186
I PHARMACEUTICAL
RESEARCH AND THE WORLD'S HEALTH
Tropical Doctor, October I977
Medical Research
Pharmaceutical research and the world's health* J. R. Vane, DSc, DPhil, FRS Group Research and Development Director, The Wellcome Foundation Ltd, London TROPICAL DOCTOR,
1977, 7, 186-188
Drugs are not synonymous with health. They are for the treatment and prevention of disease and for the regulation of the functions of the body. There are many forces for the promotion of health including nutrition, education, and hygiene. Indeed, in some parts of the world, these must take priority before more sophisticated medicine can be brought into play. Nevertheless, discoveries of the research laboratories have greatly improved health and extended the expectation and quality of life in this century. DISCOVERY OF A DRUG AND ITS DELIVERY
The discovery of a drug is not synonymous with its delivery, still less with its administration to the patient. The identification and documentation of a hitherto unknown pharmacological activity is only the start of a long process. Profitable new drugs have arisen from four broad approaches which are generally known as: (I) "empirical" or random, (2) molecular manipulation, or the examination of structures related to compounds of known activity drugs, (3) extraction and/or modifications of natural substances, and (4) "rational", as exemplified by designing chemicals to interfere with enzymes known to be vital for the life of the invading organism but not of the host. In fact, all these approaches are highly rational, although the one given that designation is the most pleasing scientifically. The boundaries between them are not always clear and when there is an overlay of serendipity, ingenuity (especially in the development of relevant tests), and inspired opportunism, all have their place in industrial research. Empirical This approach can only be regarded as "random screening" up to the point that activity is found.
Thereafter the accumulated wisdom of the chemist rapidly develops the best structural modifications. In my opinion, there is still the need to encourage the development of high throughput screens (such as measurement of an anti-enzyme activity in a test tube) which allow rapid (and cheap) assessment of very small quantities of new (or old) chemicals. Molecular manipulation Step 1 can be eliminated when structures are already known which have the desired activity. Chemists then study related structures to increase activity, reduce side-effects, change features such as absorbability by mouth, and even to discover new activities. 2.
3. Extraction and/or modification of natural substances The search in recent years for exploitable and extractable biological activity (usually of high molecular weight) has not led to immediate rewards. There is great interest in the immuno-stimulant properties of Corynebacterium paruum and a recent revival of interest in interferon. This type of biological product has a standard of crudity which is completely unacceptable when we deal with smaller molecules. Strengths in immunology and immunochemistry are vital to take this whole area on to a different scientific and chemical plane in the 1980s. Many peptide chemists believe that complicated proteins such as insulin will be made synthetically on a commercial scale within the next decade; others believe that genetic engineering will lead to easier ways of producing substances such as insulin and interferon. 4. Rational As we learn more about the workings of individual cells and of the structure of the molecules in cells with which drugs react, so we shall be better able to design drugs. This is a long-term strategy; rest ~ts come slowly, but new drugs which arise are likely to be fundamental "breakthroughs" of substantial scientific and commercial value.
I.
*Abbreviated text of an address given at the Bicentennial Dedication Programme, Upjohn Pharmaceutical Development Centre, Kalamazoo, Michigan, USA, October 18, 1976.
Most drugs work because they have a very definite molecular shape which slots neatly into a receptor which has a complementary shape - like a lock and key. It seems reasonable, therefore, to invent new drugs by manipulating the shape of a known drug. The "lock oriented" approach may also be ex-
Tropical Doctor, October £977
PHARMACEUTICAL RESEARCH AND THE WORLD'S HEALTH
ploitable in repairing defective enzymes. It may be possible to design artificial chemicals which could slot into the distorted active site of a defective enzyme, thus restoring its correct shape. Let us now consider the questions where discoveries are made, how, and who makes them? Innovation depends on creative scientists working in a fertile atmosphere under stable conditions. This combination can exist either in industry or in academia but is usually dependent on the creation of a "centre of excellence" which depends on a young scientist showing the ability to innovate, becoming recognized internationally, building a team around him, and then making sure that there is financial stability. There are several types of scientists, and each is just as important as the other. But there is one small elite group of trailblazers without whom the others cannot function. They are the scouts, the pioneers, the frontiersmen - those who find the right pathway through the undergrowth of false leads. To summarize the characteristics of this elite band, first, they can communicate enthusiasm to others. Second, they are the successful trailblazers, with a rare knack to know which path is going to be the right one. Third, they can pick the right people and create a stimulating atmosphere in which those people can develop. Fourth, and this is perhaps another facet of the same characteristic, they can recognize in others the same qualities that they have themselves. I have asked questions about where, by whom, and how discoveries are made. But further questions have been asked recently, including what kind ofdiscoveries ought to be made. To a scientific audience this last question may seem somewhat ironic. For, despite the greater sophistication of the methods of all of us, discoveries do not depend on completely structured research and we still have to take our discoveries where we can find them. DRUGS AND THE "THIRD WORLD"
A report has appeared in the United Kingdom within the past few months which accuses the international pharmaceutical companies not only of neglect but of positive malpractice towards the "Third World". The particular accusation was one of turning attention away from the diseases that oppress the developing countries and of trying to foist on to those countries the products more appropriate to the Western world. This accusation highlights the role of the pharmaceutical companies in the developments of the future. The report was entitled "Who Needs the Drug Companies?" but, however aggressively this was
I I87
framed, it is a question that has a very simply answer. The world needs the drug companies for what the drug companies can do. It needs many other things besides. Accusations of neglecting tropical medical research do not, as you can imagine, go down well at Wellcome, where research in this field has extended over some 60 years in areas of the world where malaria, schistosomiasis, intestinal helminthiasis, leishmaniasis, and filariasis are endemic. But money and skill devoted to specific research projects is not in itself the resolution of the problem. Research into tropical medicine cannot be conducted in isolation. Drugs for the prevention of malaria and of smallpox emerged as part of a continuous line of discoveries which also produced treatments for leukaemia and hyperuricaemia as well as a drug for the suppression of the rejection of transplanted organs and a broad-spectrum antibacterial. Set up a global research programme and you stand a chance of discovering contributions to tropical medicine along the way. If you concentrate on too narrow a field, you limit your chances and run the risk of making no discoveries at all. But even this is not the whole answer. Perhaps a drug to suppress the rejection of a transplanted kidney is not a high priority for the third world but a broad-spectrum antibacterial definitely is. Bacterial infections are as prevalent in developing countries as they are in the Western world and often a great deal more deadly. That same discovery which is prescribed in the United States for stubborn urinary tract infections is extremely useful in the treatment of typhoid and of salmonellosis. Whatever the situation would be in an ideal world, recent history has proved that major advances in therapeutics are likely to come from large companies, internationally organized and operating in countries where they can patent their products and make a profit out of them to provide the resources for further research. If not the discovery, then certainly the development and, most important of all, the delivery of the new drug calls for this kind of international organization. In the question of distance between the discovery of a drug and its delivery it is not enough to demonstrate the beneficial effects of a compound; we must minutely measure and chart all its pharmacological effects, desired and undesired. We must establish its efficacy beyond doubt and we must show what its effect will be when administered over a long term. All this takes a lot of time and it calls for large-scale resources. When all thi.s is done, we still need the chemical
188
I PHARMACEUTICAL
RESEARCH AND THE WORLD'S HEALTH
development which will enable a new drug to be produced in large quantities and the pharmaceutical development to arrive at formulations that will be most suitable for the patient and will stand up to storage and use, for example, in hot climates. All of this must be documented, proved, and demonstrated every bit as thoroughly as the initial experiments and trials. Then, of course, we have the different phases of clinical trials with all the expense that they involve. The economics of this operation are such that it is simply not viable if the new drug is to be introduced ill, one country alone. Unless the drug is going to be needed by a large number of patients the money to finance the initial basic research may not itself be available. Moreover, if you have an international organization capable of delivering the new drugs of world-wide application, for which there are vast markets, it is here that you have the best chance of developing alongside them those drugs of more limited application which may be needed only in certain areas. Weare coming to the much more difficult question: not who discovers the drug but who pays for it?
Tropical Doctor, October I977
Ultimately it is people who pay for it, either as individual patients or governments buying on their behalf, who may in their turn draw funds from the people in taxes. But what they are paying for is not just a few chemical ingredients made up into a tablet. Whether the research is carried out in academic or industrial laboratories, whether the delivery is effected by a commercial laboratory or by some nationalized production centre, the backing for an extremely complex and expensive technology has to be provided either by patients or by governments or by some supranational agency such as the United Nations. This highlights the situation of the developing countries. But the question is not only one of research. Besides the need for new drugs and vaccines, some of them specific to the tropical areas, there is a need to see that existing discoveries are more widely used. The wider use of such products ill, developing countries would in turn create the broader base which would make a greater concentration on the diseases of tropical countries into a more practical proposition. The question is not one of profits and of markets; it is simply one of scale.
Notes and News Long-term planning of international co-operation in cancer research The World Health Organization has completed its review of a progress report on long-term planning of international co-operation in cancer research which reveals that, in developed countries, cancer strikes two out of every three families. In Europe during the present decade an estimated 14 million people will die of cancer. The economic loss from cancer deaths in the United States of America alone amounts to almost 18,000 million dollars a year. A number of developed countries have gained wide experience in organizing cancer control activities, and it is one of WHO's tasks to pass this knowledge on to the developing countries. WHO's activities in cancer concern the development of cancer health services, standardization, establishment of a network of collaborating centres for improving methods of diagnosis and treatment, and periodic international reappraisal of various aspects of cancer control. The International Agency for Research on Cancer (IARC) at Lyon concentrates its main efforts on environmental research, particularly in the areas of epidemiology and chemical and biological carcinogenesis.
SALUBRITAS The division of International Health Programs of the American Public Health Association, in co-sponsorship with the World Federation of Public Health Associations, is publishing SALUBRITAS, a quarterly newsletter on low-cost health delivery systems in developing countries. The publication is aimed at establishing a two-way communication flow among health workers having common problems and similar goals and is published in English, Spanish, and French. The target audience includes health-related workers at the grass-roots level and the decision makers who are responsible for establishing policies and priorities within their countries' health systems. The newsletter is also distributed to government agencies, training institutions, and bilateral and multilateral organizations. It is hoped that this publication will provide a useful tool for exchanging ideas and strengthening communications between colleagues in different parts of the world. For further information write to Sylvia C. McCracken, Editor, International Health Programs, American Public Health Association, 1015 Eighteenth Street, N.W., Washington, D.C. 20036, USA.
I PHARMACEUTICAL
RESEARCH AND THE WORLD'S HEALTH
Tropical Doctor, October I977
Medical Research
Pharmaceutical research and the world's health* J. R. Vane, DSc, DPhil, FRS Group Research and Development Director, The Wellcome Foundation Ltd, London TROPICAL DOCTOR,
1977, 7, 186-188
Drugs are not synonymous with health. They are for the treatment and prevention of disease and for the regulation of the functions of the body. There are many forces for the promotion of health including nutrition, education, and hygiene. Indeed, in some parts of the world, these must take priority before more sophisticated medicine can be brought into play. Nevertheless, discoveries of the research laboratories have greatly improved health and extended the expectation and quality of life in this century. DISCOVERY OF A DRUG AND ITS DELIVERY
The discovery of a drug is not synonymous with its delivery, still less with its administration to the patient. The identification and documentation of a hitherto unknown pharmacological activity is only the start of a long process. Profitable new drugs have arisen from four broad approaches which are generally known as: (I) "empirical" or random, (2) molecular manipulation, or the examination of structures related to compounds of known activity drugs, (3) extraction and/or modifications of natural substances, and (4) "rational", as exemplified by designing chemicals to interfere with enzymes known to be vital for the life of the invading organism but not of the host. In fact, all these approaches are highly rational, although the one given that designation is the most pleasing scientifically. The boundaries between them are not always clear and when there is an overlay of serendipity, ingenuity (especially in the development of relevant tests), and inspired opportunism, all have their place in industrial research. Empirical This approach can only be regarded as "random screening" up to the point that activity is found.
Thereafter the accumulated wisdom of the chemist rapidly develops the best structural modifications. In my opinion, there is still the need to encourage the development of high throughput screens (such as measurement of an anti-enzyme activity in a test tube) which allow rapid (and cheap) assessment of very small quantities of new (or old) chemicals. Molecular manipulation Step 1 can be eliminated when structures are already known which have the desired activity. Chemists then study related structures to increase activity, reduce side-effects, change features such as absorbability by mouth, and even to discover new activities. 2.
3. Extraction and/or modification of natural substances The search in recent years for exploitable and extractable biological activity (usually of high molecular weight) has not led to immediate rewards. There is great interest in the immuno-stimulant properties of Corynebacterium paruum and a recent revival of interest in interferon. This type of biological product has a standard of crudity which is completely unacceptable when we deal with smaller molecules. Strengths in immunology and immunochemistry are vital to take this whole area on to a different scientific and chemical plane in the 1980s. Many peptide chemists believe that complicated proteins such as insulin will be made synthetically on a commercial scale within the next decade; others believe that genetic engineering will lead to easier ways of producing substances such as insulin and interferon. 4. Rational As we learn more about the workings of individual cells and of the structure of the molecules in cells with which drugs react, so we shall be better able to design drugs. This is a long-term strategy; rest ~ts come slowly, but new drugs which arise are likely to be fundamental "breakthroughs" of substantial scientific and commercial value.
I.
*Abbreviated text of an address given at the Bicentennial Dedication Programme, Upjohn Pharmaceutical Development Centre, Kalamazoo, Michigan, USA, October 18, 1976.
Most drugs work because they have a very definite molecular shape which slots neatly into a receptor which has a complementary shape - like a lock and key. It seems reasonable, therefore, to invent new drugs by manipulating the shape of a known drug. The "lock oriented" approach may also be ex-
Tropical Doctor, October £977
PHARMACEUTICAL RESEARCH AND THE WORLD'S HEALTH
ploitable in repairing defective enzymes. It may be possible to design artificial chemicals which could slot into the distorted active site of a defective enzyme, thus restoring its correct shape. Let us now consider the questions where discoveries are made, how, and who makes them? Innovation depends on creative scientists working in a fertile atmosphere under stable conditions. This combination can exist either in industry or in academia but is usually dependent on the creation of a "centre of excellence" which depends on a young scientist showing the ability to innovate, becoming recognized internationally, building a team around him, and then making sure that there is financial stability. There are several types of scientists, and each is just as important as the other. But there is one small elite group of trailblazers without whom the others cannot function. They are the scouts, the pioneers, the frontiersmen - those who find the right pathway through the undergrowth of false leads. To summarize the characteristics of this elite band, first, they can communicate enthusiasm to others. Second, they are the successful trailblazers, with a rare knack to know which path is going to be the right one. Third, they can pick the right people and create a stimulating atmosphere in which those people can develop. Fourth, and this is perhaps another facet of the same characteristic, they can recognize in others the same qualities that they have themselves. I have asked questions about where, by whom, and how discoveries are made. But further questions have been asked recently, including what kind ofdiscoveries ought to be made. To a scientific audience this last question may seem somewhat ironic. For, despite the greater sophistication of the methods of all of us, discoveries do not depend on completely structured research and we still have to take our discoveries where we can find them. DRUGS AND THE "THIRD WORLD"
A report has appeared in the United Kingdom within the past few months which accuses the international pharmaceutical companies not only of neglect but of positive malpractice towards the "Third World". The particular accusation was one of turning attention away from the diseases that oppress the developing countries and of trying to foist on to those countries the products more appropriate to the Western world. This accusation highlights the role of the pharmaceutical companies in the developments of the future. The report was entitled "Who Needs the Drug Companies?" but, however aggressively this was
I I87
framed, it is a question that has a very simply answer. The world needs the drug companies for what the drug companies can do. It needs many other things besides. Accusations of neglecting tropical medical research do not, as you can imagine, go down well at Wellcome, where research in this field has extended over some 60 years in areas of the world where malaria, schistosomiasis, intestinal helminthiasis, leishmaniasis, and filariasis are endemic. But money and skill devoted to specific research projects is not in itself the resolution of the problem. Research into tropical medicine cannot be conducted in isolation. Drugs for the prevention of malaria and of smallpox emerged as part of a continuous line of discoveries which also produced treatments for leukaemia and hyperuricaemia as well as a drug for the suppression of the rejection of transplanted organs and a broad-spectrum antibacterial. Set up a global research programme and you stand a chance of discovering contributions to tropical medicine along the way. If you concentrate on too narrow a field, you limit your chances and run the risk of making no discoveries at all. But even this is not the whole answer. Perhaps a drug to suppress the rejection of a transplanted kidney is not a high priority for the third world but a broad-spectrum antibacterial definitely is. Bacterial infections are as prevalent in developing countries as they are in the Western world and often a great deal more deadly. That same discovery which is prescribed in the United States for stubborn urinary tract infections is extremely useful in the treatment of typhoid and of salmonellosis. Whatever the situation would be in an ideal world, recent history has proved that major advances in therapeutics are likely to come from large companies, internationally organized and operating in countries where they can patent their products and make a profit out of them to provide the resources for further research. If not the discovery, then certainly the development and, most important of all, the delivery of the new drug calls for this kind of international organization. In the question of distance between the discovery of a drug and its delivery it is not enough to demonstrate the beneficial effects of a compound; we must minutely measure and chart all its pharmacological effects, desired and undesired. We must establish its efficacy beyond doubt and we must show what its effect will be when administered over a long term. All this takes a lot of time and it calls for large-scale resources. When all thi.s is done, we still need the chemical
188
I PHARMACEUTICAL
RESEARCH AND THE WORLD'S HEALTH
development which will enable a new drug to be produced in large quantities and the pharmaceutical development to arrive at formulations that will be most suitable for the patient and will stand up to storage and use, for example, in hot climates. All of this must be documented, proved, and demonstrated every bit as thoroughly as the initial experiments and trials. Then, of course, we have the different phases of clinical trials with all the expense that they involve. The economics of this operation are such that it is simply not viable if the new drug is to be introduced ill, one country alone. Unless the drug is going to be needed by a large number of patients the money to finance the initial basic research may not itself be available. Moreover, if you have an international organization capable of delivering the new drugs of world-wide application, for which there are vast markets, it is here that you have the best chance of developing alongside them those drugs of more limited application which may be needed only in certain areas. Weare coming to the much more difficult question: not who discovers the drug but who pays for it?
Tropical Doctor, October I977
Ultimately it is people who pay for it, either as individual patients or governments buying on their behalf, who may in their turn draw funds from the people in taxes. But what they are paying for is not just a few chemical ingredients made up into a tablet. Whether the research is carried out in academic or industrial laboratories, whether the delivery is effected by a commercial laboratory or by some nationalized production centre, the backing for an extremely complex and expensive technology has to be provided either by patients or by governments or by some supranational agency such as the United Nations. This highlights the situation of the developing countries. But the question is not only one of research. Besides the need for new drugs and vaccines, some of them specific to the tropical areas, there is a need to see that existing discoveries are more widely used. The wider use of such products ill, developing countries would in turn create the broader base which would make a greater concentration on the diseases of tropical countries into a more practical proposition. The question is not one of profits and of markets; it is simply one of scale.
Notes and News Long-term planning of international co-operation in cancer research The World Health Organization has completed its review of a progress report on long-term planning of international co-operation in cancer research which reveals that, in developed countries, cancer strikes two out of every three families. In Europe during the present decade an estimated 14 million people will die of cancer. The economic loss from cancer deaths in the United States of America alone amounts to almost 18,000 million dollars a year. A number of developed countries have gained wide experience in organizing cancer control activities, and it is one of WHO's tasks to pass this knowledge on to the developing countries. WHO's activities in cancer concern the development of cancer health services, standardization, establishment of a network of collaborating centres for improving methods of diagnosis and treatment, and periodic international reappraisal of various aspects of cancer control. The International Agency for Research on Cancer (IARC) at Lyon concentrates its main efforts on environmental research, particularly in the areas of epidemiology and chemical and biological carcinogenesis.
SALUBRITAS The division of International Health Programs of the American Public Health Association, in co-sponsorship with the World Federation of Public Health Associations, is publishing SALUBRITAS, a quarterly newsletter on low-cost health delivery systems in developing countries. The publication is aimed at establishing a two-way communication flow among health workers having common problems and similar goals and is published in English, Spanish, and French. The target audience includes health-related workers at the grass-roots level and the decision makers who are responsible for establishing policies and priorities within their countries' health systems. The newsletter is also distributed to government agencies, training institutions, and bilateral and multilateral organizations. It is hoped that this publication will provide a useful tool for exchanging ideas and strengthening communications between colleagues in different parts of the world. For further information write to Sylvia C. McCracken, Editor, International Health Programs, American Public Health Association, 1015 Eighteenth Street, N.W., Washington, D.C. 20036, USA.
