The Four Toughest Questions I Get

Trevor Mundel
A group of patients in the grounds of the Brewelskloof TB Hospital in Worcester, South Africa.

This year, Bill and Melinda Gates are using their Annual Letter to tackle the 10 toughest questions they get. This has inspired me to tackle tough questions I get about the work of the Gates Foundation’s Global Health Division. You may have seen that Devex featured one of my responses to those questions — “Why don’t you invest more in noncommunicable diseases?” — and today I want to share my answers to three more big questions.

As one of the world’s largest funders of R&D for global health, we feel we have an obligation to speak to the choices we make, the strategies we pursue and the risks and trade-offs we consider. I hope that what follows sheds light on our approach, and I look forward to continuing the conversation in future posts.

Why Have You Decided to Launch the Gates Medical Research Institute?

The short answer is simple: We want to jump-start the development of new tools against three incredibly tough diseases — malaria, tuberculosis (TB), and enteric and diarrheal diseases (EDD) — that remain major causes of maternal and child mortality, poverty, and inequity in developing countries.

Since 1990, the world has reduced the number of mothers and children under the age of five who die from infectious diseases and other preventable causes by half. That’s an amazing testament to what governments, philanthropies, international partners, and local communities can do when we work together toward a common goal.

But while progress is possible, it isn’t inevitable, and we will need major product development breakthroughs in the coming years to reach the 2030 Sustainable Development Goal of closing the gap between deaths and disabilities caused by infectious diseases in wealthy countries and low-income countries.

Here are the facts:

  • Malaria has been eliminated from half the nations of the world, but in sub-Saharan Africa it remains a leading cause of death among pregnant women, and it claims the life of a child every two minutes.
  • TB has been virtually eliminated as a public health challenge in wealthy countries, but it remains a huge burden in many low- and middle-income countries. It kills more people — about 1.7 million per year — than any other infectious disease, and the current rate of decline in new infections is far too slow to put the world on pace to end the epidemic.
  • While diarrheal diseases are normally just an inconvenience in wealthy countries, they cause more than half a million child deaths in sub-Saharan Africa and South Asia each year.

We believe that the Bill & Melinda Gates Medical Research Institute (Gates MRI) can help close these gaps by focusing on translational medicine — the process that evaluates promising scientific discoveries and translates them into potentially viable medical products. It will seek to capitalize on recent innovations in medical research, such as more rigorous approaches to quantitative science, to identify candidates for drug therapies, vaccines, diagnostics, and medical devices that could put the fight against malaria, TB and EDD on a whole new trajectory. It often requires multiple iterations of work in this area to come up with candidates that have all the properties required for deployment in challenging environments — we’ve learned this work is best conducted in a tightly integrated and focused setting rather than through a diffuse network of contributors.

At the Gates MRI, researchers will be able to think big, explore novel ideas, collaborate across disciplines, and be fearless in their approach to scientific inquiry in ways that aren’t always possible in the private sector or in academic research labs.

Finally, we want to ensure that the Gates MRI operates with a strong commitment to global access and open access, ensuring that its research results and any underlying data sets are made freely and openly available to all.

The Gates MRI is just getting started under the leadership of Penny Heaton, and I’m excited by the diversity of talent that Penny has recruited for her senior leadership team. She will continue to shape and clarify the initial research program as the Gates MRI moves toward becoming operational in 2018, and I encourage you to follow her on Twitter — @DrPennyHeaton — for more news over the course of the year.

How do you decide what to invest in?

This is the number-one question I get from our partners in government, academia, and the private sector.

I’ll start by repeating two key principles of the Gates Foundation, because they guide our decision-making at every step.

The first is we believe all lives have equal value, and everyone deserves the opportunity to lead a healthy and productive life.

The second is less elegant, but it’s critically important: We know that the foundation’s resources — while considerable — account for just a small portion of worldwide funding for health. As such, we concentrate our investments where:

  • Existing funds are insufficient;
  • Our support can have potentially catalytic impact; and
  • We can assume risks that others can’t.

For the Global Health Division, this means we invest in creating new tools and strategies that can close gaps in health equity between people living in wealthy countries and low- and middle-income countries.

It also means that we concentrate on solutions to the leading causes of death and disability in low- and middle-income countries. These tend to be infectious diseases like malaria, tuberculosis, neglected tropical diseases, and severe forms of pneumonia and diarrhea that have very low incidence in wealthy countries.

Additionally, it means we invest in creating high-impact health products that haven’t been developed due to market failures. There is a strong correlation between vulnerability to infectious disease and extreme poverty, and this means that governments and philanthropies have a vital role to play in financing and de-risking the creation of health products for communities living at the base of the economic pyramid.

The Global Health Division works with the foundation’s Global Policy and Advocacy Division — led by my colleague Mark Suzman — to forge partnerships between governments, philanthropies, product development partners, and the private sector to fund the end-to-end development and delivery of effective diagnostics, drugs, and vaccines.

But as anyone who works on research and development for global health knows, it can take a decade or more to translate promising lab discoveries into products that are safe, effective, approved, and available to those who need them. So, we rely on high-quality health metrics — derived from the best-available global data — to help us predict which investments could have the greatest impact in the future.

Three metrics guide this long-range scenario planning:

  1. The first is an objective estimate of the health burden of each disease, as measured by the total number of disability adjusted life years — or DALYs — that each disease creates. Each DALY represents one year of productive life lost to premature death or health-related disabilities.
  2. The second is more subjective: what is the probability of success that we’ll be able to develop a high-impact tool or technology that can substantially reduce the burden of DALYs caused by a specific disease?
  3. The third employs complex mathematical modeling to predict the future state of global health based on a wide array of variables. These include:
  • Projected reductions in extreme poverty and ill-health caused by economic growth in developing countries;
  • Potential changes in health care access caused by changes in foreign or domestic financing; and
  • Projections of the positive impact of new products (e.g., the scale up of a more efficacious vaccine) and the decreasing efficacy of existing products (e.g., the negative effect of growing drug resistance on infection rates and cure rates).

Given the large number of variables involved, these projections naturally generate greater uncertainties — and larger error bars — as we look farther into the future.

This is a lot of information for anyone to process, so we use visualizations to organize our thinking and help us prioritize our investments. (See Figure 1.)

Figure 1. Guiding our investments in global health: Intervention Costs, R&D Probabilities, Benefits in DALYs

We integrate our analysis of the first two variables into what we call a “bubble chart.” The bubbles represent the total number of DALYs that could be averted through the introduction of a new health product, and the size of each bubble represents the total projected impact — the bigger the bubble, the greater the impact.

The vertical axis represents the estimated dollar cost per DALY averted to produce and deliver a new health product. It uses a logarithmic scale (i.e., each bar represents an increase or decrease by a factor of 10). The low end of the scale represents costs that might be affordable in some wealthy countries — $10,000 per year of productive, disease-free life restored — but are essentially out of reach for both individuals and health systems in low- and middle-income countries. By contrast, the high end of the scale represents interventions that can deliver cost savings over time by preventing future payments, such as expensive drug treatments and hospitalizations.

The horizontal axis represents the probability that we can successfully create a high-impact health product — whether it be a completely novel short-course cure for tuberculosis or a high-impact method to block the transmission of malaria parasites between mosquitoes and people. As noted above, this is a subjective calculation because we know from experience that about 90 percent of promising product candidates fail to advance from early phase clinical trials to approved products ready for use. We regularly adjust our projections along this axis based on frequent analysis of early phase research data.

The value of the “bubble chart” is that is allows us to focus our attention and resources on which products are likely to:

  • Have the greatest impact in saving lives and preventing ill-health;
  • Be affordable and appropriate for use in low-resource settings; and
  • Receive regulatory approval for use in the countries where we work.

Planning for the Future

Beyond the bubble chart, we make projections about the likely future state of specific diseases. You may have seen some of these projections in the most recent Goalkeepers report. Below are three projected outcomes for HIV, TB, and malaria between now and 2030:

Figure 2. HIV Scenarios

The scenarios for HIV suggest that the epidemic is at a turning point: the nations of southern and eastern Africa, where HIV is highly prevalent, can either continue to make significant progress in reducing HIV incidence, or the number of infections can rise as Africa’s population grows over the next few decades. As Bill, Melinda, and my colleague Chris Elias have all noted in their tough questions posts, sub-Saharan Africa’s population will likely double in the next few decades. It will then level off, as has been the trend in every other world region.

On the positive side, this means that sub-Saharan Africa could “cash in” on its demographic dividend — a wealth of young people who can help power the global economy as the rest of the world ages. But there is also a worrisome challenge: With so many young people in Africa entering their reproductive years, millions of young people are at risk of acquiring HIV unless we can scale up the introduction of effective, low-cost HIV prevention methods that people — especially young women and girls — will like and want to use.

That’s why the foundation is investing in the development of long-acting methods of HIV prevention –these can dramatically reduce the risk of HIV infection through the preventive administration of antiretroviral therapies. We believe that these new tools and technologies can help keep sub-Saharan Africa on the path to controlling its HIV epidemic over the next decade.

Figure 3. Tuberculosis Scenarios

The tuberculosis figure, by contrast, shows a much more predictable path — a steady, but painfully slow decrease in global TB incidence for the foreseeable future. This chart underscores the tremendous need for new tools in the fight against TB, which has emerged as the world’s single deadliest infectious disease. Without the development of new diagnostics, treatments, or vaccines for TB, we are unlikely to “bend the curve” of its impact on the 800 million people worldwide who still live in extreme poverty (i.e., on less than $1.90 per day). This is why the foundation is doubling down on early phase R&D that could deliver breakthroughs in identifying and preventing TB among those most vulnerable to the disease.

Figure 4. Malaria Scenarios

Finally, the chart on malaria suggests that we stand at a decision point for one of humanity’s oldest and deadliest foes. We have made huge progress against malaria over the past decade, cutting deaths from the disease by 60 percent. But this progress is beginning to stall. The parasites that cause malaria and the mosquitoes that transmit them are constantly evolving new strategies to defeat the tools we deploy against them.

The foundation is working hard with partners to strengthen the impact and durability of existing tools by scaling up the use of state-of-the-art surveillance systems, data analysis, and mathematical modeling to identify the ideal combination of prevention, detection, and treatment tools for specific environments. Doing so can help donors and affected countries stretch the life-saving impact of currently available tools while creating pathways to malaria elimination over time.

We are also investing in the development of next-generation transmission-blocking technologies. If we can successfully interrupt the cyclical transmission of parasites between mosquitoes and people, we can set the stage for the rapid elimination of malaria in human populations. Accordingly, the foundation is focusing on the development of next-generation transmission-blocking vaccines, innovative mosquito-control methods such as gene drive, and highly effective treatments that could eliminate malaria parasites from the body with just one or two doses.

There are a lot of considerations and variables that guide our thinking as we decide where to invest our funding for global health R&D. That’s largely because we recognize that we don’t live in a steady-state world, and we need to anticipate change so that we can be prepared for the future. But it’s also because we feel a moral obligation to maximize the impact of every dollar entrusted to us, and we seek to do so by letting the best-available evidence guide our decision-making.

I look forward to your feedback on this question. What do you think about our approach? What potential blind spots do you see, and how would you address them? The most essential ingredient in optimizing any strategy is a feedback loop of information from expert sources, so I look forward to your reactions.

Why do you work with big pharma and biotech companies?

Bill Gates tackled this question recently at J.P. Morgan’s 36th Annual Healthcare Conference in San Francisco, where he spoke in depth about how the foundation’s work benefits from collaboration with the private sector, and provided a vision for how the private sector can also benefit from public sector and philanthropic ventures.

Underlying the question about why we work with big pharma and biotechs is a hard reality: The people who need the life-saving products and strategies that we develop generally can’t afford to buy them. As Bill has said, the private sector does a phenomenal job meeting human needs among those who can pay, but there are billions of people who have no way to express their needs in ways that matter to markets. And so they go without.

Recognizing that we live in a market-based and market-driven world, we believe that one of the most sustainable ways to create solutions to disease and poverty is by drawing on the tools, talents, and expertise of the private sector. You may have heard us refer to this as an element of catalytic philanthropy, which at its core is designed to fix market failures — places where traditional market-driven incentives fail to meet the needs of the poor.

Without the private sector, we won’t make meaningful progress on some of the world’s toughest health challenges. Industry brings unique strengths to global health innovation that can fill gaps in knowledge, skills, and abilities, producing new medical products faster than if we tried to do it alone. For instance, pharmaceutical companies are experts at translating basic science into products that improve people’s lives, while industry has the knowledge and expertise to navigate regulatory approval, manage supply strategies, and conduct clinical trials to optimize long-term solutions.

The innovation, expertise, and financing which industry brings to the table have already achieved great things in global health. Novartis helped develop Coartem Dispersible, the first malaria drug made specifically for children — two hundred million treatments have been distributed in 50 countries since 2009. The Meningitis Vaccine Project brought together non-profits and biotechnology and pharmaceutical companies to develop a much-needed vaccine at a price African countries can afford to pay. Many other companies have come together to address the challenges of neglected tropical diseases, contributing to their elimination and reaching hundreds of millions more than we were a few years ago. It’s clear we can have the biggest impact when we work together.

This is why the foundation is investing not just in new tools, but in new public-private sector approaches that we hope will accelerate our progress against some of the biggest challenges we face. The Gates MRI and the Coalition for Epidemic Preparedness Innovations are excellent examples of how we’re seeking to build new platforms for rapid vaccine development and production through partnership with pharma and other industries.

Investments in global health are not just about philanthropy, however. There are many great examples of where investing in global health and development has produced economic value for participating companies. And as health outcomes improve and low-income countries develop economically, the relationships, knowledge, experience, and goodwill built from global health investments can form the basis for sustainable, market-based solutions.

We have a great opportunity to reach our goals, but we can’t do it without the private sector’s contributions. With the sector’s science and ideas, together, we can make innovation work for everyone.

Trevor Mundel

Written by

President of Global Health at the Bill & Melinda Gates Foundation. Science is my passion.

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