Pharmaceuticals for Developing Countries: Conference Proceedings (1979)

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CURRENT PROGRAMS FOR DEVELOPMENT OF PHARMACEUTICALS

UNDP/WORLD BANK/WHO SPECIAL PROGRAM FOR RESEARCH AND TRAINING IN TROPICAL DISEASES Adetokunbo 0. Lucas This paper presents the Special Program for Research and Training in Tropical Diseases as an example of a current activity aimed at providing new and improved pharmaceutical agents that are required spe- cifically in developing countries. This Program was initiated by the World Health Organization and is co-sponsored by the United Nations Development Program and the World Bank. It is receiving support both in cash and in kind from a number of governments and agencies. It was in May 1974 that the World Health Assembly meeting in Geneva passed a resolution calling on the Director-General to "intensi- fy WHO activities in the field of research on the major tropical parasi- tic diseases (malaria, onchocerciasis, schistosomiasis, the trypanoso- miases, etc.)". Objectives After extensive consultations, a program was designed with two interrelated and interdependent objectives: 1. Development of improved tools needed to control tropical diseases The first objective is to develop new preventive, diagnostic, therapeutic and vector control methods specifically suited to prevent, treat and control selected tropical diseases in the countries most affected by them. The new methods must be susceptible to implemen- tation: - at a cost that can be borne by developing countries; - requiring minimal skills or specialized supervision; and - in a manner that allows their integration into the health services, especially the primary health care systems of developing countries. 122

2. Strengthening of biomedical research capability in tropical countries The second objective is to strengthen research capability in the countries most affected by tropical disease, through training in bio- medical sciences and various forms of institutional support. Biomedical research capability in tropical countries must be strengthened — even if it were only to accomplish the first objective — because major acti- vities in the specification, development, and testing of new tools must occur in the tropical countries where the diseases are endemic, to ensure that these tools are effective in controlling the target dis- eases in these countries. The basic assumptions guiding the design and the operation of the Program can be briefly summarized: 1. The problem The tropical parasitic and infective diseases remain a major cause of disease and death in many tropical countries, and often constitute a significant barrier to development. Furthermore, in some cases, the process of technological development, as for example the exploitation of water resources in the construction of man-made lakes and irrigation schemes, has aggravated the situation by intensifying transmission in endemic areas and by creating new foci of infection at man-made lakes. 2. Limitations of existing tools Whereas some of the common diseases in the tropics can be brought under control by the vigorous and rational application of existing know- ledge and technology, in the case of some other diseases the available tools seem inadequate for bringing them under control. The evaluation is relative, but one can cite several examples such as the challenge posed by the emergence of drug resistant malaria parasites and leprosy bacilli, insecticide resistant vectors of malaria, and the lack of a suitable drug for killing adult onchocercal worms in man. 3. Promising new lines of research A third basic assumption is that the application of new advances in fundamental biological sciences such as immunology, cell biology and biochemistry would provide a better understanding of the parasites and the vectors, and thereby yield valuable clues for designing new tools for dealing with them; and that a goal-oriented, multi-disciplinary research program involving researchers from all relevant areas of the biomedical and social sciences would accelerate the development of new or improved measures for the control of these diseases. 123

Scope of Operations On the basis of these criteria, six major diseases have been selected for initial emphasis: - malaria - schistosomiasis - filariasis (including onchocerciasis) - trypanosomiases (including both African sleeping sickness and the American form, Chagas' disease) - leishmaniasis - leprosy Research and Development The activities of the Special Program are directed towards development of any practical tool needed to solve the problems of the selected diseases, and focused on development of new drugs or modifica- tion of existing ones, search for vaccines, new methods of vector con- trol, and improved diagnostic tests. The research activities are carried out by multidisciplinary groups of scientists formed on a world-wide basis. These are called Scientific Working Groups (SWGs) and are formed in the fields of the disease and trans-disease research areas to focus research activities toward the goals of the Program. In addition, there are four other SWGs in trans-disease research areas — epidemiology, the control of vectors, basic biological sciences, and socio-economic aspects. One SWG comprises all the scientists who plan and/or carry out research on a specific aspect of the Program. Members of the Group define the research objectives, devise a strategic plan to achieve them, carry out the research according to plan, and review the plan and the research as work progresses. To develop such a plan and operate a SWG, the scientists must describe or formulate: - the detailed objectives of the SWG, e^.j;. , the specifica- tions for a malaria vaccine applicable and effective in rural India; - the current state of the art in relation to the objectives; 124

- the problems which remain to be solved, i^.je., the gaps in knowledge; - the possible research approaches and disciplines which may solve these problems, as well as the feasibility, sequence, and cost of the activities, or projects, in each line of research; a clear strategic plan including each research approach and its line(s) of research, leading towards the final objectives. One or more SWGs are now operating for each of the diseases selected by the Program. In general, three areas are covered for each disease, either by separate SWGs or by subgroups of one SWG: chemo- therapy and drug development; immunoprophylaxis and immunodiagnosis; and where relevant, epidemiology and vector control. Within this broad framework, the priorities in each component of the Program have been selected on the basis of a careful analysis of needs and opportunities, always in consideration of activities on the subject already undertaken by other agencies. The overall strategy of the Program is to identify and attempt to fill gaps in the efforts directed towards development of new tools for control of these diseases. For example, investigations showed that several pharmaceutical companies were actively engaged in development of new schistosomicidal drugs, but that one major constraint is the cli- nical evaluation of promising compounds. The Scientific Working Group on Schistosomiasis therefore accorded high priority to promotion of well-designed, multi-center clinical trials of schistosomicidal drugs. On the other hand, in the case of filariasis, where the SWG had identi- fied the need for a macrofilaricide effective against the onchocercal worm as a top priority, a major constraint is lack of validated biologi- cal screens. The SWG on filariasis has therefore supported development and validation of these screens for testing potential filaricides in a network of academic centers stretching from the United States, through the United Kingdom, Germany, and Japan to Australia. Selected compounds supplied by various pharmaceutical companies are now being tested in order to identify useful leads. In addition, clinical trials are being promoted in endemic areas. Each component of the Program is being designed in such a way as to match needs with opportunities in the most rational manner. Role of the Pharmaceutical Industry In planning and implementation of this Program, there has been a conscious and continuous effort to collaborate with all groups and agen- cies working in this field. The aim of the program is to complement 125

on-going activities, to stimulate and recruit more interest — neither to go it alone nor to compete with others active in the field. Advan- tage is therefore taken of the position of the World Health Organiza- tion, as an association of over 150 member states already engaged in collaborative efforts relating to health in many countries. One impor- tant issue in this regard is the role of the pharmaceutical industry. The following quotation from an earlier policy document is relevant: (from TDR/PK/76.1 Aims and Attributes of the Special Programme) "WHO has always had good relations with the pharmaceutical industry, especially at the technical level, where continuous communication exists between those sections of WHO concerned with the control of parasitic diseases and the representatives of industry concerned with the research and development of pharma- ceuticals and pesticides." "There is no substitute for the facilities and expertise of industry in the search for new chemo- therapeutic agents to control those parasitic diseases which concern the Special Programme. On the other hand, WHO can provide facilities for the clinicopharmacologi- cal evaluation of new drugs, thereby demonstrating to industry that an outlet exists for their products, and at the same time minimizing delay between pre-clinical experimentation and clinical use." In pursuance of this policy, collaboration with the industry has been sought in various components of the program, and the program is identifying useful modes of collaborating with industry. Four main mechanisms are in effect: - participation by industry-affiliated scientists in Scientific Working Groups; - provision of agents for screening; - technical services provided under contract; and - clinical evaluation of new drugs and vaccines. Currently some 30 scientists associated with 16 pharmaceutical enterprises are members of various Scientific Working Groups, either as participants at meetings or as recipients of research grants. By the end of the second year of the operation of the Program, 29 research projects were in progress; eight others were under discus- sion, and three had been completed. This substantial increase in the involvement of the pharmaceutical sector is very encouraging. 126

The contractual arrangements with industry are being designed in such a way as to protect the public interest and to ensure that any products developed with support from Special Program investments will be made available to affected populations on the best possible terms. What of the future? The early experience from this Program has confirmed the need for an even greater involvement of the pharmaceuti- cal industry in order to achieve the objectives of the Program. For example, if the screening tests for a macrofilaricide yield useful leads, the further testing and development of such compounds would require the resources of an interested pharmaceutical company. Close collaboration between industry and the Program will facilitate evalua- tion of promising compounds in laboratory animals and in man. Research Capability Strengthening Intimately related to the search for new tools is the equally important interdependent objective: development of manpower and strengthening of research institutions in the endemic countries of the tropics. The aim is to strengthen the research capability of these countries, and to assist them in achieving self-reliance. In the con- text of the Special Program, self-reliance for any country includes both the competence to tackle significant national problems and the ability to work to best advantage on their solution with scientists from outside the country. To this end, the Special Program has established a Research Strengthening Group (RSG) and its Executive Sub-Group (ESG), whose objectives are to: - strengthen research and training institutions in these countries, so that they can better respond to national and Special Program needs; support training of persons from the tropical countries to help meet national manpower needs; and - contribute to a rapid transfer to the affected countries from the industrialized world of the knowledge, techno- logy, and skills relevant to their health objectives and within the sphere of the Special Program. The institution strengthening and training activities of the Special Program will in return ensure an increasing involvement of scientists from the tropical countries in the Program's research and development. Strengthening of the research capability of affected countries is also a particularly relevant component of collaboration with the 127

pharmaceutical industry. One important constraint in development of new compounds for tropical diseases is the lack of suitable facilities for evaluation of these new products. The training and institution strengthening component of the Program should help in overcoming this obstacle. Already, suitable centers in endemic areas are being equip- ped, and their scientists are being trained so that they can increas- ingly participate in clinical pharmacology and field trials of new agents. Involvement of scientists in endemic countries in definition of specifications of the new tools and in their evaluation will promote more effective and more extensive use of any new technology that may emerge. Furthermore, promotion of epidemiological and field research activities in affected countries will increase awareness of the nature and extent of the problems and demonstrate how available technology can be used to best effect. Other Relevant WHO Programs The Special Program for Research and Training in Tropical Diseases must not be viewed in isolation from other WHO acitivities with regard to control of these and other diseases in the tropics. This research program is one among several efforts being made to provide new technolo- gy for dealing with problems in developing countries. It should be seen in the context of other major programs such as the Expanded Pro- gram of Immunization, which aims at reducing morbidity and mortality from diptheria, pertussis, tetanus, measles, poliomyelitis, and tuber- culosis by providing immuni zations against these diseases for every child in the world by 1990. Similar action programs exist or are being developed for control of diseases prevalent in tropical countries. In addition to the six diseases of concern to the Special Program, WHO is developing, in close collaboration with UNICEF, a program on Diarrheal Diseases Control with an immediate objective to reduce diar- rhea-related mortality and malnutrition by implementation of oral rehy- dration therapy. Research is an essential component of the program to to improve and develop new tools for better treatment, prevention, and control of these diseases. The long-term objective will be prevention and control of these diseases by ensuring adequate sanitation and water supply and improved child care practices. Conclusion The Special Program is now at the period of early growth and development. Further expansion is envisaged during the next few years. But later on the addition of new programs will be balanced by completion of old ones and rejection of unproductive approaches. Even at its high- est level of input, the direct contribution of the Special Program to research and training in tropical diseases will be small as compared with the urgent needs. The logical role of the Program is to stimulate 128

efforts of governments and other agencies, to complement and coordinate those efforts, and to seek out and identify new ideas that deserve attention. Its ultimate goals can be realized only through effective collaboration with national authorities and their institutions and scientists; with the pharmaceutical industry; and with other agencies that are tackling the difficult problems posed by these tropical diseases. Full documentation on the Program, its content, organization, and operation, is available to interested scientists, as is information on procedures for grant applications, for making a research proposal, and the relevant forms for submitting applications for grants and proposals. A Newsletter is published periodically to provide interested scientists and institutions with information on the progress and plans for research in the six diseases and trans-disease areas covered by the Special Program. Specific information on the gaps that the Program seeks to fill in the relevant research topics may be obtained on request to the Office of the Director, Special Program for Research and Training in Tropical Diseases, World Health Organization, Geneva, Switzerland. 129

THE UNITED STATES PHARMACEUTICAL INDUSTRY Lewis H. Sarett The pharmaceutical industry is unique in its research and development capability. The Third World is overwhelmed by the dimen- sions of its health problems. It probably is inevitable, therefore, that persons concerned with the agonizing plight of the third-world nations have searching questions to put to the industry. Why is your attention so strongly focused on the health needs of the rich nations? What are you doing for the poor? Why do you not do more? Given the insistent nature and the frequency of such questions, I appreciate this opportunity to provide a perspective that, I hope, is devoid of emotion but not of compassion. I'll shortly get down to specifics. But first let me suggest that because of the way the problem is often described, industry usually finds itself playing against a stacked deck. WHO can say with very little fear of contradiction that only 3 percent of the funding for biomedical research throughout the world is directed to diseases that afflict the poor nations of the tropics. The implication is that the other 97 percent of such research is oriented to the rich. But a moment's reflection makes it clear that there is a vast overlapping segment from which everyone — rich and poor — stands to benefit. When my company developed the first commercial measles vaccine, we certainly were not thinking in terms of "rich world/poor world". Yet we were well aware that measles was, and is, a major killer of undernourished and unprotected populations. Diseases lend themselves poorly to classification along political or economic lines. To mention another example, demographic studies show, hypertension to be widespread in tropical Africa. Yet hyperten- sion is not a tropical disease because it is not exclusive to the tropics. What we are talking about today, as we all recognize, is research towards therapeutic agents for diseases that are uniquely tropical In their distribution ... or, at least, endemic in the poor world. To keep the record straight, residents of the tropics stand to benefit 130

greatly from the general R&D effort now being undertaken by industry. In fairness, the work that is being done in tropical medicine per se should be seen as "in addition to" all the work that has application both to the tropics and to the temperate zones. I am not trying to absolve industry from the role in tropical-medicine research that its unique expertise imposes. What I am saying is that, as things now stand, the score is not 97 to 3. The organizational framework of current programs in the United States pharmaceutical industry that could have application to the Third World varies widely. Within it, you can find examples of almost every conceivable form of organizational accommodation. Thus, several intra- mural research projects with the necessary efforts in chemistry and bioloare supported by industrial laboratories in the traditional way. There are industrial research contracts with government agencies such as AID or WHO supplying the funds. There are cooperative projects jointly carried out between industrial groups and academic experts. And there are examples of cooperation between local physicians within an LDC and representatives of industrial medicine, frequently with the assistance of the national ministry of health. The distinguishing characteristic of research by the pharmaceutical industry is that it is multidisciplinary, involving many subdisciplines of chemistry, biology and medicine. Just as this synergy has been the key to research success by indsutry, it promises to be the key to fur- ther progress in developing new therapies for tropical medicine. It may be that cooperative efforts to share expertise can be useful in this area with something less than the "critical mass" of research com- petence that is the hallmark of the major innovative industrial labo- ratories today. It may be that a handful of advisors from industry — sharing the knowledge gained by years of experience — can help to orient indigenous programs to give them a much better chance of success. I am thinking in particular of programs such as that now being pursued by WHO to exploit to the fullest potential native plants as source materials for medicines. Such research may not be the cutting edge of medical science. But as a practical approach to finding ways to help very poor nations get workable medicines for common conditions, the idea is going to be pursued. If scientists from industry can help with advice and technical know-how, other things permitting, I believe that they should be encouraged to do so. It may be that the recently announced Foundation for International Technological Cooperation will have a role to play here. Its orienta- tion, if I understand correctly, is not merely to the very poor nations, but also to so-called "middle tier" countries, such as Mexico, Iran, and Brazil. It may well be that the Foundation — or comparable organ- izations — will act as catalysts to facilitate communication and syner- gize the efforts by those with a role to play in creating new medicines, including industrial scientists, and by the multitude of nations that need them. 131

Now, however, I would like to examine more specifically research projects targeted at Third-World diseases that are currently being undertaken by the United States pharmaceutical industry. As the source of my data, let me acknowledge the fine cooperation of the research directors of 15 leading members of American industry, who provided information about the activities of their organizations. This sample is considerable when you consider that, while the annual research budget of the 132 members of the Pharmaceutical Manufacturers Association is about $1.3 billion, 20 percent of the member companies conduct about 80 percent of the drug research and development. Additionally, I have made use of a recent survey carried out by the PMA itself, and I should qualify how I have used these data. Twenty-one companies replied that they were currently doing research in one or more areas of tropical medicine, and the same 21 indicated that they have done such work in the past decade. With regard to specific diseases, the breakdown does not distin- guish between current programs and programs that, while active in recent years, may have been discontinued. No doubt a number of companies have reduced their investment in this type of research. Notwithstanding, the survey at least gives an indication of how the work is subdivided within the American component of the pharmaceutical industry. It is in this context that I am using the data. So, while this panoramic view cannot pretend to be completely comprehensive, it should at least reflect major trends. To facilitate organization, let me discuss first the status of work with regard to the six diseases identified by WHO as prime targets for major efforts in the developing world. These are malaria, schisto- somiasis, filariasis, leishmaniasis, trypanosomiasis, and leprosy. It is important to recognize that, for each of these scourges, medications already exist and which, for many patients, are effective — if not ideal. In each of these categories, new products have been forthcoming over the past several decades. So, any impression that the pharmaceutical industry has been indifferent to the needs of the victims of these illnesses is demonstrably wrong. A major problem is that — for comprehensible reasons — existing medicines are grossly underused in nations where they could be of the most value. This, of itself, is hardly an incentive for industry to pursue the quest of trying to find improved medications. Yet work is going forward in each of these areas. Parke-Davis, with AID contracts, is studying an immunological approach to malaria and working on cell cultures of malaria parasites. Upjohn is collaborating with investigators in Brazil in the evaluation of an antimalarial agent that came as a spin-off from an antibiotic pro- gram. In the PMA survey, some 14 companies report work on malaria. Many companies have provided compounds for screening in the Walter Reed antimalarial program. 132

Eleven companies report projects in the area of schistosomiasis. Several newer agents exist. Sterling reports that between 5 and 8 per- cent of its research budget is directed to parasitology, including work in schistosomiasis and amebiasis. Several other companies also have important programs in the parasitology field, which may have analogous applications. It is important to keep in mind that pharmaceutical research is by no means limited to American companies, and we shortly will be hearing about work in the laboratories of European-based companies. Seven PMA-member companies report work in filariasis. Parke-Davis has a $155,000 contract with WHO for the synthesis of antifilarial drugs. Parke-Davis also has a $50,000 contract with the Army Medical Command for work on leishmaniasis, a research area where six PMA com- panies report activity. Squibb is collaborating with WHO to supply a compound that will probably be first tested in Africa. Merck has an active program against trypanosomiasis. The development of nifurtimox by a European company (Bayer) has provided new therapy against Chagas' disease. American companies had also worked in this area. Leprosy, the only one of the six WHO-priority diseases that is not vector-borne, is listed as the subject of R&D work by six PMA companies. Several new therapeutic approaches are in use or under investigation. When the vectorand fecally-borne diseases are considered as public health problems, medicines are often at best partial and unsatisfactory answers. The provision of adequate and safe water supplies and a more healthful environment can do much more to erase problems at their source. The broad-based nature of the challenge is clearly recognized, as the WHO/ UNICEF primary health care declaration from Alma Ata attests. Among the fecally-borne diseases, nine companies report work on typhoid and seven on cholera. Thirteen companies report work on infec- tious diarrheal diseases, and fifteen on intestinal parasitic diseases. I have already mentioned Sterling's work in amebiasis, and Pfizer has a program on helminthiasis. In passing, I might point out that our com- pany's product for human helminthiasis evolved from earlier and highly successful work to develop anthelimintics for use in animals. I men- tion this as an additional example of how misleading it can be to try to isolate as a separate entity the work that is being done by industry on tropical diseases. Wyeth also has a program on antiinfective agents. ALZA has a half-million dollar program against trachoma, and Merck is also working in this field. With onchocerciasis, ALZA is investigating new systems for the delivery of medications. In the cancer area, Bristol and the National Cancer Institute are 133

jointly developing neocarzinostatin. The agent is active against hepatoma, which is relatively common in Africa. Viral hepatitis is also known to be a precursor of hepatoma. A vaccine is being developed in our laboratories and at NIH. In some cases, the special conditions of the tropics require innovations in established therapy and preventive medicine. Measles vaccine, for example, is equally efficacious wherever it is used. But the vaccine developed by SmithKline for transportation and storage under relatively primitive conditions is intended to be particularly useful in remote areas of tropical countries. Tuberculosis, not a tropical disease per se but a scourge in primitive and impoverished societies, is addressed in work at Lederle, Sterling, and Merck. Very preliminary work with one of Merck's new antibiotics, cefoxitin, has shown promising results. Several companies, including Merck, are attacking gonorrhea — again of great importance in the tropics — and Merck has a vaccine under development. Sterling has an antigonorrhea agent undergoing clinical evaluation. Reed and Carnrick has a project in Nicaragua, the Dominican Republic and Venezuela against lice and scabies, conditions that, if not tropical, are particularly prevalent in the tropics. In the area of fertility control, of critical importance to the Third World, Upjohn is collaborating with WHO in the evaluation of a once every-three—months injectable contraceptive. Pfizer, in collabor- ation with the German Schering Company, is working to develop a prosta- glandin for fertility control. ALZA is collaborating with WHO in ferti- lity-control work, and Wyeth is also active in this field. In summary, the programs of the American pharmaceutical industry directed to the health problems of the developing world are of long standing. They represent an investment of many millions of dollars and a commensurate deployment of manpower. At the same time, and in their totality, they are only a small component — almost certainly less than 5 percent — of the overall R&D effort of the industry. The low figure, as I have tried to point out, is misleading in terms of the benefits that the Third World can expect to derive from the industry's overall effort. The great amount of work that is being done on infectious diseases alone, while its prime target is bacterial illness, does lead to agents that are useful against such diseases as malaria, leprosy, and tuberculosis. Moreover, basic studies in many laboratories intended to elicit better understanding of disease pro- cesses and drug actions have application across the board in all areas of therapy. As for research specifically targeted to the Third World's particu- lar health problems, it is very clear that the magnitude of the effort 134

has been decreasing over the past decade. Projects have been dropped or cut back in most, if not all, of the laboratories whose directors provided me with information. The reasons for this are of great inter- est and concern to this group. They will be reviewed later by Dr. Wescoe. 135

THE EUROPEAN PHARMACEUTICAL INDUSTRY Ernst Vischer and Rudi Oberholzer The chemical and pharmaceutical industries in European countries have always had a relatively small domestic market. It was therefore essential for them to expand their trade beyond their own national boundaries and become active throughout the world. At an early stage of expansion, their commercial relations also extended to the so-called Third World, and they were confronted with the problems indigenous to these developing countries. This situation provided the impetus for certain specific activities of the European pharmaceutical industries of which the following is a short account, with examples drawn from research, therapy, pest control and eradication, health education and training, and finally technical assistance. Research As to research, the discussion is confined to tropical diseases. One should, however, not forget that very common illnesses such as influenza, the common cold, rheumatism, and especially the bacterial infectious diseases and their sequelae are at least as frequent in the developing countries as in developed countries. Drugs effective against these universal diseases are therefore also important in the less industrialized world, and contribute widely to the pharmacothera- peutic part of the total health-care system. In respect to tropical diseases, it is generally accepted that medicaments are now available to combat many of them. Some of these drugs have limitations. It has repeatedly been suggested that the phar- maceutical industry makes too little effort to develop new and better therapeutic agents. That is only partially true. A survey JY per- formed among 15 research-oriented European pharmaceutical companies 2/ has shown that seven are actively engaged in this type of research. Their research efforts cover, with varying emphasis, all six tropical diseases emphasized by the WHO 3/ (Table 1). The budget allocated by these seven companies to this field of research came to about U.S. $40 million, and the trend indicates that this amount will increase in the years to come. 136

TABLE 1. NUMBERS OF EUROPEAN COMPANIES WITH MAJOR ACTIVITIES IN TROPICAL DISEASES AND FAMILY PLANNING Malaria 4 Schistosomiasis (Bilharziasis) 4 Filariasis 4 Trypanosomiasis 3 Leishmaniasis 2 Leprosy 2 Hookworm 2 Family Planning 2 Several European companies have established research organizations in Third World countries, particularly in India. The most representa- tive one is probably the CIBA/GEIGY Research Center in Goregaon near Bombay with a total staff of 260, of which 35 are scientists. The yield from these research efforts has been rather meager, and no sensational developments have taken place in the last few years. In view of the particular difficulties besetting this type of research, and taking into account the high expectations and the requirements for such newly developed drugs, this fact is not too surprising. On the other hand, we know that several existing drugs could be used to greater benefit and more economically in developing countries if the schemes for their application were better adapted to the coun- try's specific requirements and conditions, and if the country's health infrastructure were of a higher standard. It therefore seems logical that, in parallel to our research efforts, the proper use of existing drugs should be further explored. Here is a broad field where the industry, with its know-how, can be of assistance in improving therapy. Therapy As a first example of cooperation towards this end, there is a joint project undertaken by the Government of Indonesia, the Indonesian 137

Army, and our own company. Indonesia still has a high rate of tuber- culosis, and the government was therefore interested in a project to compare diverse schedules for oral treatment with various antitubercu- losis drugs aiming — and that was the important point — at achieving increased patient compliance. At the same time, emphasis was placed on health, education, and on the establishment of centers for diagnosis and therapy. Industry's participation consisted of assisting in the design of the trial plans, providing some diagnostic facilities, ana- lyzing the data, and offering drugs. This project is running satis- factorily and the results obtained so far are promising, both from the medical and from the economic points of view. A second example is a project in Senegal which WHO undertook in collaboration with the Sandoz Institute. The aim of this project was control of venereal diseases. Five centers for early diagnosis and treatment of gonorrhea, syphilis, and trichomonas infections were established. Further, ways and means for assuring effective and appro- priate information to and education of the public were studied to achieve prevention or early care. The contributions of industry were financial and technical, but the latter aspect was probably more impor- tant. It consisted in participating in the planning, organization, and evaluation of the project, including the research component. In 1978, operation of the project was taken over by the Senegal Government. The Sandoz Institute still participates in a consultative capacity. Pest Control and Eradication The aim of another joint project, an experiment known as the Lower-Mangoky Project, was to control and possibly eradicate schistoso- miasis in a well-defined region in Southwest Madagascar.4_/ It was based on an agreement between the Malagasy and the Swiss governments. By various means, this previously underpopulated area has been turned into arable land particularly suitable for the cultivation of rice and cotton. It attracted many farmers from other parts of the country. Soon it became apparent that the incidence of schistosomiasis was increasing tremendously, due both to the new arrivals and to the newly constructed irrigation system. In order to check this development, a dual approach was chosen, directed on the one hand against the vector snail and on the other hand against the parasite. Execution of the project was entrusted to the Swiss Tropical Institute, which in turn enlisted the assistance of Shell and CIBA as suppliers and technical consultants for the mollusci- cide, Frescon, and the chemotherapeutic agent, niridazole, respectively. The work included making an accurate epidemiological survey in an area of 25,000 acres, and the medical examination of the entire popula- tion of about 1l,000. Furthermore, the distribution and movements of 138

the vector snail in the watercourses had to be determined. On the basis of the data obtained, a small team of doctors and parasitologists went to work. The infected population was treated with niridazole, and Frescon was applied simultaneously to the irrigation system. After two years, the rate of infection had fallen from 15-50 percent to 2 percent. The annual costs incurred in achieving protec- tion were about 23 Swiss Francs per person. For maintaining this level of protection, the cost was 10-12 Swiss Francs. In 197l, the entire project and the responsibility for its further pursuit were handed over to the Malagasy Government. Unfortunately, in the continuation of the work, the necessary perseverance and know-how were lacking. Today the disease is no longer under control, and irrigation systems are once again breeding places for the molluscs. Despite this deplorable turn of events, the project showed that it is possible to eradicate schistosomiasis from a particu- lar area by properly applying all the necessary measures, and that the costs of doing so are not unreasonable. Health Education and Training Training has been going on ever since the multinational companies established their own subsidiary companies in developing countries. Training is offered for the benefit of their own staffs, and also for trainees nominated by government authorities. The extent of these training programs is not often realized, and a survey was therefore carried out among 15 European pharmaceutical companies._1,J/ It showed that l,976 nationals of Third World countries were trained by these 15 companies within the past two years. The average is 132 trainees per company, with a predicted increase of 15-20 percent in the years to come. Two-thirds of these trainees received instruction for up to two weeks, more than one-fourth obtained training for two weeks to three months, and the remaining 7 percent for over three months. The main fields of training were in production (45 percent), quality control (39 percent), and storage and distribution (16 percent). The majority (83 percent) of the trainees were employees of the respective subsidiary companies. The 329 (17 percent) who were not company employees were trainees nominated by the authorities. The total costs incurred in these training programs approximated U.S. $l,000 per man-week. Industry can also take an active part in other areas of health education and training, such as instruction of medical assistants. A paramedical staff is most important for development of a health-care system in rural areas of developing countries. A training center for such assistants was established in Ifakara, Tanzania, by the Swiss Tropical Institute. It was mainly financed by the Basle Foundation for 139

Aid to Developing Countries, a foundation created in 1961 by the phar- maceutical companies of Basle. To date, approximately 770 trainees have gone through this school. In 1978, the center was handed over as a gift to the Tanzanian Government, and there is good reason to hope for the successful continuation of its valuable activities. A further example is a school for laboratory assistants for public health services in Djakarta, Indonesia. This school was established jointly by the Indonesian Government and CIBA-GEIGY to fill a major gap in local education, and to provide various government agencies with qualified technical staff. The school provides an 18-month course and can accommodate 24 students. The Indonesian government has donated the necessary land, the building, and the general infrastructure. CIBA-GEIGY's contribution included the technical equipment and installations, their servicing, and teaching materials. Furthermore, CIGA-GEIGY placed two qualified teachers at the disposal of the school for an initial period of two years. After two years, the entire project was transferred to the Indonesian Ministry of Health, which is now responsible for the school. The two best qualified students in the first couse were appointed as teachers, and the school is now functioning well. Twelve to fifteen students graduate each year, and they have no difficulty in getting jobs, mostly in government laboratories; none of them work for CIBA-GEIGY. Technical Assistance Before concluding, a few comments should be made about the problems of technical assistance. This is a very tricky problem, indeed, because sometimes technical assistance is taken to mean impart- ing or receiving technological know-how at no cost. Such assistance agreements can only be successful if they are of mutual interest to both parties; namely, the pharmaceutical industry and the developing country. One such example has recently been published. This concerns collaboration between the government of Algeria and the Behringwerke, a subsidiary of the Hoechst Company of Germany. On the one hand, Behring- werke are enabling Algeria to take up production of vaccines; on the other hand, the Algerian government has undertaken to buy quantities of vaccines from Germany. The assistance rendered by the Behringwerke includes passing on the technical know-how for construction and opera- tion of a production plant for vaccines, anti-sera, and diagnostics. It also entails the training of the necessary Algerian personnel. This is a fine example of a novel approach towards technical cooperation between a developing country and industry. Two additional examples of technical assistance in the field of distribution of pharmaceuticals are worth citing. In many developing 140

countries, this is a very serious problem. The Sandoz Institute has recently entered into collaboration with the government of Mali. The project is concerned with evaluation of the management and logistic aspects of supply and distribution of drugs in a rural area with a popu- lation of 20,000. A similar project, also concerned with distribution of drugs, is being undertaken by the Sandoz Institute in a rural area of Upper-Volta. These few examples of specific activities of European pharma- ceutical companies in developing countries show that efforts made by industry towards development of health care in the Third World are probably greater than usually assumed. Yet more could clearly be done. However, not all projects are running as smoothly as those mentioned, and it is sometimes not so easy to establish meaningful cooperation between developing countries and industry. To achieve optimal condi- tions for the realization of such joint projects, the following points should be taken into account. First: The real needs of the country in question have to be properly evaluated and defined. It is essential that both partners agree on the goal of the project and stick to it. Second: There should be a minimum, proper, and functional health- care system and health-care infrastructure in the country; at least, one should be envisaged. Obviously, general health problems cannot be solved merely by applying or supplying medicaments. Third: A certain level of general education and discipline should exist, together with a willingness to cooperate. These three points actually call for a competent public administra- tion of at least a minimum intellectual standing, aware of the problems of its country and able to set logical priorities. Fourth: All joint programs between developing countries and industry depend on two conditions; namely, a sound financial basis and meaningful technical input. Where financing is concerned, it must be realized that the resources of the pharmaceutical companies are limited. They are not and cannot be charitable organizations. Nor, indeed, is charity what developing countries want or expect. Therefore, the neces- sary financial means must come from other sources. With respect to technical input, however, the pharmaceutical industry, with its inti- mate knowledge of the products, can contribute much expertise in research and development, in the production and formulation of pharma- ceuticals, and in good manufacturing practices and quality control. Generally, the most important factors for successful cooperation are mutual trust, respect, and mutual understanding. The less administration and red tape, and the fewer politics that are involved, the better. 141

REFERENCES 1. Worlock A: 9th Assembly of the International Federation of Pharmaceutical Manufacturers' Associations (IFPMA), Tokyo, 5 & 6 October, 1978 2. AB Astra, CH Boehringer Sohn Ingelheim, CIBA-GEIGY Limited, Glaxo Limited, Hoechst AG, Imperial Chemical Industries Limited, Knoll AG, E Merck, Novo Industrie GmbH, Organon International BV, Hoffmann-LaRoche, Ltd, Roussel-Uclaf SA, Sandoz Limited, Schering AG, The Wellcome Foundation Ltd 3. WHO report TDK/WP/76.5 Special Programme for Research and Training in Tropical Diseases, Introduction to the Special Programme 4. Degremont AA: Mangoky Project — Campaign against schistosomi- asis in Lower Mangoky (Madagascar). Swiss Tropical Institute, Basel, Vol I, 1973 142

CURRENT PROGRAMS IN UNITED STATES ACADEMIC LABORATORIES FOR DEVELOPMENT OF AGENTS AGAINST SELECTED INFECTIOUS DISEASES William S. Jordan, Jr. In the United States, support for biomedical research relating to the major infectious diseases of developing countries is funded by com- ponents of three cabinet-1evel departments: • Department of Health, Education, and Welfare National Institutes of Health Center for Disease Control Food and Drug Administration/Bureau of Biologics • Department of Defense Army Navy • Department of State Agency for International Development The missions and objectives of these federal agencies are quite different from each other; and the nature and extent of their commit- ment to studies on diagnosis, treatment, and prevention of infectious and parasitic diseases of tropical and subtropical countries vary accordingly. The National Institutes of Health (NIH), through extra- mural grants and contracts, support much of the basic research in the nation's academic laboratories. Because most of the extramural funds are allocated in response to investigator-originated proposals, the NIH research grant portfolio is shaped by the interests of university scien- tists. In contrast, the medical research programs of the armed forces are deliberately designed to deal with those illnesses that threaten the effectiveness of military personnel wherever they may be. The Agency for International Development (AID) and the Center for Disease Control (CDC) also target their research programs and direct support 143

for the control of specific diseases. The Bureau of Biologics (BoB) serves all groups as it monitors the development of vaccines and other biologics in discharging its licensing and regulatory responsibilities. The Bureau of Drugs, also a part of the Food and Drug Administration, fills the same role for pharmaceuticals, but conducts no research other than regulatory studies in its own laboratories. Like NIH, all of these agencies fund contracts to support research in academic laboratories. With the exception of AID, they also main- tain their own research facilities, both at home and abroad. In the tradition of Walter Reed and William Gorgas, military medicine contin- ues to make valuable contributions to international health. At home, Army investigators recently pioneered the development of meningococcal vaccine; abroad, Navy investigators last year assisted in the study of an epidemic of Rift Valley Fever in Egypt. However, with the rising tide of nationalism and anti-colonialism, military laboratories in for- eign countries may find their welcome disappearing, as may other United States research centers. As emphasized by the World Health Organiza- tion, the establishment of a true partnership is considered essential to successful collaboration. Such collaboration exists in Kuala Lumpur, Malaysia, where an Army laboratory and an NIH-sponsored International Center for Medical Research, directed by the University of California, share adjacent facilities to their mutual benefit and that of their host, the Institute for Medical Research. The research summarized in this report is conducted at locations such as these, in many university laboratories, and at the other federal research facilites listed under their respective departments. Estimates of United States Government financial support (and in- directly of the extent of effort) to develop agents and techniques for controlling specific diseases or disease categories were prepared using data provided by the agencies involved. Of particular interest was the amount of research support directed toward the six diseases target- ed by the WHO Tropical Disease Research Program, and toward the enteric infections of WHO's new Diarrheal Diseases Program (Table 1). It is frequently emphasized that inhabitants of developing countries do not have only malaria or only intestinal, urinary, or ocular parasites, or leprosy; they often have two or three of these diseases at the same time, and sometimes more. To this list of "tropical diseases" others may be added that occur throughout the world. The control of such dis- eases — exemplified by measles and poliomyelitis — is also vital to the well being of developing countries. Accordingly, data were received indicating support for other selected diseases (Table 3). The data in all tables except Table 2 reflect to the nearest thousand the estimated total expenditures (direct and indirect) for fiscal year 1978 related to the disease categories and to the research areas listed. The omis- sion of a disease category in a later table for a particular agency means that the agency reported no current work in this area. Obviously, other diseases are being studied that were not listed. The data do not include support for United States academic laboratories provided by the 144

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National Science Foundation, WHO, or private foundations. Further, it is emphasized that the estimates are just that — estimates. Agency budgets do not lend themselves to this kind of breakdown, and the place- ment of a research project in one category or another sometimes forces an arbitrary designation. Department of Health, Education, and Welfare National Institutes of Health The extramural programs of the National Institutes of Health support research in academic laboratories, with the bulk of the funds for infectious diseases coming from the National Institute of Allergy and Infectious Diseases. Thus, the data in Tables l-3 reflect the interest and judgments of university investigators, including those at the International Centers for Medical Research. The International Centers for Medical Research (ICMR) Program was established by NIAID in 1960 to advance the status of the health sciences in the United States through cooperative endeavors with other countries. An ICMR is a discrete research organization sponsored by a medical and/or public health school which provides a stable base for research and training through the development of research centers over- seas. Collectively, ICMR units have served as a national resource in creating a pool of investigators knowledgeable in treating tropical dis- eases and in stimulating young investigators to seek careers in inter- national or geographic biomedical research. In addition to the ICMR in Kuala Lumpur, three others are located in Lahore, Pakistan (University of Maryland), Cali, Colombia (Tulane University), and Panama (Johns Hopkins University). One other overseas United States supported tropical disease research laboratory that merits special mention is the Gorgas Memorial Laboratory (GML) in Panama, which just celebrated its fiftieth anniver- sary. Included among its many current programs is the testing of anti- malarial compounds in a valuable colony of owl monkeys. Separately chartered and supported by its own Congressional appropriation, the GML is administered through the Fogarty International Center of NIH. Accordingly, for convenience, its expenditures were added to those of the NIH in Tables 1 and 4. Of the parasitic infections (Table l), schistosomiasis and malaria attracted the greatest effort of extramural scientists; equal amounts of money were devoted to trypanosomiasis and filariasis. Within the developmental categories for six WHO-targeted tropical diseases, nearly equal amounts were expended for vaccines and related immunological studies and to a search for better chemoprophylactic and therapeutic agents. This latter category, of particular concern to this Conference, consumed little more than a million dollars. Indeed, exclusive of the 146

TABLE 2. NATIONAL INSTITUTES OF HEALTH EXTRAMURAL SUPPORT FOR RESEARCH AND TRAINING RELATED TO PARASITOLOGY, MEDICAL ENTOMOLOGY, AND LEPROSY (FY 1978) Number Amount Total 207 $1l,887,583 a/ Individual Grants 176 $10,382,023 Program Grants 2 317,102 Contracts 7 484,485 Training Grants 9 552,573 Fellowships 13 15l,400 a/Exclusive of $2.4 million for ICMRs and $34l,000 for GML. ICMRs and GML, NIH funded only 16 projects for pharmaceutical develop- ment, as follows: schistosomiasis, 8; malaria and leprosy, 3 each; and filariasis, 2. Table 2 identifies the nature and number of awards for research and training in parasitology, medical entomology and leprosy. Although benefits from the expenditures summarized in Table 3 may extend to all countries, the distribution of effort versus the diseases listed reflects the perception of the United States academic community of national needs and research opportunities. Apart from basic re- search, the major emphasis has been on vaccine development. Of more than 13 million dollars only two million were devoted to chemoprophy- laxis and treatment, and more than three quarters of this amount was used for development and testing of antiviral substances. The intramural laboratories of NIH, located on the Bethesda campus in Maryland and at the Rocky Mountain Laboratory in Hamilton, Montana, are very similar to those in academic medical centers or research insti- tutes, in that the investigators, once recruited in a broad general area, are free to select their own research projects. Studies of those 147

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diseases highlighted in this report are conducted largely in the Labora- tory of Parasitic Diseases and the Laboratory of Infectious Diseases of NIAID. The only mandate these intramural laboratories — and those sup- ported by extramural funds — have for research related to developing countries is found in Section 2, Clause 1 of PL 86-610: "To advance the status of the health sciences in the United States and thereby the health of the American people through cooperative endeavors with other countries in health research, and research training." Despite the apparent self-serving nature of this legislative language, intramural investigators are studying all of the five parasitic diseases within the current WHO TDR Program, with a major emphasis on malaria, particu- larly malaria vaccine (Table 4). Studies of schistosomiasis and trypa- nosomiasis ranked next, with treatment of each of these diseases receiv- ing only modest attention. Overall, less than five percent of expendi- tures for parasitic diseases were related to pharmaceutical agents. While enteritis can be caused by a variety of agents (amebae, Giardia, strongyloides, enterobacteria, etc.), the newly recognized rotaviruses and parvoviruses are currently of greatest interest. Tech- niques developed or refined by NIAID investigators have permitted rapid confirmation of the importance of these viruses as causes of diarrheal disease. The rotavirus group, especially, has been shown to be an important cause of infant diarrhea in both developed and developing countries. Center for Disease Control The CDC has participated in international health activities since its creation as the Communicable Disease Center. From a laboratory base in Atlanta, microbiologists, parasitologists, entomologists, and epidemiologists are increasingly exploiting research opportunities around the world and providing assistance to others in the implementa- tion of control measures. The contributions of CDC staff to the small- pox eradication program reflected this commitment. In recent years, CDC has contributed epidemic assistance for such diverse problems as meningitis in Brazil, rabies in Mexico, Lassa fever in Sierra Leone and Nigeria, and African hemorrhagic disease in Sudan and Zaire. In 1978, medical epidemiologists or operations offi- cers were assigned to five African countries in addition to those detailed to Somalia for smallpox eradication. For the past five years, CDC has funded and maintained the Central American Research Station in San Salvador, El Salvador. This laboratory has devoted its research effort to three vector-borne diseases: malaria, Chagas' disease, and onchocerciasis. Malaria research is directed to field surveillance and studies of sterilization of the male mosquito as a method to reduce breeding. Expenditures for these and other tropical disease programs are shown in Table 5. At CDC, only six percent of such funds were related to pharmaceutical agents. 149

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The CDC contributes international laboratory assistance as a WHO reference center for 23 different disease conditions while providing technical support and diagnostic services for United States laboratories. For all the diseases listed in Table 6, it spent nearly equal amounts on studies to improve diagnosis and on studies concerned with chemopro- phylaxis and treatment. The allocations for individual diseases appear appropriate to need and/or technical development. Bureau of Biologics As a component of the FDA, a regulatory agency, the BoB does not routinely support programs to develop new vaccines. However, several of its staff members have contributed to basic studies of antigens for use in polysaccharide and viral vaccines in recent years. The BoB is primarily concerned with assuring the safety and effectiveness of bio- logical products by control testing and by the development of new and improved test methods for assessing purity and potency (Table 7). It conducts no studies of parasitic diseases or leprosy. Its arbovirus expenditures are virtually all related to yellow fever vaccine. Department of Defense United States Army The United States Medical Research and Development Command conducts studies on the prevention, control, and treatment of infectious diseases through an extramural contract program and through intramural programs of the Walter Reed Army Institute of Research, (Washington, D.C.), the United States Army Medical Research Institute of Infectious Diseases (Frederick, Maryland), the Letterman Army Institute of Research (San Francisco, California), the United States Army Medical Bioengineering Research and Development Laboratory (Fort Detrick, Maryland), and the United States Army Institute of Surgical Research (Houston, Texas). As previously noted, field studies are conducted at a laboratory in Malay- sia; there are other overseas units in Brazil, Kenya, and Thailand. Although the Army's program is directed toward reducing or eliminating the deleterious effects of infectious diseases on military populations, the benefits derived also can be utilized by the civilian public health community, especially in developing countries. In addition to the work summarized in Table 8, studies of other diseases of special interest to developing countries were supported, including pseudomonas (burns) $1.2 million; plague, $150,000; melioidosis, $150,000. The Army clearly considers malaria the most important parasitic infection, and the $6.0 million which it devoted to the development of chemoprophylactic and therapeutic drugs for this disease was the largest expenditure of any agency for research on pharmaceutical agents. The majority of these funds supported work by commercial firms. Of the 152

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TABLE 7. BUREAU OF BIOLOGICS (FDA) SUPPORT (Estimated) FOR MONITORING BIOLOGICA1 PRODUCTS AND DEVELOPING TECHNIQUES FOR SELECTED DISEASES (FY 1978) Safety and Efficacy of Biological Products Infectious Disease All Other Research (Extramural) Total Total l,934,000 424,000 2,358,000 Enteritis 87,000 87,000 Bacterial Meningitis 205,000 24,000 229,000 Gonorrhea 12,000 12,000 Pneumococcal Infections 93,000 59,000 152,000 Tuberculosis 114,000 21l,000 325,000 Mycoses 114,000 114,000 Arboviruses 207,000 207,000 Herpes viruses (all) 59,000 59,000 Rabies 84,000 84,000 Rickettsial Diseases 25,000 25,000 Respiratory viruses Influenza Other 354,000 206,000 24,000 65,000 378,000 27l,000 Viral Hepatitis 374,000 4l,000 415,000 154

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other diseases, the Army spent as much on arbovirus infections as on malaria, but with the emphasis being placed on vaccine development at a cost of $4.0 million. United States Navy The Naval Medical Research and Development Command and the Office of Naval Research support extramural contract research at university and commercial laboratories. Intramural laboratories are located at the Naval Medical Research Institute, Bethesda, Maryland, and at overseas Naval Medical Research Units in Egypt and Taiwan, the latter with a detachment in Indonesia. In addition to the data in Table 9, the Navy cited expenditures for pseudomonas ($250,000) and relapsing fever ($44,000) as being relevant to developing countries. Included in the various categories in Table 9 are approximately $1.4 million of special foreign currency program (PL-480) funds. More than three-fifths of the Navy's R&D expenditures were used to study two parasitic diseases, malaria and schistosomiasis. The program for the latter consists of three major parts: (l) epidemiologic studies to determine prevalence and risk; (2) clinical evaluation of anti-schis- tosome drugs and studies of infections and immune responses in human schistosomiasis, and (3) development of vaccines. Field studies are being conducted in the Far East, particularly Indonesia and the Philip- pines, and a five-year longitudinal study of about 1200 persons in vil- lages near Luxor, Egypt, is in progress. Human clinical studies are being carried out in Cairo; vaccine research is conducted at the Naval Medical Research Institute. Vaccines found effective in mice are then tested in monkeys. At present, the most promising approach is immunization with (cobalt-60) radiation-attenuated cercariae or schis- tosomules; immunized animals showed a 50 to 80 percent reduction in adult worm recovery after challenge with virulent cercariae. The Navy's malaria program in 1978 was focused almost entirely on solving the many technical and theoretical problems that remain before promising beginnings can be translated into a safe and effective vac- cine. Navy scientists, along with others, have made encouraging pro- gress toward development of a malaria vaccine, and this is the subject of later general comment. The Navy's approach is based on the fact that the feasibility of a sporozoite vaccine against falciparum malaria has been demonstrated in human volunteers immunized by the bite of x-irradiated infected mosquitoes. The laboratory model being used to study approaches to the development of methods of treating mosquitoes to obtain the maximum yield of sporozoites involves Anopheles stephensi mosquitoes, Plasmodium berghei, and Swiss mice. In the process of these studies, progress has been made toward development of a highly specific inhibition test employing rabbit anti-sporozoite antiserum and fluores- cein-1abelled goat anti-rabbit IgG. If this could be converted to an ELISA test, it would present a valuable epidemiological tool and provide 156

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a simple means of measuring the persistence of protection following vaccination with sporozoite antigens. Like the Army, the Navy is con- cerned with three major rickettsial diseases: epidemic typhus, murine typhus, and scrub typhus. Epidemic typhus is still prevalent in many regions of Africa and South America; scrub typhus remains a common dis- ease in the Far East. The ultimate goals of the Navy's program are production of a combined epidemicmurine typhus vaccine and a scrub typhus vaccine. An ELISA test has been developed for both groups of organisms; if purified antigens become generally available, this test can be used for extensive surveys and for the rapid diagnosis of ricket- tsial infections of man. Another rickettsial disease, Rocky Mountain Spotted Fever, is a problem in the United States. NIAID has been collaborating with the Army on development of an improved vaccine for this tick-borne typhus. Department of State Agency for International Development Under authority of the provisions of Section 104 of the Foreign Assistance Act of 196l, as amended, in relation to disease prevention, AID provides direct support for activities in the principal tropical diseases beyond those which the agency classified as research and development. In 1978, these activities included assistance to nine national malaria control programs at about $4.5 million per year, and support of a multi-donor onchocerciasis control program in West Africa at $4.0 million per year. In addition AID contributed $800,000 to the multi-donor consortium which supports WHO's TDR program (Table 10) for six diseases, and funded additional research on malaria, schistosomia- sis, and diarrheal diseases. Research on improved chemotherapeutic drugs was limited to those for schistosomiasis (the expenditures listed for treatment of enteritis largely supported studies of oral rehydration). With reference to other chemical agents, $376,000 were devoted by the malaria program to development of pesticides. As with the other agen- cies, a significant proportion of malaria research was devoted to vac- cine development. A description of the expenditures of all the federal agencies surveyed for seven tropical diseases makes it clear that investigators have been equally interested in, or attracted to, studies of vaccines ($9.6 million) and to the development and testing of pharmaceutical agents ($10 million) (Table 1l). A major expenditure was the Army's six million dollar investment in antimalarials. Excluding this figure from the totals indicates that $3.9 million of $25.0 million, or 15.6 percent of total expenditures for seven major tropical diseases, were allocated to drug development and testing. No attempt was made to assess the reasons for this division of effort, but it is a proper subject for other Conference participants. Perhaps all that is needed are new 158

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stimuli, such as the discovery that allopurinal selectively damages certain parasites and the obvservation by Dr. Carl R. Alving at Walter Reed that a liposome-encapsulated antimonial agent eliminated leishman- iasis mortality in hamsters. There is no difficulty in explaining the emphasis on vaccines. The age of immunoparasitology has arrived, and technical developments, particularly in malaria, offer hope that vaccines may be available before all parasites are resistant to antimalarials and all mosquitoes to insecticides. Several approaches are being explored. Drs. Robert Gwadz and David Chen at NIAID have utilized the sexual states (gametes) of _P. gallinaceum to immunize chickens. When mosquitoes feed on the chickens, they ingest antibodies against gametes; the antibodies block further development of the parasites in the mosquito, and thus, inter- rupt further transmission. Dr. Wasim A. Siddiqui and associates at the University of Hawaii effectively immunized owl monkeys against _P. falci- parum using merozoites in Freund's complete adjuvant as antigen. Dr. Siddiqui and Dr. Shozo Kotani and his collaborators at Osaka University, Japan, have recently reported development of a synthetic compound which they suggest can be safely used with liposomes as an adjuvant for a mero- zoite vaccine in man. These and other studies were greatly facilitated by the technique developed by Dr. William Trager of Rockefeller Univer- sity for the in vitro cultivation of the asexual erythrocytic states of J?. falciparum. When the expenditure estimates are totaled for other infections that produce disease and death in the developing countries (Table 12), and this total is added to expenditures for tropical diseases (Table 1l), the United States investment in such research and development in FY 1978 is calculated to have been $65 million (Table 13). Because of the Army's stimulus, expenditures for pharmaceuticals for tropical diseases ranked first for that group, consuming 32 percent of the total, nearly three times that invested in drugs for the other diseases. Expenditures for vaccines and related immunological studies ranked first for the other selected diseases, 36 percent of nearly $34 million. This may simply mean that insufficient funds are being invested in the search for new drugs for all of these infectious dis- eases. It is noted with some surprise that, collectively, United States agencies spent nearly as much for the seven tropical diseases as for the eleven other selected major disease categories. Among the questions to be addressed are whether a disproportionate amount of national resources is being devoted to basic epidemiological and immunological studies and to vaccine development rather than to the development of new pharmaceuticals, or whether the total investment in tropical diseases research needs to be increased with a special empha- sis on expanded drug research. It is also appropriate to ask whether the infections considered, including those diseases selected for spe- cial emphasis by WHO, are the appropriate targets. If it is accepted 161

TABLES 12. U.S. GOVERNMENT RESEARCH SUPPORT (Estimated) FOR DEVELOPMENT OF PHARMACEUTICALS, OTHER AGENTS AND TECHNIQUES FOR OTHER MAJOR DISEASES (FY 1978) Infectious Disease Grand Total All Research a/ Total 33,683 Bacterial Meningitis l,917 Gonorrhea 2,528 Pneumococcal Infections 874 Tuberculosis l,577 Mycoses 2,255 Arboviruses 9,155 Herpes viruses 730 Rabies 309 Rickettsial Diseases 3,349 Respiratory viruses Influenza 5,520 Other l,900 Viral Hepatitis 3,569 a/xlOOO that they are, it is desirable to consider how United States institu- tions can better utilize resources to expand existing research and training programs and to create new ones that will encourage United States-supported laboratories (l) to develop closer collaborative arrangements with indigenous institutions and (2) to link operational research activities with appropriate national research and training centers. The National Institute of Allergy and Infectious Diseases has developed several new program initiatives to meet these objectives. One of these is a modification and extension of the current Internation- al Centers for Medical Research. The current and final funding period 162

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of the four ICMR grants ends May 3l, 1980, after an existence of 20 years. A new initiative, International Collaboration in Infectious Diseases Research (ICIDR), will supplant the ICMR program and will pro- vide an opportunity to expand selected research activities, to initiate new ones, and to establish additional overseas linkages. The research emphasis of the new ICIDR program is infectious diseases and the immunology of these diseases. Special attention is given to the six diseases of the WHO Special Program for Research and Training in Tropical Diseases. To provide flexibility and to ensure maximum opportunity for participation, the program is divided into Part A, International Program Project Grants, and Part B, International Exploratory/Development Research Grants. Part A, International Program Project Grants, embraces broadly based multidisciplinary research programs that have a well-defined central focus or objective, with major portions of the research being conducted overseas by a group of investigators collaborating with one or more foreign affiliates. Part B, International Exploratory/Developmental Research Grants, encourages an individual investigator to develop a biomedical research program with an overseas affiliate, with most of the work being done in the host country. As a complementary initiative, NIAID has invited the scientific community to submit program-project grant applications to establish United States-based Tropical Disease Research Units that will bring together relevant biomedical knowledge in a multidisciplinary attack on the world's major tropical and parasitic diseases. In addition to the new knowledge to be gained, it is anticipated that this program will provide badly needed institutional support in the United States and a career ladder for scientists in this area, including those re- turning home from ICIDR projects. In a very real sense, the NIAID intramural laboratories already constitute a Tropical Disease Research Unit. NIAID desires to expand the efforts of these excellent laboratories by providing additional positions and funding so that research projects in overseas locations may be undertaken in addition to linkages already established with scientists in Brazil, India, Egypt, Central America, and Africa. Finally, funds permitting, NIAID proposes to create research fellowships in tropical diseases for young investigators, and inter- national fellowships for senior scientists. Talented new investigators must be attracted to research careers in tropical and infectious dis- eases if the United States and other nations are to sustain a signifi- cant attack on the problems of developing countries. 164

Summary During fiscal year 1978, the agencies of three United States Departments — Health, Education, and Welfare (NIH, CDC, BoB), Defense (Army, Navy), and State (AID) — expended an estimated $31.5 million for research and development related to seven major tropical diseases plus an estimated $33.7 million for eleven other disease categories that are also important health problems in developing countries. For the tropical diseases, intramural and extramural investigators — the latter principally in university laboratories — devoted 32 percent of their budgets to studies of pharmaceutical agents; for the other dis- eases, 11 percent of expenditures were related to drugs for chemoprophy- laxis and/or treatment. This difference was attributable to a major emphasis on drugs for malaria by a single agency. For the two groups of diseases combined, investigator interest and/or the nature of finan- cial support favored expenditures for basic research (31 percent) and for vaccines and related immunological studies (34 percent), over work on pharmaceutical agents (21 percent). 165

DISCUSSION: CURRENT PROGRAMS FOR DEVELOPMENT OF PHARMACEUTICALS DR. CLUFF requested that Drs. Sarett and Vischer amplify their comments regarding involvement of the academic community by the phar- maceutical industry in the development of new drugs for tropical countries. DR. ERNST VISCHER replied that industry customarily enlists the advice of competent members of the academic community. For example, Professor Fox has collaborated very usefully with CIBA/GEIGY, and with local investigators in Indonesia in tuberculosis treatment trials. In other instances, industry has enlisted local faculty members from the medical schools in the countries where pharmaceuticals are to be tested. DR. CLUFF stated his impression that collaboration between industry and the academic community in Europe differs from the prac- tices utilized in the United States. DR. LEWIS SARETT noted that American pharmaceutical companies do enlist assistance from people in the academic world, both in industrial- ized and in developing countries. DR. ADETOKUNBO LUCAS added that WHO has been stimulating such col- laborative efforts as, for example, by support for screening compounds active against filariasis provided by industry at several university centers around the world. DR. MANSOUR believed that collaboration between the academic and industrial communities in the United States was very limited, in large part due to the patent problem. DR. SARETT cautioned against overestimating the importance of the patent problem as a constraint to greater involvement of university talent in new drug research for developing countries. Two other con- straints are far more significant: Drugs useful for treating tropical diseases must be tested in the countries where the diseases occur, and not in the United States, usually precluding greater involvement of United States academicians. Additionally, centers for clinical investi- gation of tropical diseases are relatively scarce in the United States, also limiting possibilities for collaboration. DR. LUCAS suggested the trend for investment spending for research on drugs for tropical diseases appeared upward in Europe and downward in the United States, and requested data from the speakers. DR. SARETT replied that there are many reasons for a slow overall decline in drug research development in the United States. The propor- tion of overall research spending for drugs against tropical diseases 166

amounted to perhaps three to four percent of the $1.3 billion industry annually spends for research. DR. VISCHER stated that the situation in Europe actually reflects a maintenance of the status quo, and not really an overall upward trend. 167