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Suggested Citation:"HISTORICAL PERSPECTIVE." Institute of Medicine. 1979. Pharmaceuticals for Developing Countries: Conference Proceedings. Washington, DC: The National Academies Press. doi: 10.17226/18441.
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Suggested Citation:"HISTORICAL PERSPECTIVE." Institute of Medicine. 1979. Pharmaceuticals for Developing Countries: Conference Proceedings. Washington, DC: The National Academies Press. doi: 10.17226/18441.
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Suggested Citation:"HISTORICAL PERSPECTIVE." Institute of Medicine. 1979. Pharmaceuticals for Developing Countries: Conference Proceedings. Washington, DC: The National Academies Press. doi: 10.17226/18441.
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Suggested Citation:"HISTORICAL PERSPECTIVE." Institute of Medicine. 1979. Pharmaceuticals for Developing Countries: Conference Proceedings. Washington, DC: The National Academies Press. doi: 10.17226/18441.
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Suggested Citation:"HISTORICAL PERSPECTIVE." Institute of Medicine. 1979. Pharmaceuticals for Developing Countries: Conference Proceedings. Washington, DC: The National Academies Press. doi: 10.17226/18441.
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Suggested Citation:"HISTORICAL PERSPECTIVE." Institute of Medicine. 1979. Pharmaceuticals for Developing Countries: Conference Proceedings. Washington, DC: The National Academies Press. doi: 10.17226/18441.
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Suggested Citation:"HISTORICAL PERSPECTIVE." Institute of Medicine. 1979. Pharmaceuticals for Developing Countries: Conference Proceedings. Washington, DC: The National Academies Press. doi: 10.17226/18441.
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Suggested Citation:"HISTORICAL PERSPECTIVE." Institute of Medicine. 1979. Pharmaceuticals for Developing Countries: Conference Proceedings. Washington, DC: The National Academies Press. doi: 10.17226/18441.
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Suggested Citation:"HISTORICAL PERSPECTIVE." Institute of Medicine. 1979. Pharmaceuticals for Developing Countries: Conference Proceedings. Washington, DC: The National Academies Press. doi: 10.17226/18441.
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Suggested Citation:"HISTORICAL PERSPECTIVE." Institute of Medicine. 1979. Pharmaceuticals for Developing Countries: Conference Proceedings. Washington, DC: The National Academies Press. doi: 10.17226/18441.
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Suggested Citation:"HISTORICAL PERSPECTIVE." Institute of Medicine. 1979. Pharmaceuticals for Developing Countries: Conference Proceedings. Washington, DC: The National Academies Press. doi: 10.17226/18441.
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Suggested Citation:"HISTORICAL PERSPECTIVE." Institute of Medicine. 1979. Pharmaceuticals for Developing Countries: Conference Proceedings. Washington, DC: The National Academies Press. doi: 10.17226/18441.
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Suggested Citation:"HISTORICAL PERSPECTIVE." Institute of Medicine. 1979. Pharmaceuticals for Developing Countries: Conference Proceedings. Washington, DC: The National Academies Press. doi: 10.17226/18441.
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Suggested Citation:"HISTORICAL PERSPECTIVE." Institute of Medicine. 1979. Pharmaceuticals for Developing Countries: Conference Proceedings. Washington, DC: The National Academies Press. doi: 10.17226/18441.
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Suggested Citation:"HISTORICAL PERSPECTIVE." Institute of Medicine. 1979. Pharmaceuticals for Developing Countries: Conference Proceedings. Washington, DC: The National Academies Press. doi: 10.17226/18441.
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Suggested Citation:"HISTORICAL PERSPECTIVE." Institute of Medicine. 1979. Pharmaceuticals for Developing Countries: Conference Proceedings. Washington, DC: The National Academies Press. doi: 10.17226/18441.
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Suggested Citation:"HISTORICAL PERSPECTIVE." Institute of Medicine. 1979. Pharmaceuticals for Developing Countries: Conference Proceedings. Washington, DC: The National Academies Press. doi: 10.17226/18441.
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Suggested Citation:"HISTORICAL PERSPECTIVE." Institute of Medicine. 1979. Pharmaceuticals for Developing Countries: Conference Proceedings. Washington, DC: The National Academies Press. doi: 10.17226/18441.
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Suggested Citation:"HISTORICAL PERSPECTIVE." Institute of Medicine. 1979. Pharmaceuticals for Developing Countries: Conference Proceedings. Washington, DC: The National Academies Press. doi: 10.17226/18441.
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Suggested Citation:"HISTORICAL PERSPECTIVE." Institute of Medicine. 1979. Pharmaceuticals for Developing Countries: Conference Proceedings. Washington, DC: The National Academies Press. doi: 10.17226/18441.
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HISTORICAL PERSPECTIVE Walsh McDermott Thirty years ago this month, on a clear and very cold January day, President Truman gave his inaugural address from a portico of the White House. It was the first inauguration covered by television and I was one of the millions who saw it in that way. As is not unusual on such occasions, the President listed a number of programs he hoped to lead to realization. Few people can today recall points one, two, and three of his list; but Point Four has had a certain immortality. For the fourth point was the announcement of a program in which the highly valued technology of the United States would be made available for the development of the badly impoverished nations of the world. Biomedical or health technology, if you will, was just coming into flower at that time. Its outstanding attribute was that virtually for the first time medicine was developing the capacity to intervene deci- sively in the course of a wide range of diseases. The diseases were some of the major ones forming the disease pattern of an industrialized society, for scientists tend to work on the diseases that are of con- siderable importance in their own world. What is this interventionist technology? In large measure it consists of medications, solutions, vaccines, and anesthetics. It also includes diagnostic and surgical techniques. For the purposes of this Conference, however, my discussion is largely concerned with drugs and vaccines. Prontosil — the first sulfonamide developed in 1935 — marks the clear begining of the present era. More potent sulfonamides were rapid- ly developed and within five or six years we went into what I call the golden decade, from 1941 to 1951. In 194l, we had only quinine, ata- brine, the arsenicals, and the sulfonamides as our antimicrobial drugs. By 195l, we had available every one of the major drug series we have today: the pencillins, the streptomycins, the tetracyclines, chloram- phenicol, and isoniazid. The antifungal drug, amphotericin B, was

developed later but, except for that, no major disease has been changed to the generally drug-treatable list in over 25 years. To say that there have been no major therapeutic breakthroughs in almost 30 years is not to say that the results of what was developed in that decade ceased when the decade ended in 1951. On the contrary, the influence has been a continuing affair and includes far greater conse- quences, both technologic and social, than are generally appreciated. Everyone knows the drugs transformed the disease pattern of the United States and ultimately that of the rest of the industrialized world. But it is not always realized, for example, that the drugs made possi- ble today's lung and heart surgery. Even less consciously considered is the role of the drugs in the development of more efficient tech- niques for handling viruses and cell cultures in the test-tube, thereby facilitating antiviral vaccine production. Virtually the entire scien- tific development involving cell biology has depended on techniques that would not have been possible or would have been immensely more difficult were it not for the antimicrobial drugs. Derivative drugs were developed, some antimicrobial, some not, as for example the thiazides and certain tranquilizers. There has been the use of antibiotics in animal feed — an issue of controversy at this time. There have been extensive changes in the workings of the health care delivery system. And not the least of the consequences has been the creation in our country of an essentially new and greatly enlarged system for the nourishment of biomedical science and technology. Next to the story of the genetic role of DNA (also in this decade*) this is the major biomedical event of the century. My assignment is not to tell this story, but to recall to you from it a few lessons that might help in forming a perspective for our view of the future. Because of the nature of what I am attempting, I am limiting my comments almost entirely to the United States experience. The research support system that developed involved the federal government, the pharmaceutical laboratories, and the academic labora- tories, and had mixed public and private support. Theoretically, the technologies derived from this system could be applied through either one of the two main avenues for the application of science for man's benefit. These are: 1. The public health system, in which an intervention is made that affects a number of people at once, «;•£. , a program to reduce the incidence of goiter by putting iodine in table salt. 2. The personal service system. This is the one most people know; *As were the explosion at Alamogordo and the bombing of Hiroshima and Nagasaki. 10

the intervention is applied not to a whole community but to an individual. This means that almost invariably it has to be applied or "delivered," if you will, by a physician or someone delegated by the physician. Irrespective of level of training, this system requires that there be one person to do something for another. These represent two forces on our health status. A third force less easy to characterize but quite real, is the way of life permitted by the material culture. Chemicals, as distinct from pharmaceuticals — for example, DDT — can be effectively delivered through the public health system. But pharmaceuticals almost by definition require some form of personal ser- vice system for delivery. Thus, when the effectiveness of that system to improve a people's health comes under challenge, it is also a chal- lenge to the United States pharmaceutical industry. For, if its output is not having too much effect on the United States people, it might not hold forth much promise for those in developing countries. Consequently, while considering the role of the United States industry in the developing countries, this issue of the health impact of the personal service system must be resolved. As I published just last year JY a detailed discussion of this issue, I shall confine my- self today to only a few points that bear directly on our subject. At the outset, may I emphasize that this has become a major issue in health policy today. Rapidly ascending costs have produced a collection of strange bed- fellows, including economists who wish to invest a considerably higher proportion of the health dollar in something other, and presumably cheaper, than our present system of personal medical care — the so- called alternative health strategies. We are interested today in only a portion of this case; namely, the nationwide health impact of the per- sonal service physician system — the system that consists of the phy- sicians, their hospitals, and the therapeutic and other technologies they employ. What is not generally understood is that we have devised no indicators to measure the effectiveness of what the doctor does on the health status of a society. For the outside critic especially, it is very easy to fail to realize when some indicator is being used to mea- sure something it could not possibly indicate. There is a general fail- ure to realize, therefore, that what are known as "the usual indices of health status" are indicators that have been developed through the years to measure the public health system, not the personal service physician system. These indicators are based on births and deaths. Deaths get counted as physician failures, but we have no way of measur- ing the successes of the personal service physician system. Everything that does show up, in effect shows up as a failure. 11

To be sure, if the personal physician system had an absolutely smashingly successful year — a major epidemic of success, so to speak — it might be picked up in the public health system indicators, even though these indicators at best can reflect only a portion of the per- sonal physician system's influence. We would have to have a situation in which within a single year a new technology, jL.£. , a new drug, would be introduced that could actually prevent the deaths of large enough numbers of people to constitute a significant reduction of our annual total of two million or so deaths. To do this, the new technology, say a pill, would have to do either of two things: be effective against many different potentially fatal diseases; or be effective against one fairly common, potentially fatal, and carefuly reported disease. These are stringent conditions to have to meet and understandably they would occur rarely, if at all. Yet they have actualy occurred at least twice in the past 30 years or so, and on both occasions there was a clear-cut fall in either the overall or the disease-specific death rate. From 1900 to the mid-1930s, the United States death rate showed a slow but steady fall. I-have presented evidence elsewhere that very little of the fall could be attributed to drugs or other therapies of the personal physician system. In November 1936, Franklin Roosevelt, Jr., a student at Harvard and the son of the then President, was admitted to Massachusetts Gener- al Hospital with a streptococcal sore throat and treated with the hitherto unknown drug, Prontosil. Diseases with words like "strepto- cocci" associated with them were quite generally feared by the public. For, roughly 10 years before that, the son of the then President, Calvin Coolidge, while a student at prep school, had died of "blood poisoning," a vernacular term then used to describe systemic bacterial infections such as those produced by staphylococci or streptococci.* Hence, all America followed young Franklin's course daily. And his prompt recovery was taken as the most effective of announcements to both the medical professions and the public-at-1arge that a new drug — the first sulfonamide — had been discovered. In actuality, as reported elsewhere,^/ the drug had been used for a very few patients the year before in New York City. Thus, at the start of the new year in 1937, an adequate supply of sulfonamide was put into the hands of the personal encounter physicians all over America and no advertisement of its value was needed. In Figure 1 may be seen death rates for men and for women from our black (i.e., "all other") and from our white populations. *In actuality, the infection appears to have been staphylococcal, thought to have arisen from a blister on a heel. 12

FIGURE 1. AGE-ADJUSTED DEATH RATES, BY COLOR AND SEX, 1933-1973 a/ Sulfonamide Whi1e Male 'AH oiher Female While Female a/Source: National Center for Health Statistics (slightly adapted). The curves start with 1935 and 1936, which were very much like previous years. In the year 1937, however, there was a sharp fall in death rate. This fall, which was sharper in the "all other" population than among the whites, started immediately with the wide use of sulfona- mide. Penicillin came into wide use about eight years later, and as mentioned earlier, virtually all of the other antimicrobials were in use by 1951. The curves are presented until the mid-70s, but it is the sharp- ness of the onset in 1937 that is the key point. There was no new vac- cine program — no major change in lifestyle. A new drug was intro- duced that was applicable to the problems of large numbers of people, young and old, and was applied only through the personal physician system. 13

Streptococcal disease was a major part of the disease pattern for these overall death rates. Tuberculosis was the disease for which changes in disease-specific rates may be seen. Both of these diseases have figured prominently in the studies of the British writer, Thomas McKeown._3/ In Figure 2 may be seen a graph that represents the death rate attributed to tuberculosis in England and Wales, decade by decade, FIGURE 2. RESPIRATORY TUBERCULOSIS, MEAN ANNUAL DEATH RATE IN ENGLAND AND WALES a/ E i X H- <J u) o 1838 1850 i860 i8TO 1880 1890 l90O 1910 l92O I93O 19401990 l960 l9TO YEAR a/Dotted line square added (see reference 3/). from 1938 to 1970. It is McKeown's graph, and a much cited one. He points out quite correctly that there is every reason to believe that the incidence of what was thought to be tuberculosis was falling throughout the 19th century. He further implies _3_/ that the 20th cen- tury control of tuberculosis in Great Britain resulted mainly from a steady continuation of these same 19th century forces that occurred long before chemotherapy. While conceding that the introduction of streptomycin was accompanied by a "quite considerable decline in tuber- culosis deaths in the age group 15 to 45 and over ...", he regards what occurred as "a very limited contribution" when put in perspective in

relating to the total period. This judgement is now widely cited in condensed form to the effect that the introduction of the antituberculo- sis drugs such as streptomycin and isoniazid have made only a limited contribution to the reduction in deaths from this disease. This inter- pretation of McKeown's viewpoint gets reinforced by his stated belief that even after 1935 the available chemotherapy is less effective than that of other influences against a whole spectrum of bacterial diseases. His concept thus gets projected into the future and is used extensively in support of the alternative health strategies "movement." In Figure 3 may be seen the same tuberculosis death rates as in Figure 1. The area within the dotted line on Figure 1 has been blown up and the data placed on a logarithmic scale. This is the area that covers the introduction of the drug therapy of tuberculosis. FIGURE 3. TUBERCULOSIS NEW CASE AND DEATH RATES IN ENGLAND AND WALES a/ Year: 19JO 1940 1990 l960 ji/Area within dotted square enlarged and placed on logarithmic scale showing death rates before and after onset of chemotherapy in 1947 (see reference 2/). 15

On this graph, the rapid fall in death rate that started immediate- ly after the wide use of drug treatment is easily seen. Occasions on which it would be possible to measure the effect of a new technology on a whole people are understandably rare, but these two examples certainly show that in the circumstances of the United Kingdom or the United States, the technology works. The next point is, how did we manage to get rid of the diseases that form such an important part of the disease pattern of the develop- ing world? The disease pattern of the urban rich is like our own and is very much the same the world over. In some developing countries, there is an emerging middle class not yet of large size, but of whom much the same could be said. It is the others in the developing countries who form the great majority and are our concern. Their disease pattern can be separated into an outer skin and a central core. The core consists of the diseases found virtually every- where in the developing countries. It is useful to separate these core diseases into those of adults, including surgical conditions, and those of early childhood. This large core is covered by an outer skin of varied thickness that differs from one locality to another and thus provides distinctive local coloration to the disease pattern of a particular region. The group forming this outer layer consists princi- pally of the helminthic or protozoan diseases — such diseases as ma- laria, Chagas1 Disease, hookworm, and schistosomiasis. This then is the technologic substrate of the developing countries; for some of it we have effective technologies and for some we have not. If I were to discuss it in detail, I would be encroaching on the assign- ments of speakers that follow. There are a few points, however, that must be cited. It is not always realized that malaria, cholera, yellow fever, and smallpox were all important diseases in the northeastern United States at one time — hookworm was well known in parts of the rural South. To all intents and purposes, these have disappeared as problems. The most important disease in the world today in terms of numbers of deaths, is the pneumonia-diarrhea complex of infants. One reason is that unlike the worms or protozoan diseases (which are certainly impor- tant, but are confined geographically) the pneumonia-diarrhea complex occurs everywhere in the conditions of poverty and can affect the same baby on repeated occasions. Any potentially fatal disease problem of infants and young children has additional significance in terms of economic development 16

because there appears to be an important association between a high youthful mortality and an unwillingness to become interested in limita- tions of family size. How have we managed this problem in our society? One way we seek answers to such questions is to find so-called experiments of nature, ^.£., situations that occur by chance but are so well recorded as to permit analysis. Such experiments on diseases that are major problems in developing countries are not too common. The reason is that two contradictory conditions must occur together. One condition is that the locality must be underdeveloped enough so that the disease is present, and present in sufficient numbers so that a change in it would be significant. The other condition is that the locality must be developed enough so that its vital statistics are believable. New York City early in this century met these two conditions. A graph of the infant mortality in New York City from 1900 to 1930 may be seen in Figure 4. At the turn of the century (shown on the left) the infant mortality was 140 instead of today's 14 per l,000 live births. The very large number of deaths from the pneumonia-diarrhea complex labelled Digestive and Respiratory may be seen in comparison with the number of deaths from all the other infectious diseases taken together. There was an impressive fall in the deaths from the pneu- monia-diarrhea complex during the three decades shown in the Figure, and it continued steadily thereafter until it was no longer a major health problem. The lesson from this three-decade, well-documented experience is that this impressive health gain on a disease pattern, similar to a most important part of the disease patterns in the Third World today, occurred before the time biomedical science and technology had devel- oped specific therapies or preventives for virtually any of the dis- eases present. Expressed differently, this considerable health achieve- ment, if you will, was obtained without help from our modern technology. Even the pasteurization of milk and chlorination of the central water supply seemed to have little or no influence. It was a period of con- siderable increase in the standard of living. So this is how things went before we had our technology. In another experiment of nature let us see how a disease pattern at a similar stage, but one including adults as well, was affected after the development of our contemporary drugs and many of our vaccines. A few years after the end of that golden decade of drug produc- tivity in the forties, my associates and I had an opportunity to sud- denly apply the most up-to-date technology in conditions that in most 17

FIGURE 4. INFANT MORTALITY BY PROMINENT CAUSES IN NEW NEW YORK CITY (RATES PER 1000 BIRTHS) a/ PNEUMONIA/DIARRHEA COMPLEX INFECTIOUS fe_////fefefe, PREMATURE BIRTH,IP I INJURY AT BIRTH, ATELECTASIS, AND OTHER DISEASES PECULIAR TO EARLY INFANCY MJALL OTHER CAUSES ? -::wA.v^'..-*.«.-..M.v.A*<i»--A-Ajt .**Af..um.-.. VAM.^cw:oot iMN iNt Ml lM4 lWt H07 Mi im illI ltd >f is itn i«i« HiT ifl* iin Af1 *CZ Ml M4 (Ml M7 Ml Mt ltM 1900 1905 1910 1915 1920 1925 1930 ji/Source: Weekly Reports of the Department of Health, New York City, - Vol. XXI, no. 50, p. 396, December 17, 1932. important particulars resemble those of a developing country. This was done as part of a large-scale project in the middle of the Navajo Reservation in Arizona and was financed in part by the tribe itself.V The people lived far from each other in dirt-floored, windowless, waterless log huts and maintained a very high birth rate — 47 as compared with the general United States rate of around 14 today. In the mid-1950s, we established a delivery system that included a well-equipped center for ambulatory care, a rudimentary satellite facility, physicians, public health nurses, bilingual allied health professionals — even radio telephones in the automobiles. There was no question that the technology was not thoroughly delivered to the people living in the 800 square mile project area. Indeed, the commun- ity was wholly cooperative. 18

The conventional wisdom was that the population was disease-ridden, with about 70 percent of the disease being microbial in origin. The answer to what happened when we introduced modern technology in these circumstances was "not as much as one might think." Of these microbial conditions, four were especially prominent. Of particular importance is the fact that the two conditions that did not require changes in household practices for their control — otitis media and the transfer of tubercle bacilli — were significantly influ- enced by the technology. By contrast, the two that did require changes in the home — trachoma and the pneumonia-diarrhea complex — were not affected. The partial technologic failure was exacerbated by the high sus- tained fertility. The high birth rate ensured that infants and young children would comprise a large portion of the people that were sick at any one time. Our medical technology has relatively little to offer infants who are located in a virtually unprotected home environment. The lessons thus far can be summed up: first the drugs invented for United States society have had demonstrable and major effects on its level of health; second a disease pattern of great importance in developing societies — the pneumonia-diarrhea complex of infants — largely disappeared from our society without the use of today's techno- logy, but in a setting of widespread economic uplift; third attempts to substitute the drugs effective in United States society for a complete lack of sanitary barriers in the home are apt to have quite limited value in developing countries. By the same token, impressive strides have been made by national and international groups in attacking this infant and early childhood disease pattern through splendid work on protein-calorie malnutrition and the development of practical oral rehydration. Achievements for both adults and children have been made by WHO, PAHO, UNICEF, and other groups with: the smallpox campaign; malaria control; the tuberculosis and leprosy programs; the development of several vaccines, notably that against measles; and the programs for the provision of a protected water supply. But when one looks at this list, it appears as if most of the technologic achievements were those applied through the public health system rather than through the person- al service, one-on-one system deemed necessary for use of the therapeu- tic drugs of the pharmaceutical industry. Now the question we face is whether the system that has done such a superb job in producing these drugs for our society can be produc- tively employed in the creation of drugs for the developing societies. In attempting to judge the fitness of that system to do the job, it is appropriate to review how the system developed and what energized 19

it. The story could be opened at various points. Strictly speaking, it began in 1910 with Ehrlich's announcement of arsphenamine for the treatment of syphilis. This is the historic watershed. Before that time, there was some fine biomedical research, but almost without excep- tion it led only to a greater comprehension of disease. A few vaccines had been developed, notably those against smallpox and diphtheria, but until arsphenamine, there had been no treatment that had emerged from a systematic program of research and development. Thus, there were two big events here: there now was a highly effective treatment for syphilis; and it had been developed on purpose. Other examples occurred with insulin in 1921 and liver extract for per- nicious anemia in 1926, but it was not until 1935 that the peak of the historic watershed was attained with the announcement of Prontosil. Arsphenamine, atabrine, sulfonamide, and the early penicillin came from Germany and the United Kingdom. The United States came into the penicillin field only after World War II had started. The first peni- cillin made in the United States for the treatment of patients was made by Dr. Gladys Hobby working with the late Martin Henry Dawson and Karl Meyer at Columbia P&S. How rapidly have we adapted to the world of high technology. Can anyone imagine that today a therapeutic substance developed abroad would be first manufactured in this country in a uni- versity laboratory? The principal United States contributions to this development had to do with the invention of highly imaginative manufacturing methods, notably deep tank production of penicillin, and the creation of a system of university-based clinical penicillin investigators financed by government contracts. This was done through the National Research Council of the National Academy of Sciences, which formed this govern- ment-supported system largely run by nongovernmental scientists. Streptomycin, an American contribution, was next discovered, but was still under wartime control and was brought through essentially the same system until 1947. At about this time, there were two important events: the instru- ment for the channelling of federal support was changed from the war- time Academy of Sciences to the National Institutes of Health of the Public Health Service; and the tetracycline series was developed in the pharmaceutical industry. The development of the tetracyclines is rele- vant to the evolution of our drug-producing system because it repre- sented the first major antimicrobial series developed in United States industry that was not under wartime regulation and thus was the first to profit by that part of the 1938 Food and Drug and Cosmetic Act that had to do with protecting the exclusiveness of the products of one's own research and development. This served as a powerful example of the benefits that might accrue from a well-organized program of research and development on antimicrobial drugs in a company that had a complete 20

system, J^.e^ , sales and full marketing capability in addition to the research and development. The lesson did not go unheeded. Indeed, there are those who mark this development as the model on which the present-day structure is organized. Be that as it may, it represented a turning point in the arrangement of roles among the three institutions all necessary for the development of new drugs and preven- tive technologies. Until this point, sometime in 1948, there was con- siderable blurring of the lines separating the scientific investigators and administrators in the government, in industry, and in the universities. What was special about the situation that melded the three sets of participants so closely together at the outset of this highly success- ful effort? One answer is that the United States entered World War II as the decade began. In short, it was wartime. This is true, but in my judg- ment there was more to it than that. For, it was also one of those times when there was a coincidence of motivations only partly attribut- able to the war; those from industry, from the university laboratories, and from the government all shared a common goal. We were not then so much looking for new drugs, as for additional diseases to conquer. For various understandable reasons, this has not always been true since. But for the brief period of some four or five years, it was the case. Each success in bringing one more disease under control registered high on the scale of values of everyone concerned. Whether in industry, the university, or government, we had that wonderfully exalting self- image that we were saving lives. The last diseases to be brought under control (except for certain fungal diseases) were typhoid fever and the rickettsial diseases. This was done by chloramphenicol and by the tetracyclines (except for typhoid). From this point on, the bonds between university and indus- trial investigators gradually loosened. By the time of the Truman inauguration in 1949, the irregular but functionally almost unified system had given way to the more formally structured, functionally separate, but intellectually-1inked system of today. Although I have been telling the story only in terms of antimicro- bial drugs, I believe it was much the same for the others. In effect, we have two parallel systems. One consists of the research and development effort in industry; it is paid from earnings. The other is supported by the federal government, through revenues obtained by taxation. It is administered chiefly through the National Institutes of Health and is conducted there and in a country-wide network of other laboratories in universities and research institutes. 21

(In state-operated medical schools the state governments also contri- bute by providing laboratories and some salaries.) Broadly speaking, the research in the university/National Insti- tutes of Health system leads to our greater understanding of various diseases — usually diseases to be found in the United States. The most vulnerable links in the pathogenetic chain may get identified. The research workers in industry carefully follow this research and indeed have made valuable contributions to it. Their primary con- cern, however, is to develop the interventionist technologies, most of which have come from industry. They too have tended to focus on the diseases of our society. As noted earlier, using this system the actual inventions or discoveries of research and development in the pharmaceutical industry have almost exclusively been therapies (or contraceptives) that fit the United States disease pattern and require some form of personal service system for their administration. The actual inventions or discoveries used in the public health system have largely come either from the university/National Institutes of Health system in the case of vaccines, or from the chemical industry in the case of water disinfectants and vector controls. Hilleman's work in industry on respiratory vaccines is a notable exception. To be sure, once the effectiveness of a vaccine has been demonstrated by government or university investigators, the pharma- ceutical industry has done fine work in making it suitable for mass administration. What are the prospects that the United States twin system that has proved so bountiful in meeting our own disease problems can be expanded as it stands to serve also in a productive attack on major problems in the developing countries? Simply to expand it as it stands would not look like the road to success. And I am talking about both arms of the system — the uni- versities and the industry. In part, the judgement reflects the con- straints both economic and biologic that characterize the situation. In large measure, however, it is based on another example from our history. Almost 20 years ago, an effort was started in the President's Science Advisory Committee to develop an institution to link the worlds of science and technology in industry and in the universities to the foreign aid effort. A system was set up along the National Institute of Health-university pattern, within the Agency for International Devel- opment; there was a first-class and hard-working Advisory Committee from outside the government, and a grants and contracts program that 22

included health, though not limited to it. After almost a decade of trial, the effort was judged a failure. The whole story is an illumi- nating chapter in the long annals of science and public policy. I do not propose to tell it here, but there was one very important lesson that came from the experience. The lesson is that in attempting to aim the weapon of research and development at a problem, it is absolutely essential that the institutional framework devised to organize, support, and monitor or manage the effort be carefully tailored to fit the key characteristics of the problem. A system of research support effective for the Department of Defense may be quite ineffective for the Department of Agriculture. The huge success we have had in mobilizing our biomedical research and development effort by inventing the twin National Institutes of Health- university and industry systems has tended to blind us to how beauti- fully the components of that system fit the key elements of the problem. But the problem to be addressed by this Conference is different. The question is no longer whether a treatment for X disease can be developed; it becomes changed to: can one be developed that can be purchased and delivered for one United States dollar per capita, per year, when the total budget for all health services is only two dollars per person, per year? Neither arm of our present system has such capa- bility, so that the plea that they do more becomes meaningless. The most needed invention is not a new drug, but a new system for their development — a new system especially tailored to both the financial and biologic needs of the problem. Does this mean there is little ground for hope — that, to use an American phrase, "there is no way to the Post Office from here"? Certainly not, but it does make it seem most likely that the prob- lem areas suitable for attack through the pharmaceutical industry will represent a far smaller portion of the total problem than is the case in our society. The hope comes from the fact that there is a consider- able variety in the specific mechanisms by which microbial diseases cause illness in one person or spread to others. Hence, they present different points of potential vulnerability to attack. Some are con- trolled by putting a chemical, ^.£. , chlorine, in a central water system used by millions of persons; for some other disease it might be necessary to have someone inject a chemical intravenously into each sick person every day. Thus, a series of trade-offs is involved between two key issues: one trade-off is the probability of signifi- cant drug toxicity versus the degree of expertise needed to staff the personal service system. For some drugs little is needed; for others the physician must be visible at least on some days, even if only in the background. The other trade-off is between whether the desired 23

effects can be produced by the drug alone or whether some significant change in household habits is also necessary. To recall the Navajo study, two of the problem diseases were tuberculosis and trachoma; both of which are clearly susceptible to antimicrobial drugs. The chain of spread of tubercle bacilli involves the contamination of the air within a dwelling space. This can be stop- ped easily by the infected person taking a daily pill. But trachoma can be spread by the momentarily contaminated fingers of small children, and how to decontaminate them is quite another matter. Two different diseases — for both there are effective drugs — but in the conditions of a developing society, one worked and one did not. What I am saying here goes quite against the conventional wisdom, for that wisdom has it that if a disease is characteristically bred, or greatly facilitated, in the conditions of poverty, it is foolish to try to attack it with a technology — one must do something about the condi- tions in which it is bred. As a general law, that is not a bad one. My point is that it is not always so. Occasionally, the poor get lucky. The classic example is the chemotherapy of tuberculosis. In Figure 5 may be seen the tuberculosis death rates among blacks and whites in New York City in the period before and after the drug treat- ment for tuberculosis was introduced in 1947. At the start of the drug era, the rate for whites was slightly less than 35, while the rate for blacks was an appalling 150, roughly four times as high. Once the drugs were introduced, however, the fall in death rate was at least as rapid, if not more so, among the black population as among the white. Whatever it was that was responsible for that difference between 35 and about 150 tuberculosis deaths per 100,000 people each year, obviously was no constraint on the effectiveness of the technology. There is reason to believe the marked pre-treatment differential reflected the living conditions of the black poor in New York City in the 1940s. In Figure 6, a graph based on New Zealand data shows the same thing. The top curve is for the Maoris, the bottom for those of Euro- pean birth or descent. Some indication of the general level of health conditions of the Maori is the infant mortality of 51 they had about that time. But as in New York City, the rapid reduction in death rate was as great or greater among the Aborigines as among the European or those of European descent. And with that I come to my close. In that inaugural address President Truman said that the material resources that could be used for the assistance of other peoples are limited. "But our imponder- able resources in technical knowledge are constantly growing and are 24

inexhaustible." The central truths in that statement for the indus- trialized societies have been gloriously affirmed. To what extent it is possible to find ways so that they have meaning for the developing world is the challenge before us. And if success comes, there will be many more a day than there is now in which one can say with some satisfaction, "Sometimes the poor get lucky." FIGURE 5. TUBERCULOSIS MORTALITY FOR BLACKS AND WHITES, NEW YORK CITY, 1905-1955 O O O O O flC LU Q- UJ tr x UJ O IOOO 800 600 4OO 200 100 80 60 40 20 10 8 6 4- 1947 StortofDrugEro 5-YEAR AVERAGES INDIVIDUAL ANNUAL RATES i i i i i i i i i t i i 05 10 15 20 25 30 35 4O 45 50 55 60 65 70 YEARS 25

FIGURE 6. TUBERCULOSIS DEATH RATES IN NEW ZEALAND ID QL O Q_ O o o ** o o cr UJ a. UJ 600 - 400 - - 200 100 80 60 40 20 10 8 DEATH RATE (EUROPEANS CHEMOTHERAPEUTIC ERA 1947- DEATH RATE (MAORIS) YEAR: 1930 1940 I960 I960 26

REFERENCES 1. McDermott W.: Medicine: The public good and one's own. Perspectives in Biology and Medicine, Vol 2l, No 2, Winter 1978 2. Lowell AM: Adv. Tuberculosis Research. White Plains, New York, S. Karger Publishers, 15:85, 1966 3. McKeown T: Historical perspective on science and health. Paper presented at the annual meeting of the Institute of Medicine, National Academy of Sciences, Washington, DC, October 1976; and Role of Medicine: dream, mirage, or nemesis. London, Nuffield Provincial Hospitals Trust, 1976 4. McDermott W, Deuschle K, Adair J, Fulmer H, Loughlin B: Science 131:197, 280 (2 parts), 1960, and McDermott W, Deuschle K, Barnett C: Science 175:23, 1972 27

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