his discovery as widely disseminated in the world as possible. But a patent cannot be obtained if a publication was made before the registration of that patent. So today we are in an important dilemma, and in my opinion it is perhaps a brake on research: the dilemma of the researcher in industry and in the university in an academic setting cannot publish his discoveries because this institute or research center will try to obtain a patent. So that is an interesting problem to discuss.
Investments in this industry are increasingly large, and I would like to give a few examples. You need to know that today, when you want to develop a drug, it is not enough to discover it. You will first have to test it in animals, that is, by doing toxicology studies. We obviously try to predict whether we will have a potential for side effects or toxicity. This means testing the product for years in several species. But you will also have to test it in humans. A few years ago you could test this product on a small number of patients, but today the regulatory authorities, rightly, demand to test this product on thousands of patients from different ethnic backgrounds, patients who will take this drug alone but also take this drug with hundreds of other drugs that are commonly prescribed today. 20 to 30% of people over 60 take a drug called statins to lower cholesterol. So if you want to use a product in people over 60, you obviously have to test the product you are developing in combination with these statins. This means that today any development of new products costs roughly 500 to 600 million euros, and very often after spending 500 million euros or 400 million euros, you face a toxicity problem and you have to throw away all that effort. The product is not usable and everything that has been spent is lost. So this explains why more and more pharmaceutical companies are merging, consolidating, buying each other. This means that there are fewer projects, fewer research centers. Before, Glaxo bought SmithKline, and with GlaxoSmithKline the research centers of Glaxo, SmithKline, and Wellcome—there were four or five research centers. Now there is one research center, one head of research. That means there are four or five times fewer projects. It also means there will be fewer possibilities to cooperate with the university because there are fewer large-scale industries. Also what must be considered, and this is the cause of these increases in investments, is the precautionary principle. The precautionary principle, which is used by many countries, tends to favor the absence of risk over efficacy. That is, many countries and many of our politicians refuse any risk. But there is no drug without risk. So we are today faced with the problem that any society, if it wants to benefit from our drugs, will have to accept risk. Unfortunately, when a product works, when a product is effective—take the case of statins for cholesterol or antihypertensive products—these products have considerably changed patient survival. We forget that today in the Western world, life expectancy increases by one year every three years, and the main cause of this improvement in lifespan is the appearance of drugs that have an effect, for example, on atherosclerosis caused by cholesterol, or on arterial hypertension. When I started my medical studies, we saw young patients who had what were called strokes. At that time, these patients had uncontrolled hypertension, had cerebrovascular accidents, and were paralyzed at age 30 or 35. Today these diseases have almost disappeared. Every patient can and should have their blood pressure controlled thanks to all the drugs that have been developed for this type of disease. But you should know that today, drugs such as aspirin would never be authorized to be put on the market because aspirin has side effects. When you give aspirin in high doses, there is a risk of bleeding. When you give aspirin to certain patients, you can have allergic effects, you can even cause vascular accidents in a small but significant number of patients. So it is very important to understand that this precautionary principle must certainly be reevaluated, and countries should try to consider not only the risk but also the potential benefit of new drugs.
As I explained, every 14 or 15 years the biotechnology industry must discover a new drug. Therefore innovation is the key to success. Without an innovative product, there will be no biotechnology industry, and without innovation there is no chance for any pharmaceutical company to survive. Unfortunately, what is very important and what I have written here is that innovation is a means to obtain a new drug to improve patient health, but it should not be the goal. Let me explain. If, for example, today certain antihypertensive products work by blocking a receptor for a hormone called angiotensin. Angiotensin increases blood pressure; it is in too great a quantity in certain hypertensive patients. So what was developed are drugs that block the effects of this hormone. The discovery of these angiotensin antagonists was a true innovation that brought a lot to patients. And after the discovery of these drugs, we saw the development of vaccines that try to immunize patients against angiotensin. For me, these vaccines do not represent a true innovation. Obviously the vaccine against angiotensin is innovative; it is a new way of blocking this hormone. But in fact I do not think this vaccine can bring anything to patients, since we already have drugs that can block this hormone. We already have effective drugs. And for me, this shows the difference between innovation as a goal in itself and innovation which must be a means. I think vaccines should be made to treat or prevent diseases that cannot be treated and that are not already treated by other means. So innovation as a means, not as a goal. It is clear, and I say that all innovation in the pharmaceutical field comes from fundamental research, and I would like to give a few examples. One of the most important advances in the field of cancer has been the recent discovery of so-called anti-angiogenic products, like Avastin, which was discovered by Genentech and later bought by Roche. This new drug is the result of fundamental research that lasted at least 20 years. This research, done in Boston in particular, tried to understand the role of new blood vessels in tumors. Each tumor is composed of many cells that grow very quickly and multiply. And since they multiply very quickly, faster than normal tissues, it has always been observed that these tumors are vascularized, receiving a greater blood supply than normal tissues. This blood supply came from new blood vessels that grew into the tumor, thus they grew faster than normal vessels. These are called neovessels. And researchers got the idea: if we suppressed these neovessels, if we suppressed the growth of these vessels, tumors would no longer receive blood and could no longer grow. And if we combine this obviously with drugs that reduce the size of the tumor, we would have a much more marked effect in combination than when chemotherapy is given alone. It was necessary to discover what factors allowed the growth of these neovessels. That was the purest fundamental research. It was necessary to know how we could block this hormone, and the discovery was made: VEGF is a growth factor for these vessels. And Genentech subsequently, after the discovery of VEGF, developed antibodies that blocked the growth of these vessels and therefore had anti-cancer effects. So you can see that this discovery of a drug was made thanks to fundamental research. And when we see some governments asking their teams doing fundamental research to do applied research, I think that is certainly the most dangerous path and the surest way to dry up the source of innovation. I repeat: fundamental research is essential for the biotechnology industry.
Obviously, all innovation is a source of risk, and I have talked about this. If we want innovative products, we will have to accept a certain level of risk. And all innovation and all the consequences of innovation are difficult to determine beforehand. I believe there is a quote that is essential for me, a quote from Bill Gates who said: we always underestimate the difficulty of putting into operation, of making functional, and we always underestimate the impact that an innovation will have on everyday life. I will give a few examples. When I first saw those small, smooth devices and those small players called MP3 that allow condensed information in a small device, I had the impression that it was a gadget that would be of little use. But when we see today everything that has been done, down to telephones including these possibilities, when we see the iPod, the iPad, the dissemination of information that can be done thanks to these new means, we see today how no one could have predicted the consequences of that discovery. And that is what I mean: the interest of fundamental research and the necessity to understand that we cannot direct this research; we cannot predict what the consequences will be. What we must do is do this research and especially not try to tell researchers: you are going to find something innovative and you are going to find something that will have such and such use. There must be fundamental research, there must be applied research, and what is important is this relationship and interaction between the two types of research. This leads to the problem of funding this innovation. And here too, I think the problem of patents, the problem of how this innovation should be paid for, only by published university research, or should industry participate in financing this innovation? That is also an interesting problem to discuss. And finally, I would end this presentation by saying that economic factors, cultural factors, and political factors mean that unfortunately many diseases today are neglected. I would like to discuss these problems of these diseases because they are serious problems that can have important public repercussions. Infectious diseases. I know well Professor Menard, who at one time was the director of public health in France. When I spoke with him while he was director of public health, he always told me that his main problem was infectious diseases. And we saw with the appearance of swine flu, avian flu, the possibility of having new diseases that from one day to the next could appear and contaminate millions of patients. Fortunately, the severity was less than feared, but one day it is possible that a virus like the Spanish flu virus of 1918, a new virus, appears and has very serious global repercussions. We have recently seen that bacteria from India have become resistant to all antibiotics. This means we risk returning to an era without antibiotics, where a simple wound could kill anyone because there was no way to cure it. So these infectious diseases must have their research. Today, most large biotechnology companies have stopped research on new antibiotics, simply because economically, and this is understandable, new antibiotics have low prices because penicillin has existed for over 50 or 60 years. Reference prices are those of old drugs, so it is economically impossible to make a profit on research that will cost hundreds of millions of euros for antibiotics that will be paid at prices incompatible with economic logic. So for infectious diseases, research must be done. For diseases of certain populations, I take the case of thalassemia and sickle cell disease. These are diseases that affect a significant number of patients, but often these patients are in economically disadvantaged areas and cannot pay for innovative drugs. This explains why in some areas there is no research. Childhood diseases: today, it is not so much the pharmaceutical industry as any government or any regulatory authority authorizing a drug in children that poses a major political problem. If a side effect appears in a child, the public cannot accept it. If a journalist publishes that a child died due to a side effect of a new antibiotic or new product, that will immediately create a major problem, not only for the pharmaceutical industry but also for the politicians and the people in the audit and registration bodies who authorized the product. This explains why many products are not tested in children or are not approved for pediatric use. Psychiatric diseases: it is clear that today psychiatric diseases, neuropsychiatry, is one of the fields with the greatest needs. There are figures saying that 1% of the population suffers from schizophrenia in a more or less severe form. However, research in the field of psychiatry is disappearing from the pharmaceutical industry. The reason is simple: a drug that affects psychiatric diseases will by definition have significant side effects. Take the example of depression. A depressed patient tends to stay home, not be active, avoid contact with those around them. If you give an antidepressant that improves their mood, the patient will be transformed; they will start to act and interact with the world. But what can happen is if the drug is a little too strong, the patient may go buy a new car, a new house, start wanting a different life. And if they buy a car and cannot pay for it, they may sue the pharmaceutical company because they bought the car because of the drug. The pharmaceutical company would be responsible for the patient buying that car. And that is what happened in the United States, where companies like Glaxo were sued by thousands of patients because those patients changed their lifestyle and the way they consumed. This explains why industries are terrified: how can we develop a drug that will change how a patient acts, thinks, and interacts with society, when needs are obviously increasing considerably? Finally, and this is why I think there is a very important consideration—and I believe the College de France is doing this by asking Professor Zerhouni, who was the head of the NIH, to give a course—it is the notion of public health that is essential. It is important that states, industry, and research try to think about what will be the best use of funds for the notion of public health to improve health. That's it. I hope I have given you a small overview; obviously this is a somewhat superficial look at the importance of fundamental and university research for biotechnology. And I believe my conclusion is simple: in the years to come, and perhaps this course will stimulate some initiatives, we will have to reinvent the way the industry or biotechnology collaborates with university research. I unfortunately do not have a solution, but I have simply been able to highlight a few problems.
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Host35:29
I thank you very much for these presentations, my dear colleague, which show, like the two previous presentations, that we are at a turning point in the scientific revolution, partly because the increasingly sophisticated means we have, as well as the effect of society, mean that scientific research is becoming more and more expensive, and therefore we will have to choose. I also thank you for showing that there is no contradiction, either in principles or in reality, between fundamental research and applied research. And I think from this point of view, the task of your opponent, my colleague Joliot, will not be made easier, although he has spent his whole life in so-called fundamental research. I believe that on the essentials there will be no disagreement.
J
Joliot36:36
I have been tasked by the organizers of this congress with the role of discussant, so theoretically to try to bring some contradiction to the speaker. And I am a bit desperate, as I just said to Mr. Fichman, because I share most of the views that were presented by Jean-Paul Clozel, even though he belongs to a world quite profoundly different from mine. So this, as was said, will not make my task easier. So I will nevertheless address the same problem: the relationships between fundamental research, academic research, applied research, and industrial research. Very quickly, for a researcher of my age, I lived through a period that was particularly regrettable where there was a true ideological barrier between these two research domains. Mistrust of academic researchers towards the industrial world, towards the world of money, and let's be honest, mistrust of the industrial world towards the academic world, which represented dangerous revolutionaries who were not keen on welcoming them into their ranks. Fortunately, this is one of the areas in which the greatest progress has been made. However, we must not neglect that such an opposition and such a logic is not completely over and we must fight to erase it completely. That being said, fundamental research and applied research, contrary to what a certain number of decision-makers and even unfortunately a certain number of scientists think, I am among those who believe that these are two profoundly different domains in terms of research practice and the mode of organization of research. Far be it from me to oppose fundamental research and applied research; it is obvious that applied research feeds on fundamental research and that fundamental research could not progress without applied research. Nevertheless, these are two different activities. Two different activities that in my opinion can and should in most cases be practiced by the same researchers, but not in the same spirit. For my part, I have the reputation of being a formidable defender of fundamental research. If I take stock of my scientific career, I perhaps had more success in certain aspects of applied research—development of new technologies—than in fundamental research, and I took great joy and pleasure from it. So I do not want to oppose one form of research against another. For me, and this was mentioned by Jean-Paul Clozel, what is characteristic of fundamental research is that it is unprogrammable: you cannot program what you do not know. And all notions of programming—and I insist on this point because in the current political world this is a notion that is being imposed on us more and more strongly—programming is the past. You can only program based on what you know, and you cannot program the future. So there is an absolute contradiction between fundamental research and programming. I would add that the worst kind of programming is what I call self-programming, that is, when the researcher himself programs, he knows what he wants to find and generally he never finds what he wants to find. So self-programming is even more sterilizing than programming from the outside, and that is something that must be condemned with real vigor. In the case of applied research, on the contrary, most of the time we rely on concepts that have been established by the research for knowledge, and the notion of programming is acceptable. It is also acceptable, I would say, at the political level in the high sense of the term: it is normal for society to make choices about the applied research it wants to develop, whereas that is impossible in the case of fundamental research. So here we are faced with two completely different attitudes in terms of the management of these two forms of research. Now I will make a point against the research that I consider statistically the worst, which is what I call oriented fundamental research, which is increasingly being imposed on us. There are exceptions of course, but statistically it is the worst form of research because very often the discoveries that truly lead to definitive breakthroughs come from such unexpected domains that we do not know which domains will lead to applications. So fundamental research must be all-encompassing, and above all avoid falling into the trap of fashion. In the same way that programming research is an expression of the past in fundamental research, fashion is also an expression of the past. When a science is fashionable, it is already too late. The job of the researcher in fundamental research is precisely to tackle subjects outside of fashion. But that is exactly what quantitative evaluation of fundamental research condemns. If I take my own research experience, I would not presume to pass judgment on the value of my research compared to that of others. However, I can make a judgment on what seems to me the best and the worst in research. Well, I have learned—this is a bit provocative what I am going to say now, but it is not completely a joke—to monitor very closely the impact factor, that is, the number of citations of my research. I noticed that every time my citation index went up, my originality decreased at about the same speed, because I was locking myself into a kind of dogma of my knowledge, and I was less and less able to imagine new ideas. I knew that when my number of citations went up, it was time to step sideways to approach a new subject and regain a quality absolutely fundamental to the researcher: a certain dose of ignorance. If you know everything, you cannot innovate. And this is also where the difference in attitude towards computing and the ease of access to information lies. Jean Perrin, Nobel Prize in Physics, said with a somewhat provocative spirit: the bibliography on a subject of fundamental research—I mean fundamental research—is done after the research, not before. And indeed, if you know everything about a subject before tackling it, the chances of imagining something new are absolutely minimal. So I recommend not overdoing access to computing via the net and all its extremely powerful means. Again, in the case of applied research, we are faced with a completely different situation where it is really necessary to take stock of everything that has been done in the field. So again, a big problem arises. Because if it is not noted, I wanted to emphasize that the big problem that remains is the problem of evaluation. Fundamental research as I conceive it is a creative activity, and creative activity is horribly difficult to evaluate. If we had to evaluate musicians, painters, and artists through committees, that is practically impossible. So that is the contradiction, and I will not bring you a definitive solution in this area. It is the great contradiction: we need high-quality fundamental research, but how to evaluate it? I know that despite all the fine speeches I give, as an evaluator I can make absolutely dramatic errors. When something is truly new, often either I do not understand it, or if I make a real effort, I can demonstrate that it is false. One could define a discovery by the fact that on average it is rejected by a conscientious evaluator because it contradicts a dogma in some way. So fundamental research is very difficult to evaluate. And here I would allow myself to mention, and I do not think I will truly contradict him, a phrase from Pierre Corvol, our administrator at the beginning of this session, who said: the researcher must be first, introducing the notion of competition. Well, there again I will make a fundamental difference, an essential difference between fundamental research and applied research. As Jean-Paul Clozel very well said, regarding applied research, to put it extremely simply, the criterion is the patent. A patent taken one day before another patent: so it is competition, being first, that is necessary. In fundamental research, I think it is also necessary to be first, but not at all in the sense generally understood. If it is a fashionable subject on which 10 or 15 very powerful laboratories are working in competition, being first is very good for my ego, maybe good for the national ego, but sociologically it has absolutely no importance, because if the discovery is not made at my place, it will be made elsewhere. For me, being first is being the first to tackle a new subject that no one else has tackled. That is being first for me, that is, at a level where the notion of competition in the classic sense does not arise. I am not fighting hand-to-hand with another laboratory; I am trying something new where for a short moment I am the only one. So that is what being first means to me. I would say, with a lot of pretension, to be first is perhaps for a short moment to be the only one. And that is, in my opinion, the fundamental job in the way I conceive fundamental research. So this notion of competition, indispensable and necessary—whether I like it or not, I do not have a competitive spirit—seems necessary in the field of applied research, but it must be conceived in a very different way in fundamental research. And I simply note that all current modes of organization of research—programming of fundamental research, all modes of quantitative evaluation that most of my colleagues criticize but apply in an entirely excessive manner—seem to me not only ineffective but negative in terms of choosing the origin to develop creativity in our fields. Fundamental research can only be evaluated retrospectively. I have received a considerable number of contracts, like any researcher my age. I made proposals where there was generally little correlation between what I had done and the program I had been funded for. I note in passing that no one has ever read one of my contracts, one of my contract reports. And as a member of committees—because I also sit on many evaluation committees—I have never had to evaluate the result of a contract. I have always had to evaluate projects that most of the time had little or no relation to what would actually be done with the money that had been distributed. So the only track I can give is that it seems to me that fundamental research must be evaluated retrospectively. When someone has done something, you can trust them for an additional three or four years, giving them maximum freedom of choice in carrying out their research. Again, what I defend for fundamental research does not seem to apply to applied research. A patent can be counted, measured. And all the conclusions I apply to fundamental research do not seem valid for the management of applied research. So I simply wanted to end by saying that fundamentally, I think with a different perspective, I thought I understood that we shared roughly the same ideas. And it is quite comforting to see that two people with such different training and professions can arrive at a certain degree of convergence.