COLLABORATIVE RESEARCH ON TROPICAL DISEASES (1985)    p. 8  of 12

4. THE UNDP/ WORLD BANK / WHO SPECIAL PROGRAM FOR RESEARCH AND TRAINING IN TROPICAL DISEASES (TDR)

          TDR is without doubt the largest single effort in tropical disease research. Beginning in 1976, up to 31 December 1984, 3700 scientists from 125 countries participated in TDR. By 1984, the program had spent over $150 million, and it continues to raise an annual operating budget of $25 million per year from over 30 donors. Denmark, at $25.5 million, was the largest contributor in that period, followed by the United States at $20 million and Sweden at $16 million. The three sponsoring agencies are each major contributors, with the World Bank now donating $2.5 million per year, or 12% of the total. Altogether, TDR represents 25-30% of the worldwide research effort on tropical diseases.

          TDR, although obviously not an American effort, is pertinent to this discussion not only because of its size and impact but because it represents an important alternative potential means of increasing our commitment to controlling tropical diseases: we could simply increase our contribution to the Special Program.

          The scientific impact of TDR has not yet received comprehensive evaluation, but the management of the effort, its goals, scope and balance, and its financing, were extensively studied by an External Review Committee reporting in April 1982. That Committee was chaired by David Bell of Harvard University, who also chairs this IOM study. Most of the information about TDR in these pages comes from the Review, but interpreted by this author, as is the case in other sections. A major scientific review of the Program is scheduled to begin in 1985.

          The organization of the TDR deserves special attention because of the scope and complexity of its tasks. The Program concentrates on six specific diseases: malaria, schistosomiasis, filariasis (including onchocerciasis or river blindness), trypanosomiasis (African sleeping sickness and Chagas disease), leprosy, and leishmaniasis. The Program has two principal, distinct, and sometimes competing, objectives:

·            research and development of improved tools for dealing with the six diseases, and

·            strengthening research capacity in the countries whose population is affected by these diseases.

          A rather elaborate structure is required to mount so extensive an effort. Its elements include:

·            A Joint Coordinating Board on which contributors and developing countries participate in directing the Program;

·            A Standing Committee of representatives of the three sponsoring agencies, which serves as an executive committee for the Board;

·            Scientific Working Groups and Steering Committees made up of scientists who guide the research program;

·            A Research Strengthening Group made up of scientists from all over the world who advise on efforts to strengthen research institutions in affected countries;

·            A Scientific and Technical Advisory Committee, made up of persons with extensive experience in scientific research and research management, from both industrialized and developing countries, who function as an independent review body, providing continuing evaluation of the scientific and technical aspects of the Program and recommending priorities and budget allocations; and

·            A Program Coordinator, a Program Director and a Secretariat, who together provide a strong focus of responsibility and authority for carrying out the work of the TDR.

          The Review made suggestions for improving the workings of this structure, but it was strongly positive about the achievement of the sponsoring agencies in setting up a framework which provides simultaneously for the responsible participation of those directly concerned, the mobilization of scientific talent worldwide, independent scientific and technical evaluation and priority-setting, a clear and strong focus of operational responsibility and authority, and effective collaboration with the regular elements of WHO. On balance, the Committee found the entire program to be well targeted, well launched and of major significance.

          The Committee also praised the networking concept chosen by the Program as its modus operandi. Instead of channeling research funds to a few new or existing centers, the Program from the beginning built on WHO’s extensive experience and contacts to develop a network of involved scientists throughout the world. Although the Committee recognized that a more concentrated approach, such as the centers program for international agricultural research, may be more efficient for the resolution of specific problems, the network concept offers the ability to mobilize scientific expertise worldwide towards common objectives, and has a widespread impact on strengthening research capacity in endemic countries. The network approach also requires less capital expenditure, and it facilitates the assumption of responsibilities by local authorities.

          A danger inherent in the network approach is the risk of dissipating efforts through a multiplicity of committees and meetings of various kinds. The Committee noted that in 1980 the Special Program organized 69 meetings, primarily for managing the scientific elements of the Program, and in 1981 there were 80. The Review recommended several measures to streamline the operation, reduce the number of Steering Committees, merge the Working Groups into the Steering Committees, and lower the number of reports generated.

          The painstaking scrutiny of the administrative processes of the Program undertaken in the Review was perhaps its greatest contribution. The Committee looked at the work of the Secretariat, at the functions of Special Program staff assigned to the WHO regional offices, and at the workings of the various working groups and committees, and made suggestions for simplifying procedures and curtailing bureaucratic sprawl. It reinforced particular accomplishments, such as the introduction of a peer review process in making research awards, and drew circles around areas of sensitivity that bear watching.

          Among the delicate areas, in addition to the tendency to bureaucratic fat inherent in the network concept, and perhaps in the UN system, is the process of strengthening research capacity in endemic country institutions. This involves training scientific personnel, providing supplies, and building up research facilities to enable research institutions to carry out not only biomedical research, but also epidemiological and operational research, and the evaluation of new drugs, vaccines and tests which by their nature need to be carried out in tropical countries.

          This task of strengthening research capacity is of critical importance, since these countries must be ultimately responsible for the application of new and improved technology to their particular situations, but it is also an inherently long and difficult task. Its success depends not only on the careful selection of recipients and efficient execution of activities, but also on the commitment of recipient countries to continued support of the established research programs once the Special Program phases out.

          The promotion of linkages between developing-country institutions and research laboratories in advanced countries can be one of the most effective means of transferring scientific standards and techniques. The twinning of institutions and arranging of exchange visits of scientists can be a demanding task, requiring sensitivity to personal, political and cultural factors as well as scientific considerations.

          The Committee expressed concern about the apparent gap between the two elements of the Program, capacity strengthening and research activities, which it found to be more organizational than substantive. The Review recommended that greater efforts be made to interrelate research capability strengthening more closely with research and development activities, so that they reinforce each other. Over the past several years, increasing numbers of institutions in developing countries that have received “research strengthening” grants have competed successfully for grants awarded by Scientific Working Groups.

          In budgetary terms, the Review found the allocations between research and capacity building, and between expenditures in developed and developing countries, to be about right. The original target of the Program was for at least 20% of the funds to be devoted to capacity building, leaving 80% to research and development. This target was exceeded, and by 1980 slightly over 25% of the program was going to institution building. In addition, half the research funds were obligated for expenditures in developing countries, so a very high proportion of funds, 62.3%, was being spent in endemic areas. Still, not enough field projects were funded in terms of scientific objectives, due to the shortage of capacity in endemic areas, mainly of trained personnel. More epidemiological and socio-economic studies are needed, not only to assess the effectiveness of new methods but also to provide information on conditions in the field that should be fed into the process of developing new tools. Dr. A.O. Lucas, director of the TDR Program, cites the lag in field research as the most serious problem he encountered. Many governments in endemic countries do still not appreciate the value of combining research with control activities.

          The Review found no new drugs or vaccines that had emerged from the efforts of TDR, but thought this was not surprising in the early years. The Committee recommended however that the second five-year review be adequately funded and staffed to examine scientific results more thoroughly. The second review, if it is to take two years as did the first one, will presumably commence in 1985.

          Intermediate results, as distinct from final cures or preventive measures, have been promising. Lucas notes that the aim of the Program to induce scientists from many disciplines to take a fresh look at these diseases has produced a response exceeding expectations. Major scientific advances occurring outside the Program in molecular biology, immunology, and in techniques for in vitro culture of parasites have added momentum to the Program.

          One example of the benefits of international cooperation and the networking concept is found in the production and sharing of leprosy bacilli. American scientists discovered ten or fifteen years ago that the injection of leprosy bacilli into the nine-banded armadillo could produce massive infection after two years. This made it possible to harvest large amounts of the bacilli for research purposes, the first step in the development of a vaccine. Instead of each participating laboratory having to keep a supply of armadillos, laboratories in Louisiana, Georgia, Florida, and Washington have been contracted to produce the bacilli. A laboratory in England purifies and stores the bacilli, and antigenic analyses take place in various parts of the world including Norway, Sweden and the United States. Skin tests and vaccine tests have been carried out in Venezuela, and epidemiological studies in Africa. The Review Committee notes that only through a mechanism such as TDR, working through WHO, could such cooperation occur.

5. COMPARATIVE COMMENTS

          Several general observations can be made about the efficacy of the grant programs for tropical disease research of the private foundations and the TDR Program of WHO, in the context of the comparative framework developed earlier in the paper.

a. Scope of the Programs

          The TDR Program endeavors to take action along the full spectrum of research needed to understand and deal with a disease, in locations from advanced microbiology laboratories to the village. As noted, TDR is not uniformly successful in sponsoring activities at all levels needed, lagging in field research, which is often most difficult to organize, and suffering from relatively scarce institutional resources and trained personnel. Nevertheless, the Program committees view their tasks in the whole, dealing with whatever research problems command priority in learning to deal with a disease, and the long-run mission of building up competence in institutions in endemic areas is squarely accepted. In recent years, some of the Scientific Working Groups responsible for setting research directions and monitoring progress have placed special emphasis on development and testing of new products and technologies for disease control that have emerged from TDR-supported research.

          Foundation programs tend to be weighted on the side of laboratory research, basic and applied. This emphasis utilizes the strengths of foundations in stressing research quality with a minimum of bureaucratic constraint. Laboratories can be selected for participation without regard for regional balance or political factors, which sometime intrude on the workings of international programs. Field programs, on the other hand, are usually expensive, carrying a bigger price tag than foundations like to accept nowadays, and require more staff for program development and management. Yet foundations, notably Rockefeller, have afforded field programs on a large scale in the past.

          Both Rockefeller and Clark attended to the communication factor, the process by which scientists keep informed of the advancing frontier. The GND annual conferences have proved invaluable for that purpose, and the annual revision of the Strategic Plan for schistosomiasis research is a useful communications device. Extending as it does from laboratory research to field research and control activities, the Strategic Plan has an impact across a broader spectrum than the GND program.

          The foundations cannot, as yet, be said to have found a way to get as large a ball rolling as they did in the case of agriculture. The leveraging of funds accomplished by the formation of the Consultative Group has no clear match in the international medical research field. This may be a reflection of the fact that there is a greater demand for the income-generating products of agricultural research than for the life-saving products of medical research. In reporting on the GND program to the Rockefeller Foundation Trustees, the problem of attracting larger, non-RF resources to the GND units was cited as the major problem area. It may be worth pondering, however, whether there may be ways for using the flexibility of the foundations to generate a larger effort than has so far been accomplished.

b. Degree of Collaboration

          TDR is striving to be a collaborative program. The 1982 Review Committee found an unnecessary and undesirable gap between the two main TDR thrusts, capacity building and research. The latter tends to be centered on advanced laboratories while the former is concentrated in developing countries. Some twinning of laboratories has occurred, but not as much as the Committee thought would be desirable. This situation appears to have improved over the last several years within the context of the TDR grant awards to developing-country scientists. Some awards include support for travel and/or training visits to laboratories in industrialized countries. TDR training awards have fostered collaborative relationships that are then continued as part of research carried out upon the trainee’s return to an institution in the tropics.

          The foundations fund collaborative work. Table 1, taken from a report to the Rockefeller Foundation Trustees, shows the location of the GND research units and the areas of overseas collaboration (pp 8 and 9).

          A third of the GND funds is spent in developing countries even though only three of the 14 participating laboratories are located there. Funding collaborative research through the more advanced partner has advantages in terms of efficiency and administrative convenience, but it sometimes leaves the other feeling like the rabbit in the elephant and rabbit stew.

          This is not the case for the three laboratories in Cairo, Bangkok and Mexico City. There the project directors have reached out for collaboration to laboratories in the United States and Europe, retaining control in the endemic country. Egypt, Thailand and Mexico are middle tier countries, where as one Rockefeller reviewer noted, “the importance of medical research has dawned and thus support from national sources will be forthcoming.”  Vesting scientific and financial control of a project in poorer, less developed countries, where the tropical disease burden is often greater than in the middle tier countries, could prove much more difficult administratively.

          It appears than neither TDR nor the foundations have quite succeeded in finding the ideal formula for promoting collaborative research, but this is a subjective judgment of a subject which will receive a great deal of attention when this draft is discussed in Cairo in April. The views of Third World scientists on this point will be of the highest interest.

c. Results:  Impact on Disease

          The External Review Committee found the results of the TDR Program up until 1982 to be inconclusive. Although some immediately usable results were noted, such as improved diagnostic tests, most of the results were intermediate in nature, needing further development before products became available which would affect disease control. A listing of specific achievements of the Program cited in the Review is found below:

·            the development of simple and accurate diagnostic field test kits for malaria, leprosy and African trypanosomiasis;

·            advancement of testing on the antimalarial drug mefloquine to the clinical evaluation stage, and the beginning of testing of gum hao-su as an antimalarial drug;

·            substantial progress in fundamental knowledge required to develop an antimalarial vaccine;

·            development of a screening mechanism for filaricidal drugs and stimulation of significant industrial interest in this field;

·            clinical trials on praziquantel, an effective schistosomiasis drug;

·            more thorough knowledge of the prevalence and distribution of Chagas’ disease and leishmaniasis;

·            rapid development of Bacillus thuringiensis H-14 as a biological agent for the control of vectors;

·            the initiation of the first global research effort into socio-economic aspects of the six diseases.

          A summary of more recent advances made in the TDR program is found in Appendix B.

          Rockefeller Foundation staff give themselves similarly mixed reviews of substantive achievements to date of the GND program. They note that the research programs are of very high quality and the achievements are cost-effective, but there is concern about the problem of translating the outcomes of the biomedical research into products or practices that will improve the health of people in the developing world.

          To some extent, the GND program measures its accomplishments in numbers of publications that flow from the laboratories receiving support. From 1978-82, 736 publications resulted from the program, many articles appearing in the most prestigious medical journals. The following are among the noteworthy substantive developments in various GND units:

·            At Harvard University, the Weizmann Institute, and the Walter and Eliza Hall Institute, test-tube production of so-called monoclonal antibodies is underway. These antibodies protect against schistosomiasis in experimental animals and provide a diagnostic test in man;

·            At Harvard University, a diagnostic test using monoclonal antibodies has been developed which differentiates infection with a minor form of leishmaniasis (oriental sore) from that of the major disfiguring form called espundia;

·            At the University of Washington, a new and more specific diagnostic test for leprosy, based on a purified antigen, has been developed. Through chemistry, Case Western Reserve University has produced a new highly specific finger prick blood test for tuberculosis;

·            At Tufts University, protective monoclonal antibodies against the Epstein-Barr virus, the causal agent of infectious mononucleosis, have been produced;

·            At the University of Virginia, the Weizmann Institute in Israel and the National Polytechnic Institute in Mexico, investigators have made important advances in understanding the mechanisms underlying amebic dysentery and liver abscess;

·            At Oxford University, a specific chemical receptor for invasion of red blood cells by the most virulent form of malaria has been discovered;

·            At Case Western Reserve University, the efficacy of the first new drug in more than 20 years for the treatment of onchocerciasis (river blindness) has been validated in collaborative studies with Mexico;

·            At the University of Virginia, investigators have demonstrated that the tranquillizer chlorpromazine has significant antibiotic activity against the causative agent of whooping cough;

·            At the Biomedical Research Center for Infectious Diseases in Cairo, evidence has been gathered in man that tuberculosis protects patients against schistosomiasis. The specific chemical mechanism is being elucidated in mice at Case Western Reserve University;

·            At Rockefeller University, a new agent for treating African sleeping sickness has been identified which can be made by boiling blood and vinegar in an iron pot.

          The Clark Foundation staff, in reporting to its Trustees, notes an explosion of knowledge about schistosomiasis in the ten years of its program, without attempting to sort out which fragments should be credited to Clark and which to other programs. Advances were particularly noted in understanding of the human immune response, in drug development and understanding of the worm’s metabolism so new drugs can be designed, and in understanding of the public health impact and epidemiology of schistosomiasis with resulting improvement in control strategies.

d. Results: Capacity Building

          Research capacity strengthening is so great a part of the TDR Program that the External Review Committee’s findings were discussed in the paragraphs above in which the Program is described. Briefly, the Review commended the allocation of between 25-30% of TDR funds to building research capacity in developing countries, a higher allotment than originally targeted but still a second priority to the urgency of making scientific progress through research. The task of strengthening research capacity is recognized as inherently difficult, requiring, as the Rockefeller reviewer put it, the “dawning” of awareness of the importance of medical research by national authorities. The Review Committee urged greater efforts to twin institutions in developing countries with advanced laboratories abroad, and special efforts to identify promising talent even in those countries where major institutional investments are not indicated.

          The GND program is essentially a capacity building program, mostly by funding work on tropical diseases in already well-established and successful laboratories. Only three of the 14 selected laboratories are in developing countries, but in those cases, the pattern of funding, local control, and international collaboration would seem to be ideal. The strategy of the Foundation is aimed at expanding the quality and quality of tropical disease research by building on existing centers of research excellence. The Foundation itself is not sure of its long-range success, however, due to its limited resources. Young researchers, attracted to the GND field by the quality of the scientific work going on there, may be forced to shift their attentions if resources are no longer available.

          The Clark approach is perhaps least effective in building capacity of the three here considered. The device of the strategic Plan, so useful in maintaining the focus of expenditure on the advancing frontier of knowledge, may inhibit expenditures with long-range capacity-building objectives unless this is an explicit program objective, as is the case with the TDR.

e. Conclusion

          Each of the grant programs has genuine strengths and each would appear to be an excellent use of private and international funds. The lingering sense of unfulfillment one has when reviewing them stems not from failures of execution but from inadequacy of design. However well run, grant programs alone don’t seem able to do the job. Networks need to be strung on fence-posts, and it is these solid support structures that seem missing from the approach. For all its shortcoming, one would be reassured by the presence of a center like ICDDR/B anchoring the research on a particular disease such as schistosomiasis. A few more fence-posts could be powerful contributors to worldwide efforts against the major diseases. The utility of a center as a base for research-capacity strengthening at the national level is strikingly demonstrated by the International Rice Research Institute in the Philippines, and the other institutes. There would seem to be no reason why similar success could not be achieved in research on schistosomiasis or other tropical diseases, but a careful study should be made to determine the pros and cons of these models for health research in the tropics.

          The Scientific Working Groups of TDR perform some of the functions of an international center, keeping track of priority needs and reviewing progress against their particular diseases. They involve some of the best scientists in the world and, together with WHO staff, do a commendable job. The WHO scientific staff with administrative responsibilities for the TDR Program, based in Geneva, numbers about 30.