Editorial: The Research Imperative: Fighting AIDS, TB and Malaria

There is plenty of good news in global health. The world as whole, and all regions of the world, became much healthier in the decades following the Second World War. This was true in rich countries and in poor countries, and among rich people and poor people. Life expectancy at birth, the principal single measure of the health status of a population, increased more in the four decades from 1950 than during previous recorded human history. Around the world today, these positive trends continue in many populations and for most diseases. There are, however, five big exceptions: global health challenges that are worsening steadily and, in some cases, worsening rapidly. Two of these are non-infectious and have been the subject of considerable international debate and action in recent years. The first is the rising epidemic of tobacco abuse and its negative health consequences. The second is the global epidemic of obesity, and the many diseases that result from this. In addition, there are three major infectious diseases which have worsened steadily over the last two decades and which together provide a major challenge for social and economic progress around the world. These are AIDS, TB and malaria. It was the recognition, around the turn of the century, that business-as-usual was not making a difference, and that AIDS, TB and malaria were continuing to expand and increase, which led to the creation, in 2002, of The Global Fund to Fight AIDS, TB and Malaria. The Global Fund is not a research financing organization and was not created with a mandate to support research. Its work, however, is dependent upon research of two main kinds, as described below. The fight against AIDS, TB and malaria is dependent on many inputs. Among these are drugs, diagnostics and vaccines. Starting with drugs, the world urgently needs drugs against the three diseases which are low-cost, easy to administer, safe, and effective. The picture today is not good. For HIV/AIDS, the current drugs prolong life but do not cure. Although prices have fallen dramatically in the past three years, they remain expensive. They have substantial side effects for many patients and need to be taken for the remainder of a person's life. For tuberculosis, the main problem is that the drugs, while effective, have to be taken for six months or more in order to effect a cure. In addition, resistance of the bacillus to a range of the more commonly used drugs is rising rapidly, creating the phenomenon of multi-drug resistant tuberculosis. This is both very expensive and very difficult to treat. For malaria, widespread resistance to the first and second generation antimalarial drugs is now forcing country after country to switch to the more expensive, but highly effective, artemisinin-combination therapies (ACTs). These products are not ideal; they have a relatively short shelf-life, their safety for pregnant women is not certain, and the production process involves cultivation of plant material in China. In the field of diagnostics, for all three diseases, considerable progress has been made in the last few years. For example, HIV diagnosis is now possible based on saliva or urine samples. Notwithstanding this progress, there is still a need for cheaper, simpler and more accurate diagnostic tests. Coming to the subject of vaccines, the needs are urgent and enormous. We have no effective vaccine against either AIDS, TB or malaria. To have any one of these, let alone all three, would represent a huge breakthrough for the world. Indeed, an effective HIV vaccine is undoubtedly the holy grail of international public health. In addition to drugs, diagnostics and vaccines, there are a variety of other products and technologies which are needed and sought after to help the fight against the three great infectious pandemics. For example, microbicides would provide a female-controlled method of limiting the transmission of HIV during sexual intercourse. Largely as a result of the leadership and financing provided by the Bill and Melinda Gates Foundation, the priority attached to these research tasks is higher today than it was in the late 1990s. Significant investments are now being made in the necessary research, both in private sector and public sector laboratories. There is also a new and very heartening focus on products that can be immediately applicable and widely used in the developing world. For too long we have seen a 20 year gap between the emergence of a new product and its widespread use in low-income countries. Many of the new research initiatives are specifically dedicated to launching products first in the developing world or, at least, simultaneously in the developing and developed worlds. The Global Fund was not created to invest in research of this kind. It can, however, provide a significant incentive for the conduct of research. Specifically, the Global Fund represents substantial purchasing power for new drugs, diagnostics and vaccines as they become available. This purchasing power operates on behalf of countries and communities that are too poor to purchase these products using their own resources. This provides a substantial ‘pull factor’ in the market dynamic and provides an incentive for further investments in research and development to bring new products to the market place. The sums of money involved are substantial. The Global Fund's current portfolio includes 300 programs in 130 countries. The five year value of these programs is 8 billion. Roughly half of this money is to be spent on commodities directly relevant to AIDS; TB and malaria and perhaps a third of it will be spent on drugs specifically. These sums of money are large enough to influence the global market place and, in particular, to provide an incentive for the private sector for research and development investment into new technologies. It is too soon to quantify the degree to which this incentive is operating. Anecdotally, positive signs are apparent, particularly in the field of third-generation malaria drugs. An equally important and substantially neglected field of research is operational research. I use this term very broadly to include any kind of research or systematic collection of information and evidence which assists the management and implementation of more effective programs. The key to operational research is ‘learning while doing’. In the field of AIDS, TB and malaria, we are witnessing the beginnings of a massive scale-up of prevention activity and access to treatment. These scale-up programs are ambitious and, in many cases, take us into new and uncharted territory. The extreme example of this is the ‘Three by Five’ campaign to bring access to antiretroviral therapy to three million people by the end of the year 2005. The world has never taken on a more challenging task in the field of international health. It is imperative that as these major programs roll out, country by country, we put in place the mechanisms to measure, to study, to learn lessons, and to share those lessons widely. So far, none of this is in place. Taking the particular example of HIV/AIDS, the three major funders of the expansion of prevention and treatment programs are the President's Emergency Plan for AIDS Relief (PEPFAR), the World Bank Multi-Country AIDS Program (MAP), and the Global Fund. None of these financing mechanisms have arrangements in place to ensure that the necessary operational research gets done, that it gets done at a high international standard, and that its results are widely disseminated. Let me take the example of the Global Fund to illustrate this point. The Global Fund encourages its applicants to build operational research into their programs and to include budget lines to fully support this research. We are ready and willing to make substantial investments in this arena. Some applicants take this advice and some do not. For those who do, there is at the present time little prospect that this money will be well spent or will lead to robust and generalizable conclusions. There is nothing new to this experience. When I joined the World Bank in 1995 to become the Director of Health, Nutrition and Population, I commissioned a review of World Bank commitments to operational research within the health, nutrition and population portfolio. I discovered that the Bank was committing something on the order of 80–100 million per year for these purposes, not large in relation to the overall cost of the programs, but huge in relation to the standards of research funding. I then inquired what results and products were arising out of these very substantial investments. The answer was ‘practically nothing’. Typically, the monies for operational research were either unspent and returned to the Bank at the end of the loan period or they were spent in a way that produced little or no tangible results. The reasons for this are clear. In programs that focus on implementation, the needs for operational research and for the proper spending of the operational research budget allocation will never feature highly in the priorities of the program managers, either in the recipient organization or in the funding agency. In addition, the individuals in the funding agency and the recipient organization who are responsible for achieving the goals of the programs will typically not be researchers, not have well-honed judgments in the field of research, and not be well connected with the research community. Therefore, researchers from local research institutes are not involved in the task of designing and conducting the studies and international support in research design and analysis is not mobilized. The opportunities for operational research in AIDS, TB and malaria are large and varied. They range on a spectrum between the simple systematic collection of data to allow program managers to make improvements during the life of the programs, right through to ambitious randomized controlled trials. It sometimes surprises people to learn that randomized control trials, the gold standard for all public health research, are possible within the context of the implementation of national programs. In certain circumstances, they are. Two very good illustrations of this are the implementation of nationwide hepatitis B vaccination in The Gambia and the implementation of the ‘Progressa’ income transfer scheme in Mexico. In both cases, researchers and the relevant government officials sat down prior to the launch of these ambitious national programs and concluded that the roll-out could be randomized in a way that was ethical and that would not disadvantage citizens in comparison with an un-randomized roll-out. The essential feature of all roll-outs is that not everybody gets the service next Monday morning. Some will get it soon and some will have to wait, and this is an inevitable consequence of the practical challenges of going from zero service to 100% coverage. With this in mind, one speculates that across the 130 countries where the Global Fund is now investing, there may be four (or eight, or twelve) where conditions exist to randomize the roll-out. This might be the roll-out of long lasting pre-impregnated nets, it might be the roll out of a particular approach to HIV education for secondary school children, or it might be the roll-out of antiretroviral therapy. In any case, if the roll-out is randomized it provides a unique opportunity for robust conclusions concerning impact, and these conclusions can greatly and positively affect future investments. If the conclusions are extremely positive, one has the best possible argument for replication of the model and for substantial additional investment. If the conclusions are negative, one is learning something early, which otherwise might not be learnt at all, and using this information to either redesign the programs or to move the investments to other more productive areas. In conclusion, the need for substantially increased research both in product development and operations is evident. The Global Fund can never be a leader in either of these arenas. In product development, it is my hope and intention that we can provide a substantial financial incentive for larger investments in research and development to bring much needed new products to the market place. In operational research, we can be a major financer (in TB and malaria, the major financer) of expanded operational research capacity and activity across the developing world. However, this desirable outcome will not occur unless other organizations, whose mandate is research and who are expert in this arena, come together, seize the opportunity, and ensure that Global Fund investments in operational research are put to good use.